USE OF STROBILURIN TYPE COMPOUNDS FOR COMBATING PHYTOPATHOGENIC FUNGI CONTAINING AN AMINO ACID SUBSTITUTION F129L IN THE MITOCHONDRIAL CYTOCHROME B PROTEIN CONFERRING RESISTANCE TO QO INHIBITORS VIII

Abstract

The present invention relates to the use of strobilurin type compounds of formula I and the N-oxides and the salts thereof for combating phytopathogenic fungi containing an amino acid substitution F129L in the mitochondrial cytochrome b protein (also referred to as F129L mutation in the mitochondrial cytochrome b gene) conferring resistance to Qo inhibitors, and to methods for combating such fungi. The invention also relates to novel compounds, processes for preparing these compounds, to compositions comprising at least one such compound, and to seeds coated with at least one such compound.

Claims

1. (canceled)

2. The method according to claim 7, wherein in formula I R.sup.1 is selected from O and NH; and R.sup.2 is selected from CH and N, provided that R.sup.2 is N in case R.sup.1 is NH.

3. The method according to claim 7, wherein in formula I R.sup.3 is selected from C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, C.sub.3-C.sub.4-cycloalkyl, —O—C.sub.1-C.sub.2-alkyl and —O—C.sub.1-C.sub.2-haloalkyl.

4. The method according to claim 7, wherein in formula I R.sup.4 is selected from C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl, —C(═O)—C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.2-C.sub.4-haloalkenyl and -(C.sub.1-C.sub.2-alkyl)-O-(C.sub.1-C.sub.2-alkyl).

5. The method according to claim 7, wherein in formula I Het is pyridyl or thiazolyl, wherein said pyridyl or thiazolyl is unsubstituted or carries 1, 2 or 3 identical or different groups R.sup.a .

6. The method according to claim 7, wherein in formula I R.sup.a is selected from is selected from C.sub.1-C.sub.3-alkyl, C.sub.2-C.sub.3-alkenyl, C.sub.2-C.sub.3-alkynyl, —O—C.sub.1-C.sub.3-alkyl, —C(═N—O—C.sub.1-C.sub.2-alkyl)-C.sub.1-C.sub.2-alkyl, —O—CH.sub.2—C(═N—O—C.sub.1-C2-alkyl)-C1-C2-alkyl, C.sub.3-C.sub.4-cycloalkyl, -C1-C2-alkyl-C.sub.3-C4-cycloalkyl, —O—C.sub.3-C4-cycloalkyl, phenyl, 3- to 5-membered heterocycloalkyl and 5- or 6-membered heteroaryl, wherein said heterocycloalkyl and heteroaryl besides carbon atoms contain 1 or 2 heteroatoms selected from N, O and S, provided that such heterocycloalkyl and heteroaryl cannot contain 2 contiguous atoms selected from O and S; and/or 2 R.sup.a substituents bound to neighboring carbon ring atoms, together with the two interjacent carbon ring atoms, form a fused phenyl ring, and wherein the aliphatic and cyclic moieties of R.sup.a and the abovementioned fused phenyl ring are unsubstituted or carry 1, 2, 3, 4 or up to the maximum number of identical or different groups R.sup.b which independently of one another are selected from halogen, CN, methyl and C.sub.1-haloalkyl.

7. A method for combating phytopathogenic fungi containing an amino acid substitution F129L in the mitochondrial cytochrome b protein conferring resistance to Qo inhibitors, comprising: treating curatively and/or preventively the plants or the plant propagation material of said plants that are at risk of being diseased from the said phytopathogenic fungi, and/or applying to the said phytopathogenic fungi with an effective amount of at least one compound of formula I ##STR00499## wherein R.sup.1 is selected from O and NH; R.sup.2 is selected from CH and N; R.sup.3 is selected from halogen, CN, C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl, C.sub.1-C.sub.4-haloalkyl, C.sub.2-C.sub.4-haloalkenyl, C.sub.2-C.sub.4-haloalkynyl, C.sub.3-C.sub.6-cycloalkyl.sub.. —O—C.sub.1-C.sub.4-alkyl, O-C.sub.1-C.sub.4-haloalkyl, —O—C.sub.3-C.sub.6-cycloalkyl, -C.sub.1-C.sub.2-alkyl-C.sub.3-C.sub.6-cycloalkyl, phenyl, 3- to 6-membered heterocycloalkyl and 5- or 6-membered heteroaryl, wherein said heterocycloalkyl and heteroaryl besides carbon atoms contain 1, 2 or 3 heteroatoms selected from N, O and S, provided that such heterocycloalkyl and heteroaryl cannot contain 2 contiguous atoms selected from O and S; wherein said phenyl, heterocycloalkyl and heteroaryl are bound directly or via an oxygen atom or via a C.sub.1-C.sub.2-alkylene linker, and wherein said phenyl and heteroaryl are unsubstituted or substituted by 1, 2 or 3 identical or different substituents selected from halogen, CN, NH.sub.2, NO.sub.2, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, —O—C.sub.1-C.sub.4-alkyl and —O—C.sub.1-C.sub.4-haloalkyl; R.sup.4 is selected from C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl, C.sub.1-C.sub.6-haloalkyl, C.sub.2-C.sub.4-haloalkenyl, C.sub.2-C.sub.4-haloalkynyl, O-C.sub.1-C.sub.4-alkyl, —C(.sub.=O)—C.sub.1-C.sub.4-alkyl, ( C.sub.1-C.sub.2-alkyl)-O-( C.sub.1-C.sub.2-alkyl), -(C.sub.1-C.sub.2-alkyl)-O-(C.sub.1-C.sub.2-haloalkyl), C.sub.3-C.sub.6-.sub.CVCI.sub.O-alkyl, C.sub.3-C.sub.6-halocycloalkyl and -C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.6-cycloalkyl; Het is 5- or 6-membered heteroaryl, wherein said heteroaryl besides carbon atoms contains 1, 2 or 3 heteroatoms selected from N, O and S, provided that such heteroaryl cannot contain 2 contiguous atoms selected from O and S; wherein said heteroaryl is unsubstituted or carries 1, 2, 3 or up to the maximum number of identical or different groups R.sup.a— R.sup.a is selected from halogen, CN, —NR.sup.5R.sup.6, C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl, —O—C.sub.1-C.sub.4-alkyl, —C(═N—O—C.sub.1-C.sub.4-alkyl)-C.sub.1-C.sub.4-alkyl, C( =O )-C.sub.1-C.sub.4 -al kvl, —O—C H.sub.2—C(═N—O—C.sub.1-C.sub.4 -al kvl)-C.sub.1-C.sub.4 -alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkenyl, —C.sub.4—C.sub.z—alkyl—C.sub.3—Ce.sub.6—cycloalkyl, —O—C.sub.3-C.sub.6-cycloalkyl, phenyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkenyl and 5- or 6-membered heteroaryl, wherein said heterocycloalkyl, heterocycloalkenyl and heteroaryl besides carbon atoms contain 1, 2 or 3 heteroatoms selected from N, O and S, provided that such heterocycloalkyl, heterocycloalkenyl and heteroaryl cannot contain 2 contiguous atoms selected from O and S; and/or 2 R.sup.a substituents bound to neighboring carbon ring atoms, together with the two interjacent carbon ring atoms, form a partially unsaturated or aromatic 5- to 6-membered fused carbo- or heterocycle, wherein the heterocycle includes beside carbon atoms 1 or 2 heteroatoms independently selected from N, O and S as ring member atoms, provided that such heterocycle cannot contain 2 contiguous atoms selected from O and S; and wherein the aliphatic and cyclic moieties of R.sup.a and the abovementioned fused carbo- or heterocycle are unsubstituted or carry 1, 2, 3, 4 or up to the maximum number of identical or different groups R.sup.b.sub.: R.sup.b is selected from halogen, CN, NH.sub.2, NO.sub.2, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, —O—C.sub.1-C.sub.4-alkyl, —O—C.sub.1-C.sub.4-haloalkyl and C.sub.3-C.sub.6-cycloalkyl; R.sup.5, R.sup.6 are independently of each other selected from the group consisting of H, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl and C.sub.2-C.sub.4-alkynyl; and in form or stereoisomers and tautomers thereof, and the N-oxides and the agriculturally acceptable salts thereof.

8. A compound of formula I ##STR00500## wherein R.sup.1 is selected from O and NH; R.sup.2 is selected from CH and N; R.sup.3 is selected from halogen, CN, C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl, C.sub.1-C.sub.4-haloalkyl, C.sub.2-C.sub.4-haloalkenyl, C.sub.2-C.sub.4-haloalkynyl, C.sub.3-C.sub.6-cycloalkyl, —O—C.sub.1-C.sub.4-alkyl, O-C.sub.1-C.sub.4-haloalkyl, —O—C.sub.3-C.sub.6-cycloalkyl, -C.sub.1-C.sub.2-alkyl-C.sub.3-C.sub.6-cycloalkyl, phenyl, 3- to 6-membered heterocycloalkyl and 5- or 6-membered heteroaryl, wherein said heterocycloalkyl and heteroaryl besides carbon atoms contain 1, 2 or 3 heteroatoms selected from N, O and S, provided that such heterocycloalkyl and heteroaryl cannot contain 2 contiguous atoms selected from O and S; wherein said phenyl, heterocycloalkyl and heteroaryl are bound directly or via an oxygen atom or via a C.sub.1-C.sub.2-alkylene linker, and wherein said phenyl and heteroaryl are unsubstituted or substituted by 1, 2 or 3 identical or different substituents selected from halogen, CN, NH.sub.2, NO.sub.2, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, —O—C.sub.1-C.sub.4-alkyl and —O—C.sub.1-C.sub.4-haloalkyl; R.sup.4 is selected from C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl, C.sub.1-C.sub.6-haloalkyl, C.sub.2-C.sub.4-haloalkenyl, C.sub.2-C.sub.4-haloalkynyl, O-C.sub.1-C.sub.4-alkyl, —C(.sub.=O)—C.sub.1-C.sub.4-alkyl, (C.sub.1-C.sub.2-alkyl)-0-(C.sub.1-C.sub.2-alkyl), -(C.sub.1-C.sub.2-alkyl)-O-(C.sub.1-C.sub.2-haloalkyl), C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halocycloalkyl and -C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.6-cycloalkyl; Het is 5- or 6-membered heteroaryl, wherein said heteroaryl besides carbon atoms contain 1, 2 or 3 heteroatoms selected from N, O and S, provided that such heteroaryl cannot contain 2 contiguous atoms selected from O and S; wherein said heteroaryl is unsubstituted or carries 1, 2, 3 or up to the maximum number of identical or different groups R.sup.a— R.sup.a is selected from halogen, CN, —NR.sup.5R.sup.6, C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl, —O—C.sub.1-C.sub.4-alkyl, —C(═N—O—C.sub.1-C.sub.4-alkyl)-C.sub.1-C.sub.4-alkyl, C(═O)-C.sub.1-C.sub.4-alkyl, —O—CH.sub.2—C(═N—O—C.sub.1-C.sub.4-alkyl)-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkenyl, -C.sub.1-C.sub.2-alkyl-C.sub.3-C.sub.6-cycloalkyl, O-C.sub.3-C.sub.6-cycloalkyl, phenyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkenyl and 5- or 6-membered heteroaryl, wherein said heterocycloalkyl, heterocycloalkenyl and heteroaryl besides carbon atoms contain 1, 2 or 3 heteroatoms selected from N, O and S, provided that such heterocycloalkyl, heterocycloalkenyl and heteroaryl cannot contain 2 contiguous atoms selected from O and S; and/or 2 R.sup.a substituents bound to neighboring carbon ring atoms, together with the two interjacent carbon ring atoms, form a partially unsaturated or aromatic 5- to 6-membered fused carbo- or heterocycle, wherein the heterocycle includes beside carbon atoms 1 or 2 heteroatoms independently selected from N, O and S as ring member atoms, provided that such heterocycle cannot contain 2 contiguous atoms selected from O and S; and wherein the aliphatic and cyclic moieties of R.sup.a and the abovementioned fused carbo- or heterocycle are unsubstituted or carry 1, 2, 3, 4 or up to the maximum number of identical or different groups R.sup.b.sub.: R.sup.b is selected from halogen, CN, NH.sub.2, NO.sub.2, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, —O—C.sub.1-C.sub.4-alkyl and —O—C.sub.1-C.sub.4-haloalkyl; R.sup.5, R.sup.6 are independently of each other selected from the group consisting of H, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl and C.sub.2-C.sub.4-alkynyl; and in form or stereoisomers and tautomers thereof, and the N-oxides and the agriculturally acceptable salts thereof.

9. The compound according to claim 8, wherein R.sup.1 is selected from O and NH; and R.sup.2 is selected from CH and N, provided that R.sup.2 is N in case R.sup.1 is NH.

10. The compound according to claim 8, wherein R.sup.3 is selected from CN, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, C.sub.3-C.sub.4-cycloalkyl, —O—C.sub.1-C.sub.2-alkyl and —O—C.sub.1-C.sub.2-haloalkyl.

11. The compound according to claim 8, wherein R.sup.4 is selected from C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.4-alkenyl, C.sub.1-C.sub.6-haloalkyl, C.sub.2-C.sub.4-haloalkenyl, -(C.sub.1-C.sub.2-alkyl)-O-(C.sub.1-C.sub.2-alkyl) and -(C.sub.1-C.sub.2-alkyl)-O-(C.sub.1-C.sub.2-haloalkyl).

12. The compound according to claim 8, wherein Het is pyridyl or thiazolyl, wherein said pyridyl or thiazolyl is unsubstituted or carries 1, 2 or 3 identical or different groups R.sup.a .

13. An agrochemical composition comprising an auxiliary and at least one compound of formula I, as defined in claim 8 or in the form of a stereoisomer or an agriculturally acceptable salt or a tautomer or N-oxide thereof.

14. (canceled)

15. A method for combating phytopathogenic fungi comprising: treating curatively and/or preventively the plants or the plant propagation material of said plants that are at risk of being diseased from the said phytopathogenic fungi, and/or applying to the said phytopathogenic fungi, at least one compound of formula I as defined in claim 8.

Description

EXAMPLES

Synthetic Process

Example 4 (numbering According to Table S Below): Methyl (2E)-2-methoxyimino-2-[3-methyl-2-[[(E)-1-[4-(trifluoromethyl)-2-pyridyl]ethylideneamino]oxymethyl]phenyl]acetate

[0242] ##STR00016##

Step 1: 1-[4-(trifluoromethyl)-2-pyridyl]ethanone

[0243] To a solution of 2-chloro-4-(trifluoromethyl)pyridine (3.0 g, 16.52 mmol) in butane-2,3-diol (10 ml), 4-vinyloxybutan-1-ol (3.06 ml, 25 mmol) was added in one portion at 25° C. Sodium carbonate (3.5 g, 33 mmol) was added and the reaction mixture was degassed for 20 min using N.sub.2 gas at 25° C. Palladium acetate (0.186 g, 0.82 mmol) and 3-diphenylphosphanylpropyl(diphenyl)phosphane (0.68 g, 2 mmol) were added and the reaction mixture was stirred for 3 h at 120° C. under N.sub.2. TLC showed the starting materials were consumed completely. The reaction mixture was cooled to 25° C. and to this 1N HCl (10 ml) was added. The reaction mixture was again heated for 1 h at 110° C. Reaction mixture was quenched with saturated solution of NaHCO.sub.3 (50 ml) and filtered through Celite bed. The aqueous phase filtrate was extracted with ethyl acetate (EtOAc, 2× 20 ml). Combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated and purified by silica gel column (EtOAc:heptane = 20:80) to give 1-[4-(trifluoromethyl)-2-pyridyl]ethanone (2.5 g, 80 %) as brown liquid. .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 9.03 (s, 1H), 8.15-8.10 (m, 1H), 8.09-8.08 (m,1H), 2.69 (s, 3H).

Step 2: 1-[4-(trifluoromethyl)-2-pyridyl]ethanone Oxime

[0244] To a solution of 1-[4-(trifluoromethyl)-2-pyridyl]ethanone (10 g, 52.87 mmol) in MeOH (100 ml), hydroxylamine hydrochloride (9.25 g, 132 mmol) and NaOAc (10.83 g, 132 mmol) were added under N.sub.2. The mixture was stirred for 2 h at 70° C. under N.sub.2. TLC showed that the reaction was completed. The reaction mixture was concentrated and then dissolved in EtOAc (100 ml) and H.sub.2O (100 ml). The aqueous phase was extracted with EtOAc (2× 50 ml). Combined organic layer was washed with brine (100 ml), dried over Na.sub.2SO.sub.4 and concentrated and purified by silica gel column (EtOAc:heptane = 20:80) to give 1-[4-(trifluoromethyl)-2-pyridyl]ethanone oxime (4.3 g, 39.8%) as white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ = 11.8 (s, 1H), 8.88 (d, J = 5.0 Hz, 1H), 8.06 (s, 1H), 7.76 (d, J = 5.0 Hz, 1H), 2.25 (s, 3H).

Step 3: Methyl (2E)-2-methoxyimino-2-[3-methyl-2-[[(E)-1-[4-(trifluoromethyl)-2-pyridyl]ethylideneamino]oxymethyl]phenyl]acetate

[0245] To a solution of 1-[4-(trifluoromethyl)-2-pyridyl]ethanone oxime (4.3 g, 21.06 mmol) in AcN (50 ml), Cs.sub.2CO.sub.3 (17.11 g, 52.65 mmol) was added. The mixture was stirred for 10 min at 25° C. Methyl (2E)-2-[2-(bromomethyl)-3-methyl-phenyl]-2-methoxyimino-acetate (6.95 g, 23.16 mmol) was added and the reaction mixture was stirred for 12 h at 25° C. TLC showed that the reaction was completed. The reaction mixture was quenched with H.sub.2O (100 ml), extracted with EtOAc (2× 100 ml). The organic phase was washed with brine (100 ml), dried over Na.sub.2SO.sub.4, concentrated and purified by silica gel column (heptane:EtOAc = ~ 90:10) to give the title compound (5.67 g, 63.6%) as off-white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ = 8.89 (d, J = 5.0 Hz, 1H), 8.00 (s, 1H), 7.81 - 7.79 (m, 1H), 7.34 - 7.30 (m, 2H), 7.03-7.02 (m, 1H), 5.12 (br s, 2H), 3.91 (s, 3H), 3.68 (s, 3H), 2.45 (s, 3H), 2.20 (s, 3H).

Example 5: (2E)-2-methoxyimino-N-methyl-2-[3-methyl-2-[[(E)-1-[4-(trifluoromethyl)-2-pyridyl]-ethylideneamino]oxymethyl]phenyl]acetamide

[0246] ##STR00017##

To a solution of methyl (2E)-2-methoxyimino-2-[3-methyl-2-[[(E)-1-[4-(trifluoromethyl)-2-pyridyl]ethylideneamino]oxymethyl]phenyl]acetate (12 g, 28.34 mmol) in THF (120 ml), MeNH.sub.2 (15 ml, 40% aq. sol.) was added. The mixture was stirred for 2 h at 25° C. TLC (EtOAc:heptane = 20:80) showed the reaction was completed. Solvent was evaporated. Crude product was diluted with H.sub.2O (150 ml), extracted with EtOAc (3× 100 ml). Organic phase was washed with brine (100 ml), dried over Na.sub.2SO.sub.4 and concentrated. Crude mass was washed with n-pentane (2× 50 ml) to give the title compound (11.0 g, 91.4%) as off-white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 8.88 (d, J = 5.0 Hz, 1H), 8.28-8.23 (m, 1H), 8.05 (s, 1H), 7.79-7.78 (m, 1H), 7.31-7.28 (m, 2H), 6.97-6.95 (m, 1H), 5.12 (br s, 2H), 3.86 (s, 3H), 2.67 (s, 3H), 2.45 (s, 3H), 2.20 (s, 3H).

Example 11: Methyl (2E)-2-[2-[[(E)-1-[5-(4-fluorophenyl)isothiazol-3-yl]ethylideneamino]oxy-methyl]-3-methyl-phenyl]-2-methoxyimino-acetate

[0247] ##STR00018##

Step 1: Methyl 3-(4-fluorophenyl)-3-oxo-propanoate

[0248] To a solution of 1-(4-fluorophenyl)ethenone (22 g, 159.26 mmol) and dimethyl oxalate (20.68 g, 175 mmol) in toluene (250 ml), potassium tertiary butoxide (26.75 g, 238.89 mmol) was added at 25° C. The mixture was stirred for 2 h at 25° C. under N.sub.2. TLC (heptane:EtOAc = 10:1) showed that the reaction was completed. The reaction mixture was quenched with 1N HCl (70 ml) and extracted with EtOAc (2× 100 ml). The organic phase was washed with brine (50 ml), dried over Na.sub.2SO.sub.4 and concentrated. Crude compound was washed with heptane (200 ml) to give pure methyl 3-(4-fluorophenyl)-3-oxo-propanoate (31 g, 86.82 %). .sup.1H NMR: (300 MHz, DMSO-d.sub.6): δ 8.18 - 8.15 (m, 2H), 8.14 (bs, 1H), 7.43 - 7.35 (m, 2H), 7.11 (s, 1H), 3.85 (3H, s).

Step 2: Methyl 3-(4-fluorophenyl)-3-oxo-propanimidate

[0249] To a solution of methyl 3-(4-fluorophenyl)-3-oxo-propanoate (31 g, 138.27 mmol) in toluene (300 ml), ammonium acetate (31.94 g, 414.83 mmol) and acetic acid (1.65 g, 0.2 mmol) were added at 25° C. The mixture was stirred for 2 h at 110° C. under N.sub.2. TLC (heptane: EtOAc = 5:1) showed that the reaction was completed. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (30 ml) and extracted with EtOAc (2× 100 ml), the organic phase was washed with brine (50 ml), dried over Na.sub.2SO.sub.4 and concentrated to give pure methyl 3-(4-fluorophenyl)-3-oxo-propanimidate (30 g, 97.2%). .sup.1H NMR: (300 MHz, DMSO-d6):δ 9.45 (br s, 1H), 8.01 - 7.94 (m, 2H), 7.89 (br s, 1H), 7.33 - 7.27 (m, 2H), 6.43 (s, 1H), 3.89 (3H, s).

Step 3: Methyl 5-(4-fluorophenyl) Isothiazole-3-carboxylate

[0250] To a solution of methyl 3-(4-fluorophenyl)-3-oxo-propanimidate (30 g, 134.4 mmol) in THF (300 ml), P.sub.2S.sub.5 (20.887 g, 94 mmol) was added at 25° C. The mixture was stirred for 2 h at 25° C. under N.sub.2 and then concentrated under reduced pressure. Crude compound was dissolved in EtOAc (200 ml) followed by dropwise addition of 30% H.sub.2O.sub.2 (7.6 ml, 67.02 mmol) at 0° C. under N.sub.2 and stirred for 2 h. TLC (petroleum ether (PE):EtOAc = 5:1) showed that the reaction was completed. Reaction was quenched with water (50 ml) and filtered through Celite. The residue was washed with EtOAc. The filtrate was concentrated. Crude compound methyl 5-(4-fluorophenyl) isothiazole-3-carboxylate (20 g) was used without purification for next reaction. .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 8.25 (s, 1H), 7.94 - 7.89 (m, 2H), 7.39 - 7.33 (m, 2H), 3.89 (3H, s).

Step 4: 5-(4-Fluorophenyl)isothiazole-3-carboxylic Acid

[0251] To a solution of methyl 5-(4-fluorophenyl) isothiazole-3-carboxylate (3 g, 12.64 mmol) in THF (12ml), MeOH (12 ml), water (6 ml) and LiOH (1.07 g, 250 mmol) were added at 25° C. The mixture was stirred for 16 h at 25° C. under N.sub.2. TLC (heptane: EtOAc = 5:1) showed that the reaction was completed. The mixture was concentrated under reduced pressure, dried and acidified with 1 N HCl (20 ml). The precipitated compound was filtered and dried under high vacuum to afford 5-(4-fluorophenyl)isothiazole-3-carboxylic acid (2.5 g, 88.6 %) as solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 8.20 (s, 1H), 7.89 - 7.83 (m, 2H), 7.52 - 7.25 (m, 2H).

Step 5: 5-(4-Fluorophenyl)isothiazole-3-carbonyl Chloride

[0252] To a solution of 5-(4-fluorophenyl)isothiazole-3-carboxylic acid (2.2 g, 9.103 mmol) in dichloromethane (DCM, 30 ml), oxalyl chloride (1.06 g, 10.92 mmol) was added in small portions at 0° C., followed by addition of a catalytic amount of DMF. The mixture was stirred for 2 h at 0° C. under N.sub.2. TLC (PE: EtOAc = 5:1) showed that the reaction was completed. The mixture was concentrated under reduced pressure. The crude compound 5-(4-fluorophenyl) isothiazole-3-carbonyl chloride (2.5 g) was used without purification for next step.

Step 6: 5-(4-Fluorophenyl)-N-methoxy-N-methyl-isothiazole-3-carboxamide

[0253] To a solution of 5-(4-fluorophenyl)isothiazole-3-carbonyl chloride (2.2 g, 9.103 mmol) in DCM (30 ml), methoxy methylamine hydrochloride (1.06 g, 10.92 mmol) was added in small portions at 0° C., followed by addition of triethyl amine (1.83 g,18.20 mmol). The mixture was stirred for 4 h at 25° C. under N.sub.2. TLC (heptane:EtOAc = 5:1) showed that the reaction was completed. The mixture was quenched with water (15 ml) and extracted with DCM (2× 50 ml). The organic phase was dried over Na.sub.2SO.sub.4 and concentrated to give 5-(4-fluorophenyl)-N-methoxy-N-methyl-isothiazole-3-carboxamide. .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 8.01 (s, 1H), 7.89 - 7.85 (m, 2H), 7.40 - 7.33 (m, 2H), 3.75 (s, 3H), 3.34 (3H, s).

Step 7: 1-[5-(4-Fluorophenyl) Isothiazol-3-yl]ethenone

[0254] To a solution of 5-(4-fluorophenyl)-N-methoxy-N-methyl-isothiazole-3-carboxamide (2 g, 8 mmol) in THF (30 ml), 2.1 M methyl magnesium bromide (5.25 ml, 15.77 mmol) was added dropwise at -70° C. The mixture was stirred for 20 minutes at -70° C. under N.sub.2. TLC (PE:EtOAc = 5:1) showed that the reaction was completed. The mixture was quenched with sat. aqueous ammonium chloride solution (15 ml) and extracted with EtOAc (2× 50 ml). The organic phase was washed with brine (25 ml), dried over Na.sub.2SO.sub.4 and concentrated to give 1-[5-(4-fluorophenyl)isothiazol-3-yl]ethenone (1.7 g, 96%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 8.19 (s, 1H), 7.93 - 7.88 (m, 2H), 7.39 - 7.32 (m, 2H), 2.62 (s, 3H).

Step 8: 1-[5-(4-Fluorophenyl) Isothiazol-3-yl] Ethenone Oxime

[0255] To a solution of 1-[5-(4-fluorophenyl) isothiazol-3-yl]ethenone (1.8 g, 8.13 mmol) in MeOH /-pyridine (20 ml / 2 ml), hydroxylamine hydrochloride (1.13 g, 16.26 mmol) was added under N.sub.2. The mixture was stirred for 4 h at 65° C. under N.sub.2. TLC (heptane:EtOAc = 5:1) showed that the reaction was completed. The mixture was concentrated and then dissolved in EtOAc (50 ml) and H.sub.2O (20 ml). The aqueous phase was extracted with EtOAc (2× 30 ml), washed with brine (20 ml), dried over Na.sub.2SO.sub.4 and concentrated to give 1-[5-(4-fluorophenyl) isothiazol-3-yl]ethenone oxime (1.75 g, 86.10%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 11.62 (s, 1H), 7.90 (s, 1H), 7.85 -7.79 (m, 2H), 7.36 - 7.27 (m, 2H), 2.22 (s, 3H).

Step 9: Methyl (2E)-2-[2-[[(E)-1-[5-(4-fluorophenyl)isothiazol-3-yl]ethylideneamino]oxymethyl]-3-methyl-phenyl]-2-methoxyimino-acetate

[0256] The solution of 1-[5-(4-fluorophenyl)isothiazol-3-yl]ethenone oxime (550 mg, 2.32 mmol) in DMF (6 ml), 60 % NaH (111 mg, 4.65 mmol) was added in small portions and stirred at 65° C. for 1.5 h followed by addition of methyl (2E)-2-[2-(bromomethyl)-3-methyl-phenyl]-2-methoxyimino-acetate (769 mg, 2.56 mmol) and stirred at 65° C. for 2 h. TLC (heptane:EtOAc = 5:1) showed that the reaction was completed. The mixture was quenched with H.sub.2O (30 ml) and extracted with EtOAc (2× 50 ml). The organic phase was washed with brine (30 ml), dried over Na.sub.2SO.sub.4, concentrated and purified by flash column chromatography to give the title compound (450 mg, 43 %). .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 7.86 - 7.84 (m, 3 H), 7.38 - 7.29 (m, 4 H), 7.04 - 7.03 (m, 1 H), 5.07 (br s, 2 H), 3.92 (s, 3 H), 3.69 (s, 3 H), 2.50 (s, 3 H), 2.18 (3H, s).

Example 12: (2E)-2-[2-[[(E)-1-[5-(4-Fluorophenyl) Isothiazol-3-yl] Ethylidene Amino] oxymethyl]-3-methyl-phenyl]-2-methoxyimino-N-methyl-acetamide

[0257] ##STR00019##

To a stirred solution of methyl (2E)-2-[2-[[(E)-1-[5-(4-fluorophenyl)isothiazol-3-yl]ethylidene-amino]oxymethyl]-3-methyl-phenyl]-2-methoxyimino-acetate (250 mg, 0.549 mmol) in THF (4 ml), methylamine (85 mg, 3 mmol) was added and the mixture was stirred for 16 h at 15° C. TLC (heptane: EtOAc = 5:1) showed that the reaction was completed. The mixture was quenched with H.sub.2O (10 ml) and extracted with EtOAc (3× 15 ml). The organic phase was washed with brine (50 ml), dried over Na.sub.2SO.sub.4 and concentrated to give the title compound (220 mg, 85.42 %) as solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 8.30 (d, J=5 Hz, 1 H), 7.94 - 7.89 (m, 3 H), 7.37 -7.26 (m, 4 H), 6.96 ( d, J=6.5 Hz, 1 H), 5.01 (br s, 2 H), 3.87 (s, 3 H), 2.66 (d, J=4.5 Hz, 3 H), 2.44 (s, 3 H), 2.19 (s, 3H).

Example 19: Methyl (2E)-2-methoxyimino-2-[2-[[(E)-1-[5-[3-(trifluoromethyl)phenyl]isoxazol-3-yl]ethylideneamino]oxymethyl]phenyl]acetate

[0258] ##STR00020##

Step 1. Methyl 2,4-dioxo-4-[3-(trifluoromethyl)phenyl]butanoate

[0259] To a solution of 1-[3-(trifluoromethyl)phenyl]ethanone (10 g, 0.05 mol) in Toluene (100 ml), dimethyl oxalate (7.532 gm, 0.064 mol) was added. The reaction mixture was stirred at room temperature for 10 min under N.sub.2 and then potassium tertiary butoxide (11.9 g, 0.106 mol) was added portion-wise. Then, the reaction mixture was stirred at room temperature for further 2 h. TLC (heptane:EtOAc = 5:1) showed that the reaction was completed. The mixture was diluted with 1N HCl (30 ml) and H.sub.2O (70 ml). The aqueous phase was extracted with EtOAc (2× 100 ml). The combined EtOAc layer was washed with brine (100 ml), dried over Na.sub.2SO.sub.4 and concentrated. Crude product was stirred in 30 ml heptane to get solid which was filtered and washed with 20 ml heptane, dried under vacuum to afford methyl 2,4-dioxo-4-[3-(trifluoromethyl)phenyl]butanoate (6.0 g, 96.1 %) as a white solid. .sup.1H NMR (500 MHz, DMSO): δ 8.264 -8.392 (m, 2H), 8.194 (t 1H), 7.802 - 7.841 (t, 1H), 7.186 (d, 1H), 3.910 (s, 3H).

Step 2: Methyl 5-[3-(trifluoromethyl)phenyl]isoxazole-3-carboxylate

[0260] The solution of methyl 2,4-dioxo-4-[3-(trifluoromethyl)phenyl]butanoate (5.0 g, 0.018 mol) in MeOH (60 ml), hydroxylamine hydrochloride (1.9 g, 0.027 mol) was added at room temperature under N.sub.2. The reaction mixture was stirred for 2 h at 50° C. TLC (heptane:EtOAc = 9:1) showed that the reaction was completed. MeOH was evaporated under vacuum to get mass which was diluted with H.sub.2O (30 ml), extracted with EtOAc (30 ml × 2 times). The organic phase was washed with brine (30 ml), dried over Na.sub.2SO.sub.4, concentrated and crude compound was stirred in diethyl ether (10 ml) and the obtained solid was filtered under vacuum and dried under vacuum to afford crude methyl 5-[3-(trifluoromethyl)phenyl]isoxazole-3-carboxylate (4.2 g, 85 %) as white solid.

Step 3: 5-[3-(Trifluoromethyl)phenyl]isoxazole-3-carboxylic Acid

[0261] To a stirred solution of methyl 5-[3-(trifluoromethyl)phenyl]isoxazole-3-carboxylate (4.2 g, 0.015 mol) in THF:MeOH (40ml:40 ml), LiOH.H.sub.2O (3.252 g, 0.077 mol) dissolved in H.sub.2O (40 ml) was added at 0° C. The reaction mixture was stirred at RT for 16 h. TLC (40% EtOAc in heptane) showed that the reaction was completed. The mass was acidified with 1 N HCl (pH 2-3) and extracted with EtOAc (3× 40 ml). The organic phase was washed with brine (50 ml), dried over Na.sub.2SO.sub.4 and concentrated to give crude residue which was stirred in heptane (20 ml). The solid was filtered off and dried to afford 5-[3-(trifluoromethyl)phenyl]isoxazole-3-carboxylic acid (3.8 g, 95.4 % as white solid). .sup.1H NMR (500 MHz, DMSO): δ 14.2 (br s, 1H), 8.31 (s, 1H), 8.261 - 8.276 (dd, 1H), 7.912 - 7.928 (dd, 1H), 7.818-7.834 (dd, 1H), 7.679 (s, 1H).

Step 4: N-methoxy-N-methyl-5-[3-(trifluoromethyl)phenyl]isoxazole-3-carboxamide

[0262] To a solution of 5-[3-(trifluoromethyl)phenyl]isoxazole-3-carboxylic acid (4.0 g, 0.016 mol) in DCM (50 ml), oxalyl chloride (2.0 ml, 0.023 mol) and catalytic amount of DMF were added at 0° C. under N.sub.2. The reaction mixture was brought to RT and stirred for 1 h. Progress of acid chloride formation was monitored by TLC (40 % EtOAc in heptane) and after complete conversion of acid, the reaction mass was concentrated under vacuum. The residue was dissolved in DCM (50 ml) and triethylamine (10.910 ml, 0.078 mol) added at 0° C. followed by N-methoxymethanamine hydrochloride (1.8 g, 0.019 mol). The resulting mixture was stirred at RT for 4 h under N.sub.2. TLC (heptane: EtOAc = 7:3) showed that the reaction was completed. The mixture was quenched with H.sub.2O (50 ml), organic layer separated and the aq. phase extracted with DCM (2× 50 ml). The combined organic phase was dried over Na.sub.2SO.sub.4 and concentrated to give crude product which was purified by flash column chromatography (30% EtOAc in heptane) to afford N-methoxy-N-methyl-5-[3-(trifluoromethyl)phenyl]isoxazole-3-carboxamide (3.1 g, 66.4 %) as white solid. .sup.1H NMR: (500 MHz, DMSO): δ 8.301 (s, 1H), 8.224 - 8.283 (dd, 1H), 8.073 - 8.093 (dd, 1H), 7.58-7.864 (t, 1H), 7.527(s, 1H), 3.749 (s, 3H), 2.5 (s, 3H).

Step 5: 1-[5-[3-(Trifluoromethyl)phenyl]isoxazol-3-yl]ethanone

[0263] To a solution of N-methoxy-N-methyl-5-[3-(trifluoromethyl)phenyl]isoxazole-3-carboxamide (2.3 g, 0.0076 mol) in THF (40 ml), methyl magnesium bromide (7.6 ml, 0.023 mol) was added dropwise at -78° C. and stirred at same temperature for 30 min under N.sub.2. Completion of reaction was indicated by TLC (heptane:EtOAc = 5:1). The reaction mass was quenched with aq. ammonium chloride solution (10 ml) and diluted with H.sub.2O (30 ml) and extracted with EtOAc (3× 40 ml). The organic phase was washed with brine (50 ml), dried over Na.sub.2SO.sub.4 and concentrated to give crude product which was purified by flash chromatography (20% EtOAc in heptane) to afford 1-[5-[3-(trifluoromethyl)phenyl]isoxazol-3-yl]ethenone (1.2 g, 61.4 %).

Step 6: 1-[5-[3-(trifluoromethyl)phenyl]isoxazol-3-yl]ethanone Oxime

[0264] To a solution of 1-[5-[3-(trifluoromethyl)phenyl]isoxazol-3-yl]ethenone (1.2 g, 0.005 mol) in MeOH (30 ml), pyridine (0.758 ml, 0.009 mol) was added at RT followed by hydroxylamine hydrochloride (0.654 g, 0.009 mol) under N.sub.2. The resulting mixture was stirred at 65° C. for 4 h. Completion of reaction was indicated by TLC (heptane:EtOAc = 5:1). The reaction mass was evaporated under vacuum. The crude mass obtained was diluted with H.sub.2O (30 ml) and extracted with EtOAc (3× 30 ml). The organic phase was washed with 1N HCl (50 ml) and brine (50 ml), dried over Na.sub.2SO.sub.4 and concentrated to give crude product which was purified by flash column chromatography (20% EtOAc in heptane) to afford 1-[5-[3-(trifluoromethyl)phenyl]-isoxazol-3-yl]ethanone oxime (1.0 g, 78.7 %). .sup.1H NMR: (500 MHz, DMSO): δ 11.9 (s, 1H), 8.342 - 8.309 (m, 3H), 7.884-7.899 (dd, 1H), 7.462(s, 1H), 3.749 (s, 3H), 2.2 (s, 3H).

Step 7: Methyl (2E)-2-methoxyimino-2-[2-[[(E)-1-[5-[3-(trifluoromethyl)phenyl]isoxazol-3-yl]ethylideneamino]oxymethyl]phenyl]acetate

[0265] To a stirred solution of sodium hydride (60% - 0.089 g, 2.221 mmol) in DMF (10 ml), 1-[5-[3-(trifluoromethyl)phenyl]isoxazol-3-yl]ethanone oxime (0.5 g, 1.850 mmol) dissolved in DMF (5.0 ml) was added dropwise under N.sub.2. The mixture was stirred at RT for 1 h. Then, methyl (2E)-2-[2-(bromomethyl)-3-methyl-phenyl]-2-methoxyimino-acetate (0.611 g, 2.035 mmol) dissolved in DMF (5.0 ml) was added and stirred for 1 h. Completion of reaction was indicated by TLC (heptane:EtOAc = 5:1). The reaction mass was quenched with 1 N HCl (5 ml), diluted with H.sub.2O (15 ml) and extracted with EtOAc (3× 20 ml). Organic phase was washed with brine (30 ml), dried over Na.sub.2SO.sub.4, concentrated and purified by flash chromatography (20% EtOAc in heptane) to give the title compound (0.6 g, 65.7%) as a white solid. .sup.1H NMR: (500 MHz, DMSO): δ 8.223 - 8.286 (m, 2H), 7.905 (d, 1H), 7.816 (t, 1H), 7.392 (m, 3H), 7.042 (d, 1H), 5.107 (br s, 2H), 3.927 (s, 3H), 3.723 (s, 3H), 2.508 (s, 3H), 2.164 (s, 3H).

Example 22: (2E)-2-Methoxyimino-N-methyl-2-[3-methyl-2-[[(E)-1-[5-[3-(trifluoromethyl)phenyl]-isoxazol-3-yl]ethylideneamino]oxymethyl]phenyl]acetamide

[0266] ##STR00021##

To a solution of methyl (2E)-2-methoxyimino-2-[2-[[(E)-1-[5-[3-trifluoromethyl)phenyl]isoxazol-3-yl]ethylideneamino]oxymethyl]phenyl]acetate (0.3 g, 0.613 mmol) in THF (5 ml), methyl amine (~33% in water, 2.0 ml) was added and the resulting mixture was stirred for 2 h at RT. TLC (PE:EtOAc = 5:1) showed the reaction was completed. The reaction mixture was quenched with saturated aq. NHCl.sub.4 (10 ml) and extracted with EtOAc (3× 10ml). The organic phase was washed with brine (10 ml), dried over Na.sub.2SO.sub.4 and concentrated to give (2E)-2-methoxyimino-N-methyl-2-[3-methyl-2-[[(E)-1-[5-[3-(trifluoromethyl)phenyl]isoxazol-3-yl]ethylideneamino]oxymethyl]phenyl]acetamide (0.2 g, yield: 66.3 %) as white solid. .sup.1H NMR: (500 MHz, DMSO): δ 8.206 - 8.307 (m, 3H), 7.769 - 7.903 (m, 2H), 7.427 (t, 1H), 7.331 (m, 2H), 6.958 (d, 1H), 5.088 (br s, 2H), 3.877 (s, 3H), 2.696 (s, 3H), 2.440 (s, 3H), 2.160 (s, 3H).

Example 27: Methyl (2E)-2-methoxyimino-2-[3-methyl-2-[[(E)-1-[3-(trifluoromethyl)-2-pyridyl]-ethylideneamino]oxymethyl]phenyl]acetate

[0267] ##STR00022##

Step 1: 3-(Trifluoromethyl)pyridine-2-carbonitrile

[0268] To a solution of 2-chloro-3-(trifluoromethyl)pyridine (5 g, 27.54 mmol) in DMF/water (50 ml/0.5 ml), Pd.sub.2(dba).sub.3 (0.58 g, 0.633 mmol) catalyst, DPPF (0.702 g, 1.267 mmol) were added and degassed for 15 min. Then, zinc cyanide (1.487 g, 12.666 mmol) was added and stirred at 120° C. for 1 h under N.sub.2. TLC (heptane:EtOAc = 10:1) showed that the reaction was completed. The reaction mixture was cooled to RT. Then, water (500 ml) was added and extracted with EtOAc (2× 50 ml). The organic phase was washed with brine (50 ml), dried over Na.sub.2SO.sub.4, concentrated and purified by silica gel column (heptane:EtOAc: 100:0~85:15) to give 3-(trifluoromethyl)pyridine-2-carbonitrile (3.7 g, 100%) as off-white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 9.06 (d, J = 4.0 Hz, 1H), 8.53 - 8.51 (m, 1H), 8.03-8.01 (m, 1H).

Step 2: 1-[3-(Trifluoromethyl)-2-pyridyl]ethanone

[0269] To a solution of 3-(trifluoromethyl) pyridine-2-carbonitrile (3.7 g, 21.50 mmol) in THF (40 ml) was added methyl magnesium bromide (3 M in diethyl ether, 14.33 ml, 42.99 mmol) dropwise at 0° C. and stirred at 0° C. for 1 hour. TLC (PE:EtOAc = 10:2) showed that the reaction was completed. To the reaction mixture, aq. ammonium chloride solution (50 ml) added and extracted with EtOAc (2× 50 ml). The organic phase was washed with brine (50 ml), dried over Na.sub.2SO.sub.4, concentrated and purified by silica gel column (heptane: EtOAc: 100:0~80:20) to give 1-[3-(trifluoromethyl)-2-pyridyl]ethenone (3.4 g, 84.6 %) as colorless oil. .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 8.81 (d, J = 5.0 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.57 (dd, J = 5.0, 8.0 Hz, 1H), 2.71 (s, 3H).

Step 3: (1E)-1-[3-(Trifluoromethyl)-2-pyridyl]ethanone Oxime

[0270] To a solution of 1-[3-(trifluoromethyl)-2-pyridyl]ethanone (2.5 g, 13.218 mmol) in methanol (25 ml), HONH.sub.2.HCl (1.01 g, 14.54 mmol) and 2,6-lutidine (1.847 ml, 15.8 mmol) were added. The mixture was stirred for 3 h at 60° C. under N.sub.2. TLC (heptane:EtOAc = 10:2) showed that the reaction was completed. The mixture was cooled to RT, evaporated to dryness, quenched with H.sub.2O (25 ml) and extracted with EtOAc (3× 25 ml). The organic phase was washed with brine (25 ml), dried over Na.sub.2SO.sub.4 and purified by silica gel column (heptane:EtOAc = 100:0~75:25) to give (1E)-1-[3-(trifluoromethyl)-2-pyridyl]ethanone oxime (2.1 g, 85%) as off-white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 11.53 (s, 1H), 8.87 (d, J = 4.5 Hz, 1H), 8.26 (d, J = 8.1 Hz, 1H), 7.665-7.649 (m, 1H), 2.15 (s, 3H).

Step 4: Methyl (2E)-2-methoxyimino-2-[3-methyl-2-[[(E)-1-[3-(trifluoromethyl)-2-pyridyl]ethylideneamino]oxymethyl]phenyl]acetate

[0271] To a solution of (1E)-1-[3-(trifluoromethyl)-2-pyridyl]ethanone oxime (0.7 g, 3.429 mmol) in DMF (7 ml), methyl (2E)-2-[2-(bromomethyl)-3-methyl-phenyl]-2-methoxyimino-acetate (1.13 g, 3.772 mmol) and Cs.sub.2CO.sub.3 (2.229 g, 6.858 mmol) were added. The mixture was stirred for 2 h at 25° C. TLC (heptane: EtOAc = 4:1) showed that the reaction was completed. The reaction mixture was quenched with H.sub.2O (70 ml) and extracted with EtOAc (3× 20 ml). The organic phase was washed with brine (25 ml), dried over Na.sub.2SO.sub.4, concentrated and purified by silica gel column (heptane:EtOAc = 100:0~80:20) to give the title compound (1 g, yield: 68.1%) as a white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 8.86 (d, J = 4.2 Hz, 1H), 8.27 (d, J = 7.5 Hz, 1H), 7.68 -7.64 (m, 1H), 7.33 - 7.26 (m, 2H), 7.02 - 6.99 (m, 1H), 4.96 (s, 2H), 3.90 (s, 3H), 3.65 (s, 3H), 2.38 (s, 3H), 2.10 (s, 3H).

Example 28: (2E)-2-methoxyimino-N-methyl-2-[3-methyl-2-[[(E)-1-[3-(trifluoromethyl)-2-pyridyl]-ethylideneamino]oxymethyl]phenyl]acetamide

[0272] ##STR00023##

To a solution of methyl (2E)-2-methoxyimino-2-[3-methyl-2-[[(E)-1-[3-(trifluoromethyl)-2-pyridyl]ethylideneamino]oxymethyl]phenyl]acetate (500 mg, 1.181 mmol) in THF (5 ml), MeNH.sub.2 (40% solution in water, 2 ml) was added and the mixture was stirred for 2 h at 25° C. TLC (PE:EtOAc = 5:1) showed that the reaction was completed. The mixture was quenched with H.sub.2O (15 ml) and extracted with EtOAc (3× 15 ml). The organic phase was washed with brine (25 ml), dried over Na.sub.2SO.sub.4 and concentrated to afford the title compound (400 mg, 79.2%) as white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 8.86 (d, J = 4.5 Hz, 1H), 8.27 (d, J = 7.2 Hz, 1H), 8.13 (d, J = 4.5 Hz, 1H), 7.68 - 7.64 (m, 1H), 7.31 - 7.24 (m, 2H), 6.95 - 6.92 (m, 1H), 4.97 (s, 2H), 3.83 (s, 3H), 2.65 (d, J = 4.5 Hz, 3H), 2.38 (s, 3H), 1.99 (s, 3H).

Example 29: Methyl (2E)-2-methoxyimino-2-[2-[[(E)-1-[4-[(E)-N-methoxy-C-methyl-carbonimidoyl]-2-pyridyl]ethylideneamino]oxymethyl]-3-methyl-phenyl]acetate

[0273] ##STR00024##

Step 1: (E)-N-Methoxy-1-(4-pyridyl)ethanimine

[0274] To a solution of 1-(4-pyridyl)ethanone (25 g, 206 mmol) in MeOH (250 ml), methoxamine hydrochloride (25.86 g, 309 mmol) and pyridine (32.64 g, 413 mmol) were added under N.sub.2. The mixture was stirred for 3 h at 70° C. under N.sub.2. TLC (heptane:EtOAc = 5:1) showed that the reaction was completed. The mixture was concentrated and dissolved in EtOAc (250 ml) and H.sub.2O (250 ml). The aqueous phase was extracted with EtOAc (2× 250 ml), washed with brine (250 ml), dried over Na.sub.2SO.sub.4 and concentrated to give (E)-N-methoxy-1-(4-pyridyl)ethanimine (21 g, 67.8%) as a light brown oil. .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 8.62-8.61 (m, 2H), 7.63-7.61 (m, 2H), 3.97 (s, 1H), 2.19 (s, 3H).

Step 2: 1-[4-[(E)-N-Methoxy-C-methyl-carbonimidoyl]-2-pyridyl]ethanone

[0275] To the solution of (E)-N-methoxy-1-(4-pyridyl)ethanimine (10 g, 67 mmol) in DCM (200 ml), 2-oxopropanoic(pyruvic) acid (17.59 g, 200 mmol), silver nitrate (0.906 g, 5.32 mmol), ammonium persulfate (22.77 g, 100 mmol) and water (200 ml) were added followed by dropwise addition of trifluoroacetic acid (22.8 g, 200 mmol). The mixture was stirred for 3 h at 40° C. TLC (heptane:EtOAc = 4:1) showed that the reaction was completed. The mixture was diluted with DCM (200 ml) and H.sub.2O (200 ml), filtered through celite and washed with DCM (200 ml). The aqueous phase was extracted with DCM (2× 200 ml), washed with brine (200 ml), dried over Na.sub.2SO.sub.4 and concentrated and purified by silica gel column (heptane: EtOAc = 100:0~70:30) to give 1-[4-[(E)-N-methoxy-C-methyl-carbonimidoyl]-2-pyridyl]ethanone oxime (2.6 g, 20.3%) as an off white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 8.71-8.76 (m, 1H), 8.16 (s, 1H), 7.89-7.87 (m, 1H), 4.00 (s, 1H), 2.66 (s, 3H), 2.35 (s, 3H).

Step 3: 1-[4-[(E)-N-Methoxy-C-methyl-carbonimidoyl]-2-pyridyl]ethanone Oxime

[0276] To a solution of 1-[4-[(E)-N-methoxy-C-methyl-carbonimidoyl]-2-pyridyl]ethanone (9 g, 47 mmol) in MeOH (90 ml), hydroxylamine hydrochloride (4.881 g, 70 mmol) and pyridine (7.407 g, 94 mmol) were added under N.sub.2. The mixture was stirred for 3 h at 70° C. under N.sub.2. TLC (heptane:EtOAc = 4:1) showed that the reaction was completed. The mixture was concentrated, then dissolved in EtOAc (100 ml) and H.sub.2O (100 ml). The aqueous phase was extracted with EtOAc (2× 100 ml), washed with brine (100 ml), dried over Na.sub.2SO.sub.4, concentrated and purified by silica gel column (heptane:EtOAc = 100:0~60:40) to give to give 1-[4-[(E)-N-methoxy-C-methyl-carbonimidoyl]-2-pyridyl]ethanone oxime (5.2 g, 53.6%) as a light brown solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 11.6 (s, 1H), 8.62-8.61 (m, 1H), 8.11 (s, 1H), 7.60-7.59 (m, 1H), 3.99 (s, 3H), 2.18 (s, 3H), 2.11 (s, 3H).

Step 4: Methyl (2E)-2-methoxyimino-2-[2-[[(E)-1-[4-[(E)-N-methoxy-C-methyl-carbonimidoyl]-2-pyridyl]ethylideneamino]oxymethyl]-3-methyl-phenyl] acetate.

[0277] To a solution of 1-[4-[(E)-N-methoxy-C-methyl-carbonimidoyl]-2-pyridyl]ethanone oxime (11 g, 53 mmol) in ACN (260 ml), methyl (2E)-2-[2-(bromomethyl)-3-methyl-phenyl]-2-methoxyimino-acetate (15.93 g, 53 mmol) and cesium carbonate (34.6 g, 106.1 mmol) were added. The mixture was stirred for 4 h at 20° C. TLC (heptane:EtOAc = 5:1) showed that the reaction was completed. The mixture was quenched with H.sub.2O (250 ml) and extracted with EtOAc (2× 200 ml). The organic phase was washed with brine (200 ml), dried over Na.sub.2SO.sub.4, concentrated and purified by silica gel column (heptane:EtOAc = 100:0~70:30) to give the title compound (20 g, yield: 85.7 %) as a white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 8.61 (d, J=5 Hz, 1H), 7.98 (s, 1H), 7.63 - 7.62 (m, 1H) 7.33-7.29 (m, 2H) 7.03-7.02 (m, 1H) 5.08 (bs, 2 H) 4.00 (s, 3H) 3.98 (s, 3H), 3.91 (s,3H), 2.51 (s, 3H), 2.20 (s, 3 H), 2.16 (s, 3 H).

Example 30: (2E)-2-Methoxyimino-2-[2-[[(E)-1-[4-[(E)-N-methoxy-C-methyl-carbonimidoyl]-2-pyridyl]ethylideneamino]oxymethyl]-3-methyl-phenyl]-N-methyl-acetamide

[0278] ##STR00025##

To a solution of methyl (2E)-2-methoxyimino-2-[2-[[(E)-1-[4-[(E)-N-methoxy-C-methyl-carbonimidoyl]-2-pyridyl]ethylideneamino]oxymethyl]-3-methyl-phenyl]acetate (6 g, 14 mmol) in THF (60 ml), methyl amine (~40% in water, 6.54 g, 211 mmol) was added. The mixture was stirred for 2 h at 20° C. TLC (heptane:EtOAc = 4:1) showed that the reaction was completed. The reaction mixture was quenched with H.sub.2O (150 ml) and extracted with EtOAc (3 × 150 ml). The organic phase was washed with brine (150 ml), dried over Na.sub.2SO.sub.4, concentrated and purified by silica gel column (heptane:EtOAc = 100:0~60:40) to give to give the title compound (5.2 g, yield: 86%) as a white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6):δ 8.61 (d, J=5 Hz, 1 H), 8.22 (d, J=5.00 Hz, 1 H), 8.01 (s, 1 H), 7.63 - 7.61 (m, 1 H), 7.31-7.27 (m, 2H), 6.96 - 6.94 (m, 1H), 5.08 (bs, 2H), 3.99 (s, 3H) 3.86 (s, 3H), 2.65(d, J=5.00 Hz, 3H), 2.47 (s, 3H) 2.21 (s, 3H), 2.16 (s, 3H).

Example 123: Methyl (2E)-2-methoxyimino-2-[3-methyl-2-[[(E)-1-[5-(trifluoromethyl)thiazol-2-yl]-ethylideneamino]oxymethyl]phenyl]acetate

[0279] ##STR00026##

Step 1: 2-(1,1-Dimethoxyethyl)thiazole

[0280] To a solution of 1-thiazol-2-ylethanone (50 g, 0.393 mol) in MeOH (300 ml), trimethoxymethane (258 ml, 2.34 mol) and p-toluene sulfonic acid (74 g, 0.393 mol) were added under N.sub.2. The reaction mixture was stirred for 16 h at 65° C. under N.sub.2. TLC (heptane:EtOAc = 10:1) showed that the reaction was completed. The reaction mixture was cooled to RT, diluted with DCM (600ml). Saturated NaHCO.sub.3 solution (250ml) was added to neutralize the acid. Aqueous phase was again extracted with DCM (2× 300 ml). The combined organic phase was washed with water (2× 300 ml) and brine (300 ml), dried over Na.sub.2SO.sub.4 and concentrated to give (2-(1,1-dimethoxyethyl)thiazole (53 g, 65.05 %) as colorless liquid. .sup.1H NMR (500 MHz, CHCl.sub.3-d): δ 7.86 (d, 1H), 7.73 (d, 1H), 3.1 (s, 6H), 1.6 (s, 3H).

Step 2: 2-(1,1-Dimethoxyethyl)-5-iodo-thiazole

[0281] To a solution of 2-(1,1-dimethoxyethyl)thiazole (42 g, 0.242 mol) in THF (420 ml) under N.sub.2 at -78° C., 2.5 M n-butyllithium in hexane (121 ml, 0.303 mol) was added dropwise under stirring. After 45 min stirring at same temperature, iodine (64 g, 0254 mol) in 100 ml THF was added dropwise under stirring. The mixture was stirred for 2 h at -78° C. under N.sub.2. TLC (heptane:EtOAc = 10:1) showed that the reaction was completed. The mixture was quenched with 100 ml sat. ammonium chloride solution. The aqueous phase was extracted with EtOAc (2× 500 ml). The combined organic phase was washed with water (300 ml) and brine (300 ml), dried over Na.sub.2SO.sub.4, concentrated and purified by flash column chromatography (10-15% EtOAc in heptane). Evaporation of solvent afforded 2-(1,1-dimethoxyethyl)-5-iodo-thiazole (48 g, 66.2 %) as light brown liquid. .sup.1H NMR (500 MHz, CHCl.sub.3-d): δ 7.85 (s, 1H), 3.2 (s, 6H), 1.72 (s, 3H).

Step 3: 2-(1,1-Dimethoxyethyl)-5-(trifluoromethyl)thiazole

[0282] To 2-(1,1-dimethoxyethyl)-5-iodo-thiazole (40 g, 133 mmol), methyl 2,2-difluoro-2-fluorosulfonyl-acetate (28 g, 415 mmol), copper iodide (28 g, 147 mmol) and DMF (320 ml) were added under N.sub.2. The reaction mixture was heated at 100° C. and stirred for 12 h. TLC (heptane:EtOAc = 10:1) showed that the reaction was completed. The reaction mass was cooled to RT. Ice water (100 ml) was added followed by EtOAc (500 ml). A solid was precipitated, filtered through Celite and washed thoroughly with EtOAc (50 ml). The organic layer was separated. The aqueous layer was extracted with EtOAc (2× 400 ml). Combined organic layer was washed with water (2 × 300 ml) and brine (300 ml). Organic layer was dried over Na.sub.2SO.sub.4 and concentrated. Crude product was purified by flash column chromatography (10-15% EtOAc in heptane). Evaporation of solvent gave 2-(1,1-dimethoxyethyl)-5-(trifluoromethyl)thiazole (10.8 g, 33 %) as light brown liquid. .sup.1H NMR (500 MHz, CHCl.sub.3-d): δ 8.11 (s, 1H), 3.27 (s, 6H), 1.74 (s, 3H).

Step 4: 1-[5-(Trifluoromethyl)thiazol-2-yl]ethenone

[0283] To a solution of 2-(1,1-dimethoxyethyl)-5-(trifluoromethyl)thiazole (10 g, 41 mmol) in DCM (15 ml), trifluoracetic acid (27 ml, 410 mmol) and water (ml) were added at 0° C. The reaction mixture was stirred for 2 h at RT. TLC (heptane:EtOAc = 10:1) showed that the reaction was completed. Reaction mass was diluted with DCM (200 ml) and neutralized with sat. NaHCO.sub.3 solution (150 ml). The aqueous phase was extracted with DCM (2× 200 ml). The combined organic phase was washed with water (100 ml) and brine (100 ml), dried over Na.sub.2SO.sub.4 and concentrated to give 1-[5-(trifluoromethyl)thiazol-2-yl]ethenone (6.7 g, 82 %) as light brown oil. .sup.1H NMR (500 MHz, CHCl.sub.3-d): δ 8.2 (s, 1H), 2.76 (s, 3H).

Step 5: 1-[5-(Trifluoromethyl)thiazol-2-yl]ethenone Oxime

[0284] To a solution of 1-[5-(trifluoromethyl)thiazol-2-yl]ethenone (6.7 g, 34 mmol) in MeOH (60 ml), hydroxylamine hydrochloride (3.5 g, 51 mmol) and pyridine (5.4 g, 69 mmol) were added under N.sub.2. The reaction mixture was stirred for 4 h at 80° C. under N.sub.2. TLC (PE: EtOAc = 10:1.5) showed that the reaction was completed. The reaction mixture was concentrated and then dissolved in EtOAc (100 ml) and H.sub.2O (100 ml). The aqueous phase was extracted with EtOAc (2× 50 ml). Combined organic layer was washed with brine (100 ml), dried over Na.sub.2SO.sub.4 and concentrated under vacuum. Crude product was stirred in MeOH (12 ml) for 15 min, filtered through Buchner funnel and dried under vacuum to afford 1-[5-(trifluoromethyl)thiazol-2-yl]-ethenone oxime (3.7 g, 51 %) as a white solid. .sup.1H NMR (500 MHz, CHCl.sub.3-d): δ 13.2 (s, 1H), 8.6 (s, 1H), 2.2 (s, 3H).

Step 6: Methyl (2E)-2-methoxyimino-2-[3-methyl-2-[[E-1-[5-(trifluoromethyl)thiazol-2-yl]ethyl-ideneamino]oxymethyl]phenyl]acetate

[0285] To a solution of 1-[5-(trifluoromethyl) thiazol-2-yl]ethenone oxime (3.7 g, 17.60 mmol) in ACN (40 ml), Cs.sub.2CO.sub.3 (11.44 g, 35.20 mmol) was added. The mixture was stirred for 10 min at 25° C. Then, methyl (2E)-2-[2-(bromomethyl)-3-methyl-phenyl]-2-methoxyimino-acetate (5.8 g, 19.36 mmol) was added. The mixture was stirred for 12 h at 25° C. TLC (PE:EtOAc = 80:20) showed that the reaction was completed. The mixture was quenched with H.sub.2O (100 ml) and extracted with EtOAc (2× 100 ml). The combined organic phase was washed with brine (100 ml), dried over Na.sub.2SO.sub.4, concentrated and purified by flash column chromatography (n-heptane:EtOAc = ~80:20) to give the title compound (5.1 g, 66.8%) as white solid. .sup.1H NMR (500 MHz, DMSO-d): δ 8.68 (s, 1H), 7.32-7.37 (m, 2H), 7.05 (d, 1H), 5.23 (br s, 2H), 3.92 (s, 3H), 3.64 (s, 3H), 2.45 (s, 3H), 2.35 (s, 3H).

Example 53: (2E)-2-Methoxyimino-N-methyl-2-[3-methyl-2-[[(E)-1-[5-(trifluoromethyl)thiazol-2-yl]ethylideneamino]oxymethyl]phenyl]acetamide

[0286] ##STR00027##

To a solution of methyl (2E)-2-methoxyimino-2-[3-methyl-2-[[(E)-1-[5-(trifluoromethyl)thiazol-2-yl]ethylideneamino]oxymethyl]phenyl]acetate (5.7 g, 13.27 mmol in THF (25 ml), methyl amine (20 ml, 40% aqueous solution) was added and the mixture was stirred for 2 h at 25° C. TLC (50% PE:EtOAc) showed that the reaction was completed. Solvent was evaporated and crude mass obtained was diluted with H.sub.2O (150 ml), extracted with EtOAc (3x 100 ml). The combined organic phase was washed with brine (100 ml), dried over Na.sub.2SO.sub.4 and concentrated. Crude product was purified by flash column chromatography (n-heptane:EtOAc = ~80:35 as eluent) to give the title compound (5.1 g, 89.7 %) as white solid. .sup.1H NMR (500 MHz, DMSO-d): δ 8.65 (s, 1H), 8.2 (d, 1H), 7.29-7.35 (m, 2H), 6.97 (d, 1H), 5.2 (br s, 2H), 3.81 (s, 3H), 2.62 (s, 3H), 2.48 (s, 3H), 2.35 (s, 3H).

Example 72: Methyl (2E)-2-[2-[[(E)-[cyclopropyl-[4-(trifluoromethyl)-2-pyridyl]methylene]amino]-oxymethyl]-3-methyl-phenyl]-2-methoxyimino-acetate

[0287] ##STR00028##

Step 1: Cyclopropyl-[4-(trifluoromethyl)-2-pyridyl]methanone

[0288] A solution of 2-bromo-4-(trifluoromethyl)pyridine (10 g, 44 mmol) in toluene (80 ml) cooled to 0° C. under N.sub.2, was charged with isopropyl magnesium chloride (2 M in THF) (24.3 ml, 48 mmol) in a dropwise manner for 10 min. The reaction was brought to RT and stirred for 1.5 h. The resulting dark brown mixture was cooled to 0° C. and a solution of N-methoxy-N-methylpyrimidine-5-carboxamide (6.28 g, 49 mmol) in toluene (10ml) was added. The reaction was stirred at 0° C. for 1 h and quenched with saturated aqueous ammonium chloride (100 ml) solution. The phases were separated and the aqueous phase was extracted with EtOAc (50 ml). The combined organic layers were dried over magnesium sulfate and concentrated in vacuum. The crude material was purified using column chromatography (5-10 % EtOAc in heptane) to give cyclopropyl-[4-(trifluoromethyl)-2-pyridyl]methanone. Yield 6.28 g (63%). .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 9.07 (s, 1H), 8.14-8.10 (m, 2H), 3.46-3.42 (m, 1H), 1.10-1.15 (m, 4H).

Step 2: Cyclopropyl-[4-(trifluoromethyl)-2-pyridyl]methanone Oxime

[0289] To a solution of cyclopropyl-[4-(trifluoromethyl)-2-pyridyl]methanone (12.0 g, 56 mmol) in methanol (120 ml), hydroxylamine hydrochloride (7.7 g, 111 mmol) and sodium acetate (9.1 g, 111 mmol) were added and stirred for 4 h under reflux. The mixture was concentrated and partitioned between EtOAc (10 ml) and water (10 ml). The organic layer was separated, dried over Na2SO4 and concentrated under vacuum. The crude mass was purified by column chromatography (20 % EtOAc in heptane) to get cyclopropyl-[4-(trifluoromethyl)-2-pyridyl]meth-anone oxime. Yield 6.7 g (52.2%). .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 11.6 (s, 1H), 8.81-8.80 (d, 1H), 7.88 (s, 1H), 7.76-7.75 (m, 1H), 2.44-2.42 (m, 1H), 1.27-1.25 (m, 2H), 0.90-0.89 (m, 2H).

Step 3: Methyl (2E)-2-[2-[[(E)-[cyclopropyl-[4-(trifluoromethyl)-2-pyridyl]methylene]amino] oxymethyl]-3-methyl-phenyl]-2-methoxyimino-acetate

[0290] A solution of cyclopropyl-[4-(trifluoromethyl)-2-pyridyl]methanone oxime (5.5 g, 24 mmol) in DMF (70 ml), methyl (2E)-2-[2-(bromomethyl)-3-methyl-phenyl]-2-methoxyimino-acetate (7.89 g, 26 mmol) and Cs.sub.2CO.sub.3 (15.5 g, 47.7 mmol) were added and stirred for 2 h at 25° C. The mixture was quenched with H.sub.2O (40 ml), extracted with EtOAc (40 ml). The organic layer was separated, washed with brine (30 ml), dried over Na2SO4 and concentrated in vacuum. The crude mass was triturated with heptane (30 ml) followed by crystallization in MeOH (10 ml) at 0° C. The solid was filtered and dried to give the title compound (yield 7.0 g, 65.2%). .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 8.82-8.81 (d, 1H), 7.80-7.79 (m, 2H) 7.34-7.30 (m, 2H), 7.04-7.02 (m, 1H), 5.03 (br s, 2H), 3.91 (s, 3 H), 3.63(s, 3H), 2.33-2.29 (m, 1H), 1.17-1.15 (m, 2H), 0.90-0.88 (m, 2H).

Example 70: (2E)-2-[2-[[(E)-[cyclopropyl-[4-(trifluoromethyl)-2-pyridyl]methylene]amino]oxymethyl]-3-methyl-phenyl]-2-methoxyimino-N-methyl-acetamide

[0291] ##STR00029##

To a solution of (2E)-2-[2-[[(E)-[cyclopropyl-[4-(trifluoromethyl)-2-pyridyl]methylene]amino]-oxymethyl]-3-methyl-phenyl]-2-methoxyimino-acetate (7.0 g, 16 mmol) in THF (50ml), methyl amine (~33% in water, 20 ml) was added and the mixture was stirred for 12 h at 25° C. The reaction was diluted with EtOAc (20 ml) and water (20 ml). The organic layer was separated and washed with water and brine, dried over Na2SO4 and concentrated under vacuum. The crude mass was purified by column chromatography (40% EtOAc in heptane) to give the title compound. Yield 6.0 g (85.3 %). .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 8.82-8.81 (d,1H), 8.23-8.22 (m,1H), 7.86-7.78 (m,2H), 7.31-7.29 (m,2H), 6.97-6.95 (m,1H), 5.03 (br s, 2 H) 3.85 (s, 3 H), 2.65(s, 3 H), 2.51 (s, 3 H), 2.34 (m,1H), 1.19-1.17 (m,2H), 0.97-0.85 (m,2H).

Example 79: (2E)-2-[2-[[(E)-1-[5-(4-Fluorophenyl)thiazol-2-yl]ethylideneamino]oxymethyl]-3-methyl-phenyl]-2-methoxyimino-N-methyl-acetamide

[0292] ##STR00030##

Step 1: 1-(5-Bromothiazol-2-yl)ethenone

[0293] To a solution of 2-(1,1-dimethoxyethyl)thiazole (2.7 g, 16 mmol, 1. eq.) in THF (60 ml), n-BuLi (15.5 ml, 2.5 M, 2.5 eq.) was added slowly over a period of 15 min at -78° C. under N.sub.2, and the reaction was continued at -78° C. under N.sub.2 for 1 h. To this reaction mixture was added CBr.sub.4 at -78° C. under N.sub.2 and continued for 2 h at same temperature. Reaction was quenched with 1 N HCl (25 ml) solution slowly at 25° C. and diluted with H.sub.2O (100 ml) and extracted with EtOAc (3x 100 ml) followed by brine wash (2x 100 ml). Organic layer was dried over Na.sub.2SO.sub.4 and concentrated to afford crude compound (1.8 g). Crude compound which was purified using combi-flash column chromatography (0-10% EtOAc in heptane) to afford 1-(5-bromothiazol-2-yl)ethenone (1.7 g, 53 % yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ = 8.24 (s, 1H), 2.60 (s, 3H).

Step 2: 1-[5-(4-Fluorophenyl)thiazol-2-yl]ethenone

[0294] To a solution of 1-(5-bromothiazol-2-yl)ethenone (2 g, 9.70 mmol, 1 eq.) in dioxane (35 ml), K.sub.2CO.sub.3 (4 g, 29 mmol, 3 eq.) was added followed by H.sub.2O (5 ml) and 4-fluorophenyboronic acid (1.6 g, 11.64 mmol, 1.2 eq.) at 25° C. The reaction mixture was degassed by purging N.sub.2 for 15 min followed by addition of PdCl.sub.2(dppf).sub.2 (0.35 g, 0.485 mmol, 0.05 eq.) under N.sub.2 and refluxed for 6 h at 110° C. Reaction mixture was diluted with H.sub.2O (50 ml) and extracted with EtOAc (3x 50 ml) followed by brine wash (2x 100 ml). Organic layer was dried over Na.sub.2SO.sub.4, concentrated and purified by flash chromatography (0-10% EtOAc in hexane) to afford 1-[5-(4-fluorophenyl)-thiazol-2-yl]ethenone as white solid (1.1 g, 50 % yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ = 8.6 (s, 1H), 8.1-7.9 (m, 2 H), 7.4-7.3 (m, 2H), 2.7 (s, 3H).

Step 3: 1-[5-(4-Fluorophenyl)thiazol-2-yl]ethanone Oxime

[0295] To a solution of 1-[5-(4-fluorophenyl)thiazol-2-yl]ethenone (1.5 g, 6.78 mmol, 1.0 eq) in MeOH (30 ml), hydroxylamine hydrochloride (0.7 g, 10 mmol, 1.5 eq) and pyridine (0.8 ml, 14 mmol, 2 eq) were added. The reaction mixture was refluxed for 6 h. The mixture was cooled to 25° C. and the solvent was removed under reduced pressure. The residue was diluted with water (50 ml) and extracted with EtOAc (3 x 50 ml). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to get the crude product which was purified by column chromatography (0-30% EtOAc in heptane) to afford 1-[5-(4-fluorophenyl)thiazol-2-yl]ethanone oxime as white solid (0.32 g, Yield: 20 % for E-isomer). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ = 11.90 (s, 1H), 8.24 (s, 1H), 7.77-7.74 (m, 2H), 7.33-7.29 (m, 2 H), 2.4 (s, 3H).

Step 4: Methyl (2E)-2-[2-[[(E)-1-[5-(4-fluorophenyl)thiazol-2-yl]ethylideneamino]oxymethyl]-3-methyl-phenyl]-2-methoxyimino-acetate

[0296] To a stirred suspension of NaH (0.076 g, 2.5 eq, 60 %, 3.174 mmol) in DMF (20 ml), 1-[5-(4-fluorophenyl)thiazol-2-yl]ethanone oxime (0.419 g, 1.397 mmol, 1. eq.) in DMF (5 ml) was added over period of 10 min at 25° C. under N.sub.2. The mixture was stirred for 2 h at RT. To this mixture, methyl (2E)-2-[2-(bromomethyl)-3-methyl-phenyl]-2-methoxyimino-acetate (0.225 g, 0.931 mmol, 1.1 eq.) was added at RT and stirred at 50° C. for 2 h. The mixture was cooled to RT, quenched by H.sub.2O (30 ml) and extracted with EtOAc (3x 30 ml), cold H.sub.2O (3x 100 ml) followed by brine wash (3 × 50 ml). Organic layer was dried over Na.sub.2SO.sub.4 and concentrated. Crude compound was purified combi-flash column chromatography (0-15% EtOAc in heptane) to afford the title compound as white solid (0.2 g, 41 % yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ = 8.4 (s, 1H), 7.7-7.8 (m, 2H), 7.3 - 7.4 (m, 4H), 7.03-7.02 (m, 1H), 5.12 (br s, 2H), 3.91 (s, 3H), 3.68 (s, 3H), 2.5 (s, 3H), 2.3 (s, 3H). MS: [M + H] + 456.

Example 78: (2E)-2-[2-[[(E)-1-[5-(4-fluorophenyl)thiazol-2-yl]ethylideneamino]oxymethyl]-3-methyl-phenyl]-2-methoxyimino-N-methyl-acetamide

[0297] ##STR00031##

To a stirred solution of methyl (2E)-2-[2-[[(E)-1-[5-(4-fluorophenyl)thiazol-2-yl]ethylidene-amino]oxymethyl]-3-methyl-phenyl]-2-methoxyimino-acetate (0.120 g, 0.272 mmol, 1 eq.) in THF (10 ml), methyl amine hydrochloride (40 % in H.sub.2O, 0.7 ml) was added and stirred for 1 h at 25° C. Then, the mixture was diluted with H.sub.2O (20 ml) and extracted with EtOAc (3× 20 ml) followed by brine wash (2× 20 ml). Organic layer was dried over Na.sub.2SO.sub.4 and concentrated. Crude compound was purified combi-flash column chromatography (0-30% EtOAc in heptane) to afford the title compound as white solid (0.1 g, 80 % yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ = 8.37 (s, 1H), 8.20-8.19 (s, 1H), 7.78-7.74 (m, 2H), 7.34 - 7.28 (m, 4H), 6.97-6.96 (br s, 1H), 5.12 (br s, 2H), 3.83 (s, 3H), 2.60 (s, 3H), 2.52 (br s, 3H), 2.30 (s, 3H).

Example 84: (2E)-2-methoxyimino-N-methyl-2-[3-methyl-2-[[(E)-1-[5-(trifluoromethyl)-3-pyridyl]-ethylideneamino]oxymethyl]phenyl]acetamide

[0298] ##STR00032##

Step 1: 1-[5-(Trifluoromethyl)-3-pyridyl]ethenone

[0299] To a solution of 3-bromo-5-(trifluoromethyl)pyridine (0.5 g, 2.212 mmol, 1 eq.) in 1,4-dioxane (20 ml), 1-methoxyvinyl(tripropyl)stannane (1.012 g, 0.003 mol, 1.5 eq) was added followed by addition of PdCl.sub.2(PPh.sub.3).sub.2 (0.070 g, 0.11 mmol, 0.05 eq) in one portion at 25° C. under N.sub.2. The reaction mixture was stirred for 6 h at 100° C. under N.sub.2. TLC (10 % EtOAc in heptane) showed that the SM was consumed completely. The reaction mixture was cooled to 25° C. and 1N HCl (10 ml) was added. The mixture was again heated for 1 h at 100° C. Reaction was quenched with saturated solution of NaHCO.sub.3 (20 ml), filtered through Celite bed and washed by EtOAc (30 ml). The filtrate aqueous phase was extracted with EtOAc (2× 20 ml). Combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated to obtain 1-[5-(trifluoromethyl)-3-pyridyl]ethanone (0.2 g, 47 %) as brown liquid. The product was used in next step without purification.

Step 2: 1-[5-(Trifluoromethyl)-3-pyridyl]ethanone Oxime

[0300] To a solution of 1-[5-(trifluoromethyl)-3-pyridyl]ethanone (3 g, 15.86 mmol, 1 eq.) in MeOH (50 ml), hydroxylamine hydrochloride (2.736 g, 39.654 mmol, 2.5 eq) and pyridine (3.13 g, 0.040 mol, 2.5 eq) were added under N.sub.2. The mixture was stirred for 2 h at 65° C. under N.sub.2. TLC (20% EtOAc in heptane) showed that the reaction was completed. The mixture was concentrated and then dissolved in EtOAc (100 ml) and H.sub.2O (100 ml). The aqueous phase was extracted with EtOAc (3× 50 ml). Combined organic layer was washed with brine (100 ml), dried over Na.sub.2SO.sub.4, concentrated and purified by silica gel column (0-20 % EtOAc in heptane) to give E-isomer 1-[5-(trifluoromethyl)-3-pyridyl]ethanone oxime (1.8 g, 54 %) as white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ = 11.8 (s, 1H), 9.12 (s, 1H), 8.96 (s, 1H), 8.31 (s, 1H), 2.23 (s, 3H). MS: [M + H].sup.+ 205.

Step 3: Methyl (2E)-2-methoxyimino-2-[3-methyl-2-[[(E)-1-[5-(trifluoromethyl)-3-pyridyl]ethyl-ideneamino]oxymethyl]phenyl]acetate

[0301] To a solution of 1-[5-(trifluoromethyl)-3-pyridyl]ethanone oxime (0.500 g, 2.44 mmol, 1 eq) in DMF (10 ml), Cs.sub.2CO.sub.3 (1.59 g, 4.89 mmol, 2 eq) was added. The mixture was stirred for 10 min at 25° C. Methyl (2E)-2-[2-(bromomethyl)-3-methyl-phenyl]-2-methoxyimino-acetate (0.978 g, 2.69 mmol, 1.1 eq) in DMF (5ml) was added and the reaction mixture was stirred for 12 h at 25° C. under N.sub.2. TLC (10 % EtOAc in heptane) showed that the reaction was completed. The mixture was quenched with cold H.sub.2O (100 ml), extracted with EtOAc (3x 50 ml). The organic phase was washed with brine (100 ml), dried over Na.sub.2SO.sub.4, concentrated and purified by silica gel column 0-10 % EtOAc in heptane to give the title compound (0.800 g, 76.5 %) as off-white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ = 9.01 (d, 2H), 8.28 (s, 1H), 7.22(d, 2H), 7.01 (s, 1H), 4.98 (br s, 2H), 4.13 (s, 3H), 3.90 (s, 3H), 2.49-2.43 (d, 3H), 2.18 (s, 3H). MS: [M + H] .sup.+ 424.

Example 85: (2E)-2-methoxyimino-N-methyl-2-[3-methyl-2-[[(E)-1-[5-(trifluoromethyl)-3-pyridyl]-ethylideneamino]oxymethyl]phenyl]acetamide:

[0302] ##STR00033##

To a solution of methyl (2E)-2-methoxyimino-2-[3-methyl-2-[[(E)-1-[5-(trifluoromethyl)-3-pyridyl]ethylideneamino]oxymethyl]phenyl]acetate (0.500 g, 1 eq) in THF (10 ml), methyl amine hydrochloride was added (4 ml, 40% in H.sub.2O) and was stirred for 2 h at 25° C. TLC (30 % EtOAc in heptane) showed that the reaction was completed. Solvent was evaporated. Crude mass obtained was diluted with H.sub.2O (30 ml), extracted with EtOAc (3× 20 ml). The organic phase was washed with brine (20 ml), dried over Na.sub.2SO.sub.4 and concentrated. Crude compound was washed with n-pentane (4× 20 ml) to give the title compound (0.300 g, 60%) as off-white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ = 9.10 (s, H), 9.0 (s,1H), 8.3 (d, 1H), 8.2 (br s, 1H), 7.31 (d, 2H), 6.9 (s, 1H), 5.12 (br s, 2H), 3.9(s, 3H), 2.70 (m, 3H), 2.55 (m, 3H), 2.20 (s, 3H).

Example 89: (2E)-2-Methoxyimino-N-methyl-2-[3-methyl-2-[[(E)-1-[6-(trifluoromethyl)pyrazin-2-yl]ethylideneamino]oxymethyl]phenyl]acetamide

[0303] ##STR00034##

Step 1: 1-[6-(Trifluoromethyl)pyrazin-2-yl]ethanone

[0304] To a solution of 1-(6-bromopyrazin-2-yl)ethanone (1.2 g, 5.97 mmol) and methyl 2,2-difluoro-2-fluorosulfonyl-acetate (3.4 g, 18 mmol) in DMF (12 ml), CuI (1.36 g, 7.16 mmol) was added under N.sub.2. The mixture was stirred for 2 h at 90° C. The colour of the mixture changed from pale brown to dark brown over time. The reaction was quenched with water and extracted with EtOAc. The emulsion formed was filtered through celite and washed with EtOAc. The layers were separated, and aqueous layer was extracted with EtOAc (10 ml). The organic layers were combined, washed with cold water, brine, dried over Na2SO4 and concentrated to dryness. The crude product was purified by column chromatography (20-25 % EtOAc in heptane) to give 1-[6-(trifluoromethyl)pyrazin-2-yl]ethenone. Yield 0.25 g, (22 %). .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 9.45-9.40 (d,1H), 9.13-9.07 (m,1H), 2.58(s, 3H).

Step 2: 1-[6-(Trifluoromethyl)pyrazin-2-yl]ethanone Oxime

[0305] To a solution of 1-[6-(trifluoromethyl)pyrazin-2-yl]ethenone (0.25 g, 1 mmol) in methanol (4 ml) was added hydroxylamine hydrochloride (0.1 g, 1.64 mmol), pyridine (0.2 g, 3 mmol) under N.sub.2. The mixture was stirred for 4 h at 66° C. The reaction mixture was concentrated, dissolved in ethylacetate (10 ml) and washed with water (10 ml). The aqueous phase was extracted with ethylacetate and the organic layers were combined. The organic layer was concentrated and purified by column chromatography using 20% ethylacetate in heptane as eluant to give [6-(trifluoromethyl)pyrazin-2-yl]ethanone oxime. Yield 0.2 g (74.1%). .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 12.2 (s,1H), 12.1 (s,1H) 9.4 (s,1H), 9.1 (s,1H), 9.0 (s,1H), 8.8 (s,1H) 2.2 (s, 6H).

Step 3: Methyl (2E)-2-methoxyimino-2-[3-methyl-2-[[(E)-1-[6-(trifluoromethyl)pyrazin-2-yl]ethylideneamino]oxymethyl]phenyl]acetate

[0306] To a solution of 1-[6-(trifluoromethyl)pyrazin-2-yl]ethanone oxime (0.24 g, 1.17 mmol) in DMF (10 ml), methyl (2E)-2-[2-(bromomethyl)-3-methyl-phenyl]-2-methoxyimino-acetate (0.57 g, 1.93 mmol) and Cs.sub.2CO.sub.3 (1.14 g, 3.5 mmol) were added. The mixture was stirred for 1 h at 25° C. and then heated to 80° C. for 2 h. The mixture was quenched with water (40 ml) and extracted with EtOAc (40 ml). The organic phase was washed with brine (30 ml), dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (20% EtOAc in heptane) to give methyl (2E)-2-methoxyimino-2-[3-methyl-2-[[(E)-1-[6-(trifluoromethyl)pyrazin-2-yl]-ethylideneamino]oxymethyl] phenyl] acetate. Yield 0.07 g (15%). .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 9.2 (s,1H), 9.2 (s,1H) 7.3 (m,2H), 7.1-7.0 (m,1H), 5.23 (br s, 2 H), 3.9 (s, 3 H), 3.7 (s, 3 H), 2.51 (s, 3 H), 2.1 (s, 3 H).

Step 4: (2E)-2-methoxyimino-N-methyl-2-[3-methyl-2-[[(E)-1-[6-(trifluoromethyl)pyrazin-2-yl]-ethylideneamino]oxymethyl]phenyl]acetamide

[0307] To a solution of methyl (2E)-2-methoxyimino-2-[3-methyl-2-[[(E)-1-[6-(trifluoromethyl)pyrazin-2-yl]ethylideneamino]oxymethyl]phenyl]acetate (0.06 g, 0.14 mmol) in THF (1 ml), methyl amine (~33% in water, 1 ml) was added. The reaction mixture was stirred for 3 h at 25° C. The mixture was quenched with water and diluted with EtOAc (5 ml). The organic layer was separated, washed with water, brine, dried over sodium sufate and concentrated. The crude mass was purified by column chromatography (50% EtOAc in heptane) to give the title compound. Yield 0.06 g, (97.5%). .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 9.3 (s,1H), 9.2 (s,1H), 8.3 (m,1H), 7.3 (m,2H), 7.0 (m,1H), 5.23 (br s, 2 H), 3.9 (s, 3 H), 2.7(s, 3 H), 2.5 (s, 3 H), 2.0(s, 3 H).

Example 96: Methyl (2E)-2-methoxyimino-2-[3-methyl-2-[[(E)-1-[5-(trifluoromethyl)pyrazin-2-yl]ethylideneamino]oxymethyl]phenyl]acetate

[0308] ##STR00035##

Step 1: 1-[5-(Trifluoromethyl)pyrazin-2-yl]ethenone

[0309] To a solution of 2-chloro-5-(trifluoromethyl)pyrazine (0.5 g, 27 mmol) in dioxane (5 ml), PdCl.sub.2(PPh.sub.3).sub.2 (0.2 g, 0.27 mmol) and tributyl(1-ethoxyvinyl)stannane (1.08 g, 3 mmol) were added. The reaction was heated to reflux and stirred for 1 h. 1 N aqueous HCl (2.5 ml) was added. The reaction was stirred at reflux for 1 h. The reaction was monitored by TLC (10% EtOAc in heptane). The mixture was cooled to RT and partitioned with EtOAc. The EtOAc layer was separated, washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. Crude mass was purified by column chromatography (5-10 % EtOAc in heptane) to give 1-[5-(trifluoromethyl)pyrazin-2-yl]-ethenone. Yield 0.3 g (57.6%). .sup.1H NMR (CDCl.sub.3, 500 MHz): δ 9.3 (s,1H), 9.0 (s,1H), 2.8 (s, 3H).

Step 2: 1-[5-(Trifluoromethyl)pyrazin-2-yl]ethanone Oxime

[0310] To a solution of 1-[5-(trifluoromethyl)pyrazin-2-yl]ethanone (0.3 g, 2 mmol) in methanol (4 ml), hydroxylamine hydrochloride (0.13 g, 2 mmol) and pyridine (0.25 g, 2.36 mmol) were added under N.sub.2. The mixture was stirred for 2 h under reflux, concentrated, dissolved in EtOAc (10 ml) and washed with water (10 ml). The aqueous phase was extracted with EtOAc (10 ml). The combined organic layer was washed with brine (20 ml), dried over Na.sub.2SO.sub.4 and concentrated. The crude mass was purified using column chromatography (20% EtOAc in heptane) to give 1-[5-(trifluoromethyl)pyrazin-2-yl]ethanone oxime. Yield 0.2 g (61.8%). .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 12.3 (s,1H), 9.2 (s,2H), 2.2 (s, 3H).

Step 3: Methyl (2E)-2-methoxyimino-2-[3-methyl-2-[[(E)-1-[5-(trifluoromethyl)pyrazin-2-yl]ethyl-ideneamino]oxymethyl]phenyl]acetate

[0311] To a solution of 1-[5-(trifluoromethyl)pyrazin-2-yl]ethanone oxime (0.2 g, 0.97 mmol) in AcN (3 ml), methyl (2E)-2-[2-(bromomethyl)-3-methyl-phenyl]-2-methoxyimino-acetate (0.29 g, 0.97 mmol) and Cs.sub.2CO.sub.3 (0.63 g, 1.95 mmol) were added. The mixture was stirred for 2 h at 25° C., quenched with water (40 ml) and extracted with EtOAc (40 ml). The organic layer was separated, washed with brine (30 ml), dried over Na2SO4 and concentrated. The crude mixture was purified by column chromatography (15% EtOAc in heptane) to give the title compound. Yield 0.4 g (97.4%). .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 9.2 (s,1H), 9.1 (s,1H) 7.3 (m,2H), 7.1-7.0 (m,1H), 5.23 (br s, 2 H), 3.9 (s, 3 H), 3.7(s, 3 H), 2.51 (s, 3 H), 2.2 (s, 3H).

Example 97: (2E)-2-methoxyimino-N-methyl-2-[3-methyl-2-[[(E)-1-[5-(trifluoromethyl)pyrazin-2-yl]ethylideneamino]oxymethyl]phenyl]acetamide

[0312] ##STR00036##

To a solution of methyl (2E)-2-methoxyimino-2-[3-methyl-2-[[(E)-1-[5-(trifluoromethyl)pyrazin-2-yl]ethylideneamino]oxymethyl]phenyl]acetate (0.2 g, 0.58 mmol) in THF (2.5 ml), methyl amine (~33% in water, 1.2 ml) was added. The reaction was stirred for 3 h at 25° C. and quenched with water. EtOAc (5 ml) was added. The organic layer was separated, washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The crude product was purified by column chromatography (20% EtOAc in heptane) to give the title compound. Yield 0.19 g (71.6%). .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 9.17 (s,1H), 9.12(s,1H); 8.3 (m,1H), 7.3 (m,2H), 7.0 (m,1H), 5.23 (br s, 2H), 3.86 (s, 3H), 2.69 (s, 3H), 2.5 (s, 3H), 2.18(s, 3H).

Example 113: Methyl (2E)-2-methoxyimino-2-[3-methyl-2-[[(E)-1-[6-(trifluoromethyl)pyrimidin-4-yl]ethylideneamino]oxymethyl]phenyl]acetate

[0313] ##STR00037##

Step 1: 1-[6-(Trifluoromethyl)pyrimidin-4-yl]ethanone

[0314] To a solution of 4-chloro-6-(trifluoromethyl)pyrimidine (1.0 g, 5.48 mmol) in dioxane (10ml), PdCl.sub.2(PPh.sub.3).sub.2 (0.4 g, 0.54 mmol) and tributyl(1-ethoxyvinyl)stannane (2.96 g, 8 mmol) were added. The reaction mixture was refluxed for 3 h, cooled to RT followed by addition of 1N aqueous HCl (2.5 ml) and stirring for further 1 h. The reaction was diluted with EtOAc (30 ml). The organic layer was separated, washed using brine (40 ml), dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The crude material was purified by column chromatography (0-30 % EtOAc in heptane) to give 1-[6-(trifluoromethyl)pyrimidin-4-yl]ethenone. Yield 0.52 g (49.9%). .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 9.7 (s,1H), 8.3 (s,1H), 2.7 (s,3H).

Step 2: 1-[6-(Trifluoromethyl)pyrimidin-4-yl]ethanone Oxime

[0315] To a solution of 1-[6-(trifluoromethyl)pyrimidin-4-yl]ethanone (0.19 g, 0.99 mmol) in MeOH (10 ml), hydroxylamine hydrochloride (0.066 g, 2 mmol) and pyridine (0.15 g, 2 mmol) were added. The mixture was refluxed for 1 h, concentrated and dissolved in EtOAc (10 ml) and washed with H.sub.2O (10 ml). The aqueous phase was extracted with EtOAc (10 ml). The combined organic layer was washed with brine (10 ml), dried over Na.sub.2SO.sub.4 and concentrated. The crude mass was purified by column chromatography (40% EtOAc in heptane) to give 1-[6-(trifluoromethyl)pyrimidin-4-yl]ethanone oxime. Yield 0.15 g (73%). .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 12.8 (s,1H), 9.46 (s,1H), 8.17-8.16 (d,1H), 2.15 (s, 3H).

Step 3: Methyl (2E)-2-methoxyimino-2-[3-methyl-2-[[(E)-1-[6-(trifluoromethyl)pyrimidin-4-yl]ethyl-ideneamino]oxymethyl]phenyl]acetate

[0316] To a solution of cyclopropyl[4-(trifluoromethyl)-2-pyridyl]methanone oxime (0.5 g, 2.4 mmol) in DMF (10 ml), methyl (2E)-2-[2-(bromomethyl)-3-methyl-phenyl]-2-methoxyimino-acetate (0.73 g, 2.4 mmol) and Cs.sub.2CO.sub.3 (1.58 g, 4.88 mmol) were added. The reaction mixture was stirred for 12 h at 25° C. The reaction was quenched with water (30 ml), extracted with EtOAc (20 ml). The organic layer was separated, washed with brine (30 ml), dried over Na.sub.2SO.sub.4 and concentrated in vacuum. The crude mass was purified by column chromatography (0-30 % EtOAc in heptane) to give the title compound as a white solid. Yield 0.38 g (36.4%). .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 9.47 (s,1H), 8.10 (s,1H), 7.33-7.31 (m,2H), 7.05-7.02 (m,1H), 5.17 (br s, 2H), 3.90 (s, 3H), 3.69 (s, 3 H) 2.50 (s, 3 H), 2.09 (s, 3 H).

Example 114: (2E)-2-methoxyimino-N-methyl-2-[3-methyl-2-[[(E)-1-[4-(trifluoromethyl)-6-vinyl-2-pyridyl]ethylideneaminoloxymethyl]phenyl]acetamide

[0317] ##STR00038##

To a solution of methyl (2E)-2-methoxyimino-2-[3-methyl-2-[[(E)-1-[6-(trifluoromethyl)pyrimi-din-4-yl]ethylideneamino]oxymethyl]phenyl]acetate (0.2 g, 0.47 mmol) in THF (10 ml), methyl amine (~33% in water, 2 ml) was added. The mixture was stirred for 5 h at 25° C. The reaction was diluted with EtOAc (10 ml) and water (10 ml). The organic layer was separated and washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The crude product was purified by column chromatography (40% EtOAc in heptane) to give the title compound. Yield 0.18 g (90%). .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 9.5 (s,1H), 8.2 (m,1H), 8.2 (s,1H), 7.32-7.30 (m,2H), 7.0-6.9 (m,1H), 5.2 (br s, 2 H), 3.9 (s, 3 H), 2.7 (s, 3 H), 2.50 (s, 3 H), 2.09 (s, 3 H).

Example 116: Methyl (2E)-2-methoxyimino-2-[3-methyl-2-[[(E)-1-[4-(trifluoromethyl)-6-vinyl-2-pyridyl]ethylideneamino]oxymethyl]phenyl]acetate

[0318] ##STR00039##

Step 1: 1-[6-Chloro-4-(trifluoromethyl)-2-pyridyl]ethanone

[0319] To a solution of 2,6-dichloro-4-(trifluoromethyl)pyridine (1.0 g, 5 mmol) in dioxane (5 ml), PdCl.sub.2(dppf) (0.17 g, 0.5 mmol) and tributyl(1-ethoxyvinyl)stannane (1.17 g, 3 mmol) were added. The reaction was stirred at reflux for 1 h under N.sub.2. 1N aqueous HCl (2.5 ml) was added and the reaction was continued for further 1h at reflux. The reaction was monitored by TLC (10 % EtOAc in heptane). The mixture was brought to room temperature and diluted with water and extracted with EtOAc (30 ml). The organic layer was separated, washed with brine, dried over Na.sub.2SO.sub.4 and evaporated to dryness. The crude mass was purified using column chromatography (5-10 % EtOAc in heptane) to give 1-[6-chloro-4-(trifluoromethyl)-2-pyridyl]ethanone. Yield 0.43 g (60%). .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 8.4 (s,1H), 8.1 (s,1H), 2.7 (s,3H).

Step 2: 1-[6-Chloro-4-(trifluoromethyl)-2-pyridyl]ethanone Oxime

[0320] To a solution of 1-[6-chloro-4-(trifluoromethyl)-2-pyridyl]ethanone (0.6 g, 2.68 mmol) in MeOH (6 ml), hydroxylamine hydrochloride (0.2 g, 4 mmol) and pyridine (0.42 g, 5 mmol) were added. The reaction was stirred for 2 h under reflux. The mixture was concentrated and partitioned between EtOAc (10 ml) and water (10 ml). Organic phase was separated, washed with brine (20 ml), dried over Na.sub.2SO.sub.4 and concentrated. Crude mass was purified by column chromatography (30% EtOAc in heptane) to give 1-[6-chloro-4-(trifluoromethyl)-2-pyridyl]ethanone oxime. Yield 0.32 g (50.4%). .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 12.1 (s,1H), 8.0 (s,2H), 2.2 (s,3H).

Step 3: Methyl (2E)-2-[2-[[(E)-1-[6-chloro-4-(trifluoromethyl)-2-pyridyl]ethylideneamino]oxymethyl]-3-methyl-phenyl]-2-methoxyimino-acetate

[0321] To a solution of 1-[6-chloro-4-(trifluoromethyl)-2-pyridyl]ethanone oxime (0.32 g, 1.34 mmol) in DMF (4ml), methyl (2E)-2-[2-(bromomethyl)-3-methyl-phenyl]-2-methoxyimino-acetate (0.4 g, 1 mmol) and cesium carbonate (0.87 g, 3 mmol) were added. The mixture was stirred for 16 h at 25° C., quenched with water (40 ml) and extracted with EtOAc (40 ml). The organic layer was separated, washed with brine (30 ml), dried over Na.sub.2SO.sub.4, concentrated and purified by column chromatography (0 - 20% EtOAc in heptane) to give methyl (2E)-2-[2-[[(E)-1-[6-chloro-4-(trifluoromethyl)-2-pyridyl]ethylideneamino]oxymethyl]-3-methyl-phenyl]-2-methoxyimino-acetate as a white solid. Yield 0.33 g (54.7%). .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 8.01 (s,1H), 7.4 (m,1H), 7.35-7.26 (m,2H), 7.03-7.0 (m,1H), 5.23 (br s, 2 H), 4.02 (s, 3 H), 3.83 (s, 3 H), 2.49 (s, 3 H), 2.23 (s, 3 H).

Step 4: Methyl (2E)-2-methoxyimino-2-[3-methyl-2-[[(E)-1-[4-(trifluoromethyl)-6-vinyl-2-pyridyl]-ethylideneamino]oxymethyl]phenyl]acetate

[0322] To a solution of methyl (2E)-2-[2-[[(E)-1-[6-chloro-4-(trifluoromethyl)-2-pyridyl]ethylidene-amino]oxymethyl]-3-methyl-phenyl]-2-methoxyimino-acetate (0.11 g, 0.24 mmol) in dioxane (1.4 ml) and water (0.6 ml), (dppf)PdCl.sub.2 (0.009 g, 0.012 mmol), potassium carbonate (0.066 g, 0.48 mmol) and potassium trifluoro(vinyl)borane (0.064 g, 0.48 mmol) were added. The reaction mixture was refluxed for 1.5 h and monitored by TLC (30% EtOAc in heptane). The reaction was brought to RT and quenched with water (50 ml). The mixture was extracted with EtOAc (50 ml). The organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuum. The crude mass was purified by column chromatography (0-30% EtOAc in heptane) to give the title compound. Yield 0.085 g (76.2%). .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 8.01 (s,1H), 7.47 (m,1H), 7.35-7.26 (m,2H), 7.03-7.0 (m,1H), 6.86-6.80 (m, 1H), 6.38-6.35 (d,1H), 5.58-5.56 (d,1H), 5.18 (br s, 2H), 4.02 (s, 3H), 3.82(s, 3H), 2.50 (s, 3H), 2.30 (s, 3H).

Example 138: (2E)-2-methoxyimino-N-methyl-2-[3-methyl-2-[[(E)-1-[4-(trifluoromethyl)-6-vinyl-2-pyridyllethylideneaminoloxymethyllphenyllacetamide

[0323] ##STR00040##

To a solution of methyl (2E)-2-methoxyimino-2-[3-methyl-2-[[(E)-1-[4-(trifluoromethyl)-6-vinyl-2-pyridyl]ethylideneamino]oxymethyl]phenyl]acetate (0.28 g, 0.62 mmol) in THF (8 ml), methyl amine (~33% in water, 1.2 ml) was added. The mixture was stirred for 3 h at 25° C. The reaction was diluted with EtOAc and washed with water. The organic layer was separated and washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The crude mass was purified via column chromatography (30% EtOAc in heptane) to give the title compound. Yield 0.25 g (99.3%). .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 8.23-8.22 (s,1H), 7.92-7.88 (m,2H), 7.31-7.27 (m,2H), 6.98-6.92 (m,2H), 6.48-6.45 (d,1H), 5.66-5.63 (d,1H), 5.12 (br s, 2H), 3.86 (s, 3H), 2.67(s, 3H), 2.50 (s, 3H), 2.22 (s, 3H).

Example 117: Methyl (2E)-2-methoxvimino-2-[3-methyl-2-[[(E)-1-[2-methyl-5-(trifluoromethyl) pyrazol-3-yl]ethylideneamino]oxymethyl]phenyl]acetate

[0324] ##STR00041##

Step 1: 2-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-one

[0325] To a solution of ethyl 4,4,4-trifluoro-3-oxo-butanoate (1.5 g, 8.1 mmol) in ethanol (20 ml), methylhydrazine (0.45 g, 10 mmol), pyridine (1.41 g, 18 mmol) and H.sub.2SO.sub.4 (1 ml) were added. The reaction mixture was stirred for 2 h at RT. The reaction was diluted with EtOAc (10 ml), washed with water, then with brine, dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The crude mass was purified by column chromatography (15-20% EtOAc in heptane) to give 2-methyl-5-(trifluoromethyl)-1H-pyrazol-3-one. Yield 0.4 g (29.4%). .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 11.69 (s,1H), 5.72 (s,1H), 3.59 (s, 3H).

Step 2: [2-Methyl-5-(trifluoromethyl)-1,3-dihydropyrazol-3-yl]trifluoromethanesulfonate

[0326] To a solution of 2-methyl-5-(trifluoromethyl)-1H-pyrazol-3-one (0.8 g, 5 mmol) in DCM (10 ml), triethylamine (0.13 g, 5.7 mmol) was added at 0° C. and the mixture was stirred for 10 minutes. The reaction was brought to RT, bis(trifluoromethyl)sulfonic anhydride (1.63 g, 5.7 mmol) was added and stirred for 30 minutes. The reaction was diluted with EtOAc (10 ml) and washed with water, brine and the organic layer was separated. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The crude mass was purified by column chromatography (15-20% EtOAc in heptane) as eluant to give [2-methyl-5-(trifluoromethyl)-1,3-dihydropyrazol-3-yl]trifluoromethanesulfonate. Yield 53.0 g (83%). .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 7.11 (s,1H), 3.91(s, 3H).

Step 3: 1-[2-Methyl-5-(trifluoromethyl)pyrazol-3-yl]ethanone

[0327] To a solution of [2-methyl-5-(trifluoromethyl)-1,3-dihydropyrazol-3-yltrifluoromethanesulfonate (0.3 g, 1 mmol) in dioxane (10 ml), PdCl.sub.2(dppf) (0.002 g, 0.1 mmol) and tributyl(1-ethoxyvinyl)-stannane (0.54 g, 2 mmol) were added and the reaction was refluxed. After 1 h, the reaction was brought to RT and 1N aqueous HCl (2.5 ml) was added and the reaction was continued for 1 h. The reaction mixture was diluted with EtOAc (30 ml). The organic layer was separated, washed with brine (20 ml), dried over Na.sub.2SO.sub.4 and concentrated in vacuum. The crude mass was purified by column chromatography (5-30 % EtOAc in heptane) to give 1-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]ethenone. Yield 0.43 g, (60 %).

Step 4: 1-[2-Methyl-5-(trifluoromethyl)pyrazol-3-yl]ethanone Oxime

[0328] To a solution of 1-[6-(trifluoromethyl)pyrimidin-4-yl]ethanone (1.2 g, 6 mmol) in MeOH (20 ml), hydroxylamine hydrochloride (0.19 g, 1.2 mmol) and pyridine (0.98 g, 1.2 mmol) were added and stirred under reflux for 3 h. The mixture was concentrated and dissolved in EtOAc (10 ml). The EtOAc extract was washed with water, brine, dried over sodium sufate and concentrated under vacuum. The crude mass was purified by column chromatography (30% EtOAc in heptane) to give 1-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]ethanone oxime. Yield 0.45 g (34.8 %). .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 11.68 (s,1H), 7.01 (s,1H), 3.96 (s, 3H), 2.09 (s, 3H).

Step 5: Methyl (2E)-2-methoxyimino-2-[3-methyl-2-[[(E)-1-[2-methyl-5-(trifluoromethyl) Pyrazol-3-yl]ethylideneamino]oxymethyl]phenyl]acetate

[0329] To a solution of 1-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]ethanone oxime (0.52 g, 2.5 mmol) in DMF (10 ml), methyl (2E)-2-[2-(bromomethyl)-3-methyl-phenyl]-2-methoxyimino-acetate (0.8 g, 2.7 mmol) and Cs.sub.2CO.sub.3 (1.63 g, 5.02 mmol) were added. The reaction mixture was stirred for 6 h at 25° C. The reaction was diluted with water (30 ml) and extracted with EtOAc (40 ml). The organic layer was separated and washed with brine (30 ml), dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The crude mass was purified by column chromatography (30 % EtOAc in heptane) to give the title compound as a white solid. Yield 0.52 g (48.1%). .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 7.32-7.28 (m,2H), 7.04-7.02 (m,1H), 5.07 (br s, 2 H), 3.90 (s, 3 H), 3.86 (s, 3 H), 3.67 (s, 3 H), 2.42 (s, 3 H), 2.1 (s, 3H).

Example 118: (2E)-2-methoxyimino-N-methyl-2-[3-methyl-2-[[(E)-1-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]ethylideneamino]oxymethyl]phenyl]acetamide

[0330] ##STR00042##

To a solution of methyl (2E)-2-methoxyimino-2-[3-methyl-2-[[(E)-1-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]ethylideneamino]oxymethyl]phenyl]acetate (0.41 g, 0.96 mmol) in THF (10 ml), methyl amine (~33% in water, 2 ml) was added. The mixture was stirred for 5 h at 25° C. The reaction was diluted with H.sub.2O (10 ml) and EtOAc (25 ml). Organic layer was separated and washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under vacuum. Crude mass was purified by column chromatography (30% EtOAc in heptane) to give title compound. Yield 0.4 g (99.8%). .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 8.23-8.22 (d,1H), 7.28-7.27 (m,2H), 7.12 (s,1H), 6.96 -6.95 (m,1H), 5.07 (br s, 2H), 3.86 (s, 3H), 2.66 (s, 3H), 2.51 (s, 3H), 2.41 (s, 3H), 2.10 (s, 3H).

[0331] The following examples in Table S were synthesized as described above and characterized by LCMS as described in Table L using Method A for compound examples 1 to 159 while using Method B for compound examples 160 to 164.

TABLE-US-00005 LCMS Methods Method details Device details Method A Column: Agilent Eclipse Plus C18 (50 mm LCMS2020 (Shimadzu) × 4.6 mm × 3 .Math.m) Ionization source: ESI Mobile Phase: Mass range: 100 - 800 amu A: 10 mM Ammonium formate in water Polarity: Dual (positive and negative B: 0.1 % Formic acid in ACN simultaneous scan) Gradient: 10 % B to 100 % B in 1.5 min. Mode: Scan Hold 1 min 100 % B. 1 min 10 % B. Run LC System: Nexera High pressure time: 3.50 or 3.75 min. gradient system, Binary pump Flow: 1.2 ml/min; Detector: PDA Column oven: 30° C./40° C. Scanning wavelength: 220 nm / max plot Method B Column: Luna-C18 (30 mm × 2.0 mm × 3 LCMS DELIVER-220 (Shimadzu) .Math.m) Ionization source: ESI Mobile Phase: Mass range: 100 - 1000 amu A: 0.037% Trifluoroacetic acid in water Polarity: Positive B: 0.018% Trifluoroacetic acid in ACN Mode: Scan Gradient: 5% B in 0.01 min, 5-95% B LC System: Nexera High pressure (0.01-1.60 min), 95-100% B (1.6-2.5 min), gradient system, Binary pump 100-5% B (2.50-2.52 min) with a hold at Detector: DAD 5% B for 0.48 min. Scanning wavelength: 220 nm / max plot Flow: 0.8 mL/min; Column oven: 40° C.

TABLE-US-00006 No. Structure R.sub.t [min] Mass No. Structure R.sub.t [min] Mass 1 [00043] 2.14 424.2 4 [00044] 2.13-2.2 424 2 [00045] 2.04-2.05 423.3 5 [00046] 2.003 432.5 3 [00047] 1.98-1.99 385.2-385.4 6 [00048] 2.14 386.4 7 [00049] 2.26 472.1 17 [00050] 2.23 509.1 8 [00051] 2.18 471.2 18 [00052] 2.27 456.1 9 [00053] 2.1 406 19 [00054] 2.26 490.2 10 [00055] 1.92 405 20 [00056] 2.19 455.2 11 [00057] 2.2 456 21 [00058] 2.16 422.3 5 12 [00059] 2.19 455 22 [00060] 2.17 489.2 13 [00061] 2.19 478.2 23 [00062] 2.05 421.4 14 [00063] 2.18 440.1 24 [00064] 2.00 406 15 [00065] 2.09 439.1 25 [00066] 1.97 370.1 5 16 [00067] 2.31 510 26 [00068] 1.82 369.2 27 [00069] 1.98 424 28 [00070] 1.85-1.87 423 38 [00071] 2.12 437 29 [00072] 2.16 427 39 [00073] 2.2 505 30 [00074] 1.95 426 40 [00075] 2.03 429.9 31 [00076] 2.38 427.1 41 [00077] 1.90 428.9 32 [00078] 2.13 426.1 42 [00079] 2.24 457.9 33 [00080] 1.84 405 43 [00081] 2.16 456.9 34 [00082] 2.00-2.07 406 44 [00083] 2.05 405.9 5 35 [00084] 2.29 506 45 [00085] 1.87 405 36 [00086] 2.21 438 46 [00087] 2.19 438 37 [00088] 1.86 405 47 [00089] 2.04 424.8 48 [00090] 1.92 423.8 49 [00091] 1.84 409 No. Structure R.sub.t [min] Mass No. Structure R.sub.t [min] Mass 50 [00092] 1.72 408.8 61 [00093] 1.88 385 51 [00094] 1.95 427 62 [00095] 1.9 420 52 [00096] 1.82 426.8 63 [00097] 2.02 414 53 [00098] 2.1 429 64 [00099] 2.11 415 54 [00100] 1.96-2.04 381 65 [00101] 2.06 370 55 [00102] 1.85 380 66 [00103] 2.09 407 56 [00104] 1.77 385.1 67 [00105] 1.93 405 57 [00106] 2.17 439 68 [00107] 2.06 420.1 5 58 [00108] 2.05 438 69 [00109] 1.92 419.1 59 [00110] 2.04 386.7 70 [00111] 2.06-2.14 449 60 [00112] 2.05 421 71 [00113] 1.96 425 72 [00114] 2.14 450 73 [00115] 1.83 424 85 [00116] 1.92 423 74 [00117] 1.91 374 86 [00118] 2.01 448 75 [00119] 1.92 374 87 [00120] 2.14 424 76 [00121] 1.77 373 88 [00122] 2.03 423 77 [00123] 1.75 373 89 [00124] 1.98 424 78 [00125] 2.08 455.8 90 [00126] 1.77 445.8 79 [00127] 2.13 424.3 91 [00128] 1.93 391 80 [00129] 2.1 437 92 [00130] 1.80 390 81 [00131] 1.90 369 93 [00132] 1.90 401 82 [00133] 2.26 457 94 [00134] 2.04 402 83 [00135] 2.05 427 95 [00136] 1.99 429 84 [00137] 2.03 424 96 [00138] 2.11 425 97 [00139] 2.08-2.16 424 98 [00140] 2.08 482 110 [00141] 2.08 419 99 [00142] 1.98 448.2 5 111 [00143] 2.08 425 100 [00144] 1.96 388 112 [00145] 1.99 424 101 [00146] 1.83 387 113 [00147] 1.97 429 102 [00148] 1.74 359 114 [00149] 2.32 449.6 5 103 [00150] 1.98 358 115 [00151] 2.01 427 104 [00152] 2.01 374 116 [00153] 1.95 426 105 [00154] 1.88 373 117 [00155] 2.15 455 106 [00156] 1.86 408 118 [00157] 2.04 454 107 [00158] 2.02 388 119 [00159] 2.18 425 108 [00160] 1.84 387 120 [00161] 2.10 424 109 [00162] 2.19 420 121 [00163] 2.22 430 122 [00164] 2.11 380 133 [00165] 1.77 355 123 [00166] 1.98 379 134 [00167] 2.09 396 124 [00168] 1.85 362 135 [00169] 1.95 395 125 [00170] 1.69 361 136 [00171] 2.26 449 126 [00172] 1.89 362 137 [00173] 2.72 456 127 [00174] 1.83 356 138 [00175] 2.17 455 128 [00176] 1.82 356 139 [00177] 1.76 359 129 [00178] 1.95 356 140 [00179] 158 358 130 [00180] 1.66 355 141 [00181] 2.11 388 131 [00182] 1.73 361 142 [00183] 1.93 388 132 [00184] 1.66 355 143 [00185] 2.07 412 144 [00186] 1.92 411 154 [00187] 1.84 423 145 [00188] 1.99 376 155 [00189] 1.92 423 146 [00190] 1.82 375 156 [00191] 2.01 424 147 [00192] 1.88 415 157 [00193] 1.87 423 148 [00194] 2.30 506 158 [00195] 1.94 423 149 [00196] 2.19 505 159 [00197] 2.02 423 150 [00198] 1.97 424 160 [00199] 1.96 464 151 [00200] 1.85 423 161 [00201] 1.95 498 152 [00202] 1.79 397 162 [00203] 1.87 497 153 [00204] 1.99 424 163 [00205] 1.83 448 164 [00206] 1.86 463

BIOLOGICAL STUDIES

A. Green House

[0332] The compound was dissolved in a mixture of acetone and/or dimethylsulfoxide and the wetting agent/emulsifier Wettol, which is based on ethoxylated alkylphenoles, in a ratio (volume) solvent-emulsifier of 99 to 1 to give a total volume of 5 ml. Subsequently, water was added to total volume of 100 ml. This stock solution was then diluted with the described solvent-emulsifier-water mixture to the final concentration given in the table below.

Use Example 1. Protective Control of Soybean Rust on Soybeans Caused by Phakopsora Pachyrhizi (PHAKPA P2)

[0333] Leaves of potted soybean seedlings were sprayed to run-off with the previously described spray solution, containing the concentration of active ingredient or their mixture as described below. The plants were allowed to air-dry. The trial plants were cultivated for 2 days in a greenhouse chamber at 23-27° C. and a relative humidity between 60 and 80 %. Then the plants were inoculated with spores of Phakopsora pachyrhizi. The strain used contains the amino acid substitution F129L in the mitochondrial cytochrome b protein conferring resistance to Qo inhibitors. To ensure the success the artificial inoculation, the plants were transferred to a humid chamber with a relative humidity of about 95 % and 20 to 24° C. for 24 hr. The trial plants were cultivated for up to 14 days in a greenhouse chamber at 23 to 27° C. and a relative humidity between 60 and 80 %. The extent of fungal attack on the leaves was visually assessed as % diseased leaf area, the disease level of untreated controls was usually higher than 85 %.

Use Example 2. Protective Control of Soybean Rust on Soybeans Caused by Phakopsora Pachyrhizi (PHAKPA P6)

[0334] Leaves of potted soybean seedlings were sprayed to run-off with the previously described spray solution, containing the concentration of active ingredient as described below. The plants were allowed to air-dry. The trial plants were cultivated for six days in a greenhouse chamber at 23-27° C. and a relative humidity between 60 and 80 %. Then the plants were inoculated with spores of Phakopsora pachyrhizi. The strain used contains the amino acid substitution F129L in the mitochondrial cytochrome b protein conferring resistance to Qo inhibitors. To ensure the success the artificial inoculation, the plants were transferred to a humid chamber with a relative humidity of about 95 % and 23 to 27° C. for 24 hr. The trial plants were cultivated for up to 14 days in a greenhouse chamber at 23 to 27° C. and a relative humidity between 60 and 80 %. The extent of fungal attack on the leaves was visually assessed as % diseased leaf area, the disease level of untreated controls was usually higher than 85 %.

[0335] The results of the abovementioned use examples are given in Table 1. All test results below are given for the control of phytopathogenic fungi containing the amino acid substitution F129L in the mitochondrial cytochrome b protein conferring resistance to Qo inhibitors.

TABLE-US-00007 Treatment PHAKPA (F129L) Disease level (%) No. Structure P2 at 16 ppm P6 at 16 ppm P2 at 4 ppm P6 at 4 ppm 1 [00207] 57 73 80 70 2 [00208] 17 27 67 59 3 [00209] 8 28 50 60 4 [00210] 0 0 3 4 5 [00211] 0 0 1 2 6 [00212] 32 67 60 73 7 [00213] 22 26 31 42 8 [00214] 27 40 73 53 9 [00215] 50 47 100 90 10 [00216] 7 11 73 87 11 [00217] 8 7 50 37 12 [00218] 12 19 73 50 13 [00219] 90 83 93 87 14 [00220] 77 65 97 87 15 [00221] 4 13 53 63 16 [00222] 100 97 100 100 17 [00223] 100 93 100 90 18 [00224] 73 83 93 90 19 [00225] 94 88 100 97 20 [00226] 40 40 63 60 21 [00227] 15 17 87 90 22 [00228] 33 26 73 67 23 [00229] 5 7 47 80 24 [00230] 33 53 87 93 25 [00231] 57 73 93 97 26 [00232] 11 73 63 90 27 [00233] 24 32 94 96 28 [00234] 1 9 27 44 29 [00235] 7 21 36 58 30 [00236] 2 13 19 45 31 [00237] 67 33 90 83 32 [00238] 13 20 70 70 33 [00239] 4.0 14 57 78 34 [00240] 7 10 28 26 35 [00241] 40 25 37 50 36 [00242] 32 28 30 28 37 [00243] 4 11 20 52 38 [00244] 12 5 20 13 39 [00245] 15 4 40 40 40 [00246] 18 25 100 83 41 [00247] 6 47 63 83 42 [00248] 28 30 60 57 43 [00249] 1 3 13 32 44 [00250] 87 63 100 83 45 [00251] 25 63 83 87 46 [00252] 21 9 48 48 47 [00253] 87 90 97 83 48 [00254] 4 33 57 83 49 [00255] 100 83 100 90 50 [00256] 47 67 97 83 51 [00257] 87 60 100 97 52 [00258] 17 37 77 73 53 [00259] 1 1 11 12 54 [00260] 6 14 95 95 55 [00261] 5 33 25 75 56 [00262] 6 1 22 57 57 [00263] 12 12 100 93 58 [00264] 6 1 22 57 59 [00265] 30 37 87 77 60 [00266] 23 20 70 70 61 [00267] 33 100 90 100 62 [00268] 7 12 48 67 63 [00269] 11 5 43 70 64 [00270] 30 12 60 63 65 [00271] 35 37 100 100 66 [00272] 38 23 60 57 67 [00273] 22 50 80 97 68 [00274] 80 87 90 87 69 [00275] 50 57 77 87 70 [00276] 0 1 5 14 71 [00277] 5 9 56 54 72 [00278] 22 18 70 77 73 [00279] 4 15 53 47 74 [00280] 28 67 97 80 75 [00281] 97 97 100 100 76 [00282] 40 70 93 97 77 [00283] 4 10 26 53 78 [00284] 90 90 87 88 79 [00285] 92 85 95 92 80 [00286] 0 0 4 15 81 [00287] 63 87 97 97 82 [00288] 20 11 67 63 83 [00289] 90 47 97 93 84 [00290] 100 83 100 90 85 [00291] 43 77 100 100 86 [00292] 90 77 100 97 87 [00293] 100 97 100 100 88 [00294] 20 28 73 93 89 [00295] 83 100 100 100 90 [00296] 95 67 95 70 91 [00297] 88 90 98 53 92 [00298] 90 53 92 53 93 [00299] 16 37 57 80 94 [00300] 97 80 100 87 95 [00301] 53 35 80 87 96 [00302] 7 10 73 77 97 [00303] 0 1 3 14 98 [00304] 32 28 57 57 99 [00305] 1 2 23 9 100 [00306] 90 73 97 100 101 [00307] 32 77 67 97 102 [00308] 100 100 100 100 103 [00309] 70 77 93 93 104 [00310] 0 6 18 53 105 [00311] 53 87 73 97 106 [00312] 100 90 100 87 107 [00313] 6 25 77 67 108 [00314] 20 17 67 67 109 [00315] 2 3 18 40 110 [00316] 7 4 28 20 111 [00317] 1 8 20 43 112 [00318] 6 25 77 67 113 [00319] 28 28 83 70 114 [00320] 57 83 100 100 115 [00321] 22 50 77 87 116 [00322] 1 3 25 60 117 [00323] 5 6 12 25 118 [00324] 41 42 62 67 119 [00325] 3 10 30 49 120 [00326] 23 14 60 50 121 [00327] 47 70 85 95 122 [00328] 33 73 90 88 123 [00329] 87 93 100 100 124 [00330] 33 73 97 90 125 [00331] 100 93 100 100 126 [00332] 76 78 90 78 127 [00333] 87 70 90 78 128 [00334] 60 40 90 82 129 [00335] 80 87 90 87 130 [00336] 42 60 75 85 131 [00337] 70 80 85 82 132 [00338] 0.8 11 19 43 133 [00339] 52 24 95 85 134 [00340] 9 15 64 69 135 [00341] 4 9 22 27 136 [00342] 90 87 100 90 137 [00343] 100 83 100 93 138 [00344] 100 100 100 100 139 [00345] 100 100 100 100 140 [00346] 100 100 100 100 141 [00347] 63 83 83 97 142 [00348] 90 77 100 100 143 [00349] 19 11 68 72 144 [00350] 87 100 100 100 145 [00351] 20 60 67 90 146 [00352] 4 67 70 100 147 [00353] 83 73 100 100 148 [00354] 67 43 100 100 149 [00355] 100 100 100 100 150 [00356] 13 53 90 90 151 [00357] 33 90 100 100 152 [00358] 100 100 100 100 153 [00359] 83 100 100 100 154 [00360] 0 0 0 16 155 [00361] 100 73 100 83 156 [00362] 67 60 100 70 157 [00363] 20 15 100 73 158 [00364] 0 7 8 23 159 [00365] 100 100 100 100 160 [00366] 0 0 6 14 161 [00367] 100 57 100 100 162 [00368] 100 100 100 100 163 [00369] 53 50 87 97

B. Microtests

[0336] The active compounds were formulated separately as a stock solution having a concentration of 10000 ppm in dimethyl sulfoxide. The stock solutions were mixed according to the ratio, pipetted onto a micro titer plate (MTP) and diluted with water to the stated concentrations.

[0337] After the addition of the respective fungal spore suspensions as described below, the plates were placed in a water vapor-saturated chamber at a temperature of 18° C. Using an absorption photometer, the MTPs were measured at 405 nm 7 days after the inoculation.

Use Example 3. Activity Against the Grey Mold Botrytis Cinerea (BOTRCI)

[0338] A spore suspension of Botriytis cinerea in an aqueous biomalt or yeast-bactopeptone-sodiumacetate solution was used.

Use Example 4. Activity Against Wheat Leaf Blotch Pathogen Septoria Tritici (SEPTTR)

[0339] A spore suspension of Septoria tritici in an aqueous biomalt or yeast-bactopeptone-glycerine or DOB solution was used.

Use Example 5. Activity Against the Late Blight Pathogen Phytophthora Infestans (PHYTIN)

[0340] A spore suspension of Phytophtora infestans containing a pea juice-based aqueous nutrient medium or DDC medium was used.

Use Example 6. Activity Against Fusarium Culmorum (FUSACU)

[0341] A spore suspension of Fusarium culmorum in an aqueous biomalt or yeast-bactopeptone-glycerine or DOB solution was used.

[0342] The measured parameters were compared to the growth of the active compound-free control variant (100%) and the fungus-free blank value to determine the relative growth in % of the pathogens in the respective active compounds.

TABLE-US-00008 Treatment Fungal growth at 31 ppm (%) No. Structure BOTRCI SEPTTR PHYTIN FUSACU 1 [00370] 20 10 2 [00371] 12 18 7 3 [00372] 8 4 0 6 4 [00373] 11 10 5 [00374] 19 20 8 6 [00375] 7 7 [00376] 11 8 [00377] 6 9 [00378] 4 5 10 [00379] 2 0 9 11 [00380] 10 12 [00381] 2 11 14 [00382] 20 15 [00383] 0 20 16 [00384] 19 17 [00385] 1 0 14 18 [00386] 16 19 [00387] 20 20 [00388] 3 17 21 [00389] 5 22 [00390] 17 23 [00391] 1 5 24 [00392] 0 18 25 [00393] 0 0 26 [00394] 7 0 12 27 [00395] 5 29 [00396] 14 0 1 12 30 [00397] 18 2 0 10 31 [00398] 13 33 [00399] 4 14 11 34 [00400] 0 1 10 35 [00401] 20 36 [00402] 10 37 [00403] 3 0 12 38 [00404] 6 16 39 [00405] 8 14 40 [00406] 0 8 41 [00407] 2 0 9 42 [00408] 10 43 [00409] 13 9 14 44 [00410] 2 15 45 [00411] 6 0 4 46 [00412] 0 0 0 1 47 [00413] 0 0 8 48 [00414] 1 17 49 [00415] 0 17 50 [00416] 0 18 51 [00417] 3 8 52 [00418] 12 53 [00419] 21 54 [00420] 4 2 14 55 [00421] 8 0 12 56 [00422] 0 11 57 [00423] 14 2 12 58 [00424] 21 11 17 61 [00425] 19 11 62 [00426] 0 11 63 [00427] 0 18 64 [00428] 17 21 65 [00429] 0 1 67 [00430] 5 0 9 68 [00431] 3 13 69 [00432] 0 11 70 [00433] 0 0 12 71 [00434] 0 0 72 [00435] 4 6 14 73 [00436] 21 1 13 74 [00437] 21 0 75 [00438] 0 76 [00439] 0 16 77 [00440] 0 11 78 [00441] 3 16 79 [00442] 17 13 80 [00443] 0 16 81 [00444] 0 9 82 [00445] 3 17 83 [00446] 21 84 [00447] 1 0 12 85 [00448] 0 16 86 [00449] 0 16 87 [00450] 1 0 17 88 [00451] 9 0 14 89 [00452] 0 13 90 [00453] 0 91 [00454] 0 16 92 [00455] 0 17 93 [00456] 13 0 17 94 [00457] 1 1 15 95 [00458] 17 96 [00459] 18 0 13 97 [00460] 0 17 99 [00461] 20 100 [00462] 19 0 12 101 [00463] 0 15 102 [00464] 0 103 [00465] 13 0 104 [00466] 0 16 105 [00467] 0 0 8 108 [00468] 0 109 [00469] 15 110 [00470] 2 21 111 [00471] 0 0 0 1 112 [00472] 0 0 0 1 113 [00473] 0 13 115 [00474] 18 18 116 [00475] 0 18 117 [00476] 0 0 9 0 119 [00477] 6 0 3 120 [00478] 0 0 0 1 121 [00479] 17 122 [00480] 12 0 10 123 [00481] 6 0 11 124 [00482] 0 125 [00483] 0 127 [00484] 0 128 [00485] 0 17 129 [00486] 17 0 130 [00487] 0 16 132 [00488] 0 20 133 [00489] 0 19 134 [00490] 13 135 [00491] 15 139 [00492] 0 17 5 142 [00493] 14 144 [00494] 20 152 [00495] 14 153 [00496] 18

COMPARATIVE TRIALS

[0343] TABLE-US-00009 PHAKPA (F129L) Disease level (%) Compound Structure P2 at 4 ppm P2 at 16 ppm P6 at 4 ppm P6 at 16 ppm Trifloxystrobin as comparative example [00497] 97 37 100 53 Ex. 4 [00498] 9 0 12 0

The results in Table C1 show that the specific substituent at position R.sup.3 together with the terminal heteroaryl ring improves the fungicidal activity against phytopathogenic fungi containing the amino acid substitution F129L in the mitochondrial cytochrome b protein conferring resistance to Qo inhibitors compared to trifloxystrobin where the position R.sup.3 is unsubstituted and the terminal ring is phenyl.