PROCESS FOR THE PREPARATION OF QUATERNIZED PYRIDAZINE DERIVATIVES

Abstract

The present invention provides, inter alia, a process for producing a compound of formula (I) wherein the substituents are as defined in claim 1. The present invention further provides intermediate compounds utilised in said process, and methods for producing said intermediate compounds.

##STR00001##

Claims

1. A process for the preparation of a compound of formula (I) or an agronomically acceptable salt or zwitterionic species thereof: ##STR00302## wherein A is a 6-membered heteroaryl selected from the group consisting of formula A-I to A-VII below ##STR00303## ##STR00304## ##STR00305## ##STR00306## ##STR00307## ##STR00308## ##STR00309## wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I), p is 0, 1 or 2; and R.sup.1 is hydrogen; R.sup.2 is hydrogen; Q is (CR.sup.1aR.sup.2b).sub.m; m is 1; each R.sup.1a and R.sup.2b are hydrogen: Z is selected from the group consisting of —CN, —CH.sub.2OR.sup.3, —CH(OR.sup.4)(OR.sup.4a), —C(OR.sup.4)(OR.sup.4a)(OR.sup.4b), —C(O)OR.sup.10, —C(O)NR.sup.6R.sup.7 and —S(O).sub.2OR.sup.10; or Z is selected from the group consisting of a group of formula Z.sub.a, Z.sub.b, Z.sub.c, Z.sub.d, Z.sub.e and Z.sub.f below ##STR00310## ##STR00311## ##STR00312## ##STR00313## ##STR00314## ##STR00315## wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I); and R.sup.3 is hydrogen or —C(O)OR.sup.10; each R.sup.4, R.sup.4a and R.sup.4b are independently selected from C.sub.1-C.sub.6alkyl; each R.sup.5, R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d R.sup.5e, R.sup.5f, R.sup.5g and R.sup.5h are independently selected from the group consisting of hydrogen and C.sub.1-C.sub.6alkyl; each R.sup.6 and R.sup.7 are independently selected from the group consisting of hydrogen and C.sub.1-C.sub.6alkyl; each R.sup.8 is independently selected from the group consisting of halo, —NH.sub.2, methyl and methoxy; R.sup.10 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, phenyl and benzyl; and R.sup.10a is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, phenyl and benzyl; said process comprising: reacting a compound of formula (IV); ##STR00316## wherein A, Q, Z, R.sup.1 and R.sup.2 are as defined above; with a compound of formula (V) or a salt or an N-oxide thereof; ##STR00317## wherein each R.sup.15, R.sup.16, R.sup.17 and R.sup.18 are independently selected from the group consisting of halogen, -OR.sup.15a, -NR.sup.16aR.sup.17a and —S(O).sub.2OR.sup.10; and/or R.sup.15 and R.sup.16 together are =O or =NR.sup.16a and/or R.sup.17 and R.sup.18 together are =O or =NR.sup.16a; or R.sup.15 and R.sup.16 together with the carbon atom to which they are attached form a 3- to 6-membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from nitrogen and oxygen; or R.sup.15 and R.sup.17 together with the carbon atom to which they are attached form a 3- to 6-membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from nitrogen and oxygen; and each R.sup.15a is independently selected from the group consisting of hydrogen and C.sub.1-C.sub.6alkyl; each R.sup.16a is independently selected from the group consisting of hydrogen and C.sub.1-C.sub.6alkyl; each R.sup.17a is independently selected from the group consisting of hydrogen and C.sub.1-C.sub.6alkyl; to give a compound of formula (I).

2. (canceled)

3. (canceled)

4. (canceled)

5. A process according to claim 1, wherein p is 0.

6. A process according to claim 1, wherein A is selected from the group consisting of formula A-Ia to A-IIIa below, ##STR00318## ##STR00319## ##STR00320## wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I).

7. A process according to claim 1, wherein Z is selected from the group consisting of —CN, —CH.sub.2OH, —C(O)OR.sup.10, —S(O).sub.2OR.sup.10 and —CH═CH.sub.2.

8. A process according to claim 1, wherein Z is —CN or —C(O)OR.sup.10.

9. A process according to claim 1, wherein the compound of formula (V) is a compound selected from the group consisting of a compound of formula (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vj), (Vk) and (Vm), ##STR00321## ##STR00322## ##STR00323## ##STR00324## ##STR00325## ##STR00326## ##STR00327## ##STR00328## ##STR00329## ##STR00330## ##STR00331## wherein each R.sup.10, R.sup.15a, R.sup.16a and R.sup.17a are as defined in claim 1.

10. A process according to claim 1, wherein the compound of formula (V) is a compound of formula (Va), ##STR00332## .

11. (canceled)

12. (canceled)

13. A process according to claim 1 wherein the compound of formula (IV) is produced by reacting a compound of formula (II): ##STR00333## wherein A is as defined in claim 1; Y is selected from the group consisting of a group of formula Y-I, Y-II and Y-III below ##STR00334## ##STR00335## ##STR00336## R.sup.13 and R.sup.14 are independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl and phenyl; or R.sup.13 and R.sup.14 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from nitrogen, oxygen and sulfur; and R.sup.14a is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl and —C(O)R.sup.14b; R.sup.14b is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl and C.sub.1-C.sub.6haloalkyl; with a compound of formula (III): ##STR00337## wherein R.sup.1, R.sup.2, Q and Z are as defined in claim 1, to give a compound of formula (IV); ##STR00338## wherein A, Q, Z, R.sup.1 and R.sup.2 are as defined in claim 1.

14. A process according to claim 1 wherein the compound of formula (I) is further subjected to a hydrolysis, oxidation and/or a salt exchange to give an agronomically acceptable salt of formula (Ia) or a zwitterion of formula (Ib), ##STR00339## ##STR00340## wherein Y.sup.1 represents an agronomically acceptable anion and j and k represent integers that may be selected from 1, 2 or 3, and A, R.sup.1, R.sup.2 and Q are as defined in claim 1 and Z.sup.2 is —C(O)OH or —S(O).sub.2OH.

15. (canceled)

16. A compound selected from the group consisting of a compound of formula (Ic) and a compound of formula (Id) or an agronomically acceptable salt thereof, ##STR00341## ##STR00342## .

17. A compound of formula (IV) ##STR00343## wherein A, Q, Z, R.sup.1 and R.sup.2 are as defined in claim 1.

18. Use of a compound of formula (II) for preparing a compound of formula (I) ##STR00344## wherein A and Y are as defined in claim 1.

19. A compound of formula (II-a) ##STR00345## wherein A is a 6-membered heteroaryl selected from the group consisting of formula A-I, A-II, A-III, A-IV, A-V and A-VII below ##STR00346## ##STR00347## ##STR00348## ##STR00349## ##STR00350## ##STR00351## wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I), p and R.sup.8 are as defined in claim 1; R.sup.13 and R.sup.14 are independently selected from the group consisting of C.sub.2-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl and phenyl; or R.sup.13 and R.sup.14 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from nitrogen, oxygen and sulfur.

20. (canceled)

21. A process according to claim 13 wherein the compound of formula (II) wherein Y is Y-I, is produced by: reacting a compound of formula (VI) ##STR00352## with a compound of formula (VII) ##STR00353## wherein R.sup.22 is C.sub.1-C.sub.6alkyl; R.sup.23 and R.sup.24 are independently selected from the group consisting of C.sub.1-C.sub.6alkoxy and -NR.sup.25R.sup.26; R.sup.25 and R.sup.26 are independently selected from C.sub.1-C.sub.6alkyl; or R.sup.25 and R.sup.26 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from nitrogen, oxygen and sulfur; and a compound of formula (VIII) ##STR00354## to produce a compound of formula (II) ##STR00355## .

22. (canceled)

23. Use of a compound of formula (VI) for preparing a compound of formula (I) ##STR00356## wherein A is as defined in claim 1.

24. Use of a compound of formula (III) for preparing a compound of formula (I) ##STR00357## wherein R.sup.1, R.sup.2 Q and Z are as defined in claim 1.

Description

EXAMPLES

[0265] The following examples further illustrate, but do not limit, the invention. Those skilled in the art will promptly recognise appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques.

[0266] The following abbreviations are used: s = singlet; br s = broad singlet; d = doublet; dd = double doublet; dt = double triplet; t = triplet, tt = triple triplet, q = quartet, quin = quintuplet, sept = septet; m = multiplet; GC = gas chromatography, RT = retention time, T.sub.i = internal temperature, MH.sup.+ = molecular mass of the molecular cation, M = molar, Q.sup.1HNMR = quantitative .sup.1HNMR, RT = room temperature, UFLC = Ultra-fast liquid chromatography.

[0267] .sup.1H NMR spectra are recorded at 400 MHz unless indicated otherwise and chemical shifts are recorded in ppm.

[0268] Some chemical yields have been calculated precisely using quantitative 1H NMR and 1,3,5-trimethoxybenzene or caffeine as an internal standard. Where the chemical yield is based on quantative 1H NMR the nature of any relevant counterion is assumed based on the reaction conditions used, however, the skilled person would appreciate that the crude reaction mixture may also include (but are not limited to) other counter ions such as chloride, bromide, iodide, fluoride, hydrogen sulfate, mesylate, oxalate, tartrate and trifluoroacetate.

LCMS Methods

Standard:

[0269] Spectra were recorded on a Mass Spectrometer from Waters (SQD, SQDII Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive and negative ions, Capillary: 3.00 kV, Cone range: 30 V, Extractor: 2.00 V, Source Temperature: 150° C., Desolvation Temperature: 350° C., Cone Gas Flow: 50 I/h, Desolvation Gas Flow: 650 I/h, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment, diode-array detector and ELSD detector. Column: Waters UPLC HSS T3, 1.8 .Math.m, 30 × 2.1 mm, Temp: 60° C., DAD Wavelength range (nm): 210 to 500, Solvent Gradient: A = water + 5% MeOH + 0.05% HCOOH, B= Acetonitrile + 0.05 % HCOOH, gradient: 10-100% B in 1.2 min; Flow (ml/min) 0.85

Standard Long

[0270] Spectra were recorded on a Mass Spectrometer from Waters (SQD, SQDII Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive and negative ions), Capillary: 3.00 kV, Cone range: 30 V, Extractor: 2.00 V, Source Temperature: 150° C., Desolvation Temperature: 350° C., Cone Gas Flow: 50 I/h, Desolvation Gas Flow: 650 I/h, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment, diode-array detector and ELSD detector. Column: Waters UPLC HSS T3, 1.8 .Math.m, 30 × 2.1 mm, Temp: 60° C., DAD Wavelength range (nm): 210 to 500, Solvent Gradient: A = water + 5% MeOH + 0.05 % HCOOH, B= Acetonitrile + 0.05 % HCOOH, gradient: 10-100% B in 2.7 min; Flow (ml/min) 0.85

Example 1: Preparation of Tert-Butyl 3-(4-Pyrimidin-2-Ylpyridazin-1-Ium-1-yl)Propanoate Trifluoroacetate Salt From Tert-Butyl 3-[2-(2-Pyrimidin-2-Ylethylidene)Hydrazinolpropanoate and Glyoxal

[0271] ##STR00263##

Procedure:

[0272] Morpholinium acetate was prepared in situ by mixing morpholine (1 eq.) and acetic acid (1eq.)).

[0273] To a solution of morpholinium acetate (0.158 g, 1.07 mmol, 0.85 eq.), glyoxal (0.366 mL, 40% in H.sub.2O) and trifluoroacetic acid (0.287 g, 2.52 mmol, 2 eq.) in dioxane (0.5 ml) was added a solution of tert-butyl 3-[2-(2-pyrimidin-2-ylethylidene)hydrazino]propanoate (0.333 g, 1.26 mmol) in dioxane (2.5 mL) via syringe pump over 3 h. The reaction mixture was stirred at room temperature for 15 h.

[0274] The mixture was then concentrated under reduced pressure. The chemical yield of tert-butyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate trifluoroacetate salt was determined using quantitative 1H NMR using 1,3,5-trimethoxybenzene as an internal standard to be 33%.

[0275] .sup.1H NMR (400 MHz, MeOH-d4) δ ppm: 10.4(d, 1H), 10.04(d, 1H), 9.43(dd, 1H), 9.14(d, 2H), 7.72(t, 1H), 5.17(t, 2H), 3.24(t, 2H), 1.45(S, 9H)

Example 2: Preparation of Tert-Butyl 3-(4-Pyrimidin-2-Ylpyridazin-1-Ium-1-yl)Propanoate Trifluoroacetate Salt From Tert-butyl 3-[2-(2-Pyrimidin-2-Ylethylidene)Hydrazino]Propanoate and 1,1,2,2-Tetramethoxyethane

[0276] ##STR00264##

Procedure

[0277] Morpholinium acetate was prepared in situ by mixing morpholine (1 eq.) and acetic acid (1eq.).

[0278] To a suspension of morpholinium acetate (0.158 g, 0.85 eq.) in dioxane (0.5 ml) were added in parallel a solution of tert-butyl 3-[2-(2-pyrimidin-2-ylethylidene)hydrazino]propanoate (0.333 g, 1.26 mmol, 1 eq.) in dioxane (1 mL) and a solution of 1,1,2,2-tetramethoxyethane (0.398 g, 2.00 eq.) and trifluoroacetic acid (0.287 g, 0.193 mL, 2.00 eq.) in dioxane (1 mL) using two syringe pumps over 2 h15 min. The chemical yield of tert-butyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate trifluoroacetate salt was determined using quantitative 1H NMR using 1,3,5-trimethoxybenzene (20 mg) as an internal standard to be 31%.

[0279] .sup.1H NMR (400 MHz, MeOH-d4) δ ppm: 10.4(d, 1H), 10.04(d, 1H), 9.43(dd, 1H), 9.14(d, 2H), 7.72(t, 1H), 5.17(t, 2H), 3.24(t, 2H), 1.45(S, 9H)

Example 3: Preparation of Tert-Butyl 3-(4-Pyrimidin-2-Ylpyridazin-1-Ium-1-yl)Propanoate Trifluoroacetate Salt From Tert-Butyl 3-[2-(2-Pyrimidin-2-Ylethylidene)Hydrazino]Propanoate and 2,2-Dimethoxyacetaldehyde

[0280] ##STR00265##

Procedure

[0281] Morpholinium acetate was prepared in situ by mixing morpholine (1 eq.) and acetic acid (1eq.). tert-butyl 3-[2-(2-pyrimidin-2-ylethylidene)hydrazino]propanoate was prepared according to the procedure described below in Example 11. from tert-butyl 3-hydrazinopropanoate (0.134 g, 1.3 eq.) and (E)-N,N-dimethyl-2-pyrimidin-2-yl-ethenamine (0.1 g, 0.67 mmol, 1 eq.).

[0282] The resulting crude tert-butyl 3-[2-(2-pyrimidin-2-ylethylidene)hydrazino]propanoate 0.67 mmol, 1 eq.) was dissolved in dioxane (0.5 mL) and morpholinium acetate was added (0.093 g, 0.63 mmol, 0.94 eq.). The resulting suspension was stirred for 30 min at rt.

[0283] In a separate vial, 2,2-dimethoxyacetaldehyde (0.219 g, 0.19 mL, 60% w/w in H.sub.2O) was mixed with trifluoroacetic acid (0.144 g, 0.096 mL, 2 eq.) and diluted with 1,4-dioxane (1.030 g, 1 mL). The resulting mixture of glyoxal-acetal/TFA dioxane solution was next added to the tert-butyl 3-[2-(2-pyrimidin-2-ylethylidene)hydrazino]propanoate solution in dioxane over 1h at RT.

[0284] The reaction mixture was further stirred at rt for 2 h, and then concentrated.1,3,5-trimethoxybenzene was added (21.5 mg) as an internal standard and the mixture was analyzed by quantitative 1H NMR in CD.sub.3OD indicating the title compound had been formed in 4.3% yield.

[0285] .sup.1H NMR (400 MHz, MeOH-d4) δ ppm: 10.4(d, 1H), 10.04(d, 1H), 9.43(dd, 1H), 9.14(d, 2H), 7.72(t, 1H), 5.17(t, 2H), 3.24(t, 2H), 1.45(S, 9H)

Example 4: Preparation of 3-(4-Pyrimidin-2-Ylpyridazin-1-Ium-1-yl)Propanenitrile Trifluoroacetate Salt From 3-[2-(2-Pyrimidin-2-Ylethylidene)Hydrazino]Propanenitrile and Glyoxal

[0286] ##STR00266##

Procedure:

[0287] Morpholinium acetate was prepared in situ by mixing morpholine (1 eq.) and acetic acid (1eq.). 3-[(2-(2-pyrimidin-2-ylethylidene)hydrazino]propanenitrile was prepared according to the procedure described in Example 15. in 70% yield

[0288] A vial was charged morpholinium acetate (0.277 g, 0.85 eq.), trifluoroacetic acid (0.340 mL, 2 eq.) and glyoxal (11.2 mL, 44 eq., 40 w/w% in H.sub.2O) which was stirred to give a colorless homogeneous solution. 3-[(2-(2-pyrimidin-2-ylethylidene)hydrazino]propanenitrile (0.5 g, 2.2 mmol, 1 eq.) was then added as a solution in water (5 mL). After stirring for 22 h at room temperature the mixture was concentrated to give a yellow foam.

[0289] The chemical yield of tert-butyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate trifluoroacetate salt was determined using quantitative 1H NMR using caffeine as an internal standard to be 70%.

[0290] .sup.1H NMR (400 MHz, D.sub.2O) δ ppm: s(10.26, 1H), 9.93(d, 1H, 6.2 Hz), 9.29(dd, 1H, J=6.2, J=2.6 Hz), 9.03(d, 2H, 5.1 Hz), 7.68(t, 1H, 4.95 Hz), 5.23(t, 2H, J=6.4 Hz), 3.42(t, 2H, J=6.4 Hz)

Example 5: Preparation of 3-(4-Pyrimidin-2-Ylpyridazin-1-Ium-1-yl)Propanenitrile Trifluoroacetate Salt From 3-[2-(2-Pyrimidin-2-Ylethylidene)Hydrazino]Propanenitrile and Glyoxal

[0291] ##STR00267##

Procedure

[0292] Morpholinium acetate was prepared in situ by mixing morpholine (1 eq.) and acetic acid (1eq.). 3-[(2-(2-pyrimidin-2-ylethylidene)hydrazino]propanenitrile was prepared according to the procedure described in Example 15 \. in 70% yield.

[0293] A vial was charged with trifluoroacetic acid (0.63 mL, 1.70 mmol, 2.00 eq, 2.67 M in H.sub.2O), morpholinium acetate (106 mg, 0.72 mmol, 0.85 eq), glyoxal (618 mg, 4.25 mmol, 5.00 eq., 40% w/w in H.sub.2O) and caffeine (0.85 mL, 0.085 mmol, 0.10 eq, 0.099 M in H.sub.2O). 3-[(2-(2-pyrimidin-2-ylethylidene)hydrazino]propanenitrile (0.85 mmol, 0.33 mL, 2.54 M in THF) was next added. The vial was then sealed and stirred at room temperature for 24 h. After 24 h, 0.1 mL of the reaction mixture was sampled and diluted in D.sub.2O (0.5 ml) and analyzed by quantitative 1H NMR, indicating the title compound had been formed in 61% chemical yield.

[0294] .sup.1H NMR (400 MHz, D.sub.2O) δ ppm: 10.26(s, 1H), 9.93(d, 1H, 6.2 Hz), 9.29(dd, 1H, J=6.2, J=2.6 Hz), 9.03(d, 2H, 5.1 Hz), 7.68(t, 1H, 4.95 Hz), 5.23(t, 2H, J=6.4 Hz), 3.42(t, 2H, J=6.4 Hz)

Example 6: Preparation of 3-(4-Pyrimidin-2-Ylpyridazin-1-Ium-1-yl)Propanenitrile Hydrogenosulfate Salt From 3-[2-(2-Pyrimidin-2-Ylethylidene)Hydrazino]Propanenitrile and Glyoxal

[0295] ##STR00268##

Procedure:

[0296] Morpholinium acetate was prepared in situ by mixing morpholine (1 eq.) and acetic acid (1eq.). 3-[(2-(2-pyrimidin-2-ylethylidene)hydrazino]propanenitrile was prepared according to the procedure described in Example 15 \. in 70% yield.

[0297] A vial was charged with KHSO.sub.4 (0.48 mL, 1.27 mmol, 1.5 eq, 2.67 M in H.sub.2O), glyoxal (618 mg, 4.25 mmol, 5.00 eq., 40% w/w in H.sub.2O) and caffeine (0.85 mL, 0.085 mmol, 0.10 eq, 0.099 M in H.sub.2O). 3-[(2-(2-pyrimidin-2-ylethylidene)hydrazino]propanenitrile (0.85 mmol, 0.33 mL, 2.54 M in THF) was next added. The vial was then sealed and stirred at room temperature for 24 h. After 24 h, 0.1 mL of the reaction mixture was sampled and diluted in D.sub.2O (0.5 ml) and analyzed by quantitative 1H NMR, indicating the title compound had been formed in 54% chemical yield.

[0298] .sup.1H NMR (400 MHz, D.sub.2O) δ ppm: s(10.26, 1H), 9.93(d, 1H, 6.2 Hz), 9.29(dd, 1H, J=6.2, J=2.6 Hz), 9.03(d, 2H, 5.1 Hz), 7.68(t, 1H, 4.95 Hz), 5.23(t, 2H, J=6.4 Hz), 3.42(t, 2H, J=6.4 Hz)

Example 7: Preparation of 3-(4-Pyrimidin-2-Ylpyridazin-1-Ium-1-yl)Propanenitrile Tartrate Salt From 3-[2-(2-Pyrimidin-2-Ylethylidene)Hydrazinolpropanenitrile and Glyoxal

[0299] ##STR00269##

Procedure:

[0300] 3-[pyrimidin-2-ylethylidene)hydrazino]propanenitrile was prepared according to the procedure described in Example 15 \. in 70% yield.

[0301] A vial was charged with tartaric acid (382 mg, 2.55 mmol, 3 eq) and glyoxal (618 mg, 4.25 mmol, 5.00 eq., 40% w/w in H.sub.2O) and caffeine (0.85 mL, 0.085 mmol, 0.10 eq, 0.099 M in H.sub.2O). 3-[(2-(2-pyrimidin-2-ylethylidene)hydrazino]propanenitrile (0.85 mmol, 0.33 mL, 2.54 M in THF) was next added. The vial was then sealed and stirred at room temperature for 24 h. After 24 h, 0.1 mL of the reaction mixture was sampled and diluted in D.sub.2O (0.5 ml) and analyzed by quantitative 1H NMR, indicating the title compound had been formed in 44% chemical yield.

[0302] .sup.1H NMR (400 MHz, D.sub.2O) δ ppm: s(10.26, 1H), 9.93(d, 1H, 6.2 Hz), 9.29(dd, 1H, J=6.2, J=2.6 Hz), 9.03(d, 2H, 5.1 Hz), 7.68(t, 1H, 4.95 Hz), 5.23(t, 2H, J=6.4 Hz),

Example 8: Preparation of 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanenitrile Trifluoroacetate Salt From 3-[2-(2-pyrimidin-2-ylethylidene)hydrazino]propanenitrile and 2,2-dimethoxyacetaldehyde

[0303] ##STR00270##

Procedure

[0304] Morpholinium acetate was prepared in situ by mixing morpholine (1 eq.) and acetic acid (1eq.). 3-[(2-(2-pyrimidin-2-ylethylidene)hydrazino]propanenitrile was prepared according to the procedure described in Example 15 \. in 70% yield

[0305] A vial was charged with trifluoroacetic acid (0.63 mL, 1.70 mmol, 2.00 eq, 2.67 M in H.sub.2O), morpholinium acetate (106 mg, 0.72 mmol, 0.85 eq), 2,2-dimethoxyacetaldehyde (736 mg, 4.25 mmol, 5.00 eq., 60% w/w in H.sub.2O) and caffeine (0.85 mL, 0.085 mmol, 0.10 eq, 0.099 M in H.sub.2O). 3-[(2-(2-pyrimidin-2-ylethylidene)hydrazino]propanenitrile (0.85 mmol, 0.33 mL, 2.54 M in THF) was next added. The vial was then sealed and stirred at room temperature for 24 h. After 24 h, 0.1 mL of the reaction mixture was sampled and diluted in D20 (0.5 ml) and analyzed by quantitative 1H NMR, indicating the title compound had been formed in 18% chemical yield.

[0306] .sup.1H NMR (400 MHz, D.sub.2O) δ ppm: (s, 10.26, 1H), 9.93(d, 1H, 6.2 Hz), 9.29(dd, 1H, J=6.2, J=2.6 Hz), 9.03(d, 2H, 5.1 Hz), 7.68(t, 1H, 4.95 Hz), 5.23(t, 2H, J=6.4 Hz), 3.42(t, 2H, J=6.4 Hz)

Example 9: Preparation of 3-(4-Pyrimidin-2-Ylpyridazin-1-Ium-1-yl)Propanenitrile Trifluoroacetate Salt From 3-[2-(2-Pyrimidin-2-Ylethylidene)Hydrazino]Propanenitrile and 1,2-Dichloro-1,2-Dimethoxy-Ethane

[0307] ##STR00271##

[0308] A vial was charged with 1,2-dichloro-1,2-dimethoxy-ethane (64 mg, 0.4 mmol, 2eq.), trifluoroacetic acid (0.80 mL, 0.4 mmol, 2.00 eq, 0.5 M in THF) and 1,3,5-trimethoxybenzene (10 mg, 0.059 mmol, 0.30 eq.). The mixture was stirred for 5 min. Acetic acid (0.34 mL, 0.17 mmol, 0.85 eq, 0.5 M in THF), morpholine (0.34 mL, 0.17 mmol, 0.85 eq, 0.5 M in THF) were added at rt and the mixture was stirred for 5 min. A THF solution of 3-[(2-(2-pyrimidin-2-ylethylidene)hydrazino]propanenitrile (0.20 mmol, 0.40 mL, 1.00 eq., 0.5 M in THF) was finally added. The vial was then sealed and stirred at room temperature for 1h. After 1 h, 0.1 mL of the reaction mixture was sampled and diluted in DMSO-d6 (0.5 ml) and analyzed by quantitative 1H NMR . Quantitative 1H NMR analysis (using 1,3,5-trimethoxybenezene as an internal standard), indicating the title compound had been formed in 23% chemical yield.

Example 10: Preparation of 3-(4-Pyrimidin-2-Ylpyridazin-1-Ium-1-yl)Propanenitrile Trifluoroacetate Salt From 3-[2-(2-Pyrimidin-2-Ylethylidene)Hydrazino]Propanenitrile and 1,4-Dioxane-2,3-Diol

[0309] ##STR00272##

[0310] A vial was charged with 1,4-dioxane-2,3-diol (48 mg, 0.4 mmol, 2eq.), trifluoroacetic acid (0.80 mL, 0.4 mmol, 2.00 eq, 0.5 M in THF) and 1,3,5-trimethoxybenzene (10 mg, 0.059 mmol, 0.30 eq.). The mixture was stirred for 5 min. Acetic acid (0.34 mL, 0.17 mmol, 0.85 eq, 0.5 M in THF), morpholine (0.34 mL, 0.17 mmol, 0.85 eq, 0.5 M in THF) were added at rt and the mixture was stirred for 5 min. A THF solution of 3-[(2-(2-pyrimidin-2-ylethylidene)hydrazino]propanenitrile (0.20 mmol, 0.40 mL, 1.00 eq., 0.5 M in THF) was finally added. The vial was then sealed and stirred at room temperature for 1 h. After 1 h, 0.1 mL of the reaction mixture was sampled and diluted in DMSO-d6 (0.5 ml) and analyzed by quantitative 1H NMR. Quantitative 1H NMR analysis (using 1,3,5-trimethoxybenezene as an internal standard), indicating the title compound had been formed in 42% chemical yield

Example 11: Preparation of Tert-Butyl 3-[2-(2-Pyrimidin-2-Ylethylidene)Hydrazino]Propanoate From Tert-Butyl 3-Hydrazinopropanoate and (E)-N,N-Dimethyl-2-Pyrimidin-2-yl-Ethenamine

[0311] ##STR00273##

[0312] A vial was charged with N,N-dimethylenamine (1.5 g, 9.4 mmol, 1.00 eq.) and t-Butyl 3-hydrazino propanoate (1.77 g, 10.4 mmol, 1.10 eq.). The orange suspension was heated at 100° C. for 40 min under a flow of argon to help removing dimethylamine. The resulting mixture was then allowed to cool to room temperature. Quantitative 1H NMR analysis (using 1,3,5-trimethoxybenezene as an internal standard) of the crude mixture indicated the title compound had been formed in 76% yield as an E/Z mixture of hydrazone isomers.

[0313] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.70 (d, 2 H), 7.34 (t, 1 H), 7.19 (m, 1 H), 6.89 (t, 1 H), 3.92 (d, 2 H), 3.39 (t, 2 H), 2.54 (t, 2 H), 1.46 (s, 9 H)

Example 12: Preparation of Tert-Butyl 3-[2-(2-Pyrimidin-2-Ylethylidene)Hydrazinolpropanoate From 2-[(2-Pyrrolidin-1-Ylvinyllpyrimidine

[0314] ##STR00274##

[0315] A vial was charged with 2-[(2-pyrrolidin-1-ylvinyl]pyrimidine (0.200 g, 1.2 mmol, 1.1 eq.) and tert-butyl 3-hydrazinopropanoate (0.256 g, 1.44 mmol, 1.1 eq.). The neat reaction mixture was warmed to 100° C. and set under 200 mbar for 1 h then under 1 mbar (to remove the pyrrolidine) for 1 h. The resulting mixture was then allowed to cool to room temperature. Quantitative 1H NMR analysis (using 1,3,5-trimethoxybenzene as an internal standard) of the crude mixture indicated the title compound had been formed in 50% chemical yield as an E/Z mixture of hydrazone isomers.

[0316] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.70 (d, 2 H), 7.34 (t, 1 H), 7.19 (m, 1 H), 6.89 (t, 1 H), 3.92 (d, 2 H), 3.39 (t, 2 H), 2.54 (t, 2 H), 1.46 (s, 9 H)

Example 13: Preparation of Tert-Butyl 3-[2-(2-Pyrimidin-2-Ylethylidene)Hydrazino]Propanoate From 4-[2-Pyrimidin-2-Ylvinyllmorpholine

[0317] ##STR00275##

[0318] A vial was charged with 2-ethynylpyrimidine (490 mg, 4.60 mmol, 1.00 eq.) and THF (1.5 mL). Morpholine (615 mg, 7.00 mmol, 1.50 eq.) was then added via syringe. The reaction mixture was heated at 100° C. for 30 min. NMR analysis indicated ca. 90% conversion of the starting 2-alkynyl pyrimidine. Used as such in the subsequent step.

[0319] 4-pyrimidin-2-ylvinyl]morpholine: .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.40 (d, 2 H), 7.65 (d, 2 H), 6.75 (t, 1 H), 5.5 (d, 1 H), 3.75 (m, 4 H), 3.25 (m, 2 H)

[0320] To the above THF solution of 4-[2-pyrimidin-2-ylvinyl]morpholine (4.60 mmol) was added a solution of tert-butyl 3-hydrazinopropanoate (0.930 g, 5.85 mmol, 1.26 eq.) in THF (0.5 mL) dropwise. The reaction mixture was heated at 100° C. for 60 min. The reaction mixture was concentrated in vacuo to give the crude product tert-butyl 3-[2-(2-pyrimidin-2-ylethylidene) hydrazino] propanoate (1.48 g) as an amber oil. The crude product was purified by flash chromatography on silica gel to give a yellow oil (0.517 g, 87% purity as determined by quant. 1H NMR using dimethylsulfone as internal standard, 51% yield).

[0321] tert-butyl 3-[2-(2-pyrimidin-2-ylethylidene)hydrazino]propanoate: .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.70 (d, 2 H), 7.34 (t, 1 H), 7.19 (m, 1 H), 6.89 (t, 1 H), 3.92 (d, 2 H), 3.39 (t, 2 H), 2.54 (t, 2 H), 1.46 (s, 9 H)

Example 14: Preparation of Tert-Butyl 3-[2-(2-Pyrimidin-2-Ylethylidene)Hydrazino]Propanoate From 2-Ethynylpyrimidine and Tert-Butyl 3-Hydrazinopropanoate

[0322] ##STR00276##

Procedure

[0323] A vial was charged with 2-ethynylpyrimidine (1000 mg, 9.42 mmol, 1.00 eq.) and THF (1.0 mL/g) and then the resulting solution was heated to 50° C. under nitrogen atmosphere. A solution of tert-butyl 3-hydrazinopropanoate (1960 mg, 1.10 eq.) in THF (1.0 mL/g) was added. The reaction was then heated at 50° C. for 1 h. The solvent was then removed in vacuo to give the title compound as a brown oil (2400 mg, 63% purity as determined by quant. 1H NMR using mesitylene as internal standard, 61% yield).

Example 15: Preparation of 3-[2-(2-Pyrimidin-2-Ylethylidene)Hydrazino]Propanenitrile From 2-[(2-Pyrrolidin-1-Ylvinyllpyrimidine

[0324] ##STR00277##

Procedure

[0325] A flask was charged with 2-[(2-pyrrolidin-1-ylvinyl]pyrimidine (20 g, 114 mmol, 1.00 eq.) and THF (280 mL). To the above solution, 3-hydrazinopropanenitrile (20.4 g, 228 mmol, 2.00 eq.) was added in one portion at 20° C. under stirring. Trifluoroacetic acid (8.90 mL, 114 mmol, 1.00 eq.) was added dropwise at room temperature (maintaining temperature between 24° C.-26° C.). The reaction mixture was stirred at this temperature for 2 h. The reaction mixture was then concentrated under vacuo. The crude product was purified flash chromatography on silica gel to give (Isco Combiflash system on NP column) (Cyclohexane/ (EtOAc+EtOH 3:1) the title compound (19.5 g, 88% purity as determined by quant. NMR, 76% yield)

[0326] .sup.1H NMR (400 MHz,CDCl.sub.3) δ ppm: 8.72-8.69(m, 2H), 7.41(t, 0.6H, J=5.7), 7.22-7.18(m, 1H), 6.93(m, 0.4H,) 3.92-3.89(m, 2H), 3.54-3.41 (m, 2H), 2.68-2.65(m, 2H)

Example 16: Preparation of 3-[2-(2-Pyrimidin-2-Ylethylidene)Hydrazino]Propanenitrile From 2-Ethynylpyrimidine

[0327] ##STR00278##

[0328] A vial was charged with 2-ethynylpyrimidine (1000 mg, 9.42 mmol, 1.00 eq.) and THF (1.0 mL/g) and then the resulting solution was heated to 50° C. under nitrogen atmosphere. A solution of 3-hydrazinopropanenitrile (900 mg, 1.1 eq.) in THF (1.0 mL/g) was added at 50° C. dropwise over 15 min then the reaction was stirred for 1h at 50° C. The solvent was then removed in vacuo to give the title compound as a brown oil (1650 mg, 68% purity as determined by quant. 1H NMR using mesitylene as internal standard, 61% yield. 50/50 mixture of E/Z hydrazone isomers).

Example 17: Preparation of 3-(4-Pyridazin-3-Ylpyridazin-1-Ium-1-yl)Propanenitrile Trifluoroacetate Salt From 3-[2-(2-Pyridazin-3-Ylethylidene)Hydrazino]Propanenitrile and Glyoxal

[0329] ##STR00279##

[0330] 3-(2-pyridazin-3-ylethylidene)hydrazino]propanenitrile was prepared according to procedure described in Example 21.

[0331] A vial was charged with trifluoroacetic acid (0.63 mL, 1.70 mmol, 2.00 eq, 2.67 M in H.sub.2O), morpholinium acetate (106 mg, 0.72 mmol, 0.85 eq), glyoxal (618 mg, 4.25 mmol, 5.00 eq., 40% w/w in H.sub.2O) and caffeine (0.85 mL, 0.085 mmol, 0.10 eq, 0.099 M in H.sub.2O). 3-[2-(2-pyrimidin-2-ylethylidene)hydrazino]propanenitrile ( 187 mg, 0.85 mmol, 86% purity) was next added. The vial was then sealed and stirred at room temperature for 24 h. After 24 h, 0.1 mL of the reaction mixture was sampled and diluted in D.sub.2O (0.5 ml) and analyzed by quantitative 1H NMR, indicating the title compound had been formed in 60% chemical yield.

[0332] 1H NMR (400 MHz, D.sub.2O) δ ppm: 10.18(s, 1H), 9.88(d, 1H, J=6.2 Hz), 9.32(d, 1H, 5.1 Hz), 9.16(dd, 1H, J=6.4, J=2.4 Hz), 8.52(d, 1H, J=8.8 Hz), 8.01-7.98,(m, 1H), 5.19(t, 2H, J=6.2 Hz), 3.37(t, 2H, 6.2 Hz)

Example 18: Preparation of 3-(4-Pyridazin-3-Ylpyridazin-1-Ium-1-yl)Propanenitrile Trifluoroacetate Salt From 3-[2-(2-Pyridazin-3-Ylethylidene)Hydrazino]Propanenitrile and 2,2-Dimethoxyacetaldehyde

[0333] ##STR00280##

[0334] 3-(2-pyridazin-3-ylethylidene)hydrazino]propanenitrile was prepared according to procedure described in Example 21.

[0335] A vial was charged with trifluoroacetic acid (0.63 mL, 1.70 mmol, 2.00 eq, 2.67 M in H.sub.2O), morpholinium acetate (106 mg, 0.72 mmol, 0.85 eq), 2,2-dimethoxyacetaldehyde (736 mg, 4.25 mmol, 5.00 eq., 40% w/w in H.sub.2O) and caffeine (0.85 mL, 0.085 mmol, 0.10 eq, 0.099 M in H.sub.2O). 3-[2-(2-pyrimidin-2-ylethylidene)hydrazino]propanenitrile ( 187 mg, 0.85 mmol, 86% purity) was next added. The vial was then sealed and stirred at room temperature for 24 h. After 24 h, 0.1 mL of the reaction mixture was sampled and diluted in D.sub.2O (0.5 ml) and analyzed by quantitative 1H NMR, indicating the title compound had been formed in 12% chemical yield.

[0336] 1H NMR (400 MHz, D.sub.2O) δ ppm: 10.18(s, 1H), 9.88(d, 1H, J=6.2 Hz), 9.32(d, 1H, 5.1 Hz), 9.16(dd, 1H, J=6.4, J=2.4 Hz), 8.52(d, 1H, J=8.8 Hz), 8.01-7.98,(m, 1H), 5.19(t, 2H, J=6.2 Hz), 3.37(t, 2H, 6.2 Hz)

Example 19: Preparation of 3-(4-Pyrimidin-2-Ylpyridazin-1-Ium-1-yl)Propanenitrile Trifluoroacetate Salt From 3-[2-(2-Pyrimidin-2-Ylethylidene)Hydrazino]Propanenitrile and 1,4-Dioxane-2,3-Diol

[0337] ##STR00281##

[0338] 3-(2-pyridazin-3-ylethylidene)hydrazino]propanenitrile was prepared according to procedure described in Example 21.

[0339] A vial was charged with trifluoroacetic acid (0.63 mL, 1.70 mmol, 2.00 eq, 2.67 M in H.sub.2O), morpholinium acetate (106 mg, 0.72 mmol, 0.85 eq), 1,4-dioxane-2,3-diol (510 mg, 4.25 mmol, 5.00 eq., 40% w/w in H.sub.2O) and caffeine (0.85 mL, 0.085 mmol, 0.10 eq, 0.099 M in H.sub.2O). 3-[2-(2-pyrimidin-2-ylethylidene)hydrazino]propanenitrile ( 187 mg, 0.85 mmol, 86% purity) was next added. The vial was then sealed and stirred at room temperature for 24 h. After 24 h, 0.1 mL of the reaction mixture was sampled and diluted in D.sub.2O (0.5 ml) and analyzed by quantitative 1H NMR, indicating the title compound had been formed in 56% chemical yield.

[0340] 1H NMR (400 MHz, D.sub.2O) δ ppm: 10.18(s, 1H), 9.88(d, 2H, J=6.2 Hz), 9.32(d, 1H, 5.1 Hz, 9.16(dd, 1H, J=6.4, J=2.4 Hz), 8.52(d, 1H, J=8.8 Hz), 8.01-7.98,(m, 1H), 5.19(t, 2H, J=6.2 Hz), 3.37(t, 6.2 Hz)

Example 20: Preparation of Tert-Butyl 3-[2-(2-Pyridazin-3-Ylethylidene)Hydrazino]Propanoate From 3-[2-Pyrrolidin-1-Ylvinyllpyridazine

[0341] ##STR00282##

[0342] A vial was charged was charged with 3-[2-pyrrolidin-1-ylvinyl]pyridazine (5.0 g, 2.7 mmol, 1.0 eq.) and t-Butyl 3-hydrazino propanoate (6.09 g g, 35.7 mmol, 1.3 eq.). The neat reaction mixture was warmed to 100° C. and set under a flow of argon for 2 h. The reaction mixture was next put under high vacuum (1 mbar) to remove the pyrrolidine. The desired compound was obtained as a mixture of E/Z compound in 79% of yield (purity=68%, quantitative 1H NMR, Trimethoxybenzene as standard)

[0343] Work up: no work up. Used as such in the same time.

[0344] NMR data: 1H NMR (400 MHz, METHANOL-d4) δ ppm: 9.11-9.07(m, 1H), 7.70-7.68(m, 2H), 7.28(t, J=5.3 Hz, 0.75H), 6.72(t, J=5.2 Hz, 0.25H), 3.88-3.85(m, 2H), 3.42(t, J=6.8 Hz, 0.5H), 3.29(t, J=6.6 Hz, 1.5H), 2.53-2.45(m, 2H), 1.46(m, 9H)

Example 21: Preparation of 3-[2-(2-Pyridazin-3-Ylethylidene)Hydrazino]Propanenitrile From 3-[2-Pyrrolidin-1-Ylvinyllpyridazine

[0345] ##STR00283##

Procedure 1

[0346] 3-hydrazinopropanenitrile (5.28 g, 1.15 equiv., 62 mmol) was dissolved in water (10 mL). H.sub.2SO.sub.4 (2.88 g, 0.53 eq., 28.73 mmol) was then added dropwise to control the strong exotherm. Isobutyronitrile (50 mL, 10 eq., 550 mmol) was next added followed by 3-[2-pyrrolidin-1-ylvinyl]pyridazine (10.0 g, 54 mmol, 1.00 eq. 95% purity). The reaction mixture was stirred at rt for 1 hour. Reaction control (1H NMR) indicated ~92% conversion.

[0347] The reaction was then poured into a separating funnel and phases were separated. The organic phase was evaporated in vacuo (first at 90 mbar then at 25 mbar for 45 minutes). The title product was obtained as a deep red brown oil. (8.2 g, 86% purity as determined by quant. 1H NMR using trimethoxybenzene as an internal standard, 68% yield)

[0348] NMR data (mixture of isomers): 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.14-9.09 (m, 1H), 7.65-7.56(m, 2H), 7.25(t, J=5.5 Hz, 0.81H), 6.82(t, J=5.7 Hz, 0.1H), 3.92(d, J=5.5 Hz, 1.5H), 3.81-3.79(m, 2H), 3.25-3.29(m, 0.5H), 3.22-3.18 (m, 1.5 H), 2.70 (t, J=6.6 Hz, 0.5H), 2.63(t, J=6.6 Hz, 1.5H)

Procedure 2

[0349] 3-pyrrolidin-1-ylvinyl]pyridazine (10.0 g, 54 mmol, 1.00 eq. 95% purity) was dissolved in THF (140 mL) and 3-hydrazinopropanenitrile (10.23 g, 2.00 equiv., 114 mmol) was added in one portion at room temperature. To this solution was added dropwise via a dropping funnel trifluoroacetic acid (4.44 mL, 54 mmol, 1.00 eq.) while maintaining the internal temperature below 26° C. The reaction mixture was then stirred at rt for 1 hour. The reaction mixture was concentrated in vacuo to give the title product as yellow oil as E/Zmixture( 75:25, unassigned) (27.0 g, 36% purity as determined by quant. 1H NMR using trimethoxy benzene as an internal standard, 93% yield)

[0350] NMR data: 1H NMR (400 MHz, CDCl3) δ ppm: 9.12-9.10( m, 1H), 7.50-7.41(m, 2H), 7.35(t, J=5.5 Hz, 0.75H), 6.83(t, J=5.7 Hz, 0.25H), 3.92(d, J=5.5 Hz, 1.5H), 3.85(d, J=5.9 Hz, 0.25H), 3.53-3.40(m, 2H), 2.67-2.63(m, 2H)

Procedure 3

[0351] A 500 mL 3-Neck Round-bottom flask equipped with a 15 cm Vigreux column, a thermometer and a magnetic stirring bar was charged with 3-[2-pyrrolidin-1-ylvinyl]pyridazine (50.0 g, 0.283 mol), 3-hydrazinopropanenitrile (26.8 g, 0.309 mol) and 3-Methyl-1-butanol (102 g). Volatiles (a mixture of pyrrolidine and 3-methyl-1-butanol) were slowly distilled off at 40-45° C. (internal temperature) under vacuum (10-14 mbar) during 5 h. To the remaining residue more 3-Methyl-1-butanol (20 g) was added and the distillation was continued for 1 h under the same conditions. The conversion was monitored by NMR. The remaining residue was dried under full vacuum at 60° C. (jacket temperature)

[0352] The title compound (final residue) was obtained in 94 % yield as a brown oil (58.8 g, mixture of E/Z isomers, 86.2% purity as determined by quantitative 1H NMR in DMSO-d6 using Diethylene glycol diethyl ether as standard)

[0353] NMR data (mixture of isomers): 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.13-9.09 (m, 1H), 7.65-7.55 (m, 2H), 7.25 (t, J=5.5 Hz, 0.75H), 6.83 (m, 1H), 6.62 (td, J=5.1 Hz, J=1.3 Hz, 0.25H), 3.81-3.78 (m, 2H), 3.35-3.30 (m, 0.5H), 3.23-3.18 (m, 1.5 H), 2.69 (t, J=6.6 Hz, 0.5H), 2.63 (t, J=6.6 Hz, 1.5H)

Example 22: Preparation 3-Hydrazinopropanoic Acid (Aqueous Solution of Its Sodium Salt)

[0354] ##STR00284##

[0355] A 20 mL vial was charged with 3-hydrazinopropanenitrile (2.00 g, 22.8 mmol) and 30% aqueous sodium hydroxide solution (3.65 g, 27.4 mmol, 1.2 eq.). The mixture was slowly heated to 70° C. When the gas evolution ceased, the mixture was heated to 110° C. and stirred at this temperature for 1 h. After cooling to room temperature, the pH of the reaction mixture was adjusted to 10.0 with 20% sulfuric acid (2.19 g, 0.20 eq). The resulting solution was concentrated by rotary evaporation to result in the title compound as a turbid pale yellow viscous oil in 77% yield. (purity=47% as for free acid, quantitative 1H NMR in D20 with Diethylene glycol diethyl ether as standard; contains sodium sulfate and the residual amount of water).

[0356] NMR data: 1H NMR (400 MHz, D.sub.2O) δ ppm: 2.98 (t, J=7.2 Hz, 2H), 2.40 (t, J=7.2 Hz, 2H). H.sub.2N-NH- protons are not visible because of H/D exchange.

Example 23: Preparation 3-[2-(2-Pyridazin-3-Ylethylidene)Hydrazino]Propanoic Acid (Sodium Salt)

[0357] ##STR00285##

[0358] A small round-bottom flask was charged with 3-[2-pyrrolidin-1-ylvinyl]pyridazine (0.241 g, 1.36 mmol), 3-hydrazinopropanoic acid (sodium salt) from the previous example (0.346 g, 1.56 mmol, 1.15 eq.) and water (2 mL). The resulting solution was slowly concentrated by rotary evaporation (30° C., 30 mbar). Water (2 mL) was added to the residue and the resulting solution was concentrated again. This procedure was repeated 3 more times. The desired compound (final residue) was obtained as a mixture of E/Z isomers in 88% yield (purity=40.3% as for free acid, quantitative 1H NMR in D.sub.2O with Diethylene glycol diethyl ether as standard)

[0359] NMR data: 1H NMR (400 MHz, D.sub.2O) δ ppm: 9.13-9.09 (m, 1H), 7.82-7.74 (m, 2H), 7.48 and 6.96 (m, together 1H), 3.94 and 3.92 (d, J=5.5 Hz, <2H due to fast H/D exchange at this position), 3.40 and 3.27 (t, J=7.0 Hz, together 2H), 2.47 and 2.42 (t, J=7.0 Hz, together 2H). NH proton is not visible because of H/D exchange.

Example 24: Preparation of 3-(4-Pyridazin-3-Ylpyridazin-1-Ium-1-yl)Propanoic Acid

Hydrogenosulfate Salt

[0360] ##STR00286##

[0361] To a round bottom flask containing 3-[2-(2-pyridazin-3-ylethylidene)hydrazino]propanoic acid (0.607 g, 1.18 mmol, purity 40.3%, sodium salt) was added a mixture of KHSO.sub.4 (0.404 g, 2.97 mmol, 2.5 eq.) and glyoxal (738 mg, 5.09 mmol, 4.3 eq., 40% w/w in H.sub.2O) in one portion. The mixture was stirred at 40° C. for 2 h. The reaction mixture was sampled and analyzed by quantitative 1H NMR (in D20 with Diethylene glycol diethyl ether as standard), indicating the title compound had been formed in 17% chemical yield.

[0362] NMR data: .sup.1H NMR (400 MHz, D.sub.2O) δ ppm: 10.23 (d, J=2.6 Hz, 1H), 10.00 (d, J=6.3 Hz, 1H), 9.45 (dd, J=5.1 Hz, 1.5 Hz, 1H), 9.23 (dd, J=6.3 Hz, 2.6 Hz, 1H), 8.63 (dd, J=8.7 Hz, 1.5 Hz, 1H), 8.12 (dd, J=8.7 Hz, 5.1 Hz, 1H), 5.24 (t, J=6.2 Hz, 2H), 3.34 (t, J=6.2 Hz, 2H).

Example 25: Preparation of 2-[(2-Pyrrolidin-1-Ylvinyl]Pyrimidine

[0363] ##STR00287##

[0364] A mixture of 2-methyl-pyrimidine (10 g, 0.1063 mol), pyrrolidine (15.2 g, 0.2125 mol) and N,N-dimethylformamide dimethyl acetal (26.1 g, 0.2125 mol) was heated at 87° C. (internal temperature) for 15 h. After cooling down to room temperature, the mixture was concentrated under vacuum to give a yellowish solid. 300 ml of tButyl-methyl-ether were added to this solid, and it was dissolved at reflux. The solution was then cooled down to 0° C., stirred for 20 minutes, the solid was filtered, washed once with cold tButyl-methyl-ether, collected and dried under high vacuum. 12.3 g of 2-[(E)-2-pyrrolidin-1-ylvinyl] pyrimidine, a white solid, pure at 97%w/w as measured by Quantitative NMR was obtained. The filtrate was concentrated under vacuum and 200ml of tButyl-methyl-ether was added. After full dissolution was achieved at reflux, the solution was then cooled down to 0° C., stirred for 20 minutes, the solid was filtered, washed once with cold tButyl-methyl-ether, collected and dried under high vacuum. 4.7 g of 2-[2-pyrrolidin-1-ylvinyl]pyrimidine, a white solid, pure at 94%w/w as measured by Quantitative NMR was obtained. The two batches were combined to deliver 17 g of the title compound, pure at 96%w/w (84.1 % yield).

[0365] 1H NMR (400 MHz, CDCl3) δ ppm 1.85 - 2.05 (m, 4 H) 3.28 - 3.44 (m, 4 H) 5.25 (d, 1 H) 6.67 (t, 1 H) 7.99 (d, 1 H) 8.38 (d, 2H).

Example 26: Preparation of 4-[2-Pyrimidin-2-Ylvinyl]Morpholine

[0366] ##STR00288##

[0367] A mixture of 2-ethynylpyrimidine (0.25 g, 2.33 mmol) and morpholine (0.43 g, 4.89 mmol) was heated at 100° C. for 20 minutes. The mixture was then cooled down to room temperature and concentrated under vacuum. The crude title compound was obtained as an orange oil which solidified on standing (0.553 g) with a purity of 75%w/w as measured by Quantitative NMR. Most of the contaminant was residual morpholine.

[0368] 1H NMR (400 MHz, CDCl3) δ ppm 3.23 - 3.33 (m, 4 H) 3.74 - 3.79 (m, 4 H) 5.49 (d, J=13.57 Hz, 1 H) 6.78 (t, J=4.95 Hz, 1 H) 7.66 (d, J=13.20 Hz, 1 H) 8.44 (d, J=4.77 Hz, 2 H)

Example 27: Preparation of 2-[2-(1-Piperidyl)Vinyl]Pyrimidine

[0369] ##STR00289##

[0370] A mixture of 2-ethynylpyrimidine (0.25 g, 2.33 mmol) and piperidine (4.89 mmol) was heated at 100° C. for 20 minutes. The mixture was then cooled down to room temperature and concentrated under vacuum. The crude title compound was obtained.

[0371] 1H-NMR (400 MHz, THF-d8) δ ppm 8.37 (d, J=4.77 Hz, 2 H), 7.76 (d, J=13.57 Hz, 1 H), 6.70 (t, J=4.77 Hz, 1 H), 5.43 (d, J=13.20 Hz, 1 H), 3.19 - 3.30 (m, 4 H), 1.56 - 1.67 (m, 6 H)

Example 28: Preparation of 3-[2-Pyrrolidin-1-Ylvinyl]Pyridazine From 3-Methylpyridazine, Triethyl Orthoformate and Pyrrolidine in the Presence of 2,6-Di-Tert-Butyl-4-Methylphenol as Catalyst

[0372] ##STR00290##

[0373] A 10 mL-microwave vial was charged with 3-methlypyridazine (0.55 g, 5.7 mmol), pyrrolidine (0.51 g, 7.2 mmol), triethyl orthoformate (1.14 g, 7.6 mmol) and 2,6-Di-tert-butyl-4-methylphenol (22 mg, 0.10 mmol, 2 mol%). The mixture was heated under stirring in a microwave reactor at 190° C. for 12 h. After cooling to room temperature, the reaction mixture was weighted, sampled and analyzed by quantitative 1H NMR (in DMSO-d6 with 1,3,5-trimethoxybenzene as standard), indicating the title compound had been formed in 55% chemical yield or 95% chemical yield based on converted starting material (58% conversion).

[0374] NMR data: 1H NMR (400 MHz, CDCl3) δ ppm: 8.60 (dd, J=4.6 Hz, 1.7 Hz, 1H), 7.80 (d, J=13.5 Hz, 1H), 7.31-7.23 (m, 2H), 5.10 (d, J=13.5 Hz, 1H), 3.28 (m, 4H), 1.88 (m, 4H).

Example 29: Preparation of 3-[2-Pyrrolidin-1-Ylvinyl]Pyridazine From 3-Methylpyridazine, Trimethyl Orthoformate and Pyrrolidine in the Presence of 2,6-Di-Tert-Butyl-4-Methylphenol As Catalyst

[0375] ##STR00291##

[0376] A 10 mL- microwave vial was charge with 3-methlypyridazine (0.97 g, 10 mmol), pyrrolidine (0.85 g, 12 mmol), trimethyl orthoformate (1.61 g, 15 mmol) and 2,6-Di-tert-butyl-4-methylphenol (45 mg, 0.20 mmol, 2 mol%). The mixture was heated under stirring in a microwave reactor at 200° C. for 9 h. After cooling to room temperature, the reaction mixture was weighted, sampled and analyzed by quantitative 1H NMR (in DMSO-d6 with 1,3,5-trimethoxybenzene as standard), indicating the title compound had been formed in 33% chemical yield or quantitative chemical yield based on converted starting material (33% conversion).

[0377] NMR data: 1H NMR (400 MHz, CDCl3) δ ppm: 8.60 (dd, J=4.6 Hz, 1.7 Hz, 1H), 7.80 (d, J=13.5 Hz, 1H), 7.31-7.23 (m, 2H), 5.10 (d, J=13.5 Hz, 1H), 3.28 (m, 4H), 1.88 (m, 4H).

Example 30: Preparation of 2-[2-Pyrrolidin-1-Ylvinyl]Pyrimidine From 2-Methylpyrimidine, Triethyl Orthoformate and Pyrrolidine in the Presence of 2,6-Di-Tert-Butyl-4-Methylphenol as Catalyst

[0378] ##STR00292##

[0379] A 10 mL- microwave vial was charge with 2-methylpyrimidine (0.94 g, 10 mmol), pyrrolidine (0.85 g, 12 mmol), triethyl orthoformate (2.25 g, 15 mmol) and 2,6-Di-tert-butyl-4-methylphenol (45 mg, 0.20 mmol, 2 mol%). The mixture was heated under stirring in a microwave reactor at 220° C. for 4 h. After cooling to room temperature, the reaction mixture was weighted, sampled and analyzed by quantitative 1H NMR (in DMSO-d6 with 1,3,5-trimethoxybenzene as standard), indicating the title compound had been formed in 39% chemical yield or quantitative chemical yield based on converted starting material (39% conversion).

[0380] NMR data: 1H NMR (400 MHz, CDCl3) δ ppm: 8.34 (d, J=4.8 Hz, 2H), 7.91 (d, J=13.1 Hz, 1H), 6.75 (t, J=4.8 Hz, 1H), 5.04 (d, J=13.1 Hz, 1H), 3.28 (m, 4H), 1.88 (m, 4H).

Example 31: Preparation of 3-(4-Pyridazin-3-Ylpyridazin-1-Ium-1-yl)Propanenitrile Chloride Salt From 3-[2-(2-Pyridazin-3-Ylethylidene)Hydrazino]Propanenitrile and Glyoxal in the Presence of ZrOCl.SUB.2.*8H.SUB.2.O

[0381] ##STR00293##

Glyoxal (38.4 G, 0.265 Mol, 2.0 Eq., 40% W/w in H.SUB.2.O) and Hydrochloric Acid (18.1 g, 0.159, 1.2 eq. 32% w/w in H.SUB.2.O) Were Mixed (Solution 1)

3-(2-Pyridazin-3-Ylethylidene)Hydrazino]Propanenitrile (29.0 G, 0.132 Mol, 86.2%) and Methanol (17.0 g, 4.0 eq.) Were Mixed (Solution 2)

[0382] Solution 1 (11.3 g, 20% of the total amount) and Zirconium(IV) oxychloride octahydrate (4.35 g, 13 mmol, 10 mol%) were charged in a flask and the resulting solution was cooled to 0° C. Methanol (4.24 g, 1 eq.) was added and the mixture was stirred at 0-5° C. for 10 min

[0383] Solution 1 and solution 2 were dosed in parallel within 1 h while keeping the temperature at 0-5° C. After the end of addition, the reaction mixture was stirred for 1 h at 0-5° C. then for 2 h at room temperature. Water (33 ml) was added and methanol was distilled off in vacuum (100 .fwdarw. 25 mbar) at 45° C. (external temperature). 3-Methyl-1-butanol (67 mL) was added and the mixture was stirred at 45° C. for 1h. The phases were separated, and the aqueous phase was stirred again with fresh 3-Methyl-1-Butanol (67 mL) at 45° C. for 1 h. The phases were separated and the aqueous phase was concentrated to dryness by rotary evaporation to result in the title compound as an black-brown amorphous (glass-like) solid in 79% yield (42.9 g, purity=60%, quantitative 1H NMR in D.sub.2O with 1-Methyl-2-pyridone as standard).

[0384] NMR data: .sup.1H NMR (400 MHz, D.sub.2O) δ ppm: 10.26 (d, J=2.6 Hz, 1H), 10.03 (d, J=6.3 Hz, 1H), 9.38 (dd, J=5.1 Hz, 1.5 Hz, 1H), 9.27 (dd, J=6.3 Hz, 2.6 Hz, 1H), 8.60 (dd, J=8.7 Hz, 1.5 Hz, 1H), 8.07 (dd, J=8.7 Hz, 5.1 Hz, 1H), 5.32 (t, J=6.2 Hz, 2H), 3.49 (t, J=6.2 Hz, 2H).

Example 32: Preparation of 3-(4-Pyridazin-3-Ylpyridazin-1-Ium-1-yl)Propanenitrile Chloride Salt From 3-[2-(2-Pyridazin-3-Ylethylidene)Hydrazino]Propanenitrile and Glyoxal in the Presence of Sc(OTf)3

[0385] ##STR00294##

[0386] A 10 mL vial was charged with glyoxal (1.26 g, 8.72 mmol, 2.0 eq., 40% w/w in H.sub.2O), hydrochloric acid (139 mg, 1.22 mmol, 1.2 eq. 32% w/w in H.sub.2O) and Scandium(III) trifluoromethanesulfonate (254 mg, 0.52 mmol, 0.5 eq.). 3-[2-(2-Pyridazin-3-ylethylidene)hydrazino]propanenitrile (247 mg, 1.04 mmol, 80%) was added in a single portion and the resulting mixture was stirred at 45° C. for 2 h. The reaction mixture was sampled and analyzed by quantitative 1H NMR (in D.sub.2O with Diethylene glycol diethyl ether as standard), indicating the title compound had been formed in 70% chemical yield. NMR data: .sup.1H NMR (400 MHz, D.sub.2O) δ ppm: 10.26 (d, J=2.6 Hz, 1H), 9.98 (d, J=6.3 Hz, 1H), 9.41 (dd, J=5.1 Hz, 1.5 Hz, 1H), 9.25 (dd, J=6.3 Hz, 2.6 Hz, 1H), 8.60 (dd, J=8.7 Hz, 1.5 Hz, 1H), 8.07 (dd, J=8.7 Hz, 5.1 Hz, 1H), 5.28 (t, J=6.2 Hz, 2H), 3.47 (t, J=6.2 Hz, 2H).

Example 33: Preparation of 3-(4-Pyridazin-3-Ylpyridazin-1-Ium-1-yl)Propanoic Acid Chloride Salt From 3-(4-Pyridazin-3-Ylpyridazin-1-Ium-1-yl)Propanenitrile Chloride Salt

[0387] ##STR00295##

[0388] 3-pyridazin-3-ylpyridazin-1-ium-1-yl)propanenitrile chloride salt (17.9 g, 40.4 mmol, 55.8%) was stirred with hydrochloric acid (46.0 g, 0.404 mol, 10 eq, 32% w/w in H.sub.2O) at 80° C. for 2.5 h. Water (31 g) was added and volatiles (HCl/Water azeotrope) were removed by rotary evaporation at 55° C. To remove excessive HCI as well as water, propionic acid (15.5 g) was added to the residue and the resulting mixture was evaporated to dryness to result in crude product as a black amorphous (glass-like) solid in 96% yield (24.9 g, purity=41.4%, quantitative 1H NMR in D.sub.2O with 1-Methyl-2-pyridone as standard).

[0389] NMR data: .sup.1H NMR (400 MHz, D.sub.2O) δ ppm: 10.13 (d, J=2.4 Hz, 1H), 9.95 (d, J=6.3 Hz, 1H), 9.34 (dd, J=5.1 Hz, 1.5 Hz, 1H), 9.15 (dd, J=6.3 Hz, 2.6 Hz, 1H), 8.57 (dd, J=8.7 Hz, 1.5 Hz, 1H), 8.04 (dd, J=8.7 Hz, 5.1 Hz, 1H), 5.18 (t, J=6.1 Hz, 2H), 3.29 (t, J=6.1 Hz, 2H).

Example 34: Preparation of 3-(4-Pyrimidin-2-Ylpyridazin-1-Ium-1-yl)Propanenitrile Chloride Salt From 3-[2-(2-Pyrimidin-2-Ylethylidene)Hydrazino]Propanenitrile and Glyoxal in the Presence of ZrOCl.SUB.2.*8H.SUB.2.O

[0390] ##STR00296##

[0391] A 10 mL vial was charged with glyoxal (0.579 g, 3.99 mmol, 2.0 eq., 40% w/w in H.sub.2O), hydrochloric acid (0.274 g, 2.40 mmol, 1.2 eq. 32% w/w in H.sub.2O), Zirconium(IV) oxychloride octahydrate (66 mg, 0.20 mmol, 10 mol%) and Methanol (1.6 mL). 3-[2-(2-pyrimidin-2-ylethylidene)hydrazino]propanenitrile (0.50 g, 1.98 mmol, 69.5%) was added in a single portion and the reaction mixture was stirred for 4 h at 0-5° C. then for 2 h at room temperature. The reaction mixture was sampled and analyzed by quantitative 1H NMR (in D.sub.2O with Diethylene glycol diethyl ether as standard), indicating the title compound had been formed in 85% chemical yield.

[0392] 3-Methyl-1-butanol (2 mL) was added and the mixture was stirred at 45° C. for 30 min. During this time precipitation of the title compound was observed. After cooling to room temperature, the mixture was filtered. The brown solid (0.50 g) was analyzed by quantitative 1H NMR (in D.sub.2O with Diethylene glycol diethyl ether as standard), indicating the following composition: 46% 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanenitrile chloride salt, 25% 3-Methyl-1-butanol and water.

[0393] NMR data: .sup.1H NMR (400 MHz, D.sub.2O) δ ppm: 10.36 (d, J=2.1 Hz, 1H), 10.01 (d, J=6.2 Hz, 1H), 9.37 (dd, J=6.2 Hz, 2.1 Hz, 1H), 9.12 (d, J=5.0 Hz, 2H), 7.77 (t, J=5.0 Hz, 1H), 5.31 (t, J=6.3 Hz, 2H), 3.50 (t, J=6.3 Hz, 2H).

Example 35: Preparation of 3-(4-Pyrimidin-2-Ylpyridazin-1-Ium-1-yl)Propanoic Acid Chloride Salt From 3-(4-Pyrimidin-2-Ylpyridazin-1-Ium-1-yl)Propanenitrile Chloride Salt

[0394] ##STR00297##

[0395] 3-Pyrimidin-2-ylpyridazin-1-ium-1-yl)propanenitrile chloride salt (1.66 g, 4.19 mmol, 62.5%) was stirred with hydrochloric acid (4.67 g, 25.6 mmol, 6 eq, 20% w/w in H.sub.2O) at 110° C. for 9 h. After cooling to room temperature, the reaction mixture was concentrated to dryness by rotary evaporation to result in crude product as a brown-black solid in 70% yield (1.78 g, purity=43.7%, quantitative 1H NMR in D.sub.2O with Diethylene glycol diethyl ether as standard).

[0396] NMR data: .sup.1H NMR (400 MHz, D.sub.2O) δ ppm: 10.14 (d, J=2.1 Hz, 1H), 9.84 (d, J=6.2 Hz, 1H), 9.17 (dd, J=6.2 Hz, 2.1 Hz, 1H), 8.98 (d, J=5.0 Hz, 2H), 7.63 (t, J=5.0 Hz, 1H), 5.10 (t, J=6.1 Hz, 2H), 3.23 (t, J=6.1 Hz, 2H).

Example 36: Preparation of 3-(4-Pyrimidin-4-Ylpyridazin-1-Ium-1-yl)Propanenitrile Chloride Salt From 3-[2-(2-Pyrimidin-4-Ylethylidene)Hydrazino]Propanenitrile

[0397] ##STR00298##

Zirconium(IV) Oxychloride Octahydrate (0.317 G, 0.966 Mmol, 10 Mol%) Was Added to a Flask, Followed by Glyoxal (2.8 g, 19.3 Mmol, 2.0 Eq., 40% w/w in H.SUB.2.O) and Hydrochloric Acid (1.36 g, 13 Mmol, 1.35 Eq. 35% w/w in H.SUB.2.O) were Mixed (Solution 1)

3-(2-Pyrimidin-4-Ylethylidene)Hydrazino]Propanenitrile (3.0 G, 9.66 Mmol, 60.9%) and Methanol (4.7 G, 15.5 Eq.) were Mixed (Solution 2)

[0398] Solution 1 was cooled to 0° C. Methanol (1.56 g, 5 eq.) was dosed to solution 1 over 30 min and then mixture was stirred at 0-5° C. for 30 min.

[0399] Solution 2 was dosed to solution 1 over a period of 2 h while keeping the temperature at 0-5° C. After the end of addition, the reaction mixture was stirred for 1 h at 0-5° C. Acetonitrile (45 mL) was added and a suspension was observed. The mixture was filtered and the solid washed twice with acetonitrile (2 × 50 mL). The filtrate was concentrated under reduced pressure to obtain a brown solid. The solid was dissolved by adding water (20 mL) and extracting with ethyl acetate (4 × 100 mL). The aqueous phase was concentrated to dryness by rotary evaporation to result in the title compound as a black-brown solid in 69% yield (2.61 g, purity=63.1%, quantitative .sup.1H NMR in DMSO-d6 with two drops of D.sub.2O with maleic acid as standard).

[0400] NMR data: .sup.1H NMR (400 MHz, DMSO-d6) δ ppm: 10.29 (d, J=2.06 Hz, 1 H), 10.14 (d, J=6.19 Hz, 1 H), 9.51 (s, 1 H), 9.37 (dd, J=6.19, 2.38 Hz, 1 H), 9.19 (br d, J=5.08 Hz, 1 H), 8.54 (d, J=4.44 Hz, 1 H), 5.21 (t, J=6.34 Hz, 2 H), 3.41 (t, J=6.34 Hz, 2 H).

Example 37: Preparation of 3-[2-(2-Pyrimidin-4-Ylethylidene)Hydrazino]Propanenitrile From 4-[2-Pyrrolidin-1-Ylvinyllpyrimidine

[0401] ##STR00299##

[0402] 4-pyrrolidin-1-ylvinyl]pyrimidine (5.0 g, 27.1 mmol, 1.00 eq., 95% purity) was added to a solution of 3-hydrazinopropanenitrile (3.65 g, 42.8 mmol, 1.58 eq.) in ethanol (50 mL) cooled at 0-5° C. Next, trifluoroacetic acid (3.12 g, 27.1 mmol, 1.0 eq., 2.11 mL) was added dropwise to the above reaction mixture while maintaining the temperature below 10° C. After two hours, the mixture was concentrated in vacuo and purified over neutral alumina (0-4% MeOH in methyl tert-butyl ether) to obtain a yellow gum as an E/Z mixture (unassigned) in 47% yield (4.0 g, purity = 60.9%, quantitative 1H NMR in DMSO-d6 with 1,3,5-trimethoxybenzene as standard).

[0403] NMR data (mixture of E/Z-isomers): .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 9.16 - 9.06 (m, 0.75 H), 8.74 - 8.68 (m, 1 H), 7.51 - 7.40 (m, 1 H), 7.20 (t, J=5.55 Hz, 0.75 H), 6.89 (t, J=4.84 Hz, 1 H), 6.80 (br s, 0.25 H), 6.60 (td, J=5.04, 1.35 Hz, 0.25 H), 3.67 - 3.59 (m, 2 H), 3.35 - 3.25 (m, 0.5 H), 3.25 - 3.15 (m, 1.5 H), 2.74 - 2.61 (m, 2 H).

Example 38: Preparation of 4-[2-Pyrrolidin-1-Ylvinyl]Pyrimidine From 4-Methylpyrimidine

[0404] ##STR00300##

[0405] A 100 mL autoclave was charged with 4-methylpyrimidine (5 g, 52 mmol), pyrrolidine (1.9 g, 26 mmol, 0.5 eq.), triethyl orthoformate (6.3 g, 42 mmol, 0.8 eq.) and 2,6-Di-tert-butyl-4-methylphenol (230 mg, 1 mmol, 2 mol%). The mixture was heated at 155° C. for 4 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo and purified over silica gel (20-35% ethyl acetate in cyclohexane) to obtain a light yellow solid in 44% yield (3.0 g, purity = 68% based on quantitative .sup.1H NMR in DMSO-d6 with 1,3,5-trimethoxybenzene as standard).

[0406] NMR data: .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.58 (s, 1 H), 8.16 (d, J=5.62 Hz, 1 H), 8.00 (d, J=12.96 Hz, 1 H), 6.94 - 6.82 (m, 1 H), 4.95 (d, J=12.96 Hz, 1 H), 3.47 - 3.16 (m, 4 H), 1.87 (m, 4 H).

Example 39: Preparation of 3-(4-Pyrimidin-4-Ylpyridazin-1-Ium-1-yl)Propanoic Acid Chloride Salt From 3-(4-Pyrimidin-4-Ylpyridazin-1-Ium-1-yl)Propanenitrile Chloride Salt

[0407] ##STR00301##

[0408] 3-pyrimidin-4-ylpyridazin-1-ium-1-yl)propanenitrile chloride salt (1.58 g, 4.03 mmol, 63.1%) was stirred with hydrochloric acid (6.29 g, 60.4 mmol, 15 eq, 35% w/w in H.sub.2O) at 80° C. for 1 h. The reaction was cooled to room temperature to result in crude product in 88% yield (6.79 g, purity=14.1%, quantitative 1H NMR in D.sub.2O with maleic acid as standard).

[0409] NMR data: .sup.1H NMR (400 MHz, D.sub.2O) δ ppm: 9.92 (d, J=2.06 Hz, 1 H), 9.75 (d, J=6.19 Hz, 1 H), 9.28 (s, 1 H), 8.99 (dd, J=6.27, 2.46 Hz, 1 H), 8.96 (d, J=5.55 Hz, 1 H), 8.30 (dd, J=5.71, 1.27 Hz, 1 H), 4.95 (t, J=6.03 Hz, 2 H), 3.03 - 3.11 (m, 2 H).