MULTIPLEX SYNTHESIS METHOD OF COMPOUND LIBRARY AND PARALLEL SYNTHESIZER OF COMPOUND LIBRARY USING SAME

Abstract

The present invention relates to a parallel synthesis method and synthesizer of a compound library, and more specifically provides a parallel synthesis method and synthesizer of a compound library, which uniformly distribute a first reactant and perform independent reactions in separate spaces, and since it is possible to confirm the results for various reaction variables at once, the synthesis time of the compound library can be reduced with a high synthesis yield of the product.

Claims

1. A parallel synthesis method of a compound library, comprising: a) introducing a first reactant at a controlled flow rate to be distributed into a plurality of accommodation spaces; b) introducing a second reactant into each of the plurality of accommodation spaces to mix with the first reactant; and c) after each independent chemical reaction is performed in the accommodating space, discharging the product of the chemical reaction through a discharge unit on one side of the accommodation space, wherein the temperature and time of the chemical reaction in the plurality of accommodation spaces can be independently controlled.

2. The parallel synthesis method of claim 1, wherein the first reactant of step a) is distributed in equal amounts into a plurality of accommodation spaces through a flow distributor.

3. The parallel synthesis method of claim 2, wherein the flow distributor comprises a baffle and a damper, and wherein the damper adjusts the flow rate of the first reactant using the baffle.

4. The parallel synthesis method of claim 1, wherein the first reactant is an aryldiazonium salt, and wherein the aryldiazonium salt comprises a cation represented by Chemical Formula 1 below: ##STR00021## In Chemical Formula 1 above, R is hydrogen, a hydroxyl group, an ether group, a halogen atom, a carbonyl group, a nitro group, a naphthyl group, a cyano group, an amino group, an amidino group, hydrazine, hydrazone, a carboxyl group, a sulfonic acid group, a phosphoric acid group, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 1 to 12 carbon atoms, an alkynyl group having 1 to 12 carbon atoms, an aryl group having 6 to 10 carbon atoms, or an arylalkyl group having 7 to 10 carbon atoms.

5. A parallel synthesizer of a compound library, comprising: a first inlet unit through which a first reactant is introduced and at least one inlet is formed; a flow distributor connected to the first inlet unit and distributing the introduced first reactant in equal amounts, and formed with a damper and a baffle; a plurality of ducts connected to the flow distributor and through which the distributed first reactant passes, respectively; a second inlet unit located at one side of the duct and formed with an inlet through which a second reactant is introduced; a plurality of reactors respectively connected to the duct and in which a product is generated by a chemical reaction of the first reactant and the second reactant transported through the duct; and a discharge unit formed on one side of the reactor to discharge the product, wherein the temperature and time of the chemical reaction can be independently controlled in each of the reactors.

6. The parallel synthesizer of claim 5, wherein the duct and the plurality of reactors are coiled capillaries.

7. The parallel synthesizer of claim 5, wherein the plurality of reactors can be independently controlled such that chemical reactions occur under different conditions.

8. The parallel synthesizer of claim 5, wherein the plurality of reactors comprise a temperature control unit.

9. The parallel synthesizer of claim 8, wherein the temperature control unit comprises a heating device or a cooling device.

10. The parallel synthesizer of claim 5, wherein the first inlet unit and the second inlet unit comprise a pump, and the pump introduces reactants into an inlet.

11. The parallel synthesizer of claim 10, wherein the pump is a syringe pump or a peristaltic pump.

12. The parallel synthesizer of claim 5, wherein the duct further comprises a peristaltic pump at a position connected to the flow distributor to control the residence time of a compound in the duct.

13. The parallel synthesizer of claim 5, wherein the first reactant is an aryldiazonium salt, and wherein the aryldiazonium salt comprises a cation represented by Chemical Formula 1 below: ##STR00022## In Chemical Formula 1 above, R is hydrogen, a hydroxyl group, an ether group, a halogen atom, a carbonyl group, a nitro group, a naphthyl group, a cyano group, an amino group, an amidino group, hydrazine, hydrazone, a carboxyl group, a sulfonic acid group, a phosphoric acid group, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 1 to 12 carbon atoms, an alkynyl group having 1 to 12 carbon atoms, an aryl group having 6 to 10 carbon atoms, or an arylalkyl group having 7 to 10 carbon atoms.

14. The parallel synthesizer of claim 5, wherein the duct has a higher hydraulic pressure than the reactor.

Description

DESCRIPTION OF DRAWINGS

[0047] FIG. 1 is an image schematically illustrating a reaction process according to an exemplary embodiment of the present invention.

[0048] FIG. 2 is a mimetic diagram comparing a known approach of a flow system and the flow parallel synthesis method according to an exemplary embodiment of the present invention.

[0049] FIGS. 3A and 3B are block diagrams of the parallel synthesizer according to the present invention.

[0050] FIGS. 4A and 4B are cross-sectional views of the parallel synthesizer according to the present invention.

[0051] FIG. 5A is a schematic diagram of the parallel synthesizer according to the flow of reactants, and FIG. 5B is an image of the parallel synthesizer according to an exemplary embodiment.

[0052] FIG. 6 is a graph showing the flow velocity in a discharge unit according to an exemplary embodiment of the present invention.

[0053] FIGS. 7A and 7B are images comparing the amounts of products synthesized by the parallel synthesizer.

[0054] FIGS. 8A, 8B and 8C are comparative graphs of the flow velocities appearing when a specific capillary is clogged according to an exemplary embodiment of the present invention.

[0055] FIG. 9 is a graph showing the flow velocities when the speed in a capillary is changed using a pump at a specific second inlet unit according to an exemplary embodiment of the present invention.

[0056] FIG. 10 is an IR photo image observed by varying the speed in each reactor.

[0057] FIGS. 11 and 12 are reaction mimetic diagrams of aryl diazonium salts.

[0058] FIG. 13 is a graph showing the synthesis yields of products according to reaction conditions when the parallel synthesizer is used according to an exemplary embodiment of the present invention.

[0059] FIG. 14 is a chart showing the products and synthesis yields according to the type of reactants.

[0060] FIGS. 15 to 58 show NMR results of each compound synthesized according to an exemplary embodiment of the present invention.

[0061] FIGS. 59A and 59B are comparative mimetic diagrams when the length and diameter of the duct are configured differently according to an exemplary embodiment of the present invention. FIG. 59A is a mimetic diagram when the duct is configured to have a length of 350 mm and a diameter of 0.75 mm, and FIG. 59B is a mimetic diagram when the duct is configured to have a length of 1,500 mm and a diameter of 0.375 mm.

[0062] FIGS. 60A and 60B are graphs comparing the average flow rate in each capillary when the length and diameter of the duct are configured differently according to an exemplary embodiment of the present invention. FIG. 60A is a graph when the duct is configured to have a length of 350 mm and a diameter of 0.75 mm, and FIG. 60B is a graph when the duct is configured to have a length of 1,500 mm and a diameter of 0.375 mm.

MODES OF THE INVENTION

[0063] The inventors of the present invention designed and developed the first flow parallel synthesizer in order to perform multiplex synthesis and optimization of complex libraries. In the present invention, numerical analysis and experimental verification were performed in order to confirm the reliable flow distribution performance of the flow parallel synthesizer in various flow velocities, concentrations, temperatures and clogging cases.

[0064] In addition, by using the synthesizer (platform), the present invention simultaneously optimized various aryl diazonium salt-based reactions on small-molecule building blocks in reaction parameters with well-controlled reaction times and concentrations. As a result, the aromatic substitution reaction (C—C, C—N, C—X and C—S bonds) and the azo-coupling reaction based on carbocycles and heterocycles were simultaneously screened for 96 different conditions, and as a result of selecting reaction variables, the optimal conditions were obtained within 1 hour. Based thereon, multiplex synthesis of 12×2 compounds was demonstrated on a single flow platform. From an academic and industrial point of view, particularly in the pharmaceutical field from laboratory to commercialization, the synthesizer of the present invention can minimize the time, labor and capital investment associated with hit-to-lead optimization success rates.

[0065] Hereinafter, the present invention will be described in detail through the Examples and Experimental Example.

Example 1

[0066] Experimental Method

[0067] All reagents and solvents were used as commercial grades. All reactions were performed in a flow parallel synthesizer or in a single capillary reactor. Parts for constructing the flow parallel synthesizer were purchased from IDEX Health & Science LCC. The tube connecting the pump and platform consisted of high-purity PFA and PTFE tubing ( 1/16′ O.D., 0.75 mm I.D.) and polyether ether ketone ¼ 4-28 nuts. Swagelok tube fittings (SS-100-1-1, SS-600-1-2, SS-100-3 and SS-100-9) were purchased from Swagelok. Stainless-steel capillaries of 1/16″ O.D and 0.75 mm I.D were connected to the main body of the distributor via Swagelok connectors. O-rings (SM9-4D, heat-resistant fluororubber, 8.5 pi O.D. and 1.5 mm thick) were purchased from Misumi Korea. Reagents were injected using SGE glass syringes (SGE Analytical Science) or PHD Ultra syringe pumps (Harvard Apparatus) equipped with constant flow gradient HPLC piston pumps (PrimeLine™ and Scientific Systems Inc.). For individual heating of the capillaries, the temperature system was configured as follows.

[0068] A k-type thermocouple from Omega Engineering Korea was connected to the NX2 PID (Proportional-Integral-Differential)-based temperature controller from HANYOUNG NUX, and the output value according to the current temperature of the capillary reactor was fed back. The output value was converted into a high-voltage current flowing into a cartridge-type rod heater from Super Heat by WYU-DG 25 SI, which is a thyristor power regulator from Woonyoung Co., Ltd. All reactions were monitored by thin layer chromatography (TLC) on Merck silica gel 60-F254-coated 0.25 mm plates detected by UV. Flash chromatography was performed on silica gel (particle size 0.064 to 0.210 mm) with the indicated solvents. The reported yields were for isolated and spectroscopically pure compounds. 1H and 13C NMR spectra were recorded on Bruker-500 MHz and Bruker-300 MHz instruments using TMS as an internal standard. Chemical shifts were provided in ppm (δ) with reference to tetramethylsilane (TMS, δ=0.00 ppm) or residual CHCl.sub.3 peak (δ=7.27 ppm) for 1H NMR and 13C-resonance (δ=77.0 ppm) of CDCl.sub.3 for 13C NMR as internal standards. Data was presented as chemical shifts, multiple (s=singlet, d=doublet, t=triplet, m=multiples, b=broad, respectively) coupling constants (J, Hz) and integrals.

Example 2

[0069] Fabrication and Assembly of Flow Parallel Synthesizer

[0070] Metal 3D printing was performed using a Direct Metal Laser Sintering printer (DMLS, ProX DMP320, 3DS Systems Inc.) with an accuracy of 50 μm. SUS630 17-4PH stainless steel powder was used for 3D printing. For CNC machining, machining of SUS316L was performed using a CTX Beta 1250 TC machine from DMG MORI. The CNC machine provides positioning accuracy within 6 μm and repeatability within 2 μm. The individually manufactured parts were joined without leaks by placing polymer O-rings between the assembled parts. The inlet unit/discharge unit tubes and stainless-steel capillaries were connected to the junctions of the main body of the distributor, inlet unit or discharge unit via union-type, T-type and bend-type Swagelok connectors. Microreactors based on stainless-steel capillaries ( 1/16″ O.D., 0.75 mm I.D.) were space efficient by bending the capillary around a cylindrical spool (11 mm I.D., 1.6 mm pitch). The position of the baffle in the fluid damper was set at a height ratio of 1:2 between the upper and lower spaces, and the porosity value of the baffle was 0.5, which was optimized for distribution performance.

Example 3

[0071] Computational Fluid Dynamics Simulation Setup

[0072] The fluid flow throughout the synthesizer, including the distributor and capillaries, may be described by the incompressible Navier-Stokes equation along with the mass conservation equation. Assuming steady state, the governing equations for fluid flow used in the present invention may be simplified as follows.

ρv.Math.∇v=−∇p+μ∇2v+ρg:  Navier-Stokes equation (1)

∇.Math.v=0:  Mass conservation equation (2)

[0073] The ρ is the fluid density, v is the fluid linear velocity, p is the pressure, μ is the fluid dynamic viscosity, and g is the gravitational acceleration. The governing equations are generally solved with appropriate boundary conditions where the outlet is set to atmospheric pressure. The corresponding flow conditions were imposed in the case of a discharge unit forced by periodic pumps. Non-slip boundary conditions for velocity and concentration were applied to the wall boundary. For boundary conditions, the physical properties of DMSO (1.1004 g.Math.cm.sup.−3, 1.996 cP at 20° C.) were imposed as conditions. The equations were discretized based on the finite volume method, and the commercially available numerical software COMSOL (COMSOL, INC.) was used for numerical simulation.

Example 4

[0074] Computational and Experimental Fluid Dynamics of Flow Parallel Synthesizer

[0075] The flow performance of the parallel synthesizer according to the present invention was evaluated through numerical analysis of computational fluid dynamics (CFD) and preliminary flow experiments of the fabricated system. The uniformity of the flow distribution was quantified using a maldistribution factor (MF).

[00001]$\begin{array}{cc}\mathrm{MF}\left(\%\right)=\sqrt{\frac{1}{n-1}{.Math.}_{i=1}^n{\left(\frac{m_i-\stackrel{\_}{m}}{\stackrel{\_}{m}}\right)}^2}\times 100& \left(3\right)\end{array}$

[0076] In the above mathematical formula, n is the number of capillaries, and mi is the mass flow rate of the i.sup.th capillary. The m.sub.i represents the average mass flow rate of each capillary. Consequently, the MF value is the standard deviation of the mass flow rate in each capillary. Therefore, a low MF value indicates a uniform flow distribution between the capillaries.

[0077] FIG. 6 is a graph comparing flow rates in the studies of experimental (black line) and numerical analyses (red line) of 16 discharge units under various flow conditions. DMSO was injected through the first inlet unit (D1 or D2) at flow velocities of 10.56, 5.28, 2.64, 1.06, 0.53 and 0.35 mL/min, respectively. Building blocks were injected through inlets I1 to I16 at flow velocities of 0.66, 0.33, 0.17, 0.066, 0.033 and 0.022 mL/min in each case. The MF values obtained through the experimental and numerical studies are shown in Table 1 below.

TABLE-US-00001 TABLE 1 MF values obtained through experimental and numerical studies for 16 outlets under various flow rate conditions Flow D1 or 10.56  5.28 2.64 1.06 0.53 0.35 Velocity D2 (mL/min) I1~I16  0.66  0.33 0.17 0.066 0.033 0.022 Residence 30   60   120 300 600 900 Time (s) Numerical  0.54  0.59 0.53 0.51 0.22 0.25 Study, MF (%) Experimental  1.27  1.85 2.27 2.61 3.06 3.86 Study, MF (%)

[0078] CFD numerical analysis and flow distribution experiments were performed under the assumption that a uniform flow distribution was required in all capillaries in order to screen for the yields of individual reactions under various residence time conditions. A DMSO solution was injected through the first inlet unit (D1 or D2 in FIG. 5) at flow velocities of 6 cases (10.56, 5.28, 2.64, 1.06, 0.53 and 0.35 mL/min). In this case, the peristaltic pumps (P1 to P3) were selectively disconnected. The boundary conditions of I1 to I16 were set such that the flow including the second reactant (building block) was coupled through the second inlet at flow velocities of 6 cases (0.66, 0.33, 0.17, 0.066, 0.033, and 0.022 mL/min). In this case, the volume of each capillary was 0.662 mL, and thus, the residence times in each capillary were 30, 60, 120, 300, 600 and 900 seconds. Finally, the outlet flow velocities were checked in 16 individual capillaries and the MF values were obtained to quantify the uniformity of flow. In the numerical and experimental results, the MF values were sufficiently low at less than 1% and 4%, respectively. Clogging which is a chronic problem of microreactors may occur in some suboptimal organic reactions.

[0079] In the present invention, when two types of liquids were separately injected at a flow velocity of 10.56 mL/min through the first inlet units D1 and D2, 16 sample vials collected from R1 to R16 were visualized to experimentally confirm the uniform flow distribution of the flow parallel synthesizer (refer to FIG. 7). In FIG. 7A, only the DMSO solvent was used, and in FIG. 7B, a diazonium salt solution at 0.77 M (mixed with DMSO) was used. The inventors of the present invention investigated the effect of clogging, which occurred in one of the capillaries (R12 to R16), on the other capillaries (FIG. 7 and Table 1). As a result, as indicated in FIG. 7 and Table 1, the MF values of the remaining capillaries except for the clogged capillary showed a uniform flow distribution of less than 3% numerically or experimentally.

[0080] Next, simulations were performed by providing various capillaries with varying residence times for the simultaneous synthesis of a compound library under optimized conditions. It was assumed that the solution was injected through the first inlet unit (D1 or D2 in FIG. 5) at a flow velocity of 5.14 mL/min. In order to reflect changes in the flow velocities of the three capillaries through the peristaltic pumps P1 to P3, the boundary conditions of the outlet flow before the T-mixer for the three outlet capillaries were set at flow velocities of 0.022, 0.17 and 0.66 mL/min, respectively. The flow of the second reactant (building block) to the three capillaries I1 to I3 was also set at flow velocities of 0.044, 0.17 and 0.66 m/min, respectively. For the other capillaries, boundary conditions were set for I4 to I16 such that a flow velocity of 0.33 mL/min was merged through each T-mixer. Finally, the flow distribution was quantified by checking the outlet flow rates of the remaining 13 capillaries except for 1 to 3 capillaries (FIG. 8).

[0081] FIG. 8 is an experimental and numerical analysis graph of flow distribution for various cases of clogging. FIG. 8A shows the flow velocity distribution during clogging in R12 when the total flow velocity passing through D1 and D2 was 4.95 m/min, and the flow velocity of all the second inlet units except I12 was 0.33 m/min. FIG. 8B shows the distribution of flow velocities when clogged in two reactors R13 and R16 when the total flow velocity was 4.62 mL/min and the flow velocity of all the second inlet units except I13 and I16 was 0.33 mL/min. Referring to (c) of FIG. 8, when the total flow velocity was 4.29 m/min and the flow velocity of all the second inlet units except I12, I13 and I15 was 0.33 mL/min, it shows the distribution of flow velocities when three reactors R12, R13 and R15 were clogged. Referring to FIG. 8, it can be seen that an even flow velocity distribution appeared overall except for the capillaries in which the clogging occurred. The MF values obtained through the experimental and numerical studies are summarized in Table 2 below.

TABLE-US-00002 TABLE 2 MF values obtained from experimental and numerical studies of clogging in three different cases. Case (a) (b) (c) Numerical Study, 0.47 0.22 0.04 MF (%) Experimental Study, 2.96 2.25 2.31 MF (%)

[0082] Through numerical analysis, the calculated MF value was less than 1% in the flow distribution of outlets except for outlets R1 to R3. According to this, it can be seen that even when the flow velocities of capillaries 1 to 3 were selectively changed through the peristaltic pumps P1 to P3, the flow rate distribution of the other capillaries except for the above was maintained uniformly. In addition, it can be seen that the experimentally confirmed MF value was less than 4%, indicating that the flow distribution was sufficiently uniform. FIG. 9 is a graph comparing the experimental (black) and numerical (red) flow rate data of 16 discharge units, assuming parallel flow synthesis when reactors R1 to R3 were individually controlled at different flow velocities (0.033, 0.16, 0.66 mL/min) by three peristaltic pumps. In this case, DMSO was injected through D1 and D2 at a flow velocity of 5.14 mL/min and through the second inlet units of I1 to I3 (0.033, 0.16, 0.66 mL/min) to merge at a 1:1 ratio. Referring to FIG. 8, the numerical MF values of R4 to R16 were 0.57, which was slightly higher than the experimental MF value of 3.37.

Example 5

[0083] Individual Control of Reactions Through Temperature Control of Capillary Including Duct and Reactor

[0084] Referring to the IR image (plan view) of FIG. 10, it can be seen that only two coiled reactors were controlled and heated in the flow parallel synthesizer according to the present invention. The corresponding temperatures were set at 100° C. (R13) and 75° C. (R15) using a Proportional-Integral-Differential (PID)-based thermostat, thermocouple and heating rod. R13 and R15 reached the setpoint stably in a short period of time (10 min), while the other reactors (coiled capillary) in the vicinity remained stable at room temperature, and for better temperature control, it is suggested to fill the space (1 mm) between the reactors with a sufficient insulating material.

Example 6

[0085] Synthesis of Starting Reagents in Batch

[0086] 6-1. General Procedure for the Synthesis of Aryl Diazonium Tetrafluoroborates Salt

##STR00003##

[0087] The appropriate aniline (214.75 mmoles, 20 g, 1 equiv.) was dissolved in a mixture of 86 mL of distilled water and 57 mL of 48 wt. % hydrofluoroboric acid. After the reaction mixture was cooled to 0° C. using an ice bath, a sodium nitrite (15.6 g in 32 mL) solution was added dropwise every 5 minutes. The resulting mixture was stirred for 1 hour, and the precipitate was collected by filtration and redissolved in a minimum amount of acetone. Diethyl ether was added until diazonium tetrafluoroborate was precipitated, and afterwards, it was filtered, washed several times with diethyl ether, and dried under vacuum.

[0088] 6-2. General Procedure for the Synthesis of Imidazopyridine and Imidazothiazole

##STR00004##

[0089] A solution of 2-aminopyridine/2-aminothiazole (5 mmol, 1 equiv.) and bromomethyl ketone 30 (5 mmol, 1 equiv.) in EtOH (30 mL) was heated at reflux for 16 hours, and the reaction progress was monitored using TLC. The solvent was removed under reduced pressure and a saturated NaHCO.sub.3 solution (30 mL) was added to the remaining solid. Afterwards, the mixture was extracted with EtOAc (30 mL, ×3) and after the organic layers were combined, it was dried over Na.sub.2SO.sub.4. The concentrated crude product was dried under vacuum overnight and then triturated with (4:1) EtOAc: n-hexane to obtain prude imidazopyridine/imidazothiazole, and it was used directly in the next step.

Example 7

[0090] Synthesis of Starting Reagents of Diazonium Salt in Batch—SNAr-Type Reactions of Diazonium in Batch

[0091] The diazonium salt was used as a first reactant and injected through the first inlet unit, and the following reaction was performed in each reactor.

[0092] 7-1. Iodination Reaction

[0093] The diazonium salt (738 mg, 3.85 mmol) was dissolved in 9 mL of DMSO. After the reaction mixture was cooled to 20° C., a solution of potassium iodide (640 mg, 3.85 mmoles) dissolved in 1 mL of H.sub.2O was added dropwise to generate nitrogen gas, and the mixture was stirred for 30 minutes. The progress of the reaction was monitored by GC. Subsequently, the product was diluted with water and extracted three times with ether. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure. The resulting compound was absorbed on silica gel and purified through column chromatography (n-pentane/n-hexane, 1:1) to obtain iodobenzene as a colorless liquid in 70% yield.

[0094] 7-2. Chlorination Reaction

[0095] The diazonium salt (738 mg, 3.85 mmol) was dissolved in 8 mL of DMSO. After the reaction mixture was cooled to 20° C., a solution of CuCl (518 mg, 3.85 mmoles) dissolved in 2 mL of HCl was added dropwise to generate nitrogen gas, and the reaction mixture was stirred for 30 minutes. The progress of the reaction was monitored using GC. Subsequently, the product was diluted with water and extracted three times with ether. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure. The resulting compound was absorbed on silica gel and purified by column chromatography (n-pentane/n-hexane, 1:1) to obtain chlorobenzene as a colorless liquid in 64% yield.

[0096] 7-3. Azidation Reaction

[0097] The diazonium salt (738 mg, 3.85 mmol) was dissolved in 9 mL of DMSO. After the reaction mixture was cooled to 20° C., a solution of sodium azide (250 mg, 3.85 mmoles) dissolved in 1 mL of H.sub.2O was added dropwise to generate nitrogen gas, and the mixture was stirred for 30 minutes. The progress of the reaction was monitored by GC. Subsequently, the product was diluted with water and extracted three times with ether. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure. The resulting compound was absorbed on silica gel and purified through column chromatography (n-pentane/n-hexane, 1:1) to obtain azidobenzene as a pale-yellow liquid in 89% yield.

[0098] 7-4. Synthesis of Diaryl Sulfides

[0099] The diazonium salt (738 mg, 3.85 mmol) was dissolved in 4 mL of DMSO. the reaction mixture was cooled to 20° C., and a solution of p-thiocresol (478 mg, 3.85 mmoles) and NaOH (154 mg, 3.85 mmoles) dissolved in 6 mL of DMSO:H.sub.2O (2:1) was added dropwise with lead to generate nitrogen gas, and the mixture was stirred for 2 hours. The progress of the reaction was monitored by TLC. Subsequently, the product was diluted with water and extracted three times with ether. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure. The resulting compound was absorbed on silica gel and purified through column chromatography (n-hexane/ethyl acetate, 98:2) to obtain diaryl sulfides as a colorless liquid in 60% yield.

[0100] 7-5. α-Arylation of Furan

[0101] The diazonium salt (738 mg, 3.85 mmol) was dissolved in 9 mL of DMSO. After the reaction mixture was cooled to 20° C., a solution of furan (5.6 mL, 77 mmoles) and 4-aminomorpholine (0.193 mmoles, 5 mol %) dissolved in 10 mL of DMSO was added dropwise to generate nitrogen gas, and the mixture was stirred for 30 minutes. The progress of the reaction was monitored by TLC. Subsequently, the product was diluted with water and extracted three times with ether. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure. The resulting compound was absorbed on silica gel and purified through column chromatography (n-hexane/ethyl acetate, 98:2) to obtain α-arylated furan as a colorless liquid in 55% yield.

[0102] 7-6. Photochemical Reactions for α-Arylation of Furan

[0103] The diazonium salt (738 mg, 3.85 mmol) and furan (38.5 mmol) were dissolved in 10 mL DMSO, and Eosin Y (0.193 mmol, 5 mol %) was added thereto, and then, the reaction mixture was stirred under a green LED for 2 hours, and the progress of the reaction was monitored by using TLC. Subsequently, the product was diluted with water and extracted three times with ether. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure. The resulting compound was absorbed on silica gel and purified through column chromatography (n-hexane/ethyl acetate, 98:2) to obtain α-arylated furan as a colorless liquid in 61% yield.

[0104] 7-7. Arylation of Imidazopyridine/Imidazothiazole in Batch

[0105] The diazonium salt (738 mg, 3.85 mmol) and imidazopyridine/imidazothiazole (2.55 mmol) were taken together and dissolved in 10 mL of DMSO, and the reaction mixture was stirred at room temperature for 8 hours, and the progress of the reaction was monitored by using TLC. Subsequently, the product was diluted with water and extracted 3 times with ethyl acetate. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure. The resulting compound was absorbed on silica gel and purified through column chromatography (n-hexane/ethyl acetate, various ratios).

[0106] 7-8. Azo-Coupling of Diazonium Salts and β-Naphthol in Batch

[0107] The diazonium salts (6.375, 5.1, 3.825, 3.1875 and 2.55 mmol, respectively) were dissolved in 10 mL of DMSO in 5 different vials. After the reaction mixture was cooled to 20° C., a solution of β-naphthol and NaOH (6.375, 5.1, 3.825, 3.1875 and 2.55 mmol, respectively) dissolved in 10 mL of DMSO:H.sub.2O (9:1) was added dropwise, and the mixture was stirred for 1 hour, and then, the progress of the reaction was monitored by using TLC. Subsequently, the product was diluted with water and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure. The resulting compound was absorbed on silica gel and purified by column chromatography (n-hexane/ethyl acetate 98:2) to obtain a reddish-orange solid in 77, 79, 78, 76 and 75% yields, respectively.

Example 8

[0108] Preparation of Solutions Using Diazonium Salts and Other Building Blocks for Single Capillary and Flow Parallel Synthesizer [0109] Diazonium Solution: A 100 mL and 0.77M solution of each diazonium salt (77 mmol) was prepared using DMSO. [0110] Building Block 1: A 10 mL and 0.77M KI solution (7.7 mmoles) was prepared using DMSO:H.sub.2O (9:1). [0111] Building Block 2: A 10 mL and 0.77M CuCl solution (7.7 mmoles) was prepared using DMSO:HCl (3:2). [0112] Building Block 3: A 10 mL and 0.77 M NaN.sub.3 solution (7.7 mmoles) was prepared using DMSO:H.sub.2O (9:1). [0113] Building Block 4: A 10 mL and 0.77M p-thiocresol and NaOH (7.7 mmol each) solution was prepared using DMSO:H.sub.2O (2.5:1). [0114] Building Block 5: 10 mL of a pure furan solution including 4-aminomorpholine (0.385 mmoles, 5 mol %). [0115] Building Block 6: A 10 mL and 7.7M furan (77 mmol) and Eosin Y (0.385 mmol, 5 mol %) solution was prepared using DMSO. [0116] Building Block 7: 10 mL β-naphthol and NaOH solutions at 0.6375, 0.51, 0.3825, 0.31875 and 0.255 M (6.375, 5.1, 3.825, 3.1875 and 2.55 mmoles, respectively) were prepared using DMSO:H.sub.2O (9:1), respectively. [0117] Building Blocks 8 to 12: A 5 mL and 0.51M imidazopyridine/imidazothiazole (2.55 mmol) solution was prepared using DMSO.

Example 9

[0118] Concurrent Optimization of Complex Libraries

[0119] Diazonium (0.77M) solutions and other building blocks were prepared according to Example 7. Stock solutions of diazonium and the building blocks were each transferred to two 10 mL NORM-JECT plastic syringes and introduced into PTFE reactors using two syringe pumps. The stock solutions of diazonium and the building blocks were pumped at specific flow velocities using two syringe pumps in order to meet the required residence times shown in Table N below (Building Block 1: 0.033 mL/min, Building Block 2: 0.16 mL/min, Building Block 3:0.66 m/min and all other Building Blocks (4 to 12): 0.33 m/min, and the flow velocity ratio of diazonium to the Building Block solution=1:1). The two solutions were met in a T-mixer and injected into a PTFE reactor (L=1,500 mm, 1/16′ O.D., 0.75 mm I.D.) which was set to room temperature. After maintaining steady state, samples were collected for each individual reaction. After work up using water, it was purified, and the purification procedure was similar to the described procedure (refer to Example 6).

[0120] FIGS. 11 and 12 show the parallel synthesis method of diazonium according to an exemplary embodiment of the present invention. Various reactions may be simultaneously performed using a diazonium salt as the first reactant. In particular, FIG. 12 is a schematic diagram of aryl diazonium chemistry enabled by multiplex reactions in the flow parallel synthesizer through two series of experiments. Referring to FIG. 12, it can be seen that a list of 12 building blocks may react with two types of diazonium salts to form 6 types of chemical bonds (C-Halogen, C—N, C—S, C—C, —N═N—) in a library of 24 compounds.

[0121] FIG. 13 shows that 96 conditions in 16 reactors may be screened in 6 sequences at different times. In order to find optimal conditions for an aryl diazonium-based chemical library, the flow parallel synthesizer according to the present invention may be used to screen for reaction variables in reaction time (30 to 900 seconds) or/and concentration.

[0122] Optimization results of 96 reaction conditions are shown in Table 3 and FIG. 14 below.

TABLE-US-00003 TABLE 3 Concentration of second reactant Batch Capillary Rx. Reactor (building Reaction Yield, % yield, % yield, % Total type # block) time Product [e] [e] [e]  1  2  3  4  5  6 a1 R3 0.77 M t.sub.r = 30 s  t.sub.r = 60 s  t.sub.r = 120 s t.sub.r = 300 s t.sub.r = 600 s t.sub.r = 900 s [00005] 65 61 63 62 60 58 72 30 min 75 30 s  7  8  9 10 11 12 a2 R2 0.77 M t.sub.r = 30 s  t.sub.r = 60 s  t.sub.r = 120 s t.sub.r = 300 s t.sub.r = 600 s t.sub.r = 900 s [00006] 30 45 57 56 53 46 64 30 min 66 120 s 13 14 15 16 17 18 a3 R9 0.77 M t.sub.r = 30 s  t.sub.r = 60 s  t.sub.r = 120 s t.sub.r = 300 s t.sub.r = 600 s t.sub.r = 900 s [00007] 70 86 87 85 82 79 89 30 min 91 60 s 19 20 21 22 23 24 a4 R10 0.77 M t.sub.r = 30 s  t.sub.r = 60 s  t.sub.r = 120 s t.sub.r = 300 s t.sub.r = 600 s t.sub.r = 900 s [00008] 48 55 54 53 51 47 60 2 h 64 60 s 25 26 27 28 29 30 a5 .sup.[c] R11 0.77 M t.sub.r = 30 s  t.sub.r = 60 s  t.sub.r = 120 s t.sub.r = 300 s t.sub.r = 600 s t.sub.r = 900 s [00009] 54 60 61 60 58 56 55 30 min 62 60 s 31 32 33 34 35 36 a6 .sup.[d] R1 2.35 M t.sub.r = 30 s  t.sub.r = 60 s  t.sub.r = 120 s t.sub.r = 300 s t.sub.r = 600 s t.sub.r = 900 s [00010] n.r  6 15 32 54 45 61 2 h 55 600 s 37 38 39 40 41 42 a7 R12 0.64 M t.sub.r = 30 s  t.sub.r = 60 s  t.sub.r = 120 s t.sub.r = 300 s t.sub.r = 600 s t.sub.r = 900 s [00011] Clog 77 1 h Clog 43 44 45 46 47 48 a7 R13 0.51 M t.sub.r = 30 s  t.sub.r = 60 s  t.sub.r = 120 s t.sub.r = 300 s t.sub.r = 600 s t.sub.r = 900 s [00012] Clog 79 1 h Clog 49 50 51 52 53 54 a7 R14 0.38 M t.sub.r = 30 s  t.sub.r = 60 s  t.sub.r = 120 s t.sub.r = 300 s t.sub.r = 600 s t.sub.r = 900 s [00013] 57 74 76 71 Clog Clog 78 1 h 79 60 s 55 56 57 58 59 60 a7 R15 0.32 M t.sub.r = 30 s  t.sub.r = 60 s  t.sub.r = 120 s t.sub.r = 300 s t.sub.r = 600 s t.sub.r = 900 s [00014] 57 73 71 70 Clog Clog 76 1 h 78 60 s 61 62 63 64 65 66 a7 R16 0.26 M t.sub.r = 30 s  t.sub.r = 60 s  t.sub.r = 120 s t.sub.r = 300 s t.sub.r = 600 s t.sub.r = 900 s [00015] 55 71 72 71 Clog Clog 75 1 h 80 60 s 67 68 69 70 71 72 a8 R4 0.51 M t.sub.r = 30 s  t.sub.r = 60 s  t.sub.r = 120 s t.sub.r = 300 s t.sub.r = 600 s t.sub.r = 900 s [00016] 61 75 76 75 70 69 78 8 h 80 60 s 73 74 75 76 77 78 a9 R5 0.51 M t.sub.r = 30 s  t.sub.r = 60 s  t.sub.r = 120 s t.sub.r = 300 s t.sub.r = 600 s t.sub.r = 900 s [00017] 66 84 83 80 78 76 79 8 h 82 60 s 79 80 81 82 83 84 a10 R6 0.51 M t.sub.r = 30 s  t.sub.r = 60 s  t.sub.r = 120 s t.sub.r = 300 s t.sub.r = 600 s t.sub.r = 900 s [00018] 69 85 87 85 81 80 83 8 h 89 60 s 85 86 87 88 89 90 a11 R7 0.51 M t.sub.r = 30 s  t.sub.r = 60 s  t.sub.r = 120 s t.sub.r = 300 s t.sub.r = 600 s t.sub.r = 900 s [00019] 64 76 75 77 71 72 74 8 h 81 60 s 91 92 93 94 95 96 a12 R8 0.51 M t.sub.r = 30 s  t.sub.r = 60 s  t.sub.r = 120 s t.sub.r = 300 s t.sub.r = 600 s t.sub.r = 900 s [00020] 60 74 76 75 71 68 78 8 h 80 60 s

[0123] In Table 3 above, [a] the concentration of the aryl diazonium salt is 0.77M, and the reaction temperature is room temperature. [b] is the residence time in each reactor. [c] Eosin-Y (5 mol %) was pre-mixed with the building block solution. A 530 nm green LED was wrapped around a transparent PFA capillary. [d] 4-Aminomorpholine (5 mol %) was pre-mixed with the building block solution. [e] is the isolated yield.

Example 10

[0124] Spectral Data of Synthetic Compounds

[0125] Spectral data of the compounds synthesized according to the present invention is as follows, and it was confirmed whether the compound was synthesized by the data of FIGS. 15 to 58.

10-1. (E)-2-Phenyl-3-(phenyldiazenyl)imidazo[1,2-a]pyridine

[0126] .sup.1H NMR (500 MHz, CDCl.sub.3) δ=10.04 (d, J=6.9 Hz, 1H), 8.51-8.43 (m, 2H), 7.95-7.85 (m, 3H), 7.59-7.48 (m, 6H), 7.45-7.40 (m, 1H), 7.14 (t, J=6.9 Hz, 1H);

[0127] .sup.13C NMR (125 MHz, CDCl.sub.3) δ=153.6, 150.3, 145.7, 132.8, 132.0, 129.9, 129.5, 129.4, 129.3, 129.1, 128.4, 122.0, 117.2, 115.3

10-2. (E)-2-Phenyl-3-(p-tolyldiazenyl)imidazo[1,2-a]pyridine

[0128] .sup.1H NMR (500 MHz, CDCl.sub.3) δ=10.05 (d, J=6.9 Hz, 1H), 8.51-8.45 (m, 2H), 7.91 (br. s., 1H), 7.83 (d, J=8.2 Hz, 2H), 7.60-7.55 (m, 3H), 7.53-7.48 (m, 1H), 7.35 (d, J=8.1 Hz, 2H), 7.15 (t, J=6.7 Hz, 1H), 2.47 (s, 3H);

[0129] .sup.13C NMR (125 MHz, CDCl.sub.3) δ=151.8, 149.4, 145.4, 140.0, 132.7, 132.0, 130.0, 129.9, 129.5, 129.4, 129.3, 128.5, 122.0, 117.2, 115.3, 21.4

10-3. (E)-3-(Phenyldiazenyl)-2-(p-tolyl)imidazo[1,2-a]pyridine

[0130] .sup.1H NMR (500 MHz, CDCl.sub.3) δ=10.03-9.98 (m, 1H), 8.36 (d, J=8.2 Hz, 2H), 7.89-7.87 (m, 2H), 7.78 (d, J=8.8 Hz, 1H), 7.54-7.47 (m, 3H), 7.42-7.38 (m, 1H), 7.36 (d, J=7.9 Hz, 2H), 7.08-7.05 (m, 1H), 2.46 (s, 3H);

[0131] .sup.13C NMR (125 MHz, CDCl.sub.3) δ=153.8, 150.7, 145.9, 139.5, 131.9, 130.1, 129.9, 129.5, 129.4, 129.3, 129.1, 122.0, 117.2, 115.2, 21.4

10-4. (E)-2-(p-Tolyl)-3-(p-tolyldiazenyl)imidazo[1,2-a]pyridine

[0132] .sup.1H NMR (500 MHz, CDCl.sub.3) δ=10.04 (d, J=6.9 Hz, 1H), 8.37 (d, J=8.1 Hz, 2H), 7.95 (d like, J=7.6 Hz, 1H), 7.80 (d, J=8.2 Hz, 2H), 7.57 (t, J=7.8 Hz, 1H), 7.37 (d, J=7.9 Hz, 2H), 7.33 (d, J=8.1 Hz, 2H), 7.14 (t, J=6.8 Hz, 1H), 2.46 (d like, J=2.7 Hz, 6H);

[0133] .sup.13C NMR (125 MHz, CDCl.sub.3) δ=151.8, 150.1, 145.7, 139.6, 139.2, 131.8, 130.3, 129.8, 129.7, 129.3, 129.2, 129.1, 121.9, 117.2, 114.9, 21.4, 21.3

10-5. (E)-2-(4-Methoxyphenyl)-3-(phenyldiazenyl)imidazo[1,2-a]pyridine

[0134] .sup.1H NMR (500 MHz, CDCl.sub.3) δ=10.07-10.01 (m, 1H), 8.49-8.42 (m, 2H), 7.91-7.86 (m, 2H), 7.84 (d, J=8.8 Hz, 1H), 7.57-7.50 (m, 3H), 7.43-7.38 (m, 1H), 7.13-7.06 (m, 3H), 3.92 (s, 3H);

[0135] .sup.13C NMR (125 MHz, CDCl.sub.3) δ=160.8, 153.8, 150.6, 146.0, 131.7, 131.3, 129.4, 129.3, 129.1, 125.6, 121.9, 117.0, 114.9, 113.9, 55.3

10-6. (E)-2-(4-Methoxyphenyl)-3-(p-tolyldiazenyl)imidazo[1,2-a]pyridine

[0136] .sup.1H NMR (500 MHz, CDCl.sub.3) δ=10.03 (d, J=6.9 Hz, 1H), 8.48-8.41 (m, 2H), 7.86 (d like, J=8.5 Hz, 1H), 7.79 (d, J=8.2 Hz, 2H), 7.53 (t, J=7.9 Hz, 1H), 7.33 (d, J=7.9 Hz, 2H), 7.12-7.05 (m, 3H), 3.92 (s, 3H), 2.45 (s, 3H);

[0137] .sup.13C NMR (125 MHz, CDCl.sub.3) δ=160.6, 151.7, 149.8, 145.7, 139.3, 131.5, 131.2, 129.6, 129.2, 129.0, 125.7, 121.7, 116.9, 114.6, 113.8, 55.2, 21.3

10-7. (E)-6-Phenyl-5-(phenyldiazenyl)imidazo[2,1-b]thiazole

[0138] .sup.1H NMR (500 MHz, CDCl.sub.3) δ=8.59 (d, J=4.4 Hz, 1H), 8.41-8.37 (m, 2H), 7.89-7.87 (m, 2H), 7.54-7.50 (m, 4H), 7.46-7.40 (m, 2H), 6.99 (d, J=4.4 Hz, 1H);

[0139] .sup.13C NMR (125 MHz, CDCl.sub.3) δ=154.2, 153.2, 149.9, 135.8, 133.0, 129.7, 129.1, 129.0, 128.9, 128.5, 123.1, 122.2, 113.3

10-8. (E)-6-Phenyl-5-(p-tolyldiazenyl)imidazo[2,1-b]thiazole

[0140] .sup.1H NMR (500 MHz, CDCl.sub.3) δ=8.58-8.53 (m, 1H), 8.43-8.35 (m, 2H), 7.82-7.74 (m, 2H), 7.51 (t, J=7.7 Hz, 2H), 7.43 (t, J=7.3 Hz, 1H), 7.31 (d, J=7.9 Hz, 2H), 6.93 (t, J=4.4 Hz, 1H), 2.45 (s, 3H)

[0141] .sup.13C NMR (125 MHz, CDCl.sub.3) δ=153.9, 151.4, 149.3, 140.2, 135.9, 133.2, 129.8, 128.9, 128.8, 128.5, 123.1, 122.2, 113.1, 21.4

10-9. (E)-6-(4-Methoxyphenyl)-5-(phenyldiazenyl)imidazo[2,1-b]thiazole

[0142] .sup.1H NMR (500 MHz, CDCl.sub.3) δ=8.53 (dd, J=1.8, 4.3 Hz, 1H), 8.35 (d, J=8.9 Hz, 2H), 7.84 (d, J=8.1 Hz, 2H), 7.50 (t, J=7.7 Hz, 2H), 7.39 (t, J=7.3 Hz, 1H), 7.04 (d, J=8.9 Hz, 2H), 6.89 (dd, J=1.4, 4.4 Hz, 1H), 3.89 (s, 3H);

[0143] .sup.13C NMR (125 MHz, CDCl.sub.3) δ=160.5, 154.5, 153.4, 150.3, 135.4, 130.4, 129.4, 129.1, 125.9, 123.2, 122.1, 114.1, 112.7, 55.3

10-10. (E)-6-(4-Methoxyphenyl)-5-(p-tolyldiazenyl)imidazo[2,1-b]thiazole

[0144] .sup.1H NMR (500 MHz, CDCl.sub.3) δ=8.54-8.47 (m, 1H), 8.34 (d, J=8.8 Hz, 2H), 7.73 (d, J=8.1 Hz, 2H), 7.31-7.26 (m, 2H), 7.03 (d, J=8.8 Hz, 2H), 6.90-6.82 (m, 1H), 3.89 (s, 3H), 2.43 (s, 3H);

[0145] .sup.13C NMR (125 MHz, CDCl.sub.3) δ=160.4, 154.1, 151.4, 149.6, 139.8, 135.4, 130.3, 129.7, 126.0, 123.2, 122.0, 114.0, 112.5, 55.3, 21.4

10-11. (E)-1-(Phenyldiazenyl) naphthalen-2-ol

[0146] .sup.1H NMR (200 MHz, CDCl.sub.3) δ=8.54 (d, J=8.2 Hz, 1H), 7.76-7.65 (m, 3H), 7.60-7.29 (m, 6H), 6.85 (d, J=9.4 Hz, 1H);

[0147] .sup.13C NMR (50 MHz, CDCl.sub.3) δ=172.0, 144.7, 140.1, 133.6, 130.0, 129.6, 128.8, 128.6, 128.0, 127.4, 125.7, 124.8, 121.7, 118.5

10-12. (E)-1-(p-Tolyldiazenyl) naphthalen-2-ol

[0148] .sup.1H NMR (500 MHz, CDCl.sub.3) δ=8.62 (d, J=8.4 Hz, 1H), 7.75 (d, J=9.3 Hz, 1H), 7.71-7.67 (m, 2H), 7.64 (d, J=7.9 Hz, 1H), 7.57 (ddd, J=1.3, 7.1, 8.3 Hz, 1H), 7.41 (ddd, J=1.2, 7.0, 7.9 Hz, 1H), 7.30 (d, J=7.9 Hz, 2H), 6.96 (d, J=9.3 Hz, 1H), 2.43 (s, 3H);

[0149] .sup.13C NMR (125 MHz, CDCl.sub.3) δ=168.3, 143.5, 138.8, 138.3, 133.5, 130.1, 129.7, 128.5, 128.4, 128.0, 125.3, 123.9, 121.6, 119.1, 21.2

10-13. Iodobenzene

[0150] .sup.1H NMR (500 MHz, CDCl.sub.3) δ=7.73 (d, J=8.1 Hz, 2H), 7.35 (dt, J=0.8, 7.5 Hz, 1H), 7.16-7.09 (m, 2H);

[0151] .sup.13C NMR (125 MHz, CDCl.sub.3) δ=137.3, 130.1, 127.3, 94.4

10-14. 1-Iodo-4-methylbenzene

[0152] .sup.1H NMR (500 MHz, CDCl.sub.3) δ=7.57 (d, J=8.2 Hz, 2H), 6.94 (d, J=7.8 Hz, 2H), 2.30 (s, 3H);

[0153] .sup.13C NMR (125 MHz, CDCl.sub.3) δ=137.4, 137.2, 131.1, 90.2, 21.0

10-15. Chlorobenzene

[0154] .sup.1H NMR (500 MHz, CDCl.sub.3) δ=7.29-7.25 (m, 2H), 7.24-7.20 (m, 2H), 7.19-7.15 (m, 1H);

[0155] .sup.13C NMR (126 MHz, CDCl.sub.3) δ=134.2, 129.7, 128.6, 126.4

10-16. 1-Chloro-4-methylbenzene

[0156] .sup.1H NMR (500 MHz, CDCl.sub.3) δ=7.28 (d, J=8.2 Hz, 2H), 7.16 (d, J=8.1 Hz, 2H), 2.38 (s, 3H);

[0157] .sup.13C NMR (125 MHz, CDCl.sub.3) δ=136.2, 131.1, 130.3, 128.2, 20.8

10-17. 2-Phenylfuran

[0158] .sup.1H NMR (500 MHz, CDCl.sub.3) δ=7.74-7.66 (m, 2H), 7.52-7.45 (m, 1H), 7.40 (t, J=7.7 Hz, 2H), 7.30-7.25 (m, 1H), 6.67 (d, J=3.4 Hz, 1H), 6.49 (dd, J=1.8, 3.4 Hz, 1H);

[0159] .sup.13C NMR (125 MHz, CDCl.sub.3) δ=154.0, 142.0, 130.9, 128.6, 127.3, 123.8, 111.6, 104.9

10-18. 2-(p-Tolyl)furan

[0160] .sup.1H NMR (500 MHz, CDCl.sub.3) δ=7.60 (d, J=8.2 Hz, 2H), 7.47 (s, 1H), 7.22 (d, J=7.9 Hz, 2H), 6.62 (d, J=3.2 Hz, 1H), 6.48 (dd, J=1.6, 3.1 Hz, 1H), 2.39 (s, 3H);

[0161] .sup.13C NMR (125 MHz, CDCl.sub.3) δ=154.2, 141.6, 137.1, 129.3, 128.2, 123.7, 111.5, 104.2, 21.1

10-19. Phenyl(p-tolyl)sulfane

[0162] .sup.1H NMR (500 MHz, CDCl.sub.3) δ=7.32 (d, J=8.2 Hz, 2H), 7.29-7.26 (m, 4H), 7.23-7.18 (m, 1H), 7.15 (d, J=7.9 Hz, 2H), 2.36 (s, 3H); .sup.13C NMR (125 MHz, CDCl.sub.3) δ=137.5, 137.1, 132.2, 131.3, 130.0, 129.8, 129.0, 126.4, 21.1

[0163] 10-20. Di-p-tolylsulfane

[0164] .sup.1H NMR (500 MHz, CDCl.sub.3) δ=7.25 (d, J=8.1 Hz, 4H), 7.12 (d, J=7.9 Hz, 4H), 2.34 (s, 6H);

[0165] .sup.13C NMR (125 MHz, CDCl.sub.3) δ=136.8, 132.7, 131.0, 129.8, 21.0

10-21. Azidobenzene

[0166] .sup.1H NMR (500 MHz, CDCl.sub.3) δ=7.39-7.34 (m, 2H), 7.18-7.13 (m, 1H), 7.07-7.02 (m, 2H);

[0167] .sup.13C NMR (75 MHz, CDCl.sub.3) δ=139.9, 129.7, 124.8, 119.0

10-22. 1-Azido-4-methylbenzene

[0168] .sup.1H NMR (500 MHz, CDCl.sub.3) δ=7.16 (d, J=7.9 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 2.34 (s, 3H);

[0169] .sup.13C NMR (75 MHz, CDCl.sub.3) δ=137.1, 134.5, 130.3, 118.8, 20.7

Experimental Example 1

[0170] Screening Method Using Parallel Synthesizer of Compound Library

[0171] As can be seen in FIG. 1, the flow parallel synthesizer according to the present invention is ready to demonstrate a wide range of flow chemistries by pre-forming the efficient parameter screening and synthesis library of aryldiazonium salts with model chemistry. First, 16×6 conditions of diazonium salt-based flow reactions were screened in parallel to find optimal conditions using benzene diazonium tetrafluoroborate (a) as the simplest and most stable diazonium precursor. In this experiment, a 0.77M solution of DMSO was pumped through two first inlets (D1 and D2, FIG. 5) at 6 different flow velocities ranging from 10.56 to 0.35 mL/min by using an HPLC pump.

[0172] The flow of a diazonium solution was uniformly distributed across 16 individual stainless-steel capillaries of the flow synthesizer with high reliability as mentioned above. In addition, the capillaries were connected with a T-shaped mixer at a flow velocity in a range of 0.66 to 0.033 m/min corresponding to 1/16 of the initial flow velocity. The flow of the diazonium solution was merged with the flow of the second reactant (building block) including other chemical components in a range of 0.66 to 0.033 m/min through 16 inlets (I1 to I16) as illustrated in FIG. 3.

[0173] In order to show the aromatic substitution reaction, the second reactant of the second inlet I1 included a 3.85M furan solution and 5 mol % Eosin Y(6) to show the photochemical reaction, and in order to show the aromatic substitution reaction, I2 included a 0.77M CuCl solution (2), I3 included a 0.77M KI solution (1), I9 included a 0.77M NaN.sub.3 solution (3), I10 included a 0.77M p-thiocresol sodium salt solution (4), and I11 included a pure solution of furan containing 5 mol % of a 4-aminomorpholine catalyst. The second inlets I12 to I16 included a mixture of β-naphthol (7) at 0.64, 0.51, 0.38, 0.32 and 0.26 M and NaOH for the concentration screening of azo-dye based carbocycles. I4 to I8 included 0.51 M imidazopyridine (8, 9, 10) and imidazothiazole derivatives (11, 12) solutions for the azo-coupling reactions of heterocycles. Various bond-forming reactions mixing the two reagents occurred simultaneously in 16 capillaries via the SNAr and radical pathways in multiple modes. Finally, the 16 second reactants (building blocks) introduced at the inlets I1 to I16 were reacted with benzene diazonium tetrafluoroborate (a) at a single concentration (0.77M) at 6 different residence times of 30, 60, 120, 300, 600 and 900 seconds, and it allowed for synthetic screening under 16×6 different conditions. The isolated yield of each sample collected during the optimization process is shown in FIG. 4.

[0174] When the experimental setup including the pump and the feed solution was prepared in the parallel synthesizer, 16 samples were obtained each time by flowing out the capillary reactors R1 to R16 at a specific flow velocity. After screening 6 different residence times by simply changing the flow velocity, a total of 16×δ=96 samples were collected to find the optimal parameters at the reaction time and concentration showing the highest yield as summarized in Table 3.

[0175] Screening Results Using the Parallel Synthesizer of Compound Library

[0176] The aromatic substitution reaction (C—C, C—N, C—S) proceeded with a residence time of 60 seconds to obtain the desired products in good yield (55% to 86%), and it included the reaction of benzene diazonium tetrafluoroborate (a) with furan (5) in capillary R11 to provide product (a5), NaN.sub.3 (3) in capillary R9 to provide product (a3) and R—SNa (4) in capillary R10 to provide product (a4). Similarly, KI (1) in capillary R3 provided product (a1), CuCl (2) in capillary R2 provided product (a2) to form C-halogen bonds based on the aromatic substitution of diazonium, and 30 seconds and 120 seconds were required to provide 65% and 57% yields of the desired products. The low yield of chlorobenzene is justified by the formation of a small amount of the Gomberg-Bachmann product, and a common side reaction which generally occurs with the use of CuCl forms an aryl radical in charge of the formation of ortho/para-chloro-1,1′-biphenyl. In contrast, aromatic substitution via organic photo-redox catalysis between diazonium and furan (a6) in capillary R1 occurred with a residence time of 600 seconds in the presence of a green LED, delivering the arylated product in 54% yield. In addition, the azo-coupling reaction of carbocycles and β-napthol (7) at five different concentrations (0.64, 0.51, 0.38, 0.32 and 0.26M) in capillaries R12 to R16 provided product (a7) in 71% to 74% yields, respectively. Finally, the azo-coupling reaction of imidazopyridine (8 to 10), which is a heterocycle in capillaries R4 to R6, provided products (a8 to a10) in 78%, 79% and 83% yields, and imidazothiazoles (11 and 12) were used in capillaries R7 and R8 to provide products (a11 and a12) in 74% and 78% yields at a residence time of 60 seconds.

[0177] Pre-decomposition of the diazonium reagent results in a lower yield than that of a single capillary reactor because of the long stay of nitrogen gas, which is produced in the distributor, in the storage space (refer to Table 3). Fortunately, since the unique design of the system according to the invention allows for an even distribution of the gas/solution mixture, the overall flow distribution is not affected, as indicated in FIG. 7.

[0178] In addition, in the case of azo-dye synthesis, since capillaries (R12 to R16) were rarely clogged at high concentrations, concentration was considered as another important variable to be considered during the screening process. This problem was overcome by screening for five concentrations of β-naphthol (0.64, 0.51, 0.38, 0.32 and 0.26 M) for 6 residence times (30, 60, 120, 300, 600 and 900 seconds), and thus, 6×5=30 concentration-based data points were generated to determine the optimal concentrations needed to achieve excellent productivity. As a result, the highest yield of 74% of the Sudan dye was obtained at a concentration of 0.38M, compared to lower concentrations of 0.32 and 0.26 M where excess diazonium was pumped into the reaction, and some impurity formation was observed.

[0179] In addition to the above, due to low flow velocities, dye deposits were often precipitated, resulting in clogging in the capillaries. However, overall, when the capillaries were clogged at concentrations of 0.64 and 0.51 M or more, it was observed that the reactions proceeded without interruption in the remaining capillaries simply by reducing the initial inflow by 6.6% for each clogged capillary. In order to solve the chronic clogging problems of microreactors, it may be adjusted by maintaining a balanced flow of the second reactants (building blocks).

[0180] According to the present invention, the total time required to screen 16×δ=96 cases in terms of performance efficiency was about 60 minutes (based on steady state required for 6 different residence times), which was much less than performing in a batch mode. Therefore, it can be seen that the parallel synthesizer according to the present invention requires minimum labor and is cost-effective, user-friendly and very efficient in terms of screening.

[0181] Control of Reaction Time of Parallel Synthesizer of Compound Library

[0182] The results obtained from the screening data suggest that the flexibility of the flow parallel synthesizer may be improved by adjusting the system to select the residence time of each capillary according to the needs of the reaction. Three peristaltic pumps P1, P2 and P3 were connected to individual reactors R1, R2 and R3 in a way that the flow rate was controlled orthogonally. Three different types of reactions, such as iodination, chlorination and photochemical transformation, were performed at three residence times (600, 120 and 30 seconds) by applying the corresponding flow velocities of diazonium reagents (0.033, 0.17 and 0.66 mL/min, respectively).

[0183] Overall, in order to show the diversity of the flow parallel synthesizer, 6 sets of screenings (16×δ=96) were performed in which aromatic substitution-based and carbocycle-based azo-coupling and heterocycle-based azo-coupling were performed.

[0184] Next, by utilizing the above optimized conditions, with time intervals of 30 minutes including washing and stabilization steps to achieve steady state, the inventors of the present invention confirmed two sets of diazonium derivatives at a total flow velocity of 5.14 mL/min, ultimately leading to the generation of a library of (12×2=24) products, by using benzenediazonium tetrafluoroborate (a) and p-tolydiazonium tetrafluoroborate (b) at a total flow velocity of 5.14 m/min. The flow velocities of the three capillaries R1, R2 and R3 were set to (0.033, 0.17 and 0.66 mL/min), respectively. Capillaries R4 to R16 were set at a flow velocity of 0.33 m/min. Finally, the yields of each sample collected at each discharge unit of the parallel flow synthesizer are summarized in Table 1.

[0185] Finally, two different types of aryl diazonium were used to demonstrate the multiplex synthesis of a library of 24 compounds. In addition, the scale-out approach for the synthesis of Sudan dyes (a7 and b7) was demonstrated using five capillaries R12 to R16 with productivities of 6.8 g/h and 7.7 g/h, and it was shown that the parallel synthesizer according to the present invention may serve a dual role for screening as well as productivity.

[0186] Regardless of the reaction mixture analysis which is a bottleneck phenomenon that promotes screening proficiency, the main advantage of the flow parallel synthesizer according to the present invention is that it allows for the multiplex screening process efficiently at various substrate effects, concentrations and residence times. In general, the chemical performance of the flow parallel synthesizer was comparable to that of batch and a single capillary when the synthesis yields were compared (refer to Table 3). All automated flow platforms developed for advanced applications so far may only perform optimization of a single reaction set or all reaction variables at a given point in time to streamline the optimization process. However, according to the present invention, several synthesis chemistries are possible at once, but these are impossible with commercially available batch parallel synthesizers or reported automated flow platforms.

[0187] Although an exemplary embodiment of the present invention has been described above, the spirit of the present invention is not limited to the exemplary embodiment presented in the present specification, and those skilled in the art who understand the spirit of the present invention will be able to easily suggest other exemplary embodiments by modifying, changing, deleting or adding components within the scope of the same spirit, but this is also said to be within the scope of the present invention.