Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:5]=[C:6]([F:8])[CH:7]=1.[OH:19][CH:20]([CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:21][NH:22][C:23]([C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][C:26]=1[CH:31]=O)=[O:24].N1CCCCC1>C(O)C>[OH:19][CH:20]([CH2:33][N:34]1[CH2:35][CH2:36][CH2:37][CH2:38]1)[CH2:21][NH:22][C:23]([C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][C:26]=1/[CH:31]=[C:11]1\[C:12](=[O:18])[NH:13][C:14]2[C:10]\1=[C:9]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)[CH:17]=[CH:16][CH:15]=2)=[O:24]
Reactant: O=C1Cc2c(cccc2-c2cc(F)cc(F)c2)N1
Reactant: Cc1cc(C(=O)NCC(O)CN2CCCC2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCC(O)CN2CCCC2)c(/C=C2\C(=O)Nc3cccc(-c4cc(F)cc(F)c4)c32)[nH]1

Procedure:
4-(3,5-Difluoro-phenyl)-1,3-dihydro-indol-2-one (73.5 mg, 0.3 mmol) was condensed with 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-pyrrolidin-1-yl-propyl)-amide (excess) and piperidine in ethanol to give 40 mg of the titled compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([OH:35])[C:17]2[C:12](=[CH:13][C:14]([C:22]#[N:23])=[CH:15][C:16]=2[C:18]([F:21])([F:20])[F:19])[N:11]([CH2:24][C@H:25]2[CH2:28][C@H:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:26]2)[C:10]1=[O:34].[OH-].[K+].C(OCC)(=[O:40])C.O>C(O)(C)(C)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([OH:35])[C:17]2[C:12](=[CH:13][C:14]([C:22]([NH2:23])=[O:40])=[CH:15][C:16]=2[C:18]([F:21])([F:20])[F:19])[N:11]([CH2:24][C@H:25]2[CH2:28][C@H:27]([N:29]([CH2:30][CH3:31])[CH2:32][CH3:33])[CH2:26]2)[C:10]1=[O:34]
Reactant: CCOC(C)=O
Reactant: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3ccc(Cl)cc3Cl)c3c2cc(C#N)cc3C(F)(F)F)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3ccc(Cl)cc3Cl)c3c2cc(C(N)=O)cc3C(F)(F)F)C1
Product: Cl
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a solution of the compound of Example 1-3 (1.76 g, 3.34 mmol) in tert-butyl alcohol (34 mL) was added potassium hydroxide (1.76 g, 31.4 mmol), and the mixture was stirred at 50° C. for 1.5 hours. To the reaction solution were added ethyl acetate (100 mL) and water (2 mL), and then the mixture was dried over magnesium sulfate and filtered. The mixture was evaporated, and then dissolved in ethyl acetate again and filtered. The filtrate was evaporated, and then thereto were added tetrahydrofuran (100 mL) and 1M hydrochloric acid (5 mL), and the mixture was evaporated, and then the residual water was removed by azeotropic distillation with toluene. The resulting solid was washed with diethyl ether, and then dried to give the titled compound (1.89 g, 97%).
Reaction SMILES: C(C1C=C(N[N:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])C=CC=1)C.[CH2:16]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21])[CH3:17].C(#N)CC#N.O.[NH2:31][NH2:32]>>[CH2:16]([C:18]1[CH:19]=[C:20]([NH:21][N:10]=[C:11]2[C:12]([NH2:13])=[N:32][N:31]=[C:14]2[NH2:15])[CH:22]=[CH:23][CH:24]=1)[CH3:17]
Reactant: CCc1cccc(NN=C(C#N)C#N)c1
Reactant: NN
Reactant: CCc1cccc(N)c1
Solvent: O
Solvent: N#CCC#N
Product: CCc1cccc(NN=C2C(N)=NN=C2N)c1

Procedure:
4-[(3-ethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine was prepared using 99 mg (0.5 mmol) of 2-[(3-ethylphenyl)hydrazono]malononitrile, which was derived from 3-ethylaniline (124 μL, 1.0 mmol) and malononitrile (1.5 mmol), and hydrazine hydrate. Precipitate formed in the reaction tube approximately 10 minutes after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, precipitated from an ethyl acetate solution by the addition of hexanes, and dried to yield 12 mg (10%) of the compound as a yellow solid.
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O.ClC([O:18][CH2:19]C)=O.C([N:23](CC)CC)C>O1CCCC1>[CH3:19][O:18][NH:23][C:9]([C:8]1[CH:7]=[C:6]([CH:14]=[CH:13][CH:12]=1)[CH:2]=[O:3])=[O:11]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cccc(C2OCCO2)c1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CONC(=O)c1cccc(C=O)c1
Reaction time: 0.17 h

Procedure:
To a solution of 5.63 g of 3-([1,3]dioxolan-2-yl)benzoic acid in 60 ml of tetrahydrofuran were added 3.3 ml of ethyl chloroformate and 4.8 ml of triethylamine under ice-cooling. After stirred for 10 minutes under ice-cooling, insolubles were filtered. This solution was added dropwise to a mixture of 3.63 g of methoxyamine hydrochloride, 20 ml of tetrahydrofuran, 6 ml of triethylamine and 20 ml of dimethylformamide. After stirred at room temperature for 8 hours, insolubles were filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 30 ml of tetrahydrofuran, and 15 ml of 2 N hydrochloric acid was added dropwise, followed by stirring at room temperature for 8 hours. 20 ml of a 2 N aqueous sodium hydroxide solution was added dropwise under ice-cooling, and this was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 1.50 g of 3-(methoxyaminocarbonyl)benzaldehyde [Compound No. (s)] as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:41])[C:16]=1[CH2:17][C@@H:18]1[CH2:22][CH2:21][N:20]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH2:25][CH2:24]2)[C:19]1=[O:40])[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.C(=O)([O-])[O-:43].[K+].[K+].OO.C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:41])[C:16]=1[CH2:17][C@@H:18]1[CH2:22][CH2:21][N:20]([N:23]2[CH2:24][CH2:25][CH:26]([O:29][Si:30]([CH:34]([CH3:35])[CH3:36])([CH:37]([CH3:39])[CH3:38])[CH:31]([CH3:32])[CH3:33])[CH2:27][CH2:28]2)[C:19]1=[O:40])[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([NH2:11])=[O:43])=[CH:8][CH:7]=1
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(Oc4ccc(C#N)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(Oc4ccc(C(N)=O)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Reaction time: 12 h
Yield: 68.9 %

Procedure:
Cool a solution of (R)-4-{3,5-dichloro-4-[2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-phenoxy}-benzonitrile (0.295 g, 0.48 mmol) in DMSO (5 mL) on an ice bath. Add to the solution potassium carbonate (0.331 g, 2.4 mmol) and hydrogen peroxide (30% in water, 1 mL) and stir the reaction at 0° C. for 1.5 hours and then at room temperature for 12 hours. Dilute the reaction with ethyl acetate, and wash three times with water and then one time with brine. Dry the organic phase over sodium sulfate, filter, and concentrate. Purify the residue by silica gel chromatography by eluting with 40% ethyl acetate in hexanes to 100% ethyl acetate gradient to afford 0.210 g (69%) of the title compound. MS (m/z): 633 (M+).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[N:4]([CH3:13])[N:3]=1.C([Mg]Cl)(C)C.[CH2:19]([Sn:23]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])Cl)[CH2:20][CH2:21][CH3:22]>C1COCC1>[CH3:12][O:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH3:13])[N:3]=[C:2]2[Sn:23]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: COc1ccc2c(c1)c(I)nn2C
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(OC)cc12
Temperature: -16 °C
Reaction time: 0.33 h

Procedure:
3-iodo-5-methoxy-1-methyl-1H-indazole (0.355 g, 1.23 mmol) was dissolved in THF (3.00 mL). The yellow solution was cooled to −16° C. (NaCl/ice bath), isopropylmagnesium chloride 2M in THF (690 μL, 1.38 mmol.12) was added dropwise at −16° C. The reaction mixture was stirred at −16° C. for 20 min where a solid precipitated. Then, tributylchlorostannane (461 mg, 384 μL, 1.42 mmol.15) was added slowly. The reaction mixture was warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with dichloromethane (3×30 mL), organics dried over MgSO4 and concentrated to a yellow oil. The residue was dried under high vacuum to give crude 5-methoxy-1-methyl-3-(tributylstannyl)-1H-indazole, which was used directly in the next step without further purification. The crude mass exceeded the expected amount so the yield was assumed to be quantitative.
Reaction SMILES: Br[C:2]1[CH:3]([OH:7])[CH2:4][CH2:5][CH:6]=1.[CH2:8]([Mg]Br)[CH:9]([CH3:11])[CH3:10]>C1COCC1.[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:8]([C:2]1[CH:3]([OH:7])[CH2:4][CH2:5][CH:6]=1)[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)C[Mg]Br
Reactant: OC1CCC=C1Br
Agent: Cl[Ni]Cl
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)CC1=CCCC1O
Temperature: 25 °C

Procedure:
The alcohol (Intermediate D3, 16 mmol) in THF (30 mL) at 0 EC was treated with isobutyl magnesium bromide (40 mmol). The catalyst, 1,3-bis(diphenylphosphino)propane nickel (II) chloride (0.75 mmol) (NiCl2dppp) was added in one portion and the mixture was heated to reflux for 3 h. (see: Organ et al. J. Org. Chem. 1997, 62, 1523, incorporated herein by reference). The reaction mixture was cooled to rt and quenched with sat. NH4Cl solution. The mixture was filtered and partitioned between brine and diethyl ether. The organic layer was removed and dried over Na2SO4, filtered and concentrated under vacuum. The oil was purified by chromatography on SiO2 with 20% EtOAc:Hx to yield 2-isobutyl-cyclopent-2-enol (Intermediate D4). Use of 2-isobutyl-cyclopent-2-enol (Intermediate D4) in Method A produced 4-(2-isobutyl-cyclopent-2-enylmethyl)-1,3-dihydro-imidazole-2-thione (Compound 20).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[NH3:12].O>CN>[NH2:12][C:4]1[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=[C:2]([Br:1])[N:3]=1
Reactant: N
Reactant: Brc1cn2ccnc2c(Br)n1
Agent: CN
Solvent: O
Product: Nc1nc(Br)cn2ccnc12
Temperature: 85 °C

Procedure:
Procedure 1: A mixture of 1.00 eq. of 6,8-imidazo[1,2-a]pyrazine 3 in 28% Ammonia/water solution or 40% aqueous methyl amine is heated to between 80 to 90° C. for 24 hr. The resulting mixture is partitioned between CH2Cl2 and H2O. The aqueous layer is extracted with CH2Cl2 and the combined organic extracts are dried over Na2SO4. The solvent is removed under reduced pressure and the resulting residue is crystallized from ethanol to yield 4.
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][C:11]=3[O:13][C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=3[F:21])[NH:6][CH:5]=2)[CH2:3][CH2:2]1.Cl[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:26]=[C:25]([NH2:33])[N:24]=1.Cl.[OH-].[Na+]>O>[CH:1]1([C:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][C:11]=3[O:13][C:14]3[CH:20]=[CH:19][C:17]([NH:18][C:23]4[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[N:26]=[C:25]([NH2:33])[N:24]=4)=[CH:16][C:15]=3[F:21])[NH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc(Oc2ccnc3[nH]cc(C4CC4)c23)c(F)c1
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(Nc2ccc(Oc3ccnc4[nH]cc(C5CC5)c34)c(F)c2)cc(C(F)(F)F)n1

Procedure:
114 mg (0.40 mmol) of 4-[(3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3-fluoroaniline and 95 mg (0.48 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are suspended in 3.5 ml of water. 0.52 ml (0.52 mmol) of 1N hydrochloric acid are added, and the mixture is heated at reflux overnight. Another 30 mg (0.15 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are then added, and the mixture is heated for another 6 hours. By addition of 1N aqueous sodium hydroxide solution, the pH is adjusted to 10, resulting in the precipitation of crystals. The crystals are filtered off with suction and purified by chromatography on silica gel (mobile phase: dichloromethane/methanol (7N ammonia) 100:1 to 100:3).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:16][N:17](C)C(=O)C.N#CCl>ClCCCl>[C:16]([N:6]1[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH:9]=[CH:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)#[N:17]
Reactant: C1=Cc2ccccc2Nc2ccccc21
Reactant: CC(=O)N(C)C
Agent: N#CCl
Solvent: ClCCCl
Product: N#CN1c2ccccc2C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
By a procedure analogous to that described in Example 1, 97.0 g of 5H-dibenz[b,f]azepine are suspended in 320 ml of 1,2-dichloroethane, and 2 ml of N,N-dimethylacetamide are added. The temperature is raised to 60°, and 50 g of cyanogen chloride are introduced in the course of 2 hours, the reflux condenser being cooled to -17° in order to avoid loss of cyanogen chloride. The mixture is kept at 60° for 16 hours; a descending condenser is then fitted, and at normal pressure 200 ml of a mixture of cyanogen chloride and 1,2-dichloroethane are distilled off into a cooled receiver. During distillation, the 1,2-dichloroethane passing over is continuously replaced by fresh solvent in order to remove residual cyanogen chloride. The contents of the flask are cooled to room temperature; 200 ml of water are added, and the mixture is rendered permanently alkaline by the addition of 30% sodium hydroxide solution. Further processing, analogous to that in Example 2, yields 96.3 g of 5-cyano-5H-dibenz[b,f]azepine, which, according to the IR spectrum, is identical to authentic material; m.p. 108°-109°. A further 4 g of final product can be obtained from the mother liquor, and the total yield is 100.3 g (92% of theory).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][N:15]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]3[CH2:26][CH2:25][C:24](=O)[C:21]=32)=[N:16]1>O1CCCC1.O>[CH3:14][N:15]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]3[CH2:26][CH2:25][C:24](=[CH:5][C:3]#[N:4])[C:21]=32)=[N:16]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Cn1cc2c3c(ccc2n1)CCC3=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc2c3c(ccc2n1)CCC3=CC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a suspension of 60% sodium hydride (116 mg, 2.90 mmol) in tetrahydrofuran (8 mL) was added diethyl cyanomethylphosphonate (516 μL, 3.19 mmol), and the mixture was stirred at room temperature for 30 min. A solution of 2-methyl-6,7-dihydrocyclopenta[e]indazol-8(2H)-one (180 mg, 0.97 mmol) in tetrahydrofuran (2 mL) was added thereto, and the mixture was stirred at 50° C. for 30 min. The reaction solution was diluted with water, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=35/65→70/30) to give the title compound (138 mg, yield 68%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[NH:4][N:3]=1.[OH-].[K+].Cl[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]#[N:24])[CH2:19][CH2:18]1)=[O:16]>CN(C)C=O.O>[CH3:1][C:2]1[N:3]([CH2:14][C:15]([N:17]2[CH2:18][CH2:19][CH:20]([C:23]#[N:24])[CH2:21][CH2:22]2)=[O:16])[N:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[CH:6]=1
Reactant: N#CC1CCN(C(=O)CCl)CC1
Reactant: Cc1cc(C(F)(F)F)[nH]n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(C#N)CC1
Temperature: 7.5 °C
Reaction time: 8 h

Procedure:
A solution of 3-methyl-5-trifluoromethylpyrazole (9.3 g, 62 mmol) and 45% aqueous potassium hydroxide solution (7.79 g, 62 mmol) in N,N-dimethylformamide (25 mL) was cooled to 5° C., and 1-(2-chloroacetyl)-4-piperidinecarbonitrile (i.e. the product of Example 8, Step A or A1) (11.2 g, 60 mmol) was added. The reaction mixture was stirred for 8 h at 5-10° C., then diluted with water (100 mL), and filtered. The filter cake was washed with water and dried at 50° C. in a vacuum-oven to give 15 g of the title compound as a solid containing 3% of its regioisomer, i.e. 1-[2-[3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinecarbonitrile.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].[C:7]1([SH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(N(CC)CC)C.CCOCC>[C:7]1([S:13][CH:3]=[CH:2][C:1]([O:5][CH3:6])=[O:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Sc1ccccc1
Reactant: C#CC(=O)OC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)C=CSc1ccccc1
Reaction time: 24 h

Procedure:
A solution of 2.45 g (24.54 mmol) methyl propiolate and 20 ml ether is treated with 2.7 g (24.54 mmol) benzenethiol with 4 drops triethylamine in 25 ml ether over 15 min at 20°. After stirring for 24 hr, the reaction mixture is rotoevaporated to yield methyl 3-phenylthio-2-propenoate.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.P(Cl)(Cl)(Cl)=O.O.CN([CH:21]=[O:22])C>>[OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: Cn1nc(C(F)(F)F)cc1O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cn1nc(C(F)(F)F)c(C=O)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.2 %

Procedure:
Into 16.6 g (100.0 mmol) of 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole in 15.4 g of N,N-dimethylformaldehyde was added 16.2 g (105.0 mmol) of phosphorus oxychloride at 0° C., followed by 1 hour of stirring at room temperature. Furthermore, the whole was stirred at 100° C. for 1 hour. After the completion of the reaction was confirmed, the reaction solution was poured into water and the pH was made 10 or more with a 25% sodium hydroxide solution and then the aqueous layer was washed with ethyl acetate. The pH of the resulting aqueous layer was made about 4 with a saturated citric acid solution and then extracted with diethyl ether. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was purified by silica gel column chromatography to obtain 4.5 g (yield: 23.2%) of 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]1CCN2C(=NCCC2)CC1>>[CH3:16][N:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: c1ccc(-c2nc3ccccc3[nH]2)cc1
Product: Cn1c(-c2ccccc2)nc2ccccc21
Temperature: 90 °C

Procedure:
To a mixture of 2-phenylbenzimidazole (1.02 g, 5.25 mmol) in DMC (10 mL), DBU (0.80 g, 5.25 mmol) was added and the resulting mixture was heated to reflux (90° C.) for 6 hours. The solvent was evaporated under vacuum and the resulting oil was dissolved in methylene chloride (2 mL) and filtered through silica gel (2:1 EtOA/hexane). The solvent was evaporated under vacuum to afford 1-methyl-2-phenylbenzimidazole as a solid. The yield of 1-methyl-2-phenylbenzimidazole as determined by HPLC analysis was 98%.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23]C(=O)CCl)=[CH:19][CH:18]=2)[CH:8]=[C:9]([O:11][C:12](=[O:14])[CH3:13])[CH:10]=1)(=[O:3])[CH3:2].Cl>N1C=CC=CC=1>[C:12]([O:11][C:9]1[CH:8]=[C:7]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:6]=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:10]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Oc1cc(C=Cc2ccc(OC(=O)CCl)cc2)cc(OC(C)=O)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(C=Cc2ccc(O)cc2)cc(OC(C)=O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.7 %

Procedure:
A solution of 3,5-diacetoxy-4′-chloroacetoxy stilbene (0.388 g, 1 mmol) in 50% aqueous pyridine, which was adjusted to pH 6.7 with hydrochloric acid, was stirred for 6 h at room temperature. The mixture was concentrated and diluted with EtOAc. The mixture was washed with 1 N aqueous HCl, saturated NaHCO3 and water. Then the EtOAc solution was dried and concentrated. After purification by radial chromatography, the product (0.28 g, 90%) was obtained. Data are: 1H NMR (Aceton-d6, 300 MHz) δ 8.55 (bs, 1H), 7.47 (m, 2H), 7.25-7.00 (m, 4H), 6.86 (m, 2H), 6.82 (t, 1H, J=2.1 Hz), 2.27 (s, 3H); 13C NMR (Aceton-d6, 75 MHz) δ169.5, 158.7, 152.7, 141.2, 131.4, 129.5, 129.2, 124.8, 117.5, 116.6, 115.1, 21.0; HRMS (EI+) found 312.0993 M+, calcd 312.0998 for C18H16O6.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:14][C@@H:15]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:16](O)=[O:17])=[O:13])[CH:9]=[N:8][C:7]=2[N:23]2[CH2:26][C:25]([F:28])([F:27])[CH2:24]2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[F:61][C:62]([F:66])([F:65])[CH2:63][NH2:64]>CN(C=O)C>[CH3:22][CH:20]([CH3:21])[CH2:19][C@H:15]([NH:14][C:12]([C:10]1[CH:9]=[N:8][C:7]([N:23]2[CH2:26][C:25]([F:27])([F:28])[CH2:24]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:13])[C:16](=[O:17])[NH:64][CH2:63][C:62]([F:66])([F:65])[F:61]
Reactant: CC(C)C[C@H](NC(=O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(=O)O
Reactant: NCC(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
(S)-2-{[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carbonyl]-amino}-4-methyl-pentanoic acid (40 mg, 100 μmol) was suspended in DMF (2 mL). TBTU (35.5 mg, 110 μmol), DIEA (85.9 μl, 0.5 mmol) and 2,2,2-trifluoro-ethanamine hydrochloride (1:1) (CAN 373-88-6, 15 mg, 135 μmol) were added and the reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo; ethyl acetate (3 mL) and 2N NaOH solution (2 mL) were added before eluting with ethyl acetate through ChemElut (10 g). The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, 10 g, 0% to 100% ethyl acetate in n-heptane) to give the desired product (36 mg, 75%) as white solid; LC-MS (UV peak area, ESI) 100%, 480.2035 (M+H).
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16]([OH:18])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:41]=[C:42]([N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)[CH2:43][NH:44][C:45]([C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:49][CH:48]=1)=[O:46]>CN(C=O)C.O>[O:41]=[C:42]([N:59]1[CH2:64][CH2:63][N:62]([C:16]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][N:10]=2)=[O:18])[CH2:61][CH2:60]1)[CH2:43][NH:44][C:45]([C:47]1[CH:48]=[CH:49][C:50]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:51][CH:52]=1)=[O:46]
Reactant: O=C(O)c1cnccn1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cnccn2)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of pyrazine-2-carboxylic acid (31.9 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 90% EtOAc in hexane as eluent) to afford 43 mg (38.9% yield) of biphenyl-4-carboxylicacid {2-oxo-2-[4-(pyrazine-2-carbonyl)-piperazin-1-yl]-ethyl}-amide, LC-MS purity: 86.93%, 1H NMR: (DMSO) δ 8.9 (s, 1H), 8.8 (s, 1H), 8.7 (q, 2H), 8.0 (d, 2H), 7.8-7.7 (q, 4H), 7.5 (t, 2H), 7.4 (t, 1H), 4.2 (dd, 2H), 3.8 (s, 1H), 3.7 (d, 3H), 3.6-3.5 (m, 4H).