Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][C:9]=1[F:16])=[O:6].Cl[CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][N:21]=1.[OH-].[K+]>>[CH3:1][O:2][C:3](=[O:17])[CH:4]([CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][N:21]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][C:9]=1[F:16])=[O:6]
Reactant: ClCc1ccncn1
Reactant: COC(=O)CC(=O)Nc1ccc(SC)cc1F
Agent: [K+]
Agent: [OH-]
Product: COC(=O)C(Cc1ccncn1)C(=O)Nc1ccc(SC)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.1 %

Procedure:
N-(2-Fluoro-4-methylsulfanyl-phenyl)-malonamic acid methyl ester (15.4 g, 59.9 mmol), 4-chloromethyl-pyrimidine (5.13 g, 39.9 mmol) and potassium hydroxide (3.36 g, 59.9 mmol) were dissolved in IMS (150 mL). The reaction mixture was stirred at room temperature for 16 hours then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (30 mL), washed with water (20 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-100% ethyl acetate in cyclohexane) to yield the title compound as an off-white solid (4.9 g, 23%). LCMS (Method B): RT=3.02 min, M+H+=350.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)([N:3]1[CH:7]=[CH:6]N=C1)=[O:2].N[C:14]1[CH:25]=[CH:24]C=C[C:15]=1[CH2:16]C1NC=CN=1>C(Cl)Cl>[N:10]1[CH:11]=[CH:12][N:8]2[C:9]=1[CH2:24][C:25]1[CH:14]=[CH:15][CH:16]=[CH:6][C:7]=1[NH:3][C:1]2=[O:2]
Reactant: Nc1ccccc1Cc1ncc[nH]1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C1Nc2ccccc2Cc2nccn21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Alternately, 0.75 g of 1,1'-carbonyldiimidazole is added at once to a suspension of 0.79 g of 2-(2-aminobenzyl)imidazole in 38 ml of methylene chloride and the mixture is stirred at room temperature overnight. The resulting precipitate is collected and recrystallized from methylene chloride to give the crude 11H-imidazo[1,2-c][1,3]benzodiazepin-5(6H)-one, m.p. 238°-40°.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)(=O)[CH3:11].[OH-].[K+]>CO>[S:14]1[CH:15]=[CH:16][N:17]=[C:13]1[C:10]1[CH:11]=[CH:4][C:3]2[C:2](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: CC(=O)c1nccs1
Reactant: Nc1ncccc1C=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: c1cnc2nc(-c3nccs3)ccc2c1
Reaction time: 3 h
Yield: 46.5 %

Procedure:
2-Aminonicotinaldehyde (1.5 g, 12.3 mmol) and 2-acetylthiazole (1.64 g, 12.9 mmol) are dissolved in 12 ml of MeOH and the mixture is treated with 1.5 ml of 40% KOH. After 3 h, the reaction is complete and the mixture is poured onto water. The solid which is deposited is filtered off with suction, washed and dried. 1.22 g (yield 46%) of the desired product are obtained. M.p. 160°-165° C.
Reaction SMILES: [OH:1][CH:2]([C:7]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[NH:15][CH:16]=[CH:17][C:9]=2[C:8]=1[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[C:3]([O:5][CH3:6])=[O:4].[C:25]([O-])([O-])=O.[Cs+].[Cs+].CI.Cl>C(#N)C.O>[CH3:25][N:15]1[C:10]2[C:11](=[O:14])[N:12]([CH3:13])[C:7]([CH:2]([OH:1])[C:3]([O:5][CH3:6])=[O:4])=[C:8]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)[C:9]=2[CH:17]=[CH:16]1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(O)c1c(-c2ccc(C)cc2)c2cc[nH]c2c(=O)n1C
Agent: Cl
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Solvent: O
Product: COC(=O)C(O)c1c(-c2ccc(C)cc2)c2ccn(C)c2c(=O)n1C
Temperature: 50 °C
Reaction time: 3 h
Yield: 101.1 %

Procedure:
A suspension of methyl 2-hydroxy-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (30 mg, 0.092 mmol) and Cs2CO3 (35.9 mg, 0.110 mmol) in Acetonitrile (1 mL) was treated with MeI (6.90 μL, 0.110 mmol) and heated to 50° C. for 3 hours. Additional MeI (10 uL) was added, the reaction was stirred at 50° C. for 3 hours. The mixture was cooled to rt, diluted with water, acidified with 1N HCl, extracted with EtOAc 3×, washed with brine, dried with Na2SO4, filtered, and concentrated. Combined with crude product from the same reaction (0.040 mol scale) and purified with column chromatography (0-100% EtOAc/Hexane) to give methyl 2-(1,6-dimethyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-hydroxyacetate (31.7 mg, 0.093 mmol, 70.6% yield) as clear oil. LCMS (m/z) ES+=341 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[C:13]3[N:14]=[CH:15][C:16]([CH2:18][N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[CH:17][C:12]=3[C:11]3=[N:25][CH:26]=[N:27][N:10]3[C:9]2=[O:28])=[CH:5][CH:4]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:13]3[N:14]=[CH:15][C:16]([CH2:18][N:19]4[CH2:24][CH2:23][N:22]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:21][CH2:20]4)=[CH:17][C:12]=3[C:11]3=[N:25][CH:26]=[N:27][N:10]3[C:9]2=[O:28])=[CH:29][CH:30]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(CN4CCNCC4)cnc32)cc1
Solvent: CC#N
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc32)cc1
Reaction time: 4 h
Yield: 39.1 %

Procedure:
6-(4-Methoxybenzyl)-9-(piperazin-1-ylmethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (Example 65, 34 mg, 0.09 mmol), ACN (1 mL), TEA (75 μl, 0.53 mmol), and methane sulfonyl chloride (50 mg, 0.44 mmol) were combined and the mixture was stirred for 4 h. The reaction was filtered through a plug of C18. Purification (HPLC, 10-70% ACN in water) afforded the title compound (17 mg, 33%) as a white solid. 1H NMR (400 MHz, CDCl3 and DMSO-d6) δ 2.48 (d, J=1.63 Hz, 2H), 2.76 (d, J=2.26 Hz, 3H), 3.09 (br s, 4H), 3.54 (br s, 4H), 3.65 (d, J=2.51 Hz, 3H), 4.21 (br s, 2H), 5.63 (d, J=1.76 Hz, 2H), 6.72 (dd, J=8.78, 2.26 Hz, 2H), 7.47 (dd, J=8.66, 2.38 Hz, 2H), 8.26 (d, J=2.38 Hz, 1H), 8.85 (br s, 1H), 9.00 (br s, 1H). [M+H]=484.2.
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([O:9]C)[C:6]([C:11]2[S:12][CH:13]=[C:14]([CH3:16])[N:15]=2)=[CH:5][N:4]=1>Cl.O1CCOCC1>[CH3:16][C:14]1[N:15]=[C:11]([C:6]2[C:7](=[O:9])[NH:8][C:3](=[O:2])[NH:4][CH:5]=2)[S:12][CH:13]=1
Reactant: COc1ncc(-c2nc(C)cs2)c(OC)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1csc(-c2c[nH]c(=O)[nH]c2=O)n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
2,4-bis(methyloxy)-5-(4-methyl-1,3-thiazol-2-yl)pyrimidine (Prep40, 280 mg, 0.861 mmol) was dissolved in 18 mL of hydrochloric acid 4M in dioxane and the resulting mixture was stirred in a round bottomed flask at 90° C. for 2 hours. Then it was cooled to rt and dried under vacuum to afford the title compound as a yellow solid (300 mg, 0.760 mmol)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=2)[NH:20][C:19](=[O:31])[C:18]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Br:38])[CH:33]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[Br:38][C:34]1[CH:33]=[C:32]([C:18]2[C:19](=[O:31])[NH:20][C:21]3[C:26]([C:17]=2[O:16][CH2:15][CH2:14][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]2)=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([Cl:30])[CH:22]=3)[CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCOc1c(-c2cccc(Br)c2)c(=O)[nH]c2cc(Cl)c([N+](=O)[O-])cc12
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2c(OCCC2CCCCN2)c1-c1cccc(Br)c1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
To a solution of 2-{2-[3-(3-bromophenyl)-7-chloro-6-nitro-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (33 mg in 1.5 mL methylene chloride) was added 2 drops of anisole followed by 1.5 mL of trifluoroacetic acid and the mixture stirred at room temperature. After 1 hour the solvents were removed in vacuo and the resulting residue purified by flash chromatography on silica gel (methylene chloride:methanol, 95:5) to give the title compound (24 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)[CH:5]=O.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:23][CH:24]=[O:25])[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-n2cncn2)c(F)c1
Product: O=CC=Cc1ccc(-n2cncn2)c(F)c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 3-fluoro-4-(l H-1,2,4-triazol-1-yl)benzaldehyde (prepared as described in Reference Example 7) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 218 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:24]([OH:34])=[CH:23][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](O)[C:11]=1[CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[CH3:2].C(C1C=C(C2C=CC(F)=CC=2)C(O)=CC=1OCCCOC1C=CC=C(O)C=1CCC(O)=O)C>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[C:24]([OH:34])=[CH:23][C:4]([O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]3[C:11]4[CH2:17][CH2:18][C:19](=[O:20])[O:21][C:12]=4[CH:13]=[CH:14][CH:15]=3)=[C:3]([CH2:1][CH3:2])[CH:26]=2)=[CH:28][CH:29]=1
Reactant: CCc1cc(-c2ccc(F)cc2)c(O)cc1OCCCOc1cccc(O)c1CCC(=O)OC
Agent: CCc1cc(-c2ccc(F)cc2)c(O)cc1OCCCOc1cccc(O)c1CCC(=O)O
Product: CCc1cc(-c2ccc(F)cc2)c(O)cc1OCCCOc1cccc2c1CCC(=O)O2

Procedure:
When methyl 3-(2-(3-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy)propoxy)-6-hydroxyphenyl)propionate (Example 12) was hydrolyzed under the conditions of Preparation 26, in addition to the desired product 3-(2-(3-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy)propoxy)-6-hydroxyphenyl)propionic acid (Example 13), the title product was isolated in 10% yield, as isolated by preparative reverse phase HPLC. NMR, MS. Analysis for C26H25FO5 : Calc: C, 76.55; H, 5.77; Found: C, 76.39; H, 5.92.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH:9](B(O)O)=[CH2:10].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([CH:9]=[CH2:10])=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: C=CB(O)O
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: C=Cc1ccc(Cl)nn1
Temperature: 80 °C
Yield: 91.8 %

Procedure:
A mixture of 3,6-dichloropyridazine (6 g, 40.3 mmol), vinyl boronic acid pinnacol ester (6.21 g, 6.83 mL, 40.3 mmol), potassium carbonate (120 mmol, 16.7 g), 1,4-dioxane (60 mL) and water (24 mL) was degassed for 15 min with nitrogen gas. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.4 mmol, 292 mg) was then added and the mixture heated to 80° C. for 4 hours. The aqueous phase was then removed via pipette and the organic phase concentrated onto silica gel and purified via flash column chromatography (SiO2, hexane:ethyl acetate 100:0-60:40) to return the title compound as a white solid (5.2 g, 92% yield). 1H NMR (CDCl3): δ 5.75 (1H, d), 6.25 (1H, d), 7.05 (1H, dd), 7.49 (1H, d), 7.59 (1H, d). MS m/z=141 (M+H+)+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([NH:16][C:17]1[S:18][NH:19][C:20]2[CH:26]=[C:25]([O:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)(=[O:30])=[O:29])[CH:24]=[CH:23][C:21]=2[N:22]=1)([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.O>[C:12]([NH:16][C:17]1[S:18](=[O:9])[NH:19][C:20]2[CH:26]=[C:25]([O:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:40])[F:38])[CH:32]=3)(=[O:30])=[O:29])[CH:24]=[CH:23][C:21]=2[N:22]=1)([O:14][CH3:15])=[O:13]
Reactant: COC(=O)NC1=Nc2ccc(OS(=O)(=O)c3cccc(C(F)(F)F)c3)cc2NS1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)NC1=Nc2ccc(OS(=O)(=O)c3cccc(C(F)(F)F)c3)cc2NS1=O
Reaction time: 0.25 h

Procedure:
A solution of 240 mg of m-chloroperbenzoic acid in 10 ml of dioxan was introduced, while stirring, into a solution of 0.54 g of 3-carbomethoxyamino-7-(3-trifluoromethyl-phenylsulfonyloxy)-1H-2,1,4-benzothiadiazine in 50 ml of dioxan. The mixture was stirred for 15 minutes, then it was diluted with 100 ml of water, neutralized with sodium carbonate solution, and subsequently the whole was shaken with ethyl acetate. After washing out the ester extract with sodium chloride solution, the ester solution was strongly concentrated, and the separated 3-carbomethoxyamino-7-(3-trifluoromethyl-phenylsulfonyloxy)-1H-2,1,4-benzothiadiazine-S-oxide was isolated by way of filtration. The yield was 120 mg.
Reaction SMILES: C(O/[CH:4]=[CH:5]\[C:6]1[C:11]([C:12]#[N:13])=[CH:10][N:9]=[C:8]([S:14][CH3:15])[N:7]=1)C.BrN1C(=O)CCC1=O.[CH2:24]([C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1)[CH3:25].C(=O)([O-])O.[Na+]>O1CCOCC1.O>[CH2:24]([C:26]1[C:27]2[N:28]([C:5]([C:6]3[C:11]([C:12]#[N:13])=[CH:10][N:9]=[C:8]([S:14][CH3:15])[N:7]=3)=[CH:4][N:32]=2)[CH:29]=[CH:30][CH:31]=1)[CH3:25]
Reactant: CCO/C=C\c1nc(SC)ncc1C#N
Reactant: CCc1cccnc1N
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1cccn2c(-c3nc(SC)ncc3C#N)cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
4.89 g of 4-[(Z)-2-ethoxyvinyl]-2-(methylthio)-5-pyrimidinecarbonitrile (synthesized according to the method disclosed in International Publication WO2006/025567, page 90 to 91) was dissolved in a mixed solvent of 50 mL of 1,4-dioxane and 5 mL of water, then 3.93 g of N-bromosuccinimide was added under an ice-cold condition, and the mixture was stirred for 1 hour at room temperature. To the reaction solution was added 2.7 g of 3-ethylpyridine-2-amine (synthesized according to the method disclosed in International Publication WO2006/025567, page 142), and the solution was stirred overnight at room temperature. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, the solution was extracted with chloroform, and the resulting organic layer was dried over anhydrous sodium sulfate. The insolubles were filtered, and the filtrate was concentrated under reduced pressure. Diethylether was added to the resulting residue, and the resultant solution was stirred for 3 hours. Thus produced solid was taken by filtration and dried under reduced pressure to obtain 4.46 g of 4-(8-ethylimidazo[1,2-a]pyridin-3-yl)-2-(methylthio)pyrimidine-5-carbonitrile [5-6] (hereinafter, referred to as the compound [5-6]) as a pale yellow solid.
Reaction SMILES: C([N:9]1[CH2:14][CH2:13][C:12]2[C:15]3[C:16]([S:39][C:11]=2[CH2:10]1)=[N:17][C:18]([CH2:33][N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])=[C:19]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:20]=3[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)(=O)C1C=CC=CC=1.Cl.[OH-].[Na+]>O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C:19]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:18]([CH2:33][N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])[N:17]=[C:16]3[S:39][C:11]4[CH2:10][NH:9][CH2:14][CH2:13][C:12]=4[C:15]=23)=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(Cl)cc1)CCN(C(=O)c1ccccc1)C3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(Cl)cc1)CCNC3
Temperature: 90 °C
Reaction time: 4 h
Yield: 78.7 %

Procedure:
A mixture of the compound obtained in Example 4A (2.09 g) and concentrated hydrochloric acid (8 ml)-water (16 ml) was stirred at 90° C. for 4 hours. After the reaction mixture was alkalinized with 1N NaOH, it was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residual solid was recrystallized from ethyl acetate-hexane to yield ethyl 4-(4-chlorophenyl)-2-(N,N-diethylaminomethyl)-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine-3-carboxylate (for structural formula, see below) (1.34 g, 79%) as colorless needle crystals having a melting point of 104 to 106° C. ##STR46##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[NH:12][C:13]([NH:15]/[N:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]=[CH:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=3)[N:25]=2)=[CH:20][CH:19]=1)=[S:14].Cl[CH2:41][C:42](=[O:44])[CH3:43].C(N(CC)CC)C.O>CC(=O)CC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1/[N:12]=[C:13]1\[S:14][CH2:41][C:42]([CH3:43])([OH:44])[N:15]\1/[N:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]=[CH:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:38])([F:39])[F:37])=[CH:31][CH:30]=3)[N:25]=2)=[CH:20][CH:19]=1
Reactant: CC(=O)CCl
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(/C=N/NC(=S)Nc4c(Cl)cccc4C(F)(F)F)cc3)n2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: CC1(O)CS/C(=N\c2c(Cl)cccc2C(F)(F)F)N1/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To a solution of (E)-N-(2-chloro-6-(trifluoromethyl)phenyl)-2-(4-(1-(4-(trifluoromethoxy)-phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (111 mg, 0.19 mmol) in butanone (2 mL) was added chloroacetone (0.02 mL, 0.27 mmol) and triethylamine (0.05 mL, 0.38 mmol), and the reaction was stirred at 75° C. for 16 hours. The mixture was allowed to cool to room temperature, transferred to a separatory funnel containing water (5 mL), and was extracted twice with dichloromethane. The organic extracts were filtered through a phase separator, adsorbed onto silica gel, and purified by flash chromatography (0-20% ethyl acetate/B, where B=1:1 dichloromethane/hexanes). The title compound was isolated as a yellow solid (60.5 mg, 50%): mp 97° C. (dec); 1H NMR (400 MHz, CDCl3) δ 9.72-9.57 (m, 1H), 8.58 (s, 1H), 8.24 (d, J=8.4 Hz, 2H), 7.88-7.72 (m, 4H), 7.56 (dt, J=18.3, 5.8 Hz, 2H), 7.40 (d, J=8.3 Hz, 2H), 7.09 (t, J=8.0 Hz, 1H), 3.49 (d, J=13.3 Hz, 1H), 3.35 (m, 2H), 1.86 (d, J=14.0 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ−58.01, −62.05, −62.22; ESIMS m/z 642 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13]CC)=O.C[S-].[Na+].IC>C(O)C.O>[Br:8][C:6]1[CH:7]=[C:2]2[C:3]([CH:9]=[CH:10][C:11](=[O:13])[NH:1]2)=[CH:4][N:5]=1
Reactant: CCOC(=O)/C=C/c1cnc(Br)cc1N
Agent: C[S-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CCO
Product: O=c1ccc2cnc(Br)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 80.5 %

Procedure:
(E)-Ethyl 3-(4-amino-6-bromopyridin-3-yl)acrylate (Preparation 68, 1.20 g 4.43 mmole) and sodium methanethiolate (320 mg 4.57 mmole) in ethanol (12 mL) were heated under microwave radiation at 80° C. for 25 minutes. Iodomethane (284 uL, 648 mg, 4.56 mmole) was added to the cooled reaction and the reaction was stirred at room temperature for 45 minutes before diluting with water (6 mL). The resulting precipitate was collected, washed with water and dried under high vacuum to afford the title compound (803 mg, 80%).
Reaction SMILES: [Li].[CH2:2]([O:4][C:5](=[O:18])[C:6](=O)[CH:7]([CH3:16])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)[CH3:3].Cl.[NH:20]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[NH2:21].[OH-].[Na+]>C(O)C>[CH2:2]([O:4][C:5]([C:6]1[C:7]([CH3:16])=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:20]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[N:21]=1)=[O:18])[CH3:3]
Reactant: NNc1cccnc1
Reactant: CCOC(=O)C(=O)C(C)C(=O)c1ccccc1
Agent: Cl
Agent: [Li]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nn(-c2cccnc2)c(-c2ccccc2)c1C

Procedure:
The above-obtained lithium salt of 3-methyl-4-phenyl-2,4-dioxobutanoic acid ethyl ester (1.502 g) was dissolved in ethanol (30 mL). To the resultant mixture were added 1M HCl in ethanol (8 mL) and 3-hydrazinopyridine (1.977 g) obtained from Referential Example 52, followed by refluxing for 2.5 hours. The mixture was cooled in air. The reaction mixture was alkalinized to pH 10 with an aqueous solution of sodium hydroxide. The mixture was partitioned between chloroform and water. The aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, and then dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-acetone), to thereby give the title compound as an oily substance (1.428 g, 34%).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([C:30]1[CH:35]=[CH:34][C:33](Br)=[CH:32][N:31]=1)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29].C([O-])(=O)C.[K+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.[OH2:69]>CS(C)=O.C(OCC)(=O)C>[F:45][C:2]([F:1])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:41])[F:42])[CH:39]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29])[C:30]1[N:31]=[CH:32][C:33]([OH:69])=[CH:34][CH:35]=1
Reactant: O
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(Br)cn1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(O)cn1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyridin-2-yl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine (475 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium methylene chloride complex (55 mg), potassium acetate (198 mg) and bis(pinacolato)diboron (256 mg) are dissolved in dimethylsulfoxide (2 ml), and the mixture is heated to 80° C. under nitrogen atmosphere and stirred for 1 hour. The reaction solution is cooled to room temperature and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed twice with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (10 ml), and thereto is added dropwise a 30% aqueous hydrogen peroxide solution (0.75 ml) under ice-cooling. The reaction solution is stirred at room temperature overnight, and thereto is added a saturated aqueous sodium thiosulfate solution under ice-cooling to consume the excess hydrogen peroxide, followed by an addition of water and diethylether, and the mixture is separated. The organic layer is washed successively with water and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give 6-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyridin-3-ol (141 mg). MS (m/z): 643 [M+H]+
Reaction SMILES: [N:1]1([C:6](=[O:24])[CH2:7][C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[N:13][C:12]=23)C=CN=[CH:2]1.CN>O1CCCC1.O>[CH3:2][NH:1][C:6](=[O:24])[CH2:7][C:8]1[C:9]([C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[N:10][N:11]2[CH:16]=[CH:15][CH:14]=[N:13][C:12]=12
Reactant: Cc1ccc(-c2nn3cccnc3c2CC(=O)n2ccnc2)cc1
Agent: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)Cc1c(-c2ccc(C)cc2)nn2cccnc12
Reaction time: 36 h
Yield: 39.2 %

Procedure:
A stirred slurry of 3.2 g (0.010 mole) of 3-[2-(1H-imidazole-1-yl)-2-oxoethyl]-2-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine (prepared from 2-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine-3-acetic acid and 1,1'-carbonyldiimidazole) in 20 ml of dry tetrahydrofuran was treated with 3 ml of monomethylamine in 10 ml of dry tetrahydrofuran added dropwise from a needle and syringe. After stirring for 36 hours the reaction mixture was diluted with 100 ml of water and the resulting solid collected by filtration (1.7 g). The crude product was recrystallized from acetonitrile to yield 1.1 g (38.9%) of beige crystals, mp 207°-208° C.