Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][C:6]1[C:7]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[N:24]([C:31]5[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=5[Cl:38])[N:25]=[CH:26][C:27]=4[CH:28]([CH3:30])[CH3:29])=[CH:17][C:16]=3[CH3:39])=[CH:11][C:8]=2[S:9][CH:10]=1)C.[OH-].[Na+]>O1CCCC1.CO>[Cl:37][C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:38])[C:31]=1[N:24]1[C:23]([CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:13]=[CH:14][C:7]4[C:6]([CH2:5][C:4]([OH:40])=[O:3])=[CH:10][S:9][C:8]=4[CH:11]=3)=[C:16]([CH3:39])[CH:17]=2)=[C:27]([CH:28]([CH3:30])[CH3:29])[CH:26]=[N:25]1
Reactant: CCOC(=O)Cc1csc2cc(-c3ccc(OCc4c(C(C)C)cnn4-c4c(Cl)cccc4Cl)cc3C)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1-c1ccc2c(CC(=O)O)csc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
A solution of (6-{4-[2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-benzo[b]thiophen-3-yl)-acetic acid ethyl ester (43 mg; 0.072 mmoles) in tetrahydrofuran (1.0 mL) and methanol (1.0 mL) is treated with sodium hydroxide (1.0 mL; 1.0 N). The mixture is stirred at room temperature for 2 hours and quenched with HCl (1.0 mL, 1.0 M). The mixture is extracted with EtOAc (10 mL×2). The combined organic layers are dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography (eluting with 30-100% EtOAc/Hexanes) and the appropriate fractions are concentrated. The material is dried in vacuo to afford the title compound (28 mg, 68%). ES/MS m/e 564.8; 566.8 (M+1); 562.8; 564.8 (M−1)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10])[CH3:2].[CH2:12]=[O:13].CC([O-])(C)C.[K+]>CS(C)=O.C(O)(C)(C)C>[N+:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH:1]([CH3:2])[CH2:12][OH:13])([O-:11])=[O:10]
Reactant: CCc1ccccc1[N+](=O)[O-]
Reactant: C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Product: CC(CO)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
1-Ethyl-2-nitrobenzene (13.5 mL, 100 mmol) was dissolved in dimethylsulfoxide (100 mL). Paraformaldehyde (4.50 g, 150 mmol) and KOtBu (2.81 g, 25 mmol) in t-butyl alcohol (30 mL) were added and the mixture was stirred at room temperature for 3 h. The solution was washed with a molar solution of HCl (25 mL), followed by brine (3×100 mL). All the aqueous layers were combined and extracted with ethyl acetate(3×100 mL). The organic portion was dried (MgSO4), filtered and the solvent was removed in vacuo. The crude product was purified on a silica gel column. Elution of the column with 20-30% ethyl acetate in hexanes gave 16.12 g (89 mmol, 89% yield) of 2-(2-nitrophenyl)propanol. 1H-NMR (600 MHz, DMSO-d6): δ 7.75 (d, J=8.10 Hz, 1H, Ar—H), 7.63 (t, J=7.62 Hz, 1H, Ar—H), 7.58 (d, J =7.80 Hz, 1H, Ar—H), 7.42 (t, J=7.50, 1H, Ar—H), 4.73 (t, J=5.30 Hz, 1H, OH), 3.50 (m, 2H, CH 2), 3.19 (m, 1H, CH), 1.21 (d, J=6.90 Hz, 3H, CH3). TLC: 20% ethyl acetate in hexane, Rf=0.3.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH:5]=[CH:4][CH2:3]1.C([O-])(O)=O.[Na+].[I:16]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[I:16][C@@H:4]1[C@@H:5]2[CH2:6][C@@H:7]([C:8](=[O:10])[O:9]2)[C@H:2]([CH3:1])[CH2:3]1
Reactant: C[C@@H]1CC=CC[C@H]1C(=O)O
Reactant: II
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1C[C@H](I)[C@@H]2C[C@H]1C(=O)O2
Reaction time: 24 h
Yield: 29022.6 %

Procedure:
To a solution of optically active 5 (16.8 g, 120 mmol), in methylene chloride (200 mL) and water (400 mL), was added NaHCO3 (20.1 g, 240 mmol), KI (120 g, 0.720 mmol) and iodine (91.0 g, 0.360 mmol). The resulting mixture was protected from light and stirred for 24 h. The solution was cooled (0° C.) and sodium thiosulfate was carefully added until the dark iodine color disappeared. This was extracted with diethyl ether (4×300 mL). The combined organics were dried (MgSO4) and the volatiles were removed in vacuo to give a yellowish solid (27.8 g, 87% yield). This was carried onto the next step without further purification. Rf 0.33 (ethyl acetate/hexane 1:9); m.p. 99-100° C.; 1H NMR (300 MHz, CDCl3) δ 4.86 (dd, J=3.6, 5.9, 1H), 4.35-4.38 (m, 1H), 2.90 (m, 1H), 2.63-2.73 (m, 1H), 2.49-2.52 (m, 1H), 2.20-2.36 (m, 2H), 1.95-2.00 (m, 1H). 1.38 (d, J=7.2, 3H); 13C NMR (75 MHz, CDCl3) δ 178.2, 81.6, 43.8, 34.3, 29.3, 27.8, 19.5, 19.1; MS (EI) m/z 266 (M+, 4), 139 ([M-I]+, 80), 95 (100), 79 (16), 67 (26), 55 (29); [α]D−3.60° (c=2.22, CHCl3).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:11])[CH2:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[CH:20]=[O:21]>>[OH:21][CH:20]([CH:9]1[C:8](=[O:11])[C:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=2[O:10]1)[C:19]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: Cc1cccc2c1C(=O)CO2
Reactant: CCOC(=O)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)C1Oc2cccc(C)c2C1=O

Procedure:
A solution of 4-methyl-2,3-dihydro-1-benzofuran-3-one (26c) (200 mg, 1.35 mmol) in ethyl glyoxylate 50% in toluene (0.40 mL, 2.02 mmol) was heated at 100° C. for 16 hours. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 95/5 to 80/20) to provide ethyl 2-hydroxy-2-(4-methyl-3-oxo-2,3-dihydro-1-benzofuran-2-yl)acetate (26d) (200 mg, 0.8 mmol) which was dissolved in a mixture of cyclohexane (2 mL) and dichloromethane (0.5 mL) before adding silver oxide (560 mg, 2.4 mmol) and tert-butyl bromide (0.54 mL, 4.8 mmol). The mixture was stirred at room temperature for 60 hours, with addition of silver oxide and tert-butyl bromide every hour of working day until the reaction stopped evolution. The mixture was filtered over Celite®, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to provide ethyl 2-(tert-butoxy)-2-(4-methyl-3-oxo-2,3-dihydro-1-benzofuran-2-yl)acetate (26e) (73 mg, 0.238 mmol) which was dissolved in a mixture of dimethylformamide (1.5 mL) and tetrahydrofuran (0.2 mL) under argon atmosphere. This mixture was cooled at −78° C. and a 1.0 M solution of potassium t-butoxide in tetrahydrofuran (0.26 mL, 0.262 mmol) was added. After 1 hour stirring at −78° C., a solution of N-phenyl-bis(trifluoromethanesulfonimide) (98 mg, 0.274 mmol) in dimethylformamide (0.07 mL) and tetrahydrofuran (0.3 mL) was slowly added and the mixture was further stirred at the same temperature for 90 minutes. The reaction was quenched by addition of saturated sodium carbonate solution (5 mL) and the mixture was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 80/20) to provide ethyl 2-(tert-butoxy)-2-{4-methyl-3-[(trifluoromethane)sulfonyloxy]-1-benzofuran-2-yl}acetate (26f) (60 mg, 0.137 mmol, 17% over 3 steps).
Reaction SMILES: S1C=CCS1.[CH2:6]1[C@@H:10]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[S:9][S:8][CH2:7]1.[BH4-].[Na+].Cl>C(=O)(O)[O-].[Na+].C1(C)C=CC=CC=1.O>[CH2:12]([CH2:11][C@@H:10]([SH:9])[CH2:6][CH2:7][SH:8])[CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Agent: C1=CSSC1
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)CCCC[C@@H](S)CCS
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 80 %

Procedure:
The synthesis of a bidentate dithiol ligand was accomplished via the reduction of the coenzyme lipoic acid. The general procedure was described in I. C. Gunsalus, L. S. Barton, W. Gruber, J. Am. Chem. Soc. 78:1763-1766 (1956). Sodium borohydride (1.2 g) was added in 30-50 mg portions to a stirring suspension of lipoic acid (6.0 g) in 117 mL of 0.25 M sodium bicarbonate in 0° C. water. The reaction was stirred for 45 minutes at 0° C., after which 100 mL toluene was added and the mixture was acidified to pH˜2 with hydrochloric acid. The toluene layer was collected and saved. The aqueous layer was washed three times with 15 mL toluene. The organic layers were combined, dried with anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum, leaving behind the product dihydrolipoic acid as a yellow oil (yield 80%).
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[CH2:11][CH2:10][N:9]([C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=2[Cl:22])[C:8]2[CH:24]=[CH:25][S:26][C:7]=2[CH2:6]1)C.[NH2:27]N>C(O)C>[Cl:22][C:14]1[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=1[C:12]([N:9]1[CH2:10][CH2:11][C:5]2[CH:4]=[N:2][NH:27][C:6]=2[C:7]2[S:26][CH:25]=[CH:24][C:8]1=2)=[O:23]
Reactant: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2Cl)c2ccsc2C1
Reactant: NN
Solvent: CCO
Product: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCc2cn[nH]c2-c2sccc21
Temperature: 60 °C

Procedure:
To a mixture of 2.2 g of 7-[(dimethyl-amino)methylene]-4,5,6,7-tetrahydro-4-(2-chloro-4-nitrobenzoyl)-8H-thieno[3,2-b]azepine in 40 ml of ethanol is added 341 μl of hydrazine followed by heating at 60° C. for 1.5 hours. The volatiles are evaporated in vacuo to a residue which is dissolved in 100 ml of ethyl acetate and filtered through a pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to give 1.85 g of the desired product as a yellow-orange solid.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[NH:5][N:4]=[C:3]1[S:8][C:9]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O.[C:22]1(=[O:29])[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH2:23]1.C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C.C[Si](C#N)(C)C>>[CH3:1][N:2]1[C:6](=[O:7])[NH:5][N:4]=[C:3]1[S:8][C:9]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:10]=1[C:11]([CH:23]1[C:24](=[O:28])[CH2:25][CH2:26][CH2:27][C:22]1=[O:29])=[O:13]
Reactant: O=C1CCCC(=O)C1
Reactant: Cn1c(Sc2cc(C(F)(F)F)ccc2C(=O)O)n[nH]c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Product: Cn1c(Sc2cc(C(F)(F)F)ccc2C(=O)C2C(=O)CCCC2=O)n[nH]c1=O
Temperature: 20 °C
Reaction time: 48 h
Yield: 67.7 %

Procedure:
A mixture of 0.80 g (2.5 mmol) of 2-[(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-sulphanyl]-4-trifluoromethyl-benzoic acid, 0.28 g (2.5 mmol) of 1,3-cyclohexanedione and 0.63 g (3.1 mmol) of N,N′-dicyclohexylcarbodiimide is stirred at room temperature (approximately 20° C.) for 48 hours. 0.7 ml (5 mmol) of triethylamine and a drop of trimethylsilyl cyanide are then added, and the mixture is stirred for a further 24 hours. The mixture is then concentrated under water pump vacuum and the residue is stirred with 10% strength aqueous sodium carbonate solution. The mixture is then filtered and the filtrate is washed twice with diethyl ether, acidified with 2N hydrochloric acid and extracted with dichloromethane. The organic phase is dried over magnesium sulphate and the solvent is removed under reduced pressure, giving 0.7 g (68% of theory) of 2-[2-[(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-sulphanyl]-4-trifluoromethyl-benzoyl]-1,3-cyclohexanedione as an oil (log P=2.00).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([O:19][CH3:20])[CH:9]=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:4])=[O:3].[C:21](Cl)(=[O:23])[CH3:22].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][S:2]([NH:5][C:6]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][C:9]([C:21]([CH3:22])=[O:23])=[C:8]([O:19][CH3:20])[CH:7]=1)(=[O:4])=[O:3]
Reactant: COc1ccc(Oc2ccccc2)c(NS(C)(=O)=O)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(NS(C)(=O)=O)c(Oc2ccccc2)cc1C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
In 100 ml of anhydrous methylene chloride were dissolved 10 g of 3-methylsulfonylamino-4-phenoxyanisole and 2.81 g of acetyl chloride. Thereto was added 9.1 g of aluminum chloride in 5 minutes with ice-cooling. The mixture was stirred for 1 hour at 20°-25° C. The reaction mixture was introduced into 100 ml of ice water. The resulting organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from isopropyl alcohol to obtain 9.83 g (yield: 86%) of methyl 4-methylsulfonylamino-2-methoxy-5-phenoxyphenyl ketone having a melting point of 108.5-110° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[F:15][C:14]([F:17])([F:16])[C:12]1[CH:11]=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([CH2:29][OH:28])=[CH:31][CH:32]=3)[CH:7]=[CH:6][CH:5]=2)[N:13]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1
Product: OCc1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)cc1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.3) (0.22 g, 0.5 mmol) and commercially available 4-hydroxymethyl-phenyl-boronic acid (0.09 g, 0.6 mmol) according to the general procedure VI. Obtained as a white solid (0.199 g, 54%). MS (ISP) 475.1 [(M+H)+]; mp 171° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([C:18]2[C:19]([CH3:29])=[N:20][N:21]([CH2:23][C:24]([O:26]CC)=[O:25])[CH:22]=2)=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])#[N:2].[OH-].[Na+]>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([C:18]2[C:19]([CH3:29])=[N:20][N:21]([CH2:23][C:24]([OH:26])=[O:25])[CH:22]=2)=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])#[N:2]
Reactant: CCOC(=O)Cn1cc(C(=O)Nc2ccc(OCC(C)(C)C)c(C#N)c2)c(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(CC(=O)O)cc1C(=O)Nc1ccc(OCC(C)(C)C)c(C#N)c1
Reaction time: 0.5 h
Yield: 30.7 %

Procedure:
Ethyl 4-[N-(3-cyano-4-neopentyloxyphenyl)carbamoyl]-3-methylpyrazol-1-ylacetate (0.7 g) was added to ethanol (5 ml) and 10% aqueous sodium hydroxide solution (5 ml) was added. The mixture was stirred at a refluxing temperature for 30 min. The solvent was evaporated under reduced pressure. To the residue was added dilute hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-diisopropyl ether to give the title compound (0.2 g), melting point: 234–245° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=4)[CH:22]=[CH:21][N:20]=3)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]3[N:24]=[C:23]([C:25]4[CH:26]=[CH:27][C:28]([NH:31][S:38]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)(=[O:40])=[O:39])=[CH:29][CH:30]=4)[CH:22]=[CH:21][N:20]=3)=[CH:16][CH:17]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(N)cc4)n3)cc2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)N1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(NS(=O)(=O)c5ccccc5)cc4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-acetyl-4-[(4-{[4-(4-aminophenyl)pyrimidin-2-yl}amino}phenyl)carbonyl}piperazine (100 mg, 0.24 mmol) in pyridine (5 mL) containing a catalytic amount of DMAP is added benzenesulfonyl chloride (50 mg, 0.29 mmol) and the solution is stirred overnight at room temperature. The pyridine is removed under vacuum and the residue extracted into methylene chloride and washed with 1N HCl. Evaporation of solvent provides the crude piperazine which is purified by preparative HPLC (10-60% CH3CN over 25 min.)to give an analytically pure sample as a yellow solid: M+1; 557.3. HPLC Retention Time; 9.59 min (Method B).
Reaction SMILES: [C:1]([CH:3]([C:7]1[C:8]([CH2:24][CH:25]2[CH2:27][CH2:26]2)=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:10]([CH:17]([F:19])[F:18])=[N:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[CH2:4][CH:5]=[CH2:6])#N.[H-].C([Al+]CC(C)C)C(C)C.Cl.CC[O:41]CC>>[CH:25]1([CH2:24][C:8]2[C:7]([CH:3]([CH:1]=[O:41])[CH2:4][CH:5]=[CH2:6])=[C:12]([C:13]([F:15])([F:16])[F:14])[N:11]=[C:10]([CH:17]([F:18])[F:19])[C:9]=2[C:20]([O:22][CH3:23])=[O:21])[CH2:26][CH2:27]1
Reactant: C=CCC(C#N)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1CC1CC1
Reactant: CCOCC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Product: C=CCC(C=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1CC1CC1
Reaction time: 0.5 h

Procedure:
To a solution of 16.5 g(68.3 mmol) of methyl 5-(1-cyano-3-butenyl)-4-(cyclopropylmethyl)-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridine-carboxylate (example 16 of U.S. Pat. No. 5,169,432) in 250 ml of ether cooled in an ice bath was added 91 ml (136 mmol) of diisobutylaluminum hydride (1.5 M in toluene). The reaction mixture was stirred on an ice bath for 30 min and was treated with 200 ml of 2.4 M HCl. The organic layer was washed with brine, dried (MgSO4), and filtered through silica gel. The filtrate was concentrated in vacuo and the residue was purified by HPLC (17% EtOAc in hexane) to give 8.1 g of methyl 4-(cyclopropylmethyl)-2-(difluoromethyl)-5-(1-formyl-3-butenyl)-6-(trifluoromethyl)-3-pyridinecarboxylate.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:22])([CH3:21])[CH:8]1[CH2:12][N:11]([CH:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10](=[O:20])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:23][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[C:1]([SiH2:5][O:6][C:7]([CH3:22])([CH3:21])[CH:8]1[CH2:12][N:11]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[C:10](=[O:20])[CH:9]1[CH3:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1CC(=O)N(C2CCCCCC2)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1C(=O)N(C2CCCCCC2)CC1C(C)(C)O[SiH2]C(C)(C)C
Reaction time: 2 h

Procedure:
A solution of Example 1B (1.09 g, 3.07 mmoles) in tetrahydrofuran (3.5 mL) was added drop wise to a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (3.7 mL, 3.7 mmoles) at room temperature and stirred for two hours at that temperature. A solution of methyl iodide (0.54 g, 3.83 mmoles) in tetrahydrofuran (1 mL) was added drop wise to the reaction mixture at room temperature and stirred for another two hours. The reaction was quenched with 10% NH4Cl (25 mL) and extracted with ethyl acetate. The organic layer was washed with brine (25 mL), dried with MgSO4, filtered, and solvent evaporated in vacuo. The crude product was purified by flash column chromatography (hexanes:ethyl acetate 95:5 to 60:40) to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12].[SH2:13].C(NCC)C>CN(C=O)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[S:13])[NH2:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12]
Reactant: S
Reactant: CCCc1cc(C#N)ccc1O
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCCc1cc(C(N)=S)ccc1O
Temperature: 7 °C
Reaction time: 54 h
Yield: 93 %

Procedure:
A solution of 4-hydroxy-3-propylbenzonitrile (35.63 g, 0.221 mol) (Example 33) in DMF (300 mL) was saturated with hydrogen sulfide at rt (moderate flow over 45 minutes). Temperature was monitored (increase of about 7° C.). To the solution was added diethylamine (45.73 mL, 0.442 mol). The temperature increased by 10° C., and the green reaction mixture became darker green. Hydrogen sulfide was passed into the dark green solution for another 30 minutes (at this point the reaction temperature was 40° C.). The reaction mixture was warmed to 60° C. Hydrogen sulfide was again passed into the solution at 60° C. over 2 h. The reaction mixture was cooled and stirred at rt for 54 h and most of the solvent removed under reduced pressure. The resultant residue was partitioned between ethyl acetate (300 mL) and water (200 mL). The organic layer was washed with water (4×100 mL), then brine, and dried over sodium sulfate, filtered, and concentrated. The resultant orange oil was triturated in hexanes (300 mL) and ether (25 mL) to give a yellow solid (39.97 g, 93%) after drying for 1 h under suction. LC/MS m/z 196.1 (M+H)+, RT 2.16 min. 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.44 (s, 1H), 9.14 (s, 1H), 7.73-7.65 (m, 2H), 6.73 (d, 1H), 2.51-2.47 (m, 2H), 1.59-1.50 (m, 2H), 0.90 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH3:27]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([F:23])([F:21])[F:22])[CH:14]=3)[N:9]2[CH3:27])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(C(F)(F)F)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1c2ccc(C(F)(F)F)cc2C(C)(C)CC1c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
To a stirred solution of 2-(3-bromo-phenyl)-4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (5.0 g, 13.06 mmol) in N,N-dimethylformamide (15 mL) was added a 60% dispersion of sodium hydride in mineral oil (1.1 g, 26.1 mmol) portionwise at 0° C. The mixture was stirred at 0° C. for 30 min and then iodomethane (2.5 mL, 39.2 mmol) was added to the above mixture dropwise at 0° C. The solution was stirred at 0° C. for 2 h and then extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The yellowish residue was purified by ISCO combi-flash chromatography (gradient elution, 10% ethyl acetate/hexane) to afford 2-(3-bromo-phenyl)-1,4,4-trimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (3.6 g, 70%) as a yellow oil: MS obsd. (ESI+) [(M+H)+] 397.9 & 399.9.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH3:12])[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[CH2:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)[CH3:17].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[O-]S([O-])(=O)=O.[Mg+2].C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[CH2:16]([N:18]1[CH2:23][CH2:22][C:21]2([NH:1][C:2]3[CH:6]=[C:5]([C:7]4[CH:8]=[N:9][NH:10][C:11]=4[CH3:12])[S:4][C:3]=3[C:13](=[O:14])[NH:15]2)[CH2:20][CH2:19]1)[CH3:17]
Reactant: Cc1[nH]ncc1-c1cc(N)c(C(N)=O)s1
Reactant: CCN1CCC(=O)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)N(C)C
Product: CCN1CCC2(CC1)NC(=O)c1sc(-c3cn[nH]c3C)cc1N2
Temperature: 100 °C
Reaction time: 4 h
Yield: 59.7 %

Procedure:
A mixture of 3-amino-5-(5-methyl-1H-pyrazol-4-yl)thiophene -2-carboxamide (100 mg, 0.45 mmol), 1-ethylpiperidin-4-one (0.067 mL, 0.50 mmol), CSA (125 mg, 0.54 mmol), MgSO4 (108 mg, 0.90 mmol) and DMA (2.0 mL) was stirred at 100° C. for 4 h. Then, the mixture was poured into saturated aqueous NaHCO3. The organic materials were extracted with EtOAc. To the aqueous layer, NaCl was added. The organic materials were extracted again with EtOAc/THF. The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (Purif, NH, 80:20 hexane/EtOAc to EtOAc then to 90:10 EtOAc/MeOH), then crystallized from MeOH/EtOAc/hexane to give the title compound (89 mg, 64%) as yellow solid: