Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][CH3:6])[CH3:3].[C:7]([C:9]1[CH:35]=[CH:34][C:12]([C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:33])=[C:20]([NH:22][C:23](=[O:32])[C:24]3[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][CH:25]=3)[CH:21]=2)=[O:14])=[CH:11][CH:10]=1)#[N:8].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:7]([C:9]1[CH:35]=[CH:34][C:12]([C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:33])=[C:20]([NH:22][C:23](=[O:32])[C:24]3[CH:29]=[CH:28][C:27]([CH2:30][N:4]([CH2:5][CH3:6])[CH2:2][CH3:3])=[CH:26][CH:25]=3)[CH:21]=2)=[O:14])=[CH:11][CH:10]=1)#[N:8]
Reactant: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1NC(=O)c1ccc(CCl)cc1
Reactant: CCNCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3ccc(C#N)cc3)ccc2C)cc1
Temperature: 55 °C
Yield: 67.2 %

Procedure:
Diethylamine hydrochloride (0.024 g) was added to a stirred mixture of N-[5-(4-cyanoberizamido)-2-methylphenyl]-4-(chloromethyl)benzamide (0.06 g), potassium carbonate (0.082 g) and acetone (5 ml) and the reaction mixture was stirred and heated to 55° C. for 16 hours. Further portions of diethylamine hydrochloride and potassium carbonate (same quanities as before) were added and the mixture was heated to 55° C. for a further 4 days. The reaction mixture was evaporated and the residue was triturated with water. The solid was isolated and dried under vacuum at 55° C. to give the title compound as a solid (0.044 g); NMR Spectrum: (CDCl3) 1.06 (t, 6H), 2.28 (s, 3H), 2.53 (m, 4H), 3.63 (s, 2H), 7.2 (d, 1H), 7.5 (d, 2H), 7.74 (m, 4H), 7.81 (d, 2H), 7.97 (d, 2H), 8.15 (s, 1H), 8.27 (s, 1H); Mass Spectrum: M−H− 439.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][C@H:38]2[CH2:43][CH2:42][CH2:41][N:40]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:39]2)[C:34]([F:51])=[CH:33][N:32]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:31]3[N:36]=[C:35]([NH:37][C@H:38]4[CH2:43][CH2:42][CH2:41][N:40]([C:44]([O:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[O:45])[CH2:39]4)[C:34]([F:51])=[CH:33][N:32]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCN(C(=O)OC(C)(C)C)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 90 °C

Procedure:
To a solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (1.8 g, 4.2 mmol) and tert-butyl (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]piperidine-1-carboxylate, 5a, (1.2 g, 3.7 mmol) in DME (15 mL) and H2O (5 mL) was added K2CO3 (1.7 g, 12.1 mmol). The mixture was purged with nitrogen for 15 min. To the mixture was added tetrakis triphenylphosphine palladium(0) (0.2 g, 0.2 mmol) and the reaction mixture was heated at 90° C. for 3 days. The reaction was cooled down to room temperature and then diluted with EtOAc/H2O. The layers were separated and the organic phase was washed with brine, dried (MgSO4), filtered and evaporated to dryness. The resulting residue was dissolved in CH2Cl2 and purified by silica gel chromatography (0-100% EtOAc/Hexanes) to afford the desired product, 1b.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([C:16]2[NH:20][C:19]3[C:21]4[C:26]([CH:27]=[CH:28][C:18]=3[N:17]=2)=[CH:25][C:24]2[C:29]3[C:34]([CH2:35][O:36][C:23]=2[CH:22]=4)=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=3)[CH2:5]1.Br[C:47]1[NH:51][C:50]([C@@H:52]2[CH2:56][CH2:55][C@H:54]([CH3:57])[N:53]2[C:58](=[O:68])[C@@H:59]([NH:63][C:64](=[O:67])[O:65][CH3:66])[CH:60]([CH3:62])[CH3:61])=[N:49][CH:48]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:66][O:65][C:64]([NH:63][C@H:59]([C:58]([N:53]1[C@@H:54]([CH3:57])[CH2:55][CH2:56][C@H:52]1[C:50]1[NH:51][C:47]([C:32]2[CH:33]=[C:34]3[CH2:35][O:36][C:23]4[CH:22]=[C:21]5[C:26]([CH:27]=[CH:28][C:18]6[NH:17][C:16]([C@@H:6]7[CH2:5][C@H:4]([CH2:3][O:2][CH3:1])[CH2:8][N:7]7[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[N:20][C:19]=65)=[CH:25][C:24]=4[C:29]3=[CH:30][CH:31]=2)=[CH:48][N:49]=1)=[O:68])[CH:60]([CH3:62])[CH3:61])=[O:67]
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1c1ncc(Br)[nH]1)C(C)C
Reactant: COC[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2-5)N(C(=O)OC(C)(C)C)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: COC[C@H]1C[C@@H](c2nc3c(ccc4cc5c(cc43)OCc3cc(-c4cnc([C@@H]6CC[C@H](C)N6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]4)ccc3-5)[nH]2)N(C(=O)OC(C)(C)C)C1
Temperature: 85 °C
Yield: 39.7 %

Procedure:
To a solution of (2S,4S)-tert-butyl 4-(methoxymethyl)-2-(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (217 mg, 0.35 mmol), methyl (S)-1-((2S,5S)-2-(5-bromo-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (170 mg, 0.39 mmol), tetrakis(triphenylphosphine) palladium(0) (21 mg, 0.02 mmol) and dichloro[1,1′-bis(diphenylphosphino) ferrocene]palladium(II) (26 mg, 0.04 mmol) in a mixture of 1,2-dimethoxyethane (4.3 mL) and dimethylformamide (0.75 mL) was added a solution of potassium carbonate (2M in water, 0.53 mL, 1.06 mmol). The resulting mixture was degassed and then heated to 85° C. under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to yield tert-butyl (2S,4S)-2-[9-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-3,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxy methyl)pyrrolidine-1-carboxylate (110 mg, 39%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2.[C:12](OC(=O)C)(=[O:14])[CH3:13]>O>[C:12]([NH:11][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][CH2:9]2)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(O)c2c1CCC2
Solvent: O
Product: CC(=O)Nc1ccc(O)c2c1CCC2

Procedure:
A mixture of 25 g of 7-hydroxy-4-amino indane and of 8 ml of acetic anhydride in 400 ml of iced water was stirred for 30 minutes. After filtering, the precipitate was washed with water and ethyl ether and was recrystallized in isopropanol.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(OCC)(=O)C>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc3cc[nH]c3c2)cc1

Procedure:
6-Bromo-1H-indole (1.00 g, 5.10 mmol) and potassium carbonate (1.41 g, 10.2 mmol) were dissolved in a mixture solution of DMF/water (4:1, 10.0 mL), and the gas included in the mixture solution was removed using ultrasonic waves and nitrogen gas. After sequentially adding 4-methoxyphenylboronic acid (853 mg, 5.61 mmol) and Pd(dppf)Cl2 (416 mg, 0.51 mmol), the mixture was stirred at room temperature in a sealed state. 2 hours later, ethyl acetate and water were added and the reaction solution was filtered using a diatomite pad. After separation of the organic layer, the aqueous layer was extracted with ethyl acetate. The collected organic layer was concentrated by drying with anhydrous magnesium sulfate. The residue was purified by chromatography (silica gel, EA:Hx=1:4). The target compound was obtained as white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH3:12])[C:5]2[N:6]=[CH:7][N:8]=[CH:9][C:10]=2[N:11]=1.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH3:12][N:4]1[C:5]2[N:6]=[CH:7][N:8]=[CH:9][C:10]=2[N:11]=[C:3]1[CH2:2][O:1][C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1c(CO)nc2cncnc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cncnc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.37 g of 2-hydroxymethyl-3-methylimidazo[5,4-d]pyrimidine (prepared as described in Preparation 50), 2.51 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4 dione, 1.34 ml of tributylphosphine, 1.36 g of 1,1'-(azodicarbonyl)dipiperidine and 50 ml of benzene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in a ratio of 2:1 by volume, and then in ratios ranging from 1:1 to 1:2 by volume, and subsequently a 6:1 by volume mixture of ethyl acetate and ethanol as the eluent. The desired fractions were collected and concentrated by evaporation under reduced pressure. The concentrate was further purified by preparative reverse-phase high speed liquid chromatography through YMC-Pack ODS-A (a product of YMC Inc.) using a 100:100:1:1 by volume mixture of acetonitrile, water, acetic acid and triethylamine as the eluent, to give 0.24 g of the title compound, melting at 55°-65° C. (softening).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[Cl:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[C:20](Cl)(=[O:24])[CH:21]([CH3:23])[CH3:22]>ClCCl.CO>[Cl:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22]
Reactant: Nc1cnc2ccccc2c1Cl
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cnc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
A solution of 3-amino-4-chloroquinoline (8.5 g, 48 mmol) in dichloromethane (100 mL) was cooled to 0° C. Triethylamine (42 mL, 0.30 mol) was added followed by a solution of isobutyryl chloride (9.6 mL, 0.10 mol) in dichloromethane (35 mL), which was added dropwise. The reaction was stirred overnight at room temperature. An analysis by LC/MS indicated the presence of starting material, and the reaction was heated at reflux for two hours. The reaction was still incomplete. The volatiles were removed under reduced pressure, and the residue was dissolved in dichloromethane (75 mL). Additional isobutyryl chloride (9.6 mL, 0.10 mol) was added, the reaction was stirred for three days at room temperature. The reaction was still incomplete, and additional isobutyryl chloride (3 mL) was added. The reaction was stirred overnight, diluted with methanol (10 mL), stirred for 30 minutes, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (150 mL), and the solution was washed with saturated aqueous sodium bicarbonate (3×50 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 9.6 g of N-(4-chloroquinolin-3-yl)-2-methylpropanamide as a brown solid.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][C:24]1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.NC1C=C(C=CC=1)C#N>C(O)(=O)C>[O:13]=[C:12]1[N:7]([C:1]2[CH:6]=[C:5]([CH:4]=[CH:3][CH:2]=2)[C:24]#[N:23])[CH:8]=[N:9][C:10]2[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][S:14][C:11]1=2
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: N#Cc1cccc(N)c1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: N#Cc1cccc(-n2cnc3c(-c4ccccc4)csc3c2=O)c1
Yield: 14 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1 ml), 3-aminobenzonitrile (96 mg, 0.81 mmol), and acetic acid (0.1 ml) were used to give 20 mg (0.061 mmol, 14% yield) of the title compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13])(=[O:8])=[O:7].[C:18]1([O:24][CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[CH3:25][O:24][C:18]1[CH:23]=[CH:22][C:21]([C:12]([C:11]2[CH:10]=[C:9]([S:6]([Cl:5])(=[O:8])=[O:7])[CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:20][CH:19]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cccc(S(=O)(=O)Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
Under a nitrogen atmosphere, aluminum chloride (7.5 g, 56.5 mmol) is slurried in dichloromethane (150 mL) then 3-chlorosulfonyl-benzoyl chloride (7.5 g, 31.4 mmol) is added and allowed to stir at ambient temperature for 10 minutes. Anisole (4.06 g, 37.65 mmol) is added. The reaction is allowed to stir at ambient temperature for 18 hours. The reaction mixture is poured over ice-cold 6 N HCl and extracted with dichloromethane to give a purple oil. Purification by silica gel chromatography (10% ethyl acetate in hexanes) yielded 4 g (41% yield) of the title compound as a yellow powder. 1H NMR (CDCl3): δ 8.5 (t, 1H, J=1.7 Hz), 8.25 (m, 1H), 8.1 (m, 1H), 7.7-7.9 (m, 3H), 7.0 (d, 2H, J=6.9 Hz), 3.9 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:31][C:32]1[N:33]=[C:34]([CH3:37])[S:35][CH:36]=1>>[CH2:1]([O:8][C:9]1([C:19]([N:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:31][C:32]2[N:33]=[C:34]([CH3:37])[S:35][CH:36]=2)=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(NC(=O)C2(OCc3ccccc3)CCCc3ccccc32)cc1
Reactant: Cc1nc(CCl)cs1
Product: COc1ccc(N(Cc2csc(C)n2)C(=O)C2(OCc3ccccc3)CCCc3ccccc32)cc1
Yield: 78.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 132 using 5 benzyloxy -N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.63 g) and 4-(chloromethyl)-2-methylthiazole (0.30 g) as starting materials, 5 benzyloxy-N-(4-methoxyphenyl)-N-[(2-methylthiazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.64 g) was obtained. By the reaction and treatment in the same manner as in Example 133 using this compound (0.50 g), 5-hydroxy-N-(4-methoxyphenyl)-N-1(2-methylthiazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.31 g) was obtained.
Reaction SMILES: C([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]([C:18]1[N:19]=[C:20]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[Cl:37])[N:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:22]=1)=[O:17])C1C=CC=CC=1.[Si](I)(C)(C)C>C(Cl)Cl.O>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([N:21]2[CH:22]=[C:18]([C:16]([NH:15][C@@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]3[OH:8])=[O:17])[N:19]=[C:20]2[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[Cl:37])=[CH:24][CH:25]=1
Reactant: O=C(N[C@@H]1CCCC[C@H]1OCc1ccccc1)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of N-[(1R, 2R)-2-(benzyloxy)cyclohexyl]-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxamide (Table entry 278, prepared according to the procedures described in Examples 13 and 14) (100 mg, 0.18 mmol) in CH2Cl2 (2 mL), TMSI (iodotrimethylsilane) (60 μL, 0.42 mmol) was added. The mixture was stirred at rt overnight, and diluted with water. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by preparative TLC (EtOAc) to afford 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-[(1R,2R)-2-hydroxycyclohexyl]-1H-imidazole-4-carboxamide (56 mg, 67% yield) as a yellow solid: LC-MS m/z 464.3 (MH+), retention time 3.19 min (method 1); Rf=0.67 (EtOAc); 1H NMR (300 MHz, CDCl3) δ 1.16-1.30 (4H, m), 1.66-1.69 (2H, m), 1.98-2.02 (2H, m), 3.37-3.39 (1H, m), 3.70-3.80 (1H, m), 3.99-4.06 (1H, m), 6.96-7.37 (8H, m), 7.78 (1H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:17]=3[N:18]=2)[C:7]([NH:10][CH2:11][CH2:12][CH3:13])=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[Cl:31]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20]([C:27]4[CH:28]=[CH:29][C:30]([Cl:31])=[C:25]([CH3:24])[CH:26]=4)=[CH:19][C:17]=3[N:18]=2)[C:7]([NH:10][CH2:11][CH2:12][CH3:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(Br)ccc2o1
Reactant: Cc1cc(B(O)O)ccc1Cl
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccc(Cl)c(C)c3)ccc2o1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-6-propylaminophenyl)-5-bromobenzoxazole (400 mg, 1.59 mmol) and 3-methyl-4-chlorophenylboronic acid (271 mg, 1.59 mmol) the subtitle compound was obtained (230 mg, 34%). The product was used directly in the next step without purification.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:25]([OH:26])=[CH:24][C:20]4[CH2:21][CH2:22][O:23][C:19]=4[CH:18]=3)[C:9]2=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:34]=[O:35].C(NC(C)C)(C)C>C1COCC1.C(OCC)(=O)C>[C:28]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[C:25]([OH:26])=[CH:24][C:20]4[CH2:21][CH2:22][O:23][C:19]=4[CH:18]=3)([CH2:34][OH:35])[C:9]2=[O:27])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C=O
Reactant: O=C1C(c2cc3c(cc2O)CCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(CO)c1cc2c(cc1O)CCO2
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.8 %

Procedure:
To a solution of 1-(diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1-benzofuran-6-yl)-1,3-dihydro-2H-indol-2-one (1.01 g, 2.30 mmol) in THF (50.0 mL) was added paraformaldehyde (1.00 g, 30.0 mmol). Argon was bubbled through the reaction mixture for one hour followed by the addition of diisopropylamine (1.00 g, 10.0 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 20 hours and diluted with ethyl acetate (100 mL). The resulting mixture was washed with water (2×50.0 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness to give 0.67 g (65%) of the title compound: MS (ES+) m/z 486.4 (M+23).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[CH:15]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[N:28][NH:27][C:26]2=[O:30])=[CH:21][CH:20]=1)([CH3:17])[CH3:16]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:27]1[C:26](=[O:30])[N:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH:15]([CH3:17])[CH3:16])=[CH:24][CH:23]=2)[CH:29]=[N:28]1)[CH3:13]
Reactant: CC(C)Oc1ccc(-n2cn[nH]c2=O)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: CC(C)Oc1ccc(-n2cnn([C@H](C)[C@@]3(c4ccc(F)cc4F)CO3)c2=O)cc1
Yield: 48.8 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.43 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.94 g of 4-(4-isopropoxyphenyl)-3(2H,4H)-1,2,4-triazolone, 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-(4-isopropoxyphenyl)-3(2H,4H)-1,2,4-triazolone (0.84 g) was obtained as a colorless oil.
Reaction SMILES: C[Li].[CH3:3][C@:4]12[CH2:21][CH2:20][C@H:19]3[C@@H:9]([CH2:10][CH2:11][C:12]4[C@:17]3([CH3:18])[CH:16]=[CH:15]C(=O)[CH:13]=4)[C@@H:8]1[CH2:7][CH2:6][C:5]2=[O:23].[C:24]([O:27][C:28](=[O:30])[CH3:29])(=O)[CH3:25].[Cl-].[NH4+]>ClC(Cl)C.O.[Cu]I>[C:28]([O:27][C:24]1[CH:13]=[C:12]2[C@:17]([CH3:18])([C@@H:16]([CH3:15])[CH:25]=1)[C@@H:19]1[C@H:9]([C@H:8]3[C@@:4]([CH2:21][CH2:20]1)([CH3:3])[C:5](=[O:23])[CH2:6][CH2:7]3)[CH2:10][CH2:11]2)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li]C
Solvent: CC(Cl)Cl
Solvent: O
Product: CC(=O)OC1=C[C@H](C)[C@@]2(C)C(=C1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: -30 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
A suspension of 15.38 g of copper(I) iodide in 50 ml of dichloroethane is cooled to -30° C., combined at this temperature with 100 ml of methyllithium solution and stirred for one hour. A solution of 12.8 g of androsta-1,4-diene-3,17-dione [J. Am. Chem. Soc. 79:3920 (1957); Tetrahedron 4:201 (1958)] in 60 ml of dichloroethane is added dropwise to this mixture in such a way that the temperature does not rise beyond -10° C. After this addition is completed, the mixture is further stirred for 2 hours at 0° C. To this yellow-brownish solution, a solution of 8.62 g of acetic anhydride in 22 ml of dichloroethane is added and the mixture is stirred for one hour at room temperature. Then a solution of 8.3 g of ammonium chloride in 83 ml of water is added dropwise thereto. The organic phase is separated, the aqueous phase is extracted with methylene chloride and the combined organic phases washed with water. After drying over sodium sulfate, the mixture is concentrated under vacuum and the resultant crude product in recrystallized from hexane/acetone, thus obtaining 8.9 g of 3-acetoxy-1α-methylandrosta-2,4-dien-17-one, mp 104°-107° C.