Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:36])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([NH:21][C:22]3[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:24][C:23]=3[CH3:35])=[O:20])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].CO.[OH-].[Na+].Cl>O>[CH3:3][C:2]([CH3:36])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([NH:21][C:22]3[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:24][C:23]=3[CH3:35])=[O:20])=[CH:17][CH:18]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:1]
Reactant: CCOC(=O)COc1ccc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(OCC(=O)O)ccc1NC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.8 %

Procedure:
To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added ethyl 2-(4-(4-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)phenylcarbonylamino)-3-methylphenoxy)acetate (1.22 g, 2.45 mmol) and 20 mL of CH3OH. To this solution was added aqueous NaOH (10 mL of a 1N solution). The mixture was stirred at ambient temperature for 18 h. The mixture was neutralized with 10 mL of 1N HCl and diluted with H2O. The product was collected on a frit and washed with a little H2O. This material was dried in vacuo to give 0.953 g (83%) of 2-(4-(4-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)phenylcarbonylamino)-3-methylphenoxy)acetic acid as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[CH:4][CH:3]=1.Cl[CH2:17][C:18](=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:17]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[CH:6][CH:7]=1)[C:18]([CH3:19])=[O:20]
Reactant: CC1=C(c2ccc(O)cc2)CCC(=O)N1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc(C2=C(C)NC(=O)CC2)cc1

Procedure:
A mixture of 3,4-dihydro-5-(4-hydroxyphenyl)-6-methyl-2(1H)-pyridinone (0.94 g), chloroacetone (0.43 g) and potassium carbonate (0.64 g), with a catalytic amount of potassium iodide, was stirred and heated under reflux in acetone (80 ml) for 16 hr. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The organic layer was dried (MgSO4) and evaporated to give 3,4-dihydro-5-(4-acetonyloxyphenyl)-6-methyl-2(1H)-pyridinone as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[O:22]=[C:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([NH:32][CH:33]=[O:34])[CH:29]=2)[NH:24]1>>[CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=[C:31]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([NH:32][CH:33]=[O:34])[CH:29]=2)[NH:24][C:23]1=[O:22]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Reactant: O=CNc1ccc2c(c1)CC(=O)N2
Product: Cc1c(C=C2C(=O)Nc3ccc(NC=O)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 78.7 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-formamide as starting materials to give N-{3-[3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-formamide (34 mg, 78.7%) as a red solid.
Reaction SMILES: [C:1]([OH:18])(=[O:17])[C:2]1[C:3](=[CH:7][C:8](=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14])[C:9]([OH:11])=[O:10])[C:4]([OH:6])=[O:5].[H][H]>[Rh].O>[CH:8]1([C:9]([OH:11])=[O:10])[CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH:2]([C:1]([OH:18])=[O:17])[CH2:16][CH:12]1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)O)cc1C(=O)O
Reactant: [H][H]
Agent: [Rh]
Solvent: O
Product: O=C(O)C1CC(C(=O)O)C(C(=O)O)CC1C(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
22.08 kg (86.88 mol) of pyromellitic acid, 8 kg of a catalyst containing rhodium supported on activated carbon (produced by N.E. Chemcat Corporation) and 80 kg of water were charged in a reactor made of Hastelloy (HC22) having a capacity of 200 L, and the interior of the reactor was replaced by nitrogen gas under stirring. The interior of the reactor was then replaced by hydrogen gas, and the temperature was increased to 50° C. under a hydrogen pressure in the reactor of 3.3 MPa. The reaction was performed for 2 hours while maintaining the hydrogen pressure to 3.3 MPa. The hydrogen gas in the reactor was replaced by nitrogen gas, the reaction liquid was taken out from the autoclave, and the reaction liquid was filtered in a hot state to separate the catalyst. The filtrate was concentrated by evaporating water under reduced pressure with a rotary evaporator to deposit crystals. The crystals thus deposited were separated by solid-liquid separation at room temperature and dried to provide 19.24 kg (73.94 mol, yield: 85.1%) of 1,2,4,5-cyclohexanetetracarboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][CH:15]=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:24])C(=O)C1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([Br:24])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCc2sccc2C1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCc2sc(Br)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (240 mg, 1.0 mmol) in acetonitrile (5 ml) cooled to 0° C. is added NBS (183 mg, 1.03 mmol, 1.03 eq.). The mixture is stirred at rt overnight. The organic phase is collected, washed with water (10 ml) and brine (10 ml), dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (hexane/EtOAc 10:1) to give the title compound. MS (+VE) m/z 318.1 (M++1).
Reaction SMILES: Cl.[F:2][C:3]([F:30])([F:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.[CH3:31][S:32]([NH2:35])(=[O:34])=[O:33]>N1C=CC=CC=1>[F:2][C:3]([F:30])([F:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:35][S:32]([CH3:31])(=[O:34])=[O:33])=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reactant: CS(N)(=O)=O
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)NC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
A solution of 25.2 g. of 4-[15-(trifluoromethyl)-pentadecylamino]benzoyl chloride hydrochloride and 5.6 g. of methanesulfonamide in 250 ml. of pyridine is stirred under reflux for 2 hours and then concentrated in vacuo. The residue is partitioned between water and diethyl ether; the aqueous layer acidified with 1 N hydrochloric acid, and the organic layer separated, dried over magnesium sulfate and evaporated. Crystallization of the residual white solid from 60% aqueous acetic acid and then from methylene chloride-hexane affords the product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:16](=[O:26])[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][N:23]=[CH:22][N:21]=4)[N:19]=[C:10]23)=[C:4]([O:28][CH3:29])[CH:3]=1.C(N(S(F)(F)[F:36])CC)C>ClCCl>[F:36][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[O:28][CH3:29])[CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]2[C:16](=[O:26])[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)[N:19]=[C:10]12
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1cc(F)ccc1C(O)C1CCCCn2c1nc(-c1ccncn1)cc2=O
Solvent: ClCCl
Product: COc1cc(F)ccc1C(F)C1CCCCn2c1nc(-c1ccncn1)cc2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.8 %

Procedure:
To a solution of 0.290 g (0.73 mmol) of (+/−)-10-[(4-fluoro-2-methoxy-phenyl)-hydroxy-methyl]-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one (example 4) in dichloromethane (14 mL) under argon at −78° C. was added 0.294 g of diethylaminosulfur trifluoride (1.83 mmol) diluted in 5 ml of dichloromethane. The reaction was allowed to increase to room temperature. The reaction was stirred at room temperature for 2 h; the mixture was quenched at 0° C. with the addition of methanol and stirred overnight. A saturated solution of ammonium chloride was added and the mixture was extracted with dichloromethane. The organic phase was washed with a saturated solution of sodium chloride and dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (dichloromethane with 2% of methanol and 0.2% of ammonia) to afford 0.072 g (25%) of a white solid as an isomer mixture (95/5).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([OH:20])[C@H:9]([OH:21])[C:8]=3[CH:7]=[CH:6][N:5]2[C:22]=1[CH3:23].S(=O)(=O)(O)O.[CH2:29](O)[CH3:30]>>[CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([OH:20])[C@H:9]([O:21][CH2:29][CH3:30])[C:8]=3[CH:7]=[CH:6][N:5]2[C:22]=1[CH3:23]
Reactant: CCO
Reactant: Cc1nc2c3c(ccn2c1C)[C@@H](O)[C@H](O)[C@@H](c1ccccc1)N3
Agent: O=S(=O)(O)O
Product: CCO[C@@H]1c2ccn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1O

Procedure:
500 mg of the title compound are obtained by reaction of (7R, 8R, 9R)-2,3-dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine with ethanol and sulfuric acid according to Example 1, Method a, after purification on silica gel (eluent:diethylether). Melting point 188–190° C.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Br)C.CON(C)[C:15]([CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16]>C1COCC1>[CH3:7][N:6]1[C:2]([C:15]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])=[CH:3][N:4]=[CH:5]1
Reactant: Cn1cncc1Br
Reactant: CON(C)C(=O)C1CCOCC1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: Cn1cncc1C(=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A clear colorless solution of 5-bromo-1-methyl-1H-imidazole (1.12 g, 6.93 mmol) in THF (10 mL) was placed in an ice bath and ethylmagnesium bromide (3.0 M in Et2O, 2.31 mL, 6.93 mmol) was added via syringe. The reaction mixture was stirred for 20 minutes at room temperature. N-Methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide (1.0 g, 5.8 mmol, Intermediate 1: step a, Procedure A) was added neat by syringe (using 1 mL THF rinse to quantitate transfer), and the resulting white suspension was stirred at room temperature for 2 days. The mixture was diluted with saturated aqueous NH4Cl followed by water, then was extracted with EtOAc (3×). The organic phase was dried (Na2SO4), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography two times (1-4% MeOH-DCM first column; 40-60% CH3CN-DCM second column) to provide the title compound as a white crystalline solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[N+:8]([CH3:11])([O-:10])=[O:9].[OH-].[Na+].Cl>CO.O>[N+:8](/[CH:11]=[CH:6]/[C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)([O-:10])=[O:9]
Reactant: O=Cc1ccsc1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])/C=C/c1ccsc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-thiophenecarboxaldehyde (57.0 g, 502 mmol) and nitromethane (29.9 mL, 552 mmol) in methanol (100 mL) was added a solution of sodium hydroxide (22.1 g, 552 mmol) in water (45 mL) at a rate that kept the temperature at less than 5° C. The mixture was allowed to stand at about 0° C. for about 30 minutes. The precipitate was collected by filtration, dissolved in a minimum amount of ice-cold water and, poured into an ice-cold mixture of concentrated hydrochloric acid (96.7 mL, 1178 mmol) and water (152 mL). The precipitate was collected by filtration and was recrystallized from aqueous ethanol to provide the desired product. MS (DCI-NH3): m/z 173 (M+NH4)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[C@@H:7]([NH2:24])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:33][O:34][C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43](Cl)(=[O:45])=[O:44])=[O:36]>CN(C)C=O>[CH3:33][O:34][C:35](=[O:36])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43](=[O:44])(=[O:45])[NH:24][C@H:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:25])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:16]=1
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)OC(C)(C)C)cc1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2C(=O)OC)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.123 g (0.35 mmol) of (2S)-2-amino-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-propionic acid tert-butyl ester was dissolved in 2 ml of dimethylformamide and treated with 0.196 ml (1.4 mmol) of triethylamine and 0.164 g (0.7 mmol) of 2-(methoxycarbonyl)-benzenesulfonyl chloride. The solution was stirred for 4 hours at room temperature. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and the solution was washed three times with water. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (1/1). Yield 75 mg. MS (ES+): m/e=549 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2oc3ccccc3c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc2oc3ccccc3c2c1
Yield: 134.3 %

Procedure:
In a Parr hydrogenation bottle, 10% Pd/C (0.77 g, 0.724 mmol) was added and the bottle purged with nitrogen. Next 2-nitrodibenzo[b,d]furan (15 g, 44.3 mmol) in 180 mL of ethyl acetate was added and the mixture was hydrogenated on a Parr Hydrogenator until no more hydrogen is taken up by the solution. The catalyst was filtered off through Celite and washed with ethyl acetate. The filtrate was evaporated and pre-absorbed onto Celite. The Celite mixture was purified using a Varian 400 g column eluting with dichloromethane. 10.9 g of product was obtained.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([CH3:27])[CH:24]=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:27][C:25]1[CH:24]=[C:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=2)[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[CH:20]=2)[N:26]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 21 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{4-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonamide (0.23 g) in dichloromethane (4 mL) was added TFA (4 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and purified by flash chromatography (heptane/ethyl acetate) and crystallization (dichloromethane/MeOH/hexane) to yield the title compound as a white solid (0.081, 21%). MS (ISP) 471.5 [(M+H)+]; mp 218.5° C.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:10]([O:13][C:14]1[C:15]([CH3:27])=[C:16]([CH3:26])[C:17]2[O:21][CH:20]([CH2:22]Br)[CH2:19][C:18]=2[C:24]=1[CH3:25])(=[O:12])[CH3:11]>CN(C)C=O.O>[C:10]([O:13][C:14]1[C:15]([CH3:27])=[C:16]([CH3:26])[C:17]2[O:21][CH:20]([CH2:22][S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:19][C:18]=2[C:24]=1[CH3:25])(=[O:12])[CH3:11]
Reactant: Sc1ccccc1
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(CBr)O2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(CSc1ccccc1)O2
Reaction time: 0.33 h
Yield: 92.2 %

Procedure:
To a solution of thiophenol [425 mg (3.8 mmol)] in dimethylformamide (10 ml) was added, under ice-cooling, sodium hydride [167 mg (4.2 mmol, content:60%)]. To the reaction mixture was added, after stirring for 20 minutes, a solution of 5-acetoxy-2-bromomethyl-4,6,7-trimethyl-2,3-dihydrobenzofuran [1.2 g (3.8 mmol)] dimethylformamide (5 ml). The mixture was stirred for further 30 minutes. The reaction mixture was diluted with water, which was subjected to extraction with ethyl acetate. The extract solution was washed with water, dried and concentrated. The concentrate was crystallized from isopropylether-hexane to afford 5-acetoxy-4,6,7-trimethyl-2-phenylthiomethyl-2,3-dihydrobenzofuran (Compound 4) [1.2 g (yield : 91.3%)]. In a manner as above, compounds 2, 6, 8, 10, 12 and 18 were synthesized by employing the corresponding thio compounds (3-mercaptopropionic acid, 1-octanethiol, 2-mercaptopyridine, 4-fluorothiophenol, 2-naphthalene thiol and benzyl mercaptan). Incidentally, when 3-mercaptopropionic acid was employed as the starting compound, 2.2 equivalents of sodium hydride was used.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]2[CH:9]=[C:10]([C:13]3[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.Cl[CH2:21][CH:22]1[CH2:24][O:23]1>CN(C=O)C.O>[CH3:3][N:4]1[C:8]2[CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:21][CH:22]4[CH2:24][O:23]4)[CH:14]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1
Reactant: ClCC1CO1
Reactant: Cn1cnc2ccc(-c3cccc(O)c3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cnc2ccc(-c3cccc(OCC4CO4)c3)cc21
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of NaH (161 mg, 6.69 mmol) in DMF (5 mL) was added 3-(1-methyl-1H-benzo[d]imidazol-6-yl)phenol (500 mg, 2.23 mmol) at 27° C. After 0.5 h, 2-(chloromethyl)oxirane (246 mg, 2.68 mmol) was added and the reaction mixture was stirred 16 h, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was used in next step without further purification. (500 mg, yield 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH:10]=[CH:11][N:12]([CH3:14])C)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.NC1[N:19]=[CH:20][NH:21][C:22]=1[C:23]([NH2:25])=[O:24]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:19]3[CH:20]=[N:21][C:22]([C:23]([NH2:25])=[O:24])=[C:14]3[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)c1[nH]cnc1N
Reactant: CN(C)C=CC(=O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CC(=O)O
Product: NC(=O)c1ncn2c(-c3ccc(Cl)c(Cl)c3)ccnc12
Reaction time: 16 h
Yield: 49.6 %

Procedure:
A stirred mixture of 12.0 g of 3',4'-dichloro-3dimethylaminoacrylophenone (prepared as described in Example 9) and 6.3 g of 4-amino-5-imidazolecarboxamide hydrochloride in 450 ml of glacial acetic acid was heated at reflux for 24 hours. The reaction mixture was allowed to stand at room temperature for 16 hours then the mixture was filtered and the crystals that were collected were washed with 300 ml of saturated sodium bicarbonate and then were washed with water. This material was dried, washed with hot methanol and filtered to give 5.9 g of the desired product as yellow crystals, mp 302°-304° C.
Reaction SMILES: [F:1][C:2]1([F:29])[C@@H:19]([O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH2:18][CH2:17][C@@:16]2([CH3:27])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=O.[CH:30]1([NH2:33])[CH2:32][CH2:31]1>CO>[CH:30]1([N:33]=[C:10]2[CH2:9][CH2:8][C@H:7]3[C@H:6]4[C@H:15]([CH2:14][CH2:13][C@:11]23[CH3:12])[C@:16]2([CH3:27])[C:3]([C:2]([F:1])([F:29])[C@@H:19]([O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[CH2:18][CH2:17]2)=[CH:4][CH2:5]4)[CH2:32][CH2:31]1
Reactant: C[C@]12CC[C@H](OC3CCCCO3)C(F)(F)C1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: NC1CC1
Solvent: CO
Product: C[C@]12CC[C@H](OC3CCCCO3)C(F)(F)C1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NC3CC3)CC[C@@H]12
Temperature: 25 °C

Procedure:
To a solution of 21 g of 4,4-difluoro-3β-(2-tetrahydropyranyloxy)androst-5-en-17-one in a mixture of 175 ml of cyclopropylamine and 150 ml of methanol there is added 5 g of molecular sieves. The reaction mixture is refluxed for 48 hours, cooled to room temperature, and filtered through magnesium sulfate. The magnesium sulfate is washed with ethyl acetate and the solvent is removed from the combined filtrates under reduced pressure to give 17-(cyclopropylimino)-4,4-difluoro-3β-(2-tetrahydropyranyloxy)androst-5-ene.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:12][N:22]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:14]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: c1cncc(-c2noc(-c3ccc4[nH]ncc4c3)n2)c1

Procedure:
The title compound was prepared according to Method C using 1H-indazole-5-carboxylic acid (ABCR) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 7.7 (dd, J=7.9, 4.8 Hz, 1 H), 7.8 (d, J=8.7 Hz, 1 H), 8.2 (dd, J=8.7, 1.6 Hz, 1 H), 8.4 (s, 1 H) 8.5 (dt, J=7.9, 1.8 Hz, 1 H), 8.7 (s, 1 H) 8.8 (dd, J=4.8, 1.6 Hz, 1 H), 9.3 (d, J=2.0 Hz, 1 H), 13.6 (s, 1 H) ppm; MS (DCI/NH3) m/z 264 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[CH:5]=[N:4][C:3]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23](Br)[CH:22]=1.O.O1[CH2:35][CH2:34]OCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[CH:5]=[N:4][C:3]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:35]2[CH:34]=[N:4][CH:3]=[CH:2][N:1]=2)[CH:22]=1
Reactant: C1COCCO1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc(C(=O)c2cccc(Br)c2)c1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc(C(=O)c2cccc(-c3cnccn3)c2)c1N
Yield: 63 %

Procedure:
A solution of 3-[5-amino-4-(3-bromobenzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide (60 mg), 2-tributyltinpyrazine (120 uL) and tetrakis(triphenylphosphine)palladium(0) (30 mg) in 1,4-dioxane (0.8 mL) was heated under microwave radiation at 160° C. for 25 min. Water (3 ml) was added and the mixture was extracted with ethyl acetate (4 mL×2). Evaporation of the solvent and purification by preparatory TLC (EtOAc:MeOH=10:1) gave the desired product (38 mg, 63%). HPLC (4 minute 10-90 gradient) tR 2.18 min; MS m/z 439.27 [M+H]+.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].CO[C:12](OC)([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[CH3:13][C:12]1([CH3:14])[O:2][C:1]2[CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=2[O:4]1
Reactant: COC(C)(C)OC
Reactant: Oc1cccc(O)c1O
Solvent: Cc1ccccc1
Product: CC1(C)Oc2cccc(O)c2O1
Yield: 16.9 %

Procedure:
A mixture of 9.0 g of pyrogallol, 7.5 g of 2,2-dimethoxypropane and 100 ml of toluene was refluxed for 4.5 hours. After cooling, the reaction mixture was worked up in a customary manner and purified by column chromatography to give 2.0 g (yield 17%) of the desired product as a pale yellow solid.