Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([S:30][CH3:31])[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:41])C=1>ClCCl>[C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([S:30]([CH3:31])=[O:41])[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1nccc(-c2cnc3c(NC4CCC(NC(=O)OC(C)(C)C)CC4)nccn23)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nccc(-c2cnc3c(NC4CCC(NC(=O)OC(C)(C)C)CC4)nccn23)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
{4-[3-(2-Methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 47 supra) (150 mg, 0.323 mmol) was dissolved in dichloromethane (20 mL), then m-CPBA (134 mg, 0.659 mmol) was added slowly. The reaction mixture was stirred at 0° C. for 2 hours. The solvent was removed under reduced pressure and the solid was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 20:1) to afford {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester. (Yield 110 mg, 70.8%). LC-MS: [M+H]+ 472.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Br:17][C:18]1[CH:19]=[C:20]([C:25]([C:27]2[O:28][CH:29]=[CH:30][N:31]=2)=O)[CH:21]=[C:22]([F:24])[CH:23]=1.Cl>C1COCC1.O>[CH2:15]([O:14][C:12](=[O:13])/[CH:11]=[C:25](/[C:20]1[CH:21]=[C:22]([F:24])[CH:23]=[C:18]([Br:17])[CH:19]=1)\[C:27]1[O:28][CH:29]=[CH:30][N:31]=1)[CH3:16]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C(c1cc(F)cc(Br)c1)c1ncco1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(/c1cc(F)cc(Br)c1)c1ncco1
Temperature: -78 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a suspension of NaH (60%, 1.6 g, 40 mmol) in dry THF (30 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (9.15 g, 40 mmol) at −78° C. After being stirred at −78° C. for 1 hour, a solution of (3-Bromo-5-fluoro-phenyl)-oxazol-2-yl-methanone (10.8 g, 40 mmol) in 20 ml THF was added drop wise over 30 min. The mixture was stirred at −78° C. for 30 min and then warmed to room temperature followed by stirring overnight. The mixture was cooled to 0° C. and treated with water (50 mL), pH value was adjusted to 6 with HCl (0.5N) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a petroleum ether/EtOAc mixture to afford 9.5 g of the desired product (Yield: 61%)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([CH3:12])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:8]=2[CH:21]=1)([OH:3])=O.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C)C=O>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:9]1[C:8]2[CH:21]=[C:4]([C:1](=[O:3])[NH:33][S:30]([C:27]3[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=3)(=[O:31])=[O:32])[CH:5]=[CH:6][C:7]=2[N:11]=[C:10]1[CH3:12]
Reactant: COc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1nc2ccc(C(=O)O)cc2n1Cc1ccccc1Cl
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)NC(=O)c2ccc3nc(C)n(Cc4ccccc4Cl)c3c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
N,N'-carbodiimidazole (0.431 g) was added at a time to a solution of 0.400 g of 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole in 15 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 1 hour. Subsequently, a solution of 0.498 g of 4-methoxybenzenesulfonamide and 0.405 g of diazabicycloundecene in 5 ml of N,N-dimethylformamide was added thereto, and the mixed solution was stirred at 100° C. for 67 hours. The reaction solution was cooled, and the solvent was distilled off under reduced pressure. Water and chloroform were added to the residue, and 10% hydrochloric acid was added thereto while being cooled until the aqueous layer was acidified. The resulting mixture was extracted twice with chloroform. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, and the solvent was distilled off under reduced pressure. The residue was purified through silica-gel column chromatography (eluent: a mixture of chloroform and methanol at a ratio of 100:2 to 100:10). The resulting product was concentrated, and was crystallized from a mixed solution of ethyl acetate and diethyl ether. The crystals were separated through filtration, and were dried to give 0.450 g of 1-(2-chlorobenzyl)-6-(4-methoxybenzenesulfonylcarbamoyl)-2-methylbenzimidazole (217).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7].C(=O)([O-])[O-].[Cs+].[Cs+].C1COCC1.Br[CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36]>CCOC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:6]([N:8]([CH2:36][CH2:35][CH2:34][CH:33]=[CH2:32])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1OC
Reactant: C=CCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCCCN(C(=O)c1ccc(OC)c(OC)c1)c1ccccc1
Temperature: 80 °C
Yield: 61.5 %

Procedure:
To a solution of 3,4-dimethoxybenzanilide 33 (1.28 g, 5 mmol) and anhydrous cesium carbonate (4 equiv) in a mixture of anhydrous THF (14 mL) and DMF (56 mL) was added 5-bromo-pent-1-ene (2.85 g, 4 equiv) at room temperature and the mixture was heated at 80° C. for 72 h. The mixture was cooled, taken up in EtOAc and washed twice with water then brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography on SiO2 (gradient of diethyl ether in petroleum ether) to afford the title compound 37 as a yellow oil (Yield 1.0 g, 62%).
Reaction SMILES: [N:1]([C:4]1[CH:15]=[CH:14][C:7]([C:8]([NH:10][CH2:11][CH2:12]Br)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].C(=O)([O-])[O-].[K+].[K+].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(#N)C>[N:1]([C:4]1[CH:15]=[CH:14][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: CN1CCNCC1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)NCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCN(CCNC(=O)c2ccc(N=[N+]=[N-])cc2)CC1
Temperature: 75 °C
Reaction time: 7 h
Yield: 32.2 %

Procedure:
4-Azido-N-(2-bromoethyl)benzamide (2.0 g) obtained in Example 63a) and potassium carbonate (1.34 g, 9.70 mmol, 1.0 eq.) were suspended in acetonitrile (40 ml), N-methylpiperazine (1.63 ml, 14.6 mmol, 1.5 eq.) was added, and the mixture was stirred at room temperature for 16 hr and at 75° C. for 7 hr. The reaction mixture was concentrated, diluted with water (40 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted twice with water (20 ml). The aqueous layers were combined, concentrated, saturated with sodium chloride and extracted with ethyl acetate (40 ml and 30 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated at 30° C. or below to give the title compound as a pale-yellow solid (0.69 g, 2.39 mmol, 24.7%).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:9][NH:8][C:7]2=[C:10]3[C:15](=[N:16][C:17]4=[CH:18][CH:19]=[CH:20][C:5](=[C:6]24)[O:4]1)[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH3:2].CC(C)([O-:24])C.[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[CH2:27]([N:8]1[C:7]2=[C:10]3[C:15](=[N:16][C:17]4=[CH:18][CH:19]=[CH:20][C:5](=[C:6]24)[O:4][CH:3]([CH2:1][CH3:2])[C:9]1=[O:24])[CH2:14][CH2:13][CH2:12][CH2:11]3)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CCC1CNc2c3c(nc4cccc(c24)O1)CCCC3
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC1Oc2cccc3nc4c(c(c23)N(Cc2ccccc2)C1=O)CCCC4
Reaction time: 0.25 h
Yield: 71 %

Procedure:
To a solution of 3-ethyl-2,3,9,10,11,12-hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepine (5.0 g) in dry tetrahydrofuran (150 ml) was added potassium t-butoxide (3.0 g). The mixture was stirred for 15 mins, benzyl bromide (3.16 ml) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was heated at reflux for 1.5 hrs, allowed to cool, concentrated and diluted with saturated sodium bicarbonate solution (250 ml). The mixture was extracted twice with ethyl acetate (250 ml), and the organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated. Trituration of the residue first with pentane and then diethyl ether, gave 4.65 g (71%) of 1-benzyl-3-ethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.O[C:17]1[CH:32]=[CH:31][C:20]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[CH:19][CH:18]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][C:17]3[CH:32]=[CH:31][C:20]([C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[CH:19][CH:18]=3)=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: CC1(C)CCSc2ccc(C(=O)O)cc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)CCSc2ccc(C(=O)Oc3ccc(C(=O)OCc4ccccc4)cc3)cc21

Procedure:
A solution of 786 mg (3.54 mmol) of 4,4-dimethyl-6-carboxythiochroman, 804 mg (3.53 mmol) of benzyl 4-hydroxybenzoate, 800 mg (3.88 mmol) of 1, 3-dicyclohexylcarbodiimide and 60 mg (0.49 mmol) of 4-dimethylaminopyridine in 50 ml of methylene chloride was stirred at room temperature for 2 hours. The reaction mixture was then filtered and the residue washed with 20 ml of methylene chloride. The filtrate was concentrated in-vacuo and the resultant crude product was purified by flash chromatography (silica, 20% ethyl acetate in hexanes) followed by recrystallization from a mixture of hexanes and ethyl acetate to give the title compound as a white, crystalline solid. PMR (CDCl3): δ1.39 (6H, s), 1.98 (2H, m), 3.08 (2H, m), 5.37 (2H, s), 7.20 (1H, d, J~8.3 Hz), 7.28 (2H, d, J~8.0 Hz), 7.34-7.48 (5H, m), 7.82 (1H, dd, J~8.3, 2.0 Hz), 8.14 (2H, d, J~8.0 Hz),
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:33][CH2:34][CH:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2([OH:48])[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[CH2:37][CH2:36]1.C([O-])(O)=O.[Na+]>O1CCCC1>[OH:48][C:42]1([CH2:41][N:38]2[CH2:39][CH2:40][CH:35]([CH2:34][NH:33][C:22]([N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]3=[O:13])=[O:24])[CH2:36][CH2:37]2)[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)n1c(=O)[nH]c2ccccc21
Reactant: NCC1CCN(CC2(O)CCOCC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)n1c(=O)n(C(=O)NCC2CCN(CC3(O)CCOCC3)CC2)c2ccccc21
Temperature: 80 °C
Yield: 66.7 %

Procedure:
To a stirred mixture of 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one (J. Med. Chem. 1999, 42, 2870-2880) (23.0 g, 130 mmol) and triethylamine (54.6 mL, 392 mmol) in tetrahydrofuran (300 mL) was added triphosgen (38.8 g, 130 mmol) in tetrahydrofuran (200 mL) gradually at room temperature. Then, the mixture was heated at 80° C. for 4 h. After cooling, a solution of 4-{[4-(aminomethyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-ol (step 2 of Example 1) (24.9 g, 109 mmol) and triethylamine (45 mL, 109 mmol) in tetrahydrofuran (500 mL) was added to the mixture. Then, the mixture was heated at 80° C. for 6 h. After cooling, sat. NaHCO3 aq was added to the mixture. The mixture was extracted with ethyl acetate (500 mL×4). The extracts were washed with brine, dried over MgSO4 and concentrated. The residue was chromatographed on a column of aminopropyl-silica gel eluting with hexane/ethyl acetate (3:1) to give 31.3 g (67%) of the title compound as a white solid.
Reaction SMILES: [C:1]([N:4]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[N:16]=[C:17](Cl)[C:18]([F:20])=[CH:19][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N1C2C=CC=CC=2C=CC2N=C(C3C=NC(OC)=CC=3)C(F)=CC=2C1)(=O)C>>[C:1]([N:4]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[N:16]=[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]([F:20])=[CH:19][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Reactant: OB(O)c1ccccc1
Agent: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Product: CC(=O)N1Cc2cc(F)c(-c3ccccc3)nc2C=Cc2ccccc21
Yield: 88.4 %

Procedure:
The title compound (20.1 mg, 88.5%) was prepared from 1D (20.0 mg, 0.066 mmol) and phenylboronic acid (12.1 mg, 0.099 mmol) by a route analogous to that used for the preparation of 2B. HPLC Rt=3.326 min; LCMS Found: (M+H)+=345.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[CH3:11].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.Cl>CCOC(C)=O.C(#N)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:6][C:5]=1[CH3:11]
Reactant: ClCc1ccccn1
Reactant: COC(=O)c1ccc(O)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccc(OCc2ccccn2)cc1C
Temperature: 90 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
To 0.85 g of 4-hydroxy-2-methyl benzoic acid methyl ester were added 12 mL of acetonitrile, 2.12 g of K2CO3 and 0.84 g of 2-(chloromethyl)pyridine hydrochloride, and the mixture was stirred at 90° C. for 4 hours. The reaction mixture was allowed to cool back to room temperature and neutralized by the addition of 5% hydrochloric acid. To this, 150 mL of AcOEt was added, and the organic layer was separated. The obtained organic layer was washed with saturated brine, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography (hexane/AcOEt system) to give 1.18 g of the title compound (89% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][C:27]=2OC)[C:14]([NH:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[O:15])=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)[C:32](=[O:33])C1.[F:38][C:39]1[CH:44]=[CH:43][N:42]=[C:41]([NH2:45])[CH:40]=1>ClCCl.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[N:42]3[CH:43]=[CH:44][C:39]([F:38])=[CH:40][C:41]3=[N:45][C:9]=2[C:11]2[CH:27]=[CH:26][C:25]([O:33][CH3:32])=[C:13]([CH:12]=2)[C:14]([NH:16][C:17]2[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=2[F:23])=[O:15])[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(C(=O)Nc2c(F)cccc2F)cc1C(=O)Cc1ccnc(Cl)n1
Reactant: Nc1cc(F)ccn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(-c2nc3cc(F)ccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
To a stirred solution of 3-[(2-chloro-4-pyrimidinyl)acetyl]-N-(2,6-difluorophenyl)-4-(methyloxy)benzamide (Intermediate Example 2, step E) (0.950 g, 2.28 mmol) in dichloromethane (23 mL) at rt under N2 was added NBS (0.426 g, 2.39 mmol). The reaction was stirred approximately 30 min, then concentrated under vacuum to a foam like solid. The solid was dissolved in dioxane (23 mL) and 4-fluoro-2-pyridinamine (Example 194, step A) (0.765 g, 6.83 mmol) was added. The reaction was stirred under N2, heated to 80° C., and stirred for approximately 16 h, then cooled to rt. The reaction was diluted with EtOAc and half-saturated aqueous NaHCO3. The organic layer was separated and washed with brine. The combined aqueous layers were extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography to give the title compound of step A (0.700 g, 1.37 mmol, 61%) as a light tan solid. MS (ESI): 510 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].C1(C)C=CC(S(O[CH2:32][CH:33]2[CH2:36][CH2:35][CH2:34]2)(=O)=O)=CC=1>>[CH:33]1([CH2:32][N:8]2[C:9]([C:10](=[O:19])[C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]2=[O:20])[CH2:36][CH2:35][CH2:34]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC2)cc1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CC2CCC2)c1
Yield: 1.3 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and (cyclobutyl)methyl para-toluenesulfonate were reacted by the same way ith the example 1 to obtain the titled compound (182 mg, yield: 1.3%).
Reaction SMILES: C([O:5][CH2:6][C@H:7]([CH3:35])[O:8][C:9]1[CH:10]=[C:11]([CH:21]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH:23]=1)[C:12]([NH:14][C:15]1[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=1)=[O:13])(C)(C)C.Cl>CO.C(OC(C)=O)(C)C.O>[OH:5][CH2:6][C@H:7]([CH3:35])[O:8][C:9]1[CH:10]=[C:11]([CH:21]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][CH:26]=2)[CH:23]=1)[C:12]([NH:14][C:15]1[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=1)=[O:13]
Reactant: C[C@@H](COC(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CC(=O)OC(C)C
Product: C[C@@H](CO)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 50 °C
Yield: 64 %

Procedure:
To a 25 ml round-bottomed flask was charged 3-[(1S)-2-tert-butoxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[4-(methylsulfonyl)phenoxy]benzamide (498.4 μmol, 250.0 mg). This was dissolved in methanol (4 ml) and HCl (4 ml) was added to the flask in one portion. The reaction was heated to 50° C. for 1.5 hours. Solvent was removed in vacuo to yield a colourless solid that quickly changed to liquid form on standing. The liquid was dissolved in iPrOAc (10 ml) and water (10 ml). The aqueous layer was extracted with further iPrOAc (10 ml). The combined organic layer was dried with MgSO4 and the solvent was removed in vacuo to yield crude title product (142 mg; 63.95% yield) as a white foamy solid.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14]3[O:21][N:22]=[CH:23][C:13]=3[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.Cl[Sn]Cl.O.C([O-])(O)=O.[Na+]>C(O)C>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14]3[O:21][N:22]=[CH:23][C:13]=3[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2cnoc2-c2ccccc21
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(C(=O)N2CCc3cnoc3-c3ccccc32)cc1
Yield: 219.6 %

Procedure:
A mixture of 0.050 g of 5,6-dihydro-6-(4-nitrobenzoyl)-4H-isoxazolo[4,5-d][1]benzazepine and 0.169 g of SnCl2 2H2O in 2 ml of ethyl alcohol is heated at reflux under argon for 1 hour. Water and 10% NaHCO3 is added until basic. The volatiles are evaporated in vacuo to a residue which is stirred with 1:1 chloroform-methanol and filtered. The filtrate is evaporated in vacuo to a residue which is dissolved in methyl alcohol, treated with activated carbon, filtered through diatomaceous earth and concentrated in vacuo to give 100 mg of the desired product as a white crystalline solid. CIMS(CH4):MH+ =306.
Reaction SMILES: OC[C@@]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)C=CC4)CCC1CCCC2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[OH:35][CH2:36][C@@:37]12[C@@H:54]3[C@H:45]([C@H:46]4[C@@:50]([CH2:52][CH2:53]3)([CH3:51])[CH2:49][CH2:48][CH2:47]4)[CH2:44][CH2:43][C:42]1=[CH:41][C:40](=[O:55])[CH2:39][CH2:38]2.O1CCOCC1>C(Cl)Cl>[OH:35][CH2:36][C@@:37]12[C@@H:54]3[C@H:45]([C@H:46]4[C@@:50]([CH2:52][CH2:53]3)([CH3:51])[CH2:49][CH2:48][CH2:47]4)[CH2:44][CH2:43][C:42]1=[CH:41][C:40](=[O:55])[CH:39]=[CH:38]2
Reactant: C[C@@]12CCC[C@H]1[C@@H]1CCC3=CC(=O)CC[C@]3(CO)[C@H]1CC2
Agent: C[C@@]12C=CC[C@H]1[C@@H]1CCC3CCCC[C@]3(CO)[C@H]1CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@]12CCC[C@H]1[C@@H]1CCC3=CC(=O)C=C[C@]3(CO)[C@H]1CC2

Procedure:
The 1,4 and 6-methylated derivatives for the 4-androstene-3,19-diones of the present invention are best prepared by introducing the desired methyl group into the 19-hydroxy-androstene and oxidizing the 19-alcohol to the aldehyde. The 1α-methyl-19-hydroxy-4-androsten-3-ones which can be oxidized to the aldehydes are prepared in two steps. The reaction of dichlorodicyanobenzoquinone with a 19-hydroxy-4-androsten-3-one in refluxing dioxane or methylenechloride for 24-72 hours to produce the corresponding 19-hydroxy-1,4-androstadien-3-one. However, two restrictions in this sequence are necessary. First, the 19-hydroxy group must be protected as an ester or an ether in order to avoid aromatization. Secondly, the 1-position must possess an axial hydrogen atom suitable for elimination. Thus, the 1α-methyl androstene is not reactive although the 1β-methyl androstane is. Following this procedure 17β,19-dihydroxy-7α-methyl-4-androsten-3-one dipropionate is converted to 17β,19-dihydroxy-7α-methyl-1,4-androstadien-3-one dipropionate. Similarly, 19-hydroxy-6α-methyl-4-androstene-3,17-dione acetate forms 19-hydroxy-6α-methyl-1,4-androstadiene-3,17-dione acetate and 1β-methyl-19-tetrahydropyranyloxy-4-androstene-3,17-dione forms 1-methyl-19-tetrahydropyranyloxy-1,4-androstadiene-3,17-dione.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[C:13]([C:15]1([CH:19]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]2)[CH2:18][CH2:17][CH2:16]1)#N.Cl.C([O-])(O)=[O:33].[Na+]>CCOCC>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:13]([C:15]1([CH:19]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]2)[CH2:18][CH2:17][CH2:16]1)=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCC(C2(C#N)CCC2)C1
Reactant: Brc1ccccn1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(C2(C(=O)c3ccccn3)CCC2)C1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 21 %

Procedure:
To a solution of 2-bromopyridine (410 mg, 2.6 mmol) in ether (10 mL) was added 2.5M n-BuLi (1.04 mL, 2.6 mmol) dropwise and the solution was stirred at −78° C. for 45 minutes. Then a solution of Example 265C (500 mg, 2.0 mmol) in ether (2 mL) was added to the solution at −78° C. and the mixture was stirred for 2 hours. 1N HCl aqueous solution was added to the mixture till pH<7 and the resulting solution was stirred at room temperature for 1 hour. The reaction mixture was basified with aqueous solution of NaHCO3 and the solution was extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain the title compound (140 mg, 21% yield) as a yellow oil. MS: m/z 275 (M−55).