Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=4)[CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:35])CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([F:35])[CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=4)[CH2:19][CH2:18][CH2:17]3)[CH2:14][CH2:15]2)=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)N(C1CCN(CC(O)c3ccc(F)cc3)CC1)CCC2
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2c(c1)N(C1CCN(CC(F)c3ccc(F)cc3)CC1)CCC2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 1-{1-[2-(4-fluorophenyl)-2-hydroxyethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline (250 mg) in methylene chloride (5 ml) was cooled to −78° C. and diethylaminosulfur trifluoride (DAST, 0.1 ml) was added thereto. Then the reaction solution was stirred at the same temperature for 45 min. After the completion of the reaction, saturated sodium bicarbonate was added to the reaction solution, which was then allowed to warm to room temperature under stirring. The reaction solution was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate. After evaporating the solvent, the resulting residue was purified by silica gel column chromatography (hexane/hexane system) to give 1-{1-[2-(4-fluorophenyl)-2-fluoroethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline as an oil. This product was dissolved in ethyl acetate. After adding hydrochloric acid, the resulting salt was recrystallized from ethanol/ether to give the title compound (60 mg) (yield: 24%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6](Br)[CH:5]=1.[CH3:16][Si:17]([CH3:22])([CH3:21])[CH2:18][CH2:19][SH:20].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:5]=[C:6]([S:20][CH2:19][CH2:18][Si:17]([CH3:22])([CH3:21])[CH3:16])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: C[Si](C)(C)CCS
Reactant: COC(=O)c1cc(Br)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)c1cc(SCC[Si](C)(C)C)cc(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A solution of 3-bromo-5-trifluoromethyl-benzoic acid methyl ester (600 mg, 2.12 mmol, CAS RN 187331-46-0) in dioxane (6 mL) and 2-(trimethylsilyl)ethanethiol (285 mg, 335 μL, 2.12 mmol, CAS RN 18143-30-1) was stirred under argon for 5 min., treated with tris(dibenzylideneacetone)dipalladium (0) (48.5 mg, 53.0 μmol, CAS RN 52522-40-4), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (61.3 mg, 106 μmol, xantphos, CAS RN 161265-03-8) and N,N-diisopropylethylamine (548 mg, 740 μL, 4.24 mmol) and stirred at 120° C. in a sealed tube for 4 h. Stirring was continued at room temperature for another 18 hours. The reaction mixture was poured on saturated aqueous ammonium chloride solution and ethyl acetate and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 80:20). Yellow liquid (587 mg, 82%). MS (EI): m/z=336 ([M]).
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].CC[O-].[Na+].[F:12][C:13]([F:33])([F:32])[C:14]1[CH:31]=[CH:30][CH:29]=[CH:28][C:15]=1[CH2:16][CH:17]([C:23](OCC)=[O:24])[C:18](OCC)=[O:19]>C(O)C>[F:12][C:13]([F:32])([F:33])[C:14]1[CH:31]=[CH:30][CH:29]=[CH:28][C:15]=1[CH2:16][CH:17]1[C:23](=[O:24])[NH:7][CH:5]=[N:6][C:18]1=[O:19]
Reactant: CCOC(=O)C(Cc1ccccc1C(F)(F)F)C(=O)OCC
Reactant: N=CN
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1N=CNC(=O)C1Cc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.63 g of formamidine acetate in 40 ml of absolute ethyl alcohol was treated with 1.2 g of sodium ethylate at room temperature, stirred at room temperature for 30 minutes and then treated dropwise at room temperature with a solution of 1.6 g of diethyl [o-(trifluoromethyl)benzyl]malonate in 8 ml of absolute ethyl alcohol. After stirring at 50° C. for 4 hours, the reaction mixture was worked-up and yielded 5-[o-(trifluoro-methyl)benzyl]-4,6(1H,5H)pyrimidinedione, melting point >290° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[S:12]1[C:16](B(O)O)=[CH:15][C:14]2[CH:20]=[CH:21][CH:22]=[CH:23][C:13]1=2.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.[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>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][CH:2]=[N:3][C:4]=1[C:16]1[S:12][C:13]2[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=2[CH:15]=1
Reactant: OB(O)c1cc2ccccc2s1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1cccnc1-c1cc2ccccc2s1
Temperature: 80 °C
Yield: 78.1 %

Procedure:
Compound 2 (5.0 g, 29.1 mmol), benzo[b]thiophene-2-ylboronic acid (6.23 g, 35.0 mmol), and tetrakis-(triphenylphosphine) palladium(0) (1.07 g, 0.87 mmol) were added to an RBF equipped with a reflux condenser and dissolved in a mixed solvent system of toluene (150 mL) and ethanol (50 mL). After addition of 50 mL of aqueous 2 N sodium carbonate solution, the reaction mixture was heated at 80° C. for 2 days. The organic phase was separated and extracted with methylene chloride. The organics were then combined, dried over Na2SO4 and filtered. The solvent was evaporated to give the crude product. The resulting crude product was then purified by silica gel column chromatography (eluent: ethyl acetate:methylene chloride=1:30 v/v) to yield 6.12 g (78%) of methyl 6-(benzo[b]thiophen-2-yl)nicotinate (Compound 3).
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl.[Cl:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:32].[CH3:24][N:23]1[C:22](=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH3:26])[N:15]=[C:14]1[S:13][CH2:12][C:11]1[CH:27]=[CH:28][C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:33][CH2:34][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:30][CH:29]=2)=[CH:9][CH:10]=1
Reactant: ClCCN1CCCC1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCCN5CCCC5)cc4)cc3)n(C)c(=O)c12
Yield: 44.8 %

Procedure:
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (384 mg), 1-(2-chloroethyl)pyrrolidine hydrochloride (181 mg) and potassium carbonate (414 mg) in DMF (5 ml) was stirred at 60° C. for 62 hours. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, and dried. Then, hydrogen chloride/ethyl acetate was added and the precipitated hydrochloride was collected by filtration to provide the title compound as colorless solid (227 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([N:18]=[CH:19][CH:20]=2)[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[C:6]([CH:8]([NH2:10])[CH3:9])[CH:7]=1.Br[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.C(O)C.C(N(CC)C(C)C)(C)C>Cl.O1CCOCC1>[Cl:1][C:2]1[C:3]2[N:4]([N:18]=[CH:19][CH:20]=2)[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[C:6]([CH:8]([NH:10][C:22]2[N:30]=[CH:29][N:28]=[C:27]3[C:23]=2[N:24]=[CH:25][NH:26]3)[CH3:9])[CH:7]=1
Reactant: Brc1ncnc2c1ncn2C1CCCCO1
Reactant: CC(N)c1cc(Cl)c2ccnn2c1-c1cccc(F)c1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2ccnn2c1-c1cccc(F)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
1-[4-Chloro-7-(3-fluorophenyl)pyrazolo[1,5-a]pyridin-6-yl]ethanamine (12 mg, 0.043 mmol) and 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.018 g, 0.064 mmol) were stirred in ethanol (0.5 mL, 9 mmol) with N,N-diisopropylethylamine (37 μL, 0.21 mmol). The mixture was heated to 100° C. for 20 hours, the reaction was mostly complete. This was allowed to cool to room temperature and concentrated in vacuo to give a semi-solid residue. The residue was taken up in 4 M HCl in dioxane and stirred at room temperature for 1 hour. This was complete by LCMS and was concentrated to give a semi-solid residue. The product was purified by preparative HPLC on a C-18 column eluting acetonitrile: water gradient buffered with ammonia to pH 10 to give N-{1-[4-chloro-7-(3-fluorophenyl)pyrazolo[1,5-a]pyridin-6-yl]ethyl}-9H-purin-6-amine (8 mg, 47%) as a white amorphous solid. LCMS calculated for C20H16ClFN7 (M+H)+: m/z=408.1. found: 408.0. 1H NMR (400 MHz, DMSO-d6/TFA): δ 8.52 (m, 1H), 8.42 (m, 1H), 7.98 (m, 1H), 7.69 (m, 1H), 7.63-7.51 (m, 2H), 7.45-7.31 (m, 2H), 6.77 (m, 1H), 5.1 (m, 1H), 1.55 (d, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.IC.[C:18](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]([F:14])([F:15])[O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:18])=[O:10])=[CH:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(COC(F)(F)F)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1ccc(COC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To a solution of 4-[(trifluoromethoxy)methyl]benzoic acid (500 mg, 2.27 mmol) in N,N-dimethylformamide (25 mL) were added iodomethane (300 μL, 4.82 mmol) and potassium carbonate (1000 mg, 7.24 mmol). The mixture was stirred at room temperature overnight, and then to the reaction solution was added water, and the mixture was extracted with ethyl acetate three times. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1→80:20) to give methyl 4-[(trifluoromethoxy)methyl]benzoate (453 mg, 85%) as a pale brown oil.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[N:13]1[C:21]2[NH:20][CH:19]=[N:18][C:17](=O)[C:16]=2[CH:15]=[N:14]1>>[Cl:3][C:17]1[N:18]=[CH:19][N:20]=[C:21]2[N:13]([C:12]3[CH:11]=[CH:10][N:9]=[CH:8][C:7]=3[CH3:6])[N:14]=[CH:15][C:16]=12
Reactant: Cc1cnccc1-n1ncc2c(=O)nc[nH]c21
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cnccc1-n1ncc2c(Cl)ncnc21
Temperature: 100 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
Phosphoryl trichloride (7.59 mL, 79.2 mmol) was added to 1-(3-methylpyridin-4-yl)-7H-pyrazolo[4,5-e]pyrimidin-4-one (Intermediate M2) (900 mg, 3.96 mmol) and the resulting suspension was stirred at 100° C. for 24 hours during which a solution formed. This was evaporated, triturated with ether (3×10 mL) and dried in vacuo. The resulting solid was suspended in DCM (50 mL) and stirred with 10 g of polymer supported carbonate for 2 hours. The mixture was filtered and evaporated to afford 4-chloro-1-(3-methylpyridin-4-yl)pyrazolo[5,4-d]pyrimidine (700 mg, 72%). 1H NMR (400 MHz, DMSO-d6) δ 2.25 (3H, s), 7.62 (1H, d), 8.64 (1H, d), 8.74 (1H, s), 8.83 (1H, s), 8.94 (1H, s); m/z (ESI+) (M+H)+=246; HPLC tR=1.22 min.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](I)[CH:3]=1.[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1.C([O-])([O-])=O.[K+].[K+]>ClC1C=CC=CC=1.C(OCC)(=O)C.[Cu]>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:4]2[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1
Reactant: COC(=O)c1ccc(Cl)cc1I
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cl)cc1Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 89 %

Procedure:
A mixture of methyl 4-chloro-2-iodobenzoate (5.93 g, 20 mmol), 4-bromo-2-nitroaniline (4.34 g, 20 mmol), copper (1.26 g, 20 mmol), and K2CO3 (2.76 g, 20 mmol) in chlorobenzene (300 mL) was heated to reflux for 2 days, cooled to room temperature, diluted with ethyl acetate, and filtered through diatomaceous earth (Celite®). The solution was washed with water and brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 9:1 hexanes/ethyl acetate to provide 6.86 g (89%) of the desired product. MS (DCI) m/e 386 (M+H)+, 403 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.28 (d, J=2.4 Hz, 1H), 7.97 (d, J=8.5 Hz, 1H), 7.82 (dd, J=9.1, 2.4 Hz, 1H), 7.63 (d, J=9.1 Hz, 1H), 7.52 (d, J=2.1 Hz, 1H), 7.17 (dd, J=8.5, 2 Hz, 1H), 3.87 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1C(=O)C2C(=CC=CC=2)C1=O.O1CCCC1>>[F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[CH2:4][NH2:5]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc([N+](=O)[O-])cc1F
Solvent: C1CCOC1
Product: NCc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 41.5 %

Procedure:
To a solution of 2-(2-fluoro-4-nitrobenzyl)isoindoline-1,3-dione (1.35 g, 4.48 mmol) in tetrahydrofurane 65% hydrazine monohydrate (1.3 mL, 4 eq) was added. The mixture was refluxed for 6 h. After the starting material was consumed, the mixture was cooled down to room temperature and treated with potassium bicarbonate to pH 12˜13. Then it was extracted with ethyl acetate and washed with brine. Drying over magnesium sulfate, evaporation of the ethyl acetate and purification by column chromatography gave (2-fluoro-4-nitrophenyl)methanamine (316 mg, 41%).
Reaction SMILES: [CH:1]1([CH:4]([CH:12]2[CH2:14][CH2:13]2)[N:5]([CH2:9][CH2:10][CH3:11])[C:6]([NH2:8])=[S:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH:23]([CH3:34])[C:24]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[Cl:33])=O>C(O)C>[Cl:33][C:27]1[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:26]=1[C:24]1[N:8]=[C:6]([N:5]([CH:4]([CH:1]2[CH2:3][CH2:2]2)[CH:12]2[CH2:13][CH2:14]2)[CH2:9][CH2:10][CH3:11])[S:7][C:23]=1[CH3:34]
Reactant: CCCN(C(N)=S)C(C1CC1)C1CC1
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(C1CC1)C1CC1
Yield: 88 %

Procedure:
To 1 g of N-(dicyclopropylmethyl)-N-propylthiourea (Compound 88) dissolved in 25 ml of anhydrous ethanol, add 0.54 ml of triethylamine, then slowly 1 g of 2-bromo-1-(2,4-dichlorophenyl)-1-propanone (Compound 15). After two hours of heating under reflux of the ethanol, evaporate to dryness. Take up the residue in methylene chloride and wash with water until bromide ions have been removed completely. Dry the organic phase over anhydrous sodium sulphate and then evaporate to dryness. Purify the residue on a silica column, using a mixture of cyclohexane and ethyl acetate (20:1 V/V) as eluent, to obtain the expected product in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([C:23]([F:26])([F:25])[F:24])[CH:15]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[Cl:1][C:2]1[C:3]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][C:16]=2[C:23]([F:24])([F:26])[F:25])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: OB(O)c1ccc(Cl)cc1C(F)(F)F
Reactant: Nc1cc(Cl)c(I)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cc(Cl)c(-c2ccc(Cl)cc2C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 95 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a solution of 5-chloro-4-iodo-2-nitroaniline (2 g, 6.70 mmol) in dioxane (100 ml) and water (10 ml) which maintained with an inert atmosphere of nitrogen was added [4-chloro-2-(trifluoromethyl)phenyl]boronic acid (1.8 g, 8.02 mmol), K3PO4 (2.6 g, 12.24 mmol), Pd(PPH3)4 (0.78 g, 335.77 mmol) with stirring overnight at 95° C. in an oil bath. The resulting mixture was concentrated under vacuum to give a residue which was purified by a silica gel column, eluting with 2% to 3% acetate in petroleum ether to produce 5-chloro-4-[4-chloro-2-(trifluoromethyl)phenyl]-2-nitroaniline as a yellow solid (800 mg, 34%). Next, to a solution of 5-chloro-4-[4-chloro-2-(trifluoromethyl)phenyl]-2-nitroaniline (1.6 g, 4.56 mmol) in ethanol (50 ml) was added Zn powder (1.8 g, 27.69 mmol), hydrogen chloride (2 ml) with stirring for 2 h at 85° C. in an oil bath. The solution was poured into water (300 ml), adjusted to pH 8 with saturated aqueous sodium carbonate and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column, eluting with 5% to 20% ethyl acetate in petroleum to produce 4-chloro-5-[4-chloro-2-(trifluoromethyl)phenyl]benzene-1,2-diamine as a crude red solid (560 mg, 76%). Finally, the solution of 4-chloro-5-[4-chloro-2-(trifluoromethyl)phenyl]benzene-1,2-diamine (100 mg, 0.31 mmol) in trifluoroacetic acid (5 m 1) and hydrogen chloride (1 ml) was stirred overnight at 80° C. in an oil bath. The mixture was quenched with water (100 ml), adjusted to pH 8 with saturated aqueous sodium carbonate solution and extracted with ethyl acetate (50 ml×3). The organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 10% ethyl acetate in petroleum ether to afford 5-chloro-6-[4-chloro-2-(trifluoromethyl)phenyl]-2-(trifluoro methyl)-1H-1,3-benzodiazole as a white solid (101.7 mg, 82%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]2[C:16]3[CH:17]=[C:18]([C:21]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)([OH:28])[C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[CH:19]=[CH:20][C:15]=3[NH:14][C:13](=[O:36])[CH2:12][S:11]2)[CH:7]=[CH:8][CH:9]=1.IC.[CH3:39]COC(C)=O>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]2[C:16]3[CH:17]=[C:18]([C:21]([C:29]4[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=4)([OH:28])[C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[CH:19]=[CH:20][C:15]=3[N:14]([CH3:39])[C:13](=[O:36])[CH2:12][S:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(C)=O
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)CSC(c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3cncn3C)ccc21
Reaction time: 0.5 h
Yield: 67 %

Procedure:
NaH 60% (0.00917 mol) was added portionwise at 5° C. under N2 flow to a mixture of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1,5-dihydro-4,1-benzothiazepin-2(3H)-one (see Example B2) (0.00705 mol) in THF (50 ml). The mixture was stirred for 30 min. Iodomethane (0.00846 mol) was added dropwise. The mixture was stirred at 5° C. for 1 hour, at room temperature for 2 hours and hydrolyzed cold. EtOAc was added. The mixture was filtered over celite, washed with EtOAc and the filtrate was extracted with EtOAc. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from 2-propanone and diethyl ether. The precipitate was filtered off and dried in vacuo, yielding 2.5 g (67%) of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1,5-dihydro-1-methyl-4,1-benzothiazepin-2(3H)-one, mp. 186° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.[C:13](OC(=O)C)(=[O:15])[CH3:14]>CO>[OH:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][CH:3]=[C:2]2[NH:1][C:13](=[O:15])[CH3:14])=[CH:7][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc2ccc(O)cc12
Solvent: CO
Product: CC(=O)Nc1cccc2ccc(O)cc12
Temperature: 25 °C
Yield: 93.2 %

Procedure:
To a solution of 8-amino-2-naphthol (149.1 g, 0.937 mol) in methanol (1 L) was added acetic anhydride (93 mL, 0.984 mol). The reaction was refluxed for 90 minutes and cooled to room temperature. The solvent was removed and the residue was filtered through a plug of silica with ethyl acetate. The solvent was removed to yield 175.8 g (93%) of the title compound as a dark purple solid. An analytical sample was further purified by reverse phase preparative HPLC to yield a pink solid: mp 161–162° C.; 1H NMR (DMSO-d6):δ 2.15 (3H, s), 7.09 (1H, dd, J=1.95 Hz, J=8.79 Hz), 7.20–7.26 (2H, m), 7.49 (1H, d, J=7.31 Hz), 7.63 (1H, d, J=8.11 Hz), 7.77 (1H, d, J=8.81 Hz), 9.76 (1H, s), 9.79 (1H, s); MS (ESI) m/z 202 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18].OS([O-])(=O)=O.[K+]>C(Cl)Cl>[Cl:15][CH2:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C. to a solution of aniline (2.45 mL) and triethylamine (0.73 mL) in methylene chloride (30 mL) a solution of chloroacetyl chloride (2.56 mL) in methylene chloride (10 mL) was added dropwise. The reaction was stirred at 0° C. for 30 min and then at room temperature for 1 hour. A 1M aqueous solution of KHSO4 was added, the phases were separated and the inorganic one was extracted with ethyl acetate (×3). The combined organic layers were washed with water, brine, dried (Na2SO4) and concentrated in vacuo to yield crude 2-chloro-N-phenyl-acetamide, which was subjected to the next reaction without further purification.
Reaction SMILES: [OH-:1].[Na+].OO.[CH3:5][C@@:6]12[C@@H:14]([OH:15])[CH2:13][CH2:12][C@H:11]1[C@@H:10]1[CH2:16][CH2:17][C:18]3[C@@:24]([CH3:25])([C@H:9]1[CH2:8][CH2:7]2)[CH2:23][CH2:22][C:20](=[O:21])[CH:19]=3>CO>[CH3:5][C@@:6]12[C@@H:14]([OH:15])[CH2:13][CH2:12][C@H:11]1[C@@H:10]1[CH2:16][CH2:17][C:18]3[C@@:24]([CH3:25])([C@H:9]1[CH2:8][CH2:7]2)[CH2:23][CH2:22][C:20](=[O:21])[CH:19]=3.[O:1]1[C:18]23[C@:24]([CH3:25])([CH2:23][CH2:22][C:20](=[O:21])[C@H:19]12)[C@@H:9]1[C@H:10]([C@H:11]2[C@@:6]([CH2:7][CH2:8]1)([CH3:5])[C@@H:14]([OH:15])[CH2:13][CH2:12]2)[CH2:16][CH2:17]3
Reactant: [OH-]
Agent: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: OO
Agent: [Na+]
Solvent: CO
Product: C[C@]12CC[C@H]3[C@@H](CCC45O[C@H]4C(=O)CC[C@]35C)[C@@H]1CC[C@@H]2O
Temperature: 3 °C
Reaction time: 3 h

Procedure:
A solution of 33g of testosterone in 1500ml of methanol is prepared and cooled in an ice bath to 3°C. Over an hour period, 191ml of 4N sodium hydroxide and 143ml of 30% hydrogen peroxide are added simultaneously. The mixture is stirred at 3° C for an additional 3 hours after which thin layer chromatography shows that the testosterone has been completely consumed. The mixture is poured into 20 gallons of ice water contain 3 pounds of salt and the title epoxide crysallizes. The crystalline material is filtered with suction and the residue is washed with water on the filter and dried to yield 10.5g of the title compound.