Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([F:16])[CH2:13][C@H:12]1[C:17]#[N:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[NH2:27][OH:28]>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([F:16])[CH2:13][C@H:12]1[C:17]([NH2:18])=[N:27][OH:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=NO)[C@@H]1C[C@H](F)CN1C(=O)OCc1ccccc1

Procedure:
Benzyl-(2S,4S)-2-cyano-4-fluoropyrrolidine-1-carboxylate dissolved in absolute ethanol was treated with triethyl amine (1.5 eq.) and hydroxylamine hydrochloride (1.3 eq.).
Reaction SMILES: C([O:3][C:4](=[O:46])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([I:28])[CH:25]=[C:24]([C:29](=[O:38])[NH:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:23]=2)[C:10]=1[CH2:39][CH2:40][C:41]([O:43]CC)=[O:42])C.[OH-].[Na+].Cl>C1COCC1>[CH2:31]([NH:30][C:29]([C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([I:28])[CH:25]=1)[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]1[C:10]([CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:46])=[O:3])=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(C(=O)NCc3ccccc3)c2)c1CCC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(I)cc(C(=O)NCc3ccccc3)c2)c1CCC(=O)O
Temperature: 55 °C
Reaction time: 4 h
Yield: 100.7 %

Procedure:
4-[3-[6-(3-Benzylcarbamoyl-5-iodo-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (8.7 g) was dissolved in THF (30 mL) and 2 M NaOH was added (30 mL). The resulting heterogeneous mixture was stirred vigorously at 55° C. for 4 h. Then it was acidified with 3 N HCl and extracted into diethyl ether. Etherate extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to produce 8.1 g (100% yield) of colorless oil which solidified upon standing.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:19](O)=[O:20])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.[BH4-].[Na+].C(O)(=O)C>C1COCC1.C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:19][OH:20])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CO)COCc1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
N-(tert-Butyloxycarbonyl)-O-benzyl-D-serine 10 (7.56 g, 25.63 mmol) was dissolved in dry THF and cooled to -20° C. under argon atmosphere. To this cold stirred solution was added TEA (3.03 g, 30 mmol) and isobutyl chloroformate (4.08 g, 30 mmol). The stirring was continued for 30 min at -20° C. under argon atmosphere. The reaction mixture was filtered immediately under a blanket of argon, the precipitate was washed with dry THF (50 ml). The combined filtrate was added slowly into a cold (0° C.) solution of NaBH4 (7.4 g, 200 mmol) in THF/water (80:20, 200 ml) during 10 min period. After the addition, the reaction mixture was stirred for 2 h at 0° C. and the pH adjusted to 7 with acetic acid. The solution was evaporated to dryness, partitioned between ethyl acetate/water (300:150 ml) and extracted in ethyl acetate. The organic extract was washed with brine (100 ml), dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by flash column chromatography over silica gel using CH2Cl2 →EtOAc as the eluent. The pure product was pooled together and evaporated to dryness to give 6.68 g (92%) of the pure product as an oil. 1HNMR (CDCl3): δ1.41 (s, 9H, Boc), 3.60-3.70 (m, 4H), 3.82 (d, 2H), 4.53 (s, 2H, OCH2Ph), 5.20 (bs, 1H, NH) and 7.30-7.40 (m, 5H, Ph).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:16])=[CH:10][CH:9]=1.Br[CH2:26][C:27]([O:29][CH3:30])=[O:28]>CC(C)=O>[C:20]([O:19][C:18]([NH:17][C@H:15]([CH3:16])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:9][CH:10]=1)=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)CBr
Reactant: C[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(C[C@@H](C)NC(=O)OC(C)(C)C)cc1

Procedure:
Potassium carbonate (1.95 g, 14.2 mMol) was added to a solution of (R)-2-(4-hydroxyphenyl)-1-methylethylcarbamic acid, t-butyl ester (2.96 g, 11.8 mMol) in acetone (50 ml) at room temperature under argon. Methyl bromoacetate (1.81 g, 11.8 mMol) was added dropwise and the reaction mixture was heated at reflux for 3 hours. The solvent was removed under reduced pressure and the residue was taken into ethyl acetate and washed with water (2×30 ml). The organic extracts were dried with sodium sulfate and the solvent evaporated in vacuo. The crude product was purified by chromatography on Kieselgel 60 (eluting with 20% ethyl acetate in pentane) to give the title compound as an oil.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([O:18][C:19]2[C:31]([CH:32]3[CH2:34][CH2:33]3)=[CH:30][C:22]([C:23]([O:25]C(C)(C)C)=[O:24])=[C:21]([F:35])[CH:20]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.FC(F)(F)C(O)=O>[CH:1]([N:14]1[CH2:15][CH:16]([O:18][C:19]2[C:31]([CH:32]3[CH2:33][CH2:34]3)=[CH:30][C:22]([C:23]([OH:25])=[O:24])=[C:21]([F:35])[CH:20]=2)[CH2:17]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc(C2CC2)c(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F

Procedure:
A solution of tert-butyl 4-(1-benzhydrylazetidin-3-yloxy)-5-cyclopropyl-2-fluorobenzoate (650 mg, 1.37 mmol) in DCM (10 mL) and trifluoroacetic acid (5 mL) was stirred at room temperature for 2 h. The solvent was removed and the residue was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])O.[K+]>CN(C)C=O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[CH:8][N:9]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1cccnc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncccc2C#N)CC1
Temperature: 90 °C

Procedure:
2-Chloro-nicotinonitrile (2.04 g, 14.7 mmol) was added to a mixture of piperazine-1-carboxylic acid tert-butyl ester (2.74 g, 14.7 mmol) and potassium hydrogencarbonate (1.77 g, 17.6 mmol) in N,N-dimethylformamide (45 mL). The mixture was heated at 90° C. overnight. The solvent was removed and residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine then dried over magnesium sulfate and filtered. The solvent was removed to give the titled compound as an oil. 1H-NMR (400 MHz, DMSO-d6) δ 8.428 (dd, 1H); 8.08 (dd 1H); 6.95 (dd, 1H); 3.58 (m, 4H); 3.47 (m, 4H); 1.42 (s, 9H).
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:7]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>O>[CH3:1][C:6]1[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:7]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C1=CCCCC1
Solvent: O
Solvent: OC1CCCCC1
Product: CC1=CCCC1

Procedure:
With respect to the manner of the hydration reaction, there is no particular limitation; the reaction can be performed in either of continuous and batchwise manners. The hydration reaction is generally performed as follows. Cyclohexene is added to a catalyst slurry comprising a hydration catalyst and water to effect hydration of cyclohexene in a suspension state to obtain a reaction mixture comprising an aqueous phase comprised of the catalyst slurry and an oil phase comprised of cyclohexanol produced and the cyclohexene remaining unreacted. The oil phase is phase-separated from the aqueous phase, and provided to a separation step. The aqueous phase containing the hydration catalyst can be recycled as the catalyst slurry to the reactor. In the hydration reaction, a small amount of methylcyclopentene is generally formed as a by-product as well as cyclohexanol as the desired intermediate. The oil phase, which contains the cyclohexanol, the methylcyclopentene and the cyclohexene, is separated into a high boiling point component containing cyclohexanol and a low boiling point component containing cyclohexene by a customary method, such as distillation. If desired, the separated cyclohexanol can be further subjected to treatment for isolation, thereby obtaining a cyclohexanol having a desired purity. In such a case, it is preferred that the obtained cyclohexanol has a purity of 99% or more. In general, it is preferred that the unreacted cyclohexene which is separated from cyclohexanol is subjected to treatment for isolation so as to obtain cyclohexene having a desired purity, followed by recycling thereof to the reactor.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[N:3]=1.[CH2:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=2)[N:20]([NH2:31])[CH:19]=1)[CH3:17].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>[CH2:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:28])([F:30])[F:29])[CH:25]=2)[N:20]([NH:31][C:8]([C:7]2[C:2]([CH3:1])=[N:3][C:4]([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)=[N:5][CH:6]=2)=[O:10])[CH:19]=1)[CH3:17]
Reactant: CCc1cn(N)c2ccc(C(F)(F)F)cc12
Reactant: Cc1nc(-c2nccs2)ncc1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCc1cn(NC(=O)c2cnc(-c3nccs3)nc2C)c2ccc(C(F)(F)F)cc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 57.9 %

Procedure:
A solution of 4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid (221 mg, 1 mmol) and 3-ethyl-5-trifluoromethyl-indol-1-ylamine (228 mg, 1 mmol) in DMF (5 mL) is stirred at 50° C. for 1 h. The mixture is treated with DMTMM (276 mg, 1 mmol) and stirred at 50° C. for 2 h. The mixture is diluted with saturated aqueous Na2CO3 (5 mL) and stirred for 5 min. The precipitate is collected by filtration and dried in vacuo to afford 4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid (3-ethyl-5-trifluoromethyl-indol-1-yl)-amide (250 mg, 58%). MS: 432 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 12.07 (s, NH, 1H), 9.25 (s, 1H), 8.15 (d, 1H), 8.09 (d, 1H), 7.99 (s, 1H), 7.68 (d, 1H), 7.51 (m, 2H), 2.77 (s, 3H), 2.74 (q, 2H), 1.29 (t, 3H).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH2:10][C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)c1ccc(Cl)cc1
Reaction time: 16 h
Yield: 96.6 %

Procedure:
Sodium metal (0.143 g, 6.21 mmol) was dissolved into ethanol (3 mL) and the resulting solution was cooled with an ice bath. A mixture of 1-(4-chlorophenyl)ethanone (0.756 mL, 5.65 mmol) and diethyl ethanedioate (0.766 mL, 5.65 mmol) were added dropwise, and the reaction mixture was stirred for 16 h. The reaction mixture was quenched with ice water (5 mL) and acidified to ˜pH 3 with 1N HCl. The precipitate was collected by filtration and dried under high vacuum to give 1.39 g (97%) of product. LCMS E-S (M+H)=255.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (m, 3 H), 4.27 (d, J=6.57 Hz, 2 H), 7.60 (d, J=7.58 Hz, 2 H), 8.02 (d, J=6.57 Hz, 2 H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH:22]1[C:35]2[C:26](=[CH:27][C:28]3[C:33]([C:34]=2[CH2:36]O)=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:25]=[CH:24][CH:23]=1>C(#N)C>[Br:20][CH2:36][C:34]1[C:35]2[C:26]([CH:27]=[C:28]3[C:33]=1[CH:32]=[CH:31][CH:30]=[CH:29]3)=[CH:25][CH:24]=[CH:23][CH:22]=2
Reactant: BrBr
Reactant: OCc1c2ccccc2cc2ccccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: BrCc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A solution of triphenylphosphine (16.44 g, 100.8 mmol) in acetonitrile (120 mL) was flushed with nitrogen for 20 minutes. Bromine (3.3 mL) was added and a solution of anthracen-9-yl-methanol (15.0 g, 72.0 mmol) in acetonitrile (100 mL) was added dropwise. The mixture was stirred for 2 hours at room temperature and refrigerated at 5° C. overnight. The solution was cooled to 0° C. for 30 minutes and filtered. The residue was washed with cold acetonitrile and purified by recrystallization from chloroform to give 9-bromomethyl-anthracene as yellow crystals (13.47 g, 69% yield). 1H NMR (CDCl3) δ 8.51 (1H, s), 8.32 (2H, d), 8.05 (2H, d), 7.66 (2H, dd), 7.52 (2H, dd), 5.56 (2H, s).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[CH3:26][C:27]([CH3:30])([O-:29])[CH3:28].[K+]>O1CCCC1>[C:27]([O:29][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[N:6]2[C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)([CH3:30])([CH3:28])[CH3:26]
Reactant: CC(C)(C)[O-]
Reactant: Clc1ccc(-n2c(-c3ccc(Cl)cc3Cl)nc3c(Cl)ncnc32)cc1
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ncnc2c1nc(-c1ccc(Cl)cc1Cl)n2-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Chloro-9-(4-chlorophenyl)-8-(2,4-dichlorophenyl)-9H-purine I-(1A-1)d, potassium tert-butoxide (20 mg, 0.15 mmol) and tetrahydrofuran (1 ml) were combined and stirred overnight at ambient temperature. The reaction mixture was concentrated to dryness and the residue was extracted into ethyl acetate from saturated aqueous NaHCO3 solution. The organic layers were combined, dried (Na2SO4), filtered, and evaporated to dryness. The crude product was purified by chromatography on a preparative TLC plate using 4% methanol/methylene chloride as the solvent to give title compound 2A-1 as a yellow oil: +ESI MS (M+1) 447.5; 1H NMR (400 MHz, CD3OD) δ 8.48 (s, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.55 (d, J=2.1 Hz, 1H), 7.49–7.44 (m, 3H), 7.34 (d, J=9.1 Hz, 2H), 1.77 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([S:16]Cl)=[C:12]([C:18]([Cl:21])([Cl:20])[Cl:19])[CH:11]=1)([O-:9])=[O:8].O>O1CCCC1>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][S:16][C:13]1[CH:14]=[CH:15][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][C:12]=1[C:18]([Cl:19])([Cl:20])[Cl:21]
Reactant: Nc1nccs1
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(SNc2nccs2)c(C(Cl)(Cl)Cl)c1
Temperature: 10 °C
Yield: 67.4 %

Procedure:
40 g of 2-aminothiazole is dissolved in 500 ml of tetrahydrofuran; while stirring and at 10° C., 61.4 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride is added. The addition of water precipitates the sulfenamide, which is filtered and recrystallized from ethyl acetate. There is obtained 50 g (70% of theory) of N-(1,3-thiazol-2-yl)-4-nitro-2-trichloromethylphenylsulfenamide; m.p.: 165° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[CH2:19][CH2:20][OH:21].[C:22](Cl)(=[O:25])[CH2:23][CH3:24].C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[CH2:19][CH2:20][O:21][C:22]([CH2:23][CH3:24])=[O:25]
Reactant: CCC(=O)Cl
Reactant: Cc1cc2c(cc1C)C(CCO)N(c1cccnc1)C2=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)OCCC1c2cc(C)c(C)cc2C(=O)N1c1cccnc1
Yield: 70.6 %

Procedure:
A solution of 5,6-dimethyl-2-(3-pyridyl)-3-(2-hydroxyethyl)isoindolin-1-one (50 mg, 0.18 mmol), propionyl chloride (16 mg, 0.18 mmol) and triethylamine (18 mg, 0.18 mmol) in dichlorometane was stirred at 25° C. for 3 hrs. The reaction solution was washed with water, dried, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=20:1) to give 43 mg of the title compound.
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]1=O.[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.O>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:20][CH:21]=1)[NH:19][C:3]1[CH:4]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][C:2]2=1
Reactant: COC(=O)C1CCCCC(Br)C1=O
Reactant: Nc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1CCCCc2c1[nH]c1ccc(Cl)cc21
Yield: 53.4 %

Procedure:
Methyl 3-bromo-2-oxocycloheptanecarboxylate (16.8 g, 67.4 mmol) and 4-chloroaniline (18.4 g, 98%, 2.13 eq, 143.6 mmol) were added to flask with thermometer, nitrogen inlet and mechanical stirring machine. As the temperature of the mixture passed 140° C. a relatively rapid exotherm and vigorous evolution of gas occurred. The reaction was cooled with water immediately. The reaction mixture was dissolved in DCM (200 mL). The material was transferred into a separatory funnel and washed with water (2×50 mL), 3HCl (3×50 mL), water (2×50 mL), brine, dried over Na2SO4, and the solvent was removed by vacuo. The crude residue was applied to a Biotage and eluted with 9/1 heptane/ethyl acetate to afford product 10 g (53%) as an off white solid, which was used for next reaction without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[C:19]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[N:20][CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:23]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.CO>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17][C:18]1[C:19]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[N:20][CH:21]=[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:23]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)/C(=C/c1cc(-c2ccccc2)cnc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C(Cc1cc(-c2ccccc2)cnc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.8 %

Procedure:
A suspension of 1E (560 mg, 1.11 mmol) and 5% wt. platinium on activated carbon (500 mg) in THF (90 mL) and MeOH (90 mL) was stirred at RT under H2 at 80 psi for 2 days. After this time, no starting material was detected by LC-MS. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel (40 g) column chromatography eluting with a gradient of EtOAc (0-60%) in hexane to give the title compound as a foam (420 mg, 75%). LC/MS (method A): retention time=3.24 min, (M+H)+=506.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]1)=[N:5]2.[CH2:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)[CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:25][CH:22]1[CH2:23][CH2:24][N:19]([CH2:17][CH3:18])[CH2:20][CH2:21]1)=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]1)=[N:5]2
Reactant: Clc1ccc2c(Cl)c3c(nc2c1)CCCC3
Reactant: CCN1CCC(N)CC1
Product: CCN1CCC(Nc2c3c(nc4cc(Cl)ccc24)CCCC3)CC1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 6,9-dichloro-1,2,3,4-tetrahydroacridine and 1-ethylpiperidin-4-amine, the title compound was obtained; MS (Found M+1=344).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1)=[C:11]2[CH2:25][CH2:26][NH:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)([CH3:7])[CH3:6])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50].C(Cl)Cl.CO>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:38])[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:18]=[C:19]([CH3:24])[CH:20]=[C:21]([CH3:23])[CH:22]=1)=[C:11]2[CH2:25][CH2:26][N:27]([C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3cccnc3)c2c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3cccnc3)C(=O)OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 3.00 g (theoretical maximum of 5.86 mmol) of crude 2-[2-(3,5-dimethylphenyl)-3-[2-[4-(pyridin-3-yl)butylamino]ethyl]-1H-indol-5-yl]-2-methylpropionic acid ethyl ester in 30 ml of dry CH2Cl2 was stirred under N2 with cooling in a dry-ice-acetone bath. To this solution was added by syringe 1.106 ml (820 mg, 6.36 mmol) of N,N-diisopropylethylamine. Then 956μ (1.14 g, 6.36 mmol) of benzyl chloroformate was added dropwise by syringe over 5-10 minutes. After 20 minutes, the solution was removed from the cooling bath and allowed to warm to room temperature. After 2 hours, the solution was diluted with 50 ml of CH2Cl2, transferred to a separatory funnel, and shaken with 80 ml of H2O. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. Flash chromatography of the residual gum on silica gel (gradient elution with 0.2-2% MeOH in CH2Cl2) gave 2.81 g (55% overall for Steps 1 and 2) of pale, golden-yellow gum; virtually homogeneous by TLC in 95:5 CH2Cl2 -MeOH. 500 MHz 1H NMR (CDCl3) was complex, owing to rotamers, but appeared to be consistent with the assigned structure. Mass spectrum (ESI): m/e 646 (M+H)+.
Reaction SMILES: FC1C(F)=C(C(F)(F)F)C(F)=C(F)C=1[O:4][C:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH:13]=[C:14]2[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:6]=1.C(O)C.Cl.[OH-].[Na+]>C1COCC1.O>[N:26]1[CH:27]=[CH:28][CH:29]=[C:24]([C:14]2[C@:15]3([CH2:17][CH2:18][C@H:19]4[C@@H:10]([CH2:9][CH2:8][C:7]5[C@:20]4([CH3:23])[CH2:21][CH2:22][C:5](=[O:4])[CH:6]=5)[C@@H:11]3[CH2:12][CH:13]=2)[CH3:16])[CH:25]=1
Reactant: C[C@]12CCC(Oc3c(F)c(F)c(C(F)(F)F)c(F)c3F)=CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Temperature: 65 °C
Reaction time: 48 h
Yield: 71 %

Procedure:
To a solution of 3-[2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy]-17-(3-pyridyl)androsta-3,5,16-triene (0.423 g, 0.75 mmol) in THF (5 ml) was added ethanol (5 ml) followed by aqueous hydrochloric acid (1M, 5 ml) and the mixture heated, with stirring, by an oil bath at 65° C. for 48 h and allowed to cool. The mixture was poured into water (20 ml), neutralised with aqueous sodium hydroxide (1M), and extracted with diethyl ether (3×30 ml). The ether extracts were combined, dried (Na2CO3), and concentrated. Chromatography, on elution with diethyl ether, afforded the title compound (185 mg, 71%) which crystallised from diethyl ether, m.p. 148°-150° C. IR νmax 1674 cm-1 ; 1H-NMR(CDCl3) inter alia δ 1.07(3H,s,18-CH3), 1.24(3H,s,19-CB3), 5.76(1H,m,Py 6-H), 5.99(1H,m,16-H), 7.23(1H,m,Py 5-H), 7.64(1H,m,Py 4-H), 8.47(1H,m,Py 6-H), 8.62(1H,m,Py 2-H); MS m/z, 347 (M+).