Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na].[CH:17](=O)[CH2:18][CH:19]([CH3:21])[CH3:20]>C([O-])(O)=O.[Na+]>[CH2:17]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1)[CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CC(C)CC=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Product: CC(C)CCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension of 1-(4-nitrophenyl)piperazine (5.00 g, 24.1 mmol, 1.0 eq), sodium triaectoxyborohydride (10.23 g, 48.3 mmol, 2 eq), and isovaleraldehyde (4.16 g, 5.18 mL, 48.3 mmol) is stirred at RT for 48 h. The reaction mixture is transferred to a separatory funnel and the solution washed with 10% aqueous NaCl solution (2×50 mL) (gas evolution). A yellow precipitate formed in the separatory funnel DCM (50 mL) was added followed by a saturated aqueous solution of NaHCO3 (50 mL) and the precipitate dissolved. The phases are separated and DCM phase is again washed with saturated aqueous solution of NaHCO3 (50 mL). The combined aqueous NaHCO3 extracts are extracted with DCM (2×50 mL), the combined DCM extracts are dried over MgSO4, filtered through a filtration tube, and the solvent is evaporated to provide a viscous oil that partially solidified on standing. The residue is triturated with hexanes (25 mL) and resulting slurry stirred at room temperature for 48 h. The precipitate which forms is collected by filtration, washed with hexanes (2×25 mL), dried briefly on the frit, and then dried under vacuum for 48 h to provide 1-isopentyl-4-(4-nitrophenyl)piperazine as a yellow solid (5.15 g, 77% recovery, 92% purity as determined by LC/MS analysis @ UV 254 nm detection). The crude product was used in the next step without further purification. LCMS-ESI (m/z): calcd for C15H23N3O2, 277; [M+H]+ found, 278.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:43][CH2:44][CH:45]([OH:57])[CH2:46][N:47]1[CH2:56][CH2:55][C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:48]1>CN(C=O)C.O>[CH2:48]1[C:49]2[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:55][CH2:56][N:47]1[CH2:46][CH:45]([OH:57])[CH2:44][NH:43][C:16]([C:15]1[CH:14]=[C:13]([CH:10]2[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)[CH:21]=[CH:20][CH:19]=1)=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)O)c2)C1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)NCC(O)CN3CCc4ccccc4C3)c2)C1
Temperature: 31 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
To a solution of 3-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)benzoic acid (200 mg, 0.69 mmol) in DMF (4 ml) was added TEA (208 mg, 2.06 mmol), HOBt (139 mg, 1.03 mmol), EDCI (197 mg, 1.03 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (170 mg, 0.82 mmol) at 33° C. The reaction mixture was stirred for 16 h at 31° C. The mixture was treated with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give the title compound which was used in next step without further purification (300 mg, Yield 92%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:7]1([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([C:32]([O:34][CH3:35])=[O:33])=[CH:18][C:19]=3[N:20]3[CH2:26][C:25](=O)[CH2:24][C:23]4[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=4[C:21]=23)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH:7]1([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([C:32]([O:34][CH3:35])=[O:33])=[CH:18][C:19]=3[N:20]3[CH2:26][CH:25]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH2:24][C:23]4[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=4[C:21]=23)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)Cc1ccccc1-3
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(N1CCOCC1)Cc1ccccc1-3
Yield: 69.9 %

Procedure:
Zinc chloride (21 mg, 0.15 mmol) and morpholine (40 μL, 0.46 mmol) were added to methyl 13-cyclohexyl-6,7-dihydro-6-oxo-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (30 mg, 0.078 mmol) in MeOH (3 mL). The mixture was heated at 60° C. for 3 hr when sodium cyanoborohydride (29 mg, 0.46 mmol) was added. Heating was continued for another hr. The mixture was concentrated and the crude product purified by chromatography on a SiO2 preparative plate using dichloromethane containing 2 N methanolic ammonia (100:1). to afford the product as a light yellow solid (25 mg, 70%). ESI-MS m/z 806 (MH+); 1H NMR (500 MHz, MeOD) δ 1.28-1.36 (m, 1 H) 1.36-1.53 (m, 2 H) 1.59-1.71 (m, 1 H) 1.74-1.86 (m, 2H) 1.92-2.19 (m, 4 H) 2.36-2.53 (m, 1 H) 2.58 (m, 1 H) 2.73 (m, 2 H) 2.89 (m, 1 H) 2.99 (m, 1 H) 3.12 (m, 1 H) 3.38 (m, 1 H) 3.58-3.77 (m, 4 H) 3.86-4.00 (m, 3 H) 4.04-4.17 (m, 1 H) 4.51-4.66 (m, 1 H) 7.35-7.50 (m, 4 H) 7.71 (d, J=8.55 Hz, 1 H) 7.88 (m, 1 H) 8.13 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:48])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][CH:40]([C:43]([O:45]CC)=[O:44])[CH2:39][CH2:38]3)=[CH:33][CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.O.[OH-].[Li+].Cl>C1COCC1.O.CCOC(C)=O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@:12]2([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@@H:9]([C:28]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH2:42][CH2:41][CH:40]([C:43]([OH:45])=[O:44])[CH2:39][CH2:38]4)=[CH:33][CH:32]=3)=[O:29])[C@@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:48])=[C:16]([F:22])[CH:17]=1
Reactant: CCOC(=O)C1CCN(c2ccc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(N3CCC(C(=O)O)CC3)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.1 %

Procedure:
To a solution of ethyl 1-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)piperidine-4-carboxylate (75 mg, 0.108 mmol) in THF (4 mL) was added a solution of LITHIUM HYDROXIDE monohydrate (19.2 mg, 0.458 mmol) in Water (2 mL) dropwise. The reaction mixture was stirred at rt for 2 hrs before it was neutralized with 1N HCl. it was then diluted with EtOAc, washed with water (2×10 mL), brine (2×10 mL), dried and evaporated to give 1-(4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-piperidine-4-carboxylic acid as a white solid (76 mg, 100%). MS (ES+) m/z Calcd: [(M+H)+]: 669. found: 669.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:21]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:22]([O:24][CH3:25])=[O:23].O>CN(C)C=O>[CH:12]([C:10]1[N:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]([CH:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]([O:24][CH3:25])=[O:23])[CH:9]=1)=[O:13]
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Reactant: COC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccccc1)n1cc(C=O)nc1-c1ccccc1
Temperature: 85 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (1.73 g) in N,N-dimethylformamide (35 mL) were added potassium carbonate (2.78 g) and methyl bromo(phenyl)acetate (2.53) and the mixture was stirred at 85° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→3:7) and crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 814 mg, yield 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Clc1cc(-c2ccccc2)ncn1
Yield: 23 %

Procedure:
First, 5.0 g of 4,6-dichloropyrimidine, 4.9 g of phenylboronic acid, 7.1 g of sodium carbonate, 0.34 g of bis(triphenylphosphine)palladium(II) dichloride, namely PdCl2(PPh3)2, 20 mL of acetonitrile, and 20 mL of water were put into a 100-mL round-bottom flask equipped with a reflux pipe, and the air in the flask was replaced with argon. Then, heating was performed by irradiation with microwaves (2.45 GHz, 100 W) for 1 hour. An organic layer was extracted from the obtained mixture with the use of dichloromethane and was washed with water and saturated brine. Magnesium sulfate was added and gravity filtration was performed. The solvent in the obtained filtrate was distilled off, and the given residue was purified by flash column chromatography using dichloromethane as a developing solvent, whereby 1.6 g of the objective substance was obtained (yield: 23%, a pale yellow solid). Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). A synthesis scheme of Step 1 is shown in (a-1) below.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]#[C:14][Si](C)(C)C)=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].C(=O)([O-])[O-].[K+].[K+]>CO>[Br:1][C:2]1[C:3]([C:13]#[CH:14])=[C:4]([CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)[NH2:5]
Reactant: C[Si](C)(C)C#Cc1c(N)cc(C(F)(F)F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1c(N)cc(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)aniline (2.70 g) in methanol (30 mL) was added potassium carbonate (1.11 g), and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, to the residue was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.56 g).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:23]([OH:25])=O)[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])(=[O:3])[CH3:2].[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][NH2:33].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:1]([NH:4][CH:5]([CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(=[O:8])=[O:9])[C:23]([NH:33][O:32][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][O:26]1)=[O:25])(=[O:3])[CH3:2]
Reactant: NOC1CCCCO1
Reactant: CC(=O)N[C@@H](CS(=O)(=O)c1ccc(Sc2ccccc2)cc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(=O)NC(CS(=O)(=O)c1ccc(Sc2ccccc2)cc1)C(=O)NOC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.1 %

Procedure:
To a solution of the title compound of Example 11c (930 mg, 2.45 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (287 mg, 2.45 mmol) in anhydrous DMF (40 mL), cooled to zero degrees C., were added EDC (493 mg, 2.57 mmol) and HOBT (393 mg, 2.57 mmol). After stirring at zero degrees C. for 1 hour and at room temperature for 3 hours, the solution was partitioned between EtOAc and H2O. The resulting organic phase was washed with 1M KHSO4 (2×50 mL), saturated NaHCO3 (2×50 mL) and brine (1×50 mL), and dried over Na2SO4. Purification by chromatography (1:1 EtOAc/hexane) yielded the title compound as a colorless oil (400 mg, 34%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH3:16])([CH:13]([CH3:15])[CH3:14])[CH:8]2[OH:12])=[CH:4][C:3]=1[O:17][CH2:18][C:19]([NH2:21])=[O:20].[C:22](OCC)(=[O:28])[C:23](OCC)=[O:24].CC(C)([O-])C.[K+]>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH3:16])([CH:13]([CH3:14])[CH3:15])[CH:8]2[OH:12])=[CH:4][C:3]=1[O:17][C:18]1[C:19](=[O:20])[NH:21][C:23](=[O:24])[C:22]=1[OH:28]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(C)C1(C)Cc2cc(OCC(N)=O)c(Cl)c(Cl)c2C1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CC(C)C1(C)Cc2cc(OC3=C(O)C(=O)NC3=O)c(Cl)c(Cl)c2C1O

Procedure:
When [6,7-dichloro-1-hydroxy-2-methyl-2-(i-propyl)-indan-5-yl]oxyacetamide is utilized as starting material in the reaction with diethyl oxalate/potassium t-butoxide there is obtained 4-[6,7-dichloro-1-hydroxy-2-methyl-2-(i-propyl)indan-5-yloxy]-3-hydroxy-3-pyrroline-2,5-dione. Where [6,7-dichloro-2-ethyl-1-hydroxy-2-(n-propyl)indan-5-yl]oxyacetamide is utilized as starting material in this reaction there is obtained 4-[6,7-dichloro-2-ethyl-1-hydroxy-2-(n-propyl)indan-5-yloxy]-3-hydroxy-3-pyrroline-2,5-dione.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:27][OH:28].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9]/[C:10](/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[N:27]\[OH:28])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(Br)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(Br)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from (R)-3-(4-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a white foam, MS (ESI+): m/z=409.2 ([M+H]+, 1Br).
Reaction SMILES: [CH2:1]([C:3]1(O)[CH:27]=[C:26]2[C@:21]([CH3:29])([CH2:22][CH2:23][C@H:24]([OH:28])[CH2:25]2)[C@@H:20]2[C@@H:4]1[C@H:5]1[C@:17]([CH3:30])([CH2:18][CH2:19]2)[C@@H:8]([C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:7][CH2:6]1)[CH3:2].C(OC)(=O)CCC#C.Cl>CS(C)=O.C(NC(C)C)(C)C.CC([O-])=O.CC([O-])=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.[Pd+2]>[CH2:1]([C:3]1[C@@H:4]2[C@@H:20]([C@:21]3([CH3:29])[C:26]([CH:27]=1)=[CH:25][C:24](=[O:28])[CH2:23][CH2:22]3)[CH2:19][CH2:18][C@@:17]1([CH3:30])[C@H:5]2[CH2:6][CH2:7][C@@H:8]1[C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH3:2]
Reactant: CCC1(O)C=C2C[C@@H](O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]21
Agent: [Pd+2]
Agent: C#CCCC(=O)OC
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Solvent: CC(C)NC(C)C
Product: CCC1=CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 17 h
Yield: 97.4 %

Procedure:
A mixture of 436 mg (1.0 mmole) of 4-methyl-17-triflluoromethylsulfonyloxy-4-aza-5α-androst-16-en-3-one (60) (Case 18730), 168 mg (1.5 mmoles) of methyl 4-pentynoate, 40 mg of bis(triphenylphosphine)palladium(II) acetate, 5 mg of cuprous iodide in 3.0 ml of DMSO and 3.0 ml of N,N-diisopropylamine was stirred at room temperature for 17 hrs. The dark reaction mixture was poured into 50 ml of 0.5M HCl and extracted with CH2Cl2 (3×). The combined extracts were washed with water (4×) and dried (MgSO4). Evaporation in vacuo and flash chromatography of the residue on silica gel with 6:1 CH2Cl2 -acetone gave 400 mg of enyne 61. The enyne was immediately hydrogenated in 20 ml of EtOH with 150 mg of 10% palladium on carbon catalyst under a hydrogen-filled balloon. After stirring at room temperature for 24 hrs, the reaction mixture was filtered through a bed of Celite., which was washed with EtOH (4×). The filtrate and washes were evaporated in vacuo and the residue flash chromatographed on silica gel with 5:1 CH2Cl2 to give 345 mg of methyl 4-methyl-3-oxo-21-nor-4-aza-5α-cholane-24-carboxylate (62).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][C@H:8]([NH2:16])[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O=C1CCC(=O)N1[O:25][C:26]([C@@H:28]1[CH2:33][CH2:32][CH2:31][N:30]([C:34](=[O:50])[CH2:35][CH2:36][CH:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]2)[CH2:29]1)=O.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C)C=O.ClCCl>[C:46]([O:45][C:43]([N:40]1[CH2:39][CH2:38][CH:37]([CH2:36][CH2:35][C:34]([N:30]2[CH2:31][CH2:32][CH2:33][C@@H:28]([C:26](=[O:25])[NH:16][C@H:8]([C:9]3[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=3)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:17])[CH2:29]2)=[O:50])[CH2:42][CH2:41]1)=[O:44])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)OC(=O)C[C@H](N)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)ON3C(=O)CCC3=O)C2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 101.9 %

Procedure:
214.0 mg (0.90 mmol) (S)-3-amino-3-(4-hydroxy-phenyl)-propionic acid tert-butyl ester were dissolved in 3.5 ml N,N-dimethylformamide and cooled to 0° C. To this solution was added a solution of 466.4 mg (1.00 mmol) tert-butyl 4-{3-[(3R)-3-{[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 5c) and 0.38 ml (2.71 mmol) triethylamine in 3.5 ml dichloromethane. The mixture was kept at 6° C. for 20 hours. Saturated ammonium chloride solution was added and the mixture extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuum to give 820 mg. Chromatography over 5 g silica gel (dichloromethane/ethanol 100/0-95/5-90/10) gave 539 mg (102%) 4-(3-{(R)-3-[(S)-2-tert-butoxycarbonyl-1-(4-hydroxy-phenyl)-ethylcarbamoyl]-piperidin-1-yl}-3-oxo-propyl)-piperidine-1-carboxylic acid tert-butyl ester
Reaction SMILES: [C:1]([C@:9]1([N+:22]([O-:24])=[O:23])[C@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:13]2[CH2:21][C@H:10]1[CH:11]=[CH:12]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1C2CCCC1CCC2.[OH-:34].[Na+].OO>C1COCC1.CCO>[C:1]([C@@:9]1([N+:22]([O-:24])=[O:23])[C@H:10]2[CH2:21][C@H:13]([CH2:12][C@@H:11]2[OH:34])[C@H:14]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)[C@@]1([N+](=O)[O-])[C@@H]2C=C[C@@H](C2)[C@H]1c1ccccc1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(c1ccccc1)[C@]1([N+](=O)[O-])[C@H](c2ccccc2)[C@H]2C[C@H](O)[C@@H]1C2
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A solution of Compound 9 (2.20 g, 6.90 mmol) in THF (18 mL, 0.38M) was treated with 9-BBN (8.62 mmol, 1.25 equiv) in THF (17.25 mL, 0.5M) and the mixture was allowed to stir at 25° C. under N2 for 10 hours. The resulting mixture was treated successively with 4.15 mL of EtOH, 1.5 mL of 20 percent aqueous NaOH, and 1.65 mL of 50 percent aqueous H2O2. The reaction solution was warmed at 50° C. for one hour, recooled to 25° C., and partitioned between EtOAc (200 mL) and H2O (200 mL). The EtOAc layer was dried (Na2SO4) and concentrated under reduced pressure. Chromatography (SiO2, 5×15 cm, 10-25 percent EtOAc-hexane gradient elution) afforded the major isomer Compound 10 (1.29 g, 55.5 percent; Rf =0.32, 20 percent EtOAc-hexane) and Compound 11 (1S*,2R*,4S*,5R*,6S*-5-benzoyl-2-hydroxy-5-nitro-6-phenyl-bicyclo[[2.2.1]heptane, 400 mg, 17.2 percent; Rf =0.26, 20 percent EtOAc-hexane) as white solids cleanly separated from one another in a 3.2:1 ratio (1.69 g total, 2.32 g theoretical, 73 percent). For Compound 10: mp 168°-169° C. (EtOAc-hexane, colorless needles); 1H NMR (CDCl3, 250 MHz) δ7.38 (d, 2H, J=8.2 Hz), 7.31-6.94 (m, 8H), 4.33 (d, 1H, J=2.4 Hz, C5-H), 3.85 (d, 1H, J=6.8, C2-H), 3.29 (s, 1H, C1-H), 2.63 (d, J=11.3 Hz, C7-H syn to ketone), 2.46 (d, 1H, J=4.3 Hz, C4-H), 2.26-2.16 (m, 2H), 1.67-1.60 (m, 2H); 13C NMR (CDCl3, 50 MHz) δ189.9, 138.8, 133.7, 133.0, 128.9, 128.5, 128.3, 127.8, 127.4, 105.0, 69.3, 55.5, 55.4, 44.6, 42.1, 35.7; IR (neat) vmax 3331, 2968, 2900, 1689, 1538, 1444, 1353, 1234, 1096, 1063 cm-1 ; FABHRMS (NBA-NaI) m/e 360.1230 (C20H19NO4+Na+ requires 360.1212). Anal. Calcd for C20H19NO4 : C, 71.20; H, 5.68; N, 4.15. Found: C, 71.13; H, 5.89; N, 4.10. For Compound 11: 1H NMR (CDCl3, 250 MHz) δ7.34 (d, 2H, J=8.0 Hz), 7.25-6.90 (m, 8H), 4.18 (m, 2H), 3.25 (m, 1H), 2.62 (d, 1H, J=11.2 Hz), 2.26 (s, 1H), 2.12 (d, 1H, J=11.4 Hz), 1.80-1.62 (m, 2H), 1.45 (m, 1H); FABHRMS (NBA-CsI) m/e 470.0368 (C2H19NO4 +Cs+ requires 470.0368).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:25])[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=2[CH3:24])[CH2:6][CH2:5][CH2:4]1.[H][H]>C(O)C.[Pt]=O>[CH3:26][N:2]([CH3:1])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:25])[C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH3:24])[CH2:6][CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)N1CCCC(N(C)C)c2ccccc21
Agent: O=[Pt]
Solvent: CCO
Product: Cc1cc(N)ccc1C(=O)N1CCCC(N(C)C)c2ccccc21
Yield: 15.6 %

Procedure:
5-Dimethylamino-1-(2-methyl-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (86.0 g) is dissolved in ethanol (800 ml), and thereto is added platinum oxide (10 g). The mixture is subjected to hydrogenation at ordinary temperature under atmospheric pressure of hydrogen for 4 hours. The catalyst is removed by filtration, and the solvent is distilled off. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=200:1→100:1), and further purified by silica gel thin layer chromatography (developer; chloroform:methanol=10:1), and recrystallized from methanol/diethyl ether to give 5-dimethylamino-1-(2-methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (G) (Rf: 0.52, 27.4 g) and 5-dimethylamino-1-(2-methyl-4-amino-benzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (H) (Rf: 0.48, 12.3 g).
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:17]2[C:12](=[C:13]([C:18]3[S:19][C:20]([C:23]4[CH:24]=[CH:25][C:26](F)=[C:27]([CH:30]=4)[C:28]#[N:29])=[CH:21][N:22]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:32][CH:33]([CH3:35])[O-:34].[Na+]>C(O)(C)C>[Si:1]([O:8][CH:9]1[C:17]2[C:12](=[C:13]([C:18]3[S:19][C:20]([C:23]4[CH:24]=[CH:25][C:26]([O:34][CH:33]([CH3:35])[CH3:32])=[C:27]([CH:30]=4)[C:28]#[N:29])=[CH:21][N:22]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)[O-]
Reactant: CC(C)(C)[Si](C)(C)OC1CCc2c(-c3ncc(-c4ccc(F)c(C#N)c4)s3)cccc21
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)Oc1ccc(-c2cnc(-c3cccc4c3CCC4O[Si](C)(C)C(C)(C)C)s2)cc1C#N
Temperature: 60 °C

Procedure:
Prepared using General Procedure 2. To a solution of 5-(2-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-fluorobenzonitrile (0.043 g, 0.095 mmol) in isopropanol (2 mL) was added sodium isopropoxide (0.07 g, 0.090 mmol). The reaction mixture was heated at 60° C. for 12 h. Upon cooling, the solvent was removed under a stream of N2 and the crude reaction mixture was carried onto the next step without further purification. LCMS-ESI (m/z) calculated for C28H34N2O2SSi: 490.7, tR=5.06 min (Method 3).