Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[NH:21])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].Br[CH2:30][C:31](=[O:36])[C:32]([F:35])([F:34])[F:33]>C(O)(C)C>[OH:36][C:31]1([C:32]([F:35])([F:34])[F:33])[CH2:30][N:10]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:8][CH:7]=2)=[N:21]1
Reactant: O=C(CBr)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(C(F)(F)F)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc(C(F)(F)F)cc2)cc1
Temperature: 72.5 °C

Procedure:
To a mixture of 4-(trifluoromethyl)-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (10 mmol) and sodium bicarbonate (20 mmol) in isopropanol (100 mL), 3-bromo-1,1,1-trifluoroacetone (20 mmol) is added. After heating the reaction mixture at 70-75° C. for 20 hours, the solvent is removed. The residue is redissolved in methylene chloride and washed with water. The organic fractions are combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product is purified by chromatography (silica gel, toluene/ethyl acetate, 7/3) to give 4-hydroxy -1-[4-(methylsulfonyl)phenyl]-2-(4-trifluoromethylphenyl)-4-trifluoromethyl-4,5-dihydro-1H-imidazole.
Reaction SMILES: [NH2:1][C@H:2]([C:14]([NH:16][C:17]1[CH:18]=[N:19][N:20]([CH3:42])[C:21]=1[NH:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:15])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[C:43]([O:47][C:48]([NH:50][CH2:51][C:52](ON1C(=O)CCC1=O)=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44].C(Cl)(Cl)Cl>O1CCCC1>[C:43]([O:47][C:48]([NH:50][CH2:51][C:52]([NH:1][C@H:2]([C:14]([NH:16][C:17]1[CH:18]=[N:19][N:20]([CH3:42])[C:21]=1[NH:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:15])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: Cn1ncc(NC(=O)[C@@H](N)CCCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)CNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.2 %

Procedure:
To a solution of tert-butyl (4S)-4-amino-5-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-5-oxopentylcarbamate (1.71 g) in tetrahydrofuran (30 ml) was added N-[2-(tert-butoxycarbonylamino)acetoxy]-succinimide (820 mg). The mixture was stirred at room temperature for 6 hours. To the reaction mixture was added chloroform (50 ml). The mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give tert-butyl (4S)-4-{[2-(tert-butoxycarbonylamino)acetyl]amino}-5-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-5-oxopentylcarbamate (2.1 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[Cl:20])[C:6]([CH3:12])=[N:7]2.[Br:21]N1C(C)(C)C(=O)N(Br)C1=O.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:21][CH2:12][C:6]1[C:5]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[Cl:20])=[N:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])[N:7]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Cc1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(Cl)c(-c2nc3c(Cl)cccc3nc2CBr)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
5-chloro-3-(2-chloro-5-fluorophenyl)-2-methylquinoxaline (0.3013 g, 0.981 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (0.280 g, 0.981 mmol) were suspended in carbon tetrachloride (9.81 mL, 0.981 mmol). To the mixture was added benzoyl peroxide (0.0317 g, 0.0981 mmol) and the mixture was heated at reflux. After 22 h, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 5% gradient of EtOAc in hexane over 10 min, then 5% isocratic of EtOAc for 25 min, then 5 to 20% gradient of EtOAc in hexane over 20 min, then 20% isocratic of EtOAc for 4 min as eluent to give 2-(bromomethyl)-5-chloro-3-(2-chloro-5-fluorophenyl)-quinoxaline as a light yellow syrupy solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.12-8.21 (2 H, m), 7.92-8.00 (1 H, m), 7.76 (1 H, dd, J=9.0, 5.1 Hz), 7.71 (1 H, dd, J=8.6, 3.1 Hz), 7.49-7.58 (1 H, m), 4.74 (2 H, br. s.); LC-MS (ESI) m/z 387.0 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[O:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1)([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[O:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc([N+](=O)[O-])c2)C1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(N)c2)C1
Reaction time: 18 h
Yield: 69.4 %

Procedure:
To a solution of tert-butyl 3-(3-nitrophenoxy)pyrrolidine-1-carboxylate (8.73 g, 28.3 mmol) in methanol (50 mL) was added Raney Nickel (1.0 g). The solution was stirred over H2 atmosphere (1 atm) 18 hours. The mixture was filtered, concentrated and purified by chromatography to obtain tert-butyl 3-(3-aminophenoxy)pyrrolidine-1-carboxylate as a white solid (5.47 g, 70% yield)
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([S:22]([CH:24]5[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]5)=[O:23])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:33]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:35].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([S:22]([CH:24]5[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:28][CH2:29]5)(=[O:35])=[O:23])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:33]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)N1CCC(S(=O)c2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)cn2CCO3)CC1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)N1CCC(S(=O)(=O)c2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)cn2CCO3)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 9-(1-isopropylpiperidine-4-sulfinyl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene 177 (214 mg, 0.456 mmol) and TFA (105 μL, 1.32 mmol) in DCM (10 mL) at 0° C. was added a solution of m-CPBA (95 mg, 0.542 mmol) in DCM (2 mL) and the resulting mixture was stirred for 2 h at RT. Volatiles were removed under reduced pressure and the crude material was purified by column chromatography (C18, gradient 10-45% MeOH in 0.5% TFA/H2O). The product containing fractions were combined and concentrated in vacuo and the resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3 in MeOH affording 178 as a white solid (115 mg, 52%). LCMS: RT 2.68 min [M+H]+ 485.2. 1H NMR (DMSO, 400 MHz): δ 8.89 (1H, d, J=2.40 Hz), 8.01 (1H, s), 7.95 (1H, d, J=0.62 Hz), 7.72 (1H, dd, J=8.63, 2.42 Hz), 7.31 (1H, d, J=8.63 Hz), 5.77-5.66 (1H, m), 4.69-4.58 (4H, m), 3.21-3.11 (1H, m), 2.85-2.77 (2H, m), 2.70-2.60 (1H, m), 2.09 (2H, bt, J=11.51 Hz), 1.92 (2H, bd, J=12.10 Hz), 1.50 (6H, d, J=6.61 Hz), 1.49-1.35 (2H, m), 0.89 (6H, d, J=6.54 Hz)
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH:7]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:16]=[C:15]2[C:11]([C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:13][NH:14]2)=[CH:10][CH:9]=1)[C:3]([O:5]C)=[O:4].O.[OH-].[Li+].O>O1CCOCC1>[CH3:1][C:2]([CH3:29])([CH:7]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:16]=[C:15]2[C:11]([C:12]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:13][NH:14]2)=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)C(c1ccccc1)c1ccc2c(-c3ccccc3)n[nH]c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C(=O)O)C(c1ccccc1)c1ccc2c(-c3ccccc3)n[nH]c2c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of methyl 2,2-dimethyl-3-phenyl-3-(3-phenyl-1H-indazol-6-yl)propanoate (45 mg, 0.12 mmol), lithium hydroxide monohydrate (50 mg, 1.2 mmol), water (2 mL), and dioxane (4 mL) was stirred at 110° C. overnight. The mixture was cooled to rt and partitioned between water (5 mL) and diethyl ether (10 mL). The ether layer was extracted with water (10 mL). The combined aqueous solutions were acidified with 6N hydrochloric acid, extracted with ethyl acetate (15 mL), washed with brine (10 mL), dried (Na2SO4) and concentrated to give 2,2-dimethyl-3-phenyl-3-(3-phenyl-1H-indazol-6-yl)propanoic acid (46 mg, 0.12 mmol, 100% yield) as a glassy solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([Br:21])[CH:13]=1)C(OC(C)(C)C)=O.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([Br:21])[CH:13]=1
Reactant: COC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1ccc([N+](=O)[O-])c(Br)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.9 %

Procedure:
The 2-(3-bromo-4-nitrophenyl)malonic acid tert-butyl ester methyl ester (1.18 g) obtained in Example 4 a) was dissolved in chloroform (10 mL), trifluoroacetic acid (10 g) was added thereto under ice-cooling, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured gradually into ice and saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate and concentrated to give the title compound (0.820 g) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22]CC)=O)[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH:26]1([NH2:30])[CH2:29][CH2:28][CH2:27]1>>[CH:26]1([NH:30][C:20]([C:14]2[C:15](=[O:19])[NH:16][C:17]3[C:12]([C:13]=2[OH:25])=[N:11][CH:10]=[C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:18]=3)=[O:22])[CH2:29][CH2:28][CH2:27]1
Reactant: NC1CCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Product: O=C(NC1CCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclobutylamine employing methods similar to those described in Example 2 and was obtained as an off-white solid: 1H NMR (d6-DMSO) δ 11.90 (1H, br), 10.50 (1H, br), 8.33 (1H, br), 7.39 (1H, br s), 7.31 (2H, m), 7.15 (2H, t, J˜9 Hz), 4.42 (1H, m, J=8 Hz), 4.06 (2H, br s), 2.29 (2H, m), 1.95 (2H, m), 1.71 (2H, m); HRMS calcd for C20H18FN3O3+H+: 368.1410. Found: 368.1410.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17](O)=[O:18])=[N:9]2)[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:51][C@@H:52]([CH:55]([CH3:57])[CH3:56])[CH2:53][OH:54]>C(C#N)(C)=O>[OH:54][CH2:53][C@@H:52]([NH:51][C:17]([C:10]1[C:11]2[CH2:12][C@H:13]3[CH2:16][C@H:14]3[C:15]=2[N:8]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)[N:9]=1)=[O:18])[CH:55]([CH3:57])[CH3:56]
Reactant: CC(C)[C@H](N)CO
Reactant: O=C(O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@H]1C[C@@H]21
Agent: CC(=O)C#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](CO)NC(=O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@H]1C[C@@H]21
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To a solution of (1aR,5aR)-2-(4-chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (68.9 mg, 0.25 mmol), HATU (95 mg, 0.25 mmol) and Et3N (25.3 mg, 0.25 mmol) in AcCN (5 mL) was added (S)-2-amino-3-methylbutan-1-ol (25.3 mg, 0.25 mmol) at room temperature. The reaction was stirred overnight and concentrated. The residue was diluted with EtOAc (50 mL) and washed with water (50 mL). The organic layer was concentrated. The residue was purified by column chromatography to give the title compound (72 mg) as a white solid. LCMS m/z=361.5 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.45 (dd, J=7.9, 4.6 Hz, 1H), 1.04 (d, J=6.8 Hz, 3H), 1.05 (d, J=6.8 Hz, 3H), 1.22-1.27 (m, 1H), 2.01-2.08 (m, 1H), 2.24-2.30 (m, 1H), 2.78-2.82 (m, 1H), 2.96 (d, J=16.8 Hz, 1H), 3.01 (dd, J=16.5, 6.3 Hz, 1H), 3.75-3.88 (m, 3H), 7.02 (d, J=7.8 Hz, 1H), 7.21 (dd, J=5.4, 1.8 Hz, 1H), 7.93 (d, J=1.8 Hz, 1H), 8.36 (d, J=5.4 Hz, 1H).
Reaction SMILES: COC([NH:5][C@:6]12[CH2:14][N:13](C(OC)=O)[CH2:12][C@H:11]1[CH:10]=[CH:9][CH:8]=[CH:7]2)=O.CO>O>[CH2:12]1[C@@H:11]2[C@@:6]([NH2:5])([CH:7]=[CH:8][CH:9]=[CH:10]2)[CH2:14][NH:13]1
Reactant: COC(=O)N[C@@]12C=CC=C[C@@H]1CN(C(=O)OC)C2
Solvent: CO
Solvent: O
Product: N[C@@]12C=CC=C[C@@H]1CNC2

Procedure:
Analogously to Step F, 11 g of crude methyl (1S,6R)-1-methoxycarbonylamino-8-azabicyclo[4.3.0]nona-2,4-diene-8-carboxylate are hydrolysed in 150 ml of water using 42 g of Ba(OH)2.8 H2O and worked up accordingly. Yield: 3 g (44.6% of theory based on Step G), boiling point: 70° C./0.1 mbar, [α]D =+235.9° (c=1,14, methanol).
Reaction SMILES: C[O:2][C@:3]1([C@@H:21]2[CH2:25][S:24][C:23](=[O:26])[N:22]2CC2C=CC(OC)=CC=2)[CH2:18][C@H:17]2[CH2:19][C@@H:5]([CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:20])[O:16]2)[O:4]1.CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[OH:2][C@:3]1([C@@H:21]2[CH2:25][S:24][C:23](=[O:26])[NH:22]2)[CH2:18][C@H:17]2[CH2:19][C@@H:5]([CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:20])[O:16]2)[O:4]1
Reactant: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCCCC(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CCCCC(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)O3)O2)cc1
Product: O=C1CCCCC=CCCC[C@@H]2C[C@H](C[C@](O)([C@@H]3CSC(=O)N3)O2)O1

Procedure:
Application of the method shown in Example 46, with the modification that (R)-4-((1R,13R,15R,Z)-15-methoxy-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadec-8-en-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one was substituted for (R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, afforded the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:12])[CH:6]=[CH:7][C:8]=1[C:9](O)=O.[BH4-].[Na+].[B].C([O:19]C(C)C)(C)C>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH3:9])[CH2:12][OH:19]
Reactant: COc1cc(C)ccc1C(=O)O
Reactant: CC(C)OC(C)C
Agent: [BH4-]
Agent: [B]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CO)ccc1C
Reaction time: 0.17 h

Procedure:
A solution of 3-methoxy-p-toluic acid (45.32 g) in tetrahydrofuran (280 ml) was added to a suspension of sodium borohydride (9.29 g) in tetrahydrofuran (45 ml) with ice bath cooling under nitrogen atmosphere. After 10 minutes stirring, boron trifuluoride diethyl etherate (41.5 ml) was added to the mixture at 3 to 15° C. and the whole was stirred at room temperature overnight. Water (210 ml) and diisopropyl ether (60 ml) were added to the mixture. The organic layer was separated and the aqueous layer was extracted with diisopropyl ether (100 ml). The combined organic layer was washed successively with 1N sodium hydroxide solution and brine, dried over sodium sulfate, and evaporated in vacuo to give 3-methoxy-4-methylbenzylalcohol (41.63 g) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Cl-].[NH4+]>C(O)C.[Fe]>[NH2:15][C:13]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([O:3][CH2:1][CH3:2])[CH:14]=1
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cc1OCC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1ccc(N)cc1OCC
Temperature: 80 °C
Yield: 92.7 %

Procedure:
To a solution of ethyl 2-ethoxy-4-nitro-benzoate (12.7 g, 53.1 mmol) in ethanol (94 mL) was added a solution of ammonium chloride (56 mL). The formation of a precipitate was observed. Iron (15.2 g, 271 mmol) was added and the reaction mixture was heated at 80° C. for 16 h. The reaction mixture was cooled and filtered through Celite, and the Celite was rinsed with methylene chloride. Water was added and the product was extracted three times with methylene chloride. The organic layers were dried over magnesium sulfate and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 0-3% methanol in chloroform) gave ethyl 4-amino-2-ethoxy-benzoate as a tan solid (10.3 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[O:13]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:15][CH2:14]1>>[Cl:9][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([Cl:1])[C:7]=1[N:22]1[CH2:23][CH2:24][CH:19]([N:16]2[CH2:17][CH2:18][O:13][CH2:14][CH2:15]2)[CH2:20][CH2:21]1)[NH2:10]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Reactant: C1CC(N2CCOCC2)CCN1
Product: Nc1cc(Cl)c(N2CCC(N3CCOCC3)CC2)c(Cl)c1

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthesis Example 40 using 3,4,5-trichloronitrobenzene and 4-morpholinopiperidine, the title compound was obtained, melting point: 144–146° C.
Reaction SMILES: [OH:1][CH:2]1[CH:9]2[CH2:10][C:5]3([C:11]4[N:19](C5CCCCO5)[C:18]5[C:17](=[O:26])[N:16]([CH2:27][CH2:28][CH3:29])[C:15](=[O:30])[N:14]([CH2:31][CH2:32][CH3:33])[C:13]=5[N:12]=4)[CH2:6][CH:7]([O:8]2)[CH:3]1[O:4]3>Cl.C1COCC1.CO>[OH:1][CH:2]1[CH:9]2[CH2:10][C:5]3([C:11]4[NH:19][C:18]5[C:17](=[O:26])[N:16]([CH2:27][CH2:28][CH3:29])[C:15](=[O:30])[N:14]([CH2:31][CH2:32][CH3:33])[C:13]=5[N:12]=4)[CH2:6][CH:7]([O:8]2)[CH:3]1[O:4]3
Reactant: CCCn1c(=O)c2c(nc(C34CC5OC(C3)C(O4)C5O)n2C2CCCCO2)n(CCC)c1=O
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C34CC5OC(C3)C(O4)C5O)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.4 %

Procedure:
To a solution of 8-(4-hydroxy-2,6-dioxa-tricyclo[3.3.1.03.7]non-1-yl)-1,3-dipropyl-7-(tetrahydro-pyran-2-yl)-3,7-dihydro-purine-2,6-dione (0.065 mmol, 0.030 g) in 1:1 THF/MeOH (6 ml) was added 1N HCl (3 drops). The reaction was stirred at room temperature 4 h and then concentrated to dryness. The residue was purified by reverse phase HPLC, providing product (0.0094 g, 38%). 1H NMR (400 MHz, d6-DMSO): 0.80-0.89 (m, 6H), 1.48-1.56 (m, 2H), 1.60-1.70 (m, 2H), 1.9-2.09 (m, 2H), 2.2-2.25 (m, 1H), 3.78-3.82 (m, 2H), 3.89-3.91 (m, 2H), 3.99 (s, 1H), 4.21 (br s, 1H), 4.51 (br s, 1H), 4.80 (m, 1H).
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16](C)[C:17](=O)OC(C)(C)C)[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=[CH:30][C:29]=2[CH:38]2[CH2:40][CH2:39]2)[C:6]2[CH:41]=[CH:42][C:43]([C:45]#[N:46])=[CH:44][C:5]1=2)(=[O:3])[CH3:2].[ClH:47]>O1CCOCC1.CCOCC>[ClH:47].[ClH:47].[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([NH:16][CH3:17])[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=[CH:30][C:29]=2[CH:38]2[CH2:39][CH2:40]2)[C:6]2[CH:41]=[CH:42][C:43]([C:45]#[N:46])=[CH:44][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cc(C#N)ccc2N(Cc2c(C3CC3)cnc3ccccc23)C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(C3CC3)cnc3ccccc23)c2ccc(C#N)cc2N(C(C)=O)[C@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A rt suspension of tert-butyl(S)-1-((3S,4S)-5-acetyl-7-cyano-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (26.8 mg, 42.9 μmol) in 4 M HCl in dioxane (214 μl) was stirred at rt for 2 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((3S,4S)-5-acetyl-7-cyano-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide dihydrochloride (21.9 mg, 85%) as a white solid. MS m/z 525 (MH)+.
Reaction SMILES: Cl[C:2]([F:14])([F:13])[C:3]([F:12])(Cl)[C:4]([F:10])(Cl)[C:5]([F:8])([F:7])Cl>[Zn]>[F:7][C:5]([F:8])=[C:4]([F:10])[C:3]([F:12])=[C:2]([F:14])[F:13]
Reactant: FC(F)(Cl)C(F)(Cl)C(F)(Cl)C(F)(F)Cl
Agent: [Zn]
Product: FC(F)=C(F)C(F)=C(F)F

Procedure:
In fact, from the reaction of 1,2,3,4-tetrachlorohexafluoro-butane with metal zinc there is obtained hexafluorobutadiene either pure or in admixture with 1,4-dichlorohexafluorobut-2-ene (Haszeldine, J. Chem. Soc., 4423 (1952)), while according to the process of the present invention from 1,2,3,4-tetrachloro -hexafluorobutadiene there is obtained pure 1,4-dichlorohexafluorobut-2-ene (see Example 8).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:37]1([C:43]2[C:47]3[CH:48]=[CH:49][C:50](O)=[C:51]([CH2:52][CH2:53][CH3:54])[C:46]=3[O:45][CH:44]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:37]1([C:43]2[C:47]3[CH:48]=[CH:49][C:50]([O:1][CH2:2][CH2:3][C:4]4[NH:5][C:6]5[C:11]([CH:12]=4)=[CH:10][C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=5)=[C:51]([CH2:52][CH2:53][CH3:54])[C:46]=3[O:45][CH:44]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CCCc1c(O)ccc2c(-c3ccccc3)coc12
Reactant: COC(=O)Cc1ccc2[nH]c(CCO)cc2c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1c(OCCc2cc3cc(CC(=O)OC)ccc3[nH]2)ccc2c(-c3ccccc3)coc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.9 %

Procedure:
To a solution of the methyl 2-(2-hydroxyethyl)indole-5-acetate (37.6 mg; 0.16 mmol), Ph3P (47 mg; 1.1 eq), 3-phenyl-6-hydroxy-7-propylbenzofuran (45 mg; 1.1 eq) and THF (5 mL) was added diisopropyl azodicarboxylate (35 ,uL; 1.1 eq), and the mixture was stirred at room temperature overnight. The mixture was concentrated and chromatographed (silica gel, hexane:ethyl acetate::9:1 to 4:1) affording 18.6 mg of the title compound.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@:14]([OH:25])([CH2:15][C@@H:16]([OH:24])[CH2:17][CH2:18]1)[C:13](=O)[CH2:12]3)([O:3][CH3:4])=[O:2].Cl.[NH2:28][OH:29].O.O.O.C([O-])(=O)C.[Na+]>C(O)C>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@:14]([OH:25])([CH2:15][C@@H:16]([OH:24])[CH2:17][CH2:18]1)[C:13](=[N:28][OH:29])[CH2:12]3)([O:3][CH3:4])=[O:2]
Reactant: NO
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC(=O)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC(=NO)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C

Procedure:
A suspension of 17β-Carbomethoxy-6-oxo-3β,5α-dihydroxy-androstane, 8 g, as prepared in example 17, hydroxylamine hydrochloride (12 g) and sodium acetate trihydrate (16 g) in ethanol (100 mL) is heated at reflux for 1 h. The reaction mixture is cooled to ambient temperature and filtered to afford 17β-carbomethoxy-6-oximino-3β,5α-dihydroxyandrostane as a white solid, mp 234°-237° C. dec. Anal. Calcd. for C21H33NO5.H2O: C, 63.34; H, 8.88; N, 3.53. Found: C, 62.91; H, 8.98; N, 3.27.