Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].FC1C=CC(C(O)=O)=CC=1[N+]([O-])=O.S(Cl)(Cl)=O.[Br:31][C:32]1[CH:38]=[C:37]([C:39]([F:48])([C:44]([F:47])([F:46])[F:45])[C:40]([F:43])([F:42])[F:41])[CH:36]=[C:35]([C:49]([F:52])([F:51])[F:50])[C:33]=1[NH2:34]>>[Br:31][C:32]1[CH:38]=[C:37]([C:39]([F:48])([C:40]([F:42])([F:43])[F:41])[C:44]([F:45])([F:47])[F:46])[CH:36]=[C:35]([C:49]([F:50])([F:51])[F:52])[C:33]=1[NH:34][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F)c1ccc(F)c([N+](=O)[O-])c1

Procedure:
According to the method of 4-3 of Example 4, a target compound was prepared from 4-fluoro-3-nitrobenzoyl chloride prepared from 4-fluoro-3-nitrobenzoic acid and thionyl chloride, and 2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)aniline obtained in 1-2 of Example 1.
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]CC)=[O:22])=[CH:16][CH:15]=1)[C:3]1[S:4][C:5]2[N:13]=[CH:12][CH:11]=[CH:10][C:6]=2[C:7](=[O:9])[N:8]=1.C(O)C.[OH-].[Na+].Cl>O>[CH3:1][N:2]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1)[C:3]1[S:4][C:5]2[N:13]=[CH:12][CH:11]=[CH:10][C:6]=2[C:7](=[O:9])[N:8]=1
Reactant: CCOC(=O)Cc1ccc(N(C)c2nc(=O)c3cccnc3s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(c1ccc(CC(=O)O)cc1)c1nc(=O)c2cccnc2s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
To a mixture of 250 mg of ethyl [4-[N-methyl-N-(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl)amino)phenyl]acetate and 1.55 ml of ethanol was added 1.55 ml of a 0.5 N aqueous solution of sodium hydroxide under cooling with ice. The mixture was then stirred at room temperature for 4 hours. The reaction mixture was diluted with 5 ml of water, and then adjusted with a 0.5 N hydrochloric acid to pH 1. The resulting crystal was collected by filtration, washed with water and then with diethyl ether, and then dried under reduced pressure to obtain 227 mg of [4-[N-methyl-N-(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl)amino]phenyl]acetic acid. Nuclear magnetic resonance spectrum (CDCl3, TMS internal standard) δ: 3.64 (3H, s), 3.77 (2H, s), 7.33 (2H, d, J=7.6 Hz), 7.38 (1H, dd, J=8.0, 4.8 Hz), 7.49 (2H, d, J=7.6 Hz), 8.54-8.60 (1H, m), 8.67 (1H, d, J=8.0 Hz)
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:10])([CH2:7][O:8][CH3:9])[CH2:5][OH:6].C(S[C:15]1[N:16]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[CH:29][CH:28]=2)[C:17](=[O:26])[C:18]2[CH:24]=[CH:23][C:22](=[O:25])[NH:21][C:19]=2[N:20]=1)CC.O>O1CCCC1>[F:3][C:4]([F:10])([CH2:7][O:8][CH3:9])[CH2:5][O:6][C:15]1[N:16]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([F:36])([F:38])[F:37])=[CH:29][CH:28]=2)[C:17](=[O:26])[C:18]2[CH:24]=[CH:23][C:22](=[O:25])[NH:21][C:19]=2[N:20]=1
Reactant: CCCSc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: COCC(F)(F)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC(F)(F)COc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 4.3 %

Procedure:
To a suspension of sodium hydride (60% in oil, 29 mg) in tetrahydrofuran (5 ml) was added 2,2-difluoro-3-methoxypropan-1-ol (151 mg) at room temperature, and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added 2-(propylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (165 mg), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and recrystallized from a mixed solvent of hexane/ethyl acetate to give the title compound (8 mg).
Reaction SMILES: O[N:2]1C(=O)C2=CC=CC=C2C1=O.[CH:13]1([CH2:21][OH:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([CH2:21][O:22][NH2:2])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: OCC1CCCCCCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Product: NOCC1CCCCCCC1

Procedure:
Prepared by a similar procedure as described for preparation 31. Starting materials: N-hydroxyphthalimide and cyclooctanemethanol (Acros). 13C-NMR (CDCl3) δ 82.3, 36.4, 29.4, 27.0, 26.5, 25.5.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.[CH3:29][NH:30][O:31][CH3:32].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:32][O:31][N:30]([CH3:29])[C:10](=[O:12])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)C
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoic acid (CAS 102185-35-3, 500 mg, 2.16 mmol) in DCM (5 mL) was added EDCI (CAS 25952-53-8, 497 mg, 2.59 mmol) and stirred for 10 min at rt. A solution of N,O-dimethylhydroxylamine hydrochloride (CAS 6638-79-5, 253 mg, 2.59 mmol) and DIPEA (0.429 mL, 2.59 mmol) in DCM (5 mL) was added and the reaction mixture was left to stir at rt over a weekend. The mixture was diluted with DCM (30 mL) and extracted with saturated aq NaHCO3 (50 mL). The organic phase was washed with water before being dried over MgSO4 and filtered. The solvent was removed in vacuo to give tert-butyl 1-(methoxy(methyl)amino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (466 mg, 79%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:14])=[O:13])=[C:8]2[S:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)(=[O:17])=[O:16])#[N:2]>CO>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:14])=[O:13])=[C:8]2[S:15]([N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)(=[O:17])=[O:16]
Reactant: N#Cc1cccc2c(S(=O)(=O)N3CCOCC3)c(C(N)=O)[nH]c12
Solvent: CO
Product: NCc1cccc2c(S(=O)(=O)N3CCOCC3)c(C(N)=O)[nH]c12
Reaction time: 18 h

Procedure:
7-Cyano-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide (8 mg, 0.024 mmol) was dissolved in 5 mL of methanol. The vessel was degassed and charged with 10% Pd(OH)2 on carbon (0.4 mg, 5 weight percent). The vessel was then charged with 1 atm. H2 and stirred vigorously for 18 hours. The reaction was filtered through a pad of Celite, the pad was washed with methanol and the filtrate was concentrated in vacuo. The title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 339.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([NH2:11])[C:3]=1[NH2:12].[F:13][CH:14]([F:18])[C:15](O)=O>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[C:3]2[N:12]=[C:15]([CH:14]([F:18])[F:13])[NH:11][C:4]=2[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=C(O)C(F)F
Reactant: Nc1cc([N+](=O)[O-])cc(Br)c1N
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Br)c2nc(C(F)F)[nH]c2c1
Temperature: 105 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
To a 100 mL round bottomed flask was added 3-bromo-5-nitrobenzene-1,2-diamine (5.5 g, 23.70 mmol) and 2,2-difluoroacetic acid (4.46 mL, 71.1 mmol) in Toluene (55 mL). The stirred solution was heated to 105° C. and monitored by LC/MS. After stirring at 105° C. for 2 hr the reaction was allowed to cool to rt, was diluted with EtOAc (20 mL) and filtered through celite. The filtrate was concentrated in-vacuo then taken up in EtOAc, washed several times with sat'd NaHCO3 soln, brine and then dried over Na2SO4 and concentrated to provide crude 4-bromo-2-(difluoromethyl)-6-nitro-1H-benzo[d]imidazole (6.7 g, 22.94 mmol, 97% yield) as a brown solid. LC/MS: MS (ES+) m/e 293.7 [M+H]+.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:29]([O:31][C:32]1C=CC([N+]([O-])=O)=CC=1)=[O:30]>ClCCl>[CH3:32][O:31][C:29](=[O:30])[NH:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH:10][C@H:1]1[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]1)[CH:20]=[CH:19]2
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Temperature: 23 °C
Reaction time: 2 h
Yield: 34.4 %

Procedure:
To a solution of (R)—N2-indan-1-yl-quinoline-2,6-diamine (1.2 g, 4.36 mmol) and pyridine (0.35 mL, 4.36 mmol) in dichloromethane (25 mL) at 0° C. was added 4-nitrophenyl chloroformate (878 mg, 4.6 mmol) and the mixture was stirred at 23° C. for 2 h resulting in a yellow suspension. Added tetrahydrofuran, filtered the solid off, dissolved in dichloromethane and methanol, coated on silica gel. Removal of the solvent in vacuum left a brown foam, which after silica gel column chromatography was crystallized from dichloromethane/diethyl ether to give the title compound as a yellow foam (500 mg, 34%); MS: m/e=334.2 (M+H+).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([NH:15][C@@H:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[C:10]1([CH3:26])[CH3:25])=O)(C)(C)C.CCN(CC)CC>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([NH:15][C@@H:16]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[C:10]1([CH3:25])[CH3:26]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H]1C[C@@H](NC(=O)OC(C)(C)C)C1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H]1C[C@@H](N)C1(C)C
Yield: 100 %

Procedure:
A stirred solution of (S)-methyl 2-((1S,3R)-3-(tert-butoxycarbonylamino)-2,2-dimethylcyclobutanecarboxamido)-4-methylpentanoate (step 1, 0.200 g, 0.54 mmol) in TFA:DCM (1:4) (4 ml) at 0° C.-room temperature for about 1 hour. After completion of the reaction, the solvent was evaporated and the crude was dissolved in DCM and basified with Et3N (0.5 ml, 3.24 mmol) then the resulting solution as such used for next reaction immediately. Wt: 0.145 g (Based on 100% yield calculated and proceeded for next reaction).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14](Cl)[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(=[O:19])[CH3:18].C1C=CC=CC=1>O>[C:17]([N:20]1[CH2:25][CH2:24][N:23]([CH:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[CH3:15])[CH2:22][CH2:21]1)(=[O:19])[CH3:18]
Reactant: CC(Cl)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC(=O)N1CCNCC1
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)N1CCN(C(C)c2ccc(-c3ccc(Cl)cc3)cc2)CC1

Procedure:
With constant stirring, reflux a solution of 25.1g of 4'-chloro-4-(1-chloroethyl)[1,1']biphenyl, 51g of 1-acetyl piperazine and 400 ml of anhydrous benzene for 24 hours. Add 200 ml of water to the reaction mixture, separate the organic phase, water-wash (5 times with 200 mls of water). Dry (over sodium sulfate), concentrate (in vacuo) and recrystallize the resulting residue from ethyl acetate to obtain the desired product.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=3)[N:13]=[N:12]2)[CH:5]=1>CO.O>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:13]=[N:12][N:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:24])=[O:2])[CH:15]=2)=[CH:21][CH:20]=1)#[N:23]
Reactant: COC(=O)c1cccc(Cn2cc(-c3ccc(C#N)cc3)nn2)c1
Solvent: O
Solvent: CO
Product: N#Cc1ccc(-c2cn(Cc3cccc(C(=O)O)c3)nn2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.4 %

Procedure:
Add LiOH monohydrate (0.10 g, 2.40 mmol) to a suspension of 3-[4-(4-cyano-phenyl)-[1,2,3]triazol-1-ylmethyl]-benzoic acid methyl ester (0.50 g, 1.60 mmol) in 15 mL of a 4:1 MeOH-water mixture and stir at room temperature for 3 days. Concentrate the mixture to remove most of the MeOH, dilute with additional H2O and neutralize by the addition of 1N aqueous HCl. Isolate the resulting solid by filtration and dry to afford 0.45 g, 94% yield of 3-[4-(4-Cyano-phenyl)-[1,2,3]triazol-1-ylmethyl]-benzoic acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:24][CH:25]([CH3:31])/[CH:26]=[CH:27]/[C:28](Cl)=[O:29]>ClCCl>[CH3:24][CH:25]([CH3:31])/[CH:26]=[CH:27]/[C:28]([N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)[CH2:5][CH2:6]1)=[O:29]
Reactant: CC(C)/C=C/C(=O)Cl
Reactant: c1ccc2c(C3CCNCC3)ccnc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)/C=C/C(=O)N1CCC(c2ccnc3ccccc23)CC1
Reaction time: 0.01 h

Procedure:
4-(4-Piperidyl)quinoline (0.1 mmol, 21 mg) was dissolved in dichloromethane (1 ml). Triethylamine (1 ml of a 0.12M solution in dichloromethane) was added, the solution was shaken for 30 seconds and (E)-4-methylpent-2-enoyl chloride was added (1 ml of a 0.12 M solution in dichloromethane. The mixture was shaken for one hour at room temperature and evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC. 5.1 mg were obtained (0.017 mmol, 17%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([O:11][C:12]([NH:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8].Br[C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[C:27]([N+:38]([O-:40])=[O:39])[CH:26]=1.C(=O)(O)[O-].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.COCCOC.O>[C:7]([O:11][C:12]([NH:14][C:15]1[CH:16]=[C:17]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])=[C:27]([N+:38]([O-:40])=[O:39])[CH:26]=2)[CH:18]=[CH:19][CH:20]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c2)c1
Temperature: 25 °C
Yield: 82.6 %

Procedure:
Water (0.6 mL), sodium carbonate (0.16 g), 3-(tert-butoxycarbonylamino)phenylboronic acid (0.14 g), and tetrakis(triphenylphosphine)palladium(0) (29 mg) were added to an ethylene glycol dimethyl ether (2.0 mL) solution of tert-butyl 4-bromo-2-nitrobenzoate (0.15 g), followed by heating to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-91% hexane/ethyl acetate] to obtain 0.17 g of tert-butyl 4-(3-(tert-butoxycarbonylamino)phenyl)-2-nitrobenzoate as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Br:23])([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(N(C)C)=C(C)C.[N-:32]=[N+:33]=[N-:34].[Na+]>ClCCl.COC(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]([N:32]=[N+:33]=[N-:34])=[O:15])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Br:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2Br)CC1
Reactant: [N-]=[N+]=[N-]
Agent: CC(C)=C(Cl)N(C)C
Agent: [Na+]
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N=[N+]=[N-])(c2ccccc2Br)CC1
Reaction time: 0.75 h
Yield: 82.7 %

Procedure:
To a solution of 2.00 g (5.20 mmol) 4-(2-bromo-phenyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester in 26 ml dichloromethane were added 0.76 ml (5.73 mmol) 1-chloro-N,N,2-trimethylpropenylamine at room temperature. After stirring for 45 min the reaction mixture was concentrated in vacuo. The residual oil was redissolved in 26 ml dry N,N-dimethylformamide and treated with 0.51 g (7.8 mmol) sodium azide. After stirring for 1 h the reaction mixture was diluted with 200 ml tert-butyl methyl ether and washed with 0.5 M aqueous sodium carbonate solution (2×50 ml). The combined aqueous layers were extracted with tert-butyl methyl ether (2×100 ml). The combined organic layers were washed with water (1×50 ml) and brine (1×50 ml), dried over sodium sulfate and concentrated in vacuo to give the crude title compound (1.76 g, 83%) as a light yellow solid.
Reaction SMILES: C[CH:2](C)[CH:3](C1C=CC=CC=1)[C:4]([NH:6][C@@H:7]1[C@H:14]2[C@H:10]([CH2:11][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[CH2:13]2)[CH2:9][CH2:8]1)=O.C(O[C:36]1(O[Si](C)(C)C)[CH2:38][CH2:37]1)C.C(O)(=O)C.C([BH3-])#N>ClCCl>[CH:4]1([N:6]([CH:36]2[CH2:37][CH2:38]2)[C@@H:7]2[C@H:14]3[C@H:10]([CH2:11][N:12]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)[CH2:13]3)[CH2:9][CH2:8]2)[CH2:2][CH2:3]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1ccccc1
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(CN2C[C@@H]3CC[C@H](N(C4CC4)C4CC4)[C@@H]3C2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(3aS*,4S*,6aR*)-2-(3-(Trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine (228 mg, 0.802 mmol) from Example 122 Step E and (1-ethoxycyclopropoxy)trimethylsilane (140 mg, 0.802 mmol) were combined in dichloromethane (1.5 mL) and 5 mL of acetic acid was added. The reaction was stirred at room temperature for 20 minutes, and then PS-cyanoborohydride (343 mg, 0.802 mmol) was added. The reaction was heated to 40° C. overnight. Silica gel chromatography eluting with 1-10% methanol (2 N ammonia)/dichloromethane to gave the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 7.58 (s, 1H), 7.48 (d, J=7.6, 2H), 7.42 (d, J=7.6, 1H), 3.64 (d, J=13.6, 1H), 3.51 (d, J=13.6, 1H), 2.94-2.82 (m, 3H), 2.80-2.71 (m, 2H), 2.55 (dd, J=5.4, 9.4, 3H), 2.41 (t, J=8.3, 1H), 2.16 (dd, J=4.7, 8.7, 1H), 1.97-1.70 (m, 7H), 1.70-1.59 (m, 3H), 1.40 (dd, J=6.7, 12.6, 1H); MS (ESI+) m/z 365 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:30])[C@:7]1([OH:29])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C:21](=[CH:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[C:13](=[CH2:27])[CH2:12]3)[CH2:9][C@@H:8]1[CH3:28])(=[O:3])[CH3:2].C1CCCCC=1>[Pd]>[C:1]([O:4][CH2:5][C:6](=[O:30])[C@:7]1([OH:29])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C:21](=[CH:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[C@@H:13]([CH3:27])[CH2:12]3)[CH2:9][C@@H:8]1[CH3:28])(=[O:3])[CH3:2]
Reactant: C=C1C[C@@H]2C(=CC[C@@]3(C)[C@H]2C[C@H](C)[C@]3(O)C(=O)COC(C)=O)[C@@]2(C)CCC(=O)C=C12
Agent: [Pd]
Solvent: C1=CCCCC1
Product: CC(=O)OCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Yield: 59 %

Procedure:
Analogously to Example 1(E), 1.4 g of 21-acetoxy-17α-hydroxy-16β-methyl-6-methylene-4,9(11)-pregnadiene-3,20-dione is hydrogenated with cyclohexene and palladium/active carbon, worked up, and purified, thus obtaining 830 mg of 21-acetoxy-17α-hydroxy-6α,16β-dimethyl-4,9(11)-pregnadiene-3,20-dione, mp 197°-199° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][OH:29])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:40][N:41]([CH3:46])[C:42](=[O:45])[CH:43]=[CH2:44].[Cl-].[NH4+]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29][CH2:44][CH2:43][C:42]([N:41]([CH3:46])[CH3:40])=[O:45])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@H](CC[C@]4(C)C(CO)=CC[C@@H]34)[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: C=CC(=O)N(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)C(=O)CCOCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-17-hydroxymethylandrosta-5,7,16-triene (951 mg, 1.75 mmol) in tetrahydrofuran (17.5 ml), was added sodium hydride (60% in oil, 105 mg, 2.62 mmol), followed by stirring under nitrogen stream at room temperature for 30 min. After adding N,N-dimethylacrylamide (540 mg, 5.44 mmol), the solution was stirred at 5° C. for 14 hours, poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate (3 times) and washed with saturated brine and water. The organic layer was dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was purified by column chromatography (hexane:ethyl acetate 2:1) to give the titled compound (1.05 g, 92.7%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:53]=[CH:52][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]4[CH2:44][CH2:43][N:42](C(OC(C)(C)C)=O)[CH2:41][CH2:40]4)[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]4[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]4)[C:10]=3[N:9]=2)=[CH:52][CH:53]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCCOc2cccc3c2nc(COc2ccc(Cl)cc2)n3CCCC2CCCN(C(=O)OC(C)(C)C)C2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(OCc2nc3c(OCCCCCC4CCNCC4)cccc3n2CCCC2CCCNC2)cc1

Procedure:
The title product is prepared from (RS) 2-(4-chlorophenoxymethyl)-4-[5-[1-(t-butoxycarbonyl)piperidin-4-yl]pentoxy]-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl]benzimidazole using a standard trifluoroacetic acid deprotection protocol.