Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:17][C@@H:16]2[N+:18]([O-:20])=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.[Br:21]C1C=CC(/C=C/[N+]([O-])=O)=CC=1>>[Br:21][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][C@H:16]2[N+:18]([O-:20])=[O:19])=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])[C@H]1C[C@@H]1c1ccc(OCc2ccccc2)cc1
Reactant: O=[N+]([O-])/C=C/c1ccc(Br)cc1
Product: O=[N+]([O-])[C@@H]1C[C@H]1c1ccc(Br)cc1
Yield: 27 %

Procedure:
This compound was synthesized using the same methodology described in Intermediate A, using the commercially available 1-bromo-4-[(trans)-2-nitrovinyl]benzene as starting material. 27% yield
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[N+:14]([O-])=O)(=O)[CH3:2]>CO.Cl.O>[NH2:14][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:4]=1[CH2:1][CH3:2])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(C(C)=O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: O
Solvent: CO
Product: CCc1ccc(C(=O)OC)cc1N

Procedure:
The method described in Step 2. of Example 1 was applied to a solution of 35 (0.17 g) in methanol (20 mL) and 10% hydrochloric acid/water (5 mL) to prepare the above named compound. NMR (300 MHz, CDCl3) δ 7.40 (1H, d, J=8 Hz), 7.34 (1H, s), 7.10 (1H, d, J=8 Hz), 3.88 (3H, s), 3.71 (2H, b), 2.54 (2H, q, J=8 Hz), 1.26 (3H, t, J=8 Hz).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH:7]([CH3:11])[C:8]([OH:10])=O)[N:4]=[CH:3]1.[NH2:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15]>>[NH:2]1[CH:6]=[C:5]([CH:7]([CH3:11])[C:8]([NH:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:21][CH:22]=2)=[O:15])=[O:10])[N:4]=[CH:3]1
Reactant: CC(C(=O)O)c1c[nH]cn1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: CC(C(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1)c1c[nH]cn1
Yield: 21 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-imidazol-4-yl)propanoic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 167, (2S)-2-(2-(1H-imidazol-4-yl)propanamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (49 mg, 21%). 1H-NMR (400 MHz, CDCl3): δ 9.80 (s, 1H), 9.46 (s, 1H), 9.38 (br s, 1H), 7.80-7.15 (m, 9H), 7.00-6.79 (m, 6H), 4.82-4.71 (m, 1H), 4.54-4.38 (m, 2H), 4.01-3.59 (m, 3H), 1.45-1.34 (m, 3H). MS (EI) for C28H27FN4O4 found 503 (MH+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[CH3:17])[C:11]([OH:13])=[O:12])=[C:5]([CH3:7])[N:6]=1.IC1NC(C2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=NC=1C.IC1NC(C)=NC=1C>>[C:33]([O:32][C:30]([N:27]1[CH2:28][CH2:29][CH:1]([C:2]2[NH:3][C:4]([C:8]3[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=3[CH3:17])[C:11]([OH:13])=[O:12])=[C:5]([CH3:7])[N:6]=2)[CH2:25][CH2:26]1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: Cc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)[nH]c1I
Reactant: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cc1nc(C)c(I)[nH]1
Product: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2CCN(C(=O)OC(C)(C)C)CC2)nc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.7, except tert-butyl 4-(5-iodo-4-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (compound 182.1) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5).
Reaction SMILES: O[CH:2]=[C:3]1[C:13](=O)[C:8]2[CH:9]=[N:10][N:11]([CH3:12])[C:7]=2[CH2:6][CH2:5][CH2:4]1.[CH3:15][NH:16][NH2:17]>CO>[CH3:15][N:16]1[C:13]2[C:8]3[CH:9]=[N:10][N:11]([CH3:12])[C:7]=3[CH2:6][CH2:5][CH2:4][C:3]=2[CH:2]=[N:17]1
Reactant: Cn1ncc2c1CCCC(=CO)C2=O
Reactant: CNN
Solvent: CO
Product: Cn1ncc2c1CCCc1cnn(C)c1-2
Temperature: 0 °C

Procedure:
To an ice-cold solution of 4 g of 5,6,7,8-tetrahydro-5-hydroxymethylene-1-methyl-4(1H) cycloheptapyrazolone in 130 ml of methanol was added, dropwise, a solution of 1.1 ml of methylhydrazine in 20 ml of methanol and the mixture was heated at reflux for 2.5 hours. Removal of the solvent under reduced pressure left a residual dark oil. The oil was flash chromatographed (7.5% 2-propanol in methylene chloride) to give 4,5,6,7-tetrahydro-1,7-dimethyl-1H-cyclohepta[1,2-c:3,4-c']dipyrazole as a yellow crystalline solid melting at about 94°-96° C. The chromatography also gave 4,5,6-tetrahydro-2,7-dimethyl-2H-cyclohepta[1,2-c:3,4-c')]dipyrazole melting at about 119°-121° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:19]([N+:26]([O-])=O)([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)(=O)C>[Zn]>[NH2:26][C:19]([C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:10]=2)[N:15]=1)([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCCCCCCOc1ccc2nc(C(C)(C(=O)OCC)[N+](=O)[O-])ccc2c1
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCCCCCOc1ccc2nc(C(C)(N)C(=O)OCC)ccc2c1
Temperature: 10 °C
Reaction time: 5 h
Yield: 19 %

Procedure:
Ethyl 2-(6-heptyloxyquinolin-2-yl)-2-nitropropanoate (325.0 mg, 0.0008366 mol) was dissolved in acetic acid (5 mL, 0.09 mol), and cooled to at 10° C., followed by zinc (547.1 mg, 0.008366 mol;) in very small portions to keep the temperature constant. The reaction mixture was then allowed to stir for additional for 5 hours, and filtered through a Celite pad. The excess of solvents were removed under vacuum, and the residue was purified via HPLC (10-100% acetonitrile with 0.1% formic acid) to give a pure product (57.0 mg, 14%). 1H NMR (CHLOROFORM-d) δ: 8.05 (d, J=8.5 Hz, 1H), 7.94 (d, J=9.3 Hz, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.36 (dd, J=9.3, 2.5 Hz, 1H), 7.06 (d, J=2.5 Hz, 1H), 4.20 (q, J=7.0 Hz, 2H), 4.07 (t, J=6.5 Hz, 2H), 1.77-1.93 (m, 5H), 1.44-1.57 (m, 2H), 1.28-1.44 (m, 6H), 1.22 (t, J=7.2 Hz, 3H), 0.90 (t, J=6.8 Hz, 3H). MS (M+1): 359.30.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([NH:13]S(C)(=O)=O)=[C:5](I)[CH:4]=1)#[N:2].[C:19]([Si:23]([O:26][C:27]([CH3:31])([CH3:30])[C:28]#[CH:29])([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20].CCN(CC)CC.O>CN(C=O)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>[C:19]([Si:23]([CH3:25])([CH3:24])[O:26][C:27]([C:28]1[NH:13][C:6]2[C:5]([CH:29]=1)=[CH:4][C:3]([C:1]#[N:2])=[C:8]([C:9]([F:12])([F:11])[F:10])[CH:7]=2)([CH3:30])[CH3:31])([CH3:22])([CH3:21])[CH3:20]
Reactant: C#CC(C)(C)O[Si](C)(C)C(C)(C)C
Reactant: CS(=O)(=O)Nc1cc(C(F)(F)F)c(C#N)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(O[Si](C)(C)C(C)(C)C)c1cc2cc(C#N)c(C(F)(F)F)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
N-(4-Cyano-2-iodo-5-trifluoromethyl-phenyl)-methanesulfonamide (1.95 g, 5.0 mmol), tert-Butyl-(1,1-dimethyl-prop-2-ynyloxy)-dimethyl-silane (992 mg, 5.0 mmol), PdCl2(PPh3)2, (175 mg, 0.25 mmol), Cul (95 mg, 0.5 mmol), NEt3 (1.4 mL, 10.0 mmol), was mixed in DMF (15 mL) and stirred at room temperature for 16 hours. Water was added and the mixture was extracted twice with ethyl acetate. The organic layers were washed with 10% LiCl solution, dried over magnesium sulfate, filtered, evaporated to a brown oil. The brown oil was purified by column chromatography eluting with 1, 3, and 10% ethyl acetate/hexanes. The product was obtained as a white solid (306 mg, 16%). 1H NMR (CDCl3) δ 8.75 (s, 1H), 7.92 S, 1H), 7.67 (s, 1H), 6.27 (d, J=1.2 Hz, 1H), 1.58 (s, 6H), 0.85 (s, 9H), 0.3 (s, 6H). MS (m/z): 405 (MNa+), 381 (MH−).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]=O)[C:4]2=[CH:3][CH:2]=1.[N+:13]([CH2:16][CH3:17])([O-:15])=[O:14]>C(O)C.CO.C(N)CCC>[C:10]1([CH:11]=[C:16]([N+:13]([O-:15])=[O:14])[CH3:17])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1cccc2ccccc12
Solvent: CCCCN
Solvent: CCO
Solvent: CO
Product: CC(=Cc1cccc2ccccc12)[N+](=O)[O-]
Yield: 89.9 %

Procedure:
A solution of 1-naphthylaldehyde (624.8 g, 4.0 mol), nitroethane (300.0 g, 4 mol) and n-butylamine (14.8 g, 0.20 mol) was refluxed in ethanol (400 mL) for 24 hours. The mixture was cooled, diluted with methanol (200 mL), and filtered to give 767 g (90% yield) of 1-naphthyl-2-nitropropene. Upon standing, an additional 60 g (97% total yield) of 1-naphthyl-2-nitropropene crystallized from solution.
Reaction SMILES: Cl[C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[CH3:17][NH2:18].O>C(O)C>[N+:11]([C:5]1[CH:4]=[C:3]([N+:14]([O-:16])=[O:15])[C:2]([NH:18][CH3:17])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8])([O-:13])=[O:12]
Reactant: CN
Reactant: NC(=O)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CCO
Solvent: O
Product: CNc1cc(C(N)=O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 98 %

Procedure:
A solution of 5-chloro-2,4-dinitrobenzamide (6.14 g, 25 mmol) [Goldstein, H.; Stamm, R.; Helv. Chim. Acta, 1952, 35, 1330-1333] and 40% aqueous methylamine (20 mL) in ethanol (80 mL) is heated in a sealed pressure vessel at 100° C. for 2 h. After cooling, dilution with water gives 2,4-dinitro-5-methylaminobenzamide (5.89 g, 98%). 1H NMR (DMSO) δ8.88 (1H, q, J=4.9 Hz), 8.76 (1H, s), 8.07 (1H, brs), 7.77 (1H, brs), 6.98 (1H,s), 3.07 (3H, d, J=5.0 Hz)
Reaction SMILES: C(S([C:8]1[N:13]=[C:12]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:15]2)[CH:11]=[CH:10][N:9]=1)(=O)=O)CCC.C([N:29]([CH:33]([CH3:35])[CH3:34])[CH:30](C)C)C>CN1C(=O)CCC1>[CH3:16][S:23]([N:29]([CH3:30])[CH:33]1[CH2:34][CH2:17][CH:22]([NH:14][C:8]2[N:13]=[C:12]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:15]3)[CH:11]=[CH:10][N:9]=2)[CH2:21][CH2:35]1)(=[O:25])=[O:24]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCCS(=O)(=O)c1nccc(-n2cc(S(N)(=O)=O)c3ccccc32)n1
Solvent: CN1CCCC1=O
Product: CN(C1CCC(Nc2nccc(-n3cc(S(N)(=O)=O)c4ccccc43)n2)CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 120.6 %

Procedure:
1-(2-Butylsulfonyl-pyrimidin-4-yl)-1H-indole-3-sulfonic acid amide (250 mg, 0.634 mmol), trans-(N-methyl-N-methylsulfonyl)cyclohexyldiamine acetate (422 mg, 1.584 mmol) and N-ethyl-diisopropylamine (205 mg, 1.584 mmol) were combined in a microwave vial, NMP added under N2, and the vial capped and stirred for 5 min at RT. The vial was then heated to 170° C. in a microwave reactor for 2.5 h, and left to stand at RT overnight. The mixture was then poured into ice water, and the resulting light yellow solid filtered, washed with water (30 mL) and Et2O (40 mL) and air-dried. The crude product was recrystallized from EtOAc-CHCl3 to provide 1-{2-[4-(methanesulfonyl-methyl-amino)-cyclohexylamino]-pyrimdin-4-yl}-1H-indole-3-sulfonic acid amide (183 mg, 60% yield) as a light yellow solid (Compound 321).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[C:26]([N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:27])[C:5]([NH:7][C@H:8]([C:13]1[NH:17][C:16]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=2[N:14]=1)[CH2:9][CH2:10][S:11][CH3:12])=[O:6].ClC1C=C(C=CC=1)C(OO)=[O:38].C(O)(=O)C.ClCl>ClCCl.ClCCl.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[C:26]([N:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1)=[O:27])[C:5]([NH:7][C@H:8]([C:13]1[NH:17][C:16]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=2[N:14]=1)[CH2:9][CH2:10][S:11]([CH3:12])=[O:38])=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCC[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(Br)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: ClCCl
Solvent: CCO
Solvent: CC(=O)O
Product: CS(=O)CC[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(Br)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 81 %

Procedure:
Prepared analogously to Example 85 from 3-bromo-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulfanylpropyl]-4-(pyrrolidin-1-ylcarbonyl)benzamide, 1 equivalent of 3-chloroperoxybenzoic acid, and glacial acetic acid in dichloromethane. Yield: 81%; Rf value: 0.20 (silica gel; dichloromethane/ethanol=9:1); C23H24BrClN4O3S (551.89); mass spectrum: (M+H)+=551/553/555 (chlorine isotope).
Reaction SMILES: [F:1]F.[S:3]1(=[O:12])(=[O:11])[CH2:8][CH2:7][CH2:6][S:5](=[O:10])(=[O:9])[NH:4]1.[F-].[Na+]>C(#N)C>[F:1][N:4]1[S:5](=[O:10])(=[O:9])[CH2:6][CH2:7][CH2:8][S:3]1(=[O:12])=[O:11]
Reactant: FF
Reactant: O=S1(=O)CCCS(=O)(=O)N1
Agent: [F-]
Agent: [Na+]
Solvent: CC#N
Product: O=S1(=O)CCCS(=O)(=O)N1F

Procedure:
0.5 l of a mixture of 10 parts by volume of fluorine and 90 parts by volume of nitrogen is introduced into a solution of 370 mg of [1,3,2]dithiazinane-1,1,3,3-tetraoxide (Geisler and Kuschmiers, "Chem. Ber." 91, p. 1881, 1958) in 23 ml of acetonitrile at -40° C. in the presence of 82 mg of sodium fluoride powder within 9 minutes. Then, it is flushed with pure nitrogen, concentrated by evaporation in a vacuum, taken up with dichloromethane, chromatographed on 60 g of silica gel, concentrated by evaporation in a vacuum, and recrystallized from acetone/hexane. 331 mg of N-fluoromethanesulfonimide is obtained as crystals with a melting point of 171°-172° C.
Reaction SMILES: Cl.C(O[C:5]([C:7]1([CH3:26])[C:24]2[C:10](=[CH:11][C:12]3[NH:16][C:15]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)=[N:14][C:13]=3[CH:23]=2)[NH:9][C:8]1=[O:25])=[O:6])C.C(O)C.O.[NH2:31][NH2:32]>CO>[NH:31]([C:5]([C:7]1([CH3:26])[C:24]2[C:10](=[CH:11][C:12]3[NH:16][C:15]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)=[N:14][C:13]=3[CH:23]=2)[NH:9][C:8]1=[O:25])=[O:6])[NH2:32]
Reactant: CCOC(=O)C1(C)C(=O)Nc2cc3[nH]c(-c4ccncc4)nc3cc21
Reactant: NN
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: O
Product: CC1(C(=O)NN)C(=O)Nc2cc3[nH]c(-c4ccncc4)nc3cc21

Procedure:
A solution of 1 g. (2.7 mmol) 7-ethoxycarbonyl-7-methyl-2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one hydrochloride in 30 ml. ethanol is stirred at 80° C. for about 8 hours with 6 ml. hydrazine hydrate. Subsequently, the reaction mixture is filtered with suction, the product obtained is boiled up with a solution of 1000 ml. methanol and 500 ml. methylene chloride, concentrated somewhat and the crystals obtained are filtered off with suction, washed with methanol and dried. Yield: 0.6 g. (70% of theory); m.p.>300° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([OH:24])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:43][CH:44]1[O:48][C:45]1([CH3:47])[CH3:46].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].O1CCCC1.[OH-].[Na+].OO>O1CCCC1.C(OCC)(=O)C>[Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24][CH2:43][CH2:44][C:45]([OH:48])([CH3:47])[CH3:46])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)OC1CBr
Reactant: CC(C)(O)C1=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
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)CCOC(C)(C)C1=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
Reaction time: 12 h
Yield: 93.2 %

Procedure:
A solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene (67.7 mg, 0.118 mmol), sodium hydride (60% in oil, 40.0 mg, 1.00 mmol) and 1-bromo-2,3-epoxy-3-methylbutane (100 mg, 0.606 mmol) in tetrahydrofuran (1 ml) was refluxed under heating for 1.5 hours. To the thus obtained reaction solution, was added 1.0M L-SELECTRIDE/tetrahydrofuran solution (1.2 ml, 1.2 mmol) at room temperature, followed by stirring at the same temperature for 12 hours. After cooling the reaction solution with ice, a 3N aqueous sodium hydroxide solution and then hydrogen peroxide solution were added to the reaction solution. Immediately after the addition, the mixture was diluted with ethyl acetate and washed with water and saturated brine. 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 preparative thin layer chromatography (2 sheets (each 0.5 mm thickness), hexane:ethyl acetate=15:1, developed once) to give the titled compound (72.5 mg, 93%) as a colorless oil.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][C:18](=[O:24])[NH:19]2.N1CCCCC1>C(O)C>[CH3:13][C:7]1[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:10][NH:9][C:8]=1[CH:11]=[C:17]1[C:16]2[C:20](=[CH:21][CH:22]=[CH:23][C:15]=2[CH3:14])[NH:19][C:18]1=[O:24]
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: Cc1cccc2c1CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cccc2c1C(=Cc1[nH]cc(CCC(=O)O)c1C)C(=O)N2
Yield: 51.9 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90 mg), 74 mg 4-methyl-2-oxindole, and 75 μL, piperidin in ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 80 mg (52%) of the title compound as a brown solid.
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)C.Cl[CH2:41][C:42]([N:44]([CH3:46])[CH3:45])=O>>[CH3:45][N:44]([CH3:46])[CH2:42][CH2:41][O:10][C:8]1[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[CH:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:35][CH:34]=1
Reactant: CN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1cc(NCCCc2ccc(OCCN(C)C)cc2)c(C2CCc3cc(O)ccc3C2)cc1OC
Yield: 29.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronap hthalen-2-yl ester (19 mg) and 2-chloro-N,N-dimethylacetamide (8.5 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.7 mg) was obtained.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.[K+].[Br-]>>[C:31]([C:28]1[CH:27]=[CH:26][C:25]([CH2:24][O:23][C:20]2[CH:21]=[CH:22][C:17]([CH2:16][S:15][C:12]3[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:35])=[O:2])=[C:7]4[C:11]=3[CH2:10][CH2:9][CH2:8]4)=[CH:18][CH:19]=2)=[CH:30][CH:29]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccc(C(C)(C)C)cc3)cc2)c2c1CCC2
Agent: [Br-]
Agent: [K+]
Product: CC(C)(C)c1ccc(COc2ccc(CSc3ccc(OCC(=O)O)c4c3CCC4)cc2)cc1

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 67A. mp 152-153° C.; IR (KBr) cm−1: 3134, 3032, 1745, 1708, 1473, 1228; 400 MHz 1H NMR (DMSO-d6): δ 12.94 (br(s), 1H), 7.25-7.39 (m, 4H), 7.01-7.14 (m, 3H) 6.80-6.89 (m, 2H), 6.57 (d, 1H, J=8.5 Hz), 4.97 (s, 2H), 4.61 (s, 2H), 3.93 (s, 2H), 2.75 (t, 2H, J=7.5 Hz), 2.67 (t, 2H, J=7.5 Hz), 1.89 (pentet, 2H), 1.22 (s, 9H); MS m/z 475 (M−1). Anal. Calc'd for C29H32O4S: C, 73.08; H, 6.77. found: C, 72.97; H, 6.84.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1C(=O)CCCC=C.[CH:20]([SH:24])([SH:23])[CH2:21][CH3:22].B(F)(F)F.[OH-].[Na+]>C(Cl)Cl>[C:14]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=[CH:16][C:17]([C:20]2([CH2:21][CH2:22][CH2:6][CH:1]=[CH2:2])[S:24][CH2:5][CH2:4][CH2:3][S:23]2)=[CH:18][CH:19]=1
Reactant: CCC(S)S
Reactant: C=CCCCC(=O)c1ccccc1-c1ccccc1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C=CCCCC1(c2ccc(-c3ccccc3)cc2)SCCCS1
Reaction time: 24 h

Procedure:
1-Biphenylyl-hex-5-en-1-one (1.5 g) was dissolved in DCM (30 ml). Propanedithiol (1.5 g) and boron trifluoride dietherate (1 ml) were added and the mixture stirred for 24 h. 5% NaOH (50 ml) was added and the mixture separated. The organic phase was washed with water, dried and evaporated to give an oil. Column chromatography (petrol/ethyl acetate) gave the title compound as a thick oil. δC (CDCl3, 62.9 MHz): 23.2, 25.3, 27.7, 33.6, 44.6, 58.9, 115.0, 127.1, 127.1, 127.4, 128.8, 129.4, 138.1, 139.6, 140.5 and 141.0. δH (CDCl3, 250 MHz): 1.40 (2H, m), 2.00 (6H, m), 2.70 (4H, m), 4.92 (2H, m), 5.68 (1H, m), 7.34 (1H, m), 7.44 (2H, m), 7.62 (4H, m) and 7.96 (2H, d, J 8.2).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]1=[O:17].[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[OH:1][CH2:2][CH2:3][N:4]1[C:5](=[O:17])[CH:6]=[CH:7][C:8]([CH:10]2[CH2:15][CH2:14][CH:13]([N:18]3[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=4)=[O:24])[CH2:19]3)[CH2:12][CH2:11]2)=[CH:9]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(c2ccc(=O)n(CCO)c2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccc(=O)n(CCO)c3)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 1-(2-hydroxy-ethyl)-5-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:12]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[NH:11][CH2:10][C:9]1(C)[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].NCC(N)C.OC1(C#N)CCCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:12]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[NH:11][CH2:10][CH:9]1[CH3:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2(CCCC2)NCC1(C)C
Agent: CC(N)CN
Agent: N#CC1(O)CCCC1
Product: CC1CNC2(CCCC2)CN1C(=O)OC(C)(C)C

Procedure:
8-Methyl-6,9-diaza-spiro[4.5]decane-9-carboxylic acid tert-butyl ester was synthesized in analogy to 8,8-dimethyl-6,9-diaza-spiro[4.5]decane-9-carboxylic acid tert-butyl ester starting from 1,2-diamino-propane and 1-hydroxycyclopentane-1-carbonitrile.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:34][CH3:35])=[C:7]([N:19]([CH3:33])[C:20](=[O:32])[C:21]2[CH:26]=[CH:25][C:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][CH:22]=2)[CH:8]=[C:9]([C:11]2[C:12]([O:17]C)=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br>CC(O)=O.CCOC(C)=O>[C:1]([C:5]1[C:6]([O:34][CH3:35])=[C:7]([N:19]([CH3:33])[C:20](=[O:32])[C:21]2[CH:22]=[CH:23][C:24]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])=[CH:25][CH:26]=2)[CH:8]=[C:9]([C:11]2[C:12](=[O:17])[NH:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ncccc1-c1cc(N(C)C(=O)c2ccc(NS(C)(=O)=O)cc2)c(OC)c(C(C)(C)C)c1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1c(N(C)C(=O)c2ccc(NS(C)(=O)=O)cc2)cc(-c2ccc[nH]c2=O)cc1C(C)(C)C
Temperature: 60 °C
Yield: 94 %

Procedure:
To a solution of 142 (0.17 g, 0.33 mmol) in HOAc (3 mL) was added concentrated aqueous HBr (48%, 0.11 mL), and the solution was heated in a sealed tube at 60° C. for 15 h. The reaction mixture was cooled to RT, diluted with EtOAc, and washed sequentially with water and saturated aqueous NaHCO3. The organic layer was dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with DCM/MeOH/NH4OH to afford 0.15 g (93%) of N-[3-tert-butyl-2-methoxy-5-(2-oxo-1,2-dihydropyridin-3-yl)phenyl]-4-methanesulfonylamino-N-methylbenzamide (I-104) as a white powder.