Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[H][H]>[Ni].C(O)C>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]2[S:6][C:5]3[CH:16]=[CH:17][C:2]([F:1])=[CH:3][C:4]=3[C:8]=2[CH:9]=1
Reactant: O=[N+]([O-])c1ccc2sc3ccc(F)cc3c2c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc2sc3ccc(F)cc3c2c1

Procedure:
A mixture of 14.33 g. (0.0605 mole) of 2-fluoro-8-nitrodibenzothiophene in 550 ml. of ethanol and about one-half teaspoonful (about 2.5 ml.) of Raney nickel is hydrogenated at about 30 psi of hydrogen gas in a Paar apparatus for about 48 hours. The mixture is filtered, and the filtrate is evaporated to dryness under vacuum to provide white needles of 2-amino-8-fluorodibenzothiophene, m.p. 131°-132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]([CH3:36])=[C:34]=[O:35]>ClCCl>[CH3:36][NH:33][C:34]([N:14]1[CH2:15][CH2:16][CH2:17][CH:12]([C:6]2([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[CH2:13]1)=[O:35]
Reactant: CN=C=O
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.2 mmol) (from Example 25a supra) in dichloromethane (2 mL) was added triethylamine (32.4 mg, 0.3 mmol) (Aldrich), followed by the addition of isocyanatomethane (14.6 mg, 0.24 mmol) (Chem Service). The mixture was stirred at room temperature for 30 minutes. The mixture was then partitioned between ethyl acetate and water. The aqueous layer was extracted with another two portions of ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was triturated with dichloromethane-hexanes to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid methylamide as a white solid. (Yield 35 mg, 50%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]1[NH:16][C:15]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:14][CH:13]=1.C(Cl)(Cl)[Cl:24]>>[Cl:24][C:13]1[N:14]=[C:15]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[NH:16][C:12]=1[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[CH3:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(C)c(-c2cnc(C3CCOCC3)[nH]2)c1
Reactant: ClC(Cl)Cl
Product: COC(=O)c1ccc(C)c(-c2[nH]c(C3CCOCC3)nc2Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of methyl 4-methyl-3-(2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoate (compound 241.2, 260 mg, 0.87 mmol) in chloroform (3 mL) NCS (116 mg, 0.87 mmol) was added to the reaction. The reaction mixture was stirred for 4 h at 25° C., then concentrated under reduced pressure. The residue was dissolved in 50 mL of EtOAc, then was washed with 3×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 313 mg (crude) of the title compound as brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:28])[C:20](Br)=[CH:21][C:22]=3[Cl:26])[C:17]2=[O:29])=[C:13]([CH3:30])[CH:12]=[C:11]([CH3:31])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][C:33]1[C:37](B2OC(C)(C)C(C)(C)O2)=[C:36]([CH3:47])[O:35][N:34]=1.[F-].[Cs+]>O1CCOCC1.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>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:28])[C:20]([C:37]4[C:33]([CH3:32])=[N:34][O:35][C:36]=4[CH3:47])=[CH:21][C:22]=3[Cl:26])[C:17]2=[O:29])=[C:13]([CH3:30])[CH:12]=[C:11]([CH3:31])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(CN2CCc3c(Cl)cc(Br)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: Cc1cc(C)c(CN2CCc3c(Cl)cc(-c4c(C)noc4C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 77.7 %

Procedure:
A mixture of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-7-bromo-5,8-dichloro-3,4-dihydroisoquinolin-1(2H)-one (253 g, 500 mg, 0.96 mmol), 3,5-Dimethylisoxazole-4-boronic acid pinacol ester (320 mg, 1.44 mmol), cesium fluoride (437 mg, 2.88 mmol) and tetrakis(triphenylphosphine)palladium(0) (70.0 mg, 0.06 mmol) in dioxane (20 mL) was degassed with nitrogen, then stirred at 100° C. for 18 hours. After cooling, the mixture was partitioned between water (15 mL) and ethyl acetate (3×20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (eluting with 10:1 petroleum ether/ethyl acetate), affording 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5,8-dichloro-7-(3,5-dimethyl-1,2-oxazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (253h, 400 mg, 78% yield) as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:16]=[CH:15][C:14]([CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][C:20]4=[O:24])=[CH:13][CH:12]=3)[S:10][C:3]=12.[F:25][C:26]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:27]=1[OH:35].C(=O)([O-])[O-].[K+].[K+]>C1(OC2C=CC=CC=2)C=CC=CC=1>[F:25][C:26]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:27]=1[O:35][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:16]=[CH:15][C:14]([CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][C:20]4=[O:24])=[CH:13][CH:12]=3)[S:10][C:3]=12
Reactant: O=C1CCCN1CCc1ccc(-c2cc3nccc(Cl)c3s2)nc1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=C1CCCN1CCc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Temperature: 200 °C
Yield: 46.7 %

Procedure:
To chlorothienopyridine 292 (1.2 g, 3.4 mmol) in diphenyl ether (20 mL) was added 2-fluoro-4-nitrophenol (1.58 g, 10.1 mmol) and potassium carbonate (2.32 g, 16.8 mmol) and the resultant mixture was heated to 200° C. for 10 h. Extra 2-fluoro-4-nitrophenol (1.58 g, 10.1 mmol) and potassium carbonate (2.32 g, 16.8 mmol) were added and the mixture was heated at 200° C. for a further 6 h. The mixture was cooled to RT, partitioned between ethyl acetate and 1M aqueous NaOH then filtered through celite. The organic phase was collected, washed with water and brine, dried (anhydrous MgSO4), filtered and concentrated. The residue was purified by silica gel chromatography (10% methanol/ethyl acetate) to afford title compound 293 (0.76 g, 47% yield), contaminated with ˜10% starting material 292, as a yellow solid. MS (M+H): 479.5
Reaction SMILES: [CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2].[Br:14][CH2:15][CH2:16]Br>>[Br:14][CH2:15][CH2:16][N:5]1[C:6]([CH3:9])=[C:7]([CH3:8])[C:3]([CH:1]=[O:2])=[C:4]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Reactant: BrCCBr
Product: COC(=O)c1c(C=O)c(C)c(C)n1CCBr

Procedure:
The title compound was prepared as ocherous crystals in 9.4% yeild in a similar procedure to that described in Referential Example 9 by using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 1,2-dibromoethane.
Reaction SMILES: [N:1]1([CH2:10][C:11]([OH:13])=O)[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].Cl.[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([N:27]1[CH2:32][CH2:31][NH:30][CH:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:28]1=[O:39])(=[O:26])=[O:25])([O-:17])=[O:16].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([N:27]1[CH2:32][CH2:31][N:30]([C:11](=[O:13])[CH2:10][N:1]2[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]2=[O:3])[CH:29]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:28]1=[O:39])(=[O:25])=[O:26])([O-:17])=[O:16]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: O=C1C(c2ccccc2)NCCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cn(CC(=O)N2CCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])C(=O)C2c2ccccc2)c(=O)[nH]c1=O
Reaction time: 27 h
Yield: 43.3 %

Procedure:
To a solution of (thymin-1-yl)-acetic acid (13 mg, 0.071 mmol), 1-(2-nitro-benzenesulfonyl)-3-phenyl-piperazin-2-one HCl salt (28 mg, 0.070 mmol), and PyBOP (40 mg, 0.077 mmol) in DMF (0.3 mL) was added N,N-diisopropylethylamine (0.018 mL) at room temperature. After stirring for additional 27 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography to give the titled compound (16 mg, 43%). 1H NMR (500 MHz; DMSO-d6) δ 11.33 (s, 1H), 8.36 (d, 1H), 8.13 (d, 1H), 8.05˜7.94 (m, 3H), 7.39˜7.29 (m, 5H), 5.93 (s, 1H), 4.87 (d, 1H), 4.67 (d, 1H), 4.22˜4.16 (m, 2H), 3.96 (m, 1H), 3.78 (m, 1H), 1.74 (s, 3H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[C:20]1([CH2:30][C:31](O)=[O:32])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:31](=[O:32])[CH2:30][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1cccc2ccccc12
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Product: O=C(Cc1cccc2ccccc12)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product from Example 86A and 2-(1-naphthyl)acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.40-8.43 (m, 1H), 8.18 (d, J=8.2 Hz, 1H), 7.95-8.01 (m, 3H), 7.88 (d, J=8.1 Hz, 1H), 7.70-7.77 (m, 1H), 7.61-7.66 (m, 4H), 7.54-7.60 (m, 3H), 7.51 (dd, J=8.2, 7.1 Hz, 1H), 4.19 (s, 2H); MS (ESI−) M/Z 438 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].C([Sn](CCCC)(CCCC)[C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)CCC.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CN(C=O)C.C(OCC)(=O)C.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>[F:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[C:16]1[O:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(F)c(-c2ccco2)c1
Temperature: 110 °C
Yield: 480.8 %

Procedure:
3-Bromo-4-fluorobenzaldehyde (1 g, 4.93 mmol) in DMF (25 ml) was treated with 2-(tributylstannyl)furan (2.4 ml, 1.05 mmol), di-tert-butyl dicarbonate (1.75 g, 4.94 mmol), and tetrakis(triphenylphosphine)palladium (0) (570 mg, 0.4 mmol). The mixture was heated at 110° C. in a sealed high pressure tube over night, allowed to cool to ambient temperature, diluted with ethyl acetate, and washed with brine. The organic layer was further washed with 1N HCl, saturated NaHCO3, brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography using hexanes:diethyl ether (20:1) as eluent to provide the title compound as a pale yellow oil (0.96 g, 98%).
Reaction SMILES: [CH:1]1([S:7]([CH2:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=2)(=[O:13])=[O:12])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S([N:34]=[N+:35]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1.Cl>ClCCl>[CH:1]1([S:7]([C:10]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][S:21]([CH3:24])(=[O:22])=[O:23])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[N+:34]=[N-:35])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CS(=O)(=O)Oc1ccc(S(=O)(=O)CS(=O)(=O)C2CCCCC2)cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc(S(=O)(=O)C(=[N+]=[N-])S(=O)(=O)C2CCCCC2)cc1
Reaction time: 0.17 h
Yield: 38 %

Procedure:
The cyclohexylsulfonyl(4-methanesulfonyloxyphenylsulfonyl)methane in Synthesis Example 12, 10 g (0.025 mol), was dispersed in 150 g of dichloromethane. To the dispersion was added 4.6 g (0.03 mol) of p-toluenesulfonylazide. With stirring under ice cooling, 4.9 g (0.025 mol) of DBU was added to the dispersion, and after 10 minutes, 100 g of a 0.2N aqueous hydrochloric acid was added to stop reaction. The organic layer was separated and washed with 100 g of water. The organic layer was concentrated and 13 g of the residue was purified by silica gel column chromatography using dichloromethane as an elute. The thus obtained oily product was combined with 20 g of hexane for crystallization, followed by filtration and vacuum drying. There was obtained 4.0 g (yield 38%) of fine yellow crystals.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:31])[CH:11]([N:15]1[C@H:18]([S:19][S:20][C:21]2[S:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)[CH2:17][C:16]1=[O:30])[C:12](=[CH2:14])[CH3:13]>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:31])[C:11]([N:15]1[C@H:18]([S:19][S:20][C:21]2[S:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)[CH2:17][C:16]1=[O:30])=[C:12]([CH3:14])[CH3:13]
Reactant: C=C(C)C(C(=O)OC)N1C(=O)C[C@H]1SSc1nc2ccccc2s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(=C(C)C)N1C(=O)C[C@H]1SSc1nc2ccccc2s1
Reaction time: 1.5 h

Procedure:
5 ml of triethylamine are added to a solution of 12 g of 2-[(4R)-4-(benzthiazol-2-yldithio)-2-oxoazetidin-1-yl]-3-methylenebutyric acid methyl ester in 500 ml of methylene chloride and the mixture is allowed to stand at room temperature for 90 minutes. The reaction mixture is washed with 5% aqueous citric acid solution, dried over sodium sulphate and freed of solvent in vacuo. The residue is purified by chromatography over silica gel (deactivated with 10% water) with toluene and toluene/ethyl acetate (19:1) and yields the title compound, which after recrystallisation from diethyl ether/pentane has a melting point of 63°-66°.
Reaction SMILES: [I:1]I.[CH3:3][C:4]1[N:9]=[C:8]([NH2:10])[N:7]=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]=1.[OH-].[Na+]>C(Cl)Cl.O>[I:1][C:5]1[C:6]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N:7][C:8]([NH2:10])=[N:9][C:4]=1[CH3:3]
Reactant: CCCCCNc1cc(C)nc(N)n1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCCCCNc1nc(N)nc(C)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
A solution of iodine (11.92 g) in DCM (300 mL) was added to a stirred mixture of the product from step (i) (8.3 g) and sodium hydroxide (3.42 g) in water (200 mL). The reaction mixture was stirred at rt overnight. The organic layer was separated and washed with sodium metabisulfate solution, then brine. The combined organic layers were dried, and the solvent evaporated under reduced pressure. The product was purified by chromatography eluting with DCM:MeOH; 95:5 to give the subtitle compound 11 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]=1[C:19]([N:21]1[CH2:25][CH2:24][C@@H:23]([OH:26])[CH2:22]1)=[O:20].Cl.[OH:28][CH2:29][C@H]1NC[C@H](O)C1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]=1[C:19]([N:21]1[CH2:22][C@H:23]([OH:26])[CH2:24][C@H:25]1[CH2:29][OH:28])=[O:20]
Reactant: O=C(c1[nH]c2ccncc2c1Nc1ccc(I)cc1F)N1CC[C@@H](O)C1
Reactant: OC[C@@H]1C[C@@H](O)CN1
Agent: Cl
Product: O=C(c1[nH]c2ccncc2c1Nc1ccc(I)cc1F)N1C[C@H](O)C[C@H]1CO

Procedure:
The title compound was prepared in an analogous fashion to [3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]pyridin-2-yl]-((R)-3-hydroxy-pyrrolidin-1-yl)-methanone, replacing (R)-pyrrolidin-3-ol hydrochloride with (3R,5S)-5-hydroxymethyl-pyrrolidin-3-ol hydrochloride. 1H-NMR (400 MHz, MeOD) 6 ppm 8.62 (d, J=1.02 Hz, 1H), 8.23 (d, J=5.99 Hz, 1H), 7.52-7.35 (m, 2H), 7.34-7.16 (m, 1H), 6.60 (t, J=8.8 Hz, 1H), 4.59-4.42 (m, 1H), 4.35-4.17 (m, 1H), 3.71-3.44 (m, 4H), 2.19-1.90 (m, 2H); LC-MS (method E): [M+H]+=497.1, RT=3.37 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:26](O)(=[O:35])[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN=C=NCCCN(C)C>>[C:29]1([CH2:28][CH2:27][C:26]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: O=C(O)CCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)CCc4ccccc4)c3)c2c1
Yield: 14.4 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with hydrocinnamic acid (0.11 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 31 mg (13% yield) of the title compound. 1H NMR (DMSO-d6) δ 13.4 (s, 1H), 10.2 (s, 1H), 8.6 (s, 1H), 8.2 (s, 1H), 8.1 (br s, 1H), 7.9 (d, 1H), 7.75 (m, 2H), 7.6 (d, 1H), 7.5 (t, 1H), 7.4–7.1 (m, 5H), 2.95 (t, 2H), 2.68 (t, 2H); ES-MS (m/z) 385 [M+H]+.
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:5][C:6]([S:9]([CH2:12][CH2:13][CH2:14][CH3:15])(=[O:11])=[O:10])=[N:7][N:8]=1)[CH3:2].[OH:16]O.O>C(O)(=O)C>[CH2:1]([S:3]([C:4]1[S:5][C:6]([S:9]([CH2:12][CH2:13][CH2:14][CH3:15])(=[O:11])=[O:10])=[N:7][N:8]=1)=[O:16])[CH3:2]
Reactant: OO
Reactant: CCCCS(=O)(=O)c1nnc(SCC)s1
Solvent: CC(=O)O
Solvent: O
Product: CCCCS(=O)(=O)c1nnc(S(=O)CC)s1

Procedure:
A solution of 53.29 g of 2-Ethylthio-5-butylsulfonyl-1,3,4-thiadiazole in 500 ml acetic acid is mixed with 23 g of 30 percent hydrogen peroxide. The reaction takes place over night upon standing at room temperature. Then one liter water is added to the reaction solution, the separated oil is extracted with dichloromethane, the extract is freed from acetic acid by extraction with soda ash solution, the dichloromethane phase is dried with magnesium sulfate and the solvent is distilled off completely, finally in vacuo. The remaining residue is recrystallized from isopropylether/isopropanol.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[CH2:15][C:16]1[N:17]=[C:18]([C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][C:24]=3[N:30]([CH3:39])[S:31]([C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)(=[O:33])=[O:32])[S:19][CH:20]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH3:39][N:30]([S:31]([C:34]1[S:35][CH:36]=[CH:37][CH:38]=1)(=[O:33])=[O:32])[C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:23]=1[NH:22][C:21]([C:18]1[S:19][CH:20]=[C:16]([CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[N:17]=1)=[CH:29]2
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CN(c1cccc2cc(-c3nc(CCl)cs3)[nH]c12)S(=O)(=O)c1cccs1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1csc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)n1)C(=O)OCC
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a suspension of sodium hydride (60% in oil, 0.15 g) in N,N-dimethylformamide (10 mL) was added diethyl malonate (0.53 g) at 0° C., and the mixture was stirred for 30 min. To the reaction mixture was added N-{2-[4-(chloromethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.45 g) at 0° C., and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added 10% citric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.43 g, yield 72%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:57]/[CH:58]=[CH:59]/[C:60]([CH2:71][CH3:72])([O:63][Si:64]([CH2:69][CH3:70])([CH2:67][CH3:68])[CH2:65][CH3:66])[CH2:61][CH3:62]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:57]/[CH:58]=[CH:59]/[C:60]([CH2:71][CH3:72])([O:63][Si:64]([CH2:69][CH3:70])([CH2:65][CH3:66])[CH2:67][CH3:68])[CH2:61][CH3:62])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H](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
Reactant: CCC(/C=C/CBr)(CC)O[Si](CC)(CC)CC
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(/C=C/CO[C@H](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)(CC)O[Si](CC)(CC)CC
Yield: 72.9 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5 (10 μl) and (E)-1-bromo-4-ethyl-4-triethylsilyloxy-2-hexene (134 mg, 0.420 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) to give the title compound as a colorless oil (62.4 mg, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[NH2:16][CH2:17][CH2:18][CH:19]1[CH2:23][C:22]2[C:24]([CH3:38])=[C:25]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]([CH3:29])=[C:27]([CH3:28])[C:21]=2[O:20]1.Cl>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:31]([O:30][C:25]1[C:26]([CH3:29])=[C:27]([CH3:28])[C:21]2[O:20][CH:19]([CH2:18][CH2:17][NH:16][C:6](=[O:7])[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=3)[CH2:23][C:22]=2[C:24]=1[CH3:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC(CCN)O2
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)NCCC2Cc3c(C)c(OCc4ccccc4)c(C)c(C)c3O2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.86 g of 3,4,5-trimethoxybenzoyl chloride in 35 ml of chloroform is slowly added to a 3.85 g solution of 2-(RS)-(2-aminoethyl)-2,3-dihydro-5-benzyloxy-4,6,7-trimethyl-benzofurane in 35 ml of chloroform and 2.0 ml of triethylamine. After stirring for one hour at room temperature, 1 M hydrochloric acid is added and the organic phase is separated and washed in a sodium bicarbonate solution, dried and evaporated. 4.42 g of--a white solid are obtained that is purified by crystallization from ethanol/ethyl acetate. m.p. 171°-173° C. IR(KBr): 3271 (νN--H), 1684, 1545 cm-1 (νCONH); 1H-NMR (CDCl3): δ7.4-7.2 (5H,m), 7.0 (2H,s), 6.8 (1H,t), 5.1-4.7 (1H,m), 4.7 (2H,s), 3.8 (9H,s), 3.8-3.4 (2H,m), 3.2-2.7 (2H,m), 2.2 (6H,s), 2.1 (3H,s), 2.1-1.8 (2H,m).