Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:9]2[CH2:12][CH:11]([C:13]([C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=3)(O)[C:14]([CH3:18])([CH3:17])[C:15]#[N:16])[CH2:10]2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:20]3[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=3)[C:14]([CH3:18])([CH3:17])[C:15]#[N:16])[CH2:10]2)=[CH:33][CH:32]=1
Reactant: CC(C)(C#N)C(O)(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C#N)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1

Procedure:
The reaction mixture of 128 mg (0.255 mmol) of 3-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-3-(3,5-difluorophenyl)-3-hydroxy-2,2-dimethylpropanenitrile and 3 mL of phosphorus oxychloride in 5 mL of pyridine was heated at reflux for 48 h. The solution was concentrated, poured into 30 mL of ether, and washed with 5 mL of aq NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate=4:1 to afford the title compound. 1NMR (CDCl3) δ 1.47 (s, 6H), 3.48 (s, 2H), 4.18 (s, 2H), 4.47 (s, 1H), 6.66-6.77 (m, 2H), 7.25-6-7.35 (r, 8H); Mass Spectrum: m/e=483 (M+1 35Cl, 35Cl) and 485 (M+1 35Cl, 37Cl).
Reaction SMILES: [C:1]1([CH:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:8]([N:10]2[CH:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:34][CH3:35])[C:16]=3[O:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=3)[CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.C1COCC1.[Pd]>[NH2:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:16]2[C:15]([O:34][CH3:35])=[CH:14][CH:13]=[C:12]3[C:17]=2[CH2:18][CH:19]([C:20]([O:22][CH3:23])=[O:21])[N:10]([C:8](=[O:9])[CH:7]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:11]3)=[CH:26][CH:27]=1
Reactant: COC(=O)C1Cc2c(ccc(OC)c2Oc2ccc([N+](=O)[O-])cc2)CN1C(=O)C(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C1Cc2c(ccc(OC)c2Oc2ccc(N)cc2)CN1C(=O)C(c1ccccc1)c1ccccc1
Yield: 99 %

Procedure:
A solution of 0.80 g (1.45 mmole) of the nitrobenzene derivative of Example 43 in 50% methanol-THF is reduced with 5% palladium-on-carbon catalyst. The filtered solution is concentrated at reduced pressure to give 0.75 g of pure product as a solid foam; mass spectrum (EI) 522 (M+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.F[C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19].[CH2:26]([S:28]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH3:27]>O>[CH2:26]([S:28]([C:31]1[CH:36]=[CH:35][C:34]([O:37][C:13]2[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([CH:22]=2)[C:18]([O:20][CH3:21])=[O:19])=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH3:27]
Reactant: COC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CCS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(C(=O)OC)c2)cc1
Temperature: 80 °C
Yield: 100.3 %

Procedure:
11 g of potassium carbonate was added to a dimethylformamide (150 ml) solution of 10.7 g of methyl 5-fluoro-2-nitrobenzoate and 11.1 g of 4-(ethylsulfonyl)phenol obtained from Reference Example 2, and stirred under heat at 80° C. for 90 minutes. The reaction liquid was restored to room temperature, then 300 ml of water was added to it, and the formed solid was taken out through filtration. This was dried under reduced pressure to obtain 19.7 g of the entitled compound as a creamy white solid.
Reaction SMILES: CN(C=O)C.[F:6][C:7]1[CH:8]=[C:9](/[CH:18]=[CH:19]/[C:20]([OH:22])=O)[CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.[NH2:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(OCC)(=O)C.O>[F:6][C:7]1[CH:8]=[C:9](/[CH:18]=[CH:19]/[C:20]([NH:23][CH:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)=[O:22])[CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: O=C(O)/C=C/c1ccc(-n2ccnc2)c(F)c1
Reactant: NC1CCc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc(-n2ccnc2)c(F)c1)NC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a DMF (4.0 mL) solution of (E)-3-[3-fluoro-4-(1H-imidazol-1-yl)phenyl]acrylic acid (100 mg), TEA (167 μL), 1-aminoindane (83.0 μL) and PYBOP (448 mg) were added one by one, and the reaction solution was agitated at room temperature overnight. After confirming disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane:ethyl acetate=1:1→ethyl acetate), and 95.0 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10](Cl)=[O:11])[CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].C(N(CC)CC)C>ClCCl>[OH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:10]([C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=1)=[O:11]
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)c1cc(Cl)c(Cl)c(Cl)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1O)c1cc(Cl)c(Cl)c(Cl)n1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
A solution of 4,5,6-trichloropyridine-2-carbonyl chloride (1.0 g, 4.1 mmol) in dichloromethane (10 mL) was added dropwise to a solution of 2-aminophenol (0.45 g, 4.1 mmol) and triethylamine (0.6 mL) in dichloromethane (30 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for an additional thirty minutes. The solvents were removed and the residue partitioned between 20% tetrahydrofuran/ethyl acetate and 1M hydrochloric acid. The organic layer was separated, washed with saturated sodium bicarbonate, brine, dried (MgSO4) and concentrated to provide N-(2-hydroxyphenyl)-4,5,6-trichloropyridine-2-carboxamide (1.26 g, 4.0 mmol), mp 240° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:24][CH2:25][NH2:26].[BH4-].[Na+]>CO>[Cl:20][C:21]1[CH:22]=[C:23]([CH2:24][CH2:25][NH:26][CH2:18][C:16]2[CH:15]=[CH:14][C:3]([O:4][C:5]3[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=3)=[C:2]([F:1])[CH:17]=2)[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cnc(Oc2ccc(CNCCc3ccc(Cl)c(Cl)c3)cc2F)cn1
Reaction time: 8 h
Yield: 44 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737, Part E) (0.400 g, 1.53 mmol), 3,4-dichlorophenethylamine (0.320 g, 1.68 mmol) and 3 Å molecular sieves in a vial. Add methanol (7.7 mL), cap and stir overnight. Add NaBH4 (0.058 g, 1.53 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 15% (2.0 M NH3 in methanol) in 80% (ethyl acetate in hexanes). Concentrate the fractions containing the product. Take the solid up in dichloromethane (100 mL) and wash with 1.0 N NaOH (2× 25 mL) to give the title compound (0.293 g, 44%): TOF MS ES+ 435.1 (M+H)+, HRMS calcd for C20H18N4O2FCl2 435.0791 (M+H)+, found 435.0815, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=12.8 min, 100% purity.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH2:11][O:12][C:13](=[O:15])[CH3:14])=[O:10])=[CH:4][C:3]=1[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[C:22]([C:24]1[O:28][C:27]([C:29](Cl)=[O:30])=[CH:26][CH:25]=1)#[N:23].CCN(C(C)C)C(C)C>>[C:22]([C:24]1[O:28][C:27]([C:29]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH2:11][O:12][C:13](=[O:15])[CH3:14])=[O:10])=[CH:4][C:3]=2[N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:30])=[CH:26][CH:25]=1)#[N:23]
Reactant: N#Cc1ccc(C(=O)Cl)o1
Reactant: CC(=O)OCC(=O)Nc1ccc(N)c(N2CCCCC2)c1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCC(=O)Nc1ccc(NC(=O)c2ccc(C#N)o2)c(N2CCCCC2)c1
Yield: 19.9 %

Procedure:
Using a procedure similar to Example 4, step (c), acetic acid (4-amino-3-piperidin-1-yl-phenylcarbamoyl)-methyl ester (80 mg, 0.27 mmol) was allowed to react with 5-cyano-furan-2-carbonyl chloride (42 mg, 0.27 mmol) in the presence of DIEA (0.10 mL, 0.59 mmol) to afford 22 mg (20%) of the title compound as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 9.66 (s, 1H), 8.40 (d, 1H, J=9.0 Hz), 7.73-7.76 (m, 2H), 7.27-7.28 (m, 1H), 7.22 (d, 1H, J=2.7 Hz), 7.08 (dd, 1H, J=2.3, 8.7 Hz), 4.68 (s, 2H), 2.84-2.86 (m, 4H), 2.24 (s, 3H), 1.82-1.84 (m, 4H), 1.68 (br s, 2H); Mass spectrum (ESI, m/z): Calcd. for C21H22N4O5, 411.1 (M+H), found 411.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:22]2[C:17]([C:18]3[CH:34]=[CH:33][O:32][C:19]=3[C:20](=[O:31])[O:21]2)=[CH:16][CH:15]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])=[C:22]2[C:17]([C:18]3[CH:34]=[CH:33][O:32][C:19]=3[C:20](=[O:31])[O:21]2)=[CH:16][CH:15]=1)(=[O:11])=[O:10]
Reactant: CC(C)(C)OC(=O)c1c(N)ccc2c1oc(=O)c1occc12
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1oc(=O)c1occc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
2-Bromo-4-fluorobenzenesulfonyl chloride (0.229 g) was added to a solution of tert-butyl 7-amino-4-oxo-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 57, 0.210 g) and pyridine (1.13 mL) in DCM (20 mL) and the mixture was stirred at room temperature overnight. The mixture was reduced to half volume in vacuo and the resultant mixture was stirred and heated at 35° C. for 6 hours. Further 2-bromo-4-fluorobenzenesulfonyl chloride (0.572 g) was added and the reaction mixture was heated at 35° C. overnight. The mixture was evaporated to dryness and the residue was partitioned between water and ethyl acetate. The combined organic layers were dried (MgSO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with ethyl acetate and cyclohexane, with a gradient of 5-20% to give tert-butyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4-oxo-4H-furo[2,3-c]chromene-6-carboxylate (0.329 g) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[NH:10][CH:9]=[C:8]3[C:14](=[O:23])[N:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:16]=[C:7]3[C:6]=2[CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][C:11]2[NH:10][CH:9]=[C:8]3[C:14](=[O:23])[N:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:16]=[C:7]3[C:6]=2[CH:5]=1
Reactant: [H][H]
Reactant: O=c1c2c[nH]c3ccc([N+](=O)[O-])cc3c-2nn1-c1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2[nH]cc3c(=O)n(-c4ccccc4)nc-3c2c1
Yield: 87 %

Procedure:
To a solution of 5a in methanol were added catalytic amounts of Pd on carbon. Reaction mixture was stirred at 20 psi of hydrogen overnight. Solid was filtered off and methanol was removed in vacuo to afford 8-amino-2-phenyl-2,5-dihydro-pyrazolo-(4,3-c) quinolin-3-one in 87% yield. 1H-NMR (DMSO-d6) δ (ppm): 6.92 (1H, dd, J=8.79, 2.47 Hz), 7.13 (1H, m), 7.28 (1H, d, J=2.47 Hz), 7.43 (3H, m), 8.20 (2H, dd, J=7.69, 1.10 Hz), 8.44 (1H, d, J=6.59 Hz). m/z 277.3 (MH+).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:31][CH2:30][CH:26]([C:27]([Cl:29])=[O:28])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[ClH:29].[N:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:24][CH2:25][CH:26]([C:27]([NH:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:16])=[O:28])[CH2:30][CH2:31]2)=[CH:19][CH:18]=1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: Nc1ccccc1C(=O)Nc1ccccc1
Product: Cl
Product: O=C(Nc1ccccc1)c1ccccc1NC(=O)C1CCN(c2ccncc2)CC1
Yield: 55 %

Procedure:
Using the procedure described in Example 138, N-phenyl-2-aminobenzamide (0.97 mmol) and N-(4-pyridyl)isonipecotoyl chloride (1.9 mmol), purifying with RPHPLC Method A, yielded 233 mg (55%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]1[NH:13][CH2:14][CH2:15][C:6]21[CH3:16].Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C@H:7]1[N:13]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14][CH2:15][C@@:6]21[CH3:16]
Reactant: BrCCc1ccccc1
Reactant: COc1ccc2c(c1)C1(C)CCNC1N2C
Product: COc1ccc2c(c1)[C@]1(C)CCN(CCc3ccccc3)[C@@H]1N2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred mixture, under nitrogen, of 8.73 g of 1,2,3,3a,8,8a-hexahydro-5-methoxy-3a,8-dimethylpyrrolo[2,3-b]-indole, 9.25 g of 2-(bromoethyl)benzene and 8.29 g of milled, anhydrous potassium carbonate in 75 ml of degassed, dry dimethylformamide is heated at 70°-75° for 8 hours and thereafter stirred at room temperature overnight. The reaction mixture is decanted into 1.5 liters of water and the product is extracted into ethyl acetate (2×250 ml). The combined organic extracts are washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue is subjected to flash chromatography over silica gel using methanol/ethyl acetate mixtures as eluent. The fractions containing the product are combined and concentrated to afford pure (3aS-cis)-1,2,3,3a,8,8a-hexahydro-5-methoxy-1-(2phenylethyl) -3a,8-dimethylpyrrolo[2,3-b]indole.
Reaction SMILES: [C:1](=[O:35])([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[O:2][CH:3]([O:5][C:6](=[O:23])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]CC1C=CC=CC=1)=[O:14])[CH3:4]>C(O)(=O)C.[Pd]>[C:1](=[O:35])([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[O:2][CH:3]([O:5][C:6](=[O:23])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH3:4]
Reactant: CCCCCCCCCCOC(=O)OC(C)OC(=O)CCCCCCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCCCCCCCOC(=O)OC(C)OC(=O)CCCCCCC(=O)O
Reaction time: 5 h

Procedure:
To a solution of 1-(7-benzyloxycarbonylheptanoyloxy)ethyl decyl carbonate (Example 1ac(iv), 4.0 g, 7.9 mmol) in acetic acid (15 ml) was added a catalytic amount of palladium on charcoal (150 mg). The mixture was hydrogenated with H2 at ambient temperature for 5 hours. Acetic acid was removed under reduced pressure. The residue was purified by column chromatography using n-heptane/ethyl acetate (4:1) as eluent.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[Se].C(N=C=[Se:43])C1C=CC=CC=1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]=[C:12]=[Se:43])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CNCCCCc1ccccc1
Reactant: [Se]=C=NCc1ccccc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Se]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [Se]=C=NCCCCc1ccccc1
Yield: 95 %

Procedure:
A mixture of phenylbutyl formamide (g, 1.5 mmol), triethylamine (6.4 mmol), 4 Å molecular sieves (g), triphosgene (0.8 mmol), and selenium powder (3.0 mmol) in CH2Cl2 was refluxed and worked up as mentioned for 2a. The crude residue thus obtained was purified by silica gel column chromatography (EtOAc/hexanes 2:98) to give 0.96 g (95%) of 2c as an oil. 1H NMR (CDCl3) δ 1.74-1.76 (m, 4H), 2.66 (t, 2H, J=6.6 Hz), 3.60 (t, 2H, J=5.6 Hz), 7.15-7.32 (m, 5H); HRMS (EI) calcd for C11H13NSe, 239.0208. found, 239.0211.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH2:20])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25].[NH:36]([C:40]1[S:41][CH:42]=[C:43]([CH2:45][S:46][CH2:47][CH2:48][NH2:49])[N:44]=1)[C:37]([NH2:39])=[NH:38]>>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH2:17][CH2:18][CH2:19][NH:20][C:24]([NH:49][CH2:48][CH2:47][S:46][CH2:45][C:43]2[N:44]=[C:40]([NH:36][C:37]([NH2:39])=[NH:38])[S:41][CH:42]=2)=[O:25])[CH3:21])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CN(CCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: CN(CCCNC(=O)NCCSCc1csc(NC(=N)N)n1)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.33 g (1.05 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,3-propanediamine and the equimolar amounts of 1,1'-carbonyldiimidazole and 2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethaneamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a dry foam. MS (+FAB method): m/z (rel. int. [%])=574 ([M+H]+, 9), 109 (100) IR (KBr): 1682 cm-1 (C=O).
Reaction SMILES: I[C:2]1[CH:7]=[N:6][C:5]([NH2:8])=[C:4]2[O:9][C:10]([C:12]3[C:13]4[S:20][N:19]=[CH:18][C:14]=4[CH:15]=[N:16][CH:17]=3)=[CH:11][C:3]=12.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][N:32]([CH:34]3[CH2:39][CH2:38][N:37]([C:40](=[O:42])[CH3:41])[CH2:36][CH2:35]3)[CH:33]=2)O1.[C:44](=O)([O-:46])[O-:45].[K+].[K+].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.O>[CH:44]([OH:46])=[O:45].[CH:44]([OH:46])=[O:45].[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:29]2[CH:30]=[N:31][N:32]([CH:34]3[CH2:35][CH2:36][N:37]([C:40](=[O:42])[CH3:41])[CH2:38][CH2:39]3)[CH:33]=2)=[C:3]2[CH:11]=[C:10]([C:12]3[C:13]4[S:20][N:19]=[CH:18][C:14]=4[CH:15]=[N:16][CH:17]=3)[O:9][C:4]=12
Reactant: CC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Nc1ncc(I)c2cc(-c3cncc4cnsc34)oc12
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5cncc6cnsc56)cc34)cn2)CC1
Product: O=CO
Yield: 31.2 %

Procedure:
A mixture of 4-iodo-2-([1,2]thiazolo[4,5-c]pyridin-7-yl)furo[2,3-c]pyridin-7-amine (7.0 mg, 0.018 mmol), 1-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidin-1-yl}ethanone (8.5 mg, 0.027 mmol), Pd(PPh3)4 (1.0 mg, 0.00089 mmol), potassium carbonate (7.4 mg, 0.053 mmol) and 4:1 dioxane:water (1 mL) was heated in a microwave reactor at 85° C. for 20 min. The solution was used directly for HPLC purification, and the fractions containing the pure product were concentrated in vacuo to afford 3.1 mg (38%) of the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ 2.03-2.16 (m, 2 H), 2.19 (s, 3 H), 2.20-2.31 (m, 2 H), 2.88 (td, J=12.9, 2.7 Hz, 1 H), 3.34-3.41 (m, 1 H), 4.08-4.17 (m, 1 H), 4.55 (tdd, J=11.4, 11.4, 4.2, 4.0 Hz, 1 H), 4.67-4.75 (m, 1 H), 7.72 (s, 1 H), 7.89 (s, 1 H), 7.92 (s, 1 H), 8.15 (s, 1 H), 8.16 (s, 2 H), 9.23 (s, 1 H), 9.28 (s, 1 H), 9.44 (s, 1 H); MS (ESI): 460.63 [M+H]+; HPLC tR=0.56 min (TOF: polar—3 min).
Reaction SMILES: [CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH:15]([F:17])[F:16])[CH:12]=3)[C:7]([C:18]#[N:19])=[CH:6]2)[CH2:4][CH2:3][CH2:2]1.[CH2:20]([Sn:24](I)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23].[Li+].CC([N-]C(C)C)C>C1COCC1>[CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH:15]([F:16])[F:17])[CH:12]=3)[C:7]([C:18]#[N:19])=[C:6]2[Sn:24]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1cn(C2CCC2)c2cc(OC(F)F)ccc12
Reactant: CCCC[Sn](I)(CCCC)CCCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1c(C#N)c2ccc(OC(F)F)cc2n1C1CCC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To 1-cyclobutyl-6-difluoromethoxy-1H-indole-3-carbonitrile (830 mg, 3.17 mmol) in THF (10 mL) was added tributyltin iodide (1.13 mL, 4.04 mmol) and the solution cooled to −78° C. A solution of LDA (1.5M in cyclohexane, 3.4 mL, 5.1 mmol) was added dropwise. After complete addition the bath was removed and the mixture stirred at room temperature for 1 hour. THF was then removed under vacuum and the residue filtered through silica gel using CH2Cl2 as an eluant and the mixture concentrated. The residue was purified by flash chromatography using 30-50% CH2Cl2/hexanes to provide 1-cyclobutyl-6-difluoromethoxy-2-tributylstannanyl-1H-indole-3-carbonitrile as a clear, colorless oil (1.23 g, 70%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:6]([C:18]([OH:20])=O)=[CH:5]2.[NH2:21][C:22]1[CH:23]=[N:24][C:25]([N:29]([CH3:31])[CH3:30])=[C:26]([CH3:28])[CH:27]=1>>[CH3:30][N:29]([CH3:31])[C:25]1[N:24]=[CH:23][C:22]([NH:21][C:18]([C:6]2[N:7]([CH2:11][C:12]3[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=3)[C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)=[O:20])=[CH:27][C:26]=1[CH3:28]
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1ccncc1
Reactant: Cc1cc(N)cnc1N(C)C
Product: Cc1cc(NC(=O)c2cc3cc(F)ccc3n2Cc2ccncc2)cnc1N(C)C

Procedure:
Compound No. 19 is prepared from 5-fluoro-1-(pyridin-4-ylmethyl)-1H-indole-2-carboxylic acid, synthesized in stage 5.1, and 3-amino-5-methyl-6-(dimethylamino)pyridine (GB 870 027) according to a process similar to that described in example No. 3.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[S:10]([CH2:13][CH:14]1[CH2:19][CH2:18][C:17]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[CH2:16][CH2:15]1)(=[O:12])=[O:11])=[O:4].[OH-].[Li+]>O1CCCC1.O>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([S:28]([C:17]2([C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=3[F:27])[CH2:18][CH2:19][CH:14]([CH2:13][S:10]([N:6]3[CH2:7][CH2:8][CH2:9][C@@H:5]3[C:3]([OH:4])=[O:2])(=[O:11])=[O:12])[CH2:15][CH2:16]2)(=[O:30])=[O:29])=[CH:32][CH:33]=1
Reactant: COC(=O)[C@H]1CCCN1S(=O)(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CCCN1S(=O)(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Reaction time: 1.5 h

Procedure:
To a stirred solution of (R)-1-[4-(4-chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl)-cyclohexylmethanesulfonyl]-pyrrolidine-2-carboxylic acid methyl ester (Example 18) (108 mg, 0.19 mmol.) in tetrahydrofuran (10 mL) was added lithium hydroxide (18 mg) in water (4 mL) and the mixture vigorously stirred for 1.5 hours. After removal of the solvent in vacuo, the aqueous residue was acidified to pH 1 with 2N aqueous hydrochloric acid and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (10 mL), dried (MgSO4) and evaporated to leave a residue which was purified by column chromatography on silica, eluting with ethyl acetate:dichloromethane:acetic acid (30:60:1), to afford the desired MS (ES+) 562 ([MH]+).