Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13](=[O:25])[N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]([CH3:18])[C:16]=2[CH3:17])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]([NH2:35])=[O:34])[CH:28]=1.[H-].[Na+]>CS(C)=O.O>[CH3:18][N:15]1[C:16]([CH3:17])=[C:12]([C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([C:33]([NH2:35])=[O:34])[CH:28]=3)=[C:2]([F:1])[CH:3]=2)=[O:11])[C:13](=[O:25])[N:14]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Cc1c(C(=O)Nc2ccc(O)c(F)c2)c(=O)n(-c2ccccc2)n1C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 160 °C
Reaction time: 20 h
Yield: 28.8 %

Procedure:
To a suspension of N-(3-fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (2.2 g, 6.4 mmol) and 4-chloropicolinamide (1 g, 6.39 mmol) in DMSO (12 mL) was added NaH (615 mg, 12.3 mmol, 50% dispersed in mineral oil). The reaction was stirred at 160° C. for 20 hours, then cooled to rt, and diluted with H2O (70 mL). The mixture was extracted with EtOAc (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=1/4) to give the title compound as a white solid (0.85 g, 29%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11]O)=[CH:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:32]I.N1C=CN=C1>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][I:32])=[CH:2]1
Reactant: OCCc1csc2ccccc12
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ICCc1csc2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-(1-benzothiophene-3-yl)ethanol (890 mg, 5 mmol) in anhydrous THF (50 ml), triphenylphosphine (1.572 g, 6 mmol), iodine (1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 4 hrs and quenched with water. It was extracted with chloroform, washed well with 5% Na2S2O3 solution and the organic layer was dried over anhydrous MgSO4. It was filtered and concentrated. The residue was purified by silica-gel column chromatography by eluting it with 30% ethyl acetate:hexane. The product, namely 2-(1-benzothiophene-3-yl)ethyl iodide, was obtained as brown liquid. Yield: 1.2 g (85%); 285 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][CH:5]=[C:4]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[C:15]([OH:17])=O)[CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[F:33][C:34]([F:38])([F:37])[CH2:35][NH2:36]>ClCCl>[Cl:1][C:2]1[N:7]=[N:6][CH:5]=[C:4]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[C:15]([NH:36][CH2:35][C:34]([F:38])([F:37])[F:33])=[O:17])[CH:3]=1
Reactant: NCC(F)(F)F
Reactant: O=C(O)[C@@H]1CCCC[C@@H]1Nc1cnnc(Cl)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NCC(F)(F)F)[C@@H]1CCCC[C@@H]1Nc1cnnc(Cl)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
(Cis)-2-[(6-chloropyridazin-4-yl)amino]cyclohexanecarboxylic acid I-22b (2.2 g, 8.60 mmol), HOBT (2.64 g, 17.21 mmol), EDC (3.30 g, 17.21 mmol) and trifluoroethyl amine hydrochloride (2.332 g, 17.21 mmol) were added to DCM (30.0 ml) followed by the addition of TEA (6.00 ml, 43.0 mmol). The slurry was allowed to stir at RT for 17 hr. The reaction was diluted with dichloromethane washed with sat. sodium bicarb., brine dried with sodium sulfate and concentrated to an oil. Purification on Biotage Normal Phase system (DCMeOH, 0-8% B) afforded the product I-22 as a solid. (1.56 g, 51.2%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][C:22]=2[CH2:31][NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])[N:16]=1)([CH3:3])[CH3:2].C1COCC1.[Li][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1.O>CCOCC>[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]=1[NH:13][CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][C:22]=2[CH2:31][NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])[N:16]=1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)([CH3:12])[CH3:11]
Reactant: [Li]c1ccccc1
Reactant: Cc1ccccc1NCc1ccc2ccccc2c1-c1cccc(C=Nc2c(C(C)C)cccc2C(C)C)n1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1NCc1ccc2ccccc2c1-c1cccc(C(Nc2c(C(C)C)cccc2C(C)C)c2ccccc2)n1
Temperature: -78 °C

Procedure:
To a solution of 1.30 g (2.54 mmol) of (2,6-diisopropylphenyl){[6-(2-{[(2-methylphenyl)amino]methyl}-1-naphthyl)pyridin-2-yl]methylene}amine in 20 ml of THF 8.60 ml (6.35 mmol) of 0.74 M PhLi in ether was added by vigorous stirring at −78° C. The reaction mixture was stirred for 10 minutes at room temperature, then 2 ml of water was added, and, finally, this mixture was poured into 50 ml of water. The product was extracted with 3×20 ml of ether. The organic extract was washed by 2×30 ml of water, dried over K2CO3, and then evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um; eluent: hexanes-ethyl acetate=5:1, vol.). Yield 1.30 g (86%) of yellow oil which crystallized at room temperature. Anal. calc. for C42H43N3: C, 85.53; H, 7.35; N, 7.12. Found: C, 85.72; H, 7.39; N, 6.95. For 1H NMR (in CDCl3) see FIG. 3—Top spectrum.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3]1.[H-].[Na+].I[CH3:19]>C1COCC1>[CH3:19][O:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:3]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@H]1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
To a solution of tert-butyl (1R,3S)-3-hydroxycyclohexylcarbamate (1.78 g, 8.27 mmol) in anhydrous THF (8 mL) was added sodium hydride (0.230 g, 9.09 mmol) in portions under nitrogen at 0° C. The mixture was warmed to room temperature and stirred for 30 min. A solution of iodomethane (0.824 mL, 13.23 mmol) in anhydrous THF (4 mL) was added drop wise to the mixture at 0° C. and the resulting mixture was stirred at room temperature for 20 h. The crude mixture was quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo, and then purified by silica gel chromatography (0-50% ethyl acetate in hexanes). The product fractions were combined and concentrated to afford tert-butyl (1R,3S)-3-methoxycyclohexylcarbamate (1.0686 g, 4.66 mmol, 56.4% yield) as a white solid; MS (ESI) m/z 230.5 [M+1]+.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)=[CH:5][N:4]=1.[CH3:22]I.[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)[CH3:22])=[CH:5][N:4]=1
Reactant: Cc1nc(Nc2ccc(N(C)C)nc2)c2ccccc2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(N(C)c2ccc(N(C)C)nc2)c2ccccc2n1

Procedure:
The title compound was prepared from (2-dimethylamino-pyridine-5-yl)-(2-methyl-quinazolin-4-yl)-amine (45 mg, 0.16 mmol), methyl iodide (0.016 ml, 0.24 mmol), sodium hydride (9.6 mg, 0.24 mmol, 60% oil dispersion) in DMF similar to example 49 to give 22 mg (47%) of paint yellow solids. 1H NMR (CDCl3): 8.07 (d, J=2.4 Hz, 1H), 7.63 (dd, J=0.9 Hz, J=8.4 Hz, 1H), 7.56-7.51 (m, 1H), 7.27-7.18 (m, 2H), 7.05-7.00 (m, 1H), 6.50 (d, J=9.3 Hz, 1H), 3.55 (s, 3H), 3.12 (s, 6H), 2.72 (s, 3H).
Reaction SMILES: COC1C=CC2C(C)CN(C(=O)C(F)(F)F)CCC=2N=1.P(Cl)(Cl)(Cl)(Cl)Cl.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+].[Cl:37][C:38]1[C:55]([O:56][CH3:57])=[N:54][C:41]2[CH2:42][CH2:43][N:44](C(=O)C(F)(F)F)[CH2:45][CH:46]([CH3:47])[C:40]=2[CH:39]=1.C([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl>[Cl:37][C:38]1[C:55]([O:56][CH3:57])=[N:54][C:41]2[CH2:42][CH2:43][NH:44][CH2:45][CH:46]([CH3:47])[C:40]=2[CH:39]=1
Reactant: COc1nc2c(cc1Cl)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: COc1ccc2c(n1)CCN(C(=O)C(F)(F)F)CC2C
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Product: COc1nc2c(cc1Cl)C(C)CNCC2
Temperature: 125 °C

Procedure:
A mixture of 2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (100 mg, 347 μmol), PCl5 (722 mg, 3.47 mmol) and POCl3 (10 ml) was heated at 125° C. in a sealed tube for 16 h. The reaction mixture was parted between DCM and sat. aq. NaHCO3. The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. Chromatographic purification rendered 23.5 mg (21%) of 3-chloro-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. A mixture of 3-chloro-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (23.5 mg, 72.8 μmol) and K2CO3 (30 mg) in MeOH (7 ml) was heated at reflux for 2 h. The reaction mixture was concentrated in vacuo and chromatographic purification of the resulting residue rendered 11.2 mg (68%) of 3-chloro-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 7.48 (s, 1H), 3.99 (s, 3H), 3.55-3.30 (m, 4H), 3.25 (m, 1H), 3.07 (m, 1H), 2.85 (dd, 1H), 1.43 (d, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:14]1(C)[CH:19]=CC=C(S(O)(=O)=O)[CH:15]=1.C(O)C=C>C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([O:7][CH2:19][CH:14]=[CH2:15])=[O:6]
Reactant: O=C(O)c1cc(F)cc([N+](=O)[O-])c1
Reactant: Cc1cccc(S(=O)(=O)O)c1
Solvent: C=CCO
Solvent: CCN(CC)CC
Product: C=CCOC(=O)c1cc(F)cc([N+](=O)[O-])c1
Reaction time: 16 h

Procedure:
3-Fluoro-5-nitrobenzoic acid (3 g, 16.2 mM), m-toluenesulfonic acid (1.54 g, 8.1 mM), and allyl alcohol (50 ml) were heated to reflux, passing the distillate through 3å molecular sieves, for 16 hours. After cooling, the mixture was neutralised with triethylamine, and solvent removed. The residue was dissolved in ethyl acetate, washed with 2M hydrochloric acid, aqueous NaHCO3, and brine, and dried over MgSO4. Crude product was purified by chromatography on silica, using a gradient elution from dichloromethane to ethyl acetate/dichloromethane (3:1), to give allyl 3-fluoro-5-nitrobenzoate. Nmr (CDCl3): δ4.89 (dt, 2H); 5.33-5.49 (m, 2H); 5.95-6.15 (m, 1H); 8.11 (m, 2H); 8.70 (t, 1H).
Reaction SMILES: [C:1]([CH:3]([C:5]1[C:14]([CH3:15])=[CH:13][C:12]2[C:11]([CH3:17])([CH3:16])[CH2:10][CH2:9][C:8]([CH3:19])([CH3:18])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].[C:20]([O:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1)(=[O:22])[CH3:21]>>[C:20]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]#[C:1][CH:3]([OH:4])[C:5]2[C:14]([CH3:15])=[CH:13][C:12]3[C:11]([CH3:17])([CH3:16])[CH2:10][CH2:9][C:8]([CH3:19])([CH3:18])[C:7]=3[CH:6]=2)=[CH:26][CH:25]=1)(=[O:22])[CH3:21]
Reactant: C#CC(O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: CC(=O)Oc1ccc(I)cc1
Product: CC(=O)Oc1ccc(C#CC(O)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1
Yield: 24.6 %

Procedure:
Following the basic procedure of Example 11(d), by reacting 1.28 g (5 mmol) of α-ethynyl-5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenemethanol with 1.44 g (5.5 mmol) of 4-iodophenyl acetate, 480 mg (25%) of the expected compound, with a melting point of 129°-130° C., were obtained.
Reaction SMILES: [C@H:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]([CH3:14])[C:12](=[O:15])[CH:11]=[C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:9]=1.Br[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:14][N:13]1[C:12](=[O:15])[CH:11]=[C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:9]=[C:8]1[N:2]1[CH2:3][CH:4]2[CH2:7][C@H:1]1[CH2:6][N:5]2[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: Brc1cccnc1
Reactant: Cn1c(N2CC3C[C@H]2CN3)nc(-c2ccncc2)cc1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Cn1c(N2CC3C[C@H]2CN3c2cccnc2)nc(-c2ccncc2)cc1=O
Yield: 46.5 %

Procedure:
A mixture containing 0.2 g (0.71 mmol) of (1S)-2-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one, 3.335 g (2.12 mmol) of 3-bromopyridine, 0.322 g (0.99 mmol) of cesium carbonate, 18 mg (0.028 mmol) of (±)-2,2′-bis(diphenylplhosphino)-1,1′-binaphthyl and 6 mg (0.028 mmol) of palladium(II) acetate in 100 ml of anhydrous tetrahydrofuran under argon atmosphere is stirred under reflux for 18 h. The mixture is filtered. Water is added to the filtrate and the resulting solution extracted with chloroform. The combined extracts are washed with saturated aqueous ammonium chloride and evaporated. The crude product is purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol in the proportions 100/0 to 95/5 to give 119 mg of pure compound as a solid.
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([N:10]2[C:14]([CH3:15])=[C:13]([C:16](Cl)=[O:17])[CH:12]=[N:11]2)[CH:5]=1.[NH3:20]>O1CCCC1>[F:1][CH:2]([F:19])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH2:20])=[O:17])[CH:12]=[N:11]2)[CH:5]=1
Reactant: Cc1c(C(=O)Cl)cnn1-c1cc(OC(F)F)n(C)n1
Reactant: N
Solvent: C1CCOC1
Product: Cc1c(C(N)=O)cnn1-c1cc(OC(F)F)n(C)n1

Procedure:
0.98 g (3.38 mmol) 1-(5-Difluoromethoxy-1-methyl-3-pyrazolyl)-5-methyl-4-pyrazolecarbonyl chloride was dissolved in 20 ml tetrahydrofuran and 50 ml aqueous ammonia (33%) was added with stirring. After stirring for 3 hours at room temperature, the mixture was concentrated to half and acidified with dilute hydrochloric acid. The precipitate was suction filtered off, washed with a small amount of water and dried.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH:5]([NH:22][C:23]([C:25]1([NH:30][C:31](=[O:40])[CH:32]([S:36][C:37](=[O:39])[CH3:38])[CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)=[CH:11][CH:12]=1)[CH3:2].[CH3:42][CH2:43][OH:44]>[Pd]>[CH2:1]([O:3][C:4](=[O:41])[CH:5]([NH:22][C:23]([C:25]1([NH:30][C:31](=[O:40])[CH:32]([S:36][C:37](=[O:39])[CH3:38])[CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:43](=[O:44])[CH3:42])[CH:14]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(-c2cccc([N+](=O)[O-])c2)nc1)NC(=O)C1(NC(=O)C(SC(C)=O)C(C)C)CCCC1
Reactant: CCO
Agent: [Pd]
Product: CCOC(=O)C(Cc1ccc(-c2cccc(NC(C)=O)c2)nc1)NC(=O)C1(NC(=O)C(SC(C)=O)C(C)C)CCCC1
Reaction time: 18 h

Procedure:
A suspension of 2-{[1-(2-acetylthio-3-methyl-butanoylamino)-cyclopentanecarbonyl]-amino}-3-[6-(3-nitro-phenyl)-pyridin-3-yl]-propanoic acid ethyl ester (110 mg) and 25 mg of 10% Pd/C in 10 mL of EtOH is stirred under a H2 atmosphere for 18 h. The catalyst is filtered off, and the reaction mixture is concentrated in vacuo. The residue is purified by chromatography on silica gel (50% EtOAc/hexane) to produce yellow product; 1H NMR (250 MHz, CDCl3) δ8.39 (d, 1H), 7.60 (s, 2H), 7.10-7.36 (m, 3H), 6.71 (d, 1H), 6.34 (d, 1H), 4.76 (app q, 1H), 4.15 (q, 2H), 3.62 (dd, 1H), 3.05-3.25 (m, 2H), 2.35, 2.32 (two s, 3H), 1.55-2.40 (m, 9H), 1.19 (t, 3H), 0.92-1.06 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH2:20][CH2:21][CH3:22]>CO.C(OCC)C>[CH2:19]([O:12][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCBr
Reactant: COC(=O)Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: CCCCOc1ccccc1CC(=O)OC
Yield: 65.3 %

Procedure:
16.6 g of methyl 2-hydroxyphenyl acetate are dissolved in 100 ml of methanol. 15 g of potassium carbonate and 18 g of n-butyl bromide are added. After 24 hours of refluxing followed by filtration, the solution is concentrated under reduced pressure. The oil obtained is taken up in diethyl ether and washed with NaHCO3 and H2O. Drying over sodium sulfate and removal of the solvent leaves 14.5 g (65%) of a yellow oil which can be purified by distillation.
Reaction SMILES: C(OC(N1CCC(N[C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[NH2:31][C@@H:32]([CH2:40][OH:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([C@@H:32]([NH:31][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15])[CH2:40][OH:41])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: N[C@@H](CO)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: O=C(N[C@@H](CO)Cc1ccccc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using (R)-phenylalaninol instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 392 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (1H, br. s.) 10.14 (1H, s) 7.98 (1H, d, J=5.47 Hz) 7.72-7.82 (2H, m) 7.40 (1H, d, J=5.37 Hz) 7.28 (1H, dd, J=3.54, 2.22 Hz) 7.14-7.22 (4H, m) 7.10 (1H, ddd, J=6.20, 2.98, 2.73 Hz) 6.73 (1H, d, J=5.52 Hz) 6.39 (1H, dd, J=3.51, 1.66 Hz) 4.82 (1H, t, J=5.56 Hz) 4.13 (1H, ddd, J=14.04, 5.58, 2.98 Hz) 3.42-3.49 (1H, m) 3.38 (1H, t, J=5.78 Hz) 2.84-2.93 (1H, m) 2.73 (1H, dd, J=13.67, 8.93 Hz)
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[C:13]#[N:14].C(N(CC)CC)C.[CH2:22]1[CH2:27][C@@H:26]([NH2:28])[C@H:25]([NH2:29])[CH2:24][CH2:23]1.O>CC#N>[NH2:28][C@@H:26]1[CH2:27][CH2:22][CH2:23][CH2:24][C@H:25]1[NH:29][C:6]1[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]([C:13]#[N:14])=[C:2]([Cl:1])[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(C#N)c1Cl
Reactant: N[C@@H]1CCCC[C@H]1N
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1c(Cl)c(Cl)c(N[C@@H]2CCCC[C@H]2N)c(C#N)c1Cl
Temperature: 25 °C
Yield: 89.8 %

Procedure:
To the suspension of 2,4,5,6-tetrachloro-1,3-dicyanobenzene (2.0 g, 7.52 mmol) and triethylamine (5 ml) in methyl cyanide (40 ml) is added a solution of (1R,2R)-diaminocyclohexane (0.85 g, 7.52 mmol) in methyl cyanide (10 ml). The mixture is mixed for 60 min. at 120° C., then cooled to room temperature and the water (10 ml) is slowly added. After cooling in a refrigerator the solid is recovered on a G4 filter and washed with water-methyl cyanide (1:1) and with methyl cyanide. Finally, the product is vacuum-dried on KOH tablets. 2.32 g (89%) of pale yellow powder are obtained, dec. at a temp. greater than 190° C.
Reaction SMILES: [CH:1]1([CH:6]([OH:17])[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1>ClCCl>[O:17]=[C:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8]
Reactant: O=C(OCc1ccccc1)C(O)C1CCCC1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C(=O)C1CCCC1
Reaction time: 15 h
Yield: 90.7 %

Procedure:
A Dess-Martinn reagent (5.8 g, 13.67 mmol) was added to a solution of benzyl 2-cyclopentyl-2-hydroxyacetate (2.0 g, 8.54 mmol) in dichloromethane (30 ml) at room temperature, and the mixture was stirred for 15 hr. The reaction mixture was quenched with 10% sodium thiosulfate and extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate and saturated brine and was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was chromatographed on silica gel column (hexane:ethyl acetate=95:5) to give the title compound as a light yellow oil (1.8 g, yield 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12](=[O:19])[C:13]3[S:17][CH:16]=[C:15]([Cl:18])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[N:4][CH:3]=1.[C:20](=[O:26])=[N:21]S(Cl)(=O)=O>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12](=[O:19])[C:13]3[S:17][CH:16]=[C:15]([Cl:18])[CH:14]=3)[C:7](=[O:11])[N:8]2[C:20]([NH2:21])=[O:26])=[N:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)cnc2C1C(=O)c1cc(Cl)cs1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Product: NC(=O)N1C(=O)C(C(=O)c2cc(Cl)cs2)c2ncc(Cl)cc21

Procedure:
The title compound was prepared from 6-chloro-3-(4-chloro-2-thenoyl)-4-azaoxindole according to the procedure of Example 2C using 6-chloro-3-(4-chloro-2-thenoyl)-4-azaoxindole (850 mg, 2.7 mmol), N-chlorosulfonyl isocyanate (0.35 mL, 4.0 mmol) and acetonitrile (30 mL). The crude product was recrystallized from acetic acid. Yield: 280 mg (29%).
Reaction SMILES: C[Si](C#N)(C)C.[CH:7](=[O:13])[C:8]1[O:12][CH:11]=[CH:10][CH:9]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>C1COCC1.[I-].[Zn+2].[I-]>[O:12]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:7](=[O:13])[CH2:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH3:27]
Reactant: O=Cc1ccco1
Reactant: Cc1ccccc1CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: Cc1ccccc1CC(=O)c1ccco1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
At 0° C., trimethylsilylcyanide (3.52 mL, 26.4 mmol) was added to a mixture of dried zinc iodide (100 mg) and furfural (1.99 mL, 24.0 mmol), followed by stirring at 0° C. for 30 minutes. THF (20 mL) was added to the reaction mixture, and at −78° C., a 1.0 mol/L solution of lithium hexamethyldisilazide in THF (24.0 mL, 24.0 mmol) was added dropwise thereto, followed by stirring at the same temperature for 15 minutes. A solution (10 mL) of 2-methylbenzyl bromide (2.68 mL, 20.0 mmol) in THF was added to the reaction mixture, followed by stirring at room temperature for 1 hour. 1.0 mol/L tetra(n-butyl)ammonium fluoride (26.4 mL, 26.4 mmol) was added to the reaction mixture, followed by stirring at room temperature for 30 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=4:1) to afford 1-(2-furyl)-2-(2-methylphenyl)ethanone (3.33 g, 83%).
Reaction SMILES: [OH-].[Na+].Cl[S:4]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][CH:8]=1)(=[O:6])=[O:5].[NH:16]([CH2:18][C:19]([OH:21])=[O:20])[CH3:17].C1(C)C=CC=CC=1>O>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([S:4]([N:16]([CH2:18][C:19]([OH:21])=[O:20])[CH3:17])(=[O:6])=[O:5])=[CH:8]1
Reactant: O=S(=O)(Cl)c1csc2ccccc12
Reactant: CNCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CN(CC(=O)O)S(=O)(=O)c1csc2ccccc12
Temperature: 60 °C
Reaction time: 6.5 h

Procedure:
6 g of NaOH, 23.27 g of 3-chlorosulphonyl-benzothiophene and 13.36 g of sarcosine are added to a mixture of 200 ml of toluene and 200 ml of water and stirred for 6.5 hours at 60° C. For working up, the aqueous phase is separated off and the organic phase is extracted with 100 ml of 2 N NaOH solution. The combined aqueous phases are acidified with conc. HCl and then extracted twice with 300 ml of ethyl acetate. After washing with saturated aqueous saline solution and drying over magnesium sulphate the organic phase is concentrated by evaporation. The crude product obtained is recrystallised from 100 ml of dichloroethane. Yield: 13.14 g. M.p.: 139-140° C.