Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]2[C:6]3[C:11]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]5[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=5)=[C:15]([Cl:28])[CH:14]=4)=[N:10][CH:9]=[N:8][C:7]=3[S:29][C:4]=2[CH:3]=1.[CH2:32]([O:34][C:35](=[O:42])[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:33].[H-].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C2C=CC=CC=2)C=CC(P(C(C)(C)C)C(C)(C)C)=CC=1>[CH2:32]([O:34][C:35](=[O:42])[CH:36]([C:2]1[CH:31]=[CH:30][C:5]2[C:6]3[C:11]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]5[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=5)=[C:15]([Cl:28])[CH:14]=4)=[N:10][CH:9]=[N:8][C:7]=3[S:29][C:4]=2[CH:3]=1)[C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:33]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4sc5cc(Br)ccc5c34)cc2Cl)c1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccc(-c2ccccc2)cc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCOC(=O)C(C(=O)OCC)c1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 137.5 °C
Reaction time: 0.33 h
Yield: 75.2 %

Procedure:
To a stirring suspension of (7-bromo-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-amine (150 mg, 0.291 mmol) in malonic acid diethyl ester (2 mL, 2 g, 12.5 mmol) was added sodium hydride (60%, 35.0 mg, 0.874 mmol). The resulting mixture was bubbled with N2 for 2 min, followed by addition of biphenyl-4-yl-di-tert-butyl-phosphane (4.35 mg, 0.015 mmol), and tris(dibenzylideneacetone)dipalladium (13.3 mg, 0.015 mmol). The mixture was bubbled with N2 for an additional 2 min. The reaction mixture was stirred at 135-140° C. for 20 min. It was cooled to rt, and concentrated in vacuo. The residue was purified by chromatography (hexane/EtOAc=2/1 to 1/1) to give the product (130 mg, 75%). 1H-NMR (CDCl3-d) δ 8.56 (s, 1H), 8.05 (d, 1H), 8.00 (s, 1H), 7.82 (b, 1H), 7.74 (s, 1H), 7.66 (d, 1H), 7.49 (q, 1H), 7.34-7.39 (m, 1H), 7.20-7.26 (m, 2H), 6.99-7.05 (m, 2H), 5.18 (s, 2H), 4.80 (s, 1H), 4.20-4.31 (m, 4H), 1.28-1.34 (m, 6H); LCMS RT=4.23 min, [M+H]+=594.1.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]2[N:9]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:11][C:3]=12>C(OCC)(=O)C.C(O)(=O)C.[Zn]>[CH:19]([Si:12]([CH:13]([CH3:15])[CH3:14])([CH:16]([CH3:18])[CH3:17])[N:9]1[C:4]2=[N:5][CH:6]=[C:7]([NH2:8])[CH:2]=[C:3]2[CH:11]=[CH:10]1)([CH3:21])[CH3:20]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)c(N)cnc21
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(N)cnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
4-Chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (10 g, 32.5 mmol) was dissolved in THF (250 mL) and cooled to −78° C. Sec-Butyllithium ( 54.8 mL, 1.3M/cyclohexane, 71.4 mmol.) was then added dropwise and the solution was stirred for 20 min. A solution of tosylazide (16 g, 81.2 mmol.) in THF (100 mL) was added and the mixture was stirred for 1 h. The reaction mixture was quenched with saturated ammonium chloride (50 mL) and warmed to RT. This mixture was extracted with hexanes (2×200 mL) and the combined organic layers were dried. The organic phase was filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 100% hexanes) to afford 5-azido-4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine as a mixture with starting material (10.2 g). This mixture was directly used in next step. B. 5-Azido-4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (1.6 g, 4.6 mmol) was dissolved in ethyl acetate (100 mL) and Pd/C (10%, 100 mg) was added. This suspension was stirred at RT and under 1 atmosphere. of hydrogen for 18 h. The solid was removed by filtration over Celite® and the solution was evaporated in vacuo. The crude product was purified by flash chromatography (silica gel, 95% hexanes, 5% ethyl acetate) to afford 4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-ylamine (730 mg, 43.5%, 2 steps). C. 4-Chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-ylamine (10.2 g, 31.5 mmol) was diluted in ethyl acetate (200 mL) and acetic acid (100 mL). Zinc dust (50 g, 0.8 mol.) was added in small portions at RT. After stirring the suspension at RT for 4 h, the mixture was filtered over Celite and the filtrate was slowly neutralized with saturated sodium bicarbonate and extracted with ethyl acetate (2×300 mL). The combined organic layers were dried, filtered and evaporated in vacuo. The crude product was purified by flash chromatography (silica gel, 5% ethyl acetate in hexanes) to afford 1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-ylamine (6.38 g).
Reaction SMILES: O.[O:2]=[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5][C:4]1=[CH:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1>CCO.C(OCC)(=O)C>[CH3:21][O:20][C:18](=[O:19])[C:17]1[CH:22]=[CH:23][C:14]([CH2:13][C:4]2[C:3](=[O:2])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][CH:5]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(C=C2COc3ccccc3C2=O)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(Cc2coc3ccccc3c2=O)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
Water (0.2 ml) and RhCl3.H2O (7 mg, 0.034 mmol) was added to a suspension of compound 260 (200 mg, 0.680 mmol) in EtOH (2 ml) and CHCL3 (2 ml). The reaction mixture was stirred 16 h at 70° C. The reaction mixture was cooled down and diluted in ethyl acetate, washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (0.5-1% MeOH/CH2Cl2) to afford the title compound 261 (118 mg, 59%) as a white solid. 1H NMR: (DMSO) δ (ppm): 8.45 (s, 1H), 8.03 (dd, J=7.9, 1.8 Hz, 1H) 7.87 (d, J=8.4 Hz, 2H), 7.83-7.77(m, 1H), 7.65 (d, J=8.3 Hz, 1H), 7.50-7.43 (m3, 1H), 3.82 (s, 3H), 3.80 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:11]=[O:12])[CH:5]=[C:6]([CH:10]=1)C(Cl)=O.[CH2:15]([NH:19][SH:20](=[O:22])=[O:21])[CH2:16][CH2:17][CH3:18].C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:10]=[C:6]([S:20]([NH:19][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:22])=[O:21])[CH:5]=[C:4]([CH:11]=[O:12])[C:3]=1[O:13][CH3:14]
Reactant: CCCCN[SH](=O)=O
Reactant: COc1c(Br)cc(C(=O)Cl)cc1C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCNS(=O)(=O)c1cc(Br)c(OC)c(C=O)c1
Temperature: 25 °C
Yield: 103.1 %

Procedure:
5-Bromo-3-formyl-4-methoxybenzoyl chloride (501 mg, 1.8 mmol) was dissolved in in dichloromethane (5 mL) and the solution was added dropwise to a vigorously stirring solution of N-butylsulfonamide (272 mg, 2.0 mmol), triethylamine (2.5 mmol) and a catalytic amount of N,N′-dimethylaminopyridine (10 mL in dichloromethane). The mixture was stirred at room temperature until the reaction was complete and concentrated under reduced pressure. The residue was partitioned between 5% citric acid and ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and the filtrate was evaporated to give 3-bromo-N-butyl-5-formyl-4-methoxy-benzenesulfonamide as a white solid (650 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1)([O-:25])=[O:24]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:33]([NH:32][C:29]2[CH:28]=[CH:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:31][CH:30]=2)=[O:34])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc([N+](=O)[O-])cc4)cc3)c2cc1OC
Yield: 88.1 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (103 mg) was dissolved in toluene (10 ml) with heat, 4-nitrophenyl isocyanate (366 mg) was added, and the admixture was refluxed with heat for 60 minutes. The separated crystals were filtered and washed with toluene to obtain 141 mg of the title compound (yield: 88%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:42])([CH3:41])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:40])([C@@:17]4([CH3:39])[CH:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([C:36]([OH:38])=O)[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4].C(Cl)(=O)C([Cl:46])=O>ClCCl>[Cl:46][C:36]([C@:20]12[CH2:32][CH2:31][C@@H:30]([C:33]([CH3:35])=[CH2:34])[C@@H:21]1[C@@H:22]1[C@@:17]([CH3:39])([CH2:18][CH2:19]2)[C@@:16]2([CH3:40])[C@@H:25]([C@:26]3([CH3:29])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:41])([CH3:42])[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[CH:28][CH2:27]3)[CH2:24][CH2:23]1)=[O:38]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)C(CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)Cl)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a flask containing (1R,3aS,5aR,5bR,7aR,11aS,11bR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (0.1-4.2 mmol scale) was added oxalyl chloride (2M in dichloromethane) (10-50 equiv.). The solution was stirred at rt for 2-5 h and was stripped of solvent. The residue was dissolved in dichloromethane and concentrated two additional times, then was used with no additional purification in the next step. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.92 (d, J=8.55 Hz, 2H), 7.19 (d, J=8.24 Hz, 2H), 5.26-5.30 (m, 1H), 4.73 (d, J=1.53 Hz, 1H), 4.62-4.64 (m, 1H), 3.90 (s, 3H), 2.81 (td, J=11.14, 4.58 Hz, 1H), 2.47 (ddd, J=13.58, 3.20, 3.05 Hz, 1H), 2.19-2.28 (m, 2H), 2.10 (dd, J=17.09, 6.41 Hz, 1H), 1.85-1.99 (m, 1H), 1.68 (s, 3H), 1.00 (s, 6H), 0.98 (s, 3H), 0.92 (s, 3H), 0.92 (s, 3H), 0.84-1.83 (m, 17H). 13C NMR (126 MHz, CHLOROFORM-d) δ ppm 177.49, 167.35, 149.46, 148.81, 146.39, 130.17 (s, 2C), 128.61 (s, 2C), 128.03, 124.12, 110.40, 68.00, 52.99, 52.11, 49.78, 49.67, 46.11, 42.54, 41.86, 40.70, 38.00, 37.60, 36.39, 36.31, 33.64, 32.3, 29.98, 29.72, 29.54, 25.60, 21.37, 21.13, 19.86, 19.48, 16.59, 15.71, 14.89.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][CH2:13][CH2:14][C:15]([OH:18])([CH3:17])[CH3:16])(=[O:11])=[O:10])=[CH:5][CH:4]=1.O.[C:22](Cl)(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([O:18][C:15]([CH3:16])([CH2:14][CH2:13][O:12][S:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:8][CH:7]=1)(=[O:11])=[O:10])[CH3:17])(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: CC(C)(O)CCOS(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)OC(C)(C)CCOS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
To a mixture of the alcohol 4 (0.500 g, 1.6 mmol), ZrOCl28.H2O (0.0025 g, 0.5 mol %) in methylene chloride (5 mL), acetyl chloride (0.251 g, 3.2 mmol) is added and the reaction is stirred for overnight at 20° C. The reaction on completion, is diluted with methylene chloride (5 mL) and washed with saturated sodium bicarbonate (2×10 mL), brine (1×10 mL) and dried. The solvent is evaporated to get the crude product. 1H NMR (400 MHz, CDCl3) δ1.56 (d, J=8.0, 6H), 1.60 (d, J=8.0, 5H), 2.14 (t, J=6.8, 2H), 4.33 (t, J=6.8, 2H), 7.82 (d, J=8.1, 2H), 8.04 (d, J=8.0, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][O:17][C:16]2=[O:20])=[CH:11][C:10]=1[CH:21]1[CH2:30][C:29]([CH3:32])([CH3:31])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:33](O)=[O:34])[CH:27]=2)[NH:22]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][O:17][C:16]2=[O:20])=[CH:11][C:10]=1[CH:21]1[CH2:30][C:29]([CH3:31])([CH3:32])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:33]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:34])[CH:27]=2)[NH:22]1
Reactant: CS(N)(=O)=O
Reactant: CC1(C)CC(c2cc(N3CCOC3=O)ccc2Cl)Nc2ccc(C(=O)O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cc(N3CCOC3=O)ccc2Cl)Nc2ccc(C(=O)NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.9 %

Procedure:
To a suspension of 60% sodium hydride (70 mg, 1.75 mmol) in N,N-dimethylformamide (3 mL) was added methanesulfonamide (166 mg, 1.75 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A26. A solution of 2-[2-chloro-5-(2-oxo-oxazolidin-3-yl)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.25 mmol) and 1,1′-carbonyldiimidazole (81 mg, 0.5 mmol) in N,N-dimethylformamide (2 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B26. Solution B26 was added to Solution A26 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-{2-[2-chloro-5-(2-oxo-oxazolidin-3-yl)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-methanesulfonamide (13 mg, 11%) as a white solid: MS (ESI) M+1=478.0.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][OH:27]>CC(=O)CC>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:24][CH2:25][CH2:26][OH:27])=[CH:12][CH:11]=1
Reactant: OCCCBr
Reactant: Oc1ccc(CCOC2CCCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: OCCCc1ccc(CCOC2CCCCO2)cc1
Yield: 73.6 %

Procedure:
To a solution of 4-(2-tetrahydropyran-2-yloxyethyl)phenol (9, 8.0 g, 36 mmoles) in 2-butanone (100 mL) were added K2CO3 (10.0 g, 72 mmoles) and 3-bromopropanol (6.5 mL, 72 mmoles). The solution was refluxed 18 hours with mechanical stirring. After cooling, the mixture was filtered and the solvent removed under reduced pressure to afford 13.0 g of crude oil. This was purified by flash chromatography on silica gel (solvent=80:20 ethyl acetate:heptane). The pure fractions were pooled and the solvent removed in vacuo to give 7.0 g of 1-[2-(tetrahydropyran-2-yloxy)ethyl]-4-(3-hydroxypropy)benzene (10). NMR (CDCl3)δppm: 7.0(q, 4H); 4.58(s, 1H)' 4.3-3.3(m, 8H); 3.06(s, 1H); 2.83(t, 2H); 1.83(m, 2H); 1.63(m, 6H). (Scheme II, Step 5.)
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].CCO>[CH:16]1([C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])[CH2:17][CH2:18]1
Reactant: O=C(C1CC1)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C(C1CC1)N1CCNCC1
Reaction time: 8 h
Yield: 96.9 %

Procedure:
10% Palladium on carbon (175 mg, 10% by wt.) was placed under an inert atmosphere and suspended in EtOH (5 mL). A solution of (4-benzyl-piperazin-1-yl)-cyclopropyl-methanone (1.75 g, 7.16 mmol) dissolved in EtOH (25 mL) was added. The reaction mixture was placed under H2 atmosphere (1 atmosphere pressure) and stirred overnight. The resulting mixture was filtered through a pad of Celite® and the solvent was concentrated in vacuo to give 1.07 g (97%) of the title compound as a clear oil. 1H-NMR (300 MHz, CD3OD) 3.74 (broad s, 2H), 3.57 (broad s, 2H), 2.87 (broad s, 2H), 2.80 (broad s, 2H), 1.97 to 1.91 (m, 1H), 0.89 to 0.78 (m, 4H); ES-MS m/z 154.9 [M+H]+, RT (min) 1.02.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH2:14][OH:15])[CH2:8][CH2:7][C:6]=2[C:16]=1[O:17][CH3:18].Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)(=[O:35])=[O:34])[C:23]([Cl:41])=[CH:22][N:21]=1>>[Cl:41][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)(=[O:35])=[O:34])=[N:25][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH2:14][OH:15])[CH2:8][CH2:7][C:6]=3[C:16]=2[O:17][CH3:18])=[N:21][CH:22]=1
Reactant: COc1c(N)ccc2c1CCC(NCCO)CC2
Reactant: O=S(=O)(c1ccccc1Nc1nc(Cl)ncc1Cl)N1CCCC1
Product: COc1c(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CCCC3)n2)ccc2c1CCC(NCCO)CC2
Yield: 27 %

Procedure:
In an analogous manner to Experimental 691, part c, 2-(2-amino-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ylamino)-ethanol and (2,5-dichloro-pyrimidin-4-yl)-[2-(pyrrolidine-1-sulfonyl)-phenyl]-amine were combined to yield 2-(2-{5-Chloro-4-[2-(pyrrolidine-1-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ylamino)-ethanol (105.68 mg, 27% yield) as a brown foam. 1H-NMR (CDCl3) δ 9.75 (2 s, 1H), 8.65 (dd, J=8.6 8.2 Hz, 1H), 8.15 (s, 1H), 7.96 (m, 2H), 7.58 (m, 1H), 7.48 (s, 1H), 7.23 (m, 1H), 6.82 (d, J=7.7 Hz, 1H), 5.30 (s, 1H), 3.73 (s, 3H), 3.26 (br s, 5H), 2.83 (m, 3H), 2.70 (m, 3H), 2.70 (m, 1H), 2.48 (m, 1H), 2.22 (m, 7H, 1.31 (m, 2H). LC/MS (ESI+)=587 (M+H).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:29][CH3:30])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[N:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[S:20][CH:21]=2)[C:12]1=[O:28])[C:4]([O:6]C(C)(C)C)=[O:5].[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>ClCCl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH3:1][C@@H:2]([CH2:29][CH3:30])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[N:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[S:20][CH:21]=2)[C:12]1=[O:28])[C:4]([OH:6])=[O:5]
Reactant: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CCN(Cc2csc(-c3ccccn3)n2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2csc(-c3ccccn3)n2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution containing the product of Example 3K (0.214 g, 0.50 mmol) in dichloromethane (2 mL) was treated with trifluoracetic acid (2 mL), stirred at 25° C. for 1 hour and concentrated. The residue was chromatographed on silica gel eluting with 0-15% methanol in dichloromethane to give the title compound (0.24 g) as the trifluoroacetic acid salt.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[O:18][CH:17]=[N:16][CH:15]=3)[CH:12]=2)[NH:7][C:6]1=[O:19])C.Cl.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[O:18]1[C:14]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:19])[C:5]3=[CH:4][NH:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:29])=[O:30])=[CH:24][CH:23]=2)=[CH:15][N:16]=[CH:17]1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CCOC=C1C(=O)Nc2ccc(-c3cnco3)cc21
Agent: Cl
Product: NS(=O)(=O)c1ccc(NC=C2C(=O)Nc3ccc(-c4cnco4)cc32)cc1
Yield: 68 %

Procedure:
The title compound was prepared in 68% yield from ethoxymethylene-5-oxazol-5-yl-1,3-dihydro-indol-2-one and 4-aminobenzenesulfonamide hydrochloride according to Procedure J: 1H NMR (DMSO-6): δ 10.79 (d,1H), 10.73 (s, 1H), 8.76 (d, 1H), 8.38 (s, 1H), 8.0 ( s, 1H), 7.77 (d, 2H), 7.56 ( d, 2H), 7.43 (s, 1H), 7.40 (d, 1H), 7.26 (s, 2H), 6.91 (d, 1H); APCI−MS: m/z 381 (MH)−.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.C(OC([NH:45][C@@H:46]([CH2:50][C:51]([OH:53])=[O:52])[C:47](O)=[O:48])=O)(C)(C)C>>[NH2:45][C@H:46]([C:47]([N:29]1[CH2:28][CH2:27][C:26]([CH2:25][NH:24][C:22](=[O:23])[C:3]2[C:2]([F:1])=[C:7]([S:8][C:9]3[S:13][C:12]([NH:14][C:15]4[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=4)=[N:11][CH:10]=3)[CH:6]=[CH:5][N:4]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:31][CH2:30]1)=[O:48])[CH2:50][C:51]([OH:53])=[O:52]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)O
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCNCC4)c3F)s2)c1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCN(C(=O)[C@@H](N)CC(=O)O)CC4)c3F)s2)c1

Procedure:
Following the procedure given for example 94, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)-N-((4-phenylpiperidin-4-yl)methyl)picolinamide (compound example 11) was reacted with (S)-2-(tert-butoxycarbonylamino)succinic acid give the title compound. LC/MS (M+H)+: 650. Ret. time: 1.12 min. (Condition G); analytical HPLC Ret. time: 6.33 min (Condition Q).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]=O)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1([C:22]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:23]2[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1CCCC1>>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[CH:14]=[C:27]2\[CH2:28][N:23]([C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:24][CH2:25][C:26]\2=[O:29])[N:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1nc(C=O)cs1
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)Nc1nc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2=O)cs1
Yield: 36.2 %

Procedure:
Following a procedure similar to that described in Example 132-(c), 2-(t-butoxycarbonylamino)-1,3-thiazole-4-carbaldehyde (3.2 g) was subjected to the reaction with 1-(triphenylmethyl)piperidin-4-one (4.8 g) and pyrrolidine (0.24 ml), and the crude product was purified by silica gel chromatography using hexane, ethyl acetate, and dichloromethane (1:3:1 to 1:5:1) as eluents to afford the title compound (2.8 g, yield: 36%) as an oil.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20]([O:24][C:25]([N:27]1[CH2:31][CH2:30][C@H:29]([C:32]([OH:34])=[O:33])[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[C:20]([O:24][C:25]([N:27]1[CH2:31][CH2:30][C@H:29]([C:32]([O:34][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:33])[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)O)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H](C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
DBU (0.764 mL) was added to a mixture of benzyl bromide (0.61 mL), (S)-1-tert-butoxycarbonyl-pyrrolidine-3-carboxylic acid (1 g) in anhydrous toluene (10 mL) and the mixture was stirred at room temperature for 24 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-35% to give benzyl (S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylate (0.859 g)