Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:9]([OH:16])[CH2:10][NH:11]OC(C)C)([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([NH:29][C:30]1[NH:31][C:32]2[CH:38]=[C:37]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:35][C:33]=2[N:34]=1)(=[O:28])=[O:27]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C@@H:9]([OH:16])[CH:10]([NH:11][S:39]([C:37]1[CH:36]=[CH:35][C:33]2[N:34]=[C:30]([NH:29][S:26]([CH3:25])(=[O:28])=[O:27])[NH:31][C:32]=2[CH:38]=1)(=[O:41])=[O:40])[O:5][CH:1]([CH3:3])[CH3:2])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)ONC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Nc1nc2ccc(S(=O)(=O)Cl)cc2[nH]1
Solvent: c1ccncc1
Product: CC(C)OC(NS(=O)(=O)c1ccc2nc(NS(C)(=O)=O)[nH]c2c1)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl-N-((1S,2R)-1-benzyl-3-(isopropyloxy)amino-2-hydroxypropyl)carbamate (86 mg, 0.25 mmol) was combined with 2-[(methylsulfonyl)amino]benzimidazol-5-ylsulfonyl chloride (77 mg, 0.25 mmol) in anhydrous pyridine (1 ml) with a catalytic amount of N,N-dimethylaminopyridine. The reaction was stirred at room temperature overnight. The solvent was evaporated under vacuum. The crude mixture was diluted in EtOAc and washed with water and brine. Organic phase was dried with MgSO4 and solvent was removed in vacuo. Purification by TLC prep (2% MeOH/CH2Cl2). Recovered 56 mg (37%) of product as a white solid. HPLC showed the material to be 98% pure; Ret. time=9.87 min. 1H NMR (CDCl3): 7.12-8.04 (m, 8H), 6.5 (m, 1H), 4.47-4.51 (m, 2H), 3.68 (m, 2H), 3.22 (s, 3H), 2.81-2.88 (m, 3H), 1.75 (m, 2H), 1.22 (s, 9H), 1.16 (d, 6H). MS (ES+): obs. M+H@ 612.1 amu.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[C:8]2[C:12]([O-:14])=[O:13])[CH3:3].[Na+].[C:24]([O:30][CH2:31]I)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].C(OCC)(=O)C>CN(C=O)C>[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)=[C:8]2[C:12]([O:14][CH2:31][O:30][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[O:13])[CH3:3]
Reactant: CC(C)(C)C(=O)OCI
Reactant: COc1ccc(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(C(=O)OCOC(=O)C(C)(C)C)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Yield: 72.5 %

Procedure:
Sodium (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.17 g) was dissolved in dry DMF (1.7 ml) and the solution was ice-cooled. Thereto was gradually dropped pivaloyloxymethyl iodide (0.12 g) in dry DMF (1.2 ml) and the mixture was stirred. Thirty minutes later, ethyl acetate was added thereto and the mixture was washed with bicarbonate solution, water and brine, successively. The organic layer was dried over sodium sulfate, concentrated and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:2˜ethyl acetate only) to give [(2,2-dimethylpropanoyl)oxymethyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.15 g, yield 70%).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=1)([CH3:9])[CH3:8])=[O:5])[CH3:2].[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][CH:28]=2)CC1>>[CH2:1]([O:3][C:4](=[O:5])[NH:6][C:7]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([N:32]2[CH2:33][CH2:34][N:29]([C:26]3[C:25]([CH3:35])=[CH:24][C:23]([CH3:20])=[CH:28][N:27]=3)[CH2:30][CH2:31]2)=[O:16])=[CH:18][CH:19]=1)([CH3:8])[CH3:9])[CH3:2]
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: CCOC(=O)NC(C)(C)c1ccc(C(=O)OC)cc1
Product: CCOC(=O)NC(C)(C)c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cc1
Yield: 84.4 %

Procedure:
Using methyl 4-(1-ethoxycarbonylamino-1-methylethyl)benzoate (174 mg) described in Preparation Example 70 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (157 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 109, the title compound (235 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([NH2:32])=[O:31])[CH:28]=4)[CH:23]=[CH:22]3)[CH2:17][CH2:16]2)=[C:11]2[C:6]([C:7](=[O:33])[CH:8]=[CH:9][O:10]2)=[CH:5][CH:4]=1.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO.O1CCCC1>[OH:33][CH:7]1[C:6]2[C:11](=[C:12]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([C:30]([NH2:32])=[O:31])[CH:28]=5)[CH:23]=[CH:22]4)[CH2:17][CH2:16]3)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:10][CH2:9][CH2:8]1
Reactant: COc1ccc2c(=O)ccoc2c1CCN1CCC(n2ccc3ccc(C(N)=O)cc32)CC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1CCN1CCC(n3ccc4ccc(C(N)=O)cc43)CC1)OCCC2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.2 %

Procedure:
52 mg of 1-(1-(2-(7-methoxy-4-oxo-4H-chromen-8-yl)ethyl)piperidin-4-yl)-1H-indole-6-carboxamide was dissolved in 6 ml of methanol-tetrahydrofuran (1:1). Thereafter, 5 mg of sodium borohydride was added to the reaction solution while cooling on ice. The obtained mixture was then stirred at room temperature for 2 hours. Thereafter, 5 mg of sodium borohydride was added to the reaction solution, and further, 5 mg each of sodium borohydride was added thereto 2 hours and 4 hours later. Thereafter, the reaction solution was stirred at the same temperature overnight. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by extraction with chloroform. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate-methanol), so as to obtain 30 mg of the subject compound.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[Br:19][CH:20](Br)[CH3:21]>O1CCCC1.CCCCC>[Br:19][CH2:20][CH2:21][C:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(Br)Br
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: BrCCc1cccc2c1Cc1ccccc1-2
Reaction time: 1 h

Procedure:
In this reaction, 8.3 g (0.05 m) of fluorene was dissolved in 150 ml of tetrahydrofuran. Then 31.8 ml (0.05 m) of butyl lithium (1.6 molar in hexane) was added dropwise to this solution. After one hour, this solution was added gradually to a stirred solution of 9 ml (0.1 m) of dibromoethane in 300 ml of pentane within 2 hours. Then the reaction mixture was treated with 50 ml of an
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:18])[CH2:16]Br)=[CH:11][C:10]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].[N-:26]=[N+:27]=[N-:28].[Na+]>CS(C)=O>[N:26]([CH2:16][C@@H:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:11]=1)[OH:18])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)Nc1cc(C(O)CBr)ccc1OCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CN=[N+]=[N-])ccc1OCc1ccccc1
Reaction time: 120 h
Yield: 93.3 %

Procedure:
To a stirred solution of N-[2-benzyloxy-5-(2-bromo-1-hydroxy-ethyl)-phenyl]-methanesulfonamide (Washburn, W. N., et al., EP 0 659 737) (15.05 g, 38 mmol) in dimethyl sulfoxide (150 ml) was added sodium iodide (3.76 g, 376 mmol) and sodium azide (9.48 g, 150 mmol). The mixture was stirred for 5 days under nitrogen atmosphere. The reaction mixture was poured onto water and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The residue was triturated with water and hexanes to give the title compound as a yellow solid (12.85 g, 94%): 1H NMR (300 MHz, CDCl3) δ2.93(s, 3 H), 3.47(d, J=5.4 Hz, 2 H), 4.84(t, J=5.4 Hz, 1 H), 5.11(s, 2 H), 6.80(s, 1 H), 6.99(d, J=8.4 Hz, 1 H), 7.15(dd, J=8.4 Hz, 2.1 Hz, 1H), 7.26(s, 1 H), 7.30-7.50(m, 5 H), 7.53(d, J=2.1 Hz, 1 H); MS (ES) m/z 361.4 ((MH)−, 70%).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:14][C@H:13]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:19]=2)=[O:17])[C:12]2[C:7](=[CH:8][C:9]([Cl:34])=[CH:10][C:11]=2[Cl:33])[NH:6]1)=[O:4].[OH-].[Li+]>O1CCCC1.O>[C:3]([C@H:5]1[CH2:14][C@H:13]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH:19]=2)=[O:17])[C:12]2[C:7](=[CH:8][C:9]([Cl:34])=[CH:10][C:11]=2[Cl:33])[NH:6]1)([OH:4])=[O:2]
Reactant: COC(=O)[C@H]1C[C@H](NC(=O)c2cccc(CNC(=O)OC(C)(C)C)c2)c2c(Cl)cc(Cl)cc2N1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cccc(C(=O)N[C@H]2C[C@H](C(=O)O)Nc3cc(Cl)cc(Cl)c32)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of trans-2-methoxycarbonyl-5,7-dichloro-4-(3-tert-butyloxycarbonylaminomethylphenyl)carbonylamino-1,2,3,4-tetrahydroquinoline (step b) (430 mg, 0.846 mmol) in a mixture of tetrahydrofuran (20 ml) and water (10 ml) was added aqueous lithium hydroxide (1.95 ml of a 0.5M solution, 0.973 mmol), and the resulting mixture was stirred at room temperature for 3 h. The organic solvent was removed in vacuo and the aqueous residue was diluted to 50 ml before acidifying to pH 1 with 1N HCl. The white precipitate was extracted into ethyl acetate (150 ml), washed with brine and dried (Na2SO4). The solution was evaporated to give a residue which was washed with diethyl ether and collected by filtration to give the title compound as a colourless crystalline solid, m.p. 192°-193° C. δ (DMSO, 360 MHz) 1.39 (9H, s, C(CH3)3, 1.73 (1H, ddd, 13.2, 13.0 and 3.8 Hz, CHACHBHCCHD), 2.26 (1H, dm, J=13.2 Hz, CHACHBHCCHD), 3.96 (1H, dd, J=13.0 and 3.0 Hz, CHACHBHCCHD), 4.14 (2H, d,J=5.6 Hz, ArCH2NH), 5.26 (1H, m, CHACHBHCCHD), 6.65 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.82 (1H, br s, ArNHCO), 6.91 (1H, d, J=2.0 Hz, 6-H or 8-H). 7.36-7.37 and 7.72-7.76 (5H, m, Ar-H and CH2NHCO), 8.66 (1H, d, J=7 Hz, NHCOAr); m/e (FAB+), 494 (M+1), 93 (100%); Found C, 55.92; H, 5.22; N, 8.35; C23H25Cl2N3O5 requires C, 55.88; H, 5.10; N, 8.50%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@@H:8]([O:21][Si:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:9][N:10]([CH2:18][CH2:19][OH:20])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.O[C:30]1[CH:38]=[C:37]2[C:33]([C:34]([CH:46]3[CH2:48][CH2:47]3)=[N:35][N:36]2[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C(=O)([O-])[O-]>C1(C)C=CC=CC=1.C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[C:4]([C@@H:8]([O:21][Si:22]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:27][CH3:28])[CH2:9][N:10]([C:11]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:17])[CH2:18][CH2:19][O:20][C:30]2[CH:38]=[C:37]3[C:33]([C:34]([CH:46]4[CH2:48][CH2:47]4)=[N:35][N:36]3[C:39]([O:41][C:42]([CH3:44])([CH3:45])[CH3:43])=[O:40])=[CH:32][CH:31]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)n1nc(C2CC2)c2ccc(O)cc21
Reactant: CC[Si](CC)(CC)O[C@@H](CN(CCO)C(=O)OC(C)(C)C)c1cccc(N)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C([O-])[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC[Si](CC)(CC)O[C@@H](CN(CCOc1ccc2c(C3CC3)nn(C(=O)OC(C)(C)C)c2c1)C(=O)OC(C)(C)C)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
(R)-Tert-butyl 2-(3-aminophenyl)-2-(triethylsilyloxy)ethyl(2-hydroxyethyl)carbamate (1.6143 g) which can be prepared according to the method described in Reference example 59, etc. and tert-butyl 6-hydroxy-3-cyclopropylindazole-1-carboxylate (924 mg) which can be prepared according to the method described in Reference example 7, etc. and triphenylphosphine (1.1419 g; manufactured by Kanto Chemical Co., Inc.) were dissolved in dehydrated toluene (18 mL), added with DIAD (808 μL; manufactured by Sigma-Aldrich Co.), and stirred overnight at room temperature. The reaction solution was purified by column chromatography (“COLUMN-A”; n-hexane:ethyl acetate=82:18→61:39) to obtain a crude product (1.669 g), which was then dissolved in CH2Cl2 (20 mL). After adding MP-Carbonate [5.15 g (2.73 mol/g); manufactured by Argonaut] to the mixture, it was stirred overnight at room temperature. After filtering the reaction solution, the filtrate was concentrated under reduced pressure to obtain the title compound (1.0644 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]5[N:36]([S:39]([CH3:42])(=[O:41])=[O:40])[CH:37]=[CH:38][C:31]=45)=[CH:28][N:27](COCC[Si](C)(C)C)[C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.FC(F)(F)C(O)=O.N>>[CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]5[N:36]([S:39]([CH3:42])(=[O:41])=[O:40])[CH:37]=[CH:38][C:31]=45)=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccnc5c3ccn5S(C)(=O)=O)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5ccnc6c5ccn6S(C)(=O)=O)c34)n(-c3ccccc3)c(=O)c12
Yield: 94.9 %

Procedure:
(S)-5-Methyl-2-(1-((5-(1-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (30 mg, 0.04 mmol) was treated with trifluoroacetic acid (1 ml, 13 mmol) and a solution of ammonia (7N in methanol, 1 ml, 60 mmol) according to the method described in Example 27 to give 22 mg (88% yield) of the title compound as a white solid. Purity 98%.
Reaction SMILES: Cl[CH:2]([O:4][C:5](=[O:32])[N:6]([C:29](=[O:31])[CH3:30])[CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[CH3:3].[Cs].[C:34]([NH:41][C@H:42]([C:47]([OH:49])=[O:48])[C@H:43]([CH2:45][CH3:46])[CH3:44])([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].[I-].[Na+]>O.C(#N)C>[C:29]([N:6]([CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[C:5]([O:4][CH:2]([O:49][C:47](=[O:48])[C@@H:42]([NH:41][C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[C@@H:43]([CH3:44])[CH2:45][CH3:46])[CH3:3])=[O:32])(=[O:31])[CH3:30]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OC(C)Cl
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [Cs]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)OC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(C)=O
Temperature: 25 °C
Yield: 79 %

Procedure:
Acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5(R)-ylmethyl}-carbamic acid 1-chloro-ethyl ester (11) (1.00 g, 2.04 mmol), the cesium salt of N-BOC-L-isoleucine (15f) (1.48 g, 4.07 mmol), sodium iodide (0.31 g, 2.07 mmol) and acetonitrile (50 mL) are heated to reflux overnight. After cooling to RT, water is added and the reaction mixture is extracted with EtOAc and then with dichloromethane. The organic phases are washed separately with brine and then the organic layers are combined, dried over MgSO4, filtered, and conc in vacuo. The isolated residue is subjected to silica gel flash chromatography, eluting with MeOH/CH2Cl2 gradient (0-4% MeOH over 1 hour and 30 minutes) to afford the title compound. Isolated yield: 79%. 1H NMR (400 MHz, CDCl3): δ 7.48-7.42 (m, 1H), 7.22-7.17 (m, 1H), 7.14-7.10 (m, 1H), 6.91-6.85 (m, 1H), 5.08 (d, 0.5H), 4.94 (d, 0.5H), 4.81-4.74 (m, 1H), 4.24-3.98 (m, 4H), 3.71-3.64 (m, 1H), 3.13-3.04 (m, 5H), 2.51 (d, 3H), 2.42-2.31 (m, 2H), 2.17-2.13 (m, 2H), 1.84-1.81 (br m, 1H), 1.57 (dd, 3H), 1.52 (s, 1H), 1.38 (d, 9H), 1.21-1.09 (m, 1H), 0.93-0.85 (m, 6H); MS-APCI (m/z+): 341, 385, 586, 686.
Reaction SMILES: [N:1]1([CH:7]=[N:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[OH:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26]>O1CCCC1>[CH3:23][N:24]([CH3:28])[C:25]([O:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[N:8]=[CH:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:26]
Reactant: Oc1cnccc1N=CN1CCCCC1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)Oc1cnccc1N=CN1CCCCC1

Procedure:
A mixture prepared from 4-[[(1-piperidinyl)methylene]amino]-3-pyridinol (3.5 g), triethylamine (3.69 mL), dimethylcarbamyl chloride (2.3 mL) and tetrahydrofuran (130 mL) was refluxed for 2 hours, filtered, poured directly onto a silica column and eluted successively with ethyl acetate and 5% Et3N/ethyl acetate to yield 4.49 g of product. Recrystallization from ethyl acetate and drying under high vacuum yielded 3.94 g of crystals, m.p. 88°-89° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12]O>[Ni]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[CH3:12]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CO
Agent: [Ni]
Product: CC1C(=O)Nc2ccc(F)cc21

Procedure:
3.0 g (20 mmol) 5-fluoro-1,3-dihydro-indol-2-one were stirred with 2.0 g Raney nickel in 50 mL methanol for 1.5 h at 200° C. in an autoclave. The catalyst was filtered off and the filtrate was concentrated to dryness by rotary evaporation. The residue was recrystallised from methanol, suction filtered and dried.
Reaction SMILES: [Br:1][C:2]([CH:9]=[CH2:10])=[CH:3][O:4][Si](C)(C)C.[O:11]([CH:14](OCC)[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:12][CH3:13]>>[Br:1][C:2](=[CH:3][CH2:4][CH:14]([O:11][CH2:12][CH3:13])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=[O:10]
Reactant: C=CC(Br)=CO[Si](C)(C)C
Reactant: CCOC(C=Cc1ccccc1)OCC
Product: CCOC(C=Cc1ccccc1)CC=C(Br)C=O
Reaction time: 2 h

Procedure:
One starts with 2.21 g of 2-bromo-1-trimethylsiloxybut-1,3-diene and 2.06 g of 3,3-diethoxyl-1-phenylprop-1-ene and proceeds in the same manner as in Example 3, except that the reaction is carried out for two hours.
Reaction SMILES: C([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16](OCCCC)=[O:17])[CH:12]=[CH:11][C:10]=1[CH3:23])=O)CCC.O=[Si]=O.[Al]>C(C1C=CC=CC=1)CCCCCCCCCCC>[CH3:23][C:10]1[CH:11]=[CH:12][C:13]([N:15]=[C:16]=[O:17])=[CH:14][C:9]=1[N:8]=[C:6]=[O:5]
Reactant: CCCCOC(=O)Nc1ccc(C)c(NC(=O)OCCCC)c1
Agent: CCCCCCCCCCCCc1ccccc1
Agent: O=[Si]=O
Agent: [Al]
Product: Cc1ccc(N=C=O)cc1N=C=O
Temperature: 320 °C

Procedure:
170 Parts of 2,4-di-(butoxycarbonylamino)-toluene were dissolved in 350 parts of dodecylbenzene. With a feed rate of 300 liters per liter of reaction volume an hour, this solution was fed into a separating reactor of quartz glass filled with an aluminum graulate having a grain size of 1 millimeter to 3 millimeters and heated to a temperature of 320° C. Using 8 liters of nitrogen per liter of reaction mixture an hour as a stripping agent, the butanol resulting from the reaction was separated in a gaseous form and condensed in a vessel cooled with dry ice. This resulted in 443 parts of reaction discharge from which 81 parts of 2,4-toluene diisocyanate (88.2 theoretical percent relative to reacted 2,4-di-(butoxycarbonylamino)-toluene) were obtained by distillation at a temperature between 76° C. and 82° C. and a pressure of 0.2 millibar. The raw material had reacted completely. A mixture of refluxable 2-butoxycarbonylamino-4-isocyanatotoluene and 4-(butoxycarbonylamino)-2-isocyanototoluene was proven in the distillation residue by means of gas chromatography.
Reaction SMILES: [CH:1]([N:4]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:5]1=2)([CH3:3])[CH3:2].Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:40][CH3:41])[C:23]([Cl:42])=[CH:22][N:21]=1>>[Cl:42][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:40][CH3:41])=[N:25][C:20]([NH:16][C:13]2[CH:14]=[CH:15][C:5]3[N:4]([CH:1]([CH3:3])[CH3:2])[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]=3[CH:12]=2)=[N:21][CH:22]=1
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CC(C)N1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Product: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3C(C)C)ncc1Cl
Yield: 42 %

Procedure:
In an analogous procedure to Example 651, part c, 1-isopropyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one was combined with (2,5-Dichloro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine to yield 7-{5-Chloro-4-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-2-ylamino}-1-isopropyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (39.63 mg, 42% yield) as a beige oil. 1H-NMR (CDCl3) δ 8.12 (d, J=8.9 Hz, 1H), 8.02 (s, 1H), 7.50 (d, J=9.5 Hz, 1H), 7.35 (d, J=8.6 Hz, 1H), 7.10 (d, J=8.6 Hz, 1H), 6.92 (s, 1H), 6.56 (s, 1H), 6.49 (d, J=8.9 Hz, 1H), 4.83 (m, 1H), 3.90 (s, 3H), 3.19 (m, 4H), 2.76 (m, 1H), 2.59 (m, 3H), 2.50 (m, 1H), 2.37 (m, 3H), 2.23 (m, 2H), 1.87 (m, 1H), 1.42 (d, J=6.8 Hz, 3H), 1.05 (d, J=7.0 Hz, 3H). LC/MS (ESI+)=550 (M+H).
Reaction SMILES: [CH2:1]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(C1C=CC(N)=CC=1)CCCCCCC.[N:32]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:33]=[O:34].N(CCC(OCC)=O)=C=O>>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH:14][C:33](=[O:34])[NH:32][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCOC(=O)CN=C=O
Reactant: CCCCCCCCc1ccc(CN)cc1
Agent: CCCCCCCCc1ccc(N)cc1
Agent: CCOC(=O)CCN=C=O
Product: CCCCCCCCc1ccc(CNC(=O)NCC(=O)OCC)cc1
Yield: 75 %

Procedure:
When the product of Example 6, Step C was substituted for 4-n-octylaniline and ethyl 2-isocyanatoacetate was substituted for ethyl 3-isocyanatopropionate in Example 11, Step A, the identical process afforded the title compound in 75% yield, as a colourless solid. 1H-NMR (CDCl3) 7.18 (d, 2H, J=8 Hz); 7.11 (d, 2H, J=8 Hz); 4.86 (m, 1H); 4.78 (m, 1H); 4.32 (d, 2H, J=5.6 Hz); 4.16 (q, 2H, J=7.1 Hz); 3.97 (d, 2H, J=5.3 Hz); 2.56 (t, 2H, J=8 Hz); 1.56 (m, 2H); 1.25 (m, 13H); 0.86 (t, 3H, J=6.9 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[Cl:24])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:24][C:16]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=1[O:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cc([N+](=O)[O-])ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Cl)c(OC[C@@H]2CCCN2)c1

Procedure:
(S)-2-(2-Chloro-5-nitro-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (6.94 g, 19.45 mmol) was stirred in 30 mL CH2Cl2 and 20 ml TFA for 3 h. The reaction was concentrated and dissolved in 0.1 N HCl (aq), which was basified to pH>12 with solid NaOH and extracted 3× with EtOAc. The organic layers were washed once with 1 N NaOH then once with a mixture of brine and 1 N NaOH. The organic layers were combined, dried over Na2SO4, filtered, and concentrated to dryness, to yield the title compound as a yellow solid.