Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(O)=O.[NH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH3:16])[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:9]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH2:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][C:29]1=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH:29]1[NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH3:16])[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:9]2[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1c(C)nc2ccc(N)cc2c1-c1ccccc1
Reactant: O=C1Cc2ccccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)nc2ccc(NC3Cc4ccccc4C3)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
A method of Abdel-Magid et al (J. Org. Chem., 61, 3849, 1996) was used: Glacial AcOH (0.25 ml) was added to a solution of the product of Step 2 (1.46 g, 4.4 mmol), 1H-inden-2(3H)-one (0.46 g, 4.5 mmol) and NaBH(OAc)3 (1.4 g, 6.55 mmol) in anhydrous 1,2-dichloroethane (17 ml). The resulting mixture was stirred overnight at room temperature under N2 and to it more of NaBH(OAc)3 (0.4 g, 1.9 mmol) was added. After 2 h of stirring at room temperature, the mixture was quenched by addition of 1N NaOH aq (5 ml). This was diluted to 60 ml with Et2O and washed with H2O and brine. The organic phase was dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (SiO2, CH2Cl2) to give pure product as a creamy solid (1.4 g, 71%). 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=9.0 Hz, 1H), 7.34-7.5(m, 5H), 7.12-7.21(m, 4H), 7.05(dd, J=2.6, 9.0 Hz, 1H), 6.49(d, J=2.6 Hz, 1H), 4.17(m, 1H), 4.08(m, 1H), 3.19-3.27(m 2H), 2.73-2.83(m, 2H), 2.7(s, 3H), 1.22(s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][OH:12].[CH3:13][C:14]([O-])(C)[CH3:15].[K+].C(Br)C=C>C1COCC1.C(OCC)(=O)C>[CH2:15]([O:12][CH2:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[NH2:1])[CH:14]=[CH2:13]
Reactant: Nc1cc([N+](=O)[O-])ccc1CO
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOCc1ccc([N+](=O)[O-])cc1N
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of 2-amino-4-nitrobenzenemethanol (14.3 g, 85 mmol) in dry THF (350 mL) at 0° C. under an argon atmosphere, is treated dropwise over 35 min with a solution of potassium tert-butylate in THF (Fluka; 85 mL of 1.0 M). The mixture is stirred at 0° C. for 15 min and then treated dropwise over 50 min with a solution of allylbromide (7.9 mL, 94 mmol) in dry THF (80 mL) at 0° C. and then stirred at 20° C. for 90 min. The mixture is diluted with ethyl acetate (800 mL). The resulting solution is washed with saturated aqueous ammonium chloride (3×400 mL), dried (MgSO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent 50% ethyl acetate in hexane, to give the title compound as a brown oil.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH:18]=C)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.C[N+]1([O-])CC[O:26]CC1.S(=O)(O)[O-].[Na+]>C1COCC1.O.CC(O)(C)C>[CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH:18]=[O:26])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCN(CC(C)(C)C)c1ccc(C#N)c(C(F)(F)F)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)CN(CC=O)c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 81.3 %

Procedure:
To a solution of 4-[(2,2-dimethylpropyl)(2-propen-1-yl)amino]-2-(trifluoromethyl)benzonitrile (1.46 g, 4.95 mmol) in THF/water (20:1, 45 mL) at rt was added a solution of OSO4 (1.02 g of a 2.5 wt % solution in t-BuOH, 0.10 mmol) in THF/water (20:1, 5 mL), followed by NMO (1.22 g, 10.4 mmol) in one portion. The resulting mixture was stirred 22 hours at rt, cooled to 0° C. and sodium bisulfite (0.300 g) was added in one portion. The mixture was stirred 1 h, filtered through a pad of Celite (EtOAc wash) and the filtrate/washings were partitioned between EtOAc/water (required addition of NaCl to separated layers). The aqueous layer was extracted with EtOAc (×1), combined organics were washed with brine and concentrated in vacuo. The residue was dissolved in acetone (50 mL), a solution of NalO4 (2.22 g; 10.4 mmol) in water (20 mL) was added, the mixture was stirred two hours at rt and partially concentrated in vacuo to an aqueous residue. The residue was partitioned between EtOAc/water and the aqueous layer was further extracted with EtOAc (×1). Combined organics were washed (water, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 1.20 g of the title compound as a colorless solid: 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 7.57 (d, J=8.8 Hz, 1H), 6.96 (d, J=2.5 Hz, 1H), 6.74 (dd, J=8.9, 2.7 Hz, 1H), 4.31 (s, 2H), 3,33 (s, 2H), 1.02 (s, 9H).
Reaction SMILES: ClC(OCC)=O.CC[N:9](CC)CC.[OH:14][B:15]1[C:19]2[C:20]([O:24][CH2:25][CH2:26][CH2:27][C:28](O)=[O:29])=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]([CH2:31][N+:32]([O-:34])=[O:33])[O:16]1.[NH4+].[OH-]>C1COCC1>[OH:14][B:15]1[C:19]2[C:20]([O:24][CH2:25][CH2:26][CH2:27][C:28]([NH2:9])=[O:29])=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]([CH2:31][N+:32]([O-:34])=[O:33])[O:16]1
Reactant: CCN(CC)CC
Reactant: O=C(O)CCCOc1cccc2c1B(O)OC2C[N+](=O)[O-]
Agent: CCOC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)CCCOc1cccc2c1B(O)OC2C[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Ethyl chloroformate (80 μL, 0.83 mmol) was added dropwise to a solution of Et3N (0.35 mL, 4.7 mmol) and 4-(1-hydroxy-3-nitromethyl-1,3-dihydro-benzo[c][1,2]oxaborol-7-yloxy)-butyric acid (111 mg, 0.38 mmol) in THF (4 mL) at 0° C. (bath temp). The mixture was stirred at 0° C. (bath temp) for 15 min and then 28% NH4OH (0.5 mL) was added dropwise at 0° C. (bath temp). The mixture was allowed to warm to rt over 20 min. The precipitate was isolated by filtration and washed with THF and H2O to give the title compound as a light yellow solid: yield 52 mg (45%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[N:9]=[C:10]([N:13]=[C:14]([NH2:16])[NH2:15])[S:11][CH:12]=2)=[CH:5][CH:4]=1.CS[C:19](SC)=[N:20][C:21]#[N:22].[CH3:25][NH2:26]>CN(C)C=O>[NH2:15][C:14](=[N:13][C:10]1[S:11][CH:12]=[C:8]([C:6]2[O:7][C:3]([CH2:2][NH:1][C:19]([NH:26][CH3:25])=[N:20][C:21]#[N:22])=[CH:4][CH:5]=2)[N:9]=1)[NH2:16]
Reactant: NCc1ccc(-c2csc(N=C(N)N)n2)o1
Reactant: CN
Reactant: CSC(=NC#N)SC
Solvent: CN(C)C=O
Product: CNC(=NC#N)NCc1ccc(-c2csc(N=C(N)N)n2)o1
Reaction time: 1 h

Procedure:
A solution of 4-(5-aminomethylfuran-2-yl)-2-(diaminomethyleneamino)thiazole (7.00 g) and dimethyl N-cyanodithioiminocarbonate (4.31 g) in N,N-dimethylformamide (70 ml) was stirred at 70° C. for two hours. 40% Aqueous methylamine by weight (14 ml) was added to the warmed solution and the mixture was stirred for an additional one hour at the same temperature. After the solvent was evaporated in vacuo, the residue was chromatographed on alumina, eluting with a mixture of chloroform and methanol (9:1, V/V), followed by recrystallization from a mixture of methanol, tetrahydrofuran and diisopropyl ether to afford 2-(diaminomethyleneamino)-4-[5-(2-cyano-3-methylguanidino)methylfuran-2-yl]thiazole (4.05 g).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=O)[NH:17][C:18](=O)[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[Br-].[C:22]([C:24]1C=CC=C[C:25]=1C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#N.[Li+].[CH3:51]C([N-]C(C)C)C>>[CH3:51][O:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](/[CH:9]=[CH:8]/[C:7]1[CH:16]=[CH:25][CH:24]=[CH:22][C:6]=1[C:18]#[N:17])=[CH:5]2
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Reactant: N#Cc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)[N-]C(C)C
Agent: [Br-]
Agent: [Li+]
Product: COc1ccc2[nH]c(/C=C/c3ccccc3C#N)cc2c1
Reaction time: 5 h

Procedure:
The 5-methoxy-1H-indole-2-carbaldehyde (1) was reacted with (2-cyanobenzyl)(triphenyl)phosphonium bromide (547) prepared as described in example 136 using the procedure described in example 37, except that the LDA and aldehyde were (sequentially) added at 0° C., the ratio of LDA:aldehyde was 1.55:1 and the reaction time was 5 h, to give (after crystallisation from CH2Cl2/hexane) the diene (548) as a yellow solid (the pure E isomer) (60%), mp 192–196° C. 1H NMR (CDCl3) δ 8.40 (br s, 1H), 7.79 (d, J=8.1 Hz, 1H), 7.66 (dd, J=8.1, 0.9 Hz, 1H), 7.58 (td, J=7.9, 1.3 Hz, 1H), 7.32 (td, J=8.0, 0.9 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.28 (d, J=16.9 Hz, 1H), 7.18 (d, J=16.4 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H), 6.91 (dd, J=8.9, 2.4 Hz, 1H), 6.64 (d, J=1.8 Hz, 1H), 3.86 (s, 3H). Found: C, 79.05; H, 5.16; N, 10.31. C18H14N2O requires C, 78.81; H, 5.14; N, 10.21.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]([F:35])([F:34])[C:24]1[CH:32]=[C:31](F)[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].C[N:37]([CH3:40])C=O>O>[N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[N:10]([C:26]([C:25]3[CH:29]=[CH:30][C:31]([N:37]4[CH:40]=[CH:9][C:8]([CH3:15])=[N:7]4)=[CH:32][C:24]=3[C:23]([F:35])([F:34])[F:22])=[O:27])[CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Reactant: CN(C)C=O
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4cccnc4Nc4ccccc43)c(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Example 1, Step B (10.6 g, 53.8 mmol) in dimethylformamide (125 mL) under nitrogen was added potassium carbonate (22.4 g, 162 mmol). The mixture was cooled and treated dropwise with a solution of crude 2-trifluoromethyl-4-fluorobenzoyl chloride of Step A (81 mmol) in dimethylformamide (25 mL). After stirring at room temperature for 2 hours, the mixture was diluted with water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate and evaporated to dryness. The crude material was dissolved in dichloromethane and purified by flash chromatography (on silica Merck-60, hexane-ethyl acetate 80:20) to provide the pure title compound (6.9 g, 33.1%) which was crystallized by sonication from ethanol-hexane, m.p. 183-185° C.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][CH2:31][CH:30]([C:34](O)=[O:35])[CH2:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34]([CH:30]5[CH2:31][CH2:32][CH2:33][O:28][CH2:29]5)=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)C1CCCOC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)C1CCCOC1

Procedure:
The title compound, white solid (99 mg, 90%), MS (ISP) m/z=443.5 [(M+H)+], mp 203° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and (RS)-tetrahydro-pyran-3-carboxylic acid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:10][N:11]([CH2:21][C:22]2[C:27]([CH3:28])=[CH:26][C:25]([Cl:29])=[CH:24][N:23]=2)[C:12]([CH3:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH3:13])=[C:7]([CH3:9])[CH:8]=1.[CH3:30][C:31](OC(C)=O)=[O:32].CCN(CC)CC.C([O-])(O)=[O:45].[Na+]>C(Cl)Cl>[Cl:29][C:25]1[CH:26]=[C:27]([CH3:28])[C:22]([CH2:21][N:11]([CH2:10][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:31](=[O:32])[CH3:30])=[CH:8][C:7]=2[CH2:9][OH:45])[C:12]([CH3:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH3:13])=[N:23][CH:24]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C([O-])O
Reactant: Cc1cc(CN)ccc1CN(Cc1ncc(Cl)cc1C)C(C)(C)c1ccccn1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc(CN(Cc2ncc(Cl)cc2C)C(C)(C)c2ccccn2)c(CO)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
To a solution of (5-aminomethyl-2-{[(5-chloro-3-methyl-pyridin-2-ylmethyl)-(1-methyl-1-pyridin-2-yl-ethyl)-amino]-methyl}-phenyl)-methane (0.0966 g, 0.23 mmol) in CH2Cl2 (3 mL) was added Ac2O (0.0213 mL, 0.23 mmol), Et3N (0.05 mL, 0.35 mmol), and KI (0.0038 g, 0.02 mmol), and stirred for 18 hours at room temperature. Saturated NaHCO3 (10 mL) was added and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (100:1:1 CH2Cl2-MeOH—NH4OH) provided 0.0573 g (52%) of COMPOUND 403 as a white solid. 1H NMR (CDCl3) δ 1.61 (s, 6H), 2.00 (s, 3H), 2.08 (s, 3H), 3.69 (s, 2H), 3.90 (s, 2H), 4.30 (d, 2H, J=5.4 Hz), 4.53 (s, 2H), 5.65 (s, 1H), 6.69 (s, 1H), 6.94 (d, 1H, J=7.5 Hz), 7.03-7.09 (m, 3H), 7.17 (s, 1H), 7.54 (t, 1H, J=7.8 Hz), 7.75 (d, 1H, J=8.1 Hz), 8.04 (s, 1H), 8.47 (d, 1H, J=6.0 Hz). 13C NMR (CDCl3) δ 18.72, 23.66, 24.47, 43.62, 51.37, 53.92, 63.30, 64.75, 122.16, 122.99, 127.27, 129.31, 130.85, 131.46, 132.38, 136.22, 137.30, 138.04, 138.13, 141.45, 144.53, 147.99, 156.81, 165.70, 170.29. ES-MS m/z 467.2 (M+H). Anal. Calcd. for C26H31N4ClO2.0.1CH2Cl2.0.4H2O: C, 64.94; H, 6.68; N, 11.61; Cl, 8.81. Found: C, 64.69; H, 6.58; N, 11.37; Cl, 9.18.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C:28]2[CH2:33][CH2:32][CH:31]([C:34]([F:37])([F:36])[F:35])[CH2:30][CH:29]=2)[C:6]2[N:10]=[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:8][C:7]=2[CH:27]=1.[H][H]>C(O)C.[Pd]>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([CH:28]2[CH2:29][CH2:30][CH:31]([C:34]([F:35])([F:36])[F:37])[CH2:32][CH2:33]2)[C:6]2[N:10]=[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:8][C:7]=2[CH:27]=1
Reactant: FC(F)(F)c1cc(C2=CCC(C(F)(F)F)CC2)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: FC(F)(F)c1cc(C2CCC(C(F)(F)F)CC2)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1

Procedure:
6-Trifluoromethyl-4-(4-trifluoromethyl-cyclohex-1-enyl)-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-1H-benzoimidazole (10 mg, Example 139b) was subjected to catalytic hydrogenation in ethanol (1 mL) using 10% Pd/C (10 mg, Aldrich) as catalyst. The reaction was conducted at room temperature under 1 atmosphere hydrogen for 2 days. The catalyst was filtered through a Celite®pad, the filter cake was washed with methanol and the filtrate was evaporated in vacuo to give the title compound as a film. MS (ESI, pos. ion) m/z: 565 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][O:31][C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: COc1cccc(O)c1
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Product: CCN1c2ncc(COc3cccc(OC)c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 54 %

Procedure:
Using a procedure analogous to that described in Example 98, the title compound, m.p. 95°-97° C., was prepared from 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 3-methoxyphenol. The yield was 54% of theory.
Reaction SMILES: ClC(N(C)C)=C(C)C.[C:9]([O:13][C:14]([NH:16][C:17]1[S:21][C:20]([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=2[F:29])=[N:19][C:18]=1[C:30]([OH:32])=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].[NH2:33][C:34]1[C:35]([N:52]2[CH2:57][CH2:56][CH2:55][C@H:54]([NH:58][C:59](=[O:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[CH2:53]2)=[C:36]2[CH:42]=[CH:41][N:40]([S:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)(=[O:45])=[O:44])[C:37]2=[N:38][CH:39]=1.N1C=CC=CC=1>C1COCC1>[C:9]([O:13][C:14]([NH:16][C:17]1[S:21][C:20]([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=2[F:29])=[N:19][C:18]=1[C:30]([NH:33][C:34]1[C:35]([N:52]2[CH2:57][CH2:56][CH2:55][C@H:54]([NH:58][C:59](=[O:65])[O:60][C:61]([CH3:63])([CH3:62])[CH3:64])[CH2:53]2)=[C:36]2[CH:42]=[CH:41][N:40]([S:43]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)(=[O:45])=[O:44])[C:37]2=[N:38][CH:39]=1)=[O:32])=[O:15])([CH3:11])([CH3:10])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.9 %

Procedure:
A solution of 1-chloro-N,N,2-trimethylpropenylamine (115.7 mg, 0.8659 mmol) in THF (1.0 mL) was added slowly to a solution of 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (Example 1, Step 6, 120.4 mg, 0.3379 mmol) in THF (1.0 mL). The mixture was stirred at room temperature for 5 h. A solution of tert-butyl {(3S)-1-[5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate (127.3 mg, 0.2699 mmol) in THF (2.0 mL) was then added, followed by pyridine (227.6 mg, 2.877 mmol) and the mixture was stirred at room temperature for a further 12 h. The mixture was then concentrated and the residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to afford the sub-title compound as a yellow solid (194.4 mg, 89%). LCMS calc. for C38H42F2N2O2S2 (M+H)+: m/z=810.2. found 810.2.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17](C)C)[CH3:15])C(Cl)=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.[C:41](O)([C:43]([F:46])([F:45])[F:44])=O.[CH2:48](Cl)Cl>>[CH:16]([N:14]([CH3:15])[C:12]1[C:41]([C:43]([F:46])([F:45])[F:44])=[CH:10][C:9]2[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1)([CH3:48])[CH3:17]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(N(C)CC(C)C)cc3NC(=O)OC(C)(C)C)c2)ccn1
Reactant: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)C(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (4-chloro-5-(isobutyl-methyl-amino)-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M277) (0.40 g, 0.71 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (269 mg, 85%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=2)[CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.C1C(=O)N([Cl:29])C(=O)C1>>[Cl:29][C:10]1[C:11]2[C:6](=[CH:5][C:4]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=3)=[CH:3][C:2]=2[F:1])[CH:7]=[CH:8][C:9]=1[OH:12]
Reactant: COc1ccc(-c2cc(F)c3cc(O)ccc3c2)cc1F
Reactant: O=C1CCC(=O)N1Cl
Product: COc1ccc(-c2cc(F)c3c(Cl)c(O)ccc3c2)cc1F

Procedure:
The title compound was prepared by reacting 8-fluoro-6-(3-fluoro-4-methoxyphenyl)-2-naphthol (0.30 g, 1.05 mmol) and NCS (0.17 g, 1.26 mmol) according to method C to yield 0.21 g (62%) of a light orange solid: mp 126–128° C.; 1H NMR (DMSO-d6): δ 3.90 (3H, s), 7.25–7.31 (1H, m), 7.35 (1H, d, J=8.91 Hz), 7.64–7.67 (1H, m), 7.70–7.78 (2H, m), 7.87 (1H, dd, J=1.58 Hz, J=9.04 Hz), 10.68 (1H, s); MS (ESI) m/z 319/321 (M−H)−.
Reaction SMILES: C(=O)=O.[Cr:4]([O-:8])([O-:7])(=[O:6])=[O:5].[Na+:9].[Na+].[C:11](=[O:14])([OH:13])[OH:12]>>[Cr:4]([O:8][Cr:4]([O-:7])(=[O:6])=[O:5])([O-:7])(=[O:6])=[O:5].[C:11](=[O:12])([O-:14])[OH:13].[Na+:9]
Reactant: O=C(O)O
Reactant: O=[Cr](=O)([O-])[O-]
Agent: O=C=O
Agent: [Na+]
Product: O=C([O-])O
Product: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]

Procedure:
For acidification with carbon dioxide, the sodium monochromate solution is adjusted to a concentration of from 750 to 1,000 g/l Na2CrO4 and is saturated with carbonic acid in autoclaves by introduction of carbon dioxide under a pressure of from 0.5 to 1.5 MPa (5 to 15 bar). 75 to 95% conversion of monochromate ions into dichromate ions is obtained with precipitation of sodium hydrogen carbonate. The remaining conversion to 100% can be obtained by introduction of carbon dioxide in another stage after concentration to 1,300 g/l Na2CrO4 (already formed Na2CrO7.2H2O expressed in Na2CrO4 equivalents). On an industrial scale, however, this final conversion step is very complicated. The final conversion step may also be carried out with sulfuric acid or by electrolysis.
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]([CH3:19])[CH2:10][C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>C(OCC)C>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11](/[CH:19]=[CH:21]/[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:10][C:9]1=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=Nc2ccccc2N(Cc2ccccc2)C(=O)C1
Reactant: O=Cc1ccncc1
Solvent: CCOCC
Product: O=C1CC(/C=C/c2ccncc2)=Nc2ccccc2N1Cc1ccccc1
Yield: 36 %

Procedure:
Using 1-benzyl-4-methyl-1,3-dihydro-1,5-benzodiazepin-2(2H)-one and isonicotinaldehyde, the titled compound was synthesized in substantially the same manner as in Working Example 144 in a yield of 36%, m.p. 208°-210° C. (diethyl ether).
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:9][C:10]1[C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1)[CH2:4][C:5]#[C:6][CH2:7][CH3:8]>CC(C)=O>[I-:2].[CH2:3]([O:9][C:10]1[C:14]([C:15]2[CH:16]=[N+:17]([CH3:1])[CH:18]=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1)[CH2:4][C:5]#[C:6][CH2:7][CH3:8]
Reactant: CCC#CCCOc1nsnc1-c1cccnc1
Reactant: CI
Solvent: CC(C)=O
Product: CCC#CCCOc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (1 ml, 15 mmol) and 3-(3-(3-hexynyloxy)-1, 2,5-thiadiazol-4-yl)pyridine (3 mmol) in acetone (5 ml) was stirred at room temperatue for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 0.85 g (71%).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: O=C(CCl)N1CCCCC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCCCC2)cc1)c1cc(OC)ccc1[C@H]1CCc2cc(O)ccc2C1
Yield: 40.9 %

Procedure:
Synthesized from pivalic acid (S)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-1-piperidin-1-ylethanone (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.4 mg) was obtained.