Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:79][CH2:80][CH2:81][NH:82][C:83](=[O:89])[O:84][C:85]([CH3:88])([CH3:87])[CH3:86]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCCCCC.CCOC(C)=O.C1(C)C=CC=CC=1>[C:85]([O:84][C:83]([NH:82][CH2:81][CH2:80][NH:79][C:3]1[C:4]2[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6][C:5]=2[CH:17]=[CH:18][C:2]=1[Cl:1])=[O:89])([CH3:88])([CH3:87])[CH3:86]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCN
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCNc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2

Procedure:
Use a method similar to the General Procedure 5-1, using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (150 mg, 0.352 mmol), palladium(II) acetate (8 mg, 0.0352 mmol), BINAP (22 mg, 0.0352 mmol), cesium carbonate (163 mg, 0.5 mmol), t-butyl N-(2-aminoethyl)-carbamate (254 mg, 1.59 mmol) and toluene (6 mL) to give, after chromatography on silica gel eluting with hexane/EtOAc (4:1), the desired intermediate (136 mg, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9](C(OC)=O)([CH3:13])[CH:8]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH2:7][C:6]=2[CH:26]=1.[I-].[Li+]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C@@H:9]([CH3:13])[C@@H:8]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[CH2:7][C:6]=2[CH:26]=1
Reactant: COC(=O)C1(C)C(=O)Nc2ccc(Cl)cc2CC1c1ccc(OC)cc1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc([C@H]2Cc3cc(Cl)ccc3NC(=O)[C@H]2C)cc1
Yield: 58.6 %

Procedure:
A mixture of 800 mg of 7-chloro-1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-3-methyl-2H-1-benzazepin-2-one (2.16 mmole), 1.14 g of lithium iodide (8.56 mmoles, 4 equiv.) in 20 ml of pyridine was refluxed for 20 hours. The cooled mixture was diluted with 200 ml of ethyl acetate, then washed with four 30 ml portions of 1N hydrochloric acid, two 30 ml portions of saturated cupric sulfate, 30 ml of water. The organic layer was dried (magnesium sulfate) and concentrated. The residue was triturated with ether to yield 400 mg of (cis)-7-chloro-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-3-methyl-2H-1-benzazepin-2-one as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.C(N(CC)CC)C.Cl[C:18]([C:20]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22][CH2:21]1)=[O:19]>O1CCCC1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18]([C:20]2([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22][CH2:21]2)=[O:19])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: CCOC(=O)C1(C(=O)Cl)CCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)Nc2ccc(Br)cc2C)CCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
Into a nitrogen-purged reaction flask was charged 2.74 grams (0.01 mole) of 4-bromo-2-methylaniline and 1.49 grams (0.0) mole) of triethylamine dissolved in 200 milliliters of tetrahydrofuran. With vigorous stirring, 2.80 grams (0.01 mole) of ethyl 1-chlorocarbonylcyclobutanecarboxylate prepared in Example XIX were added and the resulting mixture stirred at ambient temperature for 6 hours. A precipitate of triethylamine hydrochloride was removed by filtration. The filtrate was vacuum stripped and the residue taken up in methylene chloride. This solution was washed successively with 2N HCl (2×75 milliliters) and water, and then dried over magnesium sulfate. Rotary evaporation gave a crude product which was flash chromatographed on silica using 7:3 hexane-ethyl acetate to give 3.68 grams (0.01 mole) of ethyl 1-(4-bromo-2-methylphenylaminocarbonyl)cyclobutanecarboxylate as a white solid. A small sample which was recrystallized from hexane had a melting point of 61° C.-64° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)C(C)C)(C)C>ClCCl>[C:28]([N:11]([CH2:12][C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)=[CH:16][CH:17]=1)[S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)(=[O:9])=[O:10])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3cccc(Cl)c3)s2)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(-c2ccc(CN(C(=O)c3ccccc3)S(=O)(=O)c3cccc(Cl)c3)s2)c1

Procedure:
In analogy to example 6, 3-chloro-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide (example 7, step 2) was reacted with benzoyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give N-benzoyl-3-chloro-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide as a colorless solid. MS: 563.2 ([M+NH4]+)
Reaction SMILES: [CH:1]([C@H:3]1[C@@H](C2C=CC=CC=2)C[C@H]2N(C)[C@@H:4]1CC2)=O.[CH:18]([C@H:20]1[C@@H:26]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[CH2:25][C@H:24]2[N:34]([CH3:35])[C@@H:21]1[CH2:22][CH2:23]2)=O.C([PH3+])C.C([PH3+])CC.[I-].C[N+]1C=CC(C2C=CC=CC=2)=C(O)C=1>C(Cl)Cl>[CH2:18]([C@H:20]1[C@@H:26]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[CH2:25][C@H:24]2[N:34]([CH3:35])[C@@H:21]1[CH2:22][CH2:23]2)[CH2:1][CH2:3][CH3:4]
Reactant: CN1[C@H]2CC[C@@H]1[C@@H](C=O)[C@@H](c1ccccc1)C2
Reactant: Cc1ccc([C@H]2C[C@@H]3CC[C@H]([C@H]2C=O)N3C)cc1
Agent: CCC[PH3+]
Agent: CC[PH3+]
Agent: C[n+]1ccc(-c2ccccc2)c(O)c1
Solvent: ClCCl
Product: CCCC[C@H]1[C@@H](c2ccc(C)cc2)C[C@@H]2CC[C@H]1N2C

Procedure:
Using a procedure similar to that described in Example 8, except replacing the compound 18 used therein with compound 19, and replacing the ethyl phosphonium salt with the corresponding propyl phosphonium salt, the title compound 23 was prepared as a colorless oil: [α]25D −76° (c 1.5, CH2Cl2); 1H NMR (CDCl3) δ0.74 (t, 3H, J=7.2 Hz), 0.70-0.90 (m, 2H), 1.12-1.30 (m, 3H), 1.39-1.68 (m, 5H), 1.96-2.20 (m, 3H), 2.24 (s, 3H), 2.31 (s, 3H), 3.03 (dt, 1H, J=5.1 and 13.2 Hz), 3.12-3.20 (m, 1H), 3.20-3.28 (m, 1H), 7.03 (d, 2H, J=8.1 Hz), 7.08 (d, 2H, J=8.1 Hz); 13C NMR (CDCl3) δ14.2, 21.0, 22.7, 24.8, 26.4, 26.7, 30.1, 33.8, 36.0, 42.1, 46.2, 62.1, 64.7, 127.7, 128.7, 135.0, 140.7; MS m/z (%) 271 (M+, 6), 242 (2), 214 (4), 96(40), 83 (100).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.[Br:17]Br>C(O)(=O)C>[Br:17][CH2:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1
Reactant: BrBr
Reactant: CCOC(=O)c1cc(C)nc(C(F)(F)F)n1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CBr)nc(C(F)(F)F)n1
Temperature: 80 °C

Procedure:
A solution of ethyl 6-methyl-2-(trifluoromethyl)pyrimidine-4-carboxylate (2.00 g, 8.54 mmol, prepared as described in WO2007/090748) in acetic acid (12 mL) was treated with bromine (1.36 g, 8.54 mmol) and the reaction was heated to 80° C. in a sealed vial for 30 minutes, at which time it was decolorized. The mixture containing unreacted starting material, desired product, and over brominated product, was rotovapped and azeotroped once with toluene. The percent by weight of desired component was determined by NMR and the mixture used without further purification. Yield: 1.62 g (61%); LC-MS: 313.0, 315.0 (M+H)+. 1H NMR (300 MHz, CDCl3): δ 8.32 (s, 1H), 4.60 (s, 2H), 4.54 (q, 2H), 1.46 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:26]([CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[N:25]=[CH:24][C:7]=3[C:8](=[O:23])[N:9](CC3C=CC(OC)=CC=3OC)[C:10]=2[CH:11]=1.[CH3:33][O:34][C:35]1[N:40]=[C:39]([CH3:41])[C:38](B(O)O)=[C:37]([CH3:45])[CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:33][O:34][C:35]1[N:40]=[C:39]([CH3:41])[C:38]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[N:26]([CH:27]5[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)[N:25]=[CH:24][C:7]=4[C:8](=[O:23])[NH:9][C:10]=3[CH:11]=2)=[C:37]([CH3:45])[CH:36]=1
Reactant: COc1ccc(Cn2c(=O)c3cnn(C4CCOCC4)c3c3ccc(Br)cc32)c(OC)c1
Reactant: COc1cc(C)c(B(O)O)c(C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C)c(-c2ccc3c(c2)[nH]c(=O)c2cnn(C4CCOCC4)c23)c(C)n1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
7-bromo-5-(2,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one obtained in Preparation Example 1(4) (41 mg) was dissolved in DMF (2 mL). (6-methoxy-2,4-dimethylpyridin-3-yl)boronic acid obtained in Preparation Example 24 (15 mg), Pd(PPh3)4 (4.8 mg), cesium carbonate (54 mg) and water (0.5 mL) were added to the solution, and the mixture was reacted using a microwave reactor at 150° C. for two hours. The reaction mixture was returned to room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in TFA (1 mL), and the mixture was stirred at 65° C. for two hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was neutralized by adding a 5 N aqueous sodium hydroxide solution. The aqueous solution was extracted with DCM. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 50% to 100%) to give the title compound (3.7 mg).
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([OH:17])=[O:16])[CH:9]=[CH:8]2.C(N(CC)CC)C.II.Cl.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.O>[N:4]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([OH:17])=[O:16])[CH:9]=[CH:8]2)=[C:1]=[S:3]
Reactant: Nc1ccc2cc(C(=O)O)ccc2c1
Reactant: S=C=S
Agent: Cl
Agent: II
Agent: O=S([O-])[O-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cc(N=C=S)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
Carbon disulfide (0.26 mL, 4.4 mmol) was added to a mixture comprising 6-amino-2-naphthoic acid (0.28 g, 1.5 mmol), tetrahydrofuran (1.0 mL), water (1.0 mL) and triethylamine (0.51 mL, 3.6 mmol), followed by stirring at room temperature for 24 hours. To the obtained reaction mixture, a tetrahydrofuran (1.0 mL) solution of iodine (0.41 g, 1.6 mmol) was dropwise added over a period of 5 minutes at 0° C., followed by stirring at 0° C. for further two hours. Thereafter, 1M hydrochloric acid (1.5 mL) and sodium sulfite (38 mg, 0.30 mmol) were added and mixed. The formed insoluble matter was collected by filtration and dried under reduced pressure. Then, carbon disulfide (2.0 mL) was added and thoroughly mixed. Then, the insoluble matter was collected by filtration to obtain 6-isothiocyanato-2-naphthoic acid as a cream-colored solid (0.32 g, yield: 96%, HPLC purity: 94%, HPLC retention time: 3.7 min). LC-MS ES-228 (retention time: 4.5 min, condition 1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:9][C:10]2[C:20]3[CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15][C:14]=3[CH:13]=[CH:12][C:11]=2[Cl:28])=[N:6][CH:7]=1.[Br-].[CH3:30][CH:31]([CH3:35])[CH2:32][CH2:33][Zn+].C1COCC1>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[C:24]([O:23][C:21]([N:17]1[CH2:18][CH2:19][C:20]2[C:10]([S:9][CH2:8][C:5]3[CH:4]=[CH:3][C:2]([CH2:33][CH2:32][CH:31]([CH3:35])[CH3:30])=[CH:7][N:6]=3)=[C:11]([Cl:28])[CH:12]=[CH:13][C:14]=2[CH2:15][CH2:16]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)CC[Zn+]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Br)cn3)c2CC1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)CCc1ccc(CSc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To 6-(5-bromo-pyridin-2-ylmethylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (219 mg, 0.452 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (18 mg, 0.022 mmol) under dry nitrogen add with stirring a solution of 0.5M 3-methylbutylzinc bromide in THF (4.6 mL, 2.3 mmol). Degas, purge with dry nitrogen, and stir overnight at ambient temperature. Dilute with EtOAc, wash with water, dry over anhydrous MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (5:1) to give 3-tert-butoxycarbonyl-7-chloro-6-[5-(3-methyl-butyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (160 mg, 75%). MS (APCI+) m/z: 475 (M+H)+. Use a method similar to the General Procedure 1-4 to give the title compound as a tan solid. MS (APCI+) m/z: 375 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11]Cl)[C:9]=1[Cl:10])=[O:4].[C:13]([O-:16])(=[O:15])[CH3:14].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][O:16][C:13](=[O:15])[CH3:14])[C:9]=1[Cl:10])=[O:4]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1scc(CCl)c1Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1scc(COC(C)=O)c1Cl
Yield: 90 %

Procedure:
To 2-methoxycarbonyl-3-chloro4-(chloromethyl)thiophene (48 g, 0.21 mol) in glacial acetic acid (500 mL) was added sodium acetate (35 g, 0.42 mol). The reaction was heated at reflux for 24 hours, then cooled and concentrated in vacuo. The residual oil was made basic by addition of saturated aqueous sodium bicarbonate, and the resulting solution extracted with ethyl acetate (4×150 mL). The combined extracts were dried over sodium sulfate and concentrated to afford 47 g (90% yield) of 2-methoxycarbonyl-3-chloro4-(acetoxymethyl)thiophene as, a light brown oil; NMR (CDCl3) 7.6 (s, 1), 5.1 (s, 2), 3.9 (s, 3), 2.1 (s, 3) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-])=O)([CH3:4])([CH3:3])[CH3:2].NN.[O-]S([O-])(=O)=O.[Mg+2]>CO.[Ni]>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCNc1ccccc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNc1ccccc1N
Temperature: 25 °C
Yield: 72 %

Procedure:
A mixture of [2-(2-nitrophenylamino)ethyl]carbamic acid t-butyl ester (6 g, 21.3 mmol) and Raney-Nickel (0.5 g) in methanol is treated dropwise with hydrazine (0.8 mL, 25 mmol), stirred at room temperature until reaction is complete by TLC, treated with Celite and MgSO4 and filtered. The filtercake is washed with methanol. The filtrates are combined and concentrated in vacuo to give the title compound as a brown oil, 3.85 g (72% yield), identified by HPLC and mass spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)=[C:6]([CH:35]=1)[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:18]3[CH:26]=[CH:27][C:28]([C:30]([O:32][CH3:33])=[O:31])=[CH:29][C:17]=3[N:16]=2)=[C:11]([F:34])[CH:10]=1.C(N(CC)CC)C.Cl[CH2:51][CH2:52][CH2:53][C:54](Cl)=[O:55].O>C(Cl)(Cl)Cl>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:5]2[CH:4]=[CH:3][C:2]([N:1]3[CH2:51][CH2:52][CH2:53][C:54]3=[O:55])=[CH:35][C:6]=2[CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:19]([CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)[C:18]4[CH:26]=[CH:27][C:28]([C:30]([O:32][CH3:33])=[O:31])=[CH:29][C:17]=4[N:16]=3)=[C:11]([F:34])[CH:10]=2)=[CH:37][CH:38]=1
Reactant: O=C(Cl)CCCCl
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc(N)ccc3-c3ccc(Cl)cc3)cc1F)n2C1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc(N4CCCC4=O)ccc3-c3ccc(Cl)cc3)cc1F)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
Methyl 2-[4-{5-amino-2-(4-chlorophenyl)benzyloxy}-2-fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylate (500 mg) obtained in Example 338 and triethylamine (0.14 ml) were dissolved in chloroform (5 ml), and commercially available chlorobutyryl chloride (0.1 ml) was added under ice-cooling, which was followed by stirring at room temperature for 3 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylformamide (6 ml) and potassium carbonate (244 mg) was added, which was followed by stirring at 80° C. for 1 hr. The reaction mixture was allowed to cool, water was added and the precipitated crystals were collected by filtration to give the title compound (502 mg, yield 89%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC)=O.[NH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33]>>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Reactant: NCCCCCC(=O)O
Agent: CCOC(=O)Cl
Product: O=C(O)CCCCCNC(=O)CCCCCNC(=O)OCc1ccccc1

Procedure:
The second step was to activate the N-benzyloxycarbonyl-6-aminocaproic acid obtained by following the procedure of Example 3 A. above, with ethyl chloroformate followed by reaction with a second 6-aminocaproic acid linker to yield N-(N'-benzyloxycarbonyl-6-aminocaproyl)-6-aminocaproic acid. This second step was carried out as follows. A solution of 52.1 g (0.19M) of N-benzyloxycarbonyl-6-aminocaproic acid (thoroughly dried) dissolved in 640 mL of toluene and 20 mL of triethylamine, was cooled to between -5° to -10° C. in an isopropanol/dry ice bath before ethyl chloroformate (19.1 mL, 0.199M) was slowly added to give a white precipitate. The precipitate was removed by filtration and discarded. To the filtrate cooled in an ice-water bath there was added over 45 minutes a solution of 25.7 g (0.19M) of 6-aminocaproic acid in 100 mL of cold 2N NaOH. After stirring for 1 hr at 0° C. and then overnight at room temperature, the pH was adjusted to 8 with 6N NaOH and 1.2 L of H2O was added. The 1.3 L aqueous phase was washed with ethyl ether (3×200 mL), cooled in an ice bath, and acidified with concentrated HCL to give a white solid. The solid was filtered, thoroughly washed with water and stored in a desiccator. The partially dried solid was treated with 350 mL of hot ethyl acetate to give two layers. The ethyl acetate layer was dried (Na2SO4), filtered, concentrated to about 250 mL, and cooled to 4° C. to yield 19 g (27% yield) of N-(N'-benzyloxycarbonyl-6-aminocaproyl)-6-aminocaproic acid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[NH:12][CH:13]=[C:14]([C:15]([OH:17])=O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:15]([C:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[NH:12][CH:13]=1)=[O:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Reactant: NCc1ccccc1
Product: O=C(NCc1ccccc1)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Yield: 7.6 %

Procedure:
This compound is prepared according to synthesis 79 from 75 mg (0.33 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 75) and 40 μL (0.36 mmol) of benzylamine. After recrystallization from methanol, 8 mg (8%) of N-(benzyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide is obtained in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[N:5][N:6]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([NH:1][C:2]1[NH:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[N:5][N:6]=1)(=[O:13])[CH3:12]
Reactant: COC(=O)c1nnc(N)[nH]1
Reactant: CC(=O)OC(C)=O
Product: COC(=O)c1nnc(NC(C)=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of methyl 5-amino-4H-1,2,4-triazole-3-carboxylate (1.42 g, 10.0 mmol) in acetic anhydride (30 mL) was refluxed for 30 min until a clear solution was formed. The solution was evaporated to dryness and H2O (40 mL) was added. The resulting suspension was stirred at rt overnight. H2O was evaporated to afford the titled compound as a white powder (1.85 g), which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:19]3[C:11](=[CH:12][C:13]4[O:17][CH:16]=[N:15][C:14]=4[C:18]=3[F:20])[NH:10][C:9]2=[O:21])=[C:4]([Cl:22])[CH:3]=1.C(N(CC)CC)C.[CH2:30]([C:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1)[CH:31]=[CH2:32].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:30]([C:33]1([S:36]([N:10]2[C:11]3=[CH:12][C:13]4[O:17][CH:16]=[N:15][C:14]=4[C:18]([F:20])=[C:19]3[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[Cl:22])[C:9]2=[O:21])(=[O:38])=[O:37])[CH2:35][CH2:34]1)[CH:31]=[CH2:32]
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Reactant: O=c1[nH]c2cc3ocnc3c(F)c2n1-c1ccc(Br)cc1Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC1(S(=O)(=O)n2c(=O)n(-c3ccc(Br)cc3Cl)c3c(F)c4ncoc4cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a solution of 5-(4-bromo-2-chlorophenyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one (100 mg, 0.26 mmol) in DCM (10 mL) was added triethylamine (80 mg, 0.78 mmol) at 0° C. followed by 1-allylcyclopropane-1-sulfonyl chloride (71 mg, 0.39 mmol) and DMAP (15 mg). After stirring at room temperature for 1 h, the reaction was treated with saturated NaHCO3 (aq.). The aqueous layer was extracted with CH2Cl2 (20 mL×2). The combined organic phase was washed with water (20 mL) and brine (20 mL) sequentially, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (120 mg, 87.2% yield). 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.39-7.11 (d, 2H), 7.05, (m, 1H), 5.75-5.58 (m, 1H), 5.05 (m, 2H), 2.90-2.80 (m, 1H), 2.10-2.0 (m, 1H), 1.95-1.86 (m, 2H), 1.25-1.10 (m, 2H).