Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[Cl:12][C:13]1[CH:14]=[C:15]([N:20]=[C:21]=[O:22])[CH:16]=[CH:17][C:18]=1[Cl:19].Cl>CC(C)=O.O>[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]([NH:9][S:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:8])=[O:7])=[O:22])[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: NS(=O)(=O)C1CCCC1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1ccc(Cl)c(Cl)c1)NS(=O)(=O)C1CCCC1
Reaction time: 2 h
Yield: 85.2 %

Procedure:
The general method of procedure A was followed with cyclopentanesulfonamide (3 g), acetone (200 ml), 1N sodium hydroxide (20 ml), and 3,4-dichlorophenyl isocyanate (3.6 g) dissolved in acetone (50 ml). After two hours, 1N HCl (20 ml) was added and the resulting solid diluted with water and collected. After drying at 5° C., 5.5 g of solid product were obtained.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:7]([O:16][CH3:17])=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11]C)=[O:10].[ClH:18]>O.CO.[OH-].[Na+]>[Cl:18][C:6]1[C:7]([O:16][CH3:17])=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([OH:11])=[O:10]
Reactant: Cl
Reactant: COC(=O)c1cccc(N)c1OC
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1c(Cl)cccc1C(=O)O
Reaction time: 0.5 h
Yield: 24 %

Procedure:
A solution of 1.2 g of sodium nitrite in 3 mL of water was added dropwise to a solution of 2 g (0.011 mole) of methyl 3-amino-2-methoxybenzoate in 15 mL of conc. HCl kept below 10° C. After completing the addition, stirring was continued for 0.5 hour at 0° C. The cold solution was then added dropwise to a solution of 2.5 g of cuprous chloride in 6 mL of concentrated HCl at 80°-85° C. After stirring at this temperature for 0.5 hour, the solution was chilled to precipitate an oil which was taken up in methylene chloride. After drying and removing the solvent, the oil obtained above was dissolved in 75 mL of methanol containing 7 mL of 10% NaOH. The solution was heated under reflux for 0.5 hour. After evaporation, the oil was treated with 40 mL of dilute HCl. A white solid precipitated to give 0.5 g (24%) of 3-chloro-2-methoxybenzoic acid after crystallization from ethyl acetate-hexane.
Reaction SMILES: [C:1]([C:5]1[CH:42]=[CH:41][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=2)[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([NH:27][NH2:28])=[O:26])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:44](OC(Cl)(Cl)Cl)=[O:45]>O1CCOCC1>[C:1]([C:5]1[CH:42]=[CH:41][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]3[O:26][C:44](=[O:45])[NH:28][N:27]=3)=[CH:23][CH:22]=2)[CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCc2ccc(C#N)cc2)Cc2ccc(C(=O)NN)cc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCc2ccc(C#N)cc2)Cc2ccc(-c3n[nH]c(=O)o3)cc2)cc1
Yield: 96.6 %

Procedure:
A solution of 185 mg (0.29 mmol, 89% purity) of 4-{(3E)-4-{2-[(4-tert-butylbenzyl)oxy]phenyl}-2-[2-(4-cyanophenyl)ethyl]but-3-en-1-yl}benzohydrazide from Example 103A in 1 ml of dioxane is slowly added dropwise to a solution of 87.3 mg (0.44 mmol) of trichloromethyl chloroformate in 0.5 ml of dioxane. The reaction mixture is stirred under reflux for two hours. After cooling, the mixture is concentrated in vacuo, directly taken up on silica gel and purified by flash chromatography (mobile phase: dichloromethane/methanol/aq. ammonia 10:1:0.1). 166 mg (0.28 mmol, 96% yield) of an oil are isolated.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([NH:28][C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:10](=[O:18])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=1)=[O:4])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: O=C(Cc1ccccc1)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)c1c[nH]c(C(=O)NCc2ccccc2)c1
Reaction time: 24 h

Procedure:
To a solution of 2,2,2-trichloro-1-(4-phenylacetyl-1H-pyrrol-2-yl)-ethanone (1 equivalent) in DMF, at ambient temperature, was added benzylamine (1.2 equivalents). After 24 hours, the solvent was evaporated and the crude product 3 was used without purification. HPLC Method B, Rt=3.8 minutes; FIA/MS (M+1) 319.3, (M−1) 317.2.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([I:12])[CH:11]=1)[C:6]([OH:8])=[O:7].[C:13]([O-])(O)=O.[Na+]>CO>[CH3:13][O:7][C:6](=[O:8])[C:5]1[CH:4]=[C:3]([Br:2])[CH:11]=[C:10]([I:12])[CH:9]=1
Reactant: O=C(O)c1cc(Br)cc(I)c1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)cc(I)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Methanol (40 mL) was added to a 250 mL round bottom flask followed by 60 mL of a solution saturated with anhydrous hydrochloric acid. 3-bromo-5-iodobenzoic acid (Aldrich)(5.02 g, 0.015 mole) was then added and the reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into chilled saturated NaHCO3 solution (700 mL). The mixture was extracted 3× with methylene chloride (100 mL). The organic layers were combined, dried over MgSO4 and concentrated under vacuum to yield methyl-5-bromo-3-iodobenzoate (5.08 g) as a pink solid. MP=55-57° C. MS and NMR were consistent with the desired structure.
Reaction SMILES: C([N:8]1[C:37]([CH3:38])=[C:11]2[C:12](=[O:36])[N:13]([CH2:24][CH:25]([F:35])[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:14]3[CH:15]=[C:16]4[CH2:23][CH2:22][CH2:21][CH2:20][C:17]4=[CH:18][C:19]=3[C:10]2=[N:9]1)C1C=CC=CC=1>[Pd].CN(C=O)C.CO>[F:35][CH:25]([CH2:24][N:13]1[C:14]2[CH:15]=[C:16]3[CH2:23][CH2:22][CH2:21][CH2:20][C:17]3=[CH:18][C:19]=2[C:10]2=[N:9][NH:8][C:37]([CH3:38])=[C:11]2[C:12]1=[O:36])[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32]
Reactant: Cc1c2c(=O)n(CC(F)CNC(=O)OC(C)(C)C)c3cc4c(cc3c2nn1Cc1ccccc1)CCCC4
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1[nH]nc2c1c(=O)n(CC(F)CNC(=O)OC(C)(C)C)c1cc3c(cc21)CCCC3
Temperature: 23 °C
Reaction time: 72 h

Procedure:
A mixture of tert-butyl 3-(2-benzyl-3-methyl-4-oxo-2,4,7,8,9,10-hexahydro-5H-benzo[g]pyrazolo[4,3-c]quinolin-5-yl)-2-fluoropropylcarbamate (1-10) (0.10 g, 0.19 mmol, 1 equiv) and 10% palladium on carbon (300 mg) in DMF (10 mL) and methanol (10 mL) was stirred under a hydrogen balloon at 23° C. for 72 h. The resulting suspension was filtered and the filtrate was concentrated to yield tert-butyl 2-fluoro-3-(3-methyl-4-oxo-2,4,7,8,9,10-hexahydro-5H-benzo[g]pyrazolo[4,3-c]quinolin-5-yl)propylcarbamate (1-11). LRMS m/z (M+H) 429.2 found, 429.2 required.
Reaction SMILES: [P:1]([O:8]CC)([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[Br:11][CH2:12]Br>>[CH2:3]([O:2][P:1]([CH2:12][Br:11])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:4]
Reactant: BrCBr
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CBr)OCC

Procedure:
(according to P. C. Crofts, G. M. Kosolapoff J. Am. Chem. Soc. 1953, 75, 5738-40) 126 g of triethyl phosphite and 162 g of dibromomethane are heated to 170° C. in an autoclave for 4 hours. Bromomethylphosphonic acid diethyl ester may be isolated in moderate yield from the reaction mixture by distillation (b.p.: approx. 50° C., 7 Pa (0.05 Torr)). A second fractional distillation was then performed.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([C:21]3[O:22][C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[CH:25]=3)=[CH:17][C:15]=2[N:16]=1)[CH2:2][CH3:3].[CH:30]1[C:35]([C:36]([OH:38])=[O:37])=[CH:34][C:33]2[C:39]([O:41][C:42](=O)[C:32]=2[CH:31]=1)=[O:40]>>[CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:39](=[O:40])[C:33]3[C:32](=[CH:31][CH:30]=[C:35]([C:36]([OH:38])=[O:37])[CH:34]=3)[C:42]2=[O:41])=[CH:7][C:6]=1[C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([C:21]3[O:22][C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[CH:25]=3)=[CH:17][C:15]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: CCCNc1ccc(N)cc1-c1nc2cc(-c3cc4ccccc4o3)ccc2o1
Product: CCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3cc4ccccc4o3)ccc2o1

Procedure:
Prepared by the method of Example 1b), from 2-(2-propylamino-5-aminophenyl)-5-(2-benzofuranyl)benzoxazole (50 mg, 0.13 mmol) and 1,2,4-benzenetricarboxylic anhydride (30 mg, 0.13 mmol) the title compound was obtained (40 mg, 55%). 1H NMR (DMSO) δ 8.53(t, 1H), 8.46(dd, 1H), 8.37(d, 2H), 8.18(d, 1H), 8.12(d, 1H), 8.05(dd, 1H), 7.93(d, 1H), 7.72(m, 2H), 7.60(s, 1H), 7.54(dd, 1H), 7.36(m, 2H), 7.10(d, 1H), 3.44(m, 2H), 1.84(m, 2H), 1.15(t, 3H). MS 556 m/z (M−H)−.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:21](C(OC4C=CC=CC=4)=O)[C:22](=[O:30])OC4C=CC=CC=4)[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].C(N(CC)CC)C.Cl.[NH2:48][C@H:49]([CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:50]([NH2:52])=[O:51]>CN(C)C=O>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([NH:48][C@@H:49]([C:50](=[O:51])[NH2:52])[CH2:53][C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)=[O:30])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4]
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)c3)ccc21
Reactant: NC(=O)[C@H](N)Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N[C@H](Cc4ccccc4)C(N)=O)c3)ccc21
Reaction time: 18 h
Yield: 76 %

Procedure:
Phenyl N-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (104 mg, 0.200 mmol) and triethylamine (1 ml) were dissolved in N,N-dimethylformamide (3 ml), and (2R)-2-amino-3-phenylpropionamide hydrochloride (201 mg, 1.00 mmol) was added, and the reaction mixture was stirred for 18 hours. The reaction mixture was partitioned between ethyl acetate and the saturated aqueous solution of ammonium chloride. The organic layer was washed with water and brine, and was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:methanol=50:1). The crystals were precipitated from a solvent mixture of ethyl acetate-hexane, filtered off, and dried under aeration to yield the title compound (77.2 mg, 0.152 mmol, 76%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:20][CH3:21])=[C:14]([S:16](Cl)(=[O:18])=[O:17])[CH:15]=1>>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:20][CH3:21])=[C:14]([S:16]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:17])=[O:18])[CH:15]=1
Reactant: Cc1noc(N)c1Br
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Product: COc1ccc(Br)cc1S(=O)(=O)Nc1onc(C)c1Br
Yield: 61 %

Procedure:
5-Bromo-2-methoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 5-bromo-2-methoxybenzenesulfonyl chloride according to the procedures described in Example 5. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 92°-195° C., yield 61%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[NH:13][C:12](=[O:22])[C:11]=2[CH2:10][CH2:9]1.C1(OC2C=CC=CC=2)C=CC=CC=1>[Pd].C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[NH:13][C:12](=[O:22])[C:11]=2[CH:10]=[CH:9]1
Reactant: Cc1ccccc1N1CCc2c1c1cccc(C)c1[nH]c2=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ccccc1-n1ccc2c(=O)[nH]c3c(C)cccc3c21

Procedure:
1-(2-Methylphenyl)-4-oxo-6-methyl-2,3,4,5-tetrahydropyrrolo[3,2-c]quinoline(9.25 g), diphenyl ether (75 ml) and 10% palladium on charcoal (1 g) were heated at reflux for 4 hours, cooled, diluted with ethyl acetate, and filtered through celite. Further dilution with ethyl acetate induced crystallisation of 1-(2-methylphenyl)-4-oxo-6-methyl-4,5-dihydropyrrolo[3,2-c]quinoline (6.68g), m.p. 226°-232°, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH2:9][CH2:10]Cl)=[CH:4][CH:3]=1.[CH3:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH2:9][CH2:10][P:14]([CH3:13])(=[O:18])[O:15][CH2:16][CH3:17])=[CH:4][CH:3]=1
Reactant: O=C(CCCl)c1ccc(Br)cc1
Reactant: CCOP(C)OCC
Solvent: Cc1ccccc1
Product: CCOP(C)(=O)CCC(=O)c1ccc(Br)cc1

Procedure:
1-(4-bromophenyl)-3-chloropropan-1-one (4.5 g, 18.18 mmol) and diethyl methylphosphonite (6 g, 44.1 mmol) were stirred in refluxing toluene (9 mL) for 5 hours. Room temperature was attained and the solvent removed in vacuo. Purification of the residue by MPLC (0-10% MeOH-EtOAc) gave ethyl [3-(4-bromophenyl)-3-oxopropyl]methylphosphinate as a pale yellow oil that crystallised on standing.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[NH:7])=[CH:4][CH:3]=1.C([Li])CCC.Cl[P:23]([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25]>>[CH:24]([P:23]([CH:27]([CH3:29])[CH3:28])[N:7]=[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:16][CH:15]=1)([CH3:26])[CH3:25]
Reactant: CC(C)P(Cl)C(C)C
Reactant: Cc1ccc(C(=N)Nc2ccccc2)cc1
Agent: [Li]CCCC
Product: Cc1ccc(C(=NP(C(C)C)C(C)C)Nc2ccccc2)cc1

Procedure:
Procedure as described for NP Amidine I using the following amounts: 1.05 g of 4-methyl-N1-phenylbenzamidine (Amidine IX, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.80 mL chlorodiisopropylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, a yellow oil was isolated (1.62 g, 99%).
Reaction SMILES: [C:1]1([CH2:7][C:8]2([CH2:13][CH2:14][OH:15])[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.O.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:34](Cl)=[O:35]>C(OCC)(=O)C>[CH3:43][O:42][C:38]1[CH:37]=[C:33]([CH:32]=[C:31]([O:30][CH3:29])[C:39]=1[O:40][CH3:41])[C:34]([N:10]1[CH2:11][CH2:12][C:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:35]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: OCCC1(Cc2ccccc2)CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CCC(CCO)(Cc3ccccc3)C2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Combine 3-(phenylmethyl)-3-(2-hydroxyethyl)pyrrolidine (3.94 mmol) and sodium carbonate (0.21 g, 2.00 mmol) in 1/1 ethyl acetate/water (50 mL). Cool the reaction mixture to 0° C. with an ice bath. Add 3,4,5-trimethoxybenzoyl chloride (0.83 g, 3.58 mmol). Warm to ambient temperature. After 18 hours, separate the layers and extract the aqueous layer three times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give the title compound: Rf=0.09 (silica gel, ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:22])[CH3:21])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(OCC)(=O)C.CCCCCC>[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:19][C:14]2[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]3[O:10][C:9]([CH3:22])([CH3:21])[CH:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:12]=3[C:13]=2[CH3:20])=[O:29])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(F)cc1)C(C)(C)O2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(F)cc1)C(c1ccc(F)cc1)C(C)(C)O2
Yield: 75 %

Procedure:
By using 3-(4-fluorophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 75%. Melting point: 140-142° C. (Ethyl acetate-hexane)
Reaction SMILES: O[CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:42]>CN(C)C=O.O>[Cl:42][CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3ccc(CO)cc32)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3ccc(CCl)cc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
A solution of 6-hydroxymethyl-1-(4-methylphenylsulfonyl)indole (21.0 g) and triphenylphospine (21 g) in a mixture of N,N-dimethylformamide (200 ml) and carbon tetrachloride (27 ml) was stirred at room temperature for 18 hr under a nitrogen atmosphere. The solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried (MgSO4), and evaporated to give 6-chloromethyl-1-(4-methylphenylsulfonyl)indole (21.4 g, 96%) as an ivory solid partial NMR (80 MHz, CDCl3): 2.34 (s, 3H, ArCH3), 4.71(s, 2H, ClCH2), 6.62(dd, 1H, H3 -indole), 8.02(m, 1H, H7 -indole). f. 1-(4-Methylphenylsulfonyl)indole-6-acetonitrile.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:25])[C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[C:22](Br)[N:23]=[C:17]3[CH:16]=2)=[O:13])=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[N:31][CH:32]=1>>[CH3:26][C:27]1[CH:28]=[C:29]([C:22]2[N:23]=[C:17]3[CH:16]=[C:15]([NH:14][C:12]([C:11]4[N:10]([CH3:25])[N:9]=[CH:8][C:7]=4[C:5]([N:1]4[CH2:4][CH2:3][CH2:2]4)=[O:6])=[O:13])[CH:20]=[CH:19][N:18]3[N:21]=2)[CH:30]=[N:31][CH:32]=1
Reactant: Cc1cncc(B(O)O)c1
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(Br)nc2c1
Product: Cc1cncc(-c2nc3cc(NC(=O)c4c(C(=O)N5CCC5)cnn4C)ccn3n2)c1
Yield: 58.3 %

Procedure:
The product was prepared in the same manner as described in example 66 using 4-(azetidine-1-carbonyl)-N-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide (150 mg, 371 μmol) and 5-methylpyridin-3-ylboronic acid (76.2 mg, 557 μmol) as starting materials. The crude material was applied on silicagel and purified by flash chromatography over a 50 g NH2-silicagel column using heptane/ethyl acetate 20-100% as eluent affording 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid [2-(5-methyl-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (90 mg, 19.4%) as a light brown solid. mp: 262-264° C., MS: m/z=417.3 (M+H+)
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH2:32]([NH2:42])[C:33]1[CH:41]=[CH:40][C:39]2[O:38][CH2:37][O:36][C:35]=2[CH:34]=1>>[O:38]1[C:39]2[CH:40]=[CH:41][C:33]([CH2:32][NH:42][C:3]([C:5]3[N:14]4[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][O:21][C:22]5[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=5)[C:11]5[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=5[CH2:13]4)=[CH:7][CH:6]=3)=[O:4])=[CH:34][C:35]=2[O:36][CH2:37]1
Reactant: O=C(COc1ccc(Cl)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: NCc1ccc2c(c1)OCO2
Product: O=C(NCc1ccc2c(c1)OCO2)c1ccc2n1Cc1ccccc1N(C(=O)COc1ccc(Cl)cc1)C2

Procedure:
The title compound was synthesized from 2,2,2-trichloro-1-{10-[(4-chlorophenoxy) acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 67 (0.3 mmol) and piperonylamine (2.2 eq.) in the manner of Example 68, m.p. 168-169° C. MS [(+)ESI, m/z]: 530 [M+H]+ Anal. Calcd for C29H24CIN3O5: C, 65.72; H, 4.56; N, 7.93. Found: C, 65.79; H, 4.59; N, 7.89.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(C=O)cc2C)ncn1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CN3CCOCC3)cc2C)ncn1
Reaction time: 15 h
Yield: 92.4 %

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(4-formyl-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 29, 80 mg; 0.23 mmol) in DCM was treated with morpholine (40 mL; 0.46 mmol) followed by polymer supported triacetoxy borohydride (150 mg). After stirring for 15 hours the mixture was filtered and washed with water. The organic fraction was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as an of-white solid (90 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[C:13]([CH3:38])=[C:14]([N:18]([CH2:23][C:24]2[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:26]([CH3:37])[CH:25]=2)[CH2:19][CH2:20][O:21][CH3:22])[CH:15]=[CH:16][CH:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]([CH2:23][C:24]3[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[C:26]([CH3:37])[CH:25]=3)[CH2:19][CH2:20][O:21][CH3:22])[C:13]=2[CH3:38])=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1ccc(CN(CCOC)c2cccc(Br)c2C)cc1C
Reactant: OB(O)c1ccc(Cl)cc1
Product: COCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(Cl)cc2)c1C

Procedure:
Prepared from 4-chlorophenylboronic acid and ethyl (4-{[(3-bromo-2-methylphenyl)(2-methoxyethyl)amino]methyl}-2-methylphenoxy)acetate using the procedure described for Example 25 (Method A).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:18])=[C:10](F)[C:11]=2[O:13][CH:14]([F:16])[F:15])[C:6](=[O:19])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1)[CH3:2].[CH3:23][CH:24]1[CH2:29][NH:28][CH2:27][CH2:26][NH:25]1>N1C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:18])=[C:10]([N:28]3[CH2:27][CH2:26][NH:25][CH:24]([CH3:23])[CH2:29]3)[C:11]=2[O:13][CH:14]([F:16])[F:15])[C:6](=[O:19])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1)[CH3:2]
Reactant: CC1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(OC(F)F)c21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(C)C3)c(OC(F)F)c21
Reaction time: 2 h
Yield: 80.9 %

Procedure:
In 60 ml of pyridine were dissolved 3.19 g (0.01 mole) of 1-ethyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 3.0 g (0.03 mole) of 2-methylpiperazine, and the mixture was stirred at 105° to 110° C. for 2 hours. Then, the solvent was removed under reduced pressure. Water was added to the residue, and crystals precipitated were collected by filtration, washed with water and ethanol, and dried to obtain 3.23 g of 1-ethyl-6-fluoro-8-difluoromethoxy-7-(3-methylpiperazin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as pale yellow powder.