Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1.[CH3:29][C@@H:30]1[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[NH:31]1>>[CH3:28][S:25]([C:4]1[CH:3]=[C:2]([N:31]2[C@H:30]([CH3:29])[CH2:34][CH2:33][S:32]2(=[O:36])=[O:35])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=2)[CH2:12][CH2:11]1)=[O:9])(=[O:27])=[O:26]
Reactant: C[C@@H]1CCS(=O)(=O)N1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4[C@H](C)CCS4(=O)=O)cc3S(C)(=O)=O)CC2)nc1C
Yield: 48.5 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (370 mg) described in Preparation Example 122 and (R)-3-methylisothiazolidine 1,1-dioxide (107 mg) described in Preparation Example 2 and by the reaction and treatment in the same manner as in Example 4, the title compound (200 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][NH:15][C:16](OCC2C=CC=CC=2)=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].ClC1[N:37]=[C:36]([N:38]([CH3:40])[CH3:39])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=1.C([O-])(O)=O.[Na+]>CO.CC(O)C.[Pd]>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[CH2:9][CH2:10][C@@H:11]([CH2:14][NH:15][C:16]2[N:37]=[C:36]([N:38]([CH3:40])[CH3:39])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=2)[CH2:12][CH2:13]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CNC(=O)OCc2ccccc2)CC1
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Product: CN(C)c1nc(NC[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)nc2ccccc12
Temperature: 50 °C
Reaction time: 12 h
Yield: 32.7 %

Procedure:
A mixture of cis-[4-(benzyloxycarbonylamino-methyl)-cyclohexyl]-carbamic acid tert-butyl ester (4.00 g, 11.0 mmol) and 5% Pd/C (400 mg) in MeOH (40 mL) was stirred under hydrogen atmosphere at ambient temperature for 8.5 hr and at 50° C. for 12 hr, filtered through a pad of celite, and concentrated. The precipitate was suspended in hexane and the suspension was stirred at ambient temperature for 30 min. The solid was collected by filtration, washed with hexane, and dried (3.03 g). A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in step B of example 1 (1.00 g, 4.82 mmol) and the above solid (1.65 g, 7.23 mmol) in 2-propanol (10 mL) was stirred at reflux for 5 days, poured into saturated aqueous NaHCO3, and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 20% EtOAc in hexane) to give cis-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (629 mg, 43%) as a pale yellow solid.
Reaction SMILES: C([O-])(=[O:3])C.Cl[CH2:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:9](=[CH:10][C:11]3[CH2:20][CH2:19][CH2:18][C:12]=3[CH:13]=2)[N:8]=1>CN(C=O)C>[OH:3][CH2:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:9](=[CH:10][C:11]3[CH2:20][CH2:19][CH2:18][C:12]=3[CH:13]=2)[N:8]=1
Reactant: CC(=O)[O-]
Reactant: O=c1[nH]c(CCl)nc2cc3c(cc12)CCC3
Solvent: CN(C)C=O
Product: O=c1[nH]c(CO)nc2cc3c(cc12)CCC3
Temperature: 40 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
A solution of caesiun acetate (14.4 g, 75.2 mmol) in dry DMF (40 ml) was heated to 60° C. under argon for 30 min. The mixture was cooled to 40° C. and a suspension of 2-chloromethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4-one (L. Skelton, V. Bavetsias, A. Jackman, WO 00/050417-A1; 2.2 g, 9.4 mmol) in dry DMF (60 ml) was added via a cannula. The mixture was heated to 80° C. under argon for 16 h. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was suspended in water (50 ml) and MeOH (20 ml). The pH was adjusted to 12.5 with 1M sodium hydroxide solution and the brown suspension was stirred for 2 h at room temperature. The insoluble brown solid was removed by filtration and the resulting solution was acidified to pH 5 with 1M hydrochloric acid. The precipitate was collected by filtration, washed with acidified water and dried in vacuo over P2O5 to yield the product as a pale yellow solid (1.17 g, 58%); m.p. 205-210° C.; 1H NMR (DMSO-d6) δ 2.07 (quin, J=7.4 Hz, 2H, 7-H), 2.98 (q, J=6.95 Hz, 4H, 6-H and 8-H), 4.38 (s, 2H, 2-CH2), 7.46 (s, 1H, 9-H), 7.92 (s, 1H, 5-H); MS (FAB-m/z): Found 217 [(M+H)+, 100%]; HRMS: measured 217.0977; calculated for C12H13N2O2 (M+H)+: 217.0977; Found C, 64.01; H, 5.23; N, 12.34. C12H13N2O2.½H2O requires C, 63.93; H, 5.77; N, 12.43%.
Reaction SMILES: [CH:1]1[C:13]2[NH: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.ClCCl.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].Cl>C(N(CC)CC)C>[CH2:21]([O:20][C:18]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:19])[CH3:22]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)n1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.6 %

Procedure:
An argon filled RB flask containing carbazole (0.500 g, 2.99 mmol) at 0° C. was treated with dichloromethane (12.5 mL) and triethylamine (2.5 mL), followed by slow addition of ethyl chloroformate (0.59 mL, 5.98 mmol). The mixture was stirred at ambient temperature for 16 h, poured into 25 mL of 2N HCl, and extracted with chloroform. The organic portion was washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4) and concentrated. The crude product was treated with methanol (4 mL) and filtered. The filtrate was concentrated to give carbazole-9-carboxylic acid ethyl ester (169 mg). Carbazole-9-carboxylic acid ethyl ester (95 mg, 0.39 mmol) was converted to hydroxamic acid by procedure A. Purification by HPLC gave the title compound (19 mg). 1H NMR (400 MHz, CD3CN): δ 9.43 (br, 1H), 8.08 (d, 2H, J=7.7 Hz), 7.50 (d, 2H, J=8.1 Hz), 7.43 (t, 2H, J=7.1 Hz), 7.22 (t, 2H, J=7.1 Hz). 13C NMR APT (100 MHz, CD3OD): δ 125.8 (down), 120.3 (down), 119.4 (down), 110.6 (down). ESI-MS (m/z): [M+Na]+249.6. Analytical HPLC: Purity=99%, tR=8.51 min, Method A.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([OH:10])=[O:9].C1(C)C=CC=CC=1>CO>[CH3:1][O:9][C:8]([CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCCC1CC(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)CC1CCCN1C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
Trimethylsilyldiazomethane (2 M solution in hexane, 1.5 ml) was added dropwise to a mixed solution of tert-butyl 2-carboxymethylpyrrolidine-1-carboxylate (CAS No. 194154-91-1, 500 mg) in methanol (1 ml)-toluene (1 ml) under ice-cooling, and the reaction solution was stirred at the same temperature for three hours. The reaction solution was concentrated. The resulting residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 506 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][CH3:13])[CH:6]=[C:7]([Br:10])[C:8]=1[OH:9].Cl.[NH2:16][OH:17].C>[OH-].[Na+].C(O)C>[NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:11](=[N:16][OH:17])[CH2:12][CH3:13])[CH:6]=[C:7]([Br:10])[C:8]=1[OH:9]
Reactant: NO
Reactant: CCC(=O)c1cc(Br)c(O)c(CN)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(=NO)c1cc(Br)c(O)c(CN)c1
Yield: 85.1 %

Procedure:
A solution of 9.0 g of 3'-aminomethyl-5'-bromo-4'-hydroxypropiophenone and 7.0 g of hydroxylamine hydrochloride in 50 ml of 4N sodium hydroxide solution and 15 ml of ethanol is refluxed with heating for 40 minutes. To the reaction mixture is added activated charcoal and the charcoal is filtered off and then the mixture is adjusted to pH 6-7 with concentrated hydrochloric acid. After allowing to stand at room temperature, the precipitate is collected by filtration, washed with water and dried to give 8.1 g of 3'-aminomethyl-5'-bromo-4'-hydroxypropiophenone oxime, melting at 174°-175° C. with decomposition.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O>[CH2:6]([NH:13][CH2:3][CH:2]([F:5])[F:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCc1ccccc1
Reactant: FC(F)CCl
Solvent: O
Product: FC(F)CNCc1ccccc1
Yield: 48.1 %

Procedure:
An amount of 768.1 g (7.39 mol) of 2,2-difluoro-1-chloroethane and 400 g of benzylamine (3.695 mol) are heated in an autoclave at an internal temperature of 120° C. for 16 hours. Subsequently, 700 g of water are added and the aqueous phase is separated. The organic phase is distilled at standard pressure and the excess 2,2-difluoro-1-chloroethane is distilled off. Remaining traces of 2,2-difluoro-1-chloroethane are distilled off under vacuum (200 mbar). An amount of 304 g of N-benzyl-2,2-difluoroethanamine is obtained as residue with a purity of 97.2%. This corresponds to a yield of 93.4%, based on reacted benzylamine. The benzylamine hydrochloride in the aqueous phase can be rereleased by addition of sodium hydroxide solution and be used once again.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[O:10])[CH:5]=[CH:4][C:3]=1Br.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C:27](#[N:29])[CH3:28]>O1CCOCC1.O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[O:10])[CH:5]=[CH:4][C:3]=1[C:6]1[N:7]([CH3:2])[N:29]=[C:27]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:28]=1
Reactant: Nc1nc(NC(=O)c2ccccc2F)ccc1Br
Reactant: CC#N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nc(-c2ccccc2)cc1-c1ccc(NC(=O)c2ccccc2F)nc1N
Temperature: 85 °C
Yield: 4 %

Procedure:
A mixture of N-(6-amino-5-bromo(2-pyridyl))(2-fluorophenyl)carboxamide (61) (16 mg, 0.05 mmol), bis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (4 mg, 10% mol) and K3PO4 (11 mg, 0.05 mmol) in 0.5 ml ACN, 0.5 ml dioxane, 0.2 ml H2O was bubbled with argon before heated at 85° C. for 4 h. After cooling down to r.t., the reaction mixture was taken up in EA, washed with aq. NaHCO3 and brine. Org. phase was dried over Na2SO4, concentrated to dryness. Flash silica gel column purification (0-90% B, A: hexane; B: 50% EA in hexane) furnished 2.2 mg crude desired product as yellow solid which was re-purified on prep HPLC to give 0.8 mg N-[6-amino-5-(1-methyl-3-phenylpyrazol-5-yl)(2-pyridyl)](2-fluorophenyl)carboxamide (69) as off-white solid. (yield: 4%, purity>90%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[C:22]([CH3:38])=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=2[F:37])=[CH:25][CH:26]=1.O>CN(C)C=O>[F:37][C:28]1[CH:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=[CH:32][C:27]=1[C:24]1[N:23]=[C:22]([CH3:38])[C:21]([CH2:20][O:16][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[N:2]3)=[CH:15][CH:14]=2)=[CH:26][CH:25]=1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2F)ccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2F)ccc1COc1ccc(CCCCn2ccnn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
A solution of 359 mg (1.65 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 20.0 ml N,N-dimethylformamide was treated at 0° C. with 66 mg (1.65 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 500 mg (1.65 mmol) 3-Chloromethyl-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyridine were added and stirred continued at r. t. over night. After addition of 40 ml water, the precipitate was isolated, washed thoroughly with water and diisopropylether. The residue was dried at 40° C. to give 618 mg (77%) of the title compound as light brown powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:21])[C@@H:12]([NH2:20])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4].[C:22]([O:26][C:27]([NH:29][C@H:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:21])[C@@H:12]([NH:20][C:31](=[O:32])[C@H:30]([NH:29][C:27]([O:26][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:28])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: COC(=O)c1csc(NC(=O)[C@@H](N)Cc2ccccc2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccccc2)n1
Reaction time: 0.08 h

Procedure:
A solution of 2-((S)-2-amino-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester (prepared as described in example 3, step c) (0.61 g, 2.0 mmol), (R)-tert-butoxycarbonylamino-phenylacetic acid (0.55 g, 2.2 mmol), diisopropylethylamine (1.40 mL, 7.88 mmol) and 1-hydroxybenzotriazole (0.324 g, 2.40 mmol) in N,N-dimethylformamide (5 mL) was stirred in an ice bath for 5 minutes To the cooled yellow-orange solution was added O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexaflurorophosphate (0.91 g, 2.40 mmol). The reaction mixture was stirred for 5 minutes and the ice bath was removed and stirring continued for 1 hour. The reaction mixture was then diluted with ethyl acetate, washed brine and the aqueous layer extracted with ethyl acetate. The combined organic extracts were passed through a pad of sodium sulfate layered on the top of a pad of silica gel contained in a 60 mL vacuum filtration funnel. Residual material was eluted from the pad of sodium sulfate and silica gel with ethyl acetate and the filtrate was concentrated in vacuo to give —[(S)-2-((R)-2-tert-butoxycarbonylamino-2-phenyl-acetylamino)-3-phenyl-propionylamino]-thiazole-4-carboxylic acid methyl ester which was taken into dry dichloromethane (10 mL) under argon and cooled in an ice bath. To this was added trifluoroacetic acid (5 mL, 64.9 mmol) and the mixture stirred at 0° C. for 2 hours. The reaction mixture was then concentrated to dryness. The residue was taken into dichloromethane and precipited with ether and the suspension was stirred for 15 minutes. The solid was isolated by filtration and washed with ether and dried to give a tan solid. The solid was taken into dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, filtered, concentrated and dried to give 2-[(S)-2-((R)-2-amino-2-phenyl-acetylamino)-3-phenyl-propionylamino]-thiazole-4-carboxylic acid methyl ester as an off white foam (0.80 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[Cl:27][C:28]1[CH:37]=[CH:36][C:31]([C:32](=[N:34]O)[NH2:33])=[CH:30][CH:29]=1.[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]3[O:21][N:34]=[C:32]([C:31]4[CH:36]=[CH:37][C:28]([Cl:27])=[CH:29][CH:30]=4)[N:33]=3)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(C)cccc3Cl)[nH]c2=O)cc1OC
Reactant: NC(=NO)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(-n2nc(-c3c(C)cccc3Cl)[nH]c2=O)ccc1-c1nc(-c2ccc(Cl)cc2)no1
Yield: 15.6 %

Procedure:
The title compound was prepared by following the procedure as described for Example-40 by using methyl 4-(3-(2-chloro-6-methylphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-27, 0.100 g, 0.26 mmol), 4-chloro-N′-hydroxybenzimidamide (Intermediate-19, 0.069 g, 0.40 mmol), sodium hydride (0.022 g, 0.53 mmol) and dry THF (5.0 mL) to afford 0.020 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 2.33 (s, 3H), 4.00 (s, 3H), 7.41 (m, 1H), 7.51 (s, 2H), 7.67 (d, J=8.7 Hz, 2H), 7.83 (d, J=8.7 Hz, 1H), 7.90 (s, 1H), 8.10 (d, J=8.4 Hz, 2H), 8.22 (d, J=8.7 Hz, 1H), 12.63 (s, 1H); MS (m/z): 495.98 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:22][CH2:23][N:24]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=2)[CH2:25][CH2:26]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CC(=O)NC(C)c1ccc(CCl)cc1
Product: CC(=O)NC(C)c1ccc(CN2CCN(c3ccccn3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-chloromethylphenyl)ethyl)acetamide obtained in Example 48(3) instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(2-pyridyl)piperazine instead of phenylpiperazine, the title compound was obtained as pale-yellow crystals, m.p.=120-121° C.
Reaction SMILES: [CH3:1]/[C:2](=[CH:8]\[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)/[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H][H]>C(O)C.[Pd]>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:14][CH:13]=1
Reactant: [H][H]
Reactant: CCOC(=O)/C(C)=C/c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (E)-ethyl 2-methyl-3-(4-nitrophenyl)acrylate (645) (2.49 g, 10.6 mmol) in ethanol (100 mL) was added Pd/C (250 mg, 10% Degussa type). A balloon of hydrogen gas was added and the reaction was evacuated and back-filled with hydrogen three times. The reaction was stirred overnight at room temperature, was filtered through a pad of celite and concentrated in vacuo to give ethyl 3-(4-aminophenyl)-2-methylpropanoate (646).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:5]=[C:4]([C:18]2[S:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=2)[N:3]=1.[CH:27]([C:30]1[N:31]=[C:32]([Sn](CCCC)(CCCC)CCCC)[S:33][CH:34]=1)([CH3:29])[CH3:28].COC1C=C(C2SC=C(C(F)(F)F)N=2)N=C(C2SC=C(C)N=2)C=1>C(Cl)Cl>[CH:27]([C:30]1[N:31]=[C:32]([C:2]2[CH:7]=[C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[N:5]=[C:4]([C:18]3[S:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=3)[N:3]=2)[S:33][CH:34]=1)([CH3:29])[CH3:28]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(C(C)C)cs1
Reactant: COc1ccc(COc2cc(Cl)nc(-c3nc(C(F)(F)F)cs3)n2)cc1
Agent: COc1cc(-c2nc(C)cs2)nc(-c2nc(C(F)(F)F)cs2)c1
Solvent: ClCCl
Product: COc1ccc(COc2cc(-c3nc(C(C)C)cs3)nc(-c3nc(C(F)(F)F)cs3)n2)cc1

Procedure:
Compound 25 was synthesized from compound 285 (1.87 mmol) and compound 219 (2.43 mmol) as described for compound 22 at a temperature of 110° C. DCM was added and the mixture was washed sequentially with saturated NH4Cl and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was purified two times by silica gel chromatography (eluent: petroleum ether/EtOAc 5 to 10% and petroleum ether/DCM 20 to 60%) to give compound 25 as a colorless oil in 31% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:15]=[C:14]3[NH2:39])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.Cl.[CH3:50][N:51]1[CH2:56][CH2:55][N:54]([C:57]2[CH:65]=[CH:64][C:60]([C:61](Cl)=[O:62])=[C:59]([N+:66]([O-:68])=[O:67])[CH:58]=2)[CH2:53][CH2:52]1>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:15]=[C:14]3[NH:39][C:61](=[O:62])[C:60]2[CH:64]=[CH:65][C:57]([N:54]3[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]3)=[CH:58][C:59]=2[N+:66]([O-:68])=[O:67])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(S(=O)(=O)c3cccc(F)c3)cc12
Reactant: CN1CCN(c2ccc(C(=O)Cl)c([N+](=O)[O-])c2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(C(=O)Nc3nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c4ccc(S(=O)(=O)c5cccc(F)c5)cc34)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a mixture of 5-(3-fluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-ylamine (100 mg, 0.187 mmol), N,N-diisopropylethylamine (0.13 mL, 0.75 mmol) and dry-tetrahydrofuran (30 mL), at room temperature, was added 4-(4-methyl-piperazin-1-yl)-2-nitro-benzoyl chloride hydrochloride (66 mg, 0.206 mmol, prepared as described in Example 20). The mixture was stirred at room temperature for 1 hour then evaporated to dryness. The residue was dissolved in dichloromethane (50 mL), washed with saturated solution of sodium hydrogenocarbonate (50 mL), dried over sodium sulfate, evaporated to dryness and triturated with diethylether affording the title compound as a yellow powder (102 mg, 70% yield).
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([O:21][C:22]3[C:23]([CH3:32])=[N:24][C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[O:33][CH3:34].C(=O)([O-])[O-].[K+].[K+].[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>O>[CH3:34][O:33][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:11]=1[O:10][CH2:9][CH2:8][CH2:7][N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[N:18]=[CH:17][CH:16]=[C:15]2[O:21][C:22]1[C:23]([CH3:32])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2
Reactant: C1CCNCC1
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCN1CCCCC1
Temperature: 75 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
N,N-Dimethylformamide (1 ml) was added to 7-(3-chloro-propoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 375) (40 mg), potassium carbonate (41 mg), and piperidine (25 mg), and the mixture was stirred at 75° C. overnight. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (32 mg, yield 72%).