Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[F-].[Cs+].ClCCl.[CH2:16]([O:18][C:19]1[CH:28]=[C:27](I)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22])[CH3:17]>O.COCCOC>[CH2:16]([O:18][C:19]1[CH:28]=[C:27]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22])[CH3:17]
Reactant: OB(O)c1ccccc1F
Reactant: CCOc1cc(I)ccc1C(=O)OC
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: CCOc1cc(-c2ccccc2F)ccc1C(=O)OC
Yield: 95.8 %

Procedure:
(2-Fluorophenyl)boronic acid (0.918 g), cesium fluoride (1.99 g), and a dichloromethane adduct of (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (0.714 g) were added to a mixture of methyl 2-ethoxy-4-iodobenzoate (1.34 g) and DME (20 mL), and the resultant mixture was stirred at 100° C. for 15 hours in an argon atmosphere. Water was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was subjected to extraction with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.15 g).
Reaction SMILES: [CH2:1]([O:8][CH:9](O)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15].Cl.C1C[O:24]CC1>>[CH2:1]([O:8][CH2:9][CH2:10][O:24][CH2:15][CH2:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OCC
Reactant: CC(O)OCc1ccccc1
Reactant: C1CCOC1
Agent: Cl
Agent: [Na]
Product: CCOC(=O)CCOCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
8.53 ml (60.0 mmol) benzyloxy-ethanol are combined with 13 mg (0.57 mmol) sodium in 40 ml THF, then when it has dissolved 5.95 ml (54.7 mmol) ethyl acrylate are added under an argon atmosphere and stirred for 20 hours at ambient temperature. After neutralising with 0.6 ml 1-molar hydrochloric acid the reaction mixture is evaporated down i. vac., the residue is taken up in sat. sodium chloride solution and extracted with ethyl acetate. The combined organic phases are washed with sat. sodium chloride solution, dried over sodium sulphate and evaporated down i. vac. The residue is purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate=4:1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:12]([CH:16]=1)[C:13]([OH:15])=O.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[CH:26]=1.C(N(CC)CC)C>ClCCl>[OH:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:12]([CH:16]=1)[C:13]([NH:31][C:27]1[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=1)=[O:15]
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cc(O)ccc1OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnc1)c1cc(O)ccc1OCc1ccccc1
Reaction time: 2 h

Procedure:
Oxalyl chloride (1.08 ml, 12.28 mmol) was added to a mixture of 5-hydroxy-2-[(phenylmethyl)oxy]benzoic acid (1 g, 4.09 mmol) dissolved in dichloromethane. The mixture was stirred for 2 h, and then concentrated. The residue was dissolved in dichloromethane, and then added to a mixture of pyridin-3-amine (0.39 g, 4.09 mmol) and triethylamine (1.14 ml, 8.19 mmol) in dichloromethane. The mixture was stirred at 40° C. for 3 h. The mixture was filtered, and the filtrate was added to water (10 ml) and extracted with ethyl acetate (30 ml). The organic phase was concentrated to yield the title compound as a crude solid product. 0.72 g.
Reaction SMILES: [F:1][C:2]([F:17])([S:13]([O-:16])(=[O:15])=[O:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].O[C:19]1[CH:24]=[CH:23][C:22]([S+:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1.ClCCl.C(N(CC)[C:44](Cl)=[O:45])C.[CH2:49]([N:51](CC)[CH2:52][CH3:53])[CH3:50]>O>[F:17][C:2]([F:1])([S:13]([O-:16])(=[O:15])=[O:14])[C:3]([F:11])([F:12])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[CH2:49]([N:51]([O:14][C:44]([C:19]1[CH:24]=[CH:23][C:22]([S+:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)=[O:45])[CH2:52][CH3:53])[CH3:50]
Reactant: CCN(CC)C(=O)Cl
Reactant: Oc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Reactant: CCN(CC)CC
Agent: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCN(CC)OC(=O)c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Yield: 152 %

Procedure:
Into a flask, 30 g of 4-hydroxyphenyldiphenylsulfonium perfluorobutanesulfonate and 300 g of dichloromethane were added to prepare a solution. In the flask, a nitrogen gas was blown. To the solution, 17.9 g of N,N-diethylcarbamoyl chloride was added and then 10.5 g of triethylamine was added thereto. The resultant mixture was stirred at room temperature for 1 hour. To the obtained reaction mixture, 100 g of ion-exchanged water was added and an organic layer was obtained by separation. The obtained organic layer was washed with 300 mL of distillated water and then dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration and the obtained filtrate was concentrated. The obtained residue was dried under reduced pressure to obtain 26.7 g of 4-(N,N-diethylaminocarboxy)phenyldiphenylsulfonium perfluorobutanesulfonate.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[CH3:16])=[CH:4][CH:3]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([I:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1>C(O)(C)C>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([I:28])[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:11][C:10]=2[CH3:16])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reactant: Clc1ncnc2ccc(I)cc12
Solvent: CC(C)O
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(I)cc34)cc2C)cn1
Yield: 69.1 %

Procedure:
4-(6-methylpyridin-3-yloxy)-3-methylbenzenamine (812 mg, 3.79 mmol) and 4-chloro-6-iodo-quinazoline (1 g, 3.4 mmol) were dissolved in isopropanol (50 ml). The reaction mixture was refluxed for 12 hours. The solid product was collected by filtration, washed with cold isopropanol (10 mL) and ether (20 mL), and air dried to afford 1.1 g of the clean desired material.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[C:12]([C:15]1[S:19][C:18]([C:20]2[CH:21]=[C:22]([NH:26][C:27]3[N:28]=[C:29]([NH:36][C@@H:37]4[CH2:42][CH2:41][CH2:40][CH2:39][C@@H:38]4[NH2:43])[N:30]=[N:31][C:32]=3[C:33]([NH2:35])=[O:34])[CH:23]=[N:24][CH:25]=2)=[CH:17][CH:16]=1)(=[O:14])[CH3:13]>>[C:12]([C:15]1[S:19][C:18]([C:20]2[CH:25]=[N+:24]([O-:9])[CH:23]=[C:22]([NH:26][C:27]3[N:28]=[C:29]([NH:36][C@@H:37]4[CH2:42][CH2:41][CH2:40][CH2:39][C@@H:38]4[NH2:43])[N:30]=[N:31][C:32]=3[C:33](=[O:34])[NH2:35])[CH:21]=2)=[CH:17][CH:16]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1ccc(-c2cncc(Nc3nc(N[C@@H]4CCCC[C@@H]4N)nnc3C(N)=O)c2)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CC(=O)c1ccc(-c2cc(Nc3nc(N[C@@H]4CCCC[C@@H]4N)nnc3C(N)=O)c[n+]([O-])c2)s1

Procedure:
An excessive quantity of m-CPBA was used, and a method similar to that in Example 1 (Step 3) and (Step 4), a method according to these methods, or a combination of them with routine procedures was used for 3-(methylthio)-5-(5-(5-acetylthiophen-2-yl)pyridin-3-ylamino)-1,2,4-triazine-6-carboxamide obtained in Example 15 to obtain the titled compound as a white solid.
Reaction SMILES: N1CCOCC1.[N:7]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.IC1C=CC(S(Cl)(=O)=O)=CC=1.[Br:31][C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1>>[Br:31][C:32]1[CH:33]=[C:34]([S:38]([N:10]2[CH2:11][CH2:12][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:9]2)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=S(=O)(Cl)c1ccc(I)cc1
Solvent: C1COCCN1
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cccc(Br)c2)CC1

Procedure:
Identical procedure to Step A of Example 1, but the morpholine is replaced by tert-butyl piperazine-1-carboxylate and the 4-iodobenzenesulphonyl chloride by 3-bromobenzenesulphonyl chloride.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([N:6]1[CH2:5][C@@H:4]([CH3:8])[NH:3][C@@H:2]([CH3:1])[CH2:7]1)(=[O:19])=[O:18]
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(S(C)(=O)=O)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
To a solution of cis-2,6-dimethyl-piperazine (600 mg) and triethylamine (0.80 mL) in dichloromethane (10 mL) at 0° C. was added dropwise methanesulfonyl chloride (0.43 mL). The reaction mixture was stirred at room temperature for 16 h and then quenched with water (10 mL) and extracted into dichloromethane (2×20 mL). The combined organic layers were washed with saturated aqueous brine solution (2×20 mL), dried (MgSO4) and concentrated to afford (3S,5R)-1-methanesulfonyl-3,5-dimethyl-piperazine as a white solid (817 mg, 81%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:5]=1[N:15]1[CH:19]=[N:18][C:17]([SH:20])=[N:16]1.O1CCOCC1.Cl[CH:28]([F:30])[F:29]>C(OCC)(=O)C.O>[Cl:14][C:6]1[CH:7]=[C:8]([C:10]([F:11])([F:13])[F:12])[CH:9]=[C:4]([Cl:3])[C:5]=1[N:15]1[CH:19]=[N:18][C:17]([S:20][CH:28]([F:30])[F:29])=[N:16]1
Reactant: FC(F)(F)c1cc(Cl)c(-n2cnc(S)n2)c(Cl)c1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: FC(F)Sc1ncn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 25 °C

Procedure:
Sodium hydroxide (3.3 g) was added to a mixture of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-mercapto-1,2,4-triazole (0.32 g, 1 mmol), 1,4-dioxane (13 ml) and water (13 ml) at one time with blowing thereinto chlorodifluoromethane gas. The temperature rose to 60°-70° C. After the rise of temperature stopped, the mixture was cooled to room temperature and poured into water. Ethyl acetate was added and the organic layer was separated and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to give 0.29 g of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-difluoromethylsulfenyl-1,2,4-triazole.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[F:9][C:10]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:13][C:11]=1[NH2:12]>C(OCC)(=O)C>[F:9][C:10]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:13][C:11]=1[N:12]=[C:2]=[O:3]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc(OC2CCCC2)c(Cl)cc1F
Solvent: CCOC(C)=O
Product: O=C=Nc1cc(OC2CCCC2)c(Cl)cc1F

Procedure:
An ethyl acetate solution (5 ml) of trichloromethyl chloroformate (2.00 g, 10.0 mmol) was gradually dropwise added to an ethyl acetate solution (25 ml) of 2-fluoro-4-chloro-5-cyclopentyloxyaniline (2.30 g, 10.0 mmol) at room temperature. After addition, the whole was heated to remove ethyl acetate therefrom by distillation. As a result, 2-fluoro-4-chloro-5-cyclopentyloxyphenylisocyanate was obtained almost quantitatively.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][C:3]=1[C:9]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:10].[CH2:18]([NH:20][C:21]([NH2:23])=[O:22])[CH3:19].CC(C)([O-])C.[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:23][C:21](=[O:22])[NH:20][CH2:18][CH3:19])[N:5]=[CH:4][C:3]=1[C:9]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:10]
Reactant: O=C(Nc1cccnc1)c1cnc(Cl)cc1Cl
Reactant: CCNC(N)=O
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC#N
Product: CCNC(=O)Nc1cc(Cl)c(C(=O)Nc2cccnc2)cn1
Temperature: 100 °C
Reaction time: 16 h
Yield: 20.6 %

Procedure:
Compound ii (1.0 g, 3.7 mmol) and N-ethylurea (362 mg, 4.1 mmol) were dissolved in degassed dioxane (50 mL) under an atmosphere of argon. Potassium tert-butoxide (628 mg, 5.6 mmol), Xantphos (129 mg, 0.22 mmol) and palladium(0)bis(dibenzylideneacetone) (65 mg, 0.11 mmol) were added sequentially. The mixture was heated at 100° C. with stirring under argon for 16 h. Additional palladium(0)bis(dibenzylideneacetone) (65 mg, 0.11 mmol) and N-ethylurea (560 mg, 6.4 mmol) were added and the mixture heated at reflux for 5 h. The mixture was cooled to RT, diluted with acetonitrile (100 mL) and then adsorbed on to silica by concentration in vacuo. The crude product was purified by flash chromatography (40 g GraceResolv silica cartridge, 0-10% MeOH in EtOAc) to afford iii as a light brown solid (244 mg, 20%). [M+H]+ m/z=320.05.
Reaction SMILES: [N:1]#CBr.[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]2C=CC=CC=2)=[CH:7][CH:6]=1>CCOCC>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]#[N:1])=[CH:7][CH:6]=1
Reactant: N#CBr
Reactant: Brc1ccc(CNc2ccccc2)cc1
Solvent: CCOCC
Product: N#CNCc1ccc(Br)cc1
Reaction time: 72 h
Yield: 31.6 %

Procedure:
A mixture of cyanogen bromide (3.18 g, 30 mmol), and (4-bromophenyl) methyl aniline (11.25 g, 61 mmol) in ether (50 mL) was stirred for 3 days under nitrogen. The mixture was filtered, the filtrate evaporated, and the residue flash chromatographed on silica gel using 9/1 Hexane/acetone to give (4-bromophenyl)methylcyanamide (2 g, 16 %).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH2:10][S:9](=[O:14])(=[O:13])[C:8]=2[CH:15]=1)([O-])=O.[H][H]>C1COCC1.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH2:10][S:9](=[O:14])(=[O:13])[C:8]=2[CH:15]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)CCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc2c(c1)S(=O)(=O)CCO2
Yield: 46.4 %

Procedure:
0.917 g 6-Nitro-2,3-dihydro-benzo[1,4]oxathiine-4,4-dioxide (from g)) were hydrogenated in a mixture of 20 ml THF and 20 ml MeOH with 0.90 g 5% Pd—C at atmospheric hydrogen pressure for 90 min. at room temperature. The catalyst was filtered off, the filtrate evaporated and the residue chromatographed on silica to yield 370 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:12]=3[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:20]#[N:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49]O.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH2:49][CH2:48][N:47]([CH3:51])[CH3:46])=[CH:15][C:12]=3[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:20]#[N:21]
Reactant: N#Cc1cnc2cc3ccc(O)cc3cc2c1Nc1ccc(Cl)cc1Cl
Reactant: CN(C)CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(C)CCOc1ccc2cc3ncc(C#N)c(Nc4ccc(Cl)cc4Cl)c3cc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.5 %

Procedure:
To a suspension of 189.1 mg (0.50 mmol) of 4-(2,4-dichloroanilino)-7-hydroxybenzo[g]quinoline-3-carbonitrile, 207.2 mg (0.79 mmol) of triphenylphosphine and 66.9 mg (0.75 mmol) of 2-(dimethylamino)-ethanol in 3.0 mL of anhydrous methylene chloride at 0° C. is added dropwise diethyl azodicarboxylate. The resulting reaction mixture is stirred at room temperature under nitrogen for 2 days. The solvent is concentrated in vacuo and the residue is purified on preparative thin layer chromatography (developing solvent: 9:1 methylene chloride/methanol) to provide 46.3 mg (20.5%) of 4-(2,4-dichloroanilino)-7-[2-(dimethylamino)ethoxy]benzo[g]quinoline-3-carbonitrile as a yellow solid, mp 115–117° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:31])=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]=[C:11]([CH2:17][OH:18])[N:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](=[O:29])(=[O:28])[NH:26][CH3:27])[C:9]2=[O:30])=[O:5])[CH3:2].C(OC(C1C(C)=C2C(=CC=1C)N=[C:42]([CH2:48]OCC1C=CC=CC=1)[N:41](C1C=CC=CC=1S(=O)(=O)NC)[C:40]2=[O:68])=O)C.C(OCC)C>C1COCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:31])=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]=[C:11]([CH2:17][O:18][C:40](=[O:68])[NH:41][CH2:42][CH3:48])[N:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](=[O:29])(=[O:28])[NH:26][CH3:27])[C:9]2=[O:30])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)cc2nc(COCc3ccccc3)n(-c3ccccc3S(=O)(=O)NC)c(=O)c2c1C
Reactant: CCOC(=O)c1c(C)cc2nc(CO)n(-c3ccccc3S(=O)(=O)NC)c(=O)c2c1C
Agent: [Pd]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCNC(=O)OCc1nc2cc(C)c(C(=O)OCC)c(C)c2c(=O)n1-c1ccccc1S(=O)(=O)NC
Reaction time: 8 h
Yield: 43 %

Procedure:
Preparation of 2-Hydroxymethyl-5,7-dimethyl-3-(2-methylsulfamoyl-phenyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid ethyl ester: A solution of 2-Benzyloxymethyl-5,7-dimethyl-3-(2-methylsulfamoyl-phenyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid ethyl ester (15 g, 0.028 mol) in anhydrous THF (270 mL) is degassed under house vacuum. Palladium on activated charcoal (Acros, 10% Pd, 930 mg) is added and the suspension is flushed with hydrogen (balloon). The suspension is stirred under hydrogen overnight. TLC and LCMS analysis indicates that starting material remained. The reaction mixture is filtered through Celite, and the catalyst is washed sequentially with methanol, DCM and methanol. The filtrate is evaporated to give a cream solid. Trituration with diethyl ether provides a white solid which is removed by filtration and dried under high vacuum to provide the title compound (5.42 g, 0.012 mol, 43%). The ethereal filtrate, which contains un-reacted starting material, is evaporated in vacuo and the residue is subjected to a second cycle of hydrogenation (Pd—C, 920 mg): after stirring overnight under hydrogen TLC/LCMS indicated absence of starting material. The reaction mixture is worked-up as above to provide the title compound as a white solid (4.75 g, 0.01 mol, 38%). Total yield: 10.17 g, 0.022 mol, 82%.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH3:22])[CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>ClCCl>[CH3:24][N:2]([CH3:1])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=3[CH3:32])=[CH:17][C:16]=2[CH3:22])[CH2:6][CH2:5][CH2:4]1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Cc1cc(N)ccc1C(=O)N1CCCC(N(C)C)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)C)c3ccccc32)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Dimethylamino-1-(2-methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (H) (1.00 g) is dissolved in dichloromethane (30 ml), and thereto is added triethylamine (0.48 ml) under ice-cooling, and further added dropwise 2-methylbenzoyl chloride (0.44 ml). The mixture is stirred at room temperature for 1 hour. The reaction solution is washed with water, and dried over magnesium sulfate. The solvent is distilled off, and the resulting residue is crystallized by adding thereto ethyl acetate. The precipitated crystal is recrystallized from dichloromethane/ethyl acetate to give 5-dimethylamino-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.92 g) as white powder, m.p. 191-192° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[N:13]([C:14]=2[CH:15]=O)[C:12]2[CH2:17][CH2:18][CH2:19][CH2:20][C:11]=2[S:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([NH:29][NH2:30])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.C(O)C.N>O>[C:1]1([C:7]2[N:8]=[C:9]3[N:13]([C:14]=2[CH:15]=[N:30][NH:29][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:12]2[CH2:17][CH2:18][CH2:19][CH2:20][C:11]=2[S:10]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NNC(=O)c1ccccc1
Reactant: O=Cc1c(-c2ccccc2)nc2sc3c(n12)CCCC3
Agent: Cl
Agent: N
Solvent: CCO
Solvent: O
Product: O=C(NN=Cc1c(-c2ccccc2)nc2sc3c(n12)CCCC3)c1ccccc1
Yield: 84 %

Procedure:
0.28 g of 5,6,7,8-tetrahydro-2-phenyl-3-formylimidazo[2,1-b]benzothiazole and 0.15 g of benzohydrazide were stirred over night in 20 ml of a 0.1N hydrochloric acid-ethanol solution at room temperature and the precipitated crystal obtained by filtration. The crystals were dissolved in water and the solution was made alkaline by ammonia solution, then extracted by chloroform. The extract was washed with water and dried, then the solvent was distilled off and the residue was crystallized from ethyl acetate to obtain the desired substance in an amount of 0.35 g (yield of 84.0%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH2:25][C:26]([C:29](O)=[O:30])=[N:27][N:28]=2)[CH:19]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][CH2:2][NH:1][C:29]([C:26]3[CH:25]=[C:24]([C:20]4[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=4)[NH:28][N:27]=3)=[O:30])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1Cl
Reactant: O=C(O)C1=NN=C(c2cccnc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-c2ccn(CCNC(=O)c3cc(-c4cccnc4)[nH]n3)n2)cc1Cl
Yield: 3.6 %

Procedure:
The title compound was prepared from 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.361 g, 1.463 mmol), 5-Pyridin-3-yl-4H-pyrazole-3-carboxylic acid (0.305 g, 1.610 mmol), DIPEA (0.382 ml, 2.195 mmol), HOBt (0.297 g, 2.195 mmol) and EDCI (0.421 g, 2.195 mmol) using the method of Example 75(b) affording 0.022 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 3.71 (m, 2H), 4.38 (t, 2H), 6.97 (m, 1H), 7.23 (m, 1H), 7.48 (m, 1H), 7.86 (m, 2H), 7.97 (m, 1H), 8.09 (m, 1H), 8.17 (m, 1H), 8.40-8.71 (m, 2H), 8.98 (m, 1H), 13.82 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[O:20])[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:6][CH:5]=1)([OH:3])=[O:2].CO[CH:23](OC)[N:24]([CH3:26])[CH3:25].Cl.O>CN(C)C=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:11](=[O:20])[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:23][N:24]([CH3:26])[CH3:25])=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: O=C(Cc1ccc(C(=O)O)cc1)C(=O)c1ccccc1
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C=C(C(=O)C(=O)c1ccccc1)c1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 44 %

Procedure:
To a solution of 3-(4-carboxyphenyl)-1-phenyl-1,2-propanedione in 100 ml of dry dimethylformamide cooled in an ice-bath was added, with stirring, 56 ml of dimethylformamide dimethyl acetal. The reaction mixture was stirred at 0°-5° C. for 10 min. and then it was poured onto 1.2 l of ice-water and acidified with 130 ml 1N hydrochloric acid. After stirring for 5 min., 1.8 l of water was added and the precipitate was collected, washed with water and air-dried. The filter cake was dissolved in 1.7 l of methylene chloride, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to about 200 ml. Ether (200 ml) was added and the solution was concentrated to about 300 ml and allowed to stand at room temperature for 2 days. The solid was collected, washed with methylene chloride-ether (1:9) and dried at 80° C. for 3 hrs. to give 17.4 g (44%) of 2-(4-carboxyphenyl)-1-dimethylamino-4-phenyl-1-butene-3,4-dione as yellow crystals, m.p. 208°-209° C.