Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][CH:32]=O.N1CCCCC1>C(O)C>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][CH:32]=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20]
Reactant: COc1ccccc1CCC=O
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccccc1CCC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 964 mg (3.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 657 mg (4.0 mmol) of 3-(2-methoxyphenyl)-1-propanal in 20 ml of ethanol, 26 mg (0.3 mmol) of piperidine was added, followed by refluxing for 3.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=50/1) to yield 1.40 g (quant., yellow oily substance) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[C:10]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=[CH:14][C:13]([CH:16]2[CH2:22][C:21](=O)[O:20][C:18](=[O:19])[CH2:17]2)=[CH:12][CH:11]=1.Cl>ClCCl.O1CCOCC1>[ClH:1].[C:10]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:15]=[CH:14][C:13]([CH:16]([CH2:22][C:21]2[NH:9][C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=3[N:8]=2)[CH2:17][C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1
Reactant: Nc1ccc(Cl)cc1N
Reactant: O=C1CC(c2ccc(-c3ccccc3)cc2)CC(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(O)CC(Cc1nc2ccc(Cl)cc2[nH]1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
Commercial 4-chloro-1,2-phenylenediamine (214 mg) and 3-(biphenyl-4-yl)glutaric anhydride (399 mg) were dissolved in dichloromethane (5 ml) with heating. The dark solution was stirred at rt for 1 h. The precipitate formed was collected by suction filtration, washed with dichloromethane, and dried in vacuo to give a mixture of regioisomeric amides (0.48 g) as light brown solid. This solid was dissolved in 1,4-dioxane (1 ml) with heating. 4M HCl in 1,4-dioxane (3 ml) was added and the solution was heated to reflux for 1.5 h. The precipitate formed is isolated by suction filtration and washed with 1,4-dioxane and diethyl ether. The crude (0.4 g) is crystallised from acetic acid to provide 3-(biphenyl-4-yl)-4-(5-chloro-2-benzimidazolyl)butanoic acid HCl (0.27 g) as light brown crystals.
Reaction SMILES: C([C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([NH:7][CH:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:11][NH:10][CH2:9]1)=[O:6])C.[N:28]([CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][O:33]1)=[C:29]=[O:30].C(N(CC)CC)C>C1COCC1>[C:4]1([C:5]([NH:7][CH:8]2[CH2:13][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=3)[CH2:11][N:10]([C:29]([NH:28][CH2:31][CH:32]3[CH2:36][CH2:35][CH2:34][O:33]3)=[O:30])[CH2:9]2)=[O:6])[CH:24]=[CH:25][CH:26]=[CH:27][CH:3]=1
Reactant: CCc1ccccc1C(=O)NC1CNCC(c2ccc(C(F)(F)F)cc2)C1
Reactant: O=C=NCC1CCCO1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)NCC2CCCO2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
80 mg (0.23 mmol) of ethyl-N-{5-[4-(trifluoromethyl)phenyl]piperidin-3-yl}benzamide were initially charged in 2 ml of THF, and 29 mg (0.23 mmol) of 2-(isocyanatomethyl)tetrahydrofuran and 35 μl (0.25 mmol) of triethylamine were added. The mixture was stirred at RT overnight. The reaction mixture was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 88 mg (81% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH2:8][CH2:9][CH2:10][OH:11])[CH:7]=1.N1C=CC=CC=1.[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH2:8][CH2:9][CH2:10][O:11][S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:7]=1
Reactant: OCCCc1cc(Br)ccc1F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCc2cc(Br)ccc2F)cc1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
To a stirred solution of 3-(5-Bromo-2-fluoro-phenyl)-propan-1-ol (0.53 g, 2.3 mmol) in dry methylene chloride (10 mL) at 0° C. and under a nitrogen atmosphere was added pyridine (0.46 mL, 5.6 mmol) and tosyl chloride (0.47, 2.5 mmol). The cooling bath was removed and the mixture was warmed to room temperature for 12 h, and then quenched with 2 N HCl (6 mL). The mixture was partitioned between methylene chloride and H2O, and the aqueous layer was extracted with methylene chloride (2×10 mL). The organic layer was washed with brine and dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (10-20% Ethyl acetate/Petroleum Ether) to afford the titled compound (0.6 g, 69%) as a clear oil, identified by NMR and mass spectral analyses; MS (ES+): 403 (M+NH4+).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][C:7]([C:11]1[CH:12]=[C:13]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:14]3[C:19]=1[C:18]([NH2:20])=[N:17][CH:16]=[N:15]3)=[CH:6]2.Cl[CH2:34][C:35]([NH:37][CH3:38])=[O:36]>>[NH2:20][C:18]1[C:19]2=[C:11]([C:7]3[CH:8]=[CH:9][C:10]4[C:5]([CH:6]=3)=[N:4][N:3]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:2]=4[NH2:1])[CH:12]=[C:13]([CH:21]3[CH2:26][CH2:25][N:24]([CH2:34][C:35]([NH:37][CH3:38])=[O:36])[CH2:23][CH2:22]3)[N:14]2[N:15]=[CH:16][N:17]=1
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4c(N)n(-c5ccccc5)nc4c3)c12
Reactant: CNC(=O)CCl
Product: CNC(=O)CN1CCC(c2cc(-c3ccc4c(N)n(-c5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Yield: 38 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 298 and using 5-(3-amino-2-phenyl-2H-indazol-6-yl)-7-piperidin-4-yl-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and 2-chloro-N-methylacetamide as starting materials, 42.3 mg (38%) of the desired product was isolated. 1H NMR (300 MHz, CD3OD) δ 7.81 to 7.78 (m, 2H), 7.70 to 7.67 (m, 2H), 7.61 (t, 2H), 7.53 to 7.49 (m, 1H), 7.35 (s, 1H), 6.95 (dd, 1H), 6.61 (s, 1H), 3.26 to 3.19 (m, 1H), 3.07 (s, 2H), 2.99 (d, 2H), 2.79 (s, 3H), 2.36 (t, 2H), 2.11 (d, 2H), 1.97 to 1.87 (m, 2H); ES-MS m/z 496.2 [M+H]+, RT (min) 1.25.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:19][CH2:20][CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)=[CH:11][C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ClC1C(=O)C(C#N)=C(C#N)C(=[O:40])C=1Cl>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:29][CH:30]=2)=[CH:11][C:12]2[C:13](=[O:40])[CH2:14][CH2:15][CH2:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(CCCc2cc3c(cc2OCc2ccccc2)CCCC3)cc1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc(CCCc2cc3c(cc2OCc2ccccc2)CCCC3=O)cc1
Reaction time: 2 h
Yield: 18.1 %

Procedure:
To a solution of 4-[3-(3-benzyloxy-5,6,7,8-tetrahydro-2-naphthyl) propyl]benzoic acid (1.6 g) in ethyl acetate (50 ml) was added water (1 ml) and 2,3-dichloro-5,6-dicyanobenzoquinone (1.9 g). The mixture was stirred for 2 hours, the solvent evaporated and the residue subjected to chromatography on silica gel, eluting with 0.1% formic acid in EtOAc. The residue was purified by trituration with diethyl ether to give the title compound (0.3 g) mpt. 155°-160° C.
Reaction SMILES: [CH3:1][C@H:2]1N[C@@H:6](C)[CH2:5][N:4]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([C:25]4[CH:33]=[C:32]([F:34])[CH:31]=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)=[N:13][C:12]=3[CH:11]=2)[CH2:3]1.C(OC(=O)[NH:41]C1CCNCC1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:34][C:32]1[CH:31]=[C:30]2[C:26]([CH:27]=[CH:28][NH:29]2)=[C:25]([C:14]2[N:15]=[C:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:17]3[S:18][C:10]([CH2:9][N:4]4[CH2:3][CH2:2][CH:1]([NH2:41])[CH2:6][CH2:5]4)=[CH:11][C:12]=3[N:13]=2)[CH:33]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: C[C@@H]1CN(Cc2cc3nc(-c4cc(F)cc5[nH]ccc45)nc(N4CCOCC4)c3s2)C[C@H](C)N1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(Cc2cc3nc(-c4cc(F)cc5[nH]ccc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
Prepared according to the method used in the preparation of 6-(cis-3,5-dimethyl-piperazin-1-ylmethyl)-2-(6-fluoro-1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, using piperidin-4-yl-carbamic acid tert-butyl ester in place of 2,6-dimethyl-piperazine, followed by BOC-deprotection using TFA:DCM (1:1). The title compound was obtained as a white solid (25 mg, 33%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:10]([CH:12]1[CH2:17][CH2:16][CH:15]([CH:18]2[CH2:22][O:21][C:20]3([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[O:19]2)[CH2:14][CH2:13]1)=O)C.C1C[O:31][CH2:30]C1>>[O:19]1[C:20]2([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[O:21][CH2:22][CH:18]1[CH:15]1[CH2:14][CH2:13][CH:12]([CH2:10][CH2:30][OH:31])[CH2:17][CH2:16]1
Reactant: C1CCOC1
Reactant: CCOC(=O)C1CCC(C2COC3(CCCCC3)O2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCC1CCC(C2COC3(CCCCC3)O2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Dried THF (100 ml) was added to lithium aluminum hydride (17.6 g, 0.464 mol), followed by cooling the mixture down to 0° C., dropwise adding thereto a 800 ml THF solution of the above 4-(1,4-dioxaspiro[4.5]decyl)cyclohexylmethanoic acid ethyl ester (183.2 g, 0.464 mol), stirring at 0° C. for 3 hours, stirring at room temperature for 2 hours, washing the reaction solution successively with 3N HCl, a saturated aqueous solution of sodium bicarbonate and water, distilling off the solvent, and recrystallizing, to isolate colorless crystals of 2-(4-(1,4-dioxaspiro[4,5]decyl)cyclohexyl)ethanol (50.6 g, 0,179mol). Yield from bicyclohexanedione monoethylene ketal was 38%.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[NH:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)[CH:8]=[CH:9][CH:10]=1>C(N)(C)C>[CH:14]([NH:15][CH2:20][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[NH:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:16])[CH3:13]
Reactant: FC(F)(F)c1c[nH]c(-c2cccc(OCC3CO3)c2)n1
Solvent: CC(C)N
Product: CC(C)NCC(O)COc1cccc(-c2nc(C(F)(F)F)c[nH]2)c1

Procedure:
A solution of 2-[3-(2,3-epoxypropoxy)phenyl]-4-trifluoromethylimidazole (0.9 g.) in isopropylamine (10 ml.) is heated 6 hours at reflux. The excess isopropylamine is removed by distillation at atmospheric pressure over steam. The residue is triturated with nitromethane (5 ml.) and the resulting solid removed by filtration. After recrystallization from nitromethane 0.65 g. of 2-[3-(3-isopropylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole is obtained, m.p. 162.5°-163.5° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([O:14][C:15]([C@:17]1([N:39]=[N+:40]=[N-:41])[C@H:22]([S:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:21][C@@H:20]2[C@H:18]1[C@@:19]2([F:38])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:16])[CH3:13]>ClCCl>[CH2:12]([O:14][C:15]([C@:17]1([N:39]=[N+:40]=[N-:41])[C@H:22]([S:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)=[O:9])[CH2:21][C@@H:20]2[C@H:18]1[C@@:19]2([F:38])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:16])[CH3:13]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](SCc3ccc(Cl)c(Cl)c3)[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](S(=O)Cc3ccc(Cl)c(Cl)c3)[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Reaction time: 1 h
Yield: 83.5 %

Procedure:
32 mg of 3-chloroperbenzoic acid was added to 73 mg of (1R,2S,3R,5R,6R)-2-azido-3-(3,4-dichlorobenzylsulfanyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 1.46 mL of dichloromethane and the mixture was stirred for 1 hour in a dry ice-acetone bath. The mixture was stirred for 3.5 hours in an ice bath, and further stirred for 11 hours at room temperature. 15 mg of 3-chloroperbenzoic acid was further added thereto, and the mixture was stirred for 1 hour in a dry ice-acetone bath, and then stirred for 4 hours in an ice bath. The reaction solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200 (made by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=4:1 to 2:1), thereby yielding 63 mg of (1R,2S,3R,5R,6R)-2-azido-3-(3,4-dichlorobenzylsulfinyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester and 12 mg of (1R,2S,3R,5R,6R)-2-azido-3-(3,4-dichlorobenzylsulfonyl-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([C:10]2([F:25])[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[CH3:26][S:27]([Cl:30])(=[O:29])=[O:28].C(N(C(C)C)CC)(C)C>>[ClH:30].[F:25][C:10]1([C:6]2[CH:5]=[C:4]([NH:3][S:27]([CH3:26])(=[O:29])=[O:28])[CH:9]=[CH:8][CH:7]=2)[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:14][CH2:15]1
Reactant: Nc1cccc(C2(F)CCN(CCOc3ccccc3)CC2)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1cccc(C2(F)CCN(CCOc3ccccc3)CC2)c1
Yield: 64 %

Procedure:
The title compound was prepared from the reaction of 4-(3-aminophenyl)-1-(2-phenoxyethyl) 4-fluoropiperidine dihydrochloride with methanesulfonyl chloride in the presence of excess diisopropylethylamine as described in Example 17. The desired material was obtained in 64% yield as an off-white solid.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C@@H:18]([CH3:42])[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2)=[O:20]>>[CH2:1]([NH:8][C:9]([NH:10][O:11][CH2:12][C:13]([NH:17][C@@H:18]([CH3:42])[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2)=[O:20])=[O:15])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)N
Reactant: O=C(O)CONC(=O)NCc1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)NC(=O)CONC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-benzylureidooxy)acetic acid (Compound VI-1) 94 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-11) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].[C:12](Cl)(Cl)=[O:13]>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]2[C:5]([O:7][C:12](=[O:13])[NH:11][C:3]=12)=[O:6]
Reactant: Nc1c(Cl)cccc1C(=O)O
Reactant: O=C(Cl)Cl
Solvent: Clc1ccccc1
Product: O=c1[nH]c2c(Cl)cccc2c(=O)o1
Temperature: 25 °C

Procedure:
171.6 g (1.0 mol) of 99.7% 3-chloroanthranilic acid are initially introduced, in 1,720.0 g of chlorobenzene, into a four-necked flask having a stirrer, a thermometer and a reflux condenser operated at -20° C., and 440.0 g of phosgene are gassed in at 100° C. over a period of about 3 h while stirring thoroughly. After that, the mixture is stirred at 100° C. for a further 1 h, and is subsequently blown free of phosgene at this temperature using nitrogen. After cooling to about 25° C., the crystals which have precipitated out are filtered off with suction and the filter cake is washed with 2×50 ml of chlorobenzene and dried at 100° C. in vacuo. 184.9 g of 3-chloroisatoic anhydride, having a purity by GC of >99%, are obtained, corresponding to 93.6% of theory.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[SH:11].I[C:13]1[CH:14]=[C:15]([Br:19])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1
Reactant: Sc1ccc2ccccc2c1
Reactant: Brc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cccc(Sc2ccc3ccccc3c2)c1
Temperature: 25 °C
Yield: 62 %

Procedure:
A mixture of 2-naphthalenethiol (3.2 g), 3-iodobromobenzene (6.7 g), potassium carbonate (1.4 g), cuprous chloride (0.4 g) and DMF (4 ml) was heated to reflux for 1 hour. The mixture was allowed to cool to ambient temperature and was partitioned between diethyl ether and water. The mixture was filtered and the organic layer was separated, dried (MgSO4) and evaporated. The residue was taken up in ethyl acetate, decolourised by treatment with charcoal, reisolated and purified by recrystallisation from methanol to give 3-bromophenyl 2-naphthyl sulphide (3.9 g, 65%), m.p. 68°-70° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([NH:13][CH3:14])[CH:5]=1>[Pd]>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:2][CH3:1])=[O:15])=[CH:5][C:6]=1[NH:13][CH3:14]
Reactant: CNC(=O)c1ccc([N+](=O)[O-])c(NC)c1
Agent: [Pd]
Product: CNC(=O)c1ccc(N)c(NC)c1
Yield: 85.5 %

Procedure:
4-Amino-N-methyl-3-methylamino-benzamide (298 mg, 86%) was prepared by following General Procedure B starting from N-methyl-3-methylamino-4-nitro-benzamide (407 mg) and Pd/C (10% by weight, 40 mg). The crude product was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[CH2:13][C:14]([OH:16])=O.[C:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[CH2:13][C:14]([N:27]1[CH2:26][CH2:25][N:24]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:29][CH2:28]1)=[O:16]
Reactant: O=C(O)Cc1ccc(-n2cnnn2)cc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2ccc(-n3cnnn3)cc2Br)CC1

Procedure:
A solution of [2-bromo-4-(1H-tetrazol-1-yl)phenyl]acetic acid (500 mg, 1.77 mmol), Boc-piperazine (329 mg, 1.77 mmol), EDC (418 mg, 2.12 mmol), HOBt (286 mg, 2.12 mmol) and TEA (530 mg, 5.31 mmol) in 20 mL of DCM was stirred at room temperature overnight. The solvent was removed under reduce pressure and the crude was purified via prep-TLC to afford tert-butyl 4-{[2-bromo-4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazine-1-carboxylate.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[OH:11][NH:12][CH:13]([CH:45]([CH3:47])[CH3:46])[CH2:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][NH:31][C:32]([C:34]3[NH:43][C:42](=[O:44])[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[O:33])[CH:25]=2)=[CH:20][CH:19]=1)(=[O:17])=[O:16]>C1COCC1>[CH:1]([N:12]([OH:11])[CH:13]([CH:45]([CH3:47])[CH3:46])[CH2:14][S:15]([C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][NH:31][C:32]([C:34]3[NH:43][C:42](=[O:44])[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[O:33])[CH:25]=2)=[CH:22][CH:23]=1)(=[O:16])=[O:17])=[O:2]
Reactant: CC(C)C(CS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1)NO
Reactant: O=CO
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CC(C)C(CS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1)N(O)C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
To formic acid (0.217 mL) was added acetic anhydride (0.054 mL, 0.576 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hr. This solution was added to a suspension of N-[(4′-{[2-(hydroxyamino)-3-methylbutyl]sulfonyl}biphenyl-3-yl)methyl]-4-oxo-3,4-dihydroquinazoline-2-carboxamide obtained in Reference Example 107 (0.285 g, 0.430 mmol) and formic acid (2 mL) in THF (20 mL), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (GILSON 215LIQUD HANDLER, 322PUMP, UV/VIS-156, SHISEIDO CAPCELL PACK C-18 UG120 S-s (20 mmφ×50 mm), mobile phase: distilled water (containing 0.1% trifluoroacetic acid)/acetonitrile (containing 0.1% trifluoroacetic acid), gradient: distilled water/acetonitrile=90/10→0/100, time: 10 min, flow rate: 25 mL/min, detection wavelength: 220 nm), and crystallized from EtOH-ethyl acetate-diethyl ether to give the title compound as a pale-yellow powder (0.077 g, 37%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(OC([N:15]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH2:21]2)[CH2:17][CH2:16]1)=O)C1C=CC=CC=1.CCN(CC)CC>C(Cl)Cl>[C:1]([N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]2([CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)[CH2:21]1)(=[O:3])[CH3:2]
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CNc1ccccc12
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC2(CCNCC2)c2ccccc21
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
Acetyl chloride (1.4 mL, 19.9 mmol) was added to a solution of 5.35 g (16.6 mmol) of 1'-benzyloxycarbonyl-spiro(indoline-3,4'-piperidine) in 33 mL of CH2Cl2 and 3.2 mL (23.2 mmol) of Et3N keeping the temperature between 0-5° C. by cooling in ice bath. After 10 min the cold bath was removed and reaction was stirred for 30 min at which time a TLC indicated complete reaction. The solution was diluted with CH2Cl2 and washed with water, brine and dried over Na2SO4. The filtrate was concentrated to a thick oil and the oil was dissolved in 40 mL of EtOH. Acetic acid (3 mL) and 0.8 g of 10% Pd/C were added to the solution and the resulting mixture was hydrogenated on a Parr apparatus for 3 h. The catalyst was filtered and washed with EtOAc and the combined filtrate was concentrated. The residue was partitioned between CH2Cl2 and water and 2N NaOH was added to this mixture until the aqueous layer was basic. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4 and the filtrate was concentrated to give 2.93 g (77%) of the title compound sufficiently pure for use in the next reaction.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][C:10]#[N:11].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[O:7]1[C:4]2([CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:9]1[C:10]#[N:11]
Reactant: N#CCCl
Reactant: O=C1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: N#CC1OC12CCOCC2
Reaction time: 8 h

Procedure:
To a mixture of tetrahydro-4H-pyran-4-one (5.0 g, 50 mmol) and chloroacetonitrile (3.8 g, 50 mmol) was dropwise added a solution of potassium tert-butoxide in tert-butanol (1.0 M, 50 mL). The reaction mixture was stirred overnight and quenched with water (100 mL). The whole was extracted with ethyl acetate (200 mL). The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the titled compound. (5.65 g)