Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(OCC)=O.[Br:7][C:8]1[CH:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][N:9]=1.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>C(N(CC)CC)C>[Br:7][C:8]1[CH:13]=[C:12]([C:14]([N:19]([CH2:20][CH3:21])[CH2:17][CH3:18])=[O:16])[CH:11]=[CH:10][N:9]=1
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: CCNCC
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl chloroformate (1.07 g) was added dropwise to a solution of 2-bromo-4-pyridinecarboxylic acid (2 g) and triethylamine (1 g) at 0°. The mixture was stirred at room temperature for 1 h, diethylamine (3 ml) was added dropwise and the resulting suspension was stirred vigorously for 2 h. The precipitate was collected by filtration and washed with water (20 ml) to give the title compound as a white solid (1.55 g), m.p. 200°-203°.
Reaction SMILES: C(O[C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]([C:31]([CH:33]1[CH2:37][CH2:36][CH2:35][C:34]1([NH2:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])C1C=CC=CC=1>CO>[C:38]([CH2:34][CH2:33][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]([C:31]([CH:33]1[CH2:37][CH2:36][CH2:35][C:34]1([NH2:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:32])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])([OH:40])=[O:39]
Reactant: CCOC(=O)C1(N)CCCC1C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Solvent: CO
Product: CCOC(=O)C1(N)CCCC1C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)CCC(=O)O
Reaction time: 2 h

Procedure:
A solution of ethyl benzyloxycarbonylphenylalanylphenylalanyl-1-amino-1-cyclopentanecarboxylate (590 mg, 1 mmole) in methanol was hydrogenated by the procedure of Example 1. The methanolic solution was evaporated, dissolved in tetrahydrofurane, evaporated and acylated with glutaric anhydride (175 mg) in dimethylformamide for 2 hours at 80° C. The reaction mixture was evaporated and the product was precipitated with water to give the title compound, m.p. 193° to 196° C. (dimethylformamide-water).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[CH:20]([N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:31]=2[C:37]([F:40])([F:39])[F:38])[CH2:25][CH2:24]1)([CH3:22])[CH3:21]>C(Cl)Cl.CO>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:36][C:33]3[CH:34]=[CH:35][C:30]([CH2:29][N:26]4[CH2:25][CH2:24][N:23]([CH:20]([CH3:22])[CH3:21])[CH2:28][CH2:27]4)=[C:31]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)=[O:19])=[CH:14][CH:15]=2)[CH:2]=1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Reactant: CC(C)N1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Solvent: CO
Solvent: ClCCl
Product: CC(C)N1CCN(Cc2ccc(NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 7.1) and 4-(4-isopropyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (see WO 03/099771). Title compound: ES-MS: 537.0 [M+H]+; single peak at tR=3.08 min (System 1); Rf=0.12 (CH2Cl2/MeOH+1% NH3aq, 95:5).
Reaction SMILES: [NH2:1][CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[CH:3]([C:5]1[CH:9]=[CH:8][O:7][CH:6]=1)[OH:4].[F:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32](O)=[O:33])=[CH:24][CH:23]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]([NH:1][CH:2]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=2)[CH:3]([C:5]2[CH:9]=[CH:8][O:7][CH:6]=2)[OH:4])=[O:33])=[CH:24][CH:23]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccoc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccoc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3-furanyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (500 mg, 1.75 mmol) in acetonitrile (30 ml) were added 4-fluoronaphthalenecarboxylic acid (333 mg, 1.75 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (504 mg, 2.63 mmol) and 1-hydroxy-1H-benzotriazole (268 mg, 1.75 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1). Recrystallization from ethyl acetate-hexane gave the title compound (573 mg, 71%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11]/[C:12](=[CH:18]\[C:19]1[N:20]=[CH:21][N:22]([CH:24]2[CH2:29][CH2:28][CH2:27][C:26]([CH3:31])([CH3:30])[CH2:25]2)[CH:23]=1)/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[C].[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH:12]([CH2:18][C:19]1[N:20]=[CH:21][N:22]([CH:24]2[CH2:29][CH2:28][CH2:27][C:26]([CH3:30])([CH3:31])[CH2:25]2)[CH:23]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)/C(=C/c1cn(C2CCCC(C)(C)C2)cn1)CCCNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(CCCNC(=O)OC(C)(C)C)Cc1cn(C2CCCC(C)(C)C2)cn1
Temperature: 25 °C
Reaction time: 7 h
Yield: 96.7 %

Procedure:
The compound (347 mg) obtained in Step 1 of this Example was dissolved in ethanol (10 mL). To the solution, 10% palladium-carbon catalyst (hydrated, 170 mg) was added, and the mixture was stirred at room temperature for 7 hours under a hydrogen atmosphere. The catalyst was filtered off, and the solvent in the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=1/1-ethyl acetate) to obtain the title compound (337 mg).
Reaction SMILES: C(Cl)Cl.[CH2:4]([C:6]1[NH:7][C:8]2[C:13]([C:14](=[O:17])[C:15]=1[CH3:16])=[CH:12][C:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)=[C:10]([CH3:30])[CH:9]=2)[CH3:5].[OH-].[Na+].Cl[C:34]([O:36][CH3:37])=[O:35]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CC(N(C)C)=O>[C:34](=[O:35])([O:36][CH3:37])[O:17][C:14]1[C:13]2[C:8](=[CH:9][C:10]([CH3:30])=[C:11]([O:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:27])([F:28])[F:29])=[CH:21][CH:20]=3)[CH:12]=2)[N:7]=[C:6]([CH2:4][CH3:5])[C:15]=1[CH3:16]
Reactant: CCc1[nH]c2cc(C)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(=O)c1C
Reactant: COC(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCc1nc2cc(C)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(OC(=O)OC)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
Methylene chloride (1000 ml), 160 ml of dimethyl acetamide, 113.2 g of 2-ethyl-3,7-dimethyl-6-(4-(trifluoromethoxy)phenoxy)quinolin-4(1H)-one, and 4.8 g of tetrabutylammonium bromide were added to a glass vessel equipped with a stirring device, a thermometer, and a reflux condenser and having a volume of 3000 ml, and the mixture was stirred at room temperature. A 48% aqueous sodium hydroxide solution (50 g) was added dropwise at 25 to 30° C., and the mixture was stirred at the same temperature for one hr. After cooling to 10 to 15° C., 34 g of methyl chloroformate was added dropwise, and a reaction was allowed to proceed at the same temperature for one hr. Water was added to the reaction solution for washing. Methylene chloride was removed by evaporation, 990 ml of methanol was added to the residue, and the mixture was heated to dissolve the residue in methanol. Water (660 ml) was added dropwise thereto to precipitate crystals, and the precipitated solid was collected by a suction filter. The solid was dried in vacuo to give 2-ethyl-3,7-dimethyl-6-(4-(trifluoromethoxy)phenoxy)quinolin-4-yl methyl carbonate (124.4 g, yield 95.2%). It was confirmed from the results of measurement of 1H-NMR that the compound thus obtained was a compound of No. 120 described in WO2006/013896 (patent document 1).
Reaction SMILES: I[C:2]1[S:6][C:5]([NH:7][C:8](=[O:19])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[OH-].[Na+].[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[S:6][C:5]([NH:7][C:8](=[O:19])[C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)=[N:4][C:3]=2[C:20]([F:23])([F:22])[F:21])=[CH:29][CH:28]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(Nc1nc(C(F)(F)F)c(I)s1)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Nc1nc(C(F)(F)F)c(-c2ccc(F)cc2)s1)c1ccc(C(F)(F)F)cc1

Procedure:
N-(5-Iodo-4-trifluoromethylthiazol-2-yl)-4-trifluoromethylbenzamide (0.8 g), powdered sodium hydroxide (0.29 g), tetrakis(triphenylphosphine)-palladium(0) (0.2 g) and 4-fluorophenylboronic acid (0.24 g) were mixed together in tetrahydrofuran (30 ml). The resulting suspension was refluxed for 8 hr with stirring. The solvent was removed under reduced pressure and the residue was mixed with water then extracted with chloroform. The chloroform layer was dried over magnesium chloride and the solvent was removed under reduced pressure. The solid remained was recrystallized from methanol to give N-(5-(4-fluorophenyl)-4-trifluoromethylthiazol-2-yl)-4-trifluoromethylbenzamide as slightly gray needles (0.55 g), m. p. 203-205° C.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1.CC(C)=O>[N:13]1([C:2]2[C:3]3[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: Cc1[nH]c2ncnc(Cl)c2c1C
Reactant: c1ccc2c(c1)CCCN2
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: Cc1[nH]c2ncnc(N3CCCc4ccccc43)c2c1C

Procedure:
This product is prepared in a manner analogous to that described in Example 1 from 4-chloro-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine and 1,2,3,4-tetrahydroquinoline (4 equivalents, Fluka, Buchs, Switzerland). M.p: 263-264° C.; FAB-MS: (M+H)+ =279 (corresponds to C17H18N4); Rf value (toluene-acetone--(4:6))=0.29.
Reaction SMILES: [I:1]I.[CH2:3]([C:10]1[N:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)(O)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>O.C1COCC1>[CH2:3]([C:10]1[N:15]=[C:14]([I:1])[C:13]([OH:16])=[CH:12][CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: II
Reactant: Oc1ccc(Cc2ccccc2)nc1
Agent: Cl
Agent: O=C(O)O
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc(Cc2ccccc2)nc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Iodine (3.21 g, 12.6 mmol) was added to a solution of 6-benzylpyridin-3-ol (2.34 g, 12.6 mmol) and sodium carbonate anhydrous (1.06 mL, 25.3 mmol) in water (60 mL) and THF (60 mL). The mixture was allowed to stir for 1 h at room temperature, treated with sodium thiosulfate, and acidified pH 3 using 5M aqueous HCl. Extractive workup and flash chromatography using EtOAc/hexanes gave 6-benzyl-2-iodopyridin-3-ol. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.62 (s, 1H), 7.13-7.34 (m, 5H), 6.99-7.11 (m, 2H), 3.95 (s, 2H). MS (ESI) m/z: Calculated; 311.0 Observed: 311.9 (M++1).
Reaction SMILES: [CH2:1]([N:8]([CH2:14][CH2:15][OH:16])[CH2:9][CH:10](O)[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[OH-].[Na+]>O>[CH2:1]([N:8]1[CH2:14][CH2:15][O:16][CH:10]([CH2:11][CH3:12])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(O)CN(CCO)Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC1CN(Cc2ccccc2)CCO1
Temperature: 140 °C

Procedure:
To 1-(benzyl(2-hydroxyethyl)amino)butan-2-ol (2.9 g, 12.99 mmol) was added 70% H2SO4 (15 mL) and the resulting solution was heated at 140° C. for 17 h. The mixture was brough to RT, cooled to 0° C. and made alkaline with 50% NaOH. The resulting solution was diluted in water and extracted with DCM. The combined organics were dried over Na2SO4, filtered and concentrated to afford 4-benzyl-2-ethylmorpholine as a light orange oil that was used without further purification.
Reaction SMILES: [CH3:1][N:2]1C[CH2:6][O:5][CH2:4][CH2:3]1.[F:8][C:9]([F:35])([F:34])[C:10]1[N:14]2[N:15]=[C:16]([N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1.ClC1N=C(OC)N=C(OC)N=1.COCCNC>CN(C=O)C>[CH3:6][O:5][CH2:4][CH2:3][N:2]([CH3:1])[C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:25]([CH:22]2[CH2:21][CH2:20][N:19]([C:16]3[CH:17]=[CH:18][C:13]4[N:14]([C:10]([C:9]([F:34])([F:8])[F:35])=[N:11][N:12]=4)[N:15]=3)[CH2:24][CH2:23]2)=[CH:26][CH:27]=1
Reactant: CN1CCOCC1
Reactant: O=C(O)c1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: CNCCOC
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN(C)C=O
Product: COCCN(C)C(=O)c1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.4 %

Procedure:
4-Methylmorpholine (17.56 mL, 159.70 mmol) was added dropwise to 4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzoic acid (25 g, 63.88 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (13.46 g, 76.66 mmol) suspended in DMF (250 mL) at 0° C. The resulting suspension was stirred for 10 minutes, then 2-methoxy-N-methylethanamine (5.69 g, 63.88 mmol) was added and the mixture warmed to ambient temperature and stirred for 16 hours. The reaction mixture was concentrated and diluted with DCM (1000 mL) and washed with water (500 mL). The aqueous phase was re-extracted with DCM (500 mL), then the combined organics were washed with saturated NaHCO3 (500 mL) and saturated brine (250 mL), and dried over MgSO4, filtered and evaporated to afford crude product. The crude product was triturated with ether, and the resulting solid was collected by filtration and dried under vacuum, then purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford N-(2-methoxyethyl)-N-methyl-4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzamide (23.45 g, 79%) as a solid.
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24])=[O:17]>C1CCCCC1.C(Cl)Cl>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]([C:4]1[C:5]([CH3:15])=[C:6]([O:13][CH3:14])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[OH:2])=[O:17]
Reactant: COc1c(C)c(C(=O)c2ccccc2F)c(OC)c2ccccc12
Solvent: C1CCCCC1
Solvent: ClCCl
Product: COc1c(C)c(C(=O)c2ccccc2F)c(O)c2ccccc12

Procedure:
(1,4-dimethoxy-3-methylnaphthalen-2-yl)(2-fluorophenyl)methanone LJ103 (75 mg, 0.231 mmol) was treated according to general procedure 12.1. The product was obtained as a yellow powder. Rf(Cyclohexane:DCM 3:2)=0.29. Yield=68 mg (94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([C:18]2[N:22]=[CH:21][N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:19]=2)[C:13](=[O:42])[C:12]3([CH3:50])[CH2:43][C:44]2[CH:45]=[N:46][CH:47]=[N:48][CH:49]=2)[CH:5]=[CH:6][C:7]=1[F:8]>CO.ClCCl.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([C:18]2[N:22]=[CH:21][NH:20][N:19]=2)[C:13](=[O:42])[C:12]3([CH3:50])[CH2:43][C:44]2[CH:49]=[N:48][CH:47]=[N:46][CH:45]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC1(Cc2cncnc2)C(=O)N(c2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c2ccc(-c3ccc(F)c(Cl)c3)cc21
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC1(Cc2cncnc2)C(=O)N(c2nc[nH]n2)c2ccc(-c3ccc(F)c(Cl)c3)cc21

Procedure:
5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1-trityl-1,2,4-triazol-3-yl)-1,3-dihydro-2H-indol-2-one (8.25 g, 12.2 mmol) in methanol (60 mL), dichloromethane (10 mL) and 1 N aqueous HCl solution (30 mL) was stirred at 50° C. for 1.5 hours. Most of the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and water (50 mL) was added. The pH of the mixture was adjusted to pH=7 with the addition of 1 N aqueous sodium hydroxide solution. The organic layer was separated and the aqueous layer further extracted with dichloromethane (2×100 mL). The organic extracts were combined, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane and hexane was then slowly added. The product recrystallized over 3 days. The crystalline product was filtered, washed with 50% dichloromethane/hexanes and dried under reduced pressure. The filtrate was collected, concentrated under reduced pressure and purified by column chromatography on silica gel Biotage 40S, eluting with 40-100% ethyl acetate/hexanes, to give additional product. The product from crystallization and the product from column chromatography were combined, dissolved in acetonitrile/water and lyophilized to afford 5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1H-1,2,4-triazol-3-yl)-1,3-dihydro-2H-indol-2-one as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([CH2:10][NH:11][CH3:12])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[O:15]=[C:16]1[NH:25][C:24]2[N:23]=[CH:22][C:21](/[CH:26]=[CH:27]/[C:28]([OH:30])=O)=[CH:20][C:19]=2[CH2:18][CH2:17]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C.O>[F:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([CH2:10][N:11]([CH3:12])[C:28](=[O:30])/[CH:27]=[CH:26]/[C:21]3[CH:22]=[N:23][C:24]4[NH:25][C:16](=[O:15])[CH2:17][CH2:18][C:19]=4[CH:20]=3)=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CNCc1sc2ccc(F)cc2c1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)sc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a solution of (5-fluoro-3-methylbenzo[b]thiophen-2-yl)-N-methylmethanamine (168 mg, 0.8 mmol) in DMF (5 mL) were added in sequential order (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid (159 mg, 0.73 mmol), 1-hydroxybenzotriazole (111 mg, 0.8 mmol), diisopropylethylamine (381 uL, 2.19 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (160 mg, 0.8 mmol). The mixture was stirred at room temperature overnight, cooled in an ice bath and water added with rapid stirring. The product precipitated and was filtered, triturated with ether and dried to yield the title compound as a pale brown solid (224 mg, 75%): 1H NMR (300 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.37 (s, 1H), 8.08 (s, 1H), 7.76-8.00 (m, 1H), 7.39-7.63 (m, 2H), 7.02-7.33 (m, 2H), 4.87-5.11 (rotamers, 2s, 2H), 3.16 (s, 3H), 2.56-2.89 (m, 2H), 2.49-2.51 (m, 2H), 2.39 (s, 3H); MS (ESI) m/e 410 (C22H20FN3O2S+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:21][CH2:20][CH2:19][CH:18]([N:22]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:23]2[NH:27][N:26]=[N:25][N:24]=2)[C:17]2[CH:43]=[C:44]([CH3:51])[C:45]([C:47]([F:50])([F:49])[F:48])=[CH:46][C:16]1=2)=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[F:42][C:39]([F:40])([F:41])[C:31]1[CH:30]=[C:29]([CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=1)[CH2:28][N:22]([CH:18]1[CH2:19][CH2:20][CH2:21][NH:15][C:16]2[CH:46]=[C:45]([C:47]([F:48])([F:49])[F:50])[C:44]([CH3:51])=[CH:43][C:17]1=2)[C:23]1[NH:27][N:26]=[N:25][N:24]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCCC2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NCCCC2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn[nH]1
Reaction time: 1.5 h
Yield: 100.6 %

Procedure:
Add dichloromethane (5 mL) and trifluoroacetic acid (5 mL) to 5-[(3,5-bis-trifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (0.18 g, 0.24 mmol). After stirring for 1-2 h, neutralize the reaction with sodium carbonate. Wash the organic phase with water (5 mL) and brine (5 mL). Dry the organics over sodium sulfate and filter. Chromatograph the crude material, eluting with ethyl acetate/hexane (20-60%) to provide the title compound (0.13 g, 85%) as an oil. MS (ES+): 539 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9]([OH:20])[N:8]=[C:7]([CH:21]2[CH2:25][CH2:24][CH2:23][N:22]2C(OC(C)(C)C)=O)[N:6]=1)=[O:4].[C:33](O)(C(F)(F)F)=O.C(Cl)Cl>>[C:12]([O:11][C:10]1[C:9](=[O:20])[N:8]([CH3:33])[C:7]([CH:21]2[CH2:25][CH2:24][CH2:23][NH:22]2)=[N:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4])(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1nc(C2CCCN2C(=O)OC(C)(C)C)nc(O)c1OC(=O)c1ccccc1
Solvent: ClCCl
Product: COC(=O)c1nc(C2CCCN2)n(C)c(=O)c1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl-5-(benzoyloxy)-2-[1-(tert-butoxycarbonyl)pyrrolidin-2-yl]-6-hydroxypyrimidine-4-carboxylate was treated with TFA:CH2Cl2 (3:7) at 0° C. The solution was warmed to room temperature and the progress of the reaction was monitored by MS analysis. After 1 h the reaction was complete and the solvent was removed under reduced pressure using a rotatory evaporator. The title product was precipitated with Et2O and collected by filtration.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>>[C:1]([Cl:12])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccccc1
Yield: 71.2 %

Procedure:
To 12.2 g of benzoic acid, 24 g of thionyl chloride was added, and allowed to react under reflux for 2 hours. Alter the termination of the reaction, thionyl chloride was evaporated under reduced pressure, and then distilled under reduced pressure at 20 mmHg to obtain 10 g of benzoic acid chloride at a distillation temparature of 105° C. The benzoic acid chloride was dissolved in 50 ml of toluene, ant added with 8 g of 4-fluorophenol and 8 g of pyridine to react at 40 ° C. for 3 hours. After the termiration of the reaction, 100 ml of water was added, and the organic layer was separated. The organic layer was washed with dilute hydrochloric acid, dilute alkali aqueous solution and saturated sodium chloride solution successively, and then, dried by adding anhydrous sodium sulfate. Subsequently, the organic layer was filtered, and solvent was evaporated from the filtrate under reduced pressure. The reaction product was recrystallized from hexane, and then distilled under reduced pressure at 1 mmHg to collect the fractions at a distillation temperature of 160° C. Thus, 9 g of benzoic acid (4-fluorophenyl) ester represented by the following formula was obtained. The melting point of the ester was 58.0° C. The infrared absorption spectrum of the ester is shown in FIG. 1. ##STR4##