Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1>>[OH:17][C:13]1[C:5]2[C:6](=[O:12])[NH:7][C:8]3[C:3]([C:4]=2[CH:16]=[CH:15][CH:14]=1)=[C:2]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)[CH:11]=[CH:10][N:9]=3
Reactant: Nc1ccc(NC(=O)c2ccccc2)cc1
Reactant: O=c1[nH]c2nccc(Cl)c2c2cccc(O)c12
Product: O=C(Nc1ccc(Nc2ccnc3[nH]c(=O)c4c(O)cccc4c23)cc1)c1ccccc1

Procedure:
The intermediate ethyl ester was synthesized according to the procedure described for the preparation of Example 378, method 2 using 1-chloro-7-hydroxy-5H-benzo[c][1,8]naphthyridin-6-one and N-(4-amino-phenyl)-benzamide to provide 446. LC-MS (M+H=423, obsd.=423). 1H NMR (400 MHz, DMSO-d6): δ, 6.95 (d, 2H), 7.21 (d, 2H), 7.55 (m, 2H), 7.76 (d, 2H), 7.95 (d, 2H), 8.09 (d, 1H), 8.21 (d, 1H), 8.88 (s, 1H), 10.23 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[CH:39]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40]1>C1COCC1.CN(C=O)C.C1COCC1.CCOC(C)=O>[CH:39]1([C:43]([NH:1][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]4[C:19](=[O:31])[N:20]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:21]([CH3:24])[C:22]=4[CH3:23])=[O:17])=[CH:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)=[O:44])[CH2:42][CH2:41][CH2:40]1
Reactant: O=C(Cl)C1CCC1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cc2)c(=O)n(-c2ccccc2)n1C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)C4CCC4)c3)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 5 h
Yield: 25 %

Procedure:
To a suspension of N-(4-((2-aminopyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (100 mg, 0.241 mmol) in THF/DMF (15 mL/1 mL) was added Et3N (0.06 mL, 0.482 mmol). The suspension was cooled to 0° C., then a solution of cyclobutanecarbonyl chloride (31.0 mg, 0.265 mmol) in THF (5 mL) was added to the reaction system drop wise over 1 hour. The reaction was stirred at rt for 5 hours, and then diluted with EtOAc (20 mL). The resulted mixture was washed with water (25 mL×3), followed by washing with brine (25 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/EtOAc/MeOH (v/v)=100/25/1) to give the title compound as a white solid (30 mg, 25%).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH2:8][CH2:9][NH:10]C(=O)OCC2C=CC=CC=2)=[N:5][CH:4]=1)[CH3:2]>CO.[Pd]>[CH2:1]([C:3]1[O:7][C:6]([CH2:8][CH2:9][NH2:10])=[N:5][CH:4]=1)[CH3:2]
Reactant: CCc1cnc(CCNC(=O)OCc2ccccc2)o1
Agent: [Pd]
Solvent: CO
Product: CCc1cnc(CCN)o1
Reaction time: 5 h

Procedure:
2.86 g (10.43 mmol) benzyl [2-(5-ethyl-oxazol-2-yl)-ethyl]-carbamate are placed in 130 ml of methanol, 0.910 mg palladium/charcoal 10% are added, then the mixture is hydrogenated for 5 hours at ambient temperature under a pressure of 14 psi. Then the catalyst is suction filtered and the solution is evaporated down.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.I[C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]>CCCCCC.O1CCCC1.CCOCC.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:15]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccccc1I
Reactant: Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: COC(=O)c1ccccc1-c1ccc(C)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
A 1.6M solution of butyllithium in hexane (24.0 ml) was added dropwise to a stirred solution of 4-bromotoluene (6.0 g) in dry tetrahydrofuran (THF) (50 ml) at -78° C. under an atmosphere of argon. The temperature was maintained at -78° C. for 20 minutes and then a 1M solution of anhydrous zinc chloride in ether (38.6 ml) was added. The solution was kept at -78° C. for 15 minutes, and then tetrakis(triphenylphosphine)palladium (60 mg) in THF (5 ml) was added, followed by methyl 2-iodobenzoate (6.1 g) in THF (10 ml). The solution was allowed to reach ambient temperature over 1 hour, then heated under reflux for 5 hours. The solvent was removed by evaporation and the residue was dissolved in chloroform (150 ml). The solution was washed with a solution of ethylenediamine tetracetic acid (10 g) in water (100 ml) and the aqueous layer was re-extracted with chloroform (100 ml). The combined organic extracts were dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography, eluting with ethyl acetate/hexane(1:9 v/v) to give methyl 4'methylbiphenyl-2-carboxylate (B1) as a colourless oil (4.4 g); NMR: 2.4(s,3H), 3.65(s,3H), 7.2(s,4H), 7.35(m,3H), 7.5(m,1H), 7.8(d,1H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]3[O:26][C:25]([C:27]4[S:28][CH:29]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[N:31]=4)=[CH:24][C:23]=3[CH:36]=1)[CH:13]=[C:12]2[CH2:37][C:38]([OH:40])=[O:39])C1C=CC=CC=1.[CH:41]([O-])=O.[NH4+].C(O)C>O>[C:32]([C:30]1[N:31]=[C:27]([C:25]2[O:26][C:22]3[CH:21]=[CH:20][C:19]([CH2:18][N:14]4[C:15]5[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=5)[C:12]([CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:13]4)=[CH:36][C:23]=3[CH:24]=2)[S:28][CH:29]=1)([CH3:34])([CH3:35])[CH3:33]
Reactant: O=C[O-]
Reactant: CC(C)(C)c1csc(-c2cc3cc(Cn4cc(CC(=O)O)c5cc(OCc6ccccc6)ccc54)ccc3o2)n1
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(=O)Cc1cn(Cc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)c2ccc(O)cc12
Reaction time: 48 h
Yield: 68.1 %

Procedure:
A mixture of 5-benzyloxy-1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}indole-3-acetic acid (3.0 g), 10% Pd--C (0.6 g) and ammonium formate (2.0 g) in a mixed solvents of ethanol (60 ml) and water (6 ml) was stirred under reflux for 18 hours. After removal of the catalysts by filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in 10% hydrogen chloride in methanol (200 ml) and the mixture was stored in refrigerator for 2 days. The resulting solution was concentrated under reduced pressure and the residue was partitioned between aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give methyl 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-hydroxyindole-3-acetate (1.76 g).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:35]=[CH:34][C:8]([CH2:9][N:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]4[CH:21]=[C:22]([CH:29]=[CH:30][C:31]=4[CH3:32])[C:23]([NH:25][CH:26]4[CH2:28][CH2:27]4)=[O:24])[CH:16]=3)[C:11]2=[O:33])=[CH:7][CH:6]=1.[CH3:36][NH:37][CH3:38]>>[CH:26]1([NH:25][C:23](=[O:24])[C:22]2[CH:29]=[CH:30][C:31]([CH3:32])=[C:20]([C:15]3[CH:16]=[C:17]4[C:12](=[CH:13][CH:14]=3)[C:11](=[O:33])[N:10]([CH2:9][C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][N:37]([CH3:38])[CH3:36])=[CH:35][CH:34]=3)[CH:19]=[CH:18]4)[CH:21]=2)[CH2:27][CH2:28]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(OCCCl)cc3)ccc2c1
Reactant: CNC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(OCCN(C)C)cc3)ccc2c1

Procedure:
A solution of the product of step ii) (95 mg) in dimethylamine (5M in ethanol, 1.5 mL) was heated using microwave irradiation at 100° C. for 90 minutes.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[NH2:8][C:9]([CH3:30])([CH3:29])[CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:24])[C:14]=2[N:13]=[C:12]1[CH2:25][O:26][CH2:27][CH3:28].ClCCl>CN(C=O)C>[O:5]=[C:4]1[CH2:3][CH2:2][C:1](=[O:6])[N:24]1[C:15]1[C:14]2[N:13]=[C:12]([CH2:25][O:26][CH2:27][CH3:28])[N:11]([CH2:10][C:9]([NH:8][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])([CH3:29])[CH3:30])[C:23]=2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: O=C1CCC(=O)O1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOCc1nc2c(N3C(=O)CCC3=O)nc3ccccc3c2n1CC(C)(C)NC(=O)CCC(=O)O
Reaction time: 48 h
Yield: 99.8 %

Procedure:
Succinic anhydride (3.20 g, 32.0 mmol) was added to a 100° C. solution of 1-(2-amino-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in U.S. Patent Publication No. 2004/0091491, 2.00 g, 6.39 mmol) in DMF (20 mL). After 2 days, the reaction mixture was concentrated under reduced pressure to give an off-white solid. The solid was stirred with 100 mL of dichloromethane and was isolated by filtration. The filtrate was concentrated, stirred with dichloromethane (25 mL), and filtered to yield additional solid. The combined solids were dried under vacuum to give 3.16 g of 4-({2-[4-(2,5-dioxopyrrolidin-1-yl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}amino)-4-oxobutanoic acid as a white solid that was used without further purification.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH:13]3[CH2:19][CH2:18][C:17]4[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=4[N:15]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:14]3=[O:29])[CH:12]=2)=[CH:4][C:3]=1[O:30][CH3:31].[N:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:31][O:30][C:3]1[CH:4]=[C:5]([C:8]2[N:9]=[N:10][N:11]([CH:13]3[CH2:19][CH2:18][C:17]4[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=4[N:15]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:14]3=[O:29])[CH:12]=2)[CH:6]=[CH:7][C:2]=1[C:35]1[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=1
Reactant: COc1cc(-c2cn(C3CCc4ccccc4N(CC(F)(F)F)C3=O)nn2)ccc1I
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2cn(C3CCc4ccccc4N(CC(F)(F)F)C3=O)nn2)ccc1-c1ccncc1
Reaction time: 0.17 h
Yield: 90.2 %

Procedure:
3-[4-(4-Iodo-3-methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (300 mg, 0.553 mmol) was added to a 20-ml μwave vial along with 4-pyridyl boronic acid (136 mg, 1.106 mmol), PdCl2(dppf) (81 mg, 0.111 mmol), 2M sodium carbonate in water (553 μl, 1.106 mmol), water (1906 μl) and dioxane (8605 μl). The vial was sealed and μwaved at 100° C. for 10 minutes. The reaction mixture was filtered through a plug of Celite. The plug was washed with 100 ml of dioxane and the filtrates were combined and concentrated under reduced pressure. The contents of the flask were reconstituted in 100 ml of water and extracted with ˜100 ml of DCM twice. The organic layers were combined, passed through a phase separator cartridge, and concentrated under reduced pressure. The residue was dissolved in 6 ml of DMSO and purified by reverse phase chromatography (20-100 MeCN in water (half was injected with a TFA modifier, the remaining half was purified using a Formic Acid modifier). The pure fractions were pooled and concentrated under reduced pressure. The compound was dissolved in ˜300 ml of DCM and washed with NaHCO3 (3×150 ml). The organic layer was passed through a phase separator to remove water and concentrated under reduced pressure to afford 3-[4-(3-methoxy-4-pyridin-4-ylphenyl)-1H-1,2,3-triazol-1-yl]-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (246 mg, 0.499 mmol, 90% yield) as an off white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:12][C:13]1[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=1)[C:16]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)=[O:17])(=[O:11])=[O:10].CO[C:33]1C=CC=C[C:34]=1S(Cl)(=O)=O>>[CH2:33]([O:24][C:23](=[O:25])[C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:28]=[CH:29][CH:30]=[C:13]([NH:12][S:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])(=[O:11])=[O:10])[CH:14]=2)=[CH:27][CH:26]=1)[CH3:34]
Reactant: COc1ccccc1S(=O)(=O)Cl
Reactant: COc1ccccc1S(=O)(=O)Nc1cccc(C(=O)Nc2ccc(C(=O)O)cc2)c1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3ccccc3OC)c2)cc1

Procedure:
4-[3-(2-Methoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=425.1 (M−H), was prepared in analogy to example 1, steps A to D. Step C was performed using 2-methoxy-benzenesulfonyl chloride and yielded 4-[3-(2-methoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: NC1C=C(Cl)C(C)=CC=1S(N)(=O)=O.C(N=C=S)(C)C.[NH2:20][C:21]1[CH:26]=[C:25]([Cl:27])[C:24]([CH3:28])=[CH:23][C:22]=1[S:29]([NH:32][C:33]([NH:35][CH:36]([CH3:38])[CH3:37])=S)(=[O:31])=[O:30].C(Cl)(Cl)=O>>[Cl:27][C:25]1[C:24]([CH3:28])=[CH:23][C:22]2[S:29](=[O:31])(=[O:30])[N:32]=[C:33]([NH:35][CH:36]([CH3:38])[CH3:37])[NH:20][C:21]=2[CH:26]=1
Reactant: Cc1cc(S(=O)(=O)NC(=S)NC(C)C)c(N)cc1Cl
Agent: CC(C)N=C=S
Agent: Cc1cc(S(N)(=O)=O)c(N)cc1Cl
Agent: O=C(Cl)Cl
Product: Cc1cc2c(cc1Cl)NC(NC(C)C)=NS2(=O)=O

Procedure:
Starting from 2-amino-4-chloro-5-methylbenzenesulfonamide and isopropyl isothiocyanate, and following a procedure analogous to the one described in Example 4a, N-(2-amino-4-chloro-5-methylbenzenesulfonyl)-N′-isopropylthiourea was prepared; m.p. 120-122° C. Subsequent ring closure with phosgene by a procedure analogous to the one described in Example 4b gave the title compound; 1H-NMR (d6-DMSO), δ (ppm): 10.3 (br, 1H, NH), 7.68 (1H, arom.), 7.29 (1H, arom), 7.2 (br, 1H, NH), 4.0-3.8 (m, 1H, CH), 2.37 (s, 3H, CH3), 1.20 (d, 6H, CH3).
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][CH:19]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.ClC(OC(Cl)=O)C>ClCCl>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH:19]([O:18][CH:16]2[CH2:17][NH:14][CH2:15]2)[C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[CH:21][CH:22]=1
Reactant: Clc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Cl)cc2)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: Clc1ccc(C(OC2CNC2)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
To a stirred solution of 1-benzhydryl-3-(4,4′-dichlorobenzhydryloxy)azetidine (35) (8.4 mmol) in dichloromethane (50 mL) was added 1-chloroethylchloroformate (16.9 mmol) dropwise at 0° C. and the reaction mixture was stirred at reflux for 6 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo, then dissolved in methanol (50 mL) and stirred at room temperature for overnight. The reaction mixture was reduced in vacuo and triturated with diethyl ether (100 mL) to afford the desired product as a white solid (2.16 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:11]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[CH:22][CH:21]=3)[C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-:30].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[C:3]2[N:11]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH2:28])=[O:30])=[CH:22][CH:21]=3)[C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: N#CCc1ccc(-c2nn(-c3c(F)cccc3F)c3c(Cl)c[nH]c(=O)c23)cc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)Cc1ccc(-c2nn(-c3c(F)cccc3F)c3c(Cl)c[nH]c(=O)c23)cc1
Reaction time: 8 h
Yield: 74.7 %

Procedure:
To a solution of (4-(7-chloro-1-(2,6-difluorophenyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)acetonitrile (134.5 mg) obtained in Example 116 and potassium carbonate (94 mg) in DMSO (2 mL) was added 30% aqueous hydrogen peroxide (139 μL) at room temperature. The reaction mixture was stirred overnight, and poured into water. The precipitated crystals were collected by filtration, and purified by HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)), to the obtained fraction was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified to give the title compound (105 mg).
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1.CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:32][C:33](=[N:77][C:78](=[O:85])[C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[C:34]1[CH:39]=[CH:38][C:37]([NH:40][CH:41]([C:64]2[CH:69]=[C:68]([O:70][CH3:71])[CH:67]=[C:66]([O:72][CH2:73][CH2:74]O)[C:65]=2[F:76])[C:42]2[N:43]=[C:44]([O:53][CH2:54][O:55][C:56](=[O:63])[C:57]([CH3:62])([CH3:61])[CH2:58][O:59][CH3:60])[N:45]([C:47]3[N:52]=[CH:51][CH:50]=[CH:49][N:48]=3)[N:46]=2)=[CH:36][CH:35]=1>CN(C1C=CN=CC=1)C.ClCCl>[NH2:32][C:33](=[N:77][C:78](=[O:85])[C:79]1[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=1)[C:34]1[CH:39]=[CH:38][C:37]([NH:40][CH:41]([C:42]2[N:43]=[C:44]([O:53][CH2:54][O:55][C:56](=[O:63])[C:57]([CH3:62])([CH3:61])[CH2:58][O:59][CH3:60])[N:45]([C:47]3[N:52]=[CH:51][CH:50]=[CH:49][N:48]=3)[N:46]=2)[C:64]2[C:65]([F:76])=[C:66]([CH:67]=[C:68]([O:70][CH3:71])[CH:69]=2)[O:72][CH2:73][CH2:74][O:15][C:14]([C:11]2[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=2)=[O:16])=[CH:36][CH:35]=1
Reactant: O=C(O)c1ccncc1
Reactant: COCC(C)(C)C(=O)OCOc1nc(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2cc(OC)cc(OCCO)c2F)nn1-c1ncccn1
Agent: CN(C)C(F)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(C)(C)C(=O)OCOc1nc(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2cc(OC)cc(OCCOC(=O)c3ccncc3)c2F)nn1-c1ncccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under nitrogen atmosphere, triethylamine (0.112 mL) was added under ice-cooling to a mixture of 4-pyridinecarboxylic acid [CAS No. 55-22-1] (19.6 mg), TFFH (42.4 mg), and dichloromethane (6 mL), and the resulting mixture was stirred for 1 hour. To the resulting mixture, 3-methoxy-2,2-dimethylpropionic acid 5-({4-[amino(benzoylimino)methyl]phenylamino}-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl)-2-pyrimidin-2-yl-2H-[1,2,4]triazol-3-ylox ymethyl ester (14.9 mg) and DMAP (0.27 mg) were added, and the resulting mixture was stirred overnight at room temperature. Under reduced pressure, the solvent in the mixture was distilled off. The residue obtained was purified by reverse phase high-performance liquid chromatography (mixed solvent of acetonitrile-water, containing 0.1% of acetic acid) to obtain the captioned compound (10.4 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([SH:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:14])[CH3:2].[OH:15][C@:16]1([C:23]2[CH:28]=[CH:27][CH:26]=[C:25](I)[CH:24]=2)[CH2:21][CH2:20][O:19][C@@H:18]([CH3:22])[CH2:17]1>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13][C:27]3[CH:28]=[C:23]([C@@:16]4([OH:15])[CH2:21][CH2:20][O:19][C@@H:18]([CH3:22])[CH2:17]4)[CH:24]=[CH:25][CH:26]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:14])[CH3:2]
Reactant: C[C@H]1C[C@@](O)(c2cccc(I)c2)CCO1
Reactant: CCN1C(=O)CCc2cc(S)ccc21
Product: CCN1C(=O)CCc2cc(Sc3cccc([C@@]4(O)CCO[C@@H](C)C4)c3)ccc21
Yield: 55 %

Procedure:
Using an analogous procedure to that described in Example 6, 1-ethyl-6-mercapto-1,2,3,4-tetrahydroquinolin-2-one was reacted with (2S,4R)-4-hydroxy-4-(3-iodophenyl)-2-methyltetrahydropyran to give (2S,4R)-4-[3-(1-ethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)phenyl]-4-hydroxy-2-methyltetrahydropyran in 55% yield, m.p. 148°-149° C. (recrystallised from diethyl ether);
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[N:13]=[C:12]([O:14][Si](C)(C)C)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[Br:21][CH2:22][CH2:23][CH2:24]Br.C(=O)(O)[O-].[Na+]>>[Br:21][CH2:22][CH2:23][CH2:24][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12](=[O:14])[NH:13][C:4]1=[O:3]
Reactant: C[Si](C)(C)Oc1nc(O[Si](C)(C)C)c2ccccc2n1
Reactant: BrCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Product: O=c1[nH]c(=O)n(CCCBr)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
A mixture of 2,4-bis(trimethylsiloxy)-quinazoline (9.14 g) and 1,3-dibromopropane (30 g) was stirred for 2 hours at 130°-140° C. The reaction mixture was cooled at ambient temperature and a mixture of ice-water and saturated sodium bicarbonate aqueous solution was added to the reaction mixture and then the mixture was stirred vigorously to give precipitates. After the mixture was suspended with chloroform, the precipitates were collected by filtration. The precipitates were washed with water and with chloroform respectively and then dried to give 1-(3-bromopropyl)-2,4(1H, 3H)-quinazolinedione (2.12 g) as a crystal, which was used in the next step without purification. m.p. 159°-170° C.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[Cl:26][C:27]1[CH:28]=[C:29]([N:34]=[C:35]=[O:36])[CH:30]=[C:31]([Cl:33])[CH:32]=1.C(N(CC)CC)C.Cl>C(#N)C>[Cl:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:36])[CH:30]=[C:31]([Cl:33])[CH:32]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4cc(Cl)cc(Cl)c4)ccc3C2=O)C(=O)N1
Reaction time: 18 h
Yield: 78 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.37 g, 1.0 mmol) and 3,5-dichlorophenylisocyanate (0.19 g, 1.0 mmol) in acetonitrile (10 mL), was added triethylamine (0.28 mL, 2.0 mmol) at room temperature under nitrogen. After 18 h, 1 N aq. HCl (10 mL) was added and the solids were isolated by filtration and washed with water (40 mL). The solids were triturated in EtOAc (10 mL) for 18 h, then isolated by filtration, washed with EtOAc (40 mL) and dried in vacuo to give 1-(3,5-dichloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.36 g, 78% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 10/90 to 90/10 CH3CN/0.1% H3PO4 gradient over 15 mins, 9.14 min (96.29%); mp: 274-276° C.; 1H NMR (DMSO-d6) δ 1.86-2.12 (m, 1H, CHH), 2.24-2.47 (m, 1H, CHH), 2.60 (d, J=16.4 Hz, 1H, CHH), 2.77-3.05 (m, 1H, CHH), 4.31 (d, J=17.4 Hz, 1H, CHH), 4.38-4.56 (m, 3H, CHH, CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH), 7.00 (t, J=5.9 Hz, 1H, NH), 7.08 (t, J=1.7 Hz, 1H, Ar), 7.44 (d, J=7.7 Hz, 1H, Ar), 7.48-7.59 (m, 3H, Ar), 7.70 (d, J=7.7 Hz, 1H, Ar), 9.08 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.20, 42.83, 47.12, 51.58, 115.78, 120.16, 121.92, 122.94, 126.92, 130.35, 133.93, 142.39, 142.93, 144.43, 154.77, 167.92, 170.98, 172.85; LCMS: MH=461/463/465; Anal Calcd for C21H18N4O4Cl2: C, 54.68; H, 3.93; N, 12.15; Cl, 15.37. Found: C, 54.61; H, 3.78; N, 11.84; Cl, 15.10.