Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([OH:9])=[O:8].ClC(Cl)C.B(Br)(Br)Br>>[OH:14][C:11]1[CH:10]=[C:4]2[C:3](=[CH:13][CH:12]=1)[O:8][C:7](=[O:9])[CH:6]=[CH:5]2
Reactant: COc1ccc(OC)c(C=CC(=O)O)c1
Agent: BrB(Br)Br
Solvent: CC(Cl)Cl
Product: O=c1ccc2cc(O)ccc2o1
Temperature: 83 °C
Reaction time: 15 h
Yield: 118.8 %

Procedure:
Equip a 3-L, three-neck, round-bottom flask equipped with a large blade mechanical stirrer, a thermocouple, a Claisen adapter, an addition funnel, and a reflux condenser. Add 2,5-dimethoxycinnamic acid (102.8 g, 493 mmol, 1.0 equiv) and dichloroethane (1.5 L). Add boron tribromide (247.4 g, 987 mmol, 2.0 equiv) dropwise over 45 min while keeping the temperature below 40° C. Rapidly stir the resulting mixture and heat gradually to 83° C. over 45 min, monitoring the temperature increase and gas evolution. Stir for 6 h at reflux then for 15 h at 76° C. Cool the resulting mixture to room temperature and quenched carefully with water (450 mL). Filter the solid, wash with heptane and dry under vacuum to afford 6-hydroxy coumarin (95 g) as a light brown solid which is used without further purification. Equip a 2-L, three-neck, round-bottom flask with a magnetic stir bar and a thermocouple. Add 6-hydroxy coumarin (39.8 g, 245 mmol, 1.0 equiv), anhydrous acetonitrile (700 mL) and N,N-diisopropylethylamine (200 mL, 1.15 mol, 4.7 equiv). Add chloromethyl methyl ether (40.0 mL, 527 mmol, 2.1 equiv) dropwise over 30 min while keeping the temperature below 40° C. Stir the resulting mixture at room temperature for 3 h, then add an additional equiv of chloromethyl methyl ether. Stir at room temperature for 15 h, then quench the reaction mixture with saturated aqueous ammonium chloride (500 mL) and extracted with ethyl acetate. Combine the organic extracts and dry over anhydrous magnesium sulfate, filter and concentrate under reduced pressure. Purify the residue by column chromatography on silica gel (30-50% ethyl acetate/heptane) to afford a light yellow solid. Suspend the solid in a mixture of ethyl acetate/heptane (150 mL, 10:90), filter and dry to afford 6-methoxymethoxy coumarin 17a (25.6 g, 50%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J=7.8 Hz, 1H), 7.30-7.12 (m, 3H), 6.41 (d, J=7.8 Hz, 1H), 5.20 (s, 2H), 3.48 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.2, 154.0, 149.5, 143.5, 121.6, 119.6, 118.1, 117.3, 113.8, 95.3, 56.4; IR (KBr) 1714 (s), 1570 (s), 1491 (m), 1447 (m), 1266 (s), 1154 (s), 1070 (s), 1017 (s) cm−1; ESI MS m/z 207 [C11H10O4+H]+.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6](=[S:38])[NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)Nc2ccccc2NC(=O)c2ccc(F)cc2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(S(=O)(=O)Nc2ccccc2NC(=S)c2ccc(F)cc2)cc1
Temperature: 100 °C
Yield: 147.6 %

Procedure:
A mixture of 549 mg (1.371 mmol) of the compound produced in Example 82, 333 mg (0.823 mmol) of Lawesson reagent and 10 ml of toluene was heated at 100° C. After the concentration, the residue was purified by silica gel column chromatography to obtain 506 mg of the title compound.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:22]2[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=2)[C:19]2[C:28](=[O:38])[N:29](C(OC(C)(C)C)=O)[CH2:30][C:18]=2[C:17]=1[F:39])=O)(C)(C)C.Cl>CC(O)C>[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:22]2[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=2)[C:19]2[C:28](=[O:38])[NH:29][CH2:30][C:18]=2[C:17]=1[F:39]
Reactant: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)N(C(=O)OC(C)(C)C)C3)cn1
Agent: Cl
Solvent: CC(C)O
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3N)c(F)c3c2C(=O)NC3)cn1
Temperature: 65 °C
Yield: 85.5 %

Procedure:
A suspension of tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexyl-amino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (2.148 g, 3.94 mmol) in IPA (21 mL) was heated to 70° C. at which point 2M HCl aq (9.86 mL, 19.72 mmol) was added. The reaction mixture was heated at 65° C. for approximately 3 h, cooled in an ice water bath for 1 h, and then filtered. The solids were rinsed with cold IPA (15 mL) and then dried in a 50° C. vacuum oven overnight to give an HCL salt of the title compound as a light yellow solid (1.404 g, 3.37 mmol) having 1.5-2 eq of associated water (by 1H NMR). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (d, J=7.07 Hz, 2H), 1.57-1.76 (m, 3H), 1.76-2.04 (m, 3H), 3.31 (s, 3H), 3.67 (br s, 1H), 3.90 (s, 3H), 4.39 (d, J=2.53 Hz, 2H), 4.41-4.60 (m, 1H), 6.75 (d, J=6.57 Hz, 1H), 7.96 (br s, 3H), 8.22-8.31 (m, 1H), 8.34 (s, 1H), 8.84 (s, 1H). [M+H] calc'd for C17H21FN6O, 345. found 345.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:11]2([C:28]([F:31])([F:30])[F:29])[CH2:15][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C:21]3([CH2:27][NH:26][CH2:25]3)[O:20][CH2:19]4)=[N:13][CH2:12]2)[CH:6]=[C:7]([Cl:10])[C:8]=1[F:9].CCN(C(C)C)C(C)C.[C:41](O)(=[O:45])[CH:42]([CH3:44])[CH3:43].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[Cl:10][C:7]1[CH:6]=[C:5]([C:11]2([C:28]([F:30])([F:29])[F:31])[CH2:15][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C:21]3([CH2:25][N:26]([C:41](=[O:45])[CH:42]([CH3:44])[CH3:43])[CH2:27]3)[O:20][CH2:19]4)=[N:13][CH2:12]2)[CH:4]=[C:3]([Cl:2])[C:8]=1[F:9]
Reactant: Fc1c(Cl)cc(C2(C(F)(F)F)CN=C(c3ccc4c(c3)COC43CNC3)C2)cc1Cl
Reactant: CC(C)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)N1CC2(C1)OCc1cc(C3=NCC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.1 %

Procedure:
To a stirred solution of 5′-(3-(3,5-dichloro-4-fluorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]hydrochloride (Preparation 9, 1 g, 2.02mmol) in THF (20 mL) was added DIPEA (3.53 mL, 20.24 mmol), isobutyric acid (0.368 g, 4.05 mmol) and T3P (2.94 mL, 10.12 mmol, 5 eq) at room temperature. Resulting reaction mixture was stirred at room temperature for 16 hours. After complete conversion of starting material, reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3×30 mL). Combined organic layer was washed with sodium bicarbonate solution (35 mL), brine (35 mL), dried over sodium sulfate and concentrated to get brown semi solid (1.1 g, crude). Crude compound was purified by column chromatography using 100-200 mesh silica gel. Desired compound was eluted in 0.5% methanol in dichloromethane to get pale green solid (0.45 g). 1H NMR (400 MHz, DMSO-d6) δ: 1.01-1.05 (m, 6H), 2.54-2.57 (m, 1H), 3.74 (d, J=18.12 Hz, 1H), 3.86 (d, J=18.08 Hz, 1H), 4.12 (s, 2H), 4.41-4.45 (m, 3H), 4.81 (d, J=17.36 Hz, 1H), 5.12 (s, 2H), 7.66 (d, J=7.96 Hz, 1H), 7.76 (d, J=6.24 Hz, 2H), 7.85 (s, 1H), 7.93 (d, J=7.88 Hz, 1H), LC-MS (m/z): 529.1 (M+H),
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:17]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)=[CH:20][CH:21]=1
Reactant: O=C1NC(=O)c2ccc(Br)cc2C1=CNc1ccc(CN2CCCC2)cc1
Reactant: OB(O)c1ccco1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(-c3ccco3)cc2C1=CNc1ccc(CN2CCCC2)cc1
Temperature: 150 °C

Procedure:
To a suspension of 6-bromo-4-[(4-pyrrolidin-1-ylmethyl-phenylamino)-methylene]-4H-isoquinoline-1,3-dione (40 mg, 0.1 mmol) in N,N-dimethylformamide (1 mL) is added 2-furanboronic acid (11.2 mg, 0.1 mmol), followed by 60 μL of 2M aqueous cesium carbonate and tetrakis triphenylphosphine palladium (6 mg, 0.005 mmol). The reaction mixture is subjected to microwave heating at 150° C. for 100 seconds. The reaction mixture is then diluted to 2 mL with N,N-dimethylformamide and purified by C18 reverse phase HPLC. The pure fractions were combined and concentrated to yield Example 169.
Reaction SMILES: [CH:1]1([CH:6]([CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([Cl:20])=[C:14]([Cl:21])[CH:13]=2)[C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[CH:1]1([CH:6]2[CH2:10][CH2:11][C:12]3[C:13](=[C:14]([Cl:21])[C:15]([Cl:20])=[C:16]([O:18][CH3:19])[CH:17]=3)[C:7]2=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(CCC(C(=O)O)C2CCCC2)cc(Cl)c1Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)CC2
Temperature: 5 °C
Reaction time: 24 h

Procedure:
2-Cyclopentyl-4-(3,4-dichloro-5-methoxyphenyl)-butanoic acid (13.1 g., 0.04 mole), dry benzene (100 ml.) and phosphorous pentachloride (7.5 g., 0.034 mole) are refluxed for one hour with stirring. The mixture is cooled to 5° C. and anhydrous stannic chloride (5 ml.) in dry benzene (25 ml.) is added portionwise. The mixture is allowed to warm to 20°-25° C. and kept for 24 hours after which it is poured into ice water. The organic material is extracted with a suitable solvent. The extract is washed, dried and evaporated to obtain 2-cyclopentyl-6-methoxy-7,8-dichloro-1-tetralone.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].Cl>O1CCOCC1.O>[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20]([NH:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])=[O:21]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NS(=O)(=O)c1ccccc1)c1ccc(Cl)cc1Cl

Procedure:
To a mixture of phenylsulfonamide (0.16 mol; 25.12 g) and potassium carbonate (0.2 mol; 27.6 g) in 500 mL dioxane is added dropwise 2,4-dichlorobenzoyl chloride (0.13 mole; 18.0 mL). The mixture is warmed to reflux under nitrogen for 16 hr. The reaction is then diluted with water (500 mL), neutralized to pH 5 with concentrated hydrochloric acid, and extracted 3 times with ethyl acetate. The combined ethyl acetate layers are washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure to a white solid. The solid residue is subjected to silica gel chromatography, eluting with dichloromethane containing from 0–5% methanol. Fractions containing the product are combined and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [C@H:1]([N:5]([CH3:25])[C:6]1[C:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2].[N-:26]=[N+:27]=[N-:28].[Na+].Cl>CS(C)=O.O.[Zn+2].[Br-].[Br-]>[C@H:1]([N:5]([CH3:25])[C:6]1[C:7]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[N:8][C:9]2[C:14](=[CH:13][C:12]([C:16]3[NH:28][N:27]=[N:26][N:17]=3)=[CH:11][CH:10]=2)[N:15]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CC[C@@H](C)N(C)c1nc2cc(C#N)ccc2nc1-c1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC[C@@H](C)N(C)c1nc2cc(-c3nnn[nH]3)ccc2nc1-c1ccc(F)cc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
To a solution of (R)-3-(sec-butyl(methyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carbonitrile (170 mg, 0.51 mmol) in DMSO (25 mL) was added NaN3 (101 mg, 1.55 mmol), ZnBr2 (56 mg, 0.25 mmol) and water (3 mL) and the resulting mixture was stirred overnight at 130° C. The solution was diluted with water (200 mL) and adjusted to pH 4 with HCl (3N), extracted with ethyl acetate (5×50 mL), and the organic layers combined and dried over anhydrous magnesium and concentrated in vacuo to afford (R)—N-sec-butyl-3-(4-fluorophenyl)-N-methyl-7-(1H-tetrazol-5-yl)quinoxalin-2-amine as a yellow solid (72.3 mg, 37%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18].O>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccc(Br)n1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cccc(Br)n1
Temperature: 0 °C
Yield: 96.5 %

Procedure:
4.0 g (23.1 mmol) of 6-bromo-2-aminopyridine from example 14.1 were dissolved in 25 ml of dichloromethane and admixed with 4.1 ml (2.92 g, 28.9 mmol) of triethylamine. After cooling to 0° C., a solution of 3.1 ml (3.06 g, 25.4 mmol) of pivaloyl chloride in 5.0 ml of dichloromethane was added dropwise over a period of 10 min. The reaction mixture was allowed to warm to room temperature overnight and, for workup, poured onto 100 ml of dist. H2O. The phases were separated, the aqueous phase was extracted twice with 100 ml each time of ethyl acetate and the combined organic phases were dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane and filtered through a short silica gel column (3×10 cm). After the solvent had been removed under reduced pressure, 5.73 g (22.3 mmol, 96.5%) of 6-bromo-2-pivaloylaminopyridine were obtained as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:4])O.[H-].[Na+].[F:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]3[C:18]([CH2:21]Br)=[N:19][N:20]=[C:16]3[CH2:15][N:14]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:12]=2[CH:29]=1>CN(C)C=O>[F:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]3[C:18]([CH2:21][N:2]([CH3:4])[CH3:1])=[N:19][N:20]=[C:16]3[CH2:15][N:14]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:12]=2[CH:29]=1
Reactant: Fc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CBr)n1-2
Reactant: CN(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)Cc1nnc2n1-c1ccc(F)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 16, a solution of N,N-dimethylhydroxylamine in dimethylformamide is treated with sodium hydride suspended in mineral oil, and the mixture is treated with 8-fluoro-1-(bromomethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 8-fluoro-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N1 -oxide.
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]([CH2:21][CH3:22])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[C:7]1=[O:23])=[N+]=[N-].[ClH:24]>CO.[Pd]>[ClH:24].[NH2:1][CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]([CH2:21][CH3:22])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[C:7]1=[O:23]
Reactant: CCC1(c2cccc(OC)c2)CCCCN(CCN=[N+]=[N-])C1=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCC1(c2cccc(OC)c2)CCCCN(CCN)C1=O
Reaction time: 2 h

Procedure:
To a solution of 1-(2-azido-ethyl)-3-ethyl-3-(3-methoxy-phenyl)-azepan-2-one (as described above in Step B) (0.56 g, 1.94 mmol) in MeOH (20 mL) and 10% HCl (5 mL) was added 10% Pd/C (0.1 g) under argon. The mixture was placed under 1 atm of H2 and stirred for 2 hr. Filtration and concentration to dryness gave the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]12[CH2:11][CH2:10][C:9]([NH:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([CH2:8][CH2:7]1)[CH2:14][C:13]2=[O:15])=[O:5])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C1(C(C)=O)CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C12CCC(NCc3ccccc3)(CC1)CC2=O
Temperature: 20 °C

Procedure:
Toluene (310 mL) was added to 1-acetyl-4-oxocyclohexyl carboxylic acid ethyl ester (31.0 g, 146 mmol) and then the resulting mixture was stirred. To the mixture, there were added benzylamine (48.0 mL, 438 mmol) and p-toluenesulfonic acid monohydrate (251 mg, 1.32 mmol). The mixture was refluxed for 7 hours with a Dean-Stark apparatus under the dehydration conditions. The mixture was cooled to 20° C., a 3 mol/L hydrochloric acid solution (155 g) was added dropwise to the mixture and then the resulting mixture was stirred for 0.5 hours. To the mixture, there was added dropwise a 6 mol/L aqueous sodium hydroxide solution, followed by stirred for 10 minutes and the organic phase was separated. The resulting organic phase was washed twice with 155 g of a 18% aqueous ammonium chloride solution and further washed with 62 g of water. The organic phase was subjected to quantitative analysis (according to the LC technique) and as a result, the yield of the desired product was found to be 95% (the internal standard substance used was m-xylene).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][C:5]1([C:17]([O:19][CH3:20])=[O:18])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]=[C:6]1[O:15][CH3:16].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:24].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OO)(C)(C)C.O>C1C=CC=CC=1>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][C:5]1([C:17]([O:19][CH3:20])=[O:18])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:24])[CH:7]=[C:6]1[O:15][CH3:16]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: COC(=O)C1(CCC(C)(C)C)C(OC)=CCc2ccccc21
Agent: CC(C)(C)OO
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)C1(CCC(C)(C)C)C(OC)=CC(=O)c2ccccc21
Yield: 68.3 %

Procedure:
A suspension of Example 8A (0.45g, 1.48 mmol), pyridinium dichromate (2.4 g, 5.92 mmol), celite (0.53 g), 70% t-BuOOH/water (0.82 mL, 5.92 mmol) in benzene (11 mL) was stirred at 25° C. for 2 h. The benzene layer was separated and the mixture was extracted with ethyl acetate. The combined organic layers were concentrated in vacuo. Column chromatography on silica (5%→15% ethyl acetate/hexane) afforded the title compound (0.32 g, 67%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.17-0.41 (m, 1H), 0.60-0.81 (m, 10H), 2.16-2.36 (m, 2H), 3.56 (s, 3H), 3.84 (s, 3H), 6.04 (s, 1H), 7.41 (d, J=7.72 Hz, 1H), 7.51 (t, J=6.99 Hz, 1H), 7.60-7.75 (m, 1H), 7.89-8.09 (m, 1H)); MS (ESI) m/z 316.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1)=[O:5].[OH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O.CO.C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C(c1ccc(F)cc1)c1cc(Cl)ccc1Cl
Reactant: Oc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: O=C(c1ccc(Oc2ccccn2)cc1)c1cc(Cl)ccc1Cl
Reaction time: 10 h

Procedure:
Into a 2 L three-neck flask equipped with a stirrer, a thermometer, a cooling tube, a Dean-Stark tube, and a nitrogen-introducing three-way cock, 130.5 g (0.49 mol) of the above 2,5-dichloro-4′-fluorobenzophenone, 46.1 g (0.49 mol) of 2-hydroxypyridine, and 73.7 g (0.53 mol) of potassium carbonate were introduced. Then, 500 mL of N,N-dimethylacetamide (DMAc), and 100 mL of toluene were added, and in an oil bath, the mixture was heated under nitrogen atmosphere, and was reacted at 130° C. under stirring. Water resulting from the reaction was formed into an azeotropic mixture with toluene and was removed to the outside of the system through the Dean-Stark tube during the reaction. Approximately 3 hours thereafter, almost no water was recognized to be generated. Then, most of the toluene was removed, and the reaction was allowed to continue at 130° C. for 10 hours. A reaction liquid obtained was allowed to cool down, and then the reaction liquid was poured into 2 L of water/methanol (9/1). A product precipitated was filtered, and the filtrate was collected and dried. The dried product was introduced into a 2 L three-neck flask equipped with a stirrer, a thermometer, a cooling tube, a Dean-Stark tube, and a nitrogen-introducing three-way cock. The dried product was stirred in 1 L of toluene at 100° C., while the residual water content was distilled away, to thereby dissolve the dried product. After the solution was allowed to cool down, a crystallized product was filtered to thereby obtain an intended product of pale yellow, 2,5-dichloro-4′-(pyridine-2-oxy)benzophenone (30-2) in an amount of 142 g, and at an yield percentage of 83%.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH2:12][N:11](C(OC(C)(C)C)=O)[C:10](=[O:20])[CH:9]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH2:12][NH:11][C:10](=[O:20])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(F)nc2)=CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C=C(c2ccc(F)nc2)CN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl 4-(6-fluoropyridin-3-yl)-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate (315 mg, 1.132 mmol) in DCM (4 mL) was added TFA (1 mL, 12.98 mmol). The reaction mixture was stirred at room temperature for 1 h. Reaction mixture was evaporated. Azeotrope with toluene (x=3) yielding 4-(6-fluoropyridin-3-yl)-1H-pyrrol-2(5H)-one. Proceed for next step. LCMS (m/z): 179.2 (MH+), 0.373 min. The crude yield was quantitative.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([NH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][C:7]=1[N:19]([C:28]([C:30]([F:33])([F:32])[F:31])=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)=O.C(=O)([O-])[O-].[K+].[K+].O.Cl>CO>[F:32][C:30]([F:31])([F:33])[C:28]([N:19]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[C:7]1[CH:8]=[C:9]([NH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([F:12])=[CH:11][C:6]=1[NH2:5])=[O:29]
Reactant: CCOC(=O)Nc1cc(N(Cc2cccc(Cl)c2)C(=O)C(F)(F)F)c(NC(=O)C(F)(F)F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCOC(=O)Nc1cc(N(Cc2cccc(Cl)c2)C(=O)C(F)(F)F)c(N)cc1F
Yield: 105.4 %

Procedure:
A solution of 3.7 grams (0.007 mole) of N-trifluoromethylcarbonyl-2-[(trifluoromethylcarbonyl)(3-chlorophenylmethyl)amino]-4-ethoxycarbonylamino-5-fluoroaniline in 50 mL of methanol was stirred, and a solution of 1.0 gram (0.007 mole) of potassium carbonate in a minimum amount of water was added. The reaction mixture was then heated at reflux for about three hours, after which the reaction mixture was cooled, poured into cold water, and acidified to a pH of 6 with aqueous 3N hydrochloric acid. The resultant solid was collected by filtration and dried, yielding 3.2 grams of 2-[(trifluoromethylcarbonyl)(3-chlorophenylmethyl)amino]-4-ethoxycarbonylamino-5-fluoroaniline. The NMR spectrum was consistent with the proposed structure.