Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:23]=[CH:22][C:11]2[N:12]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:13](=[O:16])[N:14]([CH3:15])[C:10]=2[CH:9]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[CH3:19][C:18]([CH3:21])([CH3:20])[CH2:17][N:12]1[C:11]2[CH:22]=[CH:23][C:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:9][C:10]=2[N:14]([CH3:15])[C:13]1=[O:16]
Reactant: OB(O)c1ccccc1
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3ccccc3)cc21
Reaction time: 0.25 h

Procedure:
An aqueous solution of Cesium carbonate (54.8 mg, 0.17 mmol, 5.0 eq) in water (2 mL) was charged with a solution of 5-bromo-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (1-5, 10 mg, 0.034 mmol) and phenylboronic acid (8.21 mg, 0.067 mmol, 2.0 eq), then deoxygenated. The 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.37 mg, 1.68 μmol, 0.05 eq) was introduced and the mixture was irradiated in a microwave at 125 deg C. for 15 min. LC/MS showed complete conversion, so the reaction was partitioned between EtOAc (2×85 ml) and saturated aqueous NaHCO3 (95 ml). The combined organic layers were dried over Na2SO4 and concentrated. The crude oil was purified via reverse-phase HPLC (Acetonitrile/Water gradient with 0.1% TFA present), affording the desired compound, 1-(2,2-dimethylpropyl)-3-methyl-5-phenyl-1,3-dihydro-2H-benzimidazol-2-one (1-6), with >95% purity. 1H NMR (300 MHz, CDCl3) δ 7.59 (d, 2H, J=7.3 Hz), 7.45 (t, 2H, J=7.3 Hz), 7.30-7.36 (m, 2H), 7.19 (s, 1H), 7.10 (d, 1H, J=8.2 Hz), 3.70 (8, 2H), 3.49 (s, 3H), 1.07 (s, 9H). LRMS m/z: Calc'd for C19H22N2O (M+H) 295.4, found 295.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23]>C(Cl)Cl>[C:8]1([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[CH:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Nc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a stirring solution of 4-aminobiphenyl (9.53 g, 56.3 mmol) and triethylamine (5.70 g, 56.3 mmol, 7.85 mL) in methylene chloride (60 mL), cooled to 0° C., was added slowly isobutyryl chloride (6.0 g, 56.3 mmol, 5.90 mL). After stirring at 0° C. for 1 h, the mixture was diluted with methylene chloride (120 mL) and washed with 1N NaOH and saturated brine, then dried (MgSO4), filtered and concentrated. The residue was washed with ether and dried to provide the title compound as a pale yellow crystalline solid (9.83 g, 73%). 1HNMR (400 MHz, CDCl3/CD3OD) δ7.58 (d, 2H), 7.50 (m, 4H), 7.40-7.25 (m, 3H), 2.55-2.49 (m, 1H), 1.18 (d. 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:22][CH:23]2[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH3:30][NH:31][CH3:32].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:22][CH:23]2[CH2:24][CH2:25][CH:26]([N:31]([CH3:32])[CH3:30])[CH2:27][CH2:28]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)cc(SC3CCC(=O)CC3)c2C)c(=O)[nH]1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1cc(C)c(CNC(=O)c2cc(Cl)cc(SC3CCC(N(C)C)CC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 3.4 %

Procedure:
To a stirred solution of 5-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-((4-oxocyclohexyl)thio)benzamide (0.45 g, 1.03 mmol) and dimethylamine (0.14 g, 3.11 mmol) in dichloroethane (5 mL) was added acetic acid (0.37 g, 6.16 mmol) and the mixture stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydride (0.66 g, 3.11 mmol) was added at 0° C. and the mixture stirred overnight at room temperature. On completion of the reaction, the solvent was removed under reduced pressure. Water was added to the residue and extraction was performed using 5% MeOH/DCM. The combined organic layers were dried and concentrated to afford crude material which was purified by column chromatography to afford the title compound (0.016 g, 3.3%). Analytical Data: LCMS: 462.35 (M+1)+; HPLC: 89.00% (@ 210-370 nm) (Rt; 4.949; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 7.44 (s, 1H), 7.16 (s, 1H), 6.10 (s, 1H), 4.44 (s, 2H), 3.63 (m, 1H), 3.13 (m, 1H), 2.38 (s, 3H), 2.36 (s, 3H), 2.35 (s, 3H), 2.31 (s, 3H), 2.24 (s, 3H), 1.75-2.08 (m, 8H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([C@@H:25]4[CH2:28][C@H:27]([C:29](O)=[O:30])[CH2:26]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH3:32][NH2:33]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([C@@H:25]4[CH2:26][C@H:27]([C:29]([NH:33][CH3:32])=[O:30])[CH2:28]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H]1C[C@@H](n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)C1
Reactant: CN
Product: CNC(=O)[C@H]1C[C@@H](n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)C1

Procedure:
Following the general method as outlined in Example 61, starting from cis-3-(4-(6-fluoro-1-(phenylsulfonyl)-1H-indol-3-yl)-1H-pyrazol-1-yl)cyclobutanecarboxylic acid (Intermediate 36; 100 mg; 0.23 mmol), and MeNH2 (0.23 mL; 0.46 mmol; 2.0 M in THF), 100 mg (96%) of the title compound was obtained as a yellow oil, which was used directly without further purification.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](OCC)=[O:4].[C:10]([O:13][CH2:14][CH3:15])(=[O:12])[CH3:11].[O-]CC.[Na+]>>[F:1][C:2]([F:9])([F:8])[C:3](=[O:4])[CH2:11][C:10]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CCOC(C)=O
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)CC(=O)C(F)(F)F
Temperature: 62.5 °C
Reaction time: 3 h

Procedure:
Ethyl trifluoroacetate (142.1 g, 1.00 moles) is mixed with ethyl acetate (229.1 g, 2.60 moles) under nitrogen at 5-10° C. Sodium ethoxide (71.5 g, 1.05 moles) is added portion-wise at the same temperature. The addition is exothermic, bringing the temperature gradually to 40-55° C. The mixture is heated to 60-65° C. and kept at that temperature for 3 hours. GC indicates a conversion of 98.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To a stirring solution of 4.48 g (20 mmol) of 2-chloro-5-trifluoromethyl-benzoic acid suspended in 40 mL of conc. H2SO4 at −20° C. was added dropwise a cold solution of 1.05 eq of potassium nitrate dissolved in 12 mL of sulfuric acid. The reaction mixture was stirred −20° C. for 15 min then warmed up to r.t. overnight. The mixture was poured into a beaker containing ice. The resulting solid was collected, washed with cold water and dried to give 4.8 g (90%) of 2-chloro-3-nitro-5-trifluoromethyl-benzoic acid as a solid. LCMS: 270 (M+1)+.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=1[O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])(=[O:5])[CH3:4]>C(Cl)(Cl)Cl.CCOC(C)=O>[Br:1][CH2:4][C:3]([C:6]1[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=1[O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:5]
Reactant: BrBr
Reactant: COC(=O)COc1ccccc1C(C)=O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)COc1ccccc1C(=O)CBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromine (1.2 g, 7.2 mmol) in chloroform (5 mL) was added drop wise to a solution of methyl (2-acetylphenoxy)acetate (1.5 g, 7.2 mmol) in chloroform (45 mL) at room temperature. The reaction mixture was stirred for 1 h at room temperature, diluted with EtOAc and washed with sodium bicarbonate water, brine, dried over magnesium sulfate and concentrated to give the sub-title compound as an oil which solidified (2.1 g, 100%). LCMS calc. for C11H12BrO4 (M+H)+: m/z=287.0, 289.0. found: 287.0, 289.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH3:15][O:16][C:17](=[O:22])[C:18](Br)([CH3:20])[CH3:19].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:15][O:16][C:17](=[O:22])[C:18]([CH3:20])([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[CH3:19]
Reactant: COC(=O)C(C)(C)Br
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 90 °C

Procedure:
A mixture of 4-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (5.0 g, 0.026 mol), 2-bromo-2-methylpropionic acid methyl ester (3.50 mL, 0.0270 mol), Cs2CO3 (12 g, 39 mmol) in DMF (200 mL) was heated at 90° C. overnight. Reaction mixture was concentrated in vacuo, water was added, and the mixture was extracted with EtOAc (3×50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the title compound as a light yellow solid. MS (ES+): m/z 295.13, 296.16 (100, 50) [MH+]. HPLC: tR=3.35 min (ZQ3 polar—5 min).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:23])[N:14]([CH3:22])[CH:15]([C:18]([O:20][CH3:21])=[O:19])[C:16](=N)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(O)(=[O:27])C.OS(O)(=O)=O>CO>[CH2:1]([N:8]1[C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([OH:27])[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: COC(=O)C1C(=N)c2ccn(Cc3ccccc3)c2C(=O)N1C
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COC(=O)c1c(O)c2ccn(Cc3ccccc3)c2c(=O)n1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A solution of methyl 1-benzyl-4-imino-6-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (9.0 g, 28.9 mmol) in Methanol (100 mL) was treated with Water (40 mL) and Acetic Acid (50 mL), followed by H2SO4 (1.575 mL, 29.6 mmol), and the resultant was stirred at 90° C. overnight. The mixture was concentrated, diluted with water and then adjusted to pH>6 with saturated sodium bicarbonate. The mixture was extracted with Ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated to afford methyl 1-benzyl-4-hydroxy-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (7.0 g, 22.4 mmol, 76% yield) as a pale yellow solid which was used in the next step without any further purification. 1H NMR (400 MHz, CHLOROFORM-d) ppm 11.23 (s, 1H) 7.20-7.36 (m, 5H) 7.04-7.11 (m, 1H) 6.62-6.70 (m, 1H) 5.86 (s, 2H) 3.98 (s, 3H) 3.67 (s, 3H); LCMS (m/z) ES+=313 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][OH:8])[CH:3]=[N:2]1.C(N(CC)CC)C.[C:16](=O)([O-:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>CN(C)C1C=CN=CC=1.ClCCl>[OH:8][CH2:7][CH2:6][C:4]1[CH:5]=[N:1][N:2]([C:16]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:22])[CH:3]=1
Reactant: OCCc1cn[nH]c1
Reactant: CC(C)(C)OC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1cc(CCO)cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.10 g (9.81 mmol) 2-(1H-pyrazol-4-yl)-ethanol, 0.20 g (1.64 mmol) 4-dimethylaminopyridine and 1.50 ml (10.3 mmol) triethylamine were placed in 30 ml dichloromethane, the reaction mixture was cooled to 0° C. and 2.20 g (9.88 mmol) tert. butyl carbonate was slowly added. The mixture was stirred for 2 h at ambient temperature and then overnight at ambient temperature. It was diluted with 50 ml dichloromethane and washed with 10% citric acid solution and 15% potassium carbonate solution, the organic phase was dried, filtered and the solvent was eliminated from the filtrate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]2[CH:21]=[C:20]([CH2:22][C:23]([O:25]CC)=[O:24])[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:18]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][N:17]2[CH:21]=[C:20]([CH2:22][C:23]([OH:25])=[O:24])[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:18]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cn(CCc2ccc(OCc3ccccc3)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)Cc1cn(CCc2ccc(OCc3ccccc3)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A mixture of ethyl [1-[2-(4-benzyloxyphenyl)ethyl]-3-phenyl-1H-pyrazol-4-yl]acetate (440 mg), 1 N aqueous sodium hydroxide solution (2 ml), ethanol (2 ml), and tetrahydrofuran (2 ml) was stirred at room temperature for 2 hours. The reaction mixture was acidified with 1 N hydrochloric acid. The obtained crystals were collected by filtration, and [1-[2-(4-benzyloxyphenyl)ethyl]-3-phenyl-1H-pyrazol-4-yl]acetic acid was obtained (350 mg, yield: 85%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 199–200° C.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:5]=2[O:4][CH:3]=1.CO[CH:27]1[CH2:31][CH2:30][CH:29](OC)O1.O>C(O)(=O)C>[CH3:17][S:14]([NH:13][C:11]1[C:10]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:9][C:6]2[C:7](=[O:8])[C:2]([N:1]3[CH:27]=[CH:31][CH:30]=[CH:29]3)=[CH:3][O:4][C:5]=2[CH:12]=1)(=[O:15])=[O:16]
Reactant: CS(=O)(=O)Nc1cc2occ(N)c(=O)c2cc1Oc1ccccc1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)Nc1cc2occ(-n3cccc3)c(=O)c2cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
In 5 ml of acetic acid were dissolved 500 mg of 3-amino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one and 250 mg of 2,5-dimethoxytetrahydrofuran. The mixture was stirred for 30 minutes at 70°-80° C. and then cooled to room temperature. 50 ml of water was added thereto. The resulting crystal was collected by filtration and recrystallized from ethyl acetate-diisopropyl ether to obtain 250 mg (yield: 43.7%) of 7-methylsulfonylamino-6-phenoxy-3-(1-pyrrolyl)-4H-1-benzopyran-4-one having a melting point of 238.5°-240° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][N:21]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24][CH:23]=1>>[N:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][N:21]=2)[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[O:6])[CH:25]=[N:24][CH:23]=1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccnc(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccnc(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 69 using 2-bromo-N-(4-(trifluoromethoxy)phenyl)isonicotinamide and 5-pyrimidine boronic acid to afford a grey solid. UPLC-MS (Condition 1) tR2.31 min, m/z=361.0 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.43 (d, J=8.56 Hz, 2H) 7.92 (d, J=9.29 Hz, 3H) 8.58 (s, 1H) 8.96 (d, J=5.14 Hz, 1H) 9.31 (s, 1H) 9.53 (s, 2H) 10.74 (s, 1H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[F:27])[CH:20]=[C:19]([C:28]#[N:29])[N:18]=1>C1COCC1>[C:28]([C:19]1[N:18]=[C:17]([O:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[C:26]2[C:21]([CH:20]=1)=[CH:22][CH:23]=[CH:24][C:25]=2[F:27])#[N:29]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: N#Cc1cc2cccc(F)c2c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3cccc(F)c23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a solution of (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (2.18 g, 12 mmol) in THF (50 mL) was added NaH (0.464 g, 12 mmol) at 0° C. The mixture was stirred at RT for 30 minutes. Next, 1-chloro-8-fluoroisoquinoline-3-carbonitrile (1.6 g, 8 mmol) was added and the reaction mixture was warmed to RT and stirred for 4 hours. The reaction was subsequently quenched with H2O (20 mL) and the mixture was extracted with EtOAc (3×50 mL). The organic layers were combined and concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (1 g, 60%). 1H NMR (400 MHz, CDCl3) δ ppm 7.72 (s, 2H), 7.61-7.59 (d, J=8 Hz, 1H), 7.38-7.32 (t, J=12 Hz, 1H), 5.8 (s, 1H), 3.75-3.59 (m, 4H), 2.29-2.28 (d, J=4 Hz, 2H).
Reaction SMILES: Br[C@H:2]1[C@H:7]([OH:8])[C:6]2[CH:9]=[C:10]([CH:13]=[O:14])[CH:11]=[CH:12][C:5]=2[O:4][C:3]1([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:15][C:3]1([CH3:16])[CH:2]2[O:8][CH:7]2[C:6]2[CH:9]=[C:10]([CH:13]=[O:14])[CH:11]=[CH:12][C:5]=2[O:4]1
Reactant: CC1(C)Oc2ccc(C=O)cc2[C@@H](O)[C@@H]1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc(C=O)cc2C2OC21
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.7 %

Procedure:
A mixture of trans-3-bromo-3,4-dihydro-2,2-dimethyl-4-hydroxy-2H-1-benzopyran-6-carbaldehyde (6.9 g), potassium carbonate (6.7 g), and dimethylformamide (24 ml) was stirred at room temperature for 48 hours and followed by at 35° C. for 24 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by recrystallization from diisopropyl ether to give 3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran-6-carbaldehyde (2.9 g).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([NH:8][CH3:9])=[O:7].Cl[C:15]1[CH:20]=[C:19]([Cl:21])[N:18]=[CH:17][C:16]=1[C:22]#[N:23]>C1COCC1.CCOC(C)=O>[Cl:21][C:19]1[CH:20]=[C:15]([NH:3][C:4]2[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=2[C:6]([NH:8][CH3:9])=[O:7])[C:16]([C:22]#[N:23])=[CH:17][N:18]=1
Reactant: N#Cc1cnc(Cl)cc1Cl
Reactant: CNC(=O)c1ccccc1N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccccc1Nc1cc(Cl)ncc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.3 %

Procedure:
Sodium hydride (2.345 g, 58.64 mmol) was added portionwise to a mixture of 2-amino-N-methylbenzamide (2.201 g, 14.66 mmol), in THF (40 mL) at room temperature under an atmosphere of nitrogen. The resulting suspension was stirred at room temperature for 30 minutes and then 4,6-dichloropyridine-3-carbonitrile (2.536 g, 14.66 mmol) was added portionwise (caution—exotherm and effervescence); the mixture was then heated overnight at 60° C. The mixture was allowed to cool to room temperature and then diluted with EtOAc (200 mL). The mixture was washed sequentially with water (200 mL), water (150 mL), and finally with a saturated solution of NaCl (200 mL). The organic layer was filtered and the residue washed with water followed by EtOAc and then allowed to dry to leave 2-[(2-chloro-5-cyanopyridin-4-yl)amino]-N-methylbenzamide (0.687 g, 16% yield). The filtrate was dried over MgSO4 and then evaporated to leave a solid. The solid was crystallised from MeOH/Et2O to afford a second crop of 2-[(2-chloro-5-cyanopyridin-4-yl)amino]-N-methylbenzamide (2.471 g, 59% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 2.76 (3H, t), 7.10 (1H, d), 7.26-7.32 (1H, m), 7.57 (2H, dd), 7.72-7.74 (1H, m), 8.56 (1H, s), 8.68 (1H, d), 10.63 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=286.98 and 288.94.
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:9])[CH3:8].[C:11]1([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[C:7]([O:23][C:20]1[CH:19]=[CH:18][C:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:22][CH:21]=1)(=[O:9])[CH3:8]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2ccccc2)cc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Pyridine (2 mL) was dissolved in 15 mL of CH2Cl2. The solution was cooled to about 5° C. and stirred while while acetyl chloride (393 mg, 5 mmol) was added slowly. Next, a suspension of p-phenylphenol (0.85 g, 5 mmol) in 20 mL of CH2Cl2 was added dropwise over a 15 min period. The cooling bath was removed and stirring continued for 30 min. The solvents were removed under reduced pressure and 50 mL of ethyl acetate was added to dissolve the solids. The solution was extracted with water, dried over Na2SO4 and evaporated under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:12].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=1[CH:17]=O>CO>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=1[CH2:17][NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:12]
Reactant: Nc1ccc2nc[nH]c(=O)c2c1
Reactant: COc1ccc(OC)c(C=O)c1
Solvent: CO
Product: COc1ccc(OC)c(CNc2ccc3nc[nH]c(=O)c3c2)c1
Temperature: 25 °C

Procedure:
A mixture of 200 mg of 6-amino-3H-quinazolin-4-one and 206 mg of 2,5-dimethoxybenzaldehyde in 12 ml of dry methanol is heated to 60° for 16 hours. cooling the yellow precipitate is filtered and resuspended in 10 ml of dry methanol. This mixture is treated with 85 mg of sodium cyanoborohydride and heated for some minutes until all the materials are dissolved. After stirring for 2 at room temperature, the mixture is poured into water and extracted with acetate. The combined organic extracts are dried over magnesium sulfate and evaporated in vacuo. The pure title compound is obtained by crystallisation from ethanol as colourless crystals. mp: 203-205°.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Br:12])=[CH:7][CH:8]=2)[CH:3]=1.Cl.N([O-])=O.[Na+].[F:18][B-](F)(F)F.[Na+]>C(OC)(C)(C)C.C(OCC)C>[Br:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][CH:2]=[C:3]2[F:18])=[CH:8][CH:7]=1
Reactant: Nc1ccc2ccc(Br)cc2c1
Reactant: F[B-](F)(F)F
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CCOCC
Product: Fc1cccc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
A solution of the product from Step A (5 g, 21 mmol) in methyl tert-butyl ether (20 ml) was treated with a solution of hydrogen chloride in diethyl ether (16.9 ml, 2 M) and the resulting mixture was stirred at room temperature. After 30 minutes, solids had precipitated and were filtered and washed with methyl tert-butyl ether. These solids were added to 6 M HCl (57.7 ml) and the resulting suspension was cooled to 0° C. Sodium nitrite (4.7 g, 70 mmol) followed by sodium tetrafluoroborate (7.4 g, 70 mmol) were added portionwise keeping the temperature at 0° C. The mixture was stirred at 0° C. for 30 minutes, then filtered. The filtrate was washed with ice cold water and extracted with ice cold methyl tert-butyl ether to give 7-bromo-1-fluoronaphthalene (4 g, 85%): 1H NMR (300 MHz, DMSO-d6) δ 8.18 (d, J=1.8 Hz, 1H), 7.97 (dd, J=9.0, 1.8 Hz, 1H), 7.80 (d, J=8.1 H), 7.72 (dd, J=8.7, 2.1 Hz, 1H), 7.55 (td, J=7.8, 5.4 Hz, 1H), 7.39 (ddd, J=10.8, 7.8, 0.9 Hz, 1H).