Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([CH:11]=C)=[CH:7][N:6]=1)([F:4])[CH3:3].N1C(C)=CC=CC=1C.C1C[O:24]CC1>O.[Os](=O)(=O)(=O)=O>[F:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([CH:11]=[O:24])=[CH:7][N:6]=1)([F:4])[CH3:3]
Reactant: C1CCOC1
Reactant: C=Cc1cnc(C(C)(F)F)nc1
Agent: O=[Os](=O)(=O)=O
Solvent: Cc1cccc(C)n1
Solvent: O
Product: CC(F)(F)c1ncc(C=O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
2-(1,1-difluoroethyl)-5-vinylpyrimidine (110 mg, 0.646 mmol) was dissolved in THF (5 ml) and water (2 ml). NaIO4 (571 mg, 2.67 mmol), 2,6-lutidine (143 mg, 0.155 ml, 1.3 mmol) and osmium tetraoxide (138 mg, 0.17 ml, 0.013 mmol, 0.078 molar in tBuOH) was added. The reaction mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with diethyl ether. The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. 1H NMR showed a mixture of aldehyde and lutidine, which was used directly in the next reaction, (166 mg, 42% yield, 28% pure). 1H NMR (CDCl3 500 MHz): δ 10.24 (s, 1H), 9.30 (s, 2H), 2.12 (t, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:26]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:14]=[CH:15][C:16]=3[CH3:17])=[CH:9][N:4]2[N:3]=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>CN(C)C(=O)C.O>[CH:27]1([C:30]([NH:1][C:2]2[N:26]=[C:5]3[CH:6]=[CH:7][C:8]([O:10][C:11]4[CH:12]=[C:13]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH:14]=[CH:15][C:16]=4[CH3:17])=[CH:9][N:4]3[N:3]=2)=[O:31])[CH2:29][CH2:28]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc2nc(N)nn2c1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Yield: 89 %

Procedure:
To a solution of tert-butyl {3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-4-methylphenyl}carbamate (1.50 g, 4.22 mmol) in N,N-dimethylacetamide (5 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (1.15 mL, 12.7 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (1.59 g, 89%) as a white solid.
Reaction SMILES: [OH-].[Na+:2].[CH:3]1[N:7]2[C:8]3[C:13]([N:14]=[CH:15][C:6]2=[N:5][C:4]=1[C:16]([OH:18])=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=3.CC(C)=O>O>[CH:3]1[N:7]2[C:8]3[C:13]([N:14]=[CH:15][C:6]2=[N:5][C:4]=1[C:16]([O-:18])=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=3.[Na+:2]
Reactant: O=C(O)c1cn2c(cnc3ccccc32)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C([O-])c1cn2c(cnc3ccccc32)n1

Procedure:
Aqueous 2 N sodium hydroxide solution was added dropwise to a stirred suspension of 2 g of imidazo-[1,2-a]-quinoxaline-2-carboxylic acid in 20 ml of water until dissolution occured at a pH of 9-10. Acetone was added to the mixture to cause precipitation and the mixture was filtered to obtain 1.8 g of sodium imidazo-[1,2-a]-quinoxaline-2-carboxylate melting at >300° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25]([CH2:27][CH2:28][C:29]4[C:34]([CH2:35][C:36]([O-:38])=O)=[CH:33][N:32]=[CH:31][N:30]=4)[C:24]([C:39]([F:42])([F:41])[F:40])=[CH:23][N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].O[N:45]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CCOC(C)=O.CO.CN(C=O)C>[NH2:45][C:36](=[O:38])[CH2:35][C:34]1[C:29]([CH2:28][CH2:27][C:25]2[C:24]([C:39]([F:41])([F:40])[F:42])=[CH:23][N:22]=[C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([CH:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13][CH2:12]4)=[CH:15][CH:16]=3)[N:26]=2)=[N:30][CH:31]=[N:32][CH:33]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncncc4CC(=O)[O-])n3)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncncc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.1 %

Procedure:
Lithium 2-(4-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoro-methyl)pyrimidin-4-yl)ethyl)pyrimidin-5-yl)acetate (I113) (0.092 g, 0.16 mmol) was dissolved in dry THF (7 mL) and dry DMF (1 mL) under an atmosphere of nitrogen. To the solution were added 1-hydroxybenzotriazole (0.023 g, 0.17 mmol) and EDCl (0.033 g, 0.17 mmol) and N,N-diisopropylethylamine (0.109 mL, 0.624 mmol) and the reaction mixture was stirred at room temperature for 10 minutes. Ammonium carbonate (0.075 g, 0.78 mmol) was added in one portion, and the reaction was stirred room temperature for 24 hours. More reagents were added, 1-hydroxybenzotriazole (0.011 g) and EDCl (0.016 g) and N,N-diisopropylethylamine (0.055 mL) and ammonium carbonate (0.035 g) and the reaction was stirred for another 20 hours at 35° C. The volatiles were removed in vacuo and the residual solution was diluted with EtOAc (70 mL) and sat. aq. NaHCO3 (70 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×70 mL), the organic layers were combined and washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give an oily solid. The crude product was purified by silica gel chromatography (Isolera Biotage, 12 g Si Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-10% methanol in EtOAc) to give the title compound (I114) (0.076 g, 83% yield) as a pale yellow foam; 1H NMR (400 MHz, d6-DMSO) δ 10.03 (s, 1H), 8.94 (s, 1H), 8.64 (s, 1H), 8.53 (s, 1H), 7.64 (br s, 1H), 7.55 (d, J=7.6 Hz, 2H), 7.16 (d, J=8.6 Hz, 2H), 7.11 (brs, 1H), 4.12-4.04 (m, 2H), 3.57 (s, 2H), 3.30-3.21 (m, 4H), 2.77 (br s, 2H), 2.68-2.58 (m, 1H), 1.74 (d, J=12.7 Hz, 2H), 1.53-1.37 (m, 11H). LCMS Method C: rt 6.12 min; m/z 586.1 [M+H]+.
Reaction SMILES: OS(O)(=O)=O.C[C:7]([N:9](C)C)=O.[Cl:12][C:13]1[CH:14]=[C:15]([C:22]2[C:27]3[N:28]([CH2:40][C@H:41]4[CH2:46][CH2:45][C@H:44]([CH3:47])[CH2:43][CH2:42]4)[C:29]([N:31]4[CH2:36][CH2:35][O:34][C@@H:33]5[CH2:37][CH2:38][CH2:39][C@@H:32]45)=[N:30][C:26]=3[CH:25]=[C:24](Cl)[N:23]=2)[C:16]([N:19]([CH3:21])[CH3:20])=[N:17][CH:18]=1>CC([O-])=O.CC([O-])=O.[Pd+2].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.[Fe+2].[C-]#N.[C-]#N.[Zn+2].[Zn].O>[Cl:12][C:13]1[CH:14]=[C:15]([C:22]2[C:27]3[N:28]([CH2:40][C@H:41]4[CH2:46][CH2:45][C@H:44]([CH3:47])[CH2:43][CH2:42]4)[C:29]([N:31]4[CH2:36][CH2:35][O:34][C@@H:33]5[CH2:37][CH2:38][CH2:39][C@@H:32]45)=[N:30][C:26]=3[CH:25]=[C:24]([C:7]#[N:9])[N:23]=2)[C:16]([N:19]([CH3:20])[CH3:21])=[N:17][CH:18]=1
Reactant: CC(=O)N(C)C
Reactant: CN(C)c1ncc(Cl)cc1-c1nc(Cl)cc2nc(N3CCO[C@@H]4CCC[C@H]43)n(C[C@H]3CC[C@H](C)CC3)c12
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Product: CN(C)c1ncc(Cl)cc1-c1nc(C#N)cc2nc(N3CCO[C@@H]4CCC[C@H]43)n(C[C@H]3CC[C@H](C)CC3)c12
Temperature: 80 °C

Procedure:
A vial was charged with H2SO4 (6 mg, 0.005 mmol) and DMA (3 mL) and was degassed with N2 for 3 minutes. Pd(OAc)2 (13.5 mg, 0.005 mmol) and dppf (33.4 mg, 0.005 mmol) were added. The vial was sealed and heated at 80° C. for 30 minutes and then was cooled to room temperature. 1 mL of this solution was added to a second vial containing 5-chloro-3-{6-chloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-4-yl}-N,N-dimethylpyridin-2-amine (racemic, 81 mg, 0.14 mmol), Zn(CN)2 (7.8 mg, 0.06 mmol) and Zn (1.0 mg, 0.014 mmol) under an atmosphere of N2. The reaction was sealed and heated at 95° C. for 18 hours. Water (5 mL) was added, and the aqueous layer was extracted with EtOAc (2×5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified on a silica gel column (0 to 50% EtOAc/hexanes) to afford 4-[5-chloro-2-(dimethylamino)pyridin-3-yl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (racemic). MS ES calc'd. for C29H38ClN7O [M+H]+ 534. found 534.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH3:29][NH:30][CH:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1>>[CH3:29][N:30]([CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2)[CH:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: CNC1CCN(C)CC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN(C)C3CCN(C)CC3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with N,1-dimethylpiperidin-4-amine via General Procedure E to give 5.2 mg of 275 following reverse phase purification. MS (Q1) 490.3 (M)+
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1.[CH:8](=O)[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:11]>>[CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[OH:11])=[N:5][N:6]=1
Reactant: Cc1nnc(C)s1
Reactant: O=Cc1ccccc1O
Product: Cc1nnc(C=Cc2ccccc2O)s1
Temperature: 150 °C
Reaction time: 30 h

Procedure:
570 g (5 moles) of 2,5-dimethyl-1,3,4-thiadiazole and 275 g (2.5 moles) of salicylaldehyde are mixed and the mixture is slowly heated to 150° C. whilst passing nitrogen through it. The mixture is kept at 150° C. for 30 hours and is then cooled, the excess 2,5-dimethyl-1,3,4-thiadiazole is distilled off and the residue is recrystallized from methylglycol. 304 g (56% of theory) of yellow crystals of melting point 253°-254° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:23][C:24]1[N:28]([CH2:29][C:30](=[O:38])[NH:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[C:27]2[CH:39]=[CH:40][C:41]([C:43]#[N:44])=[CH:42][C:26]=2[N:25]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:23][C:24]3[N:28]([CH2:29][C:30](=[O:38])[NH:31][CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[C:27]4[CH:39]=[CH:40][C:41]([C:43]#[N:44])=[CH:42][C:26]=4[N:25]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Reactant: N#Cc1ccc2c(c1)nc(CCl)n2CC(=O)NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3nc4cc(C#N)ccc4n3CC(=O)NC3CCCCC3)cc2)CC1
Yield: 95.5 %

Procedure:
A solution of 4-(4-aminophenoxy)piperidine-1-carboxylic acid tert-butyl ester (8.21 g), 2-chloromethyl-1-(cyclohexylcarbamoylmethyl)-5-cyanobenzimidazole (9.29 g) and diisopropylethylamine (9.8 ml) in dimethylformamide (93 ml) was stirred at 60° C. for 14 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. To the obtained residue were added ethyl acetate and hexane and the precipitated solid was collected by filtration, washed with diisopropyl ether and dried under reduced pressure to give the title compound (15.726 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH2:21]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[C:21]1[O:1][C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[CH:4]=1
Reactant: ClCc1ccncc1Cl
Reactant: O=Cc1cc(C(F)(F)F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3Cl)cc2c1
Temperature: 150 °C
Reaction time: 4 h
Yield: 59 %

Procedure:
A mixture of 0.78 g of 2-hydroxy-5-(trifluoromethyl)benzaldehyde, 0.89 g of 3-chloro-4-(chloromethyl)pyridine, 1.94 g of potassium carbonate and 15 ml of DMF was stirred at 80° C. for 3 hours and subsequently at 150° C. for 4 hours. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with water and saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.72 g of 3-chloro-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine (hereinafter, referred to as “Present Active Compound 6”).
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[O:20][N:19]=[C:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)[CH:17]=2)[N:3]=1.[NH2:26][C:27]1[CH:31]=[C:30]([CH3:32])[NH:29][N:28]=1>>[CH3:10][O:9][CH2:8][C:6]1[N:5]=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[O:20][N:19]=[C:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)[CH:17]=2)[N:3]=[C:2]([NH:26][C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][N:28]=2)[CH:7]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: COCc1cc(O)nc(N2CCCC2c2cc(-c3nccs3)no2)n1
Product: COCc1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3nccs3)no2)n1

Procedure:
Starting materials: 4-hydroxy-6-methoxymethyl-2-[2-{3-(thiazol-2-yl)isoxazol-5-yl}pyrrolidin-1-yl]pyrimidine (Method 36) and 3-amino-5-methyl-1H-pyrazole.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]1([S:15]([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=[CH:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].O>C1COCC1.ClCCl>[C:9]1([S:15]([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=[C:19]2[C:27](=[O:29])[CH3:28])(=[O:17])=[O:16])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 41.1 %

Procedure:
Lithium diisopropylamide (19.4 mL, 35.0 mmol, 1.8M in heptane/THF/ethylbenzene) was added to a solution of 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (4.50 g, 17.4 mmol) in THF (100 mL) at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes, and then acetic anhydride (6.6 mL, 69.7 mmol) was added. The reaction mixture was warmed up to room temperature and stirred for 40 minutes. The reaction mixture was treated with water and dichloromethane, and the layers were separated. The aqueous layer was extracted once with dichloromethane. The organic layers were dried with sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography to afford 1-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)ethanone (2.15 g, 41%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1F.C(=O)([O-])[O-].[Cs+].[Cs+].[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[OH:27]>CS(C)=O.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:27][C:21]1[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=1[F:19]
Reactant: Nc1ccc(Br)c(F)c1[N+](=O)[O-]
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Nc1ccc(Br)c(Oc2ccc(F)cc2F)c1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
A solution of 4-bromo-3-fluoro-2-nitroaniline (0.100 g, 0.426 mmol) [Combi-Blocks, AN-2785] and cesium carbonate (0.167 g, 0.511 mmol) in dimethyl sulfoxide (0.47 mL) was treated with 2,4-difluorophenol (0.083 mL, 0.512 mmol) and stirred at 20° C. for 30 min and heated at 110° C. for 30 min. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated and washed with water and brine, dried with magnesium sulfate, filtered, and concentrated to give a crude residue. Purification by flash column chromatography (100% hexanes to 40% EtOAc/hexanes) gave the desired product (140 mg, 95%) as an orange/brown oil. LCMS calculated for C12H8BrF2N2O3 (M+H)+: m/z=345.0, 347.0. found: 344.9, 346.9.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][CH:26]([CH2:29][OH:30])[CH2:25][CH2:24]1.[Cl-].[NH4+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>[OH:30][CH2:29][CH:26]1[CH2:27][CH2:28][N:23]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:19]([F:22])([F:21])[F:20])[NH:8][C:9]3=[O:12])=[CH:4][CH:3]=2)[CH2:24][CH2:25]1
Reactant: OCC1CCNCC1
Reactant: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(Cl)cc12
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(N3CCC(CO)CC3)cc12
Temperature: 25 °C
Yield: 71.3 %

Procedure:
8.65 ml (8.65 mmol) of a 1 M lithium bis(trimethylsilyl)amide THF solution was added to a mixture consisting of 400 mg (1.24 mmol) of the 7-chloro-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1; 427.2 mg (3.708 mmol) of 4-piperidinemethanol; 29.2 mg (0.074 mmol) of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl; and 28.3 mg (0.0309 mmol) of tris(dibenzylideneacetone)dipalladium. The obtained mixture was stirred under heating to reflux over a day and a night. Thereafter, the reaction solution was cooled to a room temperature, and a saturated ammonium chloride aqueous solution was then added thereto, followed by extraction with methylene chloride. Thereafter, the extract was washed with a saturated saline solution, and was then dried over anhydrous sodium sulfate. The extract was concentrated, and the obtained residue was then purified by silica gel column chromatography (methylene chloride:methanol=25:1 to 20:1), so as to obtain 355.6 mg (71%) of 7-(4-hydroxymethylpiperidin-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one in the form of a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][O:11][C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=2[CH:23]=1.[Br:24][C:25]1[C:26](F)=[N:27][CH:28]=[C:29]([Br:31])[CH:30]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu](I)I.CN(C=O)C>[Br:24][C:25]1[C:26]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[C:8]([CH2:10][O:11][C:12]4[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=4)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=3[CH:23]=2)=[N:27][CH:28]=[C:29]([Br:31])[CH:30]=1
Reactant: Fc1ncc(Br)cc1Br
Reactant: COC(=O)c1cccc(OCc2nc3ccc(O)cc3n2C)c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCc2nc3ccc(Oc4ncc(Br)cc4Br)cc3n2C)c1
Yield: 74 %

Procedure:
The reaction and post-treatment were carried out according to Example (1f) using methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (2.50 g, 8.00 mmol), 3,5-dibromo-2-fluoropyridine (2.24 g, 8.81 mmol), copper iodide (0.15 g, 0.80 mmol), 1,10-phenanthroline (0.14 g, 0.80 mmol), cesium carbonate (7.82 g, 24.0 mmol) and DMF (40 mL) to obtain the title compound (3.24 g, 74%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:22][C:23]([OH:25])=O)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])=[CH:11][CH:10]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:50][NH:51][CH2:52][C:53]([OH:55])=[O:54]>CN(C)C=O.C(N(CC)CC)C>[CH3:50][N:51]([C:23](=[O:25])[CH2:22][C:4]1[CH:5]=[C:6]([Cl:21])[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:20])[CH:17]([CH3:18])[CH3:19])=[CH:11][CH:10]=2)=[C:2]([Cl:1])[CH:3]=1)[CH2:52][C:53]([OH:55])=[O:54]
Reactant: CC(C)C(=O)Nc1ccc(Oc2c(Cl)cc(CC(=O)O)cc2Cl)cc1
Reactant: CNCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Nc1ccc(Oc2c(Cl)cc(CC(=O)N(C)CC(=O)O)cc2Cl)cc1
Reaction time: 24 h

Procedure:
A solution of 3,5-dichloro-4-(4-isobutyramidophenoxy)phenylacetic acid (70 mg), 3-ethyl-1-[3-(dimethylamino)propyl]carbodiimide hydrochloride (49 mg), 1-hydroxybenzo-triazole hydrate, (45 mg) in dimethyl formamide (2 mL) was stirred at room temperature for 0.5 hours followed by addition of a solution of methyl glycine hydrochloride (46 mg) and triethylamine (56 mg) in dimethylformamide (1 mL). After stirring for one day, the reaction mixture was concentrated. The residue was purified by HPLC as described for Examples 33–90, to give methyl N-[3,5-dichloro-4-(4-isobutyramidophenoxy)phenylacetyl]glycine. The ester was hydrolyzed using the method described in Example 1(i) and purified as above, to give 25 mg (31%) of N-[3,5-dichloro-4-(4-isobutyramidophenoxy)phenylacetyl]glycine, m/z 439.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[C:15]([O:18][CH3:19])([O:16][CH3:17])[CH:10]([CH:11]=[CH:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[CH2:1]([N:8]1[CH2:14][CH:13]2[C:15]([O:18][CH3:19])([O:16][CH3:17])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1(OC)C2C=CC1CN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COC1(OC)C2CCC1CN(Cc1ccccc1)C2
Reaction time: 4 h

Procedure:
3-Benzyl-8,8-dimethoxy-3-aza-bicyclo[3.2.1]oct-6-ene (51.8 g, 0.2 mol) was dissolved in EtOAc (100 mL) in a 500 mL Parr bottle. To this was added 20% Pd(OH)2/C (Degussa type, 2.60 g) and the mixture was shaken under 45 psi of H2 for 4 h (or judged complete by TLC). The reaction was filtered through a Celite pad, rinsed with EtOAc, and concentrated to a brown liquid (50.4 g, 97%). (TLC 30% EtOAc/hexanes Rf 0.63); 1H NMR (400 MHz, CDCl3) δ 7.33–7.17 (5H), 3.51 (s, 2H), 3.22 (s, 3H), 3.16 (s, 3H), 2.50 (AB dd, J=10.4, 3.7 Hz, 2H), 2.40 (AB d, J=10.4 Hz, 2H), 2.04 (br s, 2H), 1.70–1.64 (m, 4H); APCI MS m/z 262.3 (M+1)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](B(O)O)[CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[N+:8]([C:4]1[CH:3]=[C:2]([C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: OB(O)c1cccnc1
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=[N+]([O-])c1cccc(-c2cccnc2)c1

Procedure:
To a 1-iodo-3-nitrobenzene (1.0 g, 4.01 mmol) in dry DME (20 mL) was added pyridine-3-boronic acid (641 mg, 5.22 mmol), PdCl2dppf (327 mg, 0.40 mmol), and 2M Na2CO3 (3.0 mL) The resulting mixture was heated to reflux under N2 for 15 h. Solvent was separated from inorganic solid by filtration. The solvent was removed and the residue was extracted with CHCl3. The organic layer was washed with water, brine, and dried over MgSO4. The solvent was removed to give dark brown solid which was purified by chromatography on silica gel. Elution with Hexane:acetone mixture (80:20) gave the final compound as a tan solid. MS m/z: 201.3 (M+H). Calc'd. for C11H8N2O2-200.23.