Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20]>CN(C1C=CN=CC=1)C>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:19]([C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([C:15]([F:14])([F:25])[F:26])[CH:17]=1)=[O:20])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[n+]1c(C)sc(C)c1C
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 3-(trifluoromethyl)benzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.94 (t, 3 H) 1.35-1.44 (m, 2 H) 1.61-1.68 (m, 2 H) 2.19 (s, 3H) 2.21 (s, 3 H) 4.07-4.13 (m, 2 H) 6.64 (s, 1 H) 7.66-7.70 (m, 1 H) 7.79 (d, 1 H) 8.18-8.20 (m, 1 H) 8.25 (d, 1H); MS (ESI) m/z 356 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([CH2:20][N:21]2[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:23]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[CH:22]2)[CH:14]=[CH:13]3)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([CH2:20][N:21]2[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:23]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:22]2)[CH:14]=[CH:13]3)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc3cc(OCc4cccnc4C)ccc3c2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ncccc1COc1ccc2cc(Cn3cc(CCC(=O)O)c(-c4ccccc4)c3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
A mixture of ethyl 3-[1-[6-(2-methyl-3-pyridylmethoxy)-2-naphthylmethyl]-4-phenyl-3-pyrrolyl]propionate (959 mg), 1N aqueous sodium hydroxide solution (4 ml), tetrahydrofuran (8 ml) and ethanol (8 ml) was stirred at room temperature overnight, and 1N hydrochloric acid (4 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[1-[6-(2-methyl-3-pyridylmethoxy)-2-naphthylmethyl]-4-phenyl-3-pyrrolyl]propionic acid (750 mg, yield: 83%). This was recrystallized from ethanol. Melting point: 163–164° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]([CH:22]([OH:27])[CH2:23][CH2:24][CH2:25][CH3:26])[C:12]([O:14]CC3C=CC=CC=3)=[O:13])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]([CH:22]([OH:27])[CH2:23][CH2:24][CH2:25][CH3:26])[C:12]([OH:14])=[O:13])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: CCCCC(O)C(C(=O)OCc1ccccc1)c1ccc2c(c1)OCCO2
Agent: [Pd]
Solvent: CO
Product: CCCCC(O)C(C(=O)O)c1ccc2c(c1)OCCO2
Yield: 95.6 %

Procedure:
To a solution of benzyl (2RS,3RS)-2-(1,4-benzodioxan-6-yl)-3-hydroxyheptanoate (720 mg) in methanol (10 ml) was catalytically reduced with 10% palladium on carbon (100 mg) under 3 atmospheric pressure of hydrogen for 1 hour. The catalyst was removed by filtration and the filtrate was evaporated to afford (2RS,3RS)-2-(1,4-benzodioxan-6-yl)-3-hydroxyheptanoic acid (521 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[K].[CH3:16]C(C)([O-])C.CI>CS(C)=O>[CH3:16][N:13]1[CH:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[N:11]=[CH:12]1
Reactant: O=[N+]([O-])c1ccc(-c2c[nH]cn2)cc1
Reactant: CC(C)(C)[O-]
Agent: [K]
Solvent: CS(C)=O
Solvent: CI
Product: Cn1cnc(-c2ccc([N+](=O)[O-])cc2)c1

Procedure:
Prepared by reacting 4-(4-nitro-phenyl)-imidazole in DMSO with potassium-tert.butoxide at 0° C. and then with methyliodide at 20-25° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH:14]=O)=[CH:12][NH:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:22]=1)=[O:19]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]([CH2:14][N:30]3[CH2:31][CH2:32][CH:27]([C:23]4[CH:22]=[C:21]([NH:20][C:18](=[O:19])[CH:17]([CH3:16])[CH3:33])[CH:26]=[CH:25][CH:24]=4)[CH2:28][CH2:29]3)=[CH:12][NH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2n[nH]cc2C=O)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: COc1ccc(-c2n[nH]cc2CN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1

Procedure:
Prepared by Procedure F and Scheme R using 3-(4-methoxyphenyl)-1H-pyrazole-4-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 433.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([OH:27])=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:12][C:11]([CH3:28])=[C:10]([CH3:29])[N:9]=2)[S:5][C:6]=1[CH3:7].C(=O)([O-])[O-].[K+].[K+].[CH2:36]([CH:38]1[O:40][CH2:39]1)Br>CN(C)C=O>[CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:27][CH2:36][CH:38]5[CH2:39][O:40]5)=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:12][C:11]([CH3:28])=[C:10]([CH3:29])[N:9]=2)[S:5][C:6]=1[CH3:7]
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3nc(C)c(C)s3)ccnc2cc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3nc(C)c(C)s3)ccnc2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
4-[2-(4,5-Dimethyl-thiazol-2-yl)-5,6-dimethyl-pyridin-3-yloxy]-6-methoxy-quinolin-7-ol (compound 455) (41 mg) was suspended in N,N-dimethylformamide (2 ml). Potassium carbonate (42 mg) and epibromohydrin (0.03 ml) were added to the supension, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (44 mg, yield 94%).
Reaction SMILES: C[Si](C)(C)[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:23])([P:17](=[O:22])([O:20][CH3:21])[O:18][CH3:19])[P:11](=[O:16])([O:14][CH3:15])[O:12][CH3:13])[CH:6]=[CH:7][CH:8]=1.[I:26]Cl>C(O)(=O)C>[I:26][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:23])([P:17](=[O:22])([O:20][CH3:21])[O:18][CH3:19])[P:11](=[O:16])([O:14][CH3:15])[O:12][CH3:13])[CH:6]=[CH:7][CH:8]=1
Reactant: ClI
Reactant: COP(=O)(OC)C(O)(Cc1cccc([Si](C)(C)C)c1)P(=O)(OC)OC
Solvent: CC(=O)O
Product: COP(=O)(OC)C(O)(Cc1cccc(I)c1)P(=O)(OC)OC
Reaction time: 5 h
Yield: 81.9 %

Procedure:
Tetramethyl m-trimethylsilylphenyl-1-hydroxy-ethylidenebis(phosphonate) (0.41 g, 1.0 mmol) was added to a solution of ICl (0.32 g, 2.0 mmol) in acetic acid (2 cm3) and the mixture was stirred for 5 h. The solvent was then evaporated and the residue was extracted with 1:1 hexane:Et2O (2×10 cm3). Remaining solvents were removed from the residue under reduced pressure affording the title compound (0.38 g, 81%) as an orange liquid.
Reaction SMILES: [Br:1]C(Cl)(Cl)C(Cl)(Cl)Br.C(N(CC)CC)C.[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([CH:26]2[CH2:28][CH2:27]2)=O)=[CH:19][N:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCCl>[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]([Br:1])[CH:26]2[CH2:28][CH2:27]2)=[CH:19][N:18]=1
Reactant: O=C(Nc1ccc(F)nc1)C1CC1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Fc1ccc(N=C(Br)C2CC2)cn1
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of 1,2-dibromotetrachloroethane (7.23 g, 0.022 mol) in 1,2-dichloroethane (50 ml) and triethylamine (4.49 g, 0.044 mol) was added to a stirred suspension of N-(2-fluoro-5-pyridyl)-cyclopropane carboxamide (2.0 g, 0.011 mol) - see Example 2 stage 1 and triphenylphosphine (5.83 g, 0.022 mol) in 1,2-dichloroethane (25 ml) at -10° C. under nitrogen at such a rate so that the temperature did not rise above -10° C. After complete addition (11/4 hours) the reaction mixture was allowed to warm up to room temperature and any triphenyl phosphine oxide was removed by filtration. Further quantities of triphenylphosphine oxide were removed by trituration of the residue with hexane. The filtrate was evaporated to give N-(2-fluoro-5-pyridyl)-cyclopropylmethanimidoyl bromide (2.54 g, 95%) as a yellow crystalline solid which was used in the next stage without further purification or characterisation.
Reaction SMILES: [F:1][C@H:2]1[CH2:4][C@H:3]1[NH:5][CH:6]=[C:7]([C:13](=[O:24])[C:14]1[C:19]([CH3:20])=[C:18]([F:21])[C:17]([F:22])=[CH:16][C:15]=1F)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[H-].[Na+].Cl.ClCCl>O1CCOCC1.C(OCC)C>[F:21][C:18]1[C:19]([CH3:20])=[C:14]2[C:15](=[CH:16][C:17]=1[F:22])[N:5]([C@@H:3]1[CH2:4][C@@H:2]1[F:1])[CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]2=[O:24]
Reactant: CCOC(=O)C(=CN[C@@H]1C[C@@H]1F)C(=O)c1c(F)cc(F)c(F)c1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2cc(F)c(F)c(C)c2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
In 25 ml of anhydrous dioxane was dissolved 2.40 g of ethyl 3-[(1R,2S)-2-fluorocyclopropylamino]-2-(2,4,5-trifluoro-6-methylbenzoyl)acrylate, and 338 mg of 60% sodium hydride in oil was added thereto under cooling with ice, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into a mixture of 50 ml of 1N hydrochloric acid and 50 ml of dichloromethane, followed by stirring. The organic layer was separated. The aqueous layer was extracted with 100 ml of dichloromethane, and the extract was combined with the organic layer. The combined organic layer was dried over anhydrous sodium sulfate, the dichloromethane was removed by distillation, and the residue was dried in vacuo to yield yellow crude crystals. The crude crystals to yield with diethyl ether, filtered, and dried to yield 1.76 g of the titled compound as a pale yellow powder. The product was recrystallized from acetonitrile.
Reaction SMILES: [CH3:1][N:2]([CH:28]([CH3:30])[CH3:29])[C:3]1[C:4]([C:17]2[O:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=2.[OH-].[Na+]>CO.O>[CH3:1][N:2]([CH:28]([CH3:30])[CH3:29])[C:3]1[C:4]([C:17]2[O:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2nc(-c3ccc(-c4ccccc4)o3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a solution of methyl 3-[methyl(propan-2-yl)amino]-2-(5-phenylfuran-2-yl)quinoxaline-6-carboxylate (150 mg, 0.37 mmol) in methanol (30 mL) and water (2 mL) was added sodium hydroxide (59.8 mg, 1.50 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 mL) and adjusted to pH 5 with HCl (3N). The solids were collected by filtration to afford 3-[methyl(propan-2-yl)amino]-2-(5-phenylfuran-2-yl)quinoxaline-6-carboxylic acid as a light yellow solid (100 mg, 69%).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1Br.[CH3:21][N:22]([CH3:29])[CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.Br.Cl>O.[OH-].[Na+].CN(C)P(=O)(N(C)C)N(C)C>[F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[N:26]1[CH2:27][CH2:28][CH:23]([N:22]([CH3:29])[CH3:21])[CH2:24][CH2:25]1
Reactant: CC1CCc2c(Br)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CN(C)C1CCNCC1
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1CCc2c(N3CCC(N(C)C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 150 °C
Yield: 30.1 %

Procedure:
A mixture of 7 g of 9-fluoro-8-bromo-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 12 g of 4-dimethylaminopiperidine and 50 ml of hexamethylphosphoric triamide was heated at 150° C. on an oil bath for 5 hours. After completion of reaction, hexamethylphosphoric triamide was distilled off under reduced pressure and to the residue was added ethyl acetate to form crystals. The crystals were suspended in 500 ml of water and a 47% aqueous hydrobromic acid was added thereto to adjust pH to 3 followed by heating. Then, insoluble substances were removed by filtration. The filtrate was concentrated and the residue was recrystallized from ethanol-water. Crystals which formed were dissolved in a 10% aqueous sodium hydroxide solution and the resulting solution was adjusted to pH 8 with dilute hydrochloric acid to precipitate white crystals, which then were dried to give 2.4 g of 9-fluoro-8-(4-dimethylamino-1-piperidyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. m.p. 259°-261° C., white rhombic crystals. T1 -Elemental Analysis for C21H26O3N3F? -C? H? N? -Calc'd (%): 65.10 6.76 10.85 -Found (%): 64.97 6.88 10.72 -
Reaction SMILES: C[Si](C)(C)[O:3][CH:4](N(C)C)[C:5]([Cl:11])([Cl:10])[C:6]([F:9])([F:8])[F:7].S(=O)(=O)(O)O>>[Cl:10][C:5]([Cl:11])([C:6]([F:9])([F:8])[F:7])[CH:4]=[O:3]
Reactant: CN(C)C(O[Si](C)(C)C)C(Cl)(Cl)C(F)(F)F
Agent: O=S(=O)(O)O
Product: O=CC(Cl)(Cl)C(F)(F)F

Procedure:
This compound may be prepared by reacting a dimethylformamide solution of 1,1,1-trichloro-2,2,2-trifluoromethane with chlorotrimethylsilane in the presence of zinc, forming 1-(trimethylsiloxy)-2,2-dichloro-3,3,3-trifluoro-N,N-dimethylpropylamine. The 1-(trimethylsiloxy)-2,2-dichloro-3,3,3-trifluoro-N,N-dimethyl propylamine is reacted with sulfuric acid to form 2,2-dichloro-3,3,3-trifluoropropionaldehyde. The 2,2-dichloro-3,3,3-trifluoropropionaldehyde is then reacted with sulfur tetrafluoride to produce 2,2-dichloro-1,1,1,3,3-pentafluoropropane.
Reaction SMILES: Br[C:2]1[C:18]([O:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH:23]2[CH2:25][CH2:24]2)=[CH:17][C:5]2[N:6]([CH3:16])[C:7](=[O:15])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][C:9]=3[CH3:14].[CH3:34]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+].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].C(Cl)Cl.O>[CH:23]1([CH2:22][C@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:20][O:19][C:18]2[C:2]([CH3:34])=[CH:3][C:4]3[C:13]4[C:8](=[C:9]([CH3:14])[N:10]=[CH:11][CH:12]=4)[C:7](=[O:15])[N:6]([CH3:16])[C:5]=3[CH:17]=2)[CH2:25][CH2:24]1
Reactant: CB1OB(C)OB(C)O1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC3CC3)NC(=O)OC(C)(C)C)c(Br)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Cc1cc2c3ccnc(C)c3c(=O)n(C)c2cc1OC[C@H](CC1CC1)NC(=O)OC(C)(C)C
Temperature: 75 °C
Reaction time: 12 h
Yield: 91.9 %

Procedure:
An ambient temperature mixture of (S)-tert-butyl (1-((9-bromo-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-3-cyclopropylpropan-2-yl)carbamate (51 mg, 0.099 mmol), trimethylboroxine (0.015 mL, 0.109 mmol), PdCl2(dppf)-CH2Cl2 Adduct (8.06 mg, 9.88 μmol), cesium carbonate (64.4 mg, 0.198 mmol), 1,4-dioxane (1 mL), and water (0.33 mL) was charged to a pressure rated vial and purged with a stream of nitrogen for 10 minutes. The vial was sealed and stirred under nitrogen at 75° C. for 12 h. The resulting mixture was cooled to room temperature and vacuum filtered. The filtrate was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and brine. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The pooled organics were dried over magnesium sulfate, filtered, and concentrated to an oil. The oil was purified via silica gel chromatography (1% 2M ammonia in methanol/dichloromethane) to afford (S)-tert-butyl (1-cyclopropyl-3-((4,6,9-trimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)propan-2-yl)carbamate (41 mg, 0.091 mmol, 92% yield) as a colorless oil. LC/MS, (ESI) m/z 452.3 [(M+H)+, calcd for C26H34N3O4 452.3]; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.59 (d, J=5.8 Hz, 1H), 7.90 (s, 1H), 7.78 (d, J=5.8 Hz, 1H), 6.74 (s, 1H), 4.91 (d, J=7.3 Hz, 1H), 4.35-4.04 (m, 3H), 3.71 (s, 3H), 3.14 (s, 3H), 2.31 (s, 3H), 1.72-1.59 (m, 2H), 1.48 (s, 9H), 0.86-0.70 (m, 1H), 0.60-0.44 (m, 2H), 0.21-0.00 (m, 2H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15](O)=[O:16])[CH:11]=[CH:12][CH:13]=1>>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:16])[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: C[C@H](N)C(=O)O
Product: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)O

Procedure:
The title compound was prepared using L-alanine (Nova Biochem) and 3-chlorophenyl acetic acid (Aldrich) by following General Procedures F or G, followed by hydrolysis using General Procedure D.
Reaction SMILES: [C:1]([NH:4][C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(SC)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[C:17]1(S)C=CC=CC=1.C(N(CC)CC)C>CO>[C:1]([NH:4][CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8][CH3:17])=[O:7])(=[O:3])[CH3:2]
Reactant: Sc1ccccc1
Reactant: CSC(NC(C)=O)(C(=O)O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C(NC(C)=O)c1ccccc1

Procedure:
173 Milligrams of a methanethiol ester of α-acetylamino-α-methylthiophenylacetic acid and 50 mg of thiophenol were dissolved in 10 ml of methanol. To the solution 1 ml of triethylamine was added, and the system was refluxed for 1.5 hours. Concentrating the reaction mixture under reduced pressure, the residue was parted by a column chromatography (silica gel and methylene chloride). Thus 127 mg of methyl α-acetylaminophenylacetate was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[NH:8][N:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:8]1[C:7](=[O:20])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[N:9]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Product: CCOC(=O)c1cc(-c2ccc(OC)cc2)nn(Cc2ccccc2)c1=O
Yield: 75.3 %

Procedure:
Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and benzyl bromide as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 75.3%.
Reaction SMILES: [F:1][CH:2]([F:18])[C:3]([C:14]([F:17])([F:16])[F:15])([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH2:9][CH2:8]2)[OH:4].FC(F)[C:21](C(F)(F)F)([C:23]1C=C2C(=[CH:30][CH:31]=1)N(C(=O)CC(=O)C)CC2)[OH:22]>S(=O)(=O)(O)O>[F:18][CH:2]([F:1])[C:3]([C:5]1[CH:13]=[C:12]2[C:11]3=[C:7]([CH2:8][CH2:9][N:10]3[C:21](=[O:22])[CH:23]=[C:31]2[CH3:30])[CH:6]=1)([OH:4])[C:14]([F:17])([F:15])[F:16]
Reactant: CC(=O)CC(=O)N1CCc2cc(C(O)(C(F)F)C(F)(F)F)ccc21
Reactant: OC(c1ccc2c(c1)CCN2)(C(F)F)C(F)(F)F
Agent: O=S(=O)(O)O
Product: Cc1cc(=O)n2c3c(cc(C(O)(C(F)F)C(F)(F)F)cc13)CC2

Procedure:
By the method of Example 7, α-(difluoromethyl)-α-(trifluoromethyl)-2,3-dihydro-1H-indole-5-methanol is converted to α-(difluoromethyl)-α-(trifluoromethyl)-1-(1,3-dioxobutyl)-2,3-dihydro-1H-indole-5-methanol, m.p. 140°-143°, which is cyclized by heating in sulfuric acid to give 1,2-dihydro-8-[2,2,-difluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-6-methyl-4H-pyrrolo[3,2,1-ij]quinolin-4-one, m.p. 317°-318°.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([O:10][CH3:11])=[O:9].C1C=CC(OP(O[NH2:29])(OC2C=CC=CC=2)=O)=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.C(OCC)C>[NH2:29][N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: NOP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: COC(=O)c1ccc[nH]1
Agent: O=S([O-])([O-])=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1cccn1N
Temperature: -5 °C
Yield: 82.5 %

Procedure:
Sodium hydride (4.40 g, 0.11 mol, 60% in hexanes) was suspended in DMF (550 ml) under nitrogen atmosphere. Once cooled at −5° C., methyl 1H-pyrrole-2-carboxylate (11.0 g, 0.09 mol) dissolved in DMF (182 ml) was dropwise added and vigorously stirred for 30. 277 ml more of DMF was added and then 0-(diphenylphosphoryl)hydroxylamine (32.8 g, 0.14 mol) was introduced into the reaction mixture. The reaction mixture was stirred at room temperature for 4 h. Once the reaction is over, 11 of saturated sodium thiosulfate solution (×5H2O) was added and the mixture was warmed to 80° C. for 1 h. Once at room temperature, 11 of ethyl ether was added and the phases separated. The aqueous phase was twice extracted with ethyl ether. The organic phase was washed with water and brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. 10.41 g (81.1% yield) of the final compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16](I)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1.[F:31][C:32]1[C:33]([OH:38])=[N:34][CH:35]=[CH:36][CH:37]=1.C(=O)([O-])[O-].[Cs+].[Cs+].OC1C=CC=CC=1C=NO>C(#N)C.[Cu-]=O>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([N:34]3[CH:35]=[CH:36][CH:37]=[C:32]([F:31])[C:33]3=[O:38])[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1
Reactant: Oc1ncccc1F
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Solvent: CC#N
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(-n3cccc(F)c3=O)c21
Temperature: 200 °C

Procedure:
Under argon atmosphere, 200 mg (purity 62%, 0.24 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was suspended in 2.5 ml of absolute acetonitrile, and 545 mg (4.82 mmol) of 3-fluoropyridin-2-ol, 157 mg (0.48 mmol) of caesium carbonate, 7 mg (0.05 mmol) of copper(I) oxide and 20 mg (0.15 mmol) of 2-hydroxybenzaldehyde-oxime were added. The mixture was heated in the microwave for 1 h at 200° C. The reaction solution was filtered and purified by preparative HPLC (eluent: acetonitrile/water, gradient 20:80→100:0). 20 mg (23% of theor.) of the target compound was obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1.C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:19]>O1CCCC1>[CH2:21]([O:20][C:18]([N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]1[CH2:3][CH2:2][OH:1])=[O:19])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOC(=O)Cl
Reactant: OCCC1CCCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCOC(=O)N1CCCCC1CCO

Procedure:
6.5 g (0.05 mol) of 2-(2-hydroxyethyl)-piperidine and 10 ml of triethylamine are dissolved in 300 ml of tetrahydrofuran, and 7.5 g (0.55 mol) of butyl chloroformate are added at -20° C.