Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([N:10]=[N:11][N:12]=2)[CH:9]=1.CO.[NH4+:15]>>[NH2:15][CH2:3][C@@H:2]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([N:10]=[N:11][N:12]=2)[CH:9]=1)[OH:1]
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Reactant: [NH4+]
Solvent: CO
Product: NC[C@H](O)c1ccc2nnnn2c1

Procedure:
The title compound was prepared from 6-[(2R)oxiranyl][1,2,3,4]tetraazolo[1,5-a]pyridine and saturated ammonium methanol in substantially the same manner, as described in Example 124. The product was obtained as an off-white solid; mp 153-154° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.60 (brs, 2H), 2.73-2.84 (m, 2H), 4.65-4.68 (m, 1H), 5.70 (brs, 1H), 7.83-7.87 (m, 1H), 8.14-8.16 (m, 1H), 9.08-9.09 (m, 1H); MS (ES) m/z: 180 (M+H).
Reaction SMILES: [OH-].[Na+].[CH:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][C:12]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[OH:21])=[O:13]>O.CO>[Cl:20][C:18]1[CH:17]=[CH:16][C:15]([OH:21])=[C:14]([C:12](=[O:13])/[CH:11]=[CH:3]/[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:19]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(/C=C/c1ccccc1)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.8 %

Procedure:
To an ice-cooled solution of sodium hydroxide (2.34 g, 58.6 mmol) in water (17.0 mL) was added benzaldehyde (0.746 g, 7.03 mmol) and then a solution of 5-chloro-2-hydroxyacetophenone (1.00 g, 5.86 mmol) in methanol (17.0 mL). The reaction mixture was allowed to warm to room temperature, and it was stirred for 24 hours. The bulk of the organic solvent was removed by evaporation in vacuo. The aqueous residue was extracted with EtOAc (3×30 mL). The combined extracts were washed with water (50 mL) and brine (50 mL), dried over MgSO4, filtered and evaporated to dryness in vacuo. The residue was dissolved in a minimum volume of CH2Cl2, and n-pentane was added which resulted in precipitation. The obtained suspension was filtered and the precipitate was washed with little cold pentane, and dried in vacuo to afford Compound (XVI) (695 mg, 46%) as an orange solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[O:3][C@:4]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:8][C:7](=[O:9])[CH:6]=[CH:5]1.[Li+].CC([N-]C(C)C)C.C([NH-])(C)C.C([Li])CCC.[CH:37]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])=[O:38]>O1CCCC1.CCCCCC>[CH3:1][Si:2]([CH3:18])([CH3:19])[O:3][C:4]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:8]([CH:37]([OH:38])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])[C:7](=[O:9])[CH:6]=[CH:5]1
Reactant: COC(=O)CCCCCC=O
Reactant: CCCCCCCC[C@]1(O[Si](C)(C)C)C=CC(=O)C1
Agent: CC(C)[N-]C(C)C
Agent: CC(C)[NH-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCC1(O[Si](C)(C)C)C=CC(=O)C1C(O)CCCCCC(=O)OC
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere at -78° C., a solution of 200 mg (0.71 mmole) of (4R)-4-trimethylsilyloxy-4-octyl-2-cyclopentenone in 2 ml of tetrahydrofuran was added to a solution of LDA prepared from 93 mg (0.92 mmole) of isopropylamide and 590 microliters of n-butyllithium (as a 10 W/V % hexane solution) in 3 ml of tetrahydrofuran, and the mixture was stirred for 1 hour. Then, a solution of 146 mg (0.92 mmole) of methyl 6-formylhexanoate in 2 ml of tetrahydrofuran was added, and the mixture was stirred at -78° C. for 2 hours. The reaction was terminated by adding an aqueous solution of ammonium chloride. The reaction mixture was extracted with ether, and the extract was dried over anhydrous magnesium sulfate, filtered and concentrated.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]([C:11]1[CH:16]=[N:15][C:14](Br)=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:12]=1)=[O:10]>C(#N)C>[CH3:7][O:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:12]=1)=[O:10]
Reactant: C1CCNCC1
Reactant: COC(=O)c1cnc(Br)c(-c2ccc(F)cc2)n1
Solvent: CC#N
Product: COC(=O)c1cnc(N2CCCCC2)c(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Piperidine (0.48 ml, 4.82 mmol, 2.0 eq) was added portion-wise to a acetonitrile (2 ml) solution of 5-Bromo-6-(4-fluoro-phenyl)-pyrazine-2-carboxylic acid methyl ester (0.75 g, 2.41 mmol, 1.0 eq) at room temperature. The mixture was irradiated at 100° C. in a microwave with stirring for 30 minutes. HPLC-MS indicated complete consumption of starting material. The crude mixture was cooled to room temperature concentrated. The residue was re-dissolved in ethyl acetate (10 ml), washed with water (5 ml) and the organic phase dried over MgSO4. Following filtration and evaporation in vacuo, the residue was purified by chromatography on silica gel using a gradient of heptane to 10% ethyl acetate in heptane to afford 6-(4-fluoro-phenyl)-5-piperidin-1-yl-pyrazine-2-carboxylic acid methyl ester. Yield=0.48 g (63%). 1H NMR (250 MHz, CDCl3): δ 1.42-1.53 (6H, m), 3.20-3.24 (4H, m), 3.88 (3H, s), 7.06 (2H, t, J=8.78 Hz), 7.74-7.80 (2H, m), 8.68 (1H, s).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[CH3:6][C:7]1([CH3:15])[CH2:13][C:12](=O)[O:11][C:9](=[O:10])[CH2:8]1.C(OC(=O)C)(=O)C.[OH-].[Na+]>C(OCC)C>[CH3:3][CH:2]([CH3:4])[CH2:1][N:5]1[C:9](=[O:10])[CH2:8][C:7]([CH3:15])([CH3:6])[CH2:13][C:12]1=[O:11]
Reactant: CC(C)CN
Reactant: CC1(C)CC(=O)OC(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CC(C)CN1C(=O)CC(C)(C)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Isobutylamine (7.3 g, 0.1 mol) was added slowly to 3,3-dimethylglutaric anhydride (14.2 g, 0.1 mol) stirring at room temperature in a two neck round bottom flask fitted with a water condenser. After 30 minutes, acetic anhydride (20.4 g, 0.2 mol) was added, and the resulting mixture was boiled for two hours. After cooling, the mixture was poured slowly on to an aqueous NaOH solution (2N, 100 ml) stirring at room temperature. After one hour, the mixture was diluted with diethyl ether (50 ml), and the organic layer was separated. The aqueous layer was washed with more diethyl ether (2×50 ml), and the combined organic layer dried and concentrated to give the title compound as a pale yellow oil which solidified on standing, m.p. 48°-52° C., yield 18.5 g (94%). The product was suffuciently pure by NMR spectroscopy to be used directly in the following procedure.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([C:19]([F:22])([F:21])[F:20])[CH:10]=1>[Cl-].[Na+].O>[OH:4][CH2:3][CH2:2][N:1]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([C:19]([F:22])([F:20])[F:21])[CH:10]=1)[CH2:5][CH2:6][OH:7]
Reactant: OCCNCCO
Reactant: FC(F)(F)c1cc(Cl)c2ccccc2n1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: OCCN(CCO)c1cc(C(F)(F)F)nc2ccccc12
Temperature: 80 °C
Reaction time: 19 h

Procedure:
Diethanolamine (20 mL) was added to 4-chloro-2-trifluoromethylquinoline (5.04 g), and the mixture was stirred at 80° C. for 19 hr. Brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 4-[N,N-bis(2-hydroxyethyl)amino]-2-trifluoromethylquinoline (3.40 g) as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:25][N:26]=O)CCC>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[C:14](=[O:20])[C:13](=[N:26][OH:25])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)CCC2=O
Reactant: CCCCON=O
Product: COc1cc2c(cc1OCc1ccccc1)CC(=NO)C2=O

Procedure:
Similar procedure as described in example 2a was used, starting from 5-Benzyloxy-6-methoxy-indan-1-one and n-butylnitrite to give 5-Benzyloxy-6-methoxy-indan-1,2-dione 2-oxime. LC-MS: m/e 298 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](Cl)=[O:11].[C:13]1([NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([N:19]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11]
Reactant: O=C(Cl)Cc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CCNc1ccccc1
Product: CCOC(=O)CCN(C(=O)Cc1ccc(Cl)cc1Cl)c1ccccc1

Procedure:
By a procedure similar to that of example 1.115.1, starting from 2,4-dichlorophenylacetyl chloride and ethyl N-phenyl-3-aminopropionate, ethyl 3-[2-(2,4-dichlorophenyl)-N-phenyl-acetamido]propanoate was obtained as yellowish oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1.C1C(=O)N([I:19])C(=O)C1.CCOC(C)=O>S(O)(C(F)(F)F)(=O)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[I:19]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C1OCc2cc(Br)ccc21
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C1OCc2c1ccc(Br)c2I
Temperature: 25 °C

Procedure:
To a solution of 5-bromo-2-benzofuran-1(3H)-one (5.00 g, 23.5 mmol) at 0° C. in TfOH (100 mL) was added NIS (5.55 g, 24.6 mmol). The mixture was stirred at room temperature over night; LC analysis of the reaction mixture indicated completion of the reaction. The reaction mixture was then poured slowly into ice-water (1 L) with stirring. To the solution was then added EtOAc (500 mL) and subsequently stirred for 10 min. The mixture was filtered and the organic layer separated. The aqueous layer was extracted with EtOAc (2×200 mL). The combined organic layers were washed with water (500 mL), brine (500 mL), dried over Na2SO4, filtered, and concentrated to dryness; the resulting material was absorbed onto silica gel and separated with the solvent system of (hexanes/EtOAc=1/1) to yield 5-bromo-4-iodo-2-benzofuran-1 (3H]-one.
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11]([C:13]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:14]=2[O:15][C@@H:16]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)=[O:12])/[N:7]([CH2:36][C@H:37]2[CH2:41][CH2:40][CH2:39][O:38]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:12])[C:13]2[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=[CH:28][C:14]=2[O:15][C@@H:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)/[N:7]([CH2:36][C@H:37]2[CH2:41][CH2:40][CH2:39][O:38]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(C(F)(F)F)cc2C(=O)/N=c2\sc(C(C)(C)C)cn2C[C@H]2CCCO2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2O[C@@H]2CCNC2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To a solution of Example 384A (1.223 g, 2.046 mmol) in dichloromethane (5 mL) was added 2,2,2-trifluoroacetic acid (2.333 g, 20.46 mmol). The mixture was stirred at room temperature for 2 hr and then concentrated. The mixture was taken up in dichloromethane and washed with sodium bicarbonate. The organic layers were combined, dried and concentrated to give the title compound (0.92 g, 90%). 1H NMR (300 MHz, CDCl3) δ ppm 1.37 (s, 9H) 1.58-1.72 (m, 1H) 1.79-1.94 (m, 2H) 2.01-2.15 (m, 3H) 2.96-3.06 (m, 2H) 3.23-3.34 (m, 2H) 3.74-3.89 (m, 2H) 4.14-4.21 (m, 1H) 4.24-4.32 (m, 1H) 4.39-4.46 (m, 1H) 4.97-5.03 (m, 1H) 6.88 (s, 1H) 7.05 (d, J=8.73 Hz, 1H) 7.60 (dd, J=8.72, 2.38 Hz, 1H) 8.17 (d, J=2.38 Hz, 1H); MS (DCI/NH3) m/z 498 (M+H)+. Anal. calcd C24H30F3N3O3S.1.2 H2O: C, 55.52; H, 6.29; N, 8.09. Found: C, 55.39; H, 6.63; N, 8.01.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([CH3:23])[CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].NN>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]([CH3:23])[CH2:11][NH2:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[C@@H](CN1C(=O)c2ccccc2C1=O)c1ccc([N+](=O)[O-])cc1
Agent: NN
Solvent: Cc1ccccc1
Product: C[C@@H](CN)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 97.1 %

Procedure:
A 250 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer, reflux condenser and addition funnel is charged with 2-[(2R)-2-(4-nitrophenyl)propyl]isoindoline-1,3-dione (25.02 g, 80.6 mmol) and toluene (200.0 mL). To this solution at room temperature was added anhydrous hydrazine (7.08 mL, 226.0 mmol). Reaction exothermed slightly and was stirred for 45 minutes, heated at 90° C.-95° C. until the disappearance of starting material. A massive precipitate formed by the end of the reaction. Cooled to room temperature and chilled to 0° C. before filtration. Concentration of the filtrate afforded (2R)-2-(4-nitrophenyl)propylamine (14.11 g, 97%) as an oil;
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[NH:14][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)C.[OH-].[Na+]>C(O)C.O>[C:24]1([C:15]2[N:14]=[C:13]([S:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:30])=[O:3])[NH:17][C:16]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)CCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Yield: 41.7 %

Procedure:
To a solution of 5.0 g (0.012 mole) 8-(4,5-diphenyl-1H-imidazol-2-ylthio)octanoic acid ethyl ester in 125 ml ethanol was added, dropwise, a solution of 5.0 g sodium hydroxide in 125 ml water. The reaction mixture was stirred at reflux under nitrogen for 4 hours. The solvent was concentrated to half the volume and the remaining solution was extracted with diethyl ether. This organic layer was discarded. The aqueous layer was acidified to pH=1.0 using 1N hydrochloric acid and then extracted with diethyl ether. The organic layer was dried over magnesium sulfate and the solvent removed under vacuum. The resulting solid was crystallized from ethanol and triturated with hexane to give 2.13 g (0.005 mole) of the title compound as a white solid, mp=160°-162° C. 1H NMR(DMSO-d6): δ12.7(s,1H), 12.0(s,1H), 7.6-7.1(m,10H), 3.1(t,2H,J=7Hz), 2.3(t,2H,J=7Hz), 1.8-1.2 (m,10H).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:14][CH:15]4[CH2:19][NH:18][CH2:17][CH:16]4[CH:20]=3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22].CCN(C(C)C)C(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH:13]3[CH2:14][CH:15]4[CH2:19][N:18]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:17][CH:16]4[CH2:20]3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CNCC4C3)nc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3CC4CN(S(C)(=O)=O)CC4C3)nc21
Reaction time: 0.08 h

Procedure:
1-(2,2-Dimethylpropyl)-5-(1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (11-1, 50 mg, 0.15 mmol, 1.0 equiv), and DIPEA (0.080 mL, 0.45 mmol, 3.0 equiv) were added to anhydrous methylene chloride (2 mL). Stirred for 5 min and methanesulfonyl chloride (13.0 μL, 0.16 mmol, 1.1 equiv) was added. After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 13-1 as a pale yellow oil. MS m/z (M+H): calculated=407.2113; observed=407.2115.
Reaction SMILES: [OH:1][C:2]1[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11](=[O:16])[CH2:10][CH2:9]2)=[O:5].[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[OH:1][C:2]1[CH:20]=[C:19]([O:21][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][O:22]2)[CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11](=[O:16])[CH2:10][CH2:9]2)=[O:5]
Reactant: O=C1CCc2cc(C(=O)c3ccc(O)cc3O)ccc2O1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCc2cc(C(=O)c3ccc(OC4CCCCO4)cc3O)ccc2O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
10.0 g of 6-(2,4-dihydroxybenzoyl)-2-chromanone was suspended in 100 mL of methylene chloride, to which 3.53 mL of 3,4-dihydro-2H-pyran and 0.884 g of pyridinium p-toluenesulfonate were added, and this mixture was stirred for 18 hours at room temperature. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=3:1] to yield 6.99 g of 6-[2-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)benzoyl]-2-chromanon as light yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(OCC)C>[C:25]1([NH:31][C:32]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([O:10][C:11]4[C:20]5[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=5)[N:14]=[CH:13][CH:12]=4)=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1cc2nccc(Oc3ccc4[nH]ccc4c3)c2cc1OC
Reactant: O=C=Nc1ccccc1
Solvent: CCOCC
Product: COc1cc2nccc(Oc3ccc4c(ccn4C(=O)Nc4ccccc4)c3)c2cc1OC
Yield: 32.1 %

Procedure:
4-(1H-Indol-5-yloxy)-6,7-dimethoxyquinoline (25 mg, 0.0780 mmol) and phenyl isocyanate (0.013 ml, 0.117 mmol) were used for reaction in the same manner as Example 330, the obtained crystals were suspended in diethyl ether:ethanol=10:1, and then the crystals were filtered out, washed with diethyl ether and dried by aspiration to obtain the title compound (11 mg, 0.0250 mmol, 32.09%) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6]([F:7])=[C:5]([CH:8]=[O:9])[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:17].[K+].[K+]>CC(C)=O.O.S(=O)(=O)(O)O>[CH3:1][N:2]1[C:6]([F:7])=[C:5]([C:8]([OH:17])=[O:9])[C:4]([C:10]([F:13])([F:11])[F:12])=[N:3]1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1F
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cn1nc(C(F)(F)F)c(C(=O)O)c1F
Reaction time: 8 h
Yield: 200.2 %

Procedure:
A solution of 1-methyl-3-trifluoromethyl-5-fluoro-pyrazole-4-carboxaldehyde (9.8 g) in acetone (60 mL) was stirred rapidly at RT while a solution of potassium dichromate dihydrate (5.6 g) in water (38 mL) and sulfuric acid (4.6 mL) was added. The mixture was stirred rapidly overnight then diluted with water (150 mL). The mixture was extracted with CH2Cl2 (6 ×75 mL). The combined organic solution was washed with water, dried (MgSO4), filtered and concentrated in vacuo leaving a light yellow solid (7.2 g). The solid was recrystallized from EtOAc/hexane to give the desired compound as white crystals (3.8 g). m.p. 165-166° C.
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH:9]([Si:11](Cl)(Cl)Cl)=[CH2:10]>C1(C)C=CC=CC=1>[CH:9]([Si:11]([O:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)([O:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)[O:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)=[CH2:10]
Reactant: C=C[Si](Cl)(Cl)Cl
Reactant: OCc1ccco1
Agent: [Na]
Solvent: Cc1ccccc1
Product: C=C[Si](OCc1ccco1)(OCc1ccco1)OCc1ccco1
Temperature: 100 °C

Procedure:
To a solution of 86.5 ml. furfuryl alcohol in 200 ml. toluene was slowly added 23 g. sodium metal. An additional 10 ml. furfuryl alcohol was added and the solution was heated to 100° C. with stirring to convert all the sodium. The solution was cooled to ice temperature and 43.5 ml. vinyltrichlorosilane dissolved in 50 ml. toluene was slowly added. After the addition was complete, the mixture was heated at 95° C. for 0.5 hr. The colloidal sodium chloride by-product was extracted with water. The organic phase was filtered and the toluene removed by vacuum evaporation. The residue was distilled at 2 mmHg and the product recovered at 182°-184° C.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]2[CH:12]=[N:13][NH:14][C:3]=12.[CH2:15]([NH2:19])[CH:16]([CH3:18])[CH3:17]>C1(C)C(C)=CC=CC=1>[CH2:15]([NH:19][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]2[CH:12]=[N:13][NH:14][C:3]=12)[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CN
Reactant: Clc1c2c(nc3cn[nH]c13)CCCC2
Solvent: Cc1ccccc1C
Product: CC(C)CNc1c2c(nc3cn[nH]c13)CCCC2
Yield: 14.5 %

Procedure:
9-Chloro-5,6,7,8-tetrahydro-1H-pyrazolo[4,3-b]quinoline (4.90 g, 0.024 mole) and isobutylamine (11.7 ml, 0.118 mole) were heated under reflux under nitrogen in dry xylene (50 ml) for 6 days. The solution was concentrated to dryness, the residue dissolved in water/methanol and the solution adjusted to pH 9-10 by addition of 10% sodium carbonate solution. The precipitate was filtered of, washed with water, dried and recrystallised from ethyl acetate to give the title compound as a beige solid (0.85 g, 15%), m.p. 124°-127° C. Found: C, 68.45; H, 8.55; N, 22.80%. C14H20N4 requires C, 68.80; H, 8.25; N, 22.95%.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](Cl)[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]([F:18])([F:17])[CH2:15][OH:16].[OH-].[Na+].Cl>O>[Cl:1][C:2]1[N:10]=[C:9]([O:16][CH2:15][C:14]([F:18])([F:17])[F:13])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: OCC(F)(F)F
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(F)c(OCC(F)(F)F)nc1Cl
Temperature: 80 °C
Reaction time: 40 h
Yield: 80 %

Procedure:
A mixture of 2,6-dichloro-5-fluoronicotinic acid (1.0 g, 4.8 mmol), 2,2,2-trifluoroethanol (0.69 mL, 9.5 mmol) and sodium hydroxide (0.57 g, 14.3 mmol) in water (24 mL) is stirred at 80° C. for 40 hours. After cooling to 0° C., the mixture is acidified with conc. hydrochloric acid (pH 2). The resulting white precipitate is collected by filtration and dried to give 1.05 g (80% yield) of the title compound as white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1C(O)=O.[OH-].[Na+].C[N+:15]([O-])=O>>[F:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[NH2:15]
Reactant: C[N+](=O)[O-]
Reactant: O=C(O)c1ccc(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(Cl)cc1F
Reaction time: 2.5 h

Procedure:
A mixture of 2-fluoro-4-chlorobenzoic acid (6.05 g), polyphosphoric acid (62.51 g) and CH3NO2 (5.1 g) is heated at 130°. After about 2.5 hr, the reaction mixture is poured onto ice and made basic by addition of dilute sodium hydroxide. The reaction is then worked up by extracting with ether. The combined ether extracts are washed with water and brine, dried over sodium sulfate, filtered and evaporated to yield 2-fluoro-4-chloroaniline.