Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C1COCC1.[C:8]([CH:12]([C:29]([O:31][CH3:32])=[O:30])[C:13]1[CH:14]=[CH:15][N:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:17]2=[O:28])([O:10][CH3:11])=[O:9].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>O>[C:8]([C:12]([C:13]1[CH:14]=[CH:15][N:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:17]2=[O:28])([C:29]([O:31][CH3:32])=[O:30])[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])([O:10][CH3:11])=[O:9]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)c1ccc2cc(C(C(=O)OC)C(=O)OC)ccn2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(C(=O)OC)(C(=O)OC)c1ccn2c(=O)c(C(=O)OCC)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
An oven-dried 50 ml three-necked round-bottom flask equipped with a reflux condenser was charged with NaH (160 mg, 60% suspension in oil, 4 mmol, washed with hexane) and 10 ml THF. Ethyl 8-(dicarbomethoxymethyl)-4-oxo-4H-quinolizine-3-carboxylate (19) (700 mg, 2 mmol) was added in three portions and stirring was continued for 1 h, followed by addition of ethyl bromoacetate (0.5 ml, 5.3 mmol). The reaction mixture was refluxed overnight, cooled to room temperature and poured into 100 ml water. The aqueous layer was extracted three times with 100 ml dichloromethane. The organic solvent was evaporated and the crude product was purified by flash chromatography (ethyl acetate) to give a yellow viscous oil (630 mg, 74%). 1H NMR (δ, CDCl3): 1.24 (t, J=7 Hz, 3H), 1.42 (t, J=7 Hz, 3H), 3.39 (s, 2H), 3.84 (s, 6H), 4.14 (q, J=7 Hz, 2H), 4.41 (q, J=7 Hz, 2H), 6.63 (d, J=8 Hz, 1H), 7.14 (dd, J=2 Hz, J=7 Hz, 1H), 7.61 (d, J=2 Hz, 1H), 8.40 (d, J=8 Hz, 1H), 9.29 (d, J=8 Hz, 1H). MS: m/z 433.1363; required for C21H21NO9: 433.1372.
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][C@H:4]1[C@H:6]([C:7](Cl)=[O:8])[C:5]1([CH3:11])[CH3:10].[C:13]1([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH:22]([OH:28])[CH2:23]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]([Cl:12])=[CH:3][C@H:4]1[C@H:6]([C:7]([O:28][CH:22]2[CH2:21][C:20]3[C:24](=[CH:25][CH:26]=[CH:27][C:19]=3[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:23]2)=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: OC1Cc2cccc(-c3ccccc3)c2C1
Reactant: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)OC1Cc2cccc(-c3ccccc3)c2C1

Procedure:
In a manner similar to Example 12A, the reaction of 0.41 g (0.0018 mole) of (±)-trans-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride with 0.37 g (0.0018 mole) of (+)-4-phenyl-2-indanol (EE 50%), 0.16 g (0.002 mole) of pyridine and toluene gave (+)-4-phenyl-2-indanyl (±)-trans-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate, EE 50% (alcohol moiety). The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[Cl:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:15][CH3:16])[C:13]=1[OH:14])[CH:9]=[O:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:14][C:13]1[C:12]([O:15][CH3:16])=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[Cl:5]
Reactant: COc1cc(C=O)cc(Cl)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)cc(Cl)c1OCCBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.9 %

Procedure:
1,2-Dibromoethane (46 mL, 0.54 moles) was added to a mixture of 3-chloro-4-hydroxy-5-methoxybenzaldehyde (10 g, 54 mmoles) and potassium carbonate (37 g, 0.27 moles) in DMF (180 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with saturated sodium chloride (150 mL), dried over MgSO4 and evaporated in vacuo to afford 9.33 g (59%) of 4-(2-bromoethoxy)-3-chloro-5-methoxybenzaldehyde. M.p. 52-54° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([NH:14][C:15]3[CH:39]=[CH:38][C:18]([C:19]([N:21]([CH3:37])[C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=4[O:29]CC4C=CC=CC=4)=[O:20])=[CH:17][C:16]=3[O:40][CH3:41])=[O:13])[C:5]=2[N:4]=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[NH2:1][CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([NH:14][C:15]3[CH:39]=[CH:38][C:18]([C:19]([N:21]([CH3:37])[C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=4[OH:29])=[O:20])=[CH:17][C:16]=3[O:40][CH3:41])=[O:13])[C:5]=2[N:4]=1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCc2ccccc2)ccc1NC(=O)c1cccc2[nH]c(CN)nc12
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2O)ccc1NC(=O)c1cccc2[nH]c(CN)nc12
Yield: 84.7 %

Procedure:
A solution of 4-(2-aminomethyl-1H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-(2-benzyloxy-4-methylphenyl)benzamide (120 mg) in methanol (15 ml) was stirred under atmospheric pressure of hydrogen in the presence of palladium hydroxide (20 mg) at ambient temperature overnight. After removal of the catalyst by filtration, the filtrate was evaporated in vacuo to give 4-(2-aminomethyl-1H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-(2-hydroxy-4-methylphenyl)benzamide (85 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:24]([OH:26])=[O:25])[CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:9][N:8]=[C:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:6]=2[CH:33]=1.[N+](=[CH2:36])=[N-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:24]([O:26][CH3:36])=[O:25])[CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:9][N:8]=[C:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:6]=2[CH:33]=1
Reactant: O=C(O)C(CCCN1CCOCC1)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: C=[N+]=[N-]
Product: COC(=O)C(CCCN1CCOCC1)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 14, 7-chloro-2-[(1-carboxy-4-morpholinobutylidene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine can be treated with ethereal diazomethane to give 7-chloro-2-[[1-(methoxycarbonyl)-4-morpholinobutylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].Cl.[NH2:13][OH:14]>C(O)C.O>[CH2:2]([C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[NH:1][C:2](=[O:3])[C:4]2=[N:13][OH:14])[CH2:4][CH2:6][CH2:7][CH3:8]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCCCc1cccc2c1NC(=O)C2=NO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
A suspension of the isatin described in Example 10c (5.51 g) in ethanol (20 ml) was warmed slightly followed by addition of hydroxylamine hydrochloride (2.47 g) dissolved in water (10 ml). The mixture was warmed to about 80° with stirring for 10 minutes, followed by cooling to ambient temperature and stirring for 30 minutes. The precipitated yellow solid was filtered off, washed with water and dried to afford the title product (4.50 g, 76%) as a fluffy yellow powder; tlc, Rf =0.16, silica gel, ethyl acetate:hexane (2:3).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]([OH:28])[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31]I>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]([O:28][CH3:31])[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(NC1CCCCC(O)C1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CCCCC(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-(7-chloro-4-quinolinyl)-N-(3-hydroxycycloheptyl)-1-piperazinecarboxamide (30 mg, 0.074 mmol) in DMF (3 mL) was added NaH (8.9 gm, 0.37 mmol) at rt. After 30 min, MeI (11.5 mg, 0.09 mmol) was added, and the reaction mixture was heated at rt for 2 h. After cooling to rt, the reaction mixture was quenched with MeOH, then poured into water (100 mL). The reaction mixture was extracted with EtOAc, washed with brine, and dried over Na2SO4. Concentration in vacuo followed by flash chromatography afforded the title product. LC-MS: 416 (M++1). 1H NMR (CDCl3) δ 8.75 (d, 1H), 8.05 (s, 1H), 7.95 (d, 1H), 7.45 (d, 1H), 6.85 (d, 1H), 4.40 (d, 1H), 4.10 (m, 1H), 3.65 (m, 4H), 3.45 (m, 1H), 3.36 (s, 3H), 3.20 (m, 4H), 2.15 (m, 1H) 2.05 (m, 1H), 1.50–1.90 (m, 6H), 1.40 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](N)[CH:5]=[C:4]([Br:12])[N:3]=1.N([O-])=O.[Na+].O.[ClH:18]>>[Br:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:18])[CH:5]=[C:4]([Br:12])[N:3]=1
Reactant: Nc1cc(Br)nc(Br)c1[N+](=O)[O-]
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1c(Cl)cc(Br)nc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2,6-dibromo-3-nitro-pyridin-4-ylamine (6.5 g, 21.9 mmol) was suspended in concentrated HCl (100 mL) and cooled to 0° C., then sodium nitrite (7.5 g, 109 mmol) was added. There mixture was stirred for 30 minutes then warmed to room temperature. 100 mL of cooled water were added and the mixture was extracted with 100 mL of ethyl acetate. The organic layer was washed with 100 mL of water, dried over magnesium sulphate and the solvent was removed in vacuo to give 5.8 g of 2,6-dibromo-3-nitro-4-chloro pyridine as an orange oil. The oil was dissolved in 80 mL of THF and cooled to 0° C. Benzylamine (94.9 mL, 44.9 mmol) was dissolved in 20 mL of THF and added dropwise to the reaction followed by potassium carbonate (6.6 g, 48.2 mmol). The mixture was warmed to room temperature then heated at 50° C. overnight. Once the reaction was complete, the mixture was partitioned in water (150 mL) and ethyl acetate (100 mL). The organic layer was washed with 200 mL of water and 200 mL of brine, dried over magnesium sulphate and the solvent was removed in vacuo. 100 mL of ethanol was added and the mixture was sonicated for five minutes and let in the fume hood overnight. The precipitate was filtered off and washed with 30 mL of ethanol to give 4.56 g of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccnc(Cl)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: Clc1cc(COC2CCCCO2)ccn1
Yield: 78.3 %

Procedure:
To a mixture of (2-chloropyridin-4-yl)methanol (7.0 g, 48.8 mmol) and 3,4-dihydro-2H-pyran (20.5 g, 244 mmol) in THF (80 mL), 4-methylbenzenesulfonic acid (840 mg, 4.88 mmol) was added. The reaction mixture was stirred at reflux overnight, and the solvent was removed under reduced pressure. The residue was diluted with H2O (200 mL), and the aqueous phase was extracted with EtOAc (3×200 mL). The combined organic layers were washed with H2O (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product, which was purified by silica gel column chromatography (Petroleum ether:EtOAc=4:1) to afford 2-chloro-4-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridine as a yellow oil (8.7 g, 78%). MS (ES+) C11H14ClNO2 requires: 227, found: 228[M+H]+.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[C:20]([F:28])[CH:19]=[CH:18][C:17]=1B(O)O>>[F:28][C:20]1[C:21]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)=[C:16]([F:15])[CH:17]=[CH:18][C:19]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: OB(O)c1ccc(F)c(-c2ccncc2)c1F
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)c(F)c1-c1ccncc1

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 2,4-difluoro-3-(pyridin-4-yl)benzeneboronic acid as described in Example 65 to give 3-[2,4-difluoro-3-(pyridin-4-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a white solid. Bis-hydrochloride (from ethanol/ethyl acetate): δH (400 MHz, DMSO) 7.60-7.65 (2H, m), 7.96-8.01 (1H, m), 8.16 (2H, d, J 6), 8.34 (1H, s), 9.00-9.02 (2H, m), 9.34 (1H, dd, J 7 and 3); m/z (ES+) 377 (M++H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:17]1(Br)[CH2:21][CH2:20][CH2:19][CH2:18]1>C(#N)C>[CH:17]1([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:3][CH2:2]2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: OCCCC1CCNCC1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCCC1CCN(C2CCCC2)CC1

Procedure:
To a solution of 3-(piperidin-4-yl)-1-propanol (4.7 g, 33 mmol) in acetonitril (100 mL) was added potassium carbonate (25 g, 180 mmol) and cyclopentylbromide (24.5 g, 164 mmol) and the reaction mixture was stirred at reflux temperature overnight. The mixture was allowed to cool, then filtered and the solvent evaporated. The residue was dissolved in ethyl acetate (150 mL) and the organic mixture was dried (MgSO4). The mixture was filtered and the solvent was evaporated. The residue was treated with diethyl ether (100 mL) and the organic phase was decanted and evaporated. This afforded 5.8 g of 3-(1-cyclopentylpiperidin-4-yl)-1-propanol contaminated with probably cyclopentylbromide. 1H NMR (400 MHz, CDCl3) δ 1.2-2.0 (m, 17H), 2.05-2.15 (m, 1H), 2.45 (pent., 1H), 2.95-3.05 (m, 2H), 3.55-3.65 (m, 2H), 4.28-4.36 (m, 2H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:18][CH2:19][CH:20]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH2:20][CH2:19][CH2:18][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:31][CH2:30]2)=[CH:27][CH:28]=1
Reactant: O=CCCc1cc(-c2ccccc2)n(-c2ccccc2)n1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(N2CCN(CCCc3cc(-c4ccccc4)n(-c4ccccc4)n3)CC2)cc1

Procedure:
106 mg (74%) of target compound was obtained by using a method same as in Example 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.289 mmol), 1-(4-chlorophenyl)piperazine (78 mg, 0.289 mmol), DIPEA (76 mL, 0.434 mmol) and NaBH(OAc)3 (184 mg, 0.868 mmol).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11].O>CC(C)=O>[C:1]([NH:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:4])[CH:2]=[CH2:3]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: C=CC(=O)Cl
Solvent: O
Solvent: CC(C)=O
Product: C=CC(=O)Nc1cccc(C(=O)OCC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
Propenoyl chloride (668 mg, 600 ul, 7.4 mMole) was added dropwise to an ice-cold solution of ethyl 3-aminobenzoate (2.0 gm, 12 mMole) in 10 ml of acetone. The solution was stirred for 30 minutes on ice and then for 30 minutes at room temperature. 50 ml of water was added and the yellowish oil was separated by decantation. It was washed with water and then dissolved in 15 ml of diethl ether. This solution was washed with 10% (w/v) sodium bicarbonate, water and then dried over anhydrous sodium carbonate. The ether was evaporated and a white creamy product was crystallized from ethanol. The overall yield was 37%, and the melting point of the product was 93° C. to 94° C.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.F[C:21]1[CH:22]=[CH:23][C:24]([N+:29]([O-:31])=[O:30])=[C:25]([CH:28]=1)[NH:26][CH3:27]>O>[CH2:1]([O:8][C:21]1[CH:22]=[CH:23][C:24]([N+:29]([O-:31])=[O:30])=[C:25]([CH:28]=1)[NH:26][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: CNc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Benzyl alcohol (0.93 mL, 9 mmol) and potassium carbonate (1.24 g, 9 mmol) were added to a N,N-dimethyl formamide solution (5 mL) of 5-fluoro-N-methyl-2-nitroaniline (510 mg, 3 mmol). The mixture was stirred at 60-70° C. for 8 hours. The reaction solution was cooled, then water was added thereto, and precipitated crystals were collected by filtration. The resulting crystals were washed with water, and dried at 50° C., thereby obtaining 680 mg of orange, powdery 5-benzyloxy-N-methyl-2-nitroaniline (yield: 88%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:30][C:31]1[CH:39]=[CH:38][C:34]([CH2:35][CH2:36]O)=[CH:33][CH:32]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:30][C:31]1[CH:39]=[CH:38][C:34]([CH2:35][CH2:36][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[CH:33][CH:32]=1
Reactant: OCCc1ccc(F)cc1
Reactant: Oc1ccc2[nH]ccc2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(CCOc2ccc3[nH]ccc3c2)cc1
Reaction time: 8 h
Yield: 25.7 %

Procedure:
To a solution of 1.06 g (8 mmol) 5-hydroxyindole and 2.09 g (8 mmol) triphenylphosphine in 40 ml anhydrous THF, cooled to 0° C. in ice, was added 1.0 mL (8 mmol) 4-fluorophenethylalcohol and 1.6 ml (8 mmol) diisopropylazodicarboxylate. The solution was allowed to gradually come to room temperature overnight. The solution was concentrated and the residue was chromatographed on silica using 20–25% EtOAc-hexane to afford 0.525 g 5-[2-(4-fluoro-phenyl)-ethoxy]-1H-indole as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1([CH3:13])[C:8](=[O:9])[N:7]([CH3:10])[C:6](=[O:11])[NH:5][C:4]1=[O:12].[F:14][C:15]1[C:16]([F:28])=[C:17]([F:27])[C:18]([F:26])=[C:19]2[C:24](=O)[O:23][C:21](=[O:22])[C:20]=12.CCN(CC)CC>CC(O)=O>[CH3:10][N:7]1[C:8](=[O:9])[C:3]([CH3:13])([N:2]2[C:21](=[O:22])[C:20]3[C:19](=[C:18]([F:26])[C:17]([F:27])=[C:16]([F:28])[C:15]=3[F:14])[C:24]2=[O:23])[C:4](=[O:12])[NH:5][C:6]1=[O:11]
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: CN1C(=O)NC(=O)C(C)(N)C1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CN1C(=O)NC(=O)C(C)(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C1=O
Temperature: 25 °C

Procedure:
A mixture of 5-amino-1,5-dimethylbarbituric acid hydrochloride (0.31 g, 1.50 mmol), tetrafluorophthalic anhydride (0.40 g, 1.80 mmol) and Et3N (0.21 mL, 0.15 g, 1.50 mmol) in glacial AcOH (11 mL) was stirred under reflux for 3 hours. The yellow solution was then allowed to cool down to room temperature and evaporated to dryness under reduced pressure. The oily residue was recrystallized from 70% EtOH to give 1,5-dimethyl-5-(tetrafluorophthalimido)-barbituric acid (19a) as white crystals.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].CC1(C)C(C)(C)OB([C:20]2[CH2:29][CH2:28][C:23]3([O:27][CH2:26][CH2:25][O:24]3)[CH2:22][CH:21]=2)O1>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>[F:11][C:3]1[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=1[C:20]1[CH2:29][CH2:28][C:23]2([O:27][CH2:26][CH2:25][O:24]2)[CH2:22][CH:21]=1
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Reactant: O=C(O)c1ccc(F)c(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: O=C(O)c1ccc(F)c(C2=CCC3(CC2)OCCO3)n1

Procedure:
Method 1 was followed using 6-bromo-5-fluoropicolinic acid (1.0 equiv.) and 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (2.0 equiv.) and Pd(dppf)Cl2-DCM (0.2 equiv.) to give 5-fluoro-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)picolinic acid. LC/MS=280.2 (M+H), Rt=0.66 min.
Reaction SMILES: [N+:1]([O-:4])([O-])=O.[Na+].[Br:6][CH2:7][C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]>O.C(O)(=O)C>[OH:4][N:1]=[C:9]([C:8]([CH2:7][Br:6])=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)CC(=O)CBr
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C(=O)CBr
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A solution of sodium nitrate (12.4 g.) in water (150 ml.) was dropwise added with stirring at 5° to 7° C. to a solution of ethyl 4-bromoacetoacetate (30 g.) in acetic acid (200 ml.) and the mixture was stirred for 2 hours at 10° C. Water (200 ml.) was added to the reaction mixture and the resultant mixture was extracted with ether (500 ml.). The extract was washed twice with water (200 ml.) and with a sodium chloride aqueous solution (200 ml.) and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give yellowish brown crystals of ethyl 2-hydroxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (32.6 g.).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH2:8]([O:9][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 2-phenylethanol (24.4 g, 0.2 mole) in CH2Cl2 (200 mL) is added NEt3 (30.7 mL, 0.22 mole). The reaction mixture is cooled to 0° C. and methanesulfonyl chloride (16.3 mL, 0.21 mole) is added dropwise. The reaction mixture is allowed to reach room temperature and is stirred at room temperature overnight. Solvent is removed under reduced pressure. Water is added and the aqueous phase is extracted three times with Et2O. The organic phase is washed with water, brine, dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure to give methanesulfonic acid phenethyl ester.
Reaction SMILES: [CH3:1][N:2]1[CH:15]([CH3:16])[CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1.O>CN1CCCC1=O>[CH3:1][N:2]1[CH:15]([CH3:16])[CH2:14][C:5]2[N:6]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([C:20]([F:30])([F:19])[F:29])=[CH:26][CH:25]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)C(C)C3
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C(F)(F)F)nc2)CC(C)N(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 5.5 %

Procedure:
To a solution of 2,3,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 0.935 mmol) in N-methyl-2-pyrolidone (2.5 mL) was added powdered KOH (463 mg, 8.27 mmol) and stirred for 10 min at RT. 2-Trifluoromethyl-5-vinyl pyridine (300 mg, 1.73 mmol) was added and stirred further for 4 h at RT. The reaction was monitored by TLC. After completion of reaction, water (10 mL) was added to the mixture, which was then filtered. Water was added to the filtrate, which was then extracted with EtOAc (50 mL). The organic layer was dried over sodium sulfate, concentrated in vacuum and the residue purified by column chromatography (100-200 mesh silica gel) to obtain 20 mg of desired compound. The free base compound was converted into the oxalate salt. 1HNMR (CDCl3, Freebase) d (ppm): 8.40 (s, 1H), 7.45 (d, 1H), 7.25 (m, 2H), 7.10 (d, 1H), 6.98 (d, 1H), 4.22 (t, 2H), 3.82 (d, 1H), 3.62 (d, 1H), 3.50 (m, 1H), 3.10 (t, 2H), 2.80 (m, 1H), 2.45 (s, 3H), 2.38 (s, 3H), 2.10 (dd, 1H), 1.10 (d, 3H).