Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2(O)[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[H][H]>C(O)C.CCOC(C)=O.[Pd]>[CH:9]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:10][CH2:11][CH2:12]1
Reactant: [H][H]
Reactant: COc1cccc(C2(O)CCC2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cccc(C2CCC2)c1
Yield: 89 %

Procedure:
A mixture of 1-(3-methoxy-phenyl)-cyclobutanol and 10% Pd/C (60 mg) in ethanol (10 ml) was hydrogenated under 45 psi hydrogen atmosphere for 3 hours. The mixture was diluted with EtOAc, filtered through a celite pad. The filtrate was concentrated under reduced pressure, and dried to give 1-cyclobutyl-3-methoxy-benzene (162 mg, 89%).
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:13]([CH:16](C(OC)=O)[C:17]([O:19][CH3:20])=[O:18])([O-])=[O:14].F[P-](F)(F)(F)(F)F.C([N+]1C=CN(C)C=1)CCC>C1(C)C=CC=CC=1>[CH2:3]([C:4]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[N:13][O:14][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:12])[CH3:1]
Reactant: COC(=O)C(C(=O)OC)[N+](=O)[O-]
Reactant: CC(C)CC#Cc1ccccc1
Agent: CCCC[n+]1ccn(C)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)c1noc(-c2ccccc2)c1CC(C)C
Reaction time: 6 h
Yield: 30.1 %

Procedure:
A solution of (4-methylpent-1-ynyl)benzene (0.247 g, 1.56 mmol), dimethyl 2-nitromalonate (0.421 mL, 3.12 mmol), 1-butyl-3-methylimidazoliumhexafluorophosphate (0.032 mL, 0.156 mmol) in toluene (5 mL) was subjected to the microwave at 170° C. for 150 min. By HPLC, the reaction was ˜40-50% complete and resubjected to the microwave conditions for 360 min. (170° C.). The toluene was decanted off leaving a dark gum which was triturated several times with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using 5% ethyl acetate in hexane to give methyl 4-isobutyl-5-phenylisoxazole-3-carboxylate (0.122 g, 0.470 mmol, 30.2% yield) as a clear, colorless oil. The compound had an HPLC ret. time=2.96 min.−Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=259.9. 1H NMR (500 MHz, chloroform-d) δ ppm 0.88 (s, 3H), 0.89 (s, 3H), 1.89 (dt, J=13.75, 6.87 Hz, 1H), 2.80 (d, J=7.15 Hz, 2H), 4.00 (s, 3H), 7.45-7.53 (m, 3H), 7.73 (d, J=6.60 Hz, 2H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].I[CH2:24][CH2:25][CH3:26]>CC#N>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][N:14]([CH2:24][CH2:25][CH3:26])[CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CCCI
Reactant: CS(=O)(=O)c1cccc(N2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCN(c2cccc(S(C)(=O)=O)c2)CC1

Procedure:
A suspension of 1-(3-methanesulfonyl-phenyl)-piperazine (350 mg) and ground K2CO3 (403 mg) was stirred in CH3CN (25 mL) at room temperature. 1-Iodopropane (712 μL) was added. The mixture was refluxed overnight. The reaction mixture was filtered and the volatiles were evaporated in vacuum. The oily residue was chromatographed on a silica column with MeOH:CH2Cl2 (1:30 (v/v)) as eluent. Collection of the fractions containing pure product and evaporation of the solvent afforded pure 1-(3-methanesulfonyl-phenyl)-4-propyl-piperazine (220 mg). The amine was converted into the HCl salt and recrystallized from ethanol/diethylether: m.p. 233° C. MS m/z (relative intensity, 70 eV) 282 (M+, 30), 254 (15), 253 (bp), 210 (17), 70 (21).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH:16]1([Mg]Br)[CH2:20][CH2:19][CH2:18][CH2:17]1>O1CCCC1>[CH:16]1([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Reactant: Br[Mg]C1CCCC1
Solvent: C1CCOC1
Product: CC(CNS(C)(=O)=O)c1ccc(C2CCCC2)cc1
Yield: 13 %

Procedure:
Condition 1: The product of Example 1, 0.50 g (1.71 mmol) was dissolved in anhydrous tetrahydrofuran (5 ml) under an atmosphere of nitrogen. To this was added tetrakis-(triphenylphosphine)palladium(0) (0.099 g, 0.086 mmol) followed by cyclopentyl magnesium bromide (2 M in diethyl ether, 2.14 ml, 4.28 mmol). The solution was heated to reflux for 16 hours. Upon cooling the reaction was partitioned between water and diethyl ether. The aqueous layer was back extracted with diethyl ether twice and the organic fractions combined. The organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. Chromatography (Sio2, 30% ethyl acetate/hexanes) gave the title compound 0.06 g (13%).
Reaction SMILES: Cl.[N:2]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][N:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.[CH:24]1([N:27]2[C:36]3[C:31](=[C:32]([CH3:40])[C:33]([F:39])=[C:34](F)[C:35]=3[F:37])[C:30](=[O:41])[C:29]([C:42]([OH:44])=[O:43])=[CH:28]2)[CH2:26][CH2:25]1>C(#N)C>[CH:24]1([N:27]2[C:36]3[C:31](=[C:32]([CH3:40])[C:33]([F:39])=[C:34]([N:10]4[CH2:11][CH2:12][CH:7]([N:2]5[CH:6]=[CH:5][N:4]=[N:3]5)[CH2:8][CH2:9]4)[C:35]=3[F:37])[C:30](=[O:41])[C:29]([C:42]([OH:44])=[O:43])=[CH:28]2)[CH2:25][CH2:26]1
Reactant: c1cn(C2CCNCC2)nn1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1c(F)c(N2CCC(n3ccnn3)CC2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 47.9 %

Procedure:
4-(1,2,3-triazol-1-yl)piperidine hydrochloride (126 mg, 0.66 mmol) and DBU (130 mg, 0.85 mmol) were added to a suspension of 1-cyclopropyl-5-methyl-6,7,8-trifluoro -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (100 mg, 0.34 mmol) in acetonitrile (10 ml). The reaction mixture was refluxed for 24 hrs and then concentrated to dryness. The reaction was diluted with water. The separated solid was filtered and washed with water, acetonitrile and dried to give 70 mg of desired product. m.p. 261°-263° C.; 1H NMR (TFA) δ: 9.36 (s, 1H), 8.55 (s, 1H), 8.62 (s, 1H), 5.25 (m, 1H), 4.60 (m, 1H), 4.12 (m, 2H), 3.80 (m, 2H), 2.94 (s, 3H), 2.60 (m, 4H), 1.30-1.68 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH:13]3[NH:15][CH:10]([CH2:11][CH2:12]3)[CH:9]2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([C:30]([O:32]C)=O)=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[CH3:41]COCC>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH:13]3[NH:15][CH:10]([CH2:11][CH2:12]3)[CH:9]2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH:30]([OH:32])[CH3:41])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: COC(=O)c1ccccc1-c1ccc(COC2C3CCC(CC2c2ccc(Cl)cc2)N3)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: CC(O)c1ccccc1-c1ccc(COC2C3CCC(CC2c2ccc(Cl)cc2)N3)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
A solution of 0.330 g (0.71 mmol) of methyl (1RS,2RS,3RS,5SR)-4'-[3-(4-chloro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-yloxy-methyl]-biphenyl-2-carboxylate in 10 ml of ether was slowly added dropwise to a suspension of 33 mg of lithium aluminium hydride in 5 ml of ether and the mixture was stirred at room temperature for 4 hours. After the addition of aqueous ether and subsequently water the phases were separated, the organic phase was washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. The residue was chromatographed on silica gel using a 140:10:1 mixture of methylene chloride, methanol and ammonia as the eluent. There was obtained 0.210 g (68% of theory) of [4'-[3-(4-chloro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-yloxymethyl]-biphenyl-2-yl]-ethanol as a colourless foam, Rf : 0.18 (methylene chloride:methanol:ammonia=140:10:1), MS: 434 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[N:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C([O-])(=O)C.[Na+].[N:19]#[C:20]Br.[OH-].[Na+]>C(O)(=O)C.O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([C:20]([NH2:19])=[N:13][N:12]=3)[N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: N#CBr
Reactant: NNc1ccc(-n2ccnc2)nn1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nnc2ccc(-n3ccnc3)nn12
Temperature: 0 °C
Reaction time: 8 h
Yield: 11.6 %

Procedure:
(6-Imidazol-1-ylpyridazin-3-yl)hydrazine (500 mg) were initially charged in a mixture of acetic acid (4 ml) and water (8 ml) with addition of sodium acetate (232 mg) at RT while stirring. Thereafter, the mixture was cooled to 0° C. and cyanogen bromide (330 mg) was introduced in portions. After stirring for 2.5 h, the mixture was left to stand overnight. After cooling to 0° C., the mixture was alkalized with 10 M sodium hydroxide solution and extracted repeatedly with EA. The combined EA phases were dried over sodium sulfate, filtered and concentrated. 66 mg of the title compound were isolated.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH:4]([OH:6])[CH3:5].[H-].[Na+].[CH2:10](Br)[CH:11]=[CH2:12].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[CH2:12]([O:6][CH:4]([CH3:5])[C:3]([O:2][CH3:1])=[O:7])[CH:11]=[CH2:10]
Reactant: COC(=O)C(C)O
Reactant: C=CCBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(C)C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(±)-Methyl-2-hydroxypropanoate (7.6 g, 74 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to 0° C. and treated with sodium hydride (3.6 g, 60% dispersion, 89 mmol, 1.2 equiv) portionwise over 45 minutes. The mixture was warmed to ambient temperature, stirred for 30 minutes, and then cooled to 0° C. Allyl bromide (8.4 mL, 96 mmol, 1.3 equiv) was added, the mixture was warmed to ambient temperature and stirred for an additional 14 hours. Sodium bicarbonate (10 mL, aqueous saturated) was added slowly and the mixture was stirred for 30 minutes before being poured into water (500 mL). The aqueous layer was extracted with ethyl acetate (2×300 mL) and the combined organic extracts were washed once with brine, dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]([F:37])([F:36])[CH2:27][C:28]1[S:29][CH:30]=[C:31]([C:33]([OH:35])=O)[N:32]=1.[O:38]1[C:43]2([CH2:48][CH2:47][N:46]([CH2:49][C:50]3[C:51]([F:59])=[C:52]([CH2:56][CH2:57][OH:58])[CH:53]=[CH:54][CH:55]=3)[CH2:45][CH2:44]2)[CH2:42][NH:41][CH2:40][CH2:39]1.C(N(CC)CC)C>CN(C=O)C>[F:59][C:51]1[C:52]([CH2:56][CH2:57][OH:58])=[CH:53][CH:54]=[CH:55][C:50]=1[CH2:49][N:46]1[CH2:47][CH2:48][C:43]2([O:38][CH2:39][CH2:40][N:41]([C:33]([C:31]3[N:32]=[C:28]([CH2:27][C:26]([F:25])([F:37])[F:36])[S:29][CH:30]=3)=[O:35])[CH2:42]2)[CH2:44][CH2:45]1
Reactant: O=C(O)c1csc(CC(F)(F)F)n1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1csc(CC(F)(F)F)n1)N1CCOC2(CCN(Cc3cccc(CCO)c3F)CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HATU (0.181 g) was added in one portion to a stirred solution at 0° C. of 2-(2,2,2-trifluoroethyl)thiazole-4-carboxylic acid (example 67, step d) (0.077 g) and 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-2-fluorophenyl)ethanol (example 67, step f) (0.113 g) and triethylamine (0.153 mL) in DMF (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.180 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1([CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]([CH:29]=O)=[CH:23]3)[CH2:16][CH2:15][CH2:14][CH2:13]1.N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:29][C:24]1[NH:25][C:26]2[C:22]([CH:23]=1)=[CH:21][C:20]([O:19][CH2:18][CH2:17][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[CH:28][CH:27]=2
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccc(Br)cc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Temperature: 100 °C
Yield: 79.6 %

Procedure:
A mixture of 5-bromo-2-oxindole (42 mg, 0.2 mmol), 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde (52 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 72 mg (80%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:26])[NH2:25])[CH:6]=[CH:7][CH:8]=1.Br[CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C=O)C.C(OCC)(=O)C>[F:28][C:2]([F:27])([F:1])[C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:26])[NH2:25])[CH:6]=[CH:7][CH:8]=1
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(C(F)(F)F)c1
Reactant: COC(=O)CBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(C(F)(F)F)c1
Reaction time: 0.25 h
Yield: 87.9 %

Procedure:
40% Methanolic Triton B (0.18 mL, 0.4 mM) was added to a solution of the 9-[(3-trifluoromethylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (115 mg, 0.3 mN) in 5 mL DMF at room temperature. After 15 minutes, methyl bromoacetate (95 mg, 0.6 mM) was added and the resultant mixture stirred at room temperature for 22 hours. The mixture was diluted with ethyl acetate, washed four times with H2O, 1 N HCl, H2O, sat. NaHCO3, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 120 mg (88%) of the {9-[(3-trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (CDCl3) δ7.5-7.2 (m, 7H), 7.1 (d, 1H, J=8 Hz), 7.0 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.4 (br s, 1H), 6.0 (br s, 1H), 5.55 (s, 2H), 4.9 (s, 2H), and 3.9 (s, 3H). IR (KBr, cm−1) 1763 and 1673. MS (ES) m/e 457.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:37]2([CH3:38])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:32])[C@H:18]([OH:31])[C:19]#[C:20][C:21]([O:24]C2CCCCO2)([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:40][C:41](=[O:43])[CH3:42])[CH2:6]1)(=[O:3])[CH3:2].Cl.[O:45]1CC[CH2:47][CH2:46]1>CO.C(OCC)(=O)C.[Pd]>[C:1]([O:4][C@@H:5]1[C@@:37]2([CH3:38])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:32])[C@H:18]([O:31][C:46](=[O:45])[CH3:47])[CH2:19][CH2:20][C:21]([OH:24])([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:40][C:41](=[O:43])[CH3:42])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)[C@H](O)C#CC(C)(C)OC5CCCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)[C@@H](CCC(C)(C)O)OC(C)=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
109 mg of (22S)-1α,3β-diacetoxy-25-tetrahydropyranyloxy-cholest-5-en-23-yn-22-ol (IIIa1) was dissolved in a mixture of methanol and tetrahydrofuran, and after adding thereto 3 drops of 2N-hydrochloric acid, the mixture was stirred for 3 hours at room temperature. The reaction solution was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate and water, successively. After drying with magnesium sulfate, the solvent was distilled away. The residue obtained was dissolved in 10 ml of ethyl acetate, and after adding thereto 10 mg of 10% Pd-C, the mixture was stirred for 4 hours at room temperature under an hydrogen stream atmosphere. The catalyst was filtered off, and the mixture was washed with ethyl acetate, and a combined solution of filtrate and washing was concentrated under reduced pressure. The residue was dissolved in 0.5 ml of pyridine, and after adding thereto 0.1 ml of acetic anhydride, the mixture was stirred overnight at room temperature. After adding water to the reaction solution, the mixture was extracted with ethyl acetate. The extract organic layer was washed with 2N-hydrochloric acid, satureated aqueous sodium hydrogen carbonate, and water, successively, and dried over magnesium sulfate. The solvent was distilled away, and the residue was subjected to column chromatography (n-hexane-ethyl acetate=4:1) for purification to give 71.6 mg of (22R)-1α,3β,22-triacetoxycholest-5-en-25-ol (IVa1).
Reaction SMILES: [Br-].[NH+]1C=CC=CC=1.C[O:9][C:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[CH:11]=1.[O:25]([C:27]#[N:28])[Na].Cl>C1(C)C=CC=CC=1.O>[CH:23]1[CH:22]=[CH:21][C:13]2[N:14]([C:27]([NH2:28])=[O:25])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10](=[O:9])[CH2:11][C:12]=2[CH:24]=1
Reactant: N#CO[Na]
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Agent: Cl
Agent: [Br-]
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)N1c2ccccc2CC(=O)c2ccccc21
Temperature: 89 °C
Yield: 58 %

Procedure:
The carbamoylation reaction was performed as in Example 1. After about 7–8 hours of stirring the carbamoylation reaction mixture (containing pyridinium bromide, 10-methoxy-5H-dibenz[b,f]azepine, water, toluene, and NaOCN) at room temperature (22° C.), the mixture was heated to 55–60° C., and 500 ml of 10% HCl was added drop-wise and carefully. The reaction mixture was warmed to reflux (89° C.) for 3–4 hours, and then worked up and purified as in Example 1. 32.8 g (58% yield) of crude oxcarbazepine was obtained. The crude afforded 24.9 g (44% overall yield) of pure oxcarbazepine.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][N:9]2[C:15](=[O:16])[C@H:14]3[CH2:17][CH2:18][CH2:19][C@H:13]3[NH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:26][CH2:27][C:28](Br)=[O:29]>C(OCC)(=O)C.CCCCCC>[Br:26][CH2:27][C:28]([N:12]1[C@@H:13]2[CH2:19][CH2:18][CH2:17][C@@H:14]2[C:15](=[O:16])[N:9]([CH2:8][C:7]2[CH:24]=[CH:25][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:10]2[CH:23]=[CH:22][CH:21]=[CH:20][C:11]1=2)=[O:29]
Reactant: O=C(Br)CBr
Reactant: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1Cc1ccc([N+](=O)[O-])cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1[C@H]2CCC[C@H]2N(C(=O)CBr)c2ccccc2N1Cc1ccc([N+](=O)[O-])cc1
Yield: 37 %

Procedure:
Using (3aR*,10aS*)-9-(4-nitrobenzyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]-diazepin-10(1H)-one and bromoacetyl bromide, the titled compound was synthesized in substantially the same manner as in Working Example 185 in a yield of 37%, m.p. 160.5°-161.5° C. (ethyl acetate-hexane).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]([CH2:8][N:9]1[C:13](=[O:14])[C:12](=[CH:15]OCC)[S:11][C:10]1=[S:19])([OH:7])=[O:6]>C(O)C>[CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]([CH2:8][N:9]1[C:13](=[O:14])[C:12](=[CH:15][NH:4][CH2:3][CH2:1][OH:2])[S:11][C:10]1=[S:19])([OH:7])=[O:6]
Reactant: CCOC=C1SC(=S)N(CC(=O)O)C1=O
Solvent: NCCO
Solvent: CCO
Product: O=C(O)CN1C(=O)C(=CNCCO)SC1=S
Reaction time: 1 h

Procedure:
0.62 Gram of monoethanolamine was added to a mixture of 1.2 g (0.005 mole) of 3-carboxymethyl-5ethoxymethylidenerhodanine and 10 ml of ethanol. The reaction was carried out at a temperature of 50° to 60° C. for 1 hour. The formed precipitate was separated by filtration and recrystallized from a mixture of methanol and ether (7/3 by volume) to give 0.85 g of 3-carboxymethyl-5-hydroxyethylaminomethylidenerhodanine ethanolamine salt in the form of light brown crystal (yield: 53.1 %).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11]3[N:15]([CH3:16])[C:14]4[CH:17]=[CH:18][C:19]([C:21](O)=[O:22])=[CH:20][C:13]=4[N:12]=3)=[N:7][C:6]=2[CH:24]=1.CN.[CH3:27][N:28](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:27][NH:28][C:21]([C:19]1[CH:18]=[CH:17][C:14]2[N:15]([CH3:16])[C:11]([NH:10][C:8]3[S:9][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:24][C:6]=4[N:7]=3)=[N:12][C:13]=2[CH:20]=1)=[O:22]
Reactant: Cn1c(Nc2nc3cc(F)ccc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2c(c1)nc(Nc1nc3cc(F)ccc3s1)n2C
Yield: 68 %

Procedure:
2-(5-Fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid methylamide (24 mg) was prepared by following General Procedure F using 2-(5-fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (34 mg), methylamine (0.2 ml, 2.0 M solution in THF), HBTU (38 mg), and DIEA (0.1 ml). LCMS: m/z 357.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[N:13]=[CH:14][NH:15][CH:16]=3)=[C:10]([CH2:17][O:18][CH3:19])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1>>[CH3:19][O:18][CH2:17][C:10]1[O:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]=1[C:12]1[N:13]=[CH:14][N:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:16]=1
Reactant: COCc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: Fc1ccc(C(F)(F)F)cc1
Product: COCc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(F)(F)F)cc2)cn1
Yield: 63 %

Procedure:
As described for Example 1f, 3-phenyl-4-(1H-imidazol-4-yl)-5-methoxymethyl-isoxazole (127.6 mg, 0.50 mmol) was converted, using 1-fluoro-4-trifluoromethyl-benzene instead of 1-(4-fluorophenyl)-ethanone, to the title compound (125 mg, 63%) which was obtained as an off-white solid. MS: m/e=400.1 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].[C:11]([O:15][C:16](=[O:19])[NH:17][NH2:18])([CH3:14])([CH3:13])[CH3:12]>C(O)C>[N:8]1[CH:9]=[CH:10][C:5]([C:1](=[N:18][NH:17][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:19])[CH2:2][CH3:3])=[CH:6][CH:7]=1
Reactant: CCC(=O)c1ccncc1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCO
Product: CCC(=NNC(=O)OC(C)(C)C)c1ccncc1
Yield: 42.3 %

Procedure:
A solution of 4.05 gm (0.03 mole) of 4-propionylpyridine, 3.96 gm (0.03 mole) of t-butylcarbazate and 100 ml of absolute ethanol is refluxed 6 hr. The reaction mixture is treated with decolorizing carbon and filtered. The filtrate yields crystals on cooling. The product is collected, washed with Skellysolve B and dried to yield 3.16 gm (40%) of the title compound having a melting point of 170.1° C.