Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21](/[C:23](/[CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24]\[C:25]([NH2:27])=[O:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[H][H]>C(Cl)Cl.C(O)C(F)(F)F>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C@H:23]([CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:24][C:25]([NH2:27])=[O:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn(/C(=C\C(N)=O)C4CCCC4)c3)ncnc21
Solvent: ClCCl
Solvent: OCC(F)(F)F
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn([C@@H](CC(N)=O)C4CCCC4)c3)ncnc21
Temperature: 50 °C
Reaction time: 20 h

Procedure:
A solution of (4-{1-[(1Z)-3-amino-1-cyclopentyl-3-oxoprop-1-en-1-yl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (10, 215 mg) in a mixture of methylene chloride (CH2Cl2, 12.5 mL) and trifluoroethanol (CF3CH2OH, 0.25 mL) in a pressure glass tube was treated with the catalyst Rh(COD)(SSRR-TangPhos)BF4 (8.8 mg) under nitrogen before the reaction mixture was pressurized with hydrogen gas to 40 bar pressure. The reaction mixture was stirred at 50° C. under this hydrogen pressure for 20 h. When HPLC analysis showed that the substrate was completely consumed, the reaction mixture was cooled down to room temperature. The enantiomeric excess of the reaction mixture was determined to be 88% ee (94% of the first peak, (S)-11; 6% of the second peak, (R)-11) by chiral HPLC analysis. The reaction mixture was filtered through a thin silica gel pad and the pad was washed with methylene chloride (5 mL). The filtrate was then concentrated under reduced pressure to dryness. The resultant foamy solid (180 mg) was charged with a mixture of heptane (5 mL) and ethyl acetate (EtOAc, 5 mL). White solids precipitated out upon stirring at 20° C. The slurry was stirred at 20° C. for 16 h. The solid was collected by filtration and the chiral HPLC analysis for the collected solids (52 mg) showed a 66.0% of enantiomeric excess favoring the first peak (83.0% of the first peak, (S)-11; 17.0% of the second peak, (R)-11). The filtrate obtained was then evaporated to dryness. The resultant oil (108 mg) was analyzed by chiral HPLC and showed a 99.6% of enantiomeric excess favoring the first peak (99.83% of the first peak, (S)-11; 0.17% of the second peak, (R)-11). This result showed in principle that the optical purity of the asymmetric hydrogenation product can be significantly enhanced by selective removal of the minor enantiomer by precipitation of the solid using a suitable solvent system such as ethyl acetate/heptane as described.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)[C:16]1[CH:15]=[CH:14][C:13]([CH3:12])=[CH:18][CH:17]=1)=[O:6]
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Reactant: Cc1ccc(C(CN)N2CCOCC2)cc1
Product: Cc1ccc(C(CNC(=O)c2cc(C)ccc2Cl)N2CCOCC2)cc1

Procedure:
From 2-chloro-5-methylbenzoic acid and 2-(4-methyl-phenyl)-2-morpholin-4-yl-ethylamine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=Cc1cccc(Br)c1
Solvent: CCO
Product: CCOC(=O)c1ccc(N=Cc2cccc(Br)c2)cc1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
A mixture of 4-amino-benzoic acid ethyl ester (16.5 g, 100 mmol) and 3-bromo-benzaldehyde (18.5 g, 100 mmol) in ethanol (100 mL) was heated to reflux for 2 h. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-{[1-(3-bromo-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (20 g, 60%) as a white solid: LC/MS m/e calcd for C16H14BrNO2 M+: 332.2, observed: 332.0, 334.0.
Reaction SMILES: [I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:22][C:23]([CH3:26])([O-])[CH3:24].[K+].C(C1[CH:36]([C:37]#[N:38])[CH2:35][CH:34]2[CH2:39][CH:32]1[C:33]2([CH3:41])[CH3:40])(=O)C>C1COCC1>[C:23]([CH:26]1[CH:36]([C:37]#[N:38])[CH2:35][CH:34]2[CH2:39][CH:32]1[C:33]2([CH3:41])[CH3:40])([CH3:24])=[CH2:22]
Reactant: CC(=O)C1C(C#N)CC2CC1C2(C)C
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)C1C(C#N)CC2CC1C2(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyltriphenylphosphonium iodide (3.17 g, 7.84 mmol) was suspended in anhydrous THF (20 ml) under an atmosphere of dry N2. To this solution was added a 1.0 M solution of potassium tert-butoxide (7.84 ml) in THF. After the reaction has stirred at ambient temperature for 30 min, a solution of 2-acetyl-6,6-dimethyl-bicyclo[3.1.1]heptane-3-carbonitrile (1.00 g, 5.23 mmol), prepared in step A of example 42, dissolved in anhydrous THF (10 ml) was added to the reaction. After stirring for two hours, the reaction was then partitioned between ethyl ether and water. The ethyl ether layer was washed with brine, dried over MgSO4, filtered and concentrated under vacuum to give an oil which was chromatographed on silica gel using a gradient of neat hexanes to 10% ethyl acetate in hexanes to give 490 mg of the titled compound as an oil: C.I. m/z 190 [M+1]; 1H NMR (CDCl3)δ 4.82 (m, 2H), 2.82 (m, 2H), 2.10-2.28 (m, 3H), 1.93 (m, 2H), 1.75 (s, 3H), 1.33 (d, J=9.9 Hz, 1H), 1.23 (s, 3H), 0.93 (s, 3H), 0.80-0.87 (m, 2H).
Reaction SMILES: [OH:1][CH:2]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[CH2:3][NH:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17](OCC)=[O:18])=[CH:10][CH:11]=2)[CH2:6]1.[CH3:29][NH:30][CH3:31]>O1CCCC1>[OH:1][CH:2]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[CH2:3][NH:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([N:30]([CH3:31])[CH3:29])=[O:18])=[CH:10][CH:11]=2)[CH2:6]1
Reactant: CCOC(=O)COc1ccc2c(c1)C[C@@H](NCC(O)c1ccc(O)cc1)CC2
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)COc1ccc2c(c1)C[C@@H](NCC(O)c1ccc(O)cc1)CC2

Procedure:
Ethyl 2-[(2S)-2-[[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)-ethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]acetate (250 mg) was dissolved in tetrahydrofuran (5 ml), and dimethylamine (1 ml) was added to the solution under ice-cooling. After reaction in sealed tube at 60° C. for 60 hours, the reaction mixture was concentrated in vacuo. Purification of the residue by medium pressure liquid column chromatography on aminopropyl silica gel (eluent: ethyl acetate/ethanol=10/1) gave 2-[(2S)-2-[[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)-ethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]-N,N-dimethylacetamide (189 mg) as an amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[C:13](=[O:17])[C:14]#[C:15][CH3:16].Cl.[O:19]1CCCC1>>[OH:19][CH2:16][C:15]#[C:14][C:13]([C:4]1[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1])=[O:17]
Reactant: C1CCOC1
Reactant: CC#CC(=O)c1ccc(OC)c(OC)c1OC
Agent: Cl
Product: COc1ccc(C(=O)C#CCO)c(OC)c1OC
Reaction time: 0.5 h

Procedure:
A solution of 8.3 g (27.6 mmol) of 4-1-ethoxytehoxy)- 1-(2,3.4-trimethoxyphenyl)-2 -butyn-1-one in 95 ml of tetrahydrofuran was treated at room temperature with 27.5 ml of 2N hydrochloric acid, whereupon the mixture was stirred for 30 minutes. The reaction mixture was then extracted twice with ethyl acetate. The combined organic phases were washed in succession with saturated sodium carbonate solution and with water, dried over magnesium sulphate and concentrated. Crystallization of the residue from ethyl acetate/hexane yielded 4-hydroxy-1-(2,3,4 -trimethoxyphenyl)-2-butyn-1-one of melting point 82°-83°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13]O)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Cl:15][C:16]1[S:20][C:19]([C:21]([NH:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[C:26](=[O:34])[NH:27][C:28]3=[O:33])=[O:22])=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:15][C:16]1[S:20][C:19]([C:21]([NH:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[C:26](=[O:34])[N:27]([CH2:13][CH:10]2[CH2:9][CH2:8][N:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH2:12][CH2:11]2)[C:28]3=[O:33])=[O:22])=[CH:18][CH:17]=1
Reactant: OCC1CCN(c2ccncc2)CC1
Reactant: O=C(Nc1cccc2c1C(=O)NC2=O)c1ccc(Cl)s1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(Nc1cccc2c1C(=O)N(CC1CCN(c3ccncc3)CC1)C2=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(4-Pyridyl)-4-piperidinemethanol (U.S. Pat. No. 4,968,704) (211.5 mg, 1.1 mmol), 5-chloro-N-(1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl)-2-thiophenecarboxamide (306.7 mg, 1 mmol), triphenylphosphine (1049 mg, 4 mmol) are initially charged in 40 ml of THF, and diethylazodicarboxylate (DEAD) (696.6 mg, 4 mmol, 0.63 ml) is added. The mixture is stirred at room temperature overnight and then concentrated by evaporation, the residue is dissolved in ethanol, silica gel is added, the mixture is re-concentrated by evaporation and the residue is applied to a silica gel column. Elution with toluene/ethyl acetate and toluene/ethanol (25:1) mixtures gives a main fraction of Rf (SiO2, toluene/ethanol=4:1)=0.19. This fraction is evaporated and treated with ethanol, and the resulting crystals (112 mg, 23.3% of theory) are filtered off with suction. M.p.: 123° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][N:14]=[C:13]([NH:16]C(=O)OC(C)(C)C)[C:12]=3[CH:24]=2)[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:16][C:13]1[C:12]2[CH:24]=[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[OH:25])[CH:9]=[CH:10][C:11]=2[O:15][N:14]=1
Reactant: CC(C)(C)OC(=O)Nc1noc2ccc(-c3cc(Cl)ccc3O)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1noc2ccc(-c3cc(Cl)ccc3O)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a solution of tert-butyl (5-(5-chloro-2-hydroxyphenyl)benzo[d]isoxazol-3-yl)carbamate (0.80 g, 2.21 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (3 mL). The reaction mixture was stirred at ambient temperature for 4 h and concentrated in vacuo. The residue was triturated in hexanes/diethyl ether (1:1 v/v, 5 mL) and washed with hexanes (10 mL) and ethyl acetate (5 mL) to afford 2-(3-aminobenzo[d]isoxazol-5-yl)-4-chlorophenol as a colorless solid in 97% yield (0.559 g): 1H NMR (300 MHz, DMSO-d6) δ 9.92 (s, 1H), 7.99 (d, J=1.3 Hz, 1H), 7.71 (dd, J=8.7, 1.7 Hz, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.30 (d, J=2.7 Hz, 1H), 7.22 (dd, J=8.6, 2.7 Hz, 1H), 6.98 (d, J=8.6 Hz, 1H), 6.55 (br s, 2H); MS (ES+) m/z 260.9 (M+1), 262.9 (M+1).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([C:14]2[CH:15]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:17]=[CH:18][CH:19]=2)=[CH:3][CH:2]=1.[Br:29][C:30]1[CH:31]=[C:32]([Si:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:33]=[C:34](Br)[CH:35]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:29][C:30]1[CH:31]=[C:32]([Si:37]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:33]=[C:34]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:4]3[C:5]4[S:6][C:7]5[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=5[C:9]=4[CH:1]=[CH:2][CH:3]=3)[CH:15]=2)[CH:35]=1
Reactant: Brc1cc(Br)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CC1(C)OB(c2cccc(-c3cccc4c3sc3ccccc34)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cc(-c2cccc(-c3cccc4c3sc3ccccc34)c2)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A solution of 2-(3-(dibenzo[b,d]thiophen-4-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.00 g, 5.18 mmol), (3,5-dibromophenyl)triphenylsilane (5.12 g, 10.35 mmol), Pd(PPh3)4 (0.120 g, 0.104 mmol), K2CO3 (2.147 g, 15.53 mmol) in toluene (100 mL) and water (20 mL) was refluxed under nitrogen overnight. After cooling to room temperature, the organic phase was isolated, and the solvent was evaporated. The residue was purified by column chromatography on silica gel with hexane/DCM (2/1 v/v) as eluent to yield (5-bromo-3′-(dibenzo[b,d]thiophen-4-yl)-[1,1′-biphenyl]-3-yl)triphenylsilane (2.8 g, 80% yield) as a white solid.
Reaction SMILES: C[O-].[Na+:3].CCO.CN1[CH:15]=[CH:14][C:12](=[O:13])N(C)C1=O.[C:17]([CH2:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[S:21])#[N:18]>CO>[C:17]([C:19]1[CH:15]=[CH:14][C:12](=[O:13])[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]=1[S-:21])#[N:18].[Na+:3]
Reactant: Cn1ccc(=O)n(C)c1=O
Reactant: N#CCC(=S)Nc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: N#Cc1ccc(=O)n(-c2ccccc2)c1[S-]
Temperature: 25 °C

Procedure:
A solution of sodium methoxide in MeOH (30 wt %, 202.2 g) was added to absolute EtOH (360 mL) followed by 1,3-dimethyluracil (75 g) and 2-cyano-N-phenyl-thioacetamide (Adhikari et al, Australian J. Chem., 1999, 52, 63-67) (90 g). The resulting mixture was heated at reflux for 8 h and then allowed to cool to ambient temperature overnight. The reaction mixture was then cooled to +5° and maintained at this temperature for at least an hour when the product was recovered by filtration. The filter cake was washed with cold (+5°) absolute ethanol (450 mL) and then dried to constant weight under vacuum at 45° to give the title compound as a pale pink solid (130.0 g). The product thus obtained contains residual EtOH and MeOH, estimated at 12.2 wt % by 1H nmr, corresponding to a corrected yield of 114.1 g. δH (DMSO-d6) 7.32 (2H, m), 7.27-7.18 (1H, m), 7.16 (1H, d, J 9.1 Hz), 6.92 (2H, m), 5.63 (1H, d, J 9.1 Hz). LCMS (Conditions B) (ES+) RT 2.43 minutes, 229 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[C:3]=1[F:10].C[Si]([C:15]#[N:16])(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CC#N>[Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH2:8][C:15]#[N:16])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C#N
Reactant: Fc1c(Cl)cccc1CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: N#CCc1cccc(Cl)c1F
Temperature: 25 °C
Yield: 88 %

Procedure:
To a solution of 1-chloro-3-bromomethyl-2-fluoro-benzene (2.22 g, 10 mmol) in CH3CN (30 mL) was added trimethylsilyl cyanide (1.5 mL) and TBAF (1M in THF, 12 mmol, 12 mL). The resulting reaction mixture was heated at reflux temperature for 30 min. After cooling to room temperature, the volatiles were evaporated under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was then washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography to give the title compound (1.48 g, 88%). MS: 170.1 (M+H)+.
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[CH3:14][N:15]([CH3:36])[CH2:16][CH2:17][N:18]1[C:34](=[O:35])[C:33]2[C:32]3[C:31]4[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=4[NH:25][C:24]=3[CH:23]=[CH:22][C:21]=2[C:19]1=[O:20]>[C].[Pd].C(Cl)(Cl)Cl>[CH3:14][N:15]([CH3:36])[CH2:16][CH2:17][N:18]1[C:34](=[O:35])[C:33]2[C:32]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][C:24]=3[CH:23]=[CH:22][C:21]=2[C:19]1=[O:20]
Reactant: CN(C)CCN1C(=O)c2ccc3[nH]c4c(c3c2C1=O)CCCC4
Agent: [Pd]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: CN(C)CCN1C(=O)c2ccc3[nH]c4ccccc4c3c2C1=O
Temperature: 25 °C
Yield: 56.3 %

Procedure:
3.6 g of diphenyl ether and 70 mg of 10% palladium-carbon were added to 180 mg of N-(2-dimethylaminoethyl)-5,6,7,8-tetrahydrocarbazole-3,4dicarboximide. The mixture was refluxed in a nitrogen stream for 15 minutes, and then cooled to room temperature. Thereto was added 40 ml of chloroform. The resulting insoluble material was removed by filtration. The filtrate was mixed with 25 ml of water. The mixture was adjusted to pH 1.0 with 6N hydrochloric acid. The aqueous layer was separated, washed with 10 ml of chloroform, and mixed with 20 ml of chloroform. The mixture was adjusted to pH 7.5 with an aqueous saturated sodium hydrogencarbonate solution. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from ethanol to obtain 100 mg (yield: 56%) of N-(2-dimethylaminoethyl)-carbazole-3,4-dicarboximide as yellow needles.
Reaction SMILES: [C:1]([C:3]1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[C:15]([CH:17]1[C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]=2[C:20]2[CH2:30][CH2:31][CH2:32][C:19]=2[CH:18]1[C:33]([O-:35])=[O:34])#[N:16]>C1(C)C=CC=CC=1>[C:15]([C:17]1[C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]=2[C:20]2[CH2:30][CH2:31][CH2:32][C:19]=2[C:18]=1[C:33]([O:35][CH2:1][CH3:3])=[O:34])#[N:16]
Reactant: N#CC1c2c([nH]c3ccccc23)C2=C(CCC2)C1C(=O)[O-]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c2c(c3[nH]c4ccccc4c3c1C#N)CCC2
Temperature: 60 °C
Reaction time: 3 h
Yield: 252 %

Procedure:
DDQ (1.35 g, 5.95 mmol) was added to solution of 5-cyano-1,2,3,4,5,10-hexahydrocyclopenta[a]carbazole-4-carboxylate (820 mg, 2.66 mmol) in toluene (12 mL). The solution immediately turned dark brown, and was stirred at 60° C. for 3 hr. The mixture was cooled to 20° C. overnight and filtered. The precipitate was rinsed twice with hexanes to give 2.04 g of a light green solid. This was suspended in methanol (8 mL), filtered, and the precipitate rinsed with methanol (3 mL, in portions), and ether to give 603 mg (75% yield) of product as a light green solid, mp 233–234° C. NMR (CDCl3) δ 8.80 (d, 1H), 8.20 (s, 1H), 7.52 (m, 2H), 7.38 (t, 1H), 4.52 (q, 2H), 3.42 (t, 2H), 3.19 (t, 2H), 2.31 (quintet, 2H), 1.51 (t, 3H). Anal. Calcd for C19H16N2O2-0.2H2O: C, 74.11; H, 5.37; N, 9.10. Found: C, 74.03; H, 5.06; N, 9.04.
Reaction SMILES: [OH-].[K+].[ClH:3].C([O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([CH3:24])=[C:11]2[C:25]([NH:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:30][CH2:29]1)=[O:26])(=O)C>CO>[ClH:3].[CH2:17]([N:13]1[C:14]2[C:10](=[CH:9][C:8]([OH:7])=[CH:16][CH:15]=2)[C:11]([C:25]([NH:27][CH:28]2[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:32][CH2:33]2)=[O:26])=[C:12]1[CH3:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)Oc1ccc2c(c1)c(C(=O)NC1CCN(CCc3ccccc3)CC1)c(C)n2Cc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)NC2CCN(CCc3ccccc3)CC2)c2cc(O)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7.6 g of potassium hydroxide in 500 ml of methanol was added 37 g of the hydrochloride obtained in Example 3, and the mixture was stirred at room temperature for 2 hours. The insoluble substance was filtered off and the filtrate was concentrated. To the residue was added 2 liters of water and the mixture was stirred, and then the precipitated crystals were filtered with suction. After the crystals were recrystallized from a mixture of ethyl acetate and methanol, 12.5 g of the purified crystals were redissolved in 350 ml of methanol under heating. To the solution was added 8 ml of 18% hydrochloric acid and the mixture was cooled with ice. The precipitated crystals were filtered with suction to give 1-benzyl-5-hydroxy-2-methyl-N-(1-(2-phenylethyl)-4-piperidyl)indole-3-carboxamide hydrochloride as white crystals, melting at 210°-212° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([F:11])[CH:13]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(O)cc1F
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCc2cccc(F)c2)cc1F
Temperature: 25 °C
Yield: 100.3 %

Procedure:
A mixture of 2-fluoro-4-hydroxy-benzonitrile (15.0 g, 109 mmol), 3-fluorobenzyl bromide (22.7 g, 120 mmol) and potassium carbonate (18.1 g, 131 mmol) in dry acetone (250 mL) was heated under reflux for 4 h. After cooling to room temperature the mixture was filtered and the filtrate was evaporated to leave an off-white solid which was washed with hexane to afford the title compound (26.8 g, 100%) as a white solid. MS: m/e=245.2 (M+).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[N:22]=[C:21]([N:24]2[C:28]4[CH:29]=[CH:30][C:31]([OH:33])=[CH:32][C:27]=4[N:26]=[CH:25]2)[CH:20]=[CH:19]3)[CH2:10][CH2:9]1)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].[Br-].[CH:42]1([CH3:45])[CH2:44][CH2:43]1>CN(C=O)C.C(O)(C(F)(F)F)=O>[CH:42]1([CH2:45][O:33][C:31]2[CH:30]=[CH:29][C:28]3[N:24]([C:21]4[CH:20]=[CH:19][C:18]5[C:23](=[C:14]([N:11]6[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]6)[CH:15]=[CH:16][CH:17]=5)[N:22]=4)[CH:25]=[N:26][C:27]=3[CH:32]=2)[CH2:44][CH2:43]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cccc3ccc(-n4cnc5cc(O)ccc54)nc23)CC1
Reactant: CC1CC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: NC1CCN(c2cccc3ccc(-n4cnc5cc(OCC6CC6)ccc54)nc23)CC1
Temperature: 65 °C
Reaction time: 4 h
Yield: 65.6 %

Procedure:
{1-[2-(5-Hydroxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester 3A (200 mg, 0.435 mMol) was dissolved in 1.5 mL of anhydrous DMF under an atmosphere of dry N2. To this solution was added Cs2CO3 (170 mg, 0.520 mMol) followed by cyclopropyl methane bromide (46 μL, 0.48 mMol). The reaction mixture was subsequently heated to 65° C. and stirred at this temperature for 4 hours. The reaction mixture was then cooled to ambient temperature and partitioned between EtOAc and water. The EtOAc layer was washed 4 more times with water and then with brine. The EtOAc was then dried over Na2SO4, filtered and concentrated under vacuum and the resulting green oil was chromatographed on flash silica gel eluting with MeOH/DCM (2:98) to give the a green oil. The oil was dissolved in 1.5 mL of TFA under an atmosphere of dry N2. The reaction mixture was stirred at ambient temperature for 10 minutes after which time it was concentrated under vacuum and the resulting residue was partitioned between DCM and aqueous 0.1 N NaOH. The DCM layer was then washed with basic brine (pH 10), dried over Na2SO4, filtered and concentrated under vacuum to give 118 mg of the title compound as a yellow solid 32.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[C:7]([CH3:9])[O:6][C:5](=[O:10])[CH:4]=1.[CH3:11][S:12]S(C)(=O)=O>C(O)C>[OH:2][C:3]1[CH:8]=[C:7]([CH3:9])[O:6][C:5](=[O:10])[C:4]=1[S:12][CH3:11]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: CSS(C)(=O)=O
Agent: [Na]
Solvent: CCO
Product: CSc1c(O)cc(C)oc1=O
Reaction time: 4 h

Procedure:
A mixture of 47.0 g. (0.317 mole) of the monosodium salt of 4-hydroxy-6 -methyl-2-pyrone and 40.0 g. (0.317 mole) of methyl methanethiolsulfonate in 700 ml. of 2B absolute ethanol was heated under reflux with stirring for four hours. The solvent was then removed by evaporation in vacuo, leaving a viscous semi-solid. The crude substance was washed with water and extracted with methylene chloride. The combined extracts were dried over anhydrous sodium sulfate and evaporated in vacuo to dryness, leaving 24.8 g. of a yellow solid; which, when recrystallized from isopropanol gave 10.6 g. (20 percent) of the pure product m. 141.5°-143°C.