Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:37]=[CH:36][C:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.C(N(CC)CC)C>C(#N)C>[C:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([CH2:21][O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:19][CH2:20]2)=[CH:36][CH:37]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(CCN2CCC(COC(c3ccccc3)c3ccccc3)CC2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(CCN2CCC(COC(c3ccccc3)c3ccccc3)CC2)cc1
Yield: 17.6 %

Procedure:
Acetic anhydride (68 mg, 0.67 mmol) was added dropwise to a stirred solution of 1-(4-aminophenethyl)-4-(diphenylmethoxymethyl)piperidine (180 mg, 0.45 mmol) (see Example 21) and triethylamine (55 mg, 0.54 mmol) in acetonitrile (5 ml) and the mixture heated under reflux for 2 hours and evaporated. The residue was partitioned between ethyl acetate and 10% aqueous potassium carbonate and the layers separated. The aqueous layer was extracted into ethyl acetate and the combined organic layers were dried over magnesium sulphate and evaporated. The residue was triturated with ethyl acetate and the resulting solid collected, washed with ethyl acetate and dried to give the title compound (35 mg) as an off-white solid which was characterised containing 0.25 equivalents of water.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1
Reactant: COc1cc(Cl)cc(B(O)O)c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: COc1cc(Cl)cc(-c2nnc(N)nc2-c2ccccc2)c1
Yield: 9.7 %

Procedure:
6-(3-Chloro-5-methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (36 mg, 9%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 3-chloro-5-methoxyphenylboronic acid (0.27 g, 1.43 mmol) according to the general procedure of Example 1.
Reaction SMILES: O[C:2]1([CH3:13])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14]([OH:17])(=[O:16])[CH3:15]>>[CH2:8]([C:3]1[C:4](=[O:7])[CH2:5][CH:6]([O:17][C:14](=[O:16])[CH3:15])[C:2]=1[CH3:13])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCC1C(=O)C=CC1(C)O
Reactant: CC(=O)O
Product: CCCCCC1=C(C)C(OC(C)=O)CC1=O

Procedure:
In the same apparatus as in Example 1, 3-hydroxy-2-n-pentyl-3-methyl-4-cyclopentenone (18.2 g) and acetic acid (55 ml) were charged and heated under reflux for 15 hours with agitation. After the completion of the reaction, acetic acid was evaporated off under reduced pressure. The residue was extracted with toluene (80 ml) and water (50 ml) and treated as in Example 1 to obtain 2-n-pentyl-3-methyl-4-acetoxy-2-cyclopentenone (20.6 g). Yield, 92%. B.P., 125°-135° C./0.2-0.5 mmHg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]=[O:15])[CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][Mg]Br>O1CCCC1.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@@H:14]([OH:15])[CH3:18])[CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC=O)COC1(C)C
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@H](O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution of (S)-2,2-dimethyl-4-(2-oxo-ethyl)-oxazolidine-3-carboxylic acid t-butyl ester (2.05 g, 8.43 mmol) in dry tetrahydrofuran (25 mL) was added 1.4M methyl magnesium bromide in diethyl ether (6.02 mL) at −78° C. The mixture was stirred at −78° C. for 30 min and then warmed to −5° C. The mixture was extracted with diethyl ether and ammonium chloride solution. The organic layer was dried and concentrated. The crude mixture was purified by ISCO flash chromatography (0 to 60% ethyl acetate/hexanes) to give two fractions. The first fraction afforded (S)-4-((S)-2-hydroxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid t-butyl ester as a colorless oil (870 mg): 1H NMR (300 MHz, CDCl3) δ ppm 1.20 (d, J=6.0 Hz, 3H), 1.42-1.60 (m, 1H), 1.50 (s, 12H), 1.55 (s, 3H), 1.68-1.88 (m, 1H), 3.66 (d, J=8.8 Hz, 1H), 3.69-3.80 (m, 1H), 3.94-4.08 (m, 1H), 4.17-4.30 (m, 1H), 4.62 (br. s., 1H); The second fraction afforded (S)-4-((R)-2-hydroxy-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid t-butyl ester as a white solid (740 mg): 1H NMR (300 MHz, CDCl3) δ ppm 1.22 (d, J=6.0 Hz, 3H), 1.49 (s, 12H), 1.58 (br. s., 3H), 1.75-1.90 (m, 2H), 2.56 (br. s., 1H), 3.75-3.93 (m, 2H), 3.95-4.05 (m, 1H), 4.03-4.20 (m, 1H).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([Mg]Br)=[CH:3][CH:2]=1.[C:10]1([P:16]([O-])[O:17]CC)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S(=O)(=O)(O)O>CCOCC>[C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([PH2:16]=[O:17])=[CH:11][CH:12]=1
Reactant: CCOP([O-])c1ccccc1
Reactant: Cc1ccc([Mg]Br)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: Cc1ccccc1-c1ccc([PH2]=O)cc1
Yield: 80.9 %

Procedure:
A solution of p-tolylmagnesium bromide [prepared from p-bromotoluene (29.1 g, 0.16 mol) and magnesium (4.38 g, 0.18 g-atom)] in ether (100 mL) was treated with a solution of ethyl phenylphosphonite (13,6 g, 0.08 mol) in ether (50 mL) with vigorous mechanical stirring. The mixture was heated at reflux for 1/2 hr., then 100 mL of 25% sulfuric acid was added cautiously. Three layers formed; the bottom (aqueous) layer was extracted with toluene. Addition of NaHCO3 to the combined upper layers produced a vigorous reaction and a single organic phase. The organic phase was washed with water and with saturated NaCl, dried and evaporated to give an oil (14 g). Kugelrohr distillation at 120°-160° C. (0.1 mmHg) followed by chromatography on silica gel (CHCl3), then 10% MeOH--CHCl3) gave 7.1 g of an oil. This was distilled in the Kugelrohr again (150° C., 0.1 mmHg) to give 6.2 g of product which appears to be pure by NMR and crystallized on standing. 1H NMR (CDCl3) δ8.0-7.2 (m, 9H), 8.08 (d, J=480 Hz, 1H), 2.42 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][O:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH3:17])=[CH:10][CH:9]=2)=[C:3]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][N:30]=2)[C:25]([CH:32]=O)=[CH:24]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:23]1[C:31]2=[N:30][CH:29]=[CH:28][CH:27]=[C:26]2[C:25]([CH:32]=[C:6]2[O:5][C:4]([NH:7][C:8]3[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH3:17])=[CH:12][CH:13]=3)=[C:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:2]2=[O:1])=[CH:24]1
Reactant: CCCOc1ccc(NC2=C(C(=O)OCC)C(=O)CO2)cc1
Reactant: O=Cc1c[nH]c2ncccc12
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCCOc1ccc(NC2=C(C(=O)OCC)C(=O)C(=Cc3c[nH]c4ncccc34)O2)cc1
Temperature: 25 °C
Yield: 27.7 %

Procedure:
To a solution of ethyl 4-oxo-2-{[4-(1-propoxy)phenyl]amino}-4,5-dihydrofuran-3-carboxylate (0.15 g, 0.50 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.072 g, 0.50 mmol) in ethanol (6.0 mL), L-proline (0.0060 g, 0.05 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (0.060 g, y. 28%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:11](=O)[CH3:12])[CH:6]=[CH:7][C:8]=1[CH2:9][OH:10])[CH3:2].[CH:14]1([C:20]2[CH:28]=[CH:27][C:23]([CH2:24][O:25][NH2:26])=[CH:22][C:21]=2[C:29]([F:32])([F:31])[F:30])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C>CO>[CH:14]1([C:20]2[CH:28]=[CH:27][C:23]([CH2:24][O:25][N:26]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([CH2:9][OH:10])=[C:3]([CH2:1][CH3:2])[CH:4]=3)[CH3:12])=[CH:22][C:21]=2[C:29]([F:30])([F:31])[F:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCc1cc(C(C)=O)ccc1CO
Reactant: NOCc1ccc(C2CCCCC2)c(C(F)(F)F)c1
Solvent: CO
Solvent: CC(=O)O
Product: CCc1cc(C(C)=NOCc2ccc(C3CCCCC3)c(C(F)(F)F)c2)ccc1CO
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1-(3-ethyl-4-hydroxymethyl-phenyl)-ethanone (1 eq) in methanol is added O-(4-cyclohexyl-3-trifluoromethyl-benzyl)-hydroxylamine (1 eq) followed by the addition of acetic acid (0.05 eq). The mixture is stirred at room temperature for 12 hours. After concentration, the residue is purified by column chromatography (30% EtOAc in hexane) to give 1-(3-ethyl-4-hydroxymethyl-phenyl)-ethanone O-(4-cyclohexyl-3-trifluoromethyl-benzyl)-oxime as an oil [MS: (ES+) 434.2 (M+1)+].
Reaction SMILES: Cl[C:2]1[C:11]([C@@H:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)CCC>O1CCOCC1.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>[Cl:25][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[C:11]([C@@H:12]([N:14]1[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]1=[O:24])[CH3:13])=[CH:10]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: C[C@@H](c1cc2cccc(Cl)c2nc1Cl)N1C(=O)c2ccccc2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C[C@@H](c1cc2cccc(Cl)c2nc1-c1ccccn1)N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 56.2 %

Procedure:
A mixture of (S)-2-(1-(2,8-dichloroquinolin-3-yl)ethyl)isoindoline-1,3-dione (22.7 g, 61 mmol), Pd(PPh3)4 (3.53 g, 0.05 eq) and 2-(tributylstannyl)pyridine (33.8 g, 80%, 1.2 eq) in dioxane (840 mL) was heated to 100° C. under N2. After over night, LCSM showed around 50% starting material left. The reaction mixture was heated to 110° C. for additional 2 days. LCMS showed less than 10% starting material left. The reaction was heated to 120° C. for 5 h before cool to rt. Removal of solvent followed with column chromatography on silica gel (EtOAc/hexane, 0/1 to 1/3) gave an off white foam 14.2 g and the impure portions were combined and purified in the similar manner to give a white foam. 1H NMR (400 MHz, CDCl3) δ ppm 8.69 (s, 1H), 8.66 (d, J=4.0 Hz, 1H), 7.94 (d, J=4.0 Hz, 1H), 7.85 (t, J=8.0 Hz, 1H), 7.75 (t, J=8.0 Hz, 1H), 7.70-7.65 (m, 4H), 7.50 (t, J=8.0 Hz, 1H), 7.33-7.29 (m, 1H), 6.58 (q, J=8.0 Hz, 1H), 2.02 (d, J=8.0 Hz, 3H). Mass Spectrum (ESI) m/e=414 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:22])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(C(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (1-(4-chloro-benzoyl)-piperidin-4-yl)-carbamic acid tert-butyl ester (46 g, 0.23 mmol) in CH2Cl2 (0.5 mL) was added trifluoroacetic acid (0.5 ml). The reaction mixture was stirred at room temperature for ½ hour. The reaction mixture was concentrated under reduced pressure to provide the titled compound. MS (DCI) m/z 239 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH2:38][C@@H:39]([OH:41])[CH3:40]>>[OH:41][C@@H:39]([CH3:40])[CH2:38][NH:37][C:30](=[O:32])[C:29]1[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=1[S:27][CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C[C@H](O)CN
Reactant: O=C(O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Product: C[C@H](O)CNC(=O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 66.6 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and (S)-1-amino-2-propanol (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 37 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1>C(O)(=O)C>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[N:4]1[CH:12]=[CH:16][CH:15]=[CH:14]1
Reactant: COC1CCC(OC)O1
Reactant: Cc1ccc(N)c(Br)c1
Solvent: CC(=O)O
Product: Cc1ccc(-n2cccc2)c(Br)c1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 84.6 %

Procedure:
2-Bromo-4-methylaniline (15.0 g), 2,5-dimethoxytetrahydrofuran (10.7 g) and acetic acid (81 ml) were combined under nitrogen atmosphere. The reaction mixture was stirred at 90° C. for 1.5 hours. After being cooled to room temperature, the reaction mixture was concentrated in vacuo with toluene. n-Hexane (300 ml) was added to the residue, and the suspension was filtered through Celite. Then silica gel was added to the filtrate with stirring until the colour of the solution disappeared. The suspension was filtered and the filtrate was concentrated in vacuo to give 1-(2-bromo-4-methylphenyl)pyrrole (16.1 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[Br:16]Br>C(O)(=O)C>[Br:16][C:9]1[C:7]2[N:8]=[C:3]([S:2][CH3:1])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[C:6]=2[S:11][CH:10]=1
Reactant: CCCn1c(SC)nc2ccsc2c1=O
Reactant: BrBr
Solvent: CC(=O)O
Product: CCCn1c(SC)nc2c(Br)csc2c1=O

Procedure:
The method of claim 14 wherein 7-bromo-2-(methylthio)-3-propylthieno[3,2-d]pyrimidin-4(3H)-one is prepared by treating 2-(methylthio)-3-propylthieno[3,2-d]pyrimidin-4(3H)-one with bromine in acetic acid.
Reaction SMILES: C([C:3]1[C:4](Cl)=[N:5][C:6]([Cl:9])=[N:7][CH:8]=1)C.[CH3:11][S-:12].[Na+]>O1CCCC1.C(OCC)(=O)C>[Cl:9][C:6]1[N:5]=[C:4]([S:12][CH3:11])[CH:3]=[CH:8][N:7]=1
Reactant: C[S-]
Reactant: CCc1cnc(Cl)nc1Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.6 %

Procedure:
To a solution of ethyl 2,4-dichloropyrimidine (20.0 g, 0.13 mol) in 150 mL of anhydrous tetrahydrofurane was added sodium thiomethoxide (49.30 mL, 0.15 mol) at −10° C. The reaction mixture was allowed to warm up to room temperature and then stirred for 5 hours with monitoring a reaction with LC-MS or thin layer chromatography (TLC). The reaction mixture was diluted with ethyl acetate and washed with brine (×2). The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting solid was slurrified with diethyl ether and then collected by filtration to afford the desired intermediate 10 as a white solid (11.2 g, 52%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[OH-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CS(C)=O.O>[CH2:13]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Brc1ccc2c(ccn2Cc2ccccc2)c1
Yield: 60.8 %

Procedure:
To a stirred mixture of Na0H (204 mg., 5.1 mmol., 1 eq.) in DMSO (10 mL.) was added 5-bromoindole (1.0 g., 5.1 mmol., 1 eq.). The solution was stirred for 20 hours upon complete dissolution of the NaOH (approximately 1 h.). To this solution was added benzyl bromide (0.606 mL., 5.1 mmol., 1 eq.) via syringe. After 7 h. the mixture was diluted with water and extracted 4× with diethyl ether. The organic extracts were combined, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The product was purified by crystallization (ether/hexanes) affording 888 mg of 1-benzyl-5-bromoindole.
Reaction SMILES: [C:1]1([CH2:11][NH:12][S:13]([C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][C:24]([OH:26])=O)[CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:27]CCl>CN(C)C=O>[C:1]1([CH2:11][NH:12][S:13]([C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][C:24]([Cl:27])=[O:26])[CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: ClCCl
Reactant: O=C(O)C=Cc1cccc(S(=O)(=O)NCc2cccc3ccccc23)c1
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1cccc(S(=O)(=O)NCc2cccc3ccccc23)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a suspension of 3-{3-[(naphthalen-1-ylmethyl)-sulfamoyl]-phenyl}-acrylic acid (15a) (0.32 g, 0.87 mmol) in dichloromethane (4 ml) oxalyl chloride (0.22 ml, 2.61 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give the title compound (0.33 g, 98%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18](O)=[O:19])[CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:22]1([NH:21][C:18]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:17]3)=[O:19])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(C(=O)O)cc2C1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1Cc2ccc(C(=O)Nc3ccccc3)cc2C1
Yield: 70 %

Procedure:
Using 2-(tert-butoxycarbonylamino)-5-carboxyindan (30 mg, 0.11 mmol) synthesized in Preparation Example 4, aniline (21 μl, 0.23 mmol), triethylamine (0.20 ml, 1.4 mmol), propanephosphonic acid anhydride (0.3 ml), dimethylaminopyridine (a catalytic amount) and methylene chloride (0.25 ml), a similar procedure to a) in Example 29 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=4:1 to 7:3) to obtain N-phenyl-2-(tert-butoxycarbonylamino)-5-indan carboxamide (27 mg, 0.077 mmol) having the following physical properties:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10])=[CH2:2].C(=O)([O-])[O-:14].[K+].[K+]>C(Cl)(Cl)Cl>[O:14]1[CH2:2][CH:1]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH2:12])(=[O:10])=[O:11]
Reactant: C=Cc1ccccc1S(N)(=O)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: NS(=O)(=O)c1ccccc1C1CO1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution consisting of 2-ethenylbenzenesulfonamide (1.5 g, 8.1 mmol) m-chloroperbenzoic acid (1.4 g, 8.1 mmol) and potassium carbonate (1.1 g, 8.1 mmol) in 150 ml of chloroform was stirred for 4 days at room temperature. The reaction was filtered and the filtrate was washed with saturated sodium bicarbonate. The organic layer was separated, dried and concentrated. The resulting oil was flash chromatographed (methylene chloride) to yield the subject compound as a white solid, m.p. 136°-139° C.
Reaction SMILES: [Mg].C(Br)C.[O:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[O:11][CH2:12][C:13]#[CH:14].Br[CH2:16]/[CH:17]=[CH:18]/[CH2:19][CH2:20][CH3:21]>O1CCCC1.Cl>[O:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[O:11][CH2:12][C:13]#[C:14][CH2:16]/[CH:17]=[CH:18]/[CH2:19][CH2:20][CH3:21]
Reactant: C#CCOC1CCCCO1
Reactant: CCC/C=C/CBr
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Product: CCC/C=C/CC#CCOC1CCCCO1
Yield: 73.3 %

Procedure:
To a solution of magnesium metal (8.6 g) in dry tetrahydrofuran (100 ml) was added dropwise ethyl bromide (39 g) in a nitrogen atmosphere at ambient temperature. After the mixture was stirred for an hour at the same temperature, to the mixture was added dropwise a solution of 3-(2-tetrahydropyranyloxy)-1-propyne (50 g) in dry tetrahydrofuran (75 ml) and cuprous cyanide (20 mg). The reaction mixture was stirred for 30 minutes at ambient temperature. To the mixture was added with stirring a solution of 1-bromo-trans-2-hexene (58 g) in dry tetrahydrofuran (75 ml) under ice-cooling. The reaction mixture was stirred for 30 minutes at ambient temperature and concentrated under reduced pressure to give a residue, which was dissolved in diluted hydrochloric acid and extracted with ether. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a yellowish oily residue, which was distilled under reduced pressure to give colorless oily 1-(2-tetrahydropyranyloxy)-trans-5-nonen-2-yne (58 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:10]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl.ClC[CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:41][CH2:42][N:37]3[CH2:36][CH2:40][CH2:39][CH2:38]3)=[CH:24][CH:25]=2)[C:10]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(c2ccc(O)cc2)c2cccc3c2CCCC3)cc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(c2ccc(OCCN3CCCC3)cc2)c2cccc3c2CCCC3)cc1

Procedure:
A mixture of (4-methoxyphenyl)-(4-hydroxyphenyl)-5,6,7,8-tetrahydronaphth-1-yl-methane (300 mg, 0.001 mol), anhydrous K2CO3 (2.0 gm, 0.014 mol), 1-(2-chloroethyl)piperidine hydrochloride (300 mg, 0.0015 mol) and dry acetone (25.0 ml) was refluxed for 10 hrs, K2CO3 was filtered off, acetone was distilled off and residue was diluted with water. The reaction mixture was extracted with ethyl acetate, washed with water, dried over sodium sulphate and concentrated to give an oil which was filtered through basic alumina column with benzene as the eluent and concentrated to give the title compound of formula I. Yield 218 mg. (55.89%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[Br:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:13]1[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]1
Reactant: CN1CCNCC1
Reactant: Brc1ccccc1Br
Product: CN1CCN(c2ccccc2Br)CC1

Procedure:
The title compound was prepared from dibromobenzene and 1-methylpiperazine in a similar manner to Example 110 (a).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C@@H:14]2[C@@H:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C:7]1=[O:15])C.N.O=C1[N:23](CC(N)=O)[C@H]2CCC[C@H]2C1>CO>[O:15]=[C:7]1[N:6]([CH2:5][C:4]([NH2:23])=[O:3])[C@H:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:8]1
Reactant: NC(=O)CN1C(=O)C[C@@H]2CCC[C@@H]21
Reactant: CCOC(=O)CN1C(=O)C[C@@H]2CCCC[C@@H]21
Agent: N
Solvent: CO
Product: NC(=O)CN1C(=O)C[C@@H]2CCCC[C@@H]21
Reaction time: 24 h

Procedure:
A solution of cis-octahydro-2-oxo-1H-indole-1acetic acid ethyl ester (15.43 g, 0.068 mole) in methanol (200 ml) is saturated with ammonia and stirred at ambient temperatures 24 hours. The solution is concentrated at reduced pressure to yield a solid. cis-Hexahydro-2-oxo-cyclopenta[b]pyrrole-1(2H)-acetamide with a mp 145°-145.5° C.