Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:20]([F:23])([F:22])[F:21])[N:4]=1.I([O-])(=O)(=O)=[O:25].[Na+].CN(C=O)C>CCOC(C)=O>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[C:3]([CH:2]=[O:25])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:20]([F:23])([F:22])[F:21])[CH:8]=[CH:7][CH:6]=2
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: FC(F)(F)c1cccc2nc(CBr)c(-c3ccccc3Cl)nc12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1nc2cccc(C(F)(F)F)c2nc1-c1ccccc1Cl
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(bromomethyl)-3-(2-chlorophenyl)-5-(trifluoromethyl)quinoxaline (0.5137 g, 1.279 mmol) and sodium metaperiodate (0.1416 mL, 2.558 mmol) in DMF (8.527 mL, 1.279 mmol) was heated at 150° C. with stirring. After 3 h, the mixture was cooled to room temperature, diluted with EtOAc (100 mL), washed with brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 10% gradient of EtOAc in hexane over 10 min, then 10% isocratic of EtOAc for 20 min, then 10 to 40% gradient of EtOAc in hexane over 20 min, then 40% isocratic of EtOAc for 5 min as eluent to give 3-(2-chlorophenyl)-5-(trifluoromethyl)quinoxaline-2-carbaldehyde as a yellow syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.15 (1 H, s), 8.66 (1 H, dd, J=8.6, 1.2 Hz), 8.52 (1 H, d, J=7.0 Hz), 8.18 (1 H, t, J=8.0 Hz), 7.53-7.67 (4 H, m); LC-MS (ESI) m/z 337.0 [M+H]+.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][C:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:26])[CH2:22][C:23](O)=[O:24]>>[Cl:18][C:15]1[N:14]=[CH:13][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:23](=[O:24])[CH2:22][C:21]([CH3:20])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[N:11]=2)=[CH:17][CH:16]=1
Reactant: Nn1nc(-c2ccc(Cl)nc2)c2ccccc2c1=O
Reactant: CC(C)(CC(=O)O)c1ccccc1
Product: CC(C)(CC(=O)Nn1nc(-c2ccc(Cl)nc2)c2ccccc2c1=O)c1ccccc1

Procedure:
The product from Example 4B and 3-methyl-3-phenylbutanoic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.44 (s, 1H), 8.63-8.64 (m, 1H), 8.37-8.47 (m, 1H), 8.12 (dd, J=8.2, 2.5 Hz, 1H), 7.92-8.04 (m, 2H), 7.73-7.76 (m, 2H), 7.41-7.49 (m, 2H), 7.28-7.34 (m, 2H), 7.16-7.20 (m, 1H), 2.63 (s, 2H), 1.47 (s, 6H); MS (APCI) M/Z 433 (M+H)+.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14]([OH:16])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1>>[C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14]([NH:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)=[O:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: NCCc1ccc(O)cc1
Reactant: COc1ccc(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Product: COc1ccc(C(=O)NCCc2ccc(O)cc2)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
0.03 g of the target compound is obtained as white solid in substantially the same manner as in Example 11, except for using 3-adamantan-1-yl-4-methoxybenzoic acid instead of 3-adamantan-1-yl-4-hydroxybenzoic acid and using tyramine instead of 3,4-dihydroxybenzylamine.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH3:11][O:12][C:13]1[CH:14]=[C:15](I)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CCOCC.[Cu]I>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccccc1S
Reactant: COc1cccc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1cccc(Sc2ccccc2C(=O)O)c1
Yield: 39.6 %

Procedure:
First, 2-[(3-methoxyphenyl)thio]benzoic acid was prepared. A mixture of thiosalicylic acid (1.5 g, 9.7 mmol), 3-methoxyiodobenzene (4.6 g, 19.4 mmol), copper (I) iodide (0.07 g, 0.4 mmol), potassium carbonate (4.0 g, 29.2 mmol), and N,N-dimethylformamide (25 mL) was heated at reflux for 2 h and then cooled to ambient. The reaction mixture was diluted with ether, washed twice with 10% aqueous HCl, and dried (Na2SO4). The solvent is removed at reduced pressure to deposit a brown solid. The product was purified by recrystallization from heptane to provide 1.0 g (40% of theory) of 2-[(3-methoxyphenyl)thio]benzoic acid as a tan solid. 1H NMR (CDCl3): δ 3.80 (s, 3H), 6.90 (d, 1H), 7.00 (d, 1H), 7.25 (m, 5H), 8.11 (d, 1H).
Reaction SMILES: [CH:1]([CH:3]1[CH:8]([CH3:9])[CH:7]2[CH2:10][CH:4]1[CH:5]=[CH:6]2)=O.[C:11]([CH2:13]C(O)=O)#[N:12].[OH-].[NH4+].CN(C)C=O>C1C=CC=CC=1>[C:11]([CH2:13][CH:1]=[C:3]1[CH:8]([CH3:9])[CH:7]2[CH2:10][CH:4]1[CH:5]=[CH:6]2)#[N:12]
Reactant: CC1C2C=CC(C2)C1C=O
Reactant: N#CCC(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC1C(=CCC#N)C2C=CC1C2
Yield: 75.4 %

Procedure:
A stirred solution of 136 g (1.0 mole) of 2-formyl-3-methylbicyclo[2.2.1]hept-5ene, 91 g (1.05 mol) of cyanoacetic acid, 3 g (0.05 mol) of ammonium hydroxide (58%), 132 ml of dimethylformamide, and 170 ml of benzene was heated to reflux and the water removed with a Dean-Stark trap. The reaction was allowed to continue until the carbon dioxide evolution ceased (approx. 31 hrs). Upon completion, the reaction was cooled and the solvent removed under reduced pressure. The residual oil was distilled under vacuum to give 120 g (75.5% yield) of 2(2-cyanoethylidene)-3-methylbicyclo[2.2.1]hept-5-ene: b.p. 70-80° C/1 mm; nD20 1.5080; ir 3060, 2250, 1460, 1380, 760, 740, 726, 700; nmr 1.15 (3H, d, J=7 Hz, methyl), 4.9-5.5 (1H, m, vinyl H), 5.7-6.1 (2H; m, vinyl H); ms 159.
Reaction SMILES: C([O:3][C:4](=[O:42])[C:5](=[O:41])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:20]=2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:8][CH:7]=1)C.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[C:35]1([CH2:34][O:33][C:20]2[C:21]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:9]2[CH:8]=[CH:7][C:6]([C:5](=[O:41])[C:4]([OH:42])=[O:3])=[CH:11][CH:10]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)C(=O)c1ccc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
4-[6-[2,3-bis-(Phenylmethoxy)phenyl]hexyloxy]-alpha-oxobenzeneacetic acid ethyl ester (0.5 g) in methanol (50 mL) was treated with sodium carbonate (0.121 g) in water (2 mL), and the reaction was stirred at room temperature for 3 hours. After the solvents were removed in vacuo, dichloromethane and water were added and the mixture was acidified with 3N hydrochloric acid. The dried (Na2SO4) organic layer was evaporated to yield 0.4 g of 4-[6-[2,3-bis-(phenylmethoxy)phenyl]hexyloxy]-alpha-oxobenzeneacetic acid as an oil.
Reaction SMILES: [Br:1][C:2]1[N:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(N(CC)CC)C.ClC(OCC)=O>O1CCCC1>[Br:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][CH:8]=[C:9]([Br:11])[N:10]=1
Reactant: O=C(O)c1ccc(Br)nc1Br
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OCc1ccc(Br)nc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1.51 g of 2,6-dibromonicotinic acid (Helvetica Chimica Acta, 1976, 59, 229), 0.72 ml of triethylamine and 30 ml of tetrahydrofuran was added 0.57 ml of ethyl chloroformate at 0° C. After stirring at room temperature for 30 minutes, an insoluble matter was filtered. To the filtrate was added 30 ml of tetrahydrofuran, and then 717 mg of sodium borohydride was added thereto. To this mixture was added 13 ml of methanol at 5° C. followed by stirring for 15 minutes. The reaction mixture was diluted with ethyl acetate and then washed with an aqueous solution of saturated ammonium chloride and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated to give the title compound.
Reaction SMILES: [CH:1]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:9][CH2:10][CH2:11][C:12](O)=[O:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH:1]1([O:8][C:12](=[O:13])[CH2:11][CH2:10][SH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCCC1
Reactant: O=C(O)CCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(CCS)OC1CCCCCC1

Procedure:
Into a 100 ml reaction flask equipped with stirrer, thermometer, reflux condenser and hot plate are placed 45.6 grams of cycloheptanol; 16 grams of 3-mercaptopropionic acid and 0.5 grams of paratoluene sulfonic acid. The reaction mass is heated to reflux and refluxed for a period of 12 hours. At the end of the 12 hour period, the reaction mass is cooled and distilled on a micro distillation apparatus yielding the compound having the structure: ##STR147## as confirmed by GLC, IR, NMR and mass spectral analyses.
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[N:8]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.Br[CH2:33][C:34]([O:36][CH3:37])=[O:35]>>[CH3:37][O:36][C:34](=[O:35])[CH2:33][NH:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:8]2[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=[C:7]2[CH2:6][C:5]2[CH:30]=[CH:31][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:22][CH:23]=1
Reactant: O=[N+]([O-])c1ccc(Cn2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Reactant: COC(=O)CBr
Product: COC(=O)CNc1ccc(Cn2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1

Procedure:
2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-1-(4-nitro-benzyl)-1H-imidazole (2.6 g, mmol) was reduced to amine and was reacted with methyl bromoacetate following general procedures D & E to give {-4-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-phenylamino}-acetic acid methyl ester.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[N:26]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[Cl:34])[N:25]=[C:24]([C:35](Cl)=[O:36])[CH2:23]2)=[CH:18][CH:17]=1>C(Cl)Cl>[N:2]1([NH:1][C:35]([C:24]2[CH2:23][CH:22]([C:19]3[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=3)[N:26]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[Cl:34])[N:25]=2)=[O:36])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NN1CCCCC1
Reactant: O=C(Cl)C1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Cl)cc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NN1CCCCC1)C1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Cl)cc2)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
N-Aminopiperidine (0.6 mL, 5.6 mmol) and triethylamine (4 mL) were dissolved in methylene chloride (25 mL) under nitrogen atmosphere. The resulting mixture was cooled to 0° C. and a solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid chloride in methylene chloride (15 mL) was added drop wise. The resulting reaction mixture was stirred at room temperature (approximately 25° C.) overnight. The reaction mixture was washed with water, followed by a saturated aqueous solution of sodium bicarbonate, again with water, dried over sodium sulfate, filtered and evaporated to dryness in a rotavapor. The resulting crude solid was crystallised from ethanol. The crystallised solid was removed via filtration and the mother liquors were concentrated to yield a second fraction of crystallised product. The two fractions were combined to give a total amount of 1.7 g (57% of theoretical yield) of the title compound having a melting point of 183-186° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[CH:19][N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][C:22]([CH3:27])=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:28]N1C(C)(C)C(=O)N(Br)C1=O>ClCCl>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([Br:28])[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][C:22]([CH3:27])=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Cc1nc(N)c2c(-c3ccc4cn(Cc5ccccc5)nc4c3)ccn2n1
Solvent: ClCCl
Product: Cc1nc(N)c2c(-c3ccc4cn(Cc5ccccc5)nc4c3)cc(Br)n2n1
Reaction time: 0.58 h
Yield: 186.6 %

Procedure:
A stirred solution of 5-(2-benzyl-2H-indazol-6-yl)-2-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (130 mg, 0.367 mmol) in dichloromethane (10 mL) was cooled (−30° C.) under nitrogen atmosphere, and a solution of 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (52.4 mg, 0.183 mmol) in dichloromethane (10 mL) was added dropwise. After 35 min, the mixture was concentrated in vacuo and purified via MPLC (hexanes/ethyl acetate gradient) to afford 148 mg (93%) of sand-colored solid. 1H-NMR (CD2Cl2): δ 8.04 (d, 1 H), 7.77 (dd, 1 H), 7.73 (dd, 1 H), 7.40-7.31 (m, 5 H), 7.18 (dd, 1 H), 6.75 (s, 1 H), 5.61 (s, 2 H), 5.52 (br s, 2 H), 2.41 (s, 3 H). MS: LC/MS (+esi), m/z=433 [M+H]. RT=2.88 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:15][C:14]2[C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[O:11][CH2:10][CH2:9][C:8]=2[N:7]=1)=[O:5])C.[OH-].[Na+].O>C1COCC1>[S:15]1[C:14]2[C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[O:11][CH2:10][CH2:9][C:8]=2[N:7]=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1nc2c(s1)-c1ccccc1OCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc2c(s1)-c1ccccc1OCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.7 %

Procedure:
A solution of 4,5-dihydro-6-oxa-1-thia-3-aza-benzo[e]azulene-2-carboxylic acid ethyl ester (1 eq, 1.9 mmol, 530 mg), and sodium hydroxide (5 eq, 9.6 mmol, 385 mg), in THF (5 ml) and water (5 ml) was allowed to stir at RT for 3 hrs. Reaction concentrated in vacuo and the solid washed with water to give 4,5-dihydro-6-oxa-1-thia-3-aza-benzo[e]azulene-2-carboxylic acid (290 mg, yield 58%).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH2:18])[CH3:17]>O>[CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:18][CH2:16][CH3:17])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(SCc2ccccc2)n1
Reactant: CCN
Solvent: O
Product: CCNc1cccc(SCc2ccccc2)n1

Procedure:
A mixture of 10 g of 2-benzylthio-6-bromopyridine, 70 ml of a 40% ethylamine aqueous solution, and a catalytic amount of cuprous chloride was allowed to react in an autoclave at 150° C. for 10 hours. After completion of the reaction, the reaction mixture was poured into water and extracted with methylene chloride. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane=1/4 by volume) to obtain 4.7 g of 2-benzylthio-6-ethylaminopyridine as an oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=2)[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])[CH3:2].[BH4-].[Na+].C(O)(=O)C>C(O)C>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1([C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:21][CH:22]=2)[CH:14]([OH:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]1[OH:16])[CH3:2]
Reactant: CCOC(=O)CC1(c2ccc(NC(C)=O)cc2)C(=O)c2ccccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CC1(c2ccc(NC(C)=O)cc2)C(O)c2ccccc2C1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 17.3 %

Procedure:
A stirred solution of [2-(4-acetylamino-phenyl)-1,3-dioxo-indan-2-yl]-acetic acid ethyl ester (4.0 g, Reference Example 13) in absolute ethanol (250 mL) was treated portionwise with sodium borohydride (1.7 g). After stirring at room temperature for 4 hours the reaction mixture was treated with glacial acetic acid until pH 7 and then evaporated. The residue was treated with water (100 mL) and the mixture was extracted with ethyl acetate (150 mL). The organic extract was dried over magnesium sulfate and then evaporated. The residue was subjected to chromatography on silica eluting with mixtures of dichloromethane and methanol (from 99.5:5 to 96:4, v/v) to give the title compound (0.7 g) as a solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[CH3:15][NH:16][CH3:17]>O1CCCC1.C(OCC)(=O)C>[CH3:15][N:16]([CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14]
Reactant: CNC
Reactant: OCCCCCCCCCCCCBr
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)CCCCCCCCCCCCO
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 12-bromo-1-dodecanol (1 g, 3.8 mmoles) in anhydrous tetrahydrofuran (10 mL) was treated with a 2.0 M solution of dimethylamine in tetrahydrofuran (10 mL). The reaction was stirred at room temperature for 3 days. TLC analysis on silica using 25% ethyl acetate, 75% hexanes as eluent showed the formation of a polar product with little starting material. The reaction was diluted with ethyl acetate (75 mL) and washed twice with aqueous sodium bicarbonate and water. The ethyl acetate solution was then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Yield=1.2 g (wax). TLC analysis on silica (25% methanol, 75% ethyl acetate) showed a streaking product with Rf ˜0.1. This product 4a, was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][N:10]=[C:11]3[CH:16]=[CH:15][C:14]([C:17]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)([C:19]4[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=4)[OH:18])=[CH:13][C:12]=23)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+]>O.C1COCC1>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)([OH:18])[C:19]2[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=2)=[CH:13][C:12]=1[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:9]
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2noc(-c3cccc(Cl)c3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc(N)c(C(=O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49 %

Procedure:
TiCl3/15% in H2O (200 ml) was added at room temperature to a solution of intermediate (6-c) (38 g) in THF (300 ml). The mixture was stirred at room temperature for 90 minutes. The mixture was poured out on ice, basified with K2CO3, filtered over celite, washed with ethyl acetate and decanted. The organic layer was dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1 and 95/5/0.1), yielding 18.7 g (49%) of (±)-[2-amino-5-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]phenyl](3-chlorophenyl)methanone (intern. 6-d).
Reaction SMILES: Cl.[C:2]1(/[C:8](/[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:9]/[C:10]([OH:12])=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[CH2:24][CH2:25][NH2:26]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[CH2:24][CH2:25][NH:26][C:10](=[O:12])/[CH:9]=[C:8](/[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)\[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)/C=C(/c1ccccc1)c1cccnc1
Reactant: COc1cccc(CCN)c1
Agent: Cl
Product: COc1cccc(CCNC(=O)/C=C(/c2ccccc2)c2cccnc2)c1
Yield: 97.1 %

Procedure:
Starting from (Z)-3-phenyl-3-(3-pyridyl)-2-propenoic acid hydrochloride (1.00 g) and 3-methoxyphenethylamine (0.60 g), the titled compound (1.33 g, 98%) was obtained according to the method similar to that of Example 9.
Reaction SMILES: [CH2:1]([N:3]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5])[CH3:2].[ClH:16].[NH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[O:26][C:25](=[O:28])[CH:24]=[CH:23]2>>[ClH:16].[O:26]1[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][C:18]=2[NH:17][C:4]([N:3]([CH2:1][CH3:2])[C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)=[NH:5])[CH:23]=[CH:24][C:25]1=[O:28]
Reactant: CCN(C#N)c1cccc2ccccc12
Reactant: Nc1cccc2ccc(=O)oc12
Agent: Cl
Product: CCN(C(=N)Nc1cccc2ccc(=O)oc12)c1cccc2ccccc12
Reaction time: 9 h

Procedure:
In a 5 ml round bottom flask was placed N-ethyl-N-1-naphthylcyanamide (766 mg, 3.91 mmol), 8-aminocoumarin hydrochloride (818 mg, 4.15 mmol; Clayton, J., Chem. Soc. 97: 1350 (1910)) and a stir bar. The flask was evacuated via aspirator and flushed with N2. This was immediately placed in a preheated 160° C. oil bath where it was allowed to stir under N2 for 9 h. The resulting greenish brown melt was dissolved in methanol (5 ml) and diluted with hot distilled water (20 ml). This solution was basified with 0.1N NaOH (10ml) and extracted with CHCl3 (4×15 ml) to yield a yellowish brown oil upon drying (910 mg). A TLC of this oil showed a mixture of reactants and product. Reactants were eluted by column chromatography with benzene. The product was eluted with benzene/ethanol 8:1 (TLC Rf =0.44, CHCl3 :EtOH, 1:1), 0.64g (46%). This pale yellow oil was dissolved in methanol (5 ml), then methanol (5 ml) saturated with HCl gas was added dropwise to yield a light tan foam of the HCl salt after drying. This tan foam was dissolved into ethanol (1 ml) and placed in an ether diffusion chamber for 5 days to afford white prisms, 0.28 g (29%), m.p. 193°-194° C. IR (KBr) 3343, 3303 (--NH), 1712 (carbonyl), 1653 (--C=NH). 1H-NMR (CD3OD) δ 1.12 (t, 3H, J=7.2), 3.55 (q, 2H, J=7.2), 6.47 (d, 1H, J=9.3), 7.30-8.12 (m, 11H, H-aromat and one olefinic). 13C-NMR (CD3OD) CO, 161.4; CN3, 157.6; Ar, 145.7, 136.6, 136.1,132.5, 131.7, 131.5, 131.16, 130.12, 130.0, 129.5, 129.4, 129.4, 127.3, 126.2, 124.1, 123.2, 121.9, 117.8; CH2, 58.4; CH3, 18.5. Mass Spec. m/e calcd for C22H19N3O2, 357.1477; Found, 357.1453.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:22])[O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH2:17][CH2:16]3)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].FC(F)(F)S(O[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Si](C)(C)C)(=O)=O.[F-].[Cs+]>C(#N)C.C(OCC)(=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:22])[O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:17][CH2:16]3)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(NC(=O)Oc2ccc3c(c2)CCN3)cc1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(NC(=O)Oc2ccc3c(c2)CCN3c2ccccc2)cc1
Reaction time: 8 h
Yield: 8.2 %

Procedure:
To a solution of indolin-5-yl 4-isopropylphenylcarbamate (50 mg, 0.17 mmol) in 3.4 mL of acetonitrile was added 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (41 μL, 0.17 mmol) and caesium fluoride (51 mg, 0.34 mmol) at room temperature, successively. After the reaction mixture was stirred at the same temperature overnight, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water and brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 80/20) to obtain the title compound as a white solid (5.2 mg, 8%).