Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9](O)=[O:10])=[CH:3][CH:2]=1.[CH3:26][C:27]1([CH3:35])[O:34][C:32](=[O:33])[CH2:31][C:29](=[O:30])[O:28]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:16]([O:15][C:13](=[O:14])[NH:12][C@H:8]([CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:6][CH:5]=1)[C:9]([CH:31]1[C:32](=[O:33])[O:34][C:27]([CH3:35])([CH3:26])[O:28][C:29]1=[O:30])=[O:10])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: -5 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of (R)-3-biphenyl-4-yl-2-t-butoxycarbonylamino-propionic acid (50 g, 146 mmol), Meldrum's acid (23.3 g, 161 mmol) and DMAP (27.8 g, 227 mmol) in anhydrous DCM (500 mL) was added a solution of DCC (33.3 g, 161 mmol) in anhydrous DCM (200 mL) over 1 hour at −5° C. under nitrogen. The mixture was stirred at −5° C. for 8 hours, then refrigerated overnight, during which tiny crystals of dicyclohexylurea precipitated. After filtration, the mixture was washed with 5% KHSO4 (4×200 mL) and saturated aqueous NaCl (1×200 mL), then dried under refrigeration with MgSO4 overnight. The solution was evaporated to yield the title compound (68 g, light yellow solid), which was used without further purification. LC-MS: 490 [M+Na], 957 [2M+Na].
Reaction SMILES: [C:1](CCCCCN)(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C@@H:14]2[C@@H:9]([NH:10][C:11]([NH:13]2)=[O:12])[CH2:8][S:7]1.B([O-])([O-])[O-:23]>>[OH:23][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C@@H:14]2[C@@H:9]([NH:10][C:11]([NH:13]2)=[O:12])[CH2:8][S:7]1)=[O:15]
Reactant: [O-]B([O-])[O-]
Reactant: NCCCCCC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Biotinylpentylamine (0.001 mol) and isothiocyanatobenzyl-diethylenetriamine-pentaacetic acid (ITC-DTPA, 0.001 mol) are mixed together in borate buffer, 0.1M, pH 8, and stirred for 3 hours at room temperature. The biotin-DTPA is purified on a C-18 reverse-phase HPLC column run in an acetonitrile/water gradient. The acetonitrile is removed under reduced pressure on a rotary evaporator and the water by lyophilization to give a white powdery product. The structure, biotinylpentylamino-thioureaylbenzyl-DTPA (biotin-DTPA) is confirmed by mass spectral and micro analysis.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][CH2:10][CH:9]1[C:15]([OH:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O>>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][CH2:10][CH:9]1[C:15]([Cl:21])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1COCC(=O)N1Cc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Product: O=C(Cl)C1COCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
To (RS)-4-benzyl-5-oxo-morpholine-3-carboxylic acid (2.0 g, 8.51 mmol) in MDC (40 ml) was slowly added oxalyl chloride (1.51 ml, 17.1 mmol). The mixture was stirred for 0.5 h at room temperature and then evaporated to give (RS)-4-benzyl-5-oxomorpholine-3-carbonyl chloride as a brown solid (1.99 g, 92%). Ammonia gas was bubbled steadily through a solution of (RS)-4-benzyl-5-oxomorpholine-3-carbonyl chloride (1.99 g, 7.79 mmol) in MDC (40 ml) at 0° C. for 0.5 h, and then the mixture allowed to warm to room temperature. The solid was collected by filtration, washed with MDC (30 ml) and dried in vacuo at 40° C. to give the title compound as a white solid (2.1 g, 99%). Mass spectrum (API+): Found 235 (MH30 ). C12H14N2O3 requires 234.
Reaction SMILES: [C:1]1([C@H:7]([OH:11])[CH2:8][C:9]#[N:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1>[C:1]1([C@H:7]([OH:11])[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC[C@@H](O)c1ccccc1
Solvent: C1CCOC1
Product: NCC[C@@H](O)c1ccccc1
Temperature: 25 °C

Procedure:
To a THF solution of (R)-3-phenyl-3-hydroxypropanenitrile was slowly added borane dimethyl sulfide complex at room temperature. Methyl sulfide was then distilled from the reaction vessel and the resulting THF solution refluxed for 2.5 h. After cooling to room temperature methanolic HCl was added to the reaction mixture. Methanol and methyl borate were removed by distillation and the reaction mixture neutralized with sodium hydroxide (5N). Extraction of the mixture with dichloromethane followed by concentration provided the crystalline (R)-3-phenyl-3-hydroxypropylamine.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH3:31][C:32]([CH3:34])=O>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH:32]([CH3:34])[CH3:31])[CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=C(NC(COCC1CCNCC1)c1ccccc1F)c1ccc2c(Cl)c[nH]c2c1
Product: CC(C)N1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2F)CC1
Yield: 77.6 %

Procedure:
Using alkylation method A, 3-chloro-N-[1-(2-fluoro-phenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (303 mg, 0.71 mmol) and acetone (2 mL, 27 mmol) afforded 260 mg (78%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.O1CCCC1.Cl.Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][CH2:27][NH2:28])[CH:20]=1>O>[NH2:11][C:4]1[CH:3]=[C:2]([Cl:1])[CH:10]=[CH:9][C:5]=1[C:6]([NH:28][CH2:27][CH2:26][CH2:25][C:21]1[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=1)=[O:8]
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: NCCCc1cccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(Cl)ccc1C(=O)NCCCc1cccnc1
Reaction time: 3 h

Procedure:
A mixture of 3.43 g of 4-chloroanthranilic acid, 3.24 g of N,N'-carbonyldiimidazole and 50 ml of tetrahydrofuran was stirred at 5°-25° C. for 3 hours and 4.18 g of 3-(3-pyridinyl)propylamine dihydrochloride was added. The reaction mixture was stirred at room temperature for 18 hours, heated at reflux temperature for one hour and then with 10 ml of water for 30 minutes. The mixture was concentrated and treated with 100 ml. of methylene chloride and 10 ml of 1N sodium hydroxide. The layers were separated and the organic layer was washed with water, dried over magnesium sulfate and concentrated. The residue was recrystallized from ethyl acetate and the desired product, mp 145°-147° C. was obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@@H:12]([CH:14]=[O:15])[CH3:13])=[CH:3]1.[BH4-].[Na+]>C(O)C>[OH:15][CH2:14][C@@H:12]([CH3:13])[C@@H:11]1[C@:16]2([CH3:24])[C@H:8]([C@H:7]3[C@H:19]([CH2:18][CH2:17]2)[C@:20]2([CH3:23])[C:4](=[CH:3][C:2](=[O:1])[CH2:22][CH2:21]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: C[C@H](C=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -10 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
i)—A solution of (20S)-3-oxopregn-4-ene-20-carboxaldehyde (125 g) in dry ethanol (1250 ml) was cooled to −10° C., whereupon a solution of sodium borohydride (4.4 g) in dry ethanol (80 ml) was added in 30 min. After stirring the mixture for 2 hours at −10° C., the reaction was quenched by adding a 50% aqueous solution of acetic acid. The reaction mixture was concentrated under reduced pressure to 25% of its original volume and then poured into ice-water (5 l). The resulting suspension was stirred overnight and filtered. The residue was washed with water and dried to give (20S)-21-hydroxy-20-methylpregn-4-en-3-one (124 g) which was used in the following step without further purification.
Reaction SMILES: N[C:2]1[C:7]([CH2:8][OH:9])=[N:6][C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH2:18][CH:19]([CH3:21])[CH3:20])[N+:3]=1[O-:22].C(#N)C.N(OCCC(C)C)=O.[ClH:34]>C(OCC)C>[CH2:11]([O:10][C:5]1[C:4]([CH2:18][CH:19]([CH3:21])[CH3:20])=[N+:3]([O-:22])[C:2]([Cl:34])=[C:7]([CH2:8][OH:9])[N:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cl
Reactant: CC(C)Cc1c(OCc2ccccc2)nc(CO)c(N)[n+]1[O-]
Agent: CC(C)CCON=O
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)Cc1c(OCc2ccccc2)nc(CO)c(Cl)[n+]1[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
There were mixed 2.17 g of 2-amino-5-benzyloxy-3-hydroxymethyl-6-isobutylpyrazine 1-oxide, 2.89 g of cuprous chloride, 1.42 g of cupric chloride and 22 ml of acetonitrile, and the mixture was stirred for 10 minutes at room temperature. Thereto was added 2.88 ml of isoamyl nitrite at room temperature. The mixture was stirred for 30 minutes, whereby an exothermic reaction of 40°-45° C. was taken place. (No cooling was made.) To the reaction mixture were added 60 ml of 2% hydrochloric acid and 50 ml of diethyl ether to cause phase separation. The aqueous layer was extracted with 50 ml of diethyl ether twice. The extract was combined with the above diethyl ether layer. The combined mixture was dried over magnesium sulfate. The solvent was removed by evaporation. The residue was purified by a silica gel column chromatography (eluting solvent: 50% by volume of ethyl acetate-n-hexane), followed by recrystallization by diethyl ether-n-hexane to obtain 1.73 g of 3-benzyloxy-6-chloro- 5-hydroxymethyl-2-isobutylpyrazine 1-oxide (Compound B-12) as pale yellow plate-like crystals having a melting point of 85.0°-88.0° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:16][C@H:15](CS([O-])(=O)=O)[CH2:14][C@H:10]3[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C(O)(=O)C>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH:16]=[CH:15][CH2:14][C@H:10]3[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2cccc(Cl)c2C(=O)N2C[C@H](CS(=O)(=O)[O-])C[C@@H]12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1Nc2cccc(Cl)c2C(=O)N2C=CC[C@@H]12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 17.0 g (49.3 mmol) of (2R,11aS)-6-chloro-2,3,5,10,11,11a-hexahydro-5,11-dioxo-1H-pyrrolo[2,1-c][1,4]benzodiazepin-2-yl-methanesulphonate in 80 ml of dry dimethylformamide is treated with 4.3 g (98.6 mmol) of sodium hydride (55 percent oil dispersion), the mixture is stirred at 45° for a further 2 hours, then poured into 300 ml of ice-water, neutralized with 5.6 ml of glacial acetic acid and extracted four times with methylene chloride. The organic extracts are washed once with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. By crystallization from ethanol there is obtained (S)-6-chloro-1,11a-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione of melting point 249°-251°.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH3:13])[CH2:9][CH2:10][C:11]#[N:12])(C)(C)C.[C:15]([OH:21])([C:17]([F:20])([F:19])[F:18])=[O:16]>ClCCl>[F:18][C:17]([F:20])([F:19])[C:15]([OH:21])=[O:16].[NH2:7][C@H:8]([CH3:13])[CH2:9][CH2:10][C:11]#[N:12]
Reactant: C[C@H](CCC#N)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)CCC#N
Temperature: 25 °C
Reaction time: 15 h
Yield: 68 %

Procedure:
In a 100 mL round-bottomed flask, ((R)-3-cyano-1-methyl-propyl)-carbamic acid tert-butyl ester (158 mg, 0.80 mmol) was combined with TFA (2 ml) and dichloromethane (8 mL) to give a colorless solution. The reaction mixture was stirred at 25° C. for 15 h. The solvent was evaporated to provide 53 mg (68%) of (R)-4-aminopentanenitrile trifluoroacetate which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[CH:13])=[CH:9][CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:4][CH2:3]1.I[C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1.C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=3)=[CH:9][CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:4][CH2:3]1
Reactant: C#Cc1ccc2c(c1)N(c1ccccc1)CCC2(C)C
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)N(c2ccccc2)CCC3(C)C)cc1
Temperature: 40 °C

Procedure:
To a mixture of 0.020 g (0.08 mmol) of 4,4-dimethyl-1,2,3,4-tetrahydro-N-phenyl-7-ethynylquinoline (Compound 8) and 0.51 g (1.8 mmol) of ethyl 4-iodobenzoate were added 1.5 g (2.0 mL, 14 mmol) of triethylamine, 6.2 mg(0.03 mmol) of copper(I)iodide, and 12 mg (0.02 mmol) of bis(triphenylphosphine)palladium(II) chloride, consecutively. The resulting mixture was heated at 40° C. for 5.5 hours. The reaction was cooled, methylene chloride was added, and the reaction mixture was adsorbed onto silica gel. The mixture was purified by flash chromatography (5% ethyl acetate in hexanes) to give the title compound as a yellow oil. PNMR (300 MHz, CDCl3) d 1.36 (6 H, s), 1.39 (3 H, t, J=7.2 Hz), 1.86 (2 H, t, J=6.0 Hz), 3.64 (2 H, t, J=6.0 Hz), 4.36 (2 H, q, J=7.2 Hz), 6.87 (1 H, d, J=1.6 Hz), 6.91 (1 H, dd, J=7.9, 1.6 Hz), 7.14 (1 H, t, J=7.3 Hz), 7.25 (1 H, d, J=7.9 Hz), 7.25 (2 H, d, J=7.3 Hz), 7.39 (2 H, t, J=7.3 Hz), 7.48 (2 H, d, J=8.5 Hz), 7.97 (2 H, d, J=8.5 Hz).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:8]2[CH:14]=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[CH2:16]([NH:15][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=[C:9]2[NH:12][N:13]=[CH:14][C:8]=12)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCNc1c(C(=O)OCC)cnc2[nH]ncc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCNc1c(C(=O)O)cnc2[nH]ncc12

Procedure:
2.6 of 4-butylamino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (0.01 mol) is treated with 1.1 g of sodium hydroxide in 30 ml of ethanol for 20 hours at room temperature. The solvent is removed in vacuo and the residue is dissolved in 10 ml of water. On acidification with acetic acid 4-butylamino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid solidifies and is filtered off. The product is purified by recrystallization from acetic acid, yield 1.9 g (82%), m.p. 225°.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:10]1[CH2:14][CH:13]=[CH:12][C:11]1=[O:15]>C(Cl)Cl>[CH2:3]([N:2]([CH:13]1[CH2:14][O:10][C:11](=[O:15])[CH2:12]1)[CH3:1])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNCc1ccccc1
Reactant: O=C1C=CCO1
Solvent: ClCCl
Product: CN(Cc1ccccc1)C1COC(=O)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
23.20 ml of N-methylbenzylamine are added to 15.00 g of 5H-furan-2-one in 150 ml methylene chloride. The reaction mixture is stirred for about 48 hours at ambient temperature. For working up the reaction mixture is concentrated by evaporation and chromatographed in batches over a silica gel column with ethyl acetate/petroleum ether (3:1) as eluant. The desired product is obtained as a yellowish oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.[S:9]1[CH2:13][C:12](=[O:14])[NH:11][C:10]1=[O:15].N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:13]2[S:9][C:10](=[O:15])[NH:11][C:12]2=[O:14])[S:5][CH:6]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cc(Br)cs1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cc(Br)cs2)S1
Yield: 87.2 %

Procedure:
To a mixture of 4-bromothiophene-2-carboxaldehyde (1.91 g, 10.0 mmol) and 2,4-thiazolidinedione (1.40 g, 12.0 mmol) in ethanol (30 mL) was added piperidine (1.0 mL, 10.0 mmol). The reaction mixture was heated at reflux for 3 h, then cooled on an ice-bath, and the precipitated products were collected by filtration. The cake was washed with 40% ethanol and dried to afford 5-(4-bromothiophen-2-ylmethylene)-2,4-thiazolidinedione (2.53 g, 87%).
Reaction SMILES: [CH2:1]([C:7]1[C:8](=[O:12])[CH2:9][CH2:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CC(O)([C:16]#[N:17])C.CO.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:1]([CH:7]1[CH:11]([C:16]#[N:17])[CH2:10][CH2:9][C:8]1=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCC1=CCCC1=O
Reactant: CC(C)(O)C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCC1C(=O)CCC1C#N

Procedure:
A mixture of 16,6 g of 2-n-hexyl-2-cyclopentenone (see foot note (1) under Table II) 12 g of acetone cyanhydrine (Org.Synth.Coll. Vol. 2, p. 7), 32 ml of methanol and 0,8 g of sodium carbonate in 12 ml of water, is heated at reflux temperature for 31/2 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:17]2[N:18]=[CH:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=2)(O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.CC(O)C.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC(Cc1ccccc1)(c1cccc(Cl)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: Clc1cccc(C(=Cc2ccccc2)c2c[nH]cn2)c1
Temperature: 160 °C

Procedure:
A mixture of 1-(3 Chlorophenyl)-2-phenyl-l-(1-trityl-1H-imidazol-4-yl)ethanol, (Intermediate 15) mg; 0.9 mmol) in 57% aqueous Hl (10 mL) and iPrOH (2 mL) was added red phosphorus (280 mg, 9.0 mmol) in a resealable tube was heated at 160° C. for 16 h. The mixture was then cooled to room temperature and poured into ice-water, which was then basified with NaOH and diluted with CHCl3. The residue was isolated in a typical aqueous workup using CHCl3 and purified by MPLC with 5 to 15% MeOH:.CH2Cl2 to give 4-(1-(3-chlorophenyl)-2-phenylvinyl)-1H-imidazole, as a solid, (86 rug), AGN-216677. 1HNMR (CD3OD, 300 MHz) δ 7.71 (s, 1H), 7.37-6.96 (m, 9H), 6.55 (s, 1H).
Reaction SMILES: [C:1]([N:5]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:7]([C:13]([C:15]2[CH:20]=[CH:19]C(C3OCC(C)(C)N=3)=[CH:17][CH:16]=2)=[CH2:14])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.ClCCl.[C:34]([O:37]CC)(=[O:36])[CH3:35]>C(O)C>[C:1]([N:5]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:7]([C:13]([C:15]2[CH:16]=[CH:17][C:35]([C:34]([OH:37])=[O:36])=[CH:19][CH:20]=2)=[CH2:14])=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(C)=O
Reactant: C=C(c1ccc(C2=NC(C)(C)CO2)cc1)c1cc(C(C)C)n(C(C)(C)C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: C=C(c1ccc(C(=O)O)cc1)c1cc(C(C)C)n(C(C)(C)C)n1
Temperature: 100 °C

Procedure:
To 5 ml of 130 mg of α-(1-tert-butyl-5-isopropylpyrazol-3-yl)-4-(4,4-dimethyl-1,3-oxazolin-2-yl)styrene in ethanol was added 0.4 ml of a 3N aqueous solution of an acid at room temperature. The resulting mixture wag heated under reflux for 30 minutes. To the reaction mixture was added a 5N aqueous solution of sodium hydroxide to adjust its pH to 11, followed by extraction with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a solution of the residue in 3 ml of 1,4-dioxane were added 100 mg of lithium hydroxide and the resulting mixture was heated at 100° C. for 2 hours. After the completion of the reaction, a 3N aqueous solution of hydrochloric acid was added to adjust the pH to 5, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue so obtained was subjected to chromatography on a silica gel column (developing solvent: 50% dichloromethane/ethyl acetate), whereby 4 mg of the title compound were obtained as a pale yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=1.Cl.N1C=CC=CC=1.[OH2:24]>>[OH:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:24])[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)Cc1ccccc1O2
Reactant: O
Agent: Cl
Solvent: c1ccncc1
Product: O=c1c2ccccc2oc2ccc(O)cc12
Temperature: 25 °C

Procedure:
A solid mixture of 2-methoxy-9H-xanthene 2 (3.09 g, 14.6 mmole) and pyridine hydrochloride (23.85 g, 206.4 mmole) was heated at 200-210° for 1.5 hrs. The resulting reaction mixture was cooled to about 80° and treated with water, while a white powder dropped out of solution. The suspended mixture was stirred at ambient temperature and then cooled to 0°. The solid was filtered on a Buchner funnel and washed with cold water. A large quantity of CH2Cl2 was needed to redissolve the crude product. The CH2Cl2 solution was washed with dilute HCl solution. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4. TLC showed a small by-product at the origin, but neither of the starting material nor the oxidation product, 2-hydroxy-9H-xanthene-9-one, was formed. The CH2Cl2 solution was filtered through a silica gel plug, the silica gel was flushed with 20% EtOAc-hexanes (100 ml). After concentration of the filtrate, the crude 2-hydroxy-9H-xanthene 3 (2.68 g, 93%) was collected as a slightly yellow powder: mp 137-139° C. 1H NMR (DMSO-d6): delta 9.18 (1H, s), 7.14-7.22 (2H, m), 6.97-7.03 (2H, m), 6.87 (1H, dd, J=7.3, 1.8 Hz), 6.57-6.62 (2H, m) and 3.94 (2H, s).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])C>C1COCC1.CCO.[OH-].[Na+]>[C:9]1([C@H:7]2[CH2:8][C@@H:6]2[C:4]([OH:5])=[O:3])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)[C@H]1C[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (1S,2S)-2-phenyl-cyclopropanecarboxylic acid ethyl ester (42 mg, 0.22 mmol, 1.0 eq.) in THF (0.68 mL) and EtOH (0.18 mL), 1M aq. NaOH (0.32 ml) was added. The solution was stirred at r.t. for 18 hours. The organic solvents were removed in vacuo. The residue was diluted with water and washed with AcOEt. The aq. phase was acidified with 2N aq. HCl soln. The mixture was extracted with DCM (3×). The comb. org. phases were dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a colorless oil. The product was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Br:10])[C:8]=1[Br:9])[NH2:5].[N:11]([O-])=O.[Na+].O.O.Cl[Sn]Cl>O.Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:11])[CH:6]=[C:7]([Br:10])[C:8]=1[Br:9]
Reactant: O=N[O-]
Reactant: Nc1cc(Br)c(Br)c(Br)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(Br)c(Br)c(Br)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
3,4,5-Tribromoaniline was obtained by the procedure of L. F. Tietze and T. Eicher (L. F. Tietze, T. Eicher. Reaktionen und Synthesen im organisch-chemischen Praktikum und Forschungslaboratorium. (1991) Georg Thieme Verlag, Stuttgart, New York). 7.8 g (24 mmol) of 3,4,5-tribromoaniline were stirred with a solution of 6.5 mL of concentrated hydrochloric acid and 6.5 mL of water. The mixture was cooled to about −10° C. and at this temperature the solution of 2.76 g of NaNO2 in 11 mL of water was added for 20 min with intensive stirring. The reaction mixture was stirred for 30 min at −10° C. Then the cooled solution of 16.2 g of SnCl2·2H2O in 17 mL of concentrated HCl was added dropwise at −10° C. to the suspension of diazocompound. The reaction mixture was kept at −10° C. for one hour and at 5° C. overnight. The obtained precipitate was filtered off and washed with water. The residue was resuspended in 50 mL of water and concentrated aqueous solution of NaOH was added to get alkaline medium. The 3,4,5-tribromophenylhydrazine was extracted with ether. Organic layer was dried with MgSO4 and ether was evaporated. Yield: 5.5 g (67%). 1H-NMR (200 MHz, DMSO-d6), δ, ppm: 7.09 (2H, s, arom.), 7.34 (1H, s, NH), 4.19 (2H, d, NH2).