Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][N:24]([C:25]2[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:29][CH:30]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:21][CH:22]=1
Reactant: CCCCCCCCc1ccc(NCc2ccc(Br)cc2)cc1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Product: CCCCCCCCc1ccc(N(Cc2ccc(Br)cc2)C(=O)C2CCCc3ccc(OC)cc32)cc1
Yield: 68.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.62 g) and [(4-bromophenyl)methyl](4-octylphenyl)amine (1.12 g) as starting materials, N-[(4-bromophenyl)methyl]-7-methoxy-N-(4-octylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.15 g) was obtained.
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[Cl:17])[C:4]([O:6]CC)=[O:5])#[N:2].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[C:1]([CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[Cl:17])[C:4]([OH:6])=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)Cc1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#CC(Cc1cccc(Cl)c1Cl)C(=O)O
Temperature: 65 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a solution of ethyl 2-cyano-3-(2,3-dichlorophenyl)propanoate (1.02 g, 3.63 mmol) in methanol/water (15 mL/15 mL) was added sodium carbonate (1.54 g, 14.5 mmol). The mixture was stirred at 65° C. overnight. After cooled to room temperature, the mixture was concentrated under vacuo to remove MeOH, the resulting mixture was then acidified with 4 N hydrochloric acid. This solution was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with water and brine, dried over sodium sulphate, concentrated under reduced pressure to give the titled product (0.87 g, 98%) as a white solid; LC/MS: MS (ES+) m/e 244 (MH+); 1H NMR (300 MHz, CDCl3) δ ppm 3.21 (dd, J=10.2, 13.8 Hz, 1H), 3.59 (dd, J=5.4, 13.8 Hz, 1H), 3.87-3.92 (dd, J=5.4, 10.2 Hz, 1H), 4.74 (s, br, 1H), 7.18-7.32 (m, 2H), 7.44 (dd, J=1.8, 7.8 Hz, 1H).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([OH:33])[CH:27]=1)[C:10]([O:12][CH2:13][C@H:14]([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18])[CH3:15])=[O:11])=O)(C)(C)C.[ClH:34]>O1CCOCC1>[ClH:34].[NH2:8][C@@H:9]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([OH:33])[CH:27]=1)[C:10]([O:12][CH2:13][C@H:14]([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18])[CH3:15])=[O:11]
Reactant: C[C@H](COC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C)OC(=O)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](COC(=O)[C@@H](N)Cc1ccc(O)c(O)c1)OC(=O)c1ccccc1
Yield: 87 %

Procedure:
A solution of (2R)-2-phenylcarbonyloxypropyl (2S)-2-(tert-butoxycarbonyl)amino-3-(3,4-dihydroxyphenyl)propanoate 2 (6.3 g, 13.7 mmol) in 50 mL of 4N HCl in dioxane was stirred at room temperature for 30 min. The reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in about 20 mL of anhydrous acetonitrile and 4 mL of ether. The solution was refrigerated, and the resulting white precipitate was filtered, washed with ether, and dried under vacuum to afford 4.7 g (87% yield) of the hydrochloride salt 3 as a white solid. 1H NMR (400 MHz, CD3OD): δ 1.40 (d, J=6.4 Hz, 3H), 2.99 (dd, J=7.6, 14.4 Hz, 1H), 3.10 (dd, J=5.6, 14.4 Hz, 1H), 4.24 (dd, J=6,8 Hz, 1H), 4.38 (dd, J=6.8, 11.6 Hz, 1H), 4.52 (dd, J=3.2, 11.6 Hz, 1H), 5.40 (m, 1H), 6.52 (dd, J=2.2, 8.4 Hz, 1H), 6.66 (d, J=2.2 Hz, 1H), 6.69 (d, J=8.2 Hz, 1H), 7.47 (t, J=7.6 Hz, 2H), 7.60 (t, J=7.6 Hz, 1H), 8.02 (d, J=7.6 Hz, 2H). MS (ESI) nz/z 360.15 (M+H)+ and 358.09 (M−H)−.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:12][CH:13]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)[CH3:14]>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:12][CH:13]([C:15]1[CH:20]=[C:19]([C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH:18]=[CH:17][CH:16]=1)[CH3:14]
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: CC(C)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)c1cccc(-c2cccc3nc(N)nn23)c1
Yield: 59.8 %

Procedure:
A biphasic solution of 5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine (0.800 g, 3.76 mmol, 1.00 equiv), 3-(2-propyl)phenyl boronic acid (0.739 g, 4.51 mmol, 1.20 equiv), bis(triphenylphosphine)palladium(II) chloride (0.264 g, 0.376 mmol, 0.100 equiv) in acetonitrile (6 mL) and 1.0M sodium carbonate aqueous solution (6 mL) was heated in the microwave to 160° C. for 2 min. The reaction mixture was partitioned between saturated aqueous sodium chloride solution (10 mL) and ethyl acetate (20 mL). The collected organic was dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography (2.5% methanol in dichoromethane) afforded product as a sticky solid (567 mg, 63%). 1H NMR (500 MHz, CDCl3), δ: 7.74 (m, 1H), 7.68 (m, 1H), 7.36-7.48 (m, 4H), 6.79 (dd, J=7.2, 1.3 Hz, 1H), 4.46 (br s, 2H), 3.01 (m, 1H), 1.31 (d, J=6.9 Hz, 6H).
Reaction SMILES: Br[CH2:2][C:3]1([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=2[Cl:43])[O:7][CH:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([C:29]5[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=5)[CH:23]=4)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][O:4]1.[NH:44]1[CH:48]=[CH:47][N:46]=[CH:45]1.[H-].[Na+]>CS(C)=O>[Cl:43][C:37]1[CH:38]=[C:39]([Cl:42])[CH:40]=[CH:41][C:36]=1[C:3]1([CH2:2][N:44]2[CH:48]=[CH:47][N:46]=[CH:45]2)[O:7][CH:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:17][CH2:18][N:19]([C:22]4[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([C:29]5[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=5)[CH:23]=4)[CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][O:4]1
Reactant: Cc1ccc(-c2cc(N3CCN(c4ccc(OCC5COC(CBr)(c6ccc(Cl)cc6Cl)O5)cc4)CC3)nc(C)n2)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(-c2cc(N3CCN(c4ccc(OCC5COC(Cn6ccnc6)(c6ccc(Cl)cc6Cl)O5)cc4)CC3)nc(C)n2)cc1
Temperature: 130 °C
Reaction time: 26 h
Yield: 51 %

Procedure:
6.21 g (9.1 mmol) of 2-bromomethyl-2-(2,4-dichlorophenyl)-4-[4-(4-(2-methyl-4-(4-tolyl)pyrimidin-6-yl)piperazin-1-yl)phenoxymethyl]-1,3-dioxolane (mixture of cis/trans diastereomers) were reacted with 1.244 g (18.3 mmol) of imidazole and 0.55 g (18.2 mmol) of an 80% strength sodium hydride/oil dispersion in 26 ml of absolute dimethyl sulfoxide as described in Example 8b. After stirring for 26 hours at 130° C., the dimethyl sulfoxide (DMSO) was removed by distillation in an oil-pump vacuum. The residue remaining was taken up in CH2Cl2 /water. After thorough mixing and subsequent separation of the phases, the aqueous solution was extracted three times with CH2Cl2. The combined CH2Cl2 extracts were evaporated in vacuo. The residue remaining (4.30 g) was chromatographed on a silica gel S/CH2Cl2 column (diamter 2.0 cm, height 20 cm) with elution using CH2Cl2 and CH2Cl2 /C2H5OH mixtures (0.5-3.0% by volume of C2H5OH). The fractions containing the diastereomer racemates (check using TLC) were combined and evaporated in vacuo. In this fashion, 3.12 g (=51% yield) of 2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-4-[4-(4-(2-methyl-4-(4-tolyl)pyrimidin-6-yl)piperazin-1-yl)phenoxymethyl]-1,3-dioxolane (mixture of cis/trans diastereomers) were obtained as a viscous oil;
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH2:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:33]12([C:43](Cl)=[O:44])[CH2:42][CH:37]3[CH2:38][CH:39]([CH2:41][CH:35]([CH2:36]3)[CH2:34]1)[CH2:40]2>ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH:24][C:43]([C:33]23[CH2:42][CH:37]4[CH2:36][CH:35]([CH2:41][CH:39]([CH2:38]4)[CH2:40]2)[CH2:34]3)=[O:44])[CH2:20][CH:21]([CH3:22])[CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CC(C)C[C@H](N)CN1CCC[C@H]1C(=O)NCCCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](CN1CCC[C@H]1C(=O)NCCCCc1ccccc1)NC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 22 °C
Reaction time: 12 h
Yield: 40.8 %

Procedure:
In a round bottom flask were added 1-[2-(S)-amino-4-methylpentyl]-L-proline 4-phenylbutylamide (20 mg), triethylamine (20 uL) and anhydrous dichloromethane (1 mL). 1-Adamantylcarbonyl chloride (17 mg) was added, and the reaction was stirred at 22° C. for 12 hours. The reaction mixture was washed with said aq NaHCO3, said aq NaCl, dried (MgSO4) and evaporated under reduced pressure. The crude reaction was chromatographed with acidic silica to provide 12 mg (42%) of the title compound. The 1H NMR and Mass spectrum analysis of this compound was consistent with the structure.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:6]2[CH:16]=[C:17]([CH2:19][CH3:20])[S:18][C:5]=2[N:4]2[C:21]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:22][N:23]=[C:3]12.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>C(Cl)(Cl)Cl>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[C:17]([CH2:19][CH3:20])[S:18][C:5]=2[N:4]2[C:21]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:22][N:23]=[C:3]2[CH:2]([NH:1][C:39]([NH:38][C:35]2[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)=[O:40])[N:8]=1
Reactant: CCc1cc2c(s1)-n1c(C3CCCCC3)nnc1C(N)N=C2c1ccccc1Cl
Reactant: COc1ccc(N=C=O)cc1
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(s1)-n1c(C3CCCCC3)nnc1C(NC(=O)Nc1ccc(OC)cc1)N=C2c1ccccc1Cl
Reaction time: 0.5 h

Procedure:
6-Amino-4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (0.6 g) was dissolved in chloroform (15 ml) and 4-methoxyphenyl isocyanate (0.2 ml) was added thereto. The mixture was stirred for 30 minutes. The reaction mixture was purified by silica gel column chromatography and crystals obtained were recrystallized from methanol to give 0.49 g of N-(4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N'-(4-methoxyphenyl)urea having a melting point of 268°-269° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:34][CH3:35])[CH2:11][S:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6].[I-:36].[Na+]>C(C(C)=O)C>[I:36][CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:34][CH3:35])[CH2:11][S:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6]
Reactant: [I-]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)SCC(CNS(=O)(=O)CCCCl)OC
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)SCC(CNS(=O)(=O)CCCI)OC
Yield: 85.9 %

Procedure:
To a solution of 197 mg (0.354 mM) of 3-(3-chloropropylsulfonylamino)-2-methoxy-1-octadecylcarbamoylthiopropane IIIa6 in 7 ml of methyl ethyl ketone is added 265 mg (1.77 mM) of sodium iodide and the mixture is heated under refluxing for 3 hours with stirring. After the solvent is evaporated, the residue is purified by the column chromatography on silica gel with a n-hexane-ethyl acetate (3:1) mixture as an eluent to give 197 mg (0.304 mM) of 3-(3-iodopropylsulfonylamino)-2-methoxy-1-octadecylcarbamoylthiopropane IIa6 in 86% yield.
Reaction SMILES: [O-]S([O-])(=O)=O.[Mg+2].[CH2:7]([O:9][C:10]([C:12]1[CH:40]=[CH:39][C:15]2[N:16]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[C:17]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[C:21]([CH:28]([O:31][CH3:32])[O:29][CH3:30])[CH:20]=3)=[N:18][C:14]=2[CH:13]=1)=[O:11])[CH3:8]>CO.[Pd]>[CH2:7]([O:9][C:10]([C:12]1[CH:40]=[CH:39][C:15]2[N:16]([CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]3)[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH:28]([O:29][CH3:30])[O:31][CH3:32])[CH:20]=3)=[N:18][C:14]=2[CH:13]=1)=[O:11])[CH3:8]
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc([N+](=O)[O-])c(C(OC)OC)c1)n2C1CCCCC1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(N)c(C(OC)OC)c1)n2C1CCCCC1
Reaction time: 0.5 h

Procedure:
In 20 mL methanol 100 mg of 10% Pd-C was pre-hydrogenated in the presence of 1 g MgSO4 at 30 psi for 15 minutes. Compound 354c (100 mg) dissolved in a solution of 20 mL of methanol containing 2 mL triethylamine, was added to the catalyst and the hydrogenation was continued for 30 minutes. The catalyst and the magnesium sulfate were filtered using Celite. The solution was evaporated to dryness and the oily residue was used immediately in the following step.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[H-].[Na+].F[C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:23])[NH:18][CH:19]=[N:20]2)=[CH:15][CH:14]=1>CN(C=O)C>[O:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][O:1][C:13]2[CH:22]=[C:21]3[C:16]([C:17](=[O:23])[NH:18][CH:19]=[N:20]3)=[CH:15][CH:14]=2)[CH2:5][CH2:6]1
Reactant: OCCN1CCOCC1
Reactant: O=c1[nH]cnc2cc(F)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]cnc2cc(OCCN3CCOCC3)ccc12
Temperature: 50 °C

Procedure:
A mixture of N-(2-hydroxyethyl)morpholine (2.66 ml), sodium hydride (60% dispersion in mineral oil, 0.88 g) and DMF (25 ml) was warmed to 50° C. for 3 minutes. The resulting solution was allowed to cool for 10 minutes before a solution of 7-fluoro-3,4-dihydroquinazolin-4-one (1.64 g) in DMF (25 ml) was added and the resultant mixture was heated to 125° C. for 18 hours. The solvent was evaporated and the residue was partitioned between methylene chloride and 2N hydrochloric acid solution. The organic phase was dried and evaporated to give 7-(2-morpholinoethoxy)-3,4-dihydroquinazolin-4-one (1.58 g); NMR Spectrum: (CDCl3) 2.6 (t, 4H), 2.87 (t, 2H), 3.73 (t, 4H), 4.25 (t, 2H), 7.12 (m, 2H), 8.07 (s, 1H), 8.19 (d, 1H); Mass Spectrum: M+H+ 276.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4](Cl)[N:3]=1>[Zn].O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)c(Cl)nc1Cl
Agent: [Zn]
Solvent: O
Product: Clc1cnc(Cl)c(Cl)c1

Procedure:
reacting 2,3,5,6-tetrachloropyridine in a reaction medium including zinc, an aqueous alkaline reagent, a water-immiscible organic solvent, and a phase transfer catalyst to form 2,3,5-trichloropyridine.
Reaction SMILES: [Na].C(O)C=C.[S:6]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH2:7][CH2:8][C:9]([O:11]CC=C)=O.Cl>O.C(OCC)C>[OH:11][C:9]1[CH2:8][CH2:7][S:6][CH2:15][C:16]=1[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18]
Reactant: C=CCOC(=O)CCSCCC(=O)OCC=C
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCOCC
Solvent: C=CCO
Product: C=CCOC(=O)C1=C(O)CCSC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 42.3 %

Procedure:
To a mixture of sodium sand (23 g; 1.0 mole) (Vogel's Textbook of Practical Organic Chemistry, Fourth Ed., Longman, London, 1978, p. 313) and anhydrous diethyl ether (3.4 1), allyl alcohol (65.8 ml) was slowly added. The obtained reaction mixture was stirred for two days at room temperature and then diallyl 3,3′-thiodipropionate (129.0 g; 0.5 mole) prepared according to the process disclosed in Example 1 was slowly added drop by drop. The mixture was stirred for another day at room temperature and then under ice cooling first absolute ethanol (10 ml) and then water (400 ml) and concentrated hydrochloric acid (455 ml) were added and it was stirred until the whole was dissolved. The phases were separated. The obtained organic phase was washed with water (400 ml), a 7% sodium hydrogencarbonate solution (3×400 ml) and once more with water (200 ml). The organic phase was dried with magnesium sulfate, the drying agent was filtered off, the filtrate was evaporated and dried. The title compound (42.4 g; 42%) was obtained as a crude product in the form of a yellowish oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:12])([CH3:11])[CH:9]=[CH2:10])[C:5]([Cl:13])=[CH:4][C:3]=1[O:14][CH3:15].[Li]CCCC.CN([CH:24]=[O:25])C>C1COCC1>[Cl:13][C:5]1[C:6]([C:8]([CH3:12])([CH3:11])[CH:9]=[CH2:10])=[CH:7][C:2]([CH:24]=[O:25])=[C:3]([O:14][CH3:15])[CH:4]=1
Reactant: C=CC(C)(C)c1cc(Br)c(OC)cc1Cl
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CC(C)(C)c1cc(C=O)c(OC)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-bromo-4-chloro-5-(1,1-dimethyl-allyl)-2-methoxy-benzene (3.92 g, 0.0135 mol) in dry THF (30 mL) was cooled to −78° C. under argon. n-BuLi (2.5M, 6 mL, 0.0145 mol) was added keeping the temperature below −70° C. The yellow mixture was stirred for another 15 min and quenched with dry DMF (1.2 mL, 0.015 mol). The cooling bath was removed and the mixture was allowed to warm to 25° C. A saturated solution of NaHCO3 (30 mL) was added and then extracted with EtOAc (3×50 mL). The organic phase was dried (Na2SO4) and evaporated to dryness. The crude product was recrystallized from MeOH. Yield: 3.00 g (93%). GCMS: >99%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[C:15](=O)[C:14](=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH2:13][S:12][CH2:11]2)=[CH:5][CH:4]=1.[CH2:26]([NH:29][NH2:30])[CH2:27][CH3:28]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:29]([CH2:26][CH2:27][CH3:28])[N:30]=[C:15]3[C:14](=[CH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[CH2:13][S:12][CH2:11][CH:10]23)=[CH:5][CH:4]=1
Reactant: CCCNN
Reactant: COc1ccc(C=C2CSCC(=Cc3ccc(OC)cc3)C2=O)cc1
Solvent: CO
Product: CCCN1N=C2C(=Cc3ccc(OC)cc3)CSCC2C1c1ccc(OC)cc1
Temperature: 25 °C
Yield: 34.5 %

Procedure:
A mixture of 6.0g of tetrahydro-3,5-bis-[(4-methoxyphenyl)methylene]-4H-thiopyran-4-one and 1.3g of n-propyl hydrazine in 200 ml of methanol is heated at reflux temperature for 3.5 hours, and then allowed to cool to room temperature. The resultant crystals are collected by filtration and chromatographed on a dry packed neutral alumina column (Activity I). The fractions eluted with 10-20% ethyl acetate/hexane are combined and recrystallized from acetone/hexane to give 2.4g of the title compound, melting point 149.5°-151.5°C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[N+:12]([CH:15]=[C:16](SC)[S:17][CH3:18])([O-:14])=[O:13]>N1C=CC=CC=1>[N+:12]([CH:15]=[C:16]([S:17][CH3:18])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)([O-:14])=[O:13]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCCCc1ccccn1
Solvent: c1ccncc1
Product: CSC(=C[N+](=O)[O-])NCCCCc1ccccn1

Procedure:
2-(4-Aminobutyl)pyridine was reacted with 1-nitro-2,2-bis-methylthio-ethylene in pyridine at 60° for 3.5 hours. Concentration of the reaction mixture and crystallisation yielded 1-nitro-2-methylthio-2-[4-(2-pyridyl)butylamino]ethylene, m.p. 78°.
Reaction SMILES: [OH:1][C:2]1[CH:3]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=3)=[CH:12][S:11][CH:4]2[NH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9].C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.ClCCl.CN(C)C(=O)C>[CH:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]2[CH:3]3[CH:4]([NH:5][C:6](=[O:10])[C:7]([C:8]#[N:9])=[C:2]3[OH:1])[S:11][CH:12]=2)=[CH:15][CH:16]=1)=[O:21]
Reactant: N#CC1=C(O)C2C(c3ccc(CO)cc3)=CSC2NC1=O
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: N#CC1=C(O)C2C(c3ccc(C=O)cc3)=CSC2NC1=O

Procedure:
Tetrapropylammonium perruthenate (0.16 g, 0.46 mmol) was added to a solution of 4-Hydroxy-3-(4-hydroxymethyl-phenyl)-6-oxo-3a,6,7,7a-tetrahydro-thieno[2,3-b]pyridine-5-carbonitrile (0.55 g, 1.84 mmol) and 4-methylmorpholine N-oxide (0.65 g, 5.52 mmol) in 2:1 mixture of dichloromethane/N,N-dimethylacetamide (33 mL) at room temperature. The reaction was stirred till complete consumption of the starting alcohol, filtered over celite, filtrate washed with 1N HCl, dried (MgSO4) and concentrated to a brown solid. MS (ESI) m/e 294.9 (M−H)+; 1H NMR (300 MHz, DMSO-d6): δ ppm 12.01 (br s, 1H), 10.04 (s, 1H), 7.87 (d, J=9, 2H), 7.66 (d, J=9, 2H), 7.07 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[C@@H:13]([CH2:24][O:25][Si](C(C)(C)C)(C)C)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(O)(=O)C>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18])[C@@H:13]([CH2:24][OH:25])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
(3R,4R)-1-Benzyloxycarbonyl-3-(tert-butyldimethylsilyl)oxymethyl-4-(tert-butyldimethylsilyl)oxypyrrolidine (5.46 g) was dissolved in tetrahydrofuran (23 mL). While this solution was chilled in an ice water bath, water (23 mL) and acetic acid (68 mL) were sequentially added and the mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=4:1->1:1) to give (3R,4R)-1-benzyloxycarbonyl-3-hydroxymethyl-4-(tert-butyldimethylsilyloxy)pyrrolidine as a colorless oil (2.74 g).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1)=[O:5].[C:18]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>CO.C(OCC)(=O)C>[NH:13]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[NH:1][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:23][CH:24]=1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1ccccc1C(=O)NCCc1ncc[nH]1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)NCCc2ncc[nH]2)cc1
Yield: 64.5 %

Procedure:
The titled compound was prepared substantially in accordance with the method detailed in Example 6B using 1.50 g (0.00651 mol) of 2-amino-N-[2-(1H-imidazol-2-yl)ethyl]benzamide, prepared as in Example 6A, and 2.61 g (0.01302 mol) of p-tert-butylbenzoyl chloride, with the exception that after reducing the initial reaction mixture to dryness, the resultant residue was dissolved in methanol and heated at reflux for 30 minutes. The methanol solution was then reduced to dryness under reduced pressure and the resultant residue was dissolved in an ethyl acetate/aqueous sodium bicarbonate mixture. The resulting layers were separated and the organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and reduced to dryness under reduced pressure to provide a yellow oil. This oil was purified by twice crystallizing the material from diethyl ether containing a small amount of ethyl acetate to provide 1.64 g of the desired titled compound (m.p. 127°-132° C.).