Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)(=O)C.[C:7]1([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[O:20])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C-:21]#[N:22].[K+]>O>[OH:20][CH:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:21]#[N:22]
Reactant: O=CCCCCCCc1ccccc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#CC(O)CCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A two-phase mixture of ethyl acetate (30 mL) and water (35 mL) containing 7-phenylheptanal (5.2 g) and KCN (7.1 g) was stirred vigorously at room temperature for 24 h. The layers were separated and the aqueous phase was washed with water, dried (Na2SO4) and concentrated to yield 2-hydroxy-8-phenyloctanenitrile as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([OH:15])[C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([OH:15])[C:12]([O:14][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(O)C(=O)O)cc1OC
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(O)C(=O)OCc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
To 6C (830 mg, 3.9 mmol) in DMF (15 mL) was added cesium carbonate (2.6 g, 8.0 mmol) followed by benzyl bromide (0.6 mL, 5 mmol). After stirring at rt overnight, the reaction was diluted with water, and was extracted with ethyl acetate (2×30 mL). The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The resulting residue was purified via silica gel chromatography (0-40% ethyl acetate/hexanes) to provide 6D (520 mg, 44%). LC-MS 445.31 (M+H)+.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[S:25]([NH2:28])(=[O:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[S:25](=[O:26])(=[O:27])[NH2:28])[CH:10]=1
Reactant: NCc1cc(Cl)ccc1S(N)(=O)=O
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1cc(Cl)ccc1S(N)(=O)=O
Yield: 11.8 %

Procedure:
2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.29 g), 2-(aminomethyl)-4-chlorobenzenesulfonamide hydrochloride (0.42 g) and potassium carbonate (0.52 g) were stirred in ethanol (10 ml) at 70° C. overnight. The reaction solution was filtered through celite. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). 4N Hydrochloride-ethyl acetate solution (1 ml) was added to the obtained yellow oil, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (30 mg).
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:13][CH3:14])=[O:4].[NH3:16]>>[NH2:16][CH:2]([CH3:15])[C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:13][CH3:14])=[O:4]
Reactant: CCc1cccc(C)c1NC(=O)C(C)Br
Reactant: N
Product: CCc1cccc(C)c1NC(=O)C(C)N
Temperature: 55 °C

Procedure:
A slurry of 20.9 g 2-bromo-2'-ethyl-6'-methyl propionanilide, 125 ml 95% alcohol, and 75 ml concd. ammonia was saturated with gaseous ammonia and was heated to 55° C. for 30 hours in a pressure vessel. The reaction mixture was filtered and the filtrate concentration in vacuo. The residue was dissolved in 2 M hydrochloric acid and was extracted with ethyl acetate. The acid phase was made alkaline to pH 9 and was extracted with methylene chloride to give 15.5 g of a crystallizing oil. Recrystallized from ether-petroleum ether, the compound (2-amino-2'-ethyl-6'-methylpropionanilide) melted at 68.5°-70° C.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH3:7][C:8]1([CH2:14][O:15][CH2:16][CH:17](O)[CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1(C)C=CC=CC=1>[Cl:2][CH:17]([CH2:16][O:15][CH2:14][C:8]1([CH3:7])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC1(COCC(O)CN2CCCC2)CCCCC1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1(COCC(Cl)CN2CCCC2)CCCCC1
Temperature: 10 °C
Reaction time: 1.5 h
Yield: 70.5 %

Procedure:
A 500 ml three necked round bottom flask was equipped with a mechanical stirrer, addition funnel, thermometer and an argon inlet and outlet. PCl5 (33 g; 0.159 m) and 18 ml of dry toluene was added to the reaction vessel. 38.5 g (0.151 m) of alpha-[((1-methylcyclohexyl)methoxy)methyl]-1-pyrrolidineethanol (the compound of Example 1b.) was added to the addition funnel along with 45 ml of toluene. Hydrogen chloride gas was bubbled into the addition funnel until the solution was acidic. The PCl5 suspension was cooled to 10° C. and the amino alcohol hydrochloride solution was added dropwise, maintaining the temperature between 10°-15° C. After the addition was complete, the ice bath was removed and the mixture stirred at RT for 1.5 hr. A two liter beaker containing 116 ml of 45% potassium hydroxide and 210 g of ice was cooled in an ice bath. The reaction mixture (a clear yellow solution) was transferred to a separatory funnel and added portionwise at a rate to keep the reaction temperature at 25°-35° C. Stirring was continued for 0.5 hr after the addition. The reaction was transferred to a two liter separatory funnel and diluted with water and ether. The water layer was extracted twice with ether and the combined ether extracts were washed twice with water, once with brine, dried over anhydrous potassium carbonate and concentrated in vacuo to give 29.12 g of the title compound.
Reaction SMILES: [CH:1]1([NH:8][CH2:9][CH:10]([N:12]([CH2:23][CH2:24][C:25]2[C:33]3[S:32][C:31](=[O:34])[NH:30][C:29]=3[C:28]([OH:35])=[CH:27][CH:26]=2)[C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C[Si](Cl)(C)C.[C:48](Cl)(=[O:51])[CH:49]=[CH2:50]>C(Cl)Cl>[C:48]([N:8]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)[CH2:9][CH:10]([N:12]([CH2:23][CH2:24][C:25]1[C:33]2[S:32][C:31](=[O:34])[NH:30][C:29]=2[C:28]([OH:35])=[CH:27][CH:26]=1)[C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:11])(=[O:51])[CH:49]=[CH2:50]
Reactant: C=CC(=O)Cl
Reactant: CC(CNC1CCCCCC1)N(CCc1ccc(O)c2[nH]c(=O)sc12)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N(CC(C)N(CCc1ccc(O)c2[nH]c(=O)sc12)C(=O)OCc1ccccc1)C1CCCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Benzyl [2-(cycloheptylamino)-1-methylethyl][2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]carbamate (0.46 g) in CH2Cl2 (10 mL) was added triethylamine (0.773 mL) and trimethylsilyl chloride (0.586 mL) and the mixture was stirred for 1 h at room temperature. The reaction mixture was cooled in ice and acryloyl chloride (0.0976 mL) was added. The mixture was allowed to warm slowly to RT, diluted with CH2Cl2 and washed with 2M HCl and brine. Drying and evaporation afforded an orange foam (470 mg), which was used directly in the next step.
Reaction SMILES: [CH:1]#[C:2][CH3:3].[F:4][C:5]1[CH:6]=[C:7]([CH:31]=[CH:32][CH:33]=1)[CH2:8][N:9]1[C:21]2[CH2:20][CH2:19][C@@H:18]([NH:22][C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([CH:28]=[N:29][OH:30])[CH:14]=2>C(Cl)Cl.[O-]Cl.[Na+]>[F:4][C:5]1[CH:6]=[C:7]([CH:31]=[CH:32][CH:33]=1)[CH2:8][N:9]1[C:21]2[CH2:20][CH2:19][C@@H:18]([NH:22][C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([C:28]1[CH:1]=[C:2]([CH3:3])[O:30][N:29]=1)[CH:14]=2
Reactant: C#CC
Reactant: O=C(N[C@@H]1CCc2c(c3cc(C=NO)ccc3n2Cc2cccc(F)c2)C1)C1CC1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: Cc1cc(-c2ccc3c(c2)c2c(n3Cc3cccc(F)c3)CC[C@@H](NC(=O)C3CC3)C2)no1
Temperature: 23 °C
Reaction time: 16 h

Procedure:
Bubble propyne gas through a solution of (R)-cyclopropanecarboxylic acid[9-(3-fluoro-benzyl)-6-(hydroxyimino-methyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amide (Example 203) (0.065 g, 0.16 mmol) in methylene chloride and NaOCl solution maintained in a sealed tube. Cap the tube and stir at 23° C. for 16 h. Partition the reaction between methylene chloride and water. Separate and dry the organic portion over Na2SO4 to give 0.045 g of a tan solid. Purify by silca gel chromatography, eluting with 20-80% EtOAc/gradient to give an 0.030g (42%) of an off-white solid. mp: 190-192° C.; MS (ES): m/z 444 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH:6]([CH2:8][OH:9])[CH2:5][CH2:4][O:3]1.N1C=CC=CC=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:9][CH2:8][CH:6]2[CH2:5][CH2:4][O:3][C:2]([CH3:10])([CH3:1])[CH2:7]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)CC(CO)CCO1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCOC(C)(C)C2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (2,2-dimethyltetrahydro-2H-pyran-4-yl)methanol (1 g, 6.93 mmol) in DCM (5 mL) and pyridine (5 mL, 61.8 mmol) was added para-toluenesulfonyl chloride (1.586 g, 8.32 mmol) and DMAP (0.042 g, 0.347 mmol). The mixture was stirred for 18 hr at ambient temperature. The reaction mixture was concentrated in vacuo and the resulting residue was diluted with water and DCM. The separated organic layer was washed with 0.2N aqueous HCl (1×), 1N aqueous HCl (2×), brine, dried over sodium sulfate, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 40 g, EtOAc/hexane=0/100 to 50/50; 25 min] providing (R/S)-(2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Yield: 2.05 g. LCMS (m/z): 299.1 [M+H]+; Retention time=0.96 min.
Reaction SMILES: [O:1]1[CH2:6][C:5](=S)[NH:4][C:3](=[O:8])[NH:2]1.[NH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[N:11]=1>>[CH3:16][C:14]1[CH:13]=[C:12]([CH3:17])[N:11]=[C:10]([NH:9][C:5]2[CH2:6][O:1][NH:2][C:3](=[O:8])[N:4]=2)[CH:15]=1
Reactant: O=C1NOCC(=S)N1
Reactant: Cc1cc(C)nc(N)c1
Product: Cc1cc(C)nc(NC2=NC(=O)NOC2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 68.6 %

Procedure:
To 0.5 g (0.0043 mole) of 6H-1,2,4-oxadiazin-3(2H)-one-5(4H)-thione dissolved in 10 ml of freshly distilled dry dioxane is added 0.56 g (0.0043 mole) of 2-amino-4,6-dimethyl pyridine. The reaction mixture is stirred at room temperature for 17 hours and the dioxane removed on a rotovap. The crystalline material is washed with chloroform, then with ether to give 0.65 g (69 percent) of 5-((4,6-dimethyl-2-pyridinyl)amino)-6H-1,2,4-oxadiazin-3(2H)-one.
Reaction SMILES: C(#N)C.[N:4]1[NH:5][N:6]=[N:7][C:8]=1[CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12][CH2:11]1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>C(N(CC)CC)C>[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:6]2[N:5]=[N:4][C:8]([CH2:9][C@H:10]3[CH2:15][CH2:14][C@H:13]([O:16][C:17](=[O:24])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:12][CH2:11]3)=[N:7]2)=[CH:29][CH:28]=1
Reactant: O=C(O[C@H]1CC[C@H](Cc2nn[nH]n2)CC1)c1ccccc1
Reactant: COc1ccc(CCl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(Cn2nnc(C[C@H]3CC[C@H](OC(=O)c4ccccc4)CC3)n2)cc1
Temperature: 25 °C

Procedure:
To an acetonitrile (20 mL) suspension of trans-benzoic acid 4-(2H-tetrazol-5-ylmethyl)-cyclohexyl ester (1.34 g) obtained in Example (44b), triethylamine (0.68 mL) and 4-methoxybenzyl chloride (0.70 mL) were added at room temperature. The reaction mixture was heated to reflux for 2 hours, cooled to room temperature, concentrated, then diluted with ethyl acetate, and filtered. The filtrate was washed with 1 N hydrochloric acid, then dried over sodium sulfate, and then concentrated. The residue was purified by column chromatography (hexane/ethyl acetate) to obtain the title compound (610 mg, 32%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[CH:11]=[N:12][C:13]=2[O:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:22]=[C:23]([C:27](O)=[O:28])[CH:24]=[N:25][CH:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:19][C:27](=[O:28])[C:23]3[CH:22]=[C:21]([CH3:20])[CH:26]=[N:25][CH:24]=3)[CH:11]=[N:12][C:13]=2[O:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: Cc1cncc(C(=O)O)c1
Reactant: Nc1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1
Product: Cc1cncc(C(=O)Nc2cnc(OC3CCC3)c(-c3ccc(Cl)cc3)c2)c1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-cyclobutoxy-pyridin-3-ylamine (example 78 d) and 5-methyl-3-pyridinecarboxylic acid (CAN 40473-04-9) as starting materials; MS (EI) 394.1 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([CH2:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(Cl)(Cl)Cl>[CH2:31]([O:30][C:28]([N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][CH2:17][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:16]=2)[CH2:20][CH2:21]1)=[O:29])[CH3:32]
Reactant: CCOC(=O)Cl
Reactant: c1ccc(-c2cc(CCC3CCNCC3)c3ccccc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC(CCc2cc(-c3ccccc3)nc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 104.4 %

Procedure:
A solution of 15.6 g of 2-phenyl-4-[2-(4-piperidyl)-ethyl]quinoline, prepared as indicated in Example 16, in 200 ml of chloroform is treated with stirring with 200 ml of a 1N aqueous solution of sodium hydroxide. Then 21.7 g of ethyl chloroformate are added, drop by drop, and the suspension obtained is stirred for 17 hours at the ambient temperature. After separation, the organic phase is washed with water, dried over magnesium sulphate, then evaporated under reduced pressure. 20 g of 4-[2-(1-ethoxycarbonyl-4-piperidyl)-ethyl]-2-phenyl-quinoline in the form of an oil are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][C:13]#[N:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].Br[CH2:18][CH2:19]Br>CS(C)=O>[Cl:1][C:2]1[C:11]([C:12]2([C:13]#[N:14])[CH2:19][CH2:18]2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(CC#N)c1Cl
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1cccc(C2(C#N)CC2)c1Cl
Yield: 35 %

Procedure:
Using Methyl 2-chloro-3-(cyanomethyl)benzoate (2.00 g, 9.54 mmol), sodium hydride (60% in oil, 1.14 g, 28.6 mmol), 1,2-dibromoethane (1.18 mL, 14.3 mmol) and dimethyl sulfoxide (20 mL) as starting materials, and in the same manner as in Example A1(ii), the title compound (787 mg, 35%) was obtained as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[SH:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: Oc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)ccc1Sc1ccc(O)cc1
Temperature: 100 °C
Yield: 107.3 %

Procedure:
A mixture of 4-bromo-1-fluoro-2-nitrobenzene (0.44 g, 2.0 mmol), 4-mercaptophenol (0.303 g, 2.4 mmol), and cesium carbonate (1.56 g, 4.8 mmol, 2.4 eq) in dimethylformamide (10 mL) was heated in a 100° C. oil bath for 3 hours and then cooled to room temperature. The reaction mixture was poured over ice water (50 mL), adjusted to pH 3 by the addition of 1N aqueous hydrochloric acid, and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated to provide the title compound as a thick yellow oil (0.70 g, >100%) that was utilized without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.Cl.C([O:18][N:19]=O)CCC>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=[N:19][OH:18])[CH2:6]2
Reactant: CCCCON=O
Reactant: COc1ccc2c(c1)CCC2=O
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)CC(=NO)C2=O
Reaction time: 2 h
Yield: 77.8 %

Procedure:
To a solution of 5-methoxy-1-indanone (25 g, 0.15 mol) in 300 ml MeOH was added 15 ml concentrated HCl, and then n-butylnitrite (19.5 ml, 0.17 mol) in 50 ml MeOH at 40° C. The solution was stirred for 2 hours during which time a precipitate was formed. The precipitate was collected and dried to yield a white solid (22.3 g, 75% yield). LC-MS: 192 (MH+)
Reaction SMILES: C([O:3][C:4]([C:6]1[S:18][C:17]2[CH:16]=[CH:15][C:14]3[N:13]=[C:12]([OH:19])[C:11]([OH:20])=[N:10][C:9]=3[C:8]=2[CH:7]=1)=[O:5])C>[OH-].[Na+]>[C:4]([C:6]1[S:18][C:17]2[CH:16]=[CH:15][C:14]3[N:13]=[C:12]([OH:19])[C:11]([OH:20])=[N:10][C:9]=3[C:8]=2[CH:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc2c(ccc3nc(O)c(O)nc32)s1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc2c(ccc3nc(O)c(O)nc32)s1
Yield: 51.9 %

Procedure:
8-Ethoxycarbonyl-2,3-dihydroxythieno[3,2-f]quinoxaline (2.0 g, 6.9 mmol) was stirred in 30 ml of 2N sodium hydroxide at room temperature for 2 h. The solution was filtered, and after acidification of the filtrate with 4M hydrochloric acid, the resulting precipitate was collected by filtration and washed with water. The crude product was dissolved in 2N sodium hydroxide and reprecipitated with 4M hydrochloric acid to give 0.94 g (52%) of the carboxylic acid, m.p.>350° C. dec.; IR (KBr): 3300-2200, 1690 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([OH:19])[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:19][CH2:17][CH3:18])[CH:3]=1
Reactant: CCO
Reactant: N#Cc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(Br)ccc1C#N
Temperature: 60 °C
Yield: 100.9 %

Procedure:
A mixture of 4-Bromo-2-fluoro-benzonitrile (5 g, 25.00 mmol), potassium carbonate (10.37 g, 75.0 mmol), ethanol (6.86 mL, 117 mmol) in DMF (50 mL) was heated at 60° C. for overynight. After filtration and concentration, the residue was dissolved in ethyl acetate (150 mL), and the solution was washed with water (30 mL) and brine (50 mL). After drying over Na2SO4, filtration and concentration, a light brown solid (5.7 g) was obtained without further purification. 1H NMR (400 MHz, CDCl3): δ 1.49 (t, J=7 Hz, 3H), 4.14 (q, J=7 Hz, 2H), 7.11 (d, J=1.7 Hz, 1H), 7.14 (dd, J=8.1, 1.7 Hz, 1H), 7.40 (d, J=8.1 Hz, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:23]O>CO>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S@@:12]([C@@H:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:14]([OH:16])=[O:15])=[O:23])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(SC(CCCCCC)C(=O)O)cc1
Reactant: OO
Solvent: CO
Product: CC#CCOc1ccc([S@](=O)[C@@H](CCCCCC)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 24 %

Procedure:
2-(4-But-2-ynyloxy-phenylsulfanyl)-octanoic acid hydroxamide (prepared in Example 6) (1.78 g, 5 mmol) was dissolved in methanol (50 ml) and H2O2 (30%, 10 ml) was added. The reaction mixture was stirred at room temperature for 96 hours and quenched with ice cold solution of NaHSO3 solution. The reaction mixture was concentrated under reduced pressure and the residue was extracted with chloroform. Examination of the reaction mixture showed the formation of two diastereo isomers and they were separated by silica-gel column chromatography by eluting it with 50% ethyl acetate; hexane. 411 g of (S)-2-[(R)-4-but-2-ynyloxy-phenylsulfinyl)-octanoic acid hydroxamide was isolated as a white solid, mp 132.3° C.; Yield 24%; MS: 352.0 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ0.834 (m, 3H), 1.19 (m, 9H), 1.76 (m, 1H), 1.84(t, 3H), 3.11-3.17 (dd, 2H), 3.33 (t, 3H), 4.81 (d, 2H) 7.15 (d, J=2.8, 2H), 7.36 (d, J=2.3, 2H), 9.00 (s, 1H), 10.56 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]([CH2:14][CH2:15][CH2:16][N:17]=[C:18]=[S:19])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:22]1([C:28]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:29]2[CH:33]=[C:32]([CH2:34][CH2:35][CH2:36][NH2:37])[N:31]=[CH:30]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[C:44]1([C:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:29]2[CH:33]=[C:32]([CH2:34][CH2:35][CH2:36][NH:37][C:18]([NH:17][CH2:16][CH2:15][CH2:14][N:7]([CH2:6][C:5]3[CH:20]=[CH:21][C:2]([Br:1])=[CH:3][CH:4]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)=[S:19])[N:31]=[CH:30]2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: S=C=NCCCN(Cc1ccc(Br)cc1)c1ccccn1
Reactant: NCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: ClC(Cl)Cl
Product: S=C(NCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NCCCN(Cc1ccc(Br)cc1)c1ccccn1
Yield: 78.9 %

Procedure:
N-(4-bromobenzyl)-N-(3-isothiocyanatopropyl)-N-(pyridin-2-yl)amine(1 g, 2.76 mmol) and 3-(1-triphenylmethylimidazol-4-yl)propylamine (1.014 g, 2.76 mmol) were dissolved in chloroform (10 ml) and heated at reflux for 4 h. The solvent was removed by evaporation in vacuo and the residue (3.09 g) purified by column chromatography on silica gel (400 ml) using ethyl acetate/methanol/triethylamine 9:0.5:0.5 as eluent affording 1.59 g (80%) of pure 1-[3-(1-triphenylmethylimidazol-4-yl)propyl]-3-[3[N-(4-bromobenzyl)-N-(pyridin-2-yl)amino]propyl]thiourea.
Reaction SMILES: [Na].[OH:2][NH:3][C:4]([NH2:6])=[NH:5].[C:7]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([NH2:18])[CH3:17])=[CH:12][CH:11]=1)(O)=O>C(O)C>[NH2:5][C:4]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([NH2:18])[CH3:17])=[CH:12][CH:11]=2)[O:2][N:3]=1
Reactant: N=C(N)NO
Reactant: CC(N)c1ccc(C(=O)O)cc1
Agent: [Na]
Solvent: CCO
Product: CC(N)c1ccc(-c2nc(N)no2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.8 g of sodium is dissolved in 60 ml of absolute ethanol, and 12 g of molecular sieve (4Å) and 2.63 g of N-hydroxyguanidine are added. The batch is stirred for 1 hour at room temperature and then 1.14 g of 1-(4-carboxyphenyl)ethylamine are added. The resulting turbid yellowish solution is heated under reflux for 2 hours after which time it can be established by thin layer chromatography that the reaction is complete. The batch is filtered and the solvent is removed under reduced pressure. The residue is digested in water and cooled in an ice bath, and then the precipitate is isolated by filtration, washed with a small amount of water and dried under reduced pressure to give 1-[4-(3-amino-1,2,4-oxadiazol-5-yl)phenyl]ethylamine having a melting point of 150°-151°.
Reaction SMILES: [CH:1]1([CH2:9]O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].[BrH:16]>>[CH:1]1([CH2:9][Br:16])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Br
Reactant: OCC1CCCCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Product: BrCC1CCCCCCC1
Temperature: 130 °C

Procedure:
Cyclooctylmethanol (8.16 g) was dissolved in 47% HBr-solution (70 ml) and refluxed for 1 hour at 130° C. The reaction mixture was poured onto icewater (500 ml) and saturated sodium hydrogencarbonate solution (500 ml) was added. The aqueous solution was extracted with dichloromethane. The combined organic phases were washed with water, brine and dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel in toluene as eluent. The fractions containing cyclo-octylmethyl bromide were pooled and evaporated. Yield: 9.85 g. TLC: Rf=0.95, silica gel, toluene