Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([CH:12]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[S:15][CH:14]([CH:28]([N:36]2[C:40](=[O:41])[C:39]3=[CH:42][CH:43]=[CH:44][CH:45]=[C:38]3[C:37]2=[O:46])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[NH:13]1)([OH:11])=[O:10]>CN(C)C=O>[CH2:1]([O:11][C:9]([CH:12]1[C:16]2([CH2:17][CH2:18][N:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]2)[S:15][CH:14]([CH:28]([N:36]2[C:37](=[O:46])[C:38]3=[CH:45][CH:44]=[CH:43][CH:42]=[C:39]3[C:40]2=[O:41])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[NH:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C(C1NC(C(=O)O)C2(CCN(c3ccccc3)CC2)S1)N1C(=O)c2ccccc2C1=O
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C1NC(C(=O)OCc2ccccc2)C2(CCN(c3ccccc3)CC2)S1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
17 g (0.10 mole) of benzyl bromide, dissolved in 20 ml of N,N-dimethylformamide are added to 24 g (0.0447 mole) of the alpha-isomer of tert-butyl 4-carboxy-8-phenyl-alpha-phthalimido-1-thia-3,8-diazaspiro[4.5]decane-2-acetate, obtained in 2.3, dissolved in 200 ml of N,N-dimethylformamide. The reaction mixture is stirred overnight at ambient temperature and is then poured onto ice, extracted three times with 500 ml amounts of ethyl acetate and the organic phase washed successively with a little water, with a saturated aqueous solution of sodium hydrogen carbonate and again with a little water. The solution is then dried and evaporated to dryness. After recrystallization from ethyl acetate, there are obtained 18.8 g tert-butyl 4-benzyloxycarbonyl-8-phenyl-alpha-phthalimido-1-thia-3,8-diazaspiro[4.5]decane-2-acetate. Yield: 66%; M.P. 184°-185° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.C([N:16]([CH2:19][CH3:20])CC)C.[CH2:21]1COC[CH2:22]1.C(OCC)(=O)C>O>[F:1][C:2]([F:12])([F:13])[CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:19](=[NH:16])[CH2:20][CH2:21][CH3:22])=[CH:7][CH:6]=1
Reactant: Nc1ccc(OCC(F)(F)F)cc1
Reactant: C1CCOC1
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CCCC(=N)Nc1ccc(OCC(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
A mixture of ethyl butylimidate hydrochloride (10.0 g), 4-(2,2,2-trifluoroethoxy)aniline (12.6 g), triethylamine (6.67 g) and THF (250 mL) was stirred at 70° C. for 2 days. To the reaction mixture were added ethyl acetate and water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to aminopropylsilane-bonded silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.80 g) as a solid.
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:16][NH:17][CH3:18]>C(OCC)(=O)C>[CH3:16][N:17]([CH3:18])[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccncc1)c1ccc(F)cc1
Reactant: CNC
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(C(=O)c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture consisting of 2.38 g of 4-(4-fluorobenzoyl)pyridine and 7 ml of 50% aqueous dimethylamine solution was stirred for 24 hours at room temperature, followed by addition of 100 ml of ethyl acetate. The mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate and the organic layer was dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was recrystallized from ethanol-ethyl acetate to give 1.1 g of 4-(4-dimethylaminobenzoyl)pyridine as pale yellow crystals melting at 122°-124° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].Cl.Cl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.C(OCC)(=O)C>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH2:36][CH2:35][N:34]([CH2:2][C:3]([NH:5][C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]4[CH:21]=[N:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:13]=4)[CH:7]=3)=[O:4])[CH2:33][CH2:32]2)=[CH:29][CH:30]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=C(CCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(CN1CCN(c2ccc(Cl)cc2)CC1)Nc1cccc(-c2cnc3ccccc3n2)c1
Yield: 36.4 %

Procedure:
A slurry of 2-chloro-N-(3-quinoxalin-2-ylphenyl)acetamide (100 mg, 0.336 mmol), 1-(4-chlorophenyl)piperazine dihydrochloride (100 mg, 0.367 mmol) and K2CO3 (149 mg, 1.075 mmol) in MeCN (5 mL) was heated at reflux for 24 hrs. The reaction mixture was diluted with ethyl acetate (20 mL), and the organic phase washed with water (20 mL) and then brine (20 mL), dried over MgSO4 and evaporated in vacuo. The residue was triturated with diethyl ether and dried in vacuo at 50° C. to afford 2-[4-(4-chlorophenyl)piperazin-1-yl]-N-(3-(quinoxalin-2-yl)phenyl)acetamide (56 mg, 36% yield). LCMS calculated for C26H24ClN5O (M+H): 458.17. found 458.21. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.00 (1H, br. s), 9.51 (1H, s), 8.55 (1H, m), 8.15-8.10 (2H, m), 8.05 (1H, d, 1=7.5 Hz), 7.95-7.80 (3H, m), 7.55 (1H, m), 7.21 (2H, d, J=7.5 Hz), 6.90 (2H, d, J=7.5 Hz), 3.21 (4H, m), 2.61 (4H, m).
Reaction SMILES: C(N(CC)CC)C.[C:8](=[S:10])=S.[CH3:11][C:12]1[CH:28]=[CH:27][C:15]([O:16][C:17]2[S:18][C:19]3[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][C:20]=3[N:21]=2)=[CH:14][CH:13]=1.P(Cl)(Cl)(Cl)=O>C(OCC)C>[CH3:11][C:12]1[CH:28]=[CH:27][C:15]([O:16][C:17]2[S:18][C:19]3[CH:25]=[C:24]([N:26]=[C:8]=[S:10])[CH:23]=[CH:22][C:20]=3[N:21]=2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(Oc2nc3ccc(N)cc3s2)cc1
Reactant: S=C=S
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2nc3ccc(N=C=S)cc3s2)cc1
Reaction time: 12 h

Procedure:
Additions are made dropwise, at -10° to -5°, firstly of 31 ml of triethylamine and then of 4.3 ml of carbon disulphide to 18.4 g of 2-(4'-methylphenoxy)-6-aminobenzothiazole in 360 ml of absolute diethyl ether. Stirring is continued for ca. 12 hours at room temperature; the mixture is cooled to 0°, and an addition made at this temperature, within 30 minutes, of 6.7 ml of phosphorus oxychloride in 80 ml of absolute diethyl ether. After 10 hours' stirring at room temperature, filtration is performed; the filter residue is washed firstly with diethyl ether and then with water and dried. the product is afterwards chromatographed through aluminium oxide, with methylene chloride as the eluant, to obtain 2-(4'-methylphenoxy)-6-isothiocyanobenzothiazole, M.P. 121° - 123°.
Reaction SMILES: [N:1]12[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19][N:10]([CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)[CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]2.[C:27](Cl)(=[O:30])[O:28][CH3:29]>>[C:27]([N:24]1[CH2:23][CH2:22][N:21]([C:27]([O:28][CH3:29])=[O:30])[CH2:20][CH2:19][N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][N:1]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9]2)[CH2:26][CH2:25]1)([O:28][CH3:29])=[O:30]
Reactant: C1CNCCN2CCOCCOCCN(CCN1)CCOCCOCC2
Reactant: COC(=O)Cl
Product: COC(=O)N1CCN2CCOCCOCCN(CCOCCOCC2)CCN(C(=O)OC)CC1

Procedure:
In a manner similar to that described in Example 7, treat 4,7,13,16-tetraoxa-1,10,21,24-tetraazabicyclo[8,8,8]-hexacosane (compound of Example 68B) with methyl chlorocarbonate Isolate and purify the resultant product in a manner similar to that described in Example 7 to obtain 21,24-dicarbomethoxy-4,7,13,16-tetraoxa-1,10,21,24-tetraazabicyclo[8,8,8]hexacosane, m.p. =86°C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19](C=CC)=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].[CH:38](N(CC)C(C)C)([CH3:40])[CH3:39]>C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C:13]2([CH:39]=[CH:38][CH3:40])[O:18][C:17]3[CH:19]=[C:20]([NH:23][C:28]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:29])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC=Cc1c(N)ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Solvent: CCOC(C)=O
Product: CC=CC1(COS(=O)(=O)c2ccc(C)cc2)COc2ccc(NC(=O)OCc3ccccc3)cc2O1
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
To a solution of {(2R)-7-amino-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (4.20 g, 11.2 mmole) in ethyl acetate (150 mL) was added benzyl chloroformate (8.00 mL, 56.0 mmole). The reaction mixture was stirred under nitrogen for 0.5 hour, then a solution of N,N-diisopropylethylamine (9.75 mL, 56 mmole) in ethyl acetate (75 mL) was added dropwise over a period of 0.5 hour. The mixture was stirred at room temperature under nitrogen overnight. The reaction was diluted in volume to 350 ml and was then washed with 2N HCl (2×100 mL), saturated sodium bicarbonate (150 mL) and brine (100 mL), dried over magnesium sulfate, filtered and evaporated to an oil. The crude oil was column chromatographed on silica gel with 10% ethyl acetate/hexane to remove impurities and the product eluted with 60% ethyl acetate/hexane to give the (R)-enantiomer of the title compound as a yellow oil (4.5 g, 79%). 1H (CDCl3) doublet 7.8 δ (2); multiplet 7.4 δ (7H); doublet 6.7 δ (2H); multiplet 6.0-6.2 δ (2H); singlet 5.2 δ (2H); multiplet 4.4 δ (1H); multiplet 4.2 δ (3H); multiplet 4.0 δ (1H); singlet 2.4 δ (3H); doublet 1.9 δ (3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[O:11][C:7]=2[CH:6]=1.Cl.[F:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:19][CH:18]=1.C(N(CC)CC)C>C(O)C>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH:22]2[CH2:23][CH2:24][N:25]([CH2:2][CH2:3][CH2:4][C:5]3[CH:14]=[CH:13][C:8]4[NH:9][C:10](=[O:12])[O:11][C:7]=4[CH:6]=3)[CH2:26][CH2:27]2)=[CH:28][CH:29]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: O=c1[nH]c2ccc(CCCCl)cc2o1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=c1[nH]c2ccc(CCCN3CCC(Cc4ccc(F)cc4)CC3)cc2o1
Yield: 93 %

Procedure:
A suspension of 5.5 g of 6-(3-chloropropyl)-3H-benzoxazol-2-one in 50 ml of ethanol is admixed with 5.7 g of 4-(4-fluorobenzyl)piperidine hydrochloride and 7.2 ml of triethylamine. The mixture is stirred under reflux for one hour and subjected to customary workup to give 8.5 g of 6-{3-[4-(4-fluorobenzyl)piperid-1-yl]propyl}-3H-benzoxazol-2-one, m.p. 105-107°.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]=1.[C:11](Cl)(=[O:13])[CH3:12].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1.C(N(CC)CC)C>CC#N.C(Cl)Cl>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][N:2]2[C:11](=[O:13])[CH3:12])=[CH:16]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(=O)Cl
Reactant: C1=NCCc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)N1CCc2ccccc2C1c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3,4-dihydroisoquinoline (4.00 g, 30.5 mmol) and CH3CN (50 mL) at 0° C. was added acetyl chloride (2.13 mL, 30.5 mmol) over 2 min. The reaction was stirred 30 min and 1H-indole (3.57 g, 30.5 mmol) and triethylamine (4.25 mL, 30.5 mmol) in CH3CN (5 mL) were added and the reaction warmed to RT. The reaction was stirred under N2 3 h, then quenched with 10% HCl (100 mL), and extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with NaHCO3 (100 mL), dried (Na2SO4), and concentrated to give the crude product as a white solid (9.2 g). The solid was dissolved in CH2Cl2 (50 mL) to give a suspension which was filtered and the solid collected. The white solid (3.55 g) was recrystallized from hot acetone (230 mL) and cooled at −20° C. overnight to give 1-(1-(1H-indol-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone as a white crystalline solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].[NH:9]1[CH2:16][CH2:15][CH2:14][C@@H:10]1[C:11]([OH:13])=[O:12].C(=O)(O)[O-].[Na+]>CC(C)=O.O>[CH2:5]([O:4][C:2]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:3])[CH:6]([CH3:8])[CH3:7].[CH2:5]([O:4][C:2]([N:9]1[CH2:16][CH2:15][CH2:14][C@@H:10]1[C:11]([OH:13])=[O:12])=[O:3])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)COC(=O)Cl
Reactant: O=C(O)[C@H]1CCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)COC(=O)N1CCC[C@@H]1C(=O)O
Product: CC(C)COC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 8 h

Procedure:
A solution of isobutyl chloroformate (4.4 mL, 34.04 mmol) in acetone is added dropwise to a solution of L- or D-proline (4.0 g, 34.74 mmol) and sodium bicarbonate (10 g, 125 mmol) in water (50 mL). The mixture is stirred overnight. After removal of acetone, the aqueous solution is acidified to pH 2 with hydrochloric acid while maintaining the temperature below 20° C., and then extracted with ethyl acetate (3×25 mL). The combined organic phase is dried over anhydrous magnesium sulfate and evaporated in vacuo to give (S)-N-isobutoxycarbonylproline (from L-proline) or (R)-N-isobutoxycarbonylproline (from D-proline) correspondingly, as colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=2)=[CH:5][N:4]=[N:3]1.C1C(=O)N([Cl:23])C(=O)C1>CN(C)C=O.CCOC(C)=O>[Cl:23][C:5]1[N:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=1
Reactant: COC(=O)c1cc(-c2cnnn2C)cs1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2c(Cl)nnn2C)cs1
Yield: 79.7 %

Procedure:
A solution of methyl 4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxylate (500 mg, 2.24 mmol) and NCS (1196 mg, 8.96 mmol) in N,N-Dimethylformamide (DMF) (10 ml) was heated at 50° C. for 2 hr. The reaction mixture was diluted with 50 ml of EtOAc. The organic layer was washed with H2O (50 ml×2) and brine (50 ml), and then concentrated to give 460 mg of a crude mixture, which was used in next step without further separation. LCMS (ES) m/z 258.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][C:3]=1[CH2:4][N:5](CC1C=CC=CC=1)[CH2:6][CH3:7].[H][H].C.[ClH:27]>CO>[ClH:27].[NH2:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7]
Reactant: CCOC(=O)c1ccc(N)c(CN(CC)Cc2ccccc2)c1
Reactant: [H][H]
Agent: Cl
Solvent: CO
Product: CCNCc1cc(C(=O)OCC)ccc1N

Procedure:
3.8 gm of 2-amino-N-benzyl-5-carbethoxy-N-ethyl-benzylamine were hydrogenated in a mixture of 50 ml of methanol and 1 ml of concentrated hydrochloric acid at room temperature and at a hydrogen pressure of 5 atmospheres in the presence of palladized charcoal. Then, the catalyst was filtered off, and the filtrate was evaporated to dryness in vacuo. The residue was recrystallized from ethanol by addition of ether, yielding 2-amino-5-carbethoxy-N-ethyl-benzylamine hydrochloride, m.p. 173°-176°C (decomp.).
Reaction SMILES: C1C=CC(/C=N\O)=CC=1.[C:10](=[O:13])([O-])[O-].[Cs+].[Cs+].[I:16][C:17]1[CH:22]=C([N+]([O-])=O)[CH:20]=[C:19]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:18]=1>CN(C=O)C.CCOC(C)=O>[I:16][C:17]1[CH:22]=[C:10]([OH:13])[CH:20]=[C:19]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:18]=1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)c1cc(I)cc([N+](=O)[O-])c1
Agent: O/N=C\c1ccccc1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cc(O)cc(I)c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 54.8 %

Procedure:
To a solution of syn-benzaldehyde oxime (3.71 g, 30.6 mmol) in DMF (80 mL) was added cesium carbonate (19.9 g, 61.3 mmol) and heated to 90° C. for 1-2 min before a solution of 1-iodo-3-methanesulfonyl-5-nitro-benzene (5.0 g, 15.3 mmol) in DMF (80 mL) was added. The resulting dark brown solution was stirred at 90° C. for 15 h. The reaction mixture was then cooled down and diluted with EtOAc and washed with 10% HCl. The organic phase was then washed again with brine. The combined organic extracts were dried over sodium sulfate and evaporated under reduced pressure to obtain a crude brown oil which was purified on ISCO column (330 g). The desired compound was eluted with 70% EtOAc-Hexanes. The desired fractions were combined and evaporated under reduced pressure to afford 2.5 g (55%) of 3-iodo-5-methanesulfonyl-phenol as an orange solid. HR-ES(+) m/e calcd for C7H7O3SI (M+H)+ 298.9234, found 298.9234.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][NH:16][CH2:15][CH2:14]2)=[O:10].Cl.[CH3:22][N:23]([CH3:30])[CH2:24][CH2:25][CH2:26][C:27](O)=[O:28].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[CH3:22][N:23]([CH3:30])[CH2:24][CH2:25][CH2:26][C:27]([N:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:9]([NH:8][O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[O:10])[CH:12]=2)[CH2:17]1)=[O:28]
Reactant: CN(C)CCCC(=O)O
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCNC2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CCCC(=O)N1CCc2cc(C(=O)NOC3CCCCO3)ccc2C1
Reaction time: 8 h

Procedure:
A mixture of 200 mg N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 67 mg 4-dimethylaminobutyric acid hydrochloride, 111 mg HOBt, 276 mg EDC, 0.603 ml triethylamine and 7 ml DMF is stirred overnight. The reaction mixture is quenched with 3 ml water and 5 ml dichloromethane. The organic phase is separated, the water phase extracted twice with dichloromethane. The combined organic phases are dried and evaporated. 280 ml of a yellow oil is obtained, which is further purified by preparative HPLC-methods.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][C@@H:10]([CH3:25])[C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[Br:26]Br.O>CO>[OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][C@@H:10]([CH3:25])[C@@H:11]2[C:12](=[O:14])[CH2:13][Br:26])[CH2:3]1
Reactant: CC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@@]21C
Reactant: BrBr
Solvent: CO
Solvent: O
Product: C[C@@H]1C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]2(C)[C@H]1C(=O)CBr

Procedure:
3α-Hydroxy-16α-methyl-5α-pregnane-11,20-dione (5 g.) was dissolved in dry methanol (350 ml.) and treated at 0° with a solution of bromine (1 ml.) in dry methanol (24 ml.) at such a rate that the yellow colour disappeared before further addition. After completion of the addition the mixture was poured into water. The precipitated product was dried and dissolved in chloroform (20 ml.) and put onto a column of silica gel MFC (700 g.). Elution with benzene:ethyl acetate (21/2:1) gave the title compound (3.6 g.) as a foam, [α]D + 112.4°.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH:9]=O)=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([N:16]1[C:2]2[N:3]=[CH:4][N:5]=[C:6]([Cl:11])[C:7]=2[CH:8]=[CH:9]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=CCc1c(Cl)ncnc1Cl
Reactant: CC(C)(C)N
Product: CC(C)(C)n1ccc2c(Cl)ncnc21

Procedure:
The title compound was prepared according to the method described for Preparation 1 using (4,6-dichloropyrimidin-5-yl)acetaldehyde and tert-butylamine to afford the title compound as a yellow liquid in 77% yield, 1.61 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.[N:16]1[NH:17][C:18]([NH2:21])=[CH:19][CH:20]=1>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([OH:12])[N:17]3[N:16]=[CH:20][CH:19]=[C:18]3[N:21]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Reactant: Nc1ccn[nH]1
Solvent: CCOC(C)=O
Product: Oc1cc(-c2ccc(Cl)cc2)nc2ccnn12
Temperature: 150 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
A mixture of ethyl 3-(4-chloro-phenyl)-3-oxo-propionate (5.8 g, 26.0 mmol) and 2H-pyrazol-3-ylamine (2.1 g, 26.0 mmol) was stirred at 150° C. for 2 h. EtOAc (22 mL) was successively added to the cooled mixture and stirring was continued at 0° C. for 0.5 h. The crystals were isolated by filtration to give 5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidin-7-ol (4.80 g, 75%) as a white solid. MS (ISP) 246.1 [(M+H)+]; mp 306–308° C.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:25]=[C:24]([C:23]([F:36])([F:37])[F:22])[CH:29]=[CH:28][CH:27]=3)[CH2:35][CH2:34]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)c(OC)nc1C
Yield: 67 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(α, α, α-trifluoro-m-tolyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH:1]1([SH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][S:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: SC1CCCCC1
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1cccc(CSC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of cyclohexylmercaptan (1.09 mL, 8.89 mmol), 3-bromobenzyl bromide (2.22 g, 8.882 mmol) and K2CO3 (2.54 g, 18.38 mmol) in acetone was stirred under argon at room temperature for 4 hrs then filtered. The filtrate was concentrated under reduced pressure. Purification by flash chromatography (0% to 20% EtOAc—hexanes gradient) gave (3-bromobenzyl)(cyclohexyl)sulfane as a colorless oil. Yield (2.02 g, 80%); 1H NMR (400 MHz, CDCl3) δ 7.48 (t, J=1.8 Hz, 1H), 7.33-7.37 (m, 1H), 7.22-7.26 (m, 1H), 7.16 (t, J=7.8 Hz, 1H), 3.68 (s, 2H), tt, J=3.33, 10.0 Hz, 1H), 1.87-1.96 (m, 2H), 1.69-1.77 (m, 2H), 1.53-1.61 (m, 1H), 1.18-1.38 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1OS(C(F)(F)F)(=O)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[CH:30])=[CH:25][CH:24]=1.C(N(CC)CC)C.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[C:30]#[C:29][C:26]1[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(OC)c1
Reactant: C#Cc1ccc(C)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C#Cc2ccc(C)cc2)c(OC)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
To a solution of ethyl 3-methoxy-4-trifluoromethanesulfonyloxybenzoate (3.95 g), 4-methylphenylacetylene (1.54 g) and triethylamine (5.0 ml) in DMF (40 ml) was added bistriphenylphosphine palladium dichloride (0.25 g), and the mixture was stirred at 100° C. for 3 hours and then cooled to room temperature. To the mixture was added water, and the mixture was extracted with diethylether. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified with column chromatography (ethyl acetate/hexane=1:9) and recrystallized from ethyl acetate/hexane to give pale yellow crystals of ethyl 3-methoxy-4-[2-(4-methylphenyl)ethynyl]-benzoate (2.02 g).