Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][OH:14])[CH:6]=[CH:5]2.C(N(CC)CC)C.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.ClCCl>[CH3:32][C:22]1[CH:27]=[CH:26][C:25]([S:28]([O:14][CH2:13][CH2:12][C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[N:8]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1ccc2cc(Br)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2ccc3cc(Br)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.6 %

Procedure:
A 500 mL round bottom flask was charged with the product from Example 42B (7.65 g, 0.030 mole), 4-N,N-dimethylaminopyridine (0.36 g, 0.003 mole), dichloromethane (100 mL) and triethylamine (9.3 g, 0.092 mmol). p-Toluenesulfonyl chloride (11.5 g, 0.060 mole) was added in portions, and the solution was stirred at rt for 6 hours. The solution was stripped down to dryness, and the crude product was taken into ethyl acetate (150 mL) and 5% NaHCO3 aq. solution (150 mL). The upper organic was washed with water (150 mL), concentrated, azeotroped with ethyl acetate (250 mL×2) to a volume of ˜50 mL. The slurry was diluted with heptane (50 mL), stirred at room temperature overnight, and then at 5° C. for 8 hours. The precipitate was collected by filtration, rinsed with heptane (20 mL), dried at 50° C. under vacuum overnight to afford 10.80 g of the product as an off-white solid; mp 107–109° C.; MS (ESI): 406, 408 (M+H)+; 1H-NMR (CDCl3) δ 7.92 (1H, m), 7.91 (1H, m), 7.7 (2H, m), 7.58 (2H, m), 7.25 (1H, d, J=8.4 Hz), 7.09 (2H, m), 4.56 (2H, t, J=6.3 Hz), 3.27 (2H, t, J=6.3 Hz), 2.33 (3H, s); 13C-NMR (CDCl3) δ 157.2, 145.9, 144.1, 135.0, 132.5, 132.3, 130.3, 129.2, 129.2, 127.7, 127.4, 122.5, 119.6, 69.2, 38.0, 21.8.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][O:14][C@H:13]([C@@H:17]([OH:30])[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][C:22]=3[Cl:29])=[O:19])[C:12]2=[O:31])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:32][OH:33]>CCO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][O:14][C@H:13]([C@@H:17]([OH:30])[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[N:32][OH:33])[NH2:28])=[CH:23][C:22]=3[Cl:29])=[O:19])[C:12]2=[O:31])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NO
Reactant: CC(C)(C)c1ccc(N2CCO[C@H]([C@@H](O)C(=O)Nc3ccc(C#N)cc3Cl)C2=O)cc1
Solvent: CCO
Product: CC(C)(C)c1ccc(N2CCO[C@H]([C@@H](O)C(=O)Nc3ccc(C(N)=NO)cc3Cl)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of compound 66-1 (60 mg) in EtOH (2 mL), was added 50% NH2OH aq. (22.4 microL). The reaction mixture was stirred at room temperature overnight. Then the mixture was concentrated in vacuo to obtain compound 66-2 (67 mg) as a colorless amorphous solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:8])[CH2:5][CH2:6][NH2:7].[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19])([O-:11])=[O:10]>C(Cl)Cl>[NH2:1][CH2:2][CH2:3][N:4]([CH3:8])[CH2:5][CH2:6][NH:7][S:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N+:9]([O-:11])=[O:10])(=[O:19])=[O:20]
Reactant: CN(CCN)CCN
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Product: CN(CCN)CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
To a solution of N1-(2-aminoethyl)-N1-methylethane-1,2-diamine (10.58 g, 90 mmoles) in DCM (350 mL) was added slowly a solution of 2-nitrobenzene-1-sulfonyl chloride dissolved in DCM (50 mL). After 2 h at RT, the reaction mixture (RM) was washed with water, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel with a gradient of methanol in DCM (0 to 10%), yielding to 6.9 g of N-(2-((2-aminoethyl)(methyl)-amino)ethyl)-2-nitrobenzenesulfonamide 6a and 3.9 g of N,N′-(2,2′-(methylazanediyl)-bis(ethane-2,1-diyl))bis(2-nitrobenzenesulfonamide) 6b; m/z (6a)=303 (M+H)+, m/z (6b)=488 (M+H)+.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]O)=C.[CH3:11][O:12][C:13](=[O:25])/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>O1CCCC1.C1(C)C=CC=CC=1.S(=O)(=O)(O)O.CO>[CH3:11][O:12][C:13](=[O:25])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][OH:3])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: C=COCCCCCCO
Reactant: COC(=O)/C=C/c1ccc(O)c(OC)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=S(=O)(O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1ccc(OCCCCCCO)c(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
3.92 ml (25.2 mmol) of 1,6-hexanediol vinyl ether were added to a solution of 5.0 g (24.0 mmol) of (E)-4-hydroxy-3-methoxycinnamic acid methyl ester and 6.61 g (25.2 mmol) of triphenylphosphine in 150 ml of tetrahydrofuran. The colourless solution was subsequently cooled to 0° C. and then 11.5 ml (25.3 mmol) of a 40% solution of azodicarboxylic acid diethyl ester in toluene were added dropwise thereto over a period of 30 minutes. The mixture was subsequently allowed to react first for 30 minutes at 0° C. and then for 22.5 hours at room temperature. 150 ml of methanol and 10 drops of concentrated sulfuric acid were then added to the reaction solution and the mixture was stirred for 1.5 hours. The reaction mixture was then extracted using ethyl acetate and water. The ethyl acetate was washed with a saturated sodium bicarbonate solution and repeatedly with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated by evaporation. The resulting residue was purified by column chromatography using silica gel (470 g) using toluene:ethyl acetate (1:1) as eluant. Recrystallisation from ethyl acetate:hexane (3:5) gave 6.13 g of 4-(6-hydroxyhexyloxy)-3-methoxycinnamic acid methyl ester.
Reaction SMILES: [NH3:1].C[O:3][C:4](=O)[C@H:5]([CH2:7][CH2:8][S:9][C:10]([F:13])([F:12])[F:11])[NH2:6]>CO>[F:11][C:10]([F:13])([F:12])[S:9][CH2:8][CH2:7][C@@H:5]([C:4]([NH2:1])=[O:3])[NH2:6]
Reactant: COC(=O)[C@@H](N)CCSC(F)(F)F
Reactant: N
Solvent: CO
Product: NC(=O)[C@@H](N)CCSC(F)(F)F
Temperature: -15 °C
Reaction time: 10 h
Yield: 89 %

Procedure:
5 ml of methanol was placed in an autoclave and cooled to −15° C., and ammonia gas was fed until methanol was saturated with the gas, to thereby prepare a solution of about 7 M ammonia in methanol. Trifluoromethionine methyl ester (50.4 mg, 0.199 mmol) was dissolved in methanol, and the solution was added to the solution of ammonia in methanol. The tube was sealed, and the mixture was stirred at 60° C. for 10 hours. The solvent was distilled off under reduced pressure, and recrystallization was performed with water, thereby 35.8 mg (89%) of trifluoromethionine amide(the general formula (II)) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C:7]2[S:8][C:9]3[N:10]=[C:11]([NH2:18])[N:12]=[C:13]([S:16][CH3:17])[C:14]=3[N:15]=2)=[CH:4][CH:3]=1.[OH-].[Na+].I[CH3:24].O>CS(C)=O>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH:6]([C:7]2[S:8][C:9]3[N:10]=[C:11]([NH2:18])[N:12]=[C:13]([S:16][CH3:17])[C:14]=3[N:15]=2)[CH3:24])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CSc1nc(N)nc2sc(Cc3ccc(F)cc3)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CSc1nc(N)nc2sc(C(C)c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.1 %

Procedure:
To a solution of 2-(4-fluorobenzyl)-7-(methylthio)thiazolo[5,4-d]pyrimidin-5-amine (0.4 g, 1.31 mmol) and 2N NaOH (0.65 ml, 1.31 mmol) in DMSO (7 ml) was added iodomethane (81 μl, 1.31 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into water and extracted with ethyl acetate, brine and dried over Na2SO4. After removing the solvents under reduced pressure, the residue was purified by chromatography on silica gel (hexane/EtOAc 5:1) yielding the title compound as a white solid (0.29 g, 69%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C:13]([N:15]1[C@@H:20]([CH:21]([OH:36])[CH:22]([NH2:35])[CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH2:31][CH2:32][CH3:33])[CH:27]=[C:26]([F:34])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:37][CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C@@H:16]1[CH3:43])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:36])[C@@H:22]([NH:35][C:1](=[O:3])[CH3:2])[CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH2:31][CH2:32][CH3:33])[CH:27]=[C:26]([F:34])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:37][CH2:38][C:39]([CH3:41])([CH3:40])[CH3:42])[C@@H:16]1[CH3:43])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CCCOc1cc(F)cc(CC(N)C(O)[C@H]2CO[C@@H](OCC(C)(C)C)[C@H](C)N2C(=O)OC(C)(C)C)c1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCOc1cc(F)cc(C[C@H](NC(C)=O)[C@H](O)[C@H]2CO[C@@H](OCC(C)(C)C)[C@H](C)N2C(=O)OC(C)(C)C)c1
Reaction time: 1 h
Yield: 47.8 %

Procedure:
Add acetic anhydride (0.07 g, 0.70 mmol) to (2R,3S,5R)-5-[2-Amino-3-(3-fluoro-5-propoxy-phenyl)-1-hydroxy-propyl]-2-(2,2-dimethyl-propoxy)-3-methyl-morpholine-4-carboxylic acid tert-butyl ester (0.34 g, 0.66 mmol) and triethylamine (0.10 g, 0.99 mmol) in tetrahydrofuran (6 mL) at room temperature and stir 1 hour. Dilute with ethyl acetate and wash with saturated aqueous ammonium chloride and saturated aqueous sodium chloride. Dry over magnesium sulfate, filter and concentrate. Purify on 12 g silica gel eluting with 100:0 to 20:80 hexanes:ethyl acetate to give 0.175 g of the desired compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH2:13])=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([NH:13][C:22](=[O:23])[O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cc(N)n(-c2ccc(Cl)cc2)n1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cc(NC(=O)Oc2ccccc2)n(-c2ccc(Cl)cc2)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 26.1 %

Procedure:
1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-amine (100 mg, 0.48 mmol) was dissolved in dry THF (6 mL). Pyridine (51 μL, 0.62 mmol) was added and the solution was cooled in an ice bath under nitrogen surpressure. Phenyl chloroformate (73 μL, 0.58 mmol) was slowly added and the mixture was stirred at 0° C. during 5 min and at room temperature during 1.5 h. The mixture was then diluted in EtOAc (10 mL) and the salts remaining were filtrated off. The filtrate was concentrated under reduced pressure. The resulting white solid was washed with a little amount of cold EtOAc and water to afford the title compound (41 mg, 26%) as a white solid. 1H-NMR (δ, ppm, DMSO-d6): 2.22 (s, 3H, CH3), 6.28 (s, 1H, HPyz,4), 7.11-7.60 (m, 9H, Harom), 10.14 (bs, 1H, NH). LC-MS (m/z): 328 (M+H, 100).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].[CH3:12][O:13][CH2:14][CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:15][CH2:14][O:13][CH3:12])=[CH:7][N:6]=1)=[O:4]
Reactant: COCCO
Reactant: COC(=O)c1ccc(O)cn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOc1ccc(C(=O)OC)nc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a precooled solution of 5-hydroxy-pyridine-2-carboxylic acid methyl ester (CAS registry 30766-12-2) (150 mg, 0.980 mmol) and 2-methoxyethanol (82 mg, 0.085 ml, 1.077 mmol) in THF (10 ml) was added at 0° C. triphenylphosphine (397 mg, 1.469 mmol) and the reaction mixture was stirred for 10 min at 0° C. A solution of DIAD (316 mg, 1.469 mmol) in THF (5 ml) was added and the mixture was stirred at room temperature for 19.5 h. After dilution with EtOAc, the crude mixture was extracted with water and brine, the aqueous layers were reextracted with EtOAc, the combined organic extracts dried over Na2SO4, filtered and the filtrate concentrated to yield the title compound after flash chromatography on silica gel (DCM/EtOAc gradient 0-3 min 60:40; 3-35 min 60:40 to 25:75).
Reaction SMILES: [I:1]C.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:15]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=2)[OH:16])[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12].[CH3:24]C(C)=O>C1C=CC=CC=1>[I-:1].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:15]([CH:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]2[CH3:24])[OH:16])[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: CC(C)=O
Reactant: COc1cc(C(O)c2cc(C)ccn2)cc(OC)c1OC
Reactant: CI
Solvent: c1ccccc1
Product: COc1cc(C(O)C2C=C(C)C=CN2C)cc(OC)c1OC
Product: [I-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
10 ml. of ICH3 are slowly added to a solution of 10 g. of 3,4,5-trimethoxyphenyl-(4-methyl-2-pyridyl) carbinol in 125 ml. of anhydrous acetone and 15 ml. of anhydrous benzene. The resulting mixture is agitated for 1 hour at room temperature, then refluxed for 2 hours, then left to cool, 13.04 g being obtained, with an 87% yield, of a crystalline precipitate identifiable as 3,4,5-trimethoxyphenyl-(1,4-dimethyl-2-pyridinyl)-carbinol iodide. A sample recrystallized from ethanol has a melting point of 162°-163.5° C.
Reaction SMILES: O1C2(CCC(C3C4C(=CC=CC=4)NC=3)CC2)OCC1.[O:20]1[C:24]2([CH2:29][CH2:28][C:27]([C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[C:36]([O:39][CH3:40])[CH:37]=4)[NH:32][CH:31]=3)=[CH:26][CH2:25]2)[O:23][CH2:22][CH2:21]1>>[O:23]1[C:24]2([CH2:25][CH2:26][CH:27]([C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[C:36]([O:39][CH3:40])[CH:37]=4)[NH:32][CH:31]=3)[CH2:28][CH2:29]2)[O:20][CH2:21][CH2:22]1
Reactant: COc1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Agent: c1ccc2c(C3CCC4(CC3)OCCO4)c[nH]c2c1
Product: COc1ccc2[nH]cc(C3CCC4(CC3)OCCO4)c2c1
Yield: 96 %

Procedure:
This compound was prepared in the manner described above for intermediate 2a by replacing 3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-1H-indole with 3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-5-methoxy-1H-indole to afford 7.18 g (96%) of the title compound as a white solid: mp 153-155° C.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[O:11]1[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12]1.[Na]>CN(C=O)C.O.C(O)(=O)C>[C:2]1([CH2:1][O:8][CH2:12][CH:13]([OH:11])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: CCCCCCCCC1CO1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCCCCCCCC(O)COCc1ccccc1
Temperature: 80 °C

Procedure:
Benzyl alcohol (108 g, 1.0 mol) is added to a suspension of 50% sodium hydride-mineral oil (48 g, 1.0 mol) in DMF (200 ml) at room temperature. The mixture is then heated to 80° C. for two hours. A solution of 1,2-epoxydecane* (85 ml) in DMF (50 ml) is added slowly to the sodium salt over 30 minutes and the mixture is then heated at 80° C. for 20 hours. The reaction mixture is cooled, diluted with water, neutralized with acetic acid, and extracted with ether. The ether extract is concentrated to give an oil which is distilled to give the desired product (131 g), bp 178°-180° C./4 mm.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.O[CH2:13][CH2:14][O:15][C:16]1[CH:20]=[CH:19][S:18][CH:17]=1.N1C=CC=C[CH:22]=1>>[C:3]1([CH3:22])[C:4]([S:7]([CH2:13][CH2:14][O:15][C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)(=[O:8])=[O:9])=[CH:5][CH:6]=[CH:1][CH:2]=1
Reactant: c1ccncc1
Reactant: OCCOc1ccsc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccccc1S(=O)(=O)CCOc1ccsc1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
Solid p-toluenesulphonyl chloride (0.88 g, 4.6 mmol) was added in small amounts to a cooled (-5° C.) solution of 3-(hydroxyethoxy)thiophene (0.6 g, 4.2 mmol) in dry pyridine (50 ml). The mixture was stirred for 10 minutes and then maintained at -20° C. for 48 hours. The mixture was then stirred with crushed ice for 5 hours. After filtration, the solid was recrystallised twice from hot hexane to give 3-(toluenesulphonylethoxy)thiophene as a white crystalline product, (1.0 g, 83%) M.p. 76°-77° C.; (Found: C, 52.1; H, 4.5; N, 21.8. Calculated for C13H14S2O4C, 52.3; H, 4.7; N, 21.5%); EI m/e Intensity (%): 298 (0.5 M+), 199 (57, Tosyl-OCH2CH2); δH(CDCl3) 7.3-7.7 (4H, m), 7.0 (1H, m), 6.5 (1H, m), 6.0 (1H, m), 4.2 (2H, t), 4.0 (2H, t), 2.4 (3H, s); δC(CDCl3): 21.7, 67.5, 68.0, 98.1, 119.3, 125.0, 128.0, 129.9 ppm.
Reaction SMILES: CN1CCCCC1.[CH:8]([O:11][C:12]([NH:14][C@H:15]([C:20]([OH:22])=O)[C@H:16]([CH2:18][CH3:19])[CH3:17])=[O:13])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[C:31]([C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40](=[O:44])[C@@H:41]([CH3:43])[NH2:42])=[CH:35][CH:34]=1)#[N:32]>C(Cl)Cl.O>[CH:8]([O:11][C:12]([NH:14][C@H:15]([C:20]([NH:42][C@@H:41]([C:40]([NH:39][C:36]1[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=1)=[O:44])[CH3:43])=[O:22])[C@H:16]([CH2:18][CH3:19])[CH3:17])=[O:13])([CH3:9])[CH3:10]
Reactant: C[C@@H](N)C(=O)Nc1ccc(C#N)cc1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCCCC1
Solvent: ClCCl
Solvent: O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)C)C(=O)N[C@H](C)C(=O)Nc1ccc(C#N)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
0.26 g of N-methylpiperidine was added to a solution containing 0.57 g of N-isopropoxycarbonyl-L-isoleucine dissolved in 60 ml of methylene chloride, at -20° C. After the mixture was stirred for 10 minutes at the same temperature, 0.36 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20° C. 0.5 g of N1 -(4-cyanophenyl)-D-alaninamide was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous sodium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.5 g of the desired product in the form of white powder (yield: 49%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].Cl.O.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>CO>[NH:14]1[CH2:15][CH:16]=[C:17]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:18][CH2:19]1
Reactant: O=C1CCNCC1
Reactant: c1ccc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C1=C(c2c[nH]c3ccccc23)CCNC1
Temperature: 25 °C

Procedure:
Indole (30 g, 0.26 mol) was dissolved in a solution of potassium hydroxide (77.6 g, 1.38 mol) in methanol (692 ml). 4-piperidone monohydrate hydrochloride (102.3 g, 0.66 mol) was added in one portion and the mixture was heated to reflux for 5 h. Potassium chloride precipitated upon cooling at room temperature and the salt was filtered. The liquid phase was concentrated until only one third of the liquid remained in the round-bottom flask. The solid formed during the concentration of the liquid phase was filtered and washed thoroughly with ethanol and, finally, with ethyl ether. 31.9 g (63% of yield) of the final product was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH2:14][CH:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=1)[C:16]([N:18]1[CH2:22][CH2:21][S:20][CH2:19]1)=[O:17]>>[C:30]([C:26]1[CH:25]=[C:24]([CH2:23][CH:15]([NH:14][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[O:13])[C:16]([N:18]2[CH2:22][CH2:21][S:20][CH2:19]2)=[O:17])[CH:29]=[CH:28][CH:27]=1)#[N:31]
Reactant: N#Cc1cccc(CC(N)C(=O)N2CCSC2)c1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Product: N#Cc1cccc(CC(NC(=O)c2cc3cc(Cl)ccc3[nH]2)C(=O)N2CCSC2)c1

Procedure:
From 5-chloro-1H-indole-2-carboxylic acid and (+)-2-amino-3-(3-cyano-phenyl)-1-thiazolidin-3-yl-propan-1-one. mp 183-184° C.
Reaction SMILES: C([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][P:6]([O:11]CC)(OCC)=O)C.BrC[CH:19](O)[CH2:20]O.[C:23]1(C)C=CC=C[CH:24]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:23]([P:6]([CH2:5][CH:4]1[O:3][CH2:16][CH2:15][O:14]1)([CH2:19][CH3:20])=[O:11])[CH3:24]
Reactant: OCC(O)CBr
Reactant: Cc1ccccc1
Reactant: CCOC(CP(=O)(OCC)OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCP(=O)(CC)CC1OCCO1

Procedure:
Diethylphosphonoacetaldehyde diethylacetal (VIIa) was condensed with 3-bromo-1,2-propanediol (Va) in the presence of p-toluenesulfonic acid as a catalyst and reflux in toluene to yield 2-diethylphosphinoylmethyl-1,3-dioxolane of formula (IId) as a mixture of cis and trans isomers;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:15]3[CH:24]=[C:23]4[C:18]([CH2:19][CH2:20][N:21]([C:25](=[S:27])[NH2:26])[CH2:22]4)=[CH:17][CH:16]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Cl.[CH2:29](O)C.CI>CO>[CH3:29][S:27][C:25]([N:21]1[CH2:20][CH2:19][C:18]2[C:23](=[CH:24][C:15]([O:14][CH2:13][CH:10]3[CH2:9][CH2:8][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:12][CH2:11]3)=[CH:16][CH:17]=2)[CH2:22]1)=[NH:26]
Reactant: NC(=S)N1CCc2ccc(OCC3CCN(c4ccncc4)CC3)cc2C1
Reactant: CCO
Agent: Cl
Solvent: CO
Solvent: CI
Product: CSC(=N)N1CCc2ccc(OCC3CCN(c4ccncc4)CC3)cc2C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
7-[1-(Pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carbothioamide (200 mg) was treated with hydrogen chloride—ethanol solution. To a suspension of the obtained residue in methanol (6 ml) was added methyl iodide (0.1 ml), and the mixture was stirred at 60° C. for 2 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was dissolved in water and ethanol and neutralized with ion-exchange resin (IRA-410). This was filtrated and the filtrate was concentrated and dried under reduced pressure to give the title compound (200 mg).