Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.Cl>[OH-].[Na+].O1CCOCC1.C(OCC)(=O)C>[CH3:31][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:17][CH:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[C:18]([OH:20])=[O:19])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)NC(CCCCNC(=O)OCc2ccccc2)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81024.5 %

Procedure:
Nε-Carbobenzyloxy-L-lysine (30.0g, 0.107 mmol) was dissolved in a solution of 2N NaOH (60 mL) and dioxane (150 mL) under nitrogen. After about 15 minutes at room temperature, the mixture was cooled to about 0° C. and subsequently treated with additional 2N NaOH (60 mL) and p-toluenesulfonyl chloride (20.4g, 0.107 mmol) in 5g portions over about 15 minutes. The mixture was stirred at about 0° C. for about 1 hour and at room temperature for about 18 hours before it was neutralized to pH 6 with 1N HCl. The mixture was then diluted with ethyl acetate and the organic phase was separated and washed with brine. The aqueous phase was extracted twice more with ethyl acetate and the combined organic phases were treated further as mentioned above. Following drying and solvent evaporation of the combined organic phases, the residue was first pre-columned on silica gel (elution with 10% methanol in dichloromethane) and subsequently recrystallized from ethyl acetate/hexanes (2:1 ) to give 37.67g (81%) of the title compound as a white solid, m.p. 120°-121° C.; 1H NMR (CDCl3) δ 8.37 (v br s, 0.5H), 7.71 (d, J=8.0 Hz, 2H), 7.32 (s, 5H), 7.23 (d, J=7.6 Hz, 2H), 6.49 and 4.89 (2m, 1H), 5.73 (d, J=8.4 Hz, 1H) , 5.10 and 5.04 (2s, 2H) , 3.91 (m, 1H) , 3.17-3.02 (m, 2H), 2.35 (s, 3H), 1.73-1.66 (m, 2H), 1.40-1.24 (m, 4H); 13C NMR (CDCl3) ppm 199.88, 175.06, 174.57, 158.37, 156.89, 143.66, 136.86, 136.32, 129.66, 128.54, 128.10, 127.19, 67.47, 66.89, 55.28, 40.95, 40.44, 32.25, 29.10, 28.75, 21.77, 21.46; IR (KBr, cm-1) 3382, 3264, 2950, 1738, 1656, 1550, 1334, 1286, 1160, 1092, 818, 678, 568; MS m/z (MH+) 435.1590, obsd 435.1595.
Reaction SMILES: O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[CH2:15]([N:17]([CH2:56][CH3:57])[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26][C:27]1[C@H:28]([CH3:55])[C@@H:29]2[C@@H:46]([C@H:47]([O:49][Si](C)(C)C)[CH3:48])[C:45](=[O:54])[N:30]2[C:31]=1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33])=[O:19])[CH3:16].CO>C(Cl)Cl>[CH2:56]([N:17]([CH2:15][CH3:16])[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26][C:27]1[C@H:28]([CH3:55])[C@@H:29]2[C@@H:46]([C@H:47]([OH:49])[CH3:48])[C:45](=[O:54])[N:30]2[C:31]=1[C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=1)=[O:33])=[O:19])[CH3:57]
Reactant: CCN(CC)C(=O)c1ccccc1SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C)[C@H]2[C@H]1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CCN(CC)C(=O)c1ccccc1SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 102.5 %

Procedure:
41 mg (0.195 mmol) of citric acid hydrate were added to 30 ml of a solution of 1.072 g (1.71 mmol) of 4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylthio)-1-methyl-6-[1(R)-trimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 34) in a 2:1 by volume mixture of methanol and methylene chloride, and the mixture was stirred for 20 minutes at room temperature. At the end of this time, the reaction solution was condensed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 25 g of silica gel. Elution with ethyl acetate afforded 970 mg (quantitative yield) of the title compound as a colorless foam-like solid.
Reaction SMILES: C[C:2]([CH3:4])=[O:3].C1(C)C=CC=CC=1.[C:12]([O:15][CH:16]=[CH2:17])(=[O:14])[CH3:13].[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH:20]=[CH:19]1>C(O)C>[C:12]([O:15][CH:16]=[CH2:17])(=[O:14])[CH3:13].[C:18]([O:3][CH2:2][CH3:4])(=[O:24])/[CH:19]=[CH:20]\[C:21]([O-:23])=[O:22]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)=O
Solvent: Cc1ccccc1
Solvent: C=COC(C)=O
Solvent: CCO
Product: CCOC(=O)/C=C\C(=O)[O-]

Procedure:
Part A above was repeated except that 535 ml of acetone were introduced into the kettle in place of 480 ml of toluene and the vinyl acetate/maleic anhydride polymerization was carried out at 53° C. instead of 63-65° C. Esterification of the VA/MA was achieved with 262 g of absolute ethanol by conducting the reaction at 70-75° C. for about 3 hours. The acetone was distilled off and the vinyl acetate/ethyl maleate (VA/EM) alternating copolymer was recovered as a solution of 44.18% copolymer solids in ethanol having a relative viscosity of 1.26, a specific viscosity of 0.26 and a K value of 31.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)=[N:5][CH:4]=1
Reactant: COc1cnc(-c2ccc(O)cc2)nc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 64.7 %

Procedure:
A mixture of 9.0 g of 5-methoxy-2-(4-hydroxyphenyl)pyrimidine, 8.45 g of benzyl chloride, 270 ml of dimethylformamide (DMF), and 12.3 g of potassium carbonate was stirred at 80° C. for 4 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and distilled to remove ethyl acetate to obtain 8.42 g (percent yield: 64.2%) of 5-methoxy-2-(4-benzyloxyphenyl)pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[OH:11])[C:7](=[O:12])[CH2:6][CH2:5]2.[C:13](=O)([O-])[O-].[K+].[K+].IC.CC(C)=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:13])[C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)c(O)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc2c(cc1Br)CCC2=O
Yield: 72 %

Procedure:
A round bottom flask, fitted with a stir bar and condenser was charged with 5-bromo-6-hydroxy-1-indanone (0.50 g, 2.20 mmol), potassium carbonate (0.456 g, 3.30 mmol), iodomethane (0.341 g, 2.40 mmol), and acetone (10 mL). After heating at reflux for 24 hours the mixture was diluted with ethyl acetate, washed with water (3×10 mL), brine (1×10 mL) and dried with MgSO4. The mixture was filtered and concentrated to give 0.382 g (72%) of 5-bromo-6-methoxyindan-1-one as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1 H), 7.22 (s, 1 H), 3.95 (s, 3 H), 3.10 (m, 2 H), 2.73 (m, 2 H). MS (ESI+) for C10H9BrO2 m/z 239.9787 (M+H)+. Anal. Calcd. For C10H9BrO2: C, 49.82; H, 3.76. Found: C, 49.69; H, 3.72.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[CH:7]=[C:8]([C:15](=[O:22])[NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[NH:9]2.[CH3:24][I:25]>CN(C)C=O>[I-:25].[Cl:3][C:4]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[CH:7]=[C:8]([C:15](=[O:22])[NH:16][CH2:17][CH2:18][N+:19]([CH3:24])([CH3:20])[CH3:21])[NH:9]2
Reactant: CN(C)CCNC(=O)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1
Reactant: CI
Agent: Cl
Solvent: CN(C)C=O
Product: C[N+](C)(C)CCNC(=O)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1
Product: [I-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 5,7-dichloro-2-(2-dimethylaminoethyl)carbamoyl-4-oxo-1,4-dihydroquinoline (0.5 g, Example 39) in dry dimethylformamide was added methyl iodide and the mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure to yield the crude product, which was recrystallised from ethanol-water to give 5,7-dichloro-2-(2-trimethylammonioethyl)carbamoyl-4-oxo-1,4-dihydroquinoline iodide (0.39 g), m.p.>280° C. δ (360 MHz, D2O) 3.26 (9H, s, (CH3)3), 3.62 (2H, t, CH2N), 3.94 (2H, t, CONHCH2), 6.78 (1H, s, 3-H), 7.50 (1H, d, 6-H) and 7.76 (1H, d, 8-H), (Found: C, 37.06; H, 3.91; N, 8.65; I, 26.14%. C15H18Cl2IN3O2 requires C, 36.98; H, 3.91; N, 8.62; I, 26.02%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)[CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH:23](Cl)[CH3:24]>NC1C2C(=CC=CC=2)CC1.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=3)[O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:7][CH:6]3[C:23]4[C:24](=[CH:3][CH:2]=[CH:21][CH:20]=4)[CH2:4][CH2:5]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(Cl)Cl
Reactant: Fc1ccc2c(-c3cccc(OC[C@H]4CO4)c3)noc2c1
Agent: NC1CCc2ccccc21
Solvent: CCO
Product: O[C@H](CNC1CCc2ccccc21)COc1cccc(-c2noc3cc(F)ccc23)c1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(3-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dichloroethane, 1-aminoindan and ethanol, essentially as described above in Example 57. Purity by LC/MS=91%, [M+H]+=419.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[C:7](C(OCC)=O)=[C:6]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:5]=2[CH2:25][O:26][CH3:27])[CH2:3][CH2:2]1.[OH2:28].[C:29]1(C)C=CC=CC=1>O1CCCC1>[CH:1]1([C:4]2[N:9]([CH3:29])[CH:8]([CH:10]([CH3:12])[CH3:11])[C:7]([OH:28])=[C:6]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:5]=2[CH2:25][O:26][CH3:27])[CH2:3][CH2:2]1
Reactant: O
Reactant: Cc1ccccc1
Reactant: CCOC(=O)c1c(C(C)C)nc(C2CC2)c(COC)c1-c1ccc(F)cc1
Solvent: C1CCOC1
Product: COCC1=C(C2CC2)N(C)C(C(C)C)C(O)=C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
44.3 ml (15 mmol) of a 3.5 molar solution of sodium bis-(2-methoxyethoxy)-dihydroaluminate in toluene are added under nitrogen to a solution of 1.9 g (5 mmol) of the compound from Example 83 in 50 ml of dry tetrahydrofuran and the mixture is stirred for 2 hours at room temperature and 1 hour under reflux. After cooling to 0° C., 50 ml of water are cautiously added dropwise and the mixture is extracted several times with ethyl acetate. The ethyl acetate phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13](O)=[CH:12][CH:11]=1.[CH:18]1(Br)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C)C=O>[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C2CCCCC2)cc1
Temperature: 100 °C
Yield: 11.7 %

Procedure:
Potassium carbonate (2.26 g, 16.4 mmol) was added to a solution of methyl-4-hydroxybenzoate (1.0 g, 6.6 mmol) and cyclohexyl bromide (1.62 ml, 13.1 mmol) in dimethylformamide (20 ml). The mixture was heated at 100° C. for 24 hours, cooled, filtered and concentrated in vacuo. Work up followed by flash chromatography over silica gel (hexane:ethyl acetate, 5:1) afforded methyl-4-cyclohexylbenzoate (169 mg). This was dissolved (162 mg, 0.69 mmol) in a mixture of 1,4-dioxane (10 ml) and water (5 ml) and lithium hydroxide monohydrate (32 mg, 0.76 mmol) added. The mixture was stirred at room temperature for 18 hours. A further quantity of lithium hydroxide was added (32 mg) and stirring continued for 4 hours. The mixture was added to ethyl acetate, washed with brine and concentrated to yield the title compound as a yellow solid (27 mg ).
Reaction SMILES: [Br-].[OH:2][CH2:3][CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC.C([Li])CCC.[S:36]1[CH:40]=[CH:39][C:38]([CH:41]=O)=[CH:37]1>O1CCCC1>[S:36]1[CH:40]=[CH:39][C:38](/[CH:41]=[CH:5]/[CH2:4][CH2:3][OH:2])=[CH:37]1
Reactant: O=Cc1ccsc1
Reactant: OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OCC/C=C/c1ccsc1
Reaction time: 0.5 h
Yield: 7.5 %

Procedure:
1.0 g of (3-hydroxypropyl)triphenylphosphonium bromide was dissolved in 20 ml of tetrahydrofuran, and under ice cooling, 3.4 ml of a 15% n-butyllithiumhexane solution was added. After the mixture was stirred for 30 minutes, 270 mg of 3-thiophenecarboxaldhyde was added. The mixture was stirred for 30 minutes, and then the solvent was evaporated. The residue was worked up in a customary manner, and purified by silica gel column chromatography [benzene/ethyl acetate=6/1] to give 28 mg (yield 7%) of the captioned compound as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]([OH:9])[C:6]2[CH:10]=[C:11]([CH3:13])[S:12][C:5]=2[CH2:4]1)[CH3:2].[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1F>>[ClH:14].[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[O:9][CH:7]1[CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][C:5]2[S:12][C:11]([CH3:13])=[CH:10][C:6]1=2
Reactant: Fc1cccc(Cl)c1Cl
Reactant: CCN1Cc2sc(C)cc2C(O)C1
Product: CCN1Cc2sc(C)cc2C(Oc2cccc(Cl)c2Cl)C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 6-ethyl-2-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 10) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,3-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([O:13][C:14](=O)[CH3:15])(=[O:12])[CH3:11].[CH3:17][O:18][C:19]([C:21]1[CH:22]=[N+:23]([O-])C(C)=[CH:25][CH:26]=1)=[O:20].C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:17][O:18][C:19]([C:21]1[CH:22]=[N:23][C:15]([CH2:14][O:13][C:10](=[O:12])[CH3:11])=[CH:25][CH:26]=1)=[O:20]
Reactant: COC(=O)c1ccc(C)[n+]([O-])c1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: COC(=O)c1ccc(COC(C)=O)nc1
Temperature: 120 °C
Reaction time: 2.25 h
Yield: 48 %

Procedure:
N,N-Diisopropylethylamine (2.2 mL, 13 mmol) and acetic anhydride (3.5 mL, 38 mmol) were added to a solution of 6-methylpyridine-3-carboxylic acid methyl ester N-oxide (Reference Compound No. 8-1, 2.1 g, 13 mmol) in acetic acid (14 mL), and then the reaction mixture was stirred at 120° C. for 135 minutes. After cooling, saturated aqueous sodium hydrogen carbonate solution (100 mL) was added thereto, and then sodium hydrogen carbonate was added until foam formation was ended. The whole was extracted with ethyl acetate (100 mL, 50 mL), the organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), and then the resulting solid was collected by filtration with hexane and ethyl acetate to give 1.2 g of the title reference compound as a pale yellow solid. (Yield 48%)
Reaction SMILES: FC(F)(F)C([O-])=O.[NH2:8][C:9]1[CH:17]=[CH:16][C:12]2[N:13]=[CH:14][NH:15][C:11]=2[CH:10]=1.[CH3:18][O:19][C:20]1[C:25]2[O:26][CH2:27][O:28][C:24]=2[CH:23]=[C:22]([CH:29]=O)[CH:21]=1.[Si](C#N)(C)(C)C.[N:37]1([C:42](N2C=CN=C2)=[O:43])C=CN=[CH:38]1>>[NH:13]1[C:12]2[CH:16]=[CH:17][C:9]([N:8]3[CH:29]([C:22]4[CH:21]=[C:20]([O:19][CH3:18])[C:25]5[O:26][CH2:27][O:28][C:24]=5[CH:23]=4)[CH2:38][NH:37][C:42]3=[O:43])=[CH:10][C:11]=2[N:15]=[CH:14]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(C=O)cc2c1OCO2
Reactant: Nc1ccc2nc[nH]c2c1
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])C(F)(F)F
Product: COc1cc(C2CNC(=O)N2c2ccc3[nH]cnc3c2)cc2c1OCO2

Procedure:
The compound was synthesized as trifluoroacetate salt starting from 5-aminobenzimidazole (0.585 g, 4.4 mmol), 7-methoxybenzo[d][1,3]dioxole-5-carbaldehyde (0.721 g, 4 mmol), TMSCN (0.5 mL, 4 mmol), PdC (10%, 0.02 g), TEA (0.521 mL, 3.74 mmol), di-(imidazol-1-yl)methanone (0.331 g, 2.04 mmol) as described in method 2. The product was purified by means of preparative HPLC.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[H-].[Na+].[N:7]1([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([O:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][NH:25][C:26](=[O:29])[CH2:27]Cl)[CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>O1CCCC1>[N:7]1([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([O:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][NH:25][C:26](=[O:29])[CH2:27][S:3][C:1](=[O:4])[CH3:2])[CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(CCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: CC(O)=S
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)SCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A solution of 0.47 ml of thioacetic acid in 20 ml of tetrahydrofuran was added dropwise, whilst ice-cooling and in an atmosphere of nitrogen, to a suspension of 0.29 g of sodium hydride (as a 55% w/w dispersion in mineral oil) in 20 ml of tetrahydrofuran, and the resulting mixture was stirred at room temperature for 30 minutes. At the end of this time, a solution of 2.00 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-chloroacetamide [prepared as described in step (a) above] in 20 ml of tetrahydrofuran was added dropwise to the mixture, whilst ice-cooling, after which it was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated by evaporation under reduced pressure, the residue was mixed with water, and the resulting aqueous mixture was extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 1:19 by volume mixture of methanol and ethyl acetate as the eluent, to give 1.72 g (yield 77%) of the title compound as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6]([C:8]([O:10]C)=[O:9])=[CH:5][CH2:4][CH2:3]1.[ClH:12].Cl>C(O)C>[CH3:1][NH+:2]1[CH2:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH2:4][CH2:3]1.[Cl-:12]
Reactant: COC(=O)C1=CCCN(C)C1
Reactant: Cl
Solvent: CCO
Product: C[NH+]1CCC=C(C(=O)O)C1
Product: [Cl-]
Temperature: 100 °C
Yield: 45.5 %

Procedure:
In a 250 ml flask equipped with a magnetic stirrer and a condenser, arecoline hydrochloride (4 g; 20.9 mmol) is added to a solution of 50 ml of 95% ethanol and 60 ml of concentrated HCl. The mixture is heated at 100° C. for 12 hours then at reflux for 6 hours. The solvents are evaporated off under reduced pressure leaving a solid residue. The residue is recrystallized from a 95% ethanol/ether mixture in order to produce 1.69 g of product (Yield=46%) in the form of white crystals.
Reaction SMILES: [CH:1]([C:17]1[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:18]=1[OH:19])([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:2].S(Cl)([Cl:28])(=O)=O>C(Cl)Cl>[Cl:28][C:21]1[CH:20]=[C:18]([OH:19])[C:17]([CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:2])=[CH:23][C:22]=1[OH:24]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCCCCCCCCCCCC(C)c1cc(O)ccc1O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCC(C)c1cc(O)c(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
33.5 g (0.1 mol)of 2-sec-hexadecylhydroquinone was dissolved in 300 ml of methylene chloride and to a resulting solution was added dropwise 8.1 ml (0.1 mol) of sulfuryl chloride with stirring at room temperature over a period of 30 minutes. After stirring for 6 hours at room temperature, the reaction mixture was allowed to stand overnight and extracted with ethyl acetate. The extract was washed three times with a 5% aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography (solvent: chloroform) to obtain 27 g of the desired 2-chloro-5-sec-hexadecylhydroquinone as the light from oily product. The structure thereof was confirmed by NMR and mass spectra.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[S:13][C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:16]=2)[CH:7]=[CH:8][CH:9]=1.[C:31](Cl)(=[O:33])[CH3:32].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[C:31]([N:28]1[CH2:29][CH2:30][CH:25]([C:12]2[S:13][C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:16]=3)=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=3)[N:11]=2)[CH2:26][CH2:27]1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: CC(=O)Nc1cc(-c2sc(C3CCNCC3)nc2-c2cccc(Cl)c2)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(-c2sc(C3CCN(C(C)=O)CC3)nc2-c2cccc(Cl)c2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a suspension of N-[4-[4-(3-chlorophenyl)-2-(4-piperidyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide dihydrochloride (0.41 g, 0.84 mmol) in tetrahydrofuran (20 mL) were added acetyl chloride (0.13 mL, 1.8 mmol) and triethylamine (0.50 mL, 3.6 mmol) sequentially, and the resulting mixture was stirred at room temperature for 30 minutes. Aqueous sodium hydrogen carbonate was added to the reaction mixture and extracted with ethyl acetate. The extracts were washed with water, dried, and concentrated. The residue was recrystallized from ethyl acetate-hexane to give a title compound (0.24 g, yield 62%).
Reaction SMILES: C([O:3][CH3:4])#N.N1[C:13]2[C:8](=[CH:9]C=CC=2)[CH2:7]C1.[C:14]([N:17]1[C:25]2[C:20](=[C:21]([CH3:31])[C:22](Br)=[C:23]([CH3:29])[C:24]=2[N+:26]([O-])=O)[CH:19]([CH2:32][CH2:33][O:34][C:35](=[O:37])[CH3:36])[CH2:18]1)(=[O:16])[CH3:15]>C1C=CC=CC=1.[Pd]>[C:14]([N:17]1[C:25]2[C:20](=[C:21]([CH3:31])[CH:22]=[C:23]([CH3:29])[C:24]=2[NH:26][C:4](=[O:3])[C:8]([CH3:13])([CH3:9])[CH3:7])[CH:19]([CH2:32][CH2:33][O:34][C:35](=[O:37])[CH3:36])[CH2:18]1)(=[O:16])[CH3:15]
Reactant: COC#N
Reactant: c1ccc2c(c1)CCN2
Reactant: CC(=O)OCCC1CN(C(C)=O)c2c1c(C)c(Br)c(C)c2[N+](=O)[O-]
Agent: [Pd]
Solvent: c1ccccc1
Product: CC(=O)OCCC1CN(C(C)=O)c2c(NC(=O)C(C)(C)C)c(C)cc(C)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.60·2.20 (2H, m, —CH2 CH2O—), 1.99 (3H, S, -OCOCH3), 2.21 (3H, s, >NCOCH3), 2.38 (6H, s, —CH3×2), 3.40 (1H, m, Indoline C3—H), 4.11 (2H, t, J=7.0 Hz, —CH2 CH2O—), 4.14 (2H, d, J=8.5 Hz, Indoline C2—H). (4) 1-Acetyl-3-(2-acetoxyethyl)-5-bromo-4,6-dimethyl-7-nitroindoline (1.4 g) was dissolved in benzene (20 ml) and 5% Pd—C. (500 mg) was added, which was followed by catalytic hydrogenation at room temperature under A atmospheric pressure. Pd—C. was filtered off and benzene was evaporated under reduced pressure. The residue was dissolved in CHCl3 (50 ml) and the mixture was washed successively with saturated aqueous solution of sodium hydrogencarbonate and saturated brine, and dried over anhydrous sodium sulfate. Pivaloyl chloride (440 mg) and Et3N (448 mg) were added to the obtained solution and the mixture was stirred at room temperature for 30 min. The mixture was washed successively with 5% aqueous citric acid and saturated brine, and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3/MeOH=50/1−10/1) to give 1.0 g of N-[1-acetyl-3-(2-acetoxyethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]3[CH:17]=[CH:18][O:19][C:12]=23)=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[N:21]1([CH2:27][C:28]2[S:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:31]2[S:32][C:28]([CH2:27][N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[CH:29][CH:30]=2)=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]2[CH:17]=[CH:18][O:19][C:12]=12)=[O:9]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccnc2ccoc12
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)s2)OC1(C)C
Product: Nc1ncc(-c2ccc(CN3CCOCC3)s2)cc1C(=O)Nc1ccnc2ccoc12

Procedure:
Reaction of 2-amino-5-bromo-N-furo[3,2-b]pyridin-7-yl-pyridine-3-carboxamide (synthesis described above) with 5-(4-morpholinylmethyl)thiophene-2-boronic acid pinacol ester gives the compound “A29”;