Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[C:9]([O:12][CH3:13])([O:10][CH3:11])[CH2:8][CH2:7][N:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5]1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>CN(C=O)C>[CH2:21]([O:3][CH:4]1[C:9]([O:10][CH3:11])([O:12][CH3:13])[CH2:8][CH2:7][N:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
Sodium hydride (55% content, 0.79 g, 18 mmol) was added to a solution of tert-butyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate (described in Tetrahedron Lett.; 46; 3; 2005; 447-450, 3.9 g, 15 mmol) in DMF (50 mL). Following stirring at room temperature for 30 minutes, benzyl bromide (2.82 g, 16.5 mmol) was added, and the mixture was stirred at room temperature for two hours. A 0.5 N aqueous hydrochloric acid solution was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with water (three times) and brine, and dried over anhydrous magnesium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1, 4/1, 2/1) to obtain 4.99 g of the title compound as a colorless solid (95%).
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:18][NH:19][NH2:20])[CH2:3]1.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:18][NH:19][NH:20][C:23](=[O:24])[N:22]([CH3:26])[CH3:21])[CH2:3]1
Reactant: CN1C[C@H](CNN)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: CN(C)C(=O)Cl
Product: CN(C)C(=O)NNC[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Yield: 68.7 %

Procedure:
The process is carried out as in Example 4 with the difference that 0.6 g (0.00213 moles) of 6-methyl-8β-hydrazinomethyl-ergoline and 0.25 g (0.00234 moles) of dimethylcarbamoyl chloride are used as the starting substances. 0.5 g (69%) of 6-methyl-8β-([N'-dimethylcarbamoyl-hydrazino]-methyl)-ergoline are obtained; m.p.: 205°-206° C., [α]D20 =-36.2° (c=1, in 96% ethanol).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)[CH2:2]1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>CO>[N:16]1([CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: c1ccc2c(OCC3CO3)cccc2c1
Reactant: C1CCNC1
Solvent: CO
Product: OC(COc1cccc2ccccc12)CN1CCCC1

Procedure:
A solution of 1,2-epoxy-3-(1-naphthyloxy)propane (62.0 g) and the amine of formula NHR3R3, pyrrolidine (23.5 g), in methanol (250 ml) is heated at reflux for two hours. The reaction mixture is concentrated to dryness. The oily residue is crystallized from chloroform and diethyl ether by the addition of hexane to give the title compound, mp 68-70° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:19][C:20]([OH:22])=O)[C:9](=[O:18])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:25])=O>C(Cl)Cl>[C:1]1([C:7]2[N:8]([CH2:19][C:20]([Cl:25])=[O:22])[C:9](=[O:18])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cn1c(-c2ccccc2)c(-c2ccccc2)oc1=O
Solvent: ClCCl
Product: O=C(Cl)Cn1c(-c2ccccc2)c(-c2ccccc2)oc1=O
Temperature: 25 °C

Procedure:
A mixture of 4,5-diphenyl-2-oxo-4-oxazolin-3-ylacetic acid (2.1 g, 7.1 mmol) [J. Org. Chem., 38, 3034 (1973)], thionyl chloride (5 ml) and methylene chloride (20 ml) is refluxed for 2.5 hours. After cooling to room temperature the solvent is removed in vacuo and resulting oil crystallizes on standing. The product is triturated with ether-hexane to give 4,5-diphenyl-2-oxo-4-oxazolin-3-ylacetic acid chloride; 2.0 g mp 104°-112°.
Reaction SMILES: C1(P(Cl)(Cl)(Cl)[Cl:8])C=CC=CC=1.[F:12][C:13]([F:40])([C:36]([F:39])([F:38])[F:37])[C:14]([F:35])([F:34])[C:15]([P:18]([C:21]([F:33])([F:32])[C:22]([F:31])([F:30])[C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])(=O)[OH:19])([F:17])[F:16].Cl>>[F:12][C:13]([F:40])([C:36]([F:39])([F:38])[F:37])[C:14]([F:35])([F:34])[C:15]([P:18]([Cl:8])([C:21]([F:33])([F:32])[C:22]([F:31])([F:30])[C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])=[O:19])([F:17])[F:16]
Reactant: ClP(Cl)(Cl)(Cl)c1ccccc1
Reactant: O=P(O)(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Product: O=P(Cl)(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 75.9 %

Procedure:
Variant b) The mixture of 4.6 g (18.4 mmol) of phenyltetrachlorophosphorane and 7.3 g (14.5 mmol) of bis(nonafluorobutyl)phosphinic acid is stirred at room temperature for four hours When the evolution of gas (HCl) is complete, the nonafluorobutylphosphonyl dichloride is separated off by distillation at atmospheric pressure, giving 5.73 g of bis(nonafluorobutyl)phosphinyl chloride as colourless liquid substance. This corresponds to a yield of 76%, based on the phosphinic acid employed.
Reaction SMILES: [CH2:1]([N:8]([CH2:24][CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([N+:35]([O-])=O)[CH:33]=2)[NH:28][C:27]=1[C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[CH:39]=1)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Ni]>[NH2:35][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[CH:39]=1)=[C:26]2[CH2:25][CH2:24][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=1
Reactant: [H][H]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)Cc2ccccc2)c1
Agent: [Ni]
Product: Cc1cc(C)cc(-c2[nH]c3ccc(N)cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)Cc2ccccc2)c1
Temperature: 25 °C
Yield: 74.8 %

Procedure:
To a stirred solution of N-{4-[4-(benzyl-{2-[2-(3,5-dimethylphenyl)-5-nitro-1H-indol-3-yl]ethyl}amino)butyl]phenyl}methanesulfonamide (59 mg in 4 mL absolute ethanol) was added ca. 15 mg of Raney® nickel. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 3 hours the reaction was flushed with nitrogen, filtered over diatomaceous earth and concentrated in vacuo. Purification by flash chromatography on silica gel (hexane:ethyl acetate, 1:2) gave the title compound (42 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].[CH2:8]([O:15][C:16](Cl)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+:23]>[OH-].[Na+].O>[Na+:23].[CH2:8]([O:15][C:16]([NH:1][CH2:2][CH2:3][S:4]([O-:7])(=[O:6])=[O:5])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCCS(=O)(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NCCS(=O)(=O)[O-])OCc1ccccc1
Reaction time: 4 h
Yield: 14 %

Procedure:
Taurine, 1 (about 40 g, 320 mmols), was dissolved in 4N sodium hydroxide solution (80 mL) and water (about 200 mL). To this solution was added benzyloxycarbonyl chloride, (about 48 mL, 330 mmols) dropwise, with vigorous stirring during a period of about 4 hours. The pH of the solution was maintained alkaline by the addition of 10% sodium bicarbonate solution (about 300 mL) and 4N sodium hydroxide solution (about 45 mL). The obtained reaction mixture was then washed with diethyl ether (about 1000 mL) and the aqueous layer was rotary evaporated to dryness, and further dried under high vacuum over phosphorous pentoxide overnight to yield about 12.7 g (14%) of 2. 1H-NMR (D2O): δ 7.50 (5H, s, Ar—H), 5.21 (2H, s, Ar—CH2), 3.62 (2H, t, CH2), 3.14 (2H, t, CH2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:17][CH2:16][CH2:15][C@H:14]3[N:9]2[C:10](=[O:18])[CH2:11][CH:12]=[CH:13]3)=[CH:4][CH:3]=1.[H][H]>CO.[Pt]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:17][CH2:16][CH2:15][C@H:14]3[N:9]2[C:10](=[O:18])[CH2:11][CH2:12][CH2:13]3)=[CH:4][CH:3]=1
Reactant: O=C1CC=C[C@H]2CCC[C@@H](c3ccc(Cl)cc3)N12
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: O=C1CCC[C@H]2CCC[C@@H](c3ccc(Cl)cc3)N12
Yield: 79.8 %

Procedure:
Platinum oxide (95 mg) was added to a solution of (6S,9aR)-6-(4-chlorophenyl)-3,6,7,8,9,9a-hexahydroquinolizin-4-one (1.09 g) in methanol (50 mL), and the reaction solution was stirred in a hydrogen atmosphere at room temperature for one hour. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 877 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:7])[CH2:6][CH2:5][CH2:4]1.[Cl:8][C:9]1[N:10]=[C:11](Cl)[C:12]2[C:17]([I:18])=[CH:16][N:15]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:13]=2[N:14]=1>C1COCC1>[Cl:8][C:9]1[N:10]=[C:11]([O:7][CH:3]2[CH2:6][CH2:5][CH2:4]2)[C:12]2[C:17]([I:18])=[CH:16][N:15]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:13]=2[N:14]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Reactant: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CCC3)nc(Cl)nc21
Temperature: 30 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a suspension of sodium hydride (2 equiv, 60% in mineral oil) in dry THF (0.44 M) under nitrogen atmosphere was added a solution of cyclobutanol (1.05 equiv) in dry THF (1.4 M) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes before 2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)-methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv) in dry THF (0.33 M) was added and the resulting reaction mixture was stirred at 30° C. for 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution. The organic solvent was removed under reduced pressure and the resulting aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure. The crude obtained was purified by flash column chromatography on silica gel (5% ethyl acetate in petroleum ether) to afford the title compound (95% yield) as a white solid. MS (ESI) m/z 479.2 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:13][C:12]2([C:17]([O:19]C)=[O:18])[CH2:14][CH2:15][CH2:16][CH:11]2[C:10]1=[O:21].Cl>[Li+].[OH-].CO.O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:13][C:12]2([C:17]([OH:19])=[O:18])[CH2:14][CH2:15][CH2:16][CH:11]2[C:10]1=[O:21]
Reactant: COC(=O)C12CCCC1C(=O)N(c1c(C)cccc1C)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cccc(C)c1N1CC2(C(=O)O)CCCC2C1=O
Temperature: 70 °C
Yield: 82.3 %

Procedure:
Methyl 2-(2,6-dimethylphenyl)-1-oxooctahydrocyclopenta[c]pyrrole-3a-carboxylate (400 mg, 1.4 mmol) suspended in 5 mL of 1 M LiOH in 90% methanol was heated at 70° C. After cooling to room temperature, the reaction mixture was diluted with water, the pH adjusted to ˜1 with concentrated HCl and the product was extracted twice with ethyl acetate (15 mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated to yield 2-(2,6-dimethylphenyl)-1-oxooctahydrocyclopenta[c]pyrrole-3a-carboxylic acid (315 mg, 82% yield). LC-MS Rt (retention time): 1.44 min, MS: (ES) m/z 274 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][CH:11]([CH3:22])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(N(CC)CC)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][CH:11]([CH3:22])[N:10]([C:27](=[O:29])[CH3:28])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC1Cc2cc3c(cc2C(c2ccc(N)cc2)=NN1)OCO3
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1N=C(c2ccc(N)cc2)c2cc3c(cc2CC1C)OCO3
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a solution of 3.58 g (12.1 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine in 100 ml of chloroform first 1.68 ml (12.1 mmol) of triethylamine, then under constant ice-cooling and stirring 1.15 ml (12.1 mmol) of acetic anhydride were added. Stirring was continued for additional 2 hours, then the solution was extracted with 3×100 ml of water, the organic layer was dried and evaporated under reduced pressure. The crystalline residue was recrystallized from 40 ml of isopropanol to obtain 3.50 g (85.7%) of the aimed product, m.p. 220°-222° C. After repeated recrystallization the m.p. increased to 223°-225° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:20]=[C:6]2[C:7]([C:13]3([CH2:18][CH3:19])[O:17][CH2:16][CH2:15][O:14]3)=[CH:8][CH:9]=[C:10]([CH:11]=[O:12])[N:5]2[N:4]=1)[CH3:2].[CH3:21][Mg]Br.C1COCC1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([C:3]1[CH:20]=[C:6]2[C:7]([C:13]3([CH2:18][CH3:19])[O:14][CH2:15][CH2:16][O:17]3)=[CH:8][CH:9]=[C:10]([CH:11]([OH:12])[CH3:21])[N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1cc2c(C3(CC)OCCO3)ccc(C=O)n2n1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1cc2c(C3(CC)OCCO3)ccc(C(C)O)n2n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
The compound of Example 152 (321 mg) was dissolved in THF (12.0 mL) in an argon atmosphere. While the solution was kept at −78° C., 0.90 mol/L methyl magnesium bromide/THF solution (1.70 mL) was added dropwise and the mixture was stirred for 3.5 hours as it was allowed to gradually warm to room temperature. Subsequently, a saturated aqueous solution of ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. Evaporation of the solvent afforded the title compound as a yellow oil (340 mg).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC#N.C(Cl)(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH3:22])[CH3:21])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 98.5 %

Procedure:
Amine preparation: a mixture of BOC-piperazine (1.87 g), ethyl 2-bromoisobutyrate (5.90 g) and potassium carbonate (1.53 g) in MeCN (20 mL) was heated in a sealed tube at 80° C. for 3 days. The reaction mixture was cooled, diluted with chloroform, washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash column chromatography to yield 4-(1-ethoxycarbonyl-1-methyl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (2.97 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:18]([NH2:21])(=O)=[O:19].[NH3:22]>O1CCOCC1>[NH2:22][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:18]([NH2:21])=[O:19]
Reactant: COc1ccc(C(=O)c2ccc(F)c(S(N)(=O)=O)c2)cc1
Reactant: N
Solvent: C1COCCO1
Product: COc1ccc(C(=O)c2ccc(N)c(S(N)=O)c2)cc1
Temperature: 100 °C
Yield: 81 %

Procedure:
To a solution of 2-fluoro-5-(4-methoxy-benzoyl)-benzenesulfonamide (0.25 g, 0.81 mmol) dissolved in dioxane (3 mL) is added aqueous ammonia solution (1 mL). The reaction mixture is heated at 100° C. for 6 h in sealed tube and then cooled to room temperature and concentrated in vacuo. The residue is partitioned between water and ethyl acetate, and the aqueous phase is extracted with ethyl acetate three times. The combined organic extracts are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo to provide 0.2 g (81%) of the title compound as a pale yellow solid. 1H NMR (DMSO): δ 8.05 (d, J=2 Hz, 1H), 7.70 (m, 3H), 7.40 (s, 2H), 7.05 (d, J=9 Hz, 2H), 6.92 (d, J=9 Hz, 1H), 3.88 (s, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:40]([O:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3ccccc3)CN2C1=O
Yield: 15.3 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and benzoyl chloride (41 μL, 0.35 mmol). The final trituration (diethyl ether/hexane) and filtration gave 18 mg (15%) of 18-benzoyloxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 97.0% pure (HPLC), MS m/z 673 (M+H)+, HRMS: calcd. 673.2907 and found 673.2908 (M+H)+, mp 140-142° C.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:27]3[CH2:26][CH2:25][C:24]4[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=4[C:22]=3[O+]=[C:20]3[C:15]=2[CH2:16][CH2:17][C:18]2[CH:35]=[CH:34][CH:33]=[CH:32][C:19]=23)=[CH:10][CH:9]=1.[NH3:36]>C(O)C>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:27]3[CH2:26][CH2:25][C:24]4[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=4[C:22]=3[N:36]=[C:20]3[C:15]=2[CH2:16][CH2:17][C:18]2[CH:35]=[CH:34][CH:33]=[CH:32][C:19]=23)=[CH:10][CH:9]=1
Reactant: N
Reactant: COc1ccc(-c2c3c([o+]c4c2CCc2ccccc2-4)-c2ccccc2CC3)cc1
Agent: F[B-](F)(F)F
Solvent: CCO
Product: COc1ccc(-c2c3c(nc4c2CCc2ccccc2-4)-c2ccccc2CC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
16 (6.63 g, 13.9 mmol, 1 eq) was suspended in ethanol (175 mL, denaturated with 1% methylethyl ketone). Under vigorously stirring an ammonia solution (32% aqueous solution, 18.3 g NH3, 1.075 mol, 77 eq) was added dropwise and the mixture was stirred at ambient temperature for 171/2 hours to obtain a lavender suspension. The product was isolated by filtration and purified by successive washing with ethanol (250 mL). A lavender solid (91% yield) could be obtained. The compound was directly used in the next step without any further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([OH:11])[CH:5]=1)([O-:3])=[O:2].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21]>>[OH:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][C:7]=1[NH:8][C:20]([NH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[Cl:12])=[O:21]
Reactant: O=C=Nc1ccccc1Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1Cl
Yield: 47.1 %

Procedure:
The urea was prepared from 4-nitro 2-hydroxy aniline(308 mg, 2 mmol) and 2-chloro phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.29 g, 47%). EI-MS m/z 308(M+H)+
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.[CH2:15]([CH:17]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18]O)[CH3:16]>C1(C)C=CC=CC=1>[C:1]([O:14][CH2:18][CH:17]([CH2:15][CH3:16])[CH2:20][CH2:21][CH2:22][CH3:23])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1
Reactant: CCCCC(CC)CO
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Solvent: Cc1ccccc1
Product: CCCCC(CC)COC(=O)/C=C/c1ccc(O)c(OC)c1
Temperature: 80 °C
Reaction time: 13 h
Yield: 83.2 %

Procedure:
In a three-necked flask, 19.5 g (0.1 mole) of ferulic acid, 13.0 g (0.1 mole) of 2-ethylhexanol, and 200 ml of toluene as a solvent were placed, and 1.0 g of paratoluenesulfonic acid as an acid catalyst was added. This reaction mixture was stirred at 80° C. for 13 hours. After cooled, the mixture was washed with saturated aqueous solution of sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate, and decolored by activated carbon. The solvent toluene was fully evaporated off from the organic layer under reduced pressure to obtain 25.5 g (yield: 85%) of 2-ethylhexyl ferulate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].O.[CH3:13]O>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:13])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)Cc1ccccc1Br
Yield: 96 %

Procedure:
A solution of ortho-bromophenylacetic acid (5.14 g) in dry methanol (40 ml) containing 5 drops of concentrated sulphuric acid was heated at reflux for three hours. The reaction mixture was cooled, then poured into iced water (150 ml) and extracted (2×75 ml) with ether. The ether layers were combined, washed successively with water (×3), saturated sodium bicarbonate solution (×2), water (×1) and saturated brine and then dried. Filtration and evaporation gave methyl ortho-bromophenylacetate (5.23 g, 96%) as a pale yellow liquid, IR maximum 1742 cm-1, which was used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:27][SH:28].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([S:28][CH2:27][C:26]([O:30][CH2:31][CH3:32])=[O:29])=[N:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(Cl)nc2)CC1
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1ccc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)-4-[(6-chloropyridin-3-yl)carbonyl]piperazine obtained in Example 18 (590 mg), ethyl thioglycolate (361 mg), potassium carbonate (691 mg), and N,N-dimethylformamide (10 mL) was stirred at 80° C. for 2 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 50:50-0:100 hexane/ethyl acetate) to provide the title compound (430 mg, 59%) as a solid.