Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH2:9][C:8](=[O:21])[NH:7]1.C([O:25]C(=O)CCC1CCCN1)C.Cl>[OH-].[Na+]>[O:22]=[C:3]1[NH:7][CH:6]([CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH2:9][C:8]([OH:25])=[O:21])[CH2:5][CH2:4]1.[O:21]=[C:8]1[NH:7][CH:6]([CH2:5][CH2:4][C:3]([OH:22])=[O:2])[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=2)[CH2:9]1
Reactant: COC(=O)CCC1NC(=O)CC1c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)CCC1CCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CC(c1ccc(C(F)(F)F)cc1)C1CCC(=O)N1
Product: O=C(O)CCC1NC(=O)CC1c1ccc(C(F)(F)F)cc1

Procedure:
A solution of 93.4 g of 5-oxo-3-[4-(trifluoromethyl)phenyl]-2-pyrrolidinepropanoic acid methyl ester and 5-oxo-β-[4-trifluoromethyl)phenyl]-2-pyrrolidinepropanoic acid ethyl ester in aqueous sodium hydroxide solution (1 N, 370 ml) is heated to 60° C. for four hours. Excess aqueous hydrochloric acid (1 N, 370 ml) is added and the solution is con25 centrated under reduced pressure to give 5-oxo-β-[4-(trifluoromethyl)phenyl]-2-pyrrolidinepropanoic acid and 5-oxo-3-[4-(trifluoromethyl)phenyl]-2-pyrrolidinepropanoic acid.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:12]([O:14][C:15]1[CH:24]=[CH:23][C:18]2[N:19]=[C:20]([SH:22])[S:21][C:17]=2[CH:16]=1)[CH3:13].C(NC(C(C)C)(C(C)C)C)C.O>C1COCC1.CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[S:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:3]1[CH2:2][S:22][C:20]1[S:21][C:17]2[CH:16]=[C:15]([O:14][CH2:12][CH3:13])[CH:24]=[CH:23][C:18]=2[N:19]=1
Reactant: ClCc1nc2ccccc2s1
Reactant: CCOc1ccc2nc(S)sc2c1
Agent: CCNC(C)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCOc1ccc2nc(SCc3nc4ccccc4s3)sc2c1
Temperature: 25 °C
Yield: 35 %

Procedure:
The compound 2-(chloromethyl)benzothiazole [15] (1 g, 5.45 mmol), dissolved in THF (50 ml), was added drop-wise to a stirred solution of 4 (1.15 g, 5.45 mmol), N-ethyldiisopropylethylamine (1.35 ml, 8.17 mmol) and 4-dimethylaminopyridine (0.08 g, 0.545 mmol) in THF (50 ml). The reaction mixture was refluxed overnight. Then, the solution was cooled to room temperature, and water (100 ml) followed by chloroform (100 ml) were added. The organic layer was separated, washed twice in water, dried over sodium sulfate, filtered and evaporated. The crude solid was purified by column chromatography using 100% dichloromethane as an eluting solvent. The compound was obtained as dark brown solid. Yield 35%, m.p. 78-82° C. 1H NMR (DMSO-d6): δ 1.31-1.33 (t, 3H, J=3.45), 4.02-4.08 (q, 2H, J=6.9), 5.08 (s, 2H), 7.02-7.06 (dd, 1H, J=2.5, 6.3), 7.42-7.50 (m, 2H), 7.59-7.60 (d, 1H, J=2.4), 7.74-7.77 (d, 1H, J=9.0), 7.95-8.06 (dd, 2H, J=8.1, 15.3). 13C NMR (DMSO-d6): δ 14.8, 35.1, 64.1, 104.8, 115.6, 121.6, 122.3, 125.3, 126.2, 141.9, 143.1, 152.6, 165.6, 173.0, 178.4. MS: MW=358.50 g/mol, MH+=359.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].BrC[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[O:26][CH3:27]>O1CCOCC1.[Ag]=O>[CH3:27][O:26][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:16]=1[CH2:15][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][CH:8]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: COC(=O)c1ccc(CCBr)c(OC)c1
Agent: O=[Ag]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)c(OC)c1
Yield: 55.6 %

Procedure:
Silver oxide (2.32 grams) was added to a solution of 5-nitroindole (1.62 grams) and methyl 4-bromoethyl-3-methoxybenzoate (2.6 grams) in 10 mL of dioxane. The mixture was heated at 60° for 20 hours. The dioxane was evaporated and ethyl acetate was added to the residue. The resulting suspension was filtered. The filtrate was evaporated and the residue was purified on silica with hexane/ethyl acetate to give 1.8 grams of title compound, m.p. 162°-163°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7][C:6]=2[C:13]=1[O:14][CH3:15].Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:34])=[CH:19][N:18]=1>>[Cl:34][C:20]1[C:21]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7][C:6]=3[C:13]=2[O:14][CH3:15])=[N:18][CH:19]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1c(N)ccc2c1CCC(=O)CC2
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2OC)CCC(=O)CC3)ncc1Cl

Procedure:
The title compound was prepared from 2-amino-1-methoxy-5,6,8,9-tetrahydro-benzocyclohepten-7-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide in an analogous manner as Example 179. Product was isolated as an off-white solid (12 mg, 20%). LCMS (m/e) 466 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.68 (d, 1H, J=8.8 Hz), 8.17 (d, 1H, J=8.34 Hz), 8.13 (s, 1H), 7.50 (m, 2H), 7.42 (s, 1H), 7.11 (t, 1H), 6.96 (d, 1H, J=8.34 Hz), 6.23 (broad s, 1H), 3.76 (s, 3H), 3.04 (d, 3H, J=4.8 Hz), 3.01 (m, 2H), 2.89 (m, 2H), 2.62 (m, 4H).
Reaction SMILES: [Cr]([O-])([O-])(=O)=O.[Na+].[Na+].[Cl:8][C:9]1[CH:10]=[C:11]([CH2:16][CH:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)[CH:12]=[C:13]([Cl:15])[CH:14]=1>C(OCC)C>[Cl:8][C:9]1[CH:10]=[C:11]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[CH:12]=[C:13]([Cl:15])[CH:14]=1
Reactant: OC1CCC(Cc2cc(Cl)cc(Cl)c2)CC1
Agent: O=[Cr](=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: O=C1CCC(Cc2cc(Cl)cc(Cl)c2)CC1
Reaction time: 0.08 h
Yield: 36.1 %

Procedure:
A solution of chromic acid was prepared using 5.6 grams of sodium dichromate, 16.8 mL of water, 4.1 mL of concentrated sulfuric acid, and additional water to provide 28 mL of solution. The sodium chromate solution was cooled to 0° C. and was added dropwise to a stirred, cold (0° C.) solution of 7.3 grams (0.028 mole) of 4-(3,5-dichlorophenylmethyl)cyclohexanol in 15 mL of diethyl ether. The complete addition required about 5 minutes. Upon completion of addition, the reaction mixture was stirred for 5 minutes and then was extracted with diethyl ether. The ether extract was washed with an aqueous solution saturated with sodium bicarbonate, then with water. The organic layer was concentrated under reduced pressure, yielding 2.6 grams of 4-(3,5-dichlorophenylmethyl)cyclohexanone.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]#[N:13])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=O)C.Cl.CO>O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]#[N:13])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: CC(=O)Nc1ccc(SC#N)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CO
Solvent: O
Product: N#CSc1ccc(N)c([N+](=O)[O-])c1

Procedure:
6 G. of 1-acetamido-2-nitro-4-thiocyanatobenzene is suspended in a mixture of 30 ml. concentrated hydrochloric acid and 30 ml. methanol, and the mixture stirred at room temperature for 24 hours. The water is added and the product isolated by filtration, yielding 1-amino-2-nitro-4-thiocyanatobenzene.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[C:10](Cl)(Cl)=[S:11].C(N(C(C)C)CC)(C)C>ClCCl>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[N:4]=[C:10]=[S:11]
Reactant: Nc1c(F)cccc1F
Reactant: S=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cccc(F)c1N=C=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
1,3-Difluoro-2-isothiocyanato-benzene was synthesized as follows, according to scheme 1. A solution of 2,6-difluoro aniline (0.13 g, 1.01 mmol) in dichloromethane (10.00 ml) was treated with thiophosgene (0.12 g, 1.06 mmol) and diisopropylethylamine (0.26 g, 2.01 mmol). The mixture was stirred for 1 h at room temperature. The solvent was then evaporated, leaving 1,3-difluoro-2-isothiocyanato-benzene (0.17 g, 99%) as a light brown gum, which was used crude.
Reaction SMILES: [CH2:1]([C:11]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:33][Al](C)C>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH2:1]([C:11]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCC(O)(CCCCCCCCCC)CCCCCCCCCC
Reactant: C[Al](C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCCCC(C)(CCCCCCCCCC)CCCCCCCCCC
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 70 %

Procedure:
Alternatively, the 0.1 moles of the synthesized tri-n-decylcarbinol was added to 0.2 liters of methylene chloride. The mixture was covered with a blanket of nitrogen and cooled to 0° C. 0.050 mole titanium tetrachloride was added to the mixture and the solution was stirred 2-3 hours at 0° C. 0.066 mole trimethylaluminum was added and the mixture was allowed to warm to room temperature. The reaction was quenched with water and washed with 0.1 liter of a 20% HCl solution. The organic layer was dried with magnesium sulfate and the methylene chloride removed to give a yield of 70% tri-n-decylmethylmethane.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:11]2[C:12]([O:21][CH3:22])=[CH:13][C:14]([O:19][CH3:20])=[C:15]([CH:18]=2)[CH:16]=O)=[CH:5][N:4]=1.[C:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)(=[O:25])[CH3:24]>>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:11]2[C:12]([O:21][CH3:22])=[CH:13][C:14]([O:19][CH3:20])=[C:15](/[CH:16]=[CH:24]/[C:23]([C:26]3[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=3)=[O:25])[CH:18]=2)=[CH:5][N:4]=1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1ncc(-c2cc(C=O)c(OC)cc2OC)c(OC)n1
Product: COc1ncc(-c2cc(/C=C/C(=O)c3ccc(C(=O)O)cc3)c(OC)cc2OC)c(OC)n1
Yield: 22 %

Procedure:
The title compound was prepared by condensing 5-(2,4-dimethoxy-pyrimidin-5-yl)-2,4-dimethoxy-benzaldehyde (Ex-38A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 203–205° C., 22% yield. 1H-NMR (DMSO-d6) δ 8.11–9.15 (m, 3H), 7.99–8.06 (m, 3H), 7.88 (s, 1H), 7.76 (d, J=17 Hz, 1H), 6.76 (s, 1H), 3.96 (s, 3H), 3.90 (s, 3H), 3.83 (s, 3H) 3.81 (s, 3H). MS m/z=451 ([M+H]+). HRMS (ES+) Calcd. for C24H22N2O7: 451.1505. Found: 451.1524.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14](O)=[O:15])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[CH:31]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:37][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:15])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:22][CH:23]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: NC1CCCCC1
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](Nc2ccc(N3CCOCC3)cc2)C[C@@H]1C
Product: CC(=O)N1c2ccc(C(=O)NC3CCCCC3)cc2[C@H](Nc2ccc(N3CCOCC3)cc2)C[C@@H]1C
Yield: 87.5 %

Procedure:
Reactions and treatments were carried out in the same manner as in Example 110, using 82 mg of (2S,4R)-1-acetyl-2-methyl-4-[(4-morpholinophenyl)amino]-1,2,3,4-tetrahydroquinoline-6-carboxylic acid and 60 mg of cyclohexylamine. Thus, 86 mg (87%) of the title compound was obtained as a yellow amorphous substance.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](Cl)=[O:14])=[CH:10][CH:11]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:5]1)(=O)C.[NH2:23][CH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[OH:31]>N1C=CC=CC=1>[OH:31][C@@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]1[CH2:24][NH:23][C:13]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][N:5]=[C:6]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:14]
Reactant: NC[C@@H]1CCCC[C@H]1O
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)Cl)ccc21
Solvent: c1ccncc1
Product: O=C(NCC1CCCC[C@H]1O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
To a flask containing 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carbonyl chloride (330 mg, 0.95 mmol) dissolved in pyridine (6 mL) was added trans-2-aminomethyl-1-cyclohexanol (135.6 mg, 1.05 mmol). The reaction was allowed to stir under a nitrogen atmosphere overnight. Solvent was removed and the reaction was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium bicarbonate, dried with magnesium sulfate, filtered and concentrated to yield the crude product. The product was purified by column chromatography (SiO2, 5% methanol in dichloromethane). The compound was taken up in a 3% ammonia in methanol solution (8 mL) and allowed to reflux at 60° C. for three hours. The reaction was neutralized with 1 N HCl solution and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated to yield the title compound (240 mg, 69% yield). 1H NMR (DMSO-d6) δ 13.5 (s, 1H), 8.6 (s, 2H), 8.1 (m, 2H), 7.9 (d, 1H), 7.6 (d, 1H), 7.4 (m, 2H), 4.8 (s, 1H), 3.5 (m, 1H), 3.2 (m, 1H), 1.8 (m, 2H), 1.6 (m, 2H), 1.4 (m, 2H), 0.8–1.0 (m, 3H), ES-MS m/z 368 [M+1]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O>CC#N.CCOCC.C([O-])([O-])=O.[Na+].[Na+]>[Br:14][C:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: CCOC(=O)C(C)(Br)c1ccncc1
Reaction time: 2 h

Procedure:
The above compounds were prepared according to the procedure reported in the literature: see D. Yang, J. Org. Chem. 2002, 67, 7429. MS: 258, 260 (M+1). To a solution of ethyl 2-(pyridin-4-yl)propanoate (5.3 g, 30 mmol), Mg(ClO4)2 (Aldrich, 2.0 g, 9.0 mmol) in CH3CN (60 mL) was added N-bromosuccinimide (Aldrich, 5.9 g, 33 mmol) at room temperature. After 2 h, the reaction mixture was diluted with ether (200 mL), and 10% Na2CO3. The organic phase was separated, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography. Mass Spec. m/z+ion 258, 260 (M+1).
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-:2].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>C(O)C>[CH2:7]([O:6][C:4](=[O:5])[C:3]([N+:1]#[C-:2])=[CH:11][N:12]([CH3:14])[CH3:13])[CH3:8]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: COC(OC)N(C)C
Solvent: CCO
Product: [C-]#[N+]C(=CN(C)C)C(=O)OCC
Reaction time: 0.17 h

Procedure:
To a solution of ethyl isocyanoacetate (5.0 g) in ethanol (100 mL) is added N,N-dimethyl-formamide dimethyl acetal (6.5 g) dropwise with stirring over 10 minutes. The reaction is stirred for 24 hours and the ethanol is evaporated. The resulting oil is passed through magnesium silicate using 50% ethyl acetate-hexanes as the eluant. The solvents are removed and the resulting oil is crystallized from ethyl acetate-hexanes to yield light yellow needles, 3.0 g.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1.Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[OH:10][C:7]([CH:4]1[CH2:5][CH2:6][N:1]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:2][CH2:3]1)([CH3:9])[CH3:8]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 48 h

Procedure:
2-(Piperidin-4-yl)propan-2-ol (1 g) was reacted with 1.1 eq of benzyl chloroformate and 1.3 eq of triethylamine in 30 mL of chloroform. The reaction was halted after 2 days at room temperature and purified by isco (0-60% Hexanes/Ethyl Acetate over 20 minutes) to afford 1.49 g benzyl 4-(2-hydroxypropan-2-yl)piperidine-1-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[C:13](Cl)(=[O:17])[CH2:14][CH2:15][CH3:16]>>[C:13]([NH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12])(=[O:17])[CH2:14][CH2:15][CH3:16]
Reactant: CCCC(=O)Cl
Reactant: COC(=O)c1ccc(N)c(C)c1
Product: CCCC(=O)Nc1ccc(C(=O)OC)cc1C

Procedure:
In J. Med. Chem. 1993, 4040 a synthesis of the antagonist is described which starts from methyl 4-amino-3-methylbenzoate (I) and reacts it with butyryl chloride to give methyl N-butyryl-4-amino-3-methylbenzoate (II) (see the following reaction scheme (1)).
Reaction SMILES: C(Cl)CCl.[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:14]3[C:21]([CH3:22])=[C:20]([C:23](O)=[O:24])[S:19][C:15]=3[N:16]=[CH:17][N:18]=2)=[C:8]([O:26][C@H:27]2[CH2:32][CH2:31][C@H:30]([OH:33])[CH2:29][CH2:28]2)[CH:7]=1.O[N:35]1C(=O)C[CH2:37][C:36]1=O.[CH3:42][N:43]([CH:45]=O)[CH3:44]>CCOC(C)=O>[CH3:42][N:43]([CH3:44])[CH2:45][CH2:37][CH2:36][NH:35][C:23]([C:20]1[S:19][C:15]2[N:16]=[CH:17][N:18]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([F:5])=[CH:7][C:8]=3[O:26][C@H:27]3[CH2:28][CH2:29][C@H:30]([OH:33])[CH2:31][CH2:32]3)[C:14]=2[C:21]=1[CH3:22])=[O:24]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](O)CC3)c12
Reactant: O=C1CCC(=O)N1O
Reactant: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)NCCCN(C)C)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](O)CC3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.072 g EDC were added to a mixture of 0.13 g 4-[4-fluoro-2-(trans-4-hydroxycyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and 0.054 g N-Hydroxysuccinimide in DMF (2 ml). The reaction mixture was stirred at rt overnight then diluted with EtOAc and washed with water and brine (2×). The organic phase was passed through a hydrophobic frit and evaporated. The residue was treated with 2 ml DMF and 213 μl 3-dimethylaminopropylamine were added. The mixture was stirred at rt for 40 minutes and then diluted with EtOAc and washed with water and brine (2×). The organic phase was dried with MgSO4 and passed through a hydrophobic frit.
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][CH:9]([CH2:33][NH:34][S:35]([CH2:38][CH2:39][CH2:40]Cl)(=[O:37])=[O:36])[CH2:10][O:11][C:12](=[O:32])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:7])[CH2:2][CH2:3][CH3:4].C(SCC(OC)CNS(CCC[I:69])(=O)=O)CCCCCCCCCCCCCCC>>[CH2:1]([O:5][C:6]([NH:8][CH:9]([CH2:33][NH:34][S:35]([CH2:38][CH2:39][CH2:40][I:69])(=[O:37])=[O:36])[CH2:10][O:11][C:12](=[O:32])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)NC(=O)OCCCC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCI)NC(=O)OCCCC

Procedure:
2-Butoxycarbonylamino-3-(3-chloropropylsulfonylamino)-1-octadecylcarbamoyloxypropane III e2 is allowed to react and worked up by the same procedure as described in (5). m.p. 96°-98° C. The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].[C:16]([O:20][C:21]([NH:23][CH:24]([CH2:28]C)[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(OCC)C>[O:26]=[C:25]([NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:8])[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:24]([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:28]
Reactant: CCC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nn1cccc1C(=O)Nc1ccccc1
Solvent: CCOCC
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nn1cccc1C(=O)Nc1ccccc1
Yield: 87.6 %

Procedure:
The title compound was prepared following the experimental procedure described in preparation 20a from 1.50 g (7.45 mmol) of 1-amino-N-phenyl-1H-pyrrole-2-carboxamide and 1.82 g (8.95 mmol) of racemic 2-(tert-butoxycarbonylamino)butanoic acid (purchased from ABCR, cat. no. AB154485). After recristallysation of the crude product in diethylether, 2.43 g (84% yield) of the title compound were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:24][OH:25])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([N:21]([CH3:23])[CH3:22])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(Cl)(Cl)[C:28]([N:30]=C=O)=[O:29].O>C(Cl)Cl>[C:28]([O:25][CH2:24][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([N:21]([CH3:22])[CH3:23])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)(=[O:29])[NH2:30]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CN(C)c1ccc2onc(OCC(CO)NC(=O)OC(C)(C)C)c2c1
Solvent: ClCCl
Solvent: O
Product: CN(C)c1ccc2onc(OCC(COC(N)=O)NC(=O)OC(C)(C)C)c2c1

Procedure:
To a solution of 0.58 g of 3-(2-tert-butoxycarbonylamino-3-hydroxypropoxy)-5-dimethylamino-1,2-benzoisoxazole in 12 ml of methylene chloride is added 0.26 g of trichloroacetyl isocyanate at -35° to -30° C., and the temperature is elevated to 0° C., after which they are subjected to reaction at the same temperature for one hour. To the reaction mixture is added 10 ml of water, and they are subjected to reaction at 20°-25° C. for one hour, after which the organic layer is separated. The separated organic layer is dried over anhydrous magnesium sulfate and thereafter the solvent is removed by distillation under reduced pressure, to obtain 0.94 g of brown, oily 3-(3-carbamoyloxy-2-tert-butoxycarbonylaminopropoxy)-5-dimethylamino-1,2-benzoisoxazole.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5]Cl)=[CH2:2].[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.[K].CN(C=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH:1]([O:3][CH2:4][CH2:5][C:16]1[CH:15]=[CH:14][CH:13]=[C:9]2[C:10]([NH:11][C:7](=[O:17])[C:8]=12)=[O:12])=[CH2:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=COCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: C=COCCc1cccc2c1C(=O)NC2=O

Procedure:
2-Vinyloxy Ethyl Phthalimide was prepared via reacting 2-chloroethyl vinyl ether (25 g, 0.24 mol) and potassium phthalimide (25 g, 0.135 mol) in 100° C. DMF (75 mL) using tetra n-butyl ammonium bromide (0.5 g) as the phase transfer catalyst. This solution was heated for six hours and then crashed out in water and filtered. This solid was then recrystallized twice from methanol to give white crystals.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[CH2:19][CH2:18][C@:17]4([CH3:23])[C:20]([CH3:22])([CH3:21])[C@H:13]3[CH2:14][C:15]3[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:16]=34)=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:31][Mg]I>O1CCCC1>[N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[CH2:19][CH2:18][C@:17]4([CH3:23])[C:20]([CH3:22])([CH3:21])[C@H:13]3[CH2:14][C:15]3[CH:27]=[CH:26][C:25]([C:28]([OH:30])([CH3:31])[CH3:29])=[CH:24][C:16]=34)=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1
Reactant: C[Mg]I
Reactant: CC(=O)c1ccc2c(c1)[C@]1(C)CCN(C(=O)c3ccc4nc[nH]c4c3)[C@H](C2)C1(C)C
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc2c(c1)[C@]1(C)CCN(C(=O)c3ccc4nc[nH]c4c3)[C@H](C2)C1(C)C
Temperature: 0 °C

Procedure:
A solution of 1-[(2R,6S)-3-(3H-benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-yl]-ethanone (0.10 g) in tetrahydrofuran (1 mL) is added to a solution of MeMgI (3 mol/L in Et2O, 0.25 mL) in tetrahydrofuran (1 mL) chilled in an ice bath (ca. 0° C.). Then, the cooling bath is removed and the solution is stirred at room temperature. After 5 h of stirring, more MeMgI (3 mol/L in Et2O, 0.25 mL) is added and the solution is stirred at 50° C. for 4 h. After cooling in an ice bath, aqueous NH4Cl solution is added and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are dried (MgSO4) and the solvent is removed under reduced pressure. The residue is purified by HPLC on reversed phase (MeCN/H2O).