Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.Cl[Si](CC)(CC)CC.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]=[C:34]([CH3:39])[N:33]=[C:32]3[C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[CH:41]=2)=[O:28])=[CH:23][CH:22]=1>C1COCC1>[Cl:46][C:42]1[CH:41]=[C:40]([C:32]2[C:31]3[C:36](=[CH:37][CH:38]=[C:29]([C:27]([C:24]4[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=4)([C:11]4[N:7]([CH3:6])[CH:8]=[N:9][CH:10]=4)[OH:28])[CH:30]=3)[N:35]=[C:34]([CH3:39])[N:33]=2)[CH:45]=[CH:44][CH:43]=1
Reactant: Cn1ccnc1
Reactant: Cc1nc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc2n1
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3cncn3C)ccc2n1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 39 %

Procedure:
BuLi (2.9 ml;0.0046 mol) was added dropwise at −70° C. to a solution of 1-methyl-1H-imidazole (0.0046 mol) in THF (7 ml) under N2 flow. The mixture was stirred at −70° C. for 15 min. Chlorotriethyl-silane (0.0048 mol) was added. The mixture was stirred at −70° C. for 15 min. n BuLi (2.6 ml;0.0041 mol) was added dropwise. The mixture was stirred at −70° C. for 15 min. A solution of intermediate (4) (0.00264 mol) obtained in Example A2, in THF (20 ml) was added dropwise at −70° C. The mixture was stirred at −70° C. for 1 hour, poured out into ice water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (2.1 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH; 95/5/0.2; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.59 g) was crystallized from diethylether. The precipitate was filtered off and dried, yielding 0.49 g (40%) of 4-(3-chlorophenyl)-α-(4-chlorophenyl)-2-methyl-α-(1-methyl-1H-imidazol-5-yl)-6-quinazolinemethanol, mp. 223° C.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([Sn:7](Cl)([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH3:6]>>[CH3:6][CH2:5][CH2:4][CH2:3][Sn:7]([O:1][Sn:7]([CH2:8][CH2:9][CH2:10][CH3:11])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][CH2:4][CH2:5][CH3:6])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: [OH-]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Na+]
Product: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Temperature: 50 °C

Procedure:
A four-necked flask equipped with an overflow nozzle on the side wall was provided with a stirrer, a thermometer and a reflux condenser. To the flask were continously fed 3,850 g of a 20% aqueous solution of sodium hydroxide and 1,990 g of tri-n-butyltin chloride containing 4.8% di-n-butyltin dichloride, with stirring and heating at 50° C., to perform hydrolysis for 30 minutes. The resulting reaction mixture overflowed was allowed to stand. As a result, the contents split into three distinct phases, i.e., an upper bis(tri-n-butyltin) oxide phase, an intermediate aqueous phase containing a salt, and a lower di-n-butyltin oxide phase containing 48% bis(tri-n-butyltin) oxide. The di-n-butyltin oxide had an average particle diameter of 30 μm. The specific gravities of the upper, intermediate and lower phases were 1.1, 1.2 and 1.3, respectively. The three phases were separated from one another. The upper phase was dehydrated under reduced pressure, and then a small amount of a salt which had separated out was removed by filtration, thereby obtaining 1,629 g of bis(tri-n-butyltin) oxide. Hydrochloric acid titration revealed that its purity was 98.5%, and its theoretical yield based on the starting material was 89.4%.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:7]([CH:9]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][O:11][C:12](Cl)=[O:13])[CH3:8].S(OC)(O[CH3:23])(=O)=O>C1COCC1.O>[CH2:7]([CH:9]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][O:11][C:12](=[O:13])[N:4]([CH:1]([CH3:3])[CH3:2])[CH3:23])[CH3:8]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)N
Reactant: CCCCC(CC)COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(CC)COC(=O)N(C)C(C)C
Temperature: 40 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
A solution of isopropylamine (2.95 g, 50 mmol, 1 equiv.) was added at RT to a suspension of NaH (55% in mineral oil, 2.40 g, 55 mmol, 1.1 equiv.) in THF (25 ml). The mixture was warmed to 40° C. for 18 h, then chloroformic acid 2-ethyl-hexyl ester in THF (25 ml) was added dropwise over 30 min. After 4 h further stirring a suspension of NaH (55% in mineral oil, 2.40 g, 55 mmol, 1.1 equiv.) in THF (25 ml) was added followed by a solution of dimethyl sulfate (5.2 ml, 55 mmol, 1.1 equiv.) in THF (20 ml). The mixture was heated to 70° C. for 16 h, then hydrolysed by addition of water (50 ml). The hydrolysed mixture was further heated to 70° C. for 1.5 h in order to destroy excess dimethyl sulfate, then diluted with MTBE and worked up as described in Example 1. The crude product was distilled at 0.06 mbar/94-95° C. to yield 8.8 g (77%) of product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:13]=2)[CH:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:2]2[N:7]=[C:6]3[CH2:8][CH2:9][CH2:10][C:5]3=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:13]=3)[CH:3]=2)[CH2:27][CH2:26]1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)Cc1ccc(Nc2cc(Cl)nc3c2CCC3)cc1
Product: CCOC(=O)Cc1ccc(Nc2cc(N3CCN(C)CC3)nc3c2CCC3)cc1
Yield: 14.9 %

Procedure:
Following general procedure B1, ethyl 2-(4-((2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate (0.095 g, 0.29 mmol) was reacted with 1-methylpiperazine (0.043 g, 0.44 mmol) to afford the title compound (0.017 g, 15%) as an orange oil. MW=394.51. 1H NMR (CD3OD, 500 MHz) δ 7.15 (d, J=8.3 Hz, 2H), 7.07 (d, J=8.3 Hz, 2H), 6.07 (s, 1H), 4.05 (q, J=7.0 Hz, 2H), 3.51 (s, 2H), 2.72 (t, J=7.5 Hz, 2H), 2.64 (t, J=7.5 Hz, 2H), 2.46-2.38 (m, 4H), 2.21 (s, 3H), 1.99 (quin, J=7.5 Hz, 2H), 1.15 (t, J=7.0 Hz, 3H); APCI MS m/z 395 [M+H]+.
Reaction SMILES: [N+](C1C=CC([N:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:27]([C:29](=[O:39])[CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH3:28])[CH:21]=3)=[CH:16][CH:15]=2)[C:11](=[O:13])[O-])=CC=1)([O-])=O.C[CH2:41][N:42]([CH:46]([CH3:48])C)[CH:43]([CH3:45])C.C[N:50]1CCNCC1>ClCCl>[CH3:28][N:27]([CH2:26][C:22]1[CH:21]=[C:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:10][C:11]([N:50]3[CH2:45][CH2:43][N:42]([CH3:41])[CH2:46][CH2:48]3)=[O:13])=[CH:19][CH:18]=2)[CH:25]=[CH:24][CH:23]=1)[C:29](=[O:39])[CH2:30][NH:31][C:32](=[O:33])[O:34][C:35]([CH3:37])([CH3:38])[CH3:36]
Reactant: CN1CCNCC1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(Cc1cccc(-c2ccc(N(C(=O)[O-])c3ccc([N+](=O)[O-])cc3)cc2)c1)C(=O)CNC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CN1CCN(C(=O)Nc2ccc(-c3cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c3)cc2)CC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 95.6 %

Procedure:
To a mixture of 4-nitrophenyl(3′-{[{[(tert-butoxycarbonyl)amino]acetyl}(methyl)amino]methyl}biphenyl-4-yl)carbamate (150 mg), DIPEA (36 mg), and dichloromethane (3 ml) was added 1-methylpiperazine (28 mg), followed by stirring at 50° C. for 5 hours. The reaction mixture was subjected to liquid separation with CHCl3-water, and the aqueous layer was extracted with CHCl3. The combined organic layer was dried over Na2SO4, and then the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (2% MeOH/CHCl3) to obtain tert-butyl (2-{methyl[(4′-{[(4-methylpiperazin-1-yl)carbonyl]amino}biphenyl-3-yl)methyl]amino}-2-oxoethyl)carbamate (132 mg) as a pale yellow oil.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8](S(C)(=O)=O)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][C@H:22]([OH:26])[CH2:21]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:1]([NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][C@H:22]([OH:26])[CH2:21]2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Nc1nc(S(C)(=O)=O)ncc1C(N)=O
Reactant: N[C@@H]1CCC[C@H](O)C1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Nc1nc(N[C@@H]2CCC[C@H](O)C2)ncc1C(N)=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a mixture of 4-(tert-butylamino)-2-(methylsulfonyl)pyrimidine-5-carboxamide (250 mg, 0.918 mmol; synthesis described herein) and (1S,3R)-3-aminocyclohexanol (138 mg, 1.2 mmol; prepared as described in Tetrahedron: Asymmetry 15:2051-2056 (2004)) in NMP (10 mL) was added DIEA (374 mg, 2.9 mmol). The resulting mixture was stirred at 100° C. overnight. The reaction mixture was purified by preparative HPLC to give the desired product (212.2 mg, 0.69 mmol, yield 75%). 1H NMR (400 MHz, CDCl3) δ ppm 8.86 (brs, 1H), 8.12 (s, 1H), 5.53 (brs, 3H), 3.93-3.91 (m, 1H), 3.88-3.82 (m, 1H), 2.27-2.25 (m, 1H), 1.92-1.85 (m, 3H), 1.47 (s, 9H), 1.42-1.25 (m, 4H); MS (ESI) m/z=308.2 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH:19][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])([C:14]([F:18])([F:17])[CH2:15][OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].S(=O)(=O)(O)[O-].[K+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH:19][C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])([C:14]([F:18])([F:17])[CH2:15][O:16][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(NC(=O)OCc2ccccc2)(C(F)(F)CO)C1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(NC(=O)OCc2ccccc2)(C(F)(F)COS(C)(=O)=O)C1
Reaction time: 0.83 h

Procedure:
To a solution of an optically-active compound of 3-benzyloxycarbonylamino-3-(1,1-difluoro-2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (13.6 g) and triethylamine (11.4 ml) in chloroform (136 ml) cooled to 0° C. was added methanesulfonyl chloride (7.8 ml), and the mixture was stirred for 50 minutes. To the mixture was added 5% aqueous potassium bisulfate solution, and the mixture was extracted with ethyl acetate. The separated organic layer was sequentially washed with 4M aqueous sodium hydroxide solution twice and saturated aqueous sodium chloride solution once, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the titled compound (17.1 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[O:15]1[C:19]2[CH2:20][CH2:21][CH2:22][C:23](=O)[C:18]=2[CH:17]=[CH:16]1.[Cl-].[NH4+].CC[O:29]CC>CCCCCC>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:23]1[C:18]2[CH:17]=[CH:16][O:15][C:19]=2[CH:20]([OH:29])[CH2:21][CH2:22]1
Reactant: O=C1CCCc2occc21
Reactant: c1ccc2occc2c1
Reactant: CCOCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Product: OC1CCC(c2cc3ccccc3o2)c2ccoc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of 11.1 g (0.0939 mol) of benzofuran in 150 ml of ether cooled to -20° C. was added a solution of 9.39 ml (0.0939 mol) 10M n-butyllithium in hexane, and the mixture was allowed to warm to 0° C. and stirred for 30 min. The mixture was cooled to -78° C. and 10.6 g (0.078 mol) of 4,5,6,7-tetrahydrobenzofuran-4-one in 20 ml of ether was added dropwise and the mixture was allowed to warm to room temperature, and then stirred for 1 h. To the mixture was added saturated ammonium chloride solution and the resulting mixture was extracted with ethyl acetate (3×100 ml). The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 19.3 g (97%) of 4,5,6,7-tetrahydro-4-(2-benzofuryl)benzofuran-7-ol, an oil which crystallized on standing as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=[C:17]([C:28]#[N:29])[C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[C-:30]#[N:31].[Na+].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>CN(C)C=O.O.C(Cl)(Cl)Cl>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([C:30]#[N:31])=[C:17]([C:28]#[N:29])[C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: [C-]#N
Reactant: CCn1c2ccccc2c2cc(C=C(C#N)c3ccc(C(F)(F)F)cc3)ccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Pb+4]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCn1c2ccccc2c2cc(C(C#N)=C(C#N)c3ccc(C(F)(F)F)cc3)ccc21
Reaction time: 0.17 h
Yield: 24.1 %

Procedure:
0.78 g (2.00 mmol) of N-ethyl-3-(2-cyano-2-(4-trifluoromethylphenyl)ethenyl) carbazole and 10 ml of N,N-dimethylformamide as solvent were placed in a 200 ml four-necked flask with a mechanical stirrer and bulb-shaped cooler. To this was added an aqueous solution prepared from 0.10 g (2.00 mmol) of sodium cyanide and 1.0 ml of water, which was stirred for 10 minutes. Further, 0.88 g (2.00 mmol) of lead tetraacetate was added. The resultant product was subjected to the reaction for 30 minutes. After the reaction was completed, 100 ml of chloroform was added. To the resultant solution was added 50 ml of water. The resultant liquid was washed in a separatory funnel. To the washed liquid was added sodium sulfate, which was left to stand for 30 minutes and dehydrated. The dehydrated solution was concentrated in an evaporator and dried under vacuum to obtain 0.20 g of a yellow solid. The yield of the synthesized compound was 24%, and its melting point was 180-182° C. The IR chart is shown in FIG. 17.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:17]([CH3:18])=[C:16]([NH2:19])[C:15]([CH3:20])=[N:14]1.[CH3:21][N:22]=[C:23]=[O:24]>O1CCCC1.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:17]([CH3:18])=[C:16]([NH:19][C:23]([NH:22][CH3:21])=[O:24])[C:15]([CH3:20])=[N:14]1
Reactant: Cc1nn(-c2cc(OC(C)C)c(Cl)cc2F)c(C)c1N
Reactant: CN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1c(C)nn(-c2cc(OC(C)C)c(Cl)cc2F)c1C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a solution of 1-(2-fluoro-4-chloro-5-isopropoxyphenyl)-3,5-dimethyl-4-aminopyrazole (29.8 g) in tetrahydrofuran (100 ml) was added one drop of triethylamine and then added dropwise a solution of methyl isocyanate (6.0 g) in tetrahydrofuran (50 ml). After the completion of addition, the reaction mixture was left to stand at room temperature for one hour. Removal of the solvent from the reaction solution by distillation in vacuo gave the titled compound (34.7 g) as a white crystalline solid. Recrystallization of the solid from a mixture of cyclohexane/acetone provided a white crystalline solid. m.p. 184°-185° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[Cl:13]N1C(=O)CCC1=O.O>CN(C)C=O>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12]
Reactant: Nc1cccc2c1CCCC2=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Cl)c2c1CCCC2=O
Reaction time: 60 h

Procedure:
A solution of 5-amino-1-tetralone (Itoh, K. Chem. Pharm. Bull. (1984), 32, 130-151) (0.50 g, 3.1 mmol) in dimethylformamide (15 mL) was treated with N-chlorosuccinimide (0.49 g, 3.7 mmol), stirred for 60 hours, treated with water and extracted with ether (4×30 mL). The combined ether extracts were washed with brine, dried (Na2SO4) and concentrated. Purification of the residue on silica gel with ethyl acetate:hexanes 1:1 provided the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]([OH:18])=O)[CH:12]=2)[C:7]1=[O:19].[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[CH2:30][CH2:31][CH2:32][NH2:33]>>[Cl-:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]([NH:33][CH2:32][CH2:31][CH2:30][NH+:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]3[CH3:23])=[O:18])[CH:12]=2)[C:7]1=[O:19]
Reactant: O=C(O)c1ccc2c(c1)C(=O)N(Cc1cccc(Cl)c1)C2=O
Reactant: CC1CCCCN1CCCN
Product: CC1CCCC[NH+]1CCCNC(=O)c1ccc2c(c1)C(=O)N(Cc1cccc(Cl)c1)C2=O
Product: [Cl-]

Procedure:
2-(3-chloro-benzyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-carboxylic acid (100 mg, 0.316 mmol) and 3-(2-methylpiperidin-1-yl)propan-1-amine (138 μL, 0.792 mmol) were reacted with each other. Target compound in the amount of 106 mg (68%) was obtained by following the procedure described in Example 1.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[NH2:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1>O1CCCC1>[OH:18][C:14]1[CH:13]=[C:12]([NH:11][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)=[O:7])[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cccc(O)c1
Reactant: O=C(Cl)CCCCC(=O)Cl
Solvent: C1CCOC1
Product: O=C(CCCCC(=O)Nc1cccc(O)c1)Nc1cccc(O)c1
Reaction time: 0.21 h

Procedure:
A solution of adipoyl chloride (5.5 g, 0.03 mol) in dry tetrahydrofuran (THF, 50 mL) is added dropwise to a magnetically stirred solution of 3-aminophenol (13.0 g, 0.12 mol) in 150 mL of THF. A precipitate forms after 10-15 minutes and is collected by filtration, washed with water, washed with a mixture of water and tetrahydrofuran and recrystallized from an ethanol/water mixture. Analysis of the resulting 8.86 g of white solid indicates it to have the following structure: ##STR2##
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([NH:20][S:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH2:16][CH2:15]2)=[O:13])=[CH:7][CH:6]=1)(C)(C)C.[CH:27]1[CH:32]=C(C([O-])=O)C(C(O[O-])=O)=[CH:29][CH:28]=1.[Mg+2].C[OH:42]>C(Cl)Cl.O>[CH2:32]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([NH:20][S:21]([C:23]([CH3:24])([CH3:25])[CH3:26])(=[O:42])=[O:22])[CH2:16][CH2:15]2)=[O:13])=[CH:9][CH:10]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CC(C)(C)c1ccc(NC(=O)N2CCC(NS(=O)C(C)(C)C)CC2)cc1
Reactant: CO
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: O
Product: CCCCc1ccc(NC(=O)N2CCC(NS(=O)(=O)C(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a mixture of 2 ml of methanol and 2 ml of methylene chloride, 291 mg of 4-t-butylsulfinylaminopiperidine-1-carboxylic acid(4-t-butylphenyl)amide was dissolved. To the mixture, 570 mg of 80%-MMPP (magnesium monoperoxyphthalate hexahydrate) was added and the mixture was stirred at room temperature for 2 hours. The solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate anhydride. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography to give 130 mg of 4-t-butylsulfonylaminopiperidine-1-carboxylic acid(4-butylphenyl)amide (I-120).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[C:35]1(O)[CH:40]=[CH:39]C=[CH:37][CH:36]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][C:24]2[CH:39]=[CH:40][CH:35]=[CH:36][CH:37]=2)=[CH:18][CH:17]=1
Reactant: Oc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)cc3)c2cc1OC
Yield: 69 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (151 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 10 min. Next, phenol (48 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (97 mg, yield 63%).
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1.[Cl-].[NH4+]>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[CH:34]([C:33]1[CH:36]=[CH:37][C:30]([O:29][CH3:28])=[CH:31][CH:32]=1)[OH:35])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Fc1ccc(OCc2ccccc2)c(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2cc(F)ccc2OCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (2.44 M, 2.4 mL) was added dropwise to a solution of 1-benzyloxy-2-bromo-4-fluorobenzene (1.5 g, 5.33 mmol) in THF (60 mL) at −78° C. and the mixture was stirred at the same temperature for 30 minutes. To this solution, a solution of 4-methoxybenzaldehyde (0.6 g, 4.42 mmol) in THF (20 mL) was added dropwise at −78° C. The reaction mixture was stirred at the same temperature for one hour, and then a saturated ammonium chloride aqueous solution was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (0.98 g, 66%).
Reaction SMILES: C([N:11]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([F:39])([F:38])[F:37])[C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)(OCC1C=CC=CC=1)=O.C(N(CC)CC)C.[C:47]([OH:55])(=[O:54])[CH:48]([CH2:50][C:51]([OH:53])=[O:52])[OH:49].[H][H]>O1CCCC1.[Pd].CCOCC>[F:37][C:36]([F:38])([F:39])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][NH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([O:54][C:47](=[O:55])[CH:48]([CH2:50][C:51]([OH:53])=[O:52])[OH:49])=[O:17])=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(N(CCCCCCCCCCCCCCCC(F)(F)F)C(=O)OCc2ccccc2)cc1
Reactant: O=C(O)CC(O)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(O)CC(O)C(=O)OC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
A warm solution of 4-[N-carbobenzyloxy-15-(trifluoromethyl)pentadecylamino]benzoyl chloride and 1.3 g. triethylamine in 100 ml. ether is treated with 2 g. malic acid. An immediate precipitate forms, but the mixture is refluxed for one hour and filtered while hot. The solid is washed several times with hot ether, then the ether is evaporated to yield a white solid. The product is dissolved in tetrahydrofuran (100 ml.) and hydrogenated over 600 mg. 10% palladium-on-carbon at 50 psi until hydrogen uptake stops. The catalyst is filtered, and the solution is evaporated. The residue is crystallized from acetic acid to yield the product as a white solid.