Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:22])=[O:21])=[CH:15][CH:14]=3)[C:7](=[O:12])[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.O1CCCC1.O.C([O-])=O.[NH4+]>CO>[O:12]=[C:7]1[N:6]([C:13]2[CH:14]=[CH:15][C:16]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])=[CH:17][CH:18]=2)[C:5]2[CH:29]=[CH:30][CH:2]=[CH:3][C:4]=2[NH:10][C:9](=[O:11])[CH2:8]1
Reactant: O=C1CC(=O)N(c2ccc(NS(=O)(=O)c3ccccc3)cc2)c2ccc(Cl)cc2N1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)c3ccccc3)cc2)c2ccccc2N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.7 %

Procedure:
N-[4-(7-Chloro-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)phenyl]benzenesulfonamide (28 mg, 0.06 mmol) obtained in Example 169 was dissolved in methanol (0.6 mL), tetrahydrofuran (0.6 mL), and water (0.6 mL), the solution was added with ammonium formate (38 mg, 0.6 mmol), and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was filtered through Cerite, and the solvent was evaporated under reduced pressure. The obtained residue was added with water, the mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=100/1) to obtain the title compound (19 mg, yield 77%).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[CH:9]=1)=O.[NH3:18]>CO>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:8]1[CH:9]=[C:5]([C:3]([NH2:18])=[O:2])[N:6]=[CH:7]1
Reactant: COC(=O)c1cn(Cc2ccccc2F)cn1
Reactant: N
Solvent: CO
Product: NC(=O)c1cn(Cc2ccccc2F)cn1

Procedure:
4.0 g of 1-(o-fluorobenzyl)-imidazole-4-carboxylic acid methyl ester are dissolved in 80 ml of methanol and transferred to an autoclave. 20.0 g of ammonia are introduced under pressure and the whole is heated at 100° for 19 hours. When the excess ammonia has been blown off, the resulting product is filtered off and recrystallised from ethanol. 1-(o-fluorobenzyl)-imidazole-4-carboxamide having a melting point of 204°-205° is obtained.
Reaction SMILES: Cl.O1CCOCC1.Cl[C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([NH:20][CH3:21])=[O:19])[C:12]([Cl:26])=[CH:11][N:10]=1.[CH2:27]([N:29]1[CH:38]2[CH2:39][CH2:40][CH:30]1[C:31]1[CH:32]=[C:33]([NH2:41])[CH:34]=[CH:35][C:36]=1[CH2:37]2)[CH3:28].C(=O)([O-])[O-]>COCCO>[Cl:26][C:12]1[C:13]([NH:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([NH:20][CH3:21])=[O:19])=[N:14][C:9]([NH:41][C:33]2[CH:34]=[CH:35][C:36]3[CH2:37][CH:38]4[N:29]([CH2:27][CH3:28])[CH:30]([CH2:40][CH2:39]4)[C:31]=3[CH:32]=2)=[N:10][CH:11]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C2CCC1c1cc(N)ccc1C2
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCO
Solvent: C1COCCO1
Product: CCN1C2CCC1c1cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
2-methoxyethanol (8.6 mL), 4N HCl in p-dioxane (0.215 mL, 1.2 eq) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (129 mgs, 1 eq) and (+/−)-12-Ethyl-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine was heated to 120° C. for 2 h. The mixture cooled to room temp treated with 3 equivalents of MP-carbonate and stirred for 30 min. Filtration, followed by concentration and purification by ISCO chromatography (12 gram column, SiO2, gradient 20% EtOAc/hexane to 100% EtOAc) gave (+/−)-2-[5-Chloro-2-(12-ethyl-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (45 mg, 11%). MP: 218-221° C.; 1H-NMR (CDCl3) δ 11.10 (s, 1H), 8.65 (d, J=8.1 Hz, 1H), 8.1 (s, 1H), 7.51-7.47 (m, 2H), 7.28-7.26 (m, 1H), 7.12-7.10 (m, 1H), 7.00 (s, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.52-6.49 (m, 1H), 3.89-3.84 (m, 2H), 3.58-3.55 (m, 2H), 3.05-3.03 (m, 1H), 3.04 (d, J=5.1 Hz, 3H), 2.61-2.51 (m, 3H), 2.25-2.21 (m, 2H), 1.18-1.10 (m, 3H); LC/MS (ESI+): 463.34 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:10])[CH:4]=1.N1C=CC=CC=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][S:18]([CH3:17])(=[O:20])=[O:19])=[C:5]([CH3:10])[CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(N)c(C)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(NS(C)(=O)=O)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
To a solution of 6.85 gm (50 mmol) 4-methoxy-2-methylaniline in 70 ml of methylene chloride was introduced 8.5 gm (ml; mmol) pyridine followed by dropwise addition of 6.87 gm (60 mmol) methanesulfonylchloride. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with 1N HCl and then with saturated aqueous brine. The organics were dried with sodium sulfate and then evaporated in vacuo. The residue was triturated in diethyl ether to afford 7.5 gm (79%) of a light purple solid. Mass spectrum APCI (m/z) 216 (p+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:41][OH:42])[C@@H:21]([OH:40])[C@@H:22]([OH:39])[C@H:23]([OH:38])[C:24]([NH:26][C@H:27]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:28][C:29]([OH:31])=[O:30])=[O:25])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[C:54]([O:60][CH2:61]I)(=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56].O>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:41][OH:42])[C@@H:21]([OH:40])[C@@H:22]([OH:39])[C@H:23]([OH:38])[C:24]([NH:26][C@H:27]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:28][C:29]([O:31][CH2:61][O:60][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])=[O:30])=[O:25])=[O:18])[CH2:13][CH:14]([CH3:15])[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)O)c1ccccc1
Reactant: CC(C)(C)C(=O)OCI
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OCOC(=O)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
To a solution of (S)-3-[(2S,3R,4R,5S)-5-(N-benzyloxycarbonyl-L-leucyl)amino-2,3,4,6-tetrahydroxyhexanoyl]amino-3-phenylpropionic acid (295 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.082 ml) in dimethylformamide (2 ml) was added a solution of iodomethyl pivalate (139 mg) in dimethylformamide (1 ml) and the mixture was stirred at room temperature for 1 hour. After addition of water, the reaction mixture was extracted with ethyl acetate and the extract was washed with 10% aqueous citric acid solution, saturated aqueous sodium hydrogencarbonate solution andsaturated brine respectively. The organic solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was passed through a column of silica gel, followed by elution with ethyl acetate:methanol (10:1). The effective fractions were combined and concentrated under reduced pressure. Recrystallization from chloroform provided the title compound (160 mg).
Reaction SMILES: O1C=CC=C1.[CH3:6][O:7][CH:8]1[CH2:12][CH:11]=[C:10]([O:13][CH3:14])[O:9]1>>[CH3:6][O:7][CH:8]1[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[O:9]1
Reactant: COC1=CCC(OC)O1
Solvent: c1ccoc1
Product: COC1CCC(OC)O1
Yield: 3.3 %

Procedure:
After 1 F/mol of furan, the proportion of furan in GC-percent by area had dropped from 22.7% to 16.9%, while the proportion of 2,5-dimethoxydihydrofuran in GC-percent by area remained constant at 30%. At the same time, 3.3% of 2,5-dimethoxytetrahydrofuran were formed.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.F[C:10]1[CH:11]=[C:12]([NH2:20])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1>O1CCCC1.CN1CCCC1=O.C1(C)C=CC=CC=1>[CH3:3][C:4]1[N:5]=[CH:6][N:7]([C:10]2[CH:11]=[C:12]([NH2:20])[CH:13]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:15]=2)[CH:8]=1
Reactant: Nc1cc(F)cc(C(F)(F)F)c1
Reactant: Cc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Temperature: 22.5 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (12.18 g, 55-65% m/m, Fluka 71620) is suspended in tetrahydrofuran (60 mL) and a solution of 4-methylimidazole (24.5 g) in tetrahydrofuran (65 mL) is slowly added to the stirred suspension at 20-25° C. Gentle cooling is necessary to maintain the temperature at 20-25° C. during the addition. After completion of the addition, the reaction mixture is stirred for additional 15 minutes at 20-25° C., until gas evolution had ceased. A solution of 3-fluoro-5-trifluoromethyl-phenylamine (XIX) (25 g) in 1-methyl-2-pyrrolidone (125 mL) is added slowly to the reaction mixture and the mixture is stirred for additional 15 minutes at 20-25° C. Then, the reaction mixture is heated at an oil bath temperature of 100° C. to distill off the volatile solvent (tetrahydrofuran). Finally, the temperature is raised to 165° C. (oil bath) and the reaction mixture is stirred for 22 hours at this temperature. For work up, the reaction mixture is poured onto water (500 mL) and the water phase is extracted with t-butyl methyl ether (2×500 mL). The t-butyl methyl ether phases are combined and are extracted with water (2×500 mL). The organic layer is dried on anhydrous magnesium sulfate (19 g) and the solvent is evaporated at 45° C. under reduced pressure to obtain crude 3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenylamine as a yellowish solid. The crude product is contaminated with at least 1 regioisomer. The crude product is dissolved in toluene (93.4 g) at 80-90° C. and the solution is allowed to cool down to room temperature. Crystallization occurred at ca. 35-40° C. The suspension is stirred for additional 2 hours at room temperature and the product is isolated by filtration. The filter cake is washed with ice-cold toluene (25 mL) and dried in vacuo at 50° C. to obtain pure 5-(4-methyl-imidazol-1-yl)-3-trifluoromethyl-phenylamine (I). GC-MS: m/z 241, 222, 213, 200, 186, 172, 160.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[CH3:5][O:6][C:7]([C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][NH:15]2)=[CH:11][CH:10]=1)=[O:8].C(N(CC)CC)C>C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][N:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([C:7]([O:6][CH3:5])=[O:8])[CH:17]=2)[CH2:13][CH2:14]1
Reactant: COC(=O)c1ccc2c(c1)NCC2
Reactant: BrCCBr
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)N(CCBr)CC2
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To 1,2-dibromoethane (15.7 ml) were added 6-methoxycarbonylindoline (2.41 g) and triethylamine (7.8 ml), and the mixture was stirred at 90° C. for 2 hr. Ethyl acetate (150 ml) was added to the reaction mixture, and the mixture was washed with saturated brine (300 ml) and dried over Na2SO4. Ethyl acetate was evaporated under reduced pressure. The obtained residue was purified by column chromatography to give the title compound (1.71 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH:15](OCC)(OCC)OCC.[N-:25]=[N+:26]=[N-:27].[Na+]>C(O)(=O)C.O.C(OCC)(=O)C>[N:1]1([C:2]2[N:7]=[CH:6][C:5]3[CH:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:9][CH2:10][C:4]=3[CH:3]=2)[CH:15]=[N:27][N:26]=[N:25]1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)C1CCc2cc(N)ncc21
Reactant: CCOC(OCC)OCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C1CCc2cc(-n3cnnn3)ncc21
Temperature: 80 °C

Procedure:
A mixture of methyl 3-amino-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylate (365 mg, 1.90 mmol), triethyl orthoformate (451 mg, 3.04 mmol), and sodium azide (185 mg, 2.85 mmol) in acetic acid (8 mL) was maintained in an oil bath heated at 80° C. for 3 h. After cooling to room temperature, the mixture was diluted with water and ethyl acetate and the layers separated. The aqueous was extracted with ethyl acetate (2×) and the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the resulting residue (8->80% EtOAc/hexanes eluent) provided the title compound. LC/MS (M+1)+=193.0.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].[CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH3:36])[CH3:35])[C:29]=1[N:37]=[C:38]=[O:39])([CH3:27])[CH3:26]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][N:10]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=2)[C:38]([NH:37][C:29]2[C:28]([CH:25]([CH3:26])[CH3:27])=[CH:33][CH:32]=[CH:31][C:30]=2[CH:34]([CH3:36])[CH3:35])=[O:39])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCCCCCCCc1ccc(NCc2ccc(C#N)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CCCCCCCCc1ccc(N(Cc2ccc(C#N)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 8.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using (4-cyanophenylmethyl)(4-octylphenyl)amine (3.65 g) and 2,6-diisopropylphenyl isocyanate (2.55 g) as starting materials, N-(4-cyanophenylmethyl)-N′-(2,6-diisopropylphenyl)-N-(4-octylphenyl)urea (0.49 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:13]2[CH2:18][CH2:17][CH:16]3[S:19][C:20](=[O:22])[CH:21]=[C:15]3[CH2:14]2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].ClC1C=CC(CC([O-])=O)=CC=1>>[C:23]([O:22][C:20]1[S:19][C:16]2[CH2:17][CH2:18][N:13]([C@@H:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:9]([O:11][CH3:12])=[O:10])[CH2:14][C:15]=2[CH:21]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@H](c1ccc(Cl)cc1)N1CCC2SC(=O)C=C2C1
Agent: O=C([O-])Cc1ccc(Cl)cc1
Product: COC(=O)[C@H](c1ccc(Cl)cc1)N1CCc2sc(OC(C)=O)cc2C1
Yield: 97 %

Procedure:
Following the method described in Example 4, (2S)-methyl 2-(4-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3.2-c]pyridin-5 (2H,4H,6H)-yl)-acetate (IV-3) (100 mg) was reacted with acetic anhydride (63 μl), to prepare (S)-methyl 2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(4-chlorophenyl-acetate (I-20) (110 mg). Yield 97%. 1H-NMR (300 MHz, CDCl3) δ 2.27 (s, 3H), 2.65-2.78 (m, 4H), 3.53 (s, 2H), 3.73 (s, 3H), 4.30 (s, 1H), 6.25 (s, 1H), 7.33-7.46 (m, 4H); 13C-NMR (75 MHz, CDCl3) δ 20.7, 24.7, 48.1, 50.4, 52.2, 71.9, 111.9, 125.7, 128.9, 130.1, 134.3, 134.4, 149.6, 167.7, 171.4; ESI-MS m/z 380.1 [M+H]+; HRMS Calcd for C18H19NO4SCl [M+H]+ m/z 380.0723. found 380.0735.
Reaction SMILES: O[CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[C:17]3=[N:18][CH:19]=[N:20][C:21]([NH:22][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:16]3[CH:15]=[N:14]2)[O:4]1.ClC(Cl)C(O)=O.C1CCC(N=C=NC2CCCCC2)CC1.[CH2:52]([O:54][P:55]([CH:60]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:57][CH2:58][CH3:59])=[O:56])[CH3:53]>CS(C)=O.O.CO>[C:23]([NH:22][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:13]([C@H:5]3[C@@H:6]4[O:10][C:9]([CH3:12])([CH3:11])[O:8][C@@H:7]4[C@@H:3](/[CH:2]=[CH:60]/[P:55](=[O:56])([O:57][CH2:58][CH3:59])[O:54][CH2:52][CH3:53])[O:4]3)[N:14]=[CH:15][C:16]=12)(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOP(=O)(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)OCC
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1ncc2c(NC(=O)c3ccccc3)ncnc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)C(Cl)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CO
Product: CCOP(=O)(/C=C/[C@H]1O[C@@H](n2ncc3c(NC(=O)c4ccccc4)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)OCC
Reaction time: 8 h
Yield: 27 %

Procedure:
Compound 22.3 (2.03 g, 4.93 mmol) in anhydrous dimethyl sulfoxide (25 mL, 0.2 M) was treated with dichloroacetic acid (400 μL, 4.93 mmol) and DCC (2.04 g, 9.67 mmol). The solution was stirred at room temperature for 2 h. [(Diethoxyphosphinyl)methylidene]triphenylphosphorane (2.0 g, 4.93 mmol, J. Org. Chem. 1996, 61, 7697-7701) was added and the mixture was stirred overnight. MeOH (25 mL) and H2O (25 mL) were added and the mixture was filtered over a plug of SiO2 and washed with MeOH (3×25 mL). The solvent was removed in vacuo and residue was suspended in CH2Cl2 and filtered over a plug of SiO2, and the solvent removed in vacuo. The residue was subjected to a column chromatography eluting with 0-100% EtOAc-hexanes, followed by 0-20% MeOH—CH2Cl2 to afford compound 22.4 (734 mg, 27% yield, E/Z ratio not determined) as a white solid (data for major isomer): 1H NMR (CDCl3, 300 MHz) 9.73 (br s, 1H), 8.71 (s, 2H), 7.91 (d, J=7.8 Hz, 2H), 7.50 (m, 1H), 7.35 (t, J=7.5 Hz, 2H), 6.89 (m, 1H), 6.15 (br s, 1H), 5.95 (m, 1H), 4.78 (m, 1H), 4.62 (m, 1H), 4.36 (m, 1H), 4.01 (m, 4H), 1.23 (m, 12H); 31P NMR (DMSO-d6, 121.4 MHz) 15.9; MS (ESI) m/z 544 [M+H+].
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1([CH:16]=[CH:15][C:13]([OH:14])=[CH:12][CH:11]=1)[OH:10]>>[C:3]1([CH:2]([C:11]2[CH:12]=[C:13]([OH:14])[CH:15]=[CH:16][C:9]=2[OH:10])[CH3:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Oc1ccc(O)cc1
Reactant: C=Cc1ccccc1
Product: CC(c1ccccc1)c1cc(O)ccc1O

Procedure:
Styrene and hydroquinone are reacted to produce (1-phenylethyl) hydroquinone, i.e., ##STR1##
Reaction SMILES: [CH:1]1(N=C=NC2CCCCC2)CCCC[CH2:2]1.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:24][C:25]([OH:27])=O)[CH:20]=[CH:21][C:22]=1[Cl:23].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([OH:38])[CH2:35][NH:36][CH3:37])[CH:29]=1>C(Cl)Cl>[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([OH:38])[CH2:35][N:36]([C:25](=[O:27])[CH2:24][C:19]2[CH:20]=[CH:21][C:22]([Cl:23])=[C:17]([Cl:16])[CH:18]=2)[CH2:37][CH2:1][CH3:2])[CH:29]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: CNCC(O)c1cccnc1
Solvent: ClCCl
Product: CCCN(CC(O)c1cccnc1)C(=O)Cc1ccc(Cl)c(Cl)c1
Reaction time: 0.08 h

Procedure:
To a flask containing 630 mg (3.1 mmol) of DCC (dicyclohexylcarbodiimide) was added 3 ml of methylene chloride and with stirring a solution of 625 mg (3.1 mmol) of 3,4-dichlorophenyl acetic acid in 5 ml of methylene chloride was added dropwise resulting in the formation of a precipitate. The reaction mixture was stirred for 5 minutes, and to it was added 550 mg (3.05 mmol) of 1-(3-pyridyl)-2-methylaminoethanol in 6 ml of methylene chloride, it was stirred further for 1 hour at 20° C. A precipitate formed was filtered off, and the resulting solution was evaporated. The evaporated filtrate was purified by column chromatography on silica gel (silica gel 60, mobile phase: CHCl3:CH3OH=10:0.5). This yields 0.56 g (50%) of 1-(3-pyridyl)-2-(N-(2-(3,4-dichlorophenyl)acetyl)-N-propylamino)ethanol in the form the oil (molecular weight: 367.278, gross formula: C18H20N2O2Cl2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19](O)=[O:20])[O:8][C@H:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:6]=2[CH:29]=1.CN1CCOCC1.C(Cl)(=O)OCC.[BH4-].[Na+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](=[O:17])[C@@H:9]([CH2:18][CH2:19][OH:20])[O:8][C@H:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:6]=2[CH:29]=1
Reactant: CC(C)(C)CN1C(=O)[C@@H](CC(=O)O)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)CN1C(=O)[C@@H](CCO)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
In 200 ml of tetrahydrofuran was dissolved 14.7 g of trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid obtained in Example 2 and 4.51 ml of N-methylmorpholine. To the solution was added 3.92 ml of ethyl chlorocarbonate at -10° C; the mixture was then stirred for 15 minutes. After the addition of 3.86 g of sodium borohydride, 200 ml of methanol was added dropwise to the solution. The mixture was stirred for one hour at room temperature and then concentrated. After the addition of 200 ml of 1N hydrochloric acid, the concentrate was extracted with 200 ml of ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate aqueous solution and dried over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=1:1) to yield 14.2 g of trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethanol as colorless crystals, m.p. 157° to 159° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:25][C:24]1[C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:13]=2[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cccc2c1nc([C@H](C)NC(=O)OC(C)(C)C)n2-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2c1nc([C@H](C)N)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
To a solution of [(S)-1-(4-methyl-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester (380 mg, 1.08 mmol) in DCM (5 mL) was added TFA (1 mL) and the mixture was stirred at RT for 3 h. Additional TFA (0.5 mL) was added and stirring was continued for 30 min. Volatiles were then removed under reduced pressure and the residue was then dissolved in a small amount of DCM and loaded onto an SCX-2 cartridge which was initially washed with 10% MeOH in DCM. The product was eluted with 2M NH3/MeOH affording (S)-1-(4-Methyl-1-phenyl-1H-benzoimidazol-2-yl)ethylamine as a brown solid (222 mg, 82%). LCMS: RT 2.16 [M-NH2]+ 235.1
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:19])[C:12]2([C:16](O)=[O:17])[C:13]([CH2:15][CH:9]1[CH2:10][CH2:11]2)=[O:14].O>CCOCC>[CH3:7][C:8]1([CH3:19])[CH:9]2[CH2:10][CH2:11][C:12]1([CH2:16][OH:17])[CH:13]([OH:14])[CH2:15]2
Reactant: CC1(C)C2CCC1(C(=O)O)C(=O)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC1(C)C2CCC1(CO)C(O)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cooled mixture of lithium aluminum hydride (4 g, 105.4 mmol) in ether was added dropwise a solution of camphorsulfonyl chloride (10 g, 39.88 mmol) and ketopinic acid, prepared as described in Step 1, above. After the addition was complete, the ice bath was removed and the mixture was stirred at ambient temperature for 2 hrs. The mixture was cooled again and wet ether was added cautiously. When the violent reaction subsided, water was added. The mixture was then extracted three times with ethyl acetate. The combined extracts were washed with water and brine and dried over anhydrous magnesium sulfate. Evaporation of the solution gave 4.8 g of a white powder. NMR(δ): 0.90 (s, 3H), 1.20 (s, 3H).
Reaction SMILES: Br[CH2:2][CH:3](Br)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH2:21]([NH2:24])[CH2:22][NH2:23].[OH-].[K+]>>[CH2:4]([CH:3]([CH2:2][NH:23][CH2:22][CH2:21][NH2:24])[NH:23][CH2:22][CH2:21][NH2:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: NCCN
Reactant: CCCCCCCCCCCCCCCCC(Br)CBr
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCC(CNCCN)NCCN

Procedure:
A mixture of 1,2-dibromooctadecane (80 g) and anhydrous ethylenediamine (230 g) was added to 400 ml of ehtanol, and the mixture was refluxed under heating for 10 hours. Then, potassium hydroxide (30 g) was added, and the ethanol was distilled off under reduced pressure. The residue was extracted with 400 ml of benzene and recrystallized from 180 ml of ether to produce a pale yellow product.