Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[CH3:27][O:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH2:31][CH2:32][CH2:33][CH:34]2[CH2:39][CH2:40]Br>CN(C)C=O>[CH3:27][O:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH2:31][CH2:32][CH2:33][CH:34]2[CH2:39][CH2:40][N:12]1[C:11](=[O:14])[CH:10]=[CH:9][C:8]([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:13]1
Reactant: COc1cccc2c1CCCC2CCBr
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)n[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc2c1CCCC2CCn1nc(C(c2ccccc2)c2ccccc2)ccc1=O
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 6-diphenylmethyl-3(2H)-pyridazinone (0.22 g) and potassium tert-butoxide (0.10 g) in N,N-dimethylformamide (2 ml) was added a solution of 2-(5-methoxy-1,2,3,4-tetrahydro-1-naphthyl)ethyl bromide (0.18 g) in N,N-dimethylformamide (3 ml) at room temperature. The reactIon mixture was stirred for 2 hours at the same temperature and partitioned between water and ethyl acetate. The organic layer was washed with water (3 times) and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed (n-hexane - ethyl acetate) over silica gel to afford 2-[2-(5-methoxy-1,2,3,4-tetrahydro-1-naphthyl)ethyl]-6-diphenylmethyl-3(2H)-pyridazinone (0.25 g) as an oil.
Reaction SMILES: C(N(CC)CC)C.[Cl-].[CH2:9]([O:11][C:12]1([NH3+:15])[CH2:14][CH2:13]1)[CH3:10].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH2:9]([O:11][C:12]1([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][CH2:13]1)[CH3:10]
Reactant: CCOC1([NH3+])CC1
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC1(NC(=O)c2ccccc2)CC1

Procedure:
Triethylamine (2.5 g, 25 mmol) is added dropwise at 0° to a solution of 1-ethoxycyclopropylammonium chloride (1.25 g, 9.15 mmol) and benzoyl chloride (1.4 g, 10 mmol) in dry tetrahydrofuran (20 ml). The precipitate is filtered off and the filtrate is evaporated in vacuo yielding a crystalline residue. Sublimation following by recrystallisation from cyclohexane gives N-(1-ethoxycyclopropyl)-benzamide, mp 108°-109° (0.95 g, 51%); NMR (60 MHz): δCDCl 3 = 0.90-1.38 (m, 4H), 1.16 (t, J=7 Hz, 3H), 3.77 (q, J=7 Hz, 2H), 7.0-8.0 (1 m and 1 br. s, total 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])/[C:11](=[CH:14]\N(C)C)/[CH:10]2[CH2:18][C:19]3[C:24]([CH:9]12)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[O:26]1CCCC1>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])/[C:11](=[CH:14]\[OH:26])/[CH:10]2[CH2:18][C:19]3[C:24]([CH:9]12)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CN(C)/C=C1\C(=O)N(C(=O)OC(C)(C)C)C2c3ccccc3CC12
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C(=O)/C(=C\O)C2Cc3ccccc3C21
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a solution of 3-[1-dimethylamino-meth-(Z)-ylidene]-2-oxo-3,3a,4,8b-tetrahydro-2H-indeno[1,2-b]pyrrole-1-carboxylic acid tert-butyl ester E1 (190 mg, 0.579 mmol) in tetrahydrofurane (2 mL) was added hydrogen chloride (1M, 0.87 mL). The solution was stirred at room temperature for 3 h. The solution was diluted with ethyl acetate and washed with water, brine, dried and concentrated. The residue was triturated with ethyl acetate to give 3-[1-Hydroxy-meth-(Z)-ylidene]-2-oxo-3,3a,4,8b-tetrahydro-2H-indeno[1,2-b]pyrrole-1-carboxylic acid tert-butyl ester D1 (White powder, 140 mg, 80%). C17H19NO4; MW: 301.35; LCMS (method A) RT 1.72 min; ES: 302 (MK), 246; 1H NMR (400 MHz, DMSO-d6) δ 11.04 (1H, s), 7.54 (1H, d), 7.42 (1H, d), 7.13-7.31 (3H, m), 5.59 (1H, d), 3.70 (1H, m), 3.22 (1H, dd), 3.15 (1H, dd), 1.53 (10H, s) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[N:4]=[C:5]1[NH:11][CH2:10][CH2:9][CH2:8]C[NH:6]1.CC(C)([O-])C.[K+]>>[Cl:1][C:2]1[C:3]2[N:4]=[C:5]3[NH:6][CH2:8][CH2:9][CH2:10][N:11]3[C:12]=2[C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(N=C2NCCCCN2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=[N+]([O-])c1ccc(Cl)c2nc3n(c12)CCCN3
Temperature: 60 °C
Yield: 73 %

Procedure:
2-Chloro-N-1,3-diazepan-2-ylidene-5-nitroaniline (5.0 g, 19.6 mmol) and potassium t-butoxide (440 mg, 3.93 mmol) were dissolved in N,N-dimethylsulfoxide (100 mL), and heated at 60° C. for 24 hr. After cooling to room temperature, to the reaction mixture was directly purified by silica gel column chromatography eluting with a 50-100% ethyl acetate/n-hexane gradient mixture to give the title compound (3.63 g, 14.3 mmol, 73%) as a yellow amorphous.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[C:6]([CH3:10])[CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:13])=O>C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH2:8][Cl:13])=[C:6]([CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(C)c1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ccnc(C)c1CCl
Temperature: 0 °C
Reaction time: 18 h

Procedure:
The 2,4-dimethyl-3-hydroxymethylpyridine (19.2 g, 140 mmol) was dissolved in CH2Cl2 (800 mL) and cooled under nitrogen to 0° C. and thionyl chloride (125 mL) was slowly added and the reaction was stirred for 18 hours. The solvent was removed under reduced pressure and the residue was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate. The organic layer was dried with MgSO4, filtered and the solvent removed under reduced pressure to give the desired 2,4-dimethyl-3-chloromethylpyridine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=2[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[F:40][C:41]([F:56])([S:52](F)(=[O:54])=[O:53])[C:42]([F:51])([F:50])[C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45]>CN(C)C1C=CN=CC=1.ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([O:20][S:52]([C:41]([F:40])([F:56])[C:42]([F:50])([F:51])[C:43]([F:48])([F:49])[C:44]([F:47])([F:46])[F:45])(=[O:54])=[O:53])[CH:17]=[CH:16][C:15]=2[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)CC(c2ccc(O)cc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC1(C)CC(c2ccc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Reaction time: 16 h
Yield: 95.8 %

Procedure:
A mixture of 4-[5-hydroxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (1.5 g, 3.60 mmol) produced in Example (81b), 4-dimethylaminopyridine (22.2 mg, 0.18 mmol), diisopropylethylamine (0.758 mL, 4.32 mmol) and dichloromethane (10 mL) was cooled in an ice water bath and stirred under a nitrogen atmosphere. Perfluorobutanesulfonyl fluoride (0.773 mL, 3.96 mmol) was then added dropwise thereto. After stirring for 1 hour and 20 minutes under the same conditions, stirring was continued for 16 hours at room temperature. Water was added to the reaction mixture and extraction was performed with dichloromethane. The separated organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 2.41 g of the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:27][C:28]([F:45])([F:44])[C@@H:29]([O:31][C:32](=O)[O:33]C1C=CC([N+]([O-])=O)=CC=1)[CH3:30]>>[F:27][C:28]([F:45])([F:44])[C@@H:29]([O:31][C:32]([N:23]1[CH2:24][CH2:25][CH:20]([C@:18]2([CH3:26])[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[O:33])[CH3:30]
Reactant: C[C@]1(C2CCNCC2)Cc2cc(-c3ccc(S(C)(=O)=O)cc3)ncc2O1
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Product: C[C@H](OC(=O)N1CCC([C@@]2(C)Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1)C(F)(F)F

Procedure:
The title compound is prepared from (R)-5-(4-methanesulfonyl-phenyl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and carbonic acid 4-nitro-phenyl ester (S)-2,2,2-trifluoro-1-methyl-ethyl ester following a procedure analogous to that described in Example 1. LC (method 2): tR=1.01 min; Mass spectrum (ESI+): m/z=513 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([C:13](N)=[O:14])[O:9][C:8]=2[CH:16]=1)(=[O:3])[CH3:2].[CH2:17]([OH:19])[CH3:18]>Cl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([C:13]([O:19][CH2:17][CH3:18])=[O:14])[O:9][C:8]=2[CH:16]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)OC(C(N)=O)CO2
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C1COc2ccc(C(C)=O)cc2O1
Yield: 75 %

Procedure:
Heat a solution of 3 g (13.5 mmol) of 7-acetyl-2,3-dihydro-1,4-benzodioxin-2-carboxamide dissolved in 100 cm3 of ethanol saturated with hydrochloric acid at reflux for 18 hours under a nitrogen atmosphere. After cooling, the reaction mixture is filtered, concentrated and, after neutralisation with sodium hydrogen carbonate, extracted with methylene chloride. The crude product obtained by concentrating the organic phase to dryness is purified by chromatography on a silica column (eluant: petroleum ether/diethyl ether, 50:50). Ethyl 7-acetyl-2,3-dihydro-1,4-benzodioxin-2-carboxylate is thereby obtained in a yield of 75%. Melting point: 57° C. ##STR35##
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[C:12]3[NH:13][C:14](=[O:18])[C:15](=[O:17])[NH:16][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:21].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[N:33]=[C:34]=[O:35]>>[O:18]=[C:14]1[NH:13][C:12]2[C:7]([O:6][C:5]3[CH:19]=[CH:20][C:2]([NH:1][C:34]([NH:33][C:24]4[CH:25]=[C:26]([C:29]([F:30])([F:32])[F:31])[CH:27]=[CH:28][C:23]=4[F:22])=[O:35])=[C:3]([F:21])[CH:4]=3)=[CH:8][CH:9]=[N:10][C:11]=2[NH:16][C:15]1=[O:17]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)c(=O)[nH]c23)cc1F
Product: O=C(Nc1ccc(Oc2ccnc3[nH]c(=O)c(=O)[nH]c23)cc1F)Nc1cc(C(F)(F)F)ccc1F

Procedure:
Method F2 was used with 8-(4-amino-3-fluorophenoxy)pyrido[3,2-b]pyrazine-2,3(1H,4H)-dione and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene to give the title compound as a beige solid. Yield: 52 mg (51%).
Reaction SMILES: C([O:9][C@H:10]1[CH2:14][CH2:13][N:12]([C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH3:17])[CH3:16])[CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[K+]>CO>[C:18]1([C:15]([N:12]2[CH2:13][CH2:14][C@H:10]([OH:9])[CH2:11]2)([CH3:17])[CH3:16])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(c1ccccc1)N1CC[C@H](OC(=O)c2ccccc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(c1ccccc1)N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a methanol (15 mL) solution of (3S)-1-(2-phenylpropan-2-yl)pyrrolidin-3-yl benzoate (2.50 g, 7.09 mmol) was added 4.0 M potassium hydroxide solution (3.19 mL, 12.8 mmol). The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL), washed with water (50 mL), dried (sodium sulfate), and concentrated in vacuo to afford the title compound as a white solid. This crude product was used in the subsequent step without further purification. 1H NMR (500 MHz, CDCl3) δ 7.42 (d, J=7.8 Hz, 2H), 7.32 (t, J=7.7 Hz, 2H), 7.21 (t, J=7.3 Hz, 1H), 4.52 (s, 1H), 4.40 (br s, 1H), 3.49-3.38 (m, 3H), 3.34 (d, J=11.0 Hz, 1H), 2.04-1.91 (m, 2H), 1.71 (s, 6H); LC-MS: m/z 249.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[OH:17][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: O=C(CCCn1ccnc1)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(CCCn1ccnc1)c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a 0° C. solution of 5 g. of the above ketone in 150 ml. of anhydrous methanol was added excess sodium borohydride, and the mixture stirred for 1 hour. After removal of the solvent, a small quantity of water was added and the mixture was extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and evaporated to afford 1-[4-hydroxy-4-(4-chlorophenyl)butyl]imidazole.
Reaction SMILES: C([O:8][C:9](=[O:28])[C@@H:10]([C@@H:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:17][N:18]=[N+]=[N-])[CH2:11][CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1>C(O)C.[Pd]>[NH2:18][CH2:17][CH2:16][C@@H:15]([C@@H:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:9]([OH:28])=[O:8])[C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22]
Reactant: CC(C)C[C@@H](C(=O)OCc1ccccc1)[C@H](CCN=[N+]=[N-])C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)C[C@@H](C(=O)O)[C@H](CCN)C(=O)OC(C)(C)C
Yield: 97.1 %

Procedure:
A solution of 0.880 g of benzyl-2(R)-[3-azido-1(S)-(tert-butoxycarbonyl)propyl]-4-methylvalerate in 10 ml of ethanol was hydrogenated in the presence of 0.090 g of 5% palladium-on-carbon for 12 hours. The catalyst was removed by filtration and the solvent was evaporated to give 0.600 g of 2(R)-[3-amino-1(S)-(tert-butoxycarbonyl)propyl]-4-methylvaleric acid in the form of a white solid.
Reaction SMILES: CN.N.[CH2:4]([NH:11][C:12]1[N:17]=[C:16]([NH:18]C)[N:15]=[C:14]([C:20]([Cl:23])([Cl:22])[Cl:21])[N:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[NH2:18][C:16]1[N:17]=[C:12]([NH:11][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:13]=[C:14]([C:20]([Cl:23])([Cl:22])[Cl:21])[N:15]=1
Reactant: CNc1nc(NCc2ccccc2)nc(C(Cl)(Cl)Cl)n1
Agent: CN
Agent: N
Product: Nc1nc(NCc2ccccc2)nc(C(Cl)(Cl)Cl)n1

Procedure:
In a similar manner, substituting aqueous methylamine for ammonia, 2-benzylamino-4-methylamino-6-(trichloromethyl)-s-triazine m.p. 86°-87° was prepared.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH:4]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)[CH2:3]1.[NH2:18][C:19]1[CH:27]=[C:23]([C:24]([OH:26])=[O:25])[C:22]([OH:28])=[CH:21][CH:20]=1>C(O)(=O)C>[C:24]([C:23]1[CH:27]=[C:19]([N:18]2[C:5]3[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][C:4]=3[CH:9]=[C:10]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:20]=[CH:21][C:22]=1[OH:28])([OH:26])=[O:25]
Reactant: CC1CCC(=O)C(CC(=O)c2ccccc2)C1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Solvent: CC(=O)O
Product: CC1CCc2c(cc(-c3ccccc3)n2-c2ccc(O)c(C(=O)O)c2)C1

Procedure:
a solution of 50 g. (0.22 mole) of 4-methyl-2-phenacylcyclohexanone, 33.7 g. (0.22 mole) of 5-aminosalicylic acid, and 257 ml. of glacial acetic acid was heated under reflux for 3 hours, cooled and filtered. The collected solid was washed with water and recrystallized from acetonitrile to provide 43.3 g. (57%) of yellow crystals, m.p. 213°-215°.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:15]([OH:17])=O)[CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCCCC1)C.C(Cl)(=O)C(C)(C)C.[CH3:33][O:34][C:35](=[O:53])[C@H:36]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[NH:37][C:38](=[O:45])[C@H:39]([CH2:41][C:42](=[O:44])[NH2:43])[NH2:40].Br>ClCCl.N1C=CC=CC=1>[CH3:33][O:34][C:35](=[O:53])[C@H:36]([CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[NH:37][C:38](=[O:45])[C@H:39]([CH2:41][C:42](=[O:44])[NH2:43])[NH:40][C:15](=[O:17])[C@H:12]([CH2:13][OH:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Agent: Br
Agent: CC(C)(C)C(=O)Cl
Agent: CCN1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.04 h

Procedure:
Benzyloxycarbonylserine (8.4 g; 35 mmoles), N-ethylpiperidine (4.9 ml) and pyridine (3.5 ml) in dichlormethane (100 ml) cooled to -20° C. are treated under constant stirring with pivaloylchloride (4.4 ml); the mixture is stirred and cooled (0° C.) a further 8 minutes. After that, within 2 to 3 minutes, a solution of asparaginyl-phenylalanine methyl ester, liberated from its hydrobromide (13.1 g; 35 mmoles) by the addition of N-ethylpiperidine (4.9 ml), in dichloromethane (100 ml) is added. The reaction mixture is stirred for 2 hours at room temperature and evaporated. The noncrystalline residue is dissolved in ethyl acetate and the solution is successively washed with 1 M hydrochloric acid, water, 5% sodium hydrogencarbonate and water, dried over anhydrous sodium sulfate, and evaporated, after which the residue is crystallized from methanol. The yield is 9.1 g (51%), m.p. 180°-183° C. A sample is recrystallized from the same solvent and has m.p. 184°-186° C. Rf 0.71/S1, 0.82/S2. [α]D20 -13.8° (c 0.2; methanol). Composition: C25H30N4O8.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[O:8][C:7](=[O:9])[CH2:6][C:5](=[O:10])[CH2:4]1>[Pt](=O)=O.C(OCC)(=O)C>[Cl:1][CH2:2][CH:3]1[O:8][C:7](=[O:9])[CH2:6][CH:5]([OH:10])[CH2:4]1
Reactant: O=C1CC(=O)OC(CCl)C1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: O=C1CC(O)CC(CCl)O1
Reaction time: 7 h
Yield: 73.1 %

Procedure:
A mixture of 270 mg (1.66 mmol) of (-)-6-chloromethyltetrahydropyran-2,4-dione obtained in Example 1, 10 mg platinum dioxide and 100 ml of ethyl acetate was stirred for 7 hours under hydrogen atmosphere. After completion of the reaction, the catalyst was removed by filtration, and the solvent was distilled off to obtain 199.6 mg (yield 73%) of (+)-6-chloromethyl-4-hydroxytetrahydropyran-2-one [a compound of the formula (3)] having
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]2[N:17]=[CH:18][C:19]([C:20]#[N:21])=[C:6]12)=[O:4].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=1)[CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:27][N:28]2[CH2:33][CH2:32][N:31]([CH2:2][C:3]([N:5]3[CH2:10][CH:9]=[C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:7]4[N:17]=[CH:18][C:19]([C:20]#[N:21])=[C:6]34)=[O:4])[CH2:30][CH2:29]2)[CH:34]=[CH:35][CH:36]=1
Reactant: COc1cccc(CN2CCNCC2)c1
Reactant: N#Cc1cnn2c1N(C(=O)CCl)CC=C2c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cccc(CN2CCN(CC(=O)N3CC=C(c4ccccc4)n4ncc(C#N)c43)CC2)c1
Yield: 25.2 %

Procedure:
A mixture of 3.8 g of 4-(chloroacetyl)-4,5-dihydro-7-phenylpyrazolo[1,5-a]pyrimidine-3-carbonitrile, 2.9 g of 3-methoxybenzyl piperazine and 1.6 g of sodium carbonate in 165 ml of toluene was reacted as described in Example 146. The product was recrystallized from isopropanol, giving 1.5 g of the desired product, mp 98°-100° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[N+:15]([O-:17])=[O:16].C(=O)([O-])[O-].[K+].[K+].[C:25]([O:29][C:30](=[O:33])[CH2:31]Br)([CH3:28])([CH3:27])[CH3:26]>CC(C)=O>[C:25]([O:29][C:30](=[O:33])[CH2:31][O:14][C:12]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([N+:15]([O-:17])=[O:16])=[C:4]([C:3]([O:2][CH3:1])=[O:18])[CH:13]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(OCC(=O)OC(C)(C)C)cc(C(=O)OC)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
To a solution of 2.55 g. of dimethyl-5-hydroxy-2-nitroisophthalate (prepared as in Example 15, Part B) in 25 ml. of acetone is added 0.69 g. of anhydrous potassium carbonate, followed by 1.95 g. of tert-butylbromoacetate. The mixture is stirred and refluxed for 20 hr. After this time, the cooled reaction mixture is poured with rapid stirring into 200 ml. of ice-cold 1% hydrochloric acid. The solid is collected and washed well with water. Yield 3.4 g.; m.p. 106°-108° C.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][C:4]#[N:5].NCC[C@@H:14]([OH:20])[CH2:15][CH2:16][CH2:17][CH2:18]C.O.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([OH:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[C:22]1([CH3:32])[CH:23]=[CH:24][C:25]([S:28]([OH:31])(=[O:29])=[O:30])=[CH:26][CH:27]=1.[NH2:5][CH2:4][CH2:3][C@@H:2]([O:1][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][O:20]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCC(O)CC#N
Reactant: CCCCC[C@H](O)CCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCCCC[C@@H](CCN)OC1CCCCO1

Procedure:
This compound is prepared essentially by the same method as described in Example 1, Step A-2, except that the 3-hydroxycaprylonitrile is replaced by 1-amino-3(S)-octanol and slightly more than one equivalent of p-toluenesulfonic acid. hydrate is used. This method provides the p-toluenesulfonic acid salt of the title compound which is converted to the oily title compound by distribution between dilute sodium hydroxide and ether. The organic phase is washed with saturated aqueous brine, dried over sodium sulfate, and filtered. Evaporation of the filtrate in vacuo leaves the title compound as a residual oil.
Reaction SMILES: C1(OC(N([C@@H](C2C=CC=CC=2)C)[C:11](=[O:22])[CH:12]([CH2:19][CH:20]=[CH2:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=O)C=CC=CC=1.[O:31]([CH3:33])[Li]>CO>[CH2:19]([CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:11]([O:31][CH3:33])=[O:22])[CH:20]=[CH2:21]
Reactant: [Li]OC
Reactant: C=CCC(CCCCCC)C(=O)N(C(=O)Oc1ccccc1)[C@H](C)c1ccccc1
Solvent: CO
Product: C=CCC(CCCCCC)C(=O)OC
Reaction time: 22 h
Yield: 57.5 %

Procedure:
A solution of 0.218 g (0.5 mmol) of N-phenyloxycarbonyl-N-(2-allyloctanoyl)-1-(R)-phenylethylamine in 2 ml of methanol was cooled to 0° C., 0.38 g (1.0 mmol) of LiOMe was added, and the mixture was stirred for 22 hours. The reaction was terminated by addition of 2 ml of 1 N hydrochloric acid, and the product was extracted with ethyl acetate (30 ml×2). The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was quantitated by GC. Thus was obtained 0.057 g (58%) of the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:8][CH2:9][O:10][C:11]([C:13]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[C:17]([C:26](O)=[O:27])=[C:16]([CH3:29])[NH:15][C:14]=2[CH3:30])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].CCN=C=NCCCN(C)C.Cl.Cl>CN(C)C1C=CN=CC=1.ClCCl.O>[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][N:47]([C:26]([C:17]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[C:13]([C:11]([O:10][CH2:9][CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:12])=[C:14]([CH3:30])[NH:15][C:16]=2[CH3:29])=[O:27])[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C(C(=O)OCCC(c2ccccc2)c2ccccc2)=C(C)N1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC1=C(C(=O)OCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)C(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)=C(C)N1

Procedure:
258 mg (0.510 mmol) of 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid mono (3,3-diphenylpropyl) ester, 143 mg (0.770 mmol) of 1-t-butoxycarbonylpiperazine, 117 mg (0.610 mmol) of WSC hydrochloride and 18.0 mg (0.140 mol) of 4-dimethylaminopyridine were stirred at room temperature overnight in 15 ml of dichloromethane. After adding water and 1 N hydrochloric acid, the reaction mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=1/2) to obtain the title compound.