Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([OH:18])[N:13]=[C:12]2[CH3:19])[CH:5]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O.C(OCC)(=O)C.CCCCCCC>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:27][C:26]3[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[N:13]=[C:12]2[CH3:19])[CH:5]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(O)cc2=O)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(OC)cc3)cc2=O)c1
Temperature: 60 °C
Yield: 22.3 %

Procedure:
To a solution of 3-(4-hydroxy-2-methyl-6-oxo-6H-pyrimidin-1-yl)-4-methyl-benzoic acid methyl ester from Step D (800 mg, 66% purity, 1.93 mmol) in N,N-dimethylformamide (3 mL) was added 4-methoxybenzyl chloride (0.26 mL, 1.93 mmol), potassium carbonate (666 mg, 4.82 mmol) and 18-crown-6 (80 mg). The slurry was heated at 60° C. for two hours. The solution was allowed to cool to ambient temperature and was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated to a brown oil. Normal phase chromatography (ethyl acetate/heptane) provided the alkylated product as a white solid (170 mg, 22% yield). MS (M+H): 395
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:33])[NH:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:31])([CH3:30])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=O)[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:15][C:14]=2[OH:32])[CH:10]=[CH:11][CH:12]=1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([NH:3][C:4]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:31])([CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:30])=[CH:15][C:14]=2[OH:32])[CH:10]=[CH:11][CH:12]=1)=[O:33])[CH3:2]
Reactant: CCNC(=O)NCc1cccc(-c2ccc(C(C)(C)CCCNC(=O)C(C)(C)C)cc2O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNC(=O)NCc1cccc(-c2ccc(C(C)(C)CCCNCC(C)(C)C)cc2O)c1
Temperature: 25 °C

Procedure:
To a solution of 35 (0.1 g, 0.22 mmol, 1.0 eq) in tetrahydrofuran (10 mL) under nitrogen at 0° C. was added lithium aluminum hydride (1.0 M in THF, 1.76 mL, 1.76 mmol, 4.0 eq). The mixture was slowly warmed up to room temperature over 2.5 hours. The reaction was quenched with ice chips, and then water and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate (2×20 mL), and the combined organic layer was washed with water (20 mL), brine (20 mL) and dried over anhydrous MgSO4 The solvent was removed under reduced pressure, and the residue was purified by column chromatography (silica gel, 2-10% methanol in dichloromethane).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.Cl[C:10](=[O:15])[C:11]([O:13][CH3:14])=[O:12]>>[CH3:14][O:13][C:11](=[O:12])[C:10]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1)=[O:15]
Reactant: COC(=O)C(=O)Cl
Reactant: Cc1ccc(N)nc1
Product: COC(=O)C(=O)Nc1ccc(C)cn1

Procedure:
The method described in Referential Example 242 was performed by use of 2-amino-5-methylpyridine and methyl chlorooxoacetate, whereby the title compound was obtained.
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:12][N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18].[H-].[Na+].Cl>C1(C)C=CC=CC=1.CO>[CH3:12][N:13]1[CH2:17][CH2:16][CH:15]([C:1](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=2)[C:14]1=[O:18]
Reactant: CCOC(=O)c1cccnc1
Reactant: CN1CCCC1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CN1CCC(C(=O)c2cccnc2)C1=O
Temperature: 25 °C
Reaction time: 30 h
Yield: 83.8 %

Procedure:
Ethyl nicotinate (10.3 g, 66 mmol) and N-methyl-2-pyrrolidone (6.5 mL, 66 mmol) were dissolved in a dry toluene (200 mL) and sodium hydride (4 g) was added therein in batch. The mixture was stirred for 30 h under reflux, and then cooled to room temperature, and 5 mL methanol was added to quench the reaction. The reaction solution was poured into 1 mol/L of diluted hydrochloric acid (70 mL), extracted with dichloromethane. The extract was washed with saline and concentrated till dry to give 11.3 g colorless oily product (1-methyl-3-nicotinoyl-2-pyrrolidone) with a yield of 81%. 1HNMR (CD3OD, 300 MHz) δ: 9.21 (d, 1H), 8.75 (dd, 1H), 8.48 (dt, 1H), 7.60 (dd, 1H), 4.70 (d, 1H), 3.48-3.57 (m, 1H), 3.41-3.46 (m, 1H), 2.85 (s, 3H), 2.52-2.60 (m, 1H), 2.30-2.38 (m, 1H); ESI-MS 205.0 (M+H), 243.1 (M+K).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.C(O)[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O>C(O)C>[CH:2]1([CH3:1])[CH2:3][CH2:4][CH:5]([CH:9]([CH3:10])[CH3:11])[CH:6]([OH:8])[CH2:7]1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Agent: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: CCO
Product: CC1CCC(C(C)C)C(O)C1

Procedure:
Two-hundred and sixteen parts of L-menthol and 43.2 parts of eucalyptus oil were dissolved in 100 parts of ethyl alcohol, and the resultant solution was added with 800 parts of an anhydrous maltose obtained by the method in Example for Reference 3. The resultant was granulated by spraying thereto 105 parts of a peppermint liquor, moisture content of about 50%, with stirring.
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([O:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1N)[CH:18]=[CH:17][CH:16]=2)=[O:12])[CH3:9]>CN(C)C=O.C(OCC)C>[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([O:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([F:29])[CH:28]=1)[CH:18]=[CH:17][CH:16]=2)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cc2c(Oc3cc(F)ccc3N)cccc2[nH]1
Agent: CC(C)(C)ON=O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Oc3cccc(F)c3)cccc2[nH]1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
Tert-butyl nitrite (0.46 ml, 4.45 mmol) is dissolved in 5 ml of dimethylformamide and heated to 65° C. A solution of 143 (1.4 g, 4.45 mmol) in 5 ml of dimethylformamide is added dropwise and the mixture is stirred of additional 10 minutes. The brown solution is cooled to room temperature, diluted with diethyl ether and washed with 2N HCl and brine. The organic layers are dried over sodium sulphate and evaporated. The crude product (1.0 g of a brown oil) is further purified by flash-chromatography (hexane/ethyl acetate 7:3).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12](=[O:14])[CH3:13])=[CH:10][C:5]=2[N:4]([CH3:15])[C:3]1=[O:16].[CH3:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O.N1CCCCC1>C1(C)C=CC=CC=1>[C:12]([C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3](=[O:16])[N:4]([CH3:15])[C:5]=2[CH:10]=1)=[CH:17][C:18]1[CH:19]=[C:20]([CH3:21])[CH:23]=[CH:24][CH:25]=1)(=[O:14])[CH3:13]
Reactant: Cc1cccc(C=O)c1
Reactant: CC(=O)Cc1ccc2c(c1)n(C)c(=O)n2C
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1cccc(C)c1)c1ccc2c(c1)n(C)c(=O)n2C
Reaction time: 18 h

Procedure:
1,3-Dimethyl-5-(2-oxo-propyl)-1,3-dihydro-benzoimidazol-2-one was diluted with toluene (30 mL) and treated with 3-methylbenzaldehyde (0.82 mL) and piperidine (0.3 mL). The mixture was placed in an oil bath set to a temperature of 145° C. and the flask was fitted with a pressure equalizing funnel containing 4 Å molecular sieves and equipped with a condenser. After 18 hours the mixture was allowed to cool and was concentrated. Chromatography on silica gel afforded 5-(1-Acetyl-2-m-tolyl-vinyl)-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (1.077 g).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH3:7])[CH:4]=O)[CH3:2].[CH3:8][C:9](=[O:12])[CH:10]=[CH2:11].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([C:3]1([CH2:6][CH3:7])[CH2:4][CH2:8][C:9](=[O:12])[CH:10]=[CH:11]1)[CH3:2]
Reactant: CCC(C=O)CC
Reactant: C=CC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCC1(CC)C=CC(=O)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 21.5 %

Procedure:
In 75 ml of benzene was dissolved 15.0 g of 2-ethylbutanal, to which were added 10.5 g of 3-buten-2-one and 0.15 ml of concentrated sulfuric acid at ambient temperature. While heating the mixture under reflux, an azeotropic distillation treatment was carried out for 3 hours by means of Dean Stark apparatus. The reaction mixture was poured into a mixture of ice water and ethyl acetate, pH was adjusted to 7.0 with a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by distillation under reduced pressure gave 4.90 g of 4,4-diethyl-2-cyclohexen-1-one as a light yellow oily product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5])[CH3:2].[CH3:17][O:18][CH2:19]C(O)=O.S(=O)(=O)(O)O.C(=O)=O>O.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([O:3][C:4]([C:6]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=[C:8]([CH2:17][O:18][CH3:19])[N:7]=1)=[O:5])[CH3:2]
Reactant: COCC(=O)O
Reactant: CCOC(=O)c1cccnc1C(=O)OCC
Agent: [Ag+]
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1ccc(COC)nc1C(=O)OCC

Procedure:
First of all 40 g of pyridine-2,3-dicarboxylic acid diethyl ester and then 33.3 g of methoxyacetic acid are added to a solution of 400 g of water, 36 g of concentrated sulphuric acid and 6.1 g of silver nitrate. The reaction mixture is then heated to 70° and a solution of 60.7 g of ammonium peroxydisulphate (NH4)2S2O8 in 225 ml of water is added dropwise thereto while stirring vigorously. When the evolution of CO2 has ceased, the reaction mixture is stirred for a further 20 minutes. It is then cooled to 15° and extracted twice with 200 ml of methylene chloride each time. The organic phases are collected, dried over magnesium sulphate, filtered and concentrated by evaporation. The oil that remains is chromatographed over a column of silica gel with ether/hexane 1:1, there being eluted from different fractions 9.1 g of 6-methoxymethylpyridine-2,3-dicarboxylic acid in the form of crystals having a melting point of 52°-54°, 12.9 g of 4,6-bis-methoxymethylpyridine-2,3-dicarboxylic acid diethyl ester in the form of an oil and 10.2 g of 4-methoxymethylpyridine-2,3-dicarboxylic acid diethyl ester also in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.Cl[CH2:18][CH2:19][OH:20].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl>CN(C)C=O.C(OCC)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:18][CH2:19][OH:20])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: OCCCl
Reactant: O=C(c1ccc(O)cc1)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)c1ccc(OCCO)cc1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
In an oven-dried flask placed under a nitrogen atmosphere, 4-fluorophenyl-4-hydroxyphenyl methanone (100 g), 2-chloroethanol (75 g), potassium carbonate (134 g) and potassium iodide (11.5 g) were stirred in anhydrous dimethylformamide (400 mL) using a mechanical stirrer. The reaction mixture was heated to reflux for 4 hours. It was cooled to room temperature and then poured into a beaker containing deionized water (1 L) and ice. Concentrated hydrochloric acid was added while stirring vigorously until the pH reached 3. The mixture was transferred to a separatory funnel and then extracted with chloroform (2×600 mL). The organic layers were combined and washed with a saturated aqueous solution of sodium bicarbonate (750 mL), dried over sodium sulfate and concentrated by rotary evaporation to yield a solid. The solid was slurried in a minimal amount of a solution of 10% ethyl acetate/90% hexanes and collected by vacuum filtration. 120 grams of 4-fluorophenyl-4-(2-hydroxyethoxy)phenyl methanone was isolated.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.S(Cl)([Cl:13])=O>CN(C)C=O>[Cl:1][C:2]1[S:3][C:4]([C:8]([Cl:13])=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(Cl)sc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nc(Cl)sc1C(=O)Cl

Procedure:
8.8 g of 2-chloro-4-methylthiazole-5-carboxylic acid was suspended in 7 ml of thionyl chloride, and one drop of N,N-dimethylformamide was added. The mixture was heated under reflux for 1 hour, and then the excess of thionyl chloride was evaporated under reduced pressure Benzene (10 ml) was added, and the mixture was evaporated under reduced pressure. This procedure was repeated three times to give 9.7 g of 2-chloro-4-methylthiazole-5-carboxylic acid chloride which was used in the following reaction without purification.
Reaction SMILES: C([Sn:9]([Cl:19])([Cl:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])CCCCCCC.C([Cl:28])CCCCCCC.[Cl-].C[S+](C)C>>[CH2:10]([Sn:9]([Cl:18])([Cl:19])[Cl:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCl
Reactant: CCCCCCCC[Sn](Cl)(Cl)CCCCCCCC
Agent: C[S+](C)C
Agent: [Cl-]
Product: CCCCCCCC[Sn](Cl)(Cl)Cl

Procedure:
Following the procedure outlined in Example 1, except that di-n-octyltin dichloride is used in place of dimethyltin dichloride, n-octyl chloride in place of methyl chloride, and trimethylsulfonium chloride in place of trimethylsulfonium iodide, there is obtained n-octyltin trichloride.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:23]([CH2:29][CH2:30][CH3:31])[C:24]([O:26]CC)=[O:25])[CH:8]=2)[N:3]=1.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:23]([CH2:29][CH2:30][CH3:31])[C:24]([OH:26])=[O:25])[CH:8]=2)[N:3]=1
Reactant: CCCC(C(=O)OCC)c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCC(C(=O)O)c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
1.2 g of ethyl 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]pentanoate are dissolved in 15 ml of tetrahydrofuran, and 10 ml of 2N sodium hydroxide solution are added. The mixture is stirred at 50° C. for 4 h and subsequently evaporated in vacuo. The mixture is then adjusted to pH2 using 25% hydrochloric acid with ice-cooling, with yellow crystals precipitating. The precipitate obtained is filtered off and dried in vacuo. Yield: 800 mg (72%) of 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]pentanoic acid; LC-MS retention time: 1.40 min (“nonpolar” gradient).
Reaction SMILES: C1S[C@@H](CCCCC(NCCCC[C@H](N)C(O)=O)=O)[C@H]2NC(N[C@@H]12)=O.[NH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1.C1C(=O)N([O:43][C:44]([CH2:46][CH2:47][CH2:48][CH2:49][CH:50]2[S:54][CH2:53][CH:52]3[NH:55][C:56]([NH:58][CH:51]23)=[O:57])=[O:45])C(=O)C1>>[OH:45][C:44]([CH2:46][CH2:47][CH2:48][CH2:49][C@H:50]1[C@@H:51]2[C@@H:52]([NH:55][C:56]([NH:58]2)=[O:57])[CH2:53][S:54]1)=[O:43].[NH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1
Reactant: O=C1NC2CSC(CCCCC(=O)ON3C(=O)CCC3=O)C2N1
Agent: NCCc1ccc(O)cc1
Agent: N[C@@H](CCCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(=O)O
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21

Procedure:
Para-hydroxyphenylpropionyl biocytin (HPPB) was prepared by mixing a solution of p-hydroxyphenylpropionic acid-N-hydroxysuccinimide ester (50 mg [0.2 mMol]/2 ml dimethyl sulfoxide) with biocytin (70.75 mg [0.2 mMol]/2 ml 0.1M NaHCO3) overnight at room temperature (RT). Biotin-tyramine (BT) was prepared by mixing a solution of tyramine (40 mg [0.3 mMol]/1 ml dimethyl sulfoxide) with biotin-N-hydroxysuccinimide ester (100 mg [0.3 mMol]/1 ml dimethyl sulfoxide) overnight at RT. The solutions of HPPB and BT were used as is. The calculated concentrations were 26 mg/ml for HPPB and 55 mg/ml for BT.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:6]1)=[O:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[Na+].S([O-])([O-])(=O)=O.[Mg+2].[OH-].[Na+]>C1CCCCC1>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CC(=O)N(c2ccc(O)cc2)C1
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: C1CCCCC1
Product: COC(=O)[C@@H]1CC(=O)N(c2ccc(O)cc2)C1
Yield: 44.8 %

Procedure:
213.5 mmol of (RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (98% HPLC) was suspended in 500 ml cyclohexane under moderate stirring. 2.0 l of 3 mM potassium phosphate buffer pH 6.0, containing 0.1 M sodium chloride and 50 mM magnesium sulfate, was added, and the resulting emulsion/suspension was re-adjusted to pH 6.0, and the temperature set to 30° C. Hydrolysis was started by the addition of 201 mg of cholesterase from Candida cylindracea (Roche Applied Science, Industrial Products, Enzyme Projects, Sandhofer Str. 116, D-68305 Mannheim, Germany, order number 10129046103, hereinafter: Enzyme) and the pH kept constant at 6.0 by the controlled addition of 0.1 N NaOH solution (pH-stat) under moderate stirring. After a total consumption of 1016 ml of titrating agent (overnight; 48.6% conversion) the reaction mixture was extracted with 3.5 l and 2×2.5 l dichloromethane (turbid phases in the beginning), and subsequently with 3.5 l ethyl acetate (org. phase discarded). The combined dichloromethane phases were dried over sodium sulfate, evaporated and dried under HV to give 22.5 g (95.6 mmol; 44.8%) of (R)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as white crystals. Analytics: HPLC: >99%. Enantiomeric excess: 96.3% (Chiralpak AD, 250×4.6 mm; 70% hexane+10% 0.1% TFA in hexane+20% ethanol; 1 ml/min; DAD: sig=210.8 nm, ref=360.1 nm; sample application: 0.5 μl of 2 mg/ml 1% TFA in EtOH). [δ]D=−27.7° (c=1.02; EtOH). EI-MS: m/e=235.1 (M; 67), 122.0 (100). 1H-NMR (400 MHz; CDCl3): 2.89 (ddd, 2H, —CHaHb—), 3.37 (m, 1H, —CHCOO), 3.78 (s, 3H, COOCH3), 4.03 (ddd, 2H, C(O)NCHaHb), 6.08 (s, 1H, Ph-OH), 6.77, 7.30 (AA′XX′, 2×2H, C6H4).
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.Cl[CH2:14][C:15]1[O:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=1>>[I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[N:9]([CH2:14][C:15]3[O:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[C:4]=2[CH:3]=1
Reactant: O=C1CNc2ncc(I)cc2N1
Reactant: FC(F)(F)c1ccc(CCl)o1
Product: O=C1CNc2ncc(I)cc2N1Cc1ccc(C(F)(F)F)o1
Yield: 87 %

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (659 mg) was reacted with 2-(chloromethyl)-5-(trifluoromethyl)furan as in General Procedure 1 to give the title compound as a beige solid (87% yield). M.p. 189-191° C., LCMS: m/z=424.20 (M+H+), 1H-NMR (CDCl3, 400 MHz,) δ 4.21 (s, 2H), 4.95 (bs, 1H), 5.05 (s, 2H), 6.39 (s, 1H), 6.75 (s, 1H), 7.50 (s, 1H), 7.96 (s, 1H).
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:39])[C:15]([CH3:38])([CH3:37])[CH:16]([CH:29]=[CH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH:17][C:18](=[O:28])[C:19]2[CH:24]=[CH:23][C:22]([C:25](=[NH:27])[NH2:26])=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O.O>[C:25]([C:22]1[CH:21]=[CH:20][C:19]([C:18]([NH:17][CH:16]([CH:29]=[CH:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:15]([CH3:37])([CH3:38])[C:14]([N:11]2[CH2:10][CH2:9][CH:8]([CH2:7][C:6]([OH:40])=[O:5])[CH2:13][CH2:12]2)=[O:39])=[O:28])=[CH:24][CH:23]=1)(=[NH:26])[NH2:27]
Reactant: CC(C)(C)OC(=O)CC1CCN(C(=O)C(C)(C)C(C=Cc2ccccc2)NC(=O)c2ccc(C(=N)N)cc2)CC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C(=O)N1CCC(CC(=O)O)CC1)C(C=Cc1ccccc1)NC(=O)c1ccc(C(=N)N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.7 %

Procedure:
N-4-Amidinobenzoyl-β-styryl-α,α-dimethyl-β-alanyl-4-piperidineacetic acid t-butyl ester (30 mg, 0.055 mmol) was dissolved in a mixed solution of TFA (10 ml) and water (0.5 ml). The resulting solution was stirred at room temperature for 3 hours. After the TFA was distilled off at room temperature, the residue was purified by the same method as in Example 2-(6-4) to yield N-(N-4-amidinobenzoyl-β-styryl-α,α-dimethyl-β-alanyl)-4-piperidineacetic acid (7.2 mg, 26.7%).
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][C:8]1([C:13]2[CH:18]=[CH:17][C:16]([N:19]([C:21](=[O:42])[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[CH3:39])=[O:31])=[C:25]([O:40][CH3:41])[CH:24]=3)[CH3:20])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.ClCCl>O>[CH3:41][O:40][C:25]1[CH:24]=[C:23]([CH2:22][C:21]([N:19]([CH3:20])[C:16]2[CH:17]=[CH:18][C:13]([C:8]3([CH2:7][C:6]([OH:43])=[O:5])[CH2:12][CH2:11][CH2:10][CH2:9]3)=[CH:14][CH:15]=2)=[O:42])[CH:28]=[CH:27][C:26]=1[NH:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39])=[O:31]
Reactant: COc1cc(CC(=O)N(C)c2ccc(C3(CC(=O)OC(C)(C)C)CCCC3)cc2)ccc1NC(=O)Nc1ccccc1C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(CC(=O)N(C)c2ccc(C3(CC(=O)O)CCCC3)cc2)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.9 %

Procedure:
[1-{4-[{2-[3-Methoxy-4-[3-o-tolyl-ureido]-phenyl]-acetyl}-methyl-amino]-phenyl}-cyclopentyl]-acetic acid tert-butyl ester [0.18 g, Reference Example 8(b)] was treated with a mixture of trifluoroacetic acid (6 mL), dichloromethane (1.2 mL) and water (0.75 mL)and the resulting solution was then stirred at room temperature, under argon, for 1.5 hours. The amber coloured reaction mixture was evaporated and the residue was chased twice with toluene (20 mL) to yield an amber gum. This gum was triturated with pentane and the solid obtained was washed with pentane and then dried at 60° C., under vacuum, to give the title compound (0.13 g) as a pale yellow solid, m.p. softens at 100° C. then slowly melts from 118–150° C.