Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[CH3:14][CH2:15][C@:16]12[CH2:32][C@:31]([OH:37])([C:33]([O:35][CH3:36])=[O:34])[N:30]3[C:22]4=[C:23]([CH2:38][CH2:39][N:20]([C@@H:21]14)[CH2:19][CH2:18][CH2:17]2)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=13>C(O)C.C(Cl)(Cl)Cl>[CH3:14][CH2:15][C@:16]12[CH2:32][C@:31]([OH:37])([C:33]([O:35][CH3:36])=[O:34])[N:30]3[C:22]4=[C:23]([CH2:38][CH2:39][N:20]([C@@H:21]14)[CH2:19][CH2:18][CH2:17]2)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=13.[C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([O-:9])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: CC[C@]12CCCN3CCc4c(n(c5ccccc45)[C@@](O)(C(=O)OC)C1)[C@@H]32
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1ccccc1C(=O)[O-]
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
A solution of 3.6 g (2.10-` moles) of acetylsalicylic acid in 30 mls of ethanol is added to a solution of 7.08 g (2.10-2 moles) of vincamine in 80 mls of ethanol and 60 mls of CHCl3. The mixture is maintained under stirring at 70° C. for 10 minutes and then concentrated to 60 mls. The residue is taken with ethanol (70 mls) and the solvent is evaporated to a final volume of 15 mls.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:10]([O:17][C@@H:18]1[C@@H:22]([CH2:23][OH:24])[O:21][C@@H:20]([N:25]2[CH:32]=[C:31]([F:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:19]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH2:10]([O:17][C@@H:18]1[C@@H:22]([CH2:23][O:24][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=2)[O:21][C@@H:20]([N:25]2[CH:32]=[C:31]([F:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:19]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)cc1F
Solvent: c1ccncc1
Product: O=C(OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1ccccc1)c1cccnc1
Reaction time: 3 h
Yield: 69 %

Procedure:
A 0.21 g quantity of nicotinoyl chloride (hydrochloride) was added to a solution of 0.20 g of 3'-O-benzyl-2'-deoxy-5-fluorouridine in 10 ml of pyridine, and the mixture was left to stand at 80° C. for 3 hours. The solvent was distilled off and the residue was dissolved in 30 ml of ethyl acetate. The solution was washed twice with 20 ml of water. The ethyl acetate layer was dried on anhydrous sodium sulfate and concentrated. The concentrate was placed on a silica gel column and eluted with chloroform, giving 0.18 g of the title compound in a yield of 69%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=[C:10]([CH2:14]O)[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(Cl)(Cl)Cl.C(#N)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=[C:10]([CH2:14][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cccc(CO)c2-c2ccc(C)cc2)cc1
Reactant: C1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: Cc1ccc(-c2cccc(CN3CCCCC3)c2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Compound 23 described above (0.17 g, 0.589 mmol) was dissolved in chloroform (4 mL) (Wako Pure Chemical Industries, Ltd.), and thionyl chloride (0.5 mL) (Wako Pure Chemical Industries, Ltd.) was added dropwise while cooling with ice. The mixture was returned to room temperature and stirred for 1 hour, and then the solvent was distilled off under reduced pressure, to thereby obtain a residue. The residue was dissolved in acetonitrile (4 mL) (Wako Pure Chemical Industries, Ltd.), and piperidine (0.19 g, 2.23 mmol) (Wako Pure Chemical Industries, Ltd.) was added thereto. The mixture was refluxed for 45 minutes and allowed to cool to room temperature. The solvent was distilled off under reduced pressure, and then a saturated aqueous solution of sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) was added to the concentrated residue, and mixture was extracted with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was washed with water and brine. After that, the organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to alumina column chromatography (n-hexane (Wako Pure Chemical Industries, Ltd.) as an eluent), to thereby obtain the title compound (0.17 g, 81% yield).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)=[N:12]2)[CH2:7][CH2:6]1)=[O:4].[NH:29]1[C:34](=[O:35])[CH2:33][O:32][CH2:31][C:30]1=[O:36].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:13]2[C:14]([CH3:18])([CH3:17])[C:15](=[O:16])[N:11]([CH:8]3[CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH2:2][N:29]4[C:34](=[O:35])[CH2:33][O:32][CH2:31][C:30]4=[O:36])[CH2:10][CH2:9]3)[N:12]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)CCl)CC3)C(=O)C2(C)C)cc1OC
Reactant: O=C1COCC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)COCC4=O)CC3)C(=O)C2(C)C)cc1OC

Procedure:
1.0 g 2-[1-(chloroacetyl)piperidin-4-yl]-5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound A1), 0.5 g morpholine-3,5-dione and 1.0 g K2CO3 in 20 ml of DMF is heated for 17 h at 80-100° C. The DMF is removed in vacuo and the residue dissolved in 70 ml of DCM, washed four times with 30 ml of water and 20 ml of 0.5 M H2SO4. The DCM layer is dried over MgSO4 and concentrated in vacuo. The title product is crystallized from diethyl ether.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:12][CH2:13][OH:14].CCCCCC>CO.CC(OC)(C)C>[OH:14][CH2:13][CH2:12][S:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: Oc1ccc(S)cc1
Reactant: OCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CCCCCC
Solvent: CO
Product: OCCSc1ccc(O)cc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A solution of 5.0 g (35.7 mmol) 4-mercaptophenol in 50 ml methyl alcohol was treated at −5° C. dropwise over a period of 30 min with 39.2 ml (39.2 mmol) aqueous NaOH 1N and stirred 1 h at −5° C. Afterwards a solution of 5.2 ml (39.2 mmol) 2-bromo ethanol in 16.5 ml methyl alcohol was added at −5° C. dropwise over a period of 15 min. The reaction mixture was stirred for 21 h at room temperature, concentrated and the residue treated with 10 ml water and 30 ml tBME. After extraction and phase separation, the organic phase was washed with 20 ml saturated NaHCO3 and 20 ml brine. The combined organic phases were dried over Na2SO4 and the solvent was removed under reduced pressure to yield 6.03 g crude product. The crude product was dissolved in 18 ml tBME at 40° C. and subsequently treated dropwise with 25 ml hexane. The so formed suspension was stirred 16 h at room temperature and 1 h at 4° C. The crystals were separated on a filter funnel and washed with 5 ml hexane (4° C.) to yield 4.8 g (77.7%) product as white crystals.
Reaction SMILES: CN(C)C=O.C[O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1.CC(C)([O-])C.[K+].Br[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=1>O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([O:15][C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[C:8]([OH:7])=[O:16])=[N:25][CH:26]=1
Reactant: Clc1ccc(Br)nc1
Reactant: COC(=O)c1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(Oc2ccc(Cl)cn2)c1
Temperature: 130 °C

Procedure:
To a dimethylformamide (100 mL) solution of 3-hydroxy-benzoic acid methyl ester (3.5 g, 23 mmol) was added potassium t-butoxide (3.2 g, 28 mmol). Upon stirring the reaction at room temperature for 15 min, 2-bromo-5-chloro-pyridine was added. The reaction was heated to 130° C. for 15 h. Crude reaction mass was added to water, and extracted with diethyl ether to remove unhydrolyzed methyl ester, 3-(5-chloro-pyridin-2-yloxy)-benzoic acid methyl ester (2.5 g). The aqueous layer was acidified to pH 4.0 and product was extracted with ethyl acetate to give 3-(5-chloro-pyridin-2-yloxy)-benzoic acid (2.0 g). Saponification of methyl ester (2.5 g, 9.4 mmol) using NaOH (1.0 g, 25 mmol) in methanol:THF:water (1:1:1, 60 mL) furnished additional 2.0 g of 3-(5-chloro-pyridin-2-yloxy)-benzoic acid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([OH:18])[C:12]=2[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCOCCOCCOCCOCCOCC1.[OH-].[K+]>C(O)C.O>[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([OH:18])[C:12]=2[C:13]([OH:15])=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1c(O)cccc1-c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1c(O)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 3.3 grams (0.014 mole) of ethyl 6-phenylsalicylate in 30 mL of ethanol was added a catalytic amount of 1,4,7,10,13,16-hexaoxacyclooctadecane. This was followed by the addition of a solution of 2.0 grams (0.030 mole) of 85% potassium hydroxide in 15 mL of water. Upon completion of addition, the reaction mixture was warmed to reflux where it was stirred for 4 hours. The reaction mixture was allowed to cool to ambient temperature where it stood for about 18 hours. After this time the reaction mixture was again warmed to reflux where it stirred for 4 hours. Thin layer chromatographic analysis of the reaction mixture indicated the reaction had not gone to completion. An additional 0.3 gram of 85% potassium hydroxide was added to the reaction mixture and the heating at reflux was continued for another 3 hours. After this time the reaction mixture was cooled, and volatile materials were removed under reduced pressure. The aqueous concentrate was washed with two portions of diethyl ether. The combined ether washes were backwashed with water. The water washes and the aqueous concentrate were combined, and the combination was acidified to pH 1 with concentrated hydrochloric acid. The mixture was extracted with three portions of ethyl acetate. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was dissolved in hot ethanol, and the solution was treated with decolorizing carbon. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to a residue. The residue was recrystallized from diethyl ether and hexane to yield 6-phenylsalicylic acid, m.p. 143°-146°. The filtrate from the recrystallization was concentrated under reduced pressure to a residual solid. The residue was combined with the 6-phenylsalicylic acid, m.p. 143°-146° C., yielding 2.8 grams of this material.
Reaction SMILES: [CH3:1]I.[OH-].[K+].[N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][CH:6]=1>C(O)C.O>[CH3:1][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1cnc2ccccc21

Procedure:
14.1 g of methyl iodide and 6.15 g of potassium hydroxide were added to a suspension of 11.8 g of benzimidazole in 50 ml of ethanol and 30 ml of water and the mixture was refluxed for 6 hours and was then cooled. The mixture was extracted three times with chloroform and the combined chloroform extracts were dried and filtered. The filtrate was evaporated to dryness and the oily residue was chromatographed over neutral alumina. Elution with chloroform yielded 1-methyl-benzimidazole as a crude oil which was used as is for the next step.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[N+:17]([O-:19])=[O:18])[O:9][CH2:8][CH2:7][O:6]1.[OH:20][C:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C(C(C)=O)C(C)C>[OH:20][C:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=2)[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][C:5]2([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[N+:17]([O-:19])=[O:18])[O:9][CH2:8][CH2:7][O:6]2)[CH2:23][CH2:22]1
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCNCC1
Reactant: O=[N+]([O-])c1cc(F)ccc1C1(CCCBr)OCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=[N+]([O-])c1cc(F)ccc1C1(CCCN2CCC(O)(c3cccc(C(F)(F)F)c3)CC2)OCCO1

Procedure:
A mixture of 3.7 g of 4-bromo-1-(4-fluoro-2-nitrophenyl)-1,1-ethylenedioxy-n-butane, 2.5 g of 4-hydroxy-4-(3-trifluoromethylphenyl)piperidine, 1.4 g of anhydrous potassium carbonate, a catalytic amount of potassium iodide and 20 ml of methyl isobutyl ketone was heated at 80°-90° C for 2 hours. After cooling, the reaction mixture was diluted with 100 ml of water and extracted with ethyl acetate. The extracts were washed with water and aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 4-[4-hydroxy-4-(3-trifluoromethylphenyl)piperidino]-1-(4-fluoro-2-nitrophenyl)-1,1-ethylenedioxy-n-butane as a residual oil.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([B:19]3[O:23]C(C)(C)C(C)(C)[O:20]3)[CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:14]=[C:15]([B:19]([OH:23])[OH:20])[CH:16]=[CH:17][CH:18]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc(B(O)O)c1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
4-Methoxy-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (168 mg, 0.43 mmol) was dissolved in dichloromethane (4 ml). A solution of boron tribromide (1M in dichloromethane, 4.32 mL, 4.32 mmol) was added dropwise and the reaction was stirred at room temperature overnight. The mixture was diluted with dichloromethane and washed with a solution of 4% sodium bicarbonate, water, brine and dried over sodium sulphate, filtered and evaporated under reduced pressure. The product was purified by reverse phase using SP1® Purification System to give 30 mg (23% yield) of the title compound. Purity 100%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[C:15]=2[C:23]#[N:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[C:15]=2[C:23]#[N:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc([N+](=O)[O-])c2C#N)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(N)c2C#N)CC1

Procedure:
4-(2-Cyano-3-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (12.172 g, 36.6 mmol) from step 1 was dissolved in ethanol (300 ml) in a Parr flask. The flask was flushed with N2, and Pd/C (1.3 g) was added. The solution was treated with H2 on a Parr apparatus at 30 psi overnight. The mixture was filtered through celite, then washed with EtOAc. After concentration, the residue was purified by flash chromatography to give 4-(3-amino-2-cyano-phenyl)-piperazine-1-carboxylic acid tert-butyl ester. (7.585 g, 69%) MS: (M+H)+303.2.
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.[NH2:13][C@H:14]([C:19]([NH:21][C@H:22]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH3:23])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17]>>[NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([NH:13][C@H:14]([C:19]([NH:21][C@H:22]([C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[CH3:23])=[O:20])[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:5]
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Product: CC(C)C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1

Procedure:
Boc-Gly-Leu-Ala-OBzl was prepared by coupling Boc-Gly-OH (5.70 g, 32.6 mmoles) to H-Leu-Ala-OBzl using the mixed anhydride procedure described in Example 2. The product (13.8 g) was obtained as an amorphous solid. Boc-Gly-Leu-Ala-OBzl was deblocked with trifluoroacetic acid by the procedure described for the preparation of H-Leu-Ala-OBzl except that the trifluoroacetate salt was soluble in ether. The preparation was dissolved in ethyl acetate and treated with anhydrous hydrogen chloride. The resulting product was precipitated by the addition of ether to yield 7.7 g of H-Gly-Leu-Ala-OBzl HCl in a first crop.
Reaction SMILES: [C:1]1([CH:7]([OH:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](OC=C)(=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[C:1]1([CH:7]([OH:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([CH:7]([O:13][C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=COC(=O)CCCCC
Agent: COC(=O)CC(O)c1ccccc1
Product: CCCCCC(=O)OC(CC(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 28 h

Procedure:
The mixture of 5.0 g (28 mmol) of methyl 3-phenyl-3-hydroxypropionate, 1.97 g (14 mmol) of vinyl caproate and 2.0 g of lipase PS was stirred at room temperature for 28 hours. After the lipase was removed by filtration, the filtrate was eluted by column chromatography (eluting solution; 9/1 of toluene/ethyl acetate). 2.35 g (88%ee) of (-)-methyl 3-phenyl-3-hydroxypropionate and 3.97 g (91%ee) of (+)-methyl 3-phenyl-3-hexanoyloxy-propionate were obtained, respectively.
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:22][C@H:23]([NH:25]C(=O)OC(C)(C)C)[CH3:24])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>CO.O1CCOCC1>[NH2:25][C@H:23]([CH3:24])[CH2:22][N:7]1[CH:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[S:9]/[C:8]/1=[N:10]\[C:11](=[O:21])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20]
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@@H](C)N
Reaction time: 24 h
Yield: 53.7 %

Procedure:
In a 20 mL vial, to a solution of Example 59B (75 mg, 0.156 mmol) in MeOH (1 mL) was added a solution of hydrogen chloride (0.039 mL, 0.156 mmol) in dioxane and the mixture was stirred for 24 hr. The reaction was concentrated and the residue was purified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10-100% acetonitrile (A) and 10 mM ammonium acetate in water (B), at a flow rate of 2.0 mL/min (0-0.1 min 10% A, 0.1-2.6 min 10-100% A, 2.6-2.9 min 100% A, 2.9-3.0 min 100-10% A. 0.5 min post-run delay) to obtain the title compound (32 mg, 59%). 1H NMR (300 MHz, METHANOL-d4) δ ppm 1.26 (d, J=6.78 Hz, 3H) 1.40 (s, 9H) 3.64-3.73 (m, 1H) 3.86 (s, 3H) 4.26-4.31 (m, 2H) 7.09 (d, J=8.82 Hz, 1H) 7.18 (s, 1H) 7.41 (dd, J=8.82, 2.71 Hz, 1H) 7.74 (d, J=2.71 Hz, 1H); MS (DCI) m/z 382 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:17]([OH:19])=[O:18])[N:16]=[C:11]2[C:10]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:30][O:18][C:17]([C:15]1[N:16]=[C:11]2[C:10]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:12]2=[N:13][CH:14]=1)=[O:19]
Reactant: O=C(O)c1cnc2c(n1)c(-c1ccc3ccccc3c1)nn2Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cnc2c(n1)c(-c1ccc3ccccc3c1)nn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
20 mg of 1-benzyl-3-(naphthalen-2-yl)-1H-pyrazolo[3,4-b]pyrazine-5-carboxylic acid was dissolved in 5 mL of N,N-dimethylformamide, added with 10 mg of potassium carbonate and 20 μl methyl iodide, and stirred at room temperature for 3 hours. The reaction solution was partitioned between water and ethyl acetate, and the organic layer was extracted and washed with water. The organic layer was dried over magnesium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10), to afford 20 mg the title compound as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][OH:29])=[C:22]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:49][S:50](Cl)(=[O:52])=[O:51]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][S:50]([CH3:49])(=[O:52])=[O:51])=[C:22]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCCO)c(OC(C)(C)C)c1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCCOS(C)(=O)=O)c(OC(C)(C)C)c1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.6 %

Procedure:
To a stirred solution of 100 mg (0.172 mmol) di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-[3-tert-butoxy-4-(2-hydroxyethoxy)benzyl]-L-glutamate, 25.6 mg (0.253 mmol) triethylamine in ca. 1 ml dichloromethane was added 25.5 mg (0.222 mmol) methane sulphonic acid chloride at 0° C. The reaction mixture was stirred at room temperature for 4 hours. Further 25.6 mg (0.253 mmol) triethylamine and 25.5 mg (0.222 mmol) methane sulphonic acid chloride were added. The reaction mixture is stirred for another 4 hours. The reaction mixture is diluted with dichloro methane. The organic phase washed with saturated aqueous ammonium chloride, saturated aqueous sodium hydrogen carbonate solution, dried with sodium sulfate and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, hexane/ethylacetate gradient: 5:1→1:99). The desired product was obtained in 79.6% yield (99 mg, 0.14 mmol).
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:22][C:23]1[O:27][C:26]([C:28](Cl)=[O:29])=[CH:25][CH:24]=1.[OH-].[Na+]>C1COCC1>[Br:22][C:23]1[O:27][C:26]([C:28]([CH:8]2[C:7](=[O:10])[CH2:6][CH2:5][C:4]3([O:3][CH2:2][CH2:1][O:11]3)[CH2:9]2)=[O:29])=[CH:25][CH:24]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: O=C(Cl)c1ccc(Br)o1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCC2(CC1C(=O)c1ccc(Br)o1)OCCO2
Reaction time: 1 h
Yield: 39.1 %

Procedure:
Under N2 at about −35° C., to a stirred solution of 1,4-cyclohexanedione monoethyleneacetal (2.57 g, 16.5 mmol) in THF (30 mL) was added a solution of LHMDS (20% in THF, 18 mL, 18.8 mmol) over about 1 h. After stirred for another 1 h, the resulted solution was added dropwise to the solution of 5-bromofuran-2-carbonyl chloride (3.20 g, 15.7 mmol) in THF (30 mL) at about −35° C. over about 0.5 h and then stirred without cooling for about 1 h. NaOH solution (2.51 g in 300 mL of water, 62.8 mmol) was added to the above solution, and the resultant mixture was heated under reflux for a further 0.5 h. The volatile was removed under reduced pressure and then the aqueous phase was acidified with 6N HCl to pH=5 at 0-10° C. and filtered. The collected solids were dried in vacuo and then recrystallized from ethanol to give 7-(5-bromofuran-2-carbonyl)-1,4-dioxaspiro[4.5]decan-8-one as a yellow solid (2.02 g, 36%), which was used without further purification.