Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:15][CH2:16][OH:17])[CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:20]([CH3:22])=[CH2:21]>COC(OC)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C@@H:12]([CH2:15][CH2:16][OH:17])[CH2:13][O:14][C:20]1([CH3:22])[CH3:21])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@H](CO)CCO)OCc1ccccc1
Reactant: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC1(C)OC[C@H](CCO)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 95.6 %

Procedure:
A solution of (S)—N-(benzyloxycarbonyl)-2-aminobutane-1,4-diol (8.00 g, 33.4 mmol) and toluene-4-sulfonic acid monohydrate (318 mg, 1.67 mmol) in 2,2-dimethoxypropane (320 mL) was stirred at room temperature, then after 2 h 2-methoxypropene (7.71 g, 107 mmol) was added, then after 72 h the reaction mixture was partitioned between EtOAc and sat. aq. sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate, filtered, and evaporated. The residue was taken up in DCM (200 mL), then after addition of SiO2 (80 g) and water (4.8 mL) the slurry was stirred for 64 h at room temperature. After dilution with DCM and addition of anhydrous magnesium sulfate, insoluble material was removed by filtration through diatomaceous earth. The filtrate was evaporated and chromatographed (SiO2; heptane/EtOAc 1:1) to afford the title compound (8.92 g, 96%). Light yellow oil, MS (ISP)=280.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[CH2:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.O1CCOC[CH2:14]1>C(OCC)C>[CH:11]1([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[CH:3]=[CH:4]3)[CH2:14][CH2:12]1
Reactant: C1COCCO1
Reactant: C=Cc1ccc2c(ccn2C)c1
Solvent: CCOCC
Product: Cn1ccc2cc(C3CC3)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
To a solution of 1-Methyl-5-vinyl-1H-indole (290 mg, 1.84 mmol) in dioxane (5 mL) was cooled at 0° C. and solution of CH2N2 in diethyl ether was added. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The solvents were evaporated and the residue was purified by column chromatography (ethyl acetate:hexane; 5:95) to give a product (305 mg, 96%). 1H NMR (CDCl3, 400 MHz) 0.68 (m, 2H), 0.88 (m, 2H), 2.00 (m, 1H), 3.71 (s, 1H), 6.37 (d, J=2.9 Hz, 1H), 6.97 (m, 2H), 7.18 (d, J=8.4 Hz, 1H), 7.34 (s, 1H); 13C NMR (CDCl3, 100 MHz) 8.5, 13.6, 17.5, 32.8, 100.3, 108.9, 117.5, 120.4, 128.6, 128.9, 134.4, 135.3.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]1[CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:8][CH2:7][C@H:2]1[CH2:3][O:4][CH2:5][CH2:6][O:1]1)(=[O:19])=[O:18]
Reactant: OC[C@H]1COCCO1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1COCCO1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A round bottomed flask was charged with (2S)-1,4-dioxan-2-ylmethanol (115 mg, 0.973 mmol), triethylamine (0.204 mL, 1.46 mmol), and 5 mL of dichloromethane then cooled to −10° C. Methanesulfonyl chloride (91 μL, 1.17 mmol) was added by syringe and the solution was stirred for 30 minutes at −10° C. The solution was diluted in dichloromethane, washed with 1M HCl, and the aqueous layer was extracted with dichloromethane (2×). The combined organic layers were washed with saturated aqueous sodium bicarbonate (2×) and brine, then dried over sodium sulfate and concentrated to afford (2R)-1,4-dioxan-2-ylmethyl methanesulfonate.
Reaction SMILES: [FH:1].[K].[O:3]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:4]1>C(Cl)Cl>[F:1][CH2:4][C:5]1([OH:3])[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CO2
Reactant: F
Agent: [K]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(O)(CF)CC1
Temperature: 120 °C
Reaction time: 7 h
Yield: 87 %

Procedure:
3.2 g of potassium hydrogen fluoride and 610 mg tetra-n-butyl ammonium dihydrogen trifluoride were added to 5 g of benzyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate, and it was stirred at 120° C. for 7 hr. After cooling, methylene chloride was added thereto and it was filtered through Celite. The filtrate was evaporated, and the resulting residue was subjected to silica gel column chromatography to give 4.7 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[N+:10]([O-:12])=[O:11])[C:3]=1[CH3:13].[BH4-].[Na+]>C(O)(C)C.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][N+:10]([O-:12])=[O:11])[C:3]=1[CH3:13]
Reactant: Cc1c(F)cccc1/C=C/[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: Cc1c(F)cccc1CC[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
Analogously to the procedure described in A. K. Sinhababu et al., Tetrahedron Lett. 24 (1983), 227, to a solution of the compound of step 1 (16.85 g, 93.01 mmol) in isopropanol (275 ml) and chloroform (825 ml) were added dry silica gel (110 g) and then in small portions sodium borohydride (7.038 g, 186.02 mmol). The mixture was stirred at room temperature for 0.5 h, then cooled to 0° C. and quenched by slow addition of 10 ml of 5 N hydrochloric acid. After stirring for 10 min, the silica gel was filtered off and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 150 ml of DCM and the solution washed with water (75 ml) and brine (75 ml), dried over magnesium sulfate, filtered and evaporated to dryness to give 15.02 g of the title compound as a thick orange oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][N:37]1[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:43][CH:40]3[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CN1CCC(N)CC1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(NC2CCN(C)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 81.9 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (20 mg, 0.04 mmol) in THF (3 mL) was added 1-methyl-4-piperidinamine (20 mg, 0.176 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM [90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (18 mg, 82%). LC-MS m/z 550 (M+H)+; 1H-NMR (MeOD) δ 1.26 (d, 6H), 1.48 (m, 2H), 1.88 (m, 4H), 2.24 (s, 3H), 2.29 (s, 3H), 2.75 (m, 2H), 3.18 (m, 1H), 4.09 (s, 2H), 4.23 (m, 1H), 7.15 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([I:12])[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH3:22].CCOC(C)=O>C(#N)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:21][CH3:22])=[C:7]([I:12])[CH:6]=1)[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1ccc(O)c(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1ccc(OCC)c(I)c1

Procedure:
To the resultant ester (3.10 g, 10.61 mmol) and potassium carbonate (2.87 g, 20.75 mmol) in 40 ml acetonitrile, add iodoethane (1.3 ml, 16.25 mmol) at RT while stirring vigorously. Heat the resulting white suspension under reflux for 1.5 h. Evaporate acetonitrile and replace with EtOAc. Wash the organic layer first with water, then with saturated aq. sodium chloride. Dry over anhydrous sodium sulfate, filter and concentrate to give the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=2)[CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[O:17]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=3)[CH:3]=2)=[CH:20][CH:19]=1)[CH3:16]
Reactant: COc1ccc(O)cc1
Reactant: Nc1cccc(Nc2cc(Cl)ncn2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2cc(Nc3cccc(N)n3)ncn2)cc1
Temperature: 100 °C
Yield: 57.5 %

Procedure:
To a solution of N2-(6-chloropyrimidin-4-yl)pyridine-2,6-diamine (200 mg, 0.90 mmol) in dry DMF (2 mL) was added 4-methoxyphenol (168 mg, 1.3 mmol) and anhydrous K2CO3 (179 mg, 1.3 mmol). The reaction mixture was heated at 100° C. for 16 h under N2 atmosphere. It was then cooled and DMF removed under reduced pressure to give a yellowish gummy residue that was taken in EtOAc (10 mL). The solution was washed with water (5 mL) and brine (5 mL), was dried over Na2SO4 and was then concentrated under reduced pressure to get crude product. This was further purified by column chromatography (SiO2, 60-120, hexane/EtOAc, 5/5) to give N2-(6-(4-methoxylphenoxy)pyrimidin-4-yl)pyridine-2,6-diamine (160 mg, 59.2%) as a pale yellow solid.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([O:12][CH:13]1[CH2:17][CH2:16][CH:15]([N:18]2[C:22]3[N:23]=[CH:24][N:25]=[C:26]([NH2:27])[C:21]=3[C:20]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:30][CH:29]=3)=[CH:19]2)[CH2:14]1)=[O:11])=O)(C)(C)C.[ClH:41].C(OCC)C>C(OCC)(=O)C>[ClH:41].[NH2:8][CH2:9][C:10]([O:12][CH:13]1[CH2:17][CH2:16][CH:15]([N:18]2[C:22]3[N:23]=[CH:24][N:25]=[C:26]([NH2:27])[C:21]=3[C:20]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:30][CH:29]=3)=[CH:19]2)[CH2:14]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)OC1CCC(n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: NCC(=O)OC1CCC(n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Reaction time: 0.5 h

Procedure:
3-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl 2-[(tert-butoxycarbonyl)amino]acetate (39 mg, 0.072 mmol) was dissolved in ethyl acetate (2.5 ml). Hydrogen chloride gas was passed through for 1 minute. The flask was capped and the solution stirred for additional 30 minutes. Diethyl ether was added and precipitate formed. The solid was collected by filtration to give 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl 2-aminoacetate hydrochloride. The structure was confirmed by 1H NMR and LC/MS (MH+=444).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[C:16]([NH2:18])=[O:17])[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:11]=[CH:10]3)=[CH:4][CH:3]=1.[C:25](N1C=CN=C1)([N:27]1[CH:31]=[CH:30]N=[CH:28]1)=O>C1COCC1>[CH3:25][N:27]([CH3:28])[CH2:31][CH2:30][NH:18][C:16]([C:15]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][N:12]2[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:8][C:7]=1[O:6][C:5]1[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=1)=[O:17]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(N)=O)cc21
Solvent: C1CCOC1
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(=O)NCCN(C)C)cc21
Reaction time: 18 h
Yield: 58 %

Procedure:
A solution of 5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (compound 10g, prepared as described in Example 46) in THF was treated with carbonyldiimidazole (1.2 equivalents) at room temperature under nitrogen atmosphere. After stirring for 18 hours, the reaction was treated with N1-dimethyl-ethane-1,2-diamine; 1 equivalent). After 18 additional hours, the solvent was allowed to slowly evaporate and the residue was purified in a Sep Pak cartridge eluting with a gradient of 100% CH2Cl2 to 5% MeOH/CH2Cl2 to provide compound 11g-10 as an oil in 58% yield.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH3:19])[C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>C(O)C.O>[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH:19]=[CH:27][C:26]3[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH3:22])[CH:25]=3)[C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1
Reactant: COc1cccc(C=O)c1
Reactant: C#CCOc1ccc2c(C)cc(=O)oc2c1C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C#CCOc1ccc2c(C)cc(=O)oc2c1C(=O)C=Cc1cccc(OC)c1
Temperature: 25 °C
Yield: 53.4 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 4-methyl-7-prop2-ynyloxy-8-acetylcoumarin (1.92 g, 0.0075 mol) and 3-methoxybenzaldehyde (1.01 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified. The precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 1.5 g of product m.p. 154-56° C., 1H-NMR (CDCl3) δ: 2.45 (s, 3H); 3.48 (m, 1H; 3.81 (s, 3H); 4.82 (d, 2H, J=2.2 Hz); 6.15 (s, 1H); 6.90-7.26 (m, 5H); 7.10 (d, 1H, J=8.9 Hz); 7.65 (d, 1H, J=8.9 Hz).
Reaction SMILES: [CH3:1][C:2]([CH3:46])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:45])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:44])=[CH:11]/[CH2:12][CH2:13]/[C:14](/[CH3:43])=[CH:15]/[CH2:16][CH2:17]/[C:18](/[CH3:42])=[CH:19]/[CH2:20][CH2:21]/[C:22](/[CH3:41])=[CH:23]/[CH2:24][CH2:25]/[C:26](/[CH3:40])=[CH:27]/[CH2:28][CH2:29]/[C:30](/[CH3:39])=[CH:31]/[CH2:32][CH2:33]/[C:34](/[CH3:38])=[CH:35]/[CH2:36][OH:37].[C:47](O)(=[O:65])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O>[C:47]([O:37][CH2:36][CH:35]=[C:34]([CH3:38])[CH2:33][CH2:32][CH:31]=[C:30]([CH3:39])[CH2:29][CH2:28][CH:27]=[C:26]([CH3:40])[CH2:25][CH2:24][CH:23]=[C:22]([CH3:41])[CH2:21][CH2:20][CH:19]=[C:18]([CH3:42])[CH2:17][CH2:16][CH:15]=[C:14]([CH3:43])[CH2:13][CH2:12][CH:11]=[C:10]([CH3:44])[CH2:9][CH2:8][CH:7]=[C:6]([CH3:45])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:46])[CH3:1])(=[O:65])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CO
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCC(=O)OCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Reaction time: 4 h
Yield: 54.8 %

Procedure:
16 Grams of solanesol, 7.5 g of stearic acid and 10 g of polyphosphoric acid ethyl ester were dissolved in 40 ml of chloroform and the solution was refluxed under stirring for 4 hours. After completion of the reaction, the reaction product was poured in water and added with about 10 g of sodium hydrogencarbonate to decompose the polyphosphoric acid ester. After extraction with ether, the ether layer was washed with water and subjected to distillation under reduced pressure. The residual oily substance was purified by column chromatography with 100 g of silica gel to obtain 12.5 g (54.8%) of a white solid (m.p. 36°-37° C.).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][NH:14][C:15]([C:17]1[CH:41]=[CH:40][C:20]([CH2:21][N:22]2[CH:26]=[C:25]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[C:24]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:23]2)=[CH:19][CH:18]=1)=[O:16].[OH-].[Na+].C(O)C.Cl>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][NH:14][C:15]([C:17]1[CH:41]=[CH:40][C:20]([CH2:21][N:22]2[CH:26]=[C:25]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:24]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[N:23]2)=[CH:19][CH:18]=1)=[O:16]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(C(=O)NCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CNC(=O)c1ccc(Cn2cc(CCC(=O)O)c(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A mixture of ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethylaminocarbonyl)benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (550 mg), 1 N aqueous sodium hydroxide solution (1.3 ml), ethanol (2 ml), and tetrahydrofuran (2 ml) was stirred at room temperature for two hours. The reaction mixture was acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained crystals were collected by filtration, and 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethylaminocarbonyl)benzyl]-3-phenyl-1H-pyrazol-4-yl]propionic acid (500 mg, yield: 96%) was obtained. This was recrystallized from acetone-methanol. Melting point: 177–178° C.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=[O:3].N1C=CC=CC=1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])O.[Na+]>C(OCC)C>[C:15]([O:3][C:2](=[CH2:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=C(OC(=O)c1ccccc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 54.5 %

Procedure:
While ethyl pyruvate (174 g, 1.5 mol) was being stirred at 0° C., pyridine (120 g, 1.5 mol) was dropped into the ethyl pyruvate. After it was stirred at 0° C. for 10 minutes, benzoyl chloride (210 g, 1.5 mol) was slowly dropped into this mixture. After the temperature of the reaction solution reached room temperature, the reaction solution was stirred for 48 hours. An aqueous solution of saturated sodium hydrogencarbonate and diethyl ether were added to the reaction solution, and an organic layer was separated by use of a separating funnel. Diethyl ether was again added to the aqueous layer and an organic compound was extracted. The obtained organic layer was then mixed with the organic compound, and sodium sulfate was added for dehydration. Thereafter, the sodium sulfate was removed by filtration and the solvent was removed by use of an evaporator under a reduced pressure. The concentrate was distilled under a reduced pressure (1 mmHg, 92 to 102° C.) to give ethyl α-benzoyloxyacrylate (180 g, yield: 54%).
Reaction SMILES: [NH:1]=[C:2]([C:7]#[N:8])[C:3](=[NH:6])[C:4]#[N:5].[Cl:9][C:10]1[CH:15]=[CH:14][C:13](N)=[C:12](N)[CH:11]=1.FC(F)(F)C(O)=O>O>[Cl:9][C:10]1[CH:11]=[C:12]2[C:13](=[CH:14][CH:15]=1)[N:6]=[C:3]([C:4]#[N:5])[C:2]([C:7]#[N:8])=[N:1]2
Reactant: Nc1ccc(Cl)cc1N
Reactant: N#CC(=N)C(=N)C#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1nc2ccc(Cl)cc2nc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
A mixture of 0.5 g (4.7 mmols) of the diiminosuccinonitrile and 0.67 g (4.7 mmols) of 4-chloro-1,2-phenylenediamine was slowly added to 10 ml of trifluoroacetic acid at about 20° C. over a period of 30 minutes, and the resulting mixture was stirred at room temperature for 8 hours and then allowed to stand overnight. To the reaction mixture was added 50 ml of water, and the solid precipitated was filtered and sufficiently washed with water. The solid thus obtained was dried under reduced pressure, followed by a silica gel column chromatography (eluent: hexane/ethyl acetate (75/25)) and then recrystallization from chloroform/ethanol, wherein 0.6 g (59%) of 6-chloro-2,3-dicyanoquinoxaline was obtained as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[N:16]=[C:17]=[O:18]>C1(C)C=CC=CC=1>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[NH:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: O=C=Nc1c(F)cccc1F
Reactant: Nc1ccncc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccncc1)Nc1c(F)cccc1F
Temperature: 110 °C
Reaction time: 4 h

Procedure:
4-Aminopyridine (100 mg, 1.06 mmol) and 2,6-difluorophenyl isocyanate (181.3 mg, 1.17 mmol) were dissolved in toluene, and the mixture was then stirred at 110° C. for 4 hr.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][OH:8].Cl.[CH2:17](O)[CH3:18]>>[CH2:17]([O:10][C:9](=[O:11])[C@H:6]([CH2:7][OH:8])[NH:5][CH2:4][C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[OH:1])[CH3:18]
Reactant: O=C(O)[C@H](CO)NCc1ccccc1O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@H](CO)NCc1ccccc1O
Reaction time: 8 h

Procedure:
L-serine (3.6 g) was dissolved in 17 ml of a 2N sodium hydroxide aqueous solution. To the solution were then added 3.6 ml of salicylaldehyde and 0.4 g of sodium boron hydride in this order. After the mixture was stirred for 1 hour, 3.6 ml of salicylaldehyde and 0.4 g of sodium boron hydride were added thereto again. After the resulting mixture was stirred overnight at room temperature, the insoluble matter was separated through filtration, and the filtrate was extracted with diethyl ether. The extract was adjusted to a pH of 7 with hydrochloric acid to obtain 4.8 g of N-(2-hydroxybenzyl)-L-serine. To 300 mg of the resulting N-(2-hydroxybenzyl)-L-serine were added 30 ml of ethanol to which a hydrogen chloride gas had been blown to saturation. The mixture was stirred overnight. The reaction solution was concentrated, and the resulting oil was purified through HPLC using Inertcil ODS-3 column (supplied by GL Science) in a high performance liquid chromatography (supplied by Hitachi) to obtain 114 mg of N-(2-hydroxybenzyl)-L-serine ethyl ester. Various N-(2-hydroxybenzyl) amino acid alkyl esters were obtained in the same manner. With respect to the novel compounds undescribed in the literature among these compounds, the results of the measurement of the mass spectrum are shown in Table 1.
Reaction SMILES: CS(O[CH2:6][C@H:7]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=1[CH3:24])[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-:42].C(OCC)C>CC(O)(C)C>[CH2:10]([O:9][CH2:8][C@@H:7]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=1[CH3:24])[CH2:6][F:42])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [F-]
Reactant: Cc1cc(Br)ccc1[C@H](COCc1ccccc1)COS(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: Cc1cc(Br)ccc1[C@@H](CF)COCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To 24A (0.74 g, 1.790 mmol) in tBuOH (10 mL) was added TBAF (1.0 M in THF, 5.37 mL, 5.37 mmol). The mixture was stirred at 80° C. for 2 h. Ethyl ether was added and the mixture was filtered. The filtrate was evaporated and the crude product was purified by flash chromatography (0-30% EtOAc/hexanes) to give 24B (0.46 g, 1.364 mmol, 76% yield) as colorless oil. 1H NMR (400 MHz, chloroform-d) δ ppm 7.27-7.43 (m, 7H) 7.13 (d, J=8.34 Hz, 1H) 4.74 (d, J=5.56 Hz, 1H) 4.62 (d, J=5.56 Hz, 1H) 4.47-4.59 (m, 2H) 3.71-3.81 (m, 1H) 3.60-3.70 (m, 1H) 3.37-3.57 (m, 1H) 2.33 (s, 3H); 19F NMR (376 MHz, chloroform-d) δ ppm −224.19 (s, 1F).