Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:20][NH2:21]>ClCCl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:21][O:20][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][O:14]2)=[O:13])=[CH:6][CH:7]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)CCCc1ccc(O)cc1
Solvent: ClCCl
Product: O=C(CCCc1ccc(O)cc1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
A mixture of 4-(4-Hydroxyphenyl)butanoic acid (0.90 g, 5 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.59 g, 5 mmol) and 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (1.15 g, 6 mmol) in 50 mL dichloromethane was stirred at room temperature for 2 h (monitored by TLC). The mixture was extracted with water and dried over magnesium sulfate. The residue was purified by chromatography (MeOH:DCM=1:50) to give the title compound (0.84 g, 65%). NMR (400 MHz in DMSO, Bruker AVANCE-400): δ 1.50 (m, 3H, OTHP), 1.71 (m, 3H, OTHP), 1.73 (m, 2H, CH2), 1.96 (m, 2H, CH2), 2.44 (m, 2H, CH2), 3.48 (t, 1H, J=5.0 Hz, OTHP), 3.91 (t, 1H, J=10.0 Hz, OTHP), 4.80 (s, 1H, OTHP), 6.65 (d, 2H, J=5.0 Hz, Ar—H), 6.95 (d, 2H, J=10.0 Hz, Ar—H), 9.10 (s, 1H, NH), 10.87 (s, 1H, OH).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([O:14]C)=O)=[N:10][CH:11]=1)[CH:3]([OH:5])[CH3:4].[CH3:16][NH:17][CH3:18].CO>>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([N:17]([CH3:18])[CH3:16])=[O:14])=[N:10][CH:11]=1)[CH:3]([OH:5])[CH3:4]
Reactant: CNC
Reactant: COC(=O)c1ccc(C(O)C(C)O)cn1
Solvent: CO
Product: CC(O)C(O)c1ccc(C(=O)N(C)C)nc1
Temperature: 100 °C
Yield: 80.6 %

Procedure:
A mixture of methyl 5-(1,2-dihydroxypropyl)-2-pyridinecarboxylate (52.0 mg, 0.25 mmol) and a 2.0M solution of dimethylamine in methanol (Aldrich, 15.0 ml, 30.0 mmol) was stirred and heated at a bath temperature of 100° C. in a microreactor for four nights. After cooling, the reaction mixture was concentrated in vacuo. The residue (60.3 mg) was purified by preparative TLC [Merck Kieselgel 60, Art 1.05744, 0.5 mm thick, x2; development: CH2Cl2 --MeOH (8:1); elution: CH2Cl2 --MOH (3:1), 240 ml]. The recovered white solid residue was suspended in THF, and the mixture was filtered through a short pad of Celite. The filter cake was washed with THF. The combined filtrate and washings were concentrated in vacuo to give 5-(1,2-dihydroxypropyl)-N,N-dimethyl-2-pyridinecarboxamide as a white solid (45.2 mg, 80.6%): 1H-NMR (270 MHz) δ(CDCl3): 8.41 (d, J=1.8 Hz, 1H), 7.76 (dd, J=7.9, 1.8 Hz, 1H), 7.52 (d, J=7.9 Hz, 1H), 4.86 (d, J=3.7 Hz, 1H), 4.11~3.97 (m, 1H), 3.80 (br.s, 1H), 3.13 (s, 3H), 3.04 (s, 3H), 2.68 (br.s, 1H), 1.15 (d, J=6.6 Hz, 3H) ppm; MS m/z: 225 (7.9%, M+ +1), 224 (50.9%, M+), 153 (100%).
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:5](=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:11][C:12]=3[CH:13]=2)[NH:4][C:3]1=[O:22].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][N:2]1[C:14]2[C:5](=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][CH2:18][C:19]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[O:21])=[CH:11][C:12]=3[CH:13]=2)[NH:4][C:3]1=[O:22]
Reactant: C1CCNCC1
Reactant: Cn1c(=O)[nH]c2nc3ccc(OCCCC(=O)O)cc3cc21
Product: Cn1c(=O)[nH]c2nc3ccc(OCCCC(=O)N4CCCCC4)cc3cc21

Procedure:
This compound, m.p. 215°-217° C., prepared analogous to Example 15 from 4-[(2,3-dihydro-1-methyl-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butanoic acid and piperidine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1([CH2:11][NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-])=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>CCO.[Pd]>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1([CH2:11][NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)CC1(CNC(=O)c2ccccc2[N+](=O)[O-])CCCCC1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CC1(CNC(=O)c2ccccc2N)CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
A mixture of {1-[(2-nitro-benzoylamino)-methyl]-cyclohexyl}-acetic acid methyl ester (680 mg, 2.03 mmol), 10% Pd/C (120 mg) in EtOH (25 mL) is stirred under H2 atmosphere at room temperature for 16 hours. The reaction mixture is filtered and the organic layer is concentrated to give the desired {1-[(2-amino-benzoylamino)-methyl]-cyclohexyl}-acetic acid methyl ester (619 mg, 100%).
Reaction SMILES: C(ON[C:10]([C@H:12]1[C@@H:17]([OH:18])[C@H:16]([OH:19])[C@@H:15]([OH:20])[CH2:14][N:13]1[S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)(=[O:23])=[O:22])=[O:11])C1C=CC=CC=1.C[OH:38]>[Pd]>[OH:18][C@H:17]1[C@H:16]([OH:19])[C@@H:15]([OH:20])[CH2:14][N:13]([S:21]([C:24]2[CH:25]=[CH:26][C:27]([O:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:28][CH:29]=2)(=[O:22])=[O:23])[C@H:12]1[C:10]([OH:11])=[O:38]
Reactant: CO
Reactant: O=C(NOCc1ccccc1)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: [Pd]
Product: O=C(O)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
The above compound (6) (1.68 g) was dissolved in methanol (70 mL) and 10% Pd—C (350 mg) was added, and then the mixture was stirred under a hydrogen atmosphere at 40° C. for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel medium pressure column chromatography (chloroform:methanol=20:1→9:1. 4:1) to obtain the titled compound (951 mg) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10](Br)[C:11]#[CH:12].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[F:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:9][CH2:12][C:11]#[CH:10])[C:2]=1[F:1]
Reactant: C#CCBr
Reactant: Oc1cccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C#CCOc1cccc(F)c1F

Procedure:
115.0 g (0.88 mol) of 2,3-difluorophenol are refluxed for 3 h together with 118.2 ml (17.7 mol) of propargyl bromide (80% soln. in toluene) and 146.6 g (138.2 mol) of potassium carbonate in 1.6 l of ethyl methyl ketone. The batch is filtered, and the filter residue is washed with MTBE. The filtrate is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:MTBE=3:1).
Reaction SMILES: Br[C:2]1[C:31]2=[N:32][C:28]3=[CH:29][N:30]2[C:5]([N:6]2[CH2:38][CH2:37][C:9]([CH3:39])([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([CH3:36])[O:16][C:17]4[CH:18]=[C:19]([F:35])[C:20]([F:34])=[CH:21][C:22]=4[C:23]4[CH:33]=[C:27]3[CH:26]=[CH:25][CH:24]=4)[CH2:8][CH2:7]2)=[C:4]([C@H:40]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:41]([O:43][CH3:44])=[O:42])[C:3]=1[CH3:50].[C:51](O[C@@H](C1C(C)=C(C=C)C2=NC3=CN2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(F)=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)[CH3:52]>>[C:46]([O:45][C@@H:40]([C:4]1[C:3]([CH3:50])=[C:2]([CH:51]=[CH2:52])[C:31]2=[N:32][C:28]3=[CH:29][N:30]2[C:5]=1[N:6]1[CH2:7][CH2:8][C:9]([CH3:39])([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([CH3:36])[O:16][C:17]2[CH:18]=[C:19]([F:35])[C:20]([F:34])=[CH:21][C:22]=2[C:23]2[CH:33]=[C:27]3[CH:26]=[CH:25][CH:24]=2)[CH2:37][CH2:38]1)[C:41]([O:43][CH3:44])=[O:42])([CH3:48])([CH3:49])[CH3:47]
Reactant: C=Cc1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(Br)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)c(F)cc1-c1cccc-3c1
Product: C=Cc1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)c(F)cc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 84 %

Procedure:
Prepared in 84% yield from methyl(2S)-2-[(22S)-5-bromo-17,18-difluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]-2-(tert-butoxy)acetate following the procedure for methyl(2S)-2-(tert-butoxy)-2-[(22S)-5-ethenyl-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate. LCMS (ESI, M+1): 702.4.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:11]\[C:12](Cl)=[O:13].[CH:15]1([NH2:18])[CH2:17][CH2:16]1>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:11]\[C:12]([NH:18][CH:15]1[CH2:17][CH2:16]1)=[O:13]
Reactant: NC1CC1
Reactant: O=C(Cl)/C=C1\CCc2c(Cl)cccc21
Solvent: ClCCl
Product: O=C(/C=C1\CCc2c(Cl)cccc21)NC1CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 76.4 %

Procedure:
An ice cold solution of (E)-2-(4-choro-1-indanylidene)acetyl chloride (2.95 g, 0.013 mol ) in dichloromethane (30 mL) was treated with cyclopropylamine (1.48 g, 0.026 mol, Aldrich) and the mixture was stirred for 4 h. The mixture was concentrated in vacuo and the residue was taken up in a mixture of ethyl acetate and 5% aqueous sodium bicarbonate. The ethyl acetate phase was washed with 5% aqueous sodium bicarbonate, saturated aqueous NaCl and dried (Na2SO4). Filtration and concentration gave 3.5 g of crude oil product. Chromatography on Silca gel with ethyl acetate: hexanes (1:1) as eluent and trituration of the resulting solid with hexanes gave 2.46 g (76%) of (E)-2-(4-chloro-1-indanylidene)-N-cyclopropylacetamide as an off-white solid: m.p., 140°-142° C.; NMR (DMSO-d6): d 8.16, d, 1H, NH), 7.29-7.51 (m, 3H, Ar), 6.34 (t, 1H, =CH), 2.93-3.07, 3.18-3.31 (2m's, 4H 2XCH2), 2.72 (m, 1H, CH), 0.62-0.72, 0.39-0.47 (2m's, 4H, 2XCH2); steady-state nOe: irradiation at 6.34 d, observed 20.3% nOe at 7.46 d.
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH:18][C:19](=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:5])C.[H-].[Na+].Cl>CN(C=O)C>[CH2:24]([O:23][C:21]([C:20]1[C:19](=[O:26])[NH:18][C:7]2[S:8][CH:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=3)[C:6]=2[C:4]=1[OH:5])=[O:22])[CH3:25]
Reactant: CCOC(=O)CC(=O)Nc1scc(-c2ccc(Br)cc2)c1C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(O)c2c(-c3ccc(Br)cc3)csc2[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-bromo-phenyl)-2-(2-ethoxycarbonyl-acetylamino)-thiophene-3-carboxylic acid ethyl ester (4.98 g, 11.3 mmol) in DMF (30 mL) at 0° C. was added a dispersion of sodium hydride in mineral oil (60%, 2.73 g, 68.2 mmol). After warming to ambient temperature the reaction was stirred overnight. Aqueous HCl (1.2 M, 100 mL) was added while cooling the mixture to 0° C. After stirring 1 h. the mixture was filtered and washed with H2O and hexanes giving the titled compound (2.85 g, 64%) as a gray solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=O.[C:11]([N:14]1[CH2:19][CH2:18][NH:17][CH:16]([CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:15]1)(=[O:13])[CH3:12].[ClH:26].[NH4+].[Cl-]>>[ClH:26].[C:11]([N:14]1[CH2:19][CH2:18][N:17]([C:8](=[O:10])[CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:16]([CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:15]1)(=[O:13])[CH3:12]
Reactant: CC(=O)N1CCNC(CN2CCCC2)C1
Reactant: O=C(O)Cc1ccccn1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CC(=O)N1CCN(C(=O)Cc2ccccn2)C(CN2CCCC2)C1

Procedure:
The compound was prepared by coupling of 2-pyridylacetic acid with 4-acetyl-2-(R,S)-[(1-pyrrolidinyl)methyl]piperazine; mp: (HCl salt) 127-130° C.; 1H NMR (free base, 200 MHz, CDCl3) δ1.4-1.7 (4 H, m), 2.0 (3 H, s), 2.2-3.2 (9 H, m), 3.4-4.8 (6 H, m), 6.8-7.5 (3 H, m), 8.4 (1 H, m); MS (FAB) 331 (M+H)+ ; Anal. Calcd. for C18H26N4O2.2HCl. 0.5 NH4Cl: C, 50.27; H, 7.03; N, 14.65. Found: C, 50.86; H, 6.47; N, 15.79.
Reaction SMILES: [N+:1]([CH2:4][CH:5]1[CH2:13][C:8]2(OCC[O:9]2)[CH:7]([CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:6]1[CH:23]=[CH:24][C:25]([CH3:32])([OH:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([O-:3])=[O:2].O1CCCC1.Cl>O>[OH:31][C:25]([CH3:32])([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:24]=[CH:23][CH:6]1[CH:5]([CH2:4][N+:1]([O-:3])=[O:2])[CH2:13][C:8](=[O:9])[CH:7]1[CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: CCCCCC(C)(O)C=CC1C(C[N+](=O)[O-])CC2(OCCO2)C1CC=CCCCC(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC(C)(O)C=CC1C(C[N+](=O)[O-])CC(=O)C1CC=CCCCC(=O)O

Procedure:
A solution of 0.20 g. of 7-[8-nitromethyl-7-(3-methyl-3-hydroxy-1-octenyl)-1,4-dioxaspiro[4.4]non-6-yl]-5-heptenoic acid in 4 ml. of tetrahydrofuran was treated at 0° C. with 0.4 ml. of concentrated hydrochloric acid and stirred at 0° C. for 1.5 hours. The reaction mixture was added to water and extracted with ether. After washing with water and drying over magnesium sulfate, the extract was evaporated and the residue chromatographed on silica. Elution with 15% ethyl acetate in hexane gave 0.11 g. of the title product as an oil, λmaxfilm 3.00 (shoulder), 3.50, 5.80, 6.45, 7.25, 10.30 μ. NMR: δ 1.32 (S, 15-methyl), 4.49 (M, 2, --CH2NO2), 5.80 (M, 4, olefinic --H), 5.92 (S, 2, OH) ppm. Mass spectrum: M+ --H2O at m/e 391.2402 (theory 391.2358).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([Cl:14])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1cccc(Cl)c1
Product: O=C(Cl)Cc1cccc(Cl)c1

Procedure:
3-Chlorophenylacetic acid (19.7 g) in thionyl chloride (100 ml) was heated at reflux for 3 h.
Reaction SMILES: C([O:9][CH2:10][CH2:11][C:12]1[CH:25]=[CH:24][C:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])=[CH:14][CH:13]=1)(=O)C1C=CC=CC=1.C(O[C@@H:30]1[O:47][C@H:46]([CH2:48][O:49]C(=O)C)[C@@H:41]([O:42]C(=O)C)[C@H:36]([O:37]C(=O)C)[C@H:31]1[O:32]C(=O)C)(=O)C.C(OCC)(=O)C>C1(C)C=CC=CC=1.ClCCl>[O:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][OH:9])=[CH:25][CH:24]=1)[C@@H:30]1[O:47][C@H:46]([CH2:48][OH:49])[C@@H:41]([OH:42])[C@H:36]([OH:37])[C@H:31]1[OH:32]
Reactant: O=C(OCCc1ccc(Cc2ccccc2O)cc1)c1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: OCCc1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a solution of 2-[4-(2-benzoyloxyethyl)benzyl]phenol (0.49 g) and 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose (1.7 g) in toluene (5.2 mL) and dichloromethane (2.2 mL) was added boron trifluoride diethyl ether complex (0.56 mL), and the mixture was stirred at 25° C. for 8 hours. To the reaction mixture were added ethyl acetate (70 mL) and a saturated aqueous sodium hydrogen carbonate solution (25 mL), and the organic layer was separated. The organic layer was washed with brine (25 mL) and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in methanol (5 mL) and tetrahydrofuran (2.5 mL), sodium methoxide (28% methanol solution, 0.14 mL) was added to the solution, and the resulting mixture was stirred at 25° C. for 12.5 hours. To the reaction mixture were added ethyl acetate (75 mL) and water (20 mL), and the organic layer was separated. The organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in methanol (7.5 mL), sodium methoxide (28% methanol solution, 0.085 mL) was added to the solution, and the resulting mixture was stirred at 25° C. for 5 hours. The reaction mixture was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=4/1). The solvent was removed under reduced pressure, diethyl ether was added to the residue, and the resulting precipitates were collected by filtration. The obtained solid was washed with diethyl ether and dried under reduced pressure to give 2-[4-(2-hydroxyethyl)benzyl]phenyl β-D-glucopyranoside (0.47 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([NH2:20])=[O:19].[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([CH2:30][C:31](OC)=O)=[CH:24][C:23]=2[O:22]1.[O-]CC.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([CH2:30][C:31]3[NH:20][C:18](=[O:19])[C:3]4[C:4]([CH3:17])=[N:5][N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[C:2]=4[N:1]=3)=[CH:24][C:23]=2[O:22]1
Reactant: CCCCCCC(CCC)n1nc(C)c(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCC(CCC)n1nc(C)c2c(=O)[nH]c(Cc3ccc4c(c3)OCO4)nc21
Yield: 60.6 %

Procedure:
6 mg (0.021 mmol) of 5-amino-3-methyl-1-(4-decyl)-1H-pyrazole-4-carboxamide and 20 mg (0.103 mmol) of methyl 3,4-methylenedioxyphenylacetate are refluxed for 6 hours in 0.3 ml of a 0.5M ethanolic sodium ethoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 5.4 mg (59%) of a solid, Rf=0.60 (dichloromethane/methanol=15:1).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:19][CH2:20][CH3:21])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].C(=O)([O-])[O-].[K+].[K+].F[C:31]1[CH:32]=[CH:33][C:34]([N+:39]([O-:41])=[O:40])=[C:35]([CH:38]=1)[CH:36]=[O:37].O>CN(C)C=O>[F:1][C:2]([F:22])([F:23])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:31]2[CH:32]=[CH:33][C:34]([N+:39]([O-:41])=[O:40])=[C:35]([CH:38]=2)[CH:36]=[O:37])=[C:14]([CH2:19][CH2:20][CH3:21])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:6])([F:5])[F:7]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1O
Reactant: O=Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a solution of 4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenol (500 mg, 1.44 mmol) in N,N-dimethylformamide (7.2 mL), potassium carbonate (300 mg, 2.17 mmol) was added. Under ice-cold conditions, the resultant mixture was added with 5-fluoro-2-nitrobenzaldehyde (220 mg, 1.30 mmol) and stirred at 60° C. for 1 hour. The reaction solution was cooled down to room temperature, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified using preparative thin-layer chromatography (hexane/ethyl acetate). 5-(4-(1,1,1,3,3,3-Hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)-2-nitrobenzaldehyde (576 mg, yield 89%) was obtained as a yellow oil.
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[C:13]([O:17][C:18]([NH:20][C@@:21]12[CH2:27][CH2:26][C@:25]1([CH2:28][O:29][CH3:30])[CH2:24][N:23]([C@@H:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:32])[C:22]2=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[C:13]([O:17][C:18]([NH:20][C@@:21]12[CH2:27][CH2:26][C@:25]1([CH2:28][O:29][CH3:30])[CH2:24][N:23]([C@@H:31]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH3:32])[CH2:22]2)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: COC[C@]12CC[C@@]1(NC(=O)OC(C)(C)C)C(=O)N([C@H](C)c1ccccc1)C2
Agent: COCCO[AlH2-]OCCOC
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC[C@]12CC[C@@]1(NC(=O)OC(C)(C)C)CN([C@H](C)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
A 65% solution of Red-Al™ in toluene (1.43 mL, 4.75 mmol) was added dropwise to a solution of (1S,5S)-1-(tert-butoxycarbonylamino)-5-methoxymethyl-2-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.2.0]heptane (593 mg, 1.58 mmol) in toluene in a nitrogen atmosphere at 0° C. over two minutes. The mixture was heated to room temperature, stirred for two hours, and cooled to 0° C. A 20% potassium sodium tartrate tetrahydrate solution (10 mL) was carefully added while maintaining the internal temperature of the reaction solution at 10° C. or less. The reaction solution was poured into a mixture of ethyl acetate (10 mL) and brine (10 mL), followed by extraction with ethyl acetate (100 mL). The organic layer was washed with brine (20 mL), and then dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1→9:1) to give 244 mg (43%) of the title compound as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[F:10].C([Mg]Cl)(C)C.[C:16](=[O:18])=[O:17]>C1COCC1>[Cl:8][C:6]1[C:5]([CH3:9])=[CH:4][C:3]([F:10])=[C:2]([CH:7]=1)[C:16]([OH:18])=[O:17]
Reactant: O=C=O
Reactant: Cc1cc(F)c(Br)cc1Cl
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1cc(F)c(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
To a solution of 1-bromo-5-chloro-2-fluoro-4-methylbenzene (11.3 g, 50 mmol) in dry THF (100 mL) was added isopropylmagnesium chloride (30 mL, 2 M) dropwise. After stirring at room temperature for 30 min, dry CO2 was added and the mixture was stirred at room temperature for additional 30 min. The reaction was quenched by sat. NH4Cl and extracted with EtOAc (100 mL×3). The combined organic layers were washed with water (50 mL×3), dried over anhydrous Na2SO4, filtered and concentrated to give the desired product (4.7 g, 49%). LCMS (ESI) m/z: 187.0 [M−H]−.
Reaction SMILES: O[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[K+].CN(C)C=O.S([O:30][CH2:31][C:32]1([CH2:36][CH3:37])[CH2:35][O:34][CH2:33]1)(C1C=CC(C)=CC=1)(=O)=O>C1(C)C=CC=CC=1.O>[CH2:36]([C:32]1([CH2:31][O:30][C:11]2[CH:12]=[CH:2][C:3]([C:4]([OH:6])=[O:5])=[CH:9][CH:10]=2)[CH2:35][O:34][CH2:33]1)[CH3:37]
Reactant: CCC1(COS(=O)(=O)c2ccc(C)cc2)COC1
Reactant: CCOC(=O)c1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1(COc2ccc(C(=O)O)cc2)COC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
50 g of ethyl hydroxybenzoate and 21 g of potassium hydroxide were added to 400 mL of dimethylformamide, and stirred at 70° C. for 1 hour. After decreasing the temperature to 45° C., 100 g of 3-((tosyloxy)methyl)-3-ethyloxetane was added dropwise thereto, and then stirred at 45° C. for 3 hours. Water and toluene were added thereto, and the toluene layer was separated. The toluene layer was washed with 3% hydrochloric acid, a saturated sodium carbonate solution and water, and then toluene was distilled off. 50 g of sodium hydroxide, 500 mL of ethanol and 200 mL of water were added to the resulting residue, and refluxed for 2 hours. A residue obtained by distilling ethanol off was put in 500 mL of 5% hydrochloric acid to obtain crystals. The crystals thus obtained by filtering were recrystallized from a mixed solvent of ethanol and water to obtain 60 g of 4-(3-ethyloxetane-3-ylmethoxy)benzoic acid (OX1), which had a melting point of 127.5° C.