Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:20][C:19]2[CH:18]=[CH:17][C:5]([CH2:6][CH2:7][NH:8][C:9](=O)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][C:3]=2[O:2]1.[CH2:21]1[CH2:41][O:40][C:39]2[CH:38]=[CH:37][C:25]([CH2:26][CH2:27][NH:28][C:29](=O)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][C:23]=2[O:22]1>>[CH2:1]1[O:20][C:19]2[CH:18]=[C:17]3[C:5]([CH2:6][CH2:7][N:8]=[C:9]3[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][C:3]=2[O:2]1.[CH2:21]1[CH2:41][O:40][C:39]2[CH:38]=[C:37]3[C:25]([CH2:26][CH2:27][N:28]=[C:29]3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][C:23]=2[O:22]1
Reactant: O=C(NCCc1ccc2c(c1)OCCO2)c1ccccc1
Reactant: O=C(NCCc1ccc2c(c1)OCO2)c1ccccc1
Product: c1ccc(C2=NCCc3cc4c(cc32)OCCO4)cc1
Product: c1ccc(C2=NCCc3cc4c(cc32)OCO4)cc1

Procedure:
Substitution of an equivalent quantity of N-(3,4-methylenedioxyphenethyl)benzamide or N-(3,4-ethylenedioxyphenethyl)benzamide for the substituted benzamide called for in the first paragraph of this example and substantial repetition of the procedure there detailed affords 6,7-methylenedioxy-1-phenyl-3,4-dihydroisoquinoline or 6,7-ethylenedioxy-1-phenyl-3,4-dihydroisoquinoline, respectively.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8](C=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+]>CO>[CH2:12]([NH:19][C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: O=Cc1ccc2nc[nH]c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1ccc(CNc2ccc3[nH]cnc3c2)cc1
Reaction time: 8 h

Procedure:
Benzimidazol-5-carbaldehyde (146 mg; 1 mmol; 1 eq.) was dissolved in MeOH (10 ml). Benzylamine (0.109 ml; 1 mmol; 1 eq.) was added and the mixture was stirred overnight. NaBH4 (57 mg; 1.5 mmol; 1.5 eq.) was added and stirring was continued overnight. The reaction was quenched by addition of water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flashchromatography on silica using a CHCl3/MeOH gradient. Yield: 0.045 g (19%); MS m/z: 238.4 [M+H]+; 1H-NMR (400 MHz, DMSO d6): δ 3.65 (s, 2H); 3.74 (s, 2H); 7.10-7.20 (m, 2H); 7.25-7.32 (m, 4H); 7.40-7.55 (m, 2H); 8.11 (s, 1H); 12.28 (br s, 1H); HPLC (METHOD [A]): rt 4.98 min (95.0%)
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][NH:6][C:7](=[O:10])[CH2:8][NH2:9].C(N1CCCCC1)C.ClC1C([O:27][C:28](=O)[C@H:29]([CH2:41][CH2:42][C:43](=[O:45])[NH2:44])[NH:30][C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])=C(Cl)C(Cl)=C(Cl)C=1Cl>CN(C)C=O.ClCCl>[CH3:2][O:3][C:4](=[O:11])[CH2:5][NH:6][C:7](=[O:10])[CH2:8][NH:9][C:28](=[O:27])[C@H:29]([CH2:41][CH2:42][C:43](=[O:45])[NH2:44])[NH:30][C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32]
Reactant: COC(=O)CNC(=O)CN
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: CCN1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)CNC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of glycyl-glycine methyl ester hydrochloride (1.9 g; 10 mmoles) in a dimethylformamide-dichloromethane (1:2) mixture (30 ml) is admixed with N-ethylpiperidine (1.4 ml) and stirred for 2 hours at room temperature. After that benzyloxycarbonylglutamine pentachlorphenyl ester (5.3 g; 10 mmoles) is added and the reaction mixture is stirred at room temperature a further 4 hours. After 8 hours of standing, the precipitated crystalline product is separated and crystallized from methanol - dichloromethane. Yield 2.5 g (61%), m.p. 129°-134° C., after additional crystallization from methanol 132°-134° C. Rf 0.57/S1, 0.78/S2⟦alpha⟧sub.D20 -8.5° (c 0.2; 50% acetic acid). Composition: C18H24N4O7.1/2H2O.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][O:7][C:6]=1Br)=[O:4].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:6]2[O:7][CH:8]=[CH:9][C:5]=2[C:3]([O:2][CH3:1])=[O:4])[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)c1ccoc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccoc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 75.9 %

Procedure:
2-Bromofuran-3-carboxylic acid methyl ester (3.0 g, 15 mmol, 1.0 eq.), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (4.5 g, 15 mmol, 1.0 eq.), THF (150 mL) and Na2CO3 (30 mL, 60 mmol, 4.0 eq.) were combined. The mixture was degassed and purged with nitrogen (3×). PdCl2(PPh3)2 (0.3 g, 0.4 mmol, 0.03 eq.) was added, and the mixture was again degassed and purged with nitrogen (3×), then heated at 80° C. overnight. The mixture was then cooled and the layers were separated. The THF layer was diluted with EtOAc (150 mL), washed with saturated aqueous NaCl (80 mL) and dried over Na2SO4. The material was filtered and applied onto a silica gel column and purified by chromatography with PE/EtOAc (20:1 to 10:1) to yield 4-(3-methoxycarbonylfuran-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (3.5 g) as a white solid.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH2:8][CH2:9][CH3:10])[CH:6]=[N:5][CH:4]=1.S(Cl)([Cl:13])=O>>[ClH:13].[Cl:13][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][CH3:10])[CH:6]=[N:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CCCn1cncc1CO
Product: CCCn1cncc1CCl
Product: Cl
Temperature: 90 °C

Procedure:
To 5-hydroxymethyl-1-propylimidazole (33.0 g) was portionwise added thionyl chloride (80 ml) at 0C, and the mixture was heated at 90° C. for 30 minutes under a nitrogen atmosphere. The mixture was returned to room temperature, and then the solvent was distilled off under reduced pressure. The resulting residue was dissolved in methanol, and the solvent was again distilled off under reduced pressure. The resulting solid was recrystallized from ethyl acetate to give 5-chloromethyl-1-propylimidazole hydrochloride (43.8 g) as colorless crystals.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:8])[CH2:4][CH2:3]1.[H-].[Na+].[Si:19]([O:26][CH2:27][C@H:28]1[CH2:39][CH2:38][C:37]2[S:36][C:35]3[N:34]=[CH:33][N:32]=[C:31](Cl)[C:30]=3[C:29]1=2)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C1COCC1>[Si:19]([O:26][CH2:27][C@H:28]1[CH2:39][CH2:38][C:37]2[S:36][C:35]3[N:34]=[CH:33][N:32]=[C:31]([O:1][CH:2]4[CH2:7][CH2:6][C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:8])[CH2:4][CH2:3]4)[C:30]=3[C:29]1=2)([C:22]([CH3:25])([CH3:23])[CH3:24])([CH3:21])[CH3:20]
Reactant: CC1(NC(=O)OC(C)(C)C)CCC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CCc2sc3ncnc(Cl)c3c21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CO[Si](C)(C)C(C)(C)C)CC4)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a solution of tert-butyl N-(4-hydroxy-1-methylcyclohexyl)carbamate (700 mg, 3.05 mmol, 1.00 equiv) in anhydrous THF (10 mL) was added sodium hydride (60% dispersion in mineral oil, 600 mg, 15.00 mmol, 4.91 equiv) at 0° C. under nitrogen. The resulting solution was stirred for 0.5 h at room temperature. To this was added (3S)-3-[[(tert-butyldimethylsilyl)oxy]methyl]-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene (1.18 g, 3.32 mmol, 1.09 equiv) and stirring was continued for 5 h at 30° C. The reaction was then quenched by the addition of 30 mL of NH4Cl (aq.) and extracted with 3×80 mL of ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/15) to yield 1.20 g (72%) of tert-butyl N-(4-[[(3S)-3-[[(tert-butyldimethylsilyl)oxy]methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-methylcyclohexyl)carbamate as a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:39])[CH2:35][CH:36]([NH2:38])[CH3:37]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[O:30][C:29]([CH2:31][NH:38][CH:36]([CH3:37])[CH2:35][N:34]([CH3:39])[CH3:33])=[CH:28][CH:27]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Reactant: CC(N)CN(C)C
Product: CC(CN(C)C)NCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1

Procedure:
5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde and N,N-dimethyl-1,2-propanediamine were reacted in an analogous manner to Example 10 to give the title compound; δH [2H6]-DMSO 9.83 (1H, b,), 8.70 (1H, s), 8.42 (1H, s), 8.10 (1H, d), 7.73 (1H, d), 7.64 (2H, d), 7.50-7.28 (5H, m), 7.02 (2H, d), 6.99 (1H, s), 6.52 (1H, d), 5.10 (2H, s), 3.93-3.70 (2H, m), 2.04 (9H, m), 0.92 (3H, m); m/z 508 (M+1)+.
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].Cl[C:7]1[N:12]=[N:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1>CO>[C:13]1([C:10]2[N:11]=[N:12][C:7]([S:5][CH2:2][CH:3]=[CH2:4])=[CH:8][CH:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1ccc(-c2ccccc2)nn1
Reactant: C=CCS
Agent: [Na]
Solvent: CO
Product: C=CCSc1ccc(-c2ccccc2)nn1
Reaction time: 0.17 h

Procedure:
0.23 g(0.01 mol) of metallic sodium was dissolved in 30 ml of absolute methanol and then mixed with 0.93 ml(0.01 mol) of allylmercaptan. To this mixture was added 1.90 g(0.01 mol) of 6-chloro-3-phenylpyridazine. The reaction solution was refluxed for 5 hours and concentrated under reduced pressure to remove methanol. 100 ml of diethyl ethers was added to the residue and vigorously stirred for 10 minutes. The materials insoluble in diethyl ether was removed and the remaining solution was washed twice with 50 ml of purified water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to remove diethyl ether. In this manner, the title compound was obtained as a white crystal.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[O:11]=[CH:12][C@H]([C@H]([C@H](CO)O)O)O>>[O:1]=[CH:2][C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH2:12][OH:11])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@@H](O)[C@@H](O)[C@@H](O)CO
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Product: O=C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO

Procedure:
It is also known that both D-glucose and D-mannose can be epimerized in an aqueous solution containing about 17% by weight of D-glucose or D-mannose, based on total solution weight (i.e., 20% by weight of glucose, based on the weight of water) and a small amount of molybdic acid catalyst producing a solution containing 25 percent D-mannose, remainder D-glucose on the dry basis. This epimerization is described by V. Bilik, Chem. Zvesti, 26, 183-186 (1972) and in Czech patent 149,051 (June 15, 1973). No reaction took place when sodium molybdate was used as the catalyst. Bilik and co-workers have also found that various other sugars can be epimerized in the presence of molybdate ions in aqueous solution. For example, D-fructose gives a mixture of D-sorbose, D-tagatose, and D-psicose, and sucrose gives a mixture of D-mannose and D-sorbose in a similar reaction. [Chemical Abstracts, 80, 146433s (1974)]. Also, L-arabinose gives a mixture of L-arabinose and L-ribose [Czechoslovakian Patent 149,472, July 15, 1973; C.A. 81, 78189k (1974)]; L-mannose gives a mixture of L-glucose and L-mannose [C.A. 81, 91887f (1974)]; and D-galactose gives a mixture of D-talose and D-gulose in addition to D-galactose [C.A. 81, 152523h (1974)].
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:9][CH:10]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[N:22]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[C@@H:24](O)[CH2:23]2.O.N1(O)C2C=CC=CC=2N=N1.C(=NC1CCCCC1)=NC1CCCCC1>C1COCC1>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:9][CH:10]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:11]([O:13][C@@H:24]2[CH:25]3[CH2:28][CH2:29][N:22]([CH2:27][CH2:26]3)[CH2:23]2)=[O:12])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1cccc(NC(C(=O)O)c2ccc(OC)nc2)c1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CCc1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccc(OC)nc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(3-ethylphenylamino)-2-(6-methoxypyridin-3-yl)acetic acid (I73) (265 mg, 0.93 mmol), (R)-quinuclidin-3-ol (129 mg, 1.02 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (156 mg, 1.02 mmol), and N,N′-methanediylidenedicyclohexanamine (210 mg, 1.02 mmol) was dissolved in THF (10 ml) and stirred at room temperature overnight. The solvent was evaporated, and the crude product was taken up with EtOAc and washed twice with 2M K2CO3. The organic phase was dried over Na2SO4, filtered and evaporated to dryness to obtain the title compound, which was used in the next step without any further purification.
Reaction SMILES: [C:1]1([O:7]C(Cl)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.[OH2:14].[OH-].[Na+].C(N([CH2:22][CH3:23])CC)C>>[CH:2]1[CH:3]=[C:22]([CH2:23][C:2]2[C:1]([OH:7])=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:5]([OH:14])=[CH:6][CH:1]=1
Reactant: O
Reactant: CCN(CC)CC
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Oc1ccccc1Cc1ccccc1O
Reaction time: 1 h

Procedure:
62.6 G of chloroformic acid phenyl ester are added dropwise over the course of 30 minutes to a two-phase solution of 40 g of bis-(4-hydroxyphenyl)-methane(bisphenol-F), 600 g of methylene chloride, 300 g of water, 41.4 g of 45% strength sodium hydroxide solution and 0.240 g of triethylamine at 25°C. After stirring for 1 hour, 3.1 g of unreacted bisphenol-F are again isolated from the aqueous phase and the organic phase is washed with dilute sodium hydroxide solution, then with dilute hydrochloric acid and finally with water. After drying the solution and distilling off the methylene chloride, recrystallization of the residue from 300 ml of cyclohexane yields 73.8 g (84% of theory) of bisphenol-F-bisphenyl-carbonate of melting point 97.5 to 98°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([OH:13])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:26][CH3:27].CO>CN(C=O)C.C(Cl)Cl>[CH2:26]([O:13][C:11]1[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:12]=1)[CH3:27]
Reactant: CCOC(=O)c1nn(-c2ccc(F)cc2)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1nn(-c2ccc(F)cc2)cc1OCC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of D1 (9.6 g, 38 mmol, 1.0 eq.) and K2CO3 (6.8 g, 50 mmol, 1.3 eq.) in dry DMF (100 mL) was added at RT iodoethane (4.0 mL, 7.8 g, 50 mmol, 1.3 eq.). After stirring for 72 h at RT the mixture was cooled to 0° C. MeOH (5 mL) was added, the mixture was diluted with DCM (200 mL) and washed with water and phosphate buffer. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the product D2 as a brown solid which was used without further purification in the subsequent step. MS (ES) C14H15FN2O3 requires: 278. Found: 279 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1.C([C:27]1[NH:28][CH:29]=[CH:30][N:31]=1)C.[CH3:32][C:33](CC(C)C)=O>>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][C:27]3[N:31]([CH2:32][CH3:33])[CH:30]=[CH:29][N:28]=3)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)CC(C)C
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Reactant: CCc1ncc[nH]1
Product: CCn1ccnc1CCOc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC

Procedure:
Using 1.9 g N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 138), 2.7 g 2-ethylimdazole, and 50 ml of methylisobutyketone, a reaction similar to that conducted in Example 142 was carried out. As a result, 1.78 g of N-(trans-4-methylcyclohexyl)-4-{2-[1-(2-ethyl)imidazolyl]ethoxy}-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [I:1][CH2:2][CH:3]1[CH2:7][CH2:6][O:5][CH2:4]1.[C:8]1([P:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(#N)C>[I-:1].[C:21]1([P+:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:2][CH:3]2[CH2:7][CH2:6][O:5][CH2:4]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: ICC1CCOC1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: [I-]
Product: c1ccc([P+](CC2CCOC2)(c2ccccc2)c2ccccc2)cc1
Yield: 83.2 %

Procedure:
To a solution of 3-(iodomethyl)tetrahydrofuran (10.1 g) in acetonitrile (101 mL) was added triphenylphosphine (13.1 g), followed by heating under reflux for 1 week. The solution was concentrated under reduced pressure, followed by addition of diethyl ether. The resulting solid was collected by filtration and washed with diethyl ether to obtain triphenyl(tetrahydrofuran-3-ylmethyl)phosphonium iodide (18.8 g) as a white solid.
Reaction SMILES: [CH3:1][C@H:2]([OH:7])[CH2:3][C@@H:4]([OH:6])[CH3:5].[CH3:8][O:9][P:10](OC)OC>>[CH3:8][O:9][P:10]1[O:7][C@@H:2]([CH3:1])[CH2:3][C@H:4]([CH3:5])[O:6]1
Reactant: C[C@H](O)C[C@H](C)O
Reactant: COP(OC)OC
Product: COP1O[C@@H](C)C[C@H](C)O1
Temperature: 100 °C

Procedure:
10 g of (+)-(2S,4S)pentane-2,4-diol and 13.6 g of trimethylphosphite were mixed, and heated at 100° C. on an oil bath. After completion of distilling methanol off, the residue is distilled under reduced pressure to obtain colorless transparent 2-methoxy-(4S,6S)-4,6-dimethyl-1,3,2-dioxaphosphorinane. bp: 70°-72° C./15 mmHg.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12].[C:14]1([S:20](CCl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:25]C(C)([O-])C.[K+].Cl>C1COCC1>[C:14]1([S:20]([C:7]2[CH:8]=[CH:9][C:10]([CH3:25])=[C:5]([O:4][CH2:3][CH2:2][Cl:1])[C:6]=2[N+:11]([O-:13])=[O:12])(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)[O-]
Reactant: O=[N+]([O-])c1ccccc1OCCCl
Reactant: O=S(=O)(CCl)c1ccccc1
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)c2ccccc2)c([N+](=O)[O-])c1OCCCl
Reaction time: 5 h

Procedure:
A mixture of 1-(2-chloro-ethoxy)-2-nitrobenzene (1.2 g, 6 mmoles) and chloromethyl phenyl sulfone (2.16 g, 9 mmoles) was stirred in THF (50 mL) at −78° C., in a round bottom flask under nitrogen. A solution of 1M potassium t-butoxide was added dropwise (18 mL, 18 mmoles) over a half an hour period. Temperature was allowed to rise to −40° C., and the reaction mixture was stirred at this temperature for 5 hours. The reaction mixture was poured into cold 2N HCl, extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum. Compound was recrystallized from CH2Cl2/hexane to afford the title compound as an off-white solid (1.5 g, 4.2 mmoles).
Reaction SMILES: [C:1]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[F:14][C:15]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=1O.C(N(CC)CC)C.C1(C(Cl)=O)CCC=1>C(Cl)Cl>[C:1]1([C:5]([O:7][C:16]2[C:17]([F:24])=[C:18]([F:23])[C:19]([F:22])=[C:20]([F:21])[C:15]=2[F:14])=[O:6])[CH2:4][CH2:3][CH:2]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(O)C1=CCC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)C1=CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C1=CCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 43.8 %

Procedure:
Cyclobut-1-enecarboxylic acid (0.51 mmol, 50 mg) was dissolved in 0.5 ml dry CH2Cl2. The solution was cooled to 0° C. and oxalyl dichloride (0.51 mmol, 43 μl) was added. The temperature of the solution was raised to room temperature, and the mixture was allowed to react for 1 h. The solvent was evaporated to generate a viscous oil. 2,3,4,5,6-Pentafluorophenol (0.51 mmol, 94 mg) and triethylamine (1.02 mmol, 142 μl) were dissolved in 0.5 ml dry CH2Cl2, and the solution was stirred at 0° C. for 45 min before being added to a vial containing cyclobut-1-enecarboxylic chloride. The reaction mixture was stirred for 16 h at rt. The reaction was quenched with 1 N HCl, and was extracted with CH2Cl2 (30 ml). The CH2Cl2 solution was washed with 5% NaHCO3 (2×10 ml), dried over Na2SO4, concentrated by rotary evaporation, and then purified by flash column chromatography (100% CH2Cl2) to yield 13 as a colorless oil (59 mg, 44%). 1H-NMR (500 MHz, CDCl3) δ 7.12 (s, 1H), 2.86 (m, 2H), 2.60 (m, 2H). 13C-NMR (125 MHz, CDCl3) δ 156.7, 152.6, 142.1, 140.3, 138.8, 138.3, 135.2, 53.3, 30.6, 29.2. HRMS (ESI) calcd. for C11H6O2F5 [M+H]+ 265.0293, found 265.0288.
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.Cl[CH2:39][C:40]([N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])=O>>[CH2:43]([N:42]([CH2:45][CH3:46])[CH2:40][CH2:39][O:10][C:8]1[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[C@@H:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:6][CH:7]=1)[CH3:44]
Reactant: CCN(CC)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(CC)CCOc1ccc(CCCNc2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 55.9 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N,N-diethylacetamide (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (5.6 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[NH:8][C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].C(O[CH:21]1[O:33][C@H:32]([CH3:34])[C@@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:22]1[O:23][C:24](=[O:26])[CH3:25])(=O)C>>[N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[N:8]([C@@H:21]3[O:33][C@H:32]([CH3:34])[C@@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:22]3[O:23][C:24](=[O:26])[CH3:25])[C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(C)Nc1nc2cc([N+](=O)[O-])ccc2[nH]1
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(NC(C)C)nc2cc([N+](=O)[O-])ccc21

Procedure:
5-nitro-N-(1-methylethyl)-1H-benzimidazol-2-amine (1.1 g) was coupled to 1,2,3-tri-O-acetyl-5-deoxy-D-ribofuranose according to General Procedure II. The crude product was purified by flash chromatography (1:1 ethyl acetate/hexanes) to yield the title compound (0.420 g) as a mixture of 5,6 regioisomers. MS (AP): m/z 443 (M+Na).