Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[NH:4][C:5]([O:7][CH3:8])=[O:6].[C:13](O)([CH3:16])([CH3:15])[CH3:14].CCCCCC>S(=O)(=O)(O)O>[C:13]([C:11]1[CH:10]=[CH:9][C:3]([NH:4][C:5]([O:7][CH3:8])=[O:6])=[C:2]([F:1])[CH:12]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)O
Reactant: COC(=O)Nc1ccccc1F
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Product: COC(=O)Nc1ccc(C(C)(C)C)cc1F
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 158.7 %

Procedure:
2-Fluoro-N-methoxycarbonylaniline (150 g, 0.859 mol) was dissolved in 77.6% sulfuric acid (206 g) to prepare a solution. t-Butyl alcohol (72.9 g, 1.07 mol) was added dropwise to the solution under a nitrogen atmosphere over a period of 30 min while stirring and heating the solution at 70° C. After the completion of the dropwise addition, the reaction solution was vigorously stirred at the same temperature for one hr. t-Butyl alcohol (72.9 g, 1.07 mol) was again added dropwise thereto over a period of 30 min. After the completion of the dropwise addition, the reaction solution was vigorously stirred at the same temperature for one hr. t-Butyl alcohol (72.9 g, 1.07 mol) was again added dropwise thereto over a period of 30 min. After the completion of the dropwise addition, the reaction solution was vigorously stirred at the same temperature for one hr. The reaction solution was cooled to room temperature. n-Hexane (530 mL) was then added to the cooled reaction solution to carry out extraction for separation of the mixture into a sulfuric acid layer and an organic layer. n-Hexane (530 mL) was again added to the sulfuric acid layer to carry out extraction for separation of an organic layer. The organic layers thus obtained were combined, and the combined organic layer was washed with water and saturated brine in that order. The solvent was then removed from the organic layer by distillation to give 307 g of 4-t-butyl-2-fluoro-N-methoxycarbonylaniline as an oily crude product (yield on weight basis 159%, purity as determined by gas chromatography 65.1%, 4-t-butyl form 5-t-butyl form=100:0).
Reaction SMILES: C(OCC)(OCC)O[CH2:3][CH3:4].[CH2:11]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][O:28][CH3:29])=[CH:22][CH:21]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[OH:31].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O.C1(C)C=CC=CC=1>[CH2:11]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][O:28][C:29]([CH:3]=[CH2:4])=[O:31])=[CH:22][CH:21]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCOc1ccc(C=COC)cc1
Reactant: O=C([O-])O
Reactant: CCOC(OCC)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=CC(=O)OCCc1ccc(OCCCCCCCC)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Methoxymethyl triphenylphosphonium chloride of 34.28 g was suspended in anhydrous ether of 190 ml, and potassium t-butoxide of 11.22 g was added thereto. A solution prepared by dissolving 4-n-octyloxybenzaldehyde of 22.26 g in anhydrous ether of 110 ml was added thereto, and the solution was stirred at room temperature for 12 hours. Resulting triphenylphosphine oxide was removed by filtration, and the filtrate was poured into ice and water of 300 ml. An ether layer was separated and washed with water, followed by drying the ether layer with anhydrous sodium sulfate. Then, ether was distilled off to obtain crude (4'-n-octyloxyphenyl)-2-methoxyethylene. Further, the crude product was refined by distillation under reduced pressure to obtain (4'-n-octyloxyphenyl)-2-methoxyethylene of 25.4 g. Next, a mixed solution of triethyl orthoformate of 240 g and boron trifluoride ethyl ether complex salt of 6.53 g was cooled down to 0°C., and (4'-n-octyloxyphenyl)-2-methoxyethylene of 25.39 g was added thereto. Then, after stirring the solution at room temperature for 12 hours, toluene of 200 ml and a 10 weight % sodium hydrogencarbonate aqueous solution of 150 ml were added and mixed, and then a toluene layer was separated. The toluene layer was dried with anhydrous sodium sulfate, and then toluene was distilled off to obtain 4-n-octyloxyphenyl malonotetraethyl acetal. This 4-n-octyloxyphenyl malonotetraethyl acetal of 21.2 g was added to water of 12 ml and p-tolenesulfonic acid of 0.05 g, and the reaction was carried out at 80° C. for 3 hours. After cooling the solution down to room temperature, sodium carbonate of 0.52 g was added for neutralization, and then the product was extracted with toluene. The extract was washed with a 10 weight % sodium hydroxide aqueous solution and further washed with water. Then, a toluene layer was separated and dried with anhydrous sodium sulfate, and toluene was distilled off to obtain α-(4-n-octyloxyphenyl)-β-ethoxyacrolein of 16.62 g.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[C:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:15]=2)=[N:11][CH:12]=1)[CH2:2][CH2:3][C:4]#[CH:5].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[N:28]=1.C(N(CC)CC)C>CS(C)=O.O>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[CH:20]=[C:21]2[CH2:26][CH2:25][N:24]([C:34]([NH:33][C:29]3[N:28]=[N:27][CH:32]=[CH:31][CH:30]=3)=[O:35])[CH2:23][CH2:22]2)=[N:11][CH:12]=1)[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C#CCCCOc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: C#CCCCOc1ccc(Oc2cccc(C=C3CCN(C(=O)Nc4cccnn4)CC3)c2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.2 %

Procedure:
5-(Pent-4-ynyloxy)-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine (0.26 g, 0.746 mmol) and phenyl pyridazin-3-ylcarbamate (0.16 g, 0.746 mmol) were dissolved in DMSO (3 mL) and triethylamine (0.3 mL) was added dropwise. The reaction was stirred for 12 h at RT. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography (acetone:hexane, 2:5) to give the title compound (0.225 g, 64%). 1H NMR (500 MHz, CDCl3): δ 8.77 (s, 1H), 8.40 (s, 1H), 7.89 (s, 1H), 7.46 (t, J=4.5 Hz, 1H), 7.29 (m, 2H), 6.98 (d, J=7.5 Hz, 1H), 6.92 (m, 2H), 6.87 (d, J=8.75 Hz, 1H), 6.40 (s, 1H), 4.08 (t, J=5.75 Hz, 2H), 3.70 (m, 2H), 3.59 (m, 2H), 2.60 (d, J=5.2 Hz, 2H), 2.47 (m, 2H), 2.40 (t, J=6.6 Hz, 2H), 1.99 (m, 3H); 13C NMR (125 MHz, CDCl3): δ157.48, 156.60, 155.19, 151.80, 138.72, 137.46, 133.67, 129.42, 128.15, 126.84, 124.96, 124.59, 120.58, 118.38, 112.52, 83.14, 69.12, 67.25, 45.66, 44.64, 35.76, 29.13, 28.08, 15.06; m/z (470.2 MH+); HPLC: 97.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10](Cl)[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[CH:18]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19]1.CN1CCCC1=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:23][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1
Reactant: NC1CCCC1
Reactant: Clc1ccc(-c2nc(Cl)c3c(n2)CCC3)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: Clc1ccc(-c2nc3c(c(NC4CCCC4)n2)CCC3)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.265 g of 2-(4-chlorophenyl)-4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, 0.4 g of cyclopentylamine and 1 ml of N-methylpyrrolidone were heated to 130° C. in an oil bath. After 5 hours, the mixture was diluted with 20 ml of water and stirred at room temperature. The precipitated product was filtered off with suction, washed with water and dried in vacuo at 40° C. Yield: 0.26 g. M.p.: 167° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([OH:40])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:50][CH2:51][OH:52].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:38])([F:39])[F:37])[CH:27]=3)[C:22]([O:40][CH2:50][CH2:51][OH:52])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: OCCBr
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(OCCO)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 60 °C
Reaction time: 8 h

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-hydroxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (150 mg) is dissolved in N,N-dimethylformamide (1 ml), then thereto are added potassium carbonate (200 mg) and 2-bromoethanol (162 μl), and the mixture is stirred at 60° C. overnight. To the reaction mixture is added 10% aqueous citric acid solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=2:1) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-hydroxyethoxy)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (95 mg). MS (m/z): 644 [M+H]+
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:16]3=[CH:25][C:26]([CH2:28][N:29]([CH3:31])[CH3:30])=[CH:27][N:15]3[N:14]=2)[CH:8]=1)(=O)=O.[NH3:32]>CO>[NH2:32][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[N:18]=[C:17]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:16]3=[CH:25][C:26]([CH2:28][N:29]([CH3:30])[CH3:31])=[CH:27][N:15]3[N:14]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)Cc1cc2c(N3CCOCC3)nc(-c3cccc(COS(C)(=O)=O)c3)nn2c1
Reactant: N
Solvent: CO
Product: CN(C)Cc1cc2c(N3CCOCC3)nc(-c3cccc(CN)c3)nn2c1
Reaction time: 8 h
Yield: 56.2 %

Procedure:
Compound 19 (80 mg, 0.18 mmol) was added to 20 mL of saturated ammonia solution of methanol. The reaction was carried out at 80° C. in a sealed tube for 8 h. After the reaction mixture was concentrated, it was purified by a preparative plate (dichloromethane:methanol=6:1) to obtain 37 mg of colourless oil (56.2%). 1H NMR (300 MHz, CDCl3): δ 8.20 (s, 1H), 8.17-8.13 (m, 1H), 7.64 (s, 1H), 7.41-7.39 (m, 2H), 6.86 (s, 1H), 4.11 (t, J=4.7 Hz, 4H), 3.97 (s, 2H), 3.87 (t, J=4.7 Hz, 4H), 3.69 (s, 2H), 2.41 (s, 6H). LC-MS: 367 (M+1).
Reaction SMILES: [OH:1][OH:2].[OH-:3].[Na+].[C:5]1([CH3:19])[CH:10]=[CH:9][C:8]([O:11][C:12]([CH2:14][CH2:15][C:16](Cl)=[O:17])=[O:13])=[CH:7][CH:6]=1.O=O>CCOCC>[C:5]1([CH3:19])[CH:10]=[CH:9][C:8]([O:11][C:12]([CH2:14][CH2:15][C:16]([O:1][O:2][C:16](=[O:17])[CH2:15][CH2:14][C:12]([O:11][C:8]2[CH:7]=[CH:6][C:5]([CH3:19])=[CH:10][CH:9]=2)=[O:3])=[O:17])=[O:13])=[CH:7][CH:6]=1
Reactant: OO
Reactant: Cc1ccc(OC(=O)CCC(=O)Cl)cc1
Reactant: [OH-]
Agent: O=O
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccc(OC(=O)CCC(=O)OOC(=O)CCC(=O)Oc2ccc(C)cc2)cc1
Reaction time: 3 h
Yield: 83.9 %

Procedure:
To a vigorously stirred solution of 2.0 g. (0.029 mole) of 50% H2O2 and 25.2 g. (0.063 mole) of aqueous 10% sodium hydroxide at 10°-14° C. was added slowly 10.9 g. (0.0483 mole) of 3-(p-tolyloxycarbonyl)propionyl chloride in ether solution. The resulting reaction mixture was stirred for an additional three hours. After a work-up similar to that in Example I 9.1 g. (theory, 10.0 g.) of white solid, m.p. 94°-106° C. (decomp.) was obtained. The assay according to "active oxygen" content was 92.3% and the corrected yield was 83.9%.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([CH3:54])([CH3:53])[CH2:15][N:16]1[C:24]2[CH2:23][CH2:22][CH:21]([N:25]3[C:30](=[O:31])[C:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]5[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=5)=[CH:35][CH:34]=4)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]4[N:50]=[CH:51][N:52]=[C:26]34)[CH2:20][C:19]=2[CH:18]=[N:17]1>O.C(OCC)(=O)C>[OH:13][C:14]([CH3:53])([CH3:54])[CH2:15][N:16]1[C:24]2[CH2:23][CH2:22][CH:21]([N:25]3[C:30](=[O:31])[C:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=5[C:45]5[NH:3][C:4](=[O:7])[O:5][N:46]=5)=[CH:35][CH:34]=4)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]4[N:50]=[CH:51][N:52]=[C:26]34)[CH2:20][C:19]=2[CH:18]=[N:17]1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCc3c(cnn3CC(C)(C)O)C2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCc3c(cnn3CC(C)(C)O)C2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 28.9 %

Procedure:
A mixture of hydroxylammonium chloride (0.12 g), sodium hydrogen carbonate (0.20 g) and dimethyl sulfoxide (2 mL) was stirred at 40° C. for 30 min, 4′-({4-[1-(2-hydroxy-2-methylpropyl)-4,5,6,7-tetrahydro-1H-indazol-5-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.069 g) was added, and the mixture was stirred at 90° C. for 15 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (1 mL). N,N′-Carbonyldiimidazole (0.024 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.022 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, adjusted to pH 4 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.022 g, 29%).
Reaction SMILES: [C:1]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:13]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH2:22])=[CH:19][CH:18]=1)(=[O:15])[CH3:14].[C:25]([O:30][CH2:31][CH2:32][OH:33])(=[O:29])[C:26]([CH3:28])=[CH2:27].N(C(C)(CC)C([O-])=O)=NC(C)(CC)[C:37]([O-])=[O:38]>CCCCCCC.C(C(C)=O)C(C)C>[C:1]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:13]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH2:22])=[CH:19][CH:18]=1)(=[O:15])[CH3:14].[C:25]([O:30][CH2:31][CH2:32][OH:33])(=[O:29])[C:26]([CH3:28])=[CH2:27].[C:13]([O:16][CH:17]([CH3:24])[CH2:18][O:38][CH3:37])(=[O:15])[CH3:14].[CH3:25][O:30][CH2:31][CH2:32][O:33][CH2:10][CH2:9][O:8][CH2:7][CH3:12]
Reactant: CCC(C)(N=NC(C)(CC)C(=O)[O-])C(=O)[O-]
Agent: C=C(C)C(=O)OC1CCCCO1
Agent: C=C(C)C(=O)OCCO
Agent: C=Cc1ccc(OC(C)=O)cc1
Solvent: CC(=O)CC(C)C
Solvent: CCCCCCC
Product: CCOCCOCCOC
Product: COCC(C)OC(C)=O
Reaction time: 6 h

Procedure:
Into a 500 ml-volume three-neck flask, 71.5 g (0.42 mol) of 2-tetrahydropyranyl methacrylate, 19.5 g (0.12 mol) of p-acetoxystyrene, 7.8 g (0.06 mol) of 2-hydroxyethyl methacrylate and 300 ml of methyl isobutyl ketone were charged. A catalytic amount of 2,2′-azobis(methyl 2-methylpropionate) was added thereto as a radical polymerization initiator, and polymerization was allowed to proceed at 80° C. for 6 hours in a nitrogen stream. The reaction solution was cooled and then poured in a large amount of heptane to precipitate a polymer. The crystal was collected by filtration and dissolved in a mixed solvent of propylene glycol monomethyl ether acetate and diethylene glycol ethyl methyl ether, and heptane and methyl isobutyl ketone contained in the solution were removed by distillation under reduced pressure to obtain Polymer A1-7 (2-tetrahydropyranyl methacrylate/p-acetoxystyrene/2-hydroxyethyl methacrylate) as a solution in a mixed solvent of propylene glycol monomethyl ether acetate and diethylene glycol ethyl methyl ether.
Reaction SMILES: [C:1]([O:7][CH2:8]Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[C:16]([O:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]2[C:40]([C:41]([OH:43])=[O:42])=[C:39]([C:44]([OH:47])([CH3:46])[CH3:45])[N:38]=[C:37]2[CH2:48][CH2:49][CH3:50])=[CH:31][CH:30]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(OCC)(=O)C>CN(C)C(=O)C.O>[C:16]([O:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]2[C:40]([C:41]([O:43][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:42])=[C:39]([C:44]([OH:47])([CH3:46])[CH3:45])[N:38]=[C:37]2[CH2:48][CH2:49][CH3:50])=[CH:31][CH:30]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCOC(=O)C(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.13 ml of chloromethyl pivalate and 3.99 g of potassium carbonate were added to a solution of 6 g of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid [prepared as described in step (b) above] in 70 ml of N,N-dimethylacetamide, and the resulting mixture was stirred at room temperature for 1 hour and then at 50° C. for 2 hours. At the end of this time, the reaction mixture was mixed with ethyl acetate and water. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 6.80 g of the title compound as crystals, melting at 106°-107° C.
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([CH2:10][Cl:11])[N:6]=1)[C:2]([CH3:4])=O.[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)([O-:14])=[O:13].[NH2:23]/[C:24](/[CH3:30])=[CH:25]\[C:26]([O:28][CH3:29])=[O:27]>C(O)(C)C>[CH3:4][C:2]1[NH:23][C:24]([CH3:30])=[C:25]([C:26]([O:28][CH3:29])=[O:27])[CH:18]([C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[C:1]=1[C:5]1[O:9][N:8]=[C:7]([CH2:10][Cl:11])[N:6]=1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)Cc1nc(CCl)no1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(c2nc(CCl)no2)C1c1cccc([N+](=O)[O-])c1
Yield: 63.7 %

Procedure:
A solution of 8.0 g of 5-acetonyl-3-chloromethyl-1,2,4-oxadiazole, 6.92 g of 3-nitrobenzaldehyde and 5.27 g of methyl 3-aminocrotonate in 20 ml of isopropyl alcohol was heated under reflux for 6 hours. After ice-cooling, the precipitated solid was collected by filtration, washed with cold isopropyl alcohol and dried to give 11.8 g of methyl 1,4-dihydro-2,6-dimethyl-3-(3-chloromethyl-1,2,4-oxadiazol-5-yl)-4-(3-nitrophenyl)pyridine-5-carboxylate as yellow crystals, m.p. 200.5°-201.5° C.
Reaction SMILES: [CH2:1]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([OH:26])=O)=[CH:18][CH:17]=1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:8]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:24](=[O:26])[CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([OH:15])=[CH:21][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CCCCCCNCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCN(Cc1ccccc1)C(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
N-hexylbenzylamine (0.6 g, 3.136 mmol) and 3-(4-hydroxyphenyl)propionic acid (0.52 g 3.136 mmol) were mixed in DMF (10 ml) and the mixture was cooled. HOBT (0.424 g, 3.136 mmol) and the TBTU (1 g, 3.136 mmol) reagent were added followed by DIPEA (1.216 g, 9.409 mmol). The mixture was stirred at room temperature overnight and then evaporated. The resulting mixture was partitioned between ethyl acetate and sodium hydrogencarbonate aqueous solution (sat.). The aqueous portion was extracted with ethyl acetate and the combined organic extracts dried with magnesium sulphate and then evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 5 g/25 ml) using ethyl acetate/heptane (10:90, then 25:75) as eluant gave 760 mg the desired product, yield 71%.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc([N+](=O)[O-])cc2Cl)CC1
Temperature: 80 °C
Yield: 92.6 %

Procedure:
Place 2,3-dichloro-5-nitro-pyridine (2.0 g, 10.36 mmol), piperazine-1-carboxylic acid tert-butyl ester (2.12 g, 11.40 mmol), and potassium carbonate (1.72 g, 12.43 mmol) in DMF (20 mL). Heat to 80° C. for 2.5 days. Cool to room temperature and add ethyl acetate and water. Separate organic layer and wash with water and saturated aq. sodium chloride. Collect organic layer, dry over Mg2SO4, filter, and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with 20% EtOAc:hexane to yield 3.29 g (93%) of 4-(3-chloro-5-nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester. MS(ES): m/z=341 [M+H].
Reaction SMILES: [CH2:1]([Zn]CC)C.C1(C)C=CC=CC=1.ClCI.[CH3:16]/[C:17](=[C:20](\[CH3:29])/[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])/[CH2:18][OH:19].S(=O)(=O)(O)O>>[CH3:16][C@:17]1([CH2:18][OH:19])[CH2:29][C@@:20]1([CH3:1])[C@H:21]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:22]
Reactant: C/C(CO)=C(\C)C(C)c1ccccc1
Reactant: CC[Zn]CC
Agent: ClCI
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: C[C@@H](c1ccccc1)[C@]1(C)C[C@]1(C)CO
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
Under a nitrogen atmosphere, a diethylzinc solution in toluene (concentration: 15% by weight, 10.9 g, 13.2 mmol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to −15° C. Chloroiodomethane (4.68 g, 26.5 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between −15 and −20° C. After completion of the dropwise addition, the mixture was stirred at −15° C. for 30 minutes. (Z)-2,3-Dimethyl-4-phenylpent-2-ene-1-ol (1.26 g, 6.63 mmol) was added dropwise at −10 to −15° C. over a period of 20 minutes. After completion of the dropwise addition, the stirring was continued at 12° C. for 60 minutes. Next, a 20% aqueous sulfuric acid solution (4.8 ml) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (10 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1). [(1S*,2S*)-1,2-Dimethyl-2-((S*)-1-phenylethyl)cyclopropyl]methanol (0.47 g, 2.3 mmol, 35% yield) was obtained as the main isomer, and [(1S*,2S*)-1,2-dimethyl-2-((R*)-1-phenylethyl)cyclopropyl]methanol (0.45 g, 2.2 mmol, 33% yield) was obtained as a minor isomer. The relative configurations of the main isomer and the minor isomer were determined by NOESY measurement.