Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.C[C@H]1[C@@H]2CC[C@]3(C)OO[C@]42[C@H]([C@@H](C)C(O[C@@H]4O3)=O)CC1.C(=O)=O.CC(C)=O.[Li]CCCC.C(OC(=O)C)(=O)C.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl.C1COCC1.CCOCC>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=[CH:2]1
Reactant: Brc1cc2ccccc2o1
Agent: CC[SiH](CC)CC
Agent: C[C@@H]1CC[C@H]2[C@@H](C)C(=O)O[C@@H]3O[C@]4(C)CC[C@@H]1[C@]32OO4
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: c1ccc2occc2c1
Temperature: 25 °C
Reaction time: 0.15 h

Procedure:
A 10 mL flame-dried RBF was loaded with a stir-bar, 2-bromo-1-benzofuran (160.3 mg, 0.81 mmol), and ether (3 mL). An addition 10 mL flame-dried RBF was loaded with a stir bar, artemisinin (67.4 mg, 0.24 mmol) and THF (3 mL). Both flasks were immersed into dry ice/acetone baths and n-BuLi (0.33 mL, 1.6 M sol, 0.53 mmol) was added over 14 minutes to the flask containing the 2-bromo-1-benzofuran which was then stirred at RT for nine minutes. The flask was then re-immersed in the dry ice/acetone bath. The resulting solution became pale yellow. After 41 additional minutes, the artemisinin solution was added via cannula and the resulting solution became deeper orange in color. After 30 minutes of stirring at −78° C., the TLC showed consumption of artemisinin and the formation of 2 new spots, with a lower Rf. Acetic anhydride (0.14 mL, 1.51 mmol) was added 25 minutes later. After for 2 hours, the new spot was observed to have disappeared, triethylsilane (0.68 mL, 4.21 mmol), and trimethylsilyl trifluorosulfonate (0.58 mL, 3.2 mmol) were added and the reaction became fuchsia in color. Then, TEA (2 mL) was added 2.5 hours later. The reaction was then poured into a reparatory funnel containing dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate (3×30 mL). The organic layer was then washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and evaporated. The residue was purified using two flash chromatography columns (first column: silica gel, packed with 100% hexanes, eluted with 5% ethyl acetate in hexanes; second column: silica gel, packed with 100% hexanes, eluted with 50% dichloromethane in hexanes) to give the product as a yellow film that turned into a foamy solid on prolonged high-vacuum drying (17.3 mg, 0.05 mmol, 19%). 1H NMR (CDCl3, 400 MHz): δ 7.59-7.57 (m, 1H), 7.53-7.48 (m, 2H), 7.39-7.18 (m, 2H), 6.91 (s, 1H), 5.79 (s, 1H), 2.49-2.41 (m, 1H), 2.15-2.00 (m, 5H), 2-1.92 (m, 2H), 1.79-1.73 (m 1H), 1.65-1.30 (m, 8H), 1.22-1.15 (m, 1H), 1.04-1.03 (d, J=4 Hz, 3H). 13C NMR (CDCl3, 100 MHz): δ 154.5, 152.1, 136.1, 128.3, 124.0, 122.7, 120.9, 111.2, 109.4, 105.1, 104.6, 90.1, 78.6, 50.9, 47.6, 37.7, 36.3, 34.2, 29.2, 25.8, 24.5, 20.2, 17. IR (thin film): 2927, 2365, 2331, 1459, 1134, 1027. HRMS (FAB+): calculated for C23H26O5: 382.1780, found 382.1785. [α]D26=+41.0 (c 1.25, CHCl3)
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>C1COCC1>[CH:1]1([O:6][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CBr
Reactant: OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of cyclopentanol (2.28 mL, 25.1 mmol) in THF (10 mL) was added dropwise with ice cooling to a suspension of sodium hydride (60% dispersion in oil, 1.054 g, 26.3 mmol) in THF (20 mL). The mixture was stirred with ice cooling under nitrogen for 30 minutes, and then a solution of ethyl bromoacetate (2.66 mL, 23.95 mmol) in THF (10 mL) was added dropwise, followed by a THF (10 mL) rinse. The reaction mixture was allowed to warm to room temperature and stirred for 20 hours. Water (60 mL) was added cautiously, and the resulting mixture was extracted with EtOAc (2×50 mL). The combined extract was washed with saturated brine (40 mL), dried (MgSO4), filtered, and concentrated to provide the title compound, used directly in the next step.
Reaction SMILES: [Mg].II.[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C[C@@H](CCCC(C)C)C=O.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: CC(C)CCC[C@H](C)C=O
Agent: Cl
Agent: II
Solvent: C1CCOC1
Product: c1ccc(COc2ccccc2)cc1
Yield: 47 %

Procedure:
In a 200 ml-volume flask was charged 1 704 g of metallic magnesium. After displacing the atmosphere with nitrogen, a small amount of iodine was added thereto, followed by heating to activate the magnesium. Ten milliliters of tetrahydrofuran (THF) were added thereto, and a mixture comprising 18.5 g of 4-bromophenyl benzyl ether as prepared in Example 1 and 40 ml of THF was added dropwise to the system from a dropping funnel at room temperature over a period of 30 minutes. The reaction was continued at a refluxing temperature of THF for an additional 2.5 hours to prepare a Grignard reagent. To the resulting Grignard reagent was added a mixture of 10.0 g of (S)-2,6-dimethylheptanal and 30 ml of THF at 15° C., followed by allowing the mixture to react for 2 hours while keeping at that temperature. The reaction mixture was treated with diluted hydrochloric acid, neutralized with a sodium bicarbonate aqueous solution, and washed with water to obtain 21.8 g of a crude product. Purification by silica gel column chromatography (eluent: benzene) yielded 11.8 g (theoretical yield: 47%) of the entitled compound as a viscous yellow liquid.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:8](C(O)=O)[C:7](=[O:13])[NH:6][C:5]=1[CH3:14])(=[O:3])[CH3:2].C>C(O)(C)C>[C:1]([C:4]1[CH:12]=[CH:8][C:7](=[O:13])[NH:6][C:5]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C(=O)O)c(=O)[nH]c1C
Solvent: CC(C)O
Product: CC(=O)c1ccc(=O)[nH]c1C
Temperature: 25 °C

Procedure:
C-1. 5-Acetyl-6-methyl-2(1H)-pyridinone--A 10 g portion of 5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinic acid was heated neat in a bath of a boiling mixture of diphenyl and diphenyl ether for 40 minutes and the mixture allowed to cool to room temperature. The reaction mixture was dissolved in hot isopropyl alcohol, treated with decolorizing charcoal and filtered, and the filtrate allowed to stand at room temperature for several hours. The separated product was collected and dried at 90°-95° C. to yield 4.3 g of 5-acetyl-6-methyl-2-(1H)-pyridinone, m.p. 193°-195° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([S:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[NH:3]1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)(Cl)Cl>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([S:11]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)=[O:27])[CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1Cc2cccc(Sc3ccc(Cl)cc3)c2N1
Solvent: ClC(Cl)Cl
Product: O=C1Cc2cccc(S(=O)c3ccc(Cl)cc3)c2N1
Yield: 52 %

Procedure:
A solution of 2-oxo-7-(4-chlorophenylthio)indoline (7.0 g) in chloroform (400 ml) and m-chloroperbenzoic acid (5.15 g) were treated in a similar manner to that of Preparation 28-(2) to give 2-oxo-7-(4-chlorophenylsulfinyl)indoline (3.85 g). mp 191°-194° C.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[N+:9]([O-:10])=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:7]=[C:6](Cl)[N:5]=1.[H][H]>C(O)C.[Pd]>[NH2:3][C:4]1[N+:9]([O-:10])=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:7]=[CH:6][N:5]=1
Reactant: [H][H]
Reactant: CCCCCCNc1cc(Cl)nc(N)[n+]1[O-]
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCNc1ccnc(N)[n+]1[O-]
Reaction time: 2 h
Yield: 52.9 %

Procedure:
0.7 g of potassium hydroxide was dissolved in 100 ml of absolute ethanol, in a three-necked flask. 2.2 g of 2-amino-4-hexylamino-6-chloropyrimidine 3-oxide were then added. After complete dissolution, 0.5 g of palladium-on-charcoal was added and the mixture was reacted in a hydrogenator at a hydrogen pressure of 3 bar. After 2 hours, the medium was filtered through filter paper and concentrated under vacuum. The pale yellow solid obtained was recrystallized from 20 ml of acetonitrile. It was filtered off and the filter cake was washed with 10 ml of water. The solid was dried in a desiccator under vacuum. 1 g of the expected compound was thus obtained, for a yield of 53%.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:37]=[CH:36][C:12]([NH:13][C:14]2[CH:26]=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=[CH:23][C:15]=2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][CH:10]=1.Br[C:39]1[CH:44]=[CH:43][C:42]([S:45]([NH2:48])(=[O:47])=[O:46])=[CH:41][CH:40]=1.C(=O)([O-])O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(OCC)(=O)C.C(O)C>[NH2:48][S:45]([C:42]1[CH:43]=[CH:44][C:39]([C:25]2[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[C:14]([NH:13][C:12]3[CH:36]=[CH:37][C:9]([F:8])=[CH:10][CH:11]=3)[CH:26]=2)=[CH:40][CH:41]=1)(=[O:47])=[O:46]
Reactant: CC(C)(C)OC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Nc1ccc(F)cc1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc(S(N)(=O)=O)cc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To toluene 3.0 mL solution of tert-butyl 2-(4-fluoroanilino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate 0.15 g were added ethanol 0.90 mL, water 0.45 mL, 4-bromobenzenesulfonamide 85 mg, sodium hydrogen carbonate 0.10 g and tetrakis(triphenylphosphine)palladium(0) 21 mg at room temperature, and it was heated and refluxed under nitrogen atmosphere for 2 hours. After the reaction mixture was cooled to room temperature, and ethyl acetate and water were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=2:1] to give tert-butyl 4-(4-(aminosulfonyl)phenyl)-2-(4-fluoroanilino)benzoate.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]([CH3:16])[CH2:9][C:10]([CH3:15])([N+:12]([O-:14])=[O:13])[CH3:11])(=O)=O.[C:17]([O-:20])(=[S:19])[CH3:18].[K+]>C(#N)C>[C:17](=[O:20])([S:19][CH2:6][CH2:7][N:8]([CH3:16])[CH2:9][C:10]([CH3:11])([N+:12]([O-:14])=[O:13])[CH3:15])[CH3:18]
Reactant: CC([O-])=S
Reactant: CN(CCOS(C)(=O)=O)CC(C)(C)[N+](=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)SCCN(C)CC(C)(C)[N+](=O)[O-]
Temperature: 50 °C
Yield: 61.8 %

Procedure:
2-(Methyl(2-methyl-2-nitropropyl)amino)ethyl methanesulfonate (12.0 g, 47.2 mmol) was dissolved into anhydrous acetonitrile (200 mL) and solid potassium thioacetate (5.93 g, 1.1 equiv, 51.9 mmol) was added to flask in one portion. The suspension was heated at 50° C. for 4 h. The red slurry was filtered and the solid washed with ethyl acetate (3×150 mL). The filtrate was concentrated to a red brown oil and purified on an ISCO purification system using a 120 g SiO2 column and the following gradient: isocratic 20% EA in hexanes (5 min) and a gradient to 60% EA in hexanes (15 min). The desired fractions were collected and concentrated to give a red oil (6.83 g, 61.8%). 1H NMR (CDCl3, 400 MHz): δ 1.56 (s, 6H), 2.32 (s, 3H), 2.33 (s, 3H), 2.61-2.65 (m, 2H), 2.89-2.93 (m, 4H). LRMS (ESI+) for C9H18N2O3S (234.1); Found: 235 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=[C:4](/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:5]=[C:4](/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(/C=C/c2ccccc2)nc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCC(C(=O)O)c1c(C)nc(/C=C/c2ccccc2)nc1-c1ccccc1
Yield: 41.2 %

Procedure:
A solution of (E)-methyl 2-(4-methyl-6-phenyl-2-styrylpyrimidin-5-yl)pentanoate (73 mg; 0.189 mmol) in ethanol (1 mL), tetrahydrofuran (1 mL) and 2N sodium hydroxide solution (0.944 mL; 1.889 mmol) was stirred for 24 h at room temperature. The reaction mixture was concentrated under reduced pressure, diluted with water and acidified with a 6N hydrochloric acid solution. The formed suspension was extracted twice with ethyl acetate and the organic layers were washed with water and dried by filtration over a phase separater filter (PS1). The crude material was purified first by flash chromatography on silica gel using a linear gradient of methanol (1-10%) in dichloromethane and then by preparative thick layer chromatography on silica gel eluting with 10% methanol in dichloromethane to give 29 mg (40%) of the title compound as a colorless oil. ESI/APCI(+): 373 (M+H).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][C:14](=[O:18])[C:15]([OH:17])=[O:16])=[CH:7][CH:6]=1.[BH4-].[Na+].Cl>O>[OH:18][CH:14]([CH2:13][CH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=1)[C:15]([OH:17])=[O:16]
Reactant: COc1ccc(CCCC(=O)C(=O)O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(CCCC(O)C(=O)O)cc1
Reaction time: 2 h
Yield: 94.3 %

Procedure:
Sodium hydroxide (24.0 g) and water (450 ml) were added to 5-(4-methoxyphenyl)-2-oxopentanoic acid (66.6 g) (the compound of Reference Example 2), and the resulting mixture was ice-cooled. When to this slurry was added sodium tetrahydroborate (3.99 g) in portions, the reaction mixture once became clear. After the reaction mixture was stirred for 2 hours, a 3N aqueous hydrochloric acid solution (300 ml) was added thereto, followed by extraction with ethyl acetate (300 ml×twice). The organic layer was washed with water (100 ml×three times) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2-hydroxy-5-(4-methoxyphenyl)pentanoic acid (63.4 g) as a crude product.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1)[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[N:6]=1.[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])#[CH:24].C(N(CC)CC)C.O>CN(C=O)C.[Cu]I.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>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:24]#[C:23][Si:25]([CH3:28])([CH3:27])[CH3:26])=[CH:16][CH:15]=1)[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[N:6]=1
Reactant: CC(C)(C)CN(Cc1ccc(I)cc1)c1ccnc(C#N)n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)CN(Cc1ccc(C#C[Si](C)(C)C)cc1)c1ccnc(C#N)n1
Temperature: 25 °C
Yield: 330.6 %

Procedure:
At room temperature, a soln. of 4-[(2,2-Dimethyl-propyl)-(4-iodo-benzyl)-amino]-pyrimidine-2-carbonitrile (2 g, 4.9 mmoles) and ethynyl-trimethyl-silane (3.47 ml, 24.7 mmoles) in 20 ml of DMF is treated with triethylamine (2.6 ml, 14.8 mmoles), CuI (93 mg, 0.5 mmoles) and (Ph3P)2PdCl2 (0.2 g, 0.2 mmoles). The mixture is stirred at rt for overnght. Water is added and the organic layer is extracted with AcOEt, washed with brine, dried over magnesum sulfate and concentrated. The crude product is purified by silica gel column chromatography to give 6.1 g of desired 4-[(2,2-dimethyl-propyl)-(4-trimethylsilanylethynyl-benzyl)-amino]-pyrimidine-2-carbonitrile in 82% yield. Rf=0.52 (Hexane:AcOEt=1:1)
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4](Cl)=[O:5].[CH2:13]([O:20][N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][CH:24]=[N:25][C:26]=2[NH2:30])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:13]([O:20][N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][CH:24]=[N:25][C:26]=2[N:30]1[C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]2[C:1]1=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ncnc2c1ncn2OCc1ccccc1
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1c1ncnc2c1ncn2OCc1ccccc1
Yield: 49 %

Procedure:
Phthaloyl dichloride (13.35 g; 92.2 mmol) was added to a cooled solution of 9-benzyloxyadenine (14.9 g, 61.5 mmol), 4-dimethylaminopyridine (1.5 g, 12.3 mmol) and triethylamine (25.7 ml, 184.4 mmol) in tetrahydrofuran (200 ml). After 1 hour at room temperature the solvent was removed under reduced pressure and the residue partitioned between chloroform (500 ml) and saturated potassium bicarbonate (300 ml). The organic phase was separated, washed with water (200 ml), brine (200 ml), dried (MgSO4) and evaporated to dryness. Column chromatography on silica gel eluting with chloroform-methanol (100:1) afforded the title compound (11.20 g, 49%). IR: υmax (KBr) 3070, 1800, 1740, 1730, 1605, 1585, 1450 and 1410 cm-1 ; 1H NMR δH [(CD3)2SO] 5.70(2H, s, CH2Ph), 7.55(5H, s, CH2Ph), 8.20(4H, s, Ar), 8.95(1H, s, H-2), 9.25(1H, s, H-8). Found: C, 64.71; H, 3.78; N, 18.85%; m/z 371.1025. C20H13N5O3 requires: C, 64.68; H, 3.54; N, 18.86%; m/e 371.1018.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].C[O-].[Na+].[F:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1>CO.C1COCC1>[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:18][CH:19]=1
Reactant: COC(=O)CC(=O)OC
Reactant: COC(=O)/C=C/c1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CC(c1ccc(F)cc1)C(C(=O)OC)C(=O)OC
Reaction time: 0.25 h
Yield: 73.3 %

Procedure:
Dimethyl malonate (14.7 g, 111 mmol) was added dropwise to the mixture of sodium methoxide in methanol (methanol solution 28%, 19.3 g, 100 mmol) and methanol (30 ml) under ice cooling and stirred for 15 minutes. To the mixture was added a solution of methyl (2E)-3-(4-fluorophenyl)-2-propenoate (10.0 g, 55.5 mmol) obtained in Reference Example 1 in THF (50 ml) under ice cooling and the mixture was refluxed for 12 hours. The resulting mixture was concentrated under reduced pressure, and the residue was diluted with water. The aqueous layer was acidified with dilute hydrochloric acid, extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (hexane/ethyl-acetate=8/1) to obtain 12.7 g (yield 73%) of 2-(4-fluorophenyl)-1,1,3-trimethoxy carbonyl propane via recrystallization (ethyl acetate-hexane). mp. 75–76° C.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[F:26][C:27]([F:34])([F:33])[CH2:28][CH2:29][C:30](O)=[O:31]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:30](=[O:31])[CH2:29][CH2:28][C:27]([F:34])([F:33])[F:26])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)CCC(F)(F)F
Agent: Cl
Product: O=C(CCC(F)(F)F)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (12.8 mg, 35.2%), MS (ISP) m/z=455.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (29.4 mg, 0.080 mmol) and 4,4,4-trifluorobutanoic acid
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH2:30][CH3:31])=[C:21]([C:23]([O:25]CCCC)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH2:30][CH3:31])=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)oc1CC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C(=O)O)c(CC)o3)C[C@H]2OC)nc1Cl
Yield: 63.2 %

Procedure:
The same operation as in Example (91d) was performed using butyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-ethyl-1,3-oxazole-4-carboxylate obtained in Example (110d) (0.14 g, 0.29 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (5 mL) and THF (5 mL), to obtain 78 mg of the title compound as a colorless solid (63%).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[CH:3]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)[O:4][C:5]1[C:6]([NH:15][S:16](=[O:28])(=[O:27])[NH:17][CH2:18][CH2:19][CH:20](OCC)[O:21]CC)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2.Cl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C1COCC1>[F:36][C:2]([F:1])([F:35])[CH:3]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)[O:4][C:5]1[C:6]([NH:15][S:16](=[O:27])(=[O:28])[NH:17][CH2:18][CH2:19][CH:20]=[O:21])=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: CCOC(CCNS(=O)(=O)Nc1nc2ccccc2nc1OC(c1cccnc1)C(F)(F)F)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=CCCNS(=O)(=O)Nc1nc2ccccc2nc1OC(c1cccnc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.2 %

Procedure:
Compound 272 (72.0 mg, 0.136 mmol) obtained in Example 266 was dissolved in THF (1.50 mL). To this, a 1.00 mol/L aqueous hydrochloric acid solution (1.50 mL) was added and the mixture was stirred at room temperature for 1.5 hours. The reaction was stopped by addition of a saturated aqueous sodium bicarbonate solution to the reaction mixture, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 1/1) to give Compound 273 (41.6 mg, yield: 67%).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([NH:44][CH3:45])=[O:43])[CH:37]=2)[CH:33]=[CH:34][CH:35]=1)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Cl.N1C=CC=CC=1>>[OH:1][C:2]([C:30]1[CH:31]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([NH:44][CH3:45])=[O:43])[CH:37]=2)[CH:33]=[CH:34][CH:35]=1)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CNC(=O)c1cccc(-c2cccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)c2)c1
Agent: Cl
Solvent: c1ccncc1
Product: CNC(=O)c1cccc(-c2cccc(C(O)(c3c[nH]cn3)C(C)C)c2)c1
Yield: 16.2 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 3′-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-N-methyl[1,1′-biphenyl]-3-carboxamide (576 mg) and pyridine hydrochloride (0.22 g), the title compound (55 mg) was obtained as colorless powder crystals.