(E)-3-(4-chlorophenyl)prop-2-enal

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 14 ml of methylene chloride were dissolved 294 mg (0.82 mmol) of (2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1 H-1,2,4-triazol-1-yl)-2-butanol as described in Reference example 2 and 191 mg (1.15 mmol) of trans-4-chlorocinnamaldehyde [Bull. Chem. Soc. Japan 52 555 (1979)], and 233 mg (1.23 mmol) of p-toluenesulfonic acid monohydrate and 1.5 g of molecular sieves 4A were added thereto, followed by stirring of the resulting mixture for 1 hour and 15 minutes. An aqueous sodium hydrogencarbonate solution was added to the reaction mixture and the mixture was stirred for 10 minutes, followed by removal of the molecular sieves by filtration. The organic layers were collected and dried to distil off the solvent under reduced pressure. The thus obtained oil was subjected to column chromatography using 15 g of silica gel and eluted with a mixed solvent hexane-ethyl acetate (3:2) to obtain 280 mg (yield: 67%) of the desired title compound, trans isomer (A) as an oil. Further, the oil was eluted with a mixed solvent of hexane-ethyl acetate (1:1) to obtain 35 mg (yield: 8%) of the cis isomer (B) as an oil. were added the mixture was stirred for 10 minutes followed by removal of the molecular sieves by filtration The organic layers were collected dried to distil off the solvent under reduced pressure eluted with a mixed solvent hexane-ethyl acetate (3:2)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 14 ml of methylene chloride were dissolved 294 mg (0.82 mmol) of (2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol as described in Reference example 2 and 191 mg (1.15 mmol) of trans-4-chlorocinnamaldehyde [Bull. Chem. Soc. Japan 52 555 (1979)], and 233 mg (1.23 mmol) of p-toluenesulfonic acid monohydrate and 1.5 g of molecular sieves 4A were added thereto, followed by stirring of the resulting mixture for 1 hour and 15 minutes. An aqueous sodium hydrogencarbonate solution was added to the reaction mixture and the mixture was stirred for 10 minutes, followed by removal of the molecular sieves by filtration. The organic layers were collected and dried to distil off the solvent under reduced pressure. The thus obtained oil was subjected to column chromatography using 15 g of silica gel and eluted with a mixed solvent hexane-ethyl acetate (3:2) to obtain 280 mg (yield: 67%) of the desired title compound, trans isomer (A) as an oil. Further, the oil was eluted with a mixed solvent of hexane-ethyl acetate (1:1) to obtain 35 mg (yield: 8%) of the cis isomer (B) as an oil. were added the mixture was stirred for 10 minutes followed by removal of the molecular sieves by filtration The organic layers were collected dried to distil off the solvent under reduced pressure eluted with a mixed solvent hexane-ethyl acetate (3:2)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 14 ml of methylene chloride were dissolved 294 mg (0.82 mmol) of (2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1 H-1,2,4-triazol-1-yl)-2-butanol as described in Reference example 2 and 191 mg (1.15 mmol) of trans-4-chlorocinnamaldehyde [Bull. Chem. Soc. Japan 52 555 (1979)], and 233 mg (1.23 mmol) of p-toluenesulfonic acid monohydrate and 1.5 g of molecular sieves 4A were added thereto, followed by stirring of the resulting mixture for 1 hour and 15 minutes. An aqueous sodium hydrogencarbonate solution was added to the reaction mixture and the mixture was stirred for 10 minutes, followed by removal of the molecular sieves by filtration. The organic layers were collected and dried to distil off the solvent under reduced pressure. The thus obtained oil was subjected to column chromatography using 15 g of silica gel and eluted with a mixed solvent hexane-ethyl acetate (3:2) to obtain 280 mg (yield: 67%) of the desired title compound, trans isomer (A) as an oil. Further, the oil was eluted with a mixed solvent of hexane-ethyl acetate (1:1) to obtain 35 mg (yield: 8%) of the cis isomer (B) as an oil. were added the mixture was stirred for 10 minutes followed by removal of the molecular sieves by filtration The organic layers were collected dried to distil off the solvent under reduced pressure eluted with a mixed solvent hexane-ethyl acetate (3:2)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 14 ml of methylene chloride were dissolved 294 mg (0.82 mmol) of (2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol as described in Reference example 2 and 191 mg (1.15 mmol) of trans-4-chlorocinnamaldehyde [Bull. Chem. Soc. Japan 52 555 (1979)], and 233 mg (1.23 mmol) of p-toluenesulfonic acid monohydrate and 1.5 g of molecular sieves 4A were added thereto, followed by stirring of the resulting mixture for 1 hour and 15 minutes. An aqueous sodium hydrogencarbonate solution was added to the reaction mixture and the mixture was stirred for 10 minutes, followed by removal of the molecular sieves by filtration. The organic layers were collected and dried to distil off the solvent under reduced pressure. The thus obtained oil was subjected to column chromatography using 15 g of silica gel and eluted with a mixed solvent hexane-ethyl acetate (3:2) to obtain 280 mg (yield: 67%) of the desired title compound, trans isomer (A) as an oil. Further, the oil was eluted with a mixed solvent of hexane-ethyl acetate (1:1) to obtain 35 mg (yield: 8%) of the cis isomer (B) as an oil. were added the mixture was stirred for 10 minutes followed by removal of the molecular sieves by filtration The organic layers were collected dried to distil off the solvent under reduced pressure eluted with a mixed solvent hexane-ethyl acetate (3:2)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 14 ml of methylene chloride were dissolved 294 mg (0.82 mmol) of (2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol as described in Reference example 2 and 191 mg (1.15 mmol) of trans-4-chlorocinnamaldehyde [Bull. Chem. Soc. Japan 52 555 (1979)], and 233 mg (1.23 mmol) of p-toluenesulfonic acid monohydrate and 1.5 g of molecular sieves 4A were added thereto, followed by stirring of the resulting mixture for 1 hour and 15 minutes. An aqueous sodium hydrogencarbonate solution was added to the reaction mixture and the mixture was stirred for 10 minutes, followed by removal of the molecular sieves by filtration. The organic layers were collected and dried to distil off the solvent under reduced pressure. The thus obtained oil was subjected to column chromatography using 15 g of silica gel and eluted with a mixed solvent hexane-ethyl acetate (3:2) to obtain 280 mg (yield: 67%) of the desired title compound, trans isomer (A) as an oil. Further, the oil was eluted with a mixed solvent of hexane-ethyl acetate (1:1) to obtain 35 mg (yield: 8%) of the cis isomer (B) as an oil. were added the mixture was stirred for 10 minutes followed by removal of the molecular sieves by filtration The organic layers were collected dried to distil off the solvent under reduced pressure eluted with a mixed solvent hexane-ethyl acetate (3:2)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The same synthetic procedure as described for intermediate 5d, but starting from 1,2-dichloro-4-iodobenzene gave 58% of the title compound which was characterised as follows:

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 1-chloro-4-iodobenzene (2 g, 8.39 mmol) in DMF (30 mL) were added acrolein diethyl acetal (3.84 mL, 8.39 mmol), n-Bu4NOAc (5.06 g, 16.8 mmol), K2CO3 (1.74 g, 12.6 mmol), KCl (0.63 g, 8.39 mmol) and Pd(OAc)2 (0.056 g, 0.25 mmol). The mixture was stirred for 1.5 hour at 90° C. After cooling, 2 N HCl was slowly added and the reaction mixture was stirred at room temperature for 10 minutes. Subsequently, it was diluted with ether (200 mL) and washed with water (200 mL). The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (n-hexane/ethyl acetate mixture in a volume ratio 8:2) to give intermediate 5d (74% yield) which was characterised as follows: After cooling the reaction mixture was stirred at room temperature for 10 minutes washed with water (200 mL) The organic layer was dried over MgSO4 concentrated under reduced pressure The residue was purified by flash chromatography (n-hexane/ethyl acetate mixture in a volume ratio 8:2)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 14 ml of methylene chloride were dissolved 294 mg (0.82 mmol) of (2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol as described in Reference example 2 and 191 mg (1.15 mmol) of trans-4-chlorocinnamaldehyde [Bull. Chem. Soc. Japan 52 555 (1979)], and 233 mg (1.23 mmol) of p-toluenesulfonic acid monohydrate and 1.5 g of molecular sieves 4A were added thereto, followed by stirring of the resulting mixture for 1 hour and 15 minutes. An aqueous sodium hydrogencarbonate solution was added to the reaction mixture and the mixture was stirred for 10 minutes, followed by removal of the molecular sieves by filtration. The organic layers were collected and dried to distil off the solvent under reduced pressure. The thus obtained oil was subjected to column chromatography using 15 g of silica gel and eluted with a mixed solvent hexane-ethyl acetate (3:2) to obtain 280 mg (yield: 67%) of the desired title compound, trans isomer (A) as an oil. Further, the oil was eluted with a mixed solvent of hexane-ethyl acetate (1:1) to obtain 35 mg (yield: 8%) of the cis isomer (B) as an oil. were added the mixture was stirred for 10 minutes followed by removal of the molecular sieves by filtration The organic layers were collected dried to distil off the solvent under reduced pressure eluted with a mixed solvent hexane-ethyl acetate (3:2)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and (E)-3-(4-chlorophenyl)acrylaldehyde. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 12 as a white solid (78 mg, 58%). Analytical data for 12: 1H NMR (500 MHz, CDCl3) δ 9.37 (d, J=7.9 Hz, 1H), 7.89 (ddd, J=9.2, 6.1, 3.2 Hz, 1H), 7.38-7.31 (m, 2H), 7.31-7.26 (m, 3H), 7.12-6.92 (m, 6H), 4.08 (d, J=6.8 Hz, 1H), 3.56 (ddd, J=9.8, 6.9, 4.9 Hz, 1H), 3.29 (dd, J=14.9, 5.0 Hz, 1H), 2.43 (dd, J=14.9, 9.8 Hz, 1H); 13C NMR (CDCl3, 126 MHz) δ 168.7, 159.11 (d, JCF=244.0 Hz), 155.38 (d, JCF=242.2 Hz), 148.9, 136.8, 136.5, 136.3, 132.6, 130.4, 129.3, 128.8, 128.4, 127.9, 118.32 (dd, JCF=12.4, 9.3 Hz), 117.12 (dd, JCF=25.5, 8.6 Hz), 116.64 (dd, JCF=24.8, 9.2 Hz), 114.51 (dd, JCF=26.9, 3.7 Hz), 110.69 (d, JCF=3.8 Hz), 47.2, 38.6, 32.3; IR (film) cm−1 1769, 1638, 1492, 1481, 1462, 1239, 1171, 1118, 1096, 1032, 813, 766, 741, 699; LRMS (ESI): Mass calcd for [M+H]+ C25H18ClF2N2O2: 451.1. found 451.3; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 5% IPA/3% MeOH/hexanes 0.5 mL/min, 280 nm), Rt1 (major)=40.5, Rt2 (minor)=50.6 min; er=98:2. Prepared The unpurified residue was purified by flash chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 14 ml of methylene chloride were dissolved 294 mg (0.82 mmol) of (2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1 H-1,2,4-triazol-1-yl)-2-butanol as described in Reference example 2 and 191 mg (1.15 mmol) of trans-4-chlorocinnamaldehyde [Bull. Chem. Soc. Japan 52 555 (1979)], and 233 mg (1.23 mmol) of p-toluenesulfonic acid monohydrate and 1.5 g of molecular sieves 4A were added thereto, followed by stirring of the resulting mixture for 1 hour and 15 minutes. An aqueous sodium hydrogencarbonate solution was added to the reaction mixture and the mixture was stirred for 10 minutes, followed by removal of the molecular sieves by filtration. The organic layers were collected and dried to distil off the solvent under reduced pressure. The thus obtained oil was subjected to column chromatography using 15 g of silica gel and eluted with a mixed solvent hexane-ethyl acetate (3:2) to obtain 280 mg (yield: 67%) of the desired title compound, trans isomer (A) as an oil. Further, the oil was eluted with a mixed solvent of hexane-ethyl acetate (1:1) to obtain 35 mg (yield: 8%) of the cis isomer (B) as an oil. were added the mixture was stirred for 10 minutes followed by removal of the molecular sieves by filtration The organic layers were collected dried to distil off the solvent under reduced pressure eluted with a mixed solvent hexane-ethyl acetate (3:2)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 14 ml of methylene chloride were dissolved 294 mg (0.82 mmol) of (2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol as described in Reference example 2 and 191 mg (1.15 mmol) of trans-4-chlorocinnamaldehyde [Bull. Chem. Soc. Japan 52 555 (1979)], and 233 mg (1.23 mmol) of p-toluenesulfonic acid monohydrate and 1.5 g of molecular sieves 4A were added thereto, followed by stirring of the resulting mixture for 1 hour and 15 minutes. An aqueous sodium hydrogencarbonate solution was added to the reaction mixture and the mixture was stirred for 10 minutes, followed by removal of the molecular sieves by filtration. The organic layers were collected and dried to distil off the solvent under reduced pressure. The thus obtained oil was subjected to column chromatography using 15 g of silica gel and eluted with a mixed solvent hexane-ethyl acetate (3:2) to obtain 280 mg (yield: 67%) of the desired title compound, trans isomer (A) as an oil. Further, the oil was eluted with a mixed solvent of hexane-ethyl acetate (1:1) to obtain 35 mg (yield: 8%) of the cis isomer (B) as an oil. were added the mixture was stirred for 10 minutes followed by removal of the molecular sieves by filtration The organic layers were collected dried to distil off the solvent under reduced pressure eluted with a mixed solvent hexane-ethyl acetate (3:2)