(2R,3R)-butane-2,3-diol

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

Procedure: A solution of 1.35 g (15.0 mmol) of (R,R)-(−)-2,3-butanediol in 50 ml of THF is mixed at 0° C. in portions with 480 mg (11.0 mmol) of sodium hydride (55% dispersion) and then stirred for 10 minutes at room temperature. The solution that is produced is added at 0° C. to 2.27 g (10.0 mmol) of 5-bromo-2,4-dichloropyrimidine in 25 ml of THF. The batch is slowly heated to room temperature and stirred for 12 hours. The solvent is drawn off, and the residue that is obtained is purified by chromatography (hexane/ethyl acetate 1:1). 2.29 g (8.1 mmol, corresponding to 81% of theory) of the product is obtained. The solution that is produced The batch is slowly heated to room temperature stirred for 12 hours the residue that is obtained is purified by chromatography (hexane/ethyl acetate 1:1) 2.29 g (8.1 mmol, corresponding to 81% of theory) of the product is obtained

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

Procedure: A solution of 1.35 g (15.0 mmol) of (R,R)-(−)-2,3-butanediol in 50 ml of THF is mixed at 0° C. in portions with 480 mg (11.0 mmol) of sodium hydride (55% dispersion) and then stirred for 10 minutes at room temperature. The solution that is produced is added at 0° C. to 2.27 g (10.0 mmol) of 5-bromo-2,4-dichloropyrimidine in 25 ml of THF. The batch is slowly heated to room temperature and stirred for 12 hours. The solvent is drawn off, and the residue that is obtained is purified by chromatography (hexane/ethyl acetate 1:1). 2.29 g (8.1 mmol, corresponding to 81% of theory) of the product is obtained. The solution that is produced The batch is slowly heated to room temperature stirred for 12 hours the residue that is obtained is purified by chromatography (hexane/ethyl acetate 1:1) 2.29 g (8.1 mmol, corresponding to 81% of theory) of the product is obtained

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

Procedure: (R,R)-2,3 butanediol (7.78 ml, 85 mmol) was added dropwise to an ice-cold solution of sodium hydride (3.74 g, 60% dispersion in mineral oil, 93.5 mmol) in ether (800 ml), and the solution stirred at room temperature for 30 minutes. Methyl iodide (5.6 ml, 89.3 mmol) was added dropwise and the reaction stirred under reflux for 48 hours. 1,3-Dimethyl-3,4,5,6tetrahydro-2(1H)-pyrimidinone (10.24 ml, 85 mmol) was added and stirring continued for a further 90 minutes under reflux. The cooled reaction was washed with aqueous ammonium chloride solution (500 ml), dried (MgSO4) and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using an elution gradient of ether: pentane (10:90 to 50:50) to give a pale yellow oil. The title compound of Example 78 (100 mg, 0.2 mmol) and potassium bis(trimethylsilyl)amide (121 mg, 0.61 mmol) in the intermediate alcohol (1 ml), was heated at 110° C. for 30 hours, then the reaction cooled and concentrated under reduced pressure. The residual brown solid was purified by column chromatography on silica gel using diethylamine: ethyl acetate (5:95) as eluant, and repeated using methanol: ethyl acetate (5:95) as eluant. The product was triturated with ether to afford the title compound (7 mg, 60%) as a white solid. δ (CDCl3): 1.03 (3H, t), 1.25 (3H, d), 1.40 (3H, t), 1.48 (3H, d), 2.41 (2H, q), 2.55 (4H, m), 3.03 (2H, q), 3.15 (4H, m), 3.52 (3H, s), 3.70 (1H. m), 4.09 (3H, s), 5.39 (1H, m), 8.60 (1H, s), 8.97 (1H, s). LRMS: m/z 534 (M+1)+ the reaction stirred under reflux for 48 hours stirring continued for a further 90 minutes under reflux The cooled reaction was washed with aqueous ammonium chloride solution (500 ml) dried (MgSO4) evaporated under reduced pressure The residual oil was purified by column chromatography on silica gel using an elution gradient of ether: pentane (10:90 to 50:50) to give a pale yellow oil the reaction cooled concentrated under reduced pressure The residual brown solid was purified by column chromatography on silica gel The product was triturated with ether

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5.00 g (44.6 mmol) of potassium tert.-butylate was added to a solution of 4.00 g (44.4 mmol) (2R,3R)-butane-2,3-diol in 300 ml THF at room temperature and the mixture was refluxed for 15 minutes. The mixture was cooled to approx. 50° C. and 5.3 ml (44.6 mmol) benzyl bromide was added. It was refluxed for 3 hours, and was then stirred overnight at room temperature. The mixture was diluted with ethyl acetate and sodium chloride solution and then washed with 1N hydrogen chloride solution (1×) and sodium chloride solution (2×). The organic phase was dried (Na2SO4), filtered and concentrated by evaporation. The residue obtained was purified chromatographically (hexane/ethyl acetate 1:1). 3.41 g (18.9 mmol; yield: 43%) of the product was obtained. the mixture was refluxed for 15 minutes It was refluxed for 3 hours washed with 1N hydrogen chloride solution (1×) and sodium chloride solution (2×) The organic phase was dried (Na2SO4) filtered concentrated by evaporation The residue obtained was purified chromatographically (hexane/ethyl acetate 1:1) 3.41 g (18.9 mmol; yield: 43%) of the product was obtained

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

Procedure: To a solution of (2R,3R)-butane-2,3-diol (250 mg) and 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step (ii)) (427 mg) in anhydrous tetrahydrofuran (20 ml) at ambient temperature was added 60% sodium hydride (33.4 mg). After stirring for 15 minutes the reaction mixture was partitioned between aq. ammonium chloride solution and ethyl acetate. The organics collected, dried (MgSO4) and solvents removed under vacuo to give the subtitle compound as colourless gum. Yield: 525 mg. was partitioned between aq. ammonium chloride solution and ethyl acetate The organics collected, dried (MgSO4) and solvents removed under vacuo

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

Procedure: To a solution of (2R,3R)-butane-2,3-diol (250 mg) and 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step (ii)) (427 mg) in anhydrous tetrahydrofuran (20 ml) at ambient temperature was added 60% sodium hydride (33.4 mg). After stirring for 15 minutes the reaction mixture was partitioned between aq. ammonium chloride solution and ethyl acetate. The organics collected, dried (MgSO4) and solvents removed under vacuo to give the subtitle compound as colourless gum. Yield: 525 mg. was partitioned between aq. ammonium chloride solution and ethyl acetate The organics collected, dried (MgSO4) and solvents removed under vacuo

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

Procedure: (R,R)-2,3 butanediol (7.78 ml, 85 mmol) was added dropwise to an ice-cold solution of sodium hydride (3.74 g, 60% dispersion in mineral oil, 93.5 mmol) in ether (800 ml), and the solution stirred at room temperature for 30 minutes. Methyl iodide (5.6 ml, 89.3 mmol) was added dropwise and the reaction stirred under reflux for 48 hours. 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10.24 ml, 85 mmol) was added and stirring continued for a further 90 minutes under reflux. The cooled reaction was washed with aqueous ammonium chloride solution (500 ml), dried (MgSO4) and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using an elution gradient of ether:pentane (10:90 to 50:50) to give a pale yellow oil. The title compound of Example 78 (100 mg, 0.2 mmol) and potassium bis(trimethylsilyl)amide (121 mg, 0.61 mmol) in the intermediate alcohol (1 ml), was heated at 110° C. for 30 hours, then the reaction cooled and concentrated under reduced pressure. The residual brown solid was purified by column chromatography on silica gel using diethylamine:ethyl acetate (5:95) as eluant, and repeated using methanol:ethyl acetate (5:95) as eluant. The product was triturated with ether to afford the title compound (7 mg, 6%) as a white solid. the reaction stirred under reflux for 48 hours stirring continued for a further 90 minutes under reflux The cooled reaction was washed with aqueous ammonium chloride solution (500 ml) dried (MgSO4) evaporated under reduced pressure The residual oil was purified by column chromatography on silica gel using an elution gradient of ether:pentane (10:90 to 50:50) to give a pale yellow oil the reaction cooled concentrated under reduced pressure The residual brown solid was purified by column chromatography on silica gel The product was triturated with ether

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

Procedure: (R,R)-2,3 butanediol (7.78 ml, 85 mmol) was added dropwise to an ice-cold solution of sodium hydride (3.74 g, 60% dispersion in mineral oil, 93.5 mmol) in ether (800 ml), and the solution stirred at room temperature for 30 minutes. Methyl iodide (5.6 ml, 89.3 mmol) was added dropwise and the reaction stirred under reflux for 48 hours. 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10.24 ml, 85 mmol) was added and stirring continued for a further 90 minutes under reflux. The cooled reaction was washed with aqueous ammonium chloride solution (500 ml), dried (MgSO4) and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using an elution gradient of ether:pentane (10:90 to 50:50) to give a pale yellow oil. The title compound of Example 78 (100 mg, 0.2 mmol) and potassium bis(trimethylsilyl)amide (121 mg, 0.61 mmol) in the intermediate alcohol (1 ml), was heated at 110° C. for 30 hours, then the reaction cooled and concentrated under reduced pressure. The residual brown solid was purified by column chromatography on silica gel using diethylamine:ethyl acetate (5:95) as eluant, and repeated using methanol:ethyl acetate (5:95) as eluant. The product was triturated with ether to afford the title compound (7 mg, 6%) as a white solid. the reaction stirred under reflux for 48 hours stirring continued for a further 90 minutes under reflux The cooled reaction was washed with aqueous ammonium chloride solution (500 ml) dried (MgSO4) evaporated under reduced pressure The residual oil was purified by column chromatography on silica gel using an elution gradient of ether:pentane (10:90 to 50:50) to give a pale yellow oil the reaction cooled concentrated under reduced pressure The residual brown solid was purified by column chromatography on silica gel The product was triturated with ether

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

Procedure: A mixture of 9.5 parts of 1-[2(2,4-dichlorophenyl)-2,2-dimethoxyethyl]-1H-1,2,4-triazole 4-methylbenzenesulfonate, 2 parts of (2R, 3R)(-)-2,3-butanediol, 1 part of 4-methylbenzenesulfonic acid and 90 parts of methylbenzene is stirred and refluxed for 3 days. The reaction mixture is cooled and alkalized with a sodium hydroxide solution 20%. The whole is poured onto water and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using ethyl acetate as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2,2'oxybispropane and petroleumether (1:1 by volume). The product is filtered off and dried, yielding 3.2 parts (50%) of (-)-(4R,trans)-1-[2-(2,4-dichlorophenyl)-4,5-dimethyl-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole; mp. 82.5° C.; [α]D =-30.26° (c=0.5% CHCl3) refluxed for 3 days The reaction mixture is cooled The whole is poured onto water the product is extracted with dichloromethane The extract is dried filtered evaporated The residue is purified by column-chromatography over silica gel The pure fractions are collected the eluent is evaporated The residue is crystallized from a mixture of 2,2'oxybispropane and petroleumether (1:1 by volume) The product is filtered off dried

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

Procedure: A solution of 1.35 g (15.0 mmol) of (R,R)-(−)-2,3-butanediol in 50 ml of THF is mixed at 0° C. in portions with 480 mg (11.0 mmol) of sodium hydride (55% dispersion) and then stirred for 10 minutes at room temperature. The solution that is produced is added at 0° C. to 2.27 g (10.0 mmol) of 5-bromo-2,4-dichloropyrimidine in 25 ml of THF. The batch is slowly heated to room temperature and stirred for 12 hours. The solvent is drawn off, and the residue that is obtained is purified by chromatography (hexane/ethyl acetate 1:1). 2.29 g (8.1 mmol, corresponding to 81% of theory) of the product is obtained. The solution that is produced The batch is slowly heated to room temperature stirred for 12 hours the residue that is obtained is purified by chromatography (hexane/ethyl acetate 1:1) 2.29 g (8.1 mmol, corresponding to 81% of theory) of the product is obtained

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

Procedure: A solution of 1.35 g (15.0 mmol) of (R,R)-(−)-2,3-butanediol in 50 ml of THF is mixed at 0° C. in portions with 480 mg (11.0 mmol) of sodium hydride (55% dispersion) and then stirred for 10 minutes at room temperature. The solution that is produced is added at 0° C. to 2.27 g (10.0 mmol) of 5-bromo-2,4-dichloropyrimidine in 25 ml of THF. The batch is slowly heated to room temperature and stirred for 12 hours. The solvent is drawn off, and the residue that is obtained is purified by chromatography (hexane/ethyl acetate 1:1). 2.29 g (8.1 mmol, corresponding to 81% of theory) of the product is obtained. The solution that is produced The batch is slowly heated to room temperature stirred for 12 hours the residue that is obtained is purified by chromatography (hexane/ethyl acetate 1:1) 2.29 g (8.1 mmol, corresponding to 81% of theory) of the product is obtained

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4.0 g (44.4 mmol) of (2R,3R)-butane-2,3-diol in 300 ml of THF was admixed at room temperature with 5.0 g (44.6 mmol) of potassium tert-butylate and the mixture was refluxed for 15 minutes. The mixture was cooled to ca. 50° C. and admixed with 5.3 ml (44.6 mmol) of benzyl bromide. The mixture was refluxed for 3 hours, then stirred overnight at room temperature. The mixture was diluted with ethyl acetate and sodium chloride solution and then washed with 1N hydrogen chloride solution (1×) and sodium chloride solution (2×). The organic phase was dried (Na2SO4), filtered and concentrated by evaporation. The resulting residue was purified chromatographically (hexane/ethyl acetate 1:1). This gave 3.4 g (18.9 mmol; yield: 43%) of the product. the mixture was refluxed for 15 minutes The mixture was refluxed for 3 hours washed with 1N hydrogen chloride solution (1×) and sodium chloride solution (2×) The organic phase was dried (Na2SO4) filtered concentrated by evaporation The resulting residue was purified chromatographically (hexane/ethyl acetate 1:1)