1-(4-bromophenyl)-3-methylurea

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.149 g, Example 33), N-(4-bromophenyl)-N′-methyl urea (0.225 g) 2M aqueous sodium carbonate (1.0 ml) and tetrakis(triphenylphosphine)palladium (0) (0.028 g) in ethanol (3 ml). The reaction mixture was heated in a sealed vial at 100° C. for 2 hours. After cooling, the solution was concentrated under reduced pressure. The residue was purified by chromatography over silica eluting with tetrahydrofuran:hexane (1:1). The residue was further purified by chromatography over silica gel eluting dichloromethane:ethanol (9:1). The residue was then further purified by reverse-phase HPLC eluting a gradient of 25-100% acetonitrile in 0.1 w/v aqueous ammonium acetate solution. The HPLC fractions were concentrated under reduced pressure, the residue dissolved in ethanol, filtered and concentrated under reduced pressure to give the title compound as a solid (0.050 g). Prepared After cooling the solution was concentrated under reduced pressure The residue was purified by chromatography over silica eluting with tetrahydrofuran:hexane (1:1) The residue was further purified by chromatography over silica gel eluting dichloromethane:ethanol (9:1) The residue was then further purified by reverse-phase HPLC eluting a gradient of 25-100% acetonitrile in 0.1 w/v aqueous ammonium acetate solution The HPLC fractions were concentrated under reduced pressure the residue dissolved in ethanol filtered concentrated under reduced pressure

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethane sulfenyl chloride was prepared as in Example 9 from 68 g of diethyldisulfide and 67 g of sulfuryl chloride, cooled to -40° C. and a solution of 60 g of N-methyl-N'-(4-bromophenyl)-urea in 800 ml of pyridine was added thereto. After stirring the reaction mixture for 30 minutes at -40° C., the temperature was allowed to rise to -20° C. and the mixture was stirred for 11/2 hours at this temperature. The mixture was poured into a mixture of water, ice and hydrochloric acid and was extracted with methylene chloride. The organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with a 7-3 benzene-ethyl acetate mixture. The product was dissolved in ethyl ether and the solution was treated with activated carbon, filtered and concentrated to dryness under reduced pressure. The residue was added to petroleum ether (b.p. = 65°-75° C.) and the precipitate formed was recovered by vacuum filtration to obtain 33 g of N-methyl-N-ethylthio-N'-(4-bromophenyl)-urea melting at <50° C. to rise to -20° C. the mixture was stirred for 11/2 hours at this temperature was extracted with methylene chloride The organic phase was washed with water dried evaporated to dryness under reduced pressure The residue was chromatographed over silica gel eluted with a 7-3 benzene-ethyl acetate mixture The product was dissolved in ethyl ether the solution was treated with activated carbon filtered concentrated to dryness under reduced pressure The residue was added to petroleum ether (b.p. = 65°-75° C.) the precipitate formed was recovered by vacuum filtration

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.149 g, Example 33), N-(4-bromophenyl)-N′-methyl urea (0.225 g) 2M aqueous sodium carbonate (1.0 ml) and tetrakis(triphenylphosphine)palladium (0) (0.028 g) in ethanol (3 ml). The reaction mixture was heated in a sealed vial at 100° C. for 2 hours. After cooling, the solution was concentrated under reduced pressure. The residue was purified by chromatography over silica eluting with tetrahydrofuran:hexane (1:1). The residue was further purified by chromatography over silica gel eluting dichloromethane:ethanol (9:1). The residue was then further purified by reverse-phase HPLC eluting a gradient of 25-100% acetonitrile in 0.1 w/v aqueous ammonium acetate solution. The HPLC fractions were concentrated under reduced pressure, the residue dissolved in ethanol, filtered and concentrated under reduced pressure to give the title compound as a solid (0.050 g). Prepared After cooling the solution was concentrated under reduced pressure The residue was purified by chromatography over silica eluting with tetrahydrofuran:hexane (1:1) The residue was further purified by chromatography over silica gel eluting dichloromethane:ethanol (9:1) The residue was then further purified by reverse-phase HPLC eluting a gradient of 25-100% acetonitrile in 0.1 w/v aqueous ammonium acetate solution The HPLC fractions were concentrated under reduced pressure the residue dissolved in ethanol filtered concentrated under reduced pressure

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethane sulfenyl chloride was prepared as in Example 9 from 68 g of diethyldisulfide and 67 g of sulfuryl chloride, cooled to -40° C. and a solution of 60 g of N-methyl-N'-(4-bromophenyl)-urea in 800 ml of pyridine was added thereto. After stirring the reaction mixture for 30 minutes at -40° C., the temperature was allowed to rise to -20° C. and the mixture was stirred for 11/2 hours at this temperature. The mixture was poured into a mixture of water, ice and hydrochloric acid and was extracted with methylene chloride. The organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with a 7-3 benzene-ethyl acetate mixture. The product was dissolved in ethyl ether and the solution was treated with activated carbon, filtered and concentrated to dryness under reduced pressure. The residue was added to petroleum ether (b.p. = 65°-75° C.) and the precipitate formed was recovered by vacuum filtration to obtain 33 g of N-methyl-N-ethylthio-N'-(4-bromophenyl)-urea melting at <50° C. to rise to -20° C. the mixture was stirred for 11/2 hours at this temperature was extracted with methylene chloride The organic phase was washed with water dried evaporated to dryness under reduced pressure The residue was chromatographed over silica gel eluted with a 7-3 benzene-ethyl acetate mixture The product was dissolved in ethyl ether the solution was treated with activated carbon filtered concentrated to dryness under reduced pressure The residue was added to petroleum ether (b.p. = 65°-75° C.) the precipitate formed was recovered by vacuum filtration

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.149 g, Example 33), N-(4-bromophenyl)-N′-methyl urea (0.225 g) 2M aqueous sodium carbonate (1.0 ml) and tetrakis(triphenylphosphine)palladium (0) (0.028 g) in ethanol (3 ml). The reaction mixture was heated in a sealed vial at 100° C. for 2 hours. After cooling, the solution was concentrated under reduced pressure. The residue was purified by chromatography over silica eluting with tetrahydrofuran:hexane (1:1). The residue was further purified by chromatography over silica gel eluting dichloromethane:ethanol (9:1). The residue was then further purified by reverse-phase HPLC eluting a gradient of 25-100% acetonitrile in 0.1 w/v aqueous ammonium acetate solution. The HPLC fractions were concentrated under reduced pressure, the residue dissolved in ethanol, filtered and concentrated under reduced pressure to give the title compound as a solid (0.050 g). Prepared After cooling the solution was concentrated under reduced pressure The residue was purified by chromatography over silica eluting with tetrahydrofuran:hexane (1:1) The residue was further purified by chromatography over silica gel eluting dichloromethane:ethanol (9:1) The residue was then further purified by reverse-phase HPLC eluting a gradient of 25-100% acetonitrile in 0.1 w/v aqueous ammonium acetate solution The HPLC fractions were concentrated under reduced pressure the residue dissolved in ethanol filtered concentrated under reduced pressure