[2-(4-bromophenyl)-2-oxoethyl] thiocyanate

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

Procedure: A suspension of 2-(4-bromophenyl)-2-oxoethyl thiocyanate (5.12 g, 20.0 mmol), prepared in the previous step, in 30 mL of 30% hydrogen bromide in acetic acid was stirred under nitrogen at room temperature for 7 h. The yellow suspension was poured into 200 mL of 1 N NaOH (exotherm) and the mixture stirred at room temperature for 17 h. The solid present was collected by filtration, rinsed with water, ice-cold ethanol, hexane and then dried under high vacuum to give 2-bromo-4-(4-bromophenyl)-1,3-thiazole (5.36 g, 84%) as a light yellow solid, mp 117-119° C.; MS (ES) m/z 318/320/322 [M+H]+. the mixture stirred at room temperature for 17 h The solid present was collected by filtration rinsed with water, ice-cold ethanol, hexane dried under high vacuum

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

Procedure: A mixture of 2,4′-dibromoacetophenone (56.08 g, 0.20 mol) and potassium thiocyanate (21.57 g, 0.22 mol) in 1 L of absolute ethanol was stirred under nitrogen at room temperature for 5 h. The reaction was added to 2 L of water and the mixture stirred at room temperature for 2 h. The solid present was collected by filtration, rinsed with water, ice-cold ethanol, hexane, and then dried under high vacuum to give 2-(4-bromophenyl)-2-oxoethyl thiocyanate (50.39 g, 98%) as a white solid, mp 148-149° C. the mixture stirred at room temperature for 2 h The solid present was collected by filtration rinsed with water, ice-cold ethanol, hexane dried under high vacuum

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

Procedure: A mixture of 2,4′-dibromoacetophenone (56.08 g, 0.20 mol) and potassium thiocyanate (21.57 g, 0.22 mol) in 1 L of absolute ethanol was stirred under nitrogen at room temperature for 5 h. The reaction was added to 2 L of water and the mixture stirred at room temperature for 2 h. The solid present was collected by filtration, rinsed with water, ice-cold ethanol, hexane, and then dried under high vacuum to give 2-(4-bromophenyl)-2-oxoethyl thiocyanate (50.39 g, 98%) as a white solid, mp 148-149° C. the mixture stirred at room temperature for 2 h The solid present was collected by filtration rinsed with water, ice-cold ethanol, hexane dried under high vacuum

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

Procedure: A suspension of 2-(4-bromophenyl)-2-oxoethyl thiocyanate (5.12 g, 20.0 mmol), prepared in the previous step, in 30 mL of 30% hydrogen bromide in acetic acid was stirred under nitrogen at room temperature for 7 h. The yellow suspension was poured into 200 mL of 1 N NaOH (exotherm) and the mixture stirred at room temperature for 17 h. The solid present was collected by filtration, rinsed with water, ice-cold ethanol, hexane and then dried under high vacuum to give 2-bromo-4-(4-bromophenyl)-1,3-thiazole (5.36 g, 84%) as a light yellow solid, mp 117-119° C.; MS (ES) m/z 318/320/322 [M+H]+. the mixture stirred at room temperature for 17 h The solid present was collected by filtration rinsed with water, ice-cold ethanol, hexane dried under high vacuum

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

Procedure: A mixture of 2,4′-dibromoacetophenone (56.08 g, 0.20 mol) and potassium thiocyanate (21.57 g, 0.22 mol) in 1 L of absolute ethanol was stirred under nitrogen at room temperature for 5 h. The reaction was added to 2 L of water and the mixture stirred at room temperature for 2 h. The solid present was collected by filtration, rinsed with water, ice-cold ethanol, hexane, and then dried under high vacuum to give 2-(4-bromophenyl)-2-oxoethyl thiocyanate (50.39 g, 98%) as a white solid, mp 148-149° C. the mixture stirred at room temperature for 2 h The solid present was collected by filtration rinsed with water, ice-cold ethanol, hexane dried under high vacuum

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

Procedure: A suspension of 2-(4-bromophenyl)-2-oxoethyl thiocyanate (5.12 g, 20.0 mmol), prepared in the previous step, in 30 mL of 30% hydrogen bromide in acetic acid was stirred under nitrogen at room temperature for 7 h. The yellow suspension was poured into 200 mL of 1 N NaOH (exotherm) and the mixture stirred at room temperature for 17 h. The solid present was collected by filtration, rinsed with water, ice-cold ethanol, hexane and then dried under high vacuum to give 2-bromo-4-(4-bromophenyl)-1,3-thiazole (5.36 g, 84%) as a light yellow solid, mp 117-119° C.; MS (ES) m/z 318/320/322 [M+H]+. the mixture stirred at room temperature for 17 h The solid present was collected by filtration rinsed with water, ice-cold ethanol, hexane dried under high vacuum

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

Procedure: A mixture of 2,4′-dibromoacetophenone (56.08 g, 0.20 mol) and potassium thiocyanate (21.57 g, 0.22 mol) in 1 L of absolute ethanol was stirred under nitrogen at room temperature for 5 h. The reaction was added to 2 L of water and the mixture stirred at room temperature for 2 h. The solid present was collected by filtration, rinsed with water, ice-cold ethanol, hexane, and then dried under high vacuum to give 2-(4-bromophenyl)-2-oxoethyl thiocyanate (50.39 g, 98%) as a white solid, mp 148-149° C. the mixture stirred at room temperature for 2 h The solid present was collected by filtration rinsed with water, ice-cold ethanol, hexane dried under high vacuum

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Serine methyl ester hydrochloride (1.02 g, 4 mmol) was dissolved in 50 mL of ethanol and 2-(4-bromophenyl)-2-oxoethyl thiocyanate (0.686 g, 4.4 mmol), prepared in step 1 of Example 1, was added followed by triethylamine (0.63 mL, 4.4 mmol). The mixture was heated to 60° C. for 18 h and then cooled and concentrated under reduced pressure. Flash chromatography (1% methanol/chloroform) afforded 1.1 g of 2-[4-(4-bromophenyl)-1,3-thiazol-2-ylamino]-3-hydroxy-propionic acid methyl ester (1.1 g, 79%) as a white solid. was added cooled concentrated under reduced pressure

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Amino-4,4,4-trifluoro-butyric acid methyl ester hydrochloride (1.1 g, 5.3 mmol) was dissolved in 30 mL of ethanol and 2-(4-bromophenyl)-2-oxoethyl thiocyanate, prepared in step 1 of Example 1, (1.23 g, 4.8 mmol) was added followed by triethylamine (0.73 mL, 5.3 mmol). The mixture was heated to 55° C. for 18 h then cooled and concentrated under reduced pressure. Flash chromatography (5% acetone/hexane) afforded methyl 2-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}-4,4,4-trifluorobutanoate (1.21 g, 56%) as a white solid. mp 113-114° C. HRMS: calcd for C14H12BrF3N2O2S+H+, 408.98277; found (ESI, [M+H]+), 408.9831. Analytical HPLC: retention time 11.5 min, 210-370 nm the Xterra® RP18 column, 3.5μ, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection. was added then cooled concentrated under reduced pressure

Conditions: temp:68.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Triethylamine (3.30 mL, 23.7 mmol) was added under nitrogen to a mixture of 2-(4-bromophenyl)-2-oxoethyl thiocyanate (5.50 g, 21.6 mmol), prepared in step 1 of Example 1, and ethyl 1-aminocyclobutanecarboxylate hydrochloride (4.24 g, 23.6 mmol) in 130 mL of absolute ethanol. The mixture was then stirred at 68° C. overnight. The reaction was concentrated under reduced pressure to remove the ethanol. The residue was partitioned between ethyl acetate and water. The aqueous layer was made basic by the addition of 2 N NaOH. The organic layer was separated, washed two times with water, dried (MgSO4), filtered and the solvent removed under reduced pressure. Purification of the residue on a Horizon™ Flash Collector (the Biotage FLASH 40+™ cartridge) using a linear gradient of 45% methylene chloride in hexane to 100% methylene chloride as the eluent gave ethyl 1-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}cyclobutane carboxylate (1.0 g, 12%) as a brown oil, MS (ESI) m/z 381 [M+H]+. The reaction was concentrated under reduced pressure to remove the ethanol The residue was partitioned between ethyl acetate and water The aqueous layer was made basic by the addition of 2 N NaOH The organic layer was separated washed two times with water dried (MgSO4) filtered the solvent removed under reduced pressure Purification of the residue on a Horizon™ Flash Collector (the Biotage FLASH 40+™ cartridge)

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Triethylamine (3.1 mL, 22.3 mmol) was added under nitrogen to a mixture of 2-(4-bromophenyl)-2-oxoethyl thiocyanate (5.2024 g, 20.3 mmol), prepared in step 1 of Example 1, and 1-ethoxycarbonyl-cyclopropyl-ammonium chloride (3.7001 g, 22.3 mmol), prepared in the previous step, in 400 mL of absolute ethanol. After the addition, the reaction was stirred at 65° C. for 4 days. The reaction was concentrated under reduced pressure to remove the ethanol. The residue was taken up in methylene chloride, applied to a Biotage FLASH 25+™ cartridge and the methylene chloride allowed to evaporate. Purification of the residue on the samplet on a Horizon™ Flash Collector (the Biotage FLASH 25+™ cartridge) using a linear gradient of 5% ethyl acetate-hexane to 100% ethyl acetate gave ethyl 1-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}cyclopropane carboxylate (2.66 g, 36%) as a light yellow solid, mp 152-154° C.; MS m/z 367. After the addition The reaction was concentrated under reduced pressure to remove the ethanol to evaporate Purification of the residue on the samplet on a Horizon™ Flash Collector (the Biotage FLASH 25+™ cartridge)

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

Procedure: A suspension of 2-(4-bromophenyl)-2-oxoethyl thiocyanate (5.12 g, 20.0 mmol), prepared in the previous step, in 30 mL of 30% hydrogen bromide in acetic acid was stirred under nitrogen at room temperature for 7 h. The yellow suspension was poured into 200 mL of 1 N NaOH (exotherm) and the mixture stirred at room temperature for 17 h. The solid present was collected by filtration, rinsed with water, ice-cold ethanol, hexane and then dried under high vacuum to give 2-bromo-4-(4-bromophenyl)-1,3-thiazole (5.36 g, 84%) as a light yellow solid, mp 117-119° C.; MS (ES) m/z 318/320/322 [M+H]+. the mixture stirred at room temperature for 17 h The solid present was collected by filtration rinsed with water, ice-cold ethanol, hexane dried under high vacuum