1-bromo-4-isothiocyanatobenzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 4-Bromophenylisothiocyanate (21.4 g) was dissolved in tetrahydrofuran (50 mL), and concentrated aqueous ammonia (28%) (13.7 mL) was added dropwise to the solution, followed by stirring at room temperature for 10 minutes. The solvent was concentrated under reduced pressure, and the crystals were recovered through filtration by use of water, followed by recrystallization from ethanol, to thereby yield the title compound (16.4 g). The solvent was concentrated under reduced pressure the crystals were recovered through filtration by use of water followed by recrystallization from ethanol

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

Procedure: 4-Bromophenylisothiocyanate (21.4 g) was dissolved in tetrahydrofuran (50 mL), and concentrated aqueous ammonia (28%) (13.7 mL) was added dropwise to the solution, followed by stirring at room temperature for 10 minutes. The solvent was concentrated under reduced pressure, and the crystals were recovered through filtration by use of water, followed by recrystallization from ethanol, to thereby yield the title compound (16.4 g). The solvent was concentrated under reduced pressure the crystals were recovered through filtration by use of water followed by recrystallization from ethanol

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

Procedure: 2-Amino-4-(trifluoromethyl)phenol (250 mg, 1.41 mmol) and 1-bromo-4-isothiocyanatobenzene (302 mg, 1.41 mmol) were stirred in ethyl alcohol at ambient temperature for 18 h. The flask was charged with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI) (405 mg, 2.12 mmol), and the mixture was stirred for 2 h before being heated at reflux overnight The reaction was allowed to cool to rt and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 2 N aqueous hydrochloric acid solution and water, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 85:15 hexanes/ethyl acetate to provide the title compound (315 mg, 62%). LC-MS m/z 357.1 (MH+), retention time 4.20 minutes. before being heated at reflux overnight The reaction was concentrated under reduced pressure The residue was dissolved in ethyl acetate washed with 2 N aqueous hydrochloric acid solution and water dried (Na2SO4) concentrated in vacuo The residue was purified by flash chromatography on silica gel eluting with 85:15 hexanes/ethyl acetate

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

Procedure: In a 250-mL round-bottom flask, 1-bromo-4-isothiocyanatobenzene (4.28 g, 20 mmol) and 2-amino-4-methyl-phenol (2.46 g, 20 mmol) were stirred in 120 mL ethanol at rt overnight. The formation of N-(4-bromophenyl)-N′-(2-hydroxy-5-methylphenyl)thiourea was confirmed by LC-MS. To the mixture, 1.5 eq. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) was added, and the reaction was stirred at rt for another 2 h. The reaction mixture was then heated at reflux for 6 h. The mixture was cooled to rt and the solvent was removed under reduced pressure. The solid was dissolved in EtOAc and washed with 2 N aqueous HCl and H2O. The organic layer was dried (MgSO4) and the solvent was removed under reduced pressure. The solid obtained was ultrasonicated in 30 mL ether and filtered to give the desired compound (3.64 g, 60%). 1H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 7.70 (m, 2H), 7.55 (m, 2H), 7.35 (d, 1H), 7.25 (s, 1H), 6.95 (d, 1H), 2.40 (s, 3H). LC-MS m/z 303.3 (MH+), ret. time 3.46 min. The reaction mixture was then heated at reflux for 6 h The mixture was cooled to rt the solvent was removed under reduced pressure The solid was dissolved in EtOAc washed with 2 N aqueous HCl and H2O The organic layer was dried (MgSO4) the solvent was removed under reduced pressure The solid obtained filtered

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

Procedure: In a 250-mL round-bottom flask, 1-bromo-4-isothiocyanatobenzene (4.28 g, 20 mmol) and 2-amino-4-methyl-phenol (2.46 g, 20 mmol) were stirred in 120 mL ethanol at rt overnight. The formation of N-(4-bromophenyl)-N′-(2-hydroxy-5-methylphenyl)thiourea was confirmed by LC-MS. To the mixture, 1.5 eq. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) was added, and the reaction was stirred at rt for another 2 h. The reaction mixture was then heated at reflux for 6 h. The mixture was cooled to rt and the solvent was removed under reduced pressure. The solid was dissolved in EtOAc and washed with 2 N aqueous HCl and H2O. The organic layer was dried (MgSO4) and the solvent was removed under reduced pressure. The solid obtained was ultrasonicated in 30 mL ether and filtered to give the desired compound (3.64 g, 60%). 1H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 7.70 (m, 2H), 7.55 (m, 2H), 7.35 (d, 1H), 7.25 (s, 1H), 6.95 (d, 1H), 2.40 (s, 3H). LC-MS m/z 303.3 (MH+), ret. time 3.46 min. The reaction mixture was then heated at reflux for 6 h The mixture was cooled to rt the solvent was removed under reduced pressure The solid was dissolved in EtOAc washed with 2 N aqueous HCl and H2O The organic layer was dried (MgSO4) the solvent was removed under reduced pressure The solid obtained filtered

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

Procedure: 1,2-Diamino-5-trifluoromethylbenzene (0.25 g, 1.42 mmol) was diluted in toluene (5 mL) and treated with 4-bromophenylisothiocyanate (0.30 g, 1.42 mmol). The dark solution was stirred at 100° C. for 15 minutes, then treated with 1,3-dicyclohexylcarbodiimide (0.44 g, 2.13 mmol). The reaction was maintained at 100° C. for 5 h. The reaction was concentrated and partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO4), and concentrated under reduced pressure. The dark brown oil was purified by flash chromatography on silica gel, eluting with a gradient from 9:1 hexanes/ethyl acetate to 100% ethyl acetate. The title compound was obtained as a light pink solid (0.50 g, 30%). 1H NMR (300 M, DMSO-d6) δ 11.3 (broad d, 1H), 9.87 (d, 1H) 7.50 (d, 2H), 7.61 (d, 1H), 7.55-7.42 (m, 3H), 7.35-7.30 (m, 1H); LC/MS m/z 356.2 (MH+), retention time 2.33 minutes. The reaction was maintained at 100° C. for 5 h The reaction was concentrated partitioned between ethyl acetate and water The organic layer was separated dried (MgSO4) concentrated under reduced pressure The dark brown oil was purified by flash chromatography on silica gel eluting with a gradient from 9:1 hexanes/ethyl acetate to 100% ethyl acetate

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

Procedure: A solution of 2-amino-6-isopropylphenol (0.354 g, 2.34 mmol) and 4-bromophenylisothiocyanate (0.500 g, 2.34 mmol) in tetrahydrofuran (35 mL) was stirred at room temperature for 3 h. Anhydrous copper (II) sulfate (3.361 g, 21.06 mmol), silica gel (3.361 g), and triethylamine (0.236 g, 0.33 mL, 2.34 mmol) were added, and the mixture stirred at room temperature for 18 h. The reaction mixture was filtered through a pad of Celite and the washed with diethyl ether (3×50 mL). The filtrate was concentrated to afford a brown solid. The solid material was applied to silica gel and passed through a pad a silica gel along with ethyl acetate (3×50 mL). The filtrate was concentrated to afford N2-(4-bromophenyl)-7-isopropyl-1,3-benzoxazol-2-amine (0.702 g, 91%). RP-HPLC Rt 18.066 min, 86% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 333 (MH+). The reaction mixture was filtered through a pad of Celite the washed with diethyl ether (3×50 mL) The filtrate was concentrated to afford a brown solid The filtrate was concentrated

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

Procedure: 2-Amino-4-methylphenol (1.15 g, 9.34 mmol) was added to a solution of 4-bromophenyl isothiocyanate (2.00 g, 9.34 mmol) in tetrahydrofuran (35 mL) and the reaction was stirred at room temperature for 16 h. Anhydrous copper (II) sulfate (14.06 g, 88.10 mmol), silica gel (14.06 g), and triethylamine (1.3 mL, 9.34 mmol) were added, and the mixture was stirred at room temperature for 24 h. The reaction was concentrated under reduced pressure and then added to a silica pad and purified using 1:5 ethyl acetate:heptane (2 L) followed by diethyl ether as the eluent to afford N2-(4-bromophenyl)-5-methyl-1,3-benzoxazol-2-amine as a light brown solid (2.30 g, 81%); the mixture was stirred at room temperature for 24 h The reaction was concentrated under reduced pressure added to a silica pad purified

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

Procedure: 4-Bromophenyl isothiocyanate (3.639 g, 17.00 mmol) was added to a solution of 2-amino-4-chlorophenol (2.441 g, 17.00 mmol) in acetonitrile (20 mL) and the reaction was stirred at room temperature for 2 h. The resulting brown solution was then added dropwise, via a dropping funnel, to a suspension of potassium superoxide (6.04 g, 85.0 mmol) in acetonitrile (20 mL) pre-cooled to 0° C. in an ice bath. After 20 minutes the initial exotherm had subsided and the reaction was allowed to warm to room temperature for 40 minutes. Water (120 mL) was added dropwise and the resulting off-white solid was collected by filtration, washed with additional water (60 mL) and dried overnight on a lyophilizer to afford N2-(4-bromophenyl)-5-chloro-1,3-benzoxazol-2-amine as an off-white solid (4.06 g, 74%); RP-HPLC Rt 17.229 min, 99% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 321 (M−H)− and 323 (M−H)−; 1H NMR (400 MHz, d6-DMSO) 7.17 (1H, dd, J 8.5 and 1.9 Hz), 7.53 (4H, m), 7.71 (2H, d, J 8.8 Hz), and 10.95 (1H, s). pre-cooled to 0° C. in an ice bath After 20 minutes the initial exotherm had subsided to warm to room temperature for 40 minutes the resulting off-white solid was collected by filtration washed with additional water (60 mL) dried overnight on a lyophilizer

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

Procedure: To a mixture of 2-amino-4-ethylphenol (0.89 g, 0.0065 mol) in tetrahydrofuran (80 mL) was added 4-bromophenyl isothiocyanate (1.4 g, 0.0065 mol) at room temperature. The mixture was stirred for 2 hours at room temperature. Anhydrous copper sulfate (6.2 g, 0.039 mol), triethylamine (0.9 mL, 0.0065 mol) and silica gel (11.7 g) were added to the reaction mixture. The mixture was stirred for 4 hours at room temperature. The solvent was removed under reduced pressure. The mixture was filtered through silica gel pad using 25% ethyl acetate/n-heptane as a mobile phase to give brown colored solid. The solid was purified by flash column chromatography on silica using 0%-25% ethyl acetate/n-heptane as a mobile phase. The solvent was removed, and the residue was triturated with n-heptane to give N2-(4-bromophenyl)-5-ethyl-1,3-benzoxazol-2-amine (0.96 g, 0.003 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-95% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 12.1 min. MS: MH+: 318 The mixture was stirred for 4 hours at room temperature The solvent was removed under reduced pressure The mixture was filtered through silica gel pad to give brown colored solid The solid was purified by flash column chromatography on silica using 0%-25% ethyl acetate/n-heptane as a mobile phase The solvent was removed the residue was triturated with n-heptane