1-bromo-4-isocyanatobenzene

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

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

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

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: 3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 4-bromophenylisocyanate, in a similar manner as described in Example 1.68, providing 27 mg (60% yield) of Compound 85: LCMS m/z (%)=421 (M+H81Br, 100), 419 (M+H79Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.24 (s, 1H), 8.13 (s, 1H), 7.63 (dd, J1=9.0 Hz, J2=2.6 Hz, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.48 (d, J=2.8 Hz, 1H), 7.42 (d, J=8.8 Hz, 2H), 7.38 (d, JH,F=4.4 Hz, 1H), 7.13 (d, J=9.2 Hz, 1H), 3.83 (s, 3H), 3.65 (s, 3H). 19F NMR (376 MHz, acetone-d6) δ: −177.39 (d, JH,F=5.3 Hz, 1F).

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

Procedure: 3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 4-bromophenyl isocyanate in a similar manner as described in Example 1.53, providing 2.3 mg (6%) of Compound 81: LCMS m/z (%)=437 (M+H37Cl, 100), 435 (M+H35Cl, 82). 1H NMR (400 MHz, DMSO-d6) δ: 8.97 (d, J=2 Hz, 2H), 8.80 (s, 1H), 8.70 (s, 1H), 7.61 (s, 1H), 7.53 (dd, J1=12 Hz, J2=8 Hz, 1H), 7.44 (t, J=4 Hz, 2H), 7.35 (d, J=4 Hz, 1H), 7.13 (d, J=8 Hz, 1H), 3.74 (s, 3H), 3.58 (s, 3H).

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

Procedure: 3.1 G. of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[ 2,3-e] 1,2-thiazine 1,1-dioxide are dissolved in 31 ml. of absolute dimethylsulfoxide under an atmosphere of nitrogen. 1.44 G. of freshly distilled triethylamine and 2.83 g. of 4-bromophenyl isocyanate are added to the solution and the mixture is then stirred for 24 hours at room temperature. This mixture is then poured into 225 ml. of 3-N hydrochloric acid and the precipitate which separates out is filtered on a sinter filter, washed three times with 20 ml. of distilled water each time and dried as much as possible. The precipitate is dissolved in 250 ml. of methylene chloride, dried over sodium sulfate, stirred with activated charcoal and filtered. The organic phase is shaken out four times with 250 ml. of saturated sodium bicarbonate solution each time and the aqueous phase is shaken again each time with a little methylene chloride. The combined aqueous phases are rendered strongly acid with concentrated hydrochloric acid. The product which separates out is extracted three times with 250 ml. of methylene chloride each time. The combined organic phases are dried over sodium sulfate, stirred with activated charcoal, filtered and the solvent is removed by distillation. The crystalline residue is dissolved in 50 ml. of chloroform. While boiling, activated charcoal is added and the mixture is filtered hot. The product is made to crystallize by scratching. The crystals are removed by filtration, digested with a little cold chloroform, and 4'-bromo-3-hydroxy-2-methyl-2N-thieno[[2,3-e] 1,2-thiazine-4-carboxanilide 1,1-dioxide, melting point 178° C. to 179° C. (decomposition), is obtained. This mixture is then poured into 225 ml of 3-N hydrochloric acid and the precipitate which separates out is filtered on a sinter filter washed three times with 20 ml of distilled water each time and dried as much as possible The precipitate is dissolved in 250 ml of methylene chloride, dried over sodium sulfate stirred with activated charcoal filtered The organic phase is shaken out four times with 250 ml of saturated sodium bicarbonate solution each time and the aqueous phase is shaken again each time with a little methylene chloride The product which separates out is extracted three times with 250 ml The combined organic phases are dried over sodium sulfate stirred with activated charcoal filtered the solvent is removed by distillation The crystalline residue is dissolved in 50 ml activated charcoal is added the mixture is filtered hot to crystallize The crystals are removed by filtration is obtained

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

Procedure: To a solution of 2-amino-3-(3-isopropoxy-phenyl)-3H-quinazolin-4-one (295 mg, 1.0 mmol) in anhydrous DMF (10 mL) was added 50% NaH (48 mg, 1 mmol) at room temperature and stirred for 30 minutes. To this mixture was added, 4-bromo phenyl isocyanate and stirred for 2 hours at room temperature. The reaction mixture was quenched with water and concentrated. It was then diluted with ethyl acetate and filtered. The filtrate was concentrated and chromatographed using 100% CH3Cl to isolate pure product as a white solid (70 mg, 14.2%), mp 230°-233° C. To this mixture was added The reaction mixture was quenched with water concentrated It was then diluted with ethyl acetate filtered The filtrate was concentrated chromatographed

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

Procedure: To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.37 g, 1.00 mmol) and 4-bromophenylisocyanate (0.20 g, 1.00 mmol) in acetonitrile (30 mL) at 0° C. was added TEA (0.20 g, 2.0 mmol) dropwise over 10 min. The mixture was stirred at ambient temperature for 2 h and then 10% aqueous HCl solution (30 mL) was added. The solid precipitate was filtered, washed with water (30 mL) and dried in vacuo providing 1-(4-bromo-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.42 g, 89% yield); mp 278-280° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.00 (99.50%); 1H NMR (DMSO-d6) δ 1.93-2.06 (m, 1H, CHH), 2.29-2.46 (m, 1H, CHH), 2.54-2.67 (m, 1H, CHH), 2.81-3.02 (m, 1H, CHH), 4.30 (d, 1H, CHH), 4.36-4.52 (m, 3H, CH2 and CHH), 5.11 (dd, J=4.8, 13.1 Hz, 1H, CH), 6.80 (t, J=5.7 Hz, 1H, NH), 7.31-7.47 (m, 5H, Ar), 7.51 (s, 1H, Ar), 7.69 (d, 1H, Ar), 8.81 (s, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.20, 42.77, 47.12, 51.56, 112.42, 119.66, 121.88, 122.93, 126.89, 130.30, 131.32, 139.81, 142.38, 144.69, 155.03, 167.93, 170.99, 172.85; LCMS: MH=472; Anal. Calcd for C21H19BrN4O4: C, 53.52; H, 4.06; N, 11.89. Found: C, 53.32; H, 3.97; N, 11.77. The solid precipitate was filtered washed with water (30 mL) dried in vacuo

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

Procedure: N-(2-Hydroxy-4-nitrophenyl)-N′-(4-bromo phenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 4-bromo phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded ihe title compound (0.41 g, 37%). EI-MS m/z 352 (M+H)+ The product was purified by dilution with methylene chloride and precipitation with hexanes Filtering

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

Procedure: To a solution of 9.97 g of 4-methoxybenzenesulfonamide in 54 ml of acetone were added 54 ml of a 1N sodium hydroxide solution. With stirring, a solution of 11.55 g of 4-bromophenylisocyanate in 50 ml of acetone was added. After stirring at room temperature for three days, the reaction mixture was filtered and 55 ml of 1N hydrochloric acid were added to the filtrate providing a fine white precipitate. Two hundred milliliters of water were added, and the solid was recovered by filtration to provide 18.85 g of the desired title product. After stirring at room temperature for three days the reaction mixture was filtered 55 ml of 1N hydrochloric acid were added to the filtrate providing a fine white precipitate the solid was recovered by filtration