1,3-difluoro-2-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:; See reaction.notes.procedure_details.

Procedure: Following General Procedure (5-A1) using 2,6-difluorophenyl isocyanate and (S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one, as described in Example 8-B above, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: 491 (M+H).

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

Procedure: The compound of example 19 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 2,6-difluorophenyl isocyanate. The compound of example 19 was used directly without isolation for the preparation of compound of example 20.

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

Procedure: The amine hydrochloride from. Example 12B (0.132 g, 0.35 mmol) was reacted with 2,6-difluorophenylisocyanate (0.055 g, 0.35 mmol) according to the procedure in Example 1C. The product was purified by flash chromatography on silica (eluant EtOAc:pet. eth r 70:30) and then by preparative HPLC (gradient water:acetonitrile 80:20–20:80; 0.1% TFA). The HPLC fractions were freeze-dried to give a white solid; yield 0.027 g (17%). The product was purified by flash chromatography on silica (eluant EtOAc:pet. eth r 70:30) The HPLC fractions were freeze-dried to give a white solid

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

Procedure: N-(2-Hydroxy4-nitrophenyl)-N′-(2,6-difluorophenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2,6-difluoro 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 the title compound (0.91 g, 91%). EI-MS m/z 308 (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: The title compound is prepared analogously as described in Example 105B from N-(4-morpholin-4-yl-phenyl)-pyrimidine-4,6-diamine and 2,6-difluorophenyl isocyanate. Slightly pink solid, HPLC: tR=3.53 min (purity: 100%, gradient F), ESI-MS: 427.4 [MH]+.

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-(3-dimethylamino-phenyl)-pyrimidine-4,6-diamine (458.6 mg, 2 mmol), 2,6-difluorophenyl isocyanate (341.2 mg, 2.2 mmol) in dry dioxane (5 mL) is shaken for 2.5 h at 80° C. After cooling down, the reaction mixture is treated with ethyl acetate. The precipitate is filtered off and dried in vacuo to afford the title compound. After cooling down The precipitate is filtered off dried in vacuo

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-(4-diethylamino-phenyl)-pyrimidine-4,6-diamine (257.4 mg, 1 mmol), 2,6-difluorophenyl isocyanate (170.6 mg, 1.1 mmol) in dry dioxane (4 mL) is shaken for 1.5 h at 80° C. After evaporation of the solvent in vacuo, the residue is distributed between CH2Cl2 and half-saturated K2CO3 solution. The organic layer is dried over Na2SO4, evaporated, and the residue purified by flash chromatography (CH2Cl2/CH3OH). The combined pure fractions are evaporated, the residue triturated with CH2Cl2 and the solid filtered off and dried in vacuo to afford the title compound. After evaporation of the solvent in vacuo The organic layer is dried over Na2SO4 evaporated the residue purified by flash chromatography (CH2Cl2/CH3OH) The combined pure fractions are evaporated the residue triturated with CH2Cl2 the solid filtered off dried in vacuo

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

Procedure: To a round-bottom flask with pyridine (3 mL) was added 5-(3-Amino-phenylsulfanyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (16.3 mg, 0.05 mmole) and 1,3-Difluoro-2-isocyanato-benzene (15.5 mg, 0.1 mmole). The reaction mixture was stirred at room temperature overnight and extracted with EtOAc (40 mL) and water (40 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification through flash column (methylene chloride/methanol: 96/4) gave the title compound as a light yellow solid (9.8 mg, 41%). MS: 481.1 (MH+); HPLC Rf: 7.559 min.; HPLC purity: 96%. extracted with EtOAc (40 mL) and water (40 mL) The organic layer was washed with brine dried over anhydrous sodium sulfate concentrated Purification through flash column (methylene chloride/methanol: 96/4)

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

Procedure: To a round-bottom flask with pyridine (3 mL) was added 5-(3-Amino-phenylsulfanyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (16.3 mg, 0.05 mmole) and 1,3-Difluoro-2-isocyanato-benzene (15.5 mg, 0.1 mmole). The reaction mixture was stirred at room temperature overnight and extracted with EtOAc (40 mL) and water (40 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification through flash column (methylene chloride/methanol: 96/4) gave the title compound as a light yellow solid (9.8 mg, 41%). MS: 481.1 (MH+); HPLC Rf: 7.559 min.; HPLC purity: 96%. extracted with EtOAc (40 mL) and water (40 mL) The organic layer was washed with brine dried over anhydrous sodium sulfate concentrated Purification through flash column (methylene chloride/methanol: 96/4)