O-[2-[(2-methylpropan-2-yl)oxy]ethyl]hydroxylamine

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

Procedure: Phenyl 6-(2-chloro-4-iodophenylamino)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 23; 100 mg, 0.195 mmol, 1 eq) and O-(2-tert-butoxyethyl)hydroxylamine (See, WO05/110410; 260 mg, 1.95 mmol, 10 eq) were mixed in anhydrous THF (3 ml) and heated at 100° C. for 50 minutes in a microwave reactor. The protected product Example 24 was isolated by HPLC. [M+H] calc'd for C19H24ClIN4O5, 551; found, 551. The protected product Example 24 was isolated by HPLC

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound 8e (76 mg, 0.23 mmol) was added to a suspension of O-(2-tert-butoxy-ethyl)-hydroxylamine (see, WO05/110410, 47 mg, 0.36 mmol), HATU (103 mg, 0.27 mmol), and N-methylmorpholine (0.10 mL, 0.90 mmol) in DMF (3 mL). The reaction was heated to 75° C. for 16 h and concentrated in vacuo. The resulting oil was dissolved in 3 mL of TFA and allowed to stir at RT for 2 h. Then MeOH (3 mL) was added and made basic with potassium carbonate. It was allowed to stir for 30 minutes, the solid was filtered off and the filtrate was concentrated in vacuo. The residue was taken up in DMSO (1.5 mL) and methanol (1.5 mL) and purified by preparative HPLC (25/40 water/acetonitrile) to give 4 mg (5%) of Example 8 as a white solid. 1H NMR (400 MHz, MeOD): δ 7.43 (d, 1H, J=8.9 Hz), 7.33 (d, 1H, J=7.6 Hz), 6.43 (t, 1H, J=8.6 Hz), 4.14 (t, 2H, J=7.3 Hz), 3.85 (m, 2H), 3.67 (m, 2H), 3.29 (t. 2H, J=7.6 Hz), 2.09-2.27 (m, 2H), 1.83 (s, 3H). MS (ES) [m+H] calc'd for C18H19FIN3O4, 488. found 488. concentrated in vacuo The resulting oil was dissolved in 3 mL of TFA Then MeOH (3 mL) was added to stir for 30 minutes the solid was filtered off the filtrate was concentrated in vacuo methanol (1.5 mL) and purified by preparative HPLC (25/40 water/acetonitrile)

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

Procedure: 7-Fluoro-8-(2-fluoro-4-iodophenylamino)-6-oxo-2,3,4,6-tetrahydro-1H-quinolizine-9-carboxylic acid (7e, 216 mg, 0.48 mmol, 1 eq), O-(2-tert-butoxyethyl)hydroxylamine (129 mg, 0.97 mmol, 2 eq) and N-hydroxybenzotriazole (82 mg, 0.53 mmol, 1.1 eq) were stirred in DCM (12 ml) and DMF (1.5 ml). 1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide (111 mg, 0.58 mmol, 1.2 eq) and triethylamine (101 μl, 0.73 mmol, 1.5 eq) were added and the solution stirred at RT for 16 hours. After washing with 0.1N HCl (30 ml) then brine (30 ml) the organic layer was dried over magnesium sulfate and evaporated to dryness. The residue was dissolved in TFA and stirred for 2 hours then the solvent was removed in vacuo. The residue was purified by HPLC to give the title compound as a white solid (58 mg, 24%). 1H NMR (400 MHz, MeOD) δ ppm 1.75-1.90 (m, 2H) 1.90-2.01 (m, 2H) 2.76-2.90 (m, 2H) 3.14 (d, J=3.28 Hz, 2H) 3.49 (d, J=3.28 Hz, 1H) 3.68-3.77 (m, 1H) 3.89 (t, J=4.29 Hz, 2H) 3.99-4.10 (m, 2H) 5.50 (s, 1H) 6.83-6.95 (m, 1H) 7.39-7.52 (m, 2H) [M+H] calc'd for C18H18F2IN3O4, 506. found, 506. After washing with 0.1N HCl (30 ml) brine (30 ml) the organic layer was dried over magnesium sulfate evaporated to dryness The residue was dissolved in TFA stirred for 2 hours the solvent was removed in vacuo The residue was purified by HPLC

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Example 1 (656 mg, 1.52 mmol), HATU (870 mg, 2.28 mmol) and N-Methylmorpholine (835 μL, 7.59 mmol) were stirred in DMF (7.6 mL) at r.t. for 10 min. O-(2-tert-Butoxy-ethyl)-hydroxylamine (303 mg, 2.28 mmol) was added, and the reaction stirred at 70° C. for 16 h. Purification by prep-HPLC gave 730 mg (73%) of compound 4a as a beige solid. MS (ES) [m+H] calc'd for C21H24F2IN3O4, 548. found 548. Purification

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Example 1 (656 mg, 1.52 mmol), HATU (870 mg, 2.28 mmol) and N-Methylmorpholine (835 μL, 7.59 mmol) were stirred in DMF (7.6 mL) at r.t. for 10 min. O-(2-tert-Butoxy-ethyl)-hydroxylamine (303 mg, 2.28 mmol) was added, and the reaction stirred at 70° C. for 16 h. Purification by prep-HPLC gave 730 mg (73%) of compound 4a as a beige solid. MS (ES) [m+H] calc'd for C21H24F2IN3O4, 548. found 548. Purification

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

Procedure: Phenyl 6-(2-chloro-4-iodophenylamino)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 23; 100 mg, 0.195 mmol, 1 eq) and O-(2-tert-butoxyethyl)hydroxylamine (See, WO05/110410; 260 mg, 1.95 mmol, 10 eq) were mixed in anhydrous THF (3 ml) and heated at 100° C. for 50 minutes in a microwave reactor. The protected product Example 24 was isolated by HPLC. [M+H] calc'd for C19H24ClIN4O5, 551; found, 551. The protected product Example 24 was isolated by HPLC

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

Procedure: Phenyl 6-(2-chloro-4-iodophenylamino)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 23; 100 mg, 0.195 mmol, 1 eq) and O-(2-tert-butoxyethyl)hydroxylamine (See, WO05/110410; 260 mg, 1.95 mmol, 10 eq) were mixed in anhydrous THF (3 ml) and heated at 100° C. for 50 minutes in a microwave reactor. The protected product Example 24 was isolated by HPLC. [M+H] calc'd for C19H24ClIN4O5, 551; found, 551. The protected product Example 24 was isolated by HPLC

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

Procedure: Phenyl 6-(2-chloro-4-iodophenylamino)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 23; 100 mg, 0.195 mmol, 1 eq) and O-(2-tert-butoxyethyl)hydroxylamine (See, WO05/110410; 260 mg, 1.95 mmol, 10 eq) were mixed in anhydrous THF (3 ml) and heated at 100° C. for 50 minutes in a microwave reactor. The protected product Example 24 was isolated by HPLC. [M+H] calc'd for C19H24ClIN4O5, 551. found, 551. The protected product Example 24 was isolated by HPLC

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

Procedure: Phenyl 6-(2-chloro-4-iodophenylamino)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 23; 100 mg, 0.195 mmol, 1 eq) and O-(2-tert-butoxyethyl)hydroxylamine (See, WO05/110410; 260 mg, 1.95 mmol, 10 eq) were mixed in anhydrous THF (3 ml) and heated at 100° C. for 50 minutes in a microwave reactor. The protected product Example 24 was isolated by HPLC. [M+H] calc'd for C19H24ClIN4O5, 551; found, 551. The protected product Example 24 was isolated by HPLC

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

Procedure: Phenyl 6-(2-chloro-4-iodophenylamino)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 23; 100 mg, 0.195 mmol, 1 eq) and O-(2-tert-butoxyethyl)hydroxylamine (See, WO05/110410; 260 mg, 1.95 mmol, 10 eq) were mixed in anhydrous THF (3 ml) and heated at 100° C. for 50 minutes in a microwave reactor. The protected product Example 24 was isolated by HPLC. [M+H] calc'd for C19H24ClIN4O5, 551; found, 551. The protected product Example 24 was isolated by HPLC

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

Procedure: Compound 5F (250 mg, 0.61 mmol), potassium carbonate (209 mg, 1.51 mmol) and 1-chloro-2,4-dinitronbenzene (307 mg, 1.51 mmol) were stirred in DMA at 80° C. for 1.5 h. O-(2-tert-Butoxy-ethyl)-hydroxylamine was added at r.t and the reaction was stirred for 1 h at 80° C. Purification by prep-HPLC gave 43 mg (12%) of the title compound as an off-white solid. MS (ES) [m+H] calc'd for C20H22FIN4O4, 529; found 529. Purification

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

Procedure: Compound 5F (250 mg, 0.61 mmol), potassium carbonate (209 mg, 1.51 mmol) and 1-chloro-2,4-dinitrobenzene (307 mg, 1.51 mmol) were stirred in DMA at 80° C. for 1.5 h. O-(2-tert-Butoxy-ethyl)-hydroxylamine was added at r.t and the reaction was stirred for 1 h at 80° C. Purification by prep-HPLC gave 43 mg (12%) of the title compound as an off-white solid. MS (ES) [m+H] calc'd for C20H22FIN4O4, 529; found 529. Purification