3-methylbutanehydrazide

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

Procedure: To a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (200 mg, 0.91 mmol) in methylene chloride (4.5 ml) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (212 mg, 0.91 mmol) and stirred at room temperature for 1 hour. Upon complete formation of the isothiocyanate, 3-methylbutanehydrazide (159 mg, 1.37 mmol) was added to the mixture and stirred at room temperature for overnight. EDC (315 mg, 1.64 mmol) was then added and the reaction stirred at room temperature for 14 hours. The reaction was concentrated to dryness and taken up in water to form a slurry. The slurry was filtered and washed with water to afford the crude product, which was purified by column chromatography to afford the title compound as off-white solid after drying (217 mg, 69% yield). LC/MS, ESI-MS(+) m/z 344.1, RT 1.45 (Condition R). stirred at room temperature for overnight the reaction stirred at room temperature for 14 hours The reaction was concentrated to dryness to form a slurry The slurry was filtered washed with water to afford the crude product, which was purified by column chromatography

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

Procedure: The crude 18 (0.08 mmol) was dissolved in THF (0.5 mL) and 3-methylbutanehydrazide (12 mg, 0.1 mmol) was added at rt. The reaction mixture was stirred at rt for 1 h to yield the crude N-(3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylphenyl)-2-(3-methylbutanoyl)hydrazinecarboxamide 26, which was used without purification after removal of THF. MS m/z 422.2 (M+1).

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

Procedure: The title compound was prepared as a yellow solid, using 1-pentyl-6-methoxy-isatin obtained in Example 39(A) and 3-methylbutanohydrazide according to the synthetic method E. NMR (CDCl3): δ 0.92 (t, 3H), 1.05 (d, 6H), 1.36 to 1.39 (m, 4H), 1.69-1.75 (m, 2H), 2.30 (m, 2H), 2.72 (d, 1H), 3.72 (t, 2H), 3.89 (s, 3H), 6.44 (d, 1H), 6.64 (dd, 1H), 7.54 and 7.77 (d for isomers, 1H), 12.41 and 13.03 (br s for isomers, 1H).

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

Procedure: 100 mg (0.249 mmol) of the compound from Example 44A and 32 mg (0.273 mmol) of 3-methylbutanehydrazide were reacted according to the General Method 4. Diastereomer separation of the cis/trans isomer mixture according to Method 14C gave 44 mg of the title compound (cis isomer) and 12 mg of the trans isomer. Diastereomer separation of the cis/trans isomer mixture

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

Procedure: The title compound was prepared as a yellow solid, using 1-pentyl-6-methoxy-isatin obtained in Example 39(A) and 3-methylbutanohydrazide according to the synthetic method E. NMR (CDCl3): δ 0.92 (t, 3H), 1.05 (d, 6H), 1.36 to 1.39 (m, 4H), 1.69-1.75 (m, 2H), 2.30 (m, 2H), 2.72 (d, 1H), 3.72 (t, 2H), 3.89 (s, 3H), 6.44 (d, 1H), 6.64 (dd, 1H), 7.54 and 7.77 (d for isomers, 1H), 12.41 and 13.03 (br s for isomers, 1H).

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of tert-butyl(1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (200 mg, 0.410 mmol) and 3-methylbutanehydrazide (47 mg, 0.410 mmol) in p-xylene (1.5 ml) was heated to 150° C. for 15 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure and purified by Biotage silica gel chromatography (gradient 0% to 20% ethyl acetate in n-hexanes) to give the title compound (15 mg, 5%). LCMS (Method D): RT=1.5687 min, M+1=552. 1H NMR (500 MHz, CDCl3): 7.80 (1H, s), 7.36-7.31 (5H, m), 7.30-7.27 (2H, m), 7.23-7.19 (2H, m), 5.57 (2H, s), 2.98 (2H, d), 2.54-2.41 (4H, m), 2.33-2.24 (1H, m), 2.13-2.01 (1H, m), 1.88-1.76 (1H, m), 1.44-1.26 (9H, bs), 1.11 (6H, d). The resulting reaction mixture was concentrated to dryness under reduced pressure purified by Biotage silica gel chromatography (gradient 0% to 20% ethyl acetate in n-hexanes)

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

Procedure: To a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (200 mg, 0.91 mmol) in methylene chloride (4.5 ml) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (212 mg, 0.91 mmol) and stirred at room temperature for 1 hour. Upon complete formation of the isothiocyanate, 3-methylbutanehydrazide (159 mg, 1.37 mmol) was added to the mixture and stirred at room temperature for overnight. EDC (315 mg, 1.64 mmol) was then added and the reaction stirred at room temperature for 14 hours. The reaction was concentrated to dryness and taken up in water to form a slurry. The slurry was filtered and washed with water to afford the crude product, which was purified by column chromatography to afford the title compound as off-white solid after drying (217 mg, 69% yield). LC/MS, ESI-MS(+) m/z 344.1, RT 1.45 (Condition R). stirred at room temperature for overnight the reaction stirred at room temperature for 14 hours The reaction was concentrated to dryness to form a slurry The slurry was filtered washed with water to afford the crude product, which was purified by column chromatography