3-bromo-5-chlorobenzaldehyde

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

Procedure: 3-bromo-5-chlorobenzaldehyde (502 mg, 2.3 mmol), ethyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamido)propanoate (794 mg, 2.3 mmol), Pd(dppf)Cl2 (84 mg, 0.1 mmol), and K2CO3 (632 mg, 4.6 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL) and the resulting mixture was heated to 70° C. After 3 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound. washed with water and brine dried (Na2SO4) concentrated purified via column chromatography

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

Procedure: The title compound was prepared from methyl 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoate hydrochloride salt (50 mg, 0.153 mmol; Example 1, Step 2) and 3-bromo-5-chlorobenzaldehyde (43.7 mg, 0.199 mmol) following essentially the same procedure described in Step 1 of Example 7-6. The title compound was obtained as a yellow oil (76 mg) that was used without any further purification.

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

Procedure: The title compound was prepared from methyl 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoate hydrochloride salt (50 mg, 0.153 mmol; Example 1, Step 2) and 3-bromo-5-chlorobenzaldehyde (43.7 mg, 0.199 mmol) following essentially the same procedure described in Step 1 of Example 7-6. The title compound was obtained as a yellow oil (76 mg) that was used without any further purification.

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1-chloro-3,5-dibromobenzene (Esprit) (20 g, 0.074 mole) in anhydrous ethyl ether (150 mL) in a flame dried flask under N2 and at -78° C. was added 1.6 m butyl lithium in hexane dropwise, keeping the temperature below -78° C., then warmed to -30° C. Anhydrous DMF (6.8 g, 0.092 mole) was added dropwise, keeping the temperature below -20° C. After the addition was complete, the reaction was slowly warmed to 0° C., then stirred overnight at room temperature. The reaction mixture was poured slowly into chilled 10% aqueous HCl (160 mL). After stirring for 15 minutes, the ether was separated, washed with H2O (4×), dried over MgSO4 and removed under vacuum to yield 3-bromo-5-chlorobenzaldehyde (13 g) as a white solid. MS and NMR were consistent with the desired structure. the temperature below -78° C. the temperature below -20° C After the addition the reaction was slowly warmed to 0° C. The reaction mixture was poured slowly After stirring for 15 minutes the ether was separated washed with H2O (4×) dried over MgSO4 removed under vacuum

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

Procedure: To a 4:1 (v/v) MeOH:THF solution (0.06 M) of 3-bromo-5-chlorobenzaldehyde (1 eq.) and cyclopropylamine (1.1 eq.) was added sodium cyanoborohydride (1.5 eq.) portionwise followed by neat acetic acid (3 eq.). The resulting mixture was stirred at RT for 20 h. The volatiles were then removed in vacuo. The resulting residue was taken up in ether and sat. aq. NH4Cl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were then washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded the crude title compound as a yellow oil. The volatiles were then removed in vacuo The aqueous layer was separated back-extracted with ether The combined organic extracts were then washed with brine dried over MgSO4 filtered

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

Procedure: Alkylation of 5-bromo-3-chlorobenzaldehyde with acetonitrile following the method used in Example 115 gave 3-(5-bromo-3-chlorophenyl)-3-hydroxypropanenitrile as a clear oil. Yield (3.21 g, 54%): 1H NMR (400 MHz, DMSO-d6) δ 7.62 (t, J=2.0 Hz, 1H), 7.58-7.57 (m, 1H), 7.49-4.48 (m, 1H), 6.18 (d, J=4.8 Hz, 1H), 4.93-4.90 (m, 1H), 2.93 (ABd, J=16.8, 5.2 Hz, 1H), 2.86 (ABd, J=17.2, 6.8 Hz, 1H).

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

Procedure: Alkylation of 5-bromo-3-chlorobenzaldehyde with acetonitrile following the method used in Example 115 gave 3-(5-bromo-3-chlorophenyl)-3-hydroxypropanenitrile as a clear oil. Yield (3.21 g, 54%): 1H NMR (400 MHz, DMSO-d6) δ 7.62 (t, J=2.0 Hz, 1H), 7.58-7.57 (m, 1H), 7.49-4.48 (m, 1H), 6.18 (d, J=4.8 Hz, 1H), 4.93-4.90 (m, 1H), 2.93 (ABd, J=16.8, 5.2 Hz, 1H), 2.86 (ABd, J=17.2, 6.8 Hz, 1H).

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

Procedure: Alkylation of 5-bromo-3-chlorobenzaldehyde with acetonitrile following the method used in Example 115 gave 3-(5-bromo-3-chlorophenyl)-3-hydroxypropanenitrile as a clear oil. Yield (3.21 g, 54%): 1H NMR (400 MHz, DMSO-d6) δ 7.62 (t, J=2.0 Hz, 1H), 7.58-7.57 (m, 1H), 7.49-4.48 (m, 1H), 6.18 (d, J=4.8 Hz, 1H), 4.93-4.90 (m, 1H), 2.93 (ABd, J=16.8, 5.2 Hz, 1H), 2.86 (ABd, J=17.2, 6.8 Hz, 1H).

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

Procedure: PdCl2(dppf)(37 mg, 0.046 mmol), potassium phosphate (1.93 g, 9.11 mmol) and triethylborane (1M in hexane, 0.45 g, 4.56 mmol) were added to a solution of 3-bromo-5-chloro-benzaldehyde (1.0 g, 4.56 mmol) in THF (20 mL) at ambient temperature and the mixture was refluxed for 12 h. The reaction mixture was brought to ambient temperature, diluted with EtOAc and washed with water. The organic layer was dried (Na2SO4), filtered, concentrated and the residue was purified by column chromatography on silica (100-200 mesh) eluting with 2% EtOAc in petroleum ether to afford the title compound (330 mg, 41%) as a pale yellow liquid: 1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 7.75 (d, J=1.6 Hz 1H), 7.73 (s, 1H), 7.65 (s, 1H), 2.74-2.68 (m, 2H), 1.23 (t, J=7.6 Hz, 3H); ESIMS m/z 168.0 ([M]+); IR (thin film) 3071, 1699, 692 cm−1. the mixture was refluxed for 12 h was brought to ambient temperature washed with water The organic layer was dried (Na2SO4) filtered concentrated the residue was purified by column chromatography on silica (100-200 mesh) eluting with 2% EtOAc in petroleum ether

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

Procedure: 3-bromo-5-chlorobenzaldehyde (502 mg, 2.3 mmol), ethyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamido)propanoate (794 mg, 2.3 mmol), Pd(dppf)Cl2 (84 mg, 0.1 mmol), and K2CO3 (632 mg, 4.6 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL) and the resulting mixture was heated to 70° C. After 3 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound. washed with water and brine dried (Na2SO4) concentrated purified via column chromatography

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

Procedure: The title compound was prepared from methyl 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoate hydrochloride salt (50 mg, 0.153 mmol; Example 1, Step 2) and 3-bromo-5-chlorobenzaldehyde (43.7 mg, 0.199 mmol) following essentially the same procedure described in Step 1 of Example 7-6. The title compound was obtained as a yellow oil (76 mg) that was used without any further purification.

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

Procedure: The title compound was prepared from methyl 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoate hydrochloride salt (50 mg, 0.153 mmol; Example 1, Step 2) and 3-bromo-5-chlorobenzaldehyde (43.7 mg, 0.199 mmol) following essentially the same procedure described in Step 1 of Example 7-6. The title compound was obtained as a yellow oil (76 mg) that was used without any further purification.