4-CHLORO (1H)INDAZOLE

l-(Tetrahydro-2H-pyran-2-yl)-4-(4, 4, 5, 5-tetramethyl- 1, 3, 2- dioxaborolan-2-yl)-lH-indazole 62 (Route A)[00252] Step A: Preparation of 4-chloro-lH-indazole: To a 250 ml flask with stirbar was added 2-methyl-3-chloroaniline (8.4 ml, 9.95 g, 70.6 mmol), potassium acetate (8.3 g, 84.7 mmol) and chloroform (120 ml). This mixture was cooled to 0 To a 250 ml flask with stir bar was added 2-methyl-3-chloroaniline (8.4 ml, 9.95 g, 70.6 mmol), potassium acetate (8.3 g, 84.7 mmol) and chloroform (120 ml). This mixture was cooled to 0 Step A: Preparation of 4-chloro-lH-indazole: To a 250 ml flask with stir bar was added 2-methyl-3-chloroaniline (8.4 ml, 9.95 g, 70.6 mmol), potassium acetate (8.3 g, 84.7 mmol) and chloroform (120 ml). This mixture was cooled to 0 °C with stirring. To the cooled mixture was added acetic anhydride (20.0 ml, 212 mmol) drop wise over 2 minutes. The reaction mixture was warmed to 25 °C and stirred for 1 hour. At this point, the reaction was heated to 60 °C. Isoamyl nitrite (18.9 ml, 141 mmol) was added and the reaction was stirred overnight at 60 °C. Once complete, water (75 ml) and THF (150 ml) were added and the reaction was cooled to 0 °C. LiOH (20.7 g, 494 mmol) was added and the reaction was stirred at 0 °C for 3 hours. Water (200 ml) was added and the product was extracted with EtOAc (300 ml, 100 ml). The organic layers were combined, dried with MgS0Example 4 l-(Tetrahydro-2H-pyran-2-yl)-4-(4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl)-lH-indazole 41 (Route A) [0194] Step A: Preparation of 4-chloro- lH-indazole: To a 250 ml flask with stir bar was added 2-methyl-3-chloroaniline (8.4 ml, 9.95 g, 70.6 mmol), potassium acetate (8.3 g, 84.7 mmol) and chloroform (120 ml). This mixture was cooled to 0 Acetic anhydride (69 kg, 675.9 mcI) was added to a stirred slurry of 3-chloro-2-methylaniline (30 kg, 211.9 mcI), potassium acetate (25 kg, 254.7 mcI) and methyltetrahydrofuran (302 L) at 25°C and then stirred for 2 h. Isopentyl nitrite (44.5 kg, 379.9 mcI) was added to the slurry and thecontents were heated to 73 °C for 18 h. The slurry was cooled to 20 °C, then water (90 L) was added, and the reaction was cooled to 5 °C. An aqueous solution of NaOH (105 L of a 32percentw/w) was added, the solution was heated to 40 °C and stirred for 2 h. The lower aqueous phase was removed and the organic layer washed with water (150 L) and then brine (18 kg in 90 L water). The organic layer was concentrated to 90 L by atmospheric distillation and a solvent exchange to n20 heptane performed by atmospheric distillation to a final volume of 240 L. The slurry was cooled to 7°C, stirred for 2 h and solid isolated by filtration. The cake was washed with heptane (2 x 60 L) and dried under vacuum to give the title compound (23.6 kg, 73percent).1H NMR (400MHz, MeOD-d4) = 8.08 (5, 1H), 7.48 (d, J=8.6 Hz, 1H), 7.33 (dd, J=7.5, 8.4 Hz, 1H), 7.14 (d, J=7.3 Hz, 1H)HPLC r.t — 1.94 mm.Acetic anhydride (69 kg, 675.9 mol) was added to a stirred slurry of 3-chloro-2-methylaniline (30 kg, 211.9 mol), potassium acetate (25 kg, 254.7 mol) and methyltetra hyd rof ura n (302 L) at 25°C and then stirred for 2 h. Isopentyl nitrite (44.5 kg, 379.9 mol) was added to the slurry and the contents were heated to 73 °C for 18 h. The slurry was cooled to 20 °C, then water (90 L) was added, and the reaction was cooled to 5 °C. An aqueous solution of NaOH (105 L of a 32percentw/w) was added, the solution was heated to 40 °C and stirred for 2 h. The lower aqueous phase was removed and the organic layer washed with water (150 L) and then brine (18 kg in 90 L water). The organic layer was concentrated to 90 L by atmospheric distillation and a solvent exchange to n-heptane performed by atmospheric distillation to a final volume of 240 L. The slurry was cooled to 7 °C, stirred for 2 h and solid isolated by filtration. The cake was washed with heptane (2 x 60 L) and dried under vacuum to give the title compound (23.6 kg, 73percent). (0447) *H NMR (400MHz, MeOD-dA solution of 2-chloro-6-fluorobenzaldehyde (10 g, 63.07 mmol, 1.00 equiv) and hydrazine hydrate (80percent, 20 g, 399.52 mmol, 6.30 equiv) in ethylene glycol dimethyl ether (20 mL, 206.63mmol, 3.30 equiv) was heated to reflux overnight. The reaction was quenched by water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified on a silica gel column eluting with ethyl acetate/petroleum ether (1:10) to give 6 g (62percent) of the title compound as a yellow solid. LC-MS (ES, m/z): 153 [M+H].Step 2: Synthesis of 4-chloro-3-iodo-1H-indazoleExample 174[0438] (5)-N-(benzo[ ][l, 3]dioxol-5-yl)-2-(2-(4-chloro-3-(2-hydroxyethyl)-lH-indazol- 1 -yl)acetamido)-N-methyl-3 -phenylpropanamideExample 174A. Preparation of 4-chloro-lH-indazole[0439] Hydrazine hydrate (85percent, 50 mL) was added over a period of 10 minutes to a solution of 2-chloro-6-fluorobenzaldehyde (5.0 g, 31.6 mmol, 1.0 eq) in DME (50 mL). The reaction mixture was re fluxed overnight and concentrated in vacuum to approximately 50 mL. Water (50 mL) was added to the mixture. The resulting solid precipitate was collected by filtration and dried to give 4-chloro-lH-indazole (2.5 g, 16.4 mmol, yield: 52percent), LC/MS: m/z M

Molecular Weight:152.58
XLogP3:2.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:1
Exact Mass:152.0141259
Monoisotopic Mass:152.0141259
Topological Polar Surface Area:28.7
Heavy Atom Count:10
Complexity:129
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes