Braf Pathway solvent was removed and the residue was chromatographed

Efluxed stirred for 3 h. The mixture was braf Pathway saturated Cast ttigte NaHCO3 and extracted with ether. The L Solution was dried. The L solvent was removed and the residue was chromatographed on silica gel, eluting with CH2Cl2 ether mixtures g to 8.3 Titile the HBr salt of the compound as a beige solid yield: MS m / z 301.1 one. A benzylamine 1H indazol fifth A mixture of 5 g of 5 nitroindazole, 5.76 g of benzyl bromide and 4.66 g of K2CO3 in 50 ml of DMF was heated at 75 for 4 h. After cooling the reaction mixture in 50 ml of H 2 O was poured. The solid was collected and washed with H 2 O to a mixture of two isomers: 1 Nbenzyl 5 is nitro indazole 1H and N 2 5 nitro benzyl 1Hindazole. The crude mixture was dissolved in 35 ml of acetone St. After filtration, 10.8 ml of H 2 O were slowly added with stirring to the filtrate. After 1 h, 2.9 g of N 1-benzyl-5 nitro indazole 1H collected as yellow crystals. A mixture of a N-benzyl-5-nitro indazol 1H and iron powder in 84 ml MeOH and 33 ml of HOAc was heated for 2 h under reflux. The hei E reaction mixture was filtered and the filtrate was concentrated. The residue was partitioned between EtOAc and NaHCO 3-L Distributed solution. The organic layer was concentrated to 1.3 g of the title compound as orange crystals: mmu HRMS m / z 223.1094, 4 1.6. A benzyl 2,3-dihydro-1H-indole 5-ylamine. An L Solution of 3.11 g and 2.48 ml of 5 nitroindoline benzyl bromide in 35 ml CH 3 CN was heated for 2 h under reflux. The L Solvent was removed under vacuum and the solid was washed with sat Ttigter w Ssriger stirred NaHCO 3. The resulting solid was chromatographed on silica gel and eluted with EtOAc hexane 1:09 to give 2.83 g of 1-benzyl-5-nitro 2,3-dihydro 1H-indole: mp 87 88, MS m / z 255, 0 1 A mixture of 2.54 g of 1-benzyl-5 2.3 nitro dihydro 1H-indole, 2.23 g of iron powder, and 2.14 g of NH 4 Cl in 65 ml EtOH and 10 ml of H 2 O was kr Stirred ftig and under reflux heated for 3 h. The reaction mixture was filtered through Celite and the L Solvents were removed from the filtrate under vacuum.
The residue was extracted with CH2Cl2 and the extracts were passed through Magnesol. The CH2Cl2 was removed under vacuum to give 2.04 g of 57 as a result of L. Preparation of the Michael acceptor groups. 4 Iodobut 2 eno Such as tert-butyl. Tert-butyl-4 A mixture of 4.42 g enoate bromobut 2, 6.0 g ml of NaI, and 40 of acetone was heated for 1 h under reflux. The cooled mixture was partitioned between CH2Cl2 and H2O. The organic layer was washed successively with w ssrigem NaHSO 3, H 2 O, w ssrigem NaHCO 3 and H 2 O, dried and concentrated to give a yellow liquid: 1 H NMR 6.90 ä 8.3, 14.8 Hz, 14.8 Hz, 5.86, 8.3 Hz 3.91, 1.48. 4, but 2 eno Such as Ridaforolimus tert-butyl. To a stirred L Solution of 2.08 g 4 2 iodobut eno Such as tert-butyl ester in 15.5 ml of THF was added at 0 1.29 ml pyrrolidine. The L Solution was adjusted to 25 ext rmt, Stirred for 15 min, and between toluene and m Ssriger KHCO3. The organic layer was washed with water, dried and concentrated to 1.50 g of amber oil: MS m / z 212.0 first , 4 but two hydrochloride eno That. An L Solution of 1.49 g of 4, but 2 eno As tert-butyl ester was in 14.1 ml of 1 N HCl for 15 min under reflux heated, diluted with toluene and concentrated to yield a yellow solid: MS m / z 155.8 1, 1H NMR ä 12.7, 11.4, 6.83 6.8, 14.4 Hz, 14 , 4 6.18 Hz, 3.95 Hz, 6.8, 3, 05, 1.92. , 4 but two hydrochloride eno That.