Potassium methoxy-methyltrifluoroborate

To a mixture of tributyl-methoxymethyl-tin (360 mg, 1.1 mmol) and tetrahydrofuran (3 ml) was added dropwise n-butyllithium (1.5M n-hexane solution, 0.77 ml, 1.2 mmol) at -78°C (external temperature). The reaction mixture was stirred at the same temperature for 30 minutes. The mixture was added dropwise to a mixture of triisopropyl borate (0. 30 ml, 1.3 mmol) and tetrahydrofuran (5 ml) using a cannula at -78°C (external temperature). The reaction mixture was stirred at room temperature for 20 minutes. To the mixture was added potassium hydrogen fluoride (0.51 g, 6.5 mmol) at 0°C (external temperature). Then, water (60 ml) was added dropwise to the reaction mixture. The reaction mixture was raised to room temperature, and the solvent was distilled off under reduced pressure. The resulting residue was washed with diethyl ether. To the residue was added acetone, followed by filtration. After the solvent was distilled off from the filtrate under reduced pressure, the resulting residue was recrystallized using acetone to obtain the title compound (30 mg, 0.20 mmol, 18percent). In a 4 mL vial were combined NiCl2 dimethoxyethane adduct (3.4 mg, 0.015 mmol, 0.12 equivalents) and 4, 4'-di-ter/-butyl-2, 2'-dipyridyl (4.15 mg, 0.015 mmol, 0.12 equivalents) in /V, /V-di methyl acetamide (1.0 mL). Example 1G (60 mg, 0.13 mmol, 1.0 equivalents), To a mixture of (3R)-7-chloro-3-isopropyl-8-(3-methoxypropoxy)-3, 4-dihydro-2H-1-benzoxepin-5-one (2.1 g, 6.4 mmol) and A vessel was charged with 4-[[2-(3-bromophenyl)acetyljaminoj-N-tert-butyl-pyridine-2- carboxamide (Example 54 step 1)(50 mg, 0.13 mmol) PdCl2dppf (3 mg), Example 33 Synthesis of rac-1-((1R, 2R)-2-hydroxy-7-(methoxy methyl)-4, 4-dimethyl-1, 2, 3, 4-tetrahydronaphthalen-1-yl)-3-(5-methyl-2-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)urea A crude product (82 mg) of rac-1-((1R, 2R)-7-bromo-2-hydroxy-4, 4-dimethyl-1, 2, 3, 4-tetrahydronaphthalen-1-yl)-3-(5-methyl-2-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)urea was obtained from the compound (63 mg) obtained in (Example 26) [0198] 7erf~butyl 4-(5-bromo-3-nitropyridin-2-yl)piperazine-l-carboxylate (5.28 g, 13.64 mmol), Methyl (R)-12'-(benzyloxy)-H'-chloro-8'-oxo- , 2', 8', 13b'-tetrahydrospiro[cyclopropane-l, 3'- pyrido[2, l-a]pyrrolo[l, 2-c]phthalazine]-7'-carboxylate (234 mg, 0.51 mmol) was dissolved in isopropanol (10 mL) with 2 drops of acetic acid. The mixture was stirred at reflux for 2.5 hours, then cooled to room temperature to provide isopropyl (R)-12'-(benzyloxy)-H'-chloro-8'-oxo- , 2', 8', 13b'-tetrahydrospiro[cyclopropane-l, 3'-pyrido[2, l-a]pyrrolo[l, 2-c]phthalazine]-7'- carboxylate. MS (m/z) 491.3 [M+H]+. The crude ester was combined with (0993) trifluoro(methoxymethyl)-borane, potassium salt (230 mg, 1.52 mmol), Pd RuPhos G4 (52 mg, 0.061 mmol), RuPhos (42 mg, 0.091 mmol), and cesium carbonate (823 mg, 2.53 mmol) in toluene:water (3: 1, 5 mL) under argon in a sealed vial. The mixture was heated at 110 C for 45 minutes with vigorous stirring, then cooled to room temperature, the aqueous layer was removed, and the organics were concentrated in vacuo and purified by flash column (0994) chromatography (hexanes / ethyl acetate / ethanol / triethylamine) to provide isopropyl (R)-12'- (benzyloxy)-i -(methoxymethyl)-8'-oxo- , 2', 8', 13b'-tetrahydrospiro[cyclopropane-l, 3'- pyrido[2, l-a]pyrrolo[l, 2-c]phthalazine]-7'-carboxylate. MS (m/z) 501.4 [M+H]+.Ethyl 12-(benzyloxy)- l l-chloro-3, 3-dimethyl-8-oxo-2, 3, 8, 13b-tetrahydro-lH-pyrido[2, l-a]pyrrolo[l, 2-c]phthalazine- 7-carboxylate (737 mg, 1.54 mmol) was combined with trifluoro(methoxymethyl)-borane, potassium salt (701 mg, 4.62 mmol), Pd RuPhos G3 (154 mg, 0.185 mmol), RuPhos (129 mg, 0.28 mmol), and cesium carbonate (2.51 g, 7.69 mmol) in toluene:water (3: 1, 10 mL) under argon in a sealed vial. The mixture was heated at 110 C for 90 minutes with vigorous stirring, then cooled to room temperature, the aqueous layer was removed, and the organics were concentrated in vacuo and purified by flash column chromatography (hexanes / ethyl acetate / ethanol / triethylamine) to provide ethyl 12-(benzyloxy)-l l-(methoxymethyl)-3, 3-dimethyl-8- oxo-2, 3, 8, 13b-tetrahydro-lH-pyrido[2, l-a]pyrrolo[l, 2-c]phthalazine-7-carboxylate. 'H NMR (400 MHz, Chloroform-d) delta 8.27 (s, 1H), 7.84 (s, 1H), 7.45 - 7.30 (m, 5H), 7.00 (s, 1H), 6.75 (s, 1H), 5.24 - 5.08 (m, 2H), 4.77 - 4.68 (m, 1H), 4.60 - 4.47 (m, 2H), 4.38 (q, J = 7.1 Hz, 2H), 3.51 (s, OH), 3.50 - 3.44 (m, 3H), 2.47 - 2.32 (m, 1H), 2.25 (t, J = 10.3 Hz, 1H), 1.79 (dd, J = 11.7, 8.9 Hz, 1H), 1.54 - 1.45 (m, 1H), 1.39 (t, J = 7.1 Hz, 3H), 1.32 (s, 3H), 0.67 (s, 3H). MS (m/z) 489.5 [M+H]+.Ethyl (R)-l l-chloro-12-(3-hydroxy-3-methylbut-l-yn-l-yl)-3, 3- dimethyl-8-oxo-2, 3, 8, 13b-tetrahydro-lH-pyrido[2, l-a]pyrrolo[l, 2-c]phthalazine-7-carboxylate (53 mg, 0.093 mmol) was combined with trifluoro(methoxymethyl)-borane, potassium salt (40 mg, 0.26 mmol), Ruphos Pd G2 (5.1 mg, 0.007 mmol), and potassium carbonate (52 mg, 0.37 mmol) in dioxane:water (5: 1, ImL) under argon in a sealed vial. The mixture was stirred at 110 C for 2.5 hours, after which time it was cooled to 50 C and 1M lithium hydroxide (0.19 ml) was added. The mixture was stirred for 90 minutes, then cooled to room temperature, diluted with TFA and acetonitrile, and purified by preparative HPLC to provide (R)-12-(3-hydroxy-3- methylbut- 1 -yn-1 -yl)- 11 -(methoxymethyl)-3, 3-dimethyl-8-oxo-2, 3, 8, 13b-tetrahydro- 1H- pyrido[2, l-a]pyrrolo[l, 2-c]phthalazine-7-carboxylic acid as a TFA salt. XH NMR (400 MHz, Acetonitrile-d3) delta 8.47 (s, 1H), 8.01 (s, 1H), 7.50 (d, J = 1.1 Hz, 1H), 7.29 (s, 1H), 4.88 (d, J = 5.9 Hz, 1H), 4.62 (t, J = 0.8 Hz, 2H), 3.47 (s, 3H), 2.60 - 2.43 (m, 2H), 1.94 - 1.86 (m, 1H), 1.67 - 1.60 (m, 1H), 1.58 (s, 6H), 1.37 (s, 3H), 0.63 (s, 3H). iyF NMR (376 MHz, Acetonitrile- d3) delta -77.28 . MS (m/z) 437.2 [M+H]+.

Molecular Weight:151.97
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:1
Exact Mass:152.0022609
Monoisotopic Mass:152.0022609
Topological Polar Surface Area:9.2
Heavy Atom Count:8
Complexity:55.7
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes