2,8,9-tris(2-methylpropyl)-2,5,8,9-tetraza-1-phosphabicyclo[3.3.3]undecane

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:80.01; pressure:0.00; stir:; Reaction stirred at 80 degrees Celcius for 24 hours, then cooled to room temperature and opened to air before adding the internal standard.

Procedure: Vials containing pre-plated ligand were added to a 96-well reaction block (Paradox Standard 96-Position Parallel Synthesis block) in positions C4-9 ,D4-9, E4-9, and F4-9 and equipped with magnetic stirbars in a moisture and oxygen-free glovebox. The remainder of the plate positions were filled with empty vials to ensure a proper seal with the lid could be obtained later.(cod)Pd(CH2TMS)2 (0.13 mg, 0.33 umol, 0.10 equiv) and nBu3N (4.10 uL, 16.7 umol, 5.00 equiv) were added as a solution in MeCN (150 uL) via micropipettor to each of the 24 wells. Then hydroxamic ether 3 (1.49 mg, 3.34 umol, 1.00 equiv) was added as a solution in MeCN (150 uL) via micropipettor. The reaction block was then covered with a Teflon sheet, rubber mats, and its aluminum top cover which were all affixed to the bottom plate via 9 tightly tightened screws. The plate was placed in a pre-heated temperature-controlled metal block on a stir plate in the glovebox and stirred at 80C for 24 h. The reaction block was then removed from the glovebox, cooled to rt, and opened to air. A solution of trimethoxybenzene (0.19 mg, 1.11 umol, 0.33 equiv) in MeCN (400 uL) was added as an internal standard to each vial of the 24 vials via micropipettor. After centrifugation, a 300 uL aliquot of each crude reaction was transferred to an analysis collection plate via micropipettor. The plate was sealed with aluminum sealing tape, and centrifuged for 15 min. The reactions were analyzed and quantified by LC-MS and integrated against the trimethoxybenzene internal standard to determine the yield of product formed in each reaction and the amount of unreacted starting material remaining. Yields determined by LC-MS were also validated by quantification of the 1H NMR spectrum of the indicated entries. cool to room temperature and opened to air addition of internal standard 300 microliter aliquot transferred to analysis collection plate via micropipettor, and sealed with aluminium sealing tape. centrifuged

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a nitrogen purged vessel was added Pd2 dba3 (0.0386 g, 0.0422 mmol), NaOtBu (0.169 g, 1.76 mmol), 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (0.0600 mL, 0.169 mmol), 2-chloro-5-ethylpyridine (0.100 g, 0.703 mmol) and (S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1-(piperidin-4-yl)pyrrolidin-2-one (Preparation E; 0.300 g, 0.844 mmol). Toluene (4 mL, purged with nitrogen) was added and the reaction was heated at 100° C. overnight. The mixture was cooled to ambient temperature, diluted with EtOAc, and washed with water. The organics were dried over Na2SO4, concentrated and purified on silica eluting with 100% EtOAc to give 1-(1-(5-ethylpyridin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (0.177 g, 54% yield) as white solids. Mass spectrum (apci) m/z=461.3 (M+H). The mixture was cooled to ambient temperature washed with water The organics were dried over Na2SO4 concentrated purified on silica eluting with 100% EtOAc

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

Procedure: 8.53 g of 2,2-difluoroethanol are added to a solution of 17.31 g of methyl 5-fluoro-2-nitrobenzoate, 9.64 g of NEt3 and 32.71 g of 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane in 250 ml of anhydrous THF. The mixture is stirred at AT for 30 min. The solvent is evaporated under reduced pressure. Water is added and extraction is carried out with AcOEt. The extract is washed with a 1N aqueous HCl solution, with water and then with a saturated NaCl solution. It is dried over MgSO4 and filtered, and the solvent is evaporated under reduced pressure to give 21 g of the expected product. The solvent is evaporated under reduced pressure Water is added extraction The extract is washed with a 1N aqueous HCl solution, with water It is dried over MgSO4 filtered the solvent is evaporated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Potassium t-butoxide (3.37 g, 30 mmol) and Pd2(dba)3 (0.55 g, 0.6 mmol) were added to a 100 mL round bottom flask. Toluene (50 mL) and triisobutylphosphatrane (0.82 g, 2.4 mmol) were then added, followed by 3-aminopyridine (1.88 g, 20 mmol) and 1,5-dichloroanthraquinone (2.77 g, 10 mmol). The system was flushed with argon and heated to reflux overnight. The mixture was cooled and the solvent was removed under vacuum. The residue was dissolved in dichloromethane and water. The organic layer was washed with water twice and dried over anhydrous magnesium sulfate. After the solvent was removed, the residue was purified by flash chromatography to provide Compound 27 as a red solid. The structure of Compound 27 is given below: The system was flushed with argon heated to reflux overnight The mixture was cooled the solvent was removed under vacuum The residue was dissolved in dichloromethane The organic layer was washed with water twice dried over anhydrous magnesium sulfate After the solvent was removed the residue was purified by flash chromatography

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (±)-tert-Butyl 4-((1-(5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (75 mg, 0.113 mmol), sodium tert-butoxide (16.3 mg, 0.17 mmol), and palladium(II)acetate (1.02 mg, 4.53 μmol) were combined in toluene (2 mL) and treated with 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (3.1 mg, 9.05 μmol) and morpholine (0.012 mL, 0.136 mmol) in a microwave tube and sealed. After flushing the mixture with nitrogen, the mixture was heated at 100° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated, dissolved in ethyl acetate, washed with water and brine, concentrated, and purified by flash chromatography on silica gel (30% EtOAc/Hex) to afford 44 mg (58%) as an oil. LC/MS (HPLC method 2): tR=3.185 min, 669.25(MH)+. sealed After flushing the mixture with nitrogen After cooling to room temperature the reaction mixture was concentrated dissolved in ethyl acetate washed with water and brine concentrated purified by flash chromatography on silica gel (30% EtOAc/Hex) to afford 44 mg (58%) as an oil