Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[N:21][C:22]=1[F:23].[Br:30][C:31]1[CH:32]=[CH:33][C:34]([O:50][CH2:51][O:52][CH3:53])=[C:35]([C:37](=[N:43][S@:44]([C:46]([CH3:49])([CH3:48])[CH3:47])=[O:45])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:36]=1.C(O)(=O)C>C1COCC1>[Br:30][C:31]1[CH:32]=[CH:33][C:34]([O:50][CH2:51][O:52][CH3:53])=[C:35]([C@@:37]([C:18]2[CH:19]=[C:20]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[N:21]=[C:22]([F:23])[C:17]=2[Cl:16])([NH:43][S@:44]([C:46]([CH3:49])([CH3:47])[CH3:48])=[O:45])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:36]=1
Reactant: CCOC(=O)C(=N[S@@](=O)C(C)(C)C)c1cc(Br)ccc1OCOC
Reactant: Fc1nc(N2CCOCC2)ccc1Cl
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)[C@](N[S@@](=O)C(C)(C)C)(c1cc(Br)ccc1OCOC)c1cc(N2CCOCC2)nc(F)c1Cl
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 67.1 %

Procedure:
A suspension of cesium carbonate (41.1 g, 126 mmol), 2,6-difluoropyridine (11.01 mL, 121 mmol) and morpholine (10.00 mL, 115 mmol) in ACN (100 mL) was heated to 70° C. for 12 hours in a sealed vessel. The reaction mixture was cooled to RT and filtered. The obtained filtrate was concentrated under reduced pressure. The crude material was purified by silica gel chromatography (5-25% EtOAc/hexanes) to provide 13.7 g, of 4-(6-fluoropyridin-2-yl)morpholine. Step 2: Chlorosuccinimide (10.29 g, 77 mmol) was added to a solution of 4-(6-fluoropyridin-2-yl)morpholine (11.7 g, 64.2 mmol) in ACN (15 mL). The reaction mixture was heated to 70° C. for 30 min. Water and DCM were added. The organic phase was separated, washed with aqueous NaHCO3, brine and subsequently dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (5-20% EtOAc/hexanes) to afford 3.11 g of 4-(5-chloro-6-fluoropyridin-2-yl)morpholine. Step 3: A solution of 2,2,6,6-tetramethylpiperidine (1.897 mL, 11.24 mmol) in THF (45 mL) was cooled to −78° C. and treated with n-BuLi (1.6M in hexanes) (6.77 mL, 10.83 mmol) under nitrogen atmosphere. The solution was warmed to 0° C. and stirred at that temperature for 25 minutes. The solution was cooled back down to −78° C. and treated with a solution of 4-(5-chloro-6-fluoropyridin-2-yl)morpholine (2.165 g, 9.99 mmol) in THF (11.25 mL) under nitrogen atmosphere. The solution was allowed to stir at that temperature for 40 minutes and then added drop wise via cannula to a solution of (S)-ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-(tert-butylsulfinylimino)acetate (3.5 g, 8.33 mmol) in THF (11.25 mL) also cooled to −78° C. under nitrogen atmosphere. The reaction mixture was allowed to stir at −78° C. for additional 2 hours and then quenched with acetic acid (0.715 mL, 12.49 mmol). The reaction mixture was allowed to warm to RT overnight. The solvent was removed under reduced pressure and the crude material was purified by silica gel chromatography (10-60% EtOAc/hexane) to afford 3.56 g (S)-ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-(3-chloro-2-fluoro-6-morpholinopyridin-4-yl)-2-((S)-1,1-dimethylethylsulfinamido)acetate. Step 4: A solution of (S)-ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-(3-chloro-2-fluoro-6-morpholinopyridin-4-yl)-2-((S)-1,1-dimethylethylsulfinamido)acetate (3.56 g, 5.59 mmol) in THF (60 mL) was cooled to 0° C. and treated drop wise with DIBAL (1M in THF) (22.36 mL, 22.36 mmol) under nitrogen atmosphere. After 1 h additional 10 mL DIBAL solution were added at RT. After 12 h at RT additional 10 mL DIBAL solution were added. After 30 min aqueous saturated solution of potassium sodium tartrate was added, followed by EtOAc. The reaction mixture was allowed to stir vigorously for 1 h. The organic phase was separated, washed with aqueous saturated solution of potassium sodium tartrate and dried over MgSO4. The solvent was removed under reduced pressure and the crude material was purified by silica gel chromatography (20-100% EtOAc/hexane) to provide 1.90 g of (S)—N—((S)-1-(5-bromo-2-(methoxymethoxy)phenyl)-1-(3-chloro-2-fluoro-6-morpholinopyridin-4-yl)-2-hydroxyethyl)-2-methylpropane-2-sulfinamide. Step 5: Lithium hydroxide hydrate (0.402 g, 9.58 mmol) was added to a solution of (S)—N—((S)-1-(5-bromo-2-(methoxymethoxy)phenyl)-1-(3-chloro-2-fluoro-6-morpholinopyridin-4-yl)-2-hydroxyethyl)-2-methylpropane-2-sulfinamide (1.9 g, 3.19 mmol) in THF (25 mL) at RT, followed by bromoacetonitrile (0.445 mL, 6.39 mmol). The reaction mixture was allowed to stir at RT for 12 h. The reaction mixture was treated with aqueous saturated ammonium chloride, and the mixture was extracted with EtOAc. The organic phase was washed with water, brine, dried over MgSO4 and then concentrated under reduced pressure. The remaining residue was purified by silica gel chromatography (50-100% EtOAc/hexanes) to afford 1.51 g of (S)—N—((S)-1-(5-bromo-2-(methoxymethoxy)phenyl)-1-(3-chloro-2-fluoro-6-morpholinopyridin-4-yl)-2-(cyanomethoxy)ethyl)-2-methylpropane-2-sulfinamide. Step 6-7: A solution of hydrogen chloride (5-6N in iPrOH; 1.025 mL, 5.12 mmol) was added to a solution of (S)—N—((S)-1-(5-bromo-2-(methoxymethoxy)phenyl)-1-(3-chloro-2-fluoro-6-morpholinopyridin-4-yl)-2-(cyanomethoxy)ethyl)-2-methylpropane-2-sulfinamide (1083 mg, 1.708 mmol) in THF (4 mL) under nitrogen atmosphere. The reaction mixture was stirred for 10 min at RT. The solvent was removed under reduced pressure and the residue was dissolved in DCE (2 mL). A solution of AlMe3 (2M in toluene; 2.56 mL, 5.12 mmol) was added drop wise and the reaction mixture was allowed to stir at 70 C for 3 h. The reaction mixture was cooled to RT and a solution of aqueous saturated solution of potassium sodium tartrate was added, followed by EtOAc. The reaction mixture was allowed to stir vigorously for 1 h. The organic phase was separated, washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (100% EtOAc) to afford 390 mg of (S)-2-(5-amino-3-(3-chloro-2-fluoro-6-morpholinopyridin-4-yl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-bromophenol. Step 8: A sealable vial was charged with (S)-2-(5-amino-3-(3-chloro-2-fluoro-6-morpholinopyridin-4-yl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-bromophenol (234 mg, 0.482 mmol), cesium carbonate (471 mg, 1.445 mmol) and copper chloride (9.54 mg, 0.096 mmol The vial was evacuated and back-filled with nitrogen. NMP (1.5 mL) was added and the vial was evacuated and backfilled with nitrogen. 2,2,6,6-Tetramethyl-3,5-heptanedione (0.080 mL, 0.385 mmol) was added and the reaction mixture was heated to 120° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with EtAOc and filtered through a pad of silica gel. The solvent was removed under reduced pressure and the residue was purified by preparative reversed-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 100% over 20 min to obtain 68 mg of (S)-7-bromo-1-fluoro-3-morpholino-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine.TFA. Step 9: A sealable vial was charged with (S)-7-bromo-1-fluoro-3-morpholino-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (50 mg, 0.111 mmol), 2-fluoropyridin-3-ylboronic acid (31.4 mg, 0.223 mmol), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (7.88 mg, 0.011 mmol) and potassium phosphate (0.028 mL, 0.334 mmol). The vial was evacuated and backfilled with nitrogen (procedure was repeated twice). Dioxane (1.3 mL) and water (0.433 mL) were added and the reaction mixture was purged for 1 min with nitrogen. The vial was placed in a preheated oil bath (100° C.) for start 2.5 h. The reaction mixture was cooled to RT and the solvent was removed under reduced pressure. The residue was purified by preparative reversed-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 100% over 20 min to obtain 39 mg of (S)-1-fluoro-7-(2-fluoropyridin-3-yl)-3-morpholino-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine 2,2,2-trifluoroacetate as a light-yellow powder. MS m/z=466.0 [M+H]+. Calculated for C24H21F2N5O3.C2HF3O2: 579.48 (TFA salt).