Reaction SMILES: O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[NH2:22][C:23]1[CH2:44][O:43][CH2:42][C@:25]2([C:38]3[CH:37]=[C:36](Br)[CH:35]=[C:34]([F:40])[C:33]=3[O:32][C:31]3[C:26]2=[CH:27][C:28]([OH:41])=[CH:29][CH:30]=3)[N:24]=1.C[Si](C)(C)[C:47]#[C:48][C:49]1([CH3:53])[CH2:52][O:51][CH2:50]1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[NH2:22][C:23]1[CH2:44][O:43][CH2:42][C@:25]2([C:38]3[CH:37]=[C:36]([C:47]#[C:48][C:49]4([CH3:53])[CH2:52][O:51][CH2:50]4)[CH:35]=[C:34]([F:40])[C:33]=3[O:32][C:31]3[C:26]2=[CH:27][C:28]([OH:41])=[CH:29][CH:30]=3)[N:24]=1
Reactant: NC1=N[C@@]2(COC1)c1cc(O)ccc1Oc1c(F)cc(Br)cc12
Reactant: CC1(C#C[Si](C)(C)C)COC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC1(C#Cc2cc(F)c3c(c2)[C@]2(COCC(N)=N2)c2cc(O)ccc2O3)COC1
Temperature: 80 °C

Procedure:
In a 1-L flask, the (S)-2′-bromo-4′-fluoro-7′-methoxyspiro[morpholine-3,9′-xanthen]-5-one (3.16 g, 8.02 mmol) was suspended in toluene (75 mL). Lawesson's reagent (1.864 g, 4.61 mmol) was added. An air-cooled condenser was affixed, and the mixture was heated in a 90° C. oil bath for 2 h. The mixture was cooled and concentrated to afford crude (S)-2′-bromo-4′-fluoro-7′-methoxyspiro[morpholine-3,9′-xanthene]-5-thione which was used in the next step without further purification. Step 2: In a 350-mL resealable vessel, the (S)-2′-bromo-4′-fluoro-7′-methoxyspiro[morpholine-3,9′-xanthene]-5-thione (3.0 g, 7.31 mmol) was dissolved in a dioxane solution of ammonia (0.5 M, 175 mL, 88 mmol). Mercury (II) chloride (2.98 g, 10.97 mmol) was added, and the vessel was sealed and heated in a 55° C. oil bath overnight. The reaction was cooled and then filtered through Celite, rinsing with 10% MeOH-DCM. The filtrate was concentrated, and the residue was transferred to a resealable vessel with 50 mL of dioxane. A solution of ammonia in dioxane (0.5 M, 100 mL, 50 mmol) was added, followed by mercury (II) chloride (2.0 g, 7.36 mmol). The vessel was sealed and heated in a 60° C. oil bath for 14 h. The mixture was cooled and filtered through Celite, rinsing with 10% MeOH-DCM. The filtrate was concentrated, and the residue was purified through silica gel (300 mL) using 7.5% MeOH-DCM to afford 1.33 g of (S)-2′-bromo-4′-fluoro-7′-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine Step 3: In a 50-mL flask, the (S)-2′-bromo-4′-fluoro-7′-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (0.340 g, 0.864 mmol) was taken up in DCM (15 mL). The suspension was cooled to 0° C., and a DCM solution of boron tribromide (2.59 mL, 2.59 mmol) was added. After 1 h, the reaction was quenched with 18 mL of saturated aqueous NH4Cl and 2 mL of aqueous NH4OH. The mixture was diluted further with water (10 mL), and the aqueous phase was extracted with 5% MeOH-DCM (3×50 mL). The organics were combined, washed with dilute brine (15 mL), dried over sodium sulfate and concentrated to afford 241 mg of (S)-5-amino-2′-bromo-4′-fluoro-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-7′-ol which was used in the next step without further purification. Step 4: A microwave vial was charged with tetrabutylammonium fluoride trihydrate (0.301 g, 0.952 mmol), Pd(PPh3)4 (0.073 g, 0.063 mmol), and copper(I) iodide (12.3 mg, 0.065 mmol). The (S)-5-amino-2′-bromo-4′-fluoro-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-7′-ol (0.241 g, 0.64 mmol) was added as a solution in THF (2.7 mL). Argon was blown through the vessel, and trimethyl((3-methyloxetan-3-yl)ethynyl)silane (0.161 g, 0.951 mmol) was added. The vessel was sealed and heated in an 80° C. oil bath for 1.5 h. The mixture was cooled and concentrated, diluted with water (15 mL), and the aqueous phase was extracted with 5% MeOH-DCM (3×25 mL). The organics were combined, washed with dilute brine (7 mL), dried over sodium sulfate and concentrated to afford (S)-5-amino-4′-fluoro-2′-((3-methyloxetan-3-yl)ethynyl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-7′-ol, which was used in the next step without further purification. Step 5: In a 50-mL flask, the crude (S)-5-amino-4′-fluoro-2′-((3-methyloxetan-3-yl)ethynyl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-7′-ol (0.251 g, 0.636 mmol) was dissolved in THF (12 mL). Boc2O (0.303 g, 1.39 mmol) and triethylamine (0.204 mL, 1.47 mmol) were added. After 14 h, the reaction mixture was concentrated to afford (S)-tert-butyl 4′-fluoro-7′-hydroxy-2′-((3-methyloxetan-3-yl)ethynyl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthene]-5-ylcarbamate which was used in the next step without further purification. Step 6: In a 50-mL flask, the crude (S)-tert-butyl 4′-fluoro-7′-hydroxy-2′-((3-methyloxetan-3-yl)ethynyl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthene]-5-ylcarbamate (0.315 g, 0.637 mmol) was dissolved in DCM (12 mL). The solution was cooled to 0° C., and triethylamine (0.175 mL, 1.26 mmol) and 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (0.400 g, 1.12 mmol) were added. After 2.5 h, the reaction was quenched with dilute aqueous NaHCO3 (15 mL) and the aqueous phase was extracted with 3% MeOH-DCM (3×20 mL). The organics were combined, dried over sodium sulfate and concentrated. The residue was purified through silica gel (60 mL) using 25% ethyl acetate in hexane to afford 230 mg of (S)-5-(tert-butoxycarbonylamino)-4′-fluoro-2′-((3-methyloxetan-3-yl)ethynyl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthene]-7-yl trifluoromethanesulfonate Step 7: In a microwave vial, 2-fluoropyridin-3-ylboronic acid (0.065 g, 0.459 mmol), Pd(PPh3)4 (0.042 g, 0.037 mmol) and (S)-5-(tert-butoxycarbonylamino)-4′-fluoro-2′-((3-methyloxetan-3-yl)ethynyl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthene]-7′-yl trifluoromethanesulfonate (0.230 g, 0.367 mmol) were taken up in DMF (3 mL). Aqueous sodium carbonate (1.0 M, 1.10 mL, 1.10 mmol) was added. Argon was blown through the vessel which was then sealed and heated in an 85° C. oil bath for 4 h. The reaction was cooled and concentrated, and the residue was diluted with water (15 mL) and the aqueous phase was extracted with 3% MeOH-DCM (3×25 mL). The organics were combined, washed with dilute brine (7 mL), dried over sodium sulfate and concentrated. The residue was purified through silica gel (33 mL) which had been deactivated with Et3N (3.3 mL), using 33% EtOAc in hexane. The resulting residue was transferred to a microwave vessel in DCM (3 mL), and TFA (0.283 mL, 3.67 mmol) was added. The vessel was sealed and heated in a 60° C. oil bath for 1.5 h. The reaction was cooled and concentrated, and the residue was neutralized with 0.5 M aqueous Na2CO3 (15 mL). The aqueous phase was extracted with 5% MeOH-DCM (3×25 mL). The organics were combined, washed with dilute brine (7 mL) and dried over sodium sulfate. The residue was purified through silica gel (33 mL) using 7.5% MeOH-DCM to afford 27 mg of (S)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-((3-methyloxetan-3-yl)ethynyl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine. m/z=474.0[M+H]+.