Reaction SMILES: IP(I)I.[Br:5][C:6]1[CH:7]=[C:8]2[C:18](=[CH:19][CH:20]=1)[O:17][C:11]1[CH:12]=[N:13][C:14]([Cl:16])=[CH:15][C:10]=1[C:9]2([CH2:22][O:23][CH:24]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:25][N+:26]([O-])=O)[NH2:21]>C(Cl)Cl>[NH2:21][C:9]1([CH2:22][O:23][CH:24]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:25]#[N:26])[C:10]2[CH:15]=[C:14]([Cl:16])[N:13]=[CH:12][C:11]=2[O:17][C:18]2[C:8]1=[CH:7][C:6]([Br:5])=[CH:20][CH:19]=2
Reactant: NC1(COC(C[N+](=O)[O-])C2CCCCC2)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Agent: IP(I)I
Solvent: ClCCl
Product: N#CC(OCC1(N)c2cc(Br)ccc2Oc2cnc(Cl)cc21)C1CCCCC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Steps 1 and 2: Synthesis of (E)-(2-nitrovinyl)cyclohexane Step 1: 10 M aqueous NaOH (8.31 mL, 83 mmol) was added dropwise via addition funnel to a solution of nitromethane (4.46 mL, 83 mmol) and cyclohexanecarboxaldehyde (10 mL, 83 mmol) in EtOH (20 mL) at 0° C. with vigorous stirring. The resulting white slurry was stirred 10 minutes and became a white solid. Acetic acid (4.76 mL, 83 mmol) was added and the reaction was partitioned between diethyl ether and water. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic extracts were washed with water, saturated aqueous sodium chloride, and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo and dried under vacumm to afford 1-cyclohexyl-2-nitroethanol. The product was used directly for the next step without further purification. Step 2: Methanesulfonyl chloride (2.83 mL, 36.4 mmol) was added via syringe to a solution of (E)-(2-nitrovinyl)cyclohexane and hydroquinone (0.200 g, 1.819 mmol) in DCM (35 mL) at 0° C. Next, triethylamine (10.14 mL, 72.7 mmol) was added dropwise and the solution was stirred 20 minutes (precipitate forms) before being transferred to a separatory funnel with DCM and water. The layers were separated and the organics were washed with water, 1N HCl, saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give (E)-(2-nitrovinyl)cyclohexane. The product was used directly for the next step without further purification. Step 3: Potassium t-butoxide (0.517 g, 4.61 mmol) was added in one portion to a solution of (5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)methanol (Intermediate X, 1.5 g, 4.39 mmol) in THF (30 mL) at −78° C. After stirring for 45 minutes, (E)-(2-nitrovinyl)cyclohexane (0.716 g, 4.61 mmol) in THF (15.00 mL) was added slowly via syringe. The reaction was stirred at −78° C. for 20 minutes and was quenched with acetic acid (0.502 mL, 8.78 mmol) at −78° C., diluted with saturated aqueous ammonium chloride, water and EtOAc. After warming to RT, the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water, saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel chromatography by eluting with 1:6 to 1:4 EtOAc in hexane, to provide 7-bromo-3-chloro-5-((1-cyclohexyl-2-nitroethoxy)methyl)-5H-chromeno[2,3-c]pyridin-5-amine as a yellow oil. [M+H]+=496.1. Step 4: TEA (1.263 ml, 9.06 mmol) and triiodophosphine (1.243 g, 3.02 mmol) were added to 7-bromo-3-chloro-5-((1-cyclohexyl-2-nitroethoxy)methyl)-5H-chromeno[2,3-c]pyridin-5-amine (1.5 g, 3.02 mmol) in DCM (30.2 ml) at 0° C. The reaction was stirred 10 minutes before the ice water bath was removed and the reaction was allowed to come to RT. After 1.5 hours, the solution is cooled to 0° C. and quenched with saturated aqueous sodium bicarbonate, diluted with water, and extracted with DCM. The combined organic extracts were washed with 1N NaOH, water, saturated aqueous NaCl, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel chromatography by eluting with 1:4 EtOAc in hexane, to provide 2-((5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)methoxy)-2-cyclohexylacetonitrile, [M+H]=462.0. Step 5: Trimethylaluminum, as a 2 M solution in toluene, (0.973 ml, 1.947 mmol) was added dropwise via syringe to a solution of 2-((5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)methoxy)-2-cyclohexylacetonitrile (0.563 g, 1.217 mmol) in DCE (12 ml) at RT. After stirring 14 hours, the reaction was cooled to 0° C. and 1 N aq. HCl (12 ml, 12 mmol) was added dropwise via syringe (slowly at first until vigorous reaction subsided) and the mixture was stirred at 0° C. for 10 minutes and then at RT before being diluted with DCM. The layers were separated and the aqueous layer was extracted with DCM. The combined organic extracts were washed with 1 N aq. NaOH, saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel chromatography by eluting with 1:20 MeOH in DCM, to provide 7-bromo-3-chloro-6′-cyclohexyl-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine as a mixture of racemic diastereomers. [M+H]=462.0. Step 6: A glass microwave reaction vessel was charged with 7-bromo-3-chloro-6′-cyclohexyl-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.075 g, 0.162 mmol), 2 M aqueous sodium carbonate (0.8 mL, 1.600 mmol), and dioxane (1.6 mL). The vessel was capped and the solution was degassed by bubbling nitrogen gas through the solution for 10 minutes. Next, Pd(PPh3)4 (7.49 mg, 6.48 μmol) and (2-fluoropyridin-3-yl)boronic acid (0.027 g, 0.194 mmol) were added and the vessel was sealed. The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 20 minutes. The reaction was poured into water and the mixture was extracted with EtOAc. The combined organic extracts were washed with water, saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel chromatography by eluting with 1:20 MeOH in DCM, to provide the product as a racemic mixture of diastereomers. The diastereomers were separated by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 70% over 20 min to provide racemic (3′R,6′S)-3-chloro-6′-cyclohexyl-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine and racemic (3′S,6′S)-3-chloro-6′-cyclohexyl-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine each as a white solid after isolating the free base by partitioning between DCM and 1 N NaOH. [M+H]+=479.1 for each racemic diastereomer pair.