Name: 1191237-80-5|(3aR,4R,6R,6aR)-4-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile|97%
Brand: Ambeed
SKU: A1220957
Price: 12.0 USD
Availability: InStock
Rating: 90 (25 reviews)

1
[ 1355049-94-3 ]
[ 1191237-80-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: dichloromethane / 0.17 h / -78 °C / Inert atmosphere 1.2: 1 h / -78 °C / Inert atmosphere 2.1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 3.1: sulfuric acid / acetone / 0.5 h / 45 °C
	Multi-step reaction with 3 steps 1: trimethylsilyl trifluoromethanesulfonate; trifluoroacetic acid / dichloromethane / 0.17 h / -40 - -25 °C 2: boron trichloride / dichloromethane / 1 h / -20 - -15 °C 3: sulfuric acid / acetone / 0.5 h / 45 °C
	Multi-step reaction with 4 steps 1.1: dichloromethane / 0.17 h / -78 °C / Inert atmosphere 1.2: 1 h / -78 °C / Inert atmosphere 2.1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 3.1: acetone / 0.5 h / 20 °C 4.1: potassium carbonate / water; ethyl acetate

	Multi-step reaction with 4 steps 1: trimethylsilyl trifluoromethanesulfonate; trifluoroacetic acid / dichloromethane / 0.17 h / -40 - -25 °C 2: boron trichloride / dichloromethane / 1 h / -20 - -15 °C 3: acetone / 0.5 h / 20 °C 4: potassium carbonate / water; ethyl acetate
	Multi-step reaction with 3 steps 1.1: dichloromethane / 0.17 h / 0 °C / Inert atmosphere 1.2: 1 h / 0 °C 2.1: boron trichloride / dichloromethane / 1 h / -78 °C / Inert atmosphere 3.1: sulfuric acid / acetone / 0.5 h / 45 °C
	Multi-step reaction with 5 steps 1.1: potassium hydroxide; trimethylsilyl trifluoromethanesulfonate; trifluoroacetic acid / water; dichloromethane 1.2: -30 - -10 °C 2.1: boron trichloride; Trimethyl borate / dichloromethane / 2 h / 0 - 35 °C 2.2: 12 h / 20 - 25 °C 3.1: potassium carbonate / water / 1 h / 20 °C 4.1: Isopropyl acetate; sulfuric acid / 3 h / 20 - 30 °C 5.1: potassium acetate / water; methanol / 1 h

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[2]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[3]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[4]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[5]Current Patent Assignee: GILEAD SCIENCES INC - US2017/71964, 2017, A1
[6]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/183750, 2021, A2

2
[ 1191237-68-9 ]
[ 1191237-80-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 2: sulfuric acid / acetone / 0.5 h / 45 °C
	Multi-step reaction with 3 steps 1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 2: acetone / 0.5 h / 20 °C 3: potassium carbonate / water; ethyl acetate
	Multi-step reaction with 2 steps 1: boron trichloride / dichloromethane / 1 h / -78 °C / Inert atmosphere 2: sulfuric acid / acetone / 0.5 h / 45 °C

Multi-step reaction with 2 steps 1.1: boron trichloride / dichloromethane / 3 h / -75 - 30 °C 1.2: -75 - 30 °C 2.1: toluene-4-sulfonic acid; potassium carbonate / acetone / 0.25 h / 30 °C 2.2: 1 h

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[2]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[3]Current Patent Assignee: GILEAD SCIENCES INC - US2017/71964, 2017, A1
[4]Current Patent Assignee: ANZALP PHARMASOLUTIONS PVT - US2021/161927, 2021, A1

3
[ 1191237-69-0 ]
(3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile [ No CAS ]

Reference： [1]Patent: WO2016/69826,2016,A1

4
[ 1191237-69-0 ]
[ 77-76-9 ]
(3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; In acetone; at 45℃; for 0.5h;	[0250] To a mixture of (2R,3R,4S,5R)-2-(4-aminopyrrolo[2, 1 -fj [ 1 ,2,4]triazin-7-yl)-3,4- dihydroxy-5-(hydroxymethyl)tetrahydroiuran-2-carbonitrile (5.8g, 0.02 mol), 2,2- dimethoxypropane (1 1.59 mL, 0.09 mol) and acetone (145 mL) at ambient temperature was added sulfuric acid (18M, 1.44 mL). The mixture was warmed to about 45 C. After about 30 min, the mixture was cooled to ambient temperature and sodium bicarbonate (5.8 g) and water 5.8 mL) were added. After 15 min, the mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate (150 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic phase was dried over sodium sulfate and concentrated under reduced pressure to give crude (2R,3R,4S,5R)-2-(4- aminopyrrolo[2, 1 -fj [ 1 ,2,4]triazin-7-yl)-3 ,4-dihydroxy-5-(hydroxymemyl)tetrahydrofuran-2- carbonitrile. NMR (400 MHz, CD3OD) delta 7.84 (s, 1H), 6.93 (d, J= 4.6 Hz, 1H), 6.89 (d, J= 4.6 Hz, 1H), 5.40 (d, J= 6.7 Hz, 1H), 5.00 (dd, J= 6.7, 3.3 Hz, 1H), 4.48 - 4.40 (m, 1H), 3.81 - 3.72 (m, 2H), 1.71 (s, 3H), 1.40 (s, 3H). MS m/z = 332.23 [M+l].
	With sulfuric acid; In acetone; at 45℃; for 0.5h;	To a mixture of <strong>[1191237-69-0](2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile</strong> (5.8 g, 0.02 mol), 2,2-dimethoxypropane (11.59 mL, 0.09 mol) and acetone (145 mL) at ambient temperature was added sulfuric acid (18M, 1.44 mL). The mixture was warmed to about 45 C. After about 30 min, the mixture was cooled to ambient temperature and sodium bicarbonate (5.8 g) and water 5.8 mL) were added. After 15 min, the mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate (150 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic phase was dried over sodium sulfate and concentrated under reduced pressure to give crude <strong>[1191237-69-0](2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile</strong>. 1H NMR (400 MHz, CD3OD) delta 7.84 (s, 1H), 6.93 (d, J=4.6 Hz, 1H), 6.89 (d, J=4.6 Hz, 1H), 5.40 (d, J=6.7 Hz, 1H), 5.00 (dd, J=6.7, 3.3 Hz, 1H), 4.48-4.40 (m, 1H), 3.81-3.72 (m, 2H), 1.71 (s, 3H), 1.40 (s, 3H). MS m/z=332.23 [M+1].
	With sulfuric acid; In acetone; at 45℃; for 0.5h;	To a mixture of (2R,3R,4S,5R)-2-(4-aminopyrrolo[2, l-f] [l,2,4]triazin-7-yl)-3,4- dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (5.8g, 0.02 mol), 2,2- dimethoxypropane (11.59 mL, 0.09 mol) and acetone (145 mL) at ambient temperature was added sulfuric acid (18M, 1.44 mL). The mixture was warmed to about 45 C. After about 30 min, the mixture was cooled to ambient temperature and sodium bicarbonate (5.8 g) and water 5.8 mL) were added. After 15 min, the mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate (150 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic phase was dried over sodium sulfate and concentrated under reduced pressure to give crude (2R,3R,4S,5R)-2-(4-aminopyrrolo[2, l-f] [l,2,4]triazin-7-yl)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-carbonitrile. H NMR (400 MHz, CD3OD) delta 7.84 (s, 1H), 6.93 (d, / = 4.6 Hz, 1H), 6.89 (d, / = 4.6 Hz, 1H), 5.40 (d, / = 6.7 Hz, 1H), 5.00 (dd, / = 6.7, 3.3 Hz, 1H), 4.48 - 4.40 (m, 1H), 3.81 - 3.72 (m, 2H), 1.71 (s, 3H), 1.40 (s, 3H). MS m/z = 332.23 [M+l].

Reference： [1]Patent: WO2016/69826,2016,A1 .Location in patent: Paragraph 0250
[2]Patent: US2017/71964,2017,A1 .Location in patent: Paragraph 0664-0665
[3]Patent: WO2017/184668,2017,A1 .Location in patent: Paragraph 0261

5
[ 1770840-43-1 ]
[ 1191237-80-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / 0 °C 1.2: 0.58 h / 0 - 5 °C 2.1: dichloromethane / 0.17 h / -78 °C / Inert atmosphere 2.2: 1 h / -78 °C / Inert atmosphere 3.1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 4.1: sulfuric acid / acetone / 0.5 h / 45 °C
	Multi-step reaction with 4 steps 1.1: chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / 0 °C 1.2: 0.58 h / 0 - 5 °C 2.1: trimethylsilyl trifluoromethanesulfonate; trifluoroacetic acid / dichloromethane / 0.17 h / -40 - -25 °C 3.1: boron trichloride / dichloromethane / 1 h / -20 - -15 °C 4.1: sulfuric acid / acetone / 0.5 h / 45 °C
	Multi-step reaction with 5 steps 1.1: chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / 0 °C 1.2: 0.58 h / 0 - 5 °C 2.1: dichloromethane / 0.17 h / -78 °C / Inert atmosphere 2.2: 1 h / -78 °C / Inert atmosphere 3.1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 4.1: acetone / 0.5 h / 20 °C 5.1: potassium carbonate / water; ethyl acetate

	Multi-step reaction with 5 steps 1.1: chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / 0 °C 1.2: 0.58 h / 0 - 5 °C 2.1: trimethylsilyl trifluoromethanesulfonate; trifluoroacetic acid / dichloromethane / 0.17 h / -40 - -25 °C 3.1: boron trichloride / dichloromethane / 1 h / -20 - -15 °C 4.1: acetone / 0.5 h / 20 °C 5.1: potassium carbonate / water; ethyl acetate
	Multi-step reaction with 4 steps 1.1: chloro-trimethyl-silane; phenylmagnesium chloride / tetrahydrofuran / 0.5 h / 0 - 5 °C / Inert atmosphere 1.2: 0.17 h / -15 - -12 °C 1.3: 1 h / -20 °C 2.1: dichloromethane / 0.17 h / 0 °C / Inert atmosphere 2.2: 1 h / 0 °C 3.1: boron trichloride / dichloromethane / 1 h / -78 °C / Inert atmosphere 4.1: sulfuric acid / acetone / 0.5 h / 45 °C
	Multi-step reaction with 4 steps 1: isopropylmagnesium chloride; chloro-trimethyl-silane; phenylmagnesium chloride / tetrahydrofuran / 0.11 h / Flow reactor 2: trimethylsilyl trifluoromethanesulfonate; trifluorormethanesulfonic acid / dichloromethane / 0.07 h / Flow reactor 3: boron trichloride; triethylamine; methanol / dichloromethane / 0.04 h / Flow reactor 4: sulfuric acid / acetone / 0.06 h / Flow reactor
	Multi-step reaction with 6 steps 1.1: neodymium(III) chloride; tetrabutyl-ammonium chloride / tetrahydrofuran / 0.5 h / 22 °C / Inert atmosphere 1.2: 0.5 h / 0 °C 2.1: potassium hydroxide; trimethylsilyl trifluoromethanesulfonate; trifluoroacetic acid / water; dichloromethane 2.2: -30 - -10 °C 3.1: boron trichloride; Trimethyl borate / dichloromethane / 2 h / 0 - 35 °C 3.2: 12 h / 20 - 25 °C 4.1: potassium carbonate / water / 1 h / 20 °C 5.1: Isopropyl acetate; sulfuric acid / 3 h / 20 - 30 °C 6.1: potassium acetate / water; methanol / 1 h
	Multi-step reaction with 7 steps 1.1: chloro-trimethyl-silane; phenylmagnesium chloride; isopropylmagnesium chloride / tetrahydrofuran / -20 - 0 °C 1.2: 17 h / -20 - 20 °C 2.1: dipotassium hydrogenphosphate; [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile / 22 h / 20 °C 3.1: potassium hydroxide; trimethylsilyl trifluoromethanesulfonate; trifluoroacetic acid / water; dichloromethane 3.2: -30 - -10 °C 4.1: boron trichloride; Trimethyl borate / dichloromethane / 2 h / 0 - 35 °C 4.2: 12 h / 20 - 25 °C 5.1: potassium carbonate / water / 1 h / 20 °C 6.1: Isopropyl acetate; sulfuric acid / 3 h / 20 - 30 °C 7.1: potassium acetate / water; methanol / 1 h

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[2]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[3]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[4]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[5]Current Patent Assignee: GILEAD SCIENCES INC - US2017/71964, 2017, A1
[6]Current Patent Assignee: NANJING INSTITUTE OF ADVANCED BIOMATERIALS PROC EQUIPMENT - CN112679542, 2021, A
[7]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/183750, 2021, A2
[8]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/183750, 2021, A2

6
[ 1355357-49-1 ]
[ 1191237-80-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: boron trichloride / dichloromethane / 1 h / -20 - -15 °C 2: sulfuric acid / acetone / 0.5 h / 45 °C
	Multi-step reaction with 3 steps 1: boron trichloride / dichloromethane / 1 h / -20 - -15 °C 2: acetone / 0.5 h / 20 °C 3: potassium carbonate / water; ethyl acetate
	Multi-step reaction with 2 steps 1: boron trichloride; triethylamine; methanol / dichloromethane / 0.04 h / Flow reactor 2: sulfuric acid / acetone / 0.06 h / Flow reactor

Multi-step reaction with 4 steps 1.1: boron trichloride; Trimethyl borate / dichloromethane / 2 h / 0 - 35 °C 1.2: 12 h / 20 - 25 °C 2.1: potassium carbonate / water / 1 h / 20 °C 3.1: Isopropyl acetate; sulfuric acid / 3 h / 20 - 30 °C 4.1: potassium acetate / water; methanol / 1 h

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[2]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[3]Current Patent Assignee: NANJING INSTITUTE OF ADVANCED BIOMATERIALS PROC EQUIPMENT - CN112679542, 2021, A
[4]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/183750, 2021, A2

7
[ 159326-68-8 ]
(3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile [ No CAS ]

Reference： [1]Patent: WO2016/69826,2016,A1
[2]Patent: WO2016/69826,2016,A1
[3]Patent: WO2016/69826,2016,A1
[4]Patent: WO2016/69826,2016,A1
[5]Patent: US2017/71964,2017,A1

8
(3R,4R,5R)-3,4-Bis-benzyloxy-5-benzyloxymethyl-dihydro-furan-2-one [ No CAS ]
[ 1191237-80-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: chloro-trimethyl-silane / tetrahydrofuran / 0.33 h / 20 °C / Inert atmosphere 1.2: 0.17 h / -78 °C / Inert atmosphere 2.1: dichloromethane / 0.17 h / -78 °C / Inert atmosphere 2.2: 1 h / -78 °C / Inert atmosphere 3.1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 4.1: sulfuric acid / acetone / 0.5 h / 45 °C
	Multi-step reaction with 4 steps 1.1: chloro-trimethyl-silane / tetrahydrofuran / 0.33 h / 20 °C / Inert atmosphere 1.2: 0.17 h / -78 °C / Inert atmosphere 2.1: trimethylsilyl trifluoromethanesulfonate; trifluoroacetic acid / dichloromethane / 0.17 h / -40 - -25 °C 3.1: boron trichloride / dichloromethane / 1 h / -20 - -15 °C 4.1: sulfuric acid / acetone / 0.5 h / 45 °C
	Multi-step reaction with 4 steps 1.1: chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / 0 °C 1.2: 0.58 h / 0 - 5 °C 2.1: dichloromethane / 0.17 h / -78 °C / Inert atmosphere 2.2: 1 h / -78 °C / Inert atmosphere 3.1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 4.1: sulfuric acid / acetone / 0.5 h / 45 °C

	Multi-step reaction with 4 steps 1.1: chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / 0 °C 1.2: 0.58 h / 0 - 5 °C 2.1: trimethylsilyl trifluoromethanesulfonate; trifluoroacetic acid / dichloromethane / 0.17 h / -40 - -25 °C 3.1: boron trichloride / dichloromethane / 1 h / -20 - -15 °C 4.1: sulfuric acid / acetone / 0.5 h / 45 °C
	Multi-step reaction with 5 steps 1.1: chloro-trimethyl-silane / tetrahydrofuran / 0.33 h / 20 °C / Inert atmosphere 1.2: 0.17 h / -78 °C / Inert atmosphere 2.1: dichloromethane / 0.17 h / -78 °C / Inert atmosphere 2.2: 1 h / -78 °C / Inert atmosphere 3.1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 4.1: acetone / 0.5 h / 20 °C 5.1: potassium carbonate / water; ethyl acetate
	Multi-step reaction with 5 steps 1.1: chloro-trimethyl-silane / tetrahydrofuran / 0.33 h / 20 °C / Inert atmosphere 1.2: 0.17 h / -78 °C / Inert atmosphere 2.1: trimethylsilyl trifluoromethanesulfonate; trifluoroacetic acid / dichloromethane / 0.17 h / -40 - -25 °C 3.1: boron trichloride / dichloromethane / 1 h / -20 - -15 °C 4.1: acetone / 0.5 h / 20 °C 5.1: potassium carbonate / water; ethyl acetate
	Multi-step reaction with 5 steps 1.1: chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / 0 °C 1.2: 0.58 h / 0 - 5 °C 2.1: dichloromethane / 0.17 h / -78 °C / Inert atmosphere 2.2: 1 h / -78 °C / Inert atmosphere 3.1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 4.1: acetone / 0.5 h / 20 °C 5.1: potassium carbonate / water; ethyl acetate
	Multi-step reaction with 5 steps 1.1: chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / 0 °C 1.2: 0.58 h / 0 - 5 °C 2.1: trimethylsilyl trifluoromethanesulfonate; trifluoroacetic acid / dichloromethane / 0.17 h / -40 - -25 °C 3.1: boron trichloride / dichloromethane / 1 h / -20 - -15 °C 4.1: acetone / 0.5 h / 20 °C 5.1: potassium carbonate / water; ethyl acetate
	Multi-step reaction with 4 steps 1.1: chloro-trimethyl-silane / tetrahydrofuran / 0.33 h / 20 °C / Inert atmosphere 1.2: 0.17 h / -78 °C 2.1: dichloromethane / 0.17 h / 0 °C / Inert atmosphere 2.2: 1 h / 0 °C 3.1: boron trichloride / dichloromethane / 1 h / -78 °C / Inert atmosphere 4.1: sulfuric acid / acetone / 0.5 h / 45 °C
	Multi-step reaction with 4 steps 1.1: chloro-trimethyl-silane; phenylmagnesium chloride / tetrahydrofuran / 0.5 h / 0 - 5 °C / Inert atmosphere 1.2: 0.17 h / -15 - -12 °C 1.3: 1 h / -20 °C 2.1: dichloromethane / 0.17 h / 0 °C / Inert atmosphere 2.2: 1 h / 0 °C 3.1: boron trichloride / dichloromethane / 1 h / -78 °C / Inert atmosphere 4.1: sulfuric acid / acetone / 0.5 h / 45 °C
	Multi-step reaction with 4 steps 1: isopropylmagnesium chloride; chloro-trimethyl-silane; phenylmagnesium chloride / tetrahydrofuran / 0.11 h / Flow reactor 2: trimethylsilyl trifluoromethanesulfonate; trifluorormethanesulfonic acid / dichloromethane / 0.07 h / Flow reactor 3: boron trichloride; triethylamine; methanol / dichloromethane / 0.04 h / Flow reactor 4: sulfuric acid / acetone / 0.06 h / Flow reactor
	Multi-step reaction with 6 steps 1.1: neodymium(III) chloride; tetrabutyl-ammonium chloride / tetrahydrofuran / 0.5 h / 22 °C / Inert atmosphere 1.2: 0.5 h / 0 °C 2.1: potassium hydroxide; trimethylsilyl trifluoromethanesulfonate; trifluoroacetic acid / water; dichloromethane 2.2: -30 - -10 °C 3.1: boron trichloride; Trimethyl borate / dichloromethane / 2 h / 0 - 35 °C 3.2: 12 h / 20 - 25 °C 4.1: potassium carbonate / water / 1 h / 20 °C 5.1: Isopropyl acetate; sulfuric acid / 3 h / 20 - 30 °C 6.1: potassium acetate / water; methanol / 1 h

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[2]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[3]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[4]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[5]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[6]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[7]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[8]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[9]Current Patent Assignee: GILEAD SCIENCES INC - US2017/71964, 2017, A1
[10]Current Patent Assignee: GILEAD SCIENCES INC - US2017/71964, 2017, A1
[11]Current Patent Assignee: NANJING INSTITUTE OF ADVANCED BIOMATERIALS PROC EQUIPMENT - CN112679542, 2021, A
[12]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/183750, 2021, A2

9
2-ethylbutyl (2S)-2-((S)-((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate [ No CAS ]
[ 1191237-80-5 ]
2-ethylbutyl ((S)-(((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With magnesium chloride; N-ethyl-N,N-diisopropylamine In acetonitrile at 50℃; Inert atmosphere;
	With N-ethyl-N,N-diisopropylamine; magnesium chloride In acetonitrile at 20℃; for 4h;	35 Example 35 [0253] Acetonitrile (100 mL) was combined with (2S)-2-ethylbutyl 2-(((4- nitrophenoxy)(phenoxy)phosphoiyl)-arnino)p-Opanoate (9.6 g, 21.31 mmol), the substrate alcohol (6.6 g, 0.02 mol), ), magnesium chloride ( (1.9 g, 19.91 mmol) at ambient temperature. The mixture was agitated for about 15 min and N,iV-diisopropylethylamine (8.67 mL, 49.78 mmol) was added. After about 4h, the reaction was diluted with ethyl acetate (100 mL), cooled to about 0 °C and combined with aqueous citric acid solution (5%wt, 100 mL). The organic phase was washed with aqueous citric acid solution (5%wt., 100 mL) and aqueous saturated ammonium chloride solution (40 mL), aqueous potassium carbonate solution (10%wt., 2 x 100 mL), and aqueous saturated brine solution (100 mL). The organic phase was dried with sodium sulfate and concentrated under reduced pressure to provide crude product. NMR (400 MHz, CD3OD) δ 7.86 (s, 1H), 7.31 - 7.22 (m, 2H), 7.17 - 7.09 (m, 3H), 6.93 - 6.84 (m, 2H), 5.34 (d, J = 6.7 Hz, 1H), 4.98 (dd, J= 6.6, 3.5 Hz, 1H), 4.59 - 4.50 (m, 1H), 4.36 - 4.22 (m, 2H), 4.02 (dd, J= 10.9, 5.7 Hz, 1H), 3.91 (dd, J= 10.9, 5.7 Hz, 1H), 3.83 (dq, J= 9.7, 7.1 Hz, 1H), 1.70 (s, 3H), 1.50 - 1.41 (m, 1H), 1.39 (s, 3H), 1.36 - 1.21 (m, 7H), 0.86 (t, J = 7 A Hz, 6H). MS m/z = 643.21 [M+l].
	With N-ethyl-N,N-diisopropylamine; magnesium chloride In tetrahydrofuran at 50℃;

	Stage #1: 2-ethylbutyl (2S)-2-((S)-((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate; (3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With magnesium chloride In acetonitrile at 20℃; for 0.25h; Stage #2: With N-ethyl-N,N-diisopropylamine In acetonitrile for 4h;	5 Preparation of (2S)-2-ethylbutyl 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolor2,l-firi,2,41triazin- 7-yl)-5-cvano-3,4-dihvdroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)amino)propanoate Acetonitrile (100 mL) was combined with (2S)-2-ethylbutyl 2-(((4- nitrophenoxy)(phenoxy)phosphoryl)-amino)propanoate (9.6 g, 21.31 mmol), the substrate alcohol (6.6 g, 0.02 mol), magnesium chloride (1.9 g, 19.91 mmol) at ambient temperature. The mixture was agitated for about 15 min and N,N-diisopropylethylamine (8.67 mL, 49.78 mmol) was added. After about 4h, the reaction was diluted with ethyl acetate (100 mL), cooled to about 0 °C and combined with aqueous citric acid solution (5%wt., 100 mL). The organic phase was washed with aqueous citric acid solution (5%wt., 100 mL) and aqueous saturated ammonium chloride solution (40 mL), aqueous potassium carbonate solution (10%wt., 2 x 100 mL), and aqueous saturated brine solution (100 mL). The organic phase was dried with sodium sulfate and concentrated under reduced pressure to provide crude product. H NMR (400 MHz, CD3OD) δ 7.86 (s, 1H), 7.31 - 7.22 (m, 2H), 7.17 - 7.09 (m, 3H), 6.93 - 6.84 (m, 2H), 5.34 (d, / = 6.7 Hz, 1H), 4.98 (dd, / = 6.6, 3.5 Hz, 1H), 4.59 - 4.50 (m, 1H), 4.36 - 4.22 (m, 2H), 4.02 (dd, / = 10.9, 5.7 Hz, 1H), 3.91 (dd, / = 10.9, 5.7 Hz, 1H), 3.83 (dq, / = 9.7, 7.1 Hz, 1H), 1.70 (s, 3H), 1.50 - 1.41 (m, 1H), 1.39 (s, 3H), 1.36 - 1.21 (m, 7H), 0.86 (t, / = 7.4 Hz, 6H). MS m/z = 643.21 [M+l].
	With N-ethyl-N,N-diisopropylamine; magnesium chloride In acetonitrile at 25℃;	2 Example 2: Preparation of (S)-2-(((S)-(((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4] Triazine-7-yl)-6-cyano-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxocene-4-yl)methoxy)(phenoxy)(phosphoryl)amino)propionic acid-2-ethylbutyl ester Add (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile (6.0g), N-[(S)-(4-nitrophenoxy) (phenoxy Phosphoryl)-L-alanine-2-ethylbutyl ester (10.0g) and magnesium chloride (1.5g) were added to acetonitrile (120ml), and diisopropylethylamine (10.0g) was added, Incubate at 25°C to react. After the completion of the reaction, it was extracted with ethyl acetate (120ml) and purified water (100ml), dried over anhydrous sodium sulfate (1g), and the organic phase was concentrated under reduced pressure and directly put into the next step.
	With N-ethyl-N,N-diisopropylamine; magnesium chloride In tetrahydrofuran at 25℃; for 16h;	15 Example 15. Synthesis of the Compound of Formula (X) A reactor was charged with Formula (VIII) (1.0 equiv, scaling factor) followed by magnesium chloride (1.5 equiv.) and tetrahydrofuran (10 volumes). This mixture was cooled to about 25 °C. N,N-diisopropylethylamine (2.5 equiv.) was charged and the reaction was stirred for about 16 h. at about 25 °C. The reaction was quenched into tert-butyl methyl ether (10 volumes) and 10% (w/w) citric acid (10 volumes) at about 10 °C. The layers were separated and the organic layer was washed with 10% (w/w) potassium carbonate (15 volumes), 10% (w/w) potassium carbonate (10 volumes), 10% (w/w) ammonium chloride (10 volumes), then 15% (w/w) sodium chloride (10 volumes). The organic layer was distilled to about 3.5 volumes followed by the addition of acetonitrile (10 volumes), distilled to about 3.5 volumes, charged with acetonitrile (7 volumes). The acetonitrile stock solution of Formula (X) was used in the next step.

Reference： [1]Gannedi, Veeranjaneyulu; Villuri, Bharath Kumar; Reddy, Sivakumar N.; Ku, Chiao-Chu; Wong, Chi-Huey; Hung, Shang-Cheng [Journal of Organic Chemistry, 2021, vol. 86, # 7, p. 4977 - 4985]
[2]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1 Location in patent: Paragraph 0253
[3]Siegel, Dustin; Hui, Hon C.; Doerffler, Edward; Clarke, Michael O.; Chun, Kwon; Zhang, Lijun; Neville, Sean; Carra, Ernest; Lew, Willard; Ross, Bruce; Wang, Queenie; Wolfe, Lydia; Jordan, Robert; Soloveva, Veronica; Knox, John; Perry, Jason; Perron, Michel; Stray, Kirsten M.; Barauskas, Ona; Feng, Joy Y.; Xu, Yili; Lee, Gary; Rheingold, Arnold L.; Ray, Adrian S.; Bannister, Roy; Strickley, Robert; Swaminathan, Swami; Lee, William A.; Bavari, Sina; Cihlar, Tomas; Lo, Michael K.; Warren, Travis K.; Mackman, Richard L. [Journal of Medicinal Chemistry, 2017, vol. 60, # 5, p. 1648 - 1661]
[4]Current Patent Assignee: GILEAD SCIENCES INC - WO2017/184668, 2017, A1 Location in patent: Paragraph 0262
[5]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD - CN113004330, 2021, A Location in patent: Paragraph 0036-0040
[6]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/183750, 2021, A2 Location in patent: Paragraph 0200

10
[ 1191237-80-5 ]
((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)oxidophosphoryl)alanine bis-sodium salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: magnesium chloride; N-ethyl-N,N-diisopropylamine / acetonitrile / 4 h / 20 °C 2: hydrogenchloride; water / tetrahydrofuran / 0 - 20 °C 3: sodium hydroxide / water; acetonitrile / 2 h

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1

11
[ 1191237-80-5 ]
[ 1809249-37-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: magnesium chloride; N-ethyl-N,N-diisopropylamine / acetonitrile / 4 h / 20 °C 2: hydrogenchloride; water / tetrahydrofuran / 0 - 20 °C
	Multi-step reaction with 2 steps 1.1: magnesium chloride / acetonitrile / 0.25 h / 20 °C 1.2: 4 h 2.1: hydrogenchloride / tetrahydrofuran; water / 0 - 20 °C

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[2]Current Patent Assignee: GILEAD SCIENCES INC - WO2017/184668, 2017, A1

12
(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile p-tolylsulfonic acid salt [ No CAS ]
[ 1191237-80-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In water; ethyl acetate	35 Example 35 [0252] To a mixture of (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)-3,4- dihydroxy-5-(hydroxymethyl)teh-ahydrofuran-2-carbonitrile (5 g, 17.2 mmol, 1.0 equiv.), 2,2- dimethoxypropane (10.5 mL, 86 mmol, 5.0 equiv.) and acetone (25 raL) at ambient temperature was added /?-tolylsulfonic acide (3.59 g, 1.1 equiv.). The mixture was stirred at ambient temperature. After 30 min, isopropyl acetate (25 mL) was added over one hour. The resulting slurry was filtered and rinsed with 2:1 heptane:isopropyl acetate (25 ml). The product was dried under vacuum at 40 °C. The isolated solid was added to a reactor and 5% K2CO3 solution (50 ml) and ethyl acetate (50 mL) were added. The layers were separated, and the aqueous layer washed with ethyl acetate (25 ml). The combined organic layers were washed with water (25 ml), then concentrated to ca.25 ml. The reactor was refilled with isopropyl acetate (25 ml) and concentrated to ca. 25 ml. The reactor was again refilled with isopropyl acetate (25 ml) and concentrated to 25 ml. The resulting solution was seeded, producing a thick slurry. To this was added heptane (25 ml) over one hour. The resulting slurry was filtered and rinsed with 2:1 heptane: isopropyl acetate (25 ml). The product was dried under vacuum at 40 °C. () (2R,3 R,4S,5R)-2-(4-aminopyrrolo[2, 1 -f] [ 1 ,2,4]triazin-7-yl)-3 ,4-dihydroxy-5- (hydroxymemyl)tetrahydrofuran-2-carbonitrile. 1H NMR (400 MHz, CD3OD) δ 7.84 (s, 1H), 6.93 (d, J= 4.6 Hz, 1H), 6.89 (d, J= 4.6 Hz, 1H), 5.40 (d, J= 6.7 Hz, 1H), 5.00 (dd, J= 6.7, 3.3 Hz, 1H), 4.48 - 4.40 (m, 1H), 3.81 - 3.72 (m, 2H), 1.71 (s, 3H), 1.40 (s, 3H). MS m/z = 332.23 [M+l].

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1 Location in patent: Paragraph 0252

13
[ 16838-89-4 ]
[ 1191237-80-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: acetic anhydride; dimethyl sulfoxide / 48 h / 20 °C / Inert atmosphere 2.1: chloro-trimethyl-silane / tetrahydrofuran / 0.33 h / 20 °C / Inert atmosphere 2.2: 0.17 h / -78 °C / Inert atmosphere 3.1: dichloromethane / 0.17 h / -78 °C / Inert atmosphere 3.2: 1 h / -78 °C / Inert atmosphere 4.1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 5.1: sulfuric acid / acetone / 0.5 h / 45 °C
	Multi-step reaction with 5 steps 1.1: acetic anhydride; dimethyl sulfoxide / 48 h / 20 °C / Inert atmosphere 2.1: chloro-trimethyl-silane / tetrahydrofuran / 0.33 h / 20 °C / Inert atmosphere 2.2: 0.17 h / -78 °C / Inert atmosphere 3.1: trimethylsilyl trifluoromethanesulfonate; trifluoroacetic acid / dichloromethane / 0.17 h / -40 - -25 °C 4.1: boron trichloride / dichloromethane / 1 h / -20 - -15 °C 5.1: sulfuric acid / acetone / 0.5 h / 45 °C
	Multi-step reaction with 5 steps 1.1: acetic anhydride; dimethyl sulfoxide / 48 h / 20 °C / Inert atmosphere 2.1: chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / 0 °C 2.2: 0.58 h / 0 - 5 °C 3.1: dichloromethane / 0.17 h / -78 °C / Inert atmosphere 3.2: 1 h / -78 °C / Inert atmosphere 4.1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 5.1: sulfuric acid / acetone / 0.5 h / 45 °C

	Multi-step reaction with 5 steps 1.1: acetic anhydride; dimethyl sulfoxide / 48 h / 20 °C / Inert atmosphere 2.1: chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / 0 °C 2.2: 0.58 h / 0 - 5 °C 3.1: trimethylsilyl trifluoromethanesulfonate; trifluoroacetic acid / dichloromethane / 0.17 h / -40 - -25 °C 4.1: boron trichloride / dichloromethane / 1 h / -20 - -15 °C 5.1: sulfuric acid / acetone / 0.5 h / 45 °C
	Multi-step reaction with 6 steps 1.1: acetic anhydride; dimethyl sulfoxide / 48 h / 20 °C / Inert atmosphere 2.1: chloro-trimethyl-silane / tetrahydrofuran / 0.33 h / 20 °C / Inert atmosphere 2.2: 0.17 h / -78 °C / Inert atmosphere 3.1: dichloromethane / 0.17 h / -78 °C / Inert atmosphere 3.2: 1 h / -78 °C / Inert atmosphere 4.1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 5.1: acetone / 0.5 h / 20 °C 6.1: potassium carbonate / water; ethyl acetate
	Multi-step reaction with 6 steps 1.1: acetic anhydride; dimethyl sulfoxide / 48 h / 20 °C / Inert atmosphere 2.1: chloro-trimethyl-silane / tetrahydrofuran / 0.33 h / 20 °C / Inert atmosphere 2.2: 0.17 h / -78 °C / Inert atmosphere 3.1: trimethylsilyl trifluoromethanesulfonate; trifluoroacetic acid / dichloromethane / 0.17 h / -40 - -25 °C 4.1: boron trichloride / dichloromethane / 1 h / -20 - -15 °C 5.1: acetone / 0.5 h / 20 °C 6.1: potassium carbonate / water; ethyl acetate
	Multi-step reaction with 6 steps 1.1: acetic anhydride; dimethyl sulfoxide / 48 h / 20 °C / Inert atmosphere 2.1: chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / 0 °C 2.2: 0.58 h / 0 - 5 °C 3.1: dichloromethane / 0.17 h / -78 °C / Inert atmosphere 3.2: 1 h / -78 °C / Inert atmosphere 4.1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 5.1: acetone / 0.5 h / 20 °C 6.1: potassium carbonate / water; ethyl acetate
	Multi-step reaction with 6 steps 1.1: acetic anhydride; dimethyl sulfoxide / 48 h / 20 °C / Inert atmosphere 2.1: chloro-trimethyl-silane / tetrahydrofuran / 0.5 h / 0 °C 2.2: 0.58 h / 0 - 5 °C 3.1: trimethylsilyl trifluoromethanesulfonate; trifluoroacetic acid / dichloromethane / 0.17 h / -40 - -25 °C 4.1: boron trichloride / dichloromethane / 1 h / -20 - -15 °C 5.1: acetone / 0.5 h / 20 °C 6.1: potassium carbonate / water; ethyl acetate
	Multi-step reaction with 5 steps 1.1: acetic anhydride; dimethyl sulfoxide / 48 h / 20 °C / Inert atmosphere 2.1: chloro-trimethyl-silane / tetrahydrofuran / 0.33 h / 20 °C / Inert atmosphere 2.2: 0.17 h / -78 °C 3.1: dichloromethane / 0.17 h / 0 °C / Inert atmosphere 3.2: 1 h / 0 °C 4.1: boron trichloride / dichloromethane / 1 h / -78 °C / Inert atmosphere 5.1: sulfuric acid / acetone / 0.5 h / 45 °C
	Multi-step reaction with 5 steps 1.1: acetic anhydride; dimethyl sulfoxide / 48 h / 20 °C / Inert atmosphere 2.1: chloro-trimethyl-silane; phenylmagnesium chloride / tetrahydrofuran / 0.5 h / 0 - 5 °C / Inert atmosphere 2.2: 0.17 h / -15 - -12 °C 2.3: 1 h / -20 °C 3.1: dichloromethane / 0.17 h / 0 °C / Inert atmosphere 3.2: 1 h / 0 °C 4.1: boron trichloride / dichloromethane / 1 h / -78 °C / Inert atmosphere 5.1: sulfuric acid / acetone / 0.5 h / 45 °C
	Multi-step reaction with 7 steps 1.1: chloro-trimethyl-silane; phenylmagnesium chloride; isopropylmagnesium chloride / tetrahydrofuran / -20 - 0 °C 1.2: 17 h / -20 - 20 °C 2.1: dipotassium hydrogenphosphate; [bis(acetoxy)iodo]benzene; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetonitrile / 22 h / 20 °C 3.1: potassium hydroxide; trimethylsilyl trifluoromethanesulfonate; trifluoroacetic acid / water; dichloromethane 3.2: -30 - -10 °C 4.1: boron trichloride; Trimethyl borate / dichloromethane / 2 h / 0 - 35 °C 4.2: 12 h / 20 - 25 °C 5.1: potassium carbonate / water / 1 h / 20 °C 6.1: Isopropyl acetate; sulfuric acid / 3 h / 20 - 30 °C 7.1: potassium acetate / water; methanol / 1 h

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[2]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[3]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[4]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[5]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[6]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[7]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[8]Current Patent Assignee: GILEAD SCIENCES INC; GILD SCIENCE - WO2016/69826, 2016, A1
[9]Current Patent Assignee: GILEAD SCIENCES INC - US2017/71964, 2017, A1
[10]Current Patent Assignee: GILEAD SCIENCES INC - US2017/71964, 2017, A1
[11]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/183750, 2021, A2

14
[ 1191237-80-5 ]
2-ethylbutyl ((4-nitrophenoxy)(phenoxy)phosphoryl)-D-alaninate [ No CAS ]
C₃₀H₃₉N₆O₈P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile; 2-ethylbutyl ((4-nitrophenoxy)(phenoxy)phosphoryl)-D-alaninate With magnesium chloride In tetrahydrofuran at 50℃; for 0.5h; Inert atmosphere; Stage #2: With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 50℃; for 3h; Inert atmosphere;

Reference： [1]Siegel, Dustin; Hui, Hon C.; Doerffler, Edward; Clarke, Michael O.; Chun, Kwon; Zhang, Lijun; Neville, Sean; Carra, Ernest; Lew, Willard; Ross, Bruce; Wang, Queenie; Wolfe, Lydia; Jordan, Robert; Soloveva, Veronica; Knox, John; Perry, Jason; Perron, Michel; Stray, Kirsten M.; Barauskas, Ona; Feng, Joy Y.; Xu, Yili; Lee, Gary; Rheingold, Arnold L.; Ray, Adrian S.; Bannister, Roy; Strickley, Robert; Swaminathan, Swami; Lee, William A.; Bavari, Sina; Cihlar, Tomas; Lo, Michael K.; Warren, Travis K.; Mackman, Richard L. [Journal of Medicinal Chemistry, 2017, vol. 60, # 5, p. 1648 - 1661]

15
2-ethylbutyl (2S)-2-((S)-((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate [ No CAS ]
[ 1191237-80-5 ]
[ 1809249-37-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: magnesium chloride; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 50 °C 2: hydrogenchloride / tetrahydrofuran; water / 0 °C
	With N-ethyl-N,N-diisopropylamine; magnesium chloride In tetrahydrofuran at 20℃; for 3h;	5 Example 5. Mixture I, A Mixture of Form II and Form IV (3aR,4R,6R,6aR)-4-(4-Aminopyrrolo[2, 1-f] [1 ,2,4]triazin-7-yl)-6-(hydroxymethyl)- 2,2-dimethyltetrahydrofuro[3,4-d] [1 ,3]dioxole-4-carbonitrile (20 g, 60 mmol), 2-ethylbutyl ((S)-(4-nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate (32 g, 72 mmol), and magnesiumchloride (8.6 g, 90 mmol) were added to a reaction vessel. Tetrahydrofuran (about 200 mL) was added, followed by the addition of N,N-diisopropylethylamine (26 mL, 151 mmol) at about 20 °C. After about 3 h, the reaction mixture was charged into a pre-cooled (about 15°C) mixture of 2-methyltetrahydrofuran and aqueous citric acid (10 wt%). The organic and aqueous layers were separated, and the organic layer was washed with aqueous potassiumcarbonate (10 wt%, about 300 mL), aqueous potassium carbonate (10 wt%, two times about200 mL), aqueous ammonium chloride (10 wt%, about 200 mL), and aqueous sodium chloride (15 wt%, about 200 mL). The solvent of the organic layer was exchanged to acetonitrile and the volume was adjusted to about 200 mL. The acetonitrile solution was cooled to about 0 °C and concentrated hydrochloric acid (about 40 mL) was added. After about 3 h, the reaction mixture was cooled to about -10 °C, charged into a precooled (about 10°C) mixture of 2-methyltetrahydrofuran (about 200 mL) and aqueous potassiumbicarbonate (20 wt%, about 200 mL). The organic and aqueous layers were separated, and the organic layer was washed with aqueous potassium bicarbonate (20 wt%, about 100 mL), and aqueous sodium chloride (15 wt%, about 200 mL). The organic layer was concentrated to about 140 mL, and washed with aqueous sodium chloride (15 wt%, about 100 mL). The organic layer was concentrated and distilled from 2-methyltetrahydrofuran until the solutionreached a target water content of no more than 0.2%. The 2-methyltetrahydrofuran solution (about 400 mL) was polish filtered and the solvent was exchanged to isopropyl acetate. The isopropyl acetate solution (about 100 mL) was stirred at about 21 °C. Seeds containing a mixture of Form II and Form IV (about 40 mg) were added, and the suspension was stirred at about 21 °C for about 3 days. Crystalline Formula I containing a mixture of Form II andForm IV was isolated as a solid from the suspension by filtration and characterized as discussed below.
	Multi-step reaction with 2 steps 1: magnesium chloride; N-ethyl-N,N-diisopropylamine / acetonitrile / 50 °C / Inert atmosphere 2: hydrogenchloride / tetrahydrofuran; water / 20 °C / Inert atmosphere

Reference： [1]Siegel, Dustin; Hui, Hon C.; Doerffler, Edward; Clarke, Michael O.; Chun, Kwon; Zhang, Lijun; Neville, Sean; Carra, Ernest; Lew, Willard; Ross, Bruce; Wang, Queenie; Wolfe, Lydia; Jordan, Robert; Soloveva, Veronica; Knox, John; Perry, Jason; Perron, Michel; Stray, Kirsten M.; Barauskas, Ona; Feng, Joy Y.; Xu, Yili; Lee, Gary; Rheingold, Arnold L.; Ray, Adrian S.; Bannister, Roy; Strickley, Robert; Swaminathan, Swami; Lee, William A.; Bavari, Sina; Cihlar, Tomas; Lo, Michael K.; Warren, Travis K.; Mackman, Richard L. [Journal of Medicinal Chemistry, 2017, vol. 60, # 5, p. 1648 - 1661]
[2]Current Patent Assignee: GILEAD SCIENCES INC - WO2018/204198, 2018, A1 Location in patent: Paragraph 0270; 0271; 0272; 0273
[3]Gannedi, Veeranjaneyulu; Villuri, Bharath Kumar; Reddy, Sivakumar N.; Ku, Chiao-Chu; Wong, Chi-Huey; Hung, Shang-Cheng [Journal of Organic Chemistry, 2021, vol. 86, # 7, p. 4977 - 4985]

16
[ 1439900-56-7 ]
[ 1191237-80-5 ]
2-ethylbutyl ((S)-(((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (2S)-2-ethylbutyl 2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate; (3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With magnesium chloride In acetonitrile at 20℃; for 0.25h; Stage #2: With N-ethyl-N,N-diisopropylamine In acetonitrile for 4h;	35 Preparation of (2S)-2-ethylbutyl 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate Acetonitrile (100 mL) was combined with (2S)-2-ethylbutyl 2-(((4-nitrophenoxy)(phenoxy)phosphoryl)-amino)propanoate (9.6 g, 21.31 mmol), the substrate alcohol (6.6 g, 0.02 mol), magnesium chloride (1.9 g, 19.91 mmol) at ambient temperature. The mixture was agitated for about 15 min and N,N-diisopropylethylamine (8.67 mL, 49.78 mmol) was added. After about 4 h, the reaction was diluted with ethyl acetate (100 mL), cooled to about 0° C. and combined with aqueous citric acid solution (5% wt., 100 mL). The organic phase was washed with aqueous citric acid solution (5% wt., 100 mL) and aqueous saturated ammonium chloride solution (40 mL), aqueous potassium carbonate solution (10% wt., 2×100 mL), and aqueous saturated brine solution (100 mL). The organic phase was dried with sodium sulfate and concentrated under reduced pressure to provide crude product. 1H NMR (400 MHz, CD3OD) δ 7.86 (s, 1H), 7.31-7.22 (m, 2H), 7.17-7.09 (m, 3H), 6.93-6.84 (m, 2H), 5.34 (d, J=6.7 Hz, 1H), 4.98 (dd, J=6.6, 3.5 Hz, 1H), 4.59-4.50 (m, 1H), 4.36-4.22 (m, 2H), 4.02 (dd, J=10.9, 5.7 Hz, 1H), 3.91 (dd, J=10.9, 5.7 Hz, 1H), 3.83 (dq, J=9.7, 7.1 Hz, 1H), 1.70 (s, 3H), 1.50-1.41 (m, 1H), 1.39 (s, 3H), 1.36-1.21 (m, 7H), 0.86 (t, J=7.4 Hz, 6H). MS m/z=643.21 [M+1].

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - US2017/71964, 2017, A1 Location in patent: Paragraph 0668-0669

17
[ 1191237-80-5 ]
C₂₁H₂₃F₅NO₅P [ No CAS ]
2-ethylbutyl ((S)-(((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	Stage #1: (3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With tert-butylmagnesium chloride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: C₂₁H₂₃F₅NO₅P In tetrahydrofuran at 20℃; for 48h; Inert atmosphere;	1-3 Preparation of Compound I Under nitrogen protection, compound II (200mg, 0.60mmol) and anhydrous tetrahydrofuran 10mL were added to the reaction flask and lowered to 0°C ,Then a 1.3M solution of tert-butyl magnesium chloride (1.2 mL, 1.6 mmol) was slowly added dropwise.After stirring for 30 min, compound III (560 mg, 1.13 mmol) was added.The mixture was stirred at room temperature for 48 h, and then quenched with saturated aqueous NH 4 Cl (20 mL).The mixture was partitioned between ethyl acetate (50 mL) and water.The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated.The residue was chromatographed using a gradient method of 0-4% methanol/dichloromethane,188.94mg of white solid was obtained,The molar yield was 49% (ie 0.49 mole of white solid was obtained per mole of Compound II).

Reference： [1]Current Patent Assignee: JIANGSU FURUI KANGTAI PHARMACEUTICAL - CN111116656, 2020, A Location in patent: Paragraph 0008; 0018; 0020; 0023; 0025; 0027; 0029

18
C₃₀H₃₉N₆O₈P [ No CAS ]
[ 1191237-80-5 ]

Yield	Reaction Conditions	Operation in experiment
0.038 mol	With sodium carbonate In toluene at 30℃; for 5h;	1-3 Example 2 The mother liquor (50g) was dissolved in toluene (500ml), 20% sodium carbonate solution (100g) was added dropwise, and stirred at 30°C for 5h.TLC dot plate, nucleoside phosphoramidates and compound II are completely hydrolyzed.Let stand for liquid separation to obtain the water phase and the organic phase respectively.The obtained organic phase was dried with anhydrous sodium sulfate, filtered with suction,The filtrate was concentrated under reduced pressure to obtain 0.038 mol of compound I,The recovery rate is 95%. The resulting aqueous phase was adjusted to pH=3-4 with 1N sulfuric acid at 30°C, and the reaction solution was extracted with toluene (100ml*3).Combine the organic phases, dry the organic phases with anhydrous sodium sulfate,Suction filtration, vacuum distillation of the filtrate, sequential recovery of compound IV 0.1 mol, phenol 0.053 mol, and L-alanine 0.055 mol, the recovery rates were 89%, 88%, and 93%, respectively.

Reference： [1]Current Patent Assignee: JIANGSU FURUIKANGTAI PHARMACY - CN111269248, 2020, A Location in patent: Paragraph 0030; 0042-0047

19
[ 1191237-80-5 ]
C₂₂H₂₇F₃NO₆P [ No CAS ]
2-ethylbutyl ((S)-(((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3.15 g	With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; for 48h; Inert atmosphere;	1; 2; 3 Preparation of Compound I: Under the protection of nitrogen, add compound II (3.0 g, 9.06 mmol) and 250 mL of anhydrous tetrahydrofuran into the reaction flask, reduce to 0°C, and then slowly add 2.23 g (19.9 mmol) of potassium tert-butylate.After stirring for 30-40 min, compound III (7.5 g, 15.3 mmol) was added.The mixture was stirred at room temperature for 48h, then saturated NH4Quench with Cl aqueous solution (500 mL).The mixture was partitioned between ethyl acetate (1000 mL) and water.The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated.The residue was chromatographed using a 0-4% methanol/dichloromethane gradient method to obtain 3.15 g of a white solid with a molar yield of 54.1% (that is, 0.541 moles of white solids per mole of compound II).

Reference： [1]Current Patent Assignee: ALPHA PHARMACEUTICAL JIANGSU PROVINCE - CN111233930, 2020, A Location in patent: Paragraph 008; 0020; 0023; 0025; 0027; 0029

20
[ 1191237-80-5 ]
C₂₁H₂₄⁽²⁾H₃N₂O₇P [ No CAS ]
C₃₀H₃₆⁽²⁾H₃N₆O₈P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: (3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile; C₂₁H₂₄⁽²⁾H₃N₂O₇P With magnesium chloride In acetonitrile at 50℃; for 0.166667h; Stage #2: With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 0.333333h;	1 Take compound F-1 (0.65g, 0.001mol) and compound G (0.33g, 0.001mol), magnesium chloride (0.10g, 0.001mol) and 10mL acetonitrile, stir at 50°C for 10min, then add N,N-diisopropyl Ethylamine (0.39g, 0.003mol), stirred for 20min and then cooled to 20°C, concentrated under reduced pressure at 30-40°C to remove acetonitrile, then added 100mL ethyl acetate, the reaction solution was successively used with 5percent citric acid aqueous solution (20ml), saturated chlorine Ammonium hydroxide aqueous solution (20mL), 5percent sodium bicarbonate aqueous solution (20mL), and saturated brine (20mL) washed, the organic phase was concentrated under reduced pressure and purified by column chromatography (petroleum ether-ethyl acetate = 4:1) Off-white solid is compound H-1 (0.47 g, 73.0percent).

Reference： [1]Current Patent Assignee: CHENGDU ACHI BIOPHARMACEUTICAL TECH - CN111233929, 2020, A Location in patent: Paragraph 0050; 0052; 0056

21
[ 1191237-80-5 ]
C₁₈H₁₈N₃O₇PS [ No CAS ]
C₂₇H₃₀N₇O₈PS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.45 g	With N-ethyl-N,N-diisopropylamine; magnesium chloride In acetonitrile at 50℃; for 1h;	1.1.1 At room temperature, add 16mL acetonitrile, 1.1g compound 2 (3.32mmol), 1.79g compound 3 (3.98mmol), 31.6mg magnesium chloride (3.32mmol) into a 100mL eggplant-shaped flask, heat to 50, add 1.45mL N,N-di Isopropylethylamine (3.32mmol), after reacting for 1 hour, cool to room temperature, dilute with 100mL ethyl acetate, wash with 5% citric acid water, 5% sodium bicarbonate water, saturated sodium chloride water, and distilled water. Dry with anhydrous sodium sulfate. The solvent was evaporated, and silica gel column chromatography (petroleum ether-ethyl acetate) was used to obtain 1.45 g of compound 4.

Reference： [1]Current Patent Assignee: NANJING MEDICAL UNIVERSITY - CN111320650, 2020, A Location in patent: Paragraph 0013-0016; 0019

22
(2S)-2-ethylbutyl 2-(((S)-(perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate [ No CAS ]
[ 1191237-80-5 ]
2-ethylbutyl ((((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81.6%	Stage #1: (3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With tert-butylmagnesium chloride In tetrahydrofuran at -10 - 0℃; for 1h; Inert atmosphere; Stage #2: (2S)-2-ethylbutyl 2-(((S)-(perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate In tetrahydrofuran at -5 - 0℃; Inert atmosphere;	1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 13; 14; 15; 16; 17; 18; 19; 20; 21 Example 1 Add compound 1 (33.13g, 100mmol) and tetrahydrofuran solution (200mL) to the reaction flask under the protection of N2, cool to -10-5 in an ice-salt bath, and slowly add 1.0M tert-butyl magnesium chloride tetrahydrofuran solution (110mmol, 110mL) ), keep -50 and stir for 1 hour. Compound 2 (52.01g, 105mmol) was prepared with 100mL of tetrahydrofuran solution (1.05mmol/mL) and slowly dropped into the reaction flask, kept at -50 and stirred for 23 hours. At the end of the reaction, 331mL of 10% ammonium chloride was added to quench the reaction, most of the tetrahydrofuran was removed under reduced pressure, extracted with 165mL of ethyl acetate 3 times, the organic phase was washed once with 165mL of saturated brine, concentrated, added with petroleum ether to make a slurry, and filtered to obtain the compound 3 (53.89 g, purity 97.3%, yield 81.6%).

Reference： [1]Current Patent Assignee: HANGZHOU CHEMINSPIRE TECH; SHANDONG KECHAO BIOPHARMACEUTICAL - CN111848679, 2020, A Location in patent: Paragraph 0033-0043

23
[ 1355049-92-1 ]
[ 1191237-80-5 ]
2-ethylbutyl ((S)-(((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	Stage #1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With 2,6-dimethylpyridine; C₁₇H₂₁N₃O₂ In dichloromethane at -20 - 20℃; for 0.333333h; Molecular sieve; Inert atmosphere; Stage #2: 2-ethylbutyl (2S)-2-[chloro(phenoxy)phosphoryl]amino}propanoate In dichloromethane at -20℃; for 24h; stereoselective reaction;	1.2.1 1.2.1 General Procedure for the Catalytic Asymmetric Phosphoramidation In a flame dried round bottom flask, a mixture of acetonide-nucleoside acceptor 7 (10.0 mg, 0.03 mmol) and catalyst (mol% was according to Table 1 below) were co- evaporated with anhydrous toluene (1.0 mL, 2 times), dried for 2 h on high-vacuum. The mixture was dissolved in dry CH2Cl2 (1.0 mL) and then freshly activated 4Å molecular sieves (20 mg) followed by 2,6-luditine (7.0 μL, 0.06 mmol) were added. The suspension was then stirred under N2 atmosphere at room temparature for 10 min, and then cooled to -20 °C. After 10 min, a solution of phosphochloridate 4 (15.7 mg, 0.05 mmol) in dry CH2Cl2 (0.5 mL) was added and the reaction mixture was allowed to stir at same temperature for 24 h. TLC analysis indicates the complete conversion of starting materials into the products. The whole reaction mixture was filtered through a pad of Celite, the filtrate was concentrated in vacuo. The crude residue was dissolved in MeOH and filtered off. The filtrate was subjected to HPLC analysis.
95%	Stage #1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With 2,6-dimethylpyridine; C₁₇H₂₁N₃O₂ In dichloromethane at -40 - 20℃; for 0.333333h; Inert atmosphere; Molecular sieve; Stage #2: 2-ethylbutyl (2S)-2-[chloro(phenoxy)phosphoryl]amino}propanoate In dichloromethane at 4 - 20℃; for 24h; Inert atmosphere; Molecular sieve; stereoselective reaction;
90%	Stage #1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With 2,6-dimethylpyridine; (S)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl adamantan-1-ylcarbamate In dichloromethane at -40℃; for 0.166667h; Inert atmosphere; Molecular sieve; Stage #2: 2-ethylbutyl (2S)-2-[chloro(phenoxy)phosphoryl]amino}propanoate In dichloromethane at -40℃; for 48h; Sealed tube; Molecular sieve; Inert atmosphere; diastereoselective reaction;

Reference： [1]Current Patent Assignee: ACADEMIA SINICA; SHIH MING CHE - WO2022/76638, 2022, A1 Location in patent: Paragraph 0130-0133
[2]Gannedi, Veeranjaneyulu; Villuri, Bharath Kumar; Reddy, Sivakumar N.; Ku, Chiao-Chu; Wong, Chi-Huey; Hung, Shang-Cheng [Journal of Organic Chemistry, 2021, vol. 86, # 7, p. 4977 - 4985]
[3]Chen, Jianzhong; Huo, Xiaohong; Li, Panpan; Wang, Mo; Wu, Zhengxing; Yuan, Qianjia; Zhang, Lu; Zhang, Wanbin; Zhang, Zhenfeng; Zou, Yashi [Angewandte Chemie - International Edition, 2020, vol. 59, # 47, p. 20814 - 20819][Angew. Chem., 2020, vol. 132, # 47, p. 21000 - 21005,6]

24
[ 1355049-92-1 ]
[ 1191237-80-5 ]
2-ethylbutyl ((S)-(((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate [ No CAS ]
2-ethylbutyl ((((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88.636 % de	Stage #1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With 2,6-dimethylpyridine; (S)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl adamantan-1-ylcarbamate In dichloromethane at -30℃; for 0.166667h; Inert atmosphere; Molecular sieve; Schlenk technique; Stage #2: 2-ethylbutyl (2S)-2-[chloro(phenoxy)phosphoryl]amino}propanoate In dichloromethane at -30℃; for 16h; Sealed tube; Molecular sieve; Inert atmosphere; Schlenk technique; diastereoselective reaction;
50 % de	Stage #1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With 2,6-dimethylpyridine; C₁₇H₂₁N₃O₂ In dichloromethane at -40 - 20℃; for 0.333333h; Inert atmosphere; Molecular sieve; Stage #2: 2-ethylbutyl (2S)-2-[chloro(phenoxy)phosphoryl]amino}propanoate In dichloromethane at 4 - 20℃; for 24h; Inert atmosphere; Molecular sieve; Overall yield = 67 percent; stereoselective reaction;
89.189 % de	With 2,6-dimethylpyridine; (S)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl adamantan-1-ylcarbamate In dichloromethane at -30℃; for 12h; Inert atmosphere; Molecular sieve; Overall yield = 71 percent; Overall yield = 92 mg; stereoselective reaction;	1-37 Example 30: Preparation of Phosphochiral Nucleoside Derivative (3) In a dry 10mL reaction tube, add nucleoside 1 (66.3mg, 0.2mmol, 1.0eq), bicyclic imidazole catalyst C15 (12.1mg, 0.04mmol, 0.2eq) andmolecular sieves (80.0mg), and then the system is vacuum-exchanged Nitrogen three times.Then the solvent dichloromethane (2 mL) and the base 2,6-lutidine (46.6 μL, 0.4 mmol, 2.0 eq) were added sequentially.Phosphorus oxychloride 2 (104.3 mg, 0.3 mmol, 1.5 eq) was added dropwise to the reaction system at -30°C and stirred for 12 hours.Then, 0.5 mL of methanol was added to quench for 30 minutes, and then it was brought to room temperature.The solvent was removed by rotary evaporation, and the diastereomer ratio (dr) measured by crude NMR was 17.5:1.Using petroleum ether/ethyl acetate volume ratio of 1/10 as mobile phase, silica gel column chromatography (particle size 100-200 mesh, specific surface area 300-400 m2/g) was used to isolate product 3 (92.0 mg, yield 71%).

87.2 % de	Stage #1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With 2,6-dimethylpyridine; (S)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl tert-butylcarbamate In dichloromethane at -20 - 20℃; for 0.333333h; Molecular sieve; Inert atmosphere; Stage #2: 2-ethylbutyl (2S)-2-[chloro(phenoxy)phosphoryl]amino}propanoate In dichloromethane at -20℃; for 24h; Overall yield = 94 percent;	1.2.1 1.2.1 General Procedure for the Catalytic Asymmetric Phosphoramidation In a flame dried round bottom flask, a mixture of acetonide-nucleoside acceptor 7 (10.0 mg, 0.03 mmol) and catalyst (mol% was according to Table 1 below) were co- evaporated with anhydrous toluene (1.0 mL, 2 times), dried for 2 h on high-vacuum. The mixture was dissolved in dry CH2Cl2 (1.0 mL) and then freshly activated 4Å molecular sieves (20 mg) followed by 2,6-luditine (7.0 μL, 0.06 mmol) were added. The suspension was then stirred under N2 atmosphere at room temparature for 10 min, and then cooled to -20 °C. After 10 min, a solution of phosphochloridate 4 (15.7 mg, 0.05 mmol) in dry CH2Cl2 (0.5 mL) was added and the reaction mixture was allowed to stir at same temperature for 24 h. TLC analysis indicates the complete conversion of starting materials into the products. The whole reaction mixture was filtered through a pad of Celite, the filtrate was concentrated in vacuo. The crude residue was dissolved in MeOH and filtered off. The filtrate was subjected to HPLC analysis.
43.8 % de	Stage #1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With 2,6-dimethylpyridine; C₃₈H₄₀N₆O₄ In dichloromethane at -20 - 20℃; for 0.333333h; Molecular sieve; Inert atmosphere; Stage #2: 2-ethylbutyl (2S)-2-[chloro(phenoxy)phosphoryl]amino}propanoate In dichloromethane at -20℃; for 24h; Overall yield = 96 percent;	1.2.1 1.2.1 General Procedure for the Catalytic Asymmetric Phosphoramidation In a flame dried round bottom flask, a mixture of acetonide-nucleoside acceptor 7 (10.0 mg, 0.03 mmol) and catalyst (mol% was according to Table 1 below) were co- evaporated with anhydrous toluene (1.0 mL, 2 times), dried for 2 h on high-vacuum. The mixture was dissolved in dry CH2Cl2 (1.0 mL) and then freshly activated 4Å molecular sieves (20 mg) followed by 2,6-luditine (7.0 μL, 0.06 mmol) were added. The suspension was then stirred under N2 atmosphere at room temparature for 10 min, and then cooled to -20 °C. After 10 min, a solution of phosphochloridate 4 (15.7 mg, 0.05 mmol) in dry CH2Cl2 (0.5 mL) was added and the reaction mixture was allowed to stir at same temperature for 24 h. TLC analysis indicates the complete conversion of starting materials into the products. The whole reaction mixture was filtered through a pad of Celite, the filtrate was concentrated in vacuo. The crude residue was dissolved in MeOH and filtered off. The filtrate was subjected to HPLC analysis.

Reference： [1]Chen, Jianzhong; Huo, Xiaohong; Li, Panpan; Wang, Mo; Wu, Zhengxing; Yuan, Qianjia; Zhang, Lu; Zhang, Wanbin; Zhang, Zhenfeng; Zou, Yashi [Angewandte Chemie - International Edition, 2020, vol. 59, # 47, p. 20814 - 20819][Angew. Chem., 2020, vol. 132, # 47, p. 21000 - 21005,6]
[2]Gannedi, Veeranjaneyulu; Villuri, Bharath Kumar; Reddy, Sivakumar N.; Ku, Chiao-Chu; Wong, Chi-Huey; Hung, Shang-Cheng [Journal of Organic Chemistry, 2021, vol. 86, # 7, p. 4977 - 4985]
[3]Current Patent Assignee: SHANGHAI JIAO TONG UNIVERSITY - CN113754693, 2021, A Location in patent: Paragraph 0037-0110
[4]Current Patent Assignee: ACADEMIA SINICA; SHIH MING CHE - WO2022/76638, 2022, A1 Location in patent: Paragraph 0130-0133
[5]Current Patent Assignee: ACADEMIA SINICA; SHIH MING CHE - WO2022/76638, 2022, A1 Location in patent: Paragraph 0130-0133

25
2-ethylbutyl (2S)-2-((S)-((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate [ No CAS ]
[ 1191237-80-5 ]
C₄₅H₆₀N₆O₁₃P₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21.6 g	With N-ethyl-N,N-diisopropylamine; magnesium chloride In acetonitrile at 50℃; for 3h;	Add 10.0g compound -A into the reaction flask,Then add 34.0g compound -B,120g acetonitrile,7.2g magnesium chloride.Then control the internal temperature to 50,9.8g of N,N-diisopropylethylamine was added dropwise.After 3 hours of reaction,Add 200 g of water and 200 g of ethyl acetate, and separate the layers.Use 10% citric acid solution,10% sodium carbonate solution,Wash with saturated sodium chloride aqueous solution,Concentrate under reduced pressure to remove the solvent,21.6 g of compound I-C was obtained by crystallization.

Reference： [1]Current Patent Assignee: NANJING ZHENGJI MEDICINE RES; ZENJI RES LABORATORIES - CN111961079, 2020, A Location in patent: Paragraph 0025; 0026

26
[ 1355049-92-1 ]
[ 1191237-80-5 ]
[ 1809249-37-3 ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With 2,6-dimethylpyridine; C₁₇H₂₁N₃O₂ In dichloromethane at -20 - 20℃; for 0.333333h; Inert atmosphere; Molecular sieve; Stage #2: 2-ethylbutyl (2S)-2-[chloro(phenoxy)phosphoryl]amino}propanoate In dichloromethane at -20 - 20℃; for 24h; Inert atmosphere; Molecular sieve; Stage #3: With toluene-4-sulfonic acid In methanol at 20℃; for 24h; Inert atmosphere;
73%	Stage #1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With 2,6-dimethylpyridine; C₁₇H₂₁N₃O₂ In dichloromethane at -20 - 20℃; for 0.333333h; Molecular sieve; Inert atmosphere; Stage #2: 2-ethylbutyl (2S)-2-[chloro(phenoxy)phosphoryl]amino}propanoate In dichloromethane at -20℃; for 24h; Stage #3: With toluene-4-sulfonic acid In methanol at 20℃; for 24h;	2 In a flame dried round bottom flask, a mixture of acetonide-nucleoside acceptor 7 (1.0 g, 3.02 mmol) and catalyst 29 (180 mg, 0.62 mmol) were co-evaporated with anhydrous toluene (20 mL, 2 times), dried for 2 h on high-vacuum. The mixture was dissolved in dry CH2Cl2 (50 mL) and then freshly activated 4Å molecular sieves (1.5 g) followed by 2,6-luditine (700 μL, 6.04 mmol) were added. The suspension was then stirred under N2 atmosphere at room temparature for 10 min, and then cooled to -20 °C. After 10 min, a solution of phosphochloridate 4 (1.57 g, 4.53 mmol) in dry CH2Cl2 (5 mL) was added and the reaction mixture was allowed to stir at same temperature for 24 h. TLC analysis indicates the complete conversion of starting materials into the products. Then the CH2Cl2 was evaporated by vacuum. Later on, the crude material was treated with 10.0 equiv of p-TSA in MeOH (50 mL). The reaction mixture was allowed to stir for 24 h at room temperature and the TLC analysis indicated the product formation. Then the reaction mixture was filtered through a pad of Celite to remove 4Å molecular sieves, quenched by adding Et3N and concentrated in vacuo. The crude residue was dissolved in EtOAc and washed with Saturated NaHCO3, the aqueous layer was back extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude residue was subjected to silica gel column chromatography by using EtOAc in hexane (0→ 100%) as an eluent to afford the products as a foamy solid. The diastereomeric mixture was purified by using C 18 column to give compound 1 as a foamy solid (1.39 g, 73%). 1H NMR (600 MHz, CD3OD) δ 7.87 (s, 1H), 7.30 (t, J = 7.8 Hz, 2H), 7.21- 7.14 (m, 3H), 6.91 (d, J= 4.6 Hz, 1H), 6.88 (d, J= 4.6 Hz, 1H), 4.79 (d, J= 5.4 Hz, 1H), 4.42-4.35 (m, 2H), 4.28 (dt, J= 10.5, 5.1 Hz, 1H), 4.17 (t, J= 5.6 Hz, 1H), 4.02 (dd, J= (0148) 10.9, 5.8 Hz, 1H), 3.90 (ddd, J= 23.7, 12.7, 6.4 Hz, 2H), 1.45 (dt, J= 12.3, 6.2 Hz, 1H), 1.34-1.28 (m, TH), 0.85 (t, J= 7.5 Hz, 6H). 13C NMR (150 MHz, CD3OD) δ 175.15, 175.1, 157.4, 152.3, 152.3, 148.4, (0150) 130.9, 126.2, 125.7, 121.51, 121.5, 118.1, 117.7, 112.5, 102.8, 84.44, 81.4, 84.4, 75.9, 71.8, 68.2, 67.3, 67.27, 41.8, 24.4, 24.3, 20.7, 20.6, 11.5, 11.4.
	Multi-step reaction with 2 steps 1.1: C₁₇H₂₁N₃O₂; 2,6-dimethylpyridine / dichloromethane / 0.33 h / -40 - 20 °C / Inert atmosphere; Molecular sieve 1.2: 24 h / 4 - 20 °C / Inert atmosphere; Molecular sieve 2.1: hydrogenchloride / tetrahydrofuran; lithium hydroxide monohydrate / 20 °C / Inert atmosphere

	Multi-step reaction with 2 steps 1.1: C₁₇H₂₁N₃O₂; 2,6-dimethylpyridine / dichloromethane / 0.33 h / -40 - 20 °C / Inert atmosphere; Molecular sieve 1.2: 24 h / 4 - 20 °C / Inert atmosphere; Molecular sieve 2.1: hydrogenchloride / tetrahydrofuran; lithium hydroxide monohydrate / 20 °C / Inert atmosphere
100 mg	Stage #1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With tert-butylmagnesium chloride In tetrahydrofuran at -40 - 30℃; Stage #2: 2-ethylbutyl (2S)-2-[chloro(phenoxy)phosphoryl]amino}propanoate In tetrahydrofuran at -40 - 10℃;	7 (2S)-2-ethylbutyl 2-(((((2R,3S,4R,5R)-5(4-aminopyrrolo[2, triazin-7-yl)-5-cyano-3,4-dihydroxy oxalan-2-yl]methoxy)(phenoxy)phosphoryl)amino)propanoate To the compound (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile (25 gm) of example 5 was added THF (250 ml) at 30±5° C. to obtain the homogenous mass. Gradually cooled to -40±3° C. and slowly added t-BuMgCl (87 ml) at -40±3° C. over a period of 30-45 10 mins, stirred, and slowly added 2-ethylbutyl (chloro(phenoxy)phosphoryl)-L-alaninate (56 ml) dissolved in THF(150 ml) at -40±3 oC. Gradually raised the temperature to 10±5° C., stirred. After testing with HPLC, cooled the reaction mass at -40±3° C., quenched the reaction mass with methanol (250 ml), stirred, raised the temperature to 25±5° C., charged DCM (750 ml), and 10% ammonium chloride (500 ml), stirred washed the organic layer with 5% K2CO3, allowed to settle, separated the organic layer and dried over sodium sulfate (80 gm) and distilled the solvent under vacuum at below 45° C. to obtain the solid mass. Cooled the mass to 10-15° C., added water (2000 ml) and MDC (1000 ml), stirred and allowed to settle. Separated the lower MDC layer and to the aqueous layer was added MDC (500 ml) stirred and settled and separated the lower MDC layer. To the total organic layer was added brine solution, stirred, separated lower MDC layer, cooled to 0-5° C., adjusted the pH to 6.5 with NaHCO3, stirred, settled, separated the MDC and aq. layer and to the combined organic layer was added brine. Distilled the MDC layer to obtain crude (2S)-2-ethylbutyl 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (phenoxy)phosphoryl)amino) propanoate. Yield 96 to 100 gm

Reference： [1]Gannedi, Veeranjaneyulu; Villuri, Bharath Kumar; Reddy, Sivakumar N.; Ku, Chiao-Chu; Wong, Chi-Huey; Hung, Shang-Cheng [Journal of Organic Chemistry, 2021, vol. 86, # 7, p. 4977 - 4985]
[2]Current Patent Assignee: ACADEMIA SINICA; SHIH MING CHE - WO2022/76638, 2022, A1 Location in patent: Paragraph 0137; 0139-0142
[3]Gannedi, Veeranjaneyulu; Villuri, Bharath Kumar; Reddy, Sivakumar N.; Ku, Chiao-Chu; Wong, Chi-Huey; Hung, Shang-Cheng [Journal of Organic Chemistry, 2021, vol. 86, # 7, p. 4977 - 4985]
[4]Gannedi, Veeranjaneyulu; Villuri, Bharath Kumar; Reddy, Sivakumar N.; Ku, Chiao-Chu; Wong, Chi-Huey; Hung, Shang-Cheng [Journal of Organic Chemistry, 2021, vol. 86, # 7, p. 4977 - 4985]
[5]Current Patent Assignee: ANZALP PHARMASOLUTIONS PVT - US2021/161927, 2021, A1 Location in patent: Paragraph 0088

27
(2S)-2-ethylbutyl 2-(((S)-(perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate [ No CAS ]
[ 1191237-80-5 ]
2-ethylbutyl ((S)-(((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; magnesium chloride In tetrahydrofuran at 10 - 20℃; for 2h;	1-3 Example 1 Synthesis of INT: Weigh 100.02g compound 1((3αR,4R,6R,6αR)-4-(4-aminopyrrole[2,1-f][1,2,4]triazine-7-yl)- 6-(Methoxy) -2,2-Dimethyltetrahydrofuran [3,4-d][1,3]dioxolane-4-carbonitrile), added to 800ml tetrahydrofuran solution, Stir to dissolve. Add 157.05g of compound 2 (2-ethylbutyl((S)-(pentafluorophenoxy)(phenoxy)phosphoryl)-L-alanine ester)) , Stir, then add 30.02g of magnesium chloride and stir. The temperature was lowered to 10-20°C, and 98.01g of triethylamine was added dropwise. After the dripping is completed, the reaction is incubated for 2h, sampled, and detected by HPLC. Compound 1 remains 0.97% and isomer impurities 0.09%.

Reference： [1]Current Patent Assignee: SUZHOU ZHENGJI PHARMACEUTICAL - CN112645982, 2021, A Location in patent: Paragraph 0023-0028

28
2-ethylbutyl (2S)-2-((S)-((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate [ No CAS ]
[ 1191237-80-5 ]
C₃₀H₃₉N₆O₈P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With N-ethyl-N,N-diisopropylamine; magnesium chloride In acetonitrile at 50℃; for 0.0161111h; Flow reactor;	9-12 Weigh 5.82g (20mmol, 1.0equiv) of intermediate NuC and dissolve it in acetone,Add 11.0mL 2,2-dimethoxypropane (90mmol, 4.5equiv) to make a 50mL solution,Loaded in syringe 1; measure 3.0mL sulfuric acid (10M, 30mmol, 1.5equiv),Load in syringe 2; weigh 10.8 g (24mmol, 1.2equiv) of Intermediate 6Weigh 1.9g (20mmol, 1.0equiv) of magnesium chloride (MgCl2) and add it to acetonitrile,Prepare 100mL solution and load it in Syringe 3; Measure 8.2mL (iPr)2NEt (50mmol, 2.5equiv), add to acetonitrile, make 50mL solution, and load it in Syringe 4; Measure 20mL (240mmol) of 37% hydrochloric acid ,12.0equiv), loaded in the syringe 5.Simultaneously pump the reaction solution of Syringe 1 and Syringe 2. Syringe 1 has a pumping flow rate of 2.0 mL/min, and Syringe 2 has a pumping flow rate of 0.12 mL/min. After mixing, they are transported to microchannel reactor A (inner diameter 1.0 mm, length 10m, volume 7.8 mL), the residence time is 3.7min, and the reaction temperature is 45°C.Then pump the reaction solution of Syringe 3 and Syringe 4 to mix with the above reaction solution in sequence. Syringe 3 has a pumping flow rate of 4.0 mL/min, and Syringe 4 has a pumping flow rate of 2.0 mL/min. After mixing, it is transported to the microchannel reactor B (inner diameter). 1.0mm, length 10m, volume 7.8mL) in the reaction,The residence time is 58s, and the reaction temperature is 50°C.Finally, pump the reaction liquid into the syringe 5 to mix with the above reaction liquid, and the flow rate of the pump is 0.8mL/min,After mixing, it was transported to microchannel reactor C (inner diameter 1.0 mm, length 20 m, volume 15.7 mL) for reaction, with a residence time of 1.8 min, and a reaction temperature of 25°C.The effluent was collected, extracted, distilled under reduced pressure, and silica gel column chromatography to obtain 6.62 g of Radixivir (GS-5734), with a total yield of 53%.

Reference： [1]Current Patent Assignee: NANJING INSTITUTE OF ADVANCED BIOMATERIALS PROC EQUIPMENT - CN112679542, 2021, A Location in patent: Paragraph 0046; 0096-0107; 0119

29
(2S,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol [ No CAS ]
[ 1191237-80-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: trimethylsilyl trifluoromethanesulfonate; trifluorormethanesulfonic acid / dichloromethane / 0.07 h / Flow reactor 2: boron trichloride; triethylamine; methanol / dichloromethane / 0.04 h / Flow reactor 3: sulfuric acid / acetone / 0.06 h / Flow reactor

Reference： [1]Current Patent Assignee: NANJING INSTITUTE OF ADVANCED BIOMATERIALS PROC EQUIPMENT - CN112679542, 2021, A

30
[ 1191237-80-5 ]
2-ethylbutyl ((S)-(((2R,3S,4R,5R)-5-(4-amino-5-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: Selectfluor; sodium hydrogencarbonate / acetonitrile / 24 h / 20 °C 2.1: methylmagnesium bromide / tetrahydrofuran; 2-methyltetrahydrofuran / 0.08 h / Cooling with ice 2.2: 2 h / 20 °C 3.1: hydrogenchloride / water; tetrahydrofuran / 20 °C / Cooling with ice

Reference： [1]Current Patent Assignee: Shanghai Institute of Materia Medica (in: CAS); WUHAN INST OF VIROLOGY CHINESE ACADEMY OF SCIENCE; SUZHOU WANGSHAN WANGSHUI BIOMEDICAL CO LTD; CHINESE ACADEMY OF SCIENCES - CN112778310, 2021, A

31
[ 1191237-80-5 ]
C₃₀H₃₈FN₆O₈P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: Selectfluor; sodium hydrogencarbonate / acetonitrile / 24 h / 20 °C 2.1: methylmagnesium bromide / tetrahydrofuran; 2-methyltetrahydrofuran / 0.08 h / Cooling with ice 2.2: 2 h / 20 °C

Reference： [1]Current Patent Assignee: Shanghai Institute of Materia Medica (in: CAS); WUHAN INST OF VIROLOGY CHINESE ACADEMY OF SCIENCE; SUZHOU WANGSHAN WANGSHUI BIOMEDICAL CO LTD; CHINESE ACADEMY OF SCIENCES - CN112778310, 2021, A

32
[ 1191237-80-5 ]
C₁₅H₁₅N₅O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene; sodium hydrogencarbonate In water; acetonitrile at 20℃; for 5h;	7 Compound 10-1 (0.25g, 0.75mmol) was added to acetonitrile/water (V/V=1/1, 15mL), followed by TEMPO (0.047g, 0.3mmol, 0.4eq) and iodobenzene diacetate (1.06g) , 3.3mmol, 4.4eq), sodium bicarbonate (0.25g, 3mmol, 4.0eq), after the addition, stirred at room temperature for about 5 hours, TLC showed that the reaction was complete. The reaction solution was added to 0.5M sodium hydroxide solution (20mL), ethyl acetate (20mL×2) was extracted twice, the organic phase was discarded, the aqueous layer was adjusted to pH 4-5 with dilute hydrochloric acid (2M), (50 mL×2) extraction, combined organic layers, dried, and concentrated to obtain compound 10-2, 0.23 g of white solid, with a yield of 89%.

Reference： [1]Current Patent Assignee: Shanghai Institute of Materia Medica (in: CAS); WUHAN INST OF VIROLOGY CHINESE ACADEMY OF SCIENCE; SUZHOU WANGSHAN WANGSHUI BIOMEDICAL CO LTD; CHINESE ACADEMY OF SCIENCES - CN112778310, 2021, A Location in patent: Paragraph 0315-0316; 0318

33
[ 1191237-80-5 ]
C₁₅H₁₆FN₅O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	With sodium hydrogencarbonate; Selectfluor In acetonitrile at 20℃; for 24h;	9 Preparation Example 9: Synthesis of Compound A12 Compound 10-1 (662mg, 2.0mmol) was added to acetonitrile (15mL), sodium bicarbonate (336mg, 4mmol, 2eq) and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2 .2] Octane bis(tetrafluoroborate) salt (850 mg, 2.4 mmol, 1.2 eq), stirred at room temperature for 24 hours, TLC showed that some raw materials remained. Ethyl acetate (50 mL) and water (20 mL) were added to the reaction solution, the organic phase was separated, dried, concentrated, and separated by silica gel column chromatography to obtain compound 12-1, an off-white solid 140 mg, with a yield of 20%.

Reference： [1]Current Patent Assignee: Shanghai Institute of Materia Medica (in: CAS); WUHAN INST OF VIROLOGY CHINESE ACADEMY OF SCIENCE; SUZHOU WANGSHAN WANGSHUI BIOMEDICAL CO LTD; CHINESE ACADEMY OF SCIENCES - CN112778310, 2021, A Location in patent: Paragraph 0329-0331

34
[ 1191237-80-5 ]
((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: toluene / 60 °C 2: dmap; triethylamine / dichloromethane / 20 °C 3: hydrogenchloride / water monomer; tetrahydrofuran / 3 h / 20 °C / Cooling with ice
	Multi-step reaction with 2 steps 1.1: dmap / dichloromethane / 0.17 h 1.2: 24 h / 20 °C 2.1: hydrogenchloride / tetrahydrofuran; water monomer / 6 h
	Multi-step reaction with 2 steps 1: dmap / tetrahydrofuran 2: hydrogenchloride; water monomer / tetrahydrofuran / 4 h / 20 °C

	Multi-step reaction with 2 steps 1: diisopropyl-carbodiimide; dmap / N,N-dimethyl-formamide / 4 h / 20 °C 2: hydrogenchloride; water monomer / tetrahydrofuran / 4 h / 20 °C
	Multi-step reaction with 3 steps 1: dmap / tetrahydrofuran 2: hydrogenchloride; water monomer / acetonitrile / 20 °C 3: Potassium bicarbonate / water monomer; 2-methyltetrahydrofuran / 20 °C
	Multi-step reaction with 3 steps 1: diisopropyl-carbodiimide; dmap / N,N-dimethyl-formamide / 4 h / 20 °C 2: hydrogenchloride; water monomer / acetonitrile / 20 °C 3: Potassium bicarbonate / water monomer; 2-methyltetrahydrofuran / 20 °C

Reference： [1]Current Patent Assignee: Shanghai Institute of Materia Medica (in: CAS); WUHAN INST OF VIROLOGY CHINESE ACADEMY OF SCIENCE; SUZHOU WANGSHAN WANGSHUI BIOMEDICAL CO LTD; CHINESE ACADEMY OF SCIENCES - CN112778310, 2021, A
[2]Current Patent Assignee: SOUTHERN UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA; SUN YAT-SEN UNIVERSITY (CHINA) - CN113735862, 2021, A
[3]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/47065, 2022, A2
[4]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/47065, 2022, A2
[5]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/47065, 2022, A2
[6]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/47065, 2022, A2

35
[ 1191237-80-5 ]
[ 4637-24-5 ]
C₁₉H₂₄N₆O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	In toluene at 60℃;	12 Preparation Example 12: Synthesis of Compound A50 Compound 10-1 (0.664g, 2.0mmol) was added to toluene (10mL), N,N-dimethylformamide dimethyl acetal (0.47g, 4.0mmol, 2.0eq) was added, after addition, 60 After reacting for 2-3 hours, TLC monitors that the reaction is complete. The solvent was evaporated to obtain compound 50-1, 0.65 g of yellow solid, with a yield of 84%.

Reference： [1]Current Patent Assignee: Shanghai Institute of Materia Medica (in: CAS); WUHAN INST OF VIROLOGY CHINESE ACADEMY OF SCIENCE; SUZHOU WANGSHAN WANGSHUI BIOMEDICAL CO LTD; CHINESE ACADEMY OF SCIENCES - CN112778310, 2021, A Location in patent: Paragraph 0346-0348

36
(3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile [ No CAS ]
[ 77-76-9 ]
[ 1191237-80-5 ]

Yield	Reaction Conditions	Operation in experiment
50 mg	Stage #1: (3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile; 2,2-dimethoxy-propane With potassium carbonate; toluene-4-sulfonic acid In acetone at 30℃; for 0.25h; Stage #2: With toluene-4-sulfonic acid In Isopropyl acetate for 1h;	5 Preparation of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile To the compound (3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile was added 2,2 dimethoxy propane (104 ml) in acetone (250 ml) at 30±5° C., stirred the reaction mass for 15 mins and charged PTSA at the same temperature, stirred the reaction mass, slowly added isopropyl acetate (100 ml) at the same temperature and stirred the reaction mass for an hr. After completion of the reaction (by TLC), filtered the solid and washed with heptane and isopropyl acetate (250 ml) in 2:1 ratio to obtain the solid, which is vacuum dried. Charged ethyl acetate (500 ml) and charged 5% potassium carbonate solution (500 ml) and back extracted the aqueous mass into ethyl acetate, combined the organic layers, washed with water and dried over sodium sulfate (50 gm). Distilled solvent under vacuum below 45° C., added heptane (500 ml), stirred and filtered the product, washed the product with heptane (50 ml); such dried followed by vacuum dried below 30° C. and further dried at 40° C., to obtain the product. Yield: 45-50 gm; HPLC purity: NLT 98.0%

Reference： [1]Current Patent Assignee: ANZALP PHARMASOLUTIONS PVT - US2021/161927, 2021, A1 Location in patent: Paragraph 0086

37
[ 1191237-80-5 ]
cyclobutylmethyl ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate [ No CAS ]
cyclobutylmethyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f ][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	Stage #1: (3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile; cyclobutylmethyl ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate With magnesium chloride In acetonitrile at 50℃; for 0.25h; Sealed tube; Stage #2: With N-ethyl-N,N-diisopropylamine In acetonitrile for 2h; Heating; Stage #3: With hydrogenchloride In tetrahydrofuran; water for 4h;

Reference： [1]Mackman, Richard L.; Hui, Hon C.; Perron, Michel; Murakami, Eisuke; Palmiotti, Christopher; Lee, Gary; Stray, Kirsten; Zhang, Lijun; Goyal, Bindu; Chun, Kwon; Byun, Daniel; Siegel, Dustin; Simonovich, Scott; Du Pont, Venice; Pitts, Jared; Babusis, Darius; Vijjapurapu, Arya; Lu, Xianghan; Kim, Cynthia; Zhao, Xiaofeng; Chan, Julie; Ma, Bin; Lye, Diane; Vandersteen, Adelle; Wortman, Sarah; Barrett, Kimberly T.; Toteva, Maria; Jordan, Robert; Subramanian, Raju; Bilello, John P.; Cihlar, Tomas [Journal of Medicinal Chemistry, 2021, vol. 64, # 8, p. 5001 - 5017]

38
(2S)-2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propionic acid cyclooctyl ester [ No CAS ]
[ 1191237-80-5 ]
cyclooctyl ((((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f ][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With N-ethyl-N,N-diisopropylamine; magnesium chloride In tetrahydrofuran at 50℃; for 3h;

Reference： [1]Mackman, Richard L.; Hui, Hon C.; Perron, Michel; Murakami, Eisuke; Palmiotti, Christopher; Lee, Gary; Stray, Kirsten; Zhang, Lijun; Goyal, Bindu; Chun, Kwon; Byun, Daniel; Siegel, Dustin; Simonovich, Scott; Du Pont, Venice; Pitts, Jared; Babusis, Darius; Vijjapurapu, Arya; Lu, Xianghan; Kim, Cynthia; Zhao, Xiaofeng; Chan, Julie; Ma, Bin; Lye, Diane; Vandersteen, Adelle; Wortman, Sarah; Barrett, Kimberly T.; Toteva, Maria; Jordan, Robert; Subramanian, Raju; Bilello, John P.; Cihlar, Tomas [Journal of Medicinal Chemistry, 2021, vol. 64, # 8, p. 5001 - 5017]

39
C₁₇H₂₁N₅O₆ [ No CAS ]
[ 77-76-9 ]
[ 1191237-80-5 ]

Yield	Reaction Conditions	Operation in experiment
1.9 mmol	With toluene-4-sulfonic acid In acetone at 20 - 30℃; for 2h;	15 Example 15.1 Preparation of Compound 7b Compound 5-1 (2mmol)Dissolved in acetone (10mL)And 2,2-dimethoxypropane (5mL),Adjust the pH to 1 with anhydrous p-toluenesulfonic acid,Stir at 2030 for 2h,Add sodium bicarbonate to adjust the pH of the reaction system to above 7,The reaction mixture was concentrated to dryness,Column chromatography of the residue gave 7b (1.9 mmol).

Reference： [1]Current Patent Assignee: ANHUI NATURE PHARMACEUTICAL - CN113248508, 2021, A Location in patent: Paragraph 0451; 0452; 0453

40
[ 1191237-80-5 ]
2-ethylbutyl (2S)-2-[(R)-(4-nitrophenoxy)(phenoxy)phosphoryl]amino}propanoate [ No CAS ]
2-ethylbutyl ((S)-(((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.6 mmol	With N-ethyl-N,N-diisopropylamine; magnesium chloride In acetonitrile at 0 - 10℃; for 3h;	17.1 Example 17.1 Preparation of Compound 9b Compound 7b (2mmol),Compound 8 (2.1 mmol),Magnesium chloride (2.3mmol)Suspended in anhydrous acetonitrile (30mL),DIPEA (4mmol) was added dropwise,Stir the mixture at 010 for 3h,Then add 2-methyltetrahydrofuran (20mL)And water (20mL), separate the liquids,The organic phase was successively used with citric acid aqueous solution,Wash with potassium carbonate aqueous solution and water,Concentrate the organic phase to dryness,Column chromatography of the residue yielded 9b (1.6 mmol).

Reference： [1]Current Patent Assignee: ANHUI NATURE PHARMACEUTICAL - CN113248508, 2021, A Location in patent: Paragraph 0460; 0461; 0462

41
C₁₁H₁₄N₄O₂ [ No CAS ]
[ 1191237-80-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 2 h / -70 - -50 °C 1.2: 5 h / -50 °C 2.1: trifluoroacetic acid; trimethylsilyl trifluoromethanesulfonate / dichloromethane / 0.5 h / -40 - -30 °C 3.1: boron trichloride / dichloromethane / 3 h / -60 °C 4.1: toluene-4-sulfonic acid / acetone / 2 h / 20 - 30 °C / pH 1
	Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 2 h / -70 - -50 °C 1.2: 5 h / -50 °C 2.1: trifluoroacetic acid; trimethylsilyl trifluoromethanesulfonate / dichloromethane / 0.5 h / -40 - -30 °C 3.1: boron trichloride / dichloromethane / 3 h / -60 °C 4.1: toluene-4-sulfonic acid / acetone / 2 h / 20 - 30 °C / pH 1

Reference： [1]Current Patent Assignee: ANHUI NATURE PHARMACEUTICAL - CN113248508, 2021, A
[2]Current Patent Assignee: ANHUI NATURE PHARMACEUTICAL - CN113248508, 2021, A

42
C₃₇H₄₀N₄O₇ [ No CAS ]
[ 1191237-80-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: trifluoroacetic acid; trimethylsilyl trifluoromethanesulfonate / dichloromethane / 0.5 h / -40 - -30 °C 2: boron trichloride / dichloromethane / 3 h / -60 °C 3: toluene-4-sulfonic acid / acetone / 2 h / 20 - 30 °C / pH 1
	Multi-step reaction with 3 steps 1: trifluoroacetic acid; trimethylsilyl trifluoromethanesulfonate / dichloromethane / 0.5 h / -40 - -30 °C 2: boron trichloride / dichloromethane / 3 h / -60 °C 3: toluene-4-sulfonic acid / acetone / 2 h / 20 - 30 °C / pH 1

Reference： [1]Current Patent Assignee: ANHUI NATURE PHARMACEUTICAL - CN113248508, 2021, A
[2]Current Patent Assignee: ANHUI NATURE PHARMACEUTICAL - CN113248508, 2021, A

43
C₁₅H₁₇N₅O₄*H₂O₄S [ No CAS ]
[ 1191237-80-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium acetate In methanol; water for 1h;	14 Example 14. Synthesis of the Compound of Formula (VIII) A reactor was charged with Formula (VII) (1.0 equiv, scaling factor) followed by isopropyl acetate (10 volumes), 2,2-dimethoxypropane (5.9 equiv), and cooled to about 20 °C. Concentrated sulfuric acid (1.3 equiv) was charged and the reaction was heated to about 30 °C for about 3 h. The reaction mixture was filtered and the cake was rinsed with isopropyl acetate (3 volumes). The intermediate sulfate salt was transferred back to the reactor followed by the addition of potassium acetate (2.0 equiv) and methanol (15 volumes). Water (2 volumes) was then added and the reaction mixture stirred for about 1 hr. The solution was subjected to a carbon treatment followed by a polish filtration. The carbon cartridge was rinsed with methanol (7 volumes). The solution was then distilled to about 3 volumes followed by the addition of water (8 volumes) over about 2 h. The resulting slurry was filtered and the cake was rinsed with water (3 volumes). The solids were dried to yield the compound of Formula (VIII): NMR (400 MHz, DMSO- e) d 7.91 - 7.98 (brm, 5H), 6.95 - 6.88 (m, 4H), 5.38 (d, J = 6.6 Hz, 2H), (0261) 5.02 (t, J = 5.7 Hz, 2H), 4.90 (dd, J = 6.6, 3.1 Hz, 2H), 4.32 (td, J = 5.3, 3.0 Hz, 2H), 3.53 (ddq, J = 17.3, 11.6, 5.5 Hz, 4H), 1.64 (s, 6H), 1.37 (s, 6H). 13C NMR (100 MHz, DMSO- e) d 156.05, (0262) 148.62, 122.97, 117.42, 116.71, 115.87, 111.05, 101.32, 85.87, 84.37, 82.01, 80.41, 61.35, 26.34, 25.58.

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/183750, 2021, A2 Location in patent: Paragraph 0199

44
[ 139285-65-7 ]
[ 1191237-80-5 ]
C₄₃H₆₆N₅O₉P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%	With pyridine; dmap; dicyclohexyl-carbodiimide at 90℃; for 24h;

Reference： [1]Schooley, Robert T.; Carlin, Aaron F.; Beadle, James R.; Valiaeva, Nadejda; Zhang, Xing-Quan; Clark, Alex E.; McMillan, Rachel E.; Leibel, Sandra L.; McVicar, Rachael N.; Xie, Jialei; Garretson, Aaron F.; Smith, Victoria I.; Murphy, Joyce; Hostetler, Karl Y. [Antimicrobial Agents and Chemotherapy, 2021, vol. 65, # 10]

45
[ 1191237-80-5 ]
[ 87746-71-2 ]
((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl (3-(hexadecyloxy)propyl) hydrogen phosphate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: dicyclohexyl-carbodiimide; dmap; pyridine / 24 h / 90 °C 2: hydrogenchloride / tetrahydrofuran / 3 h
	Multi-step reaction with 2 steps 1: dicyclohexyl-carbodiimide; dmap; pyridine / 24 h / 90 °C 2: hydrogenchloride / tetrahydrofuran; water / 3 h / 20 °C

Reference： [1]Schooley, Robert T.; Carlin, Aaron F.; Beadle, James R.; Valiaeva, Nadejda; Zhang, Xing-Quan; Clark, Alex E.; McMillan, Rachel E.; Leibel, Sandra L.; McVicar, Rachael N.; Xie, Jialei; Garretson, Aaron F.; Smith, Victoria I.; Murphy, Joyce; Hostetler, Karl Y. [Antimicrobial Agents and Chemotherapy, 2021, vol. 65, # 10]
[2]Current Patent Assignee: UNIVERSITY OF CALIFORNIA - WO2022/20793, 2022, A1

46
[ 1191237-80-5 ]
[ 87746-71-2 ]
C₃₄H₅₆N₅O₈P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With pyridine; dmap; dicyclohexyl-carbodiimide at 90℃; for 24h;
67%	With pyridine; dmap; dicyclohexyl-carbodiimide at 90℃; for 24h;	1 General Method B. General procedure: N,N-Dicyclohexylcarbodiimide (DCC, 1.5 eq) was added to a mixture of GS- 441524 acetonide (1 eq, CAS 1191237-80-5, purchased from Ontario Chemicals), a long- chain dihydrogen phosphate (1.0 eq), and 4-dimethylaminopyridine (DMAP, 1.0 eq) in dry pyridine, and then the mixture was heated to 90 °C and stirred for 24h. Water was added to quench the reaction and pyridine was evaporated under vacuum. The residue was adsorbed onto silica gel and purified by flash column chromatography on silica gel 60. Gradient elution (CH2Cl2/methanol 10-20%) afforded the protected phosphodiester compound.
67%	With pyridine; dmap; dicyclohexyl-carbodiimide at 90℃; for 24h;	1 General Method B. General procedure: N,N-Dicyclohexylcarbodiimide (DCC, 1.5 eq) was added to a mixture of GS- 441524 acetonide (1 eq, CAS 1191237-80-5, purchased from Ontario Chemicals), a long- chain dihydrogen phosphate (1.0 eq), and 4-dimethylaminopyridine (DMAP, 1.0 eq) in dry pyridine, and then the mixture was heated to 90 °C and stirred for 24h. Water was added to quench the reaction and pyridine was evaporated under vacuum. The residue was adsorbed onto silica gel and purified by flash column chromatography on silica gel 60. Gradient elution (CH2Cl2/methanol 10-20%) afforded the protected phosphodiester compound.

Reference： [1]Schooley, Robert T.; Carlin, Aaron F.; Beadle, James R.; Valiaeva, Nadejda; Zhang, Xing-Quan; Clark, Alex E.; McMillan, Rachel E.; Leibel, Sandra L.; McVicar, Rachael N.; Xie, Jialei; Garretson, Aaron F.; Smith, Victoria I.; Murphy, Joyce; Hostetler, Karl Y. [Antimicrobial Agents and Chemotherapy, 2021, vol. 65, # 10]
[2]Current Patent Assignee: UNIVERSITY OF CALIFORNIA - WO2022/20793, 2022, A1 Location in patent: Page/Page column 42-44
[3]Current Patent Assignee: UNIVERSITY OF CALIFORNIA - WO2022/20793, 2022, A1 Location in patent: Page/Page column 42-44

47
[ 130705-28-1 ]
[ 1191237-80-5 ]
C₃₅H₅₈N₅O₈P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With pyridine; dmap; dicyclohexyl-carbodiimide at 90℃; for 72h;
45%	With pyridine; dmap; dicyclohexyl-carbodiimide at 90℃; for 72h;	1 General Method B. General procedure: N,N-Dicyclohexylcarbodiimide (DCC, 1.5 eq) was added to a mixture of GS- 441524 acetonide (1 eq, CAS 1191237-80-5, purchased from Ontario Chemicals), a long- chain dihydrogen phosphate (1.0 eq), and 4-dimethylaminopyridine (DMAP, 1.0 eq) in dry pyridine, and then the mixture was heated to 90 °C and stirred for 24h. Water was added to quench the reaction and pyridine was evaporated under vacuum. The residue was adsorbed onto silica gel and purified by flash column chromatography on silica gel 60. Gradient elution (CH2Cl2/methanol 10-20%) afforded the protected phosphodiester compound.
45%	With pyridine; dmap; dicyclohexyl-carbodiimide at 90℃; for 72h;	1 General Method B. General procedure: N,N-Dicyclohexylcarbodiimide (DCC, 1.5 eq) was added to a mixture of GS- 441524 acetonide (1 eq, CAS 1191237-80-5, purchased from Ontario Chemicals), a long- chain dihydrogen phosphate (1.0 eq), and 4-dimethylaminopyridine (DMAP, 1.0 eq) in dry pyridine, and then the mixture was heated to 90 °C and stirred for 24h. Water was added to quench the reaction and pyridine was evaporated under vacuum. The residue was adsorbed onto silica gel and purified by flash column chromatography on silica gel 60. Gradient elution (CH2Cl2/methanol 10-20%) afforded the protected phosphodiester compound.

Reference： [1]Schooley, Robert T.; Carlin, Aaron F.; Beadle, James R.; Valiaeva, Nadejda; Zhang, Xing-Quan; Clark, Alex E.; McMillan, Rachel E.; Leibel, Sandra L.; McVicar, Rachael N.; Xie, Jialei; Garretson, Aaron F.; Smith, Victoria I.; Murphy, Joyce; Hostetler, Karl Y. [Antimicrobial Agents and Chemotherapy, 2021, vol. 65, # 10]
[2]Current Patent Assignee: UNIVERSITY OF CALIFORNIA - WO2022/20793, 2022, A1 Location in patent: Page/Page column 42-45
[3]Current Patent Assignee: UNIVERSITY OF CALIFORNIA - WO2022/20793, 2022, A1 Location in patent: Page/Page column 42-45

48
[ 1191237-80-5 ]
[ 79-31-2 ]
((3aR,4R,6R,6aR)-6-(4-aminopyrrole-[2,1-f][1,2,4]-triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuran-[3,4-d][1,3]-dioxol-4-yl)methyl isobutyrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile; isobutyric Acid With dmap In dichloromethane for 0.166667h; Stage #2: With dicyclohexyl-carbodiimide In dichloromethane at 25℃; for 24h;	2 Example 2:((3aR,4R,6R,6aR)-6-(4-aminopyrrole[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-di Synthesis of methyltetrahydrofuran[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate (compound 8) Dissolve 1.50g of compound 5 in 15ml of dichloromethane, then add 0.42mL of isobutyric acid and 55.40mg of 4-dimethylaminopyridine, stir for 10min, add 1.02g of dicyclohexylcarbodiimide, 25 Stir at for 24h. After column chromatography separation (eluent: petroleum ether/ethyl acetate (V/V) = 1/1), 1.71 g of compound 8 (white solid, yield 94%) was obtained.
94%	Stage #1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile; isobutyric Acid With dmap In dichloromethane for 0.166667h; Stage #2: With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h;	8 Example 8: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate(Compound 7) Synthesis 1.50 g of compound 5 was dissolved in 15 ml of dichloromethane, 0.42 ml of isobutyric acid and 55.40 mg of 4-dimethylaminopyridine were added, and after stirring for 10 min,1.02 g of dicyclohexylcarbodiimide was added, and the mixture was stirred at room temperature for 24 h. After separation by column chromatography (eluent: petroleum ether/ethyl acetate (V/V)=1/1), 1.71 g of compound 7 was obtained (white solid, yield 94%).
	With dmap; diisopropyl-carbodiimide In N,N-dimethyl-formamide at 20℃; for 4h;	15 Example 15: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl isobutyrate To a solution of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6- (hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile (2000 mg, 6.0 mmol) (Siegel et. al. J. Med. Chem.2017, 60, 1648-1661) and isobutyric acid (638 ng, 7.2 mmol) in DMF (5 mL), N,N'-diisopropylcarbodiimide (914 mg, 7.2 mmol) was added slowly followed by 4-dimethylaminopyridine (737 mg, 6.0 mmol) at r.t and stirred for 4 h. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried and concentrated. The resulting product was purified by flash chromatography using DCM/Methanol (20% methanol/DCM) as eluent to get the intermediate ((3aR,4R,6R,6aR)-6-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl isobutyrate. MS m/z = 402.2 (M+1)

Reference： [1]Current Patent Assignee: PINGSHAN INSTITUTE OF BIOMEDICINE SOUTHERN UNIV OF SCIENCE AND TECHNOLOGY - CN113698405, 2021, A Location in patent: Paragraph 0083-0084
[2]Current Patent Assignee: SOUTHERN UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA; SUN YAT-SEN UNIVERSITY (CHINA) - CN113735862, 2021, A Location in patent: Paragraph 0187-0191
[3]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/47065, 2022, A2 Location in patent: Paragraph 0475-0476

49
[ 1191237-80-5 ]
[ 18162-48-6 ]
C₂₁H₃₁N₅O₄Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 18h;

Reference： [1]Current Patent Assignee: AJK PHARMACEUTICAL - WO2021/222807, 2021, A1 Location in patent: Sheet 8-9

50
[ 1191237-80-5 ]
[ 107-92-6 ]
C₁₉H₂₃N₅O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	Stage #1: (3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile; butyric acid With dmap In dichloromethane for 0.166667h; Stage #2: With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h;	12 Example 12. ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl butyrate (Compound ATV009) Synthesis 1.50 g of compound 5 was dissolved in 15 ml of dichloromethane, 0.42 ml of n-butyric acid and 55.40 mg of 4-dimethylaminopyridine were added, and after stirring for 10 min, 1.02 g of dicyclohexylcarbodiimide was added a room temperature stir for 24h. After separation by column chromatography (eluent: petroleum ether/ethyl acetate (V/V) = 1/1), 1.78 g of compound 10 was obtained (yield 98%).

Reference： [1]Current Patent Assignee: SOUTHERN UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA; SUN YAT-SEN UNIVERSITY (CHINA) - CN113735862, 2021, A Location in patent: Paragraph 0210-0212

51
[ 1191237-80-5 ]
[ 802294-64-0 ]
C₁₈H₂₁N₅O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	Stage #1: (3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile; propionic acid With dmap In dichloromethane for 0.166667h; Stage #2: With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h;	11 Example 11. ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl propionate (Compound ATV008) Synthesis Dissolve 1.50 g of compound 5 in 15 ml of dichloromethane, add 0.42 mL of propionic acid and 55.40 mg of 4-dimethylaminopyridine, stir for 10 min, add 1.02 g of dicyclohexylcarbodiimide, and stir at room temperature 24h. After separation by column chromatography (eluent: petroleum ether/ethyl acetate (V/V)=1/1), 1.74 g of compound 9 was obtained (yield 99%).

Reference： [1]Current Patent Assignee: SOUTHERN UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA; SUN YAT-SEN UNIVERSITY (CHINA) - CN113735862, 2021, A Location in patent: Paragraph 0204-0206

52
[ 112-05-0 ]
[ 1191237-80-5 ]
C₂₄H₃₃N₅O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	Stage #1: nonanoic acid; (3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With dmap In dichloromethane for 0.166667h; Stage #2: With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h;	13 Example 13. ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4 dihydroxytetrahydrofuran-2-yl)methyl nonoate (Compound ATV010) Synthesis Dissolve 1.50 g of compound 5 in 15 ml of dichloromethane, add 0.42 mL of nonanoic acid and 55.40 mg of 4-dimethylaminopyridine, stir for 10 min, add 1.02 g of dicyclohexylcarbodiimide, and stir at room temperature 24h. After separation by column chromatography (eluent: petroleum ether/ethyl acetate (V/V)=1/1), 2.07 g of compound 11 was obtained (yield 97%).

Reference： [1]Current Patent Assignee: SOUTHERN UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA; SUN YAT-SEN UNIVERSITY (CHINA) - CN113735862, 2021, A Location in patent: Paragraph 0216-0218

53
[ 1191237-80-5 ]
[ 64-19-7 ]
C₁₇H₁₉N₅O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	Stage #1: (3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile; acetic acid With dmap In dichloromethane for 0.166667h; Stage #2: With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h;	10 Example 10. ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl acetate (Compound ATV007) Synthesis Dissolve 1.50 g of compound 5 in 15 ml of dichloromethane, add 0.42 mL of acetic acid and 55.40 mg of 4-dimethylaminopyridine, stir for 10 min, add 1.02 g of dicyclohexylcarbodiimide, and stir at room temperature for 24 h . After separation by column chromatography (eluent: petroleum ether/ethyl acetate (V/V) = 1/1), 1.78 g of compound 8 was obtained (yield 98%).

Reference： [1]Current Patent Assignee: SOUTHERN UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA; SUN YAT-SEN UNIVERSITY (CHINA) - CN113735862, 2021, A Location in patent: Paragraph 0198-0200

54
[ 88-09-5 ]
[ 1191237-80-5 ]
C₂₁H₂₇N₅O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	Stage #1: 2-Ethylbutanoic acid; (3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With dmap In dichloromethane for 0.166667h; Stage #2: With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h;	14 Example 14. ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl 2-ethylbutyrate (Compound ATV011) Synthesis 1.50 g of compound 5 was dissolved in 15 ml of dichloromethane, 0.42 mL of 2-ethylbutyric acid and 55.40 mg of 4-dimethylaminopyridine were added, and after stirring for 10 min, 1.02 g of dicyclohexylcarbodiimide was added. , and stirred at room temperature for 24h. After separation by column chromatography (eluent: petroleum ether/ethyl acetate (V/V) = 1/1), 1.94 g of compound 12 was obtained (yield 99%).

Reference： [1]Current Patent Assignee: SOUTHERN UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA; SUN YAT-SEN UNIVERSITY (CHINA) - CN113735862, 2021, A Location in patent: Paragraph 0222-0224

55
[ 1191237-80-5 ]
[ 1759-53-1 ]
C₁₉H₂₁N₅O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	Stage #1: (3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile; cyclopropanecarboxylic acid With dmap In dichloromethane for 0.166667h; Stage #2: With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h;	15 Example 15 : ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl 2-cyclopropanecarboxylate (Compound ATV012) Synthesis 1.50 g of compound 5 was dissolved in 15 ml of dichloromethane, 0.42 mL of cyclopropanecarboxylic acid and 55.40 mg of 4-dimethylaminopyridine were added, and after stirring for 10 min, 1.02 g of dicyclohexylcarbodiimide was added. Stir for 24h. After separation by column chromatography (eluent: petroleum ether/ethyl acetate (V/V) = 1/1), 1.52 g of compound 13 was obtained (yield 99%).

Reference： [1]Current Patent Assignee: SUN YAT-SEN UNIVERSITY (CHINA); SOUTHERN UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA - CN113735862, 2021, A Location in patent: Paragraph 0228-0230

56
[ 22838-58-0 ]
[ 1191237-80-5 ]
C₂₅H₃₄N₆O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	Stage #1: Boc-D-Val-OH; (3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With dmap In dichloromethane for 0.166667h; Stage #2: With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h;	22 Example 22. ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxol-4-yl)methyl(tert-butyl ester)-D-valine ester (Compound 7) Synthesis Dissolve 1.80g of compound 5 in 15mL of dichloromethane, then add 1.18g (D)-Boc-valine, then add 66.48mg 4-dimethylaminopyridine, stir for 10min, add 1.22g dicyclohexylcarbodiimide, stirred at room temperature for 24 h. After separation by column chromatography (eluent: petroleum ether/ethyl acetate (V/V)=1/1), 2.81 g of compound 14 was obtained (white solid, yield 97%).

Reference： [1]Current Patent Assignee: SOUTHERN UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA; SUN YAT-SEN UNIVERSITY (CHINA) - CN113735862, 2021, A Location in patent: Paragraph 0264-0269

57
[ 13734-41-3 ]
[ 1191237-80-5 ]
C₂₅H₃₄N₆O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: t-Boc-L-valine; (3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With dmap In dichloromethane for 0.166667h; Stage #2: With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h;	24 Example 24. ((3aR,4R,6R,6aR)-6-(4-aminopyrrolO[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxol-4-yl)methyl(tert-butyl ester)-L-valine ester (compound 6) synthesis 1.50g of compound 5 was dissolved in 15ml of dichloromethane, then 0.98g (L)-Boc-valine was added, 55.40mg of 4-dimethylaminopyridine was added, and after stirring for 10min,1.02 g of dicyclohexylcarbodiimide was added, and the mixture was stirred at room temperature for 24 h. After separation by column chromatography (eluent: petroleum ether/ethyl acetate (V/V)=1/1), 2.28 g of compound 15 was obtained (white solid, yield 95%).

Reference： [1]Current Patent Assignee: SOUTHERN UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA; SUN YAT-SEN UNIVERSITY (CHINA) - CN113735862, 2021, A Location in patent: Paragraph 0274-0276

58
[ 42714-96-5 ]
[ 1191237-80-5 ]
C₃₅H₅₈N₅O₇P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; 1-methyl-1H-imidazole; diisopropyl-carbodiimide at 20℃; for 48h;	1 General Method C. General procedure: N,N-Diisopropylcarbodiimide (DIC, 3.3 mmol) was added to a mixture of GS- 441524 acetonide (1.65 mmol), lipid phosphate (1.65 mmol), and 1-methylimidazole (NMI, 406 mg, 4.95 mmol) in dry pyridine (30 mL), and then the mixture was stirred for 48 h at room temperature until analysis of the reaction mixture by TLC indicated substantial formation of coupled product Water (5 mL) was then added, and the mixture was concentrated on a rotary evaporator. The residue was adsorbed onto silica gel and purified by flash column chromatography on silica gel 60. Gradient elution (100% CH2Cl2to CH2Cl2/20% methanol) afforded the protected phosphodiester analogs.
	With pyridine; 1-methyl-1H-imidazole; diisopropyl-carbodiimide at 20℃; for 48h;	1 General Method C. General procedure: N,N-Diisopropylcarbodiimide (DIC, 3.3 mmol) was added to a mixture of GS- 441524 acetonide (1.65 mmol), lipid phosphate (1.65 mmol), and 1-methylimidazole (NMI, 406 mg, 4.95 mmol) in dry pyridine (30 mL), and then the mixture was stirred for 48 h at room temperature until analysis of the reaction mixture by TLC indicated substantial formation of coupled product Water (5 mL) was then added, and the mixture was concentrated on a rotary evaporator. The residue was adsorbed onto silica gel and purified by flash column chromatography on silica gel 60. Gradient elution (100% CH2Cl2to CH2Cl2/20% methanol) afforded the protected phosphodiester analogs.

Reference： [1]Current Patent Assignee: UNIVERSITY OF CALIFORNIA - WO2022/20793, 2022, A1 Location in patent: Page/Page column 42; 44
[2]Current Patent Assignee: UNIVERSITY OF CALIFORNIA - WO2022/20793, 2022, A1 Location in patent: Page/Page column 42; 44

59
[ 1191237-80-5 ]
2-methoxy-2-methylpropyl ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate [ No CAS ]
2-methoxy-2-methylpropyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile; 2-methoxy-2-methylpropyl ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate With magnesium chloride In tetrahydrofuran at 0 - 40℃; for 0.166667h; Stage #2: With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 40℃; for 2h; Stage #3: With hydrogenchloride In water; acetonitrile at 0℃; for 4h;	24 Example 24: 2-Methoxy-2-methylpropyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate Tetrahydrofuran (11 mL) was added to a mixture of (3aR,4R,6R,6aR)-4-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxole-4-carbonitrile (prepared according to WO2016069825, 1500 mg, 4.53 mmol), intermediate H2(2480 mg, 4.98 mmol), and magnesium chloride (647 mg, 6.79 mmol) at room temperature. The mixture was heated to 40 °C for 10 min, and N,N-diisopropylethylamine (1.97 mL, 11.3 mmol) was added. After stirring for 2 hours at 40 °C, the reaction mixture was allowed to cool to room temperature and was concentrated down under reduced pressure. The crude residue was dissolved in ethyl acetate (100 mL) and the resulting mixture was washed with water (100 mL) and brine (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was dissolved in acetonitrile (75 mL) and concentrated aqueous hydrochloric acid (3.77 mL) was added dropwise at 0 °C. After 4 hours at 0 °C, the reaction mixture was diluted with ethyl acetate (100 mL) and water (100 mL) at 0 °C and the resulting mixture was washed with saturated aqueous sodium bicarbonate solution (100 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using gradient from 0-10% methanol in dichloromethane to afford the title compound. LCMS: MS m/z = 604.8 [M+1], tR= 0.72 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0-1.00 min 10%-100% acetonitrile, 1.00-1.35 min 100% acetonitrile, 1.35-1.36 min 100-10% acetonitrile at 2 μL/min.1H NMR (400 MHz, DMSO-d6) δ 8.17 - 7.81 (m, 3H), 7.41 - 7.27 (m, 2H), 7.27 - 7.06 (m, 3H), 6.89 (d, J = 4.5 Hz, 1H), 6.82 (d, J = 4.5 Hz, 1H), 6.36 (d, J = 6.1 Hz, 1H), 6.21 - 5.97 (m, 1H), 5.39 (d, J = 5.8 Hz, 1H), 4.71 - 4.51 (m, 1H), 4.35 - 4.18 (m, 2H), 4.14 - 4.03 (m, 1H), 4.01 - 3.89 (m, 2H), 3.90 - 3.74 (m, 2H), 3.06 (s, 3H), 1.22 (d, J = 7.1 Hz, 3H), 1.06 (s, 6H).31P NMR (162 MHz, DMSO-d6) δ 3.83. HPLC: tR= 2.36 min; HPLC system: Agilent 1100 series.; Column: Gemini 5m C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min-5.0 min 2-98% ACN, 5.0 min-6.0 min 98% ACN at 2 mL/min.

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/262826, 2021, A2 Location in patent: Paragraph 00341

60
[ 1191237-80-5 ]
3,3-dimethylcyclobutyl ((4-(tert-butyl)phenoxy) (perfluorophenoxy)phosphoryl)-L-alaninate [ No CAS ]
3,3-dimethylcyclobutyl ((((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(4-(tert-butyl)phenoxy)phosphoryl)-L-alaninate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile; 3,3-dimethylcyclobutyl ((4-(tert-butyl)phenoxy) (perfluorophenoxy)phosphoryl)-L-alaninate With magnesium chloride In dichloromethane; acetonitrile at 50℃; for 0.25h; Stage #2: With N-ethyl-N,N-diisopropylamine In dichloromethane; acetonitrile	Intermediate K9: 3,3-dimethylcyclobutyl ((((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methoxy)(4-(tert-butyl)phenoxy)phosphoryl)-L-alaninate To a solution of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6- (hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile (1.60 g, 4.83 mmol) in DCM, K8 (2.74 g, 4.98 mmol), and MgCl2 (0.460 g, 4.83 mmol) in ACN (5 mL) were added and stirred for 15 min at 50°C and then DIPEA (2.10 mL, 12.10 mmol) was added. The reaction mixture was allowed to cool to rt, diluted with ethyl acetate, washed saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-20% MeOH in DCM) to K9. Mixture of isomers:1H NMR (400 MHz, Acetonitrile-d3) δ 7.94 (s, 1H), 7.35 - 7.22 (m, 2H), 7.09 - 7.00 (m, 1H), 6.97 - 6.91 (m, 1.6H), 6.89 (d, J = 4.6 Hz, 0.4H), 6.82 (m, 1H), 6.37 (s, 2H), 5.27 (m, 1H), 4.98 - 4.88 (m, 1.6H), 4.89 - 4.83 (m, 0.4H), 4.65 - 4.55 (m, 1H), 4.28 - 4.18 (m, 1.6H), 4.15 - 4.04 (m, 1.4H), 3.89 - 3.73 (m, 1H), 2.27 - 2.13 (m, 2H), 1.87 - 1.75 (m, 2H), 1.71 (s, 1.8H), 1.70 (s, 1.2H), 1.41 (s, 1.8H), 1.37 (s, 1.2H), 1.32 - 1.20 (m, 12H), 1.14 (s, 6H).31P NMR (162 MHz, Acetonitrile-d3) δ 2.96, 2.85. LCMS: MS m/z = 697.22 [M+1]; tR= 1.90, 1.93 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6m XB-C18 100A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800μl/min.

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/262826, 2021, A2 Location in patent: Paragraph 00529

61
[ 1191237-80-5 ]
2-ethylbutyl ((2-isopropyl-5-methylphenoxy)(perfluorophenoxy)phosphoryl)-L-alaninate [ No CAS ]
C₃₄H₄₇N₆O₈P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile; 2-ethylbutyl ((2-isopropyl-5-methylphenoxy)(perfluorophenoxy)phosphoryl)-L-alaninate With magnesium chloride In tetrahydrofuran at 0 - 40℃; for 0.166667h; Stage #2: With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 40℃; for 2h;	26 Example 26. 2-Ethylbutyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(2-isopropy1-5- methylphenoxy)phosphoryl)-L-alaninate Tetrahydrofuran (11 mL) was added to a mixture of (3aR,4R,6R,6aR)-4-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxole-4-carbonitrile (prepared according to WO2016069825, 1000 mg, 3.02 mmol), intermediate LI (2160 mg, 3.92 mmol), and magnesium chloride (431 mg, 4.53 mmol) at room temperature. The mixture was heated to 40 °C for 10 min, and N,N-diisopropylethylamine (1.3 mL, 7.55 mmol) was added. After stirring for 2 hours at 40 °C, the reaction mixture was allowed to cool to room temperature and was concentrated down under reduced pressure. The crude residue was dissolved in ethyl acetate (30 mL) and the resulting mixture was washed with water (20 mL) and brine (20 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude intermediate L2. LCMS: MS m/z = 698.8 and 698.8 [M+1], tR= 1.15 and 1.17 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0-1.00 min 10%-100% acetonitrile, 1.00-1.35 min 100% acetonitrile, 1.35-1.36 min 100-10% acetonitrile at 2 μL/min.

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/262826, 2021, A2 Location in patent: Paragraph 00343

62
[ 1191237-80-5 ]
2-methoxy-2-methylpropyl ((4-(tert-butyl)phenoxy) (perfluorophenoxy)phosphoryl)-L-alaninate [ No CAS ]
C₃₃H₄₅N₆O₉P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; magnesium chloride In acetonitrile at 0 - 50℃; for 2.16h; Inert atmosphere;	111 Example 111: 2-methoxy-2-methylpropyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(4-(tert- butyl)phenoxy)phosphoryl)-L-alaninate To a suspension of D2, 0.366 g, 0.664 mmol), (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4- carbonitrile (Prepared according to W02017049060, 0.200 g, 0.604 mmol) and magnesium chloride (0.058 g, 0.604 mmol) in acetonitrile (6 mL) under an atmosphere of argon was added N,N-diisopropylethylamine (0.263 mL, 1.51 mmol) at 0 °C. After 10 min, the reaction was heated to 50 °C. After 2 h, the reaction was cooled to room temperature, diluted with ethyl acetate and the organics were washed with water, dried over sodium sulfate, filtered and concentrated to afford intermediate D3 (LCMS: MS m/z = 701.8 and 701.8 [M+1], tR = 1.01 and 1.03 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0-1.00 min 10%-100% acetonitrile, 1.00-1.35 min 100% acetonitrile, 1.35-1.36 min 100-10% acetonitrile at 2 μL/min). Intermediate D3 was taken up in tetrahydrofuran (2 mL) and concentrated hydrochloric acid (11.7 M, 0.400 mL, 4.66 mmol) was added. After 2 h, the reaction was diluted with ethyl acetate and neutralized with a saturated aqueous solution of sodium bicarbonate. The layers were separated, and the organics were washed with water, saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated. The product was purified by HPLC chromatography (0-100 % acetonitrile in water) to afford the title compound. Mixture of stereoisomers:1H NMR (400 MHz, Methanol- d4) δ 7.89 (s, 0.5H), 7.87 (s, 0.5H), 7.35 - 7.28 (m, 2H), 7.13 - 7.09 (m, 1H), 7.08 - 7.04 (m, 1H), 6.98 - 6.91 (m, 2H), 4.82 - 4.78 (m, 1H), 4.48 - 4.27 (m, 3H), 4.21 - 4.14 (m, 1H), 4.07 - 4.03 (m, 1H), 4.01 - 3.89 (m, 2H), 3.22 - 3.19 (m, 3H), 1.35 - 1.26 (m, 12H), 1.19 - 1.15 (m, 6H). 31P1H NMR (162 MHz, Methanol-d4) δ 3.81 - 3.59 (m). LCMS: MS m/z = 661.9, 661.9 [M+1], tR = 0.87, 0.88 min.

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/262826, 2021, A2 Location in patent: Paragraph 00580

63
[ 1191237-80-5 ]
2-ethylbutyl (2S)-2-[[(4-tert-butylphenoxy)-(2,3,4,5,6-pentafluorophenoxy)phosphoryl]amino]propanoate [ No CAS ]
C₃₄H₄₇N₆O₈P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; magnesium chloride In acetonitrile at 0 - 50℃; for 2.16h; Inert atmosphere;	13 Example 13: 2-ethylbutyl (25)-2-[[[(2R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxy-(4-tert- butylphenoxy)phosphoryl]amino]propanoate To a suspension of 2-ethylbutyl (2S)-2-[[(4-tert-butylphenoxy)-(2,3,4,5,6- pentafluorophenoxy)phosphoryl]amino]propanoate (Intermediate Al, 0.366 g, 0.664 mmol), (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile (prepared according to W02017049060, 0.200 g, 0.604 mmol) and magnesium chloride (0.058 g, 0.604 mmol) in acetonitrile (6 mL) under an atmosphere of argon was added N,N-diisopropylethylamine (0.263 mL, 1.51 mmol) at 0 °C. After 10 min, the reaction was heated to 50 °C. After 2 h, the reaction was cooled to room temperature, diluted with ethyl acetate and the organics were washed with water, dried over sodium sulfate, filtered and concentrated to afford Intermediate A2 (LCMS: MS m/z = 698.8 and 698.8 [M+1], tR= 1.13 and 1.16 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0-1.00 min10%-100% acetonitrile, 1.00-1.35 min 100% acetonitrile, 1.35-1.36 min 100-10% acetonitrile at 2 μL/min)

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/262826, 2021, A2 Location in patent: Paragraph 00317

64
[ 1191237-80-5 ]
cyclobutyl ((4-(tert-butyl)phenoxy)(perfluorophenoxy)phosphoryl)-L-alaninate [ No CAS ]
cyclobutyl (2S)-2-[[[(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methoxy-(4-tert-butylphenoxy)phosphoryl]amino]propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; magnesium chloride In acetonitrile at 20 - 50℃; for 2.16h; Inert atmosphere;	49 Example 49: cyclobutyl (2S)-2-[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7- yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxy-(4-tert- butylphenoxy)phosphoryl]amino]propanoate To a suspension of cyclobutyl (2S)-2-[[(4-tert-butylphenoxy)-(2,3,4,5,6- pentafluorophenoxy)phosphoryl]amino]propanoate (0.292 g, 0.477 mmol), (3aR,4R,6R,6aR)-4- (4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxole-4-carbonitrile (prepared according to W02017049060, 0.158 g, 0.477 mmol) and magnesium chloride (0.049 g, 0.511 mmol) in acetonitrile (10 mL) under an atmosphere of argon was added N,N-diisopropylethylamine (89 uL, 0.511 mmol) at room temperature. After 10 min, the reaction was heated to 50 °C. After 2 h, the reaction was cooled to room temperature, diluted with ethyl acetate and the organics were washed with water, dried over sodium sulfate, filtered and concentrated to afford cyclobutyl (2S)-2-[[[(3aR,4R,6R,6aR)-4-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethy1-6,6a-dihydro-3aH-furo[3,4- d] [ 1 ,3]dioxol-6-yl]methoxy-(4-tert-butylphenoxy)phosphoryl]amino]propanoate. LCMS : MS m/z = 668.9 [M+H+]

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/262826, 2021, A2 Location in patent: Paragraph 00414

65
[ 1191237-80-5 ]
1-propyl (2S)-2-[[(4-tert-butylphenoxy)-(2,3,4,5,6-pentafluorophenoxy)phosphoryl]amino]propanoate [ No CAS ]
1-Propyl (2S)-2-[[[(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methoxy-(4-tert-butylphenoxy)phosphoryl]amino]propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; magnesium chloride In acetonitrile at 20 - 50℃; for 2.16h; Inert atmosphere;	47 Example 47: 1-propyl (2S)-2-[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f[1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxy-(4-tert- butylphenoxy)phosphoryl]amino]propanoate To a suspension of 1-propyl (2S)-2-[[(4-tert-butylphenoxy)-(2,3,4,5,6- pentafluorophenoxy)phosphoryl]amino]propanoate (0.332 g, 0.554 mmol), (3aR,4R,6R,6aR)-4- (4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxole-4-carbonitrile (prepared according to W02017049060, 0.184 g, 0.554 mmol) and magnesium chloride (0.057 g, 0.594 mmol) in acetonitrile (10 mL) under an atmosphere of argon was added N,N-diisopropylethylamine (0.10 mL, 0.594 mmol) at room temperature. After 10 min, the reaction was heated to 50 °C. After 2 h, the reaction was cooled to room temperature, diluted with ethyl acetate and the organics were washed with water, dried over sodium sulfate, filtered and concentrated to afford 1-propyl (2S)-2-[[[(3aR,4R,6R,6aR)-4-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethy1-6,6a-dihydro-3aH-furo[3,4- d] [ 1 ,3]dioxol-6-yl]methoxy-(4-tert-butylphenoxy)phosphoryl]amino]propanoate. LCMS : MS m/z = 657.2 [M+H+

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/262826, 2021, A2 Location in patent: Paragraph 00404

66
[ 1191237-80-5 ]
cyclobutyl ((4-(cyclopropyl)phenoxy)(perfluorophenoxy) phosphoryl)-L-alaninate [ No CAS ]
Cyclobutyl (2S)-2-[[[(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methoxy-(cyclopropylphenoxy)phosphoryl]amino]propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; magnesium chloride In acetonitrile at 20 - 50℃; for 2.16h; Inert atmosphere;	51 Example 51: cyclobutyl (2S)-2-[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7- yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxy-(cyclopropylphenoxy)phosphoryl]amino]propanoate To a suspension of cyclobutyl (2S)-2-[[(cyclopropylphenoxy)-(2,3,4,5,6- pentafluorophenoxy)phosphoryl]amino]propanoate (0.314 g, 0.546 mmol), (3aR,4R,6R,6aR)-4- (4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxole-4-carbonitrile (prepared according to W02017049060, 0.181 g, 0.546 mmol) and magnesium chloride (0.057 g, 0.601 mmol) in acetonitrile (10 mL) under an atmosphere of argon was added N,N-diisopropylethylamine (105 uL, 0.601 mmol) at room temperature. After 10 min, the reaction was heated to 50 °C. After 2 h, the reaction was cooled to room temperature, diluted with ethyl acetate and the organics were washed with water, dried over sodium sulfate, filtered and concentrated to afford cyclobutyl (2S)-2-[[[(3aR,4R,6R,6aR)-4-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethy1-6,6a-dihydro-3aH-furo[3,4- d][1,3]dioxol-6-yl]methoxy-(cyclopropylphenoxy)phosphoryl]amino]propanoate. LCMS: MS m/z = 652.8 [M+H+]

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/262826, 2021, A2 Location in patent: Paragraph 00420

67
[ 1191237-80-5 ]
spiro[3.3]heptan-2-yl (2S)-2-[[(4-tert-butylphenoxy)-(2,3,4,5,6-pentafluorophenoxy)phosphoryl]amino]propanoate [ No CAS ]
spiro[3.3]heptan-2-yl (2S)-2-[[[(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4- cyano-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methoxy-(4-tert- butylphenoxy)phosphoryl]amino]propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; magnesium chloride In acetonitrile at 0 - 50℃; for 0.666667h;	29 Example 29. Spiro[3.3]heptan-2-yl (2S)-2-[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxy-(4-tert- butylphenoxy)phosphoryl]amino]propanoate To a suspension of spiro[3.3]heptan-2-yl (2S)-2-[[(4-tert-butylphenoxy)-(2,3,4,5,6- pentafluorophenoxy)phosphoryl]amino]propanoate (intermediate E2, 0.110 g, 0.020 mmol), (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile (prepared according to W02017049060, 0.065 g, 0.20 mmol) and magnesium chloride (0.019 g, 0.0.20 mmol) in acetonitrile (2 mL) under an atmosphere of argon was added N,N-diisopropylethylamine (0.07 mL, 0.39 mmol) at 0 °C. After 10 min, the reaction was heated to 50 °C. After 30 min, the reaction was cooled to room temperature, diluted with ethyl acetate and the organics were washed with water, dried over sodium sulfate, filtered and concentrated to afford spiro[3.3]heptan-2-yl (2S)-2-[[[(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4- cyano-2,2-dimethy1-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methoxy-(4-tert- butylphenoxy)phosphoryl]amino]propanoate (LCMS: MS m/z = 709.7 and 709.7 [M+1], tR= 1.13 and 1.16 min; LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0-1.00 min 10%-100% acetonitrile, 1.00- 1.35 min 100% acetonitrile, 1.35-1.36 min 100-10% acetonitrile at 2 μL/min).

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/262826, 2021, A2 Location in patent: Paragraph 00349

68
[ 1191237-80-5 ]
cyclobutyl ((naphthalen-1-yloxy)(perfluorophenoxy)phosphoryl)-L-alaninate [ No CAS ]
cyclobutyl ((((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(naphthalen-1-yloxy)phosphoryl)-L-alaninate. [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; magnesium chloride In acetonitrile at 20 - 50℃; for 2.16h; Inert atmosphere;	Intermediate P6a: cyclobutyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphoryl)-L- alaninate To a suspension of cyclobutyl ((naphthalen-1-yloxy)(perfluorophenoxy)phosphoryl)-L- alaninate (0.610 g, 1.07 mmol), (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile (prepared according to W02017049060, 0.353 g, 1.07 mmol) and magnesium chloride (0.101 g, 1.07 mmol) in acetonitrile (10 mL) under an atmosphere of argon was added N,N- diisopropylethylamine (204 uL, 1.17 mmol) at room temperature. After 10 min, the reaction was heated to 50 °C. After 2 h, the reaction was cooled to room temperature, diluted with ethyl acetate and the organics were washed with water, dried over sodium sulfate, filtered and concentrated to afford cyclobutyl ((((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7- yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(naphthalen-1- yloxy)phosphoryl)-L-alaninate. LCMS: MS m/z = 662.8 [M+H+].

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/262826, 2021, A2 Location in patent: Paragraph 00434

69
[ 1191237-80-5 ]
3,3-dimethylbutyl ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate [ No CAS ]
3,3-dimethylbutyl ((((3aR,4R,6R,6aR)-6-(4-aminopyrrolo [2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro [3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; magnesium chloride In acetonitrile at 20 - 50℃; for 2.16h; Inert atmosphere;	Intermediate P8a: 3,3-dimethylbutyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate To a suspension of 3,3-dimethylbutyl ((perfluorophenoxy)(phenoxy)phosphoryl)-L- alaninate (0.333 g, 0.471 mmol), (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile (prepared according to W02017049060, 0.156 g, 0.471 mmol) and magnesium chloride (0.057 g, 0.601 mmol) in acetonitrile (10 mL) under an atmosphere of argon was added N,N- diisopropylethylamine (0.105 mL, 0.601 mmol) at room temperature. After 10 min, the reaction was heated to 50 °C. After 2 h, the reaction was cooled to room temperature, diluted with ethyl acetate and the organics were washed with water, dried over sodium sulfate, filtered and concentrated to afford 3,3-dimethylbutyl ((((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate. The product was purified using chromatography, ethyl acetate/hexanes, product eluted in pure ethyl acetate. LCMS: MS m/z = 642.9 [M+H+]

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/262826, 2021, A2 Location in patent: Paragraph 00445

70
[ 1191237-80-5 ]
benzyl ((4-(tert-butyl)phenoxy)(perfluorophenoxy)phosphoryl)-L-alaninate [ No CAS ]
benzyl ((((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(4-(tert-butyl)phenoxy)phosphoryl)-L-alaninate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; magnesium chloride In acetonitrile at 20 - 50℃; for 2.16h; Inert atmosphere;	57 Example 57: Benzyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(4-(tert-butyl)phenoxy)phosphoryl)-L- alaninate To a suspension of benzyl ((4-(tert-butyl)phenoxy)(perfluorophenoxy)phosphoryl)-L- alaninate (0.305 g, 0.546 mmol), (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile (prepared according to W02017049060, 0.181 g, 0.546 mmol) and magnesium chloride (0.057 g, 0.594 mmol) in acetonitrile (10 mL) under an atmosphere of argon was added N,N- diisopropylethylamine (0.105 mL, 0.601 mmol) at room temperature. After 10 min, the reaction was heated to 50 °C. After 2 h, the reaction was cooled to room temperature, diluted with ethyl acetate and the organics were washed with water, dried over sodium sulfate, filtered and concentrated to afford benzyl ((((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(4-(tert- butyl)phenoxy)phosphoryl)-L-alaninate. LCMS: MS m/z = 705.2 [M+H+].

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/262826, 2021, A2 Location in patent: Paragraph 00451

71
[ 1191237-80-5 ]
2-(2-ethoxyethoxy)ethyl ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate [ No CAS ]
2-(2-ethoxyethoxy)ethyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile; 2-(2-ethoxyethoxy)ethyl ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate With N-ethyl-N,N-diisopropylamine; magnesium chloride In tetrahydrofuran at 0 - 40℃; for 0.166667h; Stage #2: With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 40℃; for 2h; Stage #3: With hydrogenchloride In water; acetonitrile at 0℃; for 4h;	22 Example 22: 2-(2-Ethoxyethoxy)ethyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate Tetrahydrofuran (14 mL) was added to a mixture of (3aR,4R,6R,6aR)-4-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxole-4-carbonitrile (prepared according to WO2016069825, 2.00 g, 6.04 mmol), intermediate G2 (4.14 g, 7.85 mmol), and magnesium chloride (862 mg, 9.05 mmol) at room temperature. The mixture was heated to 40 °C for 10 min, and N,N-diisopropylethylamine (2.63 mL, 15.1 mmol) was added. After stirring for 2 hours at 40 °C, the reaction mixture was allowed to cool to room temperature and was concentrated down under reduced pressure. The crude residue was dissolved in ethyl acetate (100 mL) and the resulting mixture was washed with water (100 mL) and brine (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was dissolved in acetonitrile (100 mL) and concentrated aqueous hydrochloric acid (5.03 mL) was added dropwise at 0 °C. After 4 hours at 0 °C, the reaction mixture was diluted with ethyl acetate (100 mL) and water (100 mL) at 0 °C and the resulting mixture was washed with saturated aqueous sodium bicarbonate solution (100 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using gradient from 0-10% methanol in dichloromethane to afford the title compound. LCMS: MS m/z = 634.8 [M+1], tR= 0.71 min;LC system: Agilent 1260 Infinity II HPLC; MS system: G6124B Single Quad; Column: Kinetix 2.6u C18 100A, 50 mm x 2.1 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0-1.00 min 10%-100% acetonitrile, 1.00-1.35 min 100% acetonitrile, 1.35-1.36 min 100-10% acetonitrile at 2 μL/min.1H NMR (400 MHz, DMSO-d6) δ 8.03 - 7.83 (m, 3H), 7.40 - 7.29 (m, 2H), 7.22 - 7.09 (m, 3H), 6.88 (d, J = 4.5 Hz, 1H), 6.82 (d, J = 4.5 Hz,1H), 6.35 (d, J = 6.1 Hz, 1H), 6.17 - 5.98 (m, 1H), 5.39 (d, J = 5.7 Hz, 1H), 4.70 - 4.54 (m, 1H),4.29 - 4.19 (m, 2H), 4.18 - 4.02 (m, 3H), 4.00 - 3.91 (m, 1H), 3.88 - 3.73 (m, 1H), 3.60 - 3.51 (m, 2H), 3.50 - 3.44 (m, 2H), 3.45 - 3.36 (m, 4H), 1.20 (d, J = 7.1 Hz, 3H), 1.07 (t, J = 7.0 Hz,3H).31P NMR (162 MHz, DMSO-d6) δ 3.81. HPLC: tR= 2.36 min; HPLC system: Agilent 1100 series.; Column: Gemini 5m C18 110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min-5.0 min 2-98% ACN, 5.0 min-6.0 min 98% ACN at 2 mL/min.

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/262826, 2021, A2 Location in patent: Paragraph 00339

72
[ 1191237-80-5 ]
C₁₆H₁₉N₅O₅*(x)ClH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: dmap / tetrahydrofuran 2: hydrogenchloride; water monomer / acetonitrile / 20 °C
	Multi-step reaction with 2 steps 1: diisopropyl-carbodiimide; dmap / N,N-dimethyl-formamide / 4 h / 20 °C 2: hydrogenchloride; water monomer / acetonitrile / 20 °C

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/47065, 2022, A2
[2]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/47065, 2022, A2

73
[ 1191237-80-5 ]
[ 97-72-3 ]
((3aR,4R,6R,6aR)-6-(4-aminopyrrole-[2,1-f][1,2,4]-triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuran-[3,4-d][1,3]-dioxol-4-yl)methyl isobutyrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap In tetrahydrofuran	15; 37; 41 Alternate synthesis of Compound 15: To a solution of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6- (hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile (2000 mg, 6.0 mmol) in THF, N,N-dimethyl aminopyridine (0.03 eq) was added. To the reaction mixture isobutyric anhydride (1.1 eq) was added slowly. After the completion of the staring material, the reaction mixture was concentrated and purified by flash chromatography using DCM/Methanol (20% methanol/DCM) as eluent to get the intermediate ((3aR,4R,6R,6aR)-6-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl isobutyrate. MS m/z = 402.2 (M+1).

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/47065, 2022, A2 Location in patent: Paragraph 0475; 0480; 0574; 0586-0588

74
[ 503-74-2 ]
[ 1191237-80-5 ]
((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 3-methylbutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: 3-methylbutyric acid; (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With diisopropyl-carbodiimide In N,N-dimethyl-formamide at 20℃; for 0.333333h; Stage #2: With dmap In N,N-dimethyl-formamide at 20℃; for 2h;	16 Intermediate: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 3-methylbutanoate To a mixture of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6- (hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile (200 mg, 0.6 mmol) and 3-methylbutanoic acid (92 mg, 0.91 mmol) in DMF (2 mL) was added diisopropylcarbodiimide (0.14 mL, 0.91 mmol). The mixture was stirred at rt for 20 min and DMAP (74 mg, 0.6 mmol) added. The resulting mixture was stirred at rt for 2 h and purified by reverse phase HPLC (10 to 100% ACN in water for 15min, then 100% ACN for 3 min) to provide the intermediate (188 mg, 75%). LCMS: MS m/z = 416.16 [M+1]; tR= 1.56 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6µ XB-C18100A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800µl/min.

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/47065, 2022, A2 Location in patent: Paragraph 0482

75
[ 1191237-80-5 ]
[ 4637-24-5 ]
C₁₈H₂₂N₆O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
541 mg	In N,N-dimethyl-formamide for 18h;	2’0-, 3’O-Acetonide-6A-formamidine-GS-441524 RL-3 To a solution of crude 2’0-, 3’O-Acetonide-GS-441524 RL-2 (331 mg, 1.01 mmol) in DMF (10 mL) was added /V.A-di methyl formamide dimethyl acetal (270 pL, 2.02 mmol). The reaction mixture was stirred for 18 h and then concentrated in vacuo. The residue was dissolved in DCM (10 mL), washed with water (5 mL), brine (5 mL) and dried (MgSCU). The volatiles were removed in vacuo to give 2’0-, 3’O-Acetonide-6A-formamidine-GS- 441524 RL-3 as an off-white foam (541 mg). (0487) 'H NMR (300 MHz, d6-DMSO): δ (ppm) 1.41 (s, 3H), 1.73 (s, 3H), 3.24 (s, 6H), 3.67 - 3.87 (m, 3 H), 4.47-4.57 (m, 1H), 5.08 (dd, 7= 6.6 and 3.1 Hz, 1H), 5.41 (d, 7 = 6.4 Hz, 1H), 6.94 (dd, J = 4.5 Hz, 2H), 8.05 (s, 1H) and 8.92 (s, 1H). LCMS (LCMS Method 4): Rt = 4.04. ESI MS (+ve) 387 [MH]+; calc, m/z for C18H23N6O4 [MH]+ = 387.
541 mg	In N,N-dimethyl-formamide for 18h;	2’0-, 3’O-Acetonide-6A-formamidine-GS-441524 RL-3 To a solution of crude 2’0-, 3’O-Acetonide-GS-441524 RL-2 (331 mg, 1.01 mmol) in DMF (10 mL) was added /V.A-di methyl formamide dimethyl acetal (270 pL, 2.02 mmol). The reaction mixture was stirred for 18 h and then concentrated in vacuo. The residue was dissolved in DCM (10 mL), washed with water (5 mL), brine (5 mL) and dried (MgSCU). The volatiles were removed in vacuo to give 2’0-, 3’O-Acetonide-6A-formamidine-GS- 441524 RL-3 as an off-white foam (541 mg). (0487) 'H NMR (300 MHz, d6-DMSO): δ (ppm) 1.41 (s, 3H), 1.73 (s, 3H), 3.24 (s, 6H), 3.67 - 3.87 (m, 3 H), 4.47-4.57 (m, 1H), 5.08 (dd, 7= 6.6 and 3.1 Hz, 1H), 5.41 (d, 7 = 6.4 Hz, 1H), 6.94 (dd, J = 4.5 Hz, 2H), 8.05 (s, 1H) and 8.92 (s, 1H). LCMS (LCMS Method 4): Rt = 4.04. ESI MS (+ve) 387 [MH]+; calc, m/z for C18H23N6O4 [MH]+ = 387.

Reference： [1]Current Patent Assignee: STARPHARMA HOLDINGS LIMITED - WO2022/40761, 2022, A1 Location in patent: Page/Page column 110
[2]Current Patent Assignee: STARPHARMA HOLDINGS LIMITED - WO2022/40761, 2022, A1 Location in patent: Page/Page column 110

76
[ 1191237-80-5 ]
C₁₈H₂₂NO₅P [ No CAS ]
C₂₇H₃₃N₆O₈P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20℃; for 36h;
78%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20℃; for 36h;

Reference： [1]Ying, Hanglu; Yao, Jie; Wu, Fan; Zhao, Yufen; Ni, Feng [RSC Advances, 2022, vol. 12, # 21, p. 13111 - 13115]
[2]Ying, Hanglu; Yao, Jie; Wu, Fan; Zhao, Yufen; Ni, Feng [RSC Advances, 2022, vol. 12, # 21, p. 13111 - 13115]

77
[ 1191237-80-5 ]
(2R,3aR,6S,7aR)-3a-methyl-2-((perfluorophenyl)thio)-6-(prop-1-en-2-yl)hexahydrobenzo[d][1,3,2]oxathiaphosphole 2-sulfide [ No CAS ]
(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,2-dimethyl-6-((((2S,3aR,6S,7aR)-3a-methyl-6-(prop-1-en-2-yl)-2-sulfidohexahydrobenzo[d][1,3,2]oxathiaphosphol-2-yl)oxy)methyl)tetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20℃; for 0.166667h;	Intermediate 19-0: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,2-dimethyl-6-((((2S,3aR,6S,7aR)-3a-methyl-6-(prop-1-en-2-yl)-2-sulfidohexahydrobenzo[d][1,3,2]oxathiaphosphol-2-yl)oxy)methyl)tetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile 1,8-Diazabicyclo[5.4.0]undec-7-ene (609 µL, 4.07 mmol) was added over 2 min via syringe to a vigorously stirred mixture of intermediate 1-3 (1.00 g, 3.02 mmol), (2R,3aR,6S,7aR)-3a-Methyl-2-((perfluorophenyl)thio)-6-(prop-1-en-2-yl)hexahydrobenzo[d][1,3,2]oxathiaphosphole 2-sulfide (1.75 g, 3.92 mmol), and acetonitrile (24.0 mL) at room temperature. After 10 min, saturated aqueous ammonium chloride solution (10 mL) and ethyl acetate (100 mL) were added sequentially. The organic layer was washed with water (70 mL), and the aqueous layer was extracted with ethyl acetate (40 mL). The combined organic layers were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 10% methanol in dichloromethane) to give intermediate 19-0. LCMS: 578.2.
	With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20℃; for 0.166667h;	Intermediate 19-0: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,2-dimethyl-6-((((2S,3aR,6S,7aR)-3a-methyl-6-(prop-1-en-2-yl)-2-sulfidohexahydrobenzo[d][1,3,2]oxathiaphosphol-2-yl)oxy)methyl)tetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile 1,8-Diazabicyclo[5.4.0]undec-7-ene (609 µL, 4.07 mmol) was added over 2 min via syringe to a vigorously stirred mixture of intermediate 1-3 (1.00 g, 3.02 mmol), (2R,3aR,6S,7aR)-3a-Methyl-2-((perfluorophenyl)thio)-6-(prop-1-en-2-yl)hexahydrobenzo[d][1,3,2]oxathiaphosphole 2-sulfide (1.75 g, 3.92 mmol), and acetonitrile (24.0 mL) at room temperature. After 10 min, saturated aqueous ammonium chloride solution (10 mL) and ethyl acetate (100 mL) were added sequentially. The organic layer was washed with water (70 mL), and the aqueous layer was extracted with ethyl acetate (40 mL). The combined organic layers were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 10% methanol in dichloromethane) to give intermediate 19-0. LCMS: 578.2.

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/46631, 2022, A1 Location in patent: Paragraph 0319
[2]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/46631, 2022, A1 Location in patent: Paragraph 0319

78
[ 1191237-80-5 ]
(S)-2-chloro-4-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl)benzonitrile [ No CAS ]
[ 15074-54-1 ]
((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-((3-chloro-4-cyanobenzyl)oxy)-3-(octadecyloxy)propyl) (2-chlorophenyl) phosphate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-chlorophenyl phosphorodichloridate With 1H-1,2,4-triazole; triethylamine In tetrahydrofuran at 20℃; for 0.666667h; Stage #2: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With 1-methyl-1H-imidazole In tetrahydrofuran for 1h; Stage #3: (S)-2-chloro-4-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl)benzonitrile With 1-methyl-1H-imidazole In tetrahydrofuran for 15h;	Intermediate 23-2: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-((3-chloro-4-cyanobenzyl)oxy)-3-(octadecyloxy)propyl) (2-chlorophenyl) phosphate 2-Chlorophenyl phosphorodichloridate (33.3 μL, 206 μmol) was added via syringe to a vigorously stirred mixture of 1,2,4-triazole (28.6 mg, 414 μmol), triethylamine (57.8 μL, 414 μmol), and tetrahydrofuran (0.4 mL) at room temperature. After 40 min, intermediate 1-3 (59.1 mg, 178 μmol), tetrahydrofuran (0.5 mL), and 1-methylimidazole (16.5 μL, 206 μmol) were added sequentially. After 60 min, a solution of intermediate 23-1 (76.7 mg, 155 μmol) in tetrahydrofuran (0.7 mL) was added via cannula.1-Methylimidazole (20 μL, 250 μmol) were added. After 15 h, saturated aqueous sodium bicarbonate solution (10 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (30 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 5% methanol in dichloromethane) to give intermediate 23-2. LCMS: 997.4.
	Stage #1: 2-chlorophenyl phosphorodichloridate With 1H-1,2,4-triazole; triethylamine In tetrahydrofuran at 20℃; for 0.666667h; Stage #2: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With 1-methyl-1H-imidazole In tetrahydrofuran for 1h; Stage #3: (S)-2-chloro-4-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl)benzonitrile With 1-methyl-1H-imidazole In tetrahydrofuran for 15h;	Intermediate 23-2: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-((3-chloro-4-cyanobenzyl)oxy)-3-(octadecyloxy)propyl) (2-chlorophenyl) phosphate 2-Chlorophenyl phosphorodichloridate (33.3 μL, 206 μmol) was added via syringe to a vigorously stirred mixture of 1,2,4-triazole (28.6 mg, 414 μmol), triethylamine (57.8 μL, 414 μmol), and tetrahydrofuran (0.4 mL) at room temperature. After 40 min, intermediate 1-3 (59.1 mg, 178 μmol), tetrahydrofuran (0.5 mL), and 1-methylimidazole (16.5 μL, 206 μmol) were added sequentially. After 60 min, a solution of intermediate 23-1 (76.7 mg, 155 μmol) in tetrahydrofuran (0.7 mL) was added via cannula.1-Methylimidazole (20 μL, 250 μmol) were added. After 15 h, saturated aqueous sodium bicarbonate solution (10 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (30 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 5% methanol in dichloromethane) to give intermediate 23-2. LCMS: 997.4.

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/46631, 2022, A1 Location in patent: Paragraph 0331
[2]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/46631, 2022, A1 Location in patent: Paragraph 0331

79
[ 1191237-80-5 ]
triethylammonium (R)-2-(benzyloxy)-3-(octadecyloxy)propyl (2-chlorophenyl) phosphate [ No CAS ]
((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-(benzyloxy)-3-(octadecyloxy)propyl) (2-chlorophenyl) phosphate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; 1-methyl-1H-imidazole; 1-(mesitylene-2-sulfonyl)-3-nitro-1H-1,2,4-triazole at 20℃; for 4h;	Intermediate 1-7: ((3aR,4R,6R,6aR)-6-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-(benzyloxy)-3- (octadecyloxy)propyl) (2-chlorophenyl) phosphate 1-(Mesitylsulfonyl)-3-nitro-1H-1,2,4-triazole (4.02 g, 13.6 mmol), intermediate 1-3 (3.00 g, 9.05 mmol), and 1-methylimidazole (1.08 mL, 13.6 mmol) were added sequentially to a stirred solution of intermediate 1-6 (5.92 g, 8.15 mmol) in pyridine at room temperature. After 4 h, the resulting mixture was cooled to 0 °C and saturated aqueous sodium bicarbonate solution and brine were added sequentially. The aqueous layer was extracted with dichloromethane (2 × 400 mL), and the combined organic layers were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 100% ethyl acetate in hexanes) to give intermediate 1-7.LCMS: 938.5.
	With pyridine; 1-methyl-1H-imidazole; 1-(mesitylene-2-sulfonyl)-3-nitro-1H-1,2,4-triazole at 20℃; for 4h;	Intermediate 1-7: ((3aR,4R,6R,6aR)-6-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-(benzyloxy)-3- (octadecyloxy)propyl) (2-chlorophenyl) phosphate 1-(Mesitylsulfonyl)-3-nitro-1H-1,2,4-triazole (4.02 g, 13.6 mmol), intermediate 1-3 (3.00 g, 9.05 mmol), and 1-methylimidazole (1.08 mL, 13.6 mmol) were added sequentially to a stirred solution of intermediate 1-6 (5.92 g, 8.15 mmol) in pyridine at room temperature. After 4 h, the resulting mixture was cooled to 0 °C and saturated aqueous sodium bicarbonate solution and brine were added sequentially. The aqueous layer was extracted with dichloromethane (2 × 400 mL), and the combined organic layers were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 100% ethyl acetate in hexanes) to give intermediate 1-7.LCMS: 938.5.

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/46631, 2022, A1 Location in patent: Paragraph 0267; 0299
[2]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/46631, 2022, A1 Location in patent: Paragraph 0267; 0299

80
[ 1191237-80-5 ]
(S)-2-((3,4-dichlorobenzyl)oxy)-3-(octadecyloxy)propan-1-ol [ No CAS ]
[ 15074-54-1 ]
((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl) ((R)-2-((3,4-dichlorobenzyl)oxy)-3-(octadecyloxy)propyl) phosphate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-chlorophenyl phosphorodichloridate With 1H-1,2,4-triazole; triethylamine In tetrahydrofuran at 20℃; for 0.666667h; Stage #2: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With 1-methyl-1H-imidazole In tetrahydrofuran for 1h; Stage #3: (S)-2-((3,4-dichlorobenzyl)oxy)-3-(octadecyloxy)propan-1-ol With 1-methyl-1H-imidazole In tetrahydrofuran for 15h;	Intermediate 48-3: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl) ((R)-2-((3,4-dichlorobenzyl)oxy)-3-(octadecyloxy)propyl) phosphate 2-Chlorophenyl phosphorodichloridate (64.6 μL, 392 μmol) was added via syringe to a vigorously stirred mixture of 1,2,4-triazole (54.3 mg, 786 μmol), triethylamine (110 μL, 786 μmol), and tetrahydrofuran (0.6 mL) at room temperature. After 40 min, intermediate 1-3 (97.5 mg, 294 μmol), tetrahydrofuran (0.5 mL), and 1-methylimidazole (31.3 μL, 313 μmol) were added sequentially. After 60 min, a solution of intermediate 48-2 (148 mg, 294 μmol) in tetrahydrofuran (0.7 mL) was added via cannula.1-Methylimidazole (20 μL, 392 μmol) were added. After 15 h, saturated aqueous sodium bicarbonate solution (10 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (30 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel(0 to 10% methanol in dichloromethane) to give intermediate 48-3.1H NMR (400 MHz, Chloroform-d) δ 8.01 (d, J = 1.6 Hz, 1H), 7.45 - 7.34 (m, 4H), 7.21 - 7.06 (m, 3H), 7.01 (t, J = 4.6 Hz, 1H), 6.61 (dd, J = 10.3, 4.7 Hz, 1H), 5.62 (s, 2H), 5.44 (dd, J = 17.1, 6.8 Hz, 1H), 4.99 (ddd, J = 9.2, 6.8, 4.0 Hz, 1H), 4.69 - 4.19 (m, 7H), 3.82 - 3.73 (m, 1H), 3.53 - 3.46 (m, 2H), 3.45 - 3.37 (m, 2H), 1.91 - 1.38 (m, 8H), 1.27 (d, J = 2.7 Hz, 30H), 0.90 (t, J = 6.7 Hz, 3H).
	Stage #1: 2-chlorophenyl phosphorodichloridate With 1H-1,2,4-triazole; triethylamine In tetrahydrofuran at 20℃; for 0.666667h; Stage #2: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With 1-methyl-1H-imidazole In tetrahydrofuran for 1h; Stage #3: (S)-2-((3,4-dichlorobenzyl)oxy)-3-(octadecyloxy)propan-1-ol With 1-methyl-1H-imidazole In tetrahydrofuran for 15h;	Intermediate 48-3: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl) ((R)-2-((3,4-dichlorobenzyl)oxy)-3-(octadecyloxy)propyl) phosphate 2-Chlorophenyl phosphorodichloridate (64.6 μL, 392 μmol) was added via syringe to a vigorously stirred mixture of 1,2,4-triazole (54.3 mg, 786 μmol), triethylamine (110 μL, 786 μmol), and tetrahydrofuran (0.6 mL) at room temperature. After 40 min, intermediate 1-3 (97.5 mg, 294 μmol), tetrahydrofuran (0.5 mL), and 1-methylimidazole (31.3 μL, 313 μmol) were added sequentially. After 60 min, a solution of intermediate 48-2 (148 mg, 294 μmol) in tetrahydrofuran (0.7 mL) was added via cannula.1-Methylimidazole (20 μL, 392 μmol) were added. After 15 h, saturated aqueous sodium bicarbonate solution (10 mL), diethyl ether (40 mL), and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with water (30 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel(0 to 10% methanol in dichloromethane) to give intermediate 48-3.1H NMR (400 MHz, Chloroform-d) δ 8.01 (d, J = 1.6 Hz, 1H), 7.45 - 7.34 (m, 4H), 7.21 - 7.06 (m, 3H), 7.01 (t, J = 4.6 Hz, 1H), 6.61 (dd, J = 10.3, 4.7 Hz, 1H), 5.62 (s, 2H), 5.44 (dd, J = 17.1, 6.8 Hz, 1H), 4.99 (ddd, J = 9.2, 6.8, 4.0 Hz, 1H), 4.69 - 4.19 (m, 7H), 3.82 - 3.73 (m, 1H), 3.53 - 3.46 (m, 2H), 3.45 - 3.37 (m, 2H), 1.91 - 1.38 (m, 8H), 1.27 (d, J = 2.7 Hz, 30H), 0.90 (t, J = 6.7 Hz, 3H).

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/46631, 2022, A1 Location in patent: Paragraph 0382
[2]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/46631, 2022, A1 Location in patent: Paragraph 0382

81
[ 1191237-80-5 ]
(S,Z)-3-fluoro-5-(((1-hydroxy-3-(octadec-9-en-1-yloxy)propan-2-yl)oxy)methyl)benzonitrile [ No CAS ]
[ 15074-54-1 ]
((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl) ((R)-2-((3-cyano-5-fluorobenzyl)oxy)-3-(((Z)-octadec-9-en-1-yl)oxy)propyl) phosphate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-chlorophenyl phosphorodichloridate With pyridine; 1H-1,2,4-triazole; triethylamine In acetonitrile at 20℃; for 0.666667h; Stage #2: (S,Z)-3-fluoro-5-(((1-hydroxy-3-(octadec-9-en-1-yloxy)propan-2-yl)oxy)methyl)benzonitrile With pyridine In acetonitrile at 20℃; for 1h; Stage #3: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile In acetonitrile at 20℃; for 15h;	Intermediate 69-4: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl) ((R)-2-((3-cyano-5-fluorobenzyl)oxy)-3-(((Z)-octadec-9-en-1-yl)oxy)propyl) phosphate 2-Chlorophenyl phosphorodichloridate (378 μL, 2.30 mmol) was added via syringe to a vigorously stirred mixture of 1,2,4-triazole (341 mg, 4.94 mmol), triethylamine (688 μL, 4.94 mmol), acetonitrile (5 mL), and pyridine (5 mL) at room temperature. After 40 min,intermediate 69-3 (1.06 g, 2.30 mmol) in acetonitrile (5 mL) and pyridine (5 mL) was added and stirred at room temperature for 1 h. (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7- yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile was then added at once and the resulting suspension was allowed to stir at room temperature. After 15 h, the mixture was concentrated, and to the resulting product was added citric acid (20 mL, 20%w/w in water), sodium hydroxide (5 mL, 1 N), and ethyl acetate (100 mL). The aqueous phase was extracted with additional ethyl acetate (2x 50 mL), and the combined organic fractions were washed with brine (50 mL) and dried over magnesium sulfate. After filtration and concentration, the crude residue was purified by flash column chromatography on silica gel (0 to 15% methanol in dichloromethane) to give intermediate 69-4.1H NMR (400 MHz, Acetonitrile-d3) δ 7.90 (d, J = 2.1 Hz, 1H), 7.52 - 7.32 (m, 7H), 7.22 - 7.15 (m, 2H), 6.89 (dd, J = 6.9, 4.6 Hz, 1H), 6.75 (dd, J = 7.1, 4.6 Hz, 1H), 6.37 (s, 2H), 5.48 (s, 1H), 5.36 (dd, J = 29.5, 6.6 Hz, 1H), 4.95 (dtd, J =13.8, 6.9, 3.7 Hz, 1H), 4.66 - 4.59 (m, 1H), 4.59 - 4.46 (m, 3H), 4.45 - 4.32 (m, 3H), 4.23 (dtt, J = 11.3, 7.0, 3.3 Hz, 1H), 4.08 (ddt, J = 10.9, 7.7, 5.5 Hz, 1H), 3.61 - 3.53 (m, 2H), 2.16 (d, J =15.9 Hz, 3H), 1.97 (p, J = 2.5 Hz, 14H), 1.70 (d, J = 3.1 Hz, 4H), 1.54 - 1.42 (m, 1H), 1.28 (d, J= 9.6 Hz, 46H), 0.90 (t, J = 6.6 Hz, 4H).
	Stage #1: 2-chlorophenyl phosphorodichloridate With pyridine; 1H-1,2,4-triazole; triethylamine In acetonitrile at 20℃; for 0.666667h; Stage #2: (S,Z)-3-fluoro-5-(((1-hydroxy-3-(octadec-9-en-1-yloxy)propan-2-yl)oxy)methyl)benzonitrile With pyridine In acetonitrile at 20℃; for 1h; Stage #3: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile In acetonitrile at 20℃; for 15h;	Intermediate 69-4: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl) ((R)-2-((3-cyano-5-fluorobenzyl)oxy)-3-(((Z)-octadec-9-en-1-yl)oxy)propyl) phosphate 2-Chlorophenyl phosphorodichloridate (378 μL, 2.30 mmol) was added via syringe to a vigorously stirred mixture of 1,2,4-triazole (341 mg, 4.94 mmol), triethylamine (688 μL, 4.94 mmol), acetonitrile (5 mL), and pyridine (5 mL) at room temperature. After 40 min,intermediate 69-3 (1.06 g, 2.30 mmol) in acetonitrile (5 mL) and pyridine (5 mL) was added and stirred at room temperature for 1 h. (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7- yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile was then added at once and the resulting suspension was allowed to stir at room temperature. After 15 h, the mixture was concentrated, and to the resulting product was added citric acid (20 mL, 20%w/w in water), sodium hydroxide (5 mL, 1 N), and ethyl acetate (100 mL). The aqueous phase was extracted with additional ethyl acetate (2x 50 mL), and the combined organic fractions were washed with brine (50 mL) and dried over magnesium sulfate. After filtration and concentration, the crude residue was purified by flash column chromatography on silica gel (0 to 15% methanol in dichloromethane) to give intermediate 69-4.1H NMR (400 MHz, Acetonitrile-d3) δ 7.90 (d, J = 2.1 Hz, 1H), 7.52 - 7.32 (m, 7H), 7.22 - 7.15 (m, 2H), 6.89 (dd, J = 6.9, 4.6 Hz, 1H), 6.75 (dd, J = 7.1, 4.6 Hz, 1H), 6.37 (s, 2H), 5.48 (s, 1H), 5.36 (dd, J = 29.5, 6.6 Hz, 1H), 4.95 (dtd, J =13.8, 6.9, 3.7 Hz, 1H), 4.66 - 4.59 (m, 1H), 4.59 - 4.46 (m, 3H), 4.45 - 4.32 (m, 3H), 4.23 (dtt, J = 11.3, 7.0, 3.3 Hz, 1H), 4.08 (ddt, J = 10.9, 7.7, 5.5 Hz, 1H), 3.61 - 3.53 (m, 2H), 2.16 (d, J =15.9 Hz, 3H), 1.97 (p, J = 2.5 Hz, 14H), 1.70 (d, J = 3.1 Hz, 4H), 1.54 - 1.42 (m, 1H), 1.28 (d, J= 9.6 Hz, 46H), 0.90 (t, J = 6.6 Hz, 4H).

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/46631, 2022, A1 Location in patent: Paragraph 0437
[2]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/46631, 2022, A1 Location in patent: Paragraph 0437

82
[ 1191237-80-5 ]
[ 15074-54-1 ]
((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl) hydrogen phosphate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-chlorophenyl phosphorodichloridate With 1H-1,2,4-triazole; triethylamine In tetrahydrofuran at 20℃; for 0.833333h; Stage #2: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With 1-methyl-1H-imidazole In tetrahydrofuran for 2.16667h;	Intermediate 72-3: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl) hydrogen phosphate 2-Chlorophenyl phosphorodichloridate (564 μL, 3.49 mmol) was added over 2 min via syringe to a vigorously stirred mixture of 1,2,4-triazole (484 mg, 7.01 mmol), triethylamine (977 μL, 7.01 mmol), and tetrahydrofuran (2.0 mL) at room temperature. After 50 min, intermediate 1-3 (1.00 g, 3.02 mmol), tetrahydrofuran (3.0 mL), and 1-methylimidazole (278 μL, 3.49 mmol) were added sequentially. After 130 min, water (1.0 mL) and acetonitrile (1.0 mL) were added sequentially. After 10 min, silica gel (12 g) and acetonitrile (50 mL) were added sequentially, and the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give intermediate 72-3. LCMS: 522.1.
	Stage #1: 2-chlorophenyl phosphorodichloridate With 1H-1,2,4-triazole; triethylamine In tetrahydrofuran at 20℃; for 0.833333h; Stage #2: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With 1-methyl-1H-imidazole In tetrahydrofuran for 2.16667h;	Intermediate 72-3: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl) hydrogen phosphate 2-Chlorophenyl phosphorodichloridate (564 μL, 3.49 mmol) was added over 2 min via syringe to a vigorously stirred mixture of 1,2,4-triazole (484 mg, 7.01 mmol), triethylamine (977 μL, 7.01 mmol), and tetrahydrofuran (2.0 mL) at room temperature. After 50 min, intermediate 1-3 (1.00 g, 3.02 mmol), tetrahydrofuran (3.0 mL), and 1-methylimidazole (278 μL, 3.49 mmol) were added sequentially. After 130 min, water (1.0 mL) and acetonitrile (1.0 mL) were added sequentially. After 10 min, silica gel (12 g) and acetonitrile (50 mL) were added sequentially, and the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give intermediate 72-3. LCMS: 522.1.
	Stage #1: 2-chlorophenyl phosphorodichloridate With 1H-1,2,4-triazole; triethylamine In tetrahydrofuran at 20℃; for 0.85h; Stage #2: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With 1-methyl-1H-imidazole In tetrahydrofuran for 2.16667h;	Intermediate 49-2: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano- 2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl) hydrogen phosphate 2-Chlorophenyl phosphorodichloridate (564 μL, 3.49 mmol) was added over 2 min via syringe to a vigorously stirred mixture of 1,2,4-triazole (484 mg, 7.01 mmol), triethylamine (977 μL, 7.01 mmol), and tetrahydrofuran (2.0 mL) at room temperature. After 50 min, intermediate 1-4 (1.00 g, 3.02 mmol), tetrahydrofuran (3.0 mL), and 1-methylimidazole (278 μL, 3.49 mmol) were added sequentially. After 130 min, water (1.0 mL) and acetonitrile (1.0 mL) were added sequentially. After 10 min, silica gel (12 g) and acetonitrile (50 mL) were added sequentially, and the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give intermediate 49-2. LCMS: 522.1.

Stage #1: 2-chlorophenyl phosphorodichloridate With 1H-1,2,4-triazole; triethylamine In tetrahydrofuran at 20℃; for 0.85h; Stage #2: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile With 1-methyl-1H-imidazole In tetrahydrofuran for 2.16667h;

Intermediate 49-2: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano- 2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl) hydrogen phosphate 2-Chlorophenyl phosphorodichloridate (564 μL, 3.49 mmol) was added over 2 min via syringe to a vigorously stirred mixture of 1,2,4-triazole (484 mg, 7.01 mmol), triethylamine (977 μL, 7.01 mmol), and tetrahydrofuran (2.0 mL) at room temperature. After 50 min, intermediate 1-4 (1.00 g, 3.02 mmol), tetrahydrofuran (3.0 mL), and 1-methylimidazole (278 μL, 3.49 mmol) were added sequentially. After 130 min, water (1.0 mL) and acetonitrile (1.0 mL) were added sequentially. After 10 min, silica gel (12 g) and acetonitrile (50 mL) were added sequentially, and the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give intermediate 49-2. LCMS: 522.1.

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/46631, 2022, A1 Location in patent: Paragraph 0454
[2]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/46631, 2022, A1 Location in patent: Paragraph 0454
[3]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/81973, 2022, A1 Location in patent: Paragraph 0456
[4]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/81973, 2022, A1 Location in patent: Paragraph 0456

83
[ 1191237-80-5 ]
(S)-3-fluoro-4-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl)benzonitrile [ No CAS ]
[ 72351-28-1 ]
((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl) ((R)-2-((4-cyano-2-fluorobenzyl)oxy)-3-(octadecyloxy)propyl) phosphate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile; 2-chlorophenyl phosphordi(1H-1-[1,2,4]triazolide) With 1-methyl-1H-imidazole In tetrahydrofuran for 1h; Stage #2: (S)-3-fluoro-4-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl)benzonitrile In tetrahydrofuran at 20℃;	Intermediate 53-3: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl) ((R)-2-((4-cyano-2-fluorobenzyl)oxy)-3-(octadecyloxy)propyl) phosphate To a solution of 1,2,4-trizole (43 mg, 0.62 mmol) and triethylamine (87 uL, 0.62 mmol) in anhydrous THF (0.4 mL) was added a solution of 2-chlorophenyl dichlorophosphate (76 mg, 0.31mmol) in THF (0.4 mL). The mixture was stirred for 30 min. and then filtered. To the filtrate were added sequentially, additional THF (1.2 mL), the nucleoside (77 mg, 0.232 mmol), and 1-methylimidazole (26 mg, 0.31 mmol). After 1 h, (S)-3-fluoro-4-(((1-hydroxy-3- (octadecyloxy)propan-2-yl)oxy)methyl)benzonitrile (107 mg, 0.232 mmol) was added to the mixture and stirred overnight at room temperature. The solvent was removed and the residue was purified by flash chromatography on silica gel (0-15% MeOH in CH2Cl2) to afford a compound.
	Stage #1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile; 2-chlorophenyl phosphordi(1H-1-[1,2,4]triazolide) With 1-methyl-1H-imidazole In tetrahydrofuran for 1h; Stage #2: (S)-3-fluoro-4-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl)benzonitrile In tetrahydrofuran at 20℃;	Intermediate 53-3: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl) ((R)-2-((4-cyano-2-fluorobenzyl)oxy)-3-(octadecyloxy)propyl) phosphate To a solution of 1,2,4-trizole (43 mg, 0.62 mmol) and triethylamine (87 uL, 0.62 mmol) in anhydrous THF (0.4 mL) was added a solution of 2-chlorophenyl dichlorophosphate (76 mg, 0.31mmol) in THF (0.4 mL). The mixture was stirred for 30 min. and then filtered. To the filtrate were added sequentially, additional THF (1.2 mL), the nucleoside (77 mg, 0.232 mmol), and 1-methylimidazole (26 mg, 0.31 mmol). After 1 h, (S)-3-fluoro-4-(((1-hydroxy-3- (octadecyloxy)propan-2-yl)oxy)methyl)benzonitrile (107 mg, 0.232 mmol) was added to the mixture and stirred overnight at room temperature. The solvent was removed and the residue was purified by flash chromatography on silica gel (0-15% MeOH in CH2Cl2) to afford a compound.

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/46631, 2022, A1 Location in patent: Paragraph 0399
[2]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/46631, 2022, A1 Location in patent: Paragraph 0399

84
[ 1191237-80-5 ]
(S)-4-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl)-2-methoxybenzonitrile [ No CAS ]
[ 72351-28-1 ]
C₅₁H₇₀ClN₆O₁₀P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile; 2-chlorophenyl phosphordi(1H-1-[1,2,4]triazolide) With 1-methyl-1H-imidazole In tetrahydrofuran for 1h; Stage #2: (S)-4-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl)-2-methoxybenzonitrile In tetrahydrofuran at 20℃;	Intermediate 54-3: ((3aR,4R,6R,6aR)-6-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano- 2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl) ((R)-2-((4-cyano-2- fluorobenzyl)oxy)-3-(octadecyloxy)propyl) phosphate To a solution of 1,2,4-trizole (43 mg, 0.62 mmol) and triethylamine (87 uL, 0.62 mmol) in anhydrous THF (0.4 mL) was added a solution of 2-chlorophenyl dichlorophosphate (76 mg, 0.31mmol) in THF (0.4 mL). The mixture was stirred for 30 min. and then filtered. To the filtrate were added sequentially, additional THF (1.2 mL), the nucleoside (77 mg, 0.232 mmol), and 1-methylimidazole (26 mg, 0.31 mmol). After 1 h, (S)-4-(((1-hydroxy-3- (octadecyloxy)propan-2-yl)oxy)methyl)-2-methoxybenzonitrile (115 mg, 0.235 mmol) was added to the mixture and stirred overnight at room temperature. The solvent was removed and the residue was purified by flash chromatography on silica gel (0-15% MeOH in CH2Cl2) to afford the compound.
	Stage #1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile; 2-chlorophenyl phosphordi(1H-1-[1,2,4]triazolide) With 1-methyl-1H-imidazole In tetrahydrofuran for 1h; Stage #2: (S)-4-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl)-2-methoxybenzonitrile In tetrahydrofuran at 20℃;	Intermediate 54-3: ((3aR,4R,6R,6aR)-6-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano- 2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl) ((R)-2-((4-cyano-2- fluorobenzyl)oxy)-3-(octadecyloxy)propyl) phosphate To a solution of 1,2,4-trizole (43 mg, 0.62 mmol) and triethylamine (87 uL, 0.62 mmol) in anhydrous THF (0.4 mL) was added a solution of 2-chlorophenyl dichlorophosphate (76 mg, 0.31mmol) in THF (0.4 mL). The mixture was stirred for 30 min. and then filtered. To the filtrate were added sequentially, additional THF (1.2 mL), the nucleoside (77 mg, 0.232 mmol), and 1-methylimidazole (26 mg, 0.31 mmol). After 1 h, (S)-4-(((1-hydroxy-3- (octadecyloxy)propan-2-yl)oxy)methyl)-2-methoxybenzonitrile (115 mg, 0.235 mmol) was added to the mixture and stirred overnight at room temperature. The solvent was removed and the residue was purified by flash chromatography on silica gel (0-15% MeOH in CH2Cl2) to afford the compound.

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/46631, 2022, A1 Location in patent: Paragraph 0404
[2]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/46631, 2022, A1 Location in patent: Paragraph 0404

85
[ 1191237-80-5 ]
3-(heptadecyloxy)propan-1-ol [ No CAS ]
[ 72351-28-1 ]
((3aR,4R,6R,6aR)-6-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl) (3-(octadecyloxy)propyl) phosphate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile; 2-chlorophenyl phosphordi(1H-1-[1,2,4]triazolide) With 1-methyl-1H-imidazole In tetrahydrofuran for 1h; Stage #2: 3-(heptadecyloxy)propan-1-ol In tetrahydrofuran at 20℃;	Intermediate 55-2: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl) ((R)-2-((4-cyano-2-fluorobenzyl)oxy)-3-(octadecyloxy)propyl) phosphate: To a solution of 1,2,4-trizole (43 mg, 0.62 mmol) and triethylamine (87 uL, 0.62 mmol) in anhydrous THF (0.4 mL) was added a solution of 2-chlorophenyl dichlorophosphate (76 mg, 0.31mmol) in THF (0.4 mL). The mixture was stirred for 30 min. and then filtered. To the filtrate were added sequentially, additional THF (1.2 mL), the nucleoside (77 mg, 0.232 mmol), and 1-methylimidazole (26 mg, 0.31 mmol). After 1 h, 3-(heptadecyloxy)propan-1-ol (74 mg, 0.235 mmol) was added to the mixture and stirred overnight at room temperature. The solvent was removed and the residue was purified by flash chromatography on silica gel (0-15% MeOH in CH2Cl2) to afford a compound.
	Stage #1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile; 2-chlorophenyl phosphordi(1H-1-[1,2,4]triazolide) With 1-methyl-1H-imidazole In tetrahydrofuran for 1h; Stage #2: 3-(heptadecyloxy)propan-1-ol In tetrahydrofuran at 20℃;	Intermediate 55-2: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl) ((R)-2-((4-cyano-2-fluorobenzyl)oxy)-3-(octadecyloxy)propyl) phosphate: To a solution of 1,2,4-trizole (43 mg, 0.62 mmol) and triethylamine (87 uL, 0.62 mmol) in anhydrous THF (0.4 mL) was added a solution of 2-chlorophenyl dichlorophosphate (76 mg, 0.31mmol) in THF (0.4 mL). The mixture was stirred for 30 min. and then filtered. To the filtrate were added sequentially, additional THF (1.2 mL), the nucleoside (77 mg, 0.232 mmol), and 1-methylimidazole (26 mg, 0.31 mmol). After 1 h, 3-(heptadecyloxy)propan-1-ol (74 mg, 0.235 mmol) was added to the mixture and stirred overnight at room temperature. The solvent was removed and the residue was purified by flash chromatography on silica gel (0-15% MeOH in CH2Cl2) to afford a compound.

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/46631, 2022, A1 Location in patent: Paragraph 0408
[2]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/46631, 2022, A1 Location in patent: Paragraph 0408

86
[ 1191237-80-5 ]
(S)-3-fluoro-5-(((1-(hexadecyloxy)-3-hydroxypropan-2-yl)oxy)methyl)benzonitrile [ No CAS ]
[ 72351-28-1 ]
((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl) ((R)-2-((3-cyano-5-fluorobenzyl)oxy)-3-(hexadecyloxy)propyl) phosphate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile; 2-chlorophenyl phosphordi(1H-1-[1,2,4]triazolide) With 1-methyl-1H-imidazole In tetrahydrofuran for 1h; Stage #2: (S)-3-fluoro-5-(((1-(hexadecyloxy)-3-hydroxypropan-2-yl)oxy)methyl)benzonitrile In tetrahydrofuran at 20℃;	Intermediate 71-4: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl) ((R)-2-((3-cyano-5-fluorobenzyl)oxy)-3-(hexadecyloxy)propyl) phosphate To a solution of 1,2,4-trizole (43 mg, 0.62 mmol) and triethylamine (87 uL, 0.62 mmol) in anhydrous THF (0.4 mL) was added a solution of 2-chlorophenyl dichlorophosphate (76 mg, 0.31mmol) in THF (0.4 mL). The mixture was stirred for 30 min. and then filtered. To thefiltrate were added sequentially, additional THF (1.2 mL), (3aR,4R,6R,6aR)-4-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxole-4-carbonitrile (78 mg, 0.235 mmol), and 1-methylimidazole (26 mg, 0.31 mmol).After 1 h, (S)-3-fluoro-5-(((1-(hexadecyloxy)-3-hydroxypropan-2-yl)oxy)methyl)benzonitrile(106 mg, 0.235 mmol) was added to the mixture and stirred overnight at room temperature. The solvent was evaporated, and the residue was purified by flash chromatography on silica gel (0- 15% MeOH in CH2Cl2) to afford the compound.
	Stage #1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile; 2-chlorophenyl phosphordi(1H-1-[1,2,4]triazolide) With 1-methyl-1H-imidazole In tetrahydrofuran for 1h; Stage #2: (S)-3-fluoro-5-(((1-(hexadecyloxy)-3-hydroxypropan-2-yl)oxy)methyl)benzonitrile In tetrahydrofuran at 20℃;	Intermediate 71-4: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl) ((R)-2-((3-cyano-5-fluorobenzyl)oxy)-3-(hexadecyloxy)propyl) phosphate To a solution of 1,2,4-trizole (43 mg, 0.62 mmol) and triethylamine (87 uL, 0.62 mmol) in anhydrous THF (0.4 mL) was added a solution of 2-chlorophenyl dichlorophosphate (76 mg, 0.31mmol) in THF (0.4 mL). The mixture was stirred for 30 min. and then filtered. To thefiltrate were added sequentially, additional THF (1.2 mL), (3aR,4R,6R,6aR)-4-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxole-4-carbonitrile (78 mg, 0.235 mmol), and 1-methylimidazole (26 mg, 0.31 mmol).After 1 h, (S)-3-fluoro-5-(((1-(hexadecyloxy)-3-hydroxypropan-2-yl)oxy)methyl)benzonitrile(106 mg, 0.235 mmol) was added to the mixture and stirred overnight at room temperature. The solvent was evaporated, and the residue was purified by flash chromatography on silica gel (0- 15% MeOH in CH2Cl2) to afford the compound.

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/46631, 2022, A1 Location in patent: Paragraph 0449
[2]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/46631, 2022, A1 Location in patent: Paragraph 0449

87
[ 1191237-80-5 ]
(R)-2-([1,1'-biphenyl]-4-ylmethoxy)-3-(octadecyloxy)propyl bis(4-nitrophenyl) phosphate [ No CAS ]
(R)-2-([1,1'-biphenyl]-4-ylmethoxy)-3-(octadecyloxy)propyl (((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl) (4-nitrophenyl) phosphate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; magnesium(II) chloride In tetrahydrofuran at 50℃; for 1h;	Intermediate 2-4: (R)-2-([1,1'-biphenyl]-4-ylmethoxy)-3-(octadecyloxy)propyl (((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl) (4-nitrophenyl) phosphate A vigorously stirred mixture of intermediate 2-3 (190 mg, 228 μmol), intermediate 1-3 (75.6 mg, 228 μmol), magnesium chloride (217 mg, 2.28 mmol), and tetrahydrofuran (2.5 mL) was heated to 50 °C. After 5 min, N,N-diisopropylethylamine (397 μL, 2.28 mmol) was added over 1 min via syringe. After 60 min, the resulting mixture was cooled to room temperature, and a mixture of citric acid (726 mg), aqueous sodium hydroxide solution (2.0 M, 4 mL), and water (10 mL) was added. Ethyl acetate (60 mL) was added, and the organic layer was washed with a mixture of water and brine (2:1 v:v, 30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 4.5% methanol in dichloromethane) to give intermediate 2-4. LCMS: 1025.5.
	With N-ethyl-N,N-diisopropylamine; magnesium(II) chloride In tetrahydrofuran at 50℃; for 1h;	Intermediate 2-4: (R)-2-([1,1'-biphenyl]-4-ylmethoxy)-3-(octadecyloxy)propyl (((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl) (4-nitrophenyl) phosphate A vigorously stirred mixture of intermediate 2-3 (190 mg, 228 μmol), intermediate 1-3 (75.6 mg, 228 μmol), magnesium chloride (217 mg, 2.28 mmol), and tetrahydrofuran (2.5 mL) was heated to 50 °C. After 5 min, N,N-diisopropylethylamine (397 μL, 2.28 mmol) was added over 1 min via syringe. After 60 min, the resulting mixture was cooled to room temperature, and a mixture of citric acid (726 mg), aqueous sodium hydroxide solution (2.0 M, 4 mL), and water (10 mL) was added. Ethyl acetate (60 mL) was added, and the organic layer was washed with a mixture of water and brine (2:1 v:v, 30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 4.5% methanol in dichloromethane) to give intermediate 2-4. LCMS: 1025.5.

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/46631, 2022, A1 Location in patent: Paragraph 0273
[2]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/46631, 2022, A1 Location in patent: Paragraph 0273

88
[ 1191237-80-5 ]
(S)-2-fluoro-5-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl)benzonitrile [ No CAS ]
[ 72351-28-1 ]
[(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methyl (2-chlorophenyl) [(2R)-2-[(3-cyano-4-fluorophenyl)methoxy]-3-octadecoxypropyl] phosphate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile; 2-chlorophenyl phosphordi(1H-1-[1,2,4]triazolide) With 1-methyl-1H-imidazole In tetrahydrofuran for 1h; Stage #2: (S)-2-fluoro-5-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl)benzonitrile In tetrahydrofuran at 20℃;	Intermediate 98-2: [(3aR,4R,6R,6aR)-4-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano- 2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methyl (2-chlorophenyl) [(2R)-2- [(3-cyano-4-fluoro-phenyl)methoxy]-3-octadecoxy-propyl] phosphate To a solution of 1,2,4-trizole (43 mg, 0.62 mmol) and triethylamine (87 ^L, 0.62 mmol) in anhydrous THF (0.4 mL) was added a solution of 2-chlorophenyl dichlorophosphate (76 mg, 0.31mmol) in THF (0.4 mL). The mixture was stirred for 30 min. and then filtered. To the filtrate were added sequentially, additional THF (1.2 mL), (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxole-4-carbonitrile (78 mg, 0.235 mmol), and 1-methylimidazole (26 mg, 0.31 mmol).After 1 h, intermediate 98-1 (108 mg, 0.235 mmol) was added to the mixture and stirred overnight at room temperature. The solvent was evaporated, and the residue was purified by flash chromatography on silica gel (0-15% MeOH in CH2Cl2) to afford 98-2.
	Stage #1: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile; 2-chlorophenyl phosphordi(1H-1-[1,2,4]triazolide) With 1-methyl-1H-imidazole In tetrahydrofuran for 1h; Stage #2: (S)-2-fluoro-5-(((1-hydroxy-3-(octadecyloxy)propan-2-yl)oxy)methyl)benzonitrile In tetrahydrofuran at 20℃;	Intermediate 98-2: [(3aR,4R,6R,6aR)-4-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano- 2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methyl (2-chlorophenyl) [(2R)-2- [(3-cyano-4-fluoro-phenyl)methoxy]-3-octadecoxy-propyl] phosphate To a solution of 1,2,4-trizole (43 mg, 0.62 mmol) and triethylamine (87 ^L, 0.62 mmol) in anhydrous THF (0.4 mL) was added a solution of 2-chlorophenyl dichlorophosphate (76 mg, 0.31mmol) in THF (0.4 mL). The mixture was stirred for 30 min. and then filtered. To the filtrate were added sequentially, additional THF (1.2 mL), (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxole-4-carbonitrile (78 mg, 0.235 mmol), and 1-methylimidazole (26 mg, 0.31 mmol).After 1 h, intermediate 98-1 (108 mg, 0.235 mmol) was added to the mixture and stirred overnight at room temperature. The solvent was evaporated, and the residue was purified by flash chromatography on silica gel (0-15% MeOH in CH2Cl2) to afford 98-2.

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/46631, 2022, A1 Location in patent: Paragraph 0531
[2]Current Patent Assignee: GILEAD SCIENCES INC - WO2022/46631, 2022, A1 Location in patent: Paragraph 0531

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CAS No. :	1191237-80-5	MDL No. :	MFCD32693253
Formula :	C₁₅H₁₇N₅O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IJCOKJGMVJGKBB-CGEWXTDFSA-N
M.W :	331.33	Pubchem ID :	58527338
Synonyms :	Remdesivir O-desphosphate acetonide	Chemical Name :	(3aR,4R,6R,6aR)-4-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile

Signal Word:	Warning	Class:
Precautionary Statements:	P261-P280-P301+P312-P302+P352-P305+P351+P338	UN#:
Hazard Statements:	H302-H315-H319-H335	Packing Group:
GHS Pictogram:

Precautionary Statements-General
Code	Phrase
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P103	Read label before use
Prevention
Code	Phrase
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P202	Do not handle until all safety precautions have been read and understood.
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P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
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P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
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P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
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P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
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P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
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P335	Brush off loose particles from skin.
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P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
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P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 1191237-80-5 ] {[proInfo.proName]}

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[ 1191237-80-5 ] Synthesis Path-Downstream 1~88

Precautionary Statements-General

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