Name: 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|99%
Brand: Ambeed
SKU: A1159246
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1
[ 1191237-69-0 ]
[ 1115-59-9 ]
[ 1355050-14-4 ]

Yield	Reaction Conditions	Operation in experiment
16%		f2S,2'S)-diethyl 2-2,-((((2R<3S.4R.5R)-5-(4-aminopvrrolo\| 1.2-f\| \| K2.4\|lriazin- 7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2- yI)methoxy)phosphoryl)bis(azanediyl)dipropanoate (Compound 12)The nucleoside 1 (14.6 mg, 0.05 mmol) was dissolved in anhydrous trimethyl phosphate (0.5 mL) and stirred under N2(g) at RT. POCl3 (9.2 mu,, 0.1 mmol) was added and the mixture stirred for 60 min. Alanine ethyl ester hydrochloride (61 mg, 0.4 mmol) and then Et3N (70 mu, 0.5 mmol) was added. The resultant mixture was stirred for 15 min. and then additional Et3N (70 mu, 0.5 mmol) was added to give a solution pH of 9-10. The mixture was stirred for 2 h. and then diluted with EtOAc, washed with saturated aqueous NaHC03 solution followed by saturated aqueous NaCl solution. The organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was subjected to preparative HPLC (C18 column) to yield the product 12 (5.5 mg, 16%).1H NMR (400 MHz, CD3OD) delta 8.13 (s, 1H), 7.41 (d, J = 4.8 Hz, 1H), 7.18 (d, J = 4.8 Hz, 1H), 4.78 (d, J= 5.6 Hz, 1H), 4.36 (m, 1H), 4.25-4.08 (m, 7H), 3.83 (m, 2H), 1.33-1.23 (m, 12H).31P NMR (121.4 MHz, CD3OD) delta 13.8.LCMS m/z 570.0 [M+H], 568.0 [M-H].
16%		The nucleoside 1 (14.6 mg, 0.05 mmol) was dissolved in anhydrous trimethyl phosphate (0.5 mL) and stirred under N2(g) at RT. POCl3 (9.2 muL, 0.1 mmol) was added and the mixture stirred for 60 min. Alanine ethyl ester hydrochloride (61 mg, 0.4 mmol) and then Et3N (70 muL, 0.5 mmol) was added. The resultant mixture was stirred for 15 min. and then additional Et3N (70 mul, 0.5 mmol) was added to give a solution pH of 9-10. The mixture was stirred for 2 h. and then diluted with EtOAc, washed with saturated aqueous NaHCO3 solution followed by saturated aqueous NaCl solution. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was subjected to preparative HPLC (C18 column) to yield the product 12 (5.5 mg, 16%). 1H NMR (400 MHz, CD3OD) delta 8.13 (s, 1H), 7.41 (d, J=4.8 Hz, 1H), 7.18 (d, J=4.8 Hz, 1H), 4.78 (d, J=5.6 Hz, 1H), 4.36 (m, 1H), 4.25-4.08 (m, 7H), 3.83 (m, 2H), 1.33-1.23 (m, 12H). 31P NMR (121.4 MHz, CD3OD) delta 13.8. LCMS m/z 570.0 [M+H], 568.0 [M-H].
		[0205] The nucleoside 1 (14.6 mg, 0.05 mmol) was dissolved in anhydrous trimethyl phosphate (0.5 mL) and stirred under N2(g) at RT. POCI3 (9.2 uL, 0.1 mmol) was added and the mixture stirred tor about 60 min. Alanine ethyl ester hydrochloride (61 mg, 0.4 mmol) and then Et3N (70 uL, 0.5 mmol) was added. The resultant mixture was stirred for about 15 min. and then additional Et3N (70 mu, 0.5 mmol) was added to give a solution pH of 9-10. The rnixture was stirred for about 2 h. and then diluted with EtOAc, washed with saturated aqueous NaHCC>3 solution followed by saturated aqueous NaCl solution. The organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was subjected to preparative HPLC (C18 column) to yield the product 12. NMR (400 MHz, CD3OD) delta 8.13 (s, 1H), 7.41 (d, J = 4.8 Hz, 1H). 7.18 (d, J= 4.8 Hz, 1H), 4.78 (d, J= 5.6 Hz, 1H), 4.36 (m, 1H), 4.25-4.08 (m, 7H), 3.83 (m, 2H), 1.33-1.23 (m, 12H). 31P NMR (121.4 MHz, CD3OD) delta 13.8. LCMS m/z 570.0 [M+H], 568.0 [M-H].

Reference： [1]Patent: WO2012/12776,2012,A1 .Location in patent: Page/Page column 129-130
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 1648 - 1661
[3]Patent: US2017/71964,2017,A1 .Location in patent: Paragraph 0568-0569
[4]Patent: WO2016/69826,2016,A1 .Location in patent: Paragraph 0205

2
[ 14233-64-8 ]
[ 1191237-69-0 ]

Reference： [1]Patent: WO2012/12776,2012,A1
[2]Patent: WO2016/69826,2016,A1
[3]Patent: WO2016/69826,2016,A1
[4]Patent: CN110776512,2020,A

3
[ 16838-89-4 ]
[ 1191237-69-0 ]

Reference： [1]Patent: WO2012/12776,2012,A1
[2]Patent: WO2016/69826,2016,A1
[3]Patent: WO2016/69826,2016,A1

4
[ 261909-49-3 ]
[ 1191237-69-0 ]
[ 1355050-10-0 ]

Yield	Reaction Conditions	Operation in experiment
25%	With 1-methyl-1H-imidazole; trimethyl phosphite; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;	The nucleoside 1 (45mg, 0.15mmol) was dissolved in anhydrous trimethyl phosphate (0.5 mL) and the solution stirred under N2(g) at 0C. Methyl imidazole (36 mu, 0.45 mmol) was added to the solution. Chlorophosphoramidate C (69 mg, 0.225 mmol) was dissolved in anhydrous THF (0.25 mL) and added dropwise to the nucleoside mixture. When the reaction was complete by LCMS, the reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHC03 solution, saturated NaCl, dried over anhydrous Na2S04> filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography eluting with 0-5% MeOH in CH2C12 followed by preparative HPLC to give the product (20.9 mg, 25%).1H NMR (300 MHz, CD3OD) 5 7.95 (m, 1H), 7.31-6.97 (m, 7H), 4.94 (m, 1H), 4.78 (m, 1H), 4.43 (m, 3H), 4.20 (m, 1H), 3.80 (d, 1H), 1.30-1.18 (m, 9H);31P NMR (121.4 MHz, CD3OD) delta 3.8.LCMS m/z 561.0 [M+H], 559.0 [M-H].
25%	With 1-methyl-1H-imidazole; In tetrahydrofuran; at 0℃;Inert atmosphere;	The nucleoside 1 (45 mg, 0.15 mmol) was dissolved in anhydrous trimethyl phosphate (0.5 mL) and the solution stirred under N2(g) at 0 C. Methyl imidazole (36 muL, 0.45 mmol) was added to the solution. Chlorophosphoramidate C (69 mg, 0.225 mmol) was dissolved in anhydrous THF (0.25 mL) and added dropwise to the nucleoside mixture. When the reaction was complete by LCMS, the reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution, saturated NaCl, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography eluting with 0-5% MeOH in CH2Cl2 followed by preparative HPLC to give the product (20.9 mg, 25%). 1H NMR (300 MHz, CD3OD) delta 7.95 (m, 1H), 7.31-6.97 (m, 7H), 4.94 (m, 1H), 4.78 (m, 1H), 4.43 (m, 3H), 4.20 (m, 1H), 3.80 (d, 1H), 1.30-1.18 (m, 9H). 31P NMR (121.4 MHz, CD3OD) delta 3.8. LCMS m/z 561.0 [M+H], 559.0 [M-H]
	With 1-methyl-1H-imidazole; trimethyl phosphite; In tetrahydrofuran; at 0℃;Inert atmosphere;	[0195] The nucleoside 1 (45mg, 0.15mmol) was dissolved in anhydrous trimethyl phosphate (0.5 mL) and the solution stirred under N2 (g) at about 0 C. Methyl imidazole (36 0.45 mmol) was added to the solution. CMorophosphoramidate C (69 mg, 0.225 mmol) was dissolved in anhydrous THF (0.25 mL) and added dropwise to the nucleoside mixture. When the reaction was complete by LCMS, the reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution, saturated NaCl, dried over anhydrous Na2SCO4, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography eluting with 0-5% MeOH in CH2CI2 followed by preparative HPLC to give the product. NMR (300 MHz, CD3OD) delta 7.95 (m, 1H), 7.31-6.97 (m, 7H), 4.94 (m, 1H), 4.78 (m, 1H), 4.43 (m, 3H), 4.20 (m, 1H), 3.80 (d, 1H), 1.30-1.18 (m, 9H). 3,P NMR (121.4 MHz, CD3OD) delta 3.8. LCMS m/z 561.0 [M+H], 559.0 [M-H].

Reference： [1]Patent: WO2012/12776,2012,A1 .Location in patent: Page/Page column 127
[2]Patent: US2017/71964,2017,A1 .Location in patent: Paragraph 0550-0551
[3]Patent: WO2016/69826,2016,A1 .Location in patent: Paragraph 0195

5
[ 1191237-68-9 ]
[ 1191237-69-0 ]
[ 1355049-95-4 ]

Yield	Reaction Conditions	Operation in experiment
37%; 37%		The tribenzyl cyano nucleoside (70 mg, 0.124 mmol) was dissolved in anhydrous CH2Cl2 (2 mL) and cooled to -78 C under N2(g). A solution of BC13 (IN in CH2C12, 0.506 mL, 0.506 mmol) was added and the reaction mixture stirred for 1 h. at -78 C. When the reaction was complete by LC/MS, MeOH was added to quench the reaction. The reaction mixture was allowed to warm to room RT and the solvent removed under reduced pressure. The residue was subjected to CI 8 reverse phase HPLC, eluting for 5 min with H20 (0.1 % TFA), followed by a gradient of 0-70% MeCN in H20 (0.1 % TFA) over 35 min, to elute the a-anomer (20 mg, 37%), and beta-anomer 1 (20 mg, 37%).(a-anomer)1H NMR (300 MHz, D20) delta 7.96 (s, 1H), 7.20 (d, J= 4.8 Hz, 1H), 6.91 (d, J= 4.8 Hz, 1H), 4.97 (d, J= 4.4 Hz, 1H), 4.56-4.62 (m, 1H), 4.08-4.14 (m, 1H), 3.90 (dd, J = 12.9, 2.4 Hz, 1H), 3.70 (dd, J = 13.2, 4.5 Hz, 1H).(beta-anomer) 1H NMR (400 MHz, DMSO) delta 7.91 (s, 1H), 7.80-8.00 (br s, 2H), 6.85-6.89 (m, 2H), 6.07 (d, J= 6.0 Hz, 1H), 5.17 (br s, 1H), 4.90 (br s, 1H), 4.63 (t, J= 3.9 Hz, 1H), 4.02-4.06 (m, 1H), 3.94 (br s, 1H), 3.48-3.64 (m, 2H).LCMS m/z 292.2 [M+H], 290.0 [M-H]. Tr= 0.35 min.13C NMR (400 MHZ, DMSO), 156.0, 148.3, 124.3, 117.8, 1 17.0, 111.2, 101.3, 85.8, 79.0, 74.7, 70.5, 61.4HPLC Tr = 1.32 min
37%; 37%	With boron trichloride; In dichloromethane; at -78℃; for 1h;Inert atmosphere;	The tribenzyl cyano nucleoside (70 mg, 0.124 mmol) was dissolved in anhydrous CH2Cl2 (2 mL) and cooled to -78 C. under N2(g). A solution of BCl3 (1N in CH2Cl2, 0.506 mL, 0.506 mmol) was added and the reaction mixture stirred for 1 h. at -78 C. When the reaction was complete by LC/MS, MeOH was added to quench the reaction. The reaction mixture was allowed to warm to room RT and the solvent removed under reduced pressure. The residue was subjected to C18 reverse phase HPLC, eluting for 5 min with H2O (0.1% TFA), followed by a gradient of 0-70% MeCN in H2O (0.1% TFA) over 35 min, to elute the alpha-anomer (20 mg, 37%), and beta-anomer 1 (20 mg, 37%). (alpha-anomer)1H NMR (300 MHz, D2O) delta 7.96 (s, 1H), 7.20 (d, J=4.8 Hz, 1H), 6.91 (d, J=4.8 Hz, 1H), 4.97 (d, J=4.4 Hz, 1H), 4.56-4.62 (m, 1H), 4.08-4.14 (m, 1H), 3.90 (dd, J=12.9, 2.4 Hz, 1H), 3.70 (dd, J=13.2, 4.5 Hz, 1H). (beta-anomer)1H NMR (400 MHz, DMSO) delta 7.91 (s, 1H), 7.80-8.00 (br s, 2H), 6.85-6.89 (m, 2H), 6.07 (d, J=6.0 Hz, 1H), 5.17 (br s, 1H), 4.90 (br s, 1H), 4.63 (t, J=3.9 Hz, 1H), 4.02-4.06 (m, 1H), 3.94 (br s, 1H), 3.48-3.64 (m, 2H). LCMS m/z 292.2 [M+H], 290.0 [M-H]. Tr=0.35 min. 13C NMR (400 MHZ, DMSO), 156.0, 148.3, 124.3, 117.8, 117.0, 111.2, 101.3, 85.8, 79.0, 74.7, 70.5, 61.4. HPLC Tr=1.32 min
	With boron trichloride; In dichloromethane; at -78 - -20℃; for 1h;Inert atmosphere;	[0184] The tribenzyl cyano nucleoside (70 mg, 0.124 mmol) was dissolved in anhydrous CH2C12 (2 mL) and cooled to about -20 C under N2 (g). A solution of BC13 (IN in CH2C12, 0.506 mL, 0.506 mmol) was added and the reaction mixture stirred for 1 h. at -78 C. When the reaction was complete by LC/MS, MeOH was added to quench the reaction. The reaction mixture was allowed to warm to RT and the solvent removed under reduced pressure. The residue was subjected to CI 8 reverse phase HPLC, eluting for 5 min with H2O (0.1 % TFA), followed by a gradient of 0-70% MeCN in H20 (0.1 % TFA) over 35 min, to elute the a-anomer, and beta-anomer 1. (a-anomer) NMR (300 MHz, D2O) delta 7.96 (s, 1H), 7.20 (d, J= 4.8 Hz, 1H), 6.91 (d, J= 4.8 Hz, 1H), 4.97 (d, J= 4.4 Hz, 1H), 4.56-4.62 (m, 1H), 4.08-4.14 (m, 1H), 3.90 (dd, J = 12.9, 2.4 Hz, 1H), 3.70 (dd, J = 13.2, 4.5 Hz, 1H). (beta-anomer) NMR (400 MHz, DMSO) delta 7.91 (s, 1H), 7.80-8.00 (br s, 2H), 6.85-6.89 (m, 2H), 6.07 (d, J= 6.0 Hz, 1H), 5.17 (br s, 1H), 4.90 (br s, 1H), 4.63 (t, J= 3.9 Hz, 1H), 4.02-4.06 (m, 1H), 3.94 (br s, 1H), 3.48- 3.64 (m, 2H). LCMS m/z 292.2 [M+H], 290.0 [M-H]. Tr= 0.35 min. 13C NMR (400 MHZ, DMSO), 156.0, 148.3, 124.3, 117.8, 117.0, 111.2, 101.3, 85.8, 79.0, 74.7, 70.5, 61.4. HPLC Tr = 1.32 min

Reference： [1]Patent: WO2012/12776,2012,A1 .Location in patent: Page/Page column 111-112
[2]Patent: US2017/71964,2017,A1 .Location in patent: Paragraph 0521
[3]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2705 - 2707
[4]Patent: WO2016/69826,2016,A1 .Location in patent: Paragraph 0184

6
[ 1355049-94-3 ]
[ 1191237-69-0 ]

Reference： [1]Patent: WO2012/12776,2012,A1

7
[ 1355049-94-3 ]
[ 1191237-69-0 ]
[ 1355049-95-4 ]

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

8
[ 1191237-69-0 ]
((((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 ]

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: WO2016/69826,2016,A1

9
[ 1191237-69-0 ]
(2S)-2-ethylbutyl 2-(((S)-(((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 [ No CAS ]

Reference： [1]Patent: WO2016/69826,2016,A1
[2]Patent: WO2016/69826,2016,A1
[3]Patent: US2017/71964,2017,A1
[4]Patent: WO2017/184668,2017,A1

10
[ 1191237-69-0 ]
((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl phosphate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		[0208] A mixture of about 0.05 mmol of compound 1 and about 0.5 mL of trimethylphosphate was sealed in a container for about one to about 48 h. The mixture was cooled to about -10 to about 10 C and about 0.075 mmol of phosphorus oxychloride is added. After about one to about 24 hours, the reaction was quenched with about 0.5 mL of 1M tetraemylarnmornum bircarbonate and the desired fractions were isolated by anion exchange chromatography to afford the title compound. [0209] Compound 33 was prepared as the bis-trielhylarnrnonium salt from compound 1 as previously described (WO2011150288). 1H NMR (400 MHz, D2O) delta 7.82 (s, 1H), 6.91 - 6.88 (m, 1H), 6.81 - 6.78 (m, 1H), 4.87 - 4.84 (m, 1H), 4.40 - 4.30 (m, 2H), 3.95 - 3.77 (m, 2H), 3.10 - 3.00 (m, 6H), 1.20 - 1.10 (m, 9H). 3lP NMR (162 MHz, D2O) delta 2.33. MS m/z 371.

Reference： [1]Patent: WO2016/69826,2016,A1 .Location in patent: Paragraph 0208; 0209

11
[ 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

12
[ 1191237-69-0 ]
C₃₀H₃₉N₆O₈P [ No CAS ]

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

13
[ 1191237-69-0 ]
[ 1439900-56-7 ]
(2S)-2-ethylbutyl 2-(((R)-(((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 [ No CAS ]
(2S)-2-ethylbutyl 2-(((S)-(((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 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tert-butylmagnesium chloride; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 2h;Inert atmosphere;	[0198] (2S)-2-ethylbutyl 2-(((((2R3S,4R,5R)-5-(4-aminopyrrolo[2,l-fJ U A4]triazin-7-yl)- 5-cyano-3,4-diliydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoi^l)ar-iino) propanoate. (2 S)-2-ethylbutyl 2-(((4-nitrophenoxy)(phenoxy)pho^hoiyl)amino)propanoate (1.08 g, 2.4 mmol) was dissolved in anhydrous DMF (9 mL) and stirred under a nitrogen atmosphere at RT. (2R,3R,4S,5R)-2-(4-animopyiTolo[2,l-i][l,2,4]triazin-7-yl)-3,4-dmydroxy-5 (hydroxymethyl)tetrahydrofuran-2-carbonitrile (350 mg, 1.2 mmol) was added to the reaction mixture in one portion. A solution of i-butylmagnesium chloride in THF (1M, 1.8 mL, 1.8 mmol) was then added to the reaction dropwise over about 10 minutes. The reaction was stirred for about 2 h, at which point the reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (3 x 15 mL) followed by saturated aqueous sodium chloride solution (15 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oil was purified with silica gel column chromatography (0-10% MeOH in DCM) to afford (2S)-2-ethylbutyl 2- (((((2R,3 S ,4R,5R)-5-(4-aminopyrrolo [2, 1 -fj [ 1 ,2,4]triazin-7-yl)-5-cyano-3 ,4- dihydroxyte1rahydrofui^-2-yl)memoxy)(phenoxy)phosphotyl)aniino) propanoate (311 mg, 43%, 1:0.4 diastereomeric mixture at phosphorus) as a white solid. NMR (400 MHz, CD3OD) delta 7.85 (m, 1H), 7.34 - 7.23 (m, 2H), 7.21 - 7.09 (m, 3H), 6.94 - 6.84 (m, 2H), 4.78 (d, J= 5.4 Hz, 1H), 4.46 - 4.33 (m, 2H), 4.33 - 4.24 (m, 1 H), 4.18 (m, 1H), 4.05 - 3.80 (m, 3H), 1.52 - 1.39 (m, 1H), 1.38 - 1.20 (m, 7H), 0.85 (m, 6H). 3 IP NMR (162 MHz, CD3OD) delta 3.71, 3.65. LCMS m/z 603.1 [M+H], 600.9 [M-H]. HPLC (2-98% MeCN-H20 gradient with 0.1% TFA modifier over 8.5 min, 1.5mIJmin, Column: Phenomenex Kinetex C18, 2.6 um 100 A, 4.6 x 100 mm ) tg = 5.544 min, 5.601 min was dissolved in acetonitrile. The resulting solution was loaded onto Lux Cellulose-2 chiral column, equilibrated in acetonitrile, and eluted with isocratic acetonitrile/methanol (95:5 vol/vol). The first eluting diastereomer had a retention time of 17.4 min, and the second eluting diastereomer had a retention time of 25.0 min. [0200] First Eluting Diastereomer is (S)-2-ethylbutyl 2-(((R)-(((2R,3S,4R,5R)-5-(4- ammopyiTolo[2,l-f][l,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydromran-2- yl)methoxy)(phenoxy)phosphoryl)amino)propanoate: 'HNMR (400 MHz, CD3OD) 6 8.05 (s, 1H), 7.36 (d, J= 4.8 Hz, 1 H), 7.29 (br t, J= 7.8 Hz, 2H), 7.19 - 7.13 (m, 3H), 7.1 1 (d, J= 4.8 Hz, 1H), 4.73 (d, J= 5.2 Hz, 1H), 4.48 - 4.38 (m, 2H), 4.37 - 4.28 (m, 1 H), 4.17 (t, J= 5.6 Hz, 1H), 4.08 - 3.94 (m, 2H), 3.94 - 3.80 (m, 1H), 1.48 (sep, J= 12.0, 6.1 Hz, 1H), 1.34 (p, J= 7.3 Hz, 4H), 1.29 (d, J= 7.2 Hz, 3H), 0.87 (t, J= 7.4 Hz, 6H). 3 ,PNMR (162 MHz, CD3OD) delta 3.71 (s). HPLC (2-98% MeCN-H20 gradient with 0.1% TFA modifier over 8.5 min, 1.5mIJmin, Column: Phenomenex Kinetex C18, 2.6 um 100 A, 4.6 x 100 mm ) tR = 5.585 min. [0201] Second Eluting Diastereomer is (S)-2-ethylbutyl 2-(((S)-(((2R,3 S,4R,5R)-5-(4- aminopyrrolo[2, 1 -fj [ 1 ,2,4]triazin-7-yl)-5-cyano-3 ,4-dihydroxytetrahydroiuran-2- yl)methoxy)(phenoxy)phosphoryl)amino)propanoate: 'HNMR (400 MHz, CD3OD) delta 8.08 (s, 1H), 7.36 - 7.28 (m, 3H), 7.23 - 7.14 (m, 3H), 7.08 (d, J = 4.8 Hz, 1H), 4.71 (d, J= 5.3 Hz, 1H), 4.45 - 4.34 (m, 2H), 4.32 - 4.24 (m, 1H), 4.14 (t, J = 5.8 Hz, 1H), 4.08 - 3.94 (m, 2H), 3.93 - 3.85 (m, 1H), 1.47 (sep, J= 6.2 Hz, 1H), 1.38 - 1.26 (m, 7H), 0.87 (t, J= 7.5 Hz, 6H). 31PNMR (162 MHz, CD3OD) delta 3.73 (s). HPLC (2-98% MeCN- H2O gradient with 0.1% TFA modifier over 8.5 min, 1.5mL/min, Column: Phenomenex Kinetex CI 8, 2.6 urn 100 A, 4.6 x 100 mm ) tR = 5.629 min.

Reference： [1]Patent: WO2016/69826,2016,A1 .Location in patent: Paragraph 0198-0201
[2]Patent: WO2017/184668,2017,A1

14
[ 1191237-69-0 ]
C₁₇H₁₉N₂O₇P [ No CAS ]
[ 1355050-12-2 ]

Yield	Reaction Conditions	Operation in experiment
		[0204] Compound 1 (50 mg, 0.17 mmol) was dissolved in NMP-THF (1:1 mL)) and cooled with ice bath. tBuMgCl (0.257 mL, 0.257 mmol) was then added over about 5 min. The resulting mixture was allowed to warm to RT and was stirred for about 30 min. Then a solution of compound L (Prepared according to US20120009147, 74.6 mg, 0.189 mmol) in THF (2 mL) was added. After about 30 min, the reaction mixture was purified by HPLC (acetonitrile 10 to 80% in water) to give compound 29 as a yellow solid. The solid was further purified with silica gel chromatography (MeOH 0 to 20% DCM) to afford compound 29. NMR (400 MHz, CD3OD) delta 7.76 (d, J= 6.0 Hz, 1H), 7.25 - 7.14 (m, 2H), 7.11 - 6.99 (m, 3H), 6.87 - 6.72 (m, 2H), 4.70 (d, J = 5.4 Hz, 1H), 4.39 - 4.24 (m, 2H), 4.20 (dddd, J= 9.7, 7.9, 5.1, 2.8 Hz, 1H), 4.10 (dt, J= 12.8, 5.5 Hz, 1H), 4.06 - 3.91 (m, 2H), 3.72 (ddq, J= 14.3, 9.3, 7.1 Hz, 1H), 1.17 (dd, J= 7.1, 1.0 Hz, 1H), 1.14 - 1.06 (m, 5H). 3,P NMR (162 MHz, CD3OD) 5 3.73, 3.68. MS m/z = 547 (M+l)+.

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 1648 - 1661
[2]Patent: WO2016/69826,2016,A1 .Location in patent: Paragraph 0204

15
[ 1273029-33-6 ]
[ 1191237-69-0 ]
(2S)-ethyl 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)-3-phenylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34%		Compound 1 (0.030 g, 0.103 mmol) was dissolved in DMF (1 mL) and then THF (0.5 mL) was added. t-BuMgCl (1M/THF, 154.5 muL, 0.154 mumol) was added to the reaction in a drop-wise manner with vigorous stirring. The resulting white slurry was stirred at RT for 30 min. A solution of compound D (0.058 g, 0.124 mmol) in THF (1 mL) was added in a drop-wise manner to the reaction at RT. The reaction progress was monitored by LC/MS. When the reaction progressed to 50% conversion, the reaction was cooled in an ice bath and quenched with glacial acetic acid (70 muL). The reaction was concentrated and compound 21 (22 mg, 34%, as a 2.6:1 mixture of diastereomers) was isolated from the residue by reverse phase HPLC. 1H NMR (400 MHz, DMSO-d6) delta 7.91 (d, J=4 Hz, 1H), 7.90 (brs, 2H), 7.09-7.30 (m, 8H), 7.01, (t, J=8.2 Hz, 2H), 6.89 (d, J=4.4 Hz, 1H), 6.82 (t, J=4.4 Hz, 1H), 6.27 (m, 1H), 6.14 (m, 1H), 5.34 (m, 1H), 4.62 (t, J=5.6 Hz, 1H), 4.15 (m, 1H), 3.78-4.01 (m, 6H), 2.92 (m, 1H), 2.78 (m, 1H), 1.04 (m, 3H). 31P NMR (162 MHz, DMSO-d6) delta 3.69 (s), 3.34 (s). MS m/z=623.0 [M+H].
		[0214] Compound 1 (0.030 g, 0.103 mmol) was dissolved in DMF (1 mL) and then THF (0.5 mL) was added. r-BuMgCl (1M/THF, 154.5 muL, 0.154 umol) was added to the reaction in a drop-wise manner with vigorous stirring. The resulting white slurry was stirred at RT for about 30 min. A solution of compound D (0.058 g, 0.124 mmol) in THF (1 mL) was added in a drop- wise manner to the reaction at RT. The reaction progress was monitored by LC/MS. When the reaction progressed to 50% conversion, the reaction was cooled in an ice bath and quenched with glacial acetic acid (70 mu,). The reaction was concentrated and compound 21 was isolated from the residue by reverse phase HPLC. 1H NMR (400 MHz, DMSO-d6) delta 7.91 (d, J = 4 Hz, 1H), 7.90 (brs, 2H), 7.09-7.30 (m, 8H), 7.01, (t, J = 8.2 Hz, 2H), 6.89 (d, J= 4.4 Hz, 1H), 6.82 (t, J= 4.4 Hz, 1H), 6.27 (m, 1H), 6.14 (m, 1H), 5.34 (m, 1H), 4.62 (t, J= 5.6 Hz, 1H), 4.15 (m, 1H), 3.78-4.01 (m, 6H), 2.92 (m, 1H), 2.78 (m, 1H), 1.04 (m, 3H). 3,P NMR (162 MHz, DMSO-de) delta 3.69 (s), 3.34 (s). MS m/z - 623.0 [M+H].

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 1648 - 1661
[2]Patent: US2017/71964,2017,A1 .Location in patent: Paragraph 0598-0599
[3]Patent: WO2016/69826,2016,A1 .Location in patent: Paragraph 0214

16
[ 1273029-27-8 ]
[ 1191237-69-0 ]
(2S)-ethyl 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)-3-methylbutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%		Compound 1 (0.040 g, 0.137 mmol) was dissolved in NMP (1.5 mL) and then THF (0.25 mL) was added. This solution was cooled in an ice bath and t-BuMgCl (1M/THF, 425.7 muL, 0.426 mumol) was added in a drop-wise manner with vigorous stirring. The ice bath was removed and the resulting white slurry was stirred at RT for 15 min. A solution of compound E (0.081 g, 0.192 mmol) in THF (0.5 mL) was added in a drop-wise manner to the reaction at RT. The reaction progress was monitored by LC/MS. When the reaction progressed to 50% conversion, the reaction was cooled in an ice bath and quenched with glacial acetic acid (70 muL). The reaction was concentrated and compound 22 (22 mg, 34%) was semi-purified from the residue by reverse phase HPLC. The semi-pure material was further purified by silica gel column chromatography (12 g dry load cartridge, 40 g column; eluent: 100% EtOAc ramping to 10% MeOH in EtOAc) to yield compound 22 (0.034 g, 43% as a 1.8:1 mixture of diastereomers). 1H NMR (400 MHz, DMSO-d6) delta 7.91 (d, J=1.6 Hz, 1H), 7.88 (brs, 2H), 7.32 (m, 2H), 7.15 (m, 3H), 6.90 (t, J=4.2 Hz, 1H), 6.84 (d, J=4.8 Hz, 1H), 6.26 (dd, J=13.4, 6.2 Hz, 1H), 5.87 (quart. J=11.2 Hz, 1H), 5.35 (m, 1H), 4.64 (m, 1H), 4.25 (m, 2H), 3.93-4.15 (m, 4H), 3.45 (m, 1H), 1.87 (m, 1H), 1.09-1.16 (m, 3H), 0.70-0.83 (m, 6H). 31P NMR (162 MHz, DMSO-d6) delta 4.59 (s), 4.47 (s). MS m/z=575.02 [M+H].
		[02171 Compound 1 (0.040 g, 0.137 mmol) was dissolved in NMP (1.5 mL) and then THF (0.25 mL) was added. This solution was cooled in an ice bath and t-BuMgCl (1M/THF, 425.7muL , 0.426 muetaiotaomicron) was added in a drop-wise manner with vigorous stirring. The ice bath was removed and the resulting white slurry was stirred at RT for about 15 min. A solution of compound E (0.081 g, 0.192 mmol) in THF (0.5 mL) was added in a drop-wise manner to the reaction at RT. The reaction progress was monitored by LC/MS. When the reaction progressed to 50% conversion, the reaction was cooled in an ice bath and quenched with glacial acetic acid (70 yxL). The reaction was concentrated and compound 22 was semi-purified from the residue by reverse phase HPLC. The semi-pure material was further purified by silica gel column chromatography ( 12 g dry load cartridge, 40 g column; eluent: 100% EtOAc ramping to 10% MeOH in EtOAc) to yield compound 22. 1H NMR (400 MHz, DMSO-d*) delta 7.91 (d, J= 1.6 Hz, 1H), 7.88 (brs, 2H), 7.32 (m, 2H), 7.15 (m, 3H), 6.90 (t, J= 4.2 Hz, 1 H), 6.84 (d, J= 4.8 Hz, 1H), 6.26 (dd, J= 13.4, 6.2 Hz, 1H), 5.87 (quart. J = 11.2 Hz, 1H), 5.35 (m, 1H), 4.64 (m, 1H), 4.25 (m, 2H), 3.93-4.15 (m, 4H), 3.45 (m, 1H), 1.87 (m, 1H), 1.09-1.16 (m, 3H), 0.70-0.83 (m ,6H). 3,P NMR (162 MHz, DMSO-d6) 5 4.59 (s), 4.47 (s). MS m/z - 575.02 [M+H].

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 1648 - 1661
[2]Patent: US2017/71964,2017,A1 .Location in patent: Paragraph 0604-0605
[3]Patent: WO2016/69826,2016,A1 .Location in patent: Paragraph 0217

17
[ 1256490-49-9 ]
[ 1191237-69-0 ]
(S)-isopropyl 2-(((R)-(((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 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		[0218] The preparation of (S)-isopropyl 2-(((R)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,l - fj [ 1 ,2,4]triazin-7-yl)-5-cyano-3 ,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)amino)propanoate is described below. [0219] Compound 1 (60.0 mg, 206 muetaiotaomicron) was dissolved in NMP (0.28 mL). THF (0.2 mL) was added followed by tert-butyl magnesium chloride (1.0M solution in tetrahydrofuran, 0.309 mL) at RT under an argon atmosphere. After 20 min, a solution of compound F (Prepared according to Cho, A. et al J. Med. Chem. 2014, 57, 1812-1825., 81 mg, 206 muiotaetaomicron) in THF (0.2 mL) was added, and the resulting mixture was warmed to about 50 C. After 3 h, the reaction mixture was allowed to cool to RT and was purified directly by preparatory HPLC (Phenominex Synergi 4u Hydro-RR 80A 150 x 30 mm column, 5-100% acetonitrile/water gradient) to afford compound 23. NMR (400 MHz, CD3OD) delta 7.86 (s, 1H), 7.34 - 7.26 (m, 2H), 7.21 - 7.12 (m, 3H), 6.91 (d, J= 4.6 Hz, 1H), 6.87 (d, J= 4.6 Hz, 1H), 4.92 (sept, J = 6.3 Hz, 1H), 4.80 (d, J = 5.4 Hz, 1H), 4.43 - 4.34 (m, 1H), 4.33 - 4.24 (m, 1H), 4.18 (t, J= 5.6 Hz, 1H), 3.82 (dq, J= 9.7, 7.1 Hz, 2H), 1.27 (dd, J= 7.1, 1.0 Hz, 3H), 1.18 (dd, J= 6.3, 4.8 Hz, 6H). 31P NMR (162 MHz, CD3OD) delta 3.72 (s). LC/MS: tR = 1.39 min, MS m/z = 561.1 1 [M+H]; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6mu XB-C18 100A, 50 x 4.6 mm; Solvents: ACN with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 min-2.0 min 2-100% ACN, 2.0 min-3.05 min 100% ACN, 3.05 min-3.2 min 100%-2% ACN, 3.2 min-3.5 min 2% ACN at 2mu1/iotaetaeta. HPLC: tR = 2.523 min; HPLC system: Agilent 1 100 series.; Column: Gemini 5mu CI 8 110A, 50 x 4.6 mm; Solvents: ACN 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 niL/min.

Reference： [1]Patent: WO2016/69826,2016,A1 .Location in patent: Paragraph 0218; 0219

18
[ 1191237-69-0 ]
C₁₉H₂₁N₂O₇P [ No CAS ]
(2S)-cyclobutyl 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 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; magnesium chloride; In N,N-dimethyl-formamide; at 50℃; for 2h;	[0222] Compound 1 (58 mg, 0.2 mmol) was mixed with compound G (101 mg, 0.24 mmol) in 2 mL of anhydrous DMF. Magnesium chloride (42 mg, 0.44 mmol) was added in one portion. The reaction mixture was heated to about 50 C. DIPEA (87 mu., 0.5 mmol) was added, and the reaction was stirred for about 2 h at about 50 C. The reaction mixture was cooled to room temperature, was diluted with EtOAc and was washed with 5% aqueous citric acid solution followed by saturated aqueous sodium chloride solution. The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified with silica gel column (0-2-5% MeOH in DCM) to afford compound 24. 1H NMR (400 MHz, Methanol-^) delta 7.85 (m, 1H), 7.34 - 7.22 (m, 2H), 7.22 - 7.08 (m, 3H), 6.94 - 6.84 (m, 2H), 4.95 - 4.85 (m, 1H), 4.79 (m, 1H), 4.46 - 4.34 (m, 2H), 4.34 - 4.24 (m, 1H), 4.19 (m, 1H), 3.81 (m, 1H), 2.27 (m, 2H), 2.01 (m, 2H), 1.84 - 1.68 (m, 1H), 1.62 (m, 1H), 1.30 - 1.16 (m, 3H). 3,P NMR (162 MHz, cd3od) delta 3.70, 3.65. MS m/z = 573.0 [M+H].

Reference： [1]Patent: WO2016/69826,2016,A1 .Location in patent: Paragraph 0222

19
[ 1191237-69-0 ]
(2S)-isopropyl 2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)-3-phenylpropanoate [ No CAS ]
(2S)-isopropyl 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)-3-phenylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With tert-butylmagnesium chloride; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 16.05h;Inert atmosphere;	Compound 1 (58 mg, 0.2 mmol) and compound H (116 mg, 0.24 mmol) were mixed and 2 mL of anhydrous DMF was added. The reaction mixture was stirred under a nitrogen atmosphere at room temperature. 1M tBuMgCl in THF (300 muL, 0.3 mmol) was added dropwise over 3 minutes and the reaction mixture was then stirred for 16 h. The reaction mixture was diluted with EtOAc and washed with 5% aqueous citric acid solution, saturated aqueous sodium bicarbonate solution and then saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified with silica gel column (0-5% MeOH in DCM) to give compound 25 (40 mg, 32% yield as a mixture of diastereomers). 1H NMR (400 MHz, CD3OD) delta 7.84 (m, 1H), 7.27-7.08 (m, 8H), 7.08-6.97 (m, 2H), 6.88 (m, 2H), 4.91-4.84 (m, 1H), 4.74 (m, 1H), 4.26 (m, 1H), 4.19-4.04 (m, 2H), 4.04-3.91 (m, 2H), 2.97 (m, 1H), 2.82 (m, 1H), 1.14 (m, 3H), 1.06 (m, 3H). 31P NMR (162 MHz, CD3OD) delta 3.63, 3.25. MS m/z=637.0 [M+H].
	With tert-butylmagnesium chloride; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere;	[0226] Compound 1 (58 mg, 0.2 mmol) and compound H (116 mg, 0.24 mmol) were mixed and 2 mL of anhydrous DMF was added. The reaction mixture was stirred under a nitrogen atmosphere at room temperature. 1M tBuMgCl in THF (300 muL, 0.3 mmol) was added dropwise over 3 minutes and the reaction mixture was then stirred for about 16 h. The reaction mixture was diluted with EtOAc and washed with 5% aqueous citric acid solution, saturated aqueous sodium bicarbonate solution and then saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified with silica gel column (0-5% MeOH in DCM) to give compound 25. 1H NMR (400 MHz, CD3OD) delta 7.84 (m, 1H), 7.27 - 7.08 (m, 8H), 7.08 - 6.97 (m, 2H), 6.88 (m, 2H), 4.91 - 4.84 (m, 1H), 4.74 (m, 1H), 4.26 (m, 1H), 4.19 - 4.04 (m, 2H), 4.04 - 3.91 (m, 2H), 2.97 (m, 1H), 2.82 (m, 1H), 1.14 (m, 3H), 1.06 (m, 3H). 3,P NMR (162 MHz, CD3OD) 5 3.63, 3.25. MS m/z = 637.0 [M+H].

Reference： [1]Patent: US2017/71964,2017,A1 .Location in patent: Paragraph 0620-0621
[2]Patent: WO2016/69826,2016,A1 .Location in patent: Paragraph 0226

20
[ 1191237-69-0 ]
(2S)-methyl 2-(((perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate [ No CAS ]
(S)-methyl 2-(((S)-(((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 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
6.6%		Compound 1 (100 mg, 0.34 mmol) was dissolved in THF (2 mL) and cooled with an ice water bath. Then 1M t-BuMgCl (0.52 mL, 0.77 mmol) was added dropwise slowly. The resulting mixture was stirred for 30 min at room temperature. Then compound I (Prepared according to WO 2012142085, 219 mg, 0.52 mmol) in THF (2 mL) was added over 5 min and the resulting mixture was stirred for 24 h at room temperature. The reaction mixture was then diluted with EtOAc, cooled under ice-water bath, washed with aq NaHCO3 (2 mL), washed with brine, dried with sodium sulfate, and concentrated in vacuo. The resulting mixture was purified by silica gel column chromatography (MeOH 0 to 20% in DCM) and prep-HPLC (acetonitrile 10 to 80% in water) to give compound 26 (12 mg, 6.6% as a single diastereomer). 1H NMR (400 MHz, CD3OD) delta 7.86 (s, 1H), 7.29 (dd, J=8.6, 7.2 Hz, 2H), 7.21-7.09 (m, 3H), 6.94-6.81 (m, 2H), 4.79 (d, J=5.4 Hz, 1H), 4.38 (ddq, J=10.8, 5.3, 2.7 Hz, 2H), 4.33-4.23 (m, 1H), 4.18 (t, J=5.5 Hz, 1H), 3.86 (dq, J=9.9, 7.1 Hz, 1H), 3.62 (s, 3H), 1.27 (dd, J=7.2, 1.1 Hz, 3H). MS m/z=533 (M+1)+.
		[0228] Compound 1 (100 mg, 0.34 mmol) was dissolved in THF (2 mL) and cooled with an ice water bath. Then 1M t-BuMgCl (0.52 mL, 0.77 mmol) was added dropwise slowly. The resulting mixture was stirred for about 30 min at room temperature. Then compound I (Prepared according to WO 2012142085, 219 mg, 0.52 mmol) in THF (2 mL) was added over 5 min and the resulting mixture was stirred for about 24 h at room temperature. The reaction mixture was then diluted with EtOAc, cooled under ice-water bath, washed with aq NaHC( (2 mL), washed with brine, dried with sodium sulfate, and concentrated in vacuo. The resulting mixture was purified by silica gel column chromatography (MeOH 0 to 20% in DCM) and prep- HPLC (acetonitrile 10 to 80% in water) to give compound 26. NMR (400 MHz, CD3OD) delta 7.86 (s, 1H), 7.29 (dd, J= 8.6, 7.2 Hz, 2H), 7.21 - 7.09 (m, 3H), 6.94 - 6.81 (m, 2H), 4.79 (d, J = 5.4 Hz, 1H), 4.38 (ddq, J= 10.8, 5.3, 2.7 Hz, 2H), 4.33 - 4.23 (m, 1H), 4.18 (t, J= 5.5 Hz, 1H), 3.86 (dq, J= 9.9, 7.1 Hz, 1H), 3.62 (s, 3H), 1.27 (dd, J= 7.2, 1.1 Hz, 3H). MS m/z = 533 (M+l)+.

Reference： [1]Patent: US2017/71964,2017,A1 .Location in patent: Paragraph 0622-0624
[2]Patent: WO2016/69826,2016,A1 .Location in patent: Paragraph 0228

21
[ 1191237-69-0 ]
[ 1392014-95-7 ]
(S)-neopentyl 2-(((S)-(((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 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%		Compound 1 (100 mg, 0.34 mmol) was dissolved in THF (2 mL) and cooled under ice water bath. Then 1M t-BuMgCl (0.52 mL, 0.77 mmol) was added dropwise slowly. The resulting mixture was stirred for 30 min at room temperature. Then compound J (Prepared according to WO2012075140, 248 mg, 0.52 mmol) was added over 5 min and the resulting mixture was stirred for 24 h at room temperature, diluted with EtOAc, cooled under ice-water bath, treated with aq NaHCO3 (2 mL), washed with brine, dried with sodium sulfate, and concentrated in vacuo. The resulting mixture was purified by silica gel column chromatography (MeOH 0 to 20% in DCM) and prep-HPLC (acetonitrile 10 to 80% in water) to give Compound 27 (12 mg, 10% as a single diastereomer). 1H NMR (400 MHz, CD3OD) delta 7.86 (s, 1H), 7.36-7.24 (m, 2H), 7.23-7.10 (m, 3H), 6.96-6.85 (m, 2H), 4.78 (d, J=5.4 Hz, 1H), 4.38 (tdd, J=10.0, 4.9, 2.5 Hz, 2H), 4.32-4.24 (m, 1H), 4.17 (t, J=5.6 Hz, 1H), 3.91 (dq, J=9.8, 7.1 Hz, 1H), 3.81 (d, J=10.5 Hz, 1H), 3.69 (d, J=10.5 Hz, 1H), 1.31 (dd, J=7.2, 1.1 Hz, 3H), 0.89 (s, 9H). MS m/z=589 (M+1)+.
		[0230] Compound 1 (100 mg, 0.34 mmol) was dissolved in THF (2 mL) and cooled under ice water bath. Then 1M t-BuMgCl (0.52 mL, 0.77 mmol) was added dropwise slowly. The resulting mixture was stirred for about 30 min at room temperature. Then compound J (Prepared according to WO2012075140, 248 mg, 0.52 mmol) was added over about 5 min and the resulting mixture was stirred for about 24 h at room temperature, diluted with EtOAc, cooled under ice-water bath, treated with aq NaHC< (2 mL), washed with brine, dried with sodium sulfate, and concentrated in vacuo. The resulting mixture was purified by silica gel column chromatography (MeOH 0 to 20% in DCM) and prep-HPLC (acetonitrile 10 to 80% in water) to give Compound 27. 1H NMR (400 MHz, CD3OD) delta 7.86 (s, 1H), 7.36 - 7.24 (m, 2H), 7.23 - 7.10 (m, 3H), 6.96 - 6.85 (m, 2H), 4.78 (d, J= 5.4 Hz, 1H), 4.38 (tdd, J = 10.0, 4.9, 2.5 Hz, 2H), 4.32 - 4.24 (m, 1H), 4.17 (t, J= 5.6 Hz, 1H), 3.91 (dq, J = 9.8, 7.1 Hz, 1H), 3.81 (d, J= 10.5 Hz, 1H), 3.69 (d, J= 10.5 Hz, 1H), 1.31 (dd, J= 7.2, 1.1 Hz, 3H), 0.89 (s, 9H). MS m/z = 589 (M+l)+.

Reference： [1]Patent: US2017/71964,2017,A1 .Location in patent: Paragraph 0625-0627
[2]Patent: WO2016/69826,2016,A1 .Location in patent: Paragraph 0230

22
[ 1191237-69-0 ]
cyclopentyl ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate [ No CAS ]
(2S)-cyclopentyl 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 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With tert-butylmagnesium chloride; In tetrahydrofuran; at 0 - 40℃; for 2h;	Preparation process: 1.50 g of a nucleoside compound of the formula (I-1) is added to a round bottom flask,200 mL of tetrahydrofuran and 2.47 g of active phosphate of formula (F), cooled to 0 C in an ice bath,Slowly add 10 mL of tert-butyl magnesium chloride solution (1.0M tetrahydrofuran solution) under stirring.After completion of the dropwise addition, the temperature was raised to 40 C and the reaction was carried out for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure,The concentrate was added to 200 mL of dichloromethane and washed twice with 50 mL of a saturated sodium chloride solution.The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure.The concentrated residue was separated by silica gel column chromatography using a mixture of ethyl acetate / petroleum ether = 1/1 as an eluent.1.58 g of the compound of the formula (I-6) was obtained, and the calculated yield was 52%.
23%		Compound 1 (100 mg, 0.34 mmol) was dissolved in THF (2 mL) and cooled under ice water bath. Then 1M t-BuMgCl (0.52 mL, 0.77 mmol) was added dropwise slowly. The resulting mixture was stirred for 30 min at room temperature. Then compound K (Prepared according to WO2012075140, 247 mg, 0.52 mmol) in THF (2 mL) was added over 5 min and the resulting mixture was stirred for 24 h at room temperature, diluted with EtOAc, cooled under ice-water bath, treated with aq NaHCO3 (2 mL), washed with brine, dried with sodium sulfate, and concentrated in vacuo. The resulting mixture was purified by silica gel column chromatography ( MeOH 0 to 20% in DCM) and prep-HPLC (acetonitrile 10 to 80% in water) to give example 28 (47 mg, 23% as a 27:1 mixture of diastereomers). 1H NMR (400 MHz, CD3OD) delta 7.85 (s, 1H), 7.33-7.22 (m, 2H), 7.14 (tdd, J=7.6, 2.1, 1.1 Hz, 3H), 6.95-6.87 (m, 2H), 5.13-5.00 (m, 1H), 4.78 (d, J=5.4 Hz, 1H), 4.48-4.35 (m, 2H), 4.30 (ddd, J=10.6, 5.7, 3.6 Hz, 1H), 4.19 (t, J=5.4 Hz, 1H), 3.78 (dq, J=9.2, 7.1 Hz, 1H), 1.81 (dtd, J=12.5, 5.9, 2.4 Hz, 2H), 1.74-1.49 (m, 6H), 1.21 (dd, J=7.1, 1.2 Hz, 3H). MS m/z=587 (M-1)+
		[0232] Compound 1 (100 mg, 0.34 mmol) was dissolved in THF (2 mL) and cooled under ice water bath. Then 1M t-BuMgCl (0.52 mL, 0.77 mmol) was added dropwise slowly. The resulting mixture was stirred for about 30 min at room temperature. Then compound K (Prepared according to WO2012075140, 247 mg, 0.52 mmol) in THF (2 mL) was added over about 5 min and the resulting mixture was stirred for about 24 h at room temperature, diluted with EtOAc, cooled under ice-water bath, treated with aq NaHCC>3 ( 2mL), washed with brine, dried with sodium sulfate, and concentrated in vacuo. The resulting mixture was purified by silica gel column chromatography (MeOH 0 to 20% in DCM) and prep-HPLC (acetonitrile 10 to 80% in water) to give example 28. 1H NMR (400 MHz, CD3OD) delta 7.85 (s, 1H), 7.33 - 7.22 (m, 2H), 7.14 (tdd, J= 7.6, 2.1, 1.1 Hz, 3H), 6.95 - 6.87 (m, 2H), 5.13 - 5.00 (m, 1H), 4.78 (d, J= 5.4 Hz, 1H), 4.48 - 4.35 (m, 2H), 4.30 (ddd, J= 10.6, 5.7, 3.6 Hz, 1H), 4.19 (t, J = 5.4 Hz, 1H), 3.78 (dq, J = 9.2, 7.1 Hz, 1H), 1.81 (dtd, J= 12.5, 5.9, 2.4 Hz, 2H), 1.74 - 1.49 (m, 6H), 1.21 (dd, J= 7.1, 1.2 Hz, 3H). MS m/z = 587 (M+l)+.

Reference： [1]Patent: CN110613726,2019,A .Location in patent: Paragraph 0092-0096
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 1648 - 1661
[3]Patent: US2017/71964,2017,A1 .Location in patent: Paragraph 0628-0630
[4]Patent: WO2016/69826,2016,A1 .Location in patent: Paragraph 0232

23
[ 1191237-69-0 ]
[ 1439900-33-0 ]
(2S)-cyclohexyl 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 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; magnesium chloride; In N,N-dimethyl-formamide; at 0 - 50℃; for 1h;	[0233] T o a mixture of compound 1 (50 mg, 0.343 mmol), compound M (Prepared according to US20130143835, 93 mg, 0.209 mmol), and MgCl2 (24.5 mg, 0.257 mmol) in DMF (1 mL) was added diisopropylethylamine (0.075 mL, 0.43 mmol) dropwise over about 5 min at about 0 C. The resulting mixture was stirred at about 50 C for about 1 h. The reaction mixture was then cooled with an ice- water bath, treated with 1M citric acid ( 0.5 mL), and was purified directly by prep-HPLC (ACN 0 to 70% in water) to afford compound 29. NMR (400 MHz, CD3OD) 6 7.84 (s, 1H), 7.32 - 7.23 (m, 2H), 7.18 - 7.10 (m, 3H), 6.93 - 6.87 (m, 2H), 4.78 (d, J = 5.4 Hz, 1H), 4.67 (td, J= 8.7, 4.2 Hz, 1H), 4.48 - 4.35 (m, 2H), 4.30 (ddd, J = 10.8, 5.7, 3.7 Hz, 1H), 4.20 (t, J= 5.4 Hz, 1H), 3.88 - 3.71 (m, 1H), 1.83 - 1.63 (m, 4H), 1.58 - 1.46 (m, 1H), 1.46 - 1.24 (m, 5H), 1.24 (s, 3H). 31P NMR (162 MHz, CD3OD) delta 3.75. MS m/z = 601 (M+l)+.

Reference： [1]Patent: WO2016/69826,2016,A1 .Location in patent: Paragraph 0233

24
[ 1191237-69-0 ]
ethyl 2-methyl-2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate [ No CAS ]
ethyl 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)-2-methylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%		Take up compound 1 (66 mg, 0.23 mmol) in NMP (2.0 mL). Cool the mixture to 0 C. and slowly add tBuMgCl (1.0M in THF, 0.34 mL, 0.34 mmol). Allow the reaction to stir at 0 C. for 30 min, then add a solution of compound N (139 mg, 0.34 mmol) dissolved in THF (1.0 mL). Remove the cold bath and place the reaction in a 50 C. preheated oil bath. After 2 h, the reaction was cooled to room temperature and quenched with acetic acid and methanol. The crude was concentrated and purified by reverse phase HPLC without modifier to afford compound 30 (32 mg, 25% as a mixture of diastereomers). 1H NMR (400 MHz, DMSO-d6) delta 7.89 (m, 3H), 7.31 (q, J=8.1 Hz, 2H), 7.22-7.05 (m, 3H), 6.87 (d, J=4.5, 1H), 6.80 (d, J=4.5 Hz, 1H), 6.27 (d, J=11.7, 1H), 5.81 (d, J=9.7, 1H), 5.35 (d, J=5.6 Hz, 1H), 4.64 (dt, J=9.0, 5.6 Hz, 1H), 4.24 (m, 2H), 4.11 (m, 1H), 4.04-3.90 (m, 3H), 1.39-1.23 (m, 6H), 1.10 (t, J=7.1, 3H). 31P NMR (162 MHz, DMSO-d6) delta 2.45, 2.41. LC/MS: tR=1.03 min, MS m/z=561.03 [M+1]; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6mu XB-C18 100A, 50×3.00 mm; Solvents: Acetonitrile with 0.1% formic acid, Water with 0.1% formic acid; Gradient: 0 min-2.4 min 2-100% ACN, 2.4 min-2.80 min 100% ACN, 2.8 min-2.85 min 100%-2% ACN, 2.85 min-3.0 min 2% ACN at 1.8 mL/min.
		[0238] Take up compound 1 (66 mg, 0.23 mmol) in NMP (2.0 mL). Cool the mixture to about 0 C and slowly add tBuMgCl (1.0M in THF, 0.34 mL, 0.34 mmol). Allow the reaction to stir at about 0 C for about 30 min, then add a solution of compound N (139mg, 0.34mmol) dissolved in THF (1.0 mL). Remove the cold bath and place the reaction in about 50 C preheated oil bath. After about 2 h, the reaction was cooled to room temperature and quenched with acetic acid and methanol. The crude was concentrated and purified by reverse phase HPLC without modifier to afford compound 30. NMR (400 MHz, DMSO-rf6) delta 7.89 (m, 3H), 7.31 (q, J = 8.1 Hz, 2H), 7.22 - 7.05 (m, 3H), 6.87 (d, J = 4.5, 1H), 6.80 (d, J= 4.5 Hz, 1H), 6.27 (d, J = 11.7, 1H), 5.81 (d, J= 9.7, 1H), 5.35 (d, J= 5.6 Hz, 1H), 4.64 (dt, J= 9.0, 5.6 Hz, 1H), 4.24 (m, 2H), 4.11 (m, 1H), 4.04 - 3.90 (m, 3H), 1.39 - 1.23 (m, 6H), 1.10 (t, J= 7.1, 3H). 3,P NMR (162 MHz, DMSO-cf6) delta 2.45, 2.41. LC/MS: tR = 1.03 min, MS m/z = 561.03 [M+l]; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6mu XB-C18 100A, 50 x 3.00 mm; Solvents: Acetonitrile with 0.1% formic acid, Water with 0.1% formic acid; Gradient: 0 min-2.4 min 2-100% ACN, 2.4 min-2.80 min 100% ACN, 2.8 rnin- 2.85 min 100%-2% ACN, 2.85 min-3.0 min 2% ACN at 1.8mL/min.

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 1648 - 1661
[2]Patent: US2017/71964,2017,A1 .Location in patent: Paragraph 0642-0643
[3]Patent: WO2016/69826,2016,A1 .Location in patent: Paragraph 0238

25
[ 1191237-69-0 ]
isopropyl 2-methyl-2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate [ No CAS ]
isopropyl 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)-2-methylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%		Take up compound 1 (66 mg, 0.23 mmol) in NMP (2.0 mL). Cool the mixture to 0 C. and slowly add tBuMgCl (1.0M in THF, 0.57 mL, 0.57 mmol). Allow the reaction to stir at 0 C. for 30 min, then add a solution of compound O (143 mg, 0.34 mmol) dissolved in THF (1.0 mL). Remove the cold bath and place the reaction in a 50 C. preheated oil bath. After 2 h, the reaction was cooled to room temperature and was quenched with acetic acid and methanol. The crude was concentrated and purified by reverse phase HPLC without modifier to afford compound 31 (48 mg, 37% as a mixture of diastereomers). 1H NMR (400 MHz, DMSO-d6) delta 7.88 (m, 3H), 7.30 (td, J=8.5, 7.0 Hz, 2H), 7.20-7.04 (m, 3H), 6.87 (d, J=4.5, 1H), 6.80 (d, J=4.5 Hz, 1H), 6.27 (d, 6.1 Hz, 1H), 5.75 (t, J=9.1 Hz, 1H), 5.34 (d, J=5.7 Hz, 1H), 4.81 (p, J=6.3 Hz, 1H), 4.71-4.50 (m, 1H), 4.23 (m, 2H), 4.11 (m, 1H), 4.03-3.83 (m, 1H), 1.37-1.23 (m, 6H), 1.18-1.04 (m, 6H). 31P NMR (162 MHz, dmso) delta 2.47, 2.43. LC/MS: tR=1.08 min, MS m/z=575.06 [M+1]; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6mu XB-C18 100A, 50×3.00 mm; Solvents: Acetonitrile with 0.1% formic acid, Water with 0.1% formic acid; Gradient: 0 min-2.4 min 2-100% ACN, 2.4 min-2.80 min 100% ACN, 2.8 min-2.85 min 100%-2% ACN, 2.85 min-3.0 min 2% ACN at 1.8 mL/min.
		[0243] Take up compound 1 (66 tng, 0.23 mmol) in NMP (2.0 mL). Cool the mixture to about 0 C and slowly add tBuMgCl (1 -0M in THF, 0.57mL, 0.57mmol). Allow the reaction to stir at about 0 C for about 30 min, then add a solution of compound O (143 mg, 0.34 mmol) dissolved in THF {1.0 mL). Remove the cold bath and place the reaction in an about 50 C preheated oil bath. After about 2 h, the reaction was cooled to room temperature and was quenched with acetic acid and methanol. The crude was concentrated and purified by reverse phase HPLC without modifier to afford compound 31. 1H NMR (400 MHz, DMSO-</6) delta 7.88 (m, 3H), 7.30 (td, J= 8.5, 7.0 Hz, 2H), 7.20 - 7.04 (m, 3H), 6.87 (d, J = 4.5, 1H), 6.80 (d, J= 4.5 Hz, 1H), 6.27 (d, 6.1 Hz, 1H), 5.75 (t, J= 9.1 Hz, 1H), 5.34 (d, J= 5.7 Hz, 1H), 4.81 (p, J= 6.3 Hz, 1H), 4.71 - 4.50 (m, 1H), 4.23 (m, 2H), 4.11 (m, 1H), 4.03 - 3.83 (m, 1H), 1.37 - 1.23 (m, 6H), 1.18 - 1.04 (m, 6H). 31P NMR (162 MHz, DMSO) delta 2.47, 2.43. LC/MS: tR = 1.08 min, MS m/z = 575.06 [M+l]; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6mu XB-C18 100A, 50 x 3.00 mm; Solvents: Acetonitrile with 0.1% formic acid, Water with 0.1% formic acid; Gradient: 0 min-2.4 min 2-100% ACN, 2.4 min-2.80 min 100% ACN, 2.8 min-2.85 min 100%-2% ACN, 2.85 min-3.0 min 2% ACN at 1.8mL/min.

Reference： [1]Patent: US2017/71964,2017,A1 .Location in patent: Paragraph 0652-0653
[2]Patent: WO2016/69826,2016,A1 .Location in patent: Paragraph 0243

26
[ 1191237-69-0 ]
(2S)-2-(((perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoic acid 2-ethylbutyl ester [ No CAS ]
[ 1355050-11-1 ]

Yield	Reaction Conditions	Operation in experiment
33.5%	With tert-butylmagnesium chloride; In tetrahydrofuran; at 0 - 40℃; for 2h;	Preparation process: 1.50 g of a nucleoside compound of the formula (I-1),200mL of tetrahydrofuran and 2.55g of active phosphate of formula (D), cooled to 0 C in an ice bath,Slowly add 10 mL of tert-butyl magnesium chloride solution (1.0M tetrahydrofuran solution) under stirring.After the dropwise addition was completed, the temperature was raised to 40 C, and the reaction was performed at the temperature for 2 hours.After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated solution was added to 200 mL of dichloromethane.It was washed twice with 50 mL of a saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate.It was concentrated under reduced pressure, and the concentrated residue was separated by silica gel column chromatography using a mixed solution of ethyl acetate / petroleum ether = 2/1 as an eluent.1.04 g of product was obtained with a calculated yield of 33.5%.
	With tert-butylmagnesium chloride; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 1h;	0249J The nucleoside (29 mg, 0.1 mmol) and the phosphonamide (60 mg, 0.12 mmol) and N,N-dimethylformamide (2 mL) were combined at ambient temperature. Tert-Butyl magnesium chloride (1M in THF, 0.15 mL) was slowly added. After about lh, the reaction was diluted with ethyl acetate, washed with aqueous citric acid solution (5%wt.), aqueous saturated NaHCC>3 solution and saturated brine solution. The organic phase was dried over Na2S04 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of methanol and CH2CI2 (0 to 5%). Product containing fractions were concentrated under reduced pressure to provide the product.
	With tert-butylmagnesium chloride; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 1h;	The nucleoside (29 mg, 0.1 mmol) and the phosphonamide (60 mg, 0.12 mmol) and N,N-dimethylformamide (2 mL) were combined at ambient temperature. Tert-Butyl magnesiumchloride (1M in THF, 0.15 mL) was slowly added. After about 1 h, the reaction was diluted with ethyl acetate, washed with aqueous citric acid solution (5% wt.), aqueous saturated NaHCO3 solution and saturated brine solution. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of methanol and CH2Cl2 (0 to 5%). Product containing fractions were concentrated under reduced pressure to provide the product.

With tert-butylmagnesium chloride; In tetrahydrofuran; N,N-dimethyl-formamide; for 1h;

The nucleoside (29 mg, 0.1 mmol) and the phosphonamide (60 mg, 0.12 mmol) and N,N-dimethylformamide (2 mL) were combined at ambient temperature. 7ri-Butyl magnesiumchloride (1M in THF, 0.15 mL) was slowly added. After about lh, the reaction was diluted with ethyl acetate, washed with aqueous citric acid solution (5%wt.), aqueous saturated NaHC03 solution and saturated brine solution. The organic phase was dried over Na2S04 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of methanol and CH2CI2 (0 to 5%). Product containing fractions were concentrated under reduced pressure to provide the product.

Reference： [1]Patent: CN110613726,2019,A .Location in patent: Paragraph 0082-0086
[2]Patent: WO2016/69826,2016,A1 .Location in patent: Paragraph 0249
[3]Patent: US2017/71964,2017,A1 .Location in patent: Paragraph 0664-0665
[4]Patent: WO2017/184668,2017,A1 .Location in patent: Paragraph 0260

27
[ 1191237-69-0 ]
(2S)-2-ethylbutyl 2-(((S)-(perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate [ No CAS ]
(2S)-2-ethylbutyl 2-(((S)-(((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 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; magnesium chloride; In N,N-dimethyl acetamide; at 30℃; for 5h;	[0256] To a mixture of (2R,3R,4S,5R)-2-(4-aminopyirolo[2,l-fJ[l,2,4]triazin-7-yl)-3,4- dihydroxy-5-(hydroxymemyl)tetrahydrofuran-2-carbomtri^ (0.2 g, 0.7 mmol), (S)-2-ethylbutyl 2-(((S)-(perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate (0.3 g, 0.7 mmol), and MgCl2 (0.1 g, 1 mmol), was charged N,N-dimethylacetamide (4 mL). The resulting mixture was warmed to about 30 C with constant stirring. N,N-Diisopropylethylamine (0.3 mL, 2 mmol) was then added slowly, and the reaction mixture was stirred for 5 h. Conversion to the product was confirmed through UPLC analysis.

Reference： [1]Patent: WO2016/69826,2016,A1 .Location in patent: Paragraph 0256

28
[ 1191237-69-0 ]
2-ethylbutyl (2S)-2-((S)-((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate [ No CAS ]
(2S)-2-ethylbutyl 2-(((S)-(((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 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; magnesium chloride; In N,N-dimethyl acetamide; at 30℃; for 6h;	[0255] To a mixture of (2R3R,4S,5R)-2<4-aminopyrrolo[2,l-fJ[l,2,4]triazin-7-yl)-3,4- dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitri (0.5 g, 2mmol), (S)-2-ethylbutyl 2- (((S)-(4-riitrophenoxy)(phenoxy)phosphoryl)atnino)propanoate (0.9 g, 2 mmol), and MgCk (0.2 g, 2 mmol), was charged N,N-dimethylacetamide (10 mL). The resulting mixture was warmed to about 30 C with constant stirring. N,N-Diisopropylethylamine (0.7 mL, 4 mmol) was then added slowly, and the reaction mixture was stirred for about 6 h. Water (10 mL) was charged H2O, followed by 2-MeTHF (10 mL), and the organic and aqueous phases were separated. The aqueous layer was then back-extracted with 2-MeTHF (10 mL). The organic layers were combined, and washed with 10 wt% citric acid solution (10 mL), followed by 10 wt% K2CO3 solution (10 mL), and H20 (10 mL). A small amount of brine was added to resolve emulsions in the water wash before the layers were separated. The organic layer was evaporated to dryness to afford 0.65 g of a foam. i'PrOAc (2.6 mL) was added then added, and the mixture was warmed to about 40 C to achieve dissolution. The solution was cooled to about 20 C, and the mixture was stirred for about 3 days. The solids were isolated by filtration, and the filter cake was washed with a small amount of /PrOAc. The solids were dried to afford (S)-2-ethylbutyl 2-(((S)-

Reference： [1]Patent: WO2016/69826,2016,A1 .Location in patent: Paragraph 0255

29
[ 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

30
[ 1191237-69-0 ]
[ 104-15-4 ]
[ 77-76-9 ]
(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 ]

Yield	Reaction Conditions	Operation in experiment
	In acetone; at 20℃; for 0.5h;	0251] To a mixture of (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,l-fl[l,2J4]triazin-7-yl)-3,4- dihydroxy-5-(hydroxymemyl)tetrahydromran-2-carbonitrile (5.0 g, 17.2 mmol, 1.0 equiv.), 2,2- dimethoxypropane (10.5 mL, 86 mmol, 5.0 equiv.) and acetone (25 mL) at ambient temperature was added p-tolylsulfonic acid (3.59 g, 1.1 equiv.). The mixture was stirred at ambient temperature. After about 30 min, isopropyl acetate (25 mL) was added over about one hour. The resulting slurry was filtered and rinsed with 2:1 heptane:isopropyl acetate (25 ml). The product was dried under vacuum at about 40 C.

Reference： [1]Patent: WO2016/69826,2016,A1 .Location in patent: Paragraph 0251; 0252

31
7-iodopyrrolo-[2,1-f][1,2,4]-triazin-4-amine [ No CAS ]
[ 1191237-69-0 ]

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

32
7-iodopyrrolo-[2,1-f][1,2,4]-triazin-4-amine [ No CAS ]
[ 1191237-69-0 ]
[ 1355049-95-4 ]

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

33
[ 1355357-49-1 ]
[ 1191237-69-0 ]

Yield	Reaction Conditions	Operation in experiment
	With boron trichloride; In dichloromethane; at -20 - -15℃; for 1h;	[0194] The tribenzyl cyano nucleoside (48.8 g, 86.9 mmol, 1.0 equiv.) was dissolved in anhydrous CH2C12 (244 mL) and cooled to about -20 C . A solution of BC13 (1M in CH2C12, 295 mL, 295 mmol, 3.4 equiv.) was added dropwise, maintaining the internal temperature below about -15 C. Following addition, the reaction mixture was stirred for 1 h at about -20 C. MeOH (340 ml) was added dropwise, maintaining the internal temperature below -15 C. The resulting solution was distilled to about 250 ml, then refilled with about 250 ml MeOH. The resulting solution was again distilled to about 250 ml, then refilled with about 250 ml MeOH, and finally distilled to about 125 ml. Water (125 ml) was added, followed by K2CO 3 solution (20 wt% in water, 125 ml). The pH was checked, and found to be ~3. K2C03 solution was added (20 wt% in water, 50 ml), and the pH was found to be ~8. The resulting slurry was stirred overnight, then filtered and washed with water (50 ml) and MeOH (50 ml). The wet product cake was dried overnight at about 40 C overnight. 1H NMR (300 MHz, D2O) delta 7.96 (s, 1H), 7.20 (d, J= 4.8 Hz, 1H), 6.91 (d, J= 4.8 Hz, 1H), 4.97 (d, J= 4.4 Hz, 1H), 4.56-4.62 (m, 1H), 4.08-4.14 (m, 1H), 3.90 (dd, J = 12.9, 2.4 Hz, 1H), 3.70 (dd, J = 13.2, 4.5 Hz, 1H).

Reference： [1]Patent: WO2016/69826,2016,A1 .Location in patent: Paragraph 0194

34
[ 159326-68-8 ]
[ 1191237-69-0 ]

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

35
[ 159326-68-8 ]
[ 1191237-69-0 ]
[ 1355049-95-4 ]

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

36
[ 14233-64-8 ]
[ 1191237-69-0 ]
[ 1355049-95-4 ]

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

37
[ 16838-89-4 ]
[ 1191237-69-0 ]
[ 1355049-95-4 ]

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

38
[ 1191237-69-0 ]
pentan-3-yl ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate [ No CAS ]
pentan-3-yl ((((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 ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 1648 - 1661

39
[ 1191237-69-0 ]
neopentyl ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate [ No CAS ]
(S)-neopentyl 2-(((S)-(((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 [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 1648 - 1661

40
[ 1191237-69-0 ]
[ 1439900-56-7 ]
[ 1355050-11-1 ]

Yield	Reaction Conditions	Operation in experiment
43%	With tert-butylmagnesium chloride; In tetrahydrofuran; N,N-dimethyl-formamide; for 2.16667h;Inert atmosphere;	(2S)-2-ethylbutyl 2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate (1.08 g, 2.4 mmol) was dissolved in anhydrous DMF (9 mL) and stirred under a nitrogen atmosphere at RT. <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> (350 mg, 1.2 mmol) was added to the reaction mixture in one portion. A solution of t-butylmagnesium chloride in THF (1M, 1.8 mL, 1.8 mmol) was then added to the reaction dropwise over 10 minutes. The reaction was stirred for 2 h, at which point the reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (3×15 mL) followed by saturated aqueous sodium chloride solution (15 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oil was purified with silica gel column chromatography (0-10% MeOH in DCM) to afford (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 (311 mg, 43%, 1:0.4 diastereomeric mixture at phosphorus) as a white solid. 1H NMR (400 MHz, CD3OD) delta 7.85 (m, 1H), 7.34-7.23 (m, 2H), 7.21-7.09 (m, 3H), 6.94-6.84 (m, 2H), 4.78 (d, J=5.4 Hz, 1H), 4.46-4.33 (m, 2H), 4.33-4.24 (m, 1H), 4.18 (m, 1H), 4.05-3.80 (m, 3H), 1.52-1.39 (m, 1H), 1.38-1.20 (m, 7H), 0.85 (m, 6H). 31P NMR (162 MHz, CD3OD) delta 3.71, 3.65. LCMS m/z 603.1 [M+H], 600.9 [M-H]. HPLC (2-98% MeCN-H2O gradient with 0.1% TFA modifier over 8.5 min, 1.5 mL/min, Column: Phenomenex Kinetex C18, 2.6 um 100 , 4.6×100 mm) tR=5.544 min, 5.601 min
	With tert-butylmagnesium chloride; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 2.16667h;Inert atmosphere;	(2S)-2-ethylbutyl 2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate (1.08 g, 2.4 mmol) was dissolved in anhydrous DMF (9 mL) and stirred under a nitrogen atmosphere at RT. (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)-3,4- dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (350 mg, 1.2 mmol) was added to the reaction mixture in one portion. A solution of i-butylmagnesium chloride in THF (1M, 1.8 mL, 1.8 mmol) was then added to the reaction drop wise over 10 minutes. The reaction was stirred for 2 h, at which point the reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (3 x 15 mL) followed by saturated aqueous sodium chloride solution (15 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oil was purified with silica gel column chromatography (0-10% MeOH in DCM) to afford (2S)-2- ethylbutyl 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2, l-f][l,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino) propanoate (311 mg, 43%, 1 :0.4 diastereomeric mixture at phosphorus) as a white solid. H NMR (400 MHz, CD3OD) delta 7.85 (m, 1H), 7.34 - 7.23 (m, 2H), 7.21 - 7.09 (m, 3H), 6.94 - 6.84 (m, 2H), 4.78 (d, / = 5.4 Hz, 1H), 4.46 - 4.33 (m, 2H), 4.33 - 4.24 (m, 1H), 4.18 (m, 1H), 4.05 - 3.80 (m, 3H), 1.52 - 1.39 (m, 1H), 1.38 - 1.20 (m, 7H), 0.85 (m, 6H). 31P NMR (162 MHz, CD3OD) delta 3.71, 3.65. LCMS m/z 603.1 [M+H], 600.9 [M-H]. HPLC (2-98% MeCN-H20 gradient with 0.1% TFA modifier over 8.5 min, 1.5mL/min, Column: Phenomenex Kinetex C18, 2.6 um 100 A, 4.6 x 100 mm ) tR = 5.544 min, 5.601 min

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 1648 - 1661
[2]Patent: US2017/71964,2017,A1 .Location in patent: Paragraph 0556
[3]Patent: WO2017/184668,2017,A1 .Location in patent: Paragraph 0251

41
[ 1256490-31-9 ]
[ 1191237-69-0 ]
(S)-isopropyl 2-(((S)-(((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 [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 1648 - 1661

42
[ 946511-97-3 ]
[ 1191237-69-0 ]
(2S,2'S)-bis(2-ethylbutyl) 2,2'-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)dipropanoate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 1648 - 1661

43
[ 1191237-69-0 ]
(2S)-cyclobutyl 2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate [ No CAS ]
(2S)-cyclobutyl 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 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%	With N-ethyl-N,N-diisopropylamine; magnesium chloride; In N,N-dimethyl-formamide; at 50℃; for 2h;	Compound 1 (58 mg, 0.2 mmol) was mixed with compound G (101 mg, 0.24 mmol) in 2 mL of anhydrous DMF. Magnesium chloride (42 mg, 0.44 mmol) was added in one portion. The reaction mixture was heated to 50 C. DIPEA (87 muL, 0.5 mmol) was added, and the reaction was stirred for 2 h at 50 C. The reaction mixture was cooled to room temperature, was diluted with EtOAc and was washed with 5% aqueous citric acid solution followed by saturated aqueous sodium chloride solution. The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified with silica gel column (0-2-5% MeOH in DCM) to afford compound 24 (42 mg, 37% yield, as a mixture of diastereomers). 1H NMR (400 MHz, Methanol-d4) delta 7.85 (m, 1H), 7.34-7.22 (m, 2H), 7.22-7.08 (m, 3H), 6.94-6.84 (m, 2H), 4.95-4.85 (m, 1H), 4.79 (m, 1H), 4.46-4.34 (m, 2H), 4.34-4.24 (m, 1H), 4.19 (m, 1H), 3.81 (m, 1H), 2.27 (m, 2H), 2.01 (m, 2H), 1.84-1.68 (m, 1H), 1.62 (m, 1H), 1.30-1.16 (m, 3H). 31P NMR (162 MHz, cd3od) delta 3.70, 3.65. MS m/z=573.0 [M+H].

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 1648 - 1661
[2]Patent: US2017/71964,2017,A1 .Location in patent: Paragraph 0613-0614

44
[ 1191237-69-0 ]
tert-butyl ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate [ No CAS ]
tert-butyl ((((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 ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 1648 - 1661

45
[ 1191237-69-0 ]
[ 245078-14-2 ]
[ 1355050-12-2 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-methyl-1H-imidazole; In tetrahydrofuran; at 0℃;Inert atmosphere;	General procedure: The nucleoside 1 (45 mg, 0.15 mmol) was dissolved in anhydrous trimethyl phosphate (0.5 mL) and the solution stirred under N2(g) at 0 C. Methyl imidazole (36 muL, 0.45 mmol) was added to the solution. Chlorophosphoramidate C (69 mg, 0.225 mmol) was dissolved in anhydrous THF (0.25 mL) and added dropwise to the nucleoside mixture. When the reaction was complete by LCMS, the reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution, saturated NaCl, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography eluting with 0-5% MeOH in CH2Cl2 followed by preparative HPLC to give the product (20.9 mg, 25%). 1H NMR (300 MHz, CD3OD) delta 7.95 (m, 1H), 7.31-6.97 (m, 7H), 4.94 (m, 1H), 4.78 (m, 1H), 4.43 (m, 3H), 4.20 (m, 1H), 3.80 (d, 1H), 1.30-1.18 (m, 9H). 31P NMR (121.4 MHz, CD3OD) delta 3.8. LCMS m/z 561.0 [M+H], 559.0 [M-H]

Reference： [1]Patent: US2017/71964,2017,A1 .Location in patent: Paragraph 0550-0551; 0562-0563

46
[ 1191237-69-0 ]
(2S)-2-ethylbutyl 2-(((R)-(((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 [ No CAS ]
(2S)-2-ethylbutyl 2-(((S)-(((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 [ No CAS ]

Reference： [1]Patent: US2017/71964,2017,A1
[2]Patent: US2017/71964,2017,A1

47
[ 261909-49-3 ]
[ 1191237-69-0 ]
[ 1355050-11-1 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-methyl-1H-imidazole; In tetrahydrofuran; at 0℃;Inert atmosphere;	General procedure: The nucleoside 1 (45 mg, 0.15 mmol) was dissolved in anhydrous trimethyl phosphate (0.5 mL) and the solution stirred under N2(g) at 0 C. Methyl imidazole (36 muL, 0.45 mmol) was added to the solution. Chlorophosphoramidate C (69 mg, 0.225 mmol) was dissolved in anhydrous THF (0.25 mL) and added dropwise to the nucleoside mixture. When the reaction was complete by LCMS, the reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution, saturated NaCl, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography eluting with 0-5% MeOH in CH2Cl2 followed by preparative HPLC to give the product (20.9 mg, 25%). 1H NMR (300 MHz, CD3OD) delta 7.95 (m, 1H), 7.31-6.97 (m, 7H), 4.94 (m, 1H), 4.78 (m, 1H), 4.43 (m, 3H), 4.20 (m, 1H), 3.80 (d, 1H), 1.30-1.18 (m, 9H). 31P NMR (121.4 MHz, CD3OD) delta 3.8. LCMS m/z 561.0 [M+H], 559.0 [M-H]

Reference： [1]Patent: US2017/71964,2017,A1 .Location in patent: Paragraph 0550-0554

48
[ 1191237-69-0 ]
C₁₇H₁₉N₂O₇P [ No CAS ]
(2S)-ethyl 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)phosphorylamino)propanoate [ No CAS ]
(2S)-ethyl 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)phosphorylamino)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Compound 1 (50 mg, 0.17 mmol) was dissolved in NMP-THF (1:1 mL)) and cooled with ice bath. tBuMgCl (0.257 mL, 0.257 mmol) was then added over 5 min. The resulting mixture was allowed to warm to RT and was stirred for 30 min. Then a solution of compound L (Prepared according to US20120009147, 74.6 mg, 0.189 mmol) in THF (2 mL) was added. After 30 min, the reaction mixture was purified by HPLC (acetonitrile 10 to 80% in water) to give compound 29 as a yellow solid. The solid was further purified with silica gel chromatography (MeOH 0 to 20% DCM) to afford compound 29 (23 mg, 24% as a 2.5:1 mixture of diastereomers). 1H NMR (400 MHz, CD3OD) delta 7.76 (d, J=6.0 Hz, 1H), 7.25-7.14 (m, 2H), 7.11-6.99 (m, 3H), 6.87-6.72 (m, 2H), 4.70 (d, J=5.4 Hz, 1H), 4.39-4.24 (m, 2H), 4.20 (dddd, J=9.7, 7.9, 5.1, 2.8 Hz, 1H), 4.10 (dt, J=12.8, 5.5 Hz, 1H), 4.06-3.91 (m, 2H), 3.72 (ddq, J=14.3, 9.3, 7.1 Hz, 1H), 1.17 (dd, J=7.1, 1.0 Hz, 1H), 1.14-1.06 (m, 5H). 31P NMR (162 MHz, CD3OD) delta 3.73, 3.68. MS m/z=547 (M+1)+.

Reference： [1]Patent: US2017/71964,2017,A1 .Location in patent: Paragraph 0564-0565

49
[ 1191237-69-0 ]
C₁₉H₂₃N₂O₇P [ No CAS ]
(S)-isopropyl 2-(((R)-(((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 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%		Compound 1 (60.0 mg, 206 mumol) was dissolved in NMP (0.28 mL). THF (0.2 mL) was added followed by tert-butyl magnesium chloride (1.0M solution in tetrahydrofuran, 0.309 mL) at RT under an argon atmosphere. After 20 min, a solution of compound F (Prepared according to Cho, A. et al J. Med. Chem. 2014, 57, 1812-1825, 81 mg, 206 mumol) in THF (0.2 mL) was added, and the resulting mixture was warmed to 50 C. After 3 h, the reaction mixture was allowed to cool to RT and was purified directly by preparatory HPLC (Phenominex Synergi 4u Hydro-RR 80 150×30 mm column, 5-100% acetonitrile/water gradient) to afford compound 23 (44 mg, 38% as a single diastereomer). 1H NMR (400 MHz, CD3OD) delta 7.86 (s, 1H), 7.34-7.26 (m, 2H), 7.21-7.12 (m, 3H), 6.91 (d, J=4.6 Hz, 1H), 6.87 (d, J=4.6 Hz, 1H), 4.92 (sept, J=6.3 Hz, 1H), 4.80 (d, J=5.4 Hz, 1H), 4.43-4.34 (m, 1H), 4.33-4.24 (m, 1H), 4.18 (t, J=5.6 Hz, 1H), 3.82 (dq, J=9.7, 7.1 Hz, 2H), 1.27 (dd, J=7.1, 1.0 Hz, 3H), 1.18 (dd, J=6.3, 4.8 Hz, 6H). 31P NMR (162 MHz, CD3OD) delta 3.72 (s). LC/MS: tR=1.39 min, MS m/z=561.11 [M+H]; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6mu XB-C18 100A, 50×4.6 mm; Solvents: ACN with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 min-2.0 min 2-100% ACN, 2.0 min-3.05 min 100% ACN, 3.05 min-3.2 min 100%-2% ACN, 3.2 min-3.5 min 2% ACN at 20/min. HPLC: tR=2.523 min; HPLC system: Agilent 1100 series; Column: Gemini 5mu C18 110A, 50×4.6 mm; Solvents: ACN 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]Patent: US2017/71964,2017,A1 .Location in patent: Paragraph 0606-0608

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[ 1191237-69-0 ]
(2S)-cycloheptyl 2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate [ No CAS ]
(2S)-cyclohexyl 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 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
19%	With N-ethyl-N,N-diisopropylamine; magnesium chloride; In N,N-dimethyl-formamide; at 0 - 50℃; for 1.08333h;	To a mixture of compound 1 (50 mg, 0.343 mmol), compound M (Prepared according to US20130143835, 93 mg, 0.209 mmol), and MgCl2 (24.5 mg, 0.257 mmol) in DMF (1 mL) was added diisopropylethylamine (0.075 mL, 0.43 mmol) dropwise over 5 min at 0 C. The resulting mixture was stirred at 50 C. for 1 h. The reaction mixture was then cooled with an ice-water bath, treated with 1M citric acid (0.5 mL), and was purified directly by prep-HPLC (ACN 0 to 70% in water) to afford compound 29 (20 mg, 19% as a mixture of diastereomers). 1H NMR (400 MHz, CD3OD) delta 7.84 (s, 1H), 7.32-7.23 (m, 2H), 7.18-7.10 (m, 3H), 6.93-6.87 (m, 2H), 4.78 (d, J=5.4 Hz, 1H), 4.67 (td, J=8.7, 4.2 Hz, 1H), 4.48-4.35 (m, 2H), 4.30 (ddd, J=10.8, 5.7, 3.7 Hz, 1H), 4.20 (t, J=5.4 Hz, 1H), 3.88-3.71 (m, 1H), 1.83-1.63 (m, 4H), 1.58-1.46 (m, 1H), 1.46-1.24 (m, 5H), 1.24 (s, 3H). 31P NMR (162 MHz, CD3OD) delta 3.75. MS m/z=601 (M+1)-.

Reference： [1]Patent: US2017/71964,2017,A1 .Location in patent: Paragraph 0631-0633

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[ 1191237-69-0 ]
(2S)-2-(((perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoic acid 2-ethylbutyl ester [ No CAS ]
(2S)-2-ethylbutyl 2-(((R)-(((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 [ No CAS ]
(2S)-2-ethylbutyl 2-(((S)-(((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 [ No CAS ]

Reference： [1]Patent: US2017/71964,2017,A1

52
[ 1355049-92-1 ]
[ 1191237-69-0 ]
(2S)-2-ethylbutyl 2-(((R)-(((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 [ No CAS ]
(2S)-2-ethylbutyl 2-(((S)-(((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 [ No CAS ]

Reference： [1]Patent: WO2017/184668,2017,A1

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[ 1355049-92-1 ]
[ 1191237-69-0 ]
[ 1355050-11-1 ]

Yield	Reaction Conditions	Operation in experiment
	With trimethyl phosphite;	Prepared from Compound 1 and chloridate B according to the same method as for the preparation of compound 8 as described in PCT Publication no. WO 2012/012776. 1H NMR (300 MHz, CD3OD) delta 7.87 (m, 1H), 7.31-7.16 (m, 5H), 6.92-6.89 (m, 2H), 4.78 (m, 1H), 4.50-3.80 (m, 7H), 1.45-1.24 (m, 8H), 0.95-0.84 (m, 6H). 31P NMR (121.4 MHz, CD3OD) delta 3.7. LCMS m/z 603.1 [M+H], 601.0 [M-H].

Reference： [1]Patent: WO2017/184668,2017,A1 .Location in patent: Paragraph 0250

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((2S,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate [ No CAS ]