Name: 823-62-1|Dichloro-1,2,4-triazin-5-amine|97%
Brand: Ambeed
SKU: A1014986
Rating: 92 (40 reviews)

1
[ 67-68-5 ]
[ 823-62-1 ]
[ 86536-78-9 ]

Yield	Reaction Conditions	Operation in experiment
93%	With trifluoroacetic anhydride In dichloromethane at -78 - -55℃; for 3h;

Reference： [1]Hartman, George D.; Schwering, John E.; Hartman, Richard, D. [Tetrahedron Letters, 1983, vol. 24, p. 1011 - 1014]

Yield	Reaction Conditions	Operation in experiment
	Hydrolyse;
	Hydrogenolyse;

Yield	Reaction Conditions	Operation in experiment
	Trichlortriazin II, NH3;
	Dichlormethoxytriazin XIII, NH3;
	3,5,6-Trichlor-<1,2,4>triazin I, methanol. NH4OH;

4
[ 148322-33-2 ]
[ 823-62-1 ]
3-(((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)oxy)propane-1,2-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In 1,4-dioxane at 85 - 90℃;	8.3 Step-3: Preparation of 3-(((5-amino-6-chloro-l,2,4-triazin-3-yl)amino)oxy)propane- 1 ,2-diol (Compound 42). A solution of 3,6-dichloro-l ,2,4-triazin-5-amine (Compound 2), 3- (aminooxy)propane-l,2-diol (Compound 41) (1.5 eq) and NaHC03 (2 eq) in 1,4-dioxane is stirred for 18-20 hours at 85-90 °C. After completion of the reaction, the crude product is purified by column chromatography to afford 3-(((5-amino-6-chloro-l,2,4-triazin-3- yl)amino)oxy)propane- 1 ,2-diol (Compound 42).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0306; 0307

5
4-amino-1-methoxybutan-2-ol [ No CAS ]
[ 823-62-1 ]
4-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-1-methoxybutan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate at 85 - 90℃;	9.1 Step-1 : Preparation of 4-((5-amino-6-chloro-l,2,4-triazin-3-yl)amino)-l- methoxybutan-2-ol (Compound 44). A mixture of 3,6-dichloro-l,2,4-triazin-5-amine (Compound 2), 4-amino-l- methoxybutan-2-ol (1.5 eq) and NaHC03 (2 eq) in 1,4-dioxane is stirred for 18-20 hours at 85-90 °C. After completion of the reaction, the crude product is purified by column chromatography to afford 4-((5-amino-6-chloro-l,2,4-triazin-3-yl)amino)-l-methoxybutan-2- ol (Compound 44).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0311; 0312

6
[ 111-42-2 ]
[ 823-62-1 ]
[ 151169-74-3 ]
2,2'-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)azanediyl)diethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28.3%	Stage #1: 2,2'-iminobis[ethanol]; 3,6-dichloro-1,2,4-triazine-5-amine With triethylamine at 95℃; for 2h; Inert atmosphere; Stage #2: 2,3-dichlorobenzeneboronic acid With tetrakis(triphenylphosphine) palladium⁽⁰⁾; caesium carbonate In water at 85℃; for 3h; Inert atmosphere;	153 A solution of 2,2'-azanediyldiethanol (1.402 g, 13.33 mmol), 3,6-dichloro-l ,2,4- triazin-5-amine (2 g, 12.12 mmol) and triethylamine (5.07 ml, 36.4 mmol) was stirred at 95 °C under nitrogen for two hours. LCMS showed the completion of reaction. The reaction was cooled to room temperature. To the reaction mixture were added (2,3- dichlorophenyl)boronic acid (2.78 g, 14.54 mmol), and cesium carbonate (11.85 g, 36.4 mmol) followed by water (10.00 ml). The mixture was degassed under nitrogen for ten minutes before Tetrakis (2.80 g, 2.424 mmol) was added in. The reaction mixture was stirred at 85 °C for three hours under nitrogen. Solvent was removed via rotavap. The residue was purified using CI 8 column to give desired product 2,2'-((5-amino-6-(2,3-dichlorophenyl)- 1 ,2,4-triazin-3-yl)azanediyl)diethanol (1.18 g, 3.43 mmol, 28.3 % yield) as a free base.

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0870

7
2-(2-(trifluoromethoxy)ethoxy)ethanamine [ No CAS ]
[ 823-62-1 ]
6-chloro-N3-(2-(2-(trifluoromethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With sodium hydrogencarbonate In 1,4-dioxane at 80 - 85℃;	10.1 Step 1 : Preparation of 6-chloro-N³-(2-(2-(trifJuoromethoxy)ethoxy)ethyl)- 1 ,2,4- triazine-3,5-diamine (Compound 46), 3,6-Dichloro-l,2,4-triazin-5-amine (Compound 2) (54.3 mg, 0.329 mmol) and 2-(2- (trifluoromethoxy)ethoxy)ethanamine (798 mg, 4.60mmol) were added to a round bottom flask, containing 8 mL of 1,4-dioxane. Sodium bicarbonate (414 mg, 4.93 mmol) was added to the above reaction mixture and the mixture was degassed for 10-15 minutes. The reaction mixture was stirred under heating at 80-85 °C for 8-10 hours. After completion of the reaction, the mixture was allowed to attain room temp (20-25 °C) and was thereafter filtered to remove salts. The filtrate was concentrated under vacuum and the crude thus obtained was purified by column chromatography (using dichloromethane/methanol as eluant) to give 6- chloro-N -(2-(2-(trifluoromethoxy)ethoxy)ethyl)-l,2,4-triazine-3,5-diamine (Compound 46) (540 mg, 54% yield).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0316; 0317

8
[ 115-69-5 ]
[ 823-62-1 ]
2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-2-methylpropane-1,3-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28.2%	With sodium hydrogencarbonate In 1,4-dioxane at 120 - 125℃; for 20h; Inert atmosphere;	13.1 Step 1 : Preparation of 2-((5-amino-6-chloro-l,2,4-triazin-3-yl)amino)-2- methylpropane-l ,3-diol (Compound 48) 3,6-Dichloro-l,2,4-triazin-5-amine (2.00 g, 12.12 mmol) and 2-amino-2- methylpropane-l,3-diol (1.53 g, 14.55 mmol), Dioxane (30 mL) and sodium bicarbonate (2.04 g, 24.25 mmol) were added to a round bottom flask. Nitrogen gas was purged into the reaction mixture for 10-15 minutes and the reaction mass was heated under stirring at 120- 125 °C for 20 hours. After completion of the reaction, the reaction mass was cooled to room temperature and filtered to remove salts. The filtrate dioxane solution was concentrated under vacuum to obtain the crude, which was purified by column chromatography (using DCM/Methanol as eluent) to give 2-((5-amino-6-chloro-l,2,4-triazin-3-yl)amino)-2- methylpropane- 1 ,3-diol (Compound 48) (0.80 g, 28.20% yield).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0323; 0324

9
2-amino-3-(2-methoxyethoxy)-2-methylpropan-1-ol [ No CAS ]
[ 823-62-1 ]
2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-3-(2-methoxyethoxy)-2-methylpropan-1-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39.6%	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 125℃; for 20h;	14.1 Step 1 : Preparation 2-((5-amino-6-chloro-l,2,4-triazin-3-yl)amino)-3-(2- methoxyethoxy)-2-methylpropan-l-ol (Compound 50). 3,6-Dichloro-l ,2,4-triazin-5-amine (0.50 g, 3.03 mmol) and 2-amino-3-(2- methoxyethoxy)-2-methylpropan-l-ol (0.72 g, 4.39 mmol), JV.N-diisopropylethylamine (1.96 g, 15.15 mmol) and 5 mL of DMSO were added to round bottom flask. The resulting reaction mixture was stirred under heating at 125 °C for 20 hours. At the end of reaction time, the reaction mixture was allowed to attain room temperature and 10 mL water was added to it. The product was extracted using DCM (3 x 20 mL). The crude product obtained upon evaporation of DCM was purified by column chromatography (using DCM/Methanol as eluent) affording 2-((5-amino-6-chloro- 1 ,2,4-triazin-3-yl)amino)-3-(2-methoxyethoxy)-2- methylpropan-l -ol (Compound 50) (0.35 g, 39.60% yield).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0328; 0329

10
7-methyl-2,5,9,12-tetraoxatridecan-7-amine [ No CAS ]
[ 823-62-1 ]
6-chloro-N3-(7-methyl-2,5, 9,12-tetraoxatridecan-7-yl)-1,2,4-triazine-3,5-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47.2%	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 125℃; for 20h;	15.1 Step 1 : Preparation of 6-chloro-N³-(7-methyl-2,5, 9,12-tetraoxatridecan-7-yl)- 1,2,4- triazine-3,5-diamine (Compound 52). 3,6-Dichloro-l,2,4-triazin-5-amine (0.50 g, 3.03 mmol) and 7-methyl-2,5,9,12- tetraoxatridecan-7-amine (0.805 g, 3.64 mmol), N.N-diisopropylethylamine (1.958 g, 15.15 mmol) and 5 mL of DMSO were added to round bottom flask. The resulting reaction mixture was stirred under heating at 125 °C for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and 20 mL water was added to it. The product was extracted using DCM (3 x 20 mL). The crude product obtained upon evaporation of DCM was purified by column chromatography (using DCM/Methanol as eluent) affording 6-chloro-N3-(7-methyl-2,5,9,12-tetraoxatridecan-7-yl)-l,2,4-triazine-3,5- diamine (Compound 52) (0.5 g, 47.2% yield).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0333; 0334

11
2-methyl-1-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)propan-2-amine [ No CAS ]
[ 823-62-1 ]
6-chloro-N3-(2-methyl-1-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)propan-2-yl)-1,2,4-triazine-3,5-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 80℃; for 72h;	16.1 Step 1 : Preparation of 6-chloro-N³-(2-methyl-l-(2-(2-(trifluoromethoxy)ethoxy) ethoxy)propan-2-yl)- l,2,4-triazine-3,5-diamine (Compound 54). 3,6-Dichloro-l ,2,4-triazin-5-amine (70 mg 0.424 mmol) and 2-methyl-l-(2-(2- (trifluoromethoxy)ethoxy)ethoxy)propan-2-amine (500 mg, 2.039 mol), N,N-diisopropyl- ethylamine (5 mL) and 2 mL of 1,4-dioxane were added to a round bottom flask. The reaction mixture was degassed for 10-15 minutes and stirred under heating at 80 °C for 3 days. After completion of the reaction, the reaction mass was allowed to cool to room temperature (25 °C). The reaction mass was concentrated under vacuum, and the crude compound upon purification by column chromatography yielded 6-chloro-N3-(2-methyl-l-(2- (2-(trifluoromethoxy)ethoxy) ethoxy)propan-2-yl)- 1 ,2,4-triazine-3,5-diamine (Compound 54). (130 mg, 81% yield).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0338; 0339

12
(R)-1-ethoxy-3-(piperazin-1-yl)propan-2-ol [ No CAS ]
[ 823-62-1 ]
(R)-1-(4-(5-amino-6-chloro-1,2,4-triazin-3-yl)piperazin-1-yl)-3-ethoxypropan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With sodium hydrogencarbonate In 1,4-dioxane at 80 - 85℃; for 8h; Inert atmosphere;	17.1 Step 1 : Preparation of (i-)-l-(4-(5-amino-6-chloro-l,2,4-triazin-3-yl)piperazin-l-yl)- 3-ethoxypropan-2-ol (Compound 56). 3,6-Dichloro-l ,2,4-triazin-5-amine ((1000 mg, 6.13 mmol) and (fl)-l-ethoxy-3- (piperazin-l-yl)propan-2-ol (1500 mg, 7.973mol), 1,4-dioxane (20 mL) and sodium bicarbonate (1000 mg 12.16 mmol) were added to a round bottom flask. Nitrogen gas was purged into the reaction mixture for 10-15 minutes, following which the reaction mass was stirred at 80-85 °C for 8 hours (under an inert atmosphere). After completion of the reaction, the reaction mass was allowed to come to room temperature and it was filtered to remove salts. The filtrate was concentrated under vacuum and MTBE (10 mL) was added to residue with stirring for 30 minutes, which afforded a solid product. Upon filtering and drying, the obtained product was ( ?)-l-(4-(5-amino-6-chloro-l ,2,4-triazin-3-yl)piperazin-l -yl)-3- ethoxypropan-2-ol (Compound 56) (1300 mg, 67% yield).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0343; 0344

13
2-(2-(2-(difluoromethoxy)ethoxy)ethoxy)ethanamine [ No CAS ]
[ 823-62-1 ]
6-chloro-N3-(2-(2-(2-(difluoromethoxy)ethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium hydrogencarbonate In 1,4-dioxane at 90℃; for 8h;	18.1 Step 1 : Preparation of 6-chloro-N³-(2-(2-(2-(difluoromethoxy)ethoxy)ethoxy)ethyl)- l,2,4-triazine-3,5-diamine (Compound 58). To a solution of 2-(2-(2-(difluoromethoxy)ethoxy)ethoxy)ethanamine (720 mg, 3.6 mmol) in 1,4-dioxane (10 mL) was added 5-amino-3,6-dichloro-triazine (500 mg, 3.0 mmol). The reaction mixture was then charged with sodium bicarbonate (500 mg, 6.0 mmol). The reaction mixture was stirred at 90 °C for 8 hours. Ethyl acetate (10 mL) was added into the reaction mixture. The suspension was passed through a celite bed and the filtrate was evaporated to obtain the crude product. The crude upon purification by flash chromatography yielded 6-chloro-N3-(2-(2-(2-(difluoromethoxy)ethoxy)ethoxy)ethyl)-l ,2,4-triazine-3,5- diamine (Compound 58) (0.7 g, 70% yield).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0348; 0349

14
1-(difluoromethoxy)-2-methylpropan-2-amine [ No CAS ]
[ 823-62-1 ]
6-chloro-N3-(1-(difluoromethoxy)-2-methylpropan-2-yl)-1,2,4-triazine-3,5-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 120℃; for 18h;	19.1 Step-1 : Preparation of 6-chloro-N³-(l-(difluoromethoxy)-2-methylpropan-2-yl)- l,2,4-triazine-3,5-diamine (Compound 60). To a solution of l-(difluoromethoxy)-2-methylpropan-2 -amine (400 mg, 2.8 mmol) in DMSO (10 mL) was added 5-amino-3,6-dichloro-triazine (120 mg, 0.7 mmol). The reaction mixture was then charged with DIPEA (0.6 mL, 3.6 mmol) and was stirred at 120 °C for 18 hours. After completion of the reaction, the reaction mixture was concentrated. The crude thus obtained was dissolved in 10 mL of ethyl acetate and was washed sequentially with water (2 x 50 mL) and brine (30 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated to afford 6-chloro-N3-(l-(difluoromethoxy)-2-methylpropan-2-yl)- 1 ,2,4-triazine-3,5-diamine (Compound 60) (200 mg, 99% yield).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0353; 0354

15
2-amino-3-((2-fluorobenzyl)oxy)-2-methylpropan-1-ol [ No CAS ]
[ 823-62-1 ]
2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-3-((2-fluorobenzyl)oxy)-2-methylpropan-1-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 120℃; for 18h;	20.1 Step 1 : Preparation of 2-((5-amino-6-chloro-l ,2,4-triazin-3-yl)amino)-3-((2- fluorobenzyl)oxy)-2-methylpropan-l-ol (Compound 62). To a solution of 2-amino-3-((2-fluorobenzyl)oxy)-2-methylpropan-l-ol (510 mg, 2.4 mmol) in DMSO (2 mL) was added 5-amino-3,6-dichloro-triazine (200 mg, 1.2 mmol). The reaction mixture was then charged with DIPEA (1 mL, 6.0 mmol) and was stirred at 120 °C for 18 hours. The reaction mixture was concentrated and the crude upon purification by flash chromatography yielded 2-((5-amino-6-chloro-l,2,4-triazin-3-yl)amino)-3-((2- fluorobenzyl)oxy)-2-methylpropan-l-ol (Compound 62) (0.2 g, 48% yield).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0358; 0359

16
[ 100243-39-8 ]
[ 823-62-1 ]
(S)-1-(5-amino-6-chloro-1,2,4-triazin-3-yl)pyrrolidin-3-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	With sodium hydrogencarbonate In dimethyl sulfoxide at 120℃; for 18h;	21.1 Step 1 : Preparation of (S)-l-(5-amino-6-chloro-l,2,4-triazin-3-yl)pyrrolidin-3-ol (Compound 64). To a solution of (S)-pyrrolidin-3-ol (400 mg, 4.6 mmol) in DMSO (2 mL) were added 5-amino-3,6-dichloro-triazine (660 mg, 4.0 mmol) and sodium bicarbonate (670 mg, 8.0 mmol). The reaction mixture was stirred at 120 °C for 18 hours. Upon attaining completion, the reaction mass was diluted with 10 mL of water. The precipitated product was filtered, washed with ethyl acetate (2 χ 20 mL), and was dried under vacuum affording (S)-l-(5-amino-6-chloro-l,2,4-triazin-3-yl)pyrrolidin-3-ol (Compound 64) (430 mg, 49% yield).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0363; 0364

17
2-((2-phenyl-1,3-dioxan-5-yl)oxy)ethanamine [ No CAS ]
[ 823-62-1 ]
2-(2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)ethoxy)propane-1,3-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	Stage #1: 2-((2-phenyl-1,3-dioxan-5-yl)oxy)ethanamine; 3,6-dichloro-1,2,4-triazine-5-amine With sodium hydrogencarbonate In 1,4-dioxane at 80 - 85℃; Inert atmosphere; Stage #2: With hydrogenchloride; water In 1,4-dioxane at 50℃; for 0.5h;	2.1 Step 1: Preparation of 2-(2-((5-amino-6-chloro-l,2,4-triazin-3- yl)amino)ethoxy)propane-l ,3-diol (Compound 5). 3,6-Dichloro-l,2,4-triazin-5-amine (Compound 2) (1.5 g, 9.09 mmol), 2-((2-phenyl- l,3-dioxan-5-yl)oxy)ethanamine (2.64 g, 11.64 mmol) and sodium bicarbonate (1.146 g, 13.64 mmol) were added to a round bottom flask containing 15 mL of 1,4-dioxane, and equipped with a condenser and a CaCl2 guard tube. Nitrogen was purged into the reaction mixture for 10-15 minutes and then it was stirred at 80-85 °C for 4-5 hours. After completion of the reaction, the mixture was filtered, concentrated and the residue was heated with aqueous hydrochloric acid at 50 °C for 30 minutes. The crude product was purified by column chromatography to yield 2-(2-((5-amino-6-chloro-l,2,4-triazin-3- yl)amino)ethoxy)propane-l,3-diol (Compound 5) (400 mg, 20% yield).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0197; 0198

18
[ 1499-56-5 ]
[ 823-62-1 ]
(2S,4R)-methyl-(5-amino-6-chloro-1,2,4-triazin-3-yl)-4-hydroxypyrrolidine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With triethylamine In dimethyl sulfoxide at 120℃; for 18h;	22.1 Step 1 : Preparation of (2S,4R)-met y\ l-(5-amino-6-chloro-l,2,4-triazin-3-yl)-4- hydroxypyrrolidine-2-carboxylate (Compound 66). To a solution of (2S, 4/?)-methyl 4-hydroxypyrrolidine-2-carboxylate (1.3 g, 7.2 mmol) in DMSO (2 mL) were added 5-amino-3,6-dichloro-triazine (700 mg, 4.2 mmol) and triethylamine (3.8 mL, 38.2 mmol). The reaction mixture was stirred at 120 °C for 18 hours. Excess triethylamine was removed by evaporation under vacuum and the crude upon purification by flash chromatography yielded (2S,4R)-met y l -(5-amino-6-chloro- 1 ,2,4- triazin-3-yl)-4-hydroxypyrrolidine-2-carboxylate (Compound 66) (500 mg, 43% yield).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0368; 0369

19
(3R,5S)-5-(((2-fluorobenzyl)oxy)methyl)pyrrolidin-3-ol [ No CAS ]
[ 823-62-1 ]
(3R,5S)-1-(5-amino-6-chloro-1,2,4-triazin-3-yl)-5-(((2-fluorobenzyl)oxy)methyl)pyrrolidin-3-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With triethylamine In dimethyl sulfoxide at 120℃; for 4h;	23.1 Step 1 : Preparation of (J^5S)-l-(5-amino-6-chloro-l,2,4-triazin-3-yl)-5-(((2- fluorobenzyl)oxy)methyl)pyrrolidin-3-ol (Compound 68). To a solution of (5 ?,5S)-5-(((2-fluorobenzyl)oxy)methyl)pyrrolidin-3-ol (300 mg, 1.3 mmol) in DMSO (2 mL) were added 5-amino-3,6-dichloro-triazine (150 mg, 0.9 mmol) and triethylamine (1.0 mL, 7.2 mmol). The reaction mixture was stirred at 120 °C for 4 hours. The reaction mixture was evaporated to remove excess triethylamine. The residue was taken in 30 mL of ethyl acetate, washed sequentially with water (2 x 10 mL) and brine (10 mL). The ethyl acetate layer was dried over sodium sulfate, concentrated under vacuum to afford the crude product. The crude upon purification by flash chromatography yielded (3i2,5S)-l-(5-amino-6-chloro-l,2,4-triazin-3-yl)-5-(((2-fluorobenzyl)oxy)methyl)pyrrolidin- 3-ol (Compound 68) (250 mg, 78% yield).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0373; 0374

20
(R)-1-(2-amino-2-methylpropoxy)-3-methoxypropan-2-ol [ No CAS ]
[ 823-62-1 ]
(R)-1-(2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)-3-methoxypropan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In 1,4-dioxane at 85 - 90℃;	24.1 Step-l : Preparation of (/?)-l-(2-((5-amino-6-chloro-l,2,4-triazin-3-yl)amino)-2- methylpropoxy)-3-methoxypropan-2-ol (Compound 70). 3,6-Dichloro-l,2,4-triazin-5-amine (1.00 eq), (i?)-l-(2-amino-2-methylpropoxy)-3- methoxypropan-2-ol (1.5 eq) and sodium bicarbonate (2 eq) are added to a 1,4-dioxane solution and degassed for 5-10 minutes; the reaction is then carried out for 18-20 hours at 85- 90 °C. After completion of the reaction, the crude product is purified by column chromatography to afford (i?)-l-(2-((5-amiho-6-chloro-l,2,4-triazin-3-yl)amino)-2- methylpropoxy)-3-methoxypropan-2-ol (Compound 70).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0378; 0379

21
(R)-1-methoxy-3-((S)-pyrrolidin-3-yloxy)propan-2-ol [ No CAS ]
[ 823-62-1 ]
(R)-1-(((S)-1-(5-amino-6-chloro-1,2,4-triazin-3-yl)pyrrolidin-3-yl)oxy)-3-methoxypropan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In 1,4-dioxane at 85 - 90℃; Inert atmosphere;	25.1 Step-1 : Preparation of (7?)-l-(((S)-l-(5-Amino-6-chloro-l,2,4-triazin-3^yl)pyrrolidin- 3-yl)oxy)-3-methoxypropan-2-ol (Compound 72). 3,6-Dichloro-l,2,4-triazin-5-amine (1.00 eq), (/2)-l-methoxy-3-((-S)-pyrrolidin-3- yloxy)propan-2-ol (1.5 eq) and sodium bicarbonate (2 eq) are added to 1,4-dioxane and degassed for 5-10 minutes. The reaction is performed by stirring at 85-90 °C for 18-20 hours. After completion of the reaction, a routine work-up affords crude which upon puri fication by FontWeight="Bold" FontSize="10" column chromatography affords (i-)-l -(((S)-l-(5-amino-6-chloro-l ,2,4-triazin-3- yl)pyrrolidin-3-yl)oxy)-3-methoxypropan-2-ol (Compound 72).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0383; 0384

22
(R)-1-isopropoxy-3-(piperazin-1-yl)propan-2-ol [ No CAS ]
[ 823-62-1 ]
(R)-1-(4-(5-amino-6-chloro-1,2,4-triazin-3-yl)piperazin-1-yl)-3-isopropoxy-propan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37.8%	With sodium hydrogencarbonate In 1,4-dioxane at 90℃; for 5h;	26.1 Step-1 : Preparation of (^)-l-(4-(5-amino-6-chloro-l,2,4-triazin-3-yl)piperazin-l-yl)- 3-isopropoxy-propan-2-ol (Compound 74). To a solution of ( ?)-l-isopropoxy-3-(piperazin-l-yl)propan-2-ol (2.45 g, 12.12 mmol) in 1,4-dioxane (10 mL) was added 5-amino-3,6-dichloro-triazine (2.0 g, 12.12 mmol). The reaction mixture was then charged with sodium bicarbonate (3.06 mL, 36.4 mmol). The reaction mixture was stirred at 90 °C for 5 hours. Evaporation of the solvent and purification of the residue by flash chromatography yielded (i?)-l-(4-(5-amino-6-chloro-l ,2,4-triazin-3- yl)piperazin-l-yi)-3-isopropoxy-propan-2-ol (Compound 74) (1.5 g, 37.8% yield).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0388; 0389

23
(R)-1-(azetidin-3-yloxy)-3-methoxypropan-2-ol [ No CAS ]
[ 823-62-1 ]
(R)-1-((1-(5-amino-6-chloro-1,2,4-triazin-3-yl)azetidin-3-yl)oxy)-3-methoxypropan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In 1,4-dioxane at 90℃;	27.1 Step 1 : Preparation of (i?)-l-((l-(5-amino-6-chloro-l,2,4-triazin-3-yl)azetidin-3- yl)oxy)-3-methoxypropan-2-ol (Compound 76) To a solution of (/?)- -(azetidin-3-yloxy)-3-methoxypropan-2-ol (1.0 equiv.) in 1,4- dioxane (10 mL) is added 5-amino-3,6-dichloro-triazine (1.0 equiv.). The reaction mixture is then charged with sodium bicarbonate (3.0 equiv) and stirred at 90 °C. Evaporation of the solvent and purification of the residue by flash chromatography affords ( ?)-l-((l-(5-amino-6- chloro-l,2,4-triazin-3-yl)azetidin-3-yl)oxy)-3-methoxypropan-2-ol (Compound 76).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0393; 0394

24
(S)-1-(3-aminoazetidin-1-yl)-3-methoxypropan-2-ol [ No CAS ]
[ 823-62-1 ]
(S)-1-(3-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)azetidin-1-yl)-3-methoxypropan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In 1,4-dioxane at 90℃;	28.1 Step 1 : Preparation of (S)-l-(3-((5-amino-6-chloro-l,2,4-triazin-3- yl)amino)azetidin-l-yl)-3-methoxypropan-2-ol (Compound 78). To a solution of (S)-l -(3-aminoazetidin-1 -yl)-3-methoxypropan-2-ol (1.0 equiv.) in 1,4-dioxane (10 mL) is added 5-amino-3,6-dichloro-triazine (1.0 equiv.). The reaction mixture is then charged with sodium bicarbonate (3.0 equiv) and stirred at 90 °C. Evaporation of the solvent and purification of the residue by flash chromatography affords (S)-l -(3-((5-amino-6-chloro- 1 ,2,4-triazin-3-yl)amino)azetidin- 1 -yl)-3-methoxypropan-2-ol (Compound 78).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0398; 0399

25
1-cyclobutyl-3-(piperazin-1-yl)propan-1-ol bisacetate [ No CAS ]
[ 823-62-1 ]
3-(4-(5-amino-6-chloro-1,2,4-triazin-3-yl)piperazin-1-yl)-1-cyclobutylpropan-1-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In 1,4-dioxane at 120℃; for 0.75h; Microwave irradiation;	34.5 Step 5: Preparation of 3-(4-(5-amino-6-chloro-l ,2,4-triazin-3-yl)piperazin-l-yl)-l - cyclobutylpropan-l-ol is described below. A 25 mL flask is charged with l-cyclobutyl-3-(piperazin-l-yl)propan-l-ol, bis acetate salt (0.190 g, 0.60 mmol) and 3,6-dichloro-l,2,4-triazin-5-amine (0.082 g, 0.50 mmol), dry 1,4-dioxane (1 mL) and triethylamine (0.21 mL, 1.50 mmol), and the mixture heated in a microwave vial at 120 °C for 45 min. The mixture is concentrated and the residue partitioned between dichloromethane (50 mL) and 1 M sodium carbonate (25 mL). The organic layer is dried (sodium sulfate), filtered and concentrated to afford crude 3-(4-(5- amino-6-chloro- 1 ,2,4-triazin-3-yl)piperazin- 1 -yl)- 1 -cyclobutylpropan- 1 -ol (assumed 0.50 mmol), which might be carried forward to the next step without further purification.

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0423; 0424

26
[ 6168-72-5 ]
[ 823-62-1 ]
2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)propan-1-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In 1,4-dioxane at 95℃;	41 Preparation of 2-((5-amino-6-chloro-l,2,4-triazin-3-yl)amino)propan-l-ol: 5- Amino-3,6-dichloro-l,2,4-triazine (1.5 g, 9.09 mmol) was dissolved in dioxane (60 mL) at room temperature. Triethylamine (1.9 mL, 13.6 mmol) was added, followed by addition of 2- aminopropan-l-ol (1.37g, 18.2 mmol). The resulting mixture was stirred at 95°C for overnight. After overnight reaction, the mixture was cooled down to room temperature, filtered, and the organic solution was concentrated. The residue was purified on silica gel column to afford a solid product (1.93 g). LC-MS (ESI, MH+) 413; HPLC : > 85 %

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0454

27
[ 71850-04-9 ]
[ 823-62-1 ]
2-(4-(5-amino-6-chloro-1,2,4-triazin-3-yl)piperazin-1-yl)propan-1-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
200 mg	With triethylamine In 1,4-dioxane at 95℃; for 3h; Microwave irradiation;	37 Preparation of 2-(4-(5-amino-6-chloro-l,2,4-triazin-3-yl)piperazin-l-yl)propan-l-ol: 2-(Piperazin-l-yl)propan-l-ol (171 mg, 1.185 mmol), 3,6-dichIoro-l,2,4-triazin-5-amine (170 mg, 1.03 mmol) and triethylamine (0.402 ml, 2.89 mmol) were dissolved in /?-dioxane (5 mL). The solution was heated at 95°C on microwave reactor for 3 h. Solids were filtered off and filtrate was concentrated under reduced pressure. The resulting residue was subject to flash column chromatography. Yield product as yellowish solids (200 mg, 64% yield). LC- MS [ESI-MH+]: mlz 273; 1H-NMR (500MHz, DMSO-d6) δ 1.253 (3H, d, J = 6.5 Hz), 3.143 (2H, m), 3.376 (2H, m), 3.483 (2H, m), 3.606 (1H, m), 3.751 (1H, m), 4.578 (2H, d, J= 13.0 Hz), 5.505 (l H, s), 7.480 (lH, br), 7.996 (lH, br).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0436

28
[ 321890-25-9 ]
[ 823-62-1 ]
2-(4-(5-amino-6-chloro-1,2,4-triazin-3-yl)piperazin-1-yl)-2-methylpropan-1-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
124 mg	With triethylamine In 1,4-dioxane at 95℃; for 3h; Microwave irradiation;	38 Preparation of 2-(4-(5-amino-6-chloro-l,2,4-triazin-3-yl)piperazin-l-yl)-2-methyl- propan-l-ol: 2-Methyl-2-(piperazin-l-yl)propan-l-ol (140 mg, 0.885 mmol), 3,6-dichloro- l,2,4-triazin-5-amine (127 mg, 0.769 mmol) and triethylamine (0.32 ml, 2.31 mmol) were dissolved in dioxane (5 mL). The solution was heated at 95°C on microwave reactor for 3 h. Solids were filtered off and filtrate was concentrated under reduced pressure. The resulting residue was subject to flash column chromatography to give a product as yellowish solids (124 mg, 56.2% yield). LC-MS [ESI-MH+]: mlz 287; -NMR (500MHz, DMSO-d6) δ 0.943 (6H, s), 2.568 (4H, t, J = 5.0 Hz), 3.283 (2H, d, J = 5.5 Hz ), 3.595 (4H, t, J= 5.0 Hz), 4.298 (1H, t, J= 5.0 Hz), 7.302 (1H, br), 7.766 (1H, br).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0441

29
(S)-1-amino-3-(2,2,2-trifluoroethoxy)propan-2-ol [ No CAS ]
[ 823-62-1 ]
(S)-1-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-3-(2,2,2-trifluoroethoxy)propan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38.5%	With triethylamine In 1,4-dioxane at 95℃; for 3h; Microwave irradiation;	39 Preparation of (S -l-((5-amino-6-chloro-l,2,4-triazin-3-yl)amino)-3 -(2,2,2- trifluoroethoxy)propan-2-ol: (5)-l -Amino-3-(2,2,2-trifluoroethoxy)propan-2-ol (100 mg, 0.678 mmol), 3,6-dichloro-l,2,4-triazin-5-amine (286 mg, 1.733 mmol) and triethylamine (225 iL, 1.617 mmol) were dissolved in -dioxane (5 mL). The solution was heated at 95°C on microwave reactor for 3 h. Solids were filtered off and filtrate was concentrated under reduced pressure. The resulting residue was subject to flash column chromatography to give a product as yellowish solids (67 mg, 38.5% yield). LC-MS [ESI-MH+]: m/z 302; -NMR (500MHz, CDC13) δ 3.502 (1H, m), 3.690 (oct, Ji = 6.0 Hz, J2 = 10.0 Hz, J3 = 31.0 Hz), 3.906 (2H, q, J= 9.0 Hz), 4.050 (1H, m), 5.513 (2H, br).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0445

30
1-(piperazin-1-yl)-3-(2,2,2-trifluoroethoxy)propan-2-ol acetate [ No CAS ]
[ 823-62-1 ]
1-(4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-piperazin-1-yl)-3-(2,2,2-trifluoroethoxy)propan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In 1,4-dioxane at 85℃; for 2h;	42 Preparation of (_J/?)-l-(4-(5-amino-6-chloro-l,2,4-triazin-3-yl)-piperazin-l-yl)-3- (2,2,2-trifluoroethoxy)propan-2-ol The above HAc salt product was dissolved in dioxane (7 mL) in a 100-mL flask. 3,6-dichloro-l,2,4-triazine-5-amine (324 mg, 1.96 mmol) and TEA (684 μ, 4.91 mmol) were added to the reaction solution. The reaction was set up at 85°C and LC-MS indicated the completeness of reaction in two hours. The reaction residue was evaporated and overnight high vauco drying before next step reaction. RP-HPLC (betasil C18, 0.5 mL/min, 10-100% ACN in 10 min) 5.78 min; LC-MS (ESI, MH+) 377.2; NMR (500 MHz, CDC13) δ 2.42 (IH, dd, J = 12.5, 4.0 Hz), 2.43 (2H, bs), 2.52 (1H, dd, J = 12.5, 10.0 Hz), 2.63 (2H, bs), 3.51-3.55 (4H, m), 3.63 (IH, dd, J= 10.0, 5.0 Hz), 3.72 (IH, dd, J = 5.0, 3.5 Hz), 3.90-3.97 (3H, m), 5.15 (2H, s), 7.34 -7.39 (5H, m).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0464

31
3-(2,2,2-trifluoroethoxy)azetidine [ No CAS ]
[ 823-62-1 ]
6-chloro-3-(3-(2,2,2-trifluoroethoxy)azetidin-1-yl)-1,2,4-triazin-5-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In 1,4-dioxane at 95℃; for 3h; Microwave irradiation;	46 Preparation of 6-chloro-3-(3-(2,2,2-trifluoroethoxy)azetidin-l-yl)-l,2,4-triazin-5- amine: A vial was charged with 3,6-dichloro-l ,2,4-triazin-5-amine (135 mg, 0.816 mmol ) and triethylamine (0.34 mL, 2.45 mmol), 3-(2,2,2-trifluoroethoxy)azetidine in 4 mL of dioxane. The mixture was heated at 95 °C for 3 hours using microwave reactor. Solvent was evaporated to dryness, residue was used for next step reaction without purification. LC-MS (ESI, MH+) 284

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0477

32
[ 74654-07-2 ]
[ 823-62-1 ]
5-amino-6-chloro-3-mPEG₃-amino-1,2,4-triazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With triethylamine In 1,4-dioxane at 95℃; for 7h;	47 Synthesis of 5-amino-6-chloro-3-mPEG3-amino-l,2,4-triazine: 5-Amino-3,5-dichloro-l,2,4-triazine (1.460 g, 8.85 mmol) was dissolved in dioxane (30 mL) at room temperature. Triethylamine (2.7 mL, 19.37 mmol) was added, followed by addition of mPEG3-NH2 (1.9812 g, 12.14 mmol). The resulting mixture was stirred at 95 °C for 7 h. The mixture was cooled to room temperature, filtered to remove the white solid and the solid was washed with ethyl acetate. The combined organic solution was concentrated and purified with flash column chromatography on silica gel (1-10% methanol/dichloromethane) to afford 2.1236 g of product as solid. The yield was 82%. [0485] 1H-NMR (500 MHz, CDC13): 3.691-3.654 (m, 6H, 3CH2), 3.625-3.594 (m, 6H, 3CH2), 3.436 (s, 3H, CH3). LC-MS: 292.1 (MH+/z).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0483-0485

33
[ 1844-32-2 ]
[ 823-62-1 ]
2-(2-amino-2-methylpropoxy)ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In 1,4-dioxane at 80 - 85℃;	3.5 Step-5: Preparation of 2-(2-((5-amino-6-chloro-l,2,4-triazin-3-yl)amino)-2- methylpropoxy)ethanol (Compound 11a). 3,6-Dichloro-l,2,4-triazin-5-amine (Compound 2) (1 eq), 2-(2-amino-2- methylpropoxy)ethanol (Compound 10) (1.5 eq) and NaHC03 (2 eq) are added together, in dioxane. The reaction mixture is stirred at 80-85 °C for 18-20 hours. The crude compound thus obtained is purified by column chromatography, to afford pure 2-(2-((5-amino-6-chloro- l,2,4-triazin-3-yl)amino)-2-methylpropoxy)ethanol (Compound 11a), which is characterized by mass and NMR.

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0210; 0211

34
1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperazine [ No CAS ]
[ 823-62-1 ]
5-amino-6-chloro-3-(4'-N-mPEG3-piperazinyl)-1,2,4-triazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With triethylamine In 1,4-dioxane at 95℃; for 1.5h;	50 Synthesis of 5-amino-6-chloro-3-(4'-N-mPEG₄-piperazinyl)amino-l,2,4-triazine A vial was charged With 5-amino-3,6-dichloro-l,2,4-triazine (658.8 mg, 3.99 mmol) and triethylamine (2.5 mL, 17.94 mmol), N-mPEG3-piperazine (0.9471 g, 4.08 mmol) in dioxane (7.5 mL). The mixture was heated at 95 °C for 1.5 h using microwave. The mixture was cooled to room temperature, filtered and the white solid was washed with dichloromethane. The organic solution was concentrated. The residue was purified with flash column chromatography on silica gel using 1-10% methanol/dichloromethane to afford product (1.2111 g, Yield: 84%). NMR (500 MHz, Chloroform-i ) δ 5.18 (br, 2H), 3.80 (br, 4H), 3.65-3.62 (m, 8H), 3.54-3.52 (m, 2H), 3.36 (s, 3H), 2.63 (s, 2H), 2.55 (br, 2H), 2.55 (br, 4H). LC-MS: 361.2 (MH+/z).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0505; 0506

35
[ 823-62-1 ]
6-chloro-3,5-diamino-1,2,4-triazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With ammonium hydroxide In tetrahydrofuran at 0 - 95℃; for 1h; Microwave irradiation;	59 Synthesis of 6-chloro-3,5-diamino-l,2,4-triazine: A vial was placed 5-amino-3,6-trichloro-l ,2,4-triazine (1.5805 g, 8.57 mmol). THF was added to dissolve the yellow solid. 10 mL of ammonium hydroxide was added. The mixture was stirred at 0 °C for a few min. The vial was heated at 95 °C using microwave for 1 h. The mixture was cooled to room temperature, concentrated to remove the organic solvent. The remaining mixture was filtrated and washed with water. The yellow solid was collected and dried to afford product (1.6221 g, Yield: 69%). NMR (500 MHz, DMSO-d6) δ 7.622 (br, 2H), 7.1 13 (br, 2H). I3C-NMR (500 MHz, DMSO-d6) δ 162.06, 153.10, 132.66.

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0557; 0558

36
2-(2-(2-methoxyethoxy)ethoxy)-1-(piperazin-1-yl)ethanone [ No CAS ]
[ 823-62-1 ]
5-amino-3-N-(4-mPEG2-CM piperazinyl)-6-chloro-1,2,4-triazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With triethylamine In 1,4-dioxane; water at 95℃; for 1.5h; Microwave irradiation;	52 Synthesis of 5-amino-3-N-(4-mPEG₂-CM piperazinyl)-6-chloro-l ,2,4-triazine: A vial was charged with 5-amino-3,6-dichloro-l ,2,4-triazine (586.3 mg, 3.55 mmol) and triethylamine (1.5 mL, 10.76 mmol), 2-(2-(2-methoxyethoxy)ethoxy)-l-(piperazin-l- yl)ethanone (0.898 g, 3.65 mmol) in dioxane (8.0 mL). The mixture was heated at 95 °C for 1.5 h using microwave. The mixture was cooled to room temperature, filtered and the white solid was washed with dichloromethane. The organic solution was concentrated. The residue was dissolved in dichloromethane (50 mL), washed with water. The aqueous solution was extracted with dichloromethane (30 ml). The combined organic solution was dried over anhydrous sodium sulfate, concentrated. The residue was purified with flash column chromatography on silica gel using 1-10% methanol/dichloromethane to afford product (1.0453 g, Yield: 78%). NMR (500 MHz, Chloroform-* ) δ 5.24 (br, 2H), 4.24 (s, 2H), 3.84 (t, J= 3.0 Hz, 2H), 3.77 (t, J= 3.0 Hz, 2H), 3.71-3.69 (m, 2H), 3.67-3.64 (m, 4 H), 3.63- 3.61 (m, 2H), 3.59 (t, J = 3.0 Hz, 2H), 3.54-3.52 (m, 2H), 3.35 (s, 3H). LC-MS: 375.0 (MH'Vz).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0521; 0522

37
1-(4-aminopiperidin-1-yl)-2-(2-(2-methoxyethoxy)ethoxy)ethanone [ No CAS ]
[ 823-62-1 ]
5-amino-6-chloro-3-N-(1-(2-(2-(2-methoxyethoxy)ethoxy)acetyl)piperidin-4-yl)amino-1,2,4-triazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23%	With triethylamine In 1,4-dioxane at 95℃; for 3.75h; Microwave irradiation;	54 Synthesis of 5-amino-6-chloro-3-N-(l-(2-(2-(2-methoxyethoxy)ethoxy)acetyl) piperi-din-4-yl)amino-l,2,4-triazine A vial was charged with 5-amino-3,6-dichloro-l,2,4-triazine (321.9 mg, 1.95 mmol) and triethylamine (0.3 mL, 2.152 mmol), l-(4-aminopiperidin-l-yl)-2-(2-(2-methoxyethoxy) ethoxy)ethanone (0.5219 g, 2.01 mmol) in dioxane (10.0 mL). The mixture was heated at 95 °C for 1.5 h using microwave. More of triethylamine (0.7 mL, 5.02 mmol) was added. The mixture was heated again at 95 °C for 1.5 h. More of triethylamine (0.5 mL) was added. The mixture was heated at 95 °C for 45 min. The mixture was cooled to room temperature, was concentrated to remove the solvent. The residue was dissolved in dichloromethane (50 mL), washed with saturated potassium carbonate. The aqueous solution was extracted with dichloromethane (40 ml). The combined organic solution was washed with brine, dried over anhydrous sodium sulfate, concentrated. The residue was purified with flash column chromatography on silica gel using 1-10% methanol/dichloromethane to afford product I (176.5 mg, Yield: 23%). NMR (500 MHz, Chloroform-^) δ 5.24 (s, 2H), 5.00 (br, 1H), 4.45 (d, J = 13.5 Hz, 1H), 4.26 (d, J= 13.4 Hz, 1H), 4.14 (d, J = 13.4 Hz, 1H), 4.01 (s, 1H), 3.93 (d, J = 13.7 Hz, 1H), 3.74-3.57 (m, 6H), 3.57-3.50 (m, 2H), 3.36 (s, 3H), 3.14 (t, J = 12.1 Hz, 1H), 2.82 (t, J = 12.6 Hz, 1H), 2.1 1-2.04 (m, 2H), 1.48 (m, lH), 1.37 (m, 1H). LC- MS: 389.2 (MH+/z).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0532; 0533

38
1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperidin-4-amine [ No CAS ]
[ 823-62-1 ]
5-amino-6-chloro-3-N-(1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperidin-4-yl)amino-1,2,4-triazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%	With triethylamine In 1,4-dioxane at 95℃; for 1.5h; Microwave irradiation;	55 Synthesis of 5-amino-6-chloro-3-N-(l-(2-(2-(2-methoxyethoxy)ethoxy)ethyl) A vial was charged with 5-amino-3,6-dichloro-l,2,4-triazine (700.2 mg, 4.24 mmol) and triethylamine (1.5 mL, 10.76 mmol), l-(2-(2-methoxyemoxy)ethoxy)piperidin-4-amine (1.0633 g, 4.32 mmol) in dioxane (10.0 mL). The mixture was heated at 95 °C for 1.5 h using microwave. The mixture was cooled to room temperature, was concentrated to remove the solvent. The residue was dissolved in dichloromethane (50 mL), washed with water. The aqueous solution was extracted with dichloromethane (30 ml). The combined organic solution was dried over anhydrous sodium sulfate, concentrated. The residue was purified with flash column chromatography on silica gel using 1-10% methanol/dichloromethane and 15% methanol/dichloromethane to afford product as solid (429.5 mg, 27%). 1H NMR (500 MHz, Chloroform- /) δ 5.26 (s, 2H), 4.90 (br, I H), 3.84 (br, 1H), 3.61 (m, 8H), 3.53-3.51 (m, 2H), 3.34 (s, 3H), 2.96 (m, 2H), 2.65 (m, 2H), 2.29 (m, 2H), 2.01 (m, 2H), 1.52 (m, 2H). LC- MS: 375.2 (MH+/z).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0540; 0541

39
1-N-mPEG3-2,6-dimethylpiperazine [ No CAS ]
[ 823-62-1 ]
5-amino-6-chloro-3-N-(4-mPEG₃-3,5-dimethylpiperazinyl)-1,2,4-triazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With triethylamine In 1,4-dioxane at 95℃; for 1.5h; Microwave irradiation;	58 Synthesis of 5-amino-6-chloro-3-N-(4-mPEG3-3,5-dimethylpiperazinyl)amino- 1,2,4-triazine: A vial was charged with 5 -amino-3,6-dichloro- 1,2,4-triazine (114.4 mg, 0.69 mmol) and triethylamine (0.4 mL, 2.87 mmol), l-N-mPEG3-2,6-dimethylpiperazine (0.1742 g, 0.67 mmol) in dioxane (2.5 mL). The mixture was heated at 95 °C for 1.5 h using microwave. The mixture was cooled to room temperature, filtered and the white solid was washed with dichloromethane. The organic solution was concentrated. The residue was dissolved in dichloromethane, washed with saturated potassium carbonate, dried over anhydrous sodium sulfate, concentrated. The residue was purified with flash column chromatography on silica gel using ethyl acetate and 0-10% methanol/ethyl acetate to afford product as oil (226.8 mg, Yield: 87%). NMR (500 MHz, Chloroform- ) δ 5.257 (s, 2H), 4.412 (br, 2H), 3.595- 3.547 (m, 6H), 3.509-3.467 (m, 4H), 3.334 (s, 3H), 2.898 (t, J= 7.5 Hz, 2H), 2.654-2.584 (m, 4H), 1.112 (d, J= 5.5 Hz, 6H). LC-MS: 389.2 (MH7Z).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0552; 0553

40
4-(N,N-methyl-mPEG3)amino piperidine [ No CAS ]
[ 823-62-1 ]
5-amino-6-chloro-3-(4-(N,N-methyl (mPEG3)amino)piperidin-1-yl)-1,2,4-triazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With triethylamine In 1,4-dioxane at 95℃; for 1.5h; Microwave irradiation;	60 Synthesis of 5-amino-6-chloro-3-(4-(N,N-methyl (mPEG3) amino)piperidin-l-yl)- 1,2,4-triazine: A vial was charged with 5-amino-3,6-dichloro-l,2,4-triazine (471.0 mg, 2.85 mmol), triethylamine (1.5 mL, 10.76 mmol), 4-(N,N-methyl-mPEG3) amino piperidine (774.0 mg, 2.97 mmol) in dioxane (10 mL). The mixture was heated at 95 °C for 1.5 h using microwave. The mixture was cooled to room temperature and transferred into a flask with dichloromethane, concentrated to remove the solvents. The residue was mixed with brine, extracted with dichloromethane (3 x 40 mL). The combined organic solution was dried over anhydrous sodium sulfate, concentrated. The residue was separated with flash column chromatography on silica gel using 1-10% methanol in dichloromethane to afford the product (1.0055 g) in 91%. NMR (500 MHz, Chloroform-^ δ 5.18 (s, 2H), 4.74 (d, J= 13.2 Hz, 2H), 3.66 - 3.59 (m, 6H), 3.58 - 3.50 (m, 4H), 3.36 (s, 3H), 2.81 (td, J = 12.9, 2.5 Hz, 2H), 2.67 (br, 3H), 2.30 (s, 3H), 1.83 (d, J= 12.5 Hz, 2H), 1.45 (qd, J= 12.3, 4.3 Hz, 2H). MS for C16H29CIN6O3: 389.2 (MH+).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0570; 0571

41
[ 87120-72-7 ]
[ 823-62-1 ]
tert-butyl 4-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With triethylamine In 1,4-dioxane at 95 - 100℃; for 5.5h;	62 Synthesis of 5-amino-6-chloro-3-(l-N-tert-Boc-piperidin-4-yl)amino-l,2,4-triazine: A flask was charged with 5-amino-3,6-dichloro-l,2,4-triazine (1.2659 g, 7.67 mmol) and 4-amino-l-t-Boc-piperidine (1.5894 g, 7.70 mmol) in dioxane (50 mL). Triethylamine (3.0 mL, 21.52 mmol) was added, the mixture was heated to 95 °C within 15 min and kept at 95 °C for 2 h, at 100 °C for 3.5 h. The mixture was cooled to room temperature, filtered and the white solid was washed with ethyl acetate. The organic solution was concentrated. The residue was purified with flash column chromatography on silica gel using 1-10% methanol/dichloromethane to afford product (998 mg, Yield: 40%). NMR (500 MHz, Chloroform-; ) δ 5.252 (br, 2H), 4.909 (br, 1H), 4.024-3.914 (m, 3H), 2.895 (m, 3H), 2.010- 1.989 (m, 2H), 1.444 (s, 9H), 1.398-1.315 (m, 2H). LC-MS: 329.0 (MH"7z).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0580; 0581

42
[ 823-62-1 ]
[ 1013625-96-1 ]
5-amino-3-(3,5-dimethylpiperazin-1-yl)-1,2,4-triazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With triethylamine In 1,4-dioxane at 95℃; for 1.5h; Microwave irradiation;	65 Synthesis of 5-amino-3-(3 ,5-dimethylpiperazin- 1 -yl)amino- 1 ,2-4-triazine: A vial was charged with 5-amino-3,6-dichloro-l ,2,4-triazine (495.1 mg, 4.25 mmol) and triethylamine (1.5 mL, 10.76 mmol), 2,6-dimethylpiperazine (0.7054 g, 4.28 mmol) in dioxane (11 mL). The mixture was heated at 95 °C for 1.5 h using microwave. The mixture was cooled to room temperature, filtered and the white solid was washed with dichloromethane. The organic solution was concentrated. The residue was dissolved in dichloromethane, washed with saturated potassium carbonate, dried over anhydrous sodium sulfate, concentrated. The residue was purified with flash column chromatography on silica gel using ethyl acetate and 0-10% methanol/ethyl acetate to afford product as solid (0.8916 g, yield: 86%). NMR (500 MHz, Chloroform-i/) δ 5.168 (br, 2H), 4.550 (d, J = 12.5 Hz, 2H), 2.859-2.800 (m, 2H), 2.432 (d, - J= 13.2 Hz, 1 H), 2.406 (d, J= 10.5 Hz, 1H), 1.094 (d, J = 6.5 Hz, 6H). LC-MS: 243.0 (MH+/z).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0594; 0595

43
1-(tetrahydro-2H-pyran-4-yl)piperazine dihydrochloride [ No CAS ]
[ 823-62-1 ]
5-amino-6-chloro-3-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-1,2,4-triazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With triethylamine In 1,4-dioxane at 95℃; for 1.5h;	67 Synthesis of 5-amino-6-chloro-3-(4-(tetrahydro-2H-pyran-4-yl)piperazin-l-yl)- 1,2,4-triazine A vial was charged with 5-amino-3,6-dichloro- 1,2,4-triazine (1.0521 g, 6.38 mmol), triethylamine (4.0 mL, 28.7 mmol), l-(tetrahydro-2H-pyran-4-yl)piperazine 2HC1 (1.6973 g, 6.63 mmol) in dioxane (10 mL). The mixture was heated at 95 °C for 1.5 h. The mixture was cooled to room temperature and transferred into a flask with dichloromethane, concentrated to remove the solvents. The residue was mixed with aqueous potassium carbonate, extracted with dichloromethane (3 x 60 mL). The aqueous mixture was filtered to collect the solid. The solid was dried under high vacuum to afford first batch of product (222 mg). The combined organic solution was concentrated. The residue was dissolved in warm dichloromethane, cooled to room temperature. The solid was collected and washed with dichloromethane to afford another batch of product (1.6048 g). The total yield was 99%. NMR (500 MHz, Chloroform-i δ 5.14 (s, 2H), 3.99 (dd, J = 1 1.3, 4.3 Hz, 2H), 3.76 (t, J= 5.1 Hz, 4H), 3.34" (td, J= 11.9, 1.9 Hz, 2H), 2.59 - 2.53 (m, 4H), 2.42 (tt, J= 11.4, 3.8 Hz, 1H), 1.75 -1.72 (m, 2 H), 1.62 - 1.53 (m, 2H). MS for C,2Hi9ClN60: 299.0 (MH+).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0601; 0602

44
[ 169448-87-7 ]
[ 823-62-1 ]
(R)-5-amino-6-chloro-3-[4-Boc-3-(hydroxymethyl)piperazin-1-yl]-1,2,4-triazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With triethylamine; In 1,4-dioxane; at 95℃; for 2.5h;Microwave irradiation;	A vial was charged with 5-amino-3,6-dichloro-l ,2,4-triazine (573.3 mg, 3.47 mmol), triethylamine (1.5 mL, 10.76 mmol), (R)-tert-butyl 2-(hydroxymethyl)piperazine-l- carboxylate (791.3 mg, 3.55 mmol) in dioxane (10 mL). The mixture was heated at 95 C for 1.5 h using microwave. More of (R)-tert-butyl 2-(hydroxymethyl)piperazine-l-carboxylate (69.4 mg) was added. The mixture was heated at 95 C for another 1 h using microwave. The mixture was cooled to room temperature and transferred into a flask with dichloromethane, concentrated to remove the solvents. The residue was mixed with saturated potassium carbonate solution, extracted with dichloromethane (3 x 40 mL). The combined organic solution was dried over anhydrous sodium sulfate, concentrated. The residue was mixed with small amount of dichloromethane, filtered to collect the white solid as first batch of product (649.6 mg). The solution was concentrated and the residue was separated with flash column chromatography on silica gel using 1-5% methanol in dichloromethane to afford another batch of product (174.3 mg). The total yield was 69%. NMR (500 MHz, Chloroform-af) delta 5.32 (s, 2H), 4.71 (br, I H),, 4.47 (d, J= 12.5 Hz, 1 H), 4.24 (s, IH), 3.90 (s, IH), 3.54 (s, IH), 3.44 (s, IH), 3.15 (d, J = 14.0 Hz, IH), 3.05 (t, J = 12.0 Hz, IH), 2.95 (s, IH), 1.45 (s, 9H). MS for Ci3H2iClN603: 345.0 (MH+).

Reference： [1]Patent: WO2015/92819,2015,A2 .Location in patent: Paragraph 0608; 0609

45
[ 1030377-21-9 ]
[ 823-62-1 ]
(S)-5-amino-6-chloro-3-[4-Boc-3-(hydroxymethyl)piperazin-1-yl]-1,2,4-triazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With triethylamine; In 1,4-dioxane; at 95℃; for 1.5h;Microwave irradiation;	A vial was charged with 5-amino-3,6-dichloro-l ,2,4-triazine (589.6 mg, 3.57 mmol), triethylamine (1.5 mL, 10.76 mmol), (S)-tert-butyl 2-(hydroxymethyl)piperazine-l- carboxylate (890 mg, 3.99 mmol) in dioxane (12 mL). The mixture was heated at 95 C for 1.5 h using microwave. The mixture was cooled to room temperature and transferred into a flask with dichloromethane, concentrated to remove the solvents. The residue was mixed with saturated potassium carbonate, extracted with dichloromethane (3 x 40 mL). The combined organic solution was dried over anhydrous sodium sulfate, concentrated. The residue was separated with flash column chromatography on silica gel using 1-5% methanol in dichloromethane to afford the product (955.7 mg) in 78%. NMR (500 MHz, Chloroform- d) delta 5.30 (s, 2H), 4.69 (br, 1H), 4.45 (d, J= 12.3 Hz, 1H), 4.21 (s, IH), 3.88 (s, 1H), 3.52 (s, I 1H), 3.42 (s, 1H), 3.13 (d, J = 14.2 Hz, lH), 3.02 (t, J = 12.0 Hz, 1H), 2.93 (s, 1H), 1.43 (s, 9H). MS for C3H21CIN6O3: 345.2 (MH+).

Reference： [1]Patent: WO2015/92819,2015,A2 .Location in patent: Paragraph 0617; 0618

46
[ 823-62-1 ]
[ 91188-13-5 ]
5-amino-6-chloro-3-N-(3-N-Boc-aminoazetidinyl)-1,2,4-triazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; In 1,4-dioxane; at 90℃; for 2.25h;Microwave irradiation;	A vial was charged with 5-amino-3,6-dichloro- 1,2,4-triazine (643.1 mg, 3.90 mmol), triethylamine (1.5 mL, 10.76 mmol), 3-N-Boc-amino-azetidine (698.6 mg, 3.98 mmol) in I dioxane (10 mL). The mixture was heated at 90 C for 1 .5 h using microwave. More of 3-N- Boc-amino-azetidine (56.2 mg, 0.32 mmol) was added. The mixture was heated at 90 C for another 45 min. The mixture was concentrated to remove the solvent. The residue was mixed with dichloromethane and aqueous sodium bicarbonate. The organic solution was separated and the aqueous solution was extracted with dichloromethane (2 x 30 mL). The combined organic solution was dried over anhydrous sodium sulfate, concentrated to afford white solid as product in quantitative yield. NMR (500 MHz, Chloroform-i ) delta 5.25 (s, 2H), 4.97 (s, IH), 4.59 (s, IH), 4.41 (t, J = 8.0 Hz, 2H), 3.90 (dd, J= 9.6, 5.2 Hz, 2H), 1.42 (s, 9H). MS for CI IHI7C1N6(: 301 (MH4).

Reference： [1]Patent: WO2015/92819,2015,A2 .Location in patent: Paragraph 0626; 0627

47
(R)-hexahydro-oxazolo[3,4-a]pyrazin-3-one hydrochloride [ No CAS ]
[ 823-62-1 ]
(R)-7-(5-amino-6-chloro-1,2,4-triazin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
296.4 mg	With triethylamine In 1,4-dioxane at 90 - 120℃; for 2.5h;	74 Synthesis of (R)-7-(5-amino-6-chloro-l,2,4-triazin-3-yl)tetrahydro-lH-oxazolo[3,4- a]pyrazin-3(5H)-one: A vial was charged with 5-amino-3,6-dichloro-l,2,4-triazine (457.7 mg, 2.77 mmol), triethylamine (2.0 mL, 14.35 mmol), (R)-hexahydro-oxazolo[3,4-a]pyrazin-3-one HC1 (551.8 mg, 3.09 mmol) in dioxane (10 mL). The mixture was heated at 90 °C for 1.5 h using microwave, 120 °C for 60 min. The mixture was concentrated to remove all of solvent. The residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate solution. The aqueous solution was extracted with dichloromethane (2 x 30 mL). The combined organic solution was washed with brine, dried over anhydrous sodium sulfate, concentrated. The red residue was mixed with small amount of dichloromethane (-10 mL), warmed up and cooled to room temperature. The solid was collected as product (296.4 mg). lH NMR (500 MHz, Chloroforn ) δ 5.24 (br, 2H), 4.95 - 4.88 (m, 1H), 4.70 (d, J= 12.4 Hz, IH), 4.44 (t, J = 8.6 Hz, IH), 3.99 (dd, J = 9.0, 5.5 Hz, 1H), 3.89 - 3.82 (m, 2H), 3.06 (td, J= 12.7, 3.7 Hz, 1H), 2.93 (td, J= 12.8, 3.7 Hz, IH), 2.81 (dd, J= 13.0, 11.1 Hz, IH). MS for CgHnClNfiO;.: 271.0 (MH -

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0633; 6034

48
(8aS)-hexahydro-1,3-oxazolo[3,4-a]pyrazin-3-one hydrochloride [ No CAS ]
[ 823-62-1 ]
(S)-7-(5-amino-6-chloro-1,2,4-triazin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With triethylamine In 1,4-dioxane at 120℃; for 1h;	75 Synthesis of (S)-7-(5-amino-6-chloro-l,2,4-triazin-3-yl)tetrahydro-lH-oxazolo[3,4- a]pyrazin-3(5H)-one A vial was charged with 5-amino-3,6-dichloro-l,2,4-triazine (458.3 mg, 2.78 mmol), triethylamine (2.0 mL, 14.35 mmol), (s)-hexahydro-oxazolo[3,4-a]pyrazin-3-one HC1 (561.8 mg, 3.05 mmol) in dioxane (10 mL). The^mixture was heated at 120 °C for 60 min using microwave. The mixture was concentrated to remove all of solvent. The residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate solution. The aqueous solution was extracted with dichloromethane (5 x 30 mL). The combined organic solution was washed with brine, dried over anhydrous sodium sulfate, concentrated to afford product (720.8 mg) in 96% yield. 1H NMR (500 MHz, Chloroform-c/) δ 5.27 (s, 2H), 4.92 (d, J = 10.4 Hz, 1H), 4.71 (d, J = 12 Hz, 1H), 4.45 (t, J = 8.6 Hz, 1H), 3.99 (dd, J = 9.0, 5.5 Hz, IH), 3.89 - 3.80 (m, 2H), 3.06 (td, J = 12.7, 3.7 Hz, 1H), 2.93 (td, J = 12.8, 3.7 Hz, IH), 2.81 (dd, J= 13.0, 11.1 Hz, IH). MS for C9Hi ,ClN602: 271.0 (MH+).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0638; 0639

49
[ 18621-18-6 ]
[ 823-62-1 ]
1-(5-amino-6-chloro-1,2,4-triazin-3-yl)azetidin-3-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With triethylamine In 1,4-dioxane at 90 - 120℃; for 2.5h; Microwave irradiation;	76 Synthesis of l-(5-amino-6-chloro-l ,2,4-triazin-3-yl)azetidin-3-ol: A vial was charged with 5-amino-3,6-dichloro-l,2,4-triazine (871.3 mg, 5.28 mmol), triethylamine (2.6 mL, 18.65 mmol), 3 -hydrox azetidine hydrochloride (656.3 mg, 5.81 mmol) in dioxane (10 mL). The mixture was heated at 90 °C for 1.5 h using microwave, 120 °C for 1 h. The mixture was mixed with water. Aqueous sodium bicarbonate solution was added until the solution is basic. Dichloromethane was added and sonicated for a few minutes. The mixture was filtered and the solid was washed with acetone, ether and dried under high vacuum to afford product (624 mg) in 59% yield. NMR (500 MHz, Methanol-

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0643; 0644

50
(R)-hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one hexahydrochloride [ No CAS ]
[ 823-62-1 ]
(R)-8-(5-amino-6-chloro-1,2,4-triazin-3-yl)hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With triethylamine In 1,4-dioxane at 120℃; for 1.5h; Microwave irradiation;	77 Synthesis of (R)-8-(5-amino-6-chloro-l,2,4-triazin-3-yl)hexahydropyrazino[2,l- c] [ 1 ,4]oxazin-4(3 H)-one: A vial was charged with 5-amino-3,6-dichloro-l ,2,4-triazine (331 mg, 2.006 mmol), triethylamine (1.8 mL, 12.91 mmol), (R)-hexahydropyrazino[2,l -c][l,4]oxazin-4(3H)-one Hexahydrochloride (465.5 mg, 2.102 mmol) in dioxane (10 mL). The mixture was heated at 120 degree for 1.5 h using microwave. The mixture was concentrated to remove all of solvent. The residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate solution. The aqueous solution was extracted with dichloromethane (2 x 30 mL). The combined organic solution was washed with brine, dried over anhydrous sodium sulfate, concentrated. The residue was mixed with small amount of dichloromethane, warmed up and cooled to r.t. The mixture was filtered and the solid was washed with small amount of dichloromethane. The solid was collected and dried under high vacuum (242.8 mg). The solution was collected and purified with flash column chromatography on silica gel using 1- 5% methanol in dichloromethane to afford another part of product (179.6 mg). The total yield was 74%. 1H NMR (500 MHz, Chloroform-i/) δ 5.29 (s, 2H), 4.74 - 4.60 (m, 3H), 4.24 - 4.12 (m, 2H), 4.04 (q, J= 8.0 Hz, IH), 3.65 - 3.55 (m, 2H), 2.96 (ddd, J= 13.8, 12.2, 3.6 Hz, IH), 2.85 - 2.71 (m, 2H). MS for CioH13ClN602: 285.0 (MH+).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0648; 0649

51
(9aS)-1,3,4,6,7,8,9,9a-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride [ No CAS ]
[ 823-62-1 ]
(S)-8-(5-amino-6-chloro-1,2,4-triazin-3-yl)hexahydropyrazino[2,1-c][1 ,4]oxazin-4(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With triethylamine In 1,4-dioxane at 120℃; for 1.5h;	78 Synthesis of (R)-8-(5-amino-6-chloro- 1 ,2,4-triazin-3-yl)hexahydropyrazino[2, 1 - c][l ,4]oxazin-4(3H)-one: A vial was charged with 5-amino-3,6-dichloro-l,2,4-triazine (358.7 mg, 2.174 mmol), triethylamine (1.8 mL, 12.91 mmol), (S)-octahydropyrazino[2,l-c][l,4]oxazine dihydrochloride (504.1 mg, 2.296 mmol) in dioxane (10 mL). The mixture was heated at 120 °C for 1.5 h using microwave. The mixture was concentrated to remove all of solvent. The residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate solution. The aqueous solution was extracted with dichloromethane (2 x 30 mL). The combined organic solution was washed with brine, dried over anhydrous sodium sulfate, concentrated. The residue was purified with flash column chromatography on silica gel using 1-5% methanol in dichloromethane to afford slightly pink solid (0.5041 g) in 86% yield. NMR (500 MHz, Chloroform-;/) δ 5.20 (s, 2H), 4.60 (d, J = 13.3 Hz, 1H), 4.44 (d, J = 12.8 Hz, IH), 3.85 (dd, J = 1 1.4, 3.3 Hz, IH), 3.76 (dd, J - 1 1.1 , 3.1 Hz, IH), 3.71 (t, J = 11.5 Hz, lH), 3.28 (t, J= 10.6 Hz, IH), 3.08 (t, J= 12.4 Hz, IH), 2.79 (d, J= 1 1.4 Hz, IH), 2.68 (d, J = 1 1.6 Hz, IH), 2.57 (t, J= 12.0 Hz, IH), 2.38 (t, J= 11.0 Hz, IH), 2.28 (t, J= 12.4 Hz, IH), 2.23 (s, IH). MS for C,0H,5ClN6O: 271.0 (MH+).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0653; 0654

52
[ 193269-78-2 ]
[ 823-62-1 ]
5-amino-3-(1-Boc-azetidin-3-yl)amino-6-chloro-1,2,4-triazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 120℃; for 5h; Microwave irradiation;	79 Synthesis of 5-amino-3-(l-Boc-azetidin-3-yl)amino-6-chloro-l,2,4-triazine: A vial was charged with 5-amino-3,6-dichloro-l,2,4-triazine (899.5 mg, 5.45 mmol), diisopropylethylamine (2.0 mL, 1 1.48 mmol), 3-amino-l-N-Boc azetidine(1.1452 g, 6.45 mmol) in dioxane (15 mL). The mixture was heated at 120 °C for 3 h using microwave. More of diisopropylethylamine (0.5 mL) and 3-amino-l-N-Boc azetidine (256 mg) were added. The mixture was heated at 120 °C for another 2 h. The mixture was concentrated to remove all of solvent. The residue was dissolved in dichloromethane, washed with aq. sodium bicarbonate solution. The organic solution was separated. The aqueous solution was mixed with brine, extracted with dichloromethane (2 x 35 mL). The combined organic solution was dried over anhydrous sodium sulfate, concentrated to afford a residue. The residue was mixed with small amount of dichloromethane, warmed up and cooled down to room temperature. The mixture was filtered and the solid was washed with dichloromethane and ether. The solid was collected and dried to afford first batch of product (897.1 mg). The solution was concentrated to remove all of solvents. The residue was purified with flash column chromatography on silica gel using 1 -5% methanol in dichloromethane (266.8 mg). The total yield was 71 %. NMR (500 MHz, Chlorofornw/) δ 5.28 (br, 2H), 4.60 (s, 1H), 4.31 - 4.23 (t, J = 9.0 Hz, 2H), 3.77 (dd, J = 9.4, 5.2 Hz, 2H), 1.43 (s, 9H). MS for CI \|H17C1N602: 301.0 (MH+).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0658; 0659

53
[ 848192-96-1 ]
[ 823-62-1 ]
5-amino-6-chloro-3-N-(3-hydroxy-3-trifluoromethyl)azetidinyl-1,2,4-triazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 120℃; for 0.5h;Microwave irradiation;	A vial was charged with 5-amino-3,6-dichloro-l ,2,4-triazine (290.27 mg, 1.759 mmol), diisopropylethylamine (1.5 mL, 8.61 mmol), 3-(trifluoromethyl)azetidin-3-ol HCl salt (371.5 mg, 2.093 mmol) in dioxane (3 mL). The mixture was heated at 120 C for 30 min using microwave. The mixture was concentrated to remove all of solvents. The residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate solution. Some brine was added. The organic solution was separated. The organic mixture was filtered and washed with dichloromethane to collect the white solid as product. The aqueous solution was saturated with sodium chloride, extracted with dichloromethane. The combined organic solution was concentrated to afford a residue. The residue was dissolved into a small of amount of warm dichloromethane, cooled. The solid was collected and washed with dichloromethane to afford second batch of product. The total yield was quantitative. NMR (500 MHz, Methanol-^) delta 4.30 (d, J = 10.0 Hz, 2H), 4.02 (d, J = 10.1 Hz, 2H). MS for C7H7C1F3N50: 270.0

Reference： [1]Patent: WO2015/92819,2015,A2 .Location in patent: Paragraph 0664; 0665

54
4-(trifluoromethyl)piperidin-4-ol hydrochloride [ No CAS ]
[ 823-62-1 ]
1-(5-amino-6-chloro-1,2,4-triazin-3-yl)-4-(trifluoromethyl)piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 120℃; for 1.08333h; Microwave irradiation;	80-B Synthesis of l -(5-amino-6-chloro-l ,2,4-triazin-3-yl)-4-(trifTuoromethyl)piperidin-4- ol: A vial was charged with 5-amino-3,6-dichloro-l,2,4-triazine (203.4 mg, 1.233 mmol), diisopropylethylamine (1.5 mL, 8.61 mmol), 4-(trifluoromethyl)piperidin-4-ol HC1 (268.6 mg, 1.306 mmol) in dioxane (3 mL). The mixture was heated at 120 °C for 65 min using microwave. The mixture was concentrated to remove all of solvent. The residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate solution. The organic solution was separated. The aqueous solution was mixed with brine, extracted with dichloromethane (2 x 35 mL). The combined organic solution was dried over anhydrous sodium sulfate, concentrated to afford a residue. The residue was purified with flash column chromatography on silica using 1-10% methanol in dichloromethane (273.4 mg) in 75% yield. NMR (500 MHz, Chloroform-c ) δ 4.57 (d, J = 13.5 Hz, 2H), 3.35 (s, 1H), 3.21 - 3.15 (m, 2H), 1.77 - 1.74 (m, 2H). MS for CgHuClFjNsO: 298.0 (MH+).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0669; 0670

55
[ 314741-40-7 ]
[ 823-62-1 ]
(S)-tert-butyl 4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-3-(hydroxymethyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 120℃; for 5h;Microwave irradiation;	A vial was charged with 5-amino-3,6-dichloro-l,2,4-triazine (253.3 mg, 1.535 mmol), diisopropylethylamine (2.0 mL, 1 1.48 mmol), (S)-tert-butyl 2-(3- (hydroxymethyl)piperazin-l-yl)acetate (410.9 mg, 1.731 mmol) in dioxane (2 mL). The mixture was heated at 120 C for 5 h using microwave. The mixture was concentrated to remove all of solvent. The residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate solution. The organic solution was separated. The aqueous solution was mixed with brine, extracted with dichloromethane (2 x 35 mL). The combined organic solution was dried over anhydrous sodium sulfate, concentrated to afford a residue. The residue was dissolved into small amount of dichloromethane, filtered. The solid was collected the first batch of product. The solution was purified with flash column chromatography on silica using 1-10% methanol in dichloromethane to afford another batch of product. The product was slight yellow solid (343 mg) and the yield was 65%. NMR (500 MHz, Chloroform-d) delta 5.26 (br, 2H), 4.76 (s, lH), 4.43 (d, J = 13.3 Hz, lH), 4.23 - 3.92 (s, 2H), 3.65 (m, 2H), 3.16 - 2.90 (s, 4H), 1.47 (s, 9H). MS for Ci3H21ClN603: 345.0 (MH+).

Reference： [1]Patent: WO2015/92819,2015,A2 .Location in patent: Paragraph 0683; 0684

56
(S)-1-((S)-2-(hydroxymethyl)piperazin-1-yl)-3-methoxypropan-2-ol dihydrochloride [ No CAS ]
[ 823-62-1 ]
(S)-1-((S)-4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-2-(hydroxymethyl)piperazin-1-yl)-3-methoxypropan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18%	With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 90℃; for 2.33333h;	81 Synthesis of (S)-l-((S)-4-(5-amino-6-chloro-l ,2,4-triazin-3-yl)-2- (hydroxymethyl)piperazin- 1 -yl)-3 -methoxypropan-2-ol : A mixture of 5-amino-3,6-dichloro-l,2,4-triazine (191.7 mg, 1.38 mmol), diisopropylethylamine (2.5 mL, 14.35 mmol), (S)-tert-butyl 2-(3-(hydroxymethyl)piperazin- l -yl)acetate diHCl (-344 mg, 1.24 mmol) in dioxane (10 mL) was heated at 95 °C for 2 h 20 min. The mixture was concentrated to remove all of solvents. The residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate solution. The organic solution was separated. The aqueous solution was mixed with brine, extracted with dichloromethane (2 x 35 mL). The combined organic solution was dried over anhydrous sodium sulfate, concentrated to afford a residue. The residue was purified with flash column chromatography on silica using 1-10% methanol in dichloromethane to afford product (69.5 mg) in 18% yield. MS for C12H21CIN6O3: 330 (MH+).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0678; 0679

57
1-(tert-butoxy)-3-((S)-2-(hydroxymethyl)piperazin-1-yl)propan-2-ol dihydrochloride [ No CAS ]
[ 823-62-1 ]
1-((S)-4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-2-(hydroxymethyl)piperazin-1-yl)-3-(tert-butoxy)propan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 90℃; for 3.5h;	83 Synthesis of l-((S)-4-(5-amino-6-chloro-l ,2,4-triazin-3-yl)-2- (hydroxymethyl)piperazin- 1 -yl)-3-(tert-butoxy)propan-2-ol: A mixture of 5-amino-3,6-dichloro-l,2,4-triazine (226.7 mg, 1.374 mmol), diisopropyl-ethylamine (2.5 mL, 14.35 mmol), l-(tert-butoxy)-3-((S)-2- (hydroxymethyl)piperazin-l-yl)propan-2-ol 2HC1 (-349 mg, 1.43 mmol) in dioxane (10 mL) was heated at 90 °C for 3.5 h. The mixture was concentrated to remove all of solvents. The residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate solution. The organic solution was separated. The aqueous solution was mixed with brine, extracted with dichloromethane (2 x 35 mL). The combined organic solution was dried over anhydrous sodium sulfate, concentrated to afford a residue. The residue was purified with flash column chromatography on silica using 1-10% methanol in dichloromethane to afford product in quantitative yield. NMR (500 MHz, Chloroform-*/) δ 5.26 (m, 2 H), 4.15 (d, J = 12.1 Hz, 1H), 3.85 (m, 3H), 3.78 - .3.70 (m, 1H), 3.65 - 3.53 (m, 2H), 3.46 - 3.52 (m, 2H), 3.28 - 3.25 (m, 1H), 3.00 (m, 1H), 2.87 - 2.73 (m, 2H), 2.61 - 2.37 (m, 3H), 1.18, 1.17 (2s, 9H). MS for C15H27CIN6O3: 375.2 (MH+).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0692; 0693

58
(S)-1-((S)-3-(hydroxymethyl)piperazin-1-yl)-3-methoxypropan-2-ol dihydrochloride [ No CAS ]
[ 823-62-1 ]
(S)-1-((S)-4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-3-(hydroxymethyl)piperazin-1-yl)-3-methoxypropan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%	With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 150℃; for 4h;	85 Synthesis of (S)-l-((S)-4-(5-amino-6-chloro-l,2,4-triazin-3-yl)-3- (hydroxymethyl)piperazin- 1 -yl)-3 -methoxypropan-2-ol : A mixture of 5-amino-3,6-dichloro-l,2,4-triazine (250.2 mg, 1.517 mmol), diisopropylethylamine (2.0 mL, 11.48 mmol), (S)-l-((S)-3-(hydroxymethyl)piperazin-l-yl)- 3-methoxypropan-2-ol 2HC1 (-500 mg, 1.804 mmol) in dioxane (7 mL) was heated at 1 0 °C for 4 h. The mixture was concentrated to remove all of solvents. The residue was dissolved in dichloromethane, washed with aq. sodium bicarbonate solution. The organic solution was separated. The aqueous solution was saturated with sodium chloride, extracted with dichloromethane (2 x 35 mL). The combined organic solution was dried over anhydrous sodium sulfate, concentrated to afford a residue. The residue was purified with flash column chromatography on silica using 1-10% methanol in dichloromethane to afford product (169.9 mg) in 37% yield. 1H NMR (500 MHz, Methanol-^) δ 4.62 (br, 1H), 4.38 (d, J = 13.1 Hz, lH), 3.97 - 3.88 (m, 2H), 3.70 (dd, J= 10.5, 5.6 Hz, 1H), 3.46 (dd, J= 9.9, 4.1 Hz, 1H), 3.42 - 3.33 (m, 1H), 3.37 (s, 3H), 3.19 (br, 2H), 2.95 (d, J= 11.2 Hz, 1H), 2.43 (br, 2H), 2.21 (d, J = 10.9 Hz, 2H). MS for C\|2H2iClN603: 354.2 (MH+).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0701; 0702

59
1-(tert-butoxy)-3-((S)-3-(hydroxymethyl)piperazin-1-yl)propan-2-ol dihydrochloride [ No CAS ]
[ 823-62-1 ]
1-((S)-4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-3-(hydroxymethyl)piperazin-1-yl)-3-(tert-butoxy)propan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 150℃; for 4h;	86 Synthesis of l -((S)-4-(5-amino-6-chloro-l ,2,4-triazin-3-yl)-3- (hydroxymethyl)piperazin- 1 -yl)-3-(tert-butoxy)propan-2-ol: A mixture of 5-amino-3,6-dichloro-l,2,4-triazine (251.5 mg, 1.524 mmol), diisopropylethylamine (2.0 mL, 1 1.48 mmol), (l -(tert-butoxy)-3-((S)-3-(hydroxymethyl) piperazin-l-yl)propan-2-ol di HCl (~530 mg, 1.660 mmol) in dioxane (7 mL) was heated at 150 degree for 4 h. The mixture was concentrated to remove all of solvent. The residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate solution. The organic solution was separated. The aqueous solution was saturated with sodium chloride, extracted with dichloromethane (2 x 35 mL). The combined organic solution was dried over anhydrous sodium sulfate, concentrated to afford a residue. The residue was purified with flash column chromatography on silica using 1-10% methanol in dichloromethane to afford product (229.9 mg) in 40% yield. 1H NMR (500 MHz, Chloroform-c ) δ 5.26 (br, 2H), 4.72 (s, IH), 4.46 (d, J = 13.4 Hz, IH), 4.02 - 3.83 (m, 3H), 3.42 - 3.36 (m, 2H), 3.34 - 3.29 (m, 1 H), 3.15 (ddt, J= 24.8, 1 1.8, 2.0 Hz, IH), 2.96 (ddt, J= 22.3, 11.4, 2.0 Hz, IH), 2.52 - 2.36 (m, 3H), 2.31 (m, IH), 2.29 - 2.15 (m, 1 H), 1.18 (d, 9H). MS for C15H27CIN6O3: 375.2 (MH+).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0710; 0711

60
[ 886766-28-5 ]
[ 823-62-1 ]
tert-butyl 4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 155℃; for 9.5h;Microwave irradiation;	A vial was charged with 5-amino-3,6-dichloro-l,2,4-triazine (108.5 mg, 0.658 mmol), diisopropylethylamine (0.5 mL, 2.87 mmol), tert-butyl 2-(4,7-diazaspiro[2.5]octan-7- yl)acetate (154.8 mg, 0.650 mmol) in dioxane (2.5 mL). The mixture was heated at 155 C for 9.5 h using microwave. The mixture was concentrated to remove all of solvent. The residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate solution. The organic solution was separated. The aqueous solution was mixed with brine, extracted with dichloromethane (2 x 35 mL). The combined organic solution was dried over anhydrous sulfate, concentrated to afford a residue. The residue was purified with flash column chromatography on silica using 1-10% methanol in dichloromethane to afford product (118.3 mg) in 53% yield. NMR (500 MHz, Chloroform-d) delta 5.24 (s, 2H), 3.91 (t, J = 4.5 Hz, 2H), 3.42 (m, 2H), 3.33 (s, 2H), 1.43 (s, 9H), 0.96 (m, 4H). MS for C14H21 CIN6O2: 341.2 (MH+).

Reference： [1]Patent: WO2015/92819,2015,A2 .Location in patent: Paragraph 0715; 0716

61
[ 823-62-1 ]
[ 259808-67-8 ]
tert-butyl 4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-3,3-dimethylpiperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13%	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 155℃; for 12h;Microwave irradiation;	A vial was charged with 5-amino-3,6-dichloro-l,2,4-triazine (736 mg, 4.46 mmol), diisopropylethylamine (2.0 mL, 11.48 mmol), tert-butyl 2-(3,3-dimethylpiperazin-l- yl)acetate (1.0875 g, 4.52 mmol) in dioxane (8 mL). The mixture was heated at 155 C for 12 h using microwave. The mixture was concentrated to remove all of solvent. The residue was treated with saturated sodium bicarbonate solution, extracted with dichloromethane (4 x 50 mL). The combined organic solution was washed with brine, dried over anhydrous sodium sulfate, concentrated. The residue was separated with flash column chromatography on silica gel using 1-10% methanol in dichloromethane, and 30-100% ethyl acetate/Hexane to afford product (201.8 mg) in 13% yield. NMR (500 MHz, Chloroform-*/) delta 5.12 (s, 2H), 4.06 - 4.02 (m , 2H), 3.52 - 3.46 (m, 2H), 1.50 (s, 6H), 1.44 (s, 9H). MS for C 14H23CIN6O2: 343.2 (MH+).

Reference： [1]Patent: WO2015/92819,2015,A2 .Location in patent: Paragraph 0721; 0722

62
(S)-1-(2-amino-2-methylpropoxy)-3-(2,2,2-trifluoroethoxy)propan-2-ol [ No CAS ]
[ 823-62-1 ]
(S)-1-(2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)-3-(2,2,2-trifluoroethoxy)propan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In 1,4-dioxane at 85℃; for 12h;	90.1 Step-1 : Preparation of (5 -l-(2-((5-amino-6-chloro-l,2,4-triazin-3-yl)amino)-2- methylpropoxy)-3-(2,2,2-trifluoroethoxy)propan-2-ol. 3,6-Dichloro-l,2,4-triazin-5-amine (1.00 eq.), (S)-l-(2-amino-2-methylpropoxy)-3- (2,2,2-trifluoroethoxy)propan-2-ol (1.5 eq.) and NaHC03 (2 eq.) are added to a 1,4-dioxane i solution and degassed, for 5-10 min. The reaction mixture was stirred at 85 °C for 12 h. After completion of the reaction, the crude product is purified by column chromatography to afford (S)-l-(2-((5-amino-6-chloro-l,2,4-triazin-3-yl)amino)-2-methylpropoxy)-3-(2,2,2- trifluoroethoxy)propan-2-ol

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0728; 0729

63
1-amino-3-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)propan-2-ol [ No CAS ]
[ 823-62-1 ]
1-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-3-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)propan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In 1,4-dioxane at 90℃; for 12h;	91.1 Step 1 : Preparation of l-((5-amino-6-chloro-l,2,4-triazin-3-yl)amino)-3-(2-(2- (trifluoromethoxy)-ethoxy)ethoxy)propan-2-ol : To a solution of l-amino-3-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)propan-2-ol (1.0 equiv.) in 1,4-dioxane (10 mL) is added 5-amino-3,6-dichloro-triazine (1.0 eq.). Reaction mixture is then charged with sodium bicarbonate (3.0 eq.) and stirred at 90 °C for 12 h. Evaporation of the solvent and purification of the residue by flash chromatography yields (1- ((5-amino-6-chloro-l ,2,4-triazin-3-yl)amino)-3-(2-(2-(trifluoromethoxy)- ethoxy)ethoxy)propan-2-ol.

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0733; 0734

64
1-amino-3-(2-(2-(2,2,2-trifluoroethoxy)ethoxy)ethoxy)propan-2-ol [ No CAS ]
[ 823-62-1 ]
1-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-3-(2-(2-(2,2,2-trifluoroethoxy)ethoxy)ethoxy)propan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In 1,4-dioxane at 90℃; for 10h;	92.1 Step 1 : Preparation of l-((5-amino-6-chloro-l,2,4-triazin-3-yl)amino)-3-(2-(2- (2,2,2-trifluoroethoxy)-ethoxy)ethoxy)propan-2-ol: To a solution of l-amino-3-(2-(2-(2,2,2-trifluoroethoxy)ethoxy)ethoxy)propan-2-ol (1.0 eq.) in 1,4-dioxane (10 mL) is added 5-amino-3,6-dichloro-triazine (1.0 eq.). Reaction mixture is then charged with sodium bicarbonate (3.0 eq.) and stirred at 90 °C for 10 h. Evaporation of the solvent and purification of the residue by flash chromatography yields 1- ((5-amino-6-chloro- 1 ,2,4-triazin-3-yl)amino)-3-(2-(2-(2,2,2-trifluoroethoxy)- ethoxy)ethoxy)propan-2-ol .

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0738; 0739

65
(S)-3-((2-aminoethyl)amino)-1,1,1-trifluoropropan-2-ol [ No CAS ]
[ 823-62-1 ]
(S)-3-((2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)ethyl)amino)-1,1,1-trifluoropropan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In 1,4-dioxane at 95℃; for 1h;	93.3 Step 3. The synthesis of (S)-3-((2-((5-amino-6-chloro-l ,2,4-triazin-3- yl)amino)ethyl)amino)- 1 , 1 , 1 -trifluoropropan-2-ol: (S)-3-((2-aminoethyl)amino)-l,l,l-trifluoropropan-2-ol (4.3 g, 25 mmol) and 3,6- dichloro-l,2,4-triazin-5-amine (4.53 g, 27.5 mmol) are dissolved in anhydrous dioxane (14 mL). TEA (4.4 mL, 31.6 mmol) is added into solution. The reaction solution is heated at 95 °C for 1 hour. The mixture is cooled to room temperature and white precipitate is observed. The mixture is filtered to collect the solution. The solution is concentrated to remove the solvents. The residue is used for next step without further purification

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0746; 0747

66
(R)-tert-butyl pyrrolidin-3-ylcarbamate hydrochloride [ No CAS ]
[ 823-62-1 ]
(R)-tert-butyl (1-(5-amino-6-chloro-1,2,4-triazin-3-yl)pyrrolidin-3-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In 1,4-dioxane at 120℃; for 0.75h; Microwave irradiation;	105.1 Step 1 : Preparation of (R)-tert-buty\ (l -(5-amino-6-chIoro-l ,2,4-triazin-3- yl)pyrrolidin-3-yl)carbamate: A 0.5-2 mL microwave vial was charged with (R)-ter(-buty pyrrolidin-3-ylcarbamate, hydrochloride (0.145 g, 0.65 mmol), 3,6-dichloro-l,2,4-triazin-5- amine (0.082 g, 0.50 mmol), dry 1,4-dioxane (1 mL) and triethylamine (0.21 mL, 1.50 mmol), and the mixture heated in a microwave vial at 120 °C for 45 min. The mixture was carried forward to the next step without further purification. MS (EI) for C 13H21 CIN6O2: 329.2 (MH+).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0763

67
1-amino-3-(2-(2-methoxyethoxy)ethoxy)propan-2-ol [ No CAS ]
[ 823-62-1 ]
1-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-3-(2-(2-methoxyethoxy)ethoxy)propan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54.4%	With sodium hydrogencarbonate In 1,4-dioxane at 90℃; for 10h;	110.1 Step 1 : Preparation of l -((5-amino-6-chloro-l,2,4-triazin-3-yl)amino)-3-(2-(2- methoxyethoxy)ethoxy)propan-2-ol: 3,6-Dichloro-l,2,4-triazin-5-amine (500 mg, 3.03 mmol) and l-amino-3-(2-(2- methoxyethoxy)ethoxy)propan-2-ol (703 mg, 3.64 mmol) were dissolved in 10 mL of 1,4- ' dioxane. Reaction mixture was then charged with sodium bicarbonate (382 mg, 4.55 mmol) and stirred at 90 °C for 10 h. Evaporation of the solvent and purification of the residue by column chromatography afforded l-((5-amino-6-chloro-l,2,4-triazin-3-yl)amino)-3-(2-(2- methoxyethoxy)ethoxy)propan-2-ol (compound 2) (530 mg, 54.4% yield).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0792; 0793

68
[ 248275-10-7 ]
[ 823-62-1 ]
6-chloro-3-((2-(2-(2-methoxyethoxy)ethoxy)ethoxy)amino)-1,2,4-triazin-5-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34.8%	With sodium hydrogencarbonate In 1,4-dioxane at 90℃; for 10h;	111.1 Step 1 : Preparation of 6-chloro-3-((2-(2-(2-methoxyethoxy)ethoxy)ethoxy)amino)- 1 ,2,4-triazin-5-amine: 3,6-dichloro-l,2,4-triazin-5-amine (400 mg, 2.425 mmol) and 0-(2-(2-(2- methoxyethoxy)ethoxy)ethyl)hydroxylamine (652 mg, 3.64 mmol) were dissolved in 10 mL of 1,4-dioxane. Reaction mixture is then charged with sodium bicarbonate (407 mg, 4.85 mmol) and stirred at 90 °C for 10 h. Reaction mixture was filtered to remove salt and evaporation of the solvent under vacuum gave crude product. Purification of the crude product by column chromatography yielded 6-chloro-3-((2-(2-(2- methoxyethoxy)ethoxy)ethoxy)amino)-l,2,4-triazin-5-amine (260 mg, 34.8% yield).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0797; 0798

69
2-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)ethanamine [ No CAS ]
[ 823-62-1 ]
6-chloro-N3-(2-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With sodium hydrogencarbonate In 1,4-dioxane at 90℃; for 10h;	112.1 Step 1 : Preparation of 6-chloro-N³-(2-(2-(2- (trifluoromethoxy)ethoxy)ethoxy)ethyl)-l ,2,4-triazine-3,5-diamine 3,6-Dichloro-l,2,4-triazin-5-amine (54.3mg,3.29 mmol) and 2-(2-(2- (trifluoromethoxy)ethoxy)ethoxy)ethanamine (1000 mg, 4.60mmol) were dissolved in 10 mL of 1,4-dioxane. Reaction mixture was then charged with sodium bicarbonate (414 mg, 4.93 mmol) and stirred at 90 °C for 10 h. Reaction mixture was filtered to remove salt and evaporation of the solvent under vacuum gave crude product. Purification of the crude product by column chromatography yielded 6-chloro-N3-(2-(2-(2- (trifluoromethoxy)ethoxy)ethoxy)ethyl)-l,2,4-triazine-3,5-diamine (960 mg, 86 % yield).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0802; 0803

70
[ 2038-03-1 ]
[ 823-62-1 ]
6-chloro-N₃-(2-morpholinoethyl)-1,2,4-triazine-3,5-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With triethylamine In 1,4-dioxane at 95℃; for 4h;	113 Preparation of 6-chloro-N3-(2-morpholinoethyl)-l,2,4-triazine-3,5-diamine 5- Amino-3,6-dichloro-l,2,4-triazine (165 mg, 1.00 mmol) was dissolved in dioxane (10 mL) at room temperature. Et3N (0.307 mL, 2.20 mmol) was added, followed by addition of 2- morpholinoethanamine (0.196 mL, 1.49 mmol). The resulting mixture was stirred at 95°C for 4 hours. The reaction mixture was stirred at 95°C for overnight. After cooling to ambient temperature, insoluble was filtrated and washed with 10 mL of ethyl acetate. Filtrate was concentrated at 50°C with reduced pressure. Residue was mixed with 100 mL of DCM and stirred for 10 minutes. Insoluble was collected through filtration and washed with DCM ( 10 mL x2). The precipitate was dried in vacuum for overnight to give the desired product 1 11 mg (36% yield). LC-MS (ESI, MH+) 259

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0806

71
[ 823-62-1 ]
[ 929-06-6 ]
2-(2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)ethoxy)ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With triethylamine In 1,4-dioxane at 85℃; for 18h;	114 Preparation of 2-(2-((5-amino-6-chloro-l,2,4-triazin-3-yl)amino)ethoxy)ethanol 3,6-dichloro-l,2,4-triazin-5-amine (510 mg, 3.09 mmol) was dissolved in dioxane (27 mL) at room temperature. Et3N (646 iL, 4.64 mmol) was added, following by addition of 2-(2- aminoethoxy)ethanol (616 μ,, 6.18 mmol). The resulting mixture was heated in oil-bath to 85°C (external) and the reaction was kept at this temperature for 18 hrs. After cool down to room temperature, the upper clear solution was decanted to another round bottle flask. The remaining brownish oil was washed with small amount of dioxane and decanted one more time. The combined dioxane solution was evaporated to dryness and the residue was mixed in DCM. The product precipitation was obtained in DCM after the solution was set in refrigerator at 0°C for 2 hrs. Insoluble solid product was collected through filtration and the product was carefully washed with DCM x 2. A solid product was then obtained after high vacuo drying. [0809] The DCM solution obtained from wash was combined with the above brownish residue and evaporated to dryness. The residue was dissolved in MeOH and transferred to Biotage samplet. The purification on silicone gel column was using a program 2-10% of MeOH/DCM in 20 CV. The product fractions were identified with TLC, hplc, and confirmed by LC-MS before product fractions were combined together. Rotary evaporate the solvent and high vacuo to give the product (600 mg, 83% yield). UPLC (Agilent extended C-18, 0.5 mL/min, 10-100% ACN in 5 min) 0.90 min; LC-MS (ESI, MH+) 234.0 + 235.0 (-35%); 1H > NMR (500 MHz, CDC13) δ 3.61-3.66 (4H, m), 3.68-3.74 (2H, m), 3.77-3.80 (2H, m), 5.47 (lH, bs), 5.77 (lH, bs).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0808; 0809

72
N-(2-(2-aminoethoxy)ethyl)methanesulfonamide [ No CAS ]
[ 823-62-1 ]
N-(2-(2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)ethoxy)ethyl)methanesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24%	With triethylamine In 1,4-dioxane at 85℃;	116 Preparation of N-(2-(2-((5-amino-6-chloro-l,2,4-triazin-3-yl)amino)ethoxy)ethyl)- methanesulfonamide N-(2-(2-aminoethoxy)ethyl)methanesulfonamide (437 mg, 2.4 mmol) was dissolved in 15 mL of dioxane. TEA (1.67 mL, 12 mmol) and 5-amino-3,6-dichloro- 1 ,2,4-triazine (200 mg, 1.2 mmol). The resulting mixture was stirred at 85°C for overnight. After cooling to room temperature, the solvent was evaporated to dryness. The residue was purified on silica gel column to give the desired product 176 mg (24% yield).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0814

73
[ 947723-23-1 ]
[ 823-62-1 ]
6-chloro-N3-(2-((1,3-dimethoxypropan-2-yl)oxy)ethyl)-1,2,4-triazine-3,5-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In 1,4-dioxane at 85 - 90℃;	4.7 Step-7: Preparation of 6-chloro-N³-(2-(( 1,3 -dimethoxypropan-2-yl)oxy)ethyl)- 1,2,4- triazine-3, 5 -diamine (Compound 19). A solution of 3,6-dichloro-l ,2,4-triazin-5-amine (Compound 2), 2-((l,3- dimethoxypropan-2-yl)oxy)ethanamine (Compound 18) (1.5 eq) and NaHC03 (2 eq) in 1,4- dioxane is stirred for 18-20 hours at 85-90 °C. After completion of the reaction, the crude product is purified by column chromatography to afford 6-chloro-N3-(2-((l,3- dimethoxypropan-2-yl)oxy)ethyl)-l,2,4-triazine-3, 5 -diamine (Compound 19).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0240; 0241

74
3-(2-(2-methoxyethoxy)ethoxy)-2-methylpropan-1-amine [ No CAS ]
[ 823-62-1 ]
6-chloro-N₃-(3-(2-(2-methoxyethoxy)ethoxy)-2-methylpropyl)-1,2,4-triazine-3,5-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
104 mg	With triethylamine In 1,4-dioxane at 20 - 95℃; Inert atmosphere;	121 Preparation of 6-chloro-N3-(3-(2-(2-methoxyethoxy)ethoxy)-2-methylpropyl)-l ,2,4- triazine-3,5-diamine 3-(2-(2-methoxyethoxy)ethoxy)-2-methylpropan-l-amine(132 mg, 690 mmo) and 5-Amino-3,6-dichloro-l,2,4-triazine (114 mg, 0.69 mmol) were dissolved in dioxane (15 mL) at room temperature. Et3N (0.192 mL, 1.38 mmol) was added. The resulting mixture was stirred at 95°C under nitrogen atmosphere for overnight. After cooling to room temperature, the solvent was evaporated to dryness. The residue was purified on silica gel column to give the product 104 mg (47.1 yield).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0824

75
10-((2-(2-methoxyethoxy)ethoxy)methyl)-2,5,8,11-tetraoxatridecan-13-amine [ No CAS ]
[ 823-62-1 ]
6-chloro-N₃-(10-((2-(2-methoxyethoxy)ethoxy)methyl)-2,5,8,11-tetraoxatridecan-13-yl)-1,2,4-triazine-3,5-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With triethylamine In 1,4-dioxane at 95℃; Inert atmosphere;	124 Preparation of 6-chloro-N3-(10-((2-(2-methoxyethoxy)ethoxy)methyl)-2,5,8,l 1 - tetraoxatridecan- 13-yl)- 1 ,2,4-triazine-3 ,5-diamine 10-((2-(2- methoxyethoxy)ethoxy)methyl)-2,5,8,l 1-tetraoxatridecan- 13-amine (387 mg, 1.14 mmol) and 5-Amino-3,6-dichloro-l,2,4-triazine (157 mg, 0.95 mmol) were dissolved in dioxane (20 mL) at room temperature. Et3N (0.265 mL, 1.9 mmol) was added. The resulting mixture was stirred at 95°C under nitrogen atmosphere for overnight. Solvent was evaporated to dryness. The residue was purified on silica gel column to the product 353 mg (79% yield).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0829

76
[ 109-83-1 ]
[ 823-62-1 ]
2-((5-amino-6-chloro-1,2,4-triazin-3-yl)(methyl)amino)ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With triethylamine In 1,4-dioxane at 20 - 90℃;	129 Preparation of 2-((5-amino-6-chloro-l,2,4-triazin-3-yl)(methyl)amino)ethanol: 5- Amino-3,6-dichloro-l,2,4-triazine (366 mg, 2.22 mmol) and 2-(methylamino)ethanol (213 μν, 2.66 mmol) were dissolved in dioxane (25 mL) at room temperature. Et3N (0.62 mL, 4.44 mmol) was added. The mixture was stirred at 90 °C for overnight. Solvent was evaporated to dryness, residue was redissolved in DCM (20 mL), insoluble was collected and dried in vacuum for 3 hours to give the product 392 mg (87% yield).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0837

77
[ 823-62-1 ]
[ 110-70-3 ]
6-chloro-N₃-methyl-N₃-(2-(methylamino)ethyl)-1,2,4-triazine-3,5-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In 1,4-dioxane at 95℃; for 1h;	133 Preparation of 6-chloro-N3-methyl-N3-(2-(methylamino)ethyl)-l,2,4-triazine-3,5- diamine 5-Amino-3,6-dichloro-l ,2,4-triazine (200 mg, 1.212 mmol) was dissolved in dioxane (30 mL) at room temperature. Et3N (0.17 mL, 1.21 mmol) was added, followed by addition of Nl,N2-dimethylethane-l,2-diamine(1.28 g, 14.55 mmol) in 1 ml of dioxane. The resulting mixture was stirred at 95°C for 1 hour. A sample was checked by LC-MS and showed the reaction was over. Solvent was evaporated to dryness, residue was mixed with 50 mL of hexane and liquid was decanted, precipitate was dried in high vacuum for overnight to give the product 338 mg (> 100% yield).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0843

78
N₁-(2-(2-methoxyethoxy)ethyl)-N₁,N₂-dimethylethane-1,2-diamine [ No CAS ]
[ 823-62-1 ]
6-chloro-N₃-(2-((2-(2-methoxyethoxy)ethyl)(methyl)amino)ethyl)-N₃-methyl-1,2,4-triazine-3,5-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In 1,4-dioxane at 20 - 90℃;	137 5-Amino-3,6- dichloro-l,2,4-triazine (300 mg, 1.09 mmol) was dissolved in dioxane (30 ml) at room temperature. Nl-(2-(2-methoxyethoxy)ethyl)-Nl,N2-dimethylethane-l,2-diamine (380 mg, 2.0 mmol) and TEA (0.464 mL, 3.33 mmol) were added. The resulting mixture was stirred at 90°C for overnight. The mixture directly goes to next step after adding 10 mL of deionized water

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0849

79
[ 534-03-2 ]
[ 823-62-1 ]
2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)propane-1,3-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium hydrogencarbonate In 1,4-dioxane at 80℃; Inert atmosphere;	5.1 Step 1 : Preparation of 2-((5-amino-6-chloro-l,2,4-triazin-3-yl)amino)propane-l,3- diol (Compound 21). 3,6-Dichloro-l,2,4-triazin-5-amine (Compound 2) (3.00 g, 18.18 mmol) and 2-aminopropane-l,3-diol (2.98 g, 32.7 mmol) were dissolved in 30 mL of 1,4-dioxane. NaHC03 (3.51 g, 41.8 mmol) was added to the above reaction mixture and followed by 10-15 minutes of degassing. The reaction mixture was stirred at 80 °C for 8-10 hours. After completion of the reaction, the mixture was filtered (at 40-55 °C), and the organic layer was concentrated under vacuum to afford 2-((5-amino-6-chloro-l,2,4-triazin-3-yl)amino)propane- 1 ,3-diol (Compound 21) (3.20 g, 80% yield).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0245; 0246

80
[ 823-62-1 ]
[ 144912-84-5 ]
tert-butyl (3-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-2-hydroxypropyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With triethylamine; In 1,4-dioxane; at 90℃;	5-Amino-3,6-dichloro-l,2,4-triazine (300 mg, 1.82 mmol) was dissolved in dioxane (30 ml ) at room temperature. tert-Butyl (3-amino-2- hydroxypropyl)carbamate (450 mg, 2.36 mmol) and TEA (507 mu, 3.64 mmol) were added. The resulting mixture was stirred at 90C for overnight. Insoluble was filtered and filtrate was concentrated at reduced pressure. Residue was purified on silica gel column product 474 mg (82% yield).

Reference： [1]Patent: WO2015/92819,2015,A2 .Location in patent: Paragraph 0851

81
[ 823-62-1 ]
[ 57260-71-6 ]
5-amino-6-chloro-3-N-(4-N-boc-piperazinyl)amino-1,2,4-triazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With triethylamine In 1,4-dioxane at 95℃; for 1.5h; Microwave irradiation;	6A.1 Step 1 : Preparation of 5-amino-6-chloro-3-N-(4-N-Boc-piperazinyl)amino- 1,2,4- triazine A vial was charged with 5-amino-3,6-dichloro-l,2,4-triazine (466 mg, 2.82 mmol) and triethylamine (1.0 mL, 7.17 mmol), and t-Boc-piperazine (0.5675 g, 2.96 mmol) in dioxane. The mixture was heated at 95 °C for 1.5 hours using a microwave. The mixture was cooled to room temperature, filtered and the white solid was washed with ethyl acetate. The organic solution was concentrated. The residue was purified with flash column chromatography on silica gel using 1-10% methanol/dichloromethane to afford 872.4 mg product as solid in 98% yield. NMR (500 MHz, Chloroform- /) δ 5.38 (br, 2H), 3.76-3.68 (m, 4H), 3.44 (dd, J= 6.3, 3.9 Hz, 4H), 1.42 (s, 9H). LC-MS: 315.0 (MH+/z).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0261; 0262

82
[ 1404531-84-5 ]
[ 823-62-1 ]
6-chloro-3-(4-(2-(trifluoromethoxy)ethyl)piperazin-1-yl)-1,2,4-triazin-5-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In 1,4-dioxane at 85 - 90℃;	6.4 Step-4: Preparation of 6-chloro-3-(4-(2-(trifluoromethoxy)ethyl)piperazin-l-yl)- l,2,4-triazin-5-amine (Compound 26). A solution of 3,6-dichloro-l ,2,4-triazin-5-amine (Compound 2), l-(2- (trifluoromethoxy)ethyl)piperazine (Compound 25) (1.5 eq) and NaHC03 (2 eq) in 1,4-dioxane is stirred for 18-20 hours at 85-90 °C. After completion of reaction, the crude product is purified by column chromatography to afford the 6-chloro-3-(4-(2- (trifluoromethoxy)ethyl)piperazin- 1 -yl)- 1 ,2,4-triazin-5-amine (Compound 26).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0256; 0257

83
[ 124-68-5 ]
[ 823-62-1 ]
2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-2-methylpropan-1-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15.16%	With sodium hydrogencarbonate In 1,4-dioxane at 85 - 90℃;	1.2 Step 2: Preparation of 2-((5-amino-6-chloro-l,2,4-triazin-3-yl)amino)-2- methylpropan-l-ol (Compound 3) 3,6-Dichloro-l,2,4-triazin-5-amine (Compound 2) (5.00 g, 30.3 mmol), 2-amino-2- methylpropan-l-ol (4.05 g, 45.5 mmol) and NaHC03 (5.09 g, 60.6 mmol) were added to a RB flask containing 50 mL of 1,4-dioxane. This mixture was degassed for 10-15 minutes. The degassed reaction mixture was stirred at 85-90 °C for 18-20 hours. Progress of the reaction was monitored by high performance liquid chromatography ("HPLC). The reaction mixture was allowed to attain room temp (20-25 °C) and then filtered (to remove inorganic salt and unreacted NaHC03). A 1,4-dioxane solution was concentrated and the crude thus obtained was purified by column chromatography (using DCM/MeOH as eluent) giving 2- ((5-amino-6-chloro-l,2,4-triazin-3-yl)amino)-2-methylpropan-l -ol (Compound 3) (1.00 g, 15.16% yield).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0192; 0193

84
1-(piperazin-1-yl)-3-(trifluoromethoxy)propan-2-ol [ No CAS ]
[ 823-62-1 ]
1-(2-(benzyloxy)-3-(trifluoromethoxy)propyl)piperazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With sodium hydrogencarbonate In 1,4-dioxane at 80 - 85℃; Inert atmosphere;	7.5 Step-5: Preparation of l-(4-(5-amino-6-chloro-l,2,4-triazin-3-yl)piperazin-l-yl)-3- (trifluoromethoxy)propan-2-ol (Compound 32). 3,6-Dichloro-l,2,4-triazin-5-amine (0.108 g, 0.657 mmol), l-(piperazine-l-yl)-3- (trifluoromethoxy)propan-2-ol (Compound 31) (0.18 g, 0.789 mmol) and sodium bicarbonate (0.083 g, 0.986 mmol) were added to a round bottom flask containing 10 mL of 1,4-dioxane, and equipped with a condenser and calcium chloride guard tube. Nitrogen was purged into the reaction mixture for 10-15 minutes and the reaction mass was heated under stirring at 80- 85°C for 5-6 hours. After completion of the reaction, the reaction mass was allowed to reach room temperature and was then filtered to remove salts. The filtrate was concentrated under vacuum. The obtained residue (crude) was purified by column chromatography (using dichloromethane/methanol as an eluent) to give l-(4-(5-amino-6-chloro-l,2,4-triazin-3- yl)piperazin-l-yl)-3-(trifluoromethoxy)propan-2-ol (Compound 32) (78 mg, 33% yield).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0278; 0279

85
[ 873-41-6 ]
[ 823-62-1 ]

Yield	Reaction Conditions	Operation in experiment
97%	With ammonia; triethylamine In tetrahydrofuran; 1,4-dioxane at 0 - 20℃; for 5.5h;	47 Synthesis of 5-amino-3,6-dichloro-l,2,4-triazine: 3,5,6-Trichloro-l ,2,4-triazine (4.61 14 g, 24.28 mmol) was dissolved in THF (100 mL) at room temperature. And then triethylamine (5.0 mL, 35.9 mmol) was added. The mixture was cooled to 0 °C, ammonia in dioxane (0.5 M, 51 mL, 25.5 mmol) was added. The mixture was stirred at 0 °C for 30 min, at room temperature for 5 h. The mixture was filtered to remove the solid. The solid was washed with ethyl acetate. The combined organic solution was concentrated. The crude mixture was mixed with about 50 mL of ethyl acetate and warmed up, and then cooled to room temperature. The solid was collected and washed with ether to afford the first partial product. The solution was concentrated to remove all of solvents. The residue was mixed with about 5 ml of ethyl acetate, the solid was collected and dried. The solution was purified with flash column chromatography on silica gel using 35- 100% ethyl acetate/hexanes to afford 3rd part of solid. The total of product was 3.8998 g and the yield was 97%. LC-MS: 165.1 (MH+/z).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0479; 0480

86
[ 752984-24-0 ]
[ 823-62-1 ]
6-chloro-N₃-[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-yl]-1,2,4-triazine-3,5-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With N-Methyldicyclohexylamine In 1-methyl-pyrrolidin-2-one at 160℃; for 1h; Microwave irradiation;	A 6-Chloro-N³-[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-yl]-1,2,4-triazine-3,5-diamine (Ex. 1.3) In a microwave oven, 1.100 g (6.667 mmol) of 3,6-dichloro-1,2,4-triazine-5-amine, 1.290 g (8.001 mmol) of (1R,2S)-2,6-dimethylindane-l-amine and 5.210 g (26.669 mmol) of dicyclohexylmethylamine in 10.0 ml of 1-methylpyrrolidin-2-one were heated at 160° C. for 1 h. The mixture was poured into water and extracted three times with ethyl acetate. The combined organic phases were washed successively four times with water and once with saturated aqueous sodium chloride solution and dried over sodium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by chromatography (start: ethyl acetate/ n-heptane (5:95), over 30 min to ethyl acetate/n-heptane (60:40). Crystallization of the crude product from a mixture of ethyl acetate and n-heptane (4:1) gave 1.210 g (44%) of 6-chloro-N3-[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-yl]-1,2,4-triazine-3,5-diamine.

Reference： [1]Current Patent Assignee: BAYER AG - US2019/230927, 2019, A1 Location in patent: Paragraph 0323

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CAS No. :	823-62-1	MDL No. :	MFCD18250144
Formula :	C₃H₂Cl₂N₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	164.98	Pubchem ID :	-
Synonyms :

Signal Word:	Warning	Class:
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Hazard Statements:	H302-H315-H319-H335	Packing Group:
GHS Pictogram:

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P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
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:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
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:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
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.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
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. 823-62-1 ] {[proInfo.proName]}

Quality Control of [ 823-62-1 ]

Related Doc. of [ 823-62-1 ]

Product Details of [ 823-62-1 ]

Safety of [ 823-62-1 ]

Application In Synthesis of [ 823-62-1 ]

[ 823-62-1 ] Synthesis Path-Downstream 1~86

Related Parent Nucleus of
[ 823-62-1 ]

Triazines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry