[ CAS No. 159326-68-8 ] {[proInfo.proName]}

Name: 159326-68-8|Pyrrolo[2,1-f][1,2,4]triazin-4-amine|95%
Brand: Ambeed
SKU: A424610
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Quality Control of [ 159326-68-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 159326-68-8 ]

CAS No. :	159326-68-8	MDL No. :	MFCD08234647
Formula :	C₆H₆N₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	VSPXQZSDPSOPRO-UHFFFAOYSA-N
M.W :	134.14	Pubchem ID :	10441749
Synonyms :

Calculated chemistry of [ 159326-68-8 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	37.39
TPSA :	56.21 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.07 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.25
Log Po/w (XLOGP3) :	0.07
Log Po/w (WLOGP) :	0.32
Log Po/w (MLOGP) :	0.39
Log Po/w (SILICOS-IT) :	-0.2
Consensus Log Po/w :	0.37

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.38
Solubility :	5.57 mg/ml ; 0.0415 mol/l
Class :	Very soluble
Log S (Ali) :	-0.8
Solubility :	21.1 mg/ml ; 0.157 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.32
Solubility :	6.41 mg/ml ; 0.0478 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.01

Safety of [ 159326-68-8 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P280-P305+P351+P338	UN#:
Hazard Statements:	H317-H319	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 159326-68-8 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 159326-68-8 ]
Downstream synthetic route of [ 159326-68-8 ]

[ 159326-68-8 ] Synthesis Path-Upstream 1~7

1
[ 937046-97-4 ]
[ 3473-63-0 ]
[ 159326-68-8 ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium phosphate In ethanol at 78℃; for 18 h;	To a stirred suspension of i-Amino-I H-pyrrole-2-carbonitrile hydrochloride (50 g, 0.35 mol) in absolute ethanol (800 ml.) was added formamidine acetate (181.3 g, 1.74 mol)^.bul. and potassium phosphate- (370 g, 1.74 mol). The suspension was heated for 18 hours (at)5 78 ⁰C (under N₂), then cooled, filtered and concentrated to dryness in vacuo. The residue was mixed with ice water (2L) and the dark grayish-brown solids were collected by suction filtration. The filter cake was washed with water, sucked dry and the solids were dissolved (on the funnel) with hot ethyl acetate and filtered into a collection vessel. The dark solution was filtered through a long plug of 30/40 Magnesol and the pale yellow10 filtrate was concentrated to dryness in vacuo to afford a yellow-tinged solid (20.6 g, 44.1percent yield). The plug was washed with ethyl acetate/ethanol and the washings were concentrated in vacuo to afford additional material, 10.7 g (23percent). Extraction of the aqueous work-up filtrate with ethyl acetate followed by drying, Magnesol filtration and concentration gave another 6.3 g (14percent) of clean product, bringing the total recovery to15 37.6g (81percent). ¹H-NMR (CD₃OD): δ 7.72 (s, 1H), 7.52 (dd, 1H, J =2.5, 1.6 Hz), 6.85 (dd, 1H₁ J= 4.5, 1.6 Hz), 6.64 (dd, 1 H, J= 4.5, 2.7 Hz) LC/MS (+esi): m/z=135.1 [M+H].
81%	With potassium phosphate In ethanol at 78℃; for 18 h;	To a stirred suspension of 1 -Amino- lH-pyrrole-2-carbonitrile hydrochloride (50 g, 0.35 mol) in absolute ethanol (800 mL) was added formamidine acetate (181.3 g, 1.74 mol) and potassium phosphate (370 g, 1.74 mol). The suspension was heated for 18 hours at 78 ⁰C (under N₂), then cooled, filtered and concentrated to dryness in vacuo. The residue was mixed with ice water (2L) and the dark grayish-brown solids were collected by suction filtration. The filter cake was washed with water, sucked dry and the solids were dissolved(on the funnel) with hot ethyl acetate and filtered into a collection vessel. The dark solution was filtered through a long plug of 30/40 Magnesol and the pale yellow filtrate was concentrated to dryness in vacuo to afford a yellow-tinged solid (20.6 g, 44.1percent yield). The plug was washed with ethyl acetate/ethanol and the washings were concentrated in vacuo to afford additional material, 10.7 g (23percent). Extraction of the aqueous work-up filtrate with ethyl acetate followed by drying, Magnesol filtration and concentration gave another 6.3 g (14percent) of clean product, bringing the total recovery to 37.6g (81percent). ¹H-NMR (CD₃OD): δ 7.72 (s, IH), 7.52 (dd, IH, J =2.5, 1.6 Hz), 6.85 (dd, IH, J = 4.5, 1.6 Hz), 6.64 (dd, IH, / = 4.5, 2.7 Hz) LC/MS (+esi): m/z=135.1 [M+H].

Reference： [1] Patent: WO2007/56170, 2007, A2, . Location in patent: Page/Page column 73-74
[2] Patent: WO2007/64931, 2007, A2, . Location in patent: Page/Page column 163

2
[ 937046-98-5 ]
[ 68-12-2 ]
[ 939967-94-9 ]
[ 159326-68-8 ]

Reference： [1] Patent: WO2007/64931, 2007, A2, . Location in patent: Page/Page column 168

3
[ 3473-63-0 ]
[ 159326-66-6 ]
[ 159326-68-8 ]

Reference： [1] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 4, p. 781 - 786

4
[ 159326-67-7 ]
[ 159326-68-8 ]

Reference： [1] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 4, p. 781 - 786

5
[ 1003-29-8 ]
[ 159326-68-8 ]

Reference： [1] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 4, p. 781 - 786
[2] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 4, p. 781 - 786

6
[ 159326-66-6 ]
[ 159326-68-8 ]

Reference： [1] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 4, p. 781 - 786

7
[ 159326-68-8 ]
[ 937046-98-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione In N,N-dimethyl-formamide at -20℃; for 1.5 h;	A stirred solution containing Intermediate A (21.0 g, 0.157 mol) in anhydrous DMF (200 ml_) was cooled to -20 ⁰C and 1 ,3-dibromo-5,5-dimethylhydantoin (22.4 g, 0.078 mol) was added portionwise over -45 minutes. The reaction was stirred for another 45 minutes and monitored for completion by TLC (silica gel, GHLF, 5percentCH₃OH/CH₂Cl₂). Saturated25 Na₂SO₃ solution (300 mL) was added, the resulting suspension was stirred and the solids were collected by suction filtration. The filter cake was washed with water, dried by suction and then partitioned between ethyl acetate (1 L) and 5percent sodium carbonate solution (1L). The layers were separated, the organic layer was washed with fresh sodium carbonate solution and dried over magnesium sulfate. The filtrate from the work-30 up was also extracted and combined with the main batch then filtered through a pad of <n="77"/>Magnesol and concentrated in vacuo to afford crude mono-bromide, KRAM 206-3-1 , 29.9 g, 90percent yield. Trituration of a 21.5 g quantity of the crude product in hot ethyl acetate (300 mL, 70 C) provided colorless solids (12.3 g) containing only ~2 percent of the di-brominated side-product. ¹H-NMR (CD₃OD) : δ 7.84 (s, 1 H), 6.95 (d, 1 H, J= 4.7 Hz), 6.71 (d, 1H, J = 4.7 Hz), 4.89 (s, 3H, -NH₂ + H₂O); MS: LC/MS (+esi), m/z = 213.1 [M+H].
90%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione In N,N-dimethyl-formamide at -20℃; for 1.5 h;	A stirred solution containing pyrrolo[2,l-f][l,2,4]triazin-4-ylamine (21.0 g, 0.157 mol) in anhydrous DMF (200 mL) was cooled to -20 ⁰C and l,3-dibromo-5,5-dimethylhydantoin (22.4 g, 0.078 mol) was added portionwise over -45 minutes. The reaction was stirred for another 45 minutes and monitored for completion by TLC (silica gel, GHLF, 5percentCH₃OH/CH₂C1₂). Saturated Na₂SO₃ solution (300 mL) was added, the resulting suspension was stiired and the solids were collected by suction filtration. The filter cake was washed with water, dried by suction and then partitioned between ethyl acetate (IL) and 5percent sodium carbonate solution (IL). The layers were separated, the organic layer was washed with fresh sodium carbonate solution and dried over magnesium sulfate. The filtrate from the work-up was also extracted and combined with the main batch then filtered through a pad of Magnesol and concentrated in vacuo to afford crude mono-bromide, KRAM 206-3-1, 29.9 g, 90percent yield. Trituration of a 21.5 g quantity of the crude mono-/di-bromo product in hot ethyl acetate (300 mL, 70 ⁰C) provided colorless solids (12.3 g) containing only ~2 percent of the di-brominated side-product. ¹H-NMR (CD₃OD): δ 7.84 (s, IH), 6.95 (d, IH, J = 4.7 Hz), 6.71 (d, IH, / = 4.7 Hz), 4.89 (s, 3H, -NH₂ + H₂O); MS: LC/MS (+esi), m/z = 213.1 [M+H].
77%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione In N,N-dimethyl-formamide at -20℃; for 1.5 h;	A stirred solution containing pyrrolo[2,1-f][1,2,4]-triazin-4-amine (10 g, 75 mmol) in anhydrous N,N-dimethylformamide(100 mL) was cooled to -20 °C and 1,3-dibromo-5,5-dimethylhydantoin (10.7 g, 37.4 mmol) was added portionwise over 45 min. The reaction was stirred for another45 min and monitored by TLC. After completion, the reaction mixture was washed with saturated aqueous solution of sodium sulfite (150 mL) and water. It was then partitioned between ethyl acetate (0.5 L) and 5 percent aqueous solution of sodium carbonate (500 mL). The organic layer was washed with aqueous solution of sodium carbonate, dried and concentrated to afford 13.3 g crude product. It was purified by silica gel column chromatography (CH2Cl2:MeOH = 100:1) to give the7-bromo compound as a white crystal (12.3 g, 77 percent).

Reference： [1] Patent: WO2007/56170, 2007, A2, . Location in patent: Page/Page column 74-75
[2] Patent: WO2007/64931, 2007, A2, . Location in patent: Page/Page column 164
[3] Asian Journal of Chemistry, 2014, vol. 26, # 20, p. 7083 - 7084
[4] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 1, p. 133 - 137

[ 159326-68-8 ] Synthesis Path-Downstream 1~88

1
[ 1003-29-8 ]
[ 159326-68-8 ]

Reference： [1]Journal of Heterocyclic Chemistry,1994,vol. 31,p. 781 - 786
[2]Journal of Heterocyclic Chemistry,1994,vol. 31,p. 781 - 786

2
[ 159326-66-6 ]
[ 159326-68-8 ]

Reference： [1]Journal of Heterocyclic Chemistry,1994,vol. 31,p. 781 - 786

3
[ 109-01-3 ]
[ 50-00-0 ]
[ 159326-68-8 ]
[ 937048-43-6 ]

Yield	Reaction Conditions	Operation in experiment
	In acetic acid; at 60℃; for 3h;	A mixture of Intermediate A (150 mg, 1.1 mmol), /V-methylpiperazine (0.13 mL, 1.2 mmol) and aqueous formaldehyde (0.09 mL, 1.2 mmol) was dissolved into acetic acid (3 mL).The resulting mixture was stirred for 3 hours at 60 0C and then concentrated in vacuo.The resulting residue was purified by preparative HPLC to provide the title compound. 1H NMR (CD3OD) delta 2.20 (s, 3H), 2.40 -2.80 (br, 8H), 4.00 (s, 2H), 6.60 (d, 1H), 6.90 (d, 1H),7.80 (s, 1H).

Reference： [1]Patent: WO2007/56170,2007,A2 .Location in patent: Page/Page column 202

4
[ 937046-97-4 ]
[ 3473-63-0 ]
[ 159326-68-8 ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium phosphate; In ethanol; at 78℃; for 18h;	To a stirred suspension of i-Amino-I H-pyrrole-2-carbonitrile hydrochloride (50 g, 0.35 mol) in absolute ethanol (800 ml.) was added formamidine acetate (181.3 g, 1.74 mol) ? and potassium phosphate- (370 g, 1.74 mol). The suspension was heated for 18 hours (at)5 78 0C (under N2), then cooled, filtered and concentrated to dryness in vacuo. The residue was mixed with ice water (2L) and the dark grayish-brown solids were collected by suction filtration. The filter cake was washed with water, sucked dry and the solids were dissolved (on the funnel) with hot ethyl acetate and filtered into a collection vessel. The dark solution was filtered through a long plug of 30/40 Magnesol and the pale yellow10 filtrate was concentrated to dryness in vacuo to afford a yellow-tinged solid (20.6 g, 44.1% yield). The plug was washed with ethyl acetate/ethanol and the washings were concentrated in vacuo to afford additional material, 10.7 g (23%). Extraction of the aqueous work-up filtrate with ethyl acetate followed by drying, Magnesol filtration and concentration gave another 6.3 g (14%) of clean product, bringing the total recovery to15 37.6g (81%). 1H-NMR (CD3OD): delta 7.72 (s, 1H), 7.52 (dd, 1H, J =2.5, 1.6 Hz), 6.85 (dd, 1H1 J= 4.5, 1.6 Hz), 6.64 (dd, 1 H, J= 4.5, 2.7 Hz) LC/MS (+esi): m/z=135.1 [M+H].
81%	With potassium phosphate; In ethanol; at 78℃; for 18h;	To a stirred suspension of 1 -Amino- lH-pyrrole-2-carbonitrile hydrochloride (50 g, 0.35 mol) in absolute ethanol (800 mL) was added formamidine acetate (181.3 g, 1.74 mol) and potassium phosphate (370 g, 1.74 mol). The suspension was heated for 18 hours at 78 0C (under N2), then cooled, filtered and concentrated to dryness in vacuo. The residue was mixed with ice water (2L) and the dark grayish-brown solids were collected by suction filtration. The filter cake was washed with water, sucked dry and the solids were dissolved(on the funnel) with hot ethyl acetate and filtered into a collection vessel. The dark solution was filtered through a long plug of 30/40 Magnesol and the pale yellow filtrate was concentrated to dryness in vacuo to afford a yellow-tinged solid (20.6 g, 44.1% yield). The plug was washed with ethyl acetate/ethanol and the washings were concentrated in vacuo to afford additional material, 10.7 g (23%). Extraction of the aqueous work-up filtrate with ethyl acetate followed by drying, Magnesol filtration and concentration gave another 6.3 g (14%) of clean product, bringing the total recovery to 37.6g (81%). 1H-NMR (CD3OD): delta 7.72 (s, IH), 7.52 (dd, IH, J =2.5, 1.6 Hz), 6.85 (dd, IH, J = 4.5, 1.6 Hz), 6.64 (dd, IH, / = 4.5, 2.7 Hz) LC/MS (+esi): m/z=135.1 [M+H].

Reference： [1]Patent: WO2007/56170,2007,A2 .Location in patent: Page/Page column 73-74
[2]Patent: WO2007/64931,2007,A2 .Location in patent: Page/Page column 163

5
[ 159326-68-8 ]
[ 937047-47-7 ]

Yield	Reaction Conditions	Operation in experiment
36%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; In dichloromethane; at -14 - -10℃; for 5h;	A suspension of pyrrolo[2,1-f][1 ,2,4]triazin-4-amine (0.5 g, 0.004 mol) in dichloromethane (100 mL) was stirred and cooled between -1O0C and -14C under nitrogen atmosphere. A solution of 1 ,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (544 mg, 0.002 mol) in dichloromethane (100 mL) added dropwise over a 1 h. After 4 h, 100 mL of 10% aqueous sodium thiosulfate solution was added, and the mixture was stirred vigorously for a few minutes. The phases were separated, the dichloromethane phase washed with water, then brine, dried (anhydrous sodium sulfate), filtered and concentrated in vacuo. The residue was purified by MPLC (dichloromethane/ethyl acetate gradient). Purified material was triturated with dichloromethane, filtered, washed and dried under vacuum to afford 289 mg (36%) of colorless, fluffy solid. 1H-NMR (DMSO-d6): delta 8.01 (br s, 1 H), 7.82 (s, 1 H), 7.70 (d, 1 H), 6.78 (d, br s, 2 H). MS: LC/MS (+esi), m/z = 212.5, 213.1 [M+H]. RT = 1.34 min. CaIc. for C6H5BrN4: C, 33.83; H, 2.37; Br, 37.50; N, 26.3. Found: C, 33.85; H, 2.24; Br, 38.24; N, 26.21.
4 g		A suspension of <strong>[159326-68-8]pyrrolo[2,1-f][1,2,4]triazin-4-amine</strong>(10 g, 75 mmol) in dichloromethane (100 mL) was stirred and cooled to -10 C under nitrogen. A solution of 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (10.8 g, 37.8 mmol) in dichloromethane (2 L) was added dropwise over 1 h. After4 h, 2 L of 10 % aqueous solution of Na2SO3 was added and the mixture was stirred vigorously for a few minutes. The organic phase was washed with water, then brine, dried, filtered and concentrated in vacuo to give a mixture of the 5,7-dibromocompound and the 5-bromo compound (13 g, 2:1). A suspensionof this mixture (10 g in 200 mL THF) was titrated with n-butyl lithium dropwise at -60 C and the progress was monitored by TLC and LC/MS to determine the end point.The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic phase was washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethylacetate = 3:1) to give the 5-bromo compound as a white solid (4 g).

Reference： [1]Patent: WO2007/56170,2007,A2 .Location in patent: Page/Page column 105
[2]Asian Journal of Chemistry,2014,vol. 26,p. 7083 - 7084

6
[ 159326-68-8 ]
[ 937046-98-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; In N,N-dimethyl-formamide; at -20℃; for 1.5h;	A stirred solution containing Intermediate A (21.0 g, 0.157 mol) in anhydrous DMF (200 ml_) was cooled to -20 0C and 1 ,3-dibromo-5,5-dimethylhydantoin (22.4 g, 0.078 mol) was added portionwise over -45 minutes. The reaction was stirred for another 45 minutes and monitored for completion by TLC (silica gel, GHLF, 5%CH3OH/CH2Cl2). Saturated25 Na2SO3 solution (300 mL) was added, the resulting suspension was stirred and the solids were collected by suction filtration. The filter cake was washed with water, dried by suction and then partitioned between ethyl acetate (1 L) and 5% sodium carbonate solution (1L). The layers were separated, the organic layer was washed with fresh sodium carbonate solution and dried over magnesium sulfate. The filtrate from the work-30 up was also extracted and combined with the main batch then filtered through a pad of <n="77"/>Magnesol and concentrated in vacuo to afford crude mono-bromide, KRAM 206-3-1 , 29.9 g, 90% yield. Trituration of a 21.5 g quantity of the crude product in hot ethyl acetate (300 mL, 70 C) provided colorless solids (12.3 g) containing only ~2 % of the di-brominated side-product. 1H-NMR (CD3OD) : delta 7.84 (s, 1 H), 6.95 (d, 1 H, J= 4.7 Hz), 6.71 (d, 1H, J = 4.7 Hz), 4.89 (s, 3H, -NH2 + H2O); MS: LC/MS (+esi), m/z = 213.1 [M+H].
90%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; In N,N-dimethyl-formamide; at -20℃; for 1.5h;	A stirred solution containing pyrrolo[2,l-f][l,2,4]triazin-4-ylamine (21.0 g, 0.157 mol) in anhydrous DMF (200 mL) was cooled to -20 0C and l,3-dibromo-5,5-dimethylhydantoin (22.4 g, 0.078 mol) was added portionwise over -45 minutes. The reaction was stirred for another 45 minutes and monitored for completion by TLC (silica gel, GHLF, 5%CH3OH/CH2C12). Saturated Na2SO3 solution (300 mL) was added, the resulting suspension was stiired and the solids were collected by suction filtration. The filter cake was washed with water, dried by suction and then partitioned between ethyl acetate (IL) and 5% sodium carbonate solution (IL). The layers were separated, the organic layer was washed with fresh sodium carbonate solution and dried over magnesium sulfate. The filtrate from the work-up was also extracted and combined with the main batch then filtered through a pad of Magnesol and concentrated in vacuo to afford crude mono-bromide, KRAM 206-3-1, 29.9 g, 90% yield. Trituration of a 21.5 g quantity of the crude mono-/di-bromo product in hot ethyl acetate (300 mL, 70 0C) provided colorless solids (12.3 g) containing only ~2 % of the di-brominated side-product. 1H-NMR (CD3OD): delta 7.84 (s, IH), 6.95 (d, IH, J = 4.7 Hz), 6.71 (d, IH, / = 4.7 Hz), 4.89 (s, 3H, -NH2 + H2O); MS: LC/MS (+esi), m/z = 213.1 [M+H].
77%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; In N,N-dimethyl-formamide; at -20℃; for 1.5h;	A stirred solution containing <strong>[159326-68-8]pyrrolo[2,1-f][1,2,4]-triazin-4-amine</strong> (10 g, 75 mmol) in anhydrous N,N-dimethylformamide(100 mL) was cooled to -20 C and 1,3-dibromo-5,5-dimethylhydantoin (10.7 g, 37.4 mmol) was added portionwise over 45 min. The reaction was stirred for another45 min and monitored by TLC. After completion, the reaction mixture was washed with saturated aqueous solution of sodium sulfite (150 mL) and water. It was then partitioned between ethyl acetate (0.5 L) and 5 % aqueous solution of sodium carbonate (500 mL). The organic layer was washed with aqueous solution of sodium carbonate, dried and concentrated to afford 13.3 g crude product. It was purified by silica gel column chromatography (CH2Cl2:MeOH = 100:1) to give the7-bromo compound as a white crystal (12.3 g, 77 %).

75%

With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; In N,N-dimethyl-formamide; at -20℃; for 1h;

To a solution of pyrrolo[2, 1- f][l,2,4]triazin-4-amine (2.1 g, 15.66 mmol, 1.00 equiv) in DIVIF (20 mL) was added 1,3- dibromo-5,5-dimethylimidazolidine-2,4-dione (2.24 g, 7.83 mmol, 0.53 equiv) at -20 C in batches. The resulting solution was stirred for 1 h at -20 C, then quenched by the addition of 30 mL of sat. sodium sulfite (aq). After filtration, the filter was dissolved in 200 ml of ethyl acetate, washed with 100 mL of sat. sodium carbonate (aq.), dried over sodium sulfate and concentrated under reduced pressure. This resulted in 2.50 g (75%) of the title compound as a white solid. MS mlz [M+H]b (ESI): 213, 215.

Reference： [1]Patent: WO2007/56170,2007,A2 .Location in patent: Page/Page column 74-75
[2]Patent: WO2007/64931,2007,A2 .Location in patent: Page/Page column 164
[3]Asian Journal of Chemistry,2014,vol. 26,p. 7083 - 7084
[4]Patent: WO2019/53696,2019,A1 .Location in patent: Page/Page column 92
[5]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 133 - 137

7
[ 110-91-8 ]
[ 50-00-0 ]
[ 159326-68-8 ]
[ 939967-89-2 ]

Yield	Reaction Conditions	Operation in experiment
75%	In acetic acid; at 60℃;Mannich condition;Product distribution / selectivity;	amineA solution of formaldehyde (7.9ml, 10.9g, 134mmol) and morpholine (8.0ml, 11.7g, 134mmol) in AcOH (90 mL) was allowed to stir for 20 minutes (slightly exothermic). A solution of the intermediate A (15.0Og, 112mmol) in AcOH (500 mL) was then added and the resulting mixture was heated to 60 0C over night (Note-solution gets darker in color over time). The reaction was concentrated in vacuo and the residue was dissolved in EtOAc(-300 mL) and washed with IN NaOH (pH is -10) (-300 mL). The aqueous phase was back-extracted with EtOAc (3 x 10OmL). Because the product is somewhat water soluble and the aqueous extracts still indicated heavy UV, the aqueous layer was diluted with brine (1:1) and extracted 3 x 100 mL EtOAc (note- pH of aqueous phase was checked after each extraction and re-adjusted with IN NaOH to remain in the 9-10 range). The combined organic layer was washed with brine (-200 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford a yellow solid. The crude material was recrystallized from 10% THF in EtOAc to afford 19.5g (75% yield) of a light yellow free flowing solid. Product Rf = 0.20 in 9:1 DCM:EtOH 1H-NMR (DMSO-^6) 6 7.82 (s, IH), 7.73 to 7.56 (br s, 2H), 6.84 (d, J = 4.5 Hz, IH), 6.54 (d, J = 4.4 Hz, IH), 3.76 (s, 2H), 3.52 (t, J = 4.5 Hz, 4H), 2.38 (t, J = 4.4 Hz, 4H); MS: LC/MS (+ esi) RT = 1.01 min m/z= 234 [M+H]

Reference： [1]Patent: WO2007/64931,2007,A2 .Location in patent: Page/Page column 165

8
[ 937046-98-5 ]
[ 68-12-2 ]
[ 939967-94-9 ]
[ 159326-68-8 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of Intermediate B (50mg, 0.23mmol) in THF (2ml) at -78 0C under N2 was added n-butyllithium (0.38 ml, 0.93 mmol) slowly. After stirred for 15 min, DMF (0.10 ml, 1.4 mmol) was added and the dry-ice bath was removed and the reaction was allowed to warm up to rt. The reaction mixture was diluted with ethyl acetate and was quenched with H2O. The organic was collected, dried over Na2SO4 and concentrated to yield 34 mg of a mixture of the title compound and a byproduct pyitauolo[2,l-f][l,2,4]triazin-4-amine. The mixture was not separable via column chromatography and was subject to next step reaction without further purification. 1H-NMR (DMSO-4) delta 10.3 (-CHO) . MS [M+H]+ = 163.2;LCMS RT = LlImIn.

Reference： [1]Patent: WO2007/64931,2007,A2 .Location in patent: Page/Page column 168

9
[ 75-36-5 ]
[ 159326-68-8 ]
[ 939968-16-8 ]

Yield	Reaction Conditions	Operation in experiment
34%	With aluminum (III) chloride; nitrobenzene; at 20 - 60℃; for 5h;	To a suspension of pyrrolo[2,l-f][l,2,4]triazin~4-amine (1.00 g, 7.46 mmol) in nitrobenzene (40 niL) was added AlCl3 (2.98 g, 22.36 mmol), followed by acetyl chloride (2.34 g, 29.82 mmol). The resulting solution was heated (60 0C) for 5 h and cooled to rt. The reaction mixture was poured onto ice-water and solid sodium bicarbonate was added with stirring until the solution was basic. This mixture was extracted with ethyl acetate (3 x 100 mL) and then the combined organic layers were concentrated under reduced pressure. The residue was stirred with MeOH (100 mL) and potassium carbonate (5 g) overnight. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC using a gradient of 5 - 30% MeCN in water to afforded 448.0 mg (34%) of the title compound. 1H-NMR (DMSO-^6) delta 9.63 (bs, 1 H), 8.47 (bs, 1 H), 8.03 (s, 1 H), 7.76 (d, J = 3.2 Hz, 1 H), 7.40 (d, J = 2.9 Hz, 1 H), 2.57 (s, 3 H); MS [M+H]+ = 177.1; LCMS RT = 1.37 min.

Reference： [1]Patent: WO2007/64931,2007,A2 .Location in patent: Page/Page column 189-190

10
[ 5625-67-2 ]
[ 50-00-0 ]
[ 159326-68-8 ]
[ 939967-92-7 ]

Yield	Reaction Conditions	Operation in experiment
52%	In acetic acid; at 60℃; for 2.16667h;Mannich condition;	A solution of paraformaldehyde (726 mg, 8.95 mmol) and 2-oxopiperazine (1.49 g, 14.9 mmol) in acetic acid (35 ml) was stirred under nitrogen for 10 minutes and then Intermediate A (1.00 g, 7.46 mmol) was added. The resultant mixture was heated at 60 0C for 2 hr and then evaporated in vacuo to give dark oily residue. This raw product was diluted with about 200 ml of EtOAc and then filtered twice to remove a very dark solid which was rinsed with additional EtOAc and give an orange filtrate which was mixed with saturated aqueous NaHCO3 to precipitate a cream colored solid precipitate. This material was collected by filtration, washed with water and EtOAc and then dried in vacuo to give pure 4-[(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)methyl]piperazin-2-one (948 mg, 52 %). 1H-NMR (DMSO-dbeta) delta 7.82 (s, IH), 7.6 - 7.7 (bs, 3H), 6.86 (d, IH, J = 4.8), 6.56 (d, IH, J= 4.8), 3.85 (s, 2H), 3.09 (m, 2H), 2.91 (s, 2H), and 2.55 (m, 2H); MS LC-MS [MH-H]+ = 247.3 and [M+Naf = 275.9, RT = 1.03 min.

Reference： [1]Patent: WO2007/64931,2007,A2 .Location in patent: Page/Page column 167

11
[ 50-00-0 ]
homomorpholine hydrochloride [ No CAS ]
[ 159326-68-8 ]
[ 939968-20-4 ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium acetate; In water; acetic acid; at 60℃;Mannich condition;	Pyrrolo[2,l-f][l,2,4]triazin-4-amine (4000mg, 29.8mmol) was dissolved in acetic acid(16OmL). 37% wt formaldehyde in water is added (2.9OmL, 35.8mmol) followed by 1,4- oxazepane hydrochloride (4.92g, 35.8mmol) and potassium acetate (5.27g, 53.7 mmol). The reaction was heated at 6O0C under a nitrogen atmosphere overnight then cooled to room temperature. The reaction was concentrated under vacuum. The residue was partitioned between EtOAc (30OmL) and saturated aqueous bicarbonate (15OmL). The aqueous layer is extracted with EtOAc (5X 10OmL). The combined organics were washed with brine (10OmL) then dried with Na2SO4 to yield 6.78g (92%) of desired product. 1H-NMR (DMSO-J6) 6 7.80 (s, IH), 7.63 (bs, 2H), 6.84 (d, J = 4.5 Hz, IH), 6.54 (d, J = 4.5, IH), 3.64 (t, J = 6 Hz, 2H), 3.55 (m, 2H), 2.63 (m, 4H), 1.76 (m, 2H); MS [M+H]+ =248.1 ; LCMS RT = 1.02.

Reference： [1]Patent: WO2007/64931,2007,A2 .Location in patent: Page/Page column 192

12
[ 40499-83-0 ]
[ 50-00-0 ]
[ 159326-68-8 ]
[ 1417736-69-6 ]

Yield	Reaction Conditions	Operation in experiment
11%		Intermediate 46 A 1 - [(4-Aminopyrrolo [2, 1 -fj [ 1 ,2,4]triazin-7-yl)methyl]pyrroiidin-3-ol 3-Pyrrolidinol (1.56 g, 1 7.9 mmol) and 37% formalin solution (1.45 g, 1 7.9 mmol) were dissolved in acetic acid ( 75 mL) and stirred at room temperature for 10 min. To this solution was added a solution of pyrrolo[2, 1 -fj [ 1 ,2,4]triazin-4-amine (2.0 g, 14.9 mmol) in acetic acid (75 mL), and the mixture was stirred at 60C for 4 h. After evaporation, the residue was taken up in 200 mL of 1 N aqueous potassium carbonate solution and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative 1 1 PLC (method 4) to give 390 mg (1 1% of th.) of the title compound. LC-MS (method 4): Rt = 0.22 min; MS (ESIpos): m/z (%) = 234.2 (20) [M+H]+, MS (ESIneg): m/z (%) = 223.0 (100) [M-H]~ .H NMR (400 MHz, <¾-DMSO): delta (ppm) = 1.50 (br. m, H I ). 1.94 (m, 11 1 ). 2.34 (dd, 1H), 2.44 (dd, 1H), 2.60 (dd, 1H), 2.71 (dd, 1H), 3.84 (dd, 2H), 4.15 (br, 1H), 4.65 (d, 1H), 6.52 (d, 1H), 6.83 (d, i l l ). 7.61 (br, 21 . ). 7.82 (s, 1 1 1 ).

Reference： [1]Patent: WO2013/4551,2013,A1 .Location in patent: Page/Page column 61-62

13
[ 159326-68-8 ]
[ 1417736-70-9 ]

Reference： [1]Patent: WO2013/4551,2013,A1

14
[ 159326-68-8 ]
[ 1417736-94-7 ]

Reference： [1]Patent: WO2013/4551,2013,A1

15
[ 159326-68-8 ]
[ 1417736-98-1 ]

Reference： [1]Patent: WO2013/4551,2013,A1

16
[ 159326-68-8 ]
[ 1417736-37-8 ]

Reference： [1]Patent: WO2013/4551,2013,A1

17
[ 159326-68-8 ]
[ 1417736-38-9 ]

Reference： [1]Patent: WO2013/4551,2013,A1

18
[ 159326-68-8 ]
[ 1417736-42-5 ]

Reference： [1]Patent: WO2013/4551,2013,A1

19
[ 159326-68-8 ]
[ 1417736-39-0 ]
[ 1417736-40-3 ]

Reference： [1]Patent: WO2013/4551,2013,A1

20
[ 159326-68-8 ]
[ 1369350-92-4 ]

Reference： [1]Patent: WO2013/4551,2013,A1
[2]Patent: WO2013/124316,2013,A1
[3]Patent: US2017/275290,2017,A1
[4]ChemMedChem,2018,vol. 13,p. 437 - 445

21
[ 159326-68-8 ]
[ 1417736-47-0 ]

Reference： [1]Patent: WO2013/4551,2013,A1

22
[ 159326-68-8 ]
[ 1417736-48-1 ]

Reference： [1]Patent: WO2013/4551,2013,A1

23
[ 68-12-2 ]
[ 159326-68-8 ]
[ 939967-94-9 ]

Yield	Reaction Conditions	Operation in experiment
83%		Inter. mediate ISA 4-Aminopyrrolo[2, l-fj[l ,2,4]triazine-7-carbaldehyde The starting material pyrrolo [2, 1 -fj [ 1 ,2,4]triazin-4-amine was synthesized according to the procedure described in WO 2007/056170-A2 (Intermediate A). Pyrrolo[2,l-f][l ,2,4]triazin-4-amine (20.5 g, 152 mmol) was dissolved in 150 l DMF. Under ice cooling, phosphoryl chloride (31.3 ml.. 336 mmol) was added dropwise at such a rate that the internal temperature did not rise above 30C. The mixture was then heated for 2 days at 50C. After cooling, another portion of phosphoryl chloride (14.2 ml .. 152 mmol) was added, and stirring was continued for another 24 h at 50C. After cooling, the reaction batch was slowly poured into a mixture of 2.0 1. saturated aqueous sodium bicarbonate solution and 2.0 L ethyl acetate. Solid sodium bicarbonate was added until gas evolution stopped. The layers were separated, the aqueous layer was extracted with 0.5 I. ethyl acetate, and the combined organic phases were dried over sodium sulfate and concentrated. The residue was suspended in 100 ml diisopropyl ether, stirred at room temperature for 10 min and then filtered. The dried residue was stirred in 6 N hydrochloric acid (500 mL) for 1 h at 50C and then poured into an ice/water mixture (1000 mL). The mixture was carefully neutralized with solid sodium bicarbonate, stirred for 30 min at room temperature and then filtered again. The residue was washed with water and ligroin to yield 20.6 g (83% of th.) of white crystals which were used in the next step without further purification.
73%	With trichlorophosphate; at 0 - 60℃; for 25h;	Phosphoryl chloride (104 ml) was added dropwise at 0C to a solution of pyrrolo [2,1 -f][ 1,2,4] - triazin-4-amine (30 g, 24.5 mmol; preparation described in Int. Pat. Appl. WO 2007/064931, Intermediate A) in DMF (500 ml). The resulting mixture was stirred at 60C for 25 h, then poured onto an ice-water mixture and stirred at rt for further 16 h. The mixture was adjusted to pH 8-10 by addition of 3.5 M aq. sodium hydroxide solution. The precipitated solid was filtered off and washed with water affording 28.8 g (73% of th.) of the title compound. LC-MS (method 2): Rt = 0.32 min; MS (ESIpos): m/z = 163 (M+H)+ -NMR (400 MHz, DMSO-d6): delta = 10.26 (s, 1H), 8.26 (br. s, 1H), 8.21 (br. s, 1H), 8.09 (s, 1H), 7.27 (d, 1H), 7.02 (d, 1H) ppm
16%	With trichlorophosphate; at 0 - 60℃;	Step 1: 4-Aminopyrrolo[1,2-f][1,2,4]triazine-7-carbaldehyde To a solution of <strong>[159326-68-8]pyrrolo[2,1-f][1,2,4]triazin-4-amine</strong> (1.0 g, 7.45 mmol) in DMF (15 mL) at 0 C. was added POCl3 (3.47 mL, 37.3 mmol). The reaction mixture was then stirred at 60 C. overnight, cooled to rt, quenched with saturated NaHCO3 solution, and extracted with EtOAc (30 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified via column chromatography (0% to 15% MeOH in CH2Cl2) to give the product (200 mg, 16%). LCMS calcd for C7H7N4O (M+H)+: m/z=163.1. Found: 163.1.

Reference： [1]Patent: WO2013/4551,2013,A1 .Location in patent: Page/Page column 41-42
[2]Patent: WO2013/124316,2013,A1 .Location in patent: Page/Page column 52
[3]ChemMedChem,2018,vol. 13,p. 437 - 445
[4]Patent: US2017/275290,2017,A1 .Location in patent: Paragraph 1153; 1154

24
[ 5382-16-1 ]
[ 50-00-0 ]
[ 159326-68-8 ]
[ 1417736-67-4 ]

Yield	Reaction Conditions	Operation in experiment
15%		Intermediate 44 A 1 - [(4-Aminopyrrolo [2, 1 -fj [ 1 ,2,4]triazin-7-yl)methyi]piperidin-4-ol 4-Hydroxypiperidine (3.62 g, 35.8 mmol) and 37% formalin solution (2.9 g, 35.8 mmol) were dis- solved in acetic acid (150 mL) and stirred at room temperature for 1 h. To this solution was added a solution of pyrrolo [2, 1 -fj [ 1 ,2,4]triazin-4-amine (2.0 g, 14.9 mmol; prepared according to the procedure described in WO 2007/056170-A2, Intermediate A) in acetic acid (150 mL), and the mixture was stirred at 60C for 2 h. The solvent was then evaporated, and the residue was taken up in 200 mL of half-concentrated aqueous potassium bicarbonate solution and extracted with 200 mL dichloromethane. The organic layer was washed with water (2 x 50 mL) and discarded. The combined aqueous layers were evaporated to dryness, and the residue was treated with a 10: 1 mixture of dichloromethane and methanol (2 x 100 mL). The organic extracts were evaporated, and the residue was purified by preparative 1 1 PLC (method 4) to give 1.16 g (15% of th.) of the title compound. LC -MS (method 7): t = 0.18 min; MS (ESIpos): m/z (%) = 248.3 (30) [M+H]+, MS (ESIneg): m/z (%) = 246.5 (100) [M-H]~.H NMR (400 MHz, ds-OMSO): delta (ppm) = 1.35 (br. m, 2H), 1.67 (br. m, 2H), 2.07 (t, 2H), 2.70 (br. m, 2H), 3.38 (br. m, 1H), 3.75 (s, 21 1 ). 4.5 . (br, 1H), 6.52 (d, 1H), 6.84 (d, 1 1 1 ). 7.62 (br, 2H), 7.82 (s, 1H).

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25
[ 5382-16-1 ]
[ 159326-68-8 ]
[ 1417736-68-5 ]

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26
[ 159326-68-8 ]
C₂₁H₂₄N₆OS*3ClH [ No CAS ]

Reference： [1]Patent: WO2013/124316,2013,A1

27
[ 159326-68-8 ]
[ 1451251-90-3 ]

Reference： [1]Patent: WO2013/124316,2013,A1

28
[ 159326-68-8 ]
[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl][(3S)-3-amino-3-methylpyrrolidin-1-yl]methanone dihydrochloride [ No CAS ]

Reference： [1]Patent: WO2013/124316,2013,A1
[2]ChemMedChem,2018,vol. 13,p. 437 - 445

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[ 159326-68-8 ]
[ 1451252-32-6 ]

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30
[ 159326-68-8 ]
rac-4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-N-(2-oxopyrrolidin-3-yl)pyrrolo-[2,1-f][1,2,4]triazine-7-carboxamide hydrochloride [ No CAS ]

Reference： [1]Patent: WO2013/124316,2013,A1
[2]ChemMedChem,2018,vol. 13,p. 437 - 445

31
[ 159326-68-8 ]
C₂₃H₂₆N₆O₂S*2ClH [ No CAS ]

Reference： [1]Patent: WO2013/124316,2013,A1

32
[ 159326-68-8 ]
C₂₂H₂₄N₆O₂S*2ClH [ No CAS ]

Reference： [1]Patent: WO2013/124316,2013,A1

33
[ 159326-68-8 ]
N-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-methyl}glycinamide dihydrochloride [ No CAS ]

Reference： [1]Patent: WO2013/124316,2013,A1

34
[ 159326-68-8 ]
[ 1451252-41-7 ]

Reference： [1]Patent: WO2013/124316,2013,A1

35
[ 159326-68-8 ]
7-{ [2-(dimethylamino)ethoxy]methyl}-5-(7-methoxy-5-methyl-1-benzothiphen-2-yl)pyrrolo-[2,1-f][1,2,4]triazin-4-amine dihydrochloride [ No CAS ]

Reference： [1]Patent: WO2013/124316,2013,A1

36
[ 159326-68-8 ]
[ 1451252-43-9 ]

Reference： [1]Patent: WO2013/124316,2013,A1

37
[ 159326-68-8 ]
[ 1451252-55-3 ]

Reference： [1]Patent: WO2013/124316,2013,A1

38
[ 159326-68-8 ]
[ 1451252-58-6 ]

Reference： [1]Patent: WO2013/124316,2013,A1
[2]ChemMedChem,2018,vol. 13,p. 437 - 445

39
[ 159326-68-8 ]
[ 1451252-59-7 ]

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[2]ChemMedChem,2018,vol. 13,p. 437 - 445

40
[ 159326-68-8 ]
[ 1451252-60-0 ]

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[2]ChemMedChem,2018,vol. 13,p. 437 - 445

41
[ 159326-68-8 ]
[ 1451252-61-1 ]

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42
[ 159326-68-8 ]
[ 1451252-62-2 ]

Reference： [1]Patent: WO2013/124316,2013,A1

43
[ 159326-68-8 ]
[ 1451252-63-3 ]

Reference： [1]Patent: WO2013/124316,2013,A1
[2]ChemMedChem,2018,vol. 13,p. 437 - 445

44
[ 159326-68-8 ]
[ 1451252-66-6 ]

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[2]ChemMedChem,2018,vol. 13,p. 437 - 445

45
[ 159326-68-8 ]
[ 1451252-67-7 ]

Reference： [1]Patent: WO2013/124316,2013,A1
[2]ChemMedChem,2018,vol. 13,p. 437 - 445

46
[ 159326-68-8 ]
tert-butyl [(3S)-1-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]-triazin-7-yl]carbonyl}-3-methylpyrrolidin-3-yl]carbamate [ No CAS ]

Reference： [1]Patent: WO2013/124316,2013,A1

47
[ 159326-68-8 ]
7-[(3S)-3-amino-3-methylpyrrolidin-1-yl]methyl}-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-amine trihydrochloride [ No CAS ]

Reference： [1]Patent: WO2013/124316,2013,A1
[2]ChemMedChem,2018,vol. 13,p. 437 - 445

48
[ 159326-68-8 ]
7-[(3S)-3-amino-3-methylpyrrolidin-1-yl]methyl}-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-amine trihydrochloride [ No CAS ]

Reference： [1]Patent: WO2013/124316,2013,A1
[2]ChemMedChem,2018,vol. 13,p. 437 - 445

49
[ 159326-68-8 ]
7-[(3S)-3-amino-3-methylpyrrolidin-1-yl]methyl}-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-amine trihydrochloride [ No CAS ]

Reference： [1]Patent: WO2013/124316,2013,A1

50
[ 159326-68-8 ]
4-[4-amino-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-methyl}piperazin-2-one dihydrochloride [ No CAS ]

Reference： [1]Patent: WO2013/124316,2013,A1
[2]ChemMedChem,2018,vol. 13,p. 437 - 445

51
[ 159326-68-8 ]
[ 1451251-37-8 ]

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52
[ 159326-68-8 ]
[ 1451251-38-9 ]

Reference： [1]Patent: WO2013/124316,2013,A1
[2]ChemMedChem,2018,vol. 13,p. 437 - 445

53
[ 159326-68-8 ]
[ 1451251-39-0 ]

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54
[ 159326-68-8 ]
[ 1451251-45-8 ]

Reference： [1]Patent: WO2013/124316,2013,A1

55
[ 159326-68-8 ]
7-chloropyrrolo[2,1-f][1,2,4]triazin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23%	With N-chloro-succinimide; In N,N-dimethyl-formamide; at 20℃; for 72h;Inert atmosphere;	Step A: 7-Chloropyrrolo[l,2-f\| [l, amine To a brown solution of pyrrolo[2,l-fj[l,2,4]triazin-4-amine (1.35 g, 10.1 mmol) in DMF (20 mL) was added N-chlorosuccinimide (1.34 g, 10.1 mmol) at ambient temperature under an inert atmosphere of nitrogen gas . The brown reaction mixture was stirred for 72 h. LC/MS showed approximately 80% conversion to the desired product. The reaction mixture was partitioned between brine and EtOAc (50 mL / 200 mL) and separated. The organic phase was washed with brine (50 mL), dried over MgSC , and the volatiles were removed under reduced pressure. The resulting residue was dissolved in a minimum amount of DMF, and purified by silica gel chromatography with EtOAc in Hexanes (0-50%) to afford two major peaks. The volatiles were removed under reduced pressure before the white solid was dissolved in MeOH (10 mL) and TFA (1 mL) and purified on reverse phase chromatography eluting with a water/TFA/methanol mixture. The collected fractions were neutralized by passing them through a UCT CHQAX15M25 cartridge to afford 7- chloropyrrolo[2,l-f][l,2,4]triazin-4-amine (388 mg, 2.30 mmol, 23 % yield) as an off-white powder. NMR (400MHz, DMSO-d6) delta 8.87 - 8.25 (m, 2H), 8.07 (s, 1H), 7.20 (d, ,7=4.8 Hz, 1H), 6.83 (d, .7=4.8 Hz, 1H). MS (LC/MS) R.T. = 1.24; [M+H]+ = 169.1.

Reference： [1]Patent: WO2013/177024,2013,A1 .Location in patent: Page/Page column 96; 97

56
[ 159326-68-8 ]
[ 1610426-26-0 ]

Reference： [1]Patent: WO2014/78778,2014,A2

57
[ 159326-68-8 ]
(2S,3S,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol dihydrochloride [ No CAS ]

Reference： [1]Patent: WO2014/78778,2014,A2

58
[ 159326-68-8 ]
[ 1610426-28-2 ]

Reference： [1]Patent: WO2014/78778,2014,A2

59
[ 159326-68-8 ]
[ 1610426-29-3 ]

Reference： [1]Patent: WO2014/78778,2014,A2

60
[ 3282-30-2 ]
[ 159326-68-8 ]
[ 1610426-55-5 ]

Yield	Reaction Conditions	Operation in experiment
59.6%	With pyridine; at 20℃; for 2.5h;	Step 1 : Preparation of N-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)pivalamide (30b) To a solution of pyrrolo[2,l-f][l,2,4]triazin-4-amine (30a) (23.9 gm, 178.2 mmol) in pyridine (120 mL, 5 mL/gm) at room temperature was added pivaloyl chloride (32.88 mL, 267.3 mmol) and stirred at room temperature until reaction was complete (2.5 h). The reaction mixture was concentrated in vacuum to remove pyridine and residue was purified by flash column chromatography (silica gel, eluting 0-100% ethylacetate in hexane) to furnish N- (pyrrolo[2,l-fJ[l,2,4]triazin-4-yl)pivalamide (30b) (23.2 gm, 59.6%) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) delta 10.28 (s, 1H), 8.29 (s, 1H), 8.01 (dd, J = 2.6, 1.5 Hz, 1H), 6.96 (dd, J = 4.6, 1.5 Hz, 1H), 6.90 (dd, J = 4.7, 2.6 Hz, 1H), 1.29 (s, 9H); MS (ES+) 241.2 (M+Na), (ES-) 217.3 (M-l).

Reference： [1]Patent: WO2014/78778,2014,A2 .Location in patent: Page/Page column 124

61
[ 159326-68-8 ]
C₁₂H₁₃N₅O₄ [ No CAS ]