[ CAS No. 74901-69-2 ] {[proInfo.proName]}

Name: 74901-69-2|2,4-Dichloro-6,7-dihydrothieno[3,2-d]pyrimidine|98%
Brand: Ambeed
SKU: A463204
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Quality Control of [ 74901-69-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 74901-69-2 ]

CAS No. :	74901-69-2	MDL No. :	MFCD11109461
Formula :	C₆H₄Cl₂N₂S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CUVQFHMQHBMFCI-UHFFFAOYSA-N
M.W :	207.08	Pubchem ID :	45789967
Synonyms :

Calculated chemistry of [ 74901-69-2 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.33
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	46.62
TPSA :	51.08 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.64 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.18
Log Po/w (XLOGP3) :	2.71
Log Po/w (WLOGP) :	2.43
Log Po/w (MLOGP) :	1.76
Log Po/w (SILICOS-IT) :	3.37
Consensus Log Po/w :	2.49

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.23
Solubility :	0.121 mg/ml ; 0.000582 mol/l
Class :	Soluble
Log S (Ali) :	-3.44
Solubility :	0.0759 mg/ml ; 0.000366 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.55
Solubility :	0.0581 mg/ml ; 0.000281 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.58

Safety of [ 74901-69-2 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 74901-69-2 ]

* 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 [ 74901-69-2 ]
Downstream synthetic route of [ 74901-69-2 ]

[ 74901-69-2 ] Synthesis Path-Upstream 1~9

1
[ 74901-69-2 ]
[ 1008-91-9 ]

Reference： [1] Patent: US2012/28932, 2012, A1,
[2] Patent: US2012/28932, 2012, A1,

2
[ 74901-69-2 ]
[ 26905-02-2 ]

Reference： [1] Patent: US2012/35143, 2012, A1,

3
[ 913581-92-7 ]
[ 74901-69-2 ]

Yield	Reaction Conditions	Operation in experiment
85%	at 80℃; for 22 h;	2.4-dichlorothieno[3,2-d]pyrimidine (VII)-2.4 g (14.1 mmol) of 6,7-dihydrothieno[3,2-d]pyrimidine-2,4-diol (VI) is suspended in 14 mL of phosphorus oxychloride, combined with 4.5 mL (28.2 mmol) of diethylaniline and stirred for 22 hours at 80° C. After cooling to ambient temperature, the reaction mixture is added to ice water, the precipitate formed is suction filtered and washed with water. The precipitate is dissolved in dichloromethane, any water present is separated off using a phase separator. The organic phase is evaporated to dryness. 2.5 g of the product VII (85percent) is obtained.
586 mg	With trichlorophosphate In water at 140℃; for 0.5 h; Microwave irradiation	6.01.42.01 2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidine 500 mg 6,7-Dihydro-thieno[3,2-d]pyrimidine-2,4-diol and 10 mL phosphoroxychloride was stirred 30 min at 140° C. under microwave conditions. The reaction was added to water and then dichlormethane was added. The mixture was stirred for 20 min. The layers were separated and the dichlormethane layer was evaporated to give 586 mg of the desired product. R_t: 1.23 min (method P)
586 mg	at 140℃; for 0.5 h; Microwave irradiation	6.01.42.01 2, 4-dichloro-6, 7-dihydro-thieno [3, 2-d] pyrimidine 500 mg 6, 7-Dihydro-thieno [3, 2-d] pyrimidine-2, 4-diol and 10 mL phosphoroxychloride was stirred 30 min at 140°C under microwave conditions. The reaction was added to water and then dichlormethane was added. The mixture was stirred for 20 min. The layers were seperated and the dichlormethane layer was evaporated to give 586 mg of the desired product. R_t: 1.23 min (method P) (M+H)⁺: 208/09

Reference： [1] Organic Process Research and Development, 2016, vol. 20, # 5, p. 982 - 988
[2] Patent: WO2006/111549, 2006, A1, . Location in patent: Page/Page column 61; 59; 65; 68; 69; 72; 74; 76; 84
[3] Patent: US2007/259846, 2007, A1, . Location in patent: Page/Page column 30; 31
[4] Patent: WO2013/26797, 2013, A1, . Location in patent: Page/Page column 24-25
[5] Patent: US2013/150341, 2013, A1, . Location in patent: Paragraph 0364; 0365; 0366; 0367
[6] Patent: WO2013/83741, 2013, A1, . Location in patent: Page/Page column 90
[7] Patent: US2014/228286, 2014, A1, . Location in patent: Paragraph 0246-0247
[8] Patent: WO2014/124860, 2014, A1, . Location in patent: Page/Page column 43; 44
[9] Patent: US2015/45376, 2015, A1, . Location in patent: Paragraph 0079-0080

4
[ 913581-92-7 ]
[ 74901-69-2 ]

Yield	Reaction Conditions	Operation in experiment
1 g	at 130 - 140℃; for 6 h;	Step (v)6,7-dihydrothieno[3,2-d]pyrimidine-2,4(lH,3H)-dione (1.8 g, 10.57 mmol) was suspended in 4.0 mL of phenylphosphonyl di chloride. The suspension was heated to 130-140 °C and stirred for 6 h. The resulting reaction mixture was cooled down and poured into 10.0 ml of ice-water.The mixture was extracted with ethyl acetate,the organic layers were combined, washed with saturated NaHC0₃ and brine, dried over anhydrous Na₂S0₄, filtered and evaporated. The crude product was then purified by column chromatography on silica gel (eluent: PE/EA=20: 1-10/1) to provide 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine an off-white solid (1.0 g, 46 percent).LC-MS (Method A), (ES+)207/209, RT = 4.68 min

Reference： [1] Patent: WO2013/50508, 2013, A1, . Location in patent: Page/Page column 44; 63; 64

5
[ 1196101-46-8 ]
[ 74901-69-2 ]

Reference： [1] Patent: WO2013/26797, 2013, A1,
[2] Patent: US2014/228286, 2014, A1,
[3] Patent: WO2014/124860, 2014, A1,
[4] Patent: US2015/45376, 2015, A1,
[5] Organic Process Research and Development, 2016, vol. 20, # 5, p. 982 - 988

6
[ 7400-45-5 ]
[ 74901-69-2 ]

Reference： [1] Patent: WO2013/26797, 2013, A1,
[2] Patent: WO2013/50508, 2013, A1,
[3] Patent: WO2013/50508, 2013, A1,
[4] Patent: US2014/228286, 2014, A1,
[5] Patent: WO2014/124860, 2014, A1,
[6] Patent: US2015/45376, 2015, A1,
[7] Organic Process Research and Development, 2016, vol. 20, # 5, p. 982 - 988
[8] Organic Process Research and Development, 2016, vol. 20, # 5, p. 982 - 988

7
[ 2689-69-2 ]
[ 74901-69-2 ]

Reference： [1] Patent: WO2013/26797, 2013, A1,
[2] Patent: WO2013/50508, 2013, A1,
[3] Patent: US2014/228286, 2014, A1,
[4] Patent: WO2014/124860, 2014, A1,
[5] Patent: US2015/45376, 2015, A1,
[6] Organic Process Research and Development, 2016, vol. 20, # 5, p. 982 - 988

8
[ 4900-98-5 ]
[ 74901-69-2 ]

Reference： [1] Patent: WO2013/50508, 2013, A1,

9
[ 4900-98-5 ]
[ 74901-69-2 ]

Reference： [1] Patent: WO2006/111549, 2006, A1,

[ 74901-69-2 ] Synthesis Path-Downstream 1~88

1
[ 74901-69-2 ]
[ 123207-48-7 ]
[ 954408-76-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 20h;	1.1.1 (2-chloro-6,7-dihydro-thieno[3,2-d]pyrimidin-4-yl)-(3-morpholin-4-ylmethyl-phenyl)-amine Scheme 1, Step A 1.25 g <strong>[74901-69-2]<strong>[74901-69-2]2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidin</strong>e</strong> are placed in 5 ml dimethylformamide, first 1.05 ml diisopropylethylamine, then 0.960 g 3-morpholin-4-ylmethyl-phenylamine (J. Med. Chem. 1990, 33, 327) are added. The reaction mixture is sf 20 hours at 60 C., then after cooling evaporated down. The residue is extracted with dichloromethane and water, the organic phase is dried and evaporated to dryness. The residue is crystallised with petroleum ether/ethyl acetate. 1.28 g of the product are obtained as a powder.

Reference： [1]Patent: US2008/96882,2008,A1 .Location in patent: Page/Page column 18

2
[ 74901-69-2 ]
[ 133170-58-8 ]
(R)-2-(2-chloro-6,7-dihydro-thieno[3,2-d]pyrimidin-4-ylamino)-3-methyl-butyramide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 120℃; for 2h;Microwave irradiation;	1.2.1 (R)-2-(2-chloro-6,7-dihydro-thieno[3,2-d]pyrimidin-4-ylamino)-3-methyl-butyramide Scheme 1, Step A 800 mg <strong>[74901-69-2]<strong>[74901-69-2]2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidin</strong>e</strong> and 800 mg D-valinamide hydrochloride are placed in 8 ml dioxane, then 2.7 ml diisopropylethylamine are added. The reaction mixture is heated to 120 C. in the microwave for 2 hours. The residue is mixed with water. The precipitate formed is suction filtered and dried. 820 mg of the product are obtained as a powder. Analytical HPLC (method B): RT=2.64 min

Reference： [1]Patent: US2008/96882,2008,A1 .Location in patent: Page/Page column 19-20

3
[ 372-19-0 ]
[ 74901-69-2 ]
[ 954408-77-6 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃; for 7h;	2.1.1 (2-chloro-6,7-dihydro-thieno[3,2-d]pyrimidin-4-yl)-(3-fluoro-phenyl)-amine Scheme 2, Step A 4.00 g <strong>[74901-69-2]<strong>[74901-69-2]2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidin</strong>e</strong> are placed in 15 ml dimethylformamide, then first 4.50 ml diisopropylethylamine, then 2.50 ml 3-fluoro-aniline are added. The reaction mixture is stirred for 7 hours at 120 C., and after cooling evaporated down. The residue is extracted with dichloromethane and water, the organic phase is washed with saturated sodium chloride solution, dried and evaporated to dryness. The residue is purified by chromatography (NP_MPLC, Biotage cartridge (4*15 cm)). 2.60 g of the product are obtained as a powder.
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃;	Example 1 1.1 (2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-(3-fluorophenyl)-amine (III-1) 4 g (II) are placed in 15 ml dimethylformamide, then 4.5 ml diisopropylethylamine and then 2.5 ml 3-fluorophenylamine are added. The reaction mixture is heated to 120 C., until no further reaction takes place, then cooled and evaporated down. The residue is mixed with water. The product is extracted with dichloromethane and purified by chromatography (silica gel, petroleum ether/ethyl acetate 80/20 to 60/40). 2.6 g (III-1) are obtained as a solid. Analytical HPLC (method A): RT=3.27 min.
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃;	Example 73 17.1 (2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-(3-fluorophenyl)-amine (III-7) 4 g (II) are placed in 15 ml dimethylformamide, then 4.5 ml diisopropylethylamine and then 2.5 ml 3-fluorophenylamine are added. The reaction mixture is heated to 120 C., until there is no further reaction, and cooled, then evaporated down. The residue is mixed with water. The product is extracted with dichloromethane and purified by chromatography (silica gel, petroleum ether/ethyl acetate 80/20 to 60/40). 2.6 g (III-7) are obtained as a solid. Analytical HPLC (method A): RT=3.27 min

	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃;	1.6.1 (2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-(3-fluorophenyl)-amine (III-5) 4 g (II) are placed in 15 ml dimethylformamide, combined with 4.5 ml diisopropylethylamine and then 2.5 ml 3-fluoroaniline are added. The reaction mixture is heated at 120 C until no further reaction takes place, and after cooling, evaporated down. The residue is mixed with water. The product is extracted with dichloromethane and purified by chromatography (silica gel, petroleum ether/ethyl acetate 80/20 to 60/40). 2.6 g (III-5) are obtained as a solid. Analytical HPLC (method A): RT=3.27 min
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃;	3. SYNTHESIS OF {2-[5-(4-BROMOPHENYL)-2,5-DIAZABICYCLO[2,2,1]HEPT-2-YL]-5-OXO-6,7-DIHYDRO-5H-5lambda4-THIENO[3,2-D]PYRIMIDIN-4-YL}-(3-FLUOROPHENYL)-AMINEExample 213.1 (2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-(3-fluorophenyl)-amine (III-3)4 g (II) are placed in 15 ml dimethylformamide, then 4.5 ml diisopropylethylamine followed by 2.5 ml 3-fluoro-phenylamine are added. The reaction mixture is heated to 120 C. until there is no further reaction and after cooling evaporated down. The residue is mixed with water. The product is extracted with dichloromethane and purified by chromatography (silica gel, petroleum ether/ethyl acetate 80/20 to 60/40). 2.6 g (III-3) are obtained as a solid.Analytical HPLC (method A): RT=3.27 min.
	With N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide; water;	12.1 (2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-(3-fluorophenyl)-amine (III-7) 4 g (II) are placed in 15 ml dimethylformamide, then 4.5 ml diisopropylethylamine are added followed by 2.5 ml 3-fluorophenylamine. The reaction mixture is heated to 120 C. until there is no further reaction then cooled and evaporated down. The residue is mixed with water. The product is extracted with dichloromethane and purified by chromatography (silica gel, petroleum ether/ethyl acetate 80/20 to 60/40). 2.6 g (III-7) are obtained in the form of a solid. Analytical HPLC (method A): RT=3.27 min
2.6 g	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃;	1.1 (2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-(3-fluorophenyl)-amine (III-1) 4 g (II) are placed in 15 ml dimethylformamide, then 4.5 ml diisopropylethylamine and then 2.5 ml 3-fluorophenylamine are added. The reaction mixture is heated to 120 C., until there is no further reaction, and after cooling evaporated down. The residue is mixed with water. The product is extracted with dichloromethane and purified by chromatography (silica gel, petroleum ether/ethyl acetate 80/20 to 60/40). 2.6 g (III-1) are obtained as a solid. Analytical HPLC (method A): RT=3.27 min.
2.6 g	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃;	12.1 (2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-(3-fluorophenyl)-amine (III-7) 4 g (II) are placed in 15 ml dimethylformamide, then 4.5 ml diisopropylethylamine and then 2.5 ml 3-fluorophenylamine are added. The reaction mixture is heated to 120 C. until there is no further reaction, and after cooling evaporated down. The residue is mixed with water. The product is extracted with dichloromethane and purified by chromatography (silica gel, petroleum ether/ethyl acetate 80/20 to 60/40). 2.6 g (III-7) are obtained as a solid. Analytical HPLC (method A): RT=3.27 min

Reference： [1]Patent: US2008/96882,2008,A1 .Location in patent: Page/Page column 21-22
[2]Patent: US2010/305102,2010,A1 .Location in patent: Page/Page column 12
[3]Patent: US2011/21501,2011,A1 .Location in patent: Page/Page column 71
[4]Patent: US2011/28441,2011,A1 .Location in patent: Page/Page column 17
[5]Patent: US2011/46096,2011,A1 .Location in patent: Page/Page column 22
[6]Patent: US2012/35143,2012,A1
[7]Patent: US2013/237527,2013,A1 .Location in patent: Paragraph 0197; 0198
[8]Patent: US2013/225609,2013,A1 .Location in patent: Paragraph 0340; 0341

4
[ 74901-69-2 ]
[ 1146361-93-4 ]
[ 1146361-95-6 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 80℃; for 2h;Microwave irradiation;	2.2.5 (R)-1-(2-chloro-6,7-dihydro-thieno[3,2-d]pyrimidin-4-ylamino)-1-(4-fluoro-phenyl)-2-methyl-propan-2-ol Scheme 2, Step A 533 mg <strong>[74901-69-2]<strong>[74901-69-2]2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidin</strong>e</strong>, 850 mg (R)-1-amino-1-(4-fluoro-phenyl)-2-methyl-propan-2-ol and 1.3 ml diisopropylethylamine are suspended in 9.8 ml dioxane. The reaction mixture is stirred for 2 hours in the microwave at 80 C. and then evaporated to dryness. The residue is mixed with water. The precipitate formed is suction filtered and purified by chromatography (silica gel, petroleum ether/ethyl acetate 100/0 to 60/40). 260 mg of the product are obtained as a solid
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 80℃; for 2h;Microwave irradiation;	4.5 (R)-1-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-1-(4-fluorophenyl)-2-methylpropan-2-ol (III-4) 0.533 g (II), 0.850 g (R)-1-amino-1-(4-fluorophenyl)-2-methylpropan-2-ol and 1.3 ml diisopropylethylamine are suspended in 9.8 ml dioxane. The reaction mixture is heated to 80 C. in the microwave for 2 hours and then evaporated to dryness. The residue is mixed with water. The precipitate formed is suction filtered and purified by chromatography (silica gel, petroleum ether/ethyl acetate 100/0 to 60/40). 0.260 g (III-4) are obtained as a solid. Analytical HPLC-MS (method A): 1.39 min.
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; water;	4.5 (R)-1-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-1-(4-fluorophenyl)-2-methylpropan-2-ol (III-4) 0.533 g (II), 0.850 g (R)-1-amino-1-(4-fluorophenyl)-2-methylpropan-2-ol and 1.3 ml diisopropylethylamine are suspended in 9.8 ml dioxane. The reaction mixture is heated in the microwave for 2 hours at 80 C. and then evaporated to dryness. The residue is mixed with water. The precipitate formed is suction filtered and purified by chromatography (silica gel, petroleum ether/ethyl acetate 100/0 to 60/40). 0.260 g (III-4) are obtained in the form of a solid. Analytical HPLC-MS (method A): 1.39 min.

0.260 g

With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 80℃; for 2h;Microwave irradiation;

4.5 (R)-1-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-1-(4-fluorophenyl)-2-methylpropan-2-ol (III-4) 0.533 g (II), 0.850 g (R)-1-amino-1-(4-fluorophenyl)-2-methylpropan-2-ol and 1.3 ml diisopropylethylamine are suspended in 9.8 ml dioxane. The reaction mixture is heated in the microwave for 2 hours at 80 C. and then evaporated to dryness. The residue is mixed with water. The precipitate formed is suction filtered and purified by chromatography (silica gel, petroleum ether/ethyl acetate 100/0 to 60/40). 0.260 g (III-4) are obtained as a solid. Analytical HPLC-MS (method A): 1.39 min.

Reference： [1]Patent: US2008/96882,2008,A1 .Location in patent: Page/Page column 23
[2]Patent: US2011/21501,2011,A1 .Location in patent: Page/Page column 62
[3]Patent: US2012/35143,2012,A1
[4]Patent: US2013/225609,2013,A1 .Location in patent: Paragraph 0298; 0299

5
[ 74901-69-2 ]
[ 1143576-06-0 ]

Reference： [1]Patent: US2011/46096,2011,A1
[2]Patent: US2013/225609,2013,A1

6
[ 74901-69-2 ]
[ 4276-09-9 ]
[ 1143575-83-0 ]

Reference： [1]Patent: US2013/237527,2013,A1

7
[ 107-10-8 ]
[ 74901-69-2 ]
[ 913581-93-8 ]

Yield	Reaction Conditions	Operation in experiment
86%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 20h;	(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)propylamine (VII): 10.4 g (50.2 mmol) of 2,4-dichlorothieno[3,2-d]pyrimidine (VII), 8.2 mL (100 mmol) of N-propylamine, and 17.5 mL (100 mmol) of N-ethyldiisopropylamine are placed in 100 mL of tetrahydrofuran and stirred for 20 hours at ambient temperature. The suspension is filtered, the filtrate is concentrated by evaporation. The residue is combined with 100 mL of water and treated in the ultrasound bath. Solid substance is suction filtered, dried, and stirred with 50 mL of petroleum ether. 10.0 g of the product VIII (86%) is obtained as a powder.

Reference： [1]Patent: US2007/259846,2007,A1 .Location in patent: Page/Page column 30; 31
[2]Patent: WO2006/111549,2006,A1 .Location in patent: Page/Page column 61

8
[ 74901-69-2 ]
[ 586961-34-4 ]
[ 913581-97-2 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20 - 80℃; for 74h;	Synthesis of Isoxazole-5-carboxylic acid-{(1S,2S)-2-[2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino]cyclopentyl}amide triflate (XI) (chiral) (According to Scheme 7) tert-butyl [(1S,2S)-2-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)cyclopentyl]carbamate (V) (chiral): 0.600 g (2.9 mmol) of <strong>[74901-69-2]<strong>[74901-69-2]2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidin</strong>e</strong> (III), 0.580 g (2.9 mmol) of tert-butyl (2-aminocyclopentyl)carbamate (IV), and 2.5 mL (14.5 mmol) of diisopropylethylamine are placed in 30 mL of tetrahydrofuran, the mixture is stirred for 2 hours at ambient temperature and 72 hours at 80 C. The reaction mixture is concentrated by evaporation and further reacted in the crude state.

Reference： [1]Patent: US2007/259846,2007,A1 .Location in patent: Page/Page column 39
[2]Patent: WO2006/111549,2006,A1 .Location in patent: Page/Page column 76-77

9
[ 74901-69-2 ]
[ 99-05-8 ]
[ 913582-05-5 ]

Yield	Reaction Conditions	Operation in experiment
39%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20 - 70℃; for 96h;	0.200 g (0.93 mmol) of <strong>[74901-69-2]<strong>[74901-69-2]2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidin</strong>e</strong>, 0.127 g (0.93 mmol) of 3-aminobenzoic acid, and 0.323 mL (1.85 mmol) of diisopropylethylamine are placed in 4 mL of tetrahydrofuran, stirred for 48 hours at ambient temperature and 48 hours at 70 C. Then the reaction mixture is combined with water and acidified with 1N hydrochloric acid. The precipitate formed is suction filtered and dried. 0.110 g of product I (39%) is obtained.

Reference： [1]Patent: US2007/259846,2007,A1 .Location in patent: Page/Page column 44
[2]Patent: WO2006/111549,2006,A1 .Location in patent: Page/Page column 88

10
[ 74901-69-2 ]
[ 144243-24-3 ]
[ 913582-02-2 ]

Yield	Reaction Conditions	Operation in experiment
48%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 40h;	2.07 g (10.0 mmol) of <strong>[74901-69-2]<strong>[74901-69-2]2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidin</strong>e</strong> (III), 2.0 g (10.0 mmol) of tert-butyl 3-aminopiperidin-1-carboxylate (IV), and 3.4 mL (19.3 mmol) of diisopropylethylamine are placed in 40 mL of tetrahydrofuran, then stirred for 40 hours at ambient temperature. Then the reaction mixture is suction filtered and the mother liquor is concentrated by evaporation. The residue is combined with water and extracted with dichloromethane. The organic phase is separated off using a phase separator and evaporated to dryness. The crude product is purified by chromatography through a Biotage silica gel cartridge 40M with petroleum ether/ethyl acetate 9:1. 1.77 g of product V (48%) is obtained.

Reference： [1]Patent: US2007/259846,2007,A1 .Location in patent: Page/Page column 42
[2]Patent: WO2006/111549,2006,A1 .Location in patent: Page/Page column 84-85

11
[ 913581-92-7 ]
[ 74901-69-2 ]

Yield	Reaction Conditions	Operation in experiment
85%	With N,N-diethylaniline; trichlorophosphate; at 80℃; for 22h;	2.4-dichlorothieno[3,2-d]pyrimidine (VII)-2.4 g (14.1 mmol) of 6,7-dihydrothieno[3,2-d]pyrimidine-2,4-diol (VI) is suspended in 14 mL of phosphorus oxychloride, combined with 4.5 mL (28.2 mmol) of diethylaniline and stirred for 22 hours at 80 C. After cooling to ambient temperature, the reaction mixture is added to ice water, the precipitate formed is suction filtered and washed with water. The precipitate is dissolved in dichloromethane, any water present is separated off using a phase separator. The organic phase is evaporated to dryness. 2.5 g of the product VII (85%) is obtained.
	With N,N-diethylaniline; trichlorophosphate; at 25 - 110℃;	800 g of solid Compound VI (4.66 mol) was charged into to an inert and dry jacketed reactor (reactor 1) equipped with a temperature probe, mechanical stirrer and a dropping funnel. 1.5 litre (9.31 mol) Diethylaniline was charged over 30 min to 1 h keeping the temperature at or below 25 C. The internal temperature was brought up to 105-110 C and 0.68 equiv. (868 ml,34% of the total) of phosphorus oxychloride was added into the reactor (reactor 1) over 5- 10 min. When the inside temperature began to decrease, the internal temperature was maintained at 1 10 C and addition of the remaining POCl3 (1.32 equiv. or 66% of the total) resumed over a period of 30-40 min. The internal temperature was adjusted to 105-110 C and the mixture was stirred for 18-24 h or until complete (HPLC analysis). The mixture was cooled to 45 C and THF (400 mL) was charged at 45 C. The above crude mixture was placed into a secondary dry vessel or reactor (vessel or reactor 2). 4.8 1 of water was charged into the reactor 1 and cooled to 5 C. The crude reaction mixture (in reactor or vessel 2) is then slowly charged into reactor 1 containing water keeping the temperature at 5-10 C. The mixture was stirred at 5 C for 30 min to 1 h and the resulting solid was collected by filtration. The cake was rinsed with water twice (1.6 1 per rinse) and the cake was air dried in the funnel for 6-8 h to afford 964 g (92%w/w; 88% yield) of crude Compound VII. Dichloromethane (4.6 L) is charged into a 10 L reactor. Crude Compound VII and activated carbon (46.2 g) were charged into the reactor, the mixture is heated to 40C and stirred for 20 min. The resulting solution was collected by filtration through a filter media to remove charcoal. The cake was rinsed with dichloromethane twice ( 175 ml per rinse). The solution was concentrated under reduced pressure to a minimum stirrable volume and the remaining dichloromethane was chased away by distillation with a minimum amount of petroleum ether. Additional petroleum ether (1.3 1) was charged into the reactor, the mixture was cooled to 10C and stirred for 1 hr. The resulting solid was collected by filtration and the cake was rinsed with petroleum ether twice (150 ml per rinse). The cake was air dried in the funnel (suction) until it appeared dry. The resulting solid Compound VII was transferred to a suitable tared container and dried in an oven at 50 C for 6 hr to get final product: 1H NMR (400 MHz, DMSO-d6) delta 3.45-3.56 (m, 4H); 13C NMR (400 MHz, DMSO-d6) delta 29.3, 36.5, 134.8, 151.0, 154.1, 175.9.
586 mg	With trichlorophosphate; In water; at 140℃; for 0.5h;Microwave irradiation;	6.01.42.01 2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidine 500 mg 6,7-Dihydro-thieno[3,2-d]pyrimidine-2,4-diol and 10 mL phosphoroxychloride was stirred 30 min at 140 C. under microwave conditions. The reaction was added to water and then dichlormethane was added. The mixture was stirred for 20 min. The layers were separated and the dichlormethane layer was evaporated to give 586 mg of the desired product. Rt: 1.23 min (method P)

586 mg	With trichlorophosphate; at 140℃; for 0.5h;Microwave irradiation;	6.01.42.01 2, 4-dichloro-6, 7-dihydro-thieno [3, 2-d] pyrimidine 500 mg 6, 7-Dihydro-thieno [3, 2-d] pyrimidine-2, 4-diol and 10 mL phosphoroxychloride was stirred 30 min at 140C under microwave conditions. The reaction was added to water and then dichlormethane was added. The mixture was stirred for 20 min. The layers were seperated and the dichlormethane layer was evaporated to give 586 mg of the desired product. Rt: 1.23 min (method P) (M+H)+: 208/09
	With N,N-diethylaniline; trichlorophosphate; at 25 - 110℃;	800 g of solid Compound VI (4.66 mol) was charged into to an inert and dry jacketed reactor (reactor 1) equipped with a temperature probe, mechanical stirrer and a dropping funnel. 1.5 liter (9.31 mol) diethylaniline was charged over 30 min to 1 h keeping the temperature at or below 25 C. The internal temperature was brought up to 105-110 C. and 0.68 equiv. (868 ml, 34% of the total) of phosphorus oxychloride was added into the reactor (reactor 1) over 5-10 min. When the inside temperature began to decrease, the internal temperature was maintained at 110 C. and addition of the remaining POCl3 (1.32 equiv. or 66% of the total) resumed over a period of 30-40 min. The internal temperature was adjusted to 105-110 C. and the mixture was stirred for 18-24 h or until complete (HPLC analysis). The mixture was cooled to 45 C. and THF (400 mL) was charged at 45 C. The above crude mixture was placed into a secondary dry vessel or reactor (vessel or reactor 2). 4.8 l of water was charged into the reactor 1 and cooled to 5 C. The crude reaction mixture (in reactor or vessel 2) is then slowly charged into reactor 1 containing water keeping the temperature at 5-10 C. The mixture was stirred at 5 C. for 30 min to 1 h and the resulting solid was collected by filtration. The cake was rinsed with water twice (1.6 l per rinse) and the cake was air dried in the funnel for 6-8 h to afford 964 g (92% w/w; 88% yield) of crude Compound VII. Dichloromethane (4.6 L) is charged into a 10 L reactor. Crude Compound VII and activated carbon (46.2 g) were charged into the reactor, the mixture is heated to 40 C. and stirred for 20 min. The resulting solution was collected by filtration through a filter media to remove charcoal. The cake was rinsed with dichloromethane twice (175 ml per rinse). The solution was concentrated under reduced pressure to a minimum stirrable volume and the remaining dichloromethane was chased away by distillation with a minimum amount of petroleum ether. Additional petroleum ether (1.3 l) was charged into the reactor, the mixture was cooled to 10 C. and stirred for 1 hr. The resulting solid was collected by filtration and the cake was rinsed with petroleum ether twice (150 ml per rinse). The cake was air dried in the funnel (suction) until it appeared dry. The resulting solid Compound VII was transferred to a suitable tared container and dried in an oven at 50 C. for 6 hours to get final product: 1H NMR (400 MHz, DMSO-d6) delta 3.45-3.56 (m, 4H); 13C NMR (400 MHz, DMSO-d6) delta 29.3, 36.5, 134.8, 151.0, 154.1, 175.9.
	With N,N-diethylaniline; trichlorophosphate; at 105 - 110℃;	800 g of solid Compound VI (4.66 mol) was charged into to an inert and dry jacketed reactor (reactor 1 ) equipped with a temperature probe, mechanical stirrer and a dropping funnel. 1 .5 litre (9.31 mol) Diethylaniline was charged over 30 min to 1 h keeping the temperature at or below 25 C. The internal temperature was brought up to 105-1 10 C and 0.68 equiv. (868 ml, 34% of the total) of phosphorus oxychloride was added into the reactor (reactor 1 ) over 5- 10 min. When the inside temperature began to decrease, the internal temperature was maintained at 1 10 C and addition of the remaining POCI3 (1 .32 equiv. or 66% of the total) resumed over a period of 30-40 min. The internal temperature was adjusted to 105-1 10 C and the mixture was stirred for 18-24 h or until complete (HPLC analysis). The mixture was cooled to 45 C and THF (400 mL) was charged at 45 C. The above crude mixture was placed into a secondary dry vessel or reactor (vessel or reactor 2). 4.8 I of water was charged into the reactor 1 and cooled to 5 C. The crude reaction mixture (in reactor or vessel 2) is then slowly charged into reactor 1 containing water keeping the temperature at 5- 10 C. The mixture was stirred at 5 C for 30 min to 1 h and the resulting solid was collected by filtration. The cake was rinsed with water twice (1.6 I per rinse) and the cake was air dried in the funnel for 6-8 h to afford 964 g (92%w/w; 88% yield) of crude Compound VII. Dichloromethane (4.6 L) is charged into a 10 L reactor. Crude Compound VII and activated carbon (46.2 g) were charged into the reactor, the mixture is heated to 40C and stirred for 20 min. The resulting solution was collected by filtration through a filter media to remove charcoal. The cake was rinsed with dichloromethane twice (175 ml per rinse). The solution was concentrated under reduced pressure to a minimum stirrable volume and the remaining dichloromethane was chased away by distillation with a minimum amount of petroleum ether. Additional petroleum ether (1 .3 I) was charged into the reactor, the mixture was cooled to 10C and stirred for 1 hr. The resulting solid was collected by filtration and the cake was rinsed with petroleum ether twice (150 ml per rinse). The cake was air dried in the funnel (suction) until it appeared dry. The resulting solid Compound VII was transferred to a suitable tared container and dried in an oven at 50 C for 6 hr to get final product: 1H NMR (400 MHz, DMSO-d6) delta 3.45-3.56 (m, 4H); 13C NMR (400 MHz, DMSO-d6) delta 29.3, 36.5, 134.8, 151 .0, 154.1 , 175.9.
	With N,N-diethylaniline; trichlorophosphate; at 105 - 110℃;Inert atmosphere;	800 g of solid Compound VI (4.66 mol) was charged into to an inert and dry jacketed reactor (reactor 1) equipped with a temperature probe, mechanical stirrer and a dropping funnel. 1.5 litre (9.31 mol) Diethylaniline was charged over 30 min to 1 h keeping the temperature at or below 25 C. The internal temperature was brought up to 105-110 C. and 0.68 equiv. (868 ml, 34% of the total) of phosphorus oxychloride was added into the reactor (reactor 1) over 5-10 min. When the inside temperature began to decrease, the internal temperature was maintained at 110 C. and addition of the remaining POCl3 (1.32 equiv. or 66% of the total) resumed over a period of 30-40 min. The internal temperature was adjusted to 105-110 C. and the mixture was stirred for 18-24 h or until complete (HPLC analysis). The mixture was cooled to 45 C. and THF (400 mL) was charged at 45 C. The above crude mixture was placed into a secondary dry vessel or reactor (vessel or reactor 2). 4.8 l of water was charged into the reactor 1 and cooled to 5 C. The crude reaction mixture (in reactor or vessel 2) is then slowly charged into reactor 1 containing water keeping the temperature at 5-10 C. The mixture was stirred at 5 C. for 30 min to 1 h and the resulting solid was collected by filtration. The cake was rinsed with water twice (1.6 l per rinse) and the cake was air dried in the funnel for 6-8 h to afford 964 g (92% w/w; 88% yield) of crude Compound VII. Dichloromethane (4.6 L) is charged into a 10 L reactor. Crude Compound VII and activated carbon (46.2 g) were charged into the reactor, the mixture is heated to 40 C. and stirred for 20 min. The resulting solution was collected by filtration through a filter media to remove charcoal. The cake was rinsed with dichloromethane twice (175 ml per rinse). The solution was concentrated under reduced pressure to a minimum stirrable volume and the remaining dichloromethane was chased away by distillation with a minimum amount of petroleum ether. Additional petroleum ether (1.3 l) was charged into the reactor, the mixture was cooled to 10 C. and stirred for 1 hr. The resulting solid was collected by filtration and the cake was rinsed with petroleum ether twice (150 ml per rinse). The cake was air dried in the funnel (suction) until it appeared dry. The resulting solid Compound VII was transferred to a suitable tared container and dried in an oven at 50 C. for 6 hr to get final product: 1H NMR (400 MHz, DMSO-d6) delta 3.45-3.56 (m, 4H); 13C NMR (400 MHz, DMSO-d6) delta 29.3, 36.5, 134.8, 151.0, 154.1, 175.9.

Reference： [1]Organic Process Research and Development,2016,vol. 20,p. 982 - 988
[2]Patent: WO2006/111549,2006,A1 .Location in patent: Page/Page column 61; 59; 65; 68; 69; 72; 74; 76; 84
[3]Patent: US2007/259846,2007,A1 .Location in patent: Page/Page column 30; 31
[4]Patent: WO2013/26797,2013,A1 .Location in patent: Page/Page column 24-25
[5]Patent: US2013/150341,2013,A1 .Location in patent: Paragraph 0364; 0365; 0366; 0367
[6]Patent: WO2013/83741,2013,A1 .Location in patent: Page/Page column 90
[7]Patent: US2014/228286,2014,A1 .Location in patent: Paragraph 0246-0247
[8]Patent: WO2014/124860,2014,A1 .Location in patent: Page/Page column 43; 44
[9]Patent: US2015/45376,2015,A1 .Location in patent: Paragraph 0079-0080

12
[ 74901-69-2 ]
[ 107017-72-1 ]
[ 1143575-86-3 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 160℃;	8.3 [1-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-cyclopropyl]-methanol (III-4) 1.4 g (II) are placed in 10 ml dioxane, first 3.6 ml diisopropylethylamine, then 1 g of 1-aminocyclopropanemethanol (see 8.2) are added. The reaction mixture is heated to 160 C. until no further reaction takes place, then cooled and evaporated down. The residue is treated with cyclohexane/ethyl acetate (8:2) in the ultrasound bath and the solid is suction filtered and dried. 1.24 g (III-4) are obtained as a solid. Analytical HPLC-MS (method A): RT=1.01 min.
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 160℃;	4.3 [1-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-cyclopropyl]-methanol (III-4)1.4 g (II) are placed in 10 ml dioxane, then 3.6 ml diisopropylethylamine followed by 1 g of 1-aminocyclopropanemethanol (see 4.2) are added. The reaction mixture is heated at 160 C. until there is no further reaction, and after cooling evaporated down. The residue is treated with cyclohexane/ethyl acetate (8:2) in the ultrasound bath and the solid is suction filtered and dried. 1.24 g (III-4) are obtained as a solid.Analytical HPLC-MS (method A): RT=1.01 min.
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; cyclohexane; ethyl acetate;	8.3 [1-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-cyclopropyl]-methanol (III-4) 1.4 g (II) are placed in 10 ml dioxane, then first 3.6 ml diisopropylethylamine are added followed by 1 g 1-aminocyclopropanemethanol (cf. 8.2). The reaction mixture is heated to 160 C. until there is no further reaction, then cooled and evaporated down. The residue is treated with cyclohexane/ethyl acetate (8:2) in the ultrasound bath and the solid is suction filtered and dried. 1.24 g (III-4) are obtained in the form of a solid. Analytical HPLC-MS (method A): RT=1.01 min.

	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; cyclohexane; ethyl acetate;	2.3 [1-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-cyclopropyl]-methanol (III-2) 1.4 g (II) are placed in 10 ml dioxane, then 3.6 ml diisopropylethylamine are added followed by 1 g 1-aminocyclopropanmethanol (cf. 2.2). The reaction mixture is heated to 160 C. until there is no further reaction, then cooled and evaporated down. The residue is treated with cyclohexane/ethyl acetate (4:1) in the ultrasound bath, the solid is suction filtered and dried. 1.24 g (III-2) are obtained in the form of a solid. Analytical HPLC-MS (method A): RT=1.01 min.
1.24 g	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 160℃;	2.3 [1-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-cyclopropyl]-methanol (III-2) 1.4 g (II) are placed in 10 ml dioxane, then 3.6 ml diisopropylethylamine and then 1 g of 1-aminocyclopropanemethanol (see 2.2) are added. The reaction mixture is heated to 160 C. until there is no further reaction, and after cooling evaporated down. The residue is treated with cyclohexane/ethyl acetate (4:1) in the ultrasound bath, the solid is suction filtered and dried. 1.24 g (III-2) are obtained as a solid. Analytical HPLC-MS (method A): RT=1.01 min.

Reference： [1]Patent: US2010/305102,2010,A1 .Location in patent: Page/Page column 16
[2]Patent: US2011/46096,2011,A1 .Location in patent: Page/Page column 24
[3]Patent: US2012/28932,2012,A1
[4]Patent: US2012/35143,2012,A1
[5]Patent: US2013/225609,2013,A1 .Location in patent: Paragraph 0278; 0279

13
[ 74901-69-2 ]
[ 4276-09-9 ]
[ 1143575-82-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 100℃;	Example 2 2.1 (R)-2-(2-chloro-6,7-dihydro-thieno[3,2-d]pyrimidin-4-ylamino)-3-methyl-butan-1-ol (III-2) 7.2 g <strong>[74901-69-2]2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidin</strong> (II) are placed in 36 ml dioxane, then 18 ml diisopropylethylamine and then 6.1 g (R)-(-)-2-amino-3-methyl-1-butanol are added. The reaction mixture is heated to 100 C. until no further reaction takes place, then cooled and evaporated down. The residue is treated with petroleum ether/ethyl acetate 9:1 in the ultrasound bath and the solid is suction filtered and dried. 8.3 g (III-2) are obtained as a solid. Analytical HPLC (method A): RT=2.75 min
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 100℃;	Example 1 1.1 (R)-2-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-3-methylbutan-1-ol (III-1) 7.2 g of <strong>[74901-69-2]2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidin</strong> (II) are in 36 ml dioxane placed, and then first 18 ml diisopropylethylamine, then 6.1 g (R)-(-)-2-amino-3-methyl-1-butanol are added. The reaction mixture is heated to 100 C., until there is no further reaction and cooled, then evaporated down. The residue is treated with petroleum ether/ethyl acetate (9:1) in the ultrasound bath and the solid is suction filtered and dried. 8.3 g (III-1) are obtained as a solid. Analytical HPLC (method A): RT=2.75 min
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 100℃;	1.1.1 (R)-2-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-3-methylbutan-1-ol (III-1) 7.2 g of <strong>[74901-69-2]<strong>[74901-69-2]2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidin</strong>e</strong> (II) are placed in 36 ml dioxane, then 18 ml of diisopropylethylamine are added, followed by 6.1 g (R)-(-)-2-amino-3-methyl-1-butanol. The reaction mixture is heated at 100 C, until no further reaction takes place, and after cooling, evaporated to dryness. The residue is treated with petroleum ether/ethyl acetate (9:1) in the ultrasound bath,the solid is suction filtered and dried. 8.3 g (III-1) are obtained as a solid. Analytical HPLC (method A): RT=2.75 min

	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 100℃;	1. SYNTHESIS OF (R)-2-{2-[(R)-4-(4-CHLOROPHENYL)-2-METHYLPIPERAZIN-1-YL]-5-OXO-6,7-DIHYDRO-5H-5lambda4-THIENO[3,2-D]PYRIMIDIN-4-YLAMINO}-3-METHYLBUTAN-1-OLExample 11.1 (R)-2-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-3-methylbutan-1-ol (III-1)7.2 g <strong>[74901-69-2]<strong>[74901-69-2]2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidin</strong>e</strong> (II) are placed in 36 ml dioxane, then 18 ml diisopropylethylamine and then 6.1 g (R)-(-)-2-amino-3-methyl-1-butanol are added. The reaction mixture is heated to 100 C. until there is no further reaction, and after cooling evaporated down. The residue is treated with petroleum ether/ethyl acetate 9:1 in the ultrasound bath, the solid is suction filtered and dried. 8.3 g (III-1) are obtained as a solid. Analytical HPLC (method A): RT=2.75 min
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; ethyl acetate; Petroleum ether;	2.1 (R)-2-(2-chloro-6,7-dihydro-thieno[3,2-d]pyrimidin-4-ylamino)-3-methyl-butan-1-ol (III-2) 7.2 g <strong>[74901-69-2]<strong>[74901-69-2]2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidin</strong>e</strong> (II) are placed in 36 ml dioxane, then 18 ml diisopropylethylamine are added followed by 6.1 g (R)-(-)-2-amino-3-methyl-1-butanol. The reaction mixture is heated to 100 C. until there is no further reaction, then cooled and evaporated down. The residue is treated with petroleum ether/ethyl acetate 9:1 in the ultrasound bath and the solid is suction filtered and dried. 8.3 g (III-2) are obtained in the form of a solid. Analytical HPLC (method A): RT=2.75 min
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; ethyl acetate; Petroleum ether;	1.1 (R)-2-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-3-methylbutan-1-ol (III-1) 7.2 g <strong>[74901-69-2]<strong>[74901-69-2]2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidin</strong>e</strong> (II) are placed in 36 ml dioxane, then first 18 ml diisopropylethylamine are added, followed by 6.1 g (R)-(-)-2-amino-3-methyl-1-butanol. The reaction mixture is heated to 100 C. until there is no further reaction, then cooled and evaporated down. The residue is treated with petroleum ether/ethyl acetate (9:1) in the ultrasound bath and the solid is suction filtered and dried. 8.3 g (III-1) are obtained in the form of a solid. Analytical HPLC (method A): RT=2.75 min
8.3 g	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 100℃;	2.1 (R)-2-(2-chloro-6,7-dihydro-thieno[3,2-d]pyrimidin-4-ylamino)-3-methyl-butan-1-ol (III-2) 7.2 g <strong>[74901-69-2]<strong>[74901-69-2]2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidin</strong>e</strong> (II) are placed in 36 ml dioxane, then 18 ml diisopropylethylamine and then 6.1 g (R)-(-)-2-amino-3-methyl-1-butanol are added. The reaction mixture is heated to 100 C. until there is no further reaction and after cooling it is evaporated down. The residue is treated with petroleum ether/ethyl acetate 9:1 in the ultrasound bath and the solid is suction filtered and dried. 8.3 g (III-2) are obtained as a solid. Analytical HPLC (method A): RT=2.75 min
8.3 g	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 100℃;	1.1 (R)-2-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-3-methylbutan-1-ol (III-1) 7.2 g <strong>[74901-69-2]<strong>[74901-69-2]2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidin</strong>e</strong> (II) are placed in 36 ml dioxane, first 18 ml diisopropylethylamine, then 6.1 g (R)-(-)-2-amino-3-methyl-1-butanol are added. The reaction mixture is heated to 100 C. until there is no further reaction, and after cooling evaporated down. The residue is treated with petroleum ether/ethyl acetate (9:1) in the ultrasound bath and the solid is suction filtered and dried. 8.3 g (III-1) are obtained as a solid. Analytical HPLC (method A): RT=2.75 min

Reference： [1]Patent: US2010/305102,2010,A1 .Location in patent: Page/Page column 13
[2]Patent: US2011/21501,2011,A1 .Location in patent: Page/Page column 57-58
[3]Patent: US2011/28441,2011,A1 .Location in patent: Page/Page column 12-13
[4]Patent: US2011/46096,2011,A1 .Location in patent: Page/Page column 19
[5]Patent: US2012/28932,2012,A1
[6]Patent: US2012/35143,2012,A1
[7]Patent: US2013/237527,2013,A1 .Location in patent: Paragraph 0203; 0204
[8]Patent: US2013/225609,2013,A1 .Location in patent: Paragraph 0268;<BOLD> </BOLD>0269

14
[ 74901-69-2 ]
[ 1143576-02-6 ]
[ 1143576-04-8 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 130℃;	25.4 (S)-5-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-1-methylpiperidin-2-one (III-5) 0.27 g (II) are placed in 3 ml dioxane, then 0.45 ml diisopropylethylamine and 0.25 g (S)-5-amino-1-methylpiperidin-2-one are added. The reaction mixture is heated to 130 C. until no further reaction takes place, then cooled and evaporated down. The product is extracted with dichloromethane and purified by chromatography (preparative HPLC, method B). 0.26 g (III-5) are obtained as a solid. Analytical HPLC-MS (method A): RT=1.06 min.
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 130℃;	5.4 (S)-5-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-1-methylpiperidin-2-one (III-5): 0.27 g (II) are placed in 3 ml dioxane, then first 0.45 ml diisopropylethylamine, then 0.25 g (S)-5-amino-1-methylpiperidin-2-one are added. The reaction mixture is heated to 130 C., until there is no further reaction, and cooled, then evaporated down. The product is extracted with dichloromethane and purified by chromatography (preparative HPLC, method A). 0.26 g (III-5) are obtained as a solid. Analytical HPLC-MS (method A): RT=1.06 min.
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 130℃;	1.4.4 (S)-5-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-1-methylpiperidin-2-one (III-3) 0.27 g (II) are placed in 3 ml dioxane, then first 0.45 ml diisopropylethylamine are added, followed by 0.25 g (S)-5-amino-1-methylpiperidin-2-one. The reaction mixture is heated at 130 C until no further reaction takes place, and after cooling, evaporated down. The product is extracted with dichloromethane and purified by chromatography (preparative HPLC, method A). 0.26 g (III-3) are obtained as a solid. Analytical HPLC-MS (method B): RT=1.06 min.

	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 130℃;	2.4 (S)-5-(2-chloro-6,7-dihydro-thieno[3,2-d]pyrimidin-4-ylamino)-1-methylpiperidin-2-one (III-2)0.27 g (II) are placed in 3 ml dioxane, then 0.45 ml diisopropylethylamine are added followed by 0.25 g (S)-5-amino-1-methylpiperidin-2-one. The reaction mixture is heated to 130 C. until there is no further reaction, and after cooling evaporated down. The product is extracted with dichloromethane and purified by chromatography (preparative HPLC, method A). 0.26 g (III-2) are obtained as a solid. Analytical HPLC-MS (method A): RT=1.06 min.
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane;	25.4 (S)-5-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-1-methylpiperidin-2-one (III-5) 0.27 g (II) are placed in 3 ml dioxane, then 0.45 ml diisopropylethylamine and 0.25 g (S)-5-amino-1-methylpiperidin-2-one are added. The reaction mixture is heated to 130 C. until there is no further reaction, then cooled and evaporated down. The product is extracted with dichloromethane and purified by chromatography (preparative HPLC, method B). 0.26 g (III-5) are obtained in the form of a solid. Analytical HPLC-MS (method A): RT=1.06 min.
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane;	5.4 (S)-5-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-1-methylpiperidin-2-one (III-5) 0.27 g (II) are placed in 3 ml dioxane, then first 0.45 ml diisopropylethylamine are added, followed by 0.25 g (S)-5-amino-1-methylpiperidin-2-one. The reaction mixture is heated to 130 C. until there is no further reaction then cooled and evaporated down. The product is extracted with dichloromethane and purified by chromatography (preparative HPLC, method A). 0.26 g (III-5) are obtained in the form of a solid. Analytical HPLC-MS (method A): RT=1.06 min.
0.26 g	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 130℃;	25.4 (S)-5-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-1-methylpiperidin-2-one (II-5) 0.27 g (II) are placed in 3 ml dioxane, then 0.45 ml diisopropylethylamine and 0.25 g (S)-5-amino-1-methylpiperidin-2-one are added. The reaction mixture is heated to 130 C. until there is no further reaction, cooled and then evaporated down. The product is extracted with dichloromethane and purified by chromatography (preparative HPLC, method B). 0.26 g (III-5) are obtained as a solid. Analytical HPLC-MS (method A): RT=1.06 min.
0.26 g	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 130℃;	5.4 (S)-5-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-1-methylpiperidin-2-one (III-5) 0.27 g (II) are placed in 3 ml dioxane, then first 0.45 ml diisopropylethylamine, then 0.25 g (S)-5-amino-1-methylpiperidin-2-one are added. The reaction mixture is heated to 130 C. until there is no further reaction and after cooling evaporated down. The product is extracted with dichloromethane and purified by chromatography (preparative HPLC, method A). 0.26 g (III-5) are obtained as a solid. Analytical HPLC-MS (method A): RT=1.06 min.

Reference： [1]Patent: US2010/305102,2010,A1 .Location in patent: Page/Page column 27
[2]Patent: US2011/21501,2011,A1 .Location in patent: Page/Page column 63
[3]Patent: US2011/28441,2011,A1 .Location in patent: Page/Page column 16
[4]Patent: US2011/46096,2011,A1 .Location in patent: Page/Page column 21
[5]Patent: US2012/28932,2012,A1
[6]Patent: US2012/35143,2012,A1
[7]Patent: US2013/237527,2013,A1 .Location in patent: Paragraph 0311; 0312
[8]Patent: US2013/225609,2013,A1 .Location in patent: Paragraph 0310; 0311

15
[ 38041-19-9 ]
[ 74901-69-2 ]
[ 1143575-84-1 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 130℃;	0.68 g (II) are placed in 6 ml dioxane, then 1.72 ml diisopropylethylamine and then 0.6 g 4-aminotetrahydropyran are added. The reaction mixture is heated to 130 C. until no further reaction takes place, then cooled and evaporated down. The product is treated with water in the ultrasound bath and the solid is suction filtered and dried. 0.66 g (III-3) are obtained. Analytical HPLC-MS (method A): RT=1.08 min.
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 130℃;	Example 6 6.1 (2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-(tetrahydropyran-4-yl)-amine (III-6) 0.68 g (II) are placed in 6 ml dioxane, then first 1.72 ml diisopropylethylamine, then 0.6 g 4-aminotetrahydropyran are added. The reaction mixture is heated to 130 C., until there is no further reaction, and cooled, then evaporated down. The product is treated with water in the ultrasound bath, then suction filtered and dried. 0.66 g (III-6) are obtained as a solid. Analytical HPLC-MS (method C): RT=1.08 min.
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 130℃;	1.5.1 (2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-(tetrahydropyran-4-yl)-amine (III-4) 0.68 g (II) are placed in 6 ml dioxane, then 1.72 ml diisopropylethylamine are added followed by 0.6 g of 4-aminotetrahydropyran. The reaction mixture is heated at 130 C until no further reaction takes place, and after cooling, evaporated down. The product is treated with water in the ultrasound bath, the solid is suction filtered and dried. 0.66 g (III-4) are obtained. Analytical HPLC-MS (method B): RT=1.08 min.

	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 130℃;	6. SYNTHESIS OF [2-(5-BENZOXAZOL-2-YL-2,5-DIAZABICYCLO[2,2,1]HEPT-2-YL)-5-OXO-6,7-DIHYDRO-5H-5lambda4-THIENO[3,2-D]PYRIMIDIN-4-YL]-(TETRAHYDROPYRAN-4-YL)-AMINEExample 296.1 (2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-(tetrahydropyran-4-yl)-amine (III-5)0.68 g (II) are placed in 6 ml dioxane, then 1.72 ml diisopropylethylamine followed by 0.6 g 4-aminotetrahydropyran are added. The reaction mixture is heated at 130 C. until there is no further reaction and after cooling evaporated down. The product is treated with water in the ultrasound bath, suction filtered and dried. 0.66 g (III-5) are obtained as a solid.Analytical HPLC-MS (method A): RT=1.08 min.
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; water;	4.1 (2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-(tetrahydropyran-4-yl)-amine (III-3) 0.68 g (II) are placed in 6 ml dioxane, then 1.72 ml diisopropylethylamine are added followed by 0.6 g 4-aminotetrahydropyran. The reaction mixture is heated to 130 C. until there is no further reaction, then cooled and evaporated down. The product is treated with water in the ultrasound bath and the solid is suction filtered and dried. 0.66 g (III-3) are obtained. Analytical HPLC-MS (method A): RT=1.08 min.
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; water;	6.1 (2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-(tetrahydropyran-4-yl)-amine (III-6) 0.68 g (II) are placed in 6 ml dioxane, then first 1.72 ml diisopropylethylamine are added, followed by 0.6 g of 4-aminotetrahydropyran. The reaction mixture is heated to 130 C. until there is no further reaction then cooled and evaporated down. The product is treated with water in the ultrasound bath, then suction filtered and dried. 0.66 g (III-6) are obtained in the form of a solid. Analytical HPLC-MS (method C): RT=1.08 min.
0.66 g	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 130℃;	4.1 (2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-(tetrahydropyran-4-yl)-amine (III-3) 0.68 g (II) are placed in 6 ml dioxane, then 1.72 ml diisopropylethylamine followed by 0.6 g 4-aminotetrahydropyran are added. The reaction mixture is heated to 130 C. until there is no further reaction and after cooling evaporated down. The product is treated with water in the ultrasound bath and the solid is suction filtered and dried. 0.66 g (III-3) are obtained. Analytical HPLC-MS (method A): RT=1.08 min.
0.66 g	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 130℃;	6.1 (2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-(tetrahydropyran-4-yl)-amine (III-6) 0.68 g (II) are placed in 6 ml dioxane, first 1.72 ml diisopropylethylamine, then 0.6 g 4-aminotetrahydropyran are added. The reaction mixture is heated to 130 C. until there is no further reaction and after cooling it is evaporated down. The product is treated with water in the ultrasound bath, then suction filtered and dried. 0.66 g (III-6) are obtained as a solid. Analytical HPLC-MS (method C): RT=1.08 min.
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 1h;	DIPEA (33.6 mL, 193 mmol) and tetrahydropyran-4-amine ( 11.7 g, 116 mmol) was added to a suspension of <strong>[74901-69-2]<strong>[74901-69-2]2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidin</strong>e</strong> (20.0 g, 96.6 mmol) in DMF (50 mL). The mixture was stirred at 100 C for 1 hour before it cooled to room temperature and poured into water (600 mL). The suspension was then stirred at room temperature for 10 minutes. The precipitate was filtered off, washed twice with water (2 x 100 mL) and tert-butyl methyl ether (2 x 20 mL). The solid material was dried under reduced pressure, before it was re-dissolved in a warm toluene: DCM (2 : 1) solution (300 mL). The mixture was concentrated to approximately 100 mL and left to stand for 1 hour at room temperature. The formed precipitate was filtered off, washed with toluene (20 mL) and dried under reduced pressure. The title compound was obtained as off-white solid material.1H NMR (DMSO-d6) delta: 7.14 (d, J = 7.8 Hz, 1H), 4.21 - 3.99 (m, 1H), 3.95 - 3.77 (m, 2H), 3.46 - 3.33 (m, 4H), 3.14 (td, J = 8.2, 1.1 Hz, 2H), 1.81 - 1.68 (m, 2H), 1.67 - 1.48 (m, 2H).
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 120℃; for 2h;Inert atmosphere; Sealed tube;	DIPEA (62.31 g, 483 mmol) was added at room temperature to a stirred solution of <strong>[74901-69-2]<strong>[74901-69-2]2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidin</strong>e</strong> (50.0 g, 242 mmol) and tetrahydropyran-4-amine (29.3 g, 290 mmol) in DMF (150 mL). The mixture was then heated for 2 hours under a N2 atmosphere in a sealed tube at 120C. The reaction mass allowed to cool to room temperature and poured into ice cold water. The resulting solid was filtered off and washed with water, diethyl ether and a toluene/DCM mixture (2 : 1 ratio). The solid was dried under reduced pressure to afford the pure title compound as a solid. *H NMR (400 MHz DMSO-d6) : d (ppm) 7.20-7.13 (m, 1H), 4.16 - 3.95 (m, 1H), 3.90-3.84 (m, 2H), 3.42 - 3.32 (m, 4H), 3.20 - 3.07 (m, 2H), 1.81 - 1.68 (m, 2H), 1.62-1.56 (m, 2H); LCMS (ES): m/z 272 [M + H]?; 97.6%; RT = 1.8 min; (AQUITY UPLC BEH C18 column, 0.1% FORMIC ACID in water with MeCN).
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere; Sealed tube;	DIPEA (62.31 g, 483 mmol) was added at room temperature to a stirred solution of <strong>[74901-69-2]<strong>[74901-69-2]2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidin</strong>e</strong> (50.0 g, 242 mmol) and (0173) tetrahydropyran-4-amine (29.3 g, 290 mmol) in DMF (150 mL). The mixture was then heated for 2 hours under a N2 atmosphere in a sealed tube at 120C. The reaction mass allowed to cool to room temperature and poured into ice cold water. The resulting solid was filtered off and washed with water, diethyl ether and a toluene/DCM mixture (2 : 1 ratio). The solid was dried under reduced pressure to afford the pure title compound as a solid. *H NMR (DMSO-d6, 400 MHz) : d (ppm) 7.20-7.13 (m, 1H), 4.16 - 3.95 (m, 1H), 3.90-3.84 (m, 2H), 3.42 - 3.32 (m, 4H), 3.20 - 3.07 (m, 2H), 1.81 - 1.68 (m, 2H), 1.62-1.56 (m, 2H); LCMS (ESI) : m/z 272 [M + H]?; 97.6%; RT = 1.8 min; (AQUITY UPLC BEH C18 column, 0.1% FORMIC ACID in water with MeCN).

Reference： [1]Patent: US2010/305102,2010,A1 .Location in patent: Page/Page column 14
[2]Patent: US2011/21501,2011,A1 .Location in patent: Page/Page column 64
[3]Patent: US2011/28441,2011,A1 .Location in patent: Page/Page column 16-17
[4]Patent: US2011/46096,2011,A1 .Location in patent: Page/Page column 25
[5]Patent: US2012/28932,2012,A1
[6]Patent: US2012/35143,2012,A1
[7]Patent: US2013/237527,2013,A1 .Location in patent: Paragraph 0211; 0212
[8]Patent: US2013/225609,2013,A1 .Location in patent: Paragraph 0316; 0317
[9]Patent: WO2019/57806,2019,A1 .Location in patent: Page/Page column 39-40
[10]Patent: WO2019/115775,2019,A1 .Location in patent: Page/Page column 21; 22
[11]Patent: WO2019/115774,2019,A1 .Location in patent: Page/Page column 21-22

16
[ 74901-69-2 ]
[ 67997-58-4 ]
[ 7087-68-5 ]
[ 1146362-14-2 ]

Yield	Reaction Conditions	Operation in experiment
	In 1,4-dioxane; (2S)-N-methyl-1-phenylpropan-2-amine hydrate;	25.1 2-[1-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-cyclopropyl]-propan-2-ol (III-8) 2.7 g (II) are placed in 30 ml dioxane, then 6.8 ml diisopropyl-ethylamine and 1.8 g 2-(1-aminocyclopropyl)-propan-2-ol (cf. Liebigs Ann. Chem. 1978.1194) are added. The reaction mixture is heated to 160 C. until there is no further reaction and after cooling it is evaporated to dryness. The residue is mixed with ice water. The product is extracted with dichloromethane and purified by chromatography. 125 mg (III-8) are obtained in the form of a solid. Analytical HPLC-MS (method A): RT=1.08 min.

Reference： [1]Patent: US2012/35143,2012,A1

17
[ 74901-69-2 ]
[ 80696-30-6 ]
[ 1146361-86-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 120℃;Microwave irraidation;	Example 3 3.1 (R)-2-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-pentan-1-ol (III-3) 1.4 g <strong>[74901-69-2]<strong>[74901-69-2]2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidin</strong>e</strong> (II) are placed in 9 ml dioxane, then first 3.5 ml diisopropylethylamine, then 0.9 g D-norvalinol are added. The reaction mixture is heated in the microwave at 120 C., until there is no further reaction, and cooled, then evaporated down. The residue is treated with petroleum ether/ethyl acetate 9:1 in the ultrasound bath, the solid is suction filtered and dried. 1.5 g (III-3) are obtained as a solid. 1H NMR (400 MHz, DMSO): 4.67 (1H, t); 0.86 (3H, t).
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 120℃;microwave irradiation;	3.3.1 (R)-2-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-pentan-1-ol (III-6) 1.4 g (II) are placed in 9 ml dioxane, then 3.5 ml diisopropylethylamine followed by 0.9 g of D-norvalinol are added. The reaction mixture is heated in the microwave at 120 C, until no further reaction takes place, and after cooling, evaporated to dryness. The residue is treated with petroleum ether/ethyl acetate (9:1) in the ultrasound bath, the solid is suction filtered and dried. 1.5 g (III-6) are obtained as a solid. 1H NMR (400 MHz, DMSO): 4.67 (1H, t); 0.86 (3H, t).
1.5 g	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 120℃;Microwave irradiation;	3.1 (R)-2-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-pentan-1-ol (III-3) 1.4 g <strong>[74901-69-2]<strong>[74901-69-2]2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidin</strong>e</strong> (II) are placed in 9 ml dioxane, first 3.5 ml diisopropylethylamine, then 0.9 g D-norvalinol are added. The reaction mixture is heated to 120 C. in the microwave until there is no further reaction and after cooling it is evaporated down. The residue is treated with petroleum ether/ethyl acetate 9:1 in the ultrasound bath, the solid is suction filtered and dried. 1.5 g (III-3) are obtained as a solid. 1H NMR (400 MHz, DMSO): 4.67 (1H, t); 0.86 (3H, t).

Reference： [1]Patent: US2011/21501,2011,A1 .Location in patent: Page/Page column 60
[2]Patent: US2011/28441,2011,A1 .Location in patent: Page/Page column 23
[3]Patent: US2013/225609,2013,A1 .Location in patent: Paragraph 0284; 0285

18
[ 74901-69-2 ]
[ 115652-52-3 ]
[ 1143575-86-3 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 160℃;	2.3 [1-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-cyclopropyl]-methanol (III-2) 1.4 g (II) are placed in 10 ml dioxane, then 3.6 ml diisopropylethylamine and then 1 g of 1-aminocyclopropanemethanol (see 2.2) are added. The reaction mixture is heated to 160° C., until there is no further reaction, and cooled, then evaporated down. The residue is treated with cyclohexane/ethyl acetate (4:1) in the ultrasound bath, the solid is suction filtered and dried. 1.24 g (III-2) are obtained as a solid. Analytical HPLC-MS (method A): RT=1.01 min.
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 160℃;	1.3.3 [1-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-cyclopropyl]-methanol (III-2) 1.4 g (II) are placed in 10 ml dioxane, then first 3.6 ml diisopropylethylamine are added, followed by 1 g of 1-aminocyclopropanemethanol (see 1.3.2). The reaction mixture is heated at 160° C, until no further reaction takes place, and after cooling, evaporated down. The residue is treated with cyclohexane/ethyl acetate (4:1) in the ultrasound bath and the solid is suction filtered and dried. 1.24 g (III-2) are obtained as a solid. Analytical HPLC-MS (method B): RT=1.01 min.
1.24 g	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 160℃;	8.3 [1-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-cyclopropyl]-methanol (III-4) 1.4 g (II) are placed in 10 ml dioxane, first 3.6 ml diisopropylethylamine, then 1 g of 1-aminocyclopropanmethanol (see 8.2) are added. The reaction mixture is heated to 160° C. until there is no further reaction and after cooling evaporated down. The residue is treated with cyclohexane/ethyl acetate (8:2) in the ultrasound bath and the solid is suction filtered and dried. 1.24 g (III-4) are obtained as a solid. Analytical HPLC-MS (method A): RT=1.01 min.

Reference： [1]Patent: US2011/21501,2011,A1 .Location in patent: Page/Page column 59
[2]Patent: US2011/28441,2011,A1 .Location in patent: Page/Page column 14
[3]Patent: US2013/237527,2013,A1 .Location in patent: Paragraph 0227; 0228; 0229

19
[ 74901-69-2 ]
[ 67997-58-4 ]
[ 1146362-14-2 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 160℃;	(III-8) 2.7 g (II) are placed in 30 ml dioxane, then 6.8 ml diisopropyl-ethylamine and 1.8 g 2-(1-aminocyclopropyl)-propan-2-ol (see Liebigs Ann. Chem. 1978.1194) are added. The reaction mixture is heated to 160 C., until there is no further reaction, and after cooling evaporated to dryness. The residue is combined with ice water. The product is extracted with dichloromethane and purified by chromatography. 125 mg (III-8) are obtained as a solid. Analytical HPLC-MS (method A): RT=1.08 min.
125 mg	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 160℃;	25.1 2-[1-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-cyclopropyl]-propan-2-ol (III-8) 2.7 g (II) are placed in 30 ml dioxane, then 6.8 ml diisopropyl-ethylamine and 1.8 g 2-(1-aminocyclopropyl)-propan-2-ol (see Liebigs Ann. Chem. 1978, 1194) are added. The reaction mixture is heated to 160 C. until there is no further reaction, and after cooling it is evaporated to dryness. The residue is combined with ice water. The product is extracted with dichloromethane and purified by chromatography. 125 mg (III-8) are obtained as a solid. Analytical HPLC-MS (method A): RT=1.08 min.

Reference： [1]Patent: US2011/21501,2011,A1 .Location in patent: Page/Page column 81
[2]Patent: US2013/225609,2013,A1 .Location in patent: Paragraph 0378; 0379

20
[ 74901-69-2 ]
cis-N-tert-butyloxycarbonyl-1,2-cyclopropanediamine hydrochloride [ No CAS ]
tert-butyl [2-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)cyclopropyl]carbamidate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 110℃;Microwave irradiation;	58.5 tert-butyl[2-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)-cyclopropyl]-carbamidate (III-9) 0.55 g (II) are placed in 9 ml dioxane, then 1.4 ml diisopropyl ethylamine and 0.6 g cis-N-tent-butyloxycarbonyl-1,2-cyclopropanediamin hydrochloride (see 58.4) are added. The reaction mixture is heated in the microwave at 110 C. until there is no further reaction and after cooling it is evaporated to dryness. The residue is treated with water in the ultrasound bath, the precipitate is suction filtered and washed with water. The solid is treated with 10 ml petroleum ether/ethyl acetate=7/3 and suction filtered. 520 mg (III-9) are obtained as a solid. Analytical HPLC-MS (method B): RT=1.42 min.

Reference： [1]Patent: US2011/21501,2011,A1 .Location in patent: Page/Page column 96

21
[ 372-19-0 ]
[ 74901-69-2 ]
[ 954408-78-7 ]

Reference： [1]Patent: US2011/28441,2011,A1
[2]Patent: US2013/225609,2013,A1

22
[ 38041-19-9 ]
[ 74901-69-2 ]
[ 1143575-85-2 ]

Reference： [1]Patent: US2011/28441,2011,A1
[2]Patent: US2011/46096,2011,A1
[3]Patent: US2013/237527,2013,A1
[4]Patent: US2013/225609,2013,A1

23
[ 74901-69-2 ]
[ 1143575-83-0 ]

Reference： [1]Patent: US2011/28441,2011,A1
[2]Patent: US2011/46096,2011,A1
[3]Patent: US2012/28932,2012,A1
[4]Patent: US2013/225609,2013,A1

24
[ 74901-69-2 ]
[ 1146361-87-6 ]

Reference： [1]Patent: US2011/28441,2011,A1
[2]Patent: US2013/225609,2013,A1

25
[ 74901-69-2 ]
[ 1147397-43-0 ]

Reference： [1]Patent: US2011/28441,2011,A1

26
[ 74901-69-2 ]
[ 1147398-49-9 ]

Reference： [1]Patent: US2011/28441,2011,A1

27
[ 74901-69-2 ]
[ 1143576-02-6 ]
[ 1143576-06-0 ]

Reference： [1]Patent: US2011/28441,2011,A1
[2]Patent: US2012/28932,2012,A1
[3]Patent: US2013/237527,2013,A1

28
[ 74901-69-2 ]
[ 1143575-87-4 ]

Reference： [1]Patent: US2011/46096,2011,A1

29
[ 74901-69-2 ]
[ 1146426-58-5 ]

Reference： [1]Patent: US2011/46096,2011,A1

30
[ 74901-69-2 ]
[ 954408-78-7 ]

Reference： [1]Patent: US2011/46096,2011,A1
[2]Patent: US2013/237527,2013,A1

31
[ 74901-69-2 ]
(S)-5-{2-[5-(4-chlorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-ylamino}-1-methylpiperidin-2-one [ No CAS ]

Reference： [1]Patent: US2011/46096,2011,A1

32
[ 74901-69-2 ]
{2-[5-(4-bromophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl}-(3-fluorophenyl)-amine [ No CAS ]

Reference： [1]Patent: US2011/46096,2011,A1

33
[ 74901-69-2 ]
[ 1008-91-9 ]

Reference： [1]Patent: US2012/28932,2012,A1
[2]Patent: US2012/28932,2012,A1

34
[ 74901-69-2 ]
[ 1143575-85-2 ]

Reference： [1]Patent: US2012/28932,2012,A1
[2]Patent: WO2019/57806,2019,A1

35
[ 74901-69-2 ]
[ 276237-03-7 ]

Reference： [1]Patent: US2012/35143,2012,A1

36
[ 74901-69-2 ]
[ 1146358-77-1 ]

Reference： [1]Patent: US2012/35143,2012,A1

37
[ 74901-69-2 ]
[ 67997-58-4 ]
[ 1146362-16-4 ]

Reference： [1]Patent: US2012/35143,2012,A1
[2]Patent: US2013/225609,2013,A1

38
[ 1196101-46-8 ]
[ 74901-69-2 ]

Reference： [1]Patent: WO2013/26797,2013,A1
[2]Patent: US2014/228286,2014,A1
[3]Patent: WO2014/124860,2014,A1
[4]Patent: US2015/45376,2015,A1
[5]Organic Process Research and Development,2016,vol. 20,p. 982 - 988

39
[ 74901-69-2 ]
C₁₁H₁₄ClN₃O₂S [ No CAS ]

Reference： [1]Patent: WO2013/26797,2013,A1
[2]Patent: US2014/228286,2014,A1
[3]Patent: US2015/45376,2015,A1

40
[ 74901-69-2 ]
(1-{2-[4-(4-chloro-phenyl)-piperidin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3.2-d]pyrimidin-4-yl-amino}-cyclobutyl)-methanol [ No CAS ]

Reference： [1]Patent: WO2013/26797,2013,A1
[2]Patent: US2014/228286,2014,A1
[3]Patent: US2014/228286,2014,A1
[4]Patent: US2014/228286,2014,A1
[5]Patent: US2015/45376,2015,A1

41
[ 74901-69-2 ]
(1-{2-[4-(5-chloro-pyrimidin-2-yl)-piperidin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl-amino}-cyclobutyl)-methanol [ No CAS ]

Reference： [1]Patent: WO2013/26797,2013,A1
[2]Patent: US2014/228286,2014,A1
[3]Patent: US2014/228286,2014,A1
[4]Patent: US2014/228286,2014,A1
[5]Patent: US2015/45376,2015,A1

42
[ 74901-69-2 ]
C₆H₁₃N*C₇H₈O₃S [ No CAS ]
[ 1423719-34-9 ]

Yield	Reaction Conditions	Operation in experiment
57%	With triethylamine; In acetonitrile; at 22 - 77℃; for 12h;	Intermediates VII (180 g, 852 mmol) and A (129 g, 937 mol) were sequentially charged into a multi-neck vessel equipped with a condenser, thermocouple thermometer and nitrogen line. Acetonitrile (900 ml) and triethylamine (594 ml, 4.26 mol) were then added at 22 C and the mixture was stirred at 75-77 C for 12 h. Water (1.2 1) was charged slowly over 20 min, the mixture was seeded with Compound VIII crystals (0.3 g) at 40 C and then cooled to 25 C over 2 h. The mixture was stirred for an additional 12h at normal room temperature and the resulting solid was collected by filtration. The filter cake was rinsed with 2: 1 mixture of water/MeCN (400 mL) followed by water (200 ml). The resulting solid was dried under vacuum at 50 C for 12 h to afford 132 g (57% yield) of compound VIII: 1H NMR (400 MHz, CDCls) delta 1.85-2.05 (m, 2H), 2.10-2.21 (m, 2H), 2.32-2.41 (m, 2H), 3.27 (dd, J = 8.0, 8.4 Hz, 2H), 3.43 (dd, J= 8.0, 8.4 Hz, 2H), 3.91 (s, 2H), 4.67 (s, 1H); 13C NMR (CDC13, 100 MHz) delta 14.8, 30.7, 31.2, 36.7, 59.7, 67.6, 114.7, 156.1, 156.2, 168.0.

Reference： [1]Patent: WO2013/26797,2013,A1 .Location in patent: Page/Page column 27

43
[ 7400-45-5 ]
[ 74901-69-2 ]

Reference： [1]Patent: WO2013/26797,2013,A1
[2]Patent: WO2013/50508,2013,A1
[3]Patent: WO2013/50508,2013,A1
[4]Patent: US2014/228286,2014,A1
[5]Patent: WO2014/124860,2014,A1
[6]Patent: US2015/45376,2015,A1
[7]Organic Process Research and Development,2016,vol. 20,p. 982 - 988
[8]Organic Process Research and Development,2016,vol. 20,p. 982 - 988

44
[ 350595-57-2 ]
[ 74901-69-2 ]
[ 1429639-74-6 ]

Yield	Reaction Conditions	Operation in experiment
46%	With triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃;	Step (vi)To a solution of <strong>[74901-69-2]<strong>[74901-69-2]2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidin</strong>e</strong> (200.0 mg, 0.96 mmol) and Et3N (195.5 mg, 1.93 mmol) in DMF (2.0 mL) at 0 C was added (5)-3-methylmorpholine (97.7 mg) dropwise. The mixture was stirred overnight at rt then was partitioned between H20 and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers washed with brine, dried over anhydrous Na2S04, filtered, evaporated and then the crude product which was purified by column chromatography on silica gel (eluent: PE/EA=20: 1-2/1) to provide (5)-2-chloro-4-(3-methylmorpholino)-6,7-dihydrothieno[3,2-d]pyrimidine as a light yellow solid (120 mg, 46%).LC-MS (Method A), (ES+) 272/274, RT = 4.88 min.

Reference： [1]Patent: WO2013/50508,2013,A1 .Location in patent: Page/Page column 44; 64

45
[ 4900-98-5 ]
[ 74901-69-2 ]

Reference： [1]Patent: WO2013/50508,2013,A1

46
[ 913581-92-7 ]
[ 74901-69-2 ]

Yield	Reaction Conditions	Operation in experiment
1 g	With P,P-dichlorophenylphosphine oxide; at 130 - 140℃; for 6h;	Step (v)6,7-dihydrothieno[3,2-d]pyrimidine-2,4(lH,3H)-dione (1.8 g, 10.57 mmol) was suspended in 4.0 mL of phenylphosphonyl di chloride. The suspension was heated to 130-140 C and stirred for 6 h. The resulting reaction mixture was cooled down and poured into 10.0 ml of ice-water.The mixture was extracted with ethyl acetate,the organic layers were combined, washed with saturated NaHC03 and brine, dried over anhydrous Na2S04, filtered and evaporated. The crude product was then purified by column chromatography on silica gel (eluent: PE/EA=20: 1-10/1) to provide 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine an off-white solid (1.0 g, 46 %).LC-MS (Method A), (ES+)207/209, RT = 4.68 min

Reference： [1]Patent: WO2013/50508,2013,A1 .Location in patent: Page/Page column 44; 63; 64

47
[ 74901-69-2 ]
[ 1429639-75-7 ]

Reference： [1]Patent: WO2013/50508,2013,A1

48
[ 74901-69-2 ]
[ 1429638-96-9 ]

Reference： [1]Patent: WO2013/50508,2013,A1

49
[ 74901-69-2 ]
[ 57260-71-6 ]
[ 1443256-93-6 ]

Yield	Reaction Conditions	Operation in experiment
0.83 g	In ethanol; dichloromethane; at 20 - 60℃;	6.01.42.02 4-(2-Chloro-6,7-dihydro-thieno[3,2-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester 454 mg piperazine-1-carboxylic acid tert-butyl ester in 5 mL ethanol was added to 0.5 g <strong>[74901-69-2]<strong>[74901-69-2]2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidin</strong>e</strong> in 5 mL dichlormethane. The reaction was stirred 2 h at RT, 3 h at 60 C. and over night at RT. The solvents were removed and water was added to the residue. The precipitate was filtered and dried to give 0.83 g of the desired product. Rt: 2.33 min (method I), (M+H)+: 357/359
0.83 g	In ethanol; dichloromethane; at 20 - 60℃;	6.01.42.02 4-(2-Chloro-6, 7-dihydro-thieno [3, 2-d] pyrimidin-4-yl)-piperazine-l-carboxylic acid tert-butyl ester 454 mg piperazine-l-carboxylic acid tert-butyl ester in 5 mL ethanol was added to 0.5 g 2,4- dichloro-6, 7-dihydro-thieno [3, 2-d] pyrimidine in 5 mL dichlormethane. The reaction was stirred 2 h at RT, 3h at 60C and over night at RT. The solvents were removed and water was added to the residue. The precipitate was filtered and dried to give 0.83 g of the desired product. Rt: 2.33 min (method I), (M+H)+: 357/359

Reference： [1]Patent: US2013/150341,2013,A1 .Location in patent: Paragraph 0368; 0369; 0370
[2]Patent: WO2013/83741,2013,A1 .Location in patent: Page/Page column 90

50
[ 74901-69-2 ]
[ 1443256-94-7 ]

Reference： [1]Patent: US2013/150341,2013,A1
[2]Patent: WO2013/83741,2013,A1

51
[ 74901-69-2 ]
[ 1146355-27-2 ]

Reference： [1]Patent: US2013/225609,2013,A1

52
[ 74901-69-2 ]
[ 1143573-98-1 ]

Reference： [1]Patent: US2013/237527,2013,A1

53
[ 74901-69-2 ]
[ 1143574-12-2 ]

Reference： [1]Patent: US2013/237527,2013,A1

54
[ 74901-69-2 ]
[ 1146355-24-9 ]

Reference： [1]Patent: US2013/225609,2013,A1

55
[ 74901-69-2 ]
5-(2-chloro-5,5-dioxo-6,7-dihydro-5H-5λ⁶-thieno[3,2-d]pyrimidin-4-ylamino)-1-methylpiperidin-2-one [ No CAS ]

Reference： [1]Patent: US2013/225609,2013,A1

56
[ 74901-69-2 ]
[ 1423719-33-8 ]
[ 1423719-34-9 ]

Yield	Reaction Conditions	Operation in experiment
57%	With triethylamine; In acetonitrile; at 22 - 77℃; for 12h;Inert atmosphere;	Intermediates VII (180 g, 852 mmol) and A (129 g, 937 mol) were sequentially charged into a multi-neck vessel equipped with a condenser, thermocouple thermometer and nitrogen line. Acetonitrile (900 ml) and triethylamine (594 ml, 4.26 mol) were then added at 22 C. and the mixture was stirred at 75-77 C. for 12 h. Water (1.2 l) was charged slowly over 20 min, the mixture was seeded with Compound VIII crystals (0.3 g) at 40 C. and then cooled to 25 C. over 2 h. The mixture was stirred for an additional 12 h at normal room temperature and the resulting solid was collected by filtration. The filter cake was rinsed with 2:1 mixture of water/MeCN (400 mL) followed by water (200 ml). The resulting solid was dried under vacuum at 50 C. for 12 h to afford 132 g (57% yield) of compound VIII: 1H NMR (400 MHz, CDCl3) delta 1.85-2.05 (m, 2H), 2.10-2.21 (m, 2H), 2.32-2.41 (m, 2H), 3.27 (dd, J=8.0, 8.4 Hz, 2H), 3.43 (dd, J=8.0, 8.4 Hz, 2H), 3.91 (s, 2H), 4.67 (s, 1H); 13C NMR (CDCl3, 100 MHz) delta 14.8, 30.7, 31.2, 36.7, 59.7, 67.6, 114.7, 156.1, 156.2, 168.0.
57%	With triethylamine; In acetonitrile; at 22 - 77℃; for 12h;Inert atmosphere;	Intermediates VII (180 g, 852 mmol) and A (129 g, 937 mol) were sequentially charged into a multi-neck vessel equipped with a condenser, thermocouple thermometer and nitrogen line. Acetonitrile (900 ml) and triethylamine (594 ml, 4.26 mol) were then added at 22 C and the mixture was stirred at 75-77 C for 12 h. Water (1 .2 I) was charged slowly over 20 min, the mixture was seeded with Compound VIII crystals (0.3 g) at 40 C and then cooled to 25 C over 2 h. The mixture was stirred for an additional 12h at normal room temperature and the resulting solid was collected by filtration. The filter cake was rinsed with 2:1 mixture of water/MeCN (400 mL) followed by water (200 ml). The resulting solid was dried under vacuum at 50 C for 12 h to afford 132 g (57% yield) of compound VIII: 1H NMR (400 MHz, CDCIs) delta 1 .85-2.05 (m, 2H), 2.10-2.21 (m, 2H), 2.32-2.41 (m, 2H), 3.27 (dd, J = 8.0, 8.4 Hz, 2H), 3.43 (dd, J = 8.0, 8.4 Hz, 2H), 3.91 (s, 2H), 4.67 (s, 1 H); 13C NMR (CDCI3, 100 MHz) delta 14.8, 30.7, 31 .2, 36.7, 59.7, 67.6, 1 14.7, 156.1 , 156.2, 168.0.
57%	With triethylamine; In acetonitrile; at 75 - 77℃; for 12h;Inert atmosphere;	Intermediates VII (180 g, 852 mmol) and A (129 g, 937 mol) were sequentially charged into a multi-neck vessel equipped with a condenser, thermocouple thermometer and nitrogen line. Acetonitrile (900 ml) and triethylamine (594 ml, 4.26 mol) were then added at 22 C. and the mixture was stirred at 75-77 C. for 12 h. Water (1.2 l) was charged slowly over 20 min, the mixture was seeded with Compound VIII crystals (0.3 g) at 40 C. and then cooled to 25 C. over 2 h. The mixture was stirred for an additional 12 h at normal room temperature and the resulting solid was collected by filtration. The filter cake was rinsed with 2:1 mixture of water/MeCN (400 mL) followed by water (200 ml). The resulting solid was dried under vacuum at 50 C. for 12 h to afford 132 g (57% yield) of compound VIII: 1H NMR (400 MHz, CDCl3) delta 1.85-2.05 (m, 2H), 2.10-2.21 (m, 2H), 2.32-2.41 (m, 2H), 3.27 (dd, J=8.0, 8.4 Hz, 2H), 3.43 (dd, J=8.0, 8.4 Hz, 2H), 3.91 (s, 2H), 4.67 (s, 1H); 13C NMR (CDCl3, 100 MHz) delta 14.8, 30.7, 31.2, 36.7, 59.7, 67.6, 114.7, 156.1, 156.2, 168.0.

Reference： [1]Patent: US2014/228286,2014,A1 .Location in patent: Paragraph 0251-0252
[2]Patent: WO2014/124860,2014,A1 .Location in patent: Page/Page column 45; 46
[3]Patent: US2015/45376,2015,A1 .Location in patent: Paragraph 0085-0086

57
[ 74901-69-2 ]
(1-{2-[4-(5-chloro-pyrimidin-2-yl)-piperidin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl-amino}-cyclobutyl)-methanol [ No CAS ]

Reference： [1]Patent: WO2014/124860,2014,A1

58
[ 74901-69-2 ]
(1-{2-[4-(4-chloro-phenyl)-piperidin-1-yl]-5-oxo-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl-amino}-cyclobutyl)-methanol [ No CAS ]

Reference： [1]Patent: WO2014/124860,2014,A1

59
[ 74901-69-2 ]
[ 1423719-38-3 ]

Reference： [1]Patent: WO2014/124860,2014,A1

60
[ 74901-69-2 ]
(5R)-2-chloro-5-oxido-N-tetrahydropyran-4-yl-6,7-dihydrothieno[3,2-d]pyrimidin-5-ium-4-amine [ No CAS ]

Reference： [1]Organic Process Research and Development,2016,vol. 20,p. 982 - 988
[2]Patent: WO2019/57806,2019,A1
[3]Patent: WO2019/115775,2019,A1
[4]Patent: WO2019/115774,2019,A1

61
[ 74901-69-2 ]
C₆H₄Cl₂N₂OS [ No CAS ]
C₆H₄Cl₂N₂OS [ No CAS ]

Reference： [1]Organic Process Research and Development,2016,vol. 20,p. 982 - 988

62
[ 74901-69-2 ]
(R)-2-(4-(benzo[d]oxazol-2-yl)piperazin-1-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide [ No CAS ]

Reference： [1]Organic Process Research and Development,2016,vol. 20,p. 982 - 988

63
[ 74901-69-2 ]
(R)-2-(4-(4-chlorophenoxy)piperidin-1-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide [ No CAS ]

Reference： [1]Organic Process Research and Development,2016,vol. 20,p. 982 - 988

64
[ 74901-69-2 ]
[ 33024-60-1 ]
[ 1143575-84-1 ]
C₁₁H₁₄ClN₃OS [ No CAS ]

Reference： [1]Organic Process Research and Development,2016,vol. 20,p. 982 - 988

65
[ 74901-69-2 ]
[ 4198-90-7 ]
4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%		4-Hydroxy-3,5-dimethylbenzonitrile (1.5 g, 10 mmol) and potassium carbonate (1.7 g, 12 mmol) were weighed in 30 mL of DMF and stirred at room temperature for 15 min.Then, <strong>[74901-69-2]<strong>[74901-69-2]2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidin</strong>e</strong> 6 (2.1 g, 10 mmol) was added and the mixture was stirred at room temperature for 2 h (TLC detection reaction was completed).A large amount of white solid was formed, 100 mL of ice water was slowly added thereto, filtered, dried in a vacuum oven, and recrystallized from ethanol to give Intermediate 7.White solid, yield 94%,

Reference： [1]Patent: CN108218890,2018,A .Location in patent: Paragraph 0039; 0041; 0042; 0043
[2]Journal of Medicinal Chemistry,2019,vol. 62,p. 1484 - 1501

66
[ 4900-98-5 ]
[ 74901-69-2 ]