[ CAS No. 175137-13-0 ]

Name: 175137-13-0|7-Methylthieno[3,2-d]pyrimidin-4(1H)-one|98+%
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Product Details of [ 175137-13-0 ]

CAS No. :	175137-13-0	MDL No. :	MFCD00205194
Formula :	C₇H₆N₂OS	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KJTYNZWEAIRZHT-UHFFFAOYSA-N
M.W :	166.20	Pubchem ID :	135439636
Synonyms :

Safety of [ 175137-13-0 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P261-P264-P270-P271-P280-P301+P312-P302+P352-P304+P340-P305+P351+P338-P330-P332+P313-P337+P313-P362-P403+P233-P405-P501	UN#:
Hazard Statements:	H302-H312-H315-H319-H332-H335	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 175137-13-0 ]

* 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 [ 175137-13-0 ]
Downstream synthetic route of [ 175137-13-0 ]

[ 175137-13-0 ] Synthesis Path-Upstream 1~3

1
[ 175137-13-0 ]
[ 175137-21-0 ]

Yield	Reaction Conditions	Operation in experiment
95%	for 2 h; Heating / reflux	4-Chloro-7-methylthieno[3,2-d]pyrimidine (168): A solution of 7-methyl-3H-thieno[3,2-d]pyrimid-4-one (167, 10.6 g, 64.0 mmol) in phosphorus oxychloride (42 mL) was refluxed under N₂for 2 hours. The resulting solution was allowed to cool to room temperature and then neutralized by carefully pouring into a saturated aqueous solution of sodium carbonate (300 mL). The aqueous mixture was extracted with ethyl acetate and the organic layer washed with water and brine, before drying over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue dried over P₂O₅under vacuum overnight (11.2 g, 95percent yield, white solid).
81%	With trichlorophosphate In N,N-dimethyl-formamide at 110℃; for 4 h;	7-methyl-3H-thieno[3,2-d]pyrimidin-4-one (9 g, 54.2 mmol), DMF (lmL), POCl₃ (80mL) were mixed and refluxed for 4 hours at 110°C. The reaction solution was cooled to room temperature, and the reaction mixture was concentrated under reduced pressure. The reaction mixture was added with toluene, and further concentrated under reduced pressure. The resulting residue was neutralized with sodium bicarbonate, subjected to extraction with ethyl acetate, dried, and filtered to obtain the title compound (8.1 g, 81percent). -NMR Spectrum (300 MHz, CDC1₃): δ 9.01 (s, IH), 7.69 (s, IH), 2.53 (s, 3H)
81%	at 110℃; for 4 h;	7-methyl-3H-thieno[3,2-d]pyrimidin-4-one (9 g, 54.2 mmol), DMF (1 mL), POCl₃ (80 mL) were mixed and refluxed for 4 hours at 110° C. The reaction solution was cooled to room temperature, and the reaction mixture was concentrated under reduced pressure. The reaction mixture was added with toluene, and further concentrated under reduced pressure. The resulting residue was neutralized with sodium bicarbonate, subjected to extraction with ethyl acetate, dried, and filtered to obtain the title compound (8.1 g, 81percent). ¹H-NMR Spectrum (300 MHz, CDCl₃): δ 9.01 (s, 1H), 7.69 (s, 1H), 2.53 (s, 3H)

20%	for 3 h; Reflux	Synthesis of intermediate XI 11-011-07 XIII-01A mixture of Intermediate 1-07 (4.85 g, 24.34 mnmol) and POCI₃ (20 mL) was refluxed for 3 h. On cooling, the solvents were removed in vacuo, the residue was suspended in water and the suspension was cooled to 0 °C. Aqueous saturated Na₂C0₃ was added dropwise at 0 °C up to pH~8. The resulting solid was filtered, washed with water and dried to give Intermediate XIII-01 (1.1 g, 20percent) as a white solid. H NMR (300 MHz, DMSO) δ 9.01 (s, 1H), 8.19 (q, J = 1.1 Hz, 1H), 2.39 (d, J = 1.1 Hz, 3H).
1.9 g	at 100℃; for 6 h;	Commercially available methyl 3-amino-4-methylthiophene-2-carboxylate 13 (16.5 g, 96.0 mmol) was dissolved in formamide (100 mL) and stirred at 150 °C under nitrogen atmosphere. After the starting material consumption had been confirmed by LC-MS, the reaction mixture was cooled to room temperature and then H₂O (500 mL) was added to the mixture. The suspension was filtered to collect a white solid that was dried by an oil pump to give 7-methylthieno[3,2-d]pyrimidin-4(3H)-one (12.2 g). The solid was used for the next reaction without further purification. The aforementioned 7-methylthieno[3,2-d]pyrimidin-4(3H)-one (1.85 g) was treated with POCl₃ (8.80 mL) and stirred at 100 °C for 6 h. The reaction mixture was cooled to 0 °C, poured into ice-water/ethyl acetate, and extracted with ethyl acetate twice. The organic layer was washed with brine, dried over Na₂SO₄, and filtered. The organic solvent was concentrated under reduced pressure to give a crude residue. Water (200 mL) was added to the residue and the mixture cooled at 5 °C in the refrigerator for a day. The suspension was filtered to afford 14 (1.90 g, 2 steps 72percent) as a white solid. ¹H NMR (400 MHz, DMSO-D₆) δ: 9.07 (1H, s), 8.25 (1H, d, J = 1.2 Hz), 2.45 (3H, d, J = 1.2 Hz). ¹³C NMR (100 MHz, DMSO-D₆) δ: 160.7, 153.9, 153.6, 133.9, 133.2, 130.0, 12.5. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₇H₆ClN₂S 184.9940; Found 184.9937.

Reference： [1] Patent: US2006/4002, 2006, A1, . Location in patent: Page/Page column 12; 21; 23; 30; 31-32
[2] Patent: WO2013/100632, 2013, A1, . Location in patent: Page/Page column 62
[3] Patent: US2014/371219, 2014, A1, . Location in patent: Paragraph 0436; 0437
[4] Patent: WO2012/156756, 2012, A2, . Location in patent: Page/Page column 99
[5] Patent: WO2011/93684, 2011, A2, . Location in patent: Page/Page column 33; 34
[6] Patent: WO2011/93672, 2011, A2, . Location in patent: Page/Page column 45; 46
[7] Patent: US2012/15962, 2012, A1, . Location in patent: Page/Page column 66
[8] Patent: US2012/302567, 2012, A1, . Location in patent: Page/Page column 20
[9] Patent: US2013/53370, 2013, A1, . Location in patent: Paragraph 0269-0271
[10] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 18, p. 4206 - 4217

2
[ 175137-13-0 ]
[ 175137-21-0 ]

Yield	Reaction Conditions	Operation in experiment
96%	With sodium hydrogencarbonate In trichlorophosphate	A solution of 7-methyl-3H-thieno[3,2-d]pyrimid-4-one (3, 2.9 g, 18 mmol) in phosphorus oxychloride (18 mL) under N₂ was heated at reflux for 1 hour. The resulting solution was allowed to cool to room temperature and then poured into a saturated aqueous solution of sodium bicarbonate to neutralize. The aqueous mixture was extracted with diethyl ether. The organic layer was washed with water followed by saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure to yield 4-chloro-7-methylthieno[3,2-d]pyrimidine (3.1 g, 96percent yield) as a white solid.

Reference： [1] Patent: US6503914, 2003, B1,

3
[ 443762-03-6 ]
[ 175137-13-0 ]
[ 175137-21-0 ]

Yield	Reaction Conditions	Operation in experiment
84%	With ammonium formate In formamide	To a solution of ammonium formate (5.1 g, 81 mmol) in formamide (25 mL) at 150° C. was added 3-(formylamino)-4-methyl-2-thiophenecarboxylic acid methyl ester (2, 5.0 g, 25 mmol) as a solid in small portions. The resulting solution was heated at 150° C. for 5 hours and then allowed to stand at room temperature for 12 hours. The precipitate that formed was collected by vacuum filtration to give 7-methyl-3H-thieno[3,2-d]pyrimid-4-one (3.4 g, 84percent yield) as white needles. 4-Chloro-7-methylthieno[3,2-d]pyrimidine (4).

Reference： [1] Patent: US6503914, 2003, B1,

[ 175137-13-0 ] Synthesis Path-Downstream 1~50

1
[ 175137-13-0 ]
[ 175137-21-0 ]

Yield	Reaction Conditions	Operation in experiment
95%	With trichlorophosphate; for 2h;Heating / reflux;	4-Chloro-7-methylthieno[3,2-d]pyrimidine (168): A solution of 7-methyl-3H-thieno[3,2-d]pyrimid-4-one (167, 10.6 g, 64.0 mmol) in phosphorus oxychloride (42 mL) was refluxed under N2 for 2 hours. The resulting solution was allowed to cool to room temperature and then neutralized by carefully pouring into a saturated aqueous solution of sodium carbonate (300 mL). The aqueous mixture was extracted with ethyl acetate and the organic layer washed with water and brine, before drying over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue dried over P2O5 under vacuum overnight (11.2 g, 95% yield, white solid).
81%	With trichlorophosphate; In N,N-dimethyl-formamide; at 110℃; for 4h;	7-methyl-3H-thieno[3,2-d]pyrimidin-4-one (9 g, 54.2 mmol), DMF (lmL), POCl3 (80mL) were mixed and refluxed for 4 hours at 110C. The reaction solution was cooled to room temperature, and the reaction mixture was concentrated under reduced pressure. The reaction mixture was added with toluene, and further concentrated under reduced pressure. The resulting residue was neutralized with sodium bicarbonate, subjected to extraction with ethyl acetate, dried, and filtered to obtain the title compound (8.1 g, 81%). -NMR Spectrum (300 MHz, CDC13): δ 9.01 (s, IH), 7.69 (s, IH), 2.53 (s, 3H)
81%	With N,N-dimethyl-formamide; trichlorophosphate; at 110℃; for 4h;	7-methyl-3H-thieno[3,2-d]pyrimidin-4-one (9 g, 54.2 mmol), DMF (1 mL), POCl3 (80 mL) were mixed and refluxed for 4 hours at 110 C. The reaction solution was cooled to room temperature, and the reaction mixture was concentrated under reduced pressure. The reaction mixture was added with toluene, and further concentrated under reduced pressure. The resulting residue was neutralized with sodium bicarbonate, subjected to extraction with ethyl acetate, dried, and filtered to obtain the title compound (8.1 g, 81%). 1H-NMR Spectrum (300 MHz, CDCl3): δ 9.01 (s, 1H), 7.69 (s, 1H), 2.53 (s, 3H)

20%	With trichlorophosphate; for 3h;Reflux;	Synthesis of intermediate XI 11-011-07 XIII-01A mixture of Intermediate 1-07 (4.85 g, 24.34 mnmol) and POCI3 (20 mL) was refluxed for 3 h. On cooling, the solvents were removed in vacuo, the residue was suspended in water and the suspension was cooled to 0 C. Aqueous saturated Na2C03 was added dropwise at 0 C up to pH~8. The resulting solid was filtered, washed with water and dried to give Intermediate XIII-01 (1.1 g, 20%) as a white solid. H NMR (300 MHz, DMSO) δ 9.01 (s, 1H), 8.19 (q, J = 1.1 Hz, 1H), 2.39 (d, J = 1.1 Hz, 3H).
		7-Methylthieno[3,2-d]pyrimidine-4(3H)-one (1.5g) was added to POCl3 (lOmL), and the mixture was stirred at 110C for 2 hours. The reaction mixture was cooled to room temperature, concentrated and dilluted with DCM, and sat. NaHC03 solution was added thereto. The aqueous layer was extracted with DCM to combine organic layers. The organic layer was dried with MgS04 and filtered to obtain the title compound as a white solid.1H NMR (400MHz, DMSO-d6) δ 9.06 (s, 1H), 8.24 (s, 1H), 2.43 (s, 3H).
		7-Methylthieno[3,2-d]pyrimidine-4(3H)-one(1.5g) was dissolved in phosphorous oxychloride(lOmL) and stirred at 110 C for 2 hrs. The reaction mixture was cooled to room temperature and concentrated under a reduced pressure. The resulting concentrate was added to a mixture of dichloromethane and a saturated sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane four times. The combined organic layers were dried over magnesium sulfate and concentrated under a reduced pressure to obtain the title compound as a cream and white solid.1H NMR (400MHz, DMSO-d6) δ 9.06(s, 1H), 8.24 (s, 1H), 2.43(s, 3H).
	With trichlorophosphate; at 100℃; for 1h;	A suspension of 7-methyl-3H-thieno[3,2-d]pyrimidin-4-one (2.1 g) in phosphorus oxychloride (10 mL) was heated at 100 C. for 1 hour. The reaction mixture was then cooled and poured into a mixture of ice-water and ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (DCM) to afford 2.0 g of 4-chloro-7-methyl-thieno[3,2-d]pyrimidine.
	With trichlorophosphate; at 110℃; for 2h;	b. 4-Chloro-7-methylthieno[3,2-d]pyrimidine 7-Methylthieno[3,2-d]pyrimidine-4(3H)-one (1.5 g) was dissolved in phosphorous oxychloride (10 mL) and stirred at 110 C. for 2 hrs. The reaction mixture was cooled to room temperature and concentrated under a reduced pressure. The resulting concentrate was added to a mixture of dichloromethane and a saturated sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane four times. The combined organic layers were dried over magnesium sulfate and concentrated under a reduced pressure to obtain the title compound as a cream and white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.24 (s, 1H), 2.43 (s, 3H).
	With trichlorophosphate; at 110℃; for 2h;	Step 2: 4-Chloro-7-methylthieno[3,2-d]pyrimidine 7-Methylthieno[3,2-d]pyrimidine-4(3H)-one (1.5 g) was added to POCl3 (10 mL), and the mixture was stirred at 110 C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated and diluted with DCM, and sat. NaHCO3 solution was added thereto. The aqueous layer was extracted with DCM to combine organic layers. The organic layer was dried with MgSO4 and filtered to obtain the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.24 (s, 1H), 2.43 (s, 3H).
1.9 g	With trichlorophosphate; at 100℃; for 6h;	Commercially available methyl 3-amino-4-methylthiophene-2-carboxylate 13 (16.5 g, 96.0 mmol) was dissolved in formamide (100 mL) and stirred at 150 C under nitrogen atmosphere. After the starting material consumption had been confirmed by LC-MS, the reaction mixture was cooled to room temperature and then H2O (500 mL) was added to the mixture. The suspension was filtered to collect a white solid that was dried by an oil pump to give 7-methylthieno[3,2-d]pyrimidin-4(3H)-one (12.2 g). The solid was used for the next reaction without further purification. The aforementioned 7-methylthieno[3,2-d]pyrimidin-4(3H)-one (1.85 g) was treated with POCl3 (8.80 mL) and stirred at 100 C for 6 h. The reaction mixture was cooled to 0 C, poured into ice-water/ethyl acetate, and extracted with ethyl acetate twice. The organic layer was washed with brine, dried over Na2SO4, and filtered. The organic solvent was concentrated under reduced pressure to give a crude residue. Water (200 mL) was added to the residue and the mixture cooled at 5 C in the refrigerator for a day. The suspension was filtered to afford 14 (1.90 g, 2 steps 72%) as a white solid. 1H NMR (400 MHz, DMSO-D6) δ: 9.07 (1H, s), 8.25 (1H, d, J = 1.2 Hz), 2.45 (3H, d, J = 1.2 Hz). 13C NMR (100 MHz, DMSO-D6) δ: 160.7, 153.9, 153.6, 133.9, 133.2, 130.0, 12.5. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C7H6ClN2S 184.9940; Found 184.9937.

Reference： [1]Patent: US2006/4002,2006,A1 .Location in patent: Page/Page column 12; 21; 23; 30; 31-32
[2]Patent: WO2013/100632,2013,A1 .Location in patent: Page/Page column 62
[3]Patent: US2014/371219,2014,A1 .Location in patent: Paragraph 0436; 0437
[4]Patent: WO2012/156756,2012,A2 .Location in patent: Page/Page column 99
[5]Patent: WO2011/93684,2011,A2 .Location in patent: Page/Page column 33; 34
[6]Patent: WO2011/93672,2011,A2 .Location in patent: Page/Page column 45; 46
[7]Patent: US2012/15962,2012,A1 .Location in patent: Page/Page column 66
[8]Patent: US2012/302567,2012,A1 .Location in patent: Page/Page column 20
[9]Patent: US2013/53370,2013,A1 .Location in patent: Paragraph 0269-0271
[10]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 4206 - 4217

2
[ 443762-03-6 ]
[ 175137-13-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	Stage #1: methyl 3-formamido-4-methylthiophene-2-carboxylate With ammonium formate In formamide at 160℃; for 18h; Stage #2: for 0.5h;	Synthesis of Intermediate 1-07A mixture of Intermediate 1-06 (4.65 g, 23.25 mmol) and ammonium formate (10 g, 200 mmol) in formamide (6 mL) was heated at 160 °C for 18 h. On cooling, the resulting solid was filtered, washed with acetone and dried to give Intermediate 1- 07 (3.85 g, 99%) as a white solid.1H N R (300 MHz, DMSO) δ 8.18 (s, 1H), 7.81 (d, J = 0.7 Hz, 1H), 2.31 (d, J = 0.9 Hz, 3H).
72%	With ammonium formate In formamide at 160℃; for 6h;	1; 2; 3; 4; 5 7-Methyl-3H-thieno[3,2-d]pyrimid-4-one (167): 3-(Formylamino)-4-methyl-2-thiophenecarboxylic acid methyl ester (166, 10.0 g, 50.0 mmol), ammonium formate 26.0 g, (400 mmol) and formamide (12 mL) were heated at 160° C. for 6 hours under N2 and then cooled to room temperature. The precipitate was collected by vacuum filtration, washed with acetone, and dried over P2O5 under vacuum overnight (6.0 g 72% yield, white needles).

Reference： [1]Current Patent Assignee: SPANISH NATIONAL CANCER RESEARCH CENTER - WO2012/156756, 2012, A2 Location in patent: Page/Page column 83-84
[2]Current Patent Assignee: THE UNIVERSITY OF TEXAS SYSTEM - US2006/4002, 2006, A1 Location in patent: Page/Page column 11-12; 21; 23; 30; 31

3
aqueous sodium chloride [ No CAS ]
[ 175137-13-0 ]
[ 175137-21-0 ]

Yield	Reaction Conditions	Operation in experiment
96%	With sodium hydrogencarbonate; In trichlorophosphate;	A solution of 7-methyl-3H-thieno[3,2-d]pyrimid-4-one (3, 2.9 g, 18 mmol) in phosphorus oxychloride (18 mL) under N2 was heated at reflux for 1 hour. The resulting solution was allowed to cool to room temperature and then poured into a saturated aqueous solution of sodium bicarbonate to neutralize. The aqueous mixture was extracted with diethyl ether. The organic layer was washed with water followed by saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure to yield 4-chloro-7-methylthieno[3,2-d]pyrimidine (3.1 g, 96% yield) as a white solid.

Reference： [1]Patent: US6503914,2003,B1

4
[ 443762-03-6 ]
[ 175137-13-0 ]
[ 175137-21-0 ]

Yield	Reaction Conditions	Operation in experiment
84%	With ammonium formate; In formamide;	To a solution of ammonium formate (5.1 g, 81 mmol) in formamide (25 mL) at 150 C. was added 3-(formylamino)-4-methyl-2-thiophenecarboxylic acid methyl ester (2, 5.0 g, 25 mmol) as a solid in small portions. The resulting solution was heated at 150 C. for 5 hours and then allowed to stand at room temperature for 12 hours. The precipitate that formed was collected by vacuum filtration to give 7-methyl-3H-thieno[3,2-d]pyrimid-4-one (3.4 g, 84% yield) as white needles. 4-Chloro-7-methylthieno[3,2-d]pyrimidine (4).

Reference： [1]Patent: US6503914,2003,B1

5
[ 60100-09-6 ]
[ 85006-31-1 ]
[ 175137-13-0 ]

Yield	Reaction Conditions	Operation in experiment
91%	at 200℃; for 24h;	58.1 Preparation of 7-methyl-3H-thieno[3,2-d]pyrimidin-4-one 3- amino-4-methyl-thiophene-2-carboxylic acid methyl ester (10.2 g, 59.6 mmol) was dissolved in formamide (25 mL), followed by refluxing for 24 hours at 200°C. The reaction solution was slowly cooled to room temperature. The resulting solid was filtered, washed with diethyl ether, and dried to obtain the title compound (9 g, 91%). 1H-NMR Spectrum (300 MHz, DMSO-i): δ 8.17 (s, IH), 7.81 (s, IH), 2.31 (s, 3H)
91%	at 200℃; for 24h;	58.1 Preparation of 7-methyl-3H-thieno[3,2-d]pyrimidin-4-one 3-amino-4-methyl-thiophene-2-carboxylic acid methyl ester (10.2 g, 59.6 mmol) was dissolved in formamide (25 mL), followed by refluxing for 24 hours at 200° C. The reaction solution was slowly cooled to room temperature. The resulting solid was filtered, washed with diethyl ether, and dried to obtain the title compound (9 g, 91%). 1H-NMR Spectrum (300 MHz, DMSO-d6): δ 8.17 (s, 1H), 7.81 (s, 1H), 2.31 (s, 3H)
60%	at 20℃;

	at 200℃; for 3h;	7; 3.1 Methyl 3-amino-4-methylthiophene-2-carboxylate (3.0g) was added to formamide (5mL), and the mixture was stirred at 200°C for 3 hours. After cooling to room temperature water (50mL) was added thereto and then stirred for 15 hours at room temperature to obtain a solid. The solid was filtered, washed with water and dried with N2 gas to obtain the title compound as a white solid without further purification.1H NMR (400MHz, DMSO-d6) δ 12.50 (br, 1H), 8.16 (s, 1H), 7.86 (s, 1H), 2.30 (s,3H).
	at 200℃; for 3h;	7; 107.a Methyl 3-amino-4-methylthiophene-2-carboxylate(3.0g) (Aldrich, Catalog No. 546658) was dissolved in formamide(5mL), stirred at 200 °C for 3 hrs, and cooled to room temperature. Water(50mL) was added thereto, which was stirred at room temperature for 15 hrs. The resulting solution was filtered, and the solid thus obtained was washed with water and dried. The solid was added to acetone/diethyl ether, which was stirred and filtered to obtain the title compound as a white solid. NMR (400MHz, DMSO-d6) δ 12.50 (br, 1H), 8.16(s, 1H), 7.86 (s, 1H),2.30(s, 3H).
	at 150℃;	12.A A mixture of 3-amino-4-methyl-thiophene-2-carboxylic acid methyl ester (3.0 g) and formamide (50 mL) was heated to 150° C. overnight. The reaction mixture was then cooled and diluted with water. The solid formed was collected by filtration, washed with water and dried under reduced pressure to give 2.1 g of 7-methyl-3H-thieno[3,2-d]pyrimidin-4-one without further purifications.
	at 200℃; for 3h;	107.a a. 7-Methylthieno[3,2-d]pyrimidin-4(3H)-one Methyl 3-amino-4-methylthiophene-2-carboxylate (3.0 g) (Aldrich, Catalog No. 546658) was dissolved in formamide (5 mL), stirred at 200° C. for 3 hrs, and cooled to room temperature. Water (50 mL) was added thereto, which was stirred at room temperature for 15 hrs. The resulting solution was filtered, and the solid thus obtained was washed with water and dried. The solid was added to acetone/diethyl ether, which was stirred and filtered to obtain the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.50 (br, 1H), 8.16 (s, 1H), 7.86 (s, 1H), 2.30 (s, 3H).
	Stage #1: formamide; 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester In water at 200℃; for 3h; Stage #2: In water at 20℃; for 15h;	P.3.1 Step 1: 7-Methylthieno[3,2-d]pyrimidine-4(3H)-one Methyl 3-amino-4-methylthiophene-2-carboxylate (3.0 g) was added to formamide (5 mL), and the mixture was stirred at 200° C. for 3 hours. After cooling to room temperature water (50 mL) was added thereto and then stirred for 15 hours at room temperature to obtain a solid. The solid was filtered, washed with water and dried with N2 gas to obtain the title compound as a white solid without further purification. 1H NMR (400 MHz, DMSO-d6) δ 12.50 (br, 1H), 8.16 (s, 1H), 7.86 (s, 1H), 2.30 (s, 3H).
12.2 g	at 150℃; Inert atmosphere;	Commercially available methyl 3-amino-4-methylthiophene-2-carboxylate 13 (16.5 g, 96.0 mmol) was dissolved in formamide(100 mL) and stirred at 150°C under nitrogen atmosphere. After the starting material consumption had been confirmed by LC-MS, the reaction mixture was cooled to room temperature and then H2O (500 mL) was added to the mixture. The suspension was filtered to collect a white solid that was dried by an oil pump to give 7-methylthieno[3,2-d]pyrimidin-4(3H)-one (12.2 g). The solid was used for the next reaction without further purification.

Reference： [1]Current Patent Assignee: HANMI PHARM CO LTD - WO2013/100632, 2013, A1 Location in patent: Page/Page column 62
[2]Current Patent Assignee: HANMI PHARM CO LTD - US2014/371219, 2014, A1 Location in patent: Paragraph 0434; 0435
[3]Shao, Xuwei; Abdelkhalek, Ahmed; Abutaleb, Nader S.; Velagapudi, Uday Kiran; Yoganathan, Sabesan; Seleem, Mohamed N.; Talele, Tanaji T. [Journal of Medicinal Chemistry, 2019, vol. 62, # 21, p. 9772 - 9791]
[4]Current Patent Assignee: HANMI SCIENCE CO LTD; CATHOLIC UNIVERSITY OF KOREA; KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY - WO2011/93684, 2011, A2 Location in patent: Page/Page column 33
[5]Current Patent Assignee: HANMI PHARM CO LTD; HANMI SCIENCE CO LTD - WO2011/93672, 2011, A2 Location in patent: Page/Page column 45; 46
[6]Current Patent Assignee: ROCHE HOLDING AG - US2012/15962, 2012, A1 Location in patent: Page/Page column 66
[7]Current Patent Assignee: HANMI PHARM CO LTD; HANMI SCIENCE CO LTD - US2012/302567, 2012, A1 Location in patent: Page/Page column 20
[8]Current Patent Assignee: HANMI SCIENCE CO LTD; CATHOLIC UNIVERSITY OF KOREA; KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY - US2013/53370, 2013, A1 Location in patent: Paragraph 0266-0268
[9]Muraoka, Terushige; Ide, Mitsuaki; Morikami, Kenji; Irie, Machiko; Nakamura, Mitsuaki; Miura, Takaaki; Kamikawa, Takayuki; Nishihara, Masamichi; Kashiwagi, Hirotaka [Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 18, p. 4206 - 4217]

6
[ 175137-13-0 ]
7-(bromomethyl)-4-chlorothieno[3,2-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: trichlorophosphate / 2 h / 110 °C 2: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 1 h / 100 °C
	Multi-step reaction with 2 steps 1: trichlorophosphate / 2 h / 110 °C 2: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 100 °C

Reference： [1]Current Patent Assignee: HANMI PHARM CO LTD; HANMI SCIENCE CO LTD - WO2011/93672, 2011, A2 Current Patent Assignee: HANMI SCIENCE CO LTD; CATHOLIC UNIVERSITY OF KOREA; KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY - WO2011/93684, 2011, A2 Current Patent Assignee: HANMI PHARM CO LTD; HANMI SCIENCE CO LTD - US2012/302567, 2012, A1
[2]Current Patent Assignee: HANMI SCIENCE CO LTD; CATHOLIC UNIVERSITY OF KOREA; KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY - US2013/53370, 2013, A1

7
[ 175137-13-0 ]
[ 1269667-57-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: trichlorophosphate / 2 h / 110 °C 2: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 1 h / 100 °C 3: potassium iodide / N,N-dimethyl-formamide / 4 h / 35 °C 4: sodium hydroxide / tetrahydrofuran / 0.5 h / 20 °C 5: manganese(IV) oxide / chloroform / 2 h / 70 °C 6: sodium chlorite; sodium dihydrogenphosphate dihydrate / water; dimethyl sulfoxide / 0 - 20 °C
	Multi-step reaction with 6 steps 1: trichlorophosphate / 2 h / 110 °C 2: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 100 °C 3: potassium iodide / N,N-dimethyl-formamide / 4 h / 35 °C 4: water; sodium hydroxide / tetrahydrofuran / 0.5 h 5: manganese(IV) oxide / chloroform / 2 h / 70 °C 6: sodium dihydrogenphosphate dihydrate; sodium chlorite / water; dimethyl sulfoxide / 0 - 20 °C

8
[ 175137-13-0 ]
[ 1318133-00-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: trichlorophosphate / 2 h / 110 °C 2: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 1 h / 100 °C 3: potassium iodide / N,N-dimethyl-formamide / 4 h / 35 °C
	Multi-step reaction with 3 steps 1: trichlorophosphate / 2 h / 110 °C 2: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 100 °C 3: potassium iodide / N,N-dimethyl-formamide / 4 h / 35 °C

9
[ 175137-13-0 ]
[ 1318133-02-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: trichlorophosphate / 2 h / 110 °C 2: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 1 h / 100 °C 3: potassium iodide / N,N-dimethyl-formamide / 4 h / 35 °C 4: sodium hydroxide / tetrahydrofuran / 0.5 h / 20 °C
	Multi-step reaction with 4 steps 1: trichlorophosphate / 2 h / 110 °C 2: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 100 °C 3: potassium iodide / N,N-dimethyl-formamide / 4 h / 35 °C 4: water; sodium hydroxide / tetrahydrofuran / 0.5 h

10
[ 175137-13-0 ]
[ 1318133-04-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: trichlorophosphate / 2 h / 110 °C 2: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 1 h / 100 °C 3: potassium iodide / N,N-dimethyl-formamide / 4 h / 35 °C 4: sodium hydroxide / tetrahydrofuran / 0.5 h / 20 °C 5: manganese(IV) oxide / chloroform / 2 h / 70 °C
	Multi-step reaction with 5 steps 1: trichlorophosphate / 2 h / 110 °C 2: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 100 °C 3: potassium iodide / N,N-dimethyl-formamide / 4 h / 35 °C 4: water; sodium hydroxide / tetrahydrofuran / 0.5 h 5: manganese(IV) oxide / chloroform / 2 h / 70 °C

11
[ 175137-13-0 ]
[ 1318133-05-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: trichlorophosphate / 2 h / 110 °C 2: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 1 h / 100 °C 3: potassium iodide / N,N-dimethyl-formamide / 4 h / 35 °C 4: sodium hydroxide / tetrahydrofuran / 0.5 h / 20 °C 5: manganese(IV) oxide / chloroform / 2 h / 70 °C 6: sodium chlorite; sodium dihydrogenphosphate dihydrate / water; dimethyl sulfoxide / 0 - 20 °C 7: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / acetonitrile / 15 h / 20 °C

Reference： [1]Current Patent Assignee: HANMI PHARM CO LTD; HANMI SCIENCE CO LTD - WO2011/93672, 2011, A2 Current Patent Assignee: HANMI PHARM CO LTD; HANMI SCIENCE CO LTD - US2012/302567, 2012, A1

12
[ 175137-13-0 ]
[ 1318133-07-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1: trichlorophosphate / 2 h / 110 °C 2: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 1 h / 100 °C 3: potassium iodide / N,N-dimethyl-formamide / 4 h / 35 °C 4: sodium hydroxide / tetrahydrofuran / 0.5 h / 20 °C 5: manganese(IV) oxide / chloroform / 2 h / 70 °C 6: sodium chlorite; sodium dihydrogenphosphate dihydrate / water; dimethyl sulfoxide / 0 - 20 °C 7: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / acetonitrile / 15 h / 20 °C 8: ammonia / isopropyl alcohol / 10 h / 70 °C / closed vessel
	Multi-step reaction with 8 steps 1: trichlorophosphate / 2 h / 110 °C 2: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 1 h / 100 °C 3: potassium iodide / N,N-dimethyl-formamide / 4 h / 35 °C 4: sodium hydroxide / tetrahydrofuran / 0.5 h / 20 °C 5: manganese(IV) oxide / chloroform / 2 h / 70 °C 6: sodium chlorite; sodium dihydrogenphosphate dihydrate / water; dimethyl sulfoxide / 0 - 20 °C 7: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / acetonitrile / 15 h / 20 °C 8: ammonia / isopropyl alcohol / 10 h / 70 °C

Reference： [1]Current Patent Assignee: HANMI PHARM CO LTD; HANMI SCIENCE CO LTD - WO2011/93672, 2011, A2
[2]Current Patent Assignee: HANMI PHARM CO LTD; HANMI SCIENCE CO LTD - US2012/302567, 2012, A1

13
[ 175137-13-0 ]
[ 1318128-97-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1: trichlorophosphate / 2 h / 110 °C 2: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 1 h / 100 °C 3: potassium iodide / N,N-dimethyl-formamide / 4 h / 35 °C 4: sodium hydroxide / tetrahydrofuran / 0.5 h / 20 °C 5: manganese(IV) oxide / chloroform / 2 h / 70 °C 6: sodium chlorite; sodium dihydrogenphosphate dihydrate / water; dimethyl sulfoxide / 0 - 20 °C 7: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / acetonitrile / 15 h / 20 °C 8: ammonia / isopropyl alcohol / 10 h / 70 °C / closed vessel 9: isopropyl alcohol / 15 h / 110 °C
	Multi-step reaction with 8 steps 1: trichlorophosphate / 2 h / 110 °C 2: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 1 h / 100 °C 3: potassium iodide / N,N-dimethyl-formamide / 4 h / 35 °C 4: sodium hydroxide / tetrahydrofuran / 0.5 h / 20 °C 5: manganese(IV) oxide / chloroform / 2 h / 70 °C 6: sodium chlorite; sodium dihydrogenphosphate dihydrate / water; dimethyl sulfoxide / 0 - 20 °C 7: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / acetonitrile / 15 h / 20 °C 8: isopropyl alcohol / 15 h / 110 °C

14
[ 175137-13-0 ]
[ 1318133-08-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: trichlorophosphate / 2 h / 110 °C 2: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 1 h / 100 °C 3: potassium iodide / N,N-dimethyl-formamide / 4 h / 35 °C 4: sodium hydroxide / tetrahydrofuran / 0.5 h / 20 °C 5: manganese(IV) oxide / chloroform / 2 h / 70 °C 6: sodium chlorite; sodium dihydrogenphosphate dihydrate / water; dimethyl sulfoxide / 0 - 20 °C 7: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / acetonitrile / 15 h / 20 °C

15
[ 175137-13-0 ]
[ 1318130-12-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: trichlorophosphate / 2 h / 110 °C 2.1: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 1 h / 100 °C 3.1: potassium iodide / N,N-dimethyl-formamide / 4 h / 35 °C 4.1: sodium hydroxide / tetrahydrofuran / 0.5 h / 20 °C 5.1: manganese(IV) oxide / chloroform / 2 h / 70 °C 6.1: sodium chlorite; sodium dihydrogenphosphate dihydrate / water; dimethyl sulfoxide / 0 - 20 °C 7.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / acetonitrile / 15 h / 20 °C 8.1: sulfuryl dichloride / dichloromethane; acetonitrile / 1 h / 0 - 20 °C 8.2: pH 8
	Multi-step reaction with 8 steps 1: trichlorophosphate / 2 h / 110 °C 2: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 1 h / 100 °C 3: potassium iodide / N,N-dimethyl-formamide / 4 h / 35 °C 4: sodium hydroxide / tetrahydrofuran / 0.5 h / 20 °C 5: manganese(IV) oxide / chloroform / 2 h / 70 °C 6: sodium chlorite; sodium dihydrogenphosphate dihydrate / water; dimethyl sulfoxide / 0 - 20 °C 7: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / acetonitrile / 15 h / 20 °C 8: sulfuryl dichloride / dichloromethane; acetonitrile / 1 h / 0 - 20 °C

16
[ 175137-13-0 ]
[ 1318131-14-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1.1: trichlorophosphate / 2 h / 110 °C 2.1: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 1 h / 100 °C 3.1: potassium iodide / N,N-dimethyl-formamide / 4 h / 35 °C 4.1: sodium hydroxide / tetrahydrofuran / 0.5 h / 20 °C 5.1: manganese(IV) oxide / chloroform / 2 h / 70 °C 6.1: sodium chlorite; sodium dihydrogenphosphate dihydrate / water; dimethyl sulfoxide / 0 - 20 °C 7.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / acetonitrile / 15 h / 20 °C 8.1: sulfuryl dichloride / dichloromethane; acetonitrile / 1 h / 0 - 20 °C 8.2: pH 8 9.1: caesium carbonate / 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / 1,4-dioxane / 2.5 h / 120 °C
	Multi-step reaction with 9 steps 1: trichlorophosphate / 2 h / 110 °C 2: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 1 h / 100 °C 3: potassium iodide / N,N-dimethyl-formamide / 4 h / 35 °C 4: sodium hydroxide / tetrahydrofuran / 0.5 h / 20 °C 5: manganese(IV) oxide / chloroform / 2 h / 70 °C 6: sodium chlorite; sodium dihydrogenphosphate dihydrate / water; dimethyl sulfoxide / 0 - 20 °C 7: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / acetonitrile / 15 h / 20 °C 8: sulfuryl dichloride / dichloromethane; acetonitrile / 1 h / 0 - 20 °C 9: caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / 1,4-dioxane / 2.5 h / 120 °C

17
[ 175137-13-0 ]
[ 1318241-64-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: trichlorophosphate / 2 h / 110 °C 2.1: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 1 h / 100 °C 3.1: potassium iodide / N,N-dimethyl-formamide / 4 h / 35 °C 4.1: sodium hydroxide / tetrahydrofuran / 0.5 h / 20 °C 5.1: isopropyl alcohol / 12 h / Reflux 6.1: manganese(IV) oxide / chloroform / 12 °C / Reflux 7.1: sodium dihydrogenphosphate dihydrate / water; dimethyl sulfoxide; acetone / 0.5 h / 0 °C 7.2: 0 - 20 °C 8.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.25 h / 20 °C 8.2: 16 h / 45 °C

Reference： [1]Current Patent Assignee: HANMI SCIENCE CO LTD; CATHOLIC UNIVERSITY OF KOREA; KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY - WO2011/93684, 2011, A2

18
[ 175137-13-0 ]
[ 1318241-82-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: trichlorophosphate / 2 h / 110 °C 2.1: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 1 h / 100 °C 3.1: potassium iodide / N,N-dimethyl-formamide / 4 h / 35 °C 4.1: sodium hydroxide / tetrahydrofuran / 0.5 h / 20 °C 5.1: isopropyl alcohol / 12 h / Reflux 6.1: manganese(IV) oxide / chloroform / 12 °C / Reflux 7.1: sodium dihydrogenphosphate dihydrate / water; dimethyl sulfoxide; acetone / 0.5 h / 0 °C 7.2: 0 - 20 °C 8.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.5 h / 20 °C 8.2: 17 h / 45 °C

Reference： [1]Current Patent Assignee: HANMI SCIENCE CO LTD; CATHOLIC UNIVERSITY OF KOREA; KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY - WO2011/93684, 2011, A2

19
[ 175137-13-0 ]
[ 1318243-02-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: trichlorophosphate / 2 h / 110 °C 2.1: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 1 h / 100 °C 3.1: potassium iodide / N,N-dimethyl-formamide / 4 h / 35 °C 4.1: sodium hydroxide / tetrahydrofuran / 0.5 h / 20 °C 5.1: isopropyl alcohol / 12 h / Reflux 6.1: manganese(IV) oxide / chloroform / 12 °C / Reflux 7.1: sodium dihydrogenphosphate dihydrate / water; dimethyl sulfoxide; acetone / 0.5 h / 0 °C 7.2: 0 - 20 °C 8.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 24 h / 20 °C

Reference： [1]Current Patent Assignee: HANMI SCIENCE CO LTD; CATHOLIC UNIVERSITY OF KOREA; KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY - WO2011/93684, 2011, A2

20
[ 175137-13-0 ]
[ 1318243-03-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1.1: trichlorophosphate / 2 h / 110 °C 2.1: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 1 h / 100 °C 3.1: potassium iodide / N,N-dimethyl-formamide / 4 h / 35 °C 4.1: sodium hydroxide / tetrahydrofuran / 0.5 h / 20 °C 5.1: isopropyl alcohol / 12 h / Reflux 6.1: manganese(IV) oxide / chloroform / 12 °C / Reflux 7.1: sodium dihydrogenphosphate dihydrate / water; dimethyl sulfoxide; acetone / 0.5 h / 0 °C 7.2: 0 - 20 °C 8.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 24 h / 20 °C 9.1: trifluoroacetic acid / dichloromethane / 8 h / 20 °C

Reference： [1]Current Patent Assignee: HANMI SCIENCE CO LTD; CATHOLIC UNIVERSITY OF KOREA; KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY - WO2011/93684, 2011, A2

21
[ 175137-13-0 ]
[ 1318242-86-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: trichlorophosphate / 2 h / 110 °C 2: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 1 h / 100 °C 3: potassium iodide / N,N-dimethyl-formamide / 4 h / 35 °C 4: sodium hydroxide / tetrahydrofuran / 0.5 h / 20 °C 5: isopropyl alcohol / 12 h / Reflux

Reference： [1]Current Patent Assignee: HANMI SCIENCE CO LTD; CATHOLIC UNIVERSITY OF KOREA; KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY - WO2011/93684, 2011, A2

22
[ 175137-13-0 ]
[ 1318242-87-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: trichlorophosphate / 2 h / 110 °C 2: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 1 h / 100 °C 3: potassium iodide / N,N-dimethyl-formamide / 4 h / 35 °C 4: sodium hydroxide / tetrahydrofuran / 0.5 h / 20 °C 5: isopropyl alcohol / 12 h / Reflux 6: manganese(IV) oxide / chloroform / 12 °C / Reflux

Reference： [1]Current Patent Assignee: HANMI SCIENCE CO LTD; CATHOLIC UNIVERSITY OF KOREA; KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY - WO2011/93684, 2011, A2

23
[ 175137-13-0 ]
[ 1318242-88-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: trichlorophosphate / 2 h / 110 °C 2.1: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 1 h / 100 °C 3.1: potassium iodide / N,N-dimethyl-formamide / 4 h / 35 °C 4.1: sodium hydroxide / tetrahydrofuran / 0.5 h / 20 °C 5.1: isopropyl alcohol / 12 h / Reflux 6.1: manganese(IV) oxide / chloroform / 12 °C / Reflux 7.1: sodium dihydrogenphosphate dihydrate / water; dimethyl sulfoxide; acetone / 0.5 h / 0 °C 7.2: 0 - 20 °C

Reference： [1]Current Patent Assignee: HANMI SCIENCE CO LTD; CATHOLIC UNIVERSITY OF KOREA; KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY - WO2011/93684, 2011, A2

24
[ 85006-31-1 ]
[ 175137-13-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: acetic anhydride / 18 h / 0 - 20 °C 1.2: 0.5 h 2.1: ammonium formate / formamide / 18 h / 160 °C 2.2: 0.5 h

Reference： [1]Current Patent Assignee: SPANISH NATIONAL CANCER RESEARCH CENTER - WO2012/156756, 2012, A2

25
[ 175137-13-0 ]
7-methylthieno[3,2-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: trichlorophosphate / 1 h / 100 °C 2: hydrogen; sodium acetate / 20% palladium hydroxide-activated charcoal / ethyl acetate; isopropyl alcohol / 2585.81 Torr
	Multi-step reaction with 2 steps 1: trichlorophosphate / N,N-dimethyl-formamide / 4 h / 110 °C 2: palladium(II) hydroxide; triethylamine; hydrogen / methanol / 5 h
	Multi-step reaction with 2 steps 1: trichlorophosphate; N,N-dimethyl-formamide / 4 h / 110 °C 2: palladium(II) hydroxide; triethylamine; hydrogen / methanol / 5 h

Multi-step reaction with 2 steps 1: trichlorophosphate / 6 h / 100 °C 2: hydrogen; 20% palladium hydroxide-activated charcoal; triethylamine / ethyl acetate; isopropyl alcohol; water / 20 h / 20 °C

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2012/15962, 2012, A1
[2]Current Patent Assignee: HANMI PHARM CO LTD - WO2013/100632, 2013, A1
[3]Current Patent Assignee: HANMI PHARM CO LTD - US2014/371219, 2014, A1
[4]Muraoka, Terushige; Ide, Mitsuaki; Morikami, Kenji; Irie, Machiko; Nakamura, Mitsuaki; Miura, Takaaki; Kamikawa, Takayuki; Nishihara, Masamichi; Kashiwagi, Hirotaka [Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 18, p. 4206 - 4217]

26
[ 175137-13-0 ]
[ 1211596-51-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: trichlorophosphate / 1 h / 100 °C 2.1: hydrogen; sodium acetate / 20% palladium hydroxide-activated charcoal / ethyl acetate; isopropyl alcohol / 2585.81 Torr 3.1: N-Bromosuccinimide / tetrachloromethane / 1 h / Reflux 3.2: 1 h / Reflux
	Multi-step reaction with 6 steps 1.1: trichlorophosphate / N,N-dimethyl-formamide / 4 h / 110 °C 2.1: palladium(II) hydroxide; triethylamine; hydrogen / methanol / 5 h 3.1: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / benzene / 2 h / 75 °C 4.1: potassium iodide / N,N-dimethyl-formamide / 1 h / 40 °C 4.2: 15 h / 40 °C 5.1: water; sodium hydroxide / tetrahydrofuran / 2 h / 20 °C 6.1: manganese(IV) oxide / dichloromethane / 2 h
	Multi-step reaction with 5 steps 1.1: trichlorophosphate; N,N-dimethyl-formamide / 4 h / 110 °C 2.1: palladium(II) hydroxide; triethylamine; hydrogen / methanol / 5 h 3.1: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / benzene / 2 h / 75 °C 3.2: 1 h / 40 °C 3.3: 15 h / 40 °C 4.1: sodium hydroxide; water / tetrahydrofuran / 2 h / 20 °C 5.1: manganese(IV) oxide / dichloromethane / 2 h

Multi-step reaction with 4 steps 1: trichlorophosphate / 6 h / 100 °C 2: hydrogen; 20% palladium hydroxide-activated charcoal; triethylamine / ethyl acetate; isopropyl alcohol; water / 20 h / 20 °C 3: N-Bromosuccinimide; dibenzoyl peroxide / tetrachloromethane / 2.5 h / Reflux 4: pyridine; water / 1.5 h / 100 °C

27
[ 175137-13-0 ]
(4-(cyclopropylamino)thieno[3,2-d]pyridine-7-yl)methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: trichlorophosphate / 2 h / 110 °C 2: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 100 °C 3: potassium iodide / N,N-dimethyl-formamide / 4 h / 35 °C 4: water; sodium hydroxide / tetrahydrofuran / 0.5 h 5: isopropyl alcohol / 12 h / Reflux

Reference： [1]Current Patent Assignee: HANMI SCIENCE CO LTD; CATHOLIC UNIVERSITY OF KOREA; KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY - US2013/53370, 2013, A1

28
[ 175137-13-0 ]
[ 1446113-40-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: trichlorophosphate / N,N-dimethyl-formamide / 4 h / 110 °C 2.1: palladium(II) hydroxide; triethylamine; hydrogen / methanol / 5 h 3.1: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / benzene / 2 h / 75 °C 4.1: potassium iodide / N,N-dimethyl-formamide / 1 h / 40 °C 4.2: 15 h / 40 °C
	Multi-step reaction with 3 steps 1.1: trichlorophosphate; N,N-dimethyl-formamide / 4 h / 110 °C 2.1: palladium(II) hydroxide; triethylamine; hydrogen / methanol / 5 h 3.1: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / benzene / 2 h / 75 °C 3.2: 1 h / 40 °C 3.3: 15 h / 40 °C

Reference： [1]Current Patent Assignee: HANMI PHARM CO LTD - WO2013/100632, 2013, A1
[2]Current Patent Assignee: HANMI PHARM CO LTD - US2014/371219, 2014, A1

29
[ 175137-13-0 ]
[ 1446113-41-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: trichlorophosphate / N,N-dimethyl-formamide / 4 h / 110 °C 2.1: palladium(II) hydroxide; triethylamine; hydrogen / methanol / 5 h 3.1: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / benzene / 2 h / 75 °C 4.1: potassium iodide / N,N-dimethyl-formamide / 1 h / 40 °C 4.2: 15 h / 40 °C 5.1: water; sodium hydroxide / tetrahydrofuran / 2 h / 20 °C
	Multi-step reaction with 4 steps 1.1: trichlorophosphate; N,N-dimethyl-formamide / 4 h / 110 °C 2.1: palladium(II) hydroxide; triethylamine; hydrogen / methanol / 5 h 3.1: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / benzene / 2 h / 75 °C 3.2: 1 h / 40 °C 3.3: 15 h / 40 °C 4.1: sodium hydroxide; water / tetrahydrofuran / 2 h / 20 °C

Reference： [1]Current Patent Assignee: HANMI PHARM CO LTD - WO2013/100632, 2013, A1
[2]Current Patent Assignee: HANMI PHARM CO LTD - US2014/371219, 2014, A1

30
[ 175137-13-0 ]
[ 871013-27-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: trichlorophosphate / N,N-dimethyl-formamide / 4 h / 110 °C 2: palladium(II) hydroxide; triethylamine; hydrogen / methanol / 5 h 3: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / benzene / 2 h / 75 °C

Reference： [1]Current Patent Assignee: HANMI PHARM CO LTD - WO2013/100632, 2013, A1

31
[ 175137-13-0 ]
[ 1211596-20-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: trichlorophosphate / 6 h / 100 °C 2: hydrogen; 20% palladium hydroxide-activated charcoal; triethylamine / ethyl acetate; isopropyl alcohol; water / 20 h / 20 °C 3: N-Bromosuccinimide; dibenzoyl peroxide / tetrachloromethane / 2.5 h / Reflux 4: pyridine; water / 1.5 h / 100 °C 5: sodium chlorite; aminosulfonic acid / water; acetone / 2 h / 0 - 40 °C

Reference： [1]Muraoka, Terushige; Ide, Mitsuaki; Morikami, Kenji; Irie, Machiko; Nakamura, Mitsuaki; Miura, Takaaki; Kamikawa, Takayuki; Nishihara, Masamichi; Kashiwagi, Hirotaka [Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 18, p. 4206 - 4217]

32
[ 175137-13-0 ]
4-chloro-7-(dibromomethyl)thieno[3,2-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: trichlorophosphate / 6 h / 100 °C 2: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 4 h / Reflux; Inert atmosphere

33
[ 175137-13-0 ]
N-(2-methoxy-4-((3-(4-methylpiperazin-1-yl)propyl)carbamoyl)phenyl)thieno[3,2-d]pyrimidine-7-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: trichlorophosphate / 6 h / 100 °C 2: hydrogen; 20% palladium hydroxide-activated charcoal; triethylamine / ethyl acetate; isopropyl alcohol; water / 20 h / 20 °C 3: N-Bromosuccinimide; dibenzoyl peroxide / tetrachloromethane / 2.5 h / Reflux 4: pyridine; water / 1.5 h / 100 °C 5: sodium chlorite; aminosulfonic acid / water; acetone / 2 h / 0 - 40 °C 6: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / acetonitrile / 80 °C

34
[ 175137-13-0 ]
7-(dibromomethyl)thieno[3,2-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: trichlorophosphate / 6 h / 100 °C 2: hydrogen; 20% palladium hydroxide-activated charcoal; triethylamine / ethyl acetate; isopropyl alcohol; water / 20 h / 20 °C 3: N-Bromosuccinimide; dibenzoyl peroxide / tetrachloromethane / 2.5 h / Reflux

35
[ 175137-13-0 ]
N-(2-methoxy-4-(4-methylpiperazine-1-carbonyl)phenyl)thieno[3,2-d]pyrimidine-7-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: trichlorophosphate / 6 h / 100 °C 2: hydrogen; 20% palladium hydroxide-activated charcoal; triethylamine / ethyl acetate; isopropyl alcohol; water / 20 h / 20 °C 3: N-Bromosuccinimide; dibenzoyl peroxide / tetrachloromethane / 2.5 h / Reflux 4: pyridine; water / 1.5 h / 100 °C 5: sodium chlorite; aminosulfonic acid / water; acetone / 2 h / 0 - 40 °C 6: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / acetonitrile / 80 °C

36
[ 175137-13-0 ]
N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)thieno[3,2-d]pyrimidine-7-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: trichlorophosphate / 6 h / 100 °C 2: hydrogen; 20% palladium hydroxide-activated charcoal; triethylamine / ethyl acetate; isopropyl alcohol; water / 20 h / 20 °C 3: N-Bromosuccinimide; dibenzoyl peroxide / tetrachloromethane / 2.5 h / Reflux 4: pyridine; water / 1.5 h / 100 °C 5: sodium chlorite; aminosulfonic acid / water; acetone / 2 h / 0 - 40 °C 6: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / acetonitrile / 80 °C

37
[ 175137-13-0 ]
C₁₅H₁₂N₂O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: trichlorophosphate / Reflux 2.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 0.5 h / 20 °C 2.2: 80 °C