175137-21-0|4-Chloro-7-methylthieno[3,2-d]pyrimidine| Ambeed

Structure of 175137-21-0

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Quality Control of [ 175137-21-0 ] Purity: 97% SDS Specification

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Product Details of [ 175137-21-0 ]

CAS No. :	175137-21-0
Formula :	C₇H₅ClN₂S
M.W :	184.65
SMILES Code :	CC1=CSC2=C1N=CN=C2Cl
MDL No. :	MFCD00205202
InChI Key :	IYJDOVYAFDVIDB-UHFFFAOYSA-N
Pubchem ID :	2777586

Safety of [ 175137-21-0 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 175137-21-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	9
Fraction Csp3	0.14
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	47.39
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	54.02 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.17
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.63
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.65
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.58
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	3.74
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.56

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.25
Solubility	0.105 mg/ml ; 0.000566 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-3.41
Solubility	0.0711 mg/ml ; 0.000385 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-3.6
Solubility	0.0463 mg/ml ; 0.000251 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.56 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.27

Application In Synthesis of [ 175137-21-0 ]

* 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.

Downstream synthetic route of [ 175137-21-0 ]

[ 175137-21-0 ] Synthesis Path-Downstream 1~41

1
[ 749908-75-6 ]
[ 175137-21-0 ]
[ 749908-57-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 120℃; for 6h;	The product from example 22 step b) (0.39g), 4-chloro-7-methyl-thieno [3,2- d] pyrimidine (0. 19G) and Hunigs base (0. 55ML) and NMP (5ml) was heated at 120 C for 6h. The mixture was poured into ethyl acetate and washed with brine, the organic phase was separated, dried (MGS04) and concentrated in vacuo to give a pale yellow solid. Trituration with ether : methanol gave the title compound as a white solid (0.22g). MS (APCI+) 429/431 [M+H] + IH NMR 5 (DMSO) 8.56 (s, lH), 8.46 (d, LH), 7.97 (d, LH), 7.88 (d, LH), 4.37 (d, 2H), 4.10 (t, 4H), 4.04 (t, 2H), 3.61 (t, 4H), 2. 36 (s, 3H), 2.26 (quin, 2H)

References: [1]Patent: WO2004/74287,2004,A1 .Location in patent: Page 34-35.

2
[ 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.

References: [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.

3
[ 175137-21-0 ]
[ 872190-72-2 ]

Yield	Reaction Conditions	Operation in experiment
82%		4-Chloro-6-iodo-7-methylthieno[3,2-d]pyrimidine (169): Diisopropylamine (11 mL 77.8 mmol, 1.43 eq) was dissolved in anhydrous THF 100 mL, and the solution was chilled to -78 C. 22 mL 1.6 M BuLi in hexanes (70.8 mmol, 1.3 eq) was added, and the solution was stirred for 30 minutes at -78 C. A solution of <strong>[175137-21-0]4-chloro-7-methylthieno[3,2-d]pyrimidine</strong> (168, 10.0 g 54.4 mmol) in 100 mL anhydrous THF was chilled to -78 C., and the LDA solution was then transferred via cannula to the cold solution of 168. The reaction mixture became a dark brown suspension as the LDA solution was added. After 2 hours at -78 C., a solution of I2 (20.8 g 81.6 mmol, 1.5 eq) in 50 mL THF was cannulated to the anion solution. The reaction mixture was maintained at -78 C. for 2 hours and then warmed to room temperature overnight. After overnight stirring, the reaction mixture was diluted with EtOAc and washed three times with deionized H2O, twice with saturated Na2S2O4, once with deionized H2O, three times with 10% HCl, and once with saturated NaCl. The dark solution was dried over anhydrous Na2SO4, decolorized with activated carbon, and then filtered through silica gel. The resulting light yellow filtrate was concentrated by rotary evaporation, and a light yellow solid precipitated as the solution was concentrated. After concentrating to a small volume, the precipitate was collected via filtration and was washed twice with ice cold EtOAc (13.7 g, 82% yield).
65%		To a solution of 37 (368 mg, 2 mmol, 1.0 eq.), prepared using General Synthetic Method B, in anhydrous THF (5 mL) at -30 C. was added a LDA solution (2.2 mmol, 1.1 eq) in THF (freshly prepared by mixing 0.34 mL of diisopropylamine and 0.96 mL 2.5M nBuLi at -30 C. in 5 mL of THF). The reaction turned from clear to yellow. After 20 mins, iodine (609 mg, 2.4 mmol, 1.2 eq) was added drop wise. The reaction was quenched by water after it was warmed up to room temperature, in the cold bath. The reaction was diluted with 10 mL ethyl acetate, extracted with ethyl aceate (10 mL×2). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude mixture was then absorbed on silica gel and purified by flash chromatography (eluted by 10% Hexane/Ethyl acetate) to afford compound 41 as a white solid (407 mg, 65% yield).

References: [1]Patent: US2006/4002,2006,A1 .Location in patent: Page/Page column 12; 21; 23; 30; 32.
[2]Patent: US2012/65200,2012,A1 .Location in patent: Page/Page column 15.
[3]ACS Medicinal Chemistry Letters,2021,vol. 12,p. 1794 - 1801.

4
[ 175137-21-0 ]
C₂₂H₂₀N₄OS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 2: Compound 1.2 (1.0 mmol), is treated with anhydrous 4.0 N HCl in dioxane (25 mL) at 0 C., stirred at room temperature for 2 hours and concentrated to dryness under reduced pressure. The crude amine salt, <strong>[175137-21-0]4-chloro-7-methylthieno[3,2-d]pyrimidine</strong> (1.0 equiv.) and N,N-diisopropylethylamine. (“DIEA”; 2.5 equivalents) is then heated in n-butanol (10 mL) at 135 C. for 2 hours. The reaction mixture is cooled and then partitioned between dichloromethane and water. The organic layer is separated, washed with brine, dried and concentrated under reduced pressure. The titled compound is precipitated from ethyl acetate (“EtOAc”) and methanol (“MeOH”) with hexanes.

References: [1]Patent: US2006/35908,2006,A1 .Location in patent: Page/Page column 55.

5
6,6-dimethyl-5-[(3S,8aS)-3-methylhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine [ No CAS ]
[ 175137-21-0 ]
N-(6,6-dimethyl-5-[(3S,8aS)-3-methylhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-methylthieno[3,2-d]pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; In water; at 100℃; for 1h;	Example 81 : W-(6,6-dimethyl-5-[(3S,8aS)-3-methylhexahydropyrroIo[1,2-a]pyrazin-2(1H)- yl]carbonyl}-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-methylthieno[3,2-d]pyrimidin-4-amine.Preparation of compound 81b: (3S,8aS)-3-methylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carbonyl chloride; To a stirring mixture of triphosgene (2.11g, 1eq) in CH2CI2 (10ml) at O0C was added DIPEA (1.8mi, 1.5eq) and (3S,8aS)-3-methyloctahydropyrrolo[1 ,2-a]pyrazine (81a, 1g, 7.13mmol). The resulting mixture was stirred at O0C for 30 min. The reaction mixture was evaporated in vacuo to give a residue, compound 81b, which was directly carried onto the next reaction without further purification. EPO <DP n="83"/>Preparation of compound 81c: ethyl 3-amino-6,6-dimethyl-5-[(3S,8aS)-3- methylhexahydropyrroloϖ^-alpyrazin-atifO-yllcarbony^-δ.β-dihydropyrroloIS^-clpyrazoIe^t^- carboxylate; To a stirring mixture of compound I(H) 5-fe/f-butyl 2-ethyl 3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole- 2,5(4H,6H)-dicarboxylate (5.65g, 17.4mmol) in CH2CI2 (20ml) was added 4.0M HCI in dioxane (30ml). The reaction mixture was concentrated in vacuo to give crude HCI salt of compound 54a. A portion of residue (54a, 1g, 4.46mmol) was added to a stirring mixture of (3S,8aS)-3-methylhexahydropyrrolo[1,2- a]pyrazine-2(1W)-carbonyl chloride (81b, 1.4 g, 2eq) in CH2CI2 (20ml), DIPEA (1.2ml, 2eq). The resulting mixture was stirred at room temperature for 15h. The reaction mixture was diluted with CH2CI2, and washed with saturated NaHCO3, dried over sodium sulfate, concentrated in vacuo, purified by flash chromatography. Elution with 5-15% MeOH/DCM provided compound 81c. 1H NMR (CD3)2SO δ: 1.2 (m, 2 H), 1.31 (t, 3 H), 1.52 (m, 6H), 1.64 (m, 4H), 1.93 (m, 1H), 2.18 (m, 1H), 2.77 (m, 2H), 2.93 (m, 1H), 3.77 (m, 1H), 4.18 (m, 2H), 4.33 (m, 2H) Preparation of compound 81 d: 6,6-dimethyl-5-[(3S,8aS)-3-methylhexahydropyrrolo[1,2-a]pyrazin- 2(1 rt)-yl]carbonyl}-1 ,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amineTo a stirring solution of ethyl 3-amino-6,6- dimethyl- 5-[(3S,8aS)-3-methyl hexahydropyrrolo [1,2- a]pyrazin-2(1H)-yl]carbonyl}-5,6-dihydropyrrolo[3,4-c] pyrazole-2(4W)- carboxylate (81c, 613mg, 1.δOmmol) in MeOH (3mL) was added 20% aq. NaOH (2ml). The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and saturated NaHCO3, dried, and concentrated to give compound 81 d.To a stirring solution of compound 81d (0.15Og, 0.47mmol) in 50% acetic acid / water (4ml) was added 4- chloro-7-methylthieno [3,2-cfl pyrimidine (175 mg, 2eq). The resulting mixture was heated to a temperature of 100C for 1 hr. The reaction mixture was purified by prep-HPLC to provide compound 81 as a white solid 1H NMR (CD3)2SO δ: 1.23 (m, 2 H), 1.62 (d, 6 H), 1.69 (m, 3 H), 1.83 (m, 1 H), 1.95 (m, 1 H), 2.16 (m, 1 H), 2.34 (s, 3H), 2.74 (m, 2H), 2.90 (m, 1H), 3.80 (m, 1 H), 4.52 (s, 2H), 7.83 (s, 1H), 8.56 (s, 1H).

References: [1]Patent: WO2006/72831,2006,A1 .Location in patent: Page/Page column 81-82.

6
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.

References: [1]Patent: US6503914,2003,B1 .

7
[ 175137-21-0 ]
[ 443762-04-7 ]
[ 443762-05-8 ]

Yield	Reaction Conditions	Operation in experiment
88%	With hydrazine hydrate; In ethanol;	A suspension of <strong>[175137-21-0]4-chloro-7-methylthieno[3,2-d]pyrimidine</strong> (4, 3.1 g, 17 mmol) and hydrazine monohydrate (3.5 mL, 72 mmol) in ethanol (34 mL) was heated at reflux for 1 hour. After cooling to room temperature, the solid product was collected by vacuum filtration to give (7-methylthieno[3,2-d]pyrimidin-4-yl)hydrazine hydrochloride (3.2 g, 88% yield) as a white solid. 3-Pyridinecarboxaldehyde(7-methylthieno[3,2-d]pyrimidin-4-yl)hydrazone (27).

References: [1]Patent: US6503914,2003,B1 .

8
[ 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).

References: [1]Patent: US6503914,2003,B1 .

9
[ 2975-41-9 ]
[ 175137-21-0 ]
4-(2-indanylamino)-7-methylthieno[3,2-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol;	Example 3. 4-(2-indanylamino)-7-methylthieno [3,2-d]pyrimidine <strong>[175137-21-0]4-chloro-7-methylthieno[3,2-d]pyrimidine</strong> (74 mg, 0.40 mmol) and 2-aminoindan (270 mg, 2.0 mmol) in dry ethanol (3 ml) were heated to reflux under an argon atmosphere for 1 hour. The solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to obtain the title compound (83 mg, 0.30 mmol) having the following physical properties: 1H NMR (400 MHz, DMSO-d6): δ 2.33 (3H, s), 3.03 (2H, m), 3.33 (2H, m), 4.98 (1H, m), 7.16 (2H, m), 7.24 (2H, m), 7.71 (1H, s), 7.98 (1H, d, J = 7 Hz), 8.51 (1H, s). MS (FAB): m/z 282 (M+H)+.
	In ethanol;	Production Example 192. 4-(2-indanylamino)-7-methylthieno[3,2-d]pyrimidine <strong>[175137-21-0]4-chloro-7-methylthieno[3,2-d]pyrimidine</strong> (74 mg, 0.40 mmol) and 2-aminoindan (270 mg, 2.0 mmol) in dry ethanol (3 ml) were heated to reflux under an argon atmosphere for 1 hour. The solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to obtain the title compound (83 mg, 0.30 mmol) having the following physical properties: 1H NMR (400 MHz, DMSO-d6): δ 2.33 (3H, s), 3.03 (2H, m), 3.33 (2H, m), 4.98 (1H, m), 7.16 (2H, m), 7.24 (2H, m), 7.71 (1H, s), 7.98 (1H, d, J = 7 Hz), 8.51 (1H, s). MS (FAB): m/z 282 (M+H)+.

References: [1]Patent: EP1018514,2000,A1 .
[2]Patent: EP1132093,2001,A1 .

10
[ 70338-47-5 ]
[ 175137-21-0 ]
4-(4-Benzyloxy-3-trifluoromethylanilino)-7-methylthieno[3,2-d]pyrimidine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	In isopropyl alcohol;	Example 34 4-(4-Benzyloxy-3-trifluoromethylanilino)-7-methylthieno[3,2-d]pyrimidine hydrochloride 4-Chloro-7-methylthieno[3,2-d]pyrimidine (0.111 g, 0.60 mmol) and 4-benzyloxy-3-trifluoromethylaniline (prepared according to the published method: WO 96/09294) (0.194 g, 0.78 mmol) were reacted in 2-propanol (4.5 ml) for 4 hours according to Procedure A. The product was obtained as a pale pink solid (0.257 g, 95%), m.p. 219-220 C.; (Found: C, 56.30; H, 4.91, N, 8.21. C21H18F3N3OS.HCl.iPrOH requires: C, 56.30; H, 4.89; N, 8.21%); δH [2H6]-DMSO 11.12 (1H, br s, NH), 8.81 (1H, s, 2-H), 8.12 (1H, s, 6-H), 8.02 (1H, d, J 2, 2'-H), 7.97 (1H, dd, J 9,2, 6'-H), 7.29-7.49 (6H, m, 5-H, PhH5), 5.32 (2H, s, CH2), 5.79 (1H, sept, J 6, CHOH of iPrOH), 2.45 (3H, s, 7-CH3), 1.05 (6H, d, J 6, C(CH3)2 of iPrOH); m/z (%) 415 (M+).

References: [1]Patent: US6169091,2001,A .

11
[ 93-51-6 ]
[ 175137-21-0 ]
4-(2-methoxy-4-methylphenoxy)-7-methylthieno[3,2-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With caesium carbonate; In DMA; at 100℃; for 12h;	A suspension of 4 -chloro-7-methyl-thieno [3 , 2- dl pyrimidine (500 mg, 2.71 mmol) , 2 -me thoxy- 4 -methyl -phenol <n="52"/>(393 mg, 2.84 mmol) and cesium carbonate (971 mg, 2.98 mtnol) in DMA (5 mL) was stirred at 100 C for 12 hrs. The reaction mixture was poured into water, extracted with ether for three times. The organic layer was washed with water, dried over sodium sulfate, filtered and evaporated. The solid residue was triturated in hexane and dried in vacuum, giving the Example title compound (513 rag, 66%) as a white powder which was used in the next step without further purification.

References: [1]Patent: WO2007/79173,2007,A2 .Location in patent: Page/Page column 50; 51.

12
[ 1057973-39-3 ]
[ 175137-21-0 ]
[ 1017606-57-3 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 1037 - 1041.

13
[ 1017606-58-4 ]
[ 175137-21-0 ]
[ 1017606-59-5 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 1037 - 1041.

14
[ 5961-59-1 ]
[ 175137-21-0 ]
[ 936837-14-8 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 3536 - 3540.

15
[ 1246223-39-1 ]
[ 175137-21-0 ]

References: [1]Tetrahedron Letters,2010,vol. 51,p. 4609 - 4611.

16
[ 175137-21-0 ]
[ 1301212-43-0 ]

Yield	Reaction Conditions	Operation in experiment
78%	With ammonium hydroxide; In butan-1-ol; at 90℃; for 4h;Sealed tube;	EXAMPLE 28; (3R,4R)-N-(7-Methylthieno[3,2-d]pyrimidin-4-yl)-4'H-l- azaspiro[bicyclo[2.2.1 heptane-3, 5 '-οχαζο J -2 '-amine; Step A: 7-Methylthieno[3,2-d]pyrim; In a sealed tube was added <strong>[175137-21-0]4-chloro-7-methylthieno[3,2-d]pyrimidine</strong> (2.0 g, 10.83 mmol) and ammonium hydroxide (12.65 mmol, 325 mmol) in butanol (7ml). The reaction was heated to 90C for 4 hours and then cooled to room temperature. The resulting white precipitate was collected to give 7-methylthieno[3,2-d]pyrimidin 4-amine (1.4 g, 78% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (1 H, s), 7.74 (1 H, s), 7.34 (2 H, s), 2.34 (3 H, d, J=1.00 Hz).

References: [1]Patent: WO2011/56503,2011,A1 .Location in patent: Page/Page column 68.

17
[ 1242180-17-1 ]
[ 175137-21-0 ]
[ 1307263-50-8 ]

Yield	Reaction Conditions	Operation in experiment
7%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 140℃; for 1h;microwave irradiation;	EXAMPLE 1(5V4-{8-Chloro-3-ri-(7-methylthieno[3^ yl ) piperazin-2-oneA solution of Intermediate 6 (100 mg, 0.33 mmol), 4-chloro-7-methylthieno[3,2- cfjpyrimidine (73 mg, 0.40 mmol) and DIPEA (0.29 mL, 1.65 mmol) in NMP (1.5 mL) was heated at 140C for 1 h under microwave irradiation. The crude mixture was purified by preparative HPLC to yield title compound (10.2 mg, 7%) as a white solid. 5H (DMSO- d6) 8.46 (IH, s), 8.41-8.36 (2H, m), 7.99 (IH, s), 7.85-7.81 (3H, m), 7.41 (IH, t, J7.8 Hz), 5.73 (IH, t, J6.7 Hz), 4.21 (IH, d, J 17.2 Hz), 4.13 (IH, d, J 13.2 Hz), 3.94 (IH, d, J 17.2 Hz), 3.64 (IH, d, J 10.3 Hz), 3.47-3.37 (IH, m), 3.27-3.17 (IH, m), 2.37 (3H, d, J 1.2 Hz), 1.57 (3H, d, J 6.7 Hz). LCMS (ES+) 453 (M+H)+, RT 2.31 minutes (Method 2).

References: [1]Patent: WO2011/58110,2011,A1 .Location in patent: Page/Page column 32.

18
[ 85006-31-1 ]
[ 175137-21-0 ]

References: [1]Patent: WO2011/93672,2011,A2 .
[2]Patent: US2012/15962,2012,A1 .
[3]Patent: WO2012/156756,2012,A2 .
[4]Patent: US2013/53370,2013,A1 .
[5]Patent: WO2013/100632,2013,A1 .
[6]Patent: US2014/371219,2014,A1 .
[7]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 4206 - 4217.
[8]Patent: WO2021/133915,2021,A1 .

19
[ 175137-21-0 ]
7-(bromomethyl)-4-chlorothieno[3,2-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 100℃; for 1h;	4-Chloro-7-methylthieno[3,2-d]pyrimidine (6.62g, 33.0mmol) and NBS (5.87g, 33.0mmol) were dissolved in CCL^lOOmL) and benzoylperoxide (l.Og, 80% purity) was added thereto. The reaction mixture was stirred at 100C for an hour, cooled to room temperature, filtered with Celite and concentrated to obtain the title compound having a yellow color without further purification. NMR (400MHz, DMSO-d6) δ 9.15 (s, 1H), 8.75 (s, 1H), 4.93 (s, 2H).
	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 100℃; for 1h;	4-Chloro-7-methylthieno[3,2-d]pyrimidine(6.62g, 33.0mmol) and NBS(5.87g, 33.0mmol) were dissolved in carbon tetrachloride(lOOniL). Benzoyl peroxide(1.0g, 80% purity) was added thereto and stirred at 100C for 1 hr. The reaction mixture is cooled to room temperature, filtered with a diatomite pad, and concentrated under a reduced pressure to obtain the title compound as a yellow solid.1H NMR (400MHz, DMSO-d6) 89.15(s, 1H), 8.75 (s, 1H), 4.93(s, 2H).
	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 100℃; for 1h;	c. 7-(Bromomethyl)-4-chlorothieno[3,2-d]pyrimidine 4-Chloro-7-methylthieno[3,2-d]pyrimidine (6.62 g, 33.0 mmol) and NB S (5.87 g, 33.0 mmol) were dissolved in carbon tetrachloride (100 mL). Benzoyl peroxide (1.0 g, 80% purity) was added thereto and stirred at 100 C. for 1 hr. The reaction mixture is cooled to room temperature, filtered with a diatomite pad, and concentrated under a reduced pressure to obtain the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ9.15 (s, 1H), 8.75 (s, 1H), 4.93 (s, 2H).

With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 100℃;

Step 3: 7-(Bromomethyl)-4-chlorothieno[3,2-d]pyrimidine 4-Chloro-7-methylthieno[3,2-d]pyrimidine (6.62 g, 33.0 mmol) and NBS (5.87 g, 33.0 mmol) were dissolved in CCl4 (100 mL) and benzoylperoxide (1.0 g, 80% purity) was added thereto. The reaction mixture was stirred at 100 C. for an hour, cooled to room temperature, filtered with Celite and concentrated to obtain the title compound having a yellow color without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.75 (s, 1H), 4.93 (s, 2H).

References: [1]Patent: WO2011/93684,2011,A2 .Location in patent: Page/Page column 33; 34.
[2]Patent: WO2011/93672,2011,A2 .Location in patent: Page/Page column 45-47.
[3]Patent: US2012/302567,2012,A1 .Location in patent: Page/Page column 20.
[4]Patent: US2013/53370,2013,A1 .Location in patent: Paragraph 0272-0274.

20
[ 175137-21-0 ]
[ 1269667-57-3 ]

References: [1]Patent: WO2011/93672,2011,A2 .
[2]Patent: US2013/53370,2013,A1 .

21
[ 175137-21-0 ]
[ 1318133-00-4 ]

References: [1]Patent: WO2011/93672,2011,A2 .
[2]Patent: US2013/53370,2013,A1 .

22
[ 175137-21-0 ]
[ 1318133-02-6 ]

References: [1]Patent: WO2011/93672,2011,A2 .
[2]Patent: US2013/53370,2013,A1 .

23
[ 175137-21-0 ]
[ 1318133-04-8 ]

References: [1]Patent: WO2011/93672,2011,A2 .
[2]Patent: US2013/53370,2013,A1 .

24
[ 175137-21-0 ]
[ 1318133-05-9 ]

References: [1]Patent: WO2011/93672,2011,A2 .

25
[ 175137-21-0 ]
[ 1318133-07-1 ]

References: [1]Patent: WO2011/93672,2011,A2 .
[2]Patent: US2012/302567,2012,A1 .

26
[ 175137-21-0 ]
[ 1318128-97-0 ]

References: [1]Patent: WO2011/93672,2011,A2 .
[2]Patent: US2012/302567,2012,A1 .

27
[ 175137-21-0 ]
[ 1318133-08-2 ]

References: [1]Patent: WO2011/93672,2011,A2 .

28
[ 175137-21-0 ]
[ 1318130-12-9 ]

References: [1]Patent: WO2011/93672,2011,A2 .
[2]Patent: US2012/302567,2012,A1 .

29
[ 175137-21-0 ]
[ 1318131-14-4 ]

References: [1]Patent: WO2011/93672,2011,A2 .
[2]Patent: US2012/302567,2012,A1 .

30
[ 175137-21-0 ]
[ 1318241-64-3 ]