955368-90-8|2-Allyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one| Ambeed

Structure of 955368-90-8

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Quality Control of [ 955368-90-8 ] Purity: 95% SDS Specification

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Product Details of [ 955368-90-8 ]

CAS No. :	955368-90-8
Formula :	C₉H₁₀N₄OS
M.W :	222.27
SMILES Code :	CSC1=NC2=C(C=N1)C(=O)N(CC=C)N2
MDL No. :	MFCD19443206
InChI Key :	JKBQCALHIQOSTC-UHFFFAOYSA-N
Pubchem ID :	67171470

Safety of [ 955368-90-8 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H320-H335
Precautionary Statements:	P261-P280-P301+P312-P302+P352-P305+P351+P338

Computational Chemistry of [ 955368-90-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	15
Num. arom. heavy atoms	9
Fraction Csp3	0.22
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	60.27
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	88.87 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.03
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	1.44
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.03
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.	0.8
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	1.73
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.41

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.37
Solubility	0.945 mg/ml ; 0.00425 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.	-2.91
Solubility	0.272 mg/ml ; 0.00123 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	-2.6
Solubility	0.553 mg/ml ; 0.00249 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	No
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.	-6.63 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	0.0
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	1.0 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)	2.42

Application In Synthesis of [ 955368-90-8 ]

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

Downstream synthetic route of [ 955368-90-8 ]

[ 955368-90-8 ] Synthesis Path-Downstream 1~35

1
[ 5909-24-0 ]
[ 21075-86-5 ]
[ 955368-90-8 ]

Yield	Reaction Conditions	Operation in experiment
51%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 72h;Reflux;	DIPEA (20.8 ml, 120 mmol) and allyl hydrazine 5 (8.23 g, 47.8 mmol) were added to a solution of ethyl 4-chloro-2-methylthio- 5-pyrimidinecarboxylate (6; 1 1.1 g, 47.8 mmol) in THF (150 ml). The reaction mixture was heated at reflux for 72 h, before being concentrated in vacuo. Et20 (50 ml) was added to the residue, and the resultant precipitate was collected by filtration. The filtrate was evaporated to dryness, and the residue was cooled in an ice bath, after which TFA (40 ml) was added. The resultant solution was stirred at RT for 1 h, followed by 70 C for 1 h. The solvent was removed in vacuo and the residue was dissolved in EtOH (50 ml) and cooled in an ice bath, after which 6M NaOH (75 ml) was added. The resultant solution was stirred at RT for 15 min, before 32 being acidified via the addition of cone. HCI (40 ml). The orange solution was evaporated to dryness and the resultant residue was partitioned between chloroform (100 ml) and water (100 ml), and the organic phase was washed with brine (50 ml), dried (Mg2S04), concentrated in vacuo, and triturated with hexanes. The solid precipitate was washed with EtOH and Et20, before being dried under vacuum to give the target compound as a yellow solid (5.44 g, 24.5 mmol, 51 %). Rf 0.45 (9:1 DCM:MeOH); M.p. 125- 128 C; IR (cm-1 ) 3032, 2979, 2926, 2659, 1656, 161 5, 1 566, 1 514; 1 H NMR (400 M Hz, DMSO-d6)2.53 (3H, s, -SCH3), 4.38 (2H, dapp, J = 5.2 Hz, N2-CH2), 5.06-5.20 (2H, m, allyl C-Hcis/trans), 5.87 (1 H, ddt, J = 17.2, 10.5, 5.3 Hz, alkene C-H), 8.67 (1 H, s, H-4), 12.65 (1 H, -1 ); MS [M + H] + m/z 223.1.
		260 mL of N,N-diisopropylethylamine and 106 g of the hydrazine obtained in the above 1 were added to tetrahydrofuran (1.5 L) solution of 142 g of ethyl 4-chloro-2-(methylthio)pyridine-5-carboxylate, and stirred with heating under reflux for 18 hours. After cooled to room temperature, the reaction solution was evaporated under reduced pressure, and 500 mL of diethyl ether was added to the residue, and the precipitated solid was separated through filtration. The filtrate was evaporated under reduced pressure, the residue was cooled in an ice bath, 400 mL of trifluoroacetic acid was gradually added thereto, and stirred at room temperature for 1 hour and then at 70 C. for 1 hour. The reaction solution was evaporated under reduced pressure, 500 mL of ethanol was added thereto and cooled in an ice bath, and 1.0 L of 6 N sodium hydroxide solution was added thereto and stirred at room temperature for 15 minutes. Cooled in an ice bath, the reaction solution was made acidic with 400 mL of concentrated hydrochloric acid, and then evaporated under reduced pressure. The residue was partitioned in chloroform and water, and the chloroform layer was extracted, washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the formed yellow solid was taken out through filtration, washed with ethanol and diethyl ether, and dried to obtain 99.1 g of the entitled compound as a yellow solid.1H-NMR (400 MHz, DMSO-d6) ?: 8.66 (1.0H, brs), 5.83 (1.0H, ddt, J=17.1, 9.8, 5.4 Hz), 5.13 (1.0H, d, J=9.8 Hz), 5.06 (1.0H, d, J=17.1 Hz), 4.34 (2.0H, d, J=5.4 Hz), 2.51 (3.0H, s).ESI-MS Found: m/z[M+H]+ 223.3.
		2) Production of 2-allyl-6-(methylthio)-l ,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one:260 mL of N,N-diisopropylethylamine and 106 g of the hydrazine obtained in the above 1 were added to tetrahydrofuran (1.5 L) solution of 142 g of ethyl 4-chloro-2- (methylthio)pyridine-5-carboxylate, and stirred with heating under reflux for 18 hours. After cooled to room temperature, the reaction solution was evaporated under reduced pressure, and 500 mL of diethyl ether was added to the residue, and the precipitated solid was separated through filtration. The filtrate was evaporated under reduced pressure, the residue was cooled in an ice bath, 400 mL of trifluoroacetic acid was gradually added thereto, and stirred at room temperature for 1 hour and then at 70C for 1 hour. The reaction solution was evaporated under reduced pressure, 500 mL of ethanol was added thereto and cooled in an ice bath, and 1.0 L of 6 N sodium hydroxide solution was added thereto and stirred at room temperature for 15 minutes. Cooled in an ice bath, the reaction solution was made acidic with 400 mL of concentrated hydrochloric acid, and then evaporated under reduced pressure. The residue was partitioned in chloroform and water, and the chloroform layer was extracted, washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the formed yellow solid was taken out through filtration, washed with ethanol and diethyl ether, and dried to obtain 99.1 g of the entitled compound as a yellow solid. iH-NMR (400 MHz, DMSO-d6) delta: 8.66 (1.0H, brs), 5.83 (1.0H, ddt, J=17.1, 9.8, 5.4 Hz), 5.13(l.OH, d, J=9.8 Hz), 5.06 (1.0H, d, J=I 7.1 Hz), 4.34 (2.0H, d, J=5.4 Hz), 2.51 (3.0H, s). ESI-MS Found: m/z[M+H]+ 223.3.

260 mL of N,N-diisopropylethylamine and 106 g of the hydrazine obtained in the above 1 were added to tetrahydrofuran (1.5 L) solution of 142 g of ethyl 4-chloro-2- (methylthio)pyridine-5-carboxylate, and stirred with heating under reflux for 18 hours. After cooled to room temperature, the reaction solution was evaporated under reduced pressure, and 500 mL of diethyl ether was added to the residue, and the precipitated solid was separated through filtration. (0207) The filtrate was evaporated under reduced pressure, the residue was cooled in an ice bath, 400 mL of trifluoroacetic acid was gradually added thereto, and stirred at room temperature for 1 hour and then at 70C for 1 hour

References: [1]Patent: WO2017/75629,2017,A2 .Location in patent: Page/Page column 33; 34.
[2]ChemMedChem,2018,vol. 13,p. 1681 - 1694.
[3]Patent: US2007/254892,2007,A1 .Location in patent: Page/Page column 30-31.
[4]Patent: WO2008/133866,2008,A1 .Location in patent: Page/Page column 28.
[5]ACS Chemical Biology,2016,vol. 11,p. 921 - 930.
[6]Patent: WO2019/165204,2019,A1 .Location in patent: Page/Page column 29.

2
[ 955368-90-8 ]
[ 99769-19-4 ]
[ 955369-40-1 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine;copper diacetate; In chloroform; at 20℃; for 72h;	1) Production of methyl 3-[2-allyl-6-(methylthio)-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl]benzoate 20 mL of pyridine was added to a chloroform solution of 7.5 g of <strong>[955368-90-8]2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one</strong>, 6.1 g of copper(II) acetate and 10 g of [3-(methoxycarbonyl)]phenylboronic acid, and stirred at room temperature for 3 days. Aqueous 30% ammonia solution and saturated saline water were added to the reaction liquid in that order, and extracted with chloroform. The organic layer was washed with saturated saline water, then dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The crude product was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain 6.7 g of methyl 3-[2-allyl-6-(methylthio)-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl]benzoate as a yellow oily substance. 1H-NMR (400 MHz, CDCl3) delta: 8.92 (1H, s), 8.11-8.06 (2H, m), 7.65-7.59 (2H, m), 5.68 (1H, ddd, J=17.1, 10.2, 5.9 Hz), 5.13 (1H, dd, J=10.2, 1.0 Hz), 4.97 (1H, dd, J=17.1, 1.0 Hz), 4.45 (2H, d, J=5.9 Hz), 3.96 (3H, s), 2.51 (3H, s).
	With pyridine;copper diacetate; In chloroform; at 20℃; for 72h;	Production Example 11 Production of methyl 3-[2-allyl-6-(methylthio)-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl]benzoate Pyridine (20 mL) was added to a chloroform solution of <strong>[955368-90-8]2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one</strong> (7.5 g), copper(II) acetate (6.1 g) and [3-(methoxycarbonyl)]phenylboronic acid (10 g), and stirred at room temperature for 3 days. Aqueous 30 % ammonia solution and saturated saline water were added to the reaction liquid in order, and extracted with chloroform. The organic layer was washed with saturated saline water, dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The crude product was purified through silica gel column chromatography (hexane/ethyl acetate) to give methyl 3-[2-allyl-6-(methylthio)-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl]benzoate as a yellow oil (6.7 g). 1H-NMR (400 MHz, CDCl3) delta: 8.92 (1H, s), 8.11-8.06 (2H, m), 7.65-7.59 (2H, m), 5.68 (1H, ddt, J = 17.1, 10.2, 5.9 Hz), 5.13 (1H, dd, J = 10.2, 1.0 Hz), 4.97 (1H, dd, J = 17.1, 1.0 Hz), 4.45 (2H, d, J = 5.9 Hz), 3.96 (3H, s), 2.51 (3H, s).

References: [1]Patent: US2007/254892,2007,A1 .Location in patent: Page/Page column 38-39.
[2]Patent: EP2213673,2010,A1 .Location in patent: Page/Page column 43; 44.

3
[ 5029-67-4 ]
[ 955368-90-8 ]
[ 955369-47-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; N,N`-dimethylethylenediamine;copper(l) iodide; at 95℃;	1) Production of 2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-one 2.4 mL of N,N'-dimethylethylenediamine was added to 1,4-dioxane (50 mL) solution of 4.44 g of <strong>[955368-90-8]2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one</strong>, 3.80 g of copper(I) iodide, 5.33 g of 2-iodopyridine and 3.80 g of potassium carbonate, and stirred overnight at 95 C. The reaction liquid was cooled, aqueous ammonia was added thereto and extracted with ethyl acetate, washed with saturated saline water and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and crystallized with ethyl acetate to obtain 5.15 g of the entitled compound as a white solid. 1H-NMR (400 MHz, CDCl3) delta: 8.94 (1H, s), 8.52 (1H, d, J=5.1 Hz), 7.90 (2H, d, J=3.5 Hz), 7.29-7.25 (1H, m), 5.68 (1H, ddt, J=17.0, 10.2, 6.3 Hz), 5.05 (1H, d, J=10.2 Hz), 4.91 (1H, d, J=17.0 Hz), 4.85 (1H, d, J=6.3 Hz), 2.58 (3H, s). ESI-MS Found: m/z[M+H]+ 300.
	With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 95℃;	Reference Example 1 :Production of 2-allyl-6-fmethylthio)-l-pyridin-2-yl-3H-pyrazolo[3,4-d1pyrimidin-3-one2.4 mL of N,N'-dimethyl ethyl enediamine was added to 1,4-dioxane (50 mL) solution of 4.44 g of 2-allyl-6-(methylthio)-l,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one, 3,80 <n="30"/>g of copper(I) iodide, 5.33 g of 2-iodopyridine and 3.8O g of potassium carbonate, and stirred overnight at 95C. The reaction liquid was cooled, aqueous ammonia was added thereto and extracted with ethyl acetate, washed with saturated saline water and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and crystallized with ethyl acetate to obtain 5.15 g of the entitled compound as a white solid. 1 H-NMR (400 MHz, CDCI3) delta: 8.94 (IH, s), 8.52 (IH, d, J=5.1 Hz), 7.90 (2H, d, J=3.5 Hz),7.29-7.25 (IH, m), 5.68 (IH, ddt, J=I 7.0, 10.2, 6.3 Hz), 5.05 (IH, d, J=10.2 Hz), 4.91 (IH, d, J=I 7.0 Hz), 4.85 (IH, d, J=6.3 Hz), 2.58 (3H, s). ESI-MS Found: m/z[M+H]+ 300.
	With potassium carbonate;copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 95℃;	1) Production of 2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-one: N,N'-dimethylethylenediamine (2.4 mL) was added to a 1,4-dioxane (50 mL) solution of <strong>[955368-90-8]2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one</strong> (4.44 g), copper(I) iodide (3.80 g), 2-iodopyridine (5.33 g) and potassium carbonate (3.80 g), and stirred overnight at 95C. The reaction liquid was cooled, then aqueous ammonia was added thereto and extracted with ethyl acetate, washed with saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the residue was crystallized with ethyl acetate to give the entitled compound as a white solid (5.15 g). 1H-NMR (400 MHz, CDCl3) delta: 8.94 (1H, s), 8.52 (1H, d, J = 5.1 Hz), 7.90 (2H, d, J = 3.5 Hz), 7.29-7.25 (1H, m), 5.68 (1H, ddt, J = 17.0, 10.2, 6.3 Hz), 5.05 (1H, d, J = 10.2 Hz), 4.91 (1H, d, J = 17.0 Hz), 4.85 (2H, d, J = 6.3 Hz), 2.58 (3H, s). ESI-MS Found: m/z[M+H]+ 300.

	With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 95℃;	Production of 2-allyl-6-(methylthio)- 1 -pyridin-2-yl-3 H-pyrazolo [3 ,4-d]pyrimidin-3 -one : 2.4 mL of Nu,Nu'-dimethylethylenediamine was added to 1,4-dioxane (50 mL) solution of 4.44 g of 2-allyl-6-(memyltWo)-l,2-dmydro-3H-pyrazolo[3,4-d]pyrimidin-3-one, 3,80 g of copper(I) iodide, 5.33 g of 2-iodopyridine and 3.80 g of potassium carbonate, and stirred overnight at 95 C. The reaction liquid was cooled, aqueous ammonia was added thereto and extracted with ethyl acetate, washed with saturated saline water and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and crystallized with ethyl acetate to obtain 5.15 g of the entitled compound as a white solid. iH-NMR (400 MHz, CDCI3) 5: 8.94 (IH, s), 8.52 (IH, d, J=5.1 Hz), 7.90 (2H, d, J=3.5 Hz), 7.29-7.25 (IH, m), 5.68 (IH, ddt, J=17.0, 10.2, 6.3 Hz), 5.05 (IH, d, J=10.2 Hz), 4.91 (IH, d, J=17.0 Hz), 4.85 (IH, d, J=6.3 Hz), 2.58 (3H, s).
5.15 g	With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 95℃;	Preparative Example 1-1 Production of 2-allyl-6-(methylthio)-l-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-one: 2.4 mL of Nu,Nu'-dimethylethylenediamine was added to 1,4-dioxane (50 mL) solution of 4.44 g of 2-allyl-6-(methylthio)-l,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one, 3.80 g of copper(I) iodide, 5.33 g of 2-iodopyridine and 3.80 g of potassium carbonate, and stirred overnight at 95C. The reaction liquid was cooled, aqueous ammonia was added thereto and extracted with ethyl acetate, washed with saturated saline water and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and crystallized with ethyl acetate to obtain 5.15 g of the entitled compound as a white solid. lH-NMR (400 MHz, CDCI3) delta: 8.94 (IH, s), 8.52 (IH, d, J=5.1 Hz), 7.90 (2H, d, J=3.5 Hz), 7.29-7.25 (IH, m), 5.68 (IH, ddt, J=17.0, 10.2, 6.3 Hz), 5.05 (IH, d, J=10.2 Hz), 4.91 (IH, d, J=17.0 Hz), 4.85 (IH, d, J=6.3 Hz), 2.58 (3H, s).
	With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 95℃;	2.4 mL of N,N'-dimethylethylenediamine was added to 1,4-dioxane (50 mL) solution of 4.44 g of <strong>[955368-90-8]2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one</strong>, 3.80 g of copper(I) iodide, 5.33 g of 2-iodopyridine and 3.80 g of potassium carbonate, and stirred overnight at 95 C. The reaction liquid was cooled, aqueous ammonia was added thereto and extracted with ethyl acetate, washed with saturated saline water and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and crystallized with ethyl acetate to obtain the entitled compound as a white solid. 1H-NMR (400 MHz, CDCl3) delta: 8.94 (1H, s), 8.52 (1H, d, J=5.1 Hz), 7.90 (2H, d, J=3.5 Hz), 7.29-7.25 (1H, m), 5.68 (1H, ddt, J=17.0, 10.2, 6.3 Hz), 5.05 (1H, d, J=10.2 Hz), 4.91 (1H, d, J=17.0 Hz), 4.85 (1H, d, J=6.3 Hz), 2.58 (3H, s).

References: [1]Patent: US2007/254892,2007,A1 .Location in patent: Page/Page column 45.
[2]Patent: WO2008/133866,2008,A1 .Location in patent: Page/Page column 28-29.
[3]Patent: EP2213673,2010,A1 .Location in patent: Page/Page column 44.
[4]Patent: WO2013/39854,2013,A1 .Location in patent: Page/Page column 28.
[5]Patent: WO2014/62454,2014,A1 .Location in patent: Page/Page column 32.
[6]Patent: US2016/8361,2016,A1 .Location in patent: Paragraph 0165.

4
ethyl 4-([[(tert-butoxy) carbonyl](prop-2-en-1-yl)amino]amino)-2-(methylsulfanyl)pyrimidine-5-carboxylate [ No CAS ]
[ 955368-90-8 ]

Yield	Reaction Conditions	Operation in experiment
76%	With trifluoroacetic acid; In dichloromethane; at 0 - 20℃; for 12h;	Step-2: Synthesis of 2-allyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-3-one To a stirred solution of ethyl 4-(2-allyl-2-tert-butoxycarbonyl-hydrazino)-2-methylsulfanyl-pyrimidine-5-carboxylate (3.0 g, 8.19 mmol, 1.0 eq) in CH2Cl2 (10 mL) was added TFA (10 mL) dropwise at 0 C. and allowed to stir at RT for 12 h. After completion of reaction, solvent was removed under reduced pressure. Residue was diluted with EtOH (20 mL) and 6N NaOH solution (10 mL) was added at 0 C. and allowed to stir at RT for 1 h. After completion of reaction, the mixture was acidified by using 6N HCl solution. EtOH was removed under reduced pressure; residue obtained was cooled to RT and extracted with chloroform (50 mL*3). The organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 2-allyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-3-one (1.40 g, 76%) as a yellow solid.
		N,N-diisopropylethylamine (260 mL) and the hydrazine (106 g) obtained in the above 1 were added to a tetrahydrofuran (1.5 L) solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (142 g), and stirred with heating under reflux for 18 hours. After cooled to room temperature, the reaction solution was evaporated under reduced pressure, then diethyl ether (500 mL) was added to the residue, and the precipitated solid was separated through filtration. The filtrate was evaporated under reduced pressure, the residue was cooled in an ice bath, then trifluoroacetic acid (400 mL) was gradually added thereto, stirred at room temperature for 1 hour, and further stirred at 70C for 1 hour. The reaction solution was evaporated under reduced pressure, then ethanol (500 mL) was added thereto, and cooled in an ice bath, and then 6 N potassium hydroxide solution (1.0 L) was added thereto and stirred at room temperature for 15 minutes. Cooled in an ice bath, the reaction solution was acidified with concentrated hydrochloric acid (400 mL), and then evaporated under reduced pressure. The residue was partitioned between chloroform and water, then the chloroform layer was extracted, washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, then the formed yellow solid was collected through filtration, washed with ethanol and diethyl ether, and dried to give the entitled compound as a yellow solid (99.1 g). 1H-NMR (400 MHz, DMSO-d6) delta: 8.66 (1H, brs), 5.83 (1H, ddt, J = 17.1, 9.8, 5.4 Hz), 5.13 (1H, d, J = 9.8 Hz), 5.06 (1H, d, J = 17.1 Hz), 4.34 (2H, d, J = 5.4 Hz), 2.51 (3H, s). ESI-MS Found: m/z[M+H]+ 223.

References: [1]Patent: US2019/106427,2019,A1 .Location in patent: Paragraph 0252; 0256; 0257.
[2]Patent: EP2213673,2010,A1 .Location in patent: Page/Page column 39.
[3]Patent: WO2019/165204,2019,A1 .
[4]Patent: CN110872296,2020,A .

5
[ 955368-90-8 ]
[ 189278-27-1 ]
2-allyl-6-(methylthio)-1-(6-(trifluoromethyl)pyridin-2-yl)-1_,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) iodide; potassium carbonate; N,N-dimethylethylenediamine; In 1,4-dioxane; at 95℃; for 1h;Inert atmosphere;	N,N'-dimethylethylenediamine (87.25 mg, 989.79 mumol) was added into the mixture of I1 (200.00 mg, 899.81 mumol), cuprous iodide (171.37 mg, 899.81 mumol), 2-trifluoromethyl-6-bromopyridine (209.45 mg, 926.80mumol) and potassium carbonate (174.11 mg, 1.26 mumol) in 3 mL dioxane, the mixture was heated to 95C and stirred for 1 hour under nitrogen atmosphere. The reaction was monitored to be complete by LCMS. The reaction mixture was cooled down, 30 mL ammonia was added, then extracted by EtOAc (10 mL×2), then washed by saturated brine, dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure to give the pale brown colloidal product, which was purified by column chromatography (PE/EtOAc =4/1-3/1) to give the compound 46-A. 1H NMR (400MHz, CDCl3) delta = 8.89 (s, 1H), 8.20 (d, J=8.5 Hz, 1H), 7.98 (t, J=8.0 Hz, 1H), 7.54 (d, J=7.8 Hz, 1H), 5.64 -5.54 (m 1H), 4.94 (d, J=10.4 Hz, 1H), 4.90 - 4.83 (m, 3H), 2.54 (s, 3H)

References: [1]ACS Chemical Biology,2016,vol. 11,p. 921 - 930.
[2]Patent: EP3572413,2019,A1 .Location in patent: Paragraph 0316-0318.

6
[ 40473-07-2 ]
[ 955368-90-8 ]
2-allyl-1-(6-methoxypyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3_,4-d]pyrimidin-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) iodide; potassium carbonate; N,N-dimethylethylenediamine; In 1,4-dioxane; at 95℃; for 12h;Inert atmosphere;	I1 (1.0 g, 4.5 mmol) was added into 1,4- dioxane (10 mL), and 2-bromo-6-methoxylpyridine (1.02 g, 5.4 mmol, 664 muL), potassium carbonate (622 mg, 4.5 mmol), cuprous iodide (857 mg, 4.5 mmol) and N,N'-dimethylethylenediamine (397 mg, 4.5 mmol, 490 muL) were added while stirring, heated to 95C under nitrogen atmosphere, then reacted for 12 h. 100 mL ammonia was added into the reacted mixture, then extracted by 100 mL EA, the organic phase was washed by 100 mL brine, dried over anhydrous sodium sulfate, filtered and concentrated, the crude product was crystalized by EtOAc, then purified by silica gel chromatography (PE/EA = 10/1 to 2/1), to give the compound 47-1. 1H NMR (400MHz, CDCl3) delta = 8.92 (s, 1H), 7.89 (t, J=8.0 Hz, 1H), 7.43 (d, J=7.2 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 5.83 - 5.69 (m, 1H), 5.07 (d, J=10.4 Hz, 1H), 4.96 (br d, J=17.2 Hz, 1H), 4.84 (d, J=6.0 Hz, 2H), 3.93 (s, 3H), 2.56 (s, 3H)

References: [1]ACS Chemical Biology,2016,vol. 11,p. 921 - 930.
[2]Patent: EP3572413,2019,A1 .Location in patent: Paragraph 0320-0322.

7
[ 955368-90-8 ]
2-allyl-6-((4-(dimethylamino)phenyl)amino)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3Hpyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]