848398-41-4|2,4-Dichloro-5,7-dihydrofuro[3,4-d]pyrimidine| Ambeed

Structure of 848398-41-4

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Quality Control of [ 848398-41-4 ] Purity: 97% SDS Specification

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Product Details of [ 848398-41-4 ]

CAS No. :	848398-41-4
Formula :	C₆H₄Cl₂N₂O
M.W :	191.02
SMILES Code :	ClC1=C2C(COC2)=NC(Cl)=N1
MDL No. :	MFCD13250060
InChI Key :	WRAAHQVXMZLMQR-UHFFFAOYSA-N
Pubchem ID :	23125094

Safety of [ 848398-41-4 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 848398-41-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.33
Num. rotatable bonds	0
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	40.96
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	35.01 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.07
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	1.38
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.51
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.	0.61
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	2.81
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.68

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.3
Solubility	0.963 mg/ml ; 0.00504 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.	-1.72
Solubility	3.65 mg/ml ; 0.0191 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very 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	-3.18
Solubility	0.126 mg/ml ; 0.000662 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	Yes
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.	-6.49 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)	2.23

Application In Synthesis of [ 848398-41-4 ]

* 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 [ 848398-41-4 ]

[ 848398-41-4 ] Synthesis Path-Downstream 1~35

1
[ 848398-41-4 ]
[ 142-84-7 ]
[ 848398-42-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; triethylamine; In tetrahydrofuran; at 0 - 20℃; for 4h;	Example 3 2-chloro-4-N,N-di-n-propylamino-5,7-dihydrofuro[3,4-d]pyrimidine: Under argon gas atmosphere, tetrahydrofuran (4 mL) was added to the compound prepared in Example 2 (757 mg), and then the mixture was stirred in an ice-bath. To the mixture, triethylamine (1.4 mL) and di-n-propylamine (1.3 mL) were dropped. The mixture was stirred for 4 hours at room temperature. The reaction mixture was poured into cooled 10% aqueous solution of citric acid, and then the mixture was extracted by ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (hexane : ethyl acetate = 9 : 1) to give the title compound (784 mg) having the following physical data. TLC: Rf 0.71 (n-hexane : ethyl acetate =1:1); 1H-NMR (300MHz, CDCl3): delta 5.19, 4.86, 3.32, 1.62, 0.94.

References: [1]Patent: EP1666468,2006,A1 .Location in patent: Page/Page column 33.

2
[ 848398-40-3 ]
[ 848398-41-4 ]

Yield	Reaction Conditions	Operation in experiment
49%	With N,N-dimethyl-aniline; trichlorophosphate; at 0℃; for 12h;Reflux;	To a 0C solution of the aforementioned 3 (500 mg, 3.25 mmol) in phosphorus oxychloride (30 mL) was added dimethyl aniline (500 mg, 4.13 mmol). The resulting solution was refluxed for 12 hours. The solvents were removed under reduced pressure. The resulting residue was poured into ice (lOOg) and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate. The Na2S04 was removed by filtration, and the volatiles were removed under reduced pressure. The resulting residue was purified by flash chromatography using a mixture of hexane and ethyl acetate to to provide the final product 4 (300 mg, 49%). LRMS (M + H+) m/z: calcd 192.01; found 192.10.
		Example 2 2,4-dichloro-5,7-dihydrofuro[3,4-d]pyrimidine: Under argon gas atmosphere, phenylphosphonic dichloride (16.1 mL) was added to the compound prepared in Example 1 (15.7 g). The mixture was stirred for 6 hours at 135 C, and then for 30 minutes at 165C. After the reaction mixture was cooled, it was dropped into ice-water (100 mL). Ethyl acetate (100 mL) was added to the mixture solution. An insoluble matter was removed by filtration under reduced pressure, and was washed with ethyl acetate. The filtrate and the washings were combined, and then the mixture was shaken and separated. The organic layer was washed with a saturated sodium bicarbonate and a saturated sodium chloride, successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and then dried under vacuum to give the title compound (3.66 g) having the following physical data. TLC: Rf 0.60 (hexane : ethyl acetate =1:1); 1H-NMR (300MHz, CDCl3): delta 5.17, 5.09.

References: [1]Patent: WO2014/15291,2014,A1 .Location in patent: Page/Page column 181; 182.
[2]Patent: EP1666468,2006,A1 .Location in patent: Page/Page column 32-33.

4
[ 848398-41-4 ]
[ 100-46-9 ]
[ 1542711-45-4 ]

Yield	Reaction Conditions	Operation in experiment
73%	With triethylamine; In dichloromethane; at 0 - 20℃; for 12h;	To a 0C solution of the aforementioned intermediate 4 (300 mg, 1.58 mmol) in DCM (50 mL) were added phenylmethanamine (300 mg, 3 mmol) and TEA (500 mg, 3.88 mmol). Then the reaction solution was stirred at room temperature for 12 hours. The resulting mixture was concentrated under reduces pressure. The resulting residue was purified by flash chromatography using a mixture of hexane and ethyl acetate to provide the desired 5 (300 mg, 73%). LRMS (M + H+) m/z: calcd 262.71; found 262.85.

References: [1]Patent: WO2014/15291,2014,A1 .Location in patent: Page/Page column 181; 182.

5
[ 848398-41-4 ]
[ 1542710-75-7 ]

References: [1]Patent: WO2014/15291,2014,A1 .

6
[ 89898-51-1 ]
[ 848398-41-4 ]

References: [1]Patent: WO2014/15291,2014,A1 .

7
[ 848398-41-4 ]
2-(5-fluoroisoindolin-2-yl)-N-(1H-indazol-5-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine [ No CAS ]

References: [1]Patent: WO2015/54317,2015,A1 .

8
[ 848398-41-4 ]
2-(5-chloroisoindolin-2-yl)-N-(1H-indazol-5-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine [ No CAS ]

References: [1]Patent: WO2015/54317,2015,A1 .

9
[ 848398-41-4 ]
N-(1H-indazol-5-yl)-2-(5-methoxyisoindolin-2-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine [ No CAS ]

References: [1]Patent: WO2015/54317,2015,A1 .

10
[ 848398-41-4 ]
[ 19335-11-6 ]
2-chloro-N-(1H-indazol-5-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 5h;	[0139] A mixture of <strong>[848398-41-4]2,4-dichloro-5,7-dihydrofuro[3,4-d]pyrimidine</strong> (90 mg, 0.47 mmol), lH-indazol-5-amine (62.7 mg, 0.47 mmol), and diisopropylethylamine (0.16 mL, 0.94 mmol) in DMF (0.94 mL) was heated at 100 C for 5 h. TLC showed the reaction was complete. The mixture was then diluted with water. The resulted yellow precipitate was filtered and washed with water and dried in vacuo to provide 120 mg (89%) title compound which was used directly for next step reaction without further purification.
38.3%	With sodium carbonate; In ethanol; at 15℃; for 12h;	To a solution of compound 2,4-dichloro-5 ,7- dihydro furo [3,4- d]pyrimidine (1.00 g, 5.30 mmol) in EtOH (30 mL) were addedNa2CO3(1.70g, 15.8 mmol) and compound 1H-indazol-5-amine (711 mg, 5.3 mmol). The resulting mixture was stirred for 12 h at 15C. After LCMS showed the reaction was completed, the solvent was removed under reduced pressure and the residue was dissolved in EtOAc (100 mL), washed by water (2 x 50 mL). The organic phase was dried over Na2 SO4, filtered and concentrated under reduced pressure to give compound the title compound as a solid (800 mg, yield: 38.3%).
38.3%	With sodium carbonate; In ethanol; at 15℃; for 12h;	2-chloro-N-(lH-indazol-5-yl)-5,7-dihydromro[3,4-d]pyrimidin-4-amine To a solution of compound <strong>[848398-41-4]2,4-dichloro-5,7-dihydrofuro[3,4-d]pyrimidine</strong> (1.00 g, 5.30 mmol) in EtOH (30 mL) were added Na2C03 (1.70 g, 15.8 mmol) and compound 1H- indazol-5 -amine (711 mg, 5.3 mmol). The resulting mixture was stirred for 12 h at 15C. After LCMS showed the reaction was completed, the solvent was removed under reduced pressure and the residue was dissolved in EtOAc (100 mL), washed by water (2 x 50 mL). The organic phase was dried over Na2S04, filtered and concentrated under reduced pressure to give compound the title compound as a solid (800 mg, yield: 38.3%).

References: [1]Patent: WO2016/210330,2016,A1 .Location in patent: Paragraph 0138-0139.
[2]Patent: WO2015/54317,2015,A1 .Location in patent: Paragraph 0203; 0204.
[3]Patent: WO2015/157556,2015,A1 .Location in patent: Paragraph 0375; 0376.

11
[ 848398-41-4 ]
[ 19335-11-6 ]
N-(1H-indazol-5-yl)-2-(5-methoxyisoindolin-2-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine [ No CAS ]

References: [1]Patent: WO2015/157556,2015,A1 .

12
[ 848398-41-4 ]
(R)-3-hydroxy-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino-[5',6':4,5]thieno[3,2-f]quinolin-8-one [ No CAS ]
(R)-3-((2-chloro-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%		In a 20 mL vial, INT-6 (0.05 g, 0.167 mmol) was added to 3 mL of dry DMF and sonicated briefly. To this, K2CO3 (0.231 g, 1.670 mmol) was added and the reaction was warmed to 90 C. for 10 min. The reaction was then cooled to room temperature and <strong>[848398-41-4]2,4-dichloro-5,7-dihydrofuro[3,4-d]pyrimidine</strong> (0.055 g, 0.288 mmol) was added and subsequently warmed to 90 C. for 2 h. Upon completion, the reaction was cooled, filtered to remove any undissolved potassium carbonate and the crude reaction mixture was directly purified by reverse phase prep-HPLC (10-95% MeCN/Water, 0.1% TFA) to yield I-86 (0.052 g, 0.114 mmol, 68% yield) as a yellow solid after lyophilization. 1H NMR (400 MHz, DMSO-d6): delta 9.31 (d, J=9.2 Hz, 1H), 8.13 (d, J=8.7 Hz, 1H), 8.10 (d, J=4.6 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.58 (d, J=9.2 Hz, 1H), 7.11 (br, 1H), 4.98 (s, 4H), 3.55 (m, 1H), 3.39 (m, 2H), 1.12 (d, J=6.9 Hz, 3H) MS m/z (M+H): 453.8.

References: [1]Patent: US2016/75720,2016,A1 .Location in patent: Paragraph 0527; 0528.

13
[ 848398-41-4 ]
N-(3-aminophenyl)-2-methylpropane-2-sulfonamide [ No CAS ]
2-chloro-N⁴-(3-[(1,1-dimethylethyl)sulfonamido]phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; for 48h;Reflux;	General procedure: Procedure B: A mixture of substituted 2,4-dichloropyrimidine (1.0 equiv.), and substituted aniline (1.0-1.05 equiv.), and DIPEA (1.2 equiv.) in isopropanol (0.1 M) was stirred and heated at reflux. The reaction time, work-up, and product isolation procedure are described below.

References: [1]Patent: WO2016/22460,2016,A1 .Location in patent: Page/Page column 77; 110-111.

14
[ 848398-41-4 ]
[ 118837-66-4 ]
2-chloro-N⁴-(3-[N-(1-methylethyl)sulfamoyl]phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 100℃; for 18h;	General procedure: Procedure B: A mixture of substituted 2,4-dichloropyrimidine (1.0 equiv.), and substituted aniline (1.0-1.05 equiv.), and DIPEA (1.2 equiv.) in isopropanol (0.1 M) was stirred and heated at reflux. The reaction time, work-up, and product isolation procedure are described below.

References: [1]Patent: WO2016/22460,2016,A1 .Location in patent: Page/Page column 77; 109-110.

15
[ 848398-41-4 ]
2-chloro-5,7-dihydro-furo[3,4-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69.87%	With acetic acid; zinc; In methanol; at 70℃; for 4h;	CompoundII-29 (19.10g, 0.1mol, 1.0eq.), Acetic acid (34.3mL, 0.6mol, 6.0eq.) Andmethanol(150mL) placed in a reaction flask was added portionwise at 25 to zinc dust (26.16g, 0.4mol, 4.0eq.), The addition was completed temperaturewas raised to 70 Reactionfor 4 hours, TLC the reaction was complete. Cooling, filtration and the filtercake was washed twice with methanol, and the filtrate sand columnchromatography to obtain compoundI-29 was 10.94g,69.87% yield.

References: [1]Patent: CN105859726,2016,A .Location in patent: Paragraph 0114; 0115; 0116.

16
[ 848398-41-4 ]
[ 114474-28-1 ]
N-(4-(1H-pyrazol-4-yl)phenyl)-2-chloro-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 5h;	A mixture of <strong>[848398-41-4]2,4-dichloro-5,7-dihydrofuro[3,4-d]pyrimidine</strong> (300 mg, 1.57 mmol), 4-(1H-pyrazol-4-yl)aniline (250 mg, 1.57 mmol), and diisopropylethylamine (0.55 mL, 3.14 mmol) in DIVIF (3.14 mL) was heated at 100 C for 5 h. TLC showed the reaction was complete. The mixture was then diluted with water. The resulted yellow precipitate was filtered and washed with water and dried in vacuo to provide 480 mg (97%) title compound which was used directly for next step reaction without further purification.
97%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 5h;	[0100] A mixture of <strong>[848398-41-4]2,4-dichloro-5,7-dihydrofuro[3,4-d]pyrimidine</strong> (300 mg, 1.57 mmol), 4-(lH-pyrazol-4-yl)aniline (250 mg, 1.57 mmol), and diisopropylethylamine (0.55 mL, 3.14 mmol) in DMF (3.14 mL) was heated at 100 C for 5 h. TLC showed the reaction was complete. The mixture was then diluted with water. The resulted yellow precipitate was filtered and washed with water and dried in vacuo to provide 480 mg (97%) title compound which was used directly for next step reaction without further purification.

References: [1]Patent: WO2016/210331,2016,A1 .Location in patent: Paragraph 0095; 0096.
[2]Patent: WO2016/210330,2016,A1 .Location in patent: Paragraph 0099-0100.

17
[ 848398-41-4 ]
2-(3-(4-((1H-indazol-5-yl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)phenoxy)-N-isopropylacetamide [ No CAS ]

References: [1]Patent: WO2016/210330,2016,A1 .

18
[ 848398-41-4 ]
N-(3-(4-((1H-indazol-5-yl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)phenyl)-2-morpholinoacetamide [ No CAS ]

References: [1]Patent: WO2016/210330,2016,A1 .

19
[ 459434-39-0 ]
[ 848398-41-4 ]
2-chloro-N⁴-(3-[N-cyclopropylsulfamoyl]phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 100℃; for 18h;	This was prepared from MA2-096 (0.096 g) and RJl-042 (0.212 g) using procedure B (reaction time, 18 h, reaction temperature 100 C) and isolated in the same way as MA2-030 to give the title compound MA3-002-3 as a white solid (0.165 g, 90%). Mp: 208 C (dec). NMR (400 MHz, DMSO-ifc): delta 9.86 (s, 1H, disappeared on D20 shake), 8.10 (s, 1H), 8.00 (d with unresolved fine coupling, / = 8.2, Hz, 1H), 7.96 (d, / = 2.3 Hz, 1H, disappeared on D20 shake), 7.62 (t, / = 8.0 Hz, 1H), 7.52 (d, / = 8.0 Hz, 1H), 5.02 (s, 2H), 4.87 (s, 2H), 2.22-2.12 (m, 1H), 0.56-0.48 (m, 2H), 0.47-0.38 (m, 2H). HPLC-MS (ESI+): m/z 757.1 [20%, (2M37C1+Na)+], 755.1 [30%, (2M35C1+Na)+], 369.1 [40%, (M37C1+H)+], 367.1 [100%, (M35C1 +]. Procedure B A mixture of substituted 2,4-dichloropyrimidine (1.0 equiv.), and substituted aniline (1.0-1.05 equiv.), and DIPEA (1.2 equiv.) in isopropanol (0.1 M) was stirred and heated at reflux. The reaction time, work-up, and product isolation procedure are described below.

References: [1]Patent: WO2017/66428,2017,A1 .Location in patent: Page/Page column 186; 220.

20
[ 848398-41-4 ]
2-chloro-3H,4H,5H,7H-furo[3,4-d]pyrimidin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium hydroxide; In tetrahydrofuran; water; at 20℃;	[00580] To a stirred solution of <strong>[848398-41-4]2,4-dichloro-5H,7H-furo[3,4-d]pyrimidine</strong> (EV-AQ8821- 001,1 g, 5.24 mmol) in THF (10 mL) was added 1M aq NaOH solution (10.5 mL, 10.5 mmol) and stirred at r.t. overnight. The solution was acidified to pH 4/5 with acetic acid and extracted with DCM (3 x 30 mL). The combined organic extracts were dried over MgS04 and concentrated in vacuo to afford the title compound (890 mg, 99%) as an orange powder. [00581] 1H NMR (500 MHz, DMSO-d6) delta 4.88 (t, J = 3.3 Hz, 2H), 4.81 (t, J = 3.3 Hz, 2H).

References: [1]Patent: WO2017/59191,2017,A1 .Location in patent: Paragraph 00578-00581.

21
[ 848398-41-4 ]
2-{4-[4-(trifluoromethyl)piperidine-1-carbonyl]-1H-pyrazol-1-yl}-3H,4H,5H,7H-furo[3,4-d]pyrimidin-4-one [ No CAS ]

References: [1]Patent: WO2017/59191,2017,A1 .

22
(+/-)-trans-3-aminobicyclo[2.2.2]octane-2-carboxylic acid methyl ester [ No CAS ]
[ 848398-41-4 ]
(rac)-methyl (2S,3S)-3-[(2-chloro-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)amino]bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 70℃; for 12h;	To a stirred solution of 2,4~dichioro-5,7-dihydrofuro[3,4-d]pyrimidine (870 mg, 4.55 mmoi) inTHF (5 mL) was added (rac)-(2S,3S)-methyl 3-aminobicyclo[2.2.2}octane-2-carboxylate (835 mg, 4.55 mmol) and DIPEA (1.77 g, 13.7 mmol) and the resulting reaction mixture wasstirred at 70 oc for 12 h. After cooling to room temperature, the reaction mixture was pouredinto water (100 ml) and extracted with EtOAc (150 ml twice). The combined organic layerswere washed with brine, dried over anhydrous Na2S04 , filtered and concentrated in vacuoto give a crude product, which was purified by siiica gei flash chromatography (0-40% EtOAc-hexane gradient) to afford the title compound (770 mg, 50% yieid) as yellow oiL MS::-=nx 1 ilii+i-il+

References: [1]Patent: WO2017/133664,2017,A1 .Location in patent: Page/Page column 86.

23
[ 848398-41-4 ]
(rac)-(2S,3S)-methyl 3-((2-(5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]

References: [1]Patent: WO2017/133664,2017,A1 .

24
[ 848398-41-4 ]
(rac)-(2S,3S)-3-((2-(5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid [ No CAS ]

References: [1]Patent: WO2017/133664,2017,A1 .

25
[ 848398-41-4 ]
(rac)-(2S,3S)-3-((2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid [ No CAS ]

References: [1]Patent: WO2017/133664,2017,A1 .

26
[ 848398-41-4 ]
[ 24313-88-0 ]
C₁₅H₁₆ClN₃O₄ [ No CAS ]