[ CAS No. 27631-29-4 ] {[proInfo.proName]}

Name: 27631-29-4|2,4-Dichloro-6,7-dimethoxyquinazoline|97%
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Quality Control of [ 27631-29-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 27631-29-4 ]

CAS No. :	27631-29-4	MDL No. :	MFCD00051733
Formula :	C₁₀H₈Cl₂N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DGHKCBSVAZXEPP-UHFFFAOYSA-N
M.W :	259.09	Pubchem ID :	520327
Synonyms :		Chemical Name :	2,4-Dichloro-6,7-dimethoxyquinazoline

Calculated chemistry of [ 27631-29-4 ]

Physicochemical Properties

Num. heavy atoms :	16
Num. arom. heavy atoms :	10
Fraction Csp3 :	0.2
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	62.54
TPSA :	44.24 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.46 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.75
Log Po/w (XLOGP3) :	3.41
Log Po/w (WLOGP) :	2.95
Log Po/w (MLOGP) :	1.54
Log Po/w (SILICOS-IT) :	3.17
Consensus Log Po/w :	2.76

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.93
Solubility :	0.0308 mg/ml ; 0.000119 mol/l
Class :	Soluble
Log S (Ali) :	-4.02
Solubility :	0.0248 mg/ml ; 0.0000958 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-4.82
Solubility :	0.00393 mg/ml ; 0.0000152 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	1.94

Safety of [ 27631-29-4 ]

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

Application In Synthesis of [ 27631-29-4 ]

* 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.

Upstream synthesis route of [ 27631-29-4 ]
Downstream synthetic route of [ 27631-29-4 ]

[ 27631-29-4 ] Synthesis Path-Upstream 1~12

1
[ 28888-44-0 ]
[ 27631-29-4 ]

Yield	Reaction Conditions	Operation in experiment
77%	at 100℃; for 24 h;	General procedure: In a 100mL flask equipped with a reflux condenser, the reaction mixture containing the quinazolinediones (1.00g) and POCl₃ (15mL; 24.77g; 161.53mmol) was stirred and heated at 100°C for 24h. Isolation was performed by the slow addition of the reaction medium over a mixture of ice and water with vigorous stirring. The resulting precipitate was filtered under a vacuum and purified by filtration through silica gel using dichloromethane as the eluent.
75%	With trichlorophosphate In <i>N</i>,<i>N</i>-dimethyl-aniline; toluene for 5 h; Heating / reflux	[00101] 8 gr, 36 [MM,] 6,7-dimethoxy 2,4-quinazoline dione, 23 ml, 280 nM [POC13] and 10 ml dimethyl aniline in 40 ml toluene were refluxed for 5 hours. Water and NH3 were added and the reaction was filtered and washed with [ETOAC] to give 7g light-green solid, mp-1560. 75percent yield. HPLC-97percent pure, Rt=4.87 minutes (RP 18, CH3CN: H20 70: 30, [W=254] [FLOW=1.] 0). NMR CDC13 8 7.36 [(LH,] s), 7.28 [(LH,] s), 4,07 (3H, s), 4.06 (3H, s). NMR DMSO d6 8 7.26 [(LH,] s), 6. 68 (lH, s), 3.82 (3H, s), 3.78 (3H, s).

Reference： [1] Journal of Medicinal Chemistry, 1986, vol. 29, # 5, p. 627 - 629
[2] European Journal of Medicinal Chemistry, 2014, vol. 71, p. 1 - 14
[3] Patent: WO2004/13091, 2004, A2, . Location in patent: Page 34-35
[4] The Journal of organic chemistry, 2002, vol. 67, # 23, p. 8284 - 8286
[5] Journal of the Chemical Society, 1948, p. 1759,1765
[6] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 15, p. 7254 - 7263
[7] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 16, p. 7543 - 7551
[8] Patent: US2006/36093, 2006, A1, . Location in patent: Page/Page column 40-41
[9] Arzneimittel-Forschung/Drug Research, 2012, vol. 62, # 8, p. 360 - 366

2
[ 32315-10-9 ]
[ 26961-27-3 ]
[ 27631-29-4 ]

Reference： [1] Heterocycles, 2012, vol. 85, # 6, p. 1417 - 1426

3
[ 5653-40-7 ]
[ 27631-29-4 ]

Reference： [1] Journal of Medicinal Chemistry, 1986, vol. 29, # 5, p. 627 - 629
[2] Arzneimittel-Forschung/Drug Research, 2012, vol. 62, # 8, p. 360 - 366
[3] European Journal of Medicinal Chemistry, 2014, vol. 71, p. 1 - 14
[4] Journal of Medicinal Chemistry, 2015, vol. 58, # 3, p. 1452 - 1465

4
[ 2150-38-1 ]
[ 27631-29-4 ]

Reference： [1] Organic Preparations and Procedures International, 2004, vol. 36, # 4, p. 341 - 345
[2] Organic Preparations and Procedures International, 2004, vol. 36, # 4, p. 341 - 345
[3] Journal of Medicinal Chemistry, 1986, vol. 29, # 5, p. 627 - 629

5
[ 26791-93-5 ]
[ 27631-29-4 ]

6
[ 26759-46-6 ]
[ 27631-29-4 ]

7
[ 28888-44-0 ]
[ 27631-29-4 ]

Reference： [1] Organic Preparations and Procedures International, 2004, vol. 36, # 4, p. 341 - 345
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 2, p. 580 - 590
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 3, p. 1452 - 1465

8
[ 4998-07-6 ]
[ 27631-29-4 ]

Reference： [1] Journal of the Chemical Society, 1948, p. 1759,1765
[2] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 13, p. 3959 - 3966

9
[ 4959-60-8 ]
[ 27631-29-4 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 13, p. 3959 - 3966

10
[ 5004-88-6 ]
[ 57-13-6 ]
[ 27631-29-4 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 13, p. 3959 - 3966

11
[ 859912-32-6 ]
[ 27631-29-4 ]

Reference： [1] Journal of the Chemical Society, 1948, p. 1759,1765

12
[ 27631-29-4 ]
[ 935693-62-2 ]

Reference： [1] MedChemComm, 2017, vol. 8, # 5, p. 1069 - 1092
[2] Patent: WO2018/5799, 2018, A1,

[ 27631-29-4 ] Synthesis Path-Downstream 1~60

1
[ 28888-44-0 ]
[ 27631-29-4 ]

Yield	Reaction Conditions	Operation in experiment
85%	With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate
80.4%	With trichlorophosphate In N,N-dimethyl-formamide at 105℃; for 4h;	Preparation of 2,4-dichloro-6,7-dimethoxyquinazoline: In a dry and clean 1000mL three-necked flask, 6,7-dimethoxy-2,4-(1H,3H)-quinazolindione (VIII) 66.6g (0.3mol), and 380g of phosphorus oxychloride ( 2.5mol) and 3mL of DMF were sequentially added, heated to 105°C and refluxed, and reacted for 4h under reduced pressure, the temperature of the reaction solution was controlled to be below 80°C, and excess phosphorus oxychloride was distilled off. The vacuum distillation residue was cooled to 15°C, and the residue was poured Into 500g of crushed ice for quenching; when extracting, use 300 mL of dichloromethane × 2 times, the extract was washed once with tap water, then with saturated brine, and dried with 50 grams of anhydrous sodium sulfate; sodium sulfate was removed by suction filtration. The dichloromethane was distilled off under reduced pressure to obtain 80.8 g of 2,4-dichloro-6,7-dimethoxyquinazoline concentrate; 150 mL of petroleum ether was added to the obtained concentrate, and the mixture was stirred and cooled for crystallization; filtered, tviiihe filter cake was collected and dried at 40° C. for 5 hours to obtain 62.5 g of light yellow crystalline solid powder, mp: 171-172° C., yield: 80.4%, purity 98.8%.
77%	With trichlorophosphate at 100℃; for 24h;	4.1.8 General methodology for the synthesis of 2,4-dichloroquinazolines General procedure: In a 100mL flask equipped with a reflux condenser, the reaction mixture containing the quinazolinediones (1.00g) and POCl3 (15mL; 24.77g; 161.53mmol) was stirred and heated at 100°C for 24h. Isolation was performed by the slow addition of the reaction medium over a mixture of ice and water with vigorous stirring. The resulting precipitate was filtered under a vacuum and purified by filtration through silica gel using dichloromethane as the eluent.

75%	With trichlorophosphate In <i>N</i>,<i>N</i>-dimethyl-aniline; toluene for 5h; Heating / reflux;	AG 1560 [2,4-dichloro-6, 7-dimethoxyquinazoline] [00101] 8 gr, 36 [MM,] 6,7-dimethoxy 2,4-quinazoline dione, 23 ml, 280 nM [POC13] and 10 ml dimethyl aniline in 40 ml toluene were refluxed for 5 hours. Water and NH3 were added and the reaction was filtered and washed with [ETOAC] to give 7g light-green solid, mp-1560. 75% yield. HPLC-97% pure, Rt=4.87 minutes (RP 18, CH3CN: H20 70: 30, [W=254] [FLOW=1.] 0). NMR CDC13 8 7.36 [(LH,] s), 7.28 [(LH,] s), 4,07 (3H, s), 4.06 (3H, s). NMR DMSO d6 8 7.26 [(LH,] s), 6. 68 (lH, s), 3.82 (3H, s), 3.78 (3H, s).
72%	With trichlorophosphate at 120℃; for 12h;	2.2 Step-2: Synthesis of 2,4-dichloro-6,7-dimethoxyquinazoline: A mixture of 6,7- dimethoxyquinazolin-4(3H)-one (360 mg, 1.62 mmol, 1 eq) in POCl3 (0.5 mL) was allowed to stir at 120 °C for 12 h. Progress of reaction was monitored by TLC. After completion, reaction mixture was cooled to RT, diluted with cold water (100 mL) and allowed to stir for 5 minutes. Solid was filtered, washed with water and dried under vacuum to afford 2,4- dichloro-6,7-dimethoxyquinazoline (300 mg, 72%). LCMS: 258[M+1]+
68%	With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate for 4.5h; Heating;
60.8%	With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate at 20℃; for 6.16667h; Reflux;	1.2 (2) 3.0g (13.5mmol) of 6,7-dimethoxyquinazoline-2,4(1H,3H)-dione and 8.18g (67.5mmol) of phosphorus oxychloride were added to a 100mL single-necked flask, 1.03g (6.75mmol) N,N-dimethylaniline was added at room temperature, stirred for 10min and then heated to reflux for 6h, most of the phosphorus oxychloride was evaporated under reduced pressure, 30 mL of dichloromethane (DCM) was added while still hot to dissolve the residual oil, and poured into 40 mL of water with stirring, separation to obtain a DCM layer and an aqueous layer, the aqueous layer was extracted with DCM twice (the volume of single use of DCM was 30 mL), the DCM layers were combined, washed twice with water, once with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was evaporated to dryness. The resulting dark red solid (2.53 g) was subjected to flash column chromatography (eluent: EA:PE:AcOH volume ratio = 1:1:0.001) to give 2,4-dichloro-6,7-dimethoxy Quinazoline (white solid, 2.12 g, 60.8% yield).
	With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate
	With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate Heating;
	With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate
	With trichlorophosphate In 1,2-dichloro-ethane for 3h; Heating / reflux;	78 6,7-dimethoxy-1H-quinazoline-2,4-dione (22.2 g, 100 mmol) and POCl3 (20 mL) were added in 1,2-dichloroethane (30 mL) and the mixture was kept under reflux for 3 hours. Subsequently, the mixture was poured into ice water. The precipitate thus obtained was filtered and dried under vacuum to give 17.0 g of Intermediate XIX.
	With trichlorophosphate In <i>N</i>,<i>N</i>-dimethyl-aniline

Reference： [1]DeRuiter; Brubaker; Millen; Riley [Journal of Medicinal Chemistry, 1986, vol. 29, # 5, p. 627 - 629]
[2]Current Patent Assignee: CHONGQING WORLD HAORUI PHARM CHEM - CN111138371, 2020, A Location in patent: Paragraph 0039-0041
[3]Barbosa, Maria Letícia De Castro; Lima, Lídia Moreira; Tesch, Roberta; Sant'Anna, Carlos Mauricio R.; Totzke, Frank; Kubbutat, Michael H.G.; Schächtele, Christoph; Laufer, Stefan A.; Barreiro, Eliezer J. [European Journal of Medicinal Chemistry, 2014, vol. 71, p. 1 - 14]
[4]Current Patent Assignee: Yissum Research & Development (in: Hebrew University); HEBREW UNIVERSITY OF JERUSALEM - WO2004/13091, 2004, A2 Location in patent: Page 34-35
[5]Current Patent Assignee: INTEGRAL BIOSCIENCES PRIVATE LTD - WO2022/91048, 2022, A1 Location in patent: Paragraph 195; 196
[6]Andrus, Merritt B; Mettath, Sashikumar N; Song, Chun [Journal of Organic Chemistry, 2002, vol. 67, # 23, p. 8284 - 8286]
[7]Current Patent Assignee: UNIV SHENYANG PHARMACEUTICAL - CN114409636, 2022, A Location in patent: Paragraph 0112; 0114
[8]Curd et al. [Journal of the Chemical Society, 1948, p. 1759,1765]
[9]da Silva, Joaquim Fernando Mendes; Walters, Marcus; Al-Damluji, Saad; Ganellin, C. Robin [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 15, p. 7254 - 7263]
[10]Abouzid, Khaled; Shouman, Samia [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 16, p. 7543 - 7551]
[11]Current Patent Assignee: TAIGEN BIOPHARMACEUTICALS HOLDINGS LTD. - US2006/36093, 2006, A1 Location in patent: Page/Page column 40-41
[12]El Ella; Saleh; Hassan; Hamdy; El-Araby; Abouzid [Arzneimittel-Forschung/Drug Research, 2012, vol. 62, # 8, p. 360 - 366]

2
[ 27631-29-4 ]
[ 20197-86-8 ]
[ 94644-47-0 ]

Yield	Reaction Conditions	Operation in experiment
37%	With sodium tetrahydroborate

Reference： [1]Kung, Pei-Pei; Casper, Martin D.; Cook, Kimberley L.; Wilson-Lingardo, Laura; Risen, Lisa M.; Vickers, Timothy A.; Ranken, Ray; Blyn, Lawrence B.; Wyatt, Jacqueline R.; Cook, P. Dan; Ecker, David J. [Journal of Medicinal Chemistry, 1999, vol. 42, # 22, p. 4705 - 4713]

3
[ 27631-29-4 ]
[ 23680-84-4 ]

Yield	Reaction Conditions	Operation in experiment
68%	With ammonia In tetrahydrofuran at 20℃; for 44h;
	With ammonia In tetrahydrofuran; water at 20℃; for 24h;
	With ammonium hydroxide In tetrahydrofuran

	With ammonia
	With ammonia In acetonitrile at 35 - 50℃;	3.2 General procedure a (for 2-chloro-6,7-dimethoxyquinazolin-4-amines [intermediates]): General procedure: To a solution of commercially obtained 2,4-dichloro-6,7-dimethoxyquinazoline (1.04g, 4mmol), 2-2.5 equivalents of the selected amine in acetonitrile (10mL) was added, and the solution was heated and stirred at 35-50°C for 3-5h. After insoluble solids were filtered off, the filtrate was poured into water to afford the intermediates at 70-95% yield. The purity of the obtained intermediates was>95% (high-performance liquid chromatography [HPLC] analysis), and they were used in the final step without further purification.

Reference： [1]Andrus, Merritt B; Mettath, Sashikumar N; Song, Chun [Journal of Organic Chemistry, 2002, vol. 67, # 23, p. 8284 - 8286]
[2]Kumaraswamy; Jena, Nivedita; Sastry; Kumar, B. Ashok [Organic Preparations and Procedures International, 2004, vol. 36, # 4, p. 341 - 345]
[3]da Silva, Joaquim Fernando Mendes; Walters, Marcus; Al-Damluji, Saad; Ganellin, C. Robin [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 15, p. 7254 - 7263]
[4]Yadav; Naik; Gandhi; Chauhan; Giridhar [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 13, p. 3959 - 3966]
[5]Mizukawa, Yuki; Ikegami-Kawai, Mayumi; Horiuchi, Masako; Kaiser, Marcel; Kojima, Masayoshi; Sakanoue, Seiki; Miyagi, Seiya; Nanga Chick, Christian; Togashi, Hiroyuki; Tsubuki, Masayoshi; Ihara, Masataka; Usuki, Toyonobu; Itoh, Isamu [Bioorganic and Medicinal Chemistry, 2021, vol. 33]

4
[ 27631-29-4 ]
[ 94644-47-0 ]

Yield	Reaction Conditions	Operation in experiment
37%	With sodium borohydrid In ethanol; dichloromethane; ethyl acetate	32 2-Chloro-6,7-dimethoxyquinazoline (QH) Example 32 2-Chloro-6,7-dimethoxyquinazoline (QH) 2-Chloro-6,7-dimethoxyquinazoline (QH). Sodium borohydride (0.23 g, 6.1 mmole) was added to a solution of 2,4-dichloro-6,7-dimethoxyquinazoline (1.0 g, 4 mmol) in EtOH/CH2 Cl2 (40 mL; 1:1; v/v) at 25° C. The mixture was stirred at 25° C. for 12 h then was poured into cold HCl aqueous solution (0.4 M, 200 mL). The resulting mixture was basicified with saturated NaHCO3 (aq) and then extracted with EtOAc (3100 mL). The combined organic layers were dried (Na2 SO4), filtered, and concentrated in vacuo to give a yellowish white solid reside. Purification of the residue by flash column chromatography (gradient elution 20 to 35% EtOAc/hexanes) provided the title compound (0.33 g, 37%): TLC (Rf =0.50; 50% EtOAc/hexanes); 1 H NMR (DMSO) δ 9.25 (s, 1H), 7.55 (s, 1H), 7.36 (s, 1H), 3.98 (s, 3H), 3.93 (s, 3H); 3 C NMR (CDCl3) δ 159.1, 157.3, 156.1, 150.9, 150.1, 119.4, 105.9, 103.7, 56.6, 56.4; HRMS (FAB) m/z 225.0431 (M+H)+ (C10 H9 N2 O2 Cl requires 225.0431); Anal. (C10 H9 N2 O2 Cl3/4H2 O*1/4CH3 OH) C, H, N.
14%	With sodium tetrahydroborate In isopropyl alcohol at 70 - 80℃; for 120h;

Reference： [1]Current Patent Assignee: IONIS PHARMACEUTICALS - US6156758, 2000, A
[2]Zunszain, Patricia A.; Federico, Cesare; Sechi, Mario; Al-Damluji, Saad; Ganellin, C. Robin [Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 11, p. 3681 - 3689]

5
[ 27631-29-4 ]
[ 87120-72-7 ]
[ 1000207-60-2 ]

Yield	Reaction Conditions	Operation in experiment
71%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 50℃;	General procedure: To a solution of 2,4-dichloro-6,7-dimethoxyquinazoline (1.0 equiv.) in DMF or THF (3.0mL), corresponding alicyclic amine (2.2 equiv) was added followed by the addition of DIPEA (1.05 equiv). The reaction mixture was stirred at room temperature until TLC showed the consumption of the starting material. The reaction mixture was quenched with water, which was further extracted with EA (3×20mL). The combined organic phases were washed with 0.5% acetic acid and subsequently with brine, to remove the excess amine. The organic layer was dried over anhydrous Na2SO4, concentrated in vacuo to yield the crude product, which was purified by flash chromatography using silica gel.
34%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 20℃; for 18h;	Intermediate C13; (2-Chloro-6,7-dimethoxy-quinazolin-4-yl)-piperidin-4-yl-amine dihydrochloride; Step 1: 4-(2-Chloro-6,7-dimethoxy-quinazolin-4-ylamino)-piperidine-l-carboxylic acid tert-butyl ester; To a solution of 2,4-dichloro-6,7-dimethoxyquinazoline (5.12 g, 19.8 mmol, 1.0 equiv) in THF (50 mL) was added 4-amino-piperidine-l-carboxylic acid tert-butyl ester (4.34 g, 21.7 mmol, 1.1 equiv) and 1,8-diazabicyclo [5.4.0] undec-7-ene (3.31 g, 3.25 mL, 21.7 mmol, 1.1 equiv) and the reaction mixture stirred at rt for 16 h. Additional 4- amino-piperidine-1-carboxylic acid tert-butyl ester (0.87 g, 4.3 mmol, 0.2 equiv) and 1,8- diazabicyclo [5.4.0] undec-7-ene (0.66 g, 0.65 mL, 4.3 mmol, 0.2 equiv) were added and the mixture was stirred for 2 h. The solvent was evaporated under reduced pressure and the mixture dissolved in dichloromethane (100 mL). The solution was washed with water (2 x 20 mL) and a sat. solution of NaCl (20 mL), the aqueous layers were combined and extracted with dichloromethane (20 mL). The combined organic layers were dried over MgSCU and evaporated under reduced pressure to give an amber solid. The solid was crystallized from MeOH (500 mL) to afford 4-(2-chloro-6,7-dimethoxy- quinazolin-4-ylamino)-piperidine-l-carboxylic acid tert-butyl ester (2.67 g, 22%) as a white solid. The mother liquours were evaporated and purified with column chromatography on silica eluting with a gradient of heptane/ ethyl acetate (1:1) ? ethyl acetate and the fractions combined to afford additional 4-(2-chloro-6,7-dimethoxy- quinazolin-4-ylamino)-piperidine-l-carboxylic acid tert-butyl ester (1.0 g, 12%). 1H NMR (250 MHz, CDCl3): delta 1.49-1.51 (m, 2H), 1.61 (s, 9H), 2.30-2.48 (m, 2H), 2.89-3.10 <n="77"/>(m, 2H), 4.04 (s, 3H), 4.09 (s, 3H), 4.29-4.48 (m, 2H), 4.75-4.50 (m, IH), 5.61 (d, / = 8.0 Hz, IH), 6.87 (s, IH), 7.18 (s, IH). MS (ESP): 423.5 [M+H]+.

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 184
[2]Patent: WO2008/692,2008,A2 .Location in patent: Page/Page column 75-76
[3]Journal of Medicinal Chemistry,2015,vol. 58,p. 2315 - 2325
[4]Journal of Medicinal Chemistry,2015,vol. 58,p. 1452 - 1465
[5]European Journal of Medicinal Chemistry,2019,vol. 161,p. 277 - 291

6
[ 27631-29-4 ]
[ 452972-09-7 ]
2-chloro-6,7-dimethoxy-4-(5-bromo-3-pyridyl)quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Starting from 2.40 g of 2-chloro-6,7-dimethoxy-4-(5-bromo-3-pyridyl)quinazoline obtained from 3,4-dichloro-6,7-dimethoxyquinazoline and 5-bromo-3-pyridylboric acid in the same manner as in Production Example 1, 1.46 g of the title compound was obtained as pale yellow crystals in the same manner as in Example 46. m.p. 228-230 C. MASS 375, 377 (MH+). 1H-NMR (400 MHz, CDCl3) delta 3.12 (3H, d, J=5.0 Hz), 3.85 (3H, s), 4.04 (3H, s), 5.15 (1H,br s), 6.96 (1H, s), 7.07 (1H, s), 8.21 (1H, t, J=2.0 Hz), 8.83 (1H, d, J=2.0 Hz), 8.88 (1H, d, J=2.0 Hz).

Reference： [1]Patent: US6352989,2002,B1 .Location in patent: Page column 70

7
[ 27631-29-4 ]
[ 221006-66-2 ]
2-chloro-6,7-dimethoxy-4-(3-phenoxyphenyl)quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		73 EXAMPLE 73 6,7-dimethoxy-2-methylamino-4-(3-phenoxylphenyl)quinazoline Starting from 250 mg of 2-chloro-6,7-dimethoxy-4-(3-phenoxyphenyl)quinazoline obtained from 3,4-dichloro-6,7-dimethoxyquinazoline and 3-phenoxyphenyl boric acid in the same manner as in Production Example 1, 146 mg of the title compound was obtained as yellow crystals in the same manner as in Example 46. m.p. 157-159° C. MASS 388 (MH+). 1H-NMR (400 MHz, CDCl3) δ 3.11 (3H, d, J=4.8 Hz) 3.79 (3H, s), 4.02 (3H, s), 4.12 (1H,brs), 7.05 (1H, s), 7.06 (1H, s), 7.08 (2H, m), 7.12 (1H, m), 7.17 (1H, m), 7.32-7.37 (3H, m), 7.43 (1H, dt, J=7.6,1.2 Hz), 7.50 (1H, t, J=7.6 Hz).

Reference： [1]Current Patent Assignee: EISAI CO LTD - US6352989, 2002, B1 Location in patent: Page column 68

8
[ 27631-29-4 ]
[ 5961-59-1 ]
2-chloro-6,7-dimethoxy-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With sodium acetate In tetrahydrofuran; water at 20℃; for 48h;	20 (2-chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine A mixture of 2, 4-dichloro-6,7-dimethoxyquinazoline (100 mg, 0.386 mmol), 4-methoxy-N-methylaniline (55 mg, 0. 401MMOL) and sodium acetate (60 mg, 0.732 mmol) in tetrahydrofuran (5 mL) and water (2.5 mL) was stirred at room temperature for 48 h. The reaction mixture was evaporated to dryness and the residue was crystallized using ethanol/water and isolated as white solid (60 mg, 60%). H NMR (CDC13) : 8. 19 (s, 1H), 7.32-7. 26 (m, 2H), 7.09-7. 07 (m, 2H), 6.16 (s, 1H), 4.03 (s, 3H), 3.87 (s, 3H), 3.75 (s, 3H), 3.32 (s, 3H).
60%	With sodium acetate In tetrahydrofuran; water at 60℃;

Reference： [1]Current Patent Assignee: MYRIAD GENETICS INC; IMMUNE PHARMACEUTICALS INC; MYREXIS, INC. - WO2005/3100, 2005, A2 Location in patent: Page 164-165
[2]Location in patent: experimental part Sirisoma, Nilantha; Kasibhatla, Shailaja; Pervin, Azra; Zhang, Hong; Jiang, Songchun; Willardsen, J. Adam; Anderson, Mark B.; Baichwal, Vijay; Mather, Gary G.; Jessing, Kevin; Hussain, Raouf; Hoang, Khanh; Pleiman, Christopher M.; Tseng, Ben; Drewe, John; Sui, Xiong Cai [Journal of Medicinal Chemistry, 2008, vol. 51, # 15, p. 4771 - 4779]

9
[ 27631-29-4 ]
[ 1993-03-9 ]
[ 871507-13-0 ]

Yield	Reaction Conditions	Operation in experiment
59%	With caesium carbonate In 1,4-dioxane at 100℃; for 18h;	1 Step 1: To solution of 2,4-dichloro-6,7-dimethoxy-quinazoline (555 mg, 2.14 mmol) in dioxane (3.6 ml, 0.5M) was added 2-fluoro phenyl boronic acid (250 mg, 1.78 mmol), tricyclohexyl phosphine (30 mg, 0.06 eq. ), Cesium carbonate (867 mg, 1.5 eq. ) and tris(dibenzylideneacetone)dipalladium (32 mg, 0.02 eq. ). The reaction mixture was heated at 100°C under N2 for 18 hours. The reaction mixture was filtered through celite and concentrated. MPLC purification using a biotage 40M column eluting with 5- 40% ethyl acetate/hexans afforded the title compound as a white solid (333 mg, 59%).

Reference： [1]Current Patent Assignee: PFIZER INC - WO2005/120514, 2005, A1 Location in patent: Page/Page column 20

10
[ 50541-93-0 ]
[ 27631-29-4 ]
N-(1-benzylpiperidin-4-yl)-2-chloro-6,7-dimethoxyquinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h;
92%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h;
79%	With triethylamine In tetrahydrofuran at 20℃; for 20h;

59%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 50℃; for 3h;	4.5 General procedure for 4-substituted 2-chloro-6,7-dimethoxyquinazolines General procedure: To a solution of 2,4-dichloro-6,7-dimethoxyquinazoline (1.0 equiv.) in DMF or THF (3.0mL), corresponding alicyclic amine (2.2 equiv) was added followed by the addition of DIPEA (1.05 equiv). The reaction mixture was stirred at room temperature until TLC showed the consumption of the starting material. The reaction mixture was quenched with water, which was further extracted with EA (3×20mL). The combined organic phases were washed with 0.5% acetic acid and subsequently with brine, to remove the excess amine. The organic layer was dried over anhydrous Na2SO4, concentrated in vacuo to yield the crude product, which was purified by flash chromatography using silica gel.
	In N,N-dimethyl-formamide at 20℃; for 10h;
	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃;	1 Method 1 A mixture of the appropriate 2,4-dichloroquinazoline (1 eq.), primary amine (1.5 eq.) and DIPEA (3 eq.) in dry THF was stirred overnight at room temperature and then concentrated under reduced pressure. The crude product was purified by flash chromatography (DCM/MeOH 100:0 to 96:4) to afford the expected 4-substituted quinazoline.
	With triethylamine In tetrahydrofuran at 0 - 20℃;	1.14. General procedure for the synthesis of 4-aminosubstituted-2-chloroquinazolines 72-77. General procedure: 2,4-Dichloroquinazolines 67, 68 or 69 (1.07 mmol) and triethylamine (3.23 mmol) were added to asolution of the appropriate amine (1.18 mmol) in dry THF (10 mL) at 0 °C. After 4-6.5 h of stirring at rtthe reaction was stopped, and the suspension was filtered and washed with dry THF. The filtrate and thewashes were concentrated under vacuum. The obtained crude solid was purified by silica gel columnchromatography eluting with a mixture ethyl acetate/n-hexane/methanol (4:11:1) to afford the requiredintermediate compound.
	With N-ethyl-N,N-diisopropylamine at 20℃;

Reference： [1]Liu, Feng; Chen, Xin; Allali-Hassani, Abdellah; Quinn, Amy M.; Wasney, Gregory A.; Dong, Aiping; Barsyte, Dalia; Kozieradzki, Ivona; Senisterra, Guillermo; Chau, Irene; Siarheyeva, Alena; Kireev, Dmitri B.; Jadhav, Ajit; Herold, J. Martin; Frye, Stephen V.; Arrowsmith, Cheryl H.; Brown, Peter J.; Simeonov, Anton; Vedadi, Masoud; Jin, Jian [Journal of Medicinal Chemistry, 2009, vol. 52, # 24, p. 7950 - 7953]
[2]Location in patent: experimental part Liu, Feng; Chen, Xin; Allali-Hassani, Abdellah; Quinn, Amy M.; Wigle, Tim J.; Wasney, Gregory A.; Dong, Aiping; Senisterra, Guillermo; Chau, Irene; Siarheyeva, Alena; Norris, Jacqueline L.; Kireev, Dmitri B.; Jadhav, Ajit; Herold, J. Martin; Janzen, William P.; Arrowsmith, Cheryl H.; Frye, Stephen V.; Brown, Peter J.; Simeonov, Anton; Vedadi, Masoud; Jin, Jian [Journal of Medicinal Chemistry, 2010, vol. 53, # 15, p. 5844 - 5857]
[3]Sundriyal, Sandeep; Chen, Patty B.; Lubin, Alexandra S.; Lueg, Gregor A.; Li, Fengling; White, Andrew J. P.; Malmquist, Nicholas A.; Vedadi, Masoud; Scherf, Artur; Fuchter, Matthew J. [MedChemComm, 2017, vol. 8, # 5, p. 1069 - 1092]
[4]Soumyanarayanan, Uttara; Ramanujulu, Pondy Murugappan; Mustafa, Nurulhuda; Haider, Shozeb; Fang Nee, Adina Huey; Tong, Jie Xin; Tan, Kevin S.W.; Chng, Wee Joo; Dymock, Brian W. [European Journal of Medicinal Chemistry, 2019, vol. 184]
[5]Yokoyama, Kazuhiro; Ishikawa, Noriko; Igarashi, Susumu; Kawano, Noriyuki; Hattori, Kazuyuki; Miyazaki, Takahiro; Ogino, Shin-ichi; Matsumoto, Yuzo; Takeuchi, Makoto; Ohta, Mitsuaki [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 14, p. 7021 - 7032]
[6]Current Patent Assignee: IP21PO INNOVATIONS LIMITED; EMORY UNIVERSITY - WO2013/140148, 2013, A1 Location in patent: Page/Page column 61; 63
[7]Bouchut, Anne; Rotili, Dante; Pierrot, Christine; Valente, Sergio; Lafitte, Sophia; Schultz, Johan; Hoglund, Urban; Mazzone, Roberta; Lucidi, Alessia; Fabrizi, Giancarlo; Pechalrieu, Dany; Arimondo, Paola B.; Skinner-Adams, Tina S.; Chua, Ming Jang; Andrews, Kathy T.; Mai, Antonello; Khalife, Jamal [European Journal of Medicinal Chemistry, 2019, vol. 161, p. 277 - 291]
[8]Zheng, Haoting; Dai, Qiuzi; Yuan, Zigao; Fan, Tingting; Zhang, Cunlong; Liu, Zijian; Chu, Bizhu; Sun, Qinsheng; Chen, Yan; Jiang, Yuyang [Bioorganic and Medicinal Chemistry, 2022, vol. 53]

11
[ 94-12-2 ]
[ 27631-29-4 ]
[ 1061768-22-6 ]

Yield	Reaction Conditions	Operation in experiment
74%	In isopropyl alcohol for 2h; Heating;

Reference： [1]Abouzid, Khaled; Shouman, Samia [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 16, p. 7543 - 7551]

12
[ 27631-29-4 ]
[ 27106-51-0 ]
[ 1061767-97-2 ]

Yield	Reaction Conditions	Operation in experiment
67%	In tetrahydrofuran

Reference： [1]Abouzid, Khaled; Shouman, Samia [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 16, p. 7543 - 7551]

13
[ 27631-29-4 ]
[ 380430-68-2 ]
[ 1119772-74-5 ]

Yield	Reaction Conditions	Operation in experiment
91.5%	With sodium carbonate;1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; In tetrahydrofuran; at 60℃; for 6.5h;Inert atmosphere;	Example 1 Synthesis of t-butyl [3-(2-chloro-6,7-dimethoxyquinazolin-4-yl)phenyl]carbamate To a mixture of 1.00 g (3.86 mmol) of 2,4-dichloro-6,7-dimethoxyquinazoline, 1.14 g (4.63 mmol) of 3-(N-t-butoxycarbonylamino)phenyl borate, tetrahydrofuran (25 mL), and 2 M sodium carbonate aqueous solution (5 mL) were added palladium acetate (8.84 mg) and 1,1'-bis(diphenylphosphino)ferrocene (21.4 mg) in this order, and the mixture was stirred at 60C for 6.5 hours under a nitrogen atomosphere. The reaction mixture was allowed to cool, and ethyl acetate (25 mL) and 5% w/w sodium chloride solution (20 mL) were added to extract the organic layer. The organic layer was washed twice with 5% w/w sodium chloride solution (20 mL) and then concentrated under reduced pressure. To the concentration residue were added ethyl acetate (1 mL) and 2-propanol (4 mL), and the mixture was suspended by stirring at 40C for 0.5 hours. The suspension was cooled, and the precipitated crystals were collected by filtration and dried to give 1.48 g of a target product (yield: 91.5%). 1H-NMR (CDCl3) delta (ppm): 1.52 (9H, s), 3.97 (3H, s), 4.07 (3H, s), 6.62 (1H, br), 7.33 (1H, s), 7.38-7.43 (1H, m), 7.48-7.53 (3H, m), 8.00 (1H, br). ESI MS: m/z 438 (M+Na)+.
91.5%	With sodium carbonate;1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; In tetrahydrofuran; water; at 60℃; for 6.5h;Inert atmosphere;	Production example 22 Synthesis of t-butyl [3-(2-chloro-6,7-dimethoxyquinazolin-4-yl)phenyl]carbamate To a mixture of 1.00 g (3.86 mmol) of 2,4-dichloro-6,7-dimethoxyquinazoline, 1.14 g (4.63 mmol) of 3-(N-t-butoxycarbonylamino)phenyl borate, tetrahydrofuran (25 mL), and 2 M sodium carbonate aqueous solution (5 mL) were added palladium acetate (8.84 mg) and 1,1'-bis(diphenylphosphino)ferrocene (21.4 mg) in this order, and the mixture was stirred at 60C for 6.5 hours under a nitrogen atmosphere. The reaction solution was allowed to cool, and ethyl acetate (25 mL) and 5% w/w sodium chloride solution (20 mL) were added to extract the organic layer. The organic layer was washed twice with 5% w/w sodium chloride solution (20 mL) and then concentrated under reduced pressure. To the concentration residue were added ethyl acetate (1 mL) and 2-propanol (4 mL), and the mixture was suspended by stirring at 40C for 0.5 hours. The suspension was cooled, and the precipitated crystals were collected by filtration and dried to give 1.48 g of a target product (yield: 91.5%, HPLC purity: 99.02%). 1H-NMP (CDCl3) delta (ppm): 1.52 (9H, s), 3.97 (3H, s), 4.07 (3H, s), 6.62 (1H, br), 7.33 (1H, s), 7.38-7.43 (1H, m), 7.48-7.53 (3H, m), 8.00 (1H, br). ESI MS: m/z 438 (M+Na)+.

Reference： [1]Patent: EP2189450,2010,A1 .Location in patent: Page/Page column 8
[2]Patent: EP2202229,2010,A1 .Location in patent: Page/Page column 22; 23

14
[ 480425-37-4 ]
[ 27631-29-4 ]
[ 1119772-78-9 ]

Yield	Reaction Conditions	Operation in experiment
91.3%	With sodium carbonate In tetrahydrofuran; water at 60℃; for 6h;	5 Example 5 Synthesis of N-[3-(2-chloro-6,7-dimethoxyquinazolin-4-yl)phenyl]formamide To a mixture of 2.00 g (7.72 mmol) of 2,4-dichloro-6,7-dimethoxyquinazoline, 2.38 g (9.26 mmol) of N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]formamide, tetrahydrofuran (50 mL), and 2 M aqueous sodium carbonate solution (10 mL) were added palladium acetate (17.7 mg) and 1,1'-bis(diphenylphosphino)ferrocene (42.8 mg) in this order, and the mixture was stirred at 60°C for 6 hours. The mixture was allowed to cool, then 5% w/w sodium chloride solution (50 mL) and ethyl acetate (50 mL) were added followed by stirring for 5 minutes, and the insoluble matter was collected by filtration. The filtrate was transferred to a separatory funnel to extract the organic layer. The organic layer was washed twice with 5% w/w sodium chloride solution (50 mL) and then concentrated under reduced pressure. To the concentration residue were added 2-propanol (15 mL) and ethyl acetate (10 mL), and the mixture was suspended by stirring at 50°C for 2 hours. The suspension was allowed to cool, and then the precipitated crystals were collected by filtration and dried to give 667 mg of a target product. Meanwhile, the insoluble matter collected by filtration was dissolved in a mixed solution of dichloromethane/methanol (300 mL/100 mL), the mixture was filtered to remove the insoluble matter, and the filtrate was concentrated under reduced pressure. To the concentration residue were added 2-propanol (15 mL) and ethyl acetate (10 mL), and the mixture was suspended by stirring at 50°C for 2 hours. The mixture was allowed to cool, and then the precipitated crystals were collected by filtration and dried to give 1.78 g of a target product. A total of 2.45 g was yielded, and the yield was 91.3%. 1H-NMR (DMSO-d6) δ (ppm): 3.86 (3H, s), 4.00 (3H, s), 7.41 (1H, s), 7.44 (1H, s), 7.45-7.60 (3H, m), 7.68-7.73 (1H, m), 8.14-8.18 (1H, m), 8.34 (1H, s), 10.47 (1H, br). ESI MS: m/z 366 (M+Na)+.

Reference： [1]Current Patent Assignee: EISAI CO LTD - EP2189450, 2010, A1 Location in patent: Page/Page column 10

15
[ 13035-19-3 ]
[ 27631-29-4 ]
[ 1000335-32-9 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 7950 - 7953
[2]Journal of Medicinal Chemistry,2010,vol. 53,p. 5844 - 5857

16
[ 6278-73-5 ]
[ 27631-29-4 ]
[ 74-89-5 ]
N₄-(4-benzothiazol-2-yl-phenyl)-6,7-dimethoxy-N₂-methyl-quinazoline-2,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-(4-aminophenyl)benzothiazole; 2-chloro-6,7-dimethoxy-3H-quinazolin-4-one With N-ethyl-N,N-diisopropylamine In butan-1-ol at 120℃; Stage #2: methylamine In butan-1-ol at 140℃; for 3h; Sealed vial;	10 General procedure 10: Regioselective twofold 2,4-diamination of 2,4-dichloroquinazolines: A mixture of 3- or 4-(benzothiazol-2-yl)-phenylamine (1.0 equiv.), 2,4-dichloroquinazoline (1.0 equiv.) and DIEA (1.0 equiv.) in n-BuOH was stirred at 120°C over night. The respective amine (2.0 equiv.) was added and the mixture was overheated to 140°C in a sealed vial for 3 h. If amine was used as a hydrochloride, additional DIEA had to be added (0.5 equiv.). For weakly nucleophilic amines like 3-amino-5-methylpyrazole, NaI (1.0 equiv.) was used as additive.

Reference： [1]Current Patent Assignee: 4 SC AG - EP1746096, 2007, A1 Location in patent: Page/Page column 36-37; 44

17
[ 27631-29-4 ]
[ 18655-50-0 ]
[ 864291-56-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 64 - 73

18
[ 27631-29-4 ]
[ 210240-20-3 ]
[ 1103521-34-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 64 - 73

19
[ 27631-29-4 ]
[ 1262849-90-0 ]
1-tert-butyl 3-ethyl (3R,4S)-4-(2-chloro-6,7-dimethoxyquinazolin-4-ylamino)pyrrolidine-1,3-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.189 g	With triethylamine In dichloromethane for 96h; Reflux;

Reference： [1]Caldwell, John J.; Welsh, Emma J.; Matijssen, Cornelis; Anderson, Victoria E.; Antoni, Laurent; Boxall, Kathy; Urban, Frederique; Hayes, Angela; Raynaud, Florence I.; Rigoreau, Laurent J. M.; Raynham, Tony; Aherne, G. Wynne; Pearl, Laurence H.; Oliver, Antony W.; Garrett, Michelle D.; Collins, Ian [Journal of Medicinal Chemistry, 2011, vol. 54, # 2, p. 580 - 590]

20
[ 32315-10-9 ]
[ 26961-27-3 ]
[ 27631-29-4 ]

Yield	Reaction Conditions	Operation in experiment
94.8%	Stage #1: bis(trichloromethyl) carbonate With triethylamine; Triphenylphosphine oxide In chlorobenzene at 20℃; for 0.5h; Cooling with ice; Stage #2: 2-amino-4,5-dimethoxybenzonitrile In chlorobenzene at 120℃; for 8h;

Reference： [1]Location in patent: experimental part Li, Zhenhua; Wu, Danli; Zhong, Weihui [Heterocycles, 2012, vol. 85, # 6, p. 1417 - 1426]

21
[ 27631-29-4 ]
[ 54060-30-9 ]
[ 1403933-69-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	With hydrogenchloride In water; isopropyl alcohol at 60℃; for 2h;	2 General procedure for the synthesis of compounds 1-10 General procedure: Aniline derivative (0.8 mmol) was added to a solution of 2,4-dichloro- 6,7-dimethoxyquinazoline (1.0 mmol) in isopropyl alcohol (5 ml), followed by the addition of a drop of concentrated HCl (100 ll). The resulting mixture was stirred at 60 C for 2 h. The mixture was filtered, and the solid was washed with isopropyl alcohol then dried under vacuum to give compounds 1-10. This procedure afforded the expected coupling product as a white or yellow solid (yield: 21-95%).
94%	With hydrogenchloride In isopropyl alcohol at 60℃; for 2h;	3 Compound 8: 2-Chioro-N-(3-ethynylphenyl)-6,7-dimethoxyquinazoline-4-amine 10053] The general synthesis procedure of the mono-substituted quinazoline derivatives are stated as follow. Substituted phenyl amine (0.8 mmol) was added to a solution of 2,4-dichloro-6,7-dimethoxyquinazoline (1.0 mmol) in isopropyl alcohol (5 ml), followed by the addition of a drop of concentrated HC1 (100 jtl). The resulting mixture was stirred at 60° C. for 2 hours. The mixture was filtered, and the solid was washed with isopropyl alcohol then dried under vacuum to give compounds 8, and 10-17. This procedure afforded the expected coupling product as a white or yellow solid (yield:21%-95%). 10056] ‘H NMR (400 MHz, DMSO-d5): ö 3.93 (s, 3H),3.99 (s, 3H), 4.21 (s, 1H), 7.18 (s, 1H), 7.26 (d, J=8.OHz, 1H),7.43 (t, J=8.O Hz, 1H), 7.85 (d, J=8.O Hz, 1H), 7.89 (s, 1H),7.94 (s, 1H), 10.00 (s, 1H); ‘3C NMR (100 MHz, DMSO-d5):ö 56.4, 57.2, 81.1, 83.8, 103.9, 106.6, 107.9, 122.2, 123.8,126.0, 127.6, 129.2, 139.5, 148.1, 149.5, 154.1, 155.5, 158.4;HRMS calculated for C,8H,4C1N302 (M+H): 340.0853.Found: 340.0850. Yield: 94%.

Reference： [1]Chen, Kuen-Feng; Pao, Kuan-Chuan; Su, Jung-Chen; Chou, Yi-Chieh; Liu, Chun-Yu; Chen, Hui-Ju; Huang, Jui-Wen; Kim, Inki; Shiau, Chung-Wai [Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 20, p. 6144 - 6153]
[2]Current Patent Assignee: NATIONAL YANG MING CHIAO TUNG UNIVERSITY; NATIONAL TAIWAN UNIVERSITY - US2014/80848, 2014, A1 Location in patent: Paragraph 0053; 0056

22
[ 27631-29-4 ]
[ 452-84-6 ]
[ 1403933-71-0 ]

Yield	Reaction Conditions	Operation in experiment
60%	With hydrogenchloride; In water; isopropyl alcohol; at 60℃; for 2h;	General procedure: Aniline derivative (0.8 mmol) was added to a solution of 2,4-dichloro- 6,7-dimethoxyquinazoline (1.0 mmol) in isopropyl alcohol (5 ml), followed by the addition of a drop of concentrated HCl (100 ll). The resulting mixture was stirred at 60 C for 2 h. The mixture was filtered, and the solid was washed with isopropyl alcohol then dried under vacuum to give compounds 1-10. This procedure afforded the expected coupling product as a white or yellow solid (yield: 21-95%).

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 6144 - 6153

23
[ 27631-29-4 ]
[ 100-46-9 ]
[ 71406-74-1 ]

Yield	Reaction Conditions	Operation in experiment
27%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 20℃; for 8.5h;Cooling with ice;	General procedure: To a solution of 2,4-dichloropyrimidine (1.0 mmol) and DIPEA (100 ll) in isopropyl alcohol was added 0.7 mmol aniline derivatives and the mixtures stirred under ice-bath condition for 30 min. The resulting mixture was stirred at room temperature for 8 h. After the reaction was completed, the reaction mixture was washed with water, extracted with EtOAc, and the organic layer was dried over MgSO4. After removal of MgSO4 by filtration and evaporation of solvents, the crude residue was purified by chromatography on a silica gel column using MeOH/DCM as eluent (0% to 2%) to give compounds 11-17 (yield: 3-27%).

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 6144 - 6153

24
[ 27631-29-4 ]
[ 5470-49-5 ]
[ 1424336-75-3 ]

Yield	Reaction Conditions	Operation in experiment
75%	With hydrogenchloride; In ethanol; water; at 60℃;	To the solution of 2,4-dichloro-6,7-dimethoxyquinazoline (0.52 g, 2.0 mmol) in EtOH (20 ml) were added <strong>[5470-49-5]4-methylsulfonylaniline</strong> (0.34 g, 2.0 mmol) and 1 N HCl aqueous solution (2 ml) and the reaction mixture was stirred at 60 °C for overnight. The reaction mixture was neutralized with 1 N NaOH aqueous solution and the precipitate was filtered and washed

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 1349 - 1356

25
[ 207405-68-3 ]
[ 27631-29-4 ]
[ 1424336-90-2 ]

Yield	Reaction Conditions	Operation in experiment
80%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 20℃;	General procedure: Azabicyclic amine (7a-c, 1.2 mmol) and Hunig?s base (2.0 mmol) were added to a solution of 2,4-dichloro-6,7-dimethoxyquinazoline (1.0 mmol) in i-PrOH (4 ml) and the resulting mixture was stirred at room temperature for overnight and then concentrated in vacuo. The residue was purified by column chromatography (CHCl3/MeOH 200:1) to obtain product.

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 1349 - 1356

26
[ 27631-29-4 ]
[ 273207-53-7 ]
[ 1424336-92-4 ]

Yield	Reaction Conditions	Operation in experiment
82%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 20℃;	1 4.4. General procedure to generate 4-alkylamino-2-chloro-6,7-dimethoxyquinazoline (8-10) General procedure: Azabicyclic amine (7a-c, 1.2 mmol) and Hunig’s base (2.0 mmol) were added to a solution of 2,4-dichloro-6,7-dimethoxyquinazoline (1.0 mmol) in i-PrOH (4 ml) and the resulting mixture was stirred at room temperature for overnight and then concentrated in vacuo. The residue was purified by column chromatography (CHCl3/MeOH 200:1) to obtain product.

Reference： [1]Pham, Tuan-Anh N.; Yang, Zunhua; Fang, Yuanying; Luo, Jun; Lee, Jongkook; Park, Haeil [Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 5, p. 1349 - 1356]

27
[ 5004-88-6 ]
[ 57-13-6 ]
[ 27631-29-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 3959 - 3966

28
[ 27631-29-4 ]
[ 7006-50-0 ]
[ 1458639-54-7 ]

Yield	Reaction Conditions	Operation in experiment
47%	With triethylamine; In tetrahydrofuran; at 20℃;	To a mixture of 2,4-dichloro-6,7-dimethoxyquinazoline (650 mg, 2.51 mmol) and 1-benzyl- N-methylpiperidin-4-amine (680 mg, 3.34 mmol) in dry THF (16 mL) was added Et3N (1.4 mL, 1.02 g, 10.0 mmol). The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was purified by flash chromatography (DCM/MeOH 100:0 to 98:2) to furnish N-(l-benzylpiperidin-4-yl)-2-chloro-6,7-dimethoxy- N-methylquinazolin-4-amine (500 mg, 47%) as a white solid

Reference： [1]Patent: WO2013/140148,2013,A1 .Location in patent: Page/Page column 65

29
[ 4727-72-4 ]
[ 27631-29-4 ]
[ 1458639-53-6 ]

Yield	Reaction Conditions	Operation in experiment
67%	With potassium tert-butylate; In dimethyl sulfoxide; at 20℃; for 2h;	To a mixture of 2,4-dichloro-6,7-dimethoxyquinazoline (515 mg, 2.0 mmol, provided by Sigma-Aldrich) and l-benzylpiperidin-4-ol (430 mg, 2.25 mmol, provided by Sigma-Aldrich) in dry DMSO (7.5 mL) was added slowly at room temperature KOt-Bu (335 mg, 3.0 mmol). The reaction mixture was stirred at room temperature for 2 hours. Water (20 mL) was added and the aqueous layer was extracted with DCM (3 chi 30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous MgS04 and then concentrated under reduced pressure. The crude product was purified by flash chromatography (EtOAc/Pet. Ether 1 : 1) to furnish 4-((l-benzylpiperidin-4-yl)oxy)-2-chloro-6,7-dimethoxyquinazoline (550 mg, 67%) as a pale yellow solid.

Reference： [1]Patent: WO2013/140148,2013,A1 .Location in patent: Page/Page column 64

30
[ 27631-29-4 ]
[ 134464-79-2 ]
[ 1458639-55-8 ]

Yield	Reaction Conditions	Operation in experiment
80%		To a suspension of sodium hydride (60% in mineral oil, 70 mg, 1.75 mmol) in dry THF (4 mL) was added dropwise at 0 C a solution of tert-butyl 4-mercaptopiperidine-l-carboxylate (350 mg, 1.61 mmol, prepared following the procedure described in PCT Int. Appl., 2008077552) in dry THF (4 mL). Reaction mixture was stirred at 0 C for 20 minutes and a solution of 2,4-dichloro-6,7-dimethoxyquinazoline (415 mg, 1.60 mmol) in dry THF (4 mL) was added dropwise. The mixture was stirred for 1 hour at 0 C and then overnight at room temperature. An aqueous ammonium chloride solution (20 mL) was added and the aqueous phase was extracted with diethyl ether (2x50 mL). The combined organic extracts were washed with brine (40 mL), dried over anhydrous MgS04 and concentrated under reduced pressure. The crude product was purified by flash chromatography (Pet. Ether/Et20 2: 1 to 1 : 1) to furnish tert-butyl 4-((2-chloro-6,7-dimethoxyquinazolin-4-yl)thio)piperidine-l- carboxylate (560 mg, 80%) as a colourless solid

Reference： [1]Patent: WO2013/140148,2013,A1 .Location in patent: Page/Page column 66

31
[ 27631-29-4 ]
[ 1709-52-0 ]
4-((2-chloro-6,7-dimethoxyquinazolin-4-yl)amino)-N-methylbenzene sulfonamide hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	In ethanol for 24h; Reflux;	4.1.15 General procedure for S_NAr General procedure: A mixture of 0.80mmol aryl chloride and 0.80mmol aniline in 20mL ethanol or isopropyl alcohol was stirred at reflux for 24h. The resulting precipitate was filtered while hot and purified as described below.

Reference： [1]Barbosa, Maria Letícia De Castro; Lima, Lídia Moreira; Tesch, Roberta; Sant'Anna, Carlos Mauricio R.; Totzke, Frank; Kubbutat, Michael H.G.; Schächtele, Christoph; Laufer, Stefan A.; Barreiro, Eliezer J. [European Journal of Medicinal Chemistry, 2014, vol. 71, p. 1 - 14]

32
[ 1709-59-7 ]
[ 27631-29-4 ]
4-((2-chloro-6,7-dimethoxyquinazolin-4-yl)amino)-N,N-dimethyl benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With palladium diacetate; sodium t-butanolate; XPhos; In toluene; tert-butyl alcohol; at 90℃; for 1h;Inert atmosphere;	General procedure: A mixture of 0.63mmol aryl chloride, 0.63mmol aniline, 1.89mmol t-BuONa, 0.19mmol 2-(dicyclohexylphosphino)-2?,4?,6?-triisopropylbiphenyl (X-Phos) and 0.03mmol Pd(OAc)2 in 6mL tert-butanol and 10mL toluene was stirred at 90C for 1h under an argon atmosphere. When the reaction was complete, the mixture was cooled to room temperature, diluted with water and subsequently extracted with dichloromethane. The extracts were combined, washed with saturated saline solution, and dried over anhydrous Na2SO4. The solvent was removed under vacuum, and the residue was purified by recrystallization from a mixture of dichloromethane and hexane.

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 71,p. 1 - 14

33
[ 27631-29-4 ]
[ 3209-46-9 ]
N1-(2-chloro-6,7-dimethoxyquinazolin-4-yl)-N5,N5-dimethylpentane-1,5-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃;

Reference： [1]Ma, Anqi; Yu, Wenyu; Li, Fengling; Bleich, Rachel M.; Herold, J. Martin; Butler, Kyle V.; Norris, Jacqueline L.; Korboukh, Victoria; Tripathy, Ashutosh; Janzen, William P.; Arrowsmith, Cheryl H.; Frye, Stephen V.; Vedadi, Masoud; Brown, Peter J.; Jin, Jian [Journal of Medicinal Chemistry, 2014, vol. 57, # 15, p. 6822 - 6833]

34
[ 27631-29-4 ]
[ 3209-46-9 ]
N1-(6,7-dimethoxy-2-(pyrrolidin-1-yl)quinazolin-4-yl)-N5,N5-dimethylpentane-1,5-diamine trifluoroacetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 20 °C 2: N-ethyl-N,N-diisopropylamine; hydrogenchloride / butan-1-ol; isopropyl alcohol; 1,4-dioxane / 160 °C / Microwave irradiation

35
[ 123-75-1 ]
[ 27631-29-4 ]
[ 3209-46-9 ]
N1-(6,7-dimethoxy-2-(pyrrolidin-1-yl)quinazolin-4-yl)-N5,N5-dimethylpentane-1,5-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-chloro-6,7-dimethoxy-3H-quinazolin-4-one; N,N-dimethyl-1,5-pentanediamine With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; Stage #2: pyrrolidine With N-ethyl-N,N-diisopropylamine In butan-1-ol Microwave irradiation; Heating;

Reference： [1]Ma, Anqi; Yu, Wenyu; Xiong, Yan; Butler, Kyle V.; Brown, Peter J.; Jin, Jian [MedChemComm, 2014, vol. 5, # 12, p. 1892 - 1898]

36
[ 27631-29-4 ]
[ 1938-58-5 ]
[ 1808081-66-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 6h;

Reference： [1]Ma, Anqi; Yu, Wenyu; Xiong, Yan; Butler, Kyle V.; Brown, Peter J.; Jin, Jian [MedChemComm, 2014, vol. 5, # 12, p. 1892 - 1898]

37
[ 27631-29-4 ]
[ 1938-58-5 ]
[ 1808080-84-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 6 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / butan-1-ol / 1 h / 180 °C / Microwave irradiation

Reference： [1]Ma, Anqi; Yu, Wenyu; Xiong, Yan; Butler, Kyle V.; Brown, Peter J.; Jin, Jian [MedChemComm, 2014, vol. 5, # 12, p. 1892 - 1898]

38
[ 150349-65-8 ]
[ 27631-29-4 ]
tert-butyl 4-(3-((2-chloro-6,7-dimethoxyquinazolin-4-yl)amino)propyl)piperidine-1-carboxylate [ No CAS ]

Reference： [1]MedChemComm,2014,vol. 5,p. 1892 - 1898

39
[ 123-75-1 ]
[ 71302-71-1 ]
[ 27631-29-4 ]
[ 1620401-82-2 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 5-(pyrrolidin-1-yl)pentan-1-amine; 2-chloro-6,7-dimethoxy-3H-quinazolin-4-one With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; Stage #2: pyrrolidine With N-ethyl-N,N-diisopropylamine In butan-1-ol Microwave irradiation; Heating;

Reference： [1]Ma, Anqi; Yu, Wenyu; Xiong, Yan; Butler, Kyle V.; Brown, Peter J.; Jin, Jian [MedChemComm, 2014, vol. 5, # 12, p. 1892 - 1898]

40
[ 101080-15-3 ]
[ 27631-29-4 ]
N₄-(5-isopropylthiazol-2-yl)-6,7-dimethoxy-N₂-(2-(tetrahydro-2H-pyran-4-yl)ethyl)quinazoline-2,4-diamine [ No CAS ]

Reference： [1]MedChemComm,2016,vol. 7,p. 1022 - 1032

41
[ 101080-15-3 ]
[ 27631-29-4 ]
C₁₆H₁₇ClN₄O₂S [ No CAS ]

Reference： [1]MedChemComm,2016,vol. 7,p. 1022 - 1032

42
[ 867012-70-2 ]
[ 27631-29-4 ]
C₁₇H₁₇ClN₄O₃ [ No CAS ]

Reference： [1]MedChemComm,2016,vol. 7,p. 1022 - 1032

43
[ 123-75-1 ]
[ 27631-29-4 ]
[ 442514-22-9 ]
tert-butyl (3-((6,7-dimethoxy-2-(pyrrolidin-1-yl)quinazolin-4-yl)(methyl)amino)propyl)-carbamate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 9881 - 9889

44
[ 27631-29-4 ]
[ 42389-59-3 ]
C₁₈H₂₅ClN₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2h;

Reference： [1]Xiong, Yan; Li, Fengling; Babault, Nicolas; Dong, Aiping; Zeng, Hong; Wu, Hong; Chen, Xin; Arrowsmith, Cheryl H.; Brown, Peter J.; Liu, Jing; Vedadi, Masoud; Jin, Jian [Journal of Medicinal Chemistry, 2017, vol. 60, # 5, p. 1876 - 1891]

45
[ 27631-29-4 ]
[ 42389-59-3 ]
6,7-dimethoxy-2-morpholino-N-(1-propylpiperidin-4-yl)-quinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 20 °C 2: hydrogenchloride / isopropyl alcohol; 1,4-dioxane / 0.25 h / 160 °C / Microwave irradiation

46
[ 27631-29-4 ]
[ 127285-08-9 ]
C₁₈H₂₅ClN₄O₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 1876 - 1891
[2]MedChemComm,2017,vol. 8,p. 1069 - 1092

47
[ 27631-29-4 ]
[ 127285-08-9 ]
N-(1-isopropylpiperidin-4-yl)-6,7-dimethoxy-2-morpholinoquinazolin-4-amine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 1876 - 1891

48
[ 27631-29-4 ]
[ 935693-62-2 ]

Reference： [1]MedChemComm,2017,vol. 8,p. 1069 - 1092
[2]Patent: WO2018/5799,2018,A1

49
[ 27631-29-4 ]
[ 18471-40-4 ]
C₂₁H₂₃ClN₄O₂ [ No CAS ]

Reference： [1]MedChemComm,2017,vol. 8,p. 1069 - 1092

50
[ 27631-29-4 ]
[ 60407-35-4 ]
C₂₂H₂₅ClN₄O₂ [ No CAS ]

Reference： [1]MedChemComm,2017,vol. 8,p. 1069 - 1092

51
[ 27631-29-4 ]
[ 160357-94-8 ]
C₁₇H₂₁ClN₄O₃ [ No CAS ]

Reference： [1]MedChemComm,2017,vol. 8,p. 1069 - 1092

52
[ 27631-29-4 ]
[ 160357-94-8 ]
[ 1458639-16-1 ]

Reference： [1]MedChemComm,2017,vol. 8,p. 1069 - 1092

53
[ 29608-05-7 ]
[ 27631-29-4 ]
C₂₂H₂₅ClN₄O₂ [ No CAS ]

Reference： [1]Patent: WO2018/5799,2018,A1 .Location in patent: Page/Page column 46

54
[ 27631-29-4 ]
[ 132834-58-3 ]
2-chloro-6,7-dimethoxy-4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With triethylamine; In tetrahydrofuran; for 72h;	A solution of 2,4-dichloro-6,7-dimethoxyquinazoline (100 mg, 0.39 mmol) and 1 -(5- (trifluoromethyl)pyridin-2-yl)piperazine (89 mg, 0.41 mmol) in THF (4 mL) was treated with triethylamine (54 μΙ_, 0.77 mmol) and stirred for 72 h. The mixture was concentrated in vacuo to afford a residue that was subjected to flash column chromatography [silica, 1 :20 v/v MeOH/DCM elution] to give, after concentration of the appropriate fractions 2-chloro-6,7-dimethoxy-4-(4-(5- (trifluoromethyl)pyridin-2-yl)piperazin-1 -yl)quinazoline as a white powder (170 mg, 97%). 1H NMR (DMSO-d6, 400 MHz) δ 8.45 (s, 1 H), 7.85 (dd, J = 9.1 , 2.6 Hz, 1 H), 7.25 (s, 1 H), 7.19 (s, 1 H), 6.95 (d, J = 9.1 Hz, 1 H), 3.93 (s, 3H), 3.92 (s, 3H), 3.92 - 3.86 (m, 8H); 3C NMR (DMSO-d6, 100 MHz) δ 163.6, 159.9, 154.8, 153.7, 150.0, 147.9, 145.3 (q, JC-F = 4.0 Hz), 134.6 (q, JC-F = 2.9 Hz), 124.9 (d, JC-F = 270.3 Hz), 1 13.4 (q, JC-F = 32.3 Hz), 108.3, 106.6, 106.1 , 104.2, 56.0, 55.7, 48.1 (2C), 43.5 (2C); (+)-LRESIMS m/z (rel. int.) 454 (100) [M + H]+; (+)-HRESIMS calcd. for C20H20CIF3N5O2 [M + H]+ 454.1252, found 454.1246; vmax 1609, 1581 , 1503, 1420, 1316, 1237, 1213, 1078, 854 cm"1. A portion of the above material (33 mg, 73 μιηοΙ) was then reacted according to General Procedure C with phenylboronic acid (13 mg, 0.1 1 mmol) to afford a residue after workup, that was subjected to flash column chromatography [silica, 1 :20 v/v ammoniacal MeOH/DCM elution] to give, after concentration of the appropriate fractions the compound BT2036 as a white powder (15 mg, 42%). 1H NMR (CDCI3, 400 MHz) δ 8.56 - 8.50 (m, 2H), 8.45 (s, 1 H), 7.69 (dd, J = 9.0, 2.5 Hz, 1 H), 7.53 - 7.42 (m, 3H), 7.37 (s, 1 H), 7.19 (s, 1 H), 6.73 (d, J = 9.0 Hz, 1 H), 4.07 (s, 3H), 4.02 (s, 3H), 3.96 - 3.86 (m, 8H); 3C NMR (CDCI3, 100 MHz) δ 163.9, 160.4, 158.6, 154.6, 150.1 , 148.5, 145.7 (1 , JC-F = 4.3 Hz), 138.6, 134.6 (q, JC-F = 3.1 Hz), 129.9, 128.4 (2C), 128.0 (2C), 124.5 (q, JC-F = 270.6 Hz), 1 15.7 (q, JC-F = 33.0 Hz), 1 10.1 , 108.0, 105.7, 102.9, 56.3, 56.1 , 49.3 (2C), 44.5 (2C). (+)-LRESIMS m/z (rel. int.) 496 (100) [M + H]+; (+)-HRESIMS calcd. for C26H25F3N5O2 [M + H]+ 496.1955, found 496.1960; vmax 2963, 1612, 1505, 1413, 1259, 1246, 1097, 1083, 1019, 998, 952, 846, 794, 702 cm"1.

Reference： [1]Patent: WO2018/107200,2018,A1 .Location in patent: Paragraph 0164

55
[ 27631-29-4 ]
[ 947620-48-6 ]

Reference： [1]Patent: US2007/299094,2007,A1
[2]Patent: US2007/299094,2007,A1
[3]Patent: EP1992622,2008,A1
[4]Patent: EP1992622,2008,A1

56
[ 27631-29-4 ]
[ 184475-35-2 ]

Reference： [1]Synlett,2019,vol. 30,p. 471 - 476

57
[ 90924-12-2 ]
[ 27631-29-4 ]
6,7-dimethoxy-2-chloro-4-[(3-phenylisoxazol-5-yl)methoxy]quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In isopropyl alcohol; at 50℃; for 0.5h;	0.259 g (1 mmol) of 6,7-dimethoxy-2,4-dichloro-quinazoline was dissolved in 5 mL of dry isopropanol, then a solution of 0.175 g (1 mmol) of 5-hydroxymethyl-3-phenyl-isoxazole in 5 mL of isopropanol was slowly added dropwise to the reaction system with stirring, followed by the addition of 0.101 g (1 mmol) of freshly distilled triethylamine, after the system was stirred at room temperature for 30 min, the reaction was carried out at 50 C. After the TLC detection reaction was completed, the reaction liquid was concentrated in a vacuum, and the residue is directly subjected to column separation (V petroleum ether: V ethyl acetate 5:1~2:1) to obtain target compound [6,7-bis(methoxyethoxy)]-4-[3-(4-methyl-phenyl)-isoxazol-5-yl]-methoxy-}-quinazoline ( Q-1). The remaining compound was synthesized according to the synthesis of 6,7-dimethoxy-2-chloro-4-[(3-phenylisoxazol-5-yl)methoxy]quinazoline.

Reference： [1]Patent: CN103819467,2019,B .Location in patent: Paragraph 0088-0092

58
[ 27631-29-4 ]
[ 60547-96-8 ]

Yield	Reaction Conditions	Operation in experiment
90.5%	With [1,3-bis(diphenylphosphino)propane]nickel(II) chloride; ammonia In methanol at 30℃; for 5h;	1-2 Example 1 Mix 20g of raw material 2,4-dichloro-6,7-dimethoxyquinazoline, 350ml of 10% ammonia solution in methanol, 0.4g of 1,3-bis(diphenylphosphine)propane nickel dichloride In a 500ml three-necked reaction flask, magnetic stirring, heated to 30°C in an oil bath for 5h, and then naturally cooled to room temperature. Remove methanol by rotary evaporation, add 50ml*2 of 70°C hot water to make slurry twice, filter with suction, rinse with hot water, and blow dry at 70°C to constant weight to obtain 17.9g of off-white solid, yield: 90.5%.

Reference： [1]Current Patent Assignee: SHANDONG BAIKI BIOMEDICAL - CN114276302, 2022, A Location in patent: Paragraph 0019-0020

59
[ 27631-29-4 ]
[ 1170905-43-7 ]
[ 2769819-79-4 ]

Yield	Reaction Conditions	Operation in experiment
47%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 80℃; for 2h;	2.3 Step-3: Synthesis of tert-butyl 2-(1-(2-chloro-6,7-dimethoxyquinazolin-4- yl)azetidin-3-yl)ethylcarbamate: A suspension of to 2,4-dichloro-6,7-dimethoxyquinazoline (50 mg, 0.19 mmol, 1.0 eq), tert-butyl 2-(azetidin-3-yl)ethylcarbamate hydrochloride (45.7 mg, 0.19 mmol, 1.0 eq) and N,N diisopropylethylamine (50 mg, 0.38 mmol, 2.0 eq) in DMF (5 mL) was allowed to stir at 80 °C for 2 h. Progress of reaction was monitored by TLC. Reaction mixture was cooled to RT, diluted with cold water (10 mL) and extracted with ethyl acetate (3 × 20 mL). Combined organic layer was dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave crude which was purified by Combi-Flash to afford tert-butyl 2-(1-(2-chloro-6,7-dimethoxyquinazolin-4-yl)azetidin-3- yl)ethylcarbamate (38 mg, 47%). LCMS: 422 [M+1]+
47%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 80℃; for 2h;	2.3 Step-3: Synthesis of tert-butyl 2-(1-(2-chloro-6,7-dimethoxyquinazolin-4- yl)azetidin-3-yl)ethylcarbamate: A suspension of to 2,4-dichloro-6,7-dimethoxyquinazoline (50 mg, 0.19 mmol, 1.0 eq), tert-butyl 2-(azetidin-3-yl)ethylcarbamate hydrochloride (45.7 mg, 0.19 mmol, 1.0 eq) and N,N diisopropylethylamine (50 mg, 0.38 mmol, 2.0 eq) in DMF (5 mL) was allowed to stir at 80 °C for 2 h. Progress of reaction was monitored by TLC. Reaction mixture was cooled to RT, diluted with cold water (10 mL) and extracted with ethyl acetate (3 × 20 mL). Combined organic layer was dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave crude which was purified by Combi-Flash to afford tert-butyl 2-(1-(2-chloro-6,7-dimethoxyquinazolin-4-yl)azetidin-3- yl)ethylcarbamate (38 mg, 47%). LCMS: 422 [M+1]+

Reference： [1]Current Patent Assignee: 1CBIO - WO2022/91048, 2022, A1 Location in patent: Paragraph 195; 197
[2]Current Patent Assignee: 1CBIO - WO2022/91048, 2022, A1 Location in patent: Paragraph 195; 197

60
[ 27631-29-4 ]
[ 4742-01-2 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
85%	With triethylamine In tetrahydrofuran at 20℃; for 24h;	General Procedure for the Synthesis of the Intermediates33-35,39,41,42. General procedure: The specific commercially available amine (2.89mmol, 3 eq.) was added to a solution of the 2,4-dichloroquinazoline 31[39] (0.96 mmol, 1 eq.) in dry THF (5.5 mL) in the presence of triethylamine(0.40 mL, 3 eq.), and the resulting suspension was left stirringat room temperature for about 24 h. Upon completion of the reaction,the salt was filtered under vacuum, and the filtrate was concentrated invacuo. The resulting crude product was triturated with petroleum ether,collected by filtration, and finally purified by silica gel column chromatographyby eluting with the appropriate mixture chloroform/methanol to provide the intermediates 33-35,39,41,42.
85%	With triethylamine In tetrahydrofuran at 20℃; for 24h;	General Procedure for the Synthesis of the Intermediates33-35,39,41,42. General procedure: The specific commercially available amine (2.89mmol, 3 eq.) was added to a solution of the 2,4-dichloroquinazoline 31[39] (0.96 mmol, 1 eq.) in dry THF (5.5 mL) in the presence of triethylamine(0.40 mL, 3 eq.), and the resulting suspension was left stirringat room temperature for about 24 h. Upon completion of the reaction,the salt was filtered under vacuum, and the filtrate was concentrated invacuo. The resulting crude product was triturated with petroleum ether,collected by filtration, and finally purified by silica gel column chromatographyby eluting with the appropriate mixture chloroform/methanol to provide the intermediates 33-35,39,41,42.

Reference： [1]Menna, Martina; Fiorentino, Francesco; Marrocco, Biagina; Lucidi, Alessia; Tomassi, Stefano; Cilli, Domenica; Romanenghi, Mauro; Cassandri, Matteo; Pomella, Silvia; Pezzella, Michele; Del Bufalo, Donatella; Zeya Ansari, Mohammad Salik; Tomašević, Nevena; Mladenović, Milan; Viviano, Monica; Sbardella, Gianluca; Rota, Rossella; Trisciuoglio, Daniela; Minucci, Saverio; Mattevi, Andrea; Rotili, Dante; Mai, Antonello [European Journal of Medicinal Chemistry, 2022, vol. 237]
[2]Menna, Martina; Fiorentino, Francesco; Marrocco, Biagina; Lucidi, Alessia; Tomassi, Stefano; Cilli, Domenica; Romanenghi, Mauro; Cassandri, Matteo; Pomella, Silvia; Pezzella, Michele; Del Bufalo, Donatella; Zeya Ansari, Mohammad Salik; Tomašević, Nevena; Mladenović, Milan; Viviano, Monica; Sbardella, Gianluca; Rota, Rossella; Trisciuoglio, Daniela; Minucci, Saverio; Mattevi, Andrea; Rotili, Dante; Mai, Antonello [European Journal of Medicinal Chemistry, 2022, vol. 237]

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P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 27631-29-4 ] {[proInfo.proName]}

Quality Control of [ 27631-29-4 ]

Related Doc. of [ 27631-29-4 ]

Product Details of [ 27631-29-4 ]

Calculated chemistry of [ 27631-29-4 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 27631-29-4 ]

Application In Synthesis of [ 27631-29-4 ]

[ 27631-29-4 ] Synthesis Path-Upstream 1~12

[ 27631-29-4 ] Synthesis Path-Downstream 1~60

Related Functional Groups of [ 27631-29-4 ]

Chlorides

Ethers

Related Parent Nucleus of [ 27631-29-4 ]

Quinazolines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 27631-29-4 ]

Related Parent Nucleus of
[ 27631-29-4 ]