[ CAS No. 38267-96-8 ]

Name: 38267-96-8|6-Bromo-4-chloroquinazoline|97%
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Quality Control of [ 38267-96-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 38267-96-8 ]

CAS No. :	38267-96-8	MDL No. :	MFCD01862191
Formula :	C₈H₄BrClN₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	243.49	Pubchem ID :	-
Synonyms :

Calculated chemistry of [ 38267-96-8 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	10
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	52.25
TPSA :	25.78 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.52 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.29
Log Po/w (XLOGP3) :	3.19
Log Po/w (WLOGP) :	3.05
Log Po/w (MLOGP) :	2.58
Log Po/w (SILICOS-IT) :	3.25
Consensus Log Po/w :	2.87

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.98
Solubility :	0.0257 mg/ml ; 0.000106 mol/l
Class :	Soluble
Log S (Ali) :	-3.4
Solubility :	0.0963 mg/ml ; 0.000396 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.8
Solubility :	0.00384 mg/ml ; 0.0000158 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.48

Safety of [ 38267-96-8 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 38267-96-8 ]

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

Upstream synthesis route of [ 38267-96-8 ]
Downstream synthetic route of [ 38267-96-8 ]

[ 38267-96-8 ] Synthesis Path-Upstream 1~6

1
[ 32084-59-6 ]
[ 38267-96-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	at 140℃; for 3 h;	6-Bromo-3H-quinazolin-4-one (20g, 89 mmol) was suspended in 140 ml. of POCI₃ and stirred 3h at 140°C. The reaction mixture was concentrated under vacuum, the residue was dissolved in 500 ml. of dry CH₂CI₂ and neutralized with 200g of solid NaHC0₃. The mixture was filtered and the filtrate evaporated under vacuum to gave the title compound (21 g, 95percent yield) as a beige solid. ¹H-NMR (400 MHz, CDCI3_, 298 K): ? ppm 7.98 (d, 1 H) 8.09 (d, 1 H) 8.5 (s, 1 H) 9.1 (s, 1 H). MS: 243.0-244.9 [M+1]⁺, Rt ⁽¹⁾ = 1.24 min
95%	at 140℃; for 3 h;	6-Bromo-3H-quinazolin-4-one (20g, 89 mmol) was suspended in 140 mL of POCI₃ and stirred 3h at 140°C. The reaction mixture was concentrated under vacuum, the residue was dissolved in 500 mL of dry CH₂CI₂ and neutralized with 200g of solid NaHC03. The mixture was filtered and the filtrate evaporated under vacuum to gave the title compound (21 g, 95percent yield) as a beige solid. ¹H-NMR (400 MHz, CDCI3.298 K): δ ppm 7.98 (d, 1 H) 8.09 (d, 1 H) 8.5 (s, 1 H) 9.1 (s, 1 H). MS: 243.0-244.9 [M+1]⁺, Rt ^{(1 ,)} = 1.24 min.
95%	With trichlorophosphate In dichloromethane at 140℃; for 3 h;	6-Bromo-4-chloro-quinazoline 6-Bromo-3H-quinazolin-4-one (20 g, 89 mmol) was suspended in 140 mL of POCl₃ and stirred 3 h at 140° C. The reaction mixture was concentrated under vacuum, the residue was dissolved in 500 mL of dry CH₂Cl₂ and neutralized with 200 g of solid NaHCO₃. The mixture was filtered and the filtrate evaporated under vacuum to gave the title compound (21 g, 95percent yield) as a beige solid. ¹H-NMR (400 MHz, CDCl3, 298 K): δ ppm 7.98 (d, 1H) 8.09 (d, 1H) 8.5 (s, 1H) 9.1 (s, 1H). MS: 243.0-244.9 [M+1]⁺, Rt^(1')=1.24 min.

95%

With triethylamine; trichlorophosphate In 1,4-dioxane for 12 h; Reflux

then, In a dioxane solution containing 6-bromo-3H-quinazolin-4-one (B, 15.0 g, 66.7 mmol, 1.0 equiv)Was added phosphorus oxychloride (20.0 ml, d = 1.67,33.4 g, 219 mmol, 3.3 equiv),Followed by the addition of triethylamine (30.0 mL, d = 0.726, 21.8 g, 215 mmol)The mixture was heated under reflux for 12 hours,Until the solution drops to room temperature,Pour it into a mixed solution containing ice and water.The precipitate obtained after filtration was washed with 100 ml of water,And dried to give 6-bromo-4-chloro-quinazoline (C, 15.4 g, 63.2 mmol)Yield 95percent

Reference： [1] Patent: WO2013/57711, 2013, A1, . Location in patent: Page/Page column 57
[2] Patent: WO2013/88404, 2013, A1, . Location in patent: Page/Page column 186
[3] Patent: US2015/342951, 2015, A1, . Location in patent: Paragraph 0974-0975
[4] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 8, p. 762 - 767
[5] Patent: TWI557109, 2016, B, . Location in patent: Page/Page column 48; 49; 83
[6] Tetrahedron, 2003, vol. 59, # 9, p. 1413 - 1419
[7] Pharmaceuticals, 2017, vol. 10, # 4,
[8] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 22, p. 6373 - 6377
[9] Journal of the Indian Chemical Society, 1959, vol. 36, p. 787,789, 790
[10] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 4, p. 545 - 548
[11] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 3, p. 383 - 391
[12] Patent: WO2008/9077, 2008, A2, . Location in patent: Page/Page column 94-95
[13] Patent: WO2008/12326, 2008, A1, . Location in patent: Page/Page column 60
[14] Patent: WO2008/89307, 2008, A2, . Location in patent: Page/Page column 44-45
[15] Patent: WO2008/89310, 2008, A2, . Location in patent: Page/Page column 47
[16] Tetrahedron Letters, 2014, vol. 55, # 43, p. 6007 - 6010

2
[ 32084-59-6 ]
[ 38267-96-8 ]

Yield	Reaction Conditions	Operation in experiment
92%	at 120℃; for 6 h;	Example 3. Synthesis of 6-bromo-4-chloroquinazoline (4): To the solution of 6-bromoquinazolin-4-oI (3, 1 g, 4.44 mmol) in phosphoryl chloride (5 mL) was refluxed for 6 hat 120 °C. The mixture was cooled to room temperature and poured into ice-watercontaining sodium bicarbonate to quench excess phosphoryl chloride. The mixture wasextracted with dichloromethane (3 x 100 ml) and the solvent was evaporated to get the 6-bromo-4-chloroquinazoline 4 as a light yellow solid. Yield: 92percent, light yellow solid, m. p. 273-275 °C; 1H NMR (CDCI3, 500 MHz): O 9.07 (s, IH), 8.44 (d, IH, J= 2.0 Hz), 8.04 (d, 1H, J2.0 Hz), 7.96 (d, IH, J = 8.9 Hz); HRMS: m/z 224.9633 calcd for C8H6BrN2O + H(224.9664).
75%	for 6 h; Reflux	General procedure: To the suspension of 6-bromopyrido[2,3-d]pyrimidin-4-ol (3) (15.0 g, 0.066 mol) in thionyl chloride 150 mL was added a few drops of DMF, then the mixture was stirred at reflux for 6 h. After removing thionyl chloride under vacuum, the residue was recrystallized from EtOAc to gave 4 as pale yellow solid (11.8 g, yield, 73percent).
75%	With thionyl chloride In N,N-dimethyl-formamide for 1 h; Reflux	Equipped with a blender,Reflux condenser 250mL three-necked flask,15 g (0.067 mol) of 6-bromo-4 (3H) -quinazolinone was added,150 mL (2.1 mol) of thionyl chloride was added,3-4 drops of DMF,Heating reflux,After about 1h the reaction was clarified,Continue to react 5h,Distillation recovery of thionyl chloride,The residual thionyl chloride was distilled off under reduced pressure,Continue to join 50mL dichloromethane distillation residual thionyl chloride out,Repeated three timesFinally, 180 mL of ethyl acetate was heated to reflux for several minutes,Place to room temperature,filter,Vacuum dried,Got light yellow needles solid 12.2g,Yield 75percent.

74%	at 120℃; for 6 h;	General procedure: The solution of 6-bromoquinazolin-4-ol (12, 1 g, 4.44 mmol) or6,7-dimethoxyquinazolin-4-ol (17, 1 g, 4.13 mmol) in phosphorousoxy chloride (5 mL) was refluxed for 6 h at 120 C. The mixture was cooled to room temperature and poured into ice-water containingsodium bicarbonate to quench phosphorous oxychloride. The mixture was extracted with dichloromethane (3 100 ml) and thesolvent was evaporated to get chlorinated products 13 or 18.4.4.1. 6-Bromo-4-chloroquinazoline (13)Yield: 74percent; light yellow solid; m.p. 161e163 C; 1H NMR (CDCl3,500 MHz): d 9.07 (s, 1H), 8.44 (d,1H, J 2.0 Hz), 8.05 (dd, 1H, J 8.9,2.2 Hz), 7.96 (d, 1H, J 8.9 Hz); IR (CHCl3): nmax 2922, 1632, 1559,1546, 1474, 1461, 1388, 1360, 1241, 1160, 1019 cm1; HR-ESIMS: m/z242.9326 calcd for C8H4BrClN2H (242.9319).
65%	for 3 h; Reflux	Synthesis of compound 2.2. To a mixture of 6-bromoquinazolin-4-ol, compound 2.1 (1.2 g, 5.33 mmol, 1.00 equiv) in POCl₃ (20 mL) was added N,N-diethylaniline (2.0 g, 13.40 mmol, 2.50 equiv). Reaction was stirred for 3 hours at reflux temperature. Upon completion of the reaction mixture was concentrated under vacuum. The residue was poured into 20 mL of cold water. Resulting solids were collected by filtration and dried in an oven to provide 850 mg (65percent) of 6-bromo-4-chloroquinazoline, compound 2.2 as an orange solid

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 9, p. 1972 - 1977
[2] Letters in Drug Design and Discovery, 2017, vol. 14, # 2, p. 167 - 174
[3] Patent: WO2015/128873, 2015, A1, . Location in patent: Page/Page column 18
[4] European Journal of Medicinal Chemistry, 2016, vol. 118, p. 276 - 289
[5] Patent: CN106565684, 2017, A, . Location in patent: Paragraph 0104; 0106; 0220; 0222
[6] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 731 - 743
[7] Patent: WO2015/164374, 2015, A1, . Location in patent: Paragraph 00274; 00275
[8] European Journal of Medicinal Chemistry, 2014, vol. 75, p. 96 - 105
[9] Patent: WO2014/151147, 2014, A1, . Location in patent: Paragraph 00641
[10] Patent: US2015/30588, 2015, A1, . Location in patent: Page/Page column 73
[11] Patent: US9295673, 2016, B2, . Location in patent: Page/Page column 354
[12] Patent: WO2005/51304, 2005, A2, . Location in patent: Page/Page column 64
[13] Patent: WO2005/51304, 2005, A2, . Location in patent: Page/Page column 64
[14] Patent: WO2005/105761, 2005, A1, . Location in patent: Page/Page column 20

3
[ 32084-59-6 ]
[ 38267-96-8 ]

Yield	Reaction Conditions	Operation in experiment
18%	at 100℃; for 2 h;	Formamide (4 ml) was added to methyl 2-amino-5-bromo-benzoate (400 mg), and the mixture was stirred with a microwave reactor at 220°C for 20 min. The above reaction was carried out using the same amount of starting materials by additional two batches. The reaction mixtures were cooled to room temperature and were combined together. The precipitated crystal was collected by filtration and was washed with ether. The crystal (968 mg) thus obtained as such was used in the next reaction without further purification. A part (300 mg) of the crystal obtained above was suspended in diisopropylethylamine (1.16 ml), phosphorus oxychloride (0.62 ml) was added to the suspension, and the mixture was stirred at 100°C for 2 hr. The solvent was removed by distillation under the reduced pressure, and water was added to the residue under ice cooling. The aqueous layer was neutralized with an aqueous sodium hydrogencarbonate solution, and the organic layer was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography with a methanol-chloroform system to give 6-bromo-4-chloro-quinazoline (58 mg, yield 18percent).

Reference： [1] Patent: EP1724268, 2006, A1, . Location in patent: Page/Page column 49

4
[ 5794-88-7 ]
[ 38267-96-8 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 3, p. 383 - 391
[2] Tetrahedron, 2003, vol. 59, # 9, p. 1413 - 1419
[3] Journal of the Indian Chemical Society, 1959, vol. 36, p. 787,789, 790
[4] Patent: WO2014/151147, 2014, A1,
[5] Patent: US2015/30588, 2015, A1,
[6] Patent: US9295673, 2016, B2,
[7] Patent: WO2015/128873, 2015, A1,
[8] European Journal of Medicinal Chemistry, 2016, vol. 118, p. 276 - 289
[9] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 731 - 743
[10] Patent: TWI557109, 2016, B,
[11] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 9, p. 1972 - 1977
[12] Patent: CN106565684, 2017, A,
[13] Letters in Drug Design and Discovery, 2017, vol. 14, # 2, p. 167 - 174
[14] Patent: WO2005/105761, 2005, A1,

5
[ 16313-66-9 ]
[ 38267-96-8 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 3, p. 383 - 391
[2] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 4, p. 545 - 548
[3] Pharmaceuticals, 2017, vol. 10, # 4,

6
[ 118-92-3 ]
[ 38267-96-8 ]

Reference： [1] Patent: WO2015/128873, 2015, A1,
[2] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 731 - 743

[ 38267-96-8 ] Synthesis Path-Downstream 1~68

1
[ 32084-59-6 ]
[ 38267-96-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	With trichlorophosphate; at 140℃; for 3h;	6-Bromo-3H-quinazolin-4-one (20g, 89 mmol) was suspended in 140 ml. of POCI3 and stirred 3h at 140C. The reaction mixture was concentrated under vacuum, the residue was dissolved in 500 ml. of dry CH2CI2 and neutralized with 200g of solid NaHC03. The mixture was filtered and the filtrate evaporated under vacuum to gave the title compound (21 g, 95% yield) as a beige solid. 1H-NMR (400 MHz, CDCI3, 298 K): ? ppm 7.98 (d, 1 H) 8.09 (d, 1 H) 8.5 (s, 1 H) 9.1 (s, 1 H). MS: 243.0-244.9 [M+1]+, Rt (1) = 1.24 min
95%	With trichlorophosphate; at 140℃; for 3h;	6-Bromo-3H-quinazolin-4-one (20g, 89 mmol) was suspended in 140 mL of POCI3 and stirred 3h at 140C. The reaction mixture was concentrated under vacuum, the residue was dissolved in 500 mL of dry CH2CI2 and neutralized with 200g of solid NaHC03. The mixture was filtered and the filtrate evaporated under vacuum to gave the title compound (21 g, 95% yield) as a beige solid. 1H-NMR (400 MHz, CDCI3.298 K): delta ppm 7.98 (d, 1 H) 8.09 (d, 1 H) 8.5 (s, 1 H) 9.1 (s, 1 H). MS: 243.0-244.9 [M+1]+, Rt (1 ,) = 1.24 min.
95%	With trichlorophosphate; In dichloromethane; at 140℃; for 3h;	6-Bromo-4-chloro-quinazoline 6-Bromo-3H-quinazolin-4-one (20 g, 89 mmol) was suspended in 140 mL of POCl3 and stirred 3 h at 140 C. The reaction mixture was concentrated under vacuum, the residue was dissolved in 500 mL of dry CH2Cl2 and neutralized with 200 g of solid NaHCO3. The mixture was filtered and the filtrate evaporated under vacuum to gave the title compound (21 g, 95% yield) as a beige solid. 1H-NMR (400 MHz, CDCl3, 298 K): delta ppm 7.98 (d, 1H) 8.09 (d, 1H) 8.5 (s, 1H) 9.1 (s, 1H). MS: 243.0-244.9 [M+1]+, Rt(1')=1.24 min.

95%	With triethylamine; trichlorophosphate; In 1,4-dioxane; for 12h;Reflux;	then, In a dioxane solution containing 6-bromo-3H-quinazolin-4-one (B, 15.0 g, 66.7 mmol, 1.0 equiv)Was added phosphorus oxychloride (20.0 ml, d = 1.67,33.4 g, 219 mmol, 3.3 equiv),Followed by the addition of triethylamine (30.0 mL, d = 0.726, 21.8 g, 215 mmol)The mixture was heated under reflux for 12 hours,Until the solution drops to room temperature,Pour it into a mixed solution containing ice and water.The precipitate obtained after filtration was washed with 100 ml of water,And dried to give 6-bromo-4-chloro-quinazoline (C, 15.4 g, 63.2 mmol)Yield 95%
47%		A solution of quinazolinone liv (30 g, 0.13 mol) in phosphorous oxychloride (300 mL) is heated to 95C for 1 hour. /V,/V-Diethylaniline lxxviii (42.2 mL, 0.26 mol) is added slowly, and the mixture is heated to l20C for 12 hours. The mixture is concentrated under vacuum, then 10% aqueous sodium bicarbonate is added until the pH reached 7. The mixture is extracted into ethyl acetate, filtered, and concentrated under vacuum. The residue is purified by flash column chromatography (30% ethyl acetate in petroleum ether) to give chloride lxxix (15 g, 0.06 mol) as a yellow solid in 47% yield.
	With triethylamine; trichlorophosphate; In 1,4-dioxane; at 20 - 80℃; for 0.666667h;	Synthesis of 6-Bromo-4-chloro-quinazolineTo a suspension of 6-Bromo-3H-quinazolin-4-one (1.5 g, 6.65 mmole) in 1 ,4- dioxane (30 ml) under nitrogen was added triethylamine (2.8 ml, 19.9 mmole). The resulting suspension was rapidly stirred while phosphorous oxychloride (1.85 ml, 19.9 mmole) was added over 5 minutes. The reaction was stirred at room temperature for 5 minutes, then heated at 8O0C for 30 minutes, when no starting material was detectable by LC/MS. After cooling to room temperature, the reaction mixture was <n="97"/>concentrated in vacuo. The resulting residue was partitioned between ethyl acetate and water. The insoluble material was collected by filtration and washed with water. The layers of the filtrate where separated and the organic layer was washed twice with water and once with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The resulting solid was combined with the collected precipitate and the mixture was recrystallized from ethyl acetate/hexanes to give 760mg after drying in vacuo. The resulting compound was characterized as follows: masspectrometry: M/Z= 244; HPLC: method A, Rt 1.51 minutes.
	With N,N-diethylaniline; trichlorophosphate; at 125℃; for 3h;	A mixture of 0.5 g (2.2 mmol) of 6-bromo-3H-quinazolin-4-one (Example 1 d), 0.7 ml (4.4 mmol) diethylamide and 4 ml POCI3 is stirred for 3 h at 125C. After this time, the reaction mixture is cooled to rt and dropped into icy water. The precipitate is filtered and dried in vacuo overnight to give the title compound as a violet solid. Analytical HPLC: W= 3.51 min (Grad 1 , partial hydrolysis in HPLC conditions); 1H-NMR (CDCI3): delta 9.08/s (1 H), 8.46/d (1 H), 8.06/dd (1 H), 7.97/d (1 H).
	With trichlorophosphate; for 6h;Heating / reflux;	To a solution of 2-amino-5-bromo benzoic acid (2.16 g, 10 mmol, 1.0 equiv.) in 100 ml ethanol was added formamidine acetate (1.30 g, 12.5 mmol, 1.25 equiv.), and the reaction mixture was heated to reflux for 16 hrs. After the reaction was cooled to room temperature, the resulting white precipitate was collected via filtration and washed with water to afford 6- bromoquinazolin-4(3H)-one as a pale yellow prism, 1.78 g.A suspension of 6-bromoquinazolin-4(3H)-one (1.45 g, 6.44 mmol, 1.0 equiv.) in 10 ml POCI3 was heated to reflux for 6 hours. The resulting clear solution was then cooled to room temperature and concentrated in vacuo to afford 4-chloro-6-bromoquinazoline as an off- white crystal which was carried to the next step without further purification.To the mixture of 4-chloro-6-bromoquinazoline (crude, 1.60 g) in isopropanol (20 ml) was added 3-chloroaniline (0.84 ml, 0.79 mmol, 1.2 equiv.). After heating to 8O0C for 2 hours, the reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The resulting residue was diluted with 100 ml ethyl acetate, washed with sat. NaHCO3 (aq.) and brine, dried over Na2SO4, and concentrated in vacuo. Flash chromatography purification afforded 6-bromoquinazoline as an off-white solid of 1 g.To a 5 ml microwave vial was added 6-bromoquinazoline (34 mg, 0.1 mmol, 1.0 equiv.), N-Morpholinyl-4-boronbenzene sulfonylamide (27 mg, 0.1 mmol, 1.0 equiv.), Pd(PPh3)2Cl2 (7 mg, 0.01 mmol, 0.1 equiv.) 2 ml acetonitrile and 0.3 ml aq. NaHCO3 (1 M) were added and the reaction mixture was kept under microwave heating at 160 0C for 800 seconds. After cooling to the room temperature, the crude mixture was diluted with water and extracted twice with EtOAc. Preparative TLC purification afforded the desired product as a white solid of 9 mg. <n="46"/>1H NMR (CDCl3) delta: 8.84 (IH, brs), 8.36 (IH, br), 7.98-8.08 (4H, m), 7.75-7.90 (4H, m), 7.39 (IH, t, J= 8.1 Hz), 7.21 (IH, d, J= 8.1 Hz), 3.74 (4H, s), 3.04 (4H, s); M+H+ = 481.
	With trichlorophosphate; for 6h;Heating / reflux;	To a solution of 2-amino-5-bromo benzoic acid (2.16 g, 10 mmol, 1.0 equiv.) in 100 ml ethanol was added formamidine acetate (1.30 g, 12.5 mmol, 1.25 equiv.), and the reaction mixture was heated to reflux for 16 hrs. After the reaction was cooled to room temperature, the resulting white precipitate was collected via filtration and washed with water to afford 6- bromoquinazolin-4(3H)-one as a pale yellow prism, 1.78 g.A suspension of 6-bromoquinazolin-4(3H)-one (1.45 g, 6.44 mmol, 1.0 equiv.) in 10 ml POCI3 was heated to reflux for 6 hours. The resulting clear solution was then cooled to room temperature and concentrated in vacuo to afford 4-chloro-6-bromoquinazoline as an off- white crystal which was carried to the next step without further purification.To the mixture of 4-chloro-6-bromoquinazoline (crude, 1.60 g) in isopropanol (20 ml) was added 3-chloroaniline (0.84 ml, 0.79 mmol, 1.2 equiv.). After heating to 8O0C for 2 hours, the reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The resulting residue was diluted with 100 ml ethyl acetate, washed with sat. NaHCO3 (aq.) and brine, dried over Na2SO4, and concentrated in vacuo. Flash chromatography purification afforded 6-bromoquinazoline as an off-white solid of 1 g.To a 5 ml microwave vial was added 6-bromoquinazoline (34 mg, 0.1 mmol, 1.0 equiv.), N-Morpholinyl-4-boronbenzene sulfonylamide (27 mg, 0.1 mmol, 1.0 equiv.),Pd(PPh3)2Cl2 (7 mg, 0.01 mmol, 0.1 equiv.) 2 ml acetonitrile and 0.3 ml aq. NaHCO3 (1 M) were added and the reaction mixture was kept under microwave heating at 160 0C for 800 seconds. After cooling to the room temperature, the crude mixture was diluted with water and extracted twice with EtOAc. Preparative TLC purification afforded the desired product as a white solid of 9 mg.1H NMR (CDCl3) delta: 8.84 (IH, brs), 8.36 (IH, br), 7.98-8.08 (4H, m), 7.75-7.90 (4H, m), 7.39 (IH, t, J= 8.1 Hz), 7.21 (IH, d, J= 8.1 Hz), 3.74 (4H, s), 3.04 (4H, s); M+H+ = 481.
	With tributyl-amine; trichlorophosphate; In toluene; at 70 - 90℃;	A suspension of 6-bromoquinazolin-4(3H)-one (700 g,3.11 mol), toluene (3.5 L) and tributylamine (692 g, 3.73 mol) was heated to 70-80C. To the suspension was added phosphorus oxychloride (525 g, 3.42 mol) at arate to keep the reaction temperature below 90 C. Once the addition wascomplete, the reaction was heated to reflux and held until the reaction wascomplete. The resultant solution was cooled to 75-85 C and toluene, (3.3 L)was added. To the solution was charged 3-chloro-4-((3-fluorobenzyl)oxy)aniline(19) (806 g, 3.20 mol). Theresultant slurry was reheated to 75-85 C and stirred until the reaction wascomplete. Toluene (1.4 L) was charged and the slurry adjusted to 65-75 C. A30% aquous NaOH solution (1.4 L) was added at a rate to keep the suspensiontemperature below 75 C. Once the addition was complete, water (4.2 L) wascharged and the suspension held at 70-80 C for 1 h. The reaction was cooled to20-25 C over 1 h and held at ambient for at least 1 h. The product wascollected by vacuum filtration and the product cake washed successively withwater (4.2 L), 0.1M NaOH (3.5 L), water (3.5 L) and ethanol (2 x 3.5L). Afterdrying on the filter for 1 h, the product was transferred to the vacuum ovenand dried at 60 C to give 9 asoff-white solid (1.33 kg, 93% yield). 1HNMR (500 MHz, DMSO-d6) delta 5.26 (s, 2H), 7.18 (m, 1H), 7.28 (d, J = 8.82 Hz, 1H),7.33 (m, 2H), 7.47 (m, 1H), 7.73 (d, J = 8.78 Hz, 1H), 7.75 (dd, J = 8.82, 2.51Hz, 1H), 7.98 (dd, J = 8.83, 2.20 Hz, 1H), 8.04 (d, J = 2.51 Hz, 1H), 8.63 (s,1H), 8.82 (d, J = 1.91 Hz, 1H), 9.85 (s, 1H); 13C NMR (125 MHz, DMSO-d5)delta 67.0, 114.4 (d, J = 21.5 Hz), 114.7, 115.1 (d, J = 20.2 Hz), 116.8, 119.2,121.7, 122.3, 123.6 (d, J = 3.0 Hz),124.3, 125.7, 130.4, 130.9 (d, J = 8.6 Hz), 133.6, 136.2, 140.1 (d, J = 7.5Hz), 146.9, 150.2, 155.2, 157.0, 162.7 (d, J = 245.4 Hz).

Reference： [1]Patent: WO2013/57711,2013,A1 .Location in patent: Page/Page column 57
[2]Patent: WO2013/88404,2013,A1 .Location in patent: Page/Page column 186
[3]Patent: US2015/342951,2015,A1 .Location in patent: Paragraph 0974-0975
[4]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 762 - 767
[5]Patent: TWI557109,2016,B .Location in patent: Page/Page column 48; 49; 83
[6]Tetrahedron,2003,vol. 59,p. 1413 - 1419
[7]Pharmaceuticals,2017,vol. 10
[8]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 6373 - 6377
[9]Patent: WO2020/41562,2020,A1 .Location in patent: Paragraph 00119
[10]Journal of Heterocyclic Chemistry,2020,vol. 57,p. 497 - 502
[11]Journal of the Indian Chemical Society,1959,vol. 36,p. 787,789, 790
[12]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 545 - 548
[13]Bioorganic and Medicinal Chemistry,2003,vol. 11,p. 383 - 391
[14]Patent: WO2008/9077,2008,A2 .Location in patent: Page/Page column 94-95
[15]Patent: WO2008/12326,2008,A1 .Location in patent: Page/Page column 60
[16]Patent: WO2008/89307,2008,A2 .Location in patent: Page/Page column 44-45
[17]Patent: WO2008/89310,2008,A2 .Location in patent: Page/Page column 47
[18]Tetrahedron Letters,2014,vol. 55,p. 6007 - 6010
[19]Archiv der Pharmazie,2019,vol. 352

2
[ 38267-96-8 ]
[ 67-63-0 ]
6-bromo-4-isopropoxy-quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium tert-butylate; In tetrahydrofuran; at 50℃; for 0.5h;	Synthesis of 6-Bromo-4-isopropoxy-quinazoline:Potassium f-butoxide (4.1 ml, 4.1 mmol; 1M in THF) was added to a suspension mixture of <strong>[38267-96-8]6-bromo-4-chloro-quinazoline</strong> (1.0 g, 4.0 mmol) and 2- propanol (0.313 ml, 4.1 mmol) in THF (20 ml). After stirring at 5O0C for 30 minutes, the mixture was cooled to room temperature and the THF was removed in vacuo. The residue was taken up in ethyl acetate (50 ml) and the organic layer was washed with water followed by brine. The organic layer was dried over Na2SO4 and the residue purified by silica gel chromatography with gradient of 11 to 32% ethylacetate- hexane. Product containing fractions were pooled and concentrated to afford the title compound as beige solid (0.93 g, yield: 85%). The resulting compound was characterized as follows: MS (m/z) 266.75 [M+H]+; HPLC Rt = 1.68 minutes (Method A).

Reference： [1]Patent: WO2008/9077,2008,A2 .Location in patent: Page/Page column 95

3
[ 38267-96-8 ]
[ 367-21-5 ]
[ 195457-61-5 ]

Yield	Reaction Conditions	Operation in experiment
94.4%	In isopropyl alcohol; at 90℃; for 4h;	General procedure: A solution of the 4 (0.48 g, 2 mmol), 3-fluoroaniline (0.24g,2.2 mmol) in isopropanol (30 ml) were stirred at 90 C for 4 h.Isopropanol was removed under reduced pressure and the residuewas purified through a column chromatography on silica withchloroform/methanol (V:V 50:1) as a white solid (0.58 g, 91.8%yield).
91%	In isopropyl alcohol; at 100℃; for 4h;	In a 50 mL round bottom flask,Add 3-chloro-4-fluoroaniline 0.29 g (2 mmol),<strong>[38267-96-8]4-chloro-6-bromoquinazoline</strong> 0.48 g (2 mmol),Isopropyl alcohol 20ml,Stir at 100 C for 4 hours.Cool, precipitate a white solid, suction filtration,Drying gave 0.65 g of 4-(3-chloro-4-fluorophenylamino)quinazoline in a yield of 91%.
85%	In isopropyl alcohol; at 80℃;Inert atmosphere;	To a solution consisting of <strong>[38267-96-8]6-bromo-4-chloroquinazoline</strong> (0.3 g, 1.30 mmol) in 2- propanol (30 mL) was added 3-chloro-4-fluoroaniline (0.189 g, 1.30 mmol). The reaction mixture was heated (80 C) and stirred overnight under a flow of N2. The reaction mixture wascooled to room temperature and then the reaction mixture was filtered over a fritted funnel. The filtered solid was rinsed with excess 2-propanol and dried under high vacuum to afford 6-bromo- N-(3-chloro-4-fluorophenyl)quinazolin-4-amine (3A) as an off-white solid (350 mg, 85% yield).+ .MS: (ESI m/z 353.9, ESI m/z 351.9) A solution consisting of 6-bromo-N-(3-chloro-4- fluorophenyl)quinazolin-4-amine (0.185 g, 0.526 mmol) in anhydrous ethanol (3 mL) was placedin a 5 ml. microwave reaction vial containing a stir bar. Next, 5-(methylsulfonamido)pyridine-3-yl boronic acid pinacol ester (4, 0.164 g, 0.553 mmol) was added followed by SiliCat DPP-Pd (5 mol %, 0.26 mmol/g loading, 0.101 g) and 10% aqueous potassium carbonate solution (2 equivalents, 0.76 mL, 1.05 mmol). The reaction mixture was placed under N2 atmosphere, capped, and then heated at 125 C for one hour in a Biotage Emrys Optimizer microwave. Thereaction mixture was allowed to cool to room temperature and then filtered over a fritted funnel to collect SiliCat DPP-Pd. The filtered solid was rinsed with excess ethanol and the filtrate was concentrated under reduced pressure to afford the crude product. Purification of the crude product by Biotage Isolera flash chromatography using a gradient of 4-100% ethyl acetate in heptane, followed by 0-10% methanol in dichloromethane afforded N-(5-(4-((3-chloro-4- fluorophenyl)amino)quinazolin-6-yl)pyridin-3 -yl)methanesulfonamide (5A, MOL- 160, 96 mg,41% yield, 96% purity) as a white solid; ?H NMR (400MHz, DMSO-d6) oe 10.17 (br. s, 1H),10.03 (s, 1H), 8.83-8.87 (m, 2H), 8.66 (s, 1H), 8.49 (d, J=2.38Hz, 1H), 8.13-8.20 (m, 2H), 7.90-7.98 (m, 2H), 7.83 (ddd, J2.65, 4.25, 9.01 Hz, 1H), 7.47 (t, J=9.15 Hz, 1H), 3.14 (s, 3H); MS:(ESI + m/z 444.1, ESI - m/z 442.0); TLC: (90:10:0.5, DCM:MeOH:NH4OH) Rf = 0.32.

80%	With hydrogenchloride; In water; acetone; for 3h;Reflux;	To a solution of compound 10 (2.43 g, 0.01 mol) and 3-chloro-4-fluoroaniline 1.45 g (0.01 mol) in acetone: H2O (4:1) (25 mL), followed by a few drops of hydrochloric acid. The reaction mixture stirred at reflux for 3 h, after cooling to room temperature, the pH was adjusted to neutral using ammonium hydroxide. The resulting precipitate was filtered and washed with water and dried overnight under high vacuum to give 11d as a earthy yellow solid (2.80 g, yield, 80%). 1H NMR (400 MHz, DMSO-d6) delta 11.73 (s, 1H), 9.28 (d, J = 2.0 Hz, 1H), 8.97 (s, 1H), 8.23 (dd, J = 2.0, 8.8 Hz, 1H), 8.10 (dd, J = 2.4, 6.8 Hz, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.80 (ddd, J = 2.8, 4.4, 7.2 Hz, 1H), 7.55 (t, J = 9.0 Hz, 1H). ESI-MS m/z: 354.3 [M+H]+.
80%	With hydrogenchloride; In water; acetone; for 3h;Reflux;	In a 100 mL three-necked flask,Was added 2.45 g (0.01 mol) of <strong>[38267-96-8]6-bromo-4-chloro-quinazoline</strong>,3-chloro-4-fluoroaniline (1.45 g, 0.01 mol)Acetone 20mL,H2O 5 mL,Concentrated hydrochloric acid 2-3 drops,Heating reflux 3h,Place room temperature,With concentrated ammonia to neutral,filter,Water washing,dry,The ground yellow solid was 2.8 g,Yield 80%.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 146,p. 460 - 470
[2]Patent: CN108727342,2018,A .Location in patent: Paragraph 0066; 0067; 0068; 0069
[3]Patent: WO2016/100347,2016,A2 .Location in patent: Page/Page column 66; 67
[4]European Journal of Medicinal Chemistry,2016,vol. 118,p. 276 - 289
[5]Patent: CN106565684,2017,A .Location in patent: Paragraph 0116; 0117; 0118; 0119
[6]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 6373 - 6377
[7]Journal of Medicinal Chemistry,2015,vol. 58,p. 3548 - 3571

4
[ 38267-96-8 ]
[ 6373-46-2 ]
[ 179246-97-0 ]

Yield	Reaction Conditions	Operation in experiment
88%	In isopropyl alcohol for 0.166667h; Heating / reflux;	(4-Benzyloxyphenyl)-(6-bromoquinazolin-4-yl)-amine hydrochloride (4-Benzyloxyphenyl)-(6-bromoquinazolin-4-yl)-amine hydrochloride 4-Chloro-6-bromoquinazoline (0.25 g, 1.0 mmol) and 4-benzyloxyaniline (0.25 g, 1.3 mmol) were mixed in 2-propanol (6 ml) and heated at reflux for 10 mins (Procedure A). The solution was allowed to cool at room temperature and the 2-propanol removed in vacuo. The resulting solid was triturated with acetone to give the product as a yellow solid (0.39 g, 88%); δH [2H6]-DMSO 11.60 (1H, b, NH), 9.21 (1H, s, 5-H), 8.86 (1H, s, 2-H), 8.20 (1H, d, 7-H), 7.90 (1H, d, 8-H), 7.65 (2H, d, 2'-H, 6'-H), 7.50-7.25 (5H, m, Ph-H), 7.10 (2H, d, 3'-H, 5'-H), 5.15 (2H, s, CH2); m/z 405/407 (M+).
88%	In isopropyl alcohol for 0.166667h; Reflux;	(4-Benzyloxyphenyl)-(6-bromoquinazolin-4-yl)-amine hydrochloride (0636) 4-Chloro-6-bromoquinazoline (0.25 g, 1.0 mmol) and 4-benzyloxyaniline (0.25 g, 1.3 mmol) were mixed in 2-propanol (6 ml) and heated at reflux for 10 mins (Procedure A). The solution was allowed to cool at room temperature and the 2-propanol removed in vacuo. The resulting solid was triturated with acetone to give the product as a yellow solid (0.39 g, 88%); δH [2H6]-DMSO 11.60 (1H, b, NH), 9.21 (1H, s, 5-H), 8.86 (1H, s, 2-H), 8.20 (1H, d, 7-H), 7.90 (1H, d, 8-H), 7.65 (2H, d, 2′-H, 6′-H), 7.50-7.25 (5H, m, Ph-H), 7.10 (2H, d, 3′-H, 5′-H), 5.15 (2H, s, CH2); m/z 405/407 (M+).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - US6933299, 2005, B1 Location in patent: Page/Page column 77
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - US9199973, 2015, B2 Location in patent: Page/Page column 44

5
[ 32084-59-6 ]
[ 38267-96-8 ]

Yield	Reaction Conditions	Operation in experiment
92%	With trichlorophosphate; at 120℃; for 6h;	Example 3. Synthesis of 6-bromo-4-chloroquinazoline (4): To the solution of 6-bromoquinazolin-4-oI (3, 1 g, 4.44 mmol) in phosphoryl chloride (5 mL) was refluxed for 6 hat 120 C. The mixture was cooled to room temperature and poured into ice-watercontaining sodium bicarbonate to quench excess phosphoryl chloride. The mixture wasextracted with dichloromethane (3 x 100 ml) and the solvent was evaporated to get the 6-bromo-4-chloroquinazoline 4 as a light yellow solid. Yield: 92%, light yellow solid, m. p. 273-275 C; 1H NMR (CDCI3, 500 MHz): O 9.07 (s, IH), 8.44 (d, IH, J= 2.0 Hz), 8.04 (d, 1H, J2.0 Hz), 7.96 (d, IH, J = 8.9 Hz); HRMS: m/z 224.9633 calcd for C8H6BrN2O + H(224.9664).
75%	With thionyl chloride; N,N-dimethyl-formamide; for 6h;Reflux;	General procedure: To the suspension of 6-bromopyrido[2,3-d]pyrimidin-4-ol (3) (15.0 g, 0.066 mol) in thionyl chloride 150 mL was added a few drops of DMF, then the mixture was stirred at reflux for 6 h. After removing thionyl chloride under vacuum, the residue was recrystallized from EtOAc to gave 4 as pale yellow solid (11.8 g, yield, 73%).
75%	With thionyl chloride; In N,N-dimethyl-formamide; for 1h;Reflux;	Equipped with a blender,Reflux condenser 250mL three-necked flask,15 g (0.067 mol) of 6-bromo-4 (3H) -quinazolinone was added,150 mL (2.1 mol) of thionyl chloride was added,3-4 drops of DMF,Heating reflux,After about 1h the reaction was clarified,Continue to react 5h,Distillation recovery of thionyl chloride,The residual thionyl chloride was distilled off under reduced pressure,Continue to join 50mL dichloromethane distillation residual thionyl chloride out,Repeated three timesFinally, 180 mL of ethyl acetate was heated to reflux for several minutes,Place to room temperature,filter,Vacuum dried,Got light yellow needles solid 12.2g,Yield 75%.

74%	With trichlorophosphate; at 120℃; for 6h;	General procedure: The solution of 6-bromoquinazolin-4-ol (12, 1 g, 4.44 mmol) or6,7-dimethoxyquinazolin-4-ol (17, 1 g, 4.13 mmol) in phosphorousoxy chloride (5 mL) was refluxed for 6 h at 120 C. The mixture was cooled to room temperature and poured into ice-water containingsodium bicarbonate to quench phosphorous oxychloride. The mixture was extracted with dichloromethane (3 100 ml) and thesolvent was evaporated to get chlorinated products 13 or 18.4.4.1. 6-Bromo-4-chloroquinazoline (13)Yield: 74%; light yellow solid; m.p. 161e163 C; 1H NMR (CDCl3,500 MHz): d 9.07 (s, 1H), 8.44 (d,1H, J 2.0 Hz), 8.05 (dd, 1H, J 8.9,2.2 Hz), 7.96 (d, 1H, J 8.9 Hz); IR (CHCl3): nmax 2922, 1632, 1559,1546, 1474, 1461, 1388, 1360, 1241, 1160, 1019 cm1; HR-ESIMS: m/z242.9326 calcd for C8H4BrClN2H (242.9319).
65%	With N,N-diethylaniline; trichlorophosphate; for 3h;Reflux;	Synthesis of compound 2.2. To a mixture of 6-bromoquinazolin-4-ol, compound 2.1 (1.2 g, 5.33 mmol, 1.00 equiv) in POCl3 (20 mL) was added N,N-diethylaniline (2.0 g, 13.40 mmol, 2.50 equiv). Reaction was stirred for 3 hours at reflux temperature. Upon completion of the reaction mixture was concentrated under vacuum. The residue was poured into 20 mL of cold water. Resulting solids were collected by filtration and dried in an oven to provide 850 mg (65%) of 6-bromo-4-chloroquinazoline, compound 2.2 as an orange solid
64.7%	With thionyl chloride; N,N-dimethyl-formamide; at 80℃;	6-bromo-4-chloroquinazoline 2 (2 g, 8.89 mmol) was added to 20 ml of dichlorosulfoxide, 5-10 drops of DMF were added dropwise, and the reaction was carried out at 80 C for 12-18 hours. Dichlorosulfoxide was distilled off under reduced pressure, and the product was subjected to water analysis, drying, and column chromatography to obtain a bright yellow solid 3 (1.40 g, 64.7%).
	With trichlorophosphate; In N,N-dimethyl-formamide; for 6h;Reflux; Inert atmosphere;	General procedure: To a mixture of 6-bromo-4-hydroxyquinazoline (7.9 g,35.1 mmol) in POCl3 (60 ml) was added DMF (1 ml). Then themixture was heated to reflux under N2 for 6 h. The dark clear solutionwas cooled to room temperature and concentrated in vacuumto produce a brown solid. To the mixture of above brown solidin 2-propanol (150 ml) was added morpholine (12.2 ml,140.5 mmol). Then the mixture was heated to reflux under N2 for1 h, concentrated in vacuum to give a residue which was dissolvedin ethyl acetate (200 ml). The ethyl acetate solution was washedwith brine (80 ml 5), dried over Na2SO4 and concentrated to give abrown oil, which was solidified on keeping to produce 6a (8.9 g).
	With trichlorophosphate; at 110℃;	A solution of 6-bromoquinazolin-4-ol (1.0 g, 4.44 mmol) in POC13 (10 mL) was stirred and heated at 110 C in a sealed tube overnight. The solution was cooled to room temperature and poured onto ice (200 g. ) The solution was extracted with DCM (300 mL), washed with water (200 mL), dried over Na2SO4 and concentrated in vacuo to give the impure 6-bromo-4-chloroquinazoline as a brown solid that was not purified further (1.5 g. ) MS (APCI+) [M+H] + 243. 1.
	With thionyl chloride; In DMF (N,N-dimethyl-formamide); for 5h;Heating / reflux;	Example 1: (6-Bromo-quinazolin-4-yl)-(4-morpholin-4-yl-phenyl)-amine; 5-Bromo-2-aminobenzoic acid (5g, 23.1mmol) was suspended in formamide (5eq) and heated to 155C under N2 for 16h. The mixture was allowed to cool and added to water. The resulting precipitate was isolated by filtration and dried to give an intermediate 6-bromoquinazolin-4-ol. A portion of this material (1 g) was dissolved in thionyl chloride (10ml) and DMF (0.3ml) added before being refluxed for 5h. The solvents were removed and the residue azeotroped with toluene (3x10ml) to remove traces of thionyl chloride. The resulting material was dissolved in MeCN (10ml), 4- morpholinoaniline (l.leq, Lancaster) added and the reaction mixture heated to reflux for 24hr. On cooling the precipitate was isolated by filtration to give the title compound as a beige solid (867mg). 8(DMSO) 11.5 (1H, br s) ; 9.17 (1H, d, J2.5Hz); 8.9 (lH, s) ; 8.22 (1H, dd, J 8.8, 1.9Hz); 7.88 (1H, d, J 8.8Hz); 7.61 (2H, d, J 8.8Hz); 7.06 (2H, d, J 8.8Hz); 3.78 (4H, m) ; 3.18 (4H, m) LC-MS ES+=385, rt 3.89

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1972 - 1977
[2]Letters in drug design and discovery,2017,vol. 14,p. 167 - 174
[3]Bioorganic and Medicinal Chemistry,2019,vol. 27
[4]Patent: WO2015/128873,2015,A1 .Location in patent: Page/Page column 18
[5]European Journal of Medicinal Chemistry,2016,vol. 118,p. 276 - 289
[6]Patent: CN106565684,2017,A .Location in patent: Paragraph 0104; 0106; 0220; 0222
[7]European Journal of Medicinal Chemistry,2016,vol. 122,p. 731 - 743
[8]Patent: WO2015/164374,2015,A1 .Location in patent: Paragraph 00274; 00275
[9]Patent: CN110357852,2019,A .Location in patent: Paragraph 0040; 0041; 0063-0065
[10]European Journal of Medicinal Chemistry,2014,vol. 75,p. 96 - 105
[11]Patent: WO2014/151147,2014,A1 .Location in patent: Paragraph 00641
[12]Patent: US2015/30588,2015,A1 .Location in patent: Page/Page column 73
[13]Patent: US9295673,2016,B2 .Location in patent: Page/Page column 354
[14]Patent: WO2005/51304,2005,A2 .Location in patent: Page/Page column 64
[15]Patent: WO2005/105761,2005,A1 .Location in patent: Page/Page column 20

6
[ 38267-96-8 ]
[ 666735-37-1 ]
6-Bromo-4-(2-phenyl-[1,8]naphthyridin-3-yloxy)-quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With dmap; In 1,2-dichloro-benzene; at 130℃; for 2h;	6-Bromo-4-chloro-quinazoline (100 mg), 2-phenyl-[1,8]naphthyridin-3-ol (91 mg), and 4-dimethylaminopyridine (151 mg) were suspended in 1,2-dichlorobenzene (2 ml), and the suspension was stirred at 130C for 2 hr. The reaction mixture was cooled to room temperature, and an aqueous sodium hydrogencarbonate solution was added to the reaction mixture. The organic layer was extracted with chloroform, and the chloroform layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography with a methanol-chloroform system to give the title compound (165 mg, yield 94%). 1H-NMR (CDCl3, 400 MHz): delta 7.30 - 7.36 (m, 3H), 7.57 (dd, J = 4.4, 8.3 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.96 - 8.01 (m, 3H), 8.23 (s, 1H), 8.28 (dd, J = 2.0, 8.3 Hz, 1H), 8.51 (d, J = 2.2 Hz, 1H), 8.62 (s, 1H), 9.20 (dd, J = 2.0, 4.1 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 451 (M+Na)+

Reference： [1]Patent: EP1724268,2006,A1 .Location in patent: Page/Page column 64

7
[ 110-91-8 ]
[ 38267-96-8 ]
[ 307538-52-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	In 1,4-dioxane; at 150℃; for 0.333333h;Microwave;	A solution of 6-bromo-4- chloroquinazoline (147.7 mg, 0.608 mmol.) and morpholine (53 mul_, 0.608 mmol.) in dioxane (2.0 ml.) was stirred and heated in a microwave reactor at 150 0C for 20 min. An aliquot was analyzed by LCMS, MS(ES+) m/e 294[M+H]+, and was 100% pure 6-bromo-4-(4-morpholinyl)quinazoline. Material used in next step without further workup. To the above mixture was added tributyl vinyl tin (195mul_, 0.608 mmol) and palladium tetrakis triphenylphosphine (70 mg, 0.0608 mmol) in DMF (2 ml_). The reactants were stirred and heated in a microwave reactor at 150 0C for 20 min.Purification by flash-chromatography (silica gel, 10-100% 10% methanol in chloroform) afforded the title compound (125 mg; 85%) as an off white solid. Ci4H15N3O MS(ES+) m/e 242 [M+H]+
98%	With triethylamine; In dichloromethane; at 0 - 45℃; for 2.08333h;	Intermediate 34Preparation of 6-bromo-4-(4-morpholinyl)quinazolineTo a cooled (ice bath) suspension of <strong>[38267-96-8]6-bromo-4-chloroquinazoline</strong> (16 g, 65.7 mmol) in dichloromethane (DCM) (200 ml) was added triethylamine (18.32 ml, 131 mmol). Morpholine (11.50 ml, 131 mmol) was added dropwise over 5 minutes, at which time the ice bath was removed and the mixture heated at 45 0C for 2 h (reaction quickly became homogeneous). The reaction was diluted with methylene chloride (100 mL) and washed with sat. aq. NH4Cl (2 x 200 mL), sat. aq. NaHCO3 (200 mL) and brine (200 mL). The organic layer was dried over MgSO4 and concentrated to give 6-bromo-4-(4- morpholinyl)quinazoline (19 g, 64.6 mmol, 98 % yield) MS (ES) m/e 293.8, 295.9 (M + H)+.
	In 1,4-dioxane; at 150℃; for 0.333333h;	A solution of <strong>[38267-96-8]6-bromo-4-chloroquinazoline</strong> (147.7 mg, 0.608 mmol.) and morpholine (53 mul_,0.608 mmol.) in dioxane (2.0 ml_) was stirred and heated in a microwave reactor at 150 0C for 20 min. An aliquot was analyzed by LCMS, MS(ES+) m/e 294 [M+H]+, and was 100% pure 6-bromo-4-(4-morpholinyl)quinazoline. Material used in next step without further workup. To the above mixture was added tributyl vinyl tin (195muL, 0.608 mmol) and palladium tetrakis triphenylphosphine(70 mg, 0.0608 mmol) in DMF (2 ml_). The reactants were stirred and heated in a microwave reactor at 150 0C for 20 min. Purification by flash-chromatography (silica gel, 10-100% 10% methanol in chloroform) afforded the title compound (125 mg; 85%) as an off white solid. C14H15N3O MS(ES+) m/e 242 [M+H]+

8.9 g

In isopropyl alcohol; for 1h;Reflux; Inert atmosphere;

General procedure: To a mixture of 6-bromo-4-hydroxyquinazoline (7.9 g,35.1 mmol) in POCl3 (60 ml) was added DMF (1 ml). Then themixture was heated to reflux under N2 for 6 h. The dark clear solutionwas cooled to room temperature and concentrated in vacuumto produce a brown solid. To the mixture of above brown solidin 2-propanol (150 ml) was added morpholine (12.2 ml,140.5 mmol). Then the mixture was heated to reflux under N2 for1 h, concentrated in vacuum to give a residue which was dissolvedin ethyl acetate (200 ml). The ethyl acetate solution was washedwith brine (80 ml 5), dried over Na2SO4 and concentrated to give abrown oil, which was solidified on keeping to produce 6a (8.9 g).Yield 85.7%, mp 112.0e114.0 C. 1H NMR (CDCl3) d: 8.75 (1H, s, AreH), 8.00 (1H, d, J 1.6 Hz, AreH), 7.82 (1H, d, J 8.8 Hz, AreH), 7.80(1H, dd, J 9.2, 2.0 Hz, AreH), 3.90 (4H, t, J 4.4 Hz, NCH2), 3.79(4H, t, J 4.4 Hz, OCH2). ESI-HRMS m/z: calcd for C12H12BrClN3O[M H]: 293.0164; found 293.0166, 295.0140

Reference： [1]Patent: WO2007/103759,2007,A2 .Location in patent: Page/Page column 47
[2]Patent: WO2008/157191,2008,A2 .Location in patent: Page/Page column 89
[3]Patent: WO2007/38331,2007,A2 .Location in patent: Page/Page column 29
[4]European Journal of Medicinal Chemistry,2014,vol. 75,p. 96 - 105

8
[ 38267-96-8 ]
[ 916813-33-7 ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium azide; In N,N-dimethyl-formamide; at 120℃; for 2h;	A solution of the compound from Example 1 b) (0.430 g; 1.77 mmol) and sodium azide (0.138 g; 2.12 mmol) inlambda/,lambda/-dimethylformamide (5.0 ml_) was heated to 120 0C for 2 h. Upon cooling to ambient temperature, water was added and the resulting precipitate was collected by filtration, washed with water, and dried in vacuo to afford the title compound (0.403 g; 91 %) as a light orange solid. 1H NMR (400 MHz, CHLOROFORM-d) D ppm 9.58 (s, 1 H) 8.84 (d, J=2.0 Hz, 1 H) 8.20 (d, J=8.8 Hz,1 H) 7.99 (dd, J=8.7, 2.1 Hz, 1 H).

Reference： [1]Patent: WO2007/38331,2007,A2 .Location in patent: Page/Page column 38

9
[ 38267-96-8 ]
[ 108-42-9 ]
[ 307538-20-1 ]

Yield	Reaction Conditions	Operation in experiment
79%	In isopropyl alcohol; at 80℃;Inert atmosphere;	To a solution consisting of <strong>[38267-96-8]6-bromo-4-chloroquinazoline</strong> (0.448 g, 1.84 mmol) in 2-propanol (10 mL) was added 3-chloroaniline (0.246 g, 1.93 mmol). The reaction mixture was heated (80 C) and stirred overnight under a flow of N2. The reaction mixture was cooled to room temperature and then the reaction mixture was filtered over a fritted funnel. The filteredsolid was rinsed with excess 2-propanol and dried under high vacuum to afford 6-bromo-N-(3- chlorophenyl)quinazolin-4-amine (3B) as an off-white solid (490 mg, 79% yield, 98% purity). MS (ESIm/z 335.9, ESI m/z 333.9.) A solution consisting of 6-bromo-N-(3- chlorophenyl)quinazolin-4-amine (0.200 g, 0.597 mmol) in anhydrous ethanol (3 mL) was placed in a 5 mL microwave reaction vial containing a stir bar. Next, 5-(methylsulfonamido)pyridine-3-yl boronic acid pinacol ester (4, 0.187 g, 0.627 mmol) was added followed by SiliCat DPP-Pd (5 mol %, 0.26mmol/g loading, 0.115 g) and 10% aqueous potassium carbonate solution (2 equivalents, 0.87 mL, 1.20 mmol). The reaction mixture was placed under N2 atmosphere, capped, and then heated at 100 C for 30 minutes in a Biotage Emrys Optimizer microwave. The reaction mixture was allowed to cool to room temperatureand then filtered over a fritted funnel to collect SiliCat DPP-Pd. The filtered solid was rinsed with excess ethanol and the filtrate was concentrated under reduced pressure to afford the crude product. Purification of the crude product by Biotage Isolera flash chromatography using a gradient of 4-100% ethyl acetate in heptane, followed by 0-10% methanol in dichloromethane afforded N-(5 -(4-((3 -chlorophenyl)amino)quinazolin-6-yl)pyridin-3-yl)methanesulfonamide (SB,MOL-162, 78 mg, 31% yield, 97% purity) as a white solid; ?H NMR (400MHz, DMSO-d6) oe10.20 (br. s., 1H), 10.04 (s, 1H), 8.89 (dd, J-1.74, 13.45 Hz, 1H), 8.70 (s, 1H), 8.50 (d, J=2.38Hz, 1H), 8.19 (dd,J=1.65, 8.60 Hz, 1H), 8.11 (t, J2.01 Hz, 1H), 7.91-8.04 (m, 1H), 7.67-7.91 (m, 1H), 7.45 (t, J=8. 14 Hz, 1H), 7.22 (m, 1H), 3.16 (s, 3H); MS: (ESI + m/z 426.1, ESI - m/z 424.0); TLC: (90:10:0.5, DCM:MeOH:NH4OH) Rf= 0.49.
		To a solution of 2-amino-5-bromo benzoic acid (2.16 g, 10 mmol, 1.0 equiv.) in 100 ml ethanol was added formamidine acetate (1.30 g, 12.5 mmol, 1.25 equiv.), and the reaction mixture was heated to reflux for 16 hrs. After the reaction was cooled to room temperature, the resulting white precipitate was collected via filtration and washed with water to afford 6- bromoquinazolin-4(3H)-one as a pale yellow prism, 1.78 g.A suspension of 6-bromoquinazolin-4(3H)-one (1.45 g, 6.44 mmol, 1.0 equiv.) in 10 ml POCI3 was heated to reflux for 6 hours. The resulting clear solution was then cooled to room temperature and concentrated in vacuo to afford <strong>[38267-96-8]4-chloro-6-bromoquinazoline</strong> as an off- white crystal which was carried to the next step without further purification.To the mixture of <strong>[38267-96-8]4-chloro-6-bromoquinazoline</strong> (crude, 1.60 g) in isopropanol (20 ml) was added 3-chloroaniline (0.84 ml, 0.79 mmol, 1.2 equiv.). After heating to 8O0C for 2 hours, the reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The resulting residue was diluted with 100 ml ethyl acetate, washed with sat. NaHCO3 (aq.) and brine, dried over Na2SO4, and concentrated in vacuo. Flash chromatography purification afforded 6-bromoquinazoline as an off-white solid of 1 g.To a 5 ml microwave vial was added 6-bromoquinazoline (34 mg, 0.1 mmol, 1.0 equiv.), N-Morpholinyl-4-boronbenzene sulfonylamide (27 mg, 0.1 mmol, 1.0 equiv.), Pd(PPh3)2Cl2 (7 mg, 0.01 mmol, 0.1 equiv.) 2 ml acetonitrile and 0.3 ml aq. NaHCO3 (1 M) were added and the reaction mixture was kept under microwave heating at 160 0C for 800 seconds. After cooling to the room temperature, the crude mixture was diluted with water and extracted twice with EtOAc. Preparative TLC purification afforded the desired product as a white solid of 9 mg. <n="46"/>1H NMR (CDCl3) delta: 8.84 (IH, brs), 8.36 (IH, br), 7.98-8.08 (4H, m), 7.75-7.90 (4H, m), 7.39 (IH, t, J= 8.1 Hz), 7.21 (IH, d, J= 8.1 Hz), 3.74 (4H, s), 3.04 (4H, s); M+H+ = 481.
		To a solution of 2-amino-5-bromo benzoic acid (2.16 g, 10 mmol, 1.0 equiv.) in 100 ml ethanol was added formamidine acetate (1.30 g, 12.5 mmol, 1.25 equiv.), and the reaction mixture was heated to reflux for 16 hrs. After the reaction was cooled to room temperature, the resulting white precipitate was collected via filtration and washed with water to afford 6- bromoquinazolin-4(3H)-one as a pale yellow prism, 1.78 g.A suspension of 6-bromoquinazolin-4(3H)-one (1.45 g, 6.44 mmol, 1.0 equiv.) in 10 ml POCI3 was heated to reflux for 6 hours. The resulting clear solution was then cooled to room temperature and concentrated in vacuo to afford <strong>[38267-96-8]4-chloro-6-bromoquinazoline</strong> as an off- white crystal which was carried to the next step without further purification.To the mixture of <strong>[38267-96-8]4-chloro-6-bromoquinazoline</strong> (crude, 1.60 g) in isopropanol (20 ml) was added 3-chloroaniline (0.84 ml, 0.79 mmol, 1.2 equiv.). After heating to 8O0C for 2 hours, the reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The resulting residue was diluted with 100 ml ethyl acetate, washed with sat. NaHCO3 (aq.) and brine, dried over Na2SO4, and concentrated in vacuo. Flash chromatography purification afforded 6-bromoquinazoline as an off-white solid of 1 g.To a 5 ml microwave vial was added 6-bromoquinazoline (34 mg, 0.1 mmol, 1.0 equiv.), N-Morpholinyl-4-boronbenzene sulfonylamide (27 mg, 0.1 mmol, 1.0 equiv.),Pd(PPh3)2Cl2 (7 mg, 0.01 mmol, 0.1 equiv.) 2 ml acetonitrile and 0.3 ml aq. NaHCO3 (1 M) were added and the reaction mixture was kept under microwave heating at 160 0C for 800 seconds. After cooling to the room temperature, the crude mixture was diluted with water and extracted twice with EtOAc. Preparative TLC purification afforded the desired product as a white solid of 9 mg.1H NMR (CDCl3) delta: 8.84 (IH, brs), 8.36 (IH, br), 7.98-8.08 (4H, m), 7.75-7.90 (4H, m), 7.39 (IH, t, J= 8.1 Hz), 7.21 (IH, d, J= 8.1 Hz), 3.74 (4H, s), 3.04 (4H, s); M+H+ = 481.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 6623 - 6626
[2]Patent: WO2016/100347,2016,A2 .Location in patent: Page/Page column 67; 68
[3]Pharmaceuticals,2017,vol. 10
[4]Patent: WO2008/89307,2008,A2 .Location in patent: Page/Page column 44-45
[5]Patent: WO2008/89310,2008,A2 .Location in patent: Page/Page column 47
[6]Journal of Medicinal Chemistry,2015,vol. 58,p. 3548 - 3571

10
[ 38267-96-8 ]
[ 57260-71-6 ]
[ 474710-31-1 ]

Yield	Reaction Conditions	Operation in experiment
85%	With triethylamine; In 1-methyl-pyrrolidin-2-one; at 80℃; for 2h;	A solution of the crude product from Step 1 (1.5 g), piperazine-1- carboxylic acid tert-butyl ester (2.29 g, 12.3 mmol) and triethylamine (2.15 mL, 15.4 mmol) in N-methylpyrrolidinone (50 mL) was stirred and heated at 80 C for 2 hours. The solution was cooled to room temperature, diluted with EtOAc (200 mL), washed with water (3 x 200 mL) and dried over Na2S04. The mixture was purified by silica gel column chromatography (50% EtOAc/hexanes) to give 4-(6-bromo-quinazolin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester as a colorless oil (1. 5g, 3.8 mmol, 85% from Step 1. ) MS (APCI+) [M+H] + 394.9 and 392. 9. in NMR (CDC13, 400 MHz) 8 8.76 (1H, s), 8.02 (1H, s), 7.84-7. 78 (2H, m), 3.74 (4H, s), 3.66 (4H, s), 1.51 (9H, s.)

Reference： [1]Patent: WO2005/51304,2005,A2 .Location in patent: Page/Page column 64

11
[ 38267-96-8 ]
[ 1093819-23-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium iodide; In propiononitrile; at 100℃; for 5h;	a) 6-bromo-4-iodoquinazolineA sealable reaction vessel was charged with <strong>[38267-96-8]6-bromo-4-chloroquinazoline</strong> (1.02 g, 3.64 mmol), dry sodium iodide (2.73 g, 18.2 mmol) and dry propionitrile (35 mL). The reaction vessel was purged with nitrogen, sealed and heated to 100 0C. After 5 h, the reaction was allowed to cool to rt, diluted with EtOAc and washed with sat. aq. NaHCO3 followed by sat. aq. Na2S2O3. The combined aqueous layers were extracted with EtOAc and the combined EtOAc layers were dried (Na2SO4), filtered and concentrated under reduced pressure to give 1.26 g (100%) of the title compound as a yellow solid which was used without further purification. MS(ES)+ m/e 334.8, 336.9 [M+H]+.

Reference： [1]Patent: WO2008/157191,2008,A2 .Location in patent: Page/Page column 71; 51-52

12
[ 372-19-0 ]
[ 38267-96-8 ]
[ 929411-71-2 ]

Yield	Reaction Conditions	Operation in experiment
91.8%	In isopropyl alcohol; at 90℃; for 4h;	A solution of the 4 (0.48 g, 2 mmol), 3-fluoroaniline (0.24g,2.2 mmol) in isopropanol (30 ml) were stirred at 90 C for 4 h.Isopropanol was removed under reduced pressure and the residuewas purified through a column chromatography on silica withchloroform/methanol (V:V 50:1) as a white solid (0.58 g, 91.8%yield). mp 167e169 C. 1H NMR (400 MHz, DMSO) d 12.05 (s, 1H,NH), 9.45 (s, 1H, Ar-H), 9.03 (s, 1H, Ar-H), 8.26 (d, J 8.9 Hz, 1H, Ar-H), 8.02 (d, J 8.9 Hz, 1H, Ar-H), 7.78 (d, J 10.9 Hz, 1H, Ar-H), 7.67(d, J 8.1 Hz, 1H, Ar-H), 7.53 (dd, J 15.1, 8.0 Hz, 1H, Ar-H), 7.18 (td,J 8.4, 1.8 Hz, 1H, Ar-H). ESI-MS: m/z 315.9 [M H].

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 146,p. 460 - 470
[2]Pharmaceuticals,2017,vol. 10
[3]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 6623 - 6626
[4]Journal of Medicinal Chemistry,2015,vol. 58,p. 3548 - 3571

13
[ 38267-96-8 ]
[ 66584-32-5 ]
[ 1202228-33-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 6623 - 6626

14
[ 27757-85-3 ]
[ 38267-96-8 ]
[ 1225440-72-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;	[0085] Procedure for the preparation of 6-bromo-N-(thiophen-2-ylmethyl)quinazolin- 4-amine: To a solution of <strong>[38267-96-8]6-bromo-4-chloroquinazoline</strong> (0.3 g, 1.23 mmol) in DMF (8 mL)were added thiophen-2-ylmethanamine (0.139 g, 1.23 mmol) and Hunig's base (0.21 mL, 1.23 mmol). The reaction mixture was stirred at room temperature for 2 h. Upon completion, the reaction mixture was diluted with EtOAc (100 mL) and washed with 10% KHS04 (25 mL) and three times with 3N LiCl (3 x 30 mL). The organic layer was extracted, dried on MgS04, filtered, and concentrated in vacuo. The residue was purified directly on silica column. Gradient elution with ethyl acetate (15?75%) in hexanes provided the title compound as a colorless solid: yield (0.39 g, 1.22 mmol, 99 %).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 6700 - 6705
[2]Patent: WO2011/41655,2011,A1 .Location in patent: Page/Page column 25
[3]Journal of Agricultural and Food Chemistry,2019,vol. 67,p. 11005 - 11017

15
[ 38267-96-8 ]
[ 871329-85-0 ]
[ 1431542-48-1 ]

Yield	Reaction Conditions	Operation in experiment
61%	With bis-triphenylphosphine-palladium(II) chloride; potassium phosphate; In water; acetonitrile; at 120℃; for 0.166667h;Microwave irradiation; Inert atmosphere;	A mixture of <strong>[38267-96-8]6-bromo-4-chloroquinazoline</strong> (1 .5 g, 6.16 mmol), 3-(ethoxycarbonyl)-5- fluorophenylboronic acid (1.306 g, 6.16 mmol), K3P04 (1.961 g, 9.24 mmol) andPdCI2(PPh3)2 (216 mg, 0.308 mmol) was flushed with argon for few minutes. To the mixture was then added 24 ml of Acetonitrile followed by 2.4 ml of water. The vial was capped and the reaction mixture was heated to 120C for 10 min using a microwave oven. The mixture was then cooled down to rt, diluted with CH2CI2 and filtered through a Celite pad. The organic layer was washed with sat. Bicarbonate solution, dried by passing through a phase separating cartridge and evaporated. Purification by Flash chromatography using Biotage Isolera system (amine functionalized silica KP-NH, eluting with Cyclohexane/EtOAc 0 to 30%) gave the title compound (1 .417 g, 61 % yield) as a solid. MS: 375.1 -377.1 [M+1]+, Rt(1) = 1.54 min.
61%	With bis-triphenylphosphine-palladium(II) chloride; In water; acetonitrile; at 120℃; for 0.166667h;Inert atmosphere; Microwave irradiation;	A mixture of <strong>[38267-96-8]6-bromo-4-chloroquinazoline</strong> (1.5 g, 6.16 mmol), 3-(ethoxycarbonyl)-5- fluorophenylboronic acid (1.306 g, 6.16 mmol), K3P04 (1.961 g, 9.24 mmol) and PdCI2(PPh3)2 (216 mg, 0.308 mmol) was flushed with argon for few minutes. To the mixture was then added 24 ml of Acetonitrile followed by 2.4 ml of water. The vial was capped and the reaction mixture was heated to 120C for 10 min using a microwave oven. The mixture was then cooled down to rt, diluted with CH2CI2 and filtered through a Celite pad. The organic layer was washed with sat. Bicarbonate solution, dried by passing through a phase separating cartridge and evaporated. Purification by Flash chromatography using Biotage Isolera system (amine functionalized silica KP-NH, eluting with Cyclohexane/EtOAc 0 to 30%) gave the title compound (1 .417 g, 61 % yield) as a solid. MS: 375.1 -377.1 [M+1 ]+, Rt(1,) = 1.54 min.
61%	With bis-triphenylphosphine-palladium(II) chloride; potassium phosphate; In water; acetonitrile; at 120℃; for 0.166667h;Inert atmosphere; Microwave irradiation;	3-(6-Bromo-quinazolin-4-yl)-5-fluoro-benzoic acid ethyl ester A mixture of <strong>[38267-96-8]6-bromo-4-chloroquinazoline</strong> (1.5 g, 6.16 mmol), 3-(ethoxycarbonyl)-5-fluorophenylboronic acid (1.306 g, 6.16 mmol), K3PO4 (1.961 g, 9.24 mmol) and PdCl2(PPh3)2 (216 mg, 0.308 mmol) was flushed with argon for few minutes. To the mixture was then added 24 ml of Acetonitrile followed by 2.4 ml of water. The vial was capped and the reaction mixture was heated to 120 C. for 10 min using a microwave oven. The mixture was then cooled down to rt, diluted with CH2Cl2 and filtered through a Celite pad. The organic layer was washed with sat. Bicarbonate solution, dried by passing through a phase separating cartridge and evaporated. Purification by Flash chromatography using Biotage Isolera system (amine functionalized silica KP-NH, eluting with Cyclohexane/EtOAc 0 to 30%) gave the title compound (1.417 g, 61% yield) as a solid. MS: 375.1-377.1 [M+1]+, Rt(1')=1.54 min.

Reference： [1]Patent: WO2013/57711,2013,A1 .Location in patent: Page/Page column 133-134
[2]Patent: WO2013/88404,2013,A1 .Location in patent: Page/Page column 262; 263
[3]Patent: US2015/342951,2015,A1 .Location in patent: Paragraph 1072-1073

16
[ 38267-96-8 ]
[ 1431542-20-9 ]
[ 1431542-45-8 ]

Yield	Reaction Conditions	Operation in experiment
49%	With bis-triphenylphosphine-palladium(II) chloride; potassium phosphate; In water; acetonitrile; at 120℃; for 0.166667h;Microwave irradiation; Inert atmosphere;	A mixture of <strong>[38267-96-8]6-bromo-4-chloroquinazoline</strong> (1 .8 g, 7.39 mmol) (commercial source), 1 -{4-[2- methyl-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-benzoyl]-piperazin-1-yl}-ethanone (4.23 g, 7.39 mmol, 65%purity(UPLC)), K3P04 (2.354 g, 1 1.09 mmol) and PdCI2(PPh3)2 (0.259 g, 0.370 mmol) was flushed with argon for few minutes. To the mixture was then added 15 ml of Acetonitrile followed by 1 .5 ml of water. The vial was capped and the reaction mixture was heated to 120C for 10 min using a microwave oven. The mixture was then cooled down to rt, diluted with CH2CI2 and filtered through a Celite pad. The organic layer was washed with sat. Bicarbonate solution, dried by passing through a phase separating cartridge and evaporated. Purification by Flash chromatography using Biotage Isolera system (amine functionalized silica KP-NH, eluting with Cyclohexane/EtOAc 0 to 100%) gave the title compound (1.65 g, 49% yield) as a yellow powder. MS: 453.2-455.1 [M+1]+ , Rt(1) = 0.99 min.
49%	With bis-triphenylphosphine-palladium(II) chloride; potassium phosphate; In acetonitrile; at 120℃; for 0.166667h;Inert atmosphere; Microwave irradiation;	A mixture of <strong>[38267-96-8]6-bromo-4-chloroquinazoline</strong> (1 .8 g, 7.39 mmol) (commercial source), 1-{4-[2- met yl-5-(4,4,5,5 etramethyl-[1 :3,2]dioxaborolari-2-yl)-benzoyl]-pip8razin-1-yl}-ethanone (4.23 g, 7.39 mmol, 65%purity(UPLC)), K3P04 (2.354 g, 1 1 .09 mmol) and PdCI2(PPh3)2 (0.259 g, 0.370 mmol) was flushed with argon for few minutes. To the mixture was then added 15 ml of Acetoniirile followed by 1.5 ml of water. The vial was capped and the reaction mixture was heated to 120C for 10 min using a microwave oven. The mixture was then cooled down to rt, diluted with CH2CI2 and filtered through a Celite pad. The organic layer was washed with sat. Bicarbonate solution, dried by passing through a phase separating cartridge and evaporated. Purification by Flash chromatography using Biotage Isolera system (amine functionalized silica KP-NH, eluting with Cyclohexane/EtOAc 0 to 100%) gave the title compound (1 .65 g, 49% yield) as a yellow powder. MS: 453.2-455.1 [M+1 ]+ , Rt(1 ,) = 0.99 min
1.65 g	With bis-triphenylphosphine-palladium(II) chloride; potassium phosphate; In water; acetonitrile; at 120℃; for 0.166667h;Inert atmosphere; Microwave irradiation;	1-{4-[5-(6-Bromo-quinazolin-4-yl)-2-methyl-benzoyl]-piperazin-1-yl}-ethanone A mixture of <strong>[38267-96-8]6-bromo-4-chloroquinazoline</strong> (1.8 g, 7.39 mmol) (commercial source), 1-{4-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoyl]-piperazin-1-yl}-ethanone (4.23 g, 7.39 mmol, 65% purity (UPLC)), K3PO4 (2.354 g, 11.09 mmol) and PdCl2(PPh3)2 (0.259 g, 0.370 mmol) was flushed with argon for few minutes. To the mixture was then added 15 ml of Acetonitrile followed by 1.5 ml of water. The vial was capped and the reaction mixture was heated to 120 C. for 10 min using a microwave oven. The mixture was then cooled down to rt, diluted with CH2Cl2 and filtered through a Celite pad. The organic layer was washed with sat. Bicarbonate solution, dried by passing through a phase separating cartridge and evaporated. Purification by Flash chromatography using Biotage Isolera system (amine functionalized silica KP-NH, eluting with Cyclohexane/EtOAc 0 to 100%) gave the title compound (1.65 g, 49% yield) as a yellow powder. MS: 453.2-455.1 [M+1]+, Rt(1')=0.99 min.

Reference： [1]Patent: WO2013/57711,2013,A1 .Location in patent: Page/Page column 125
[2]Patent: WO2013/88404,2013,A1 .Location in patent: Page/Page column 254
[3]Patent: US2015/342951,2015,A1 .Location in patent: Paragraph 1059-1060

17
[ 38267-96-8 ]
[ 4334-87-6 ]
[ 1431542-29-8 ]

Yield	Reaction Conditions	Operation in experiment
2.12 g	With bis-triphenylphosphine-palladium(II) chloride; potassium phosphate; In water; acetonitrile; at 100℃; for 0.25h;Microwave irradiation;	To a mixture of 6-Bromo-4-chloro-quinazoline (2g, 8.21 mmol), 3-(ethoxycarbonyl)phenyl- boronic acid (1 .673g, 8.62 mmol), Pd(PPh3)2CI2 (0.288g, 0.41 1 mmol) and K3P04 (2.62g, 12.32 mmol) was added 16 mL of acetonitrile. The reaction mixture was flushed with argon, 2mL of water was added, the tube was capped, heated to 100C for 15min using a microwave oven and then cooled down to rt. The formed yellow solid was filtered, washed with ether and dried under vacuum to gave the title compound (1.54g) as a yellow solid. The filtrate was diluted with EtOAc, the organic layer washed with brine, dried over MgS04, filtered and evaporated. The obtained residue was triturated in MeOH to afford the title compound as a yellow solid (580 mg). The two solids were combined to gave 2.12g of the title compound as a yellow solid. 1H-NMR (400 MHz, MeOD, 298 K): ? ppm 1 .42 (t, 3 H) 4.43 (q, 2 H) 7.77 (t, 1 H) 7.97-8.07 (m, 2 H) 8.16 (dd, 1 H) 8.22 (d, 1 H) 8.29 (d, 1 H) 8.41 (s, 1 H) 9.34 (s, 1 H). MS: 357.0-359.0 [M+1 ]+, Rt (1) = 1 .52 min.
2.12 g	With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In water; acetonitrile; at 100℃; for 0.25h;Inert atmosphere; Microwave irradiation;	To a mixture of 6-Bromo-4-chloro-quinazoline (2g, 8.21 mmol), 3-(ethoxycarbonyl)phenyl- boronic acid (1.673g, 8.62 mmol), Pd(PPh3)2Cl2 (0.288g, 0.41 1 mmol) and K3P04 (2.62g, 12.32 mmol) was added 16 mL of acetonitrile. The reaction mixture was flushed with argon, 2ml_ of water was added, the tube was capped, heated to 100C for 15min using a microwave oven and then cooled down to rt. The formed yellow solid was filtered, washed with ether and dried under vacuum to gave the title compound (1.54g) as a yellow solid. The filtrate was diluted with EtOAc, the organic layer washed with brine, dried over MgS04, filtered and evaporated. The obtained residue was triturated in MeOH to afford the title compound as a yellow solid (580 mg). The two solids were combined to gave 2.12g of the title compound as a yellow solid. 1H-NMR (400 MHz, MeOD 298 K): delta ppm 1.42 (t, 3 H) 4.43 (q, 2 H) 7.77 (t, 1 H) 7.97-8.07 (m, 2 H) 8.16 (dd, 1 H) 8.22 (d, 1 H) 8.29 (d, 1 H) 8.41 (s, 1 H) 9.34 (s, 1 H). MS: 357.0-359.0 [M+1]+, Rt = 1.52 min.
2.12 g	With bis-triphenylphosphine-palladium(II) chloride; potassium phosphate; In water; acetonitrile; at 100℃; for 0.25h;Inert atmosphere; Microwave irradiation;	3-(6-Bromo-quinazolin-4-yl)-benzoic acid ethyl ester To a mixture of 6-Bromo-4-chloro-quinazoline (2 g, 8.21 mmol), 3-(ethoxycarbonyl)phenyl-boronic acid (1.673 g, 8.62 mmol), Pd(PPh3)2Cl2 (0.288 g, 0.411 mmol) and K3PO4 (2.62 g, 12.32 mmol) was added 16 mL of acetonitrile. The reaction mixture was flushed with argon, 2 mL of water was added, the tube was capped, heated to 100 C. for 15 min using a microwave oven and then cooled down to rt. The formed yellow solid was filtered, washed with ether and dried under vacuum to gave the title compound (1.54 g) as a yellow solid. The filtrate was diluted with EtOAc, the organic layer washed with brine, dried over MgSO4, filtered and evaporated. The obtained residue was triturated in MeOH to afford the title compound as a yellow solid (580 mg). The two solids were combined to gave 2.12 g of the title compound as a yellow solid. 1H-NMR (400 MHz, MeOD, 298 K): delta ppm 1.42 (t, 3H) 4.43 (q, 2H) 7.77 (t, 1H) 7.97-8.07 (m, 2H) 8.16 (dd, 1H) 8.22 (d, 1H) 8.29 (d, 1H) 8.41 (s, 1H) 9.34 (s, 1H). MS: 357.0-359.0 [M+1]+, Rt(1')=1.52 min.

Reference： [1]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 762 - 767
[2]Patent: WO2013/57711,2013,A1 .Location in patent: Page/Page column 56-57
[3]Patent: WO2013/88404,2013,A1 .Location in patent: Page/Page column 185; 186
[4]Patent: US2015/342951,2015,A1 .Location in patent: Paragraph 0972-0973

18
[ 38267-96-8 ]
[ 916326-10-8 ]
[ 1431542-39-0 ]

Yield	Reaction Conditions	Operation in experiment
60%	With bis-triphenylphosphine-palladium(II) chloride; potassium phosphate; In water; acetonitrile; at 100℃; for 0.2h;Microwave irradiation; Inert atmosphere;	To a mixture of <strong>[38267-96-8]6-bromo-4-chloro-quinazoline</strong> (6g, 23.41 mmol), boronic acid 5-(4,4,5,5- tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-nicotinic acid ethyl ester (6.81 g, 24.58 mmol), Pd(PPh3)2CI2 (0.822g, 1.17 mmol) and K3P04 (7.45g, 35.1 mmol) was added 96 mL of acetonitril. The reaction mixture was flushed with argon and 12ml water was added and the vial capped. The reaction mixture was heated to 100C for 12min using a microwave oven and then cooled down to rt. The mixture was quenched with water, extracted with dichloromethane. The organic layer was washed with brine, dried over MgS04, filtered through a Celite pad and evaporated. The obtained residue was triturated in MeOH to afford the title compound as a light orange solid (5.3g, 95%purity, 60% yield). 1H-NMR (400 MHz, DMSO-d6, 298 K): ? ppm 1.38 (t, 3 H) 4.41 (q, 2 H) 8.1 (d, 1 H) 8.25 (d, 2 H) 8.65 (s, 1 H) 9.22 (s, 1 H) 9.32 (s, 1 H) 9.48 (s, 1 H) . MS: 358.1-360.1 [M+1 ]+, Rt(1) = 1 .28 min.
60%	With bis-triphenylphosphine-palladium(II) chloride; potassium phosphate; In acetonitrile; at 100℃; for 0.2h;Inert atmosphere; Microwave irradiation;	5-(6-Bromo-quinazolin-4-yl)-nicotinic acid ethyl ester To a mixture of <strong>[38267-96-8]6-bromo-4-chloro-quinazoline</strong> (6 g, 23.41 mmol), boronic acid 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinic acid ethyl ester (6.81 g, 24.58 mmol), Pd(PPh3)2Cl2 (0.822 g, 1.17 mmol) and K3PO4 (7.45 g, 35.1 mmol) was added 96 mL of acetonitril. The reaction mixture was flushed with argon and 12 ml water was added and the vial capped. The reaction mixture was heated to 100 C. for 12 min using a microwave oven and then cooled down to rt. The mixture was quenched with water, extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered through a Celite pad and evaporated. The obtained residue was triturated in MeOH to afford the title compound as a light orange solid (5.3 g, 95% purity, 60% yield). 1H-NMR (400 MHz, DMSO-d6, 298 K): delta ppm 1.38 (t, 3H) 4.41 (q, 2H) 8.1 (d, 1H) 8.25 (d, 2H) 8.65 (s, 1H) 9.22 (s, 1H) 9.32 (s, 1H) 9.48 (s, 1H). MS: 358.1-360.1 [M+1]+, Rt(1')=1.28 min.

Reference： [1]Patent: WO2013/57711,2013,A1 .Location in patent: Page/Page column 91-92
[2]Patent: US2015/342951,2015,A1 .Location in patent: Paragraph 1023-1024

19
[ 38267-96-8 ]
[ 371-40-4 ]
[ 459418-63-4 ]

Yield	Reaction Conditions	Operation in experiment
90.6%	In isopropyl alcohol; at 90℃; for 4h;	General procedure: A solution of the 4 (0.48 g, 2 mmol), 3-fluoroaniline (0.24g,2.2 mmol) in isopropanol (30 ml) were stirred at 90 C for 4 h.Isopropanol was removed under reduced pressure and the residuewas purified through a column chromatography on silica withchloroform/methanol (V:V 50:1) as a white solid (0.58 g, 91.8%yield).

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 146,p. 460 - 470
[2]Pharmaceuticals,2017,vol. 10
[3]ChemMedChem,2019
[4]Journal of Medicinal Chemistry,2015,vol. 58,p. 3548 - 3571

20
[ 38267-96-8 ]
[ 53250-82-1 ]
N-{4-[(6-bromo-4-quinazolinyl)amino]phenyl}methanesulfonamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3548 - 3571

21
[ 38267-96-8 ]
[ 53250-82-1 ]
N-(4-[6-(1,3-thiazol-5-yl)-4-quinazolinyl]amino}phenyl)methanesulfonamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3548 - 3571

22
[ 38267-96-8 ]
[ 35216-39-8 ]
6-bromo-N-[3-(methylsulfonyl)phenyl]-4-quinazolinamine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3548 - 3571

23
[ 38267-96-8 ]
[ 35216-39-8 ]
N-[3-(methylsulfonyl)phenyl]-6-(1,3-thiazol-5-yl)-4-quinazolinamine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3548 - 3571

24
[ 38267-96-8 ]
[ 1008-95-3 ]
6-bromo-N-[4-(1,3-oxazol-5-yl)phenyl]-4-quinazolinamine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3548 - 3571

25
[ 38267-96-8 ]
[ 1008-95-3 ]
N-[4-(1,3-oxazol-5-yl)phenyl]-6-(1,3-thiazol-5-yl)-4-quinazolinamine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3548 - 3571

26
[ 38267-96-8 ]
[ 2221-00-3 ]
6-bromo-N-[4-(1H-imidazol-1-yl)phenyl]-4-quinazolinamine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3548 - 3571

27
[ 38267-96-8 ]
[ 2221-00-3 ]
N-[4-(1H-imidazol-1-yl)phenyl]-6-(1,3-thiazol-5-yl)-4-quinazolinamine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3548 - 3571

28
[ 38267-96-8 ]
[ 13691-22-0 ]
1-{4-[(6-bromo-4-quinazolinyl)amino]phenyl}-2-pyrrolidinone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile at 20℃;

Reference： [1]Haffner, Curt D.; Becherer, J. David; Boros, Eric E.; Cadilla, Rodolfo; Carpenter, Tiffany; Cowan, David; Deaton, David N.; Guo, Yu; Harrington, Wallace; Henke, Brad R.; Jeune, Michael R.; Kaldor, Istvan; Milliken, Naphtali; Petrov, Kim G.; Preugschat, Frank; Schulte, Christie; Shearer, Barry G.; Shearer, Todd; Smalley, Terrence L.; Stewart, Eugene L.; Stuart, J. Darren; Ulrich, John C. [Journal of Medicinal Chemistry, 2015, vol. 58, # 8, p. 3548 - 3571]

29
[ 88675-24-5 ]
[ 38267-96-8 ]
6-bromo-N-(tetrahydro-3-furanyl)-4-quinazolinamine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3548 - 3571

30
[ 54012-73-6 ]
[ 38267-96-8 ]
N-3-piperidinyl-6-(1,3-thiazol-5-yl)-4-quinazolinamine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3548 - 3571

31
[ 54012-73-6 ]
[ 38267-96-8 ]
C₁₃H₁₅BrN₄ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3548 - 3571

32
[ 38267-96-8 ]
[ 210240-20-3 ]
N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6-(1,3-thiazol-5-yl)-4-quinazolinamine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3548 - 3571

33
[ 38267-96-8 ]
[ 210240-20-3 ]
6-bromo-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-4-quinazolinamine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3548 - 3571

34
[ 38267-96-8 ]
[ 3685-23-2 ]
cis-4-[6-(1,3-thiazol-5-yl)-4-quinazolinyl]amino}cyclohexane carboxylic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3548 - 3571

35
[ 38267-96-8 ]
[ 3685-23-2 ]
cis-4-((6-bromoquinazolin-4-yl)amino)cyclohexanecarboxylic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3548 - 3571

36
[ 38267-96-8 ]
[ 1776-53-0 ]
trans-4-[6-(1,3-thiazol-5-yl)-4-quinazolinyl]amino}cyclohexanecarboxylic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3548 - 3571

37
[ 38267-96-8 ]
[ 1776-53-0 ]
trans-4-[(6-bromo-4-quinazolinyl)amino]cyclohexanecarboxylic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3548 - 3571

38
[ 38267-96-8 ]
[ 1228947-14-5 ]
4-((1r,4r)-4-((6-bromoquinazolin-4-yl)oxy)cyclohexyl)morpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%		To a solution of trans-4-(morpholin-4-yl)cyclohexan-l-ol, compound 4.1 (364 mg, 1.96 mmol, 1.20 equiv) in distilled THF (10 mL) was added NaHDMS (2.45 mL, 3.00 equiv, 2 M in THF) dropwise via syringe at 0 C under nitrogen. Subsequently a solution of 6-bromo-4- chloroquinazoline (400 mg, 1.64 mmol, 1.00 equiv) in THF (5 mL) was added slowly at 0C and the reaction was stirred for 1 hour at this temperature. The reaction was then quenched with saturated aqueous NH4C1, extracted with 3 x 60 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. Crude was purified via flash column chromatography to furnish 357 mg (55%) of 4- ((lr,4r)-4-((6-bromoquinazolin-4-yl)oxy)cyclohexyl)morpholine, 1-4, as a white solid. LCMS (ES, m/z): 393 [M+H]+; 1H NMR (300 MHz, CD3OD) delta 8.75 (s, 1H), 8.30 (d, 1H), 8.02 (dd, 1H), 7.80 (d, 1H), 5.40-5.30 (m, 1H), 3.73 (t, 4H), 2.64 (t, 4H), 2.42-2.35 (m, 3H), 2.12 (d, 2H), 1.78- 1.60 (m, 2H), 1.58-1.49 (m, 2H).
	With sodium hydride; In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 18h;	Trans-4-morpholinocyclohexanol (0.134 g, 0.723 mmol) was dissolved in THF (10.95 ml) and added to a slurry of 6-bromo-4-chloroquinazoline (0.16 g, 0.657 mmol) in N,N- dimethylformamide (0.349 mL). The reaction was cooled to 0 C and sodium hydride (0.053 g, 1.31 mmol) was added to the reaction mixture at 0 C and the reaction was allowed to stir at rt for 18 h. The reaction was quenched with saturated aqeuous sodium bicarbonate and the aqueous layer was extracted with 25% IPA/CHCI3 (2x), dried over anhydrous sodium sulfate, filtered and purified by mass triggered reverse phase HPLC (ACN/water with 0.1% NH4OH modifier) to afford the title compound. MS: 392/394 (M + 1). 1H NMR (600 MHz, dmso) delta 8.78 (s, 1H), 8.21 (d, J= 2.2, 1H), 8.04 (dd, J= 2.3, 8.9, 1H), 7.82 (d, J= 8.9, 1H), 5.26 - 5.17 (m, 1H), 3.57 - 3.51 (m, 4H), 2.46 - 2.42 (m, 4H), 2.30 - 2.22 (m, 1H), 2.21 - 2.13 (m, 2H), 1.92 - 1.83 (m, 2H), 1.62 - 1.50 (m, 2H), 1.46 - 1.33 (m, 2H).

Reference： [1]Patent: WO2015/164374,2015,A1 .Location in patent: Paragraph 00280; 00281
[2]Patent: WO2016/53772,2016,A1 .Location in patent: Page/Page column 39

39
[ 38267-96-8 ]
(1r,4r)-4-(morpholin-4-yl)cyclohexan-1-amine dihydrochloride [ No CAS ]
6-bromo-N-[trans-4-(morpholin-4-yl)cyclohexyl]quinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With triethylamine; In acetonitrile; at 120℃; for 0.75h;Microwave irradiation;	Synthesis of compound 1-2. A 10 mL microwave vial containing 6-bromo-4- chloroquinazoline, compound 2.2 (122 mg, 0.50 mmol, 1.00 equiv), triethylamine (404 mg, 3.99 mmol, 7.97 equiv) and trans-4-(morpholin-4-yl)cyclohexan-l -amine dihydrochloride, 1.2 (129 mg, 0.50 mmol, 1.00 equiv) in CH3CN (5 mL) was irradiated in microwave for 45 min at 120C. Resulting solution was diluted with 100 mL of EtOAc, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. Crude was purified via flash column chromatography to furnish 143 mg (73%) of 6-bromo-N-((lr,4r)-4- morpholinocyclohexyl)quinazolin-4-amine, 1-2, as off- white solid. LCMS (ES, m/z): 391 and 393 [M+H]+; 1H-NMR (300 MHz, CD3OD) delta 8.46 (d, 1H), 8.44 (s, 1H), 7.88 (dd, 1H), 7.61 (d, 1H), 4.28-4.12 (m, 1H), 3.73 (t, 4H), 2.64 (t, 4H), 2.42-2.25 (m, 1H), 2.18 (d, 2H), 2.08 (d, 2H), 1.60-1.40 (m, 4H).
	With triethylamine; In N,N-dimethyl-formamide; at 23 - 90℃; for 16h;	6-Bromo-4-chloroquinazoline (53.4 g, 0.219 mol) and triethylamine (1 14.5 g, 1.132 mol) were added to a mixture of ?ras-4-morpholinocyclohexanamine dihydrochloride (46.0 g, 0.178 mol) in DMF (600 mL) at 23 C. The resulting mixture was heated to 90 C and stirred for 16 h, then was cooled to 23 C. After cooling, water was added and the mixture was stirred for 20 min. The solid was filtered and washed with water. The resulting filter cake was dried to afford the compound 6-bromo-N-((?ras)-4-morpholinocyclohexyl)quinazolin-4-amine as a solid.
	With triethylamine; In N,N-dimethyl-formamide; at 90℃; for 16h;Inert atmosphere;	To a solution of (trans)-4-morpholinocyclohexanamine bis-hydrochloride (50.00 g, 226.51 mmol) and <strong>[38267-96-8]6-bromo-4-chloroquinazoline</strong> (66.18 g, 271.81 mmol) in DMF (600 mL) was added a solution of TEA (137.52 g, 1.36 mol) drop-wise at rt under N2. The reaction mixture was heated to 90 C for 16 h, and then cooled to rt, poured into ice/water and filtered. The filtered cake washed with water and dried to give the title compound as a solid. MS: 391/393 (M+l). 1H NMR (600 MHz, cd3od) delta 8.43 (d, J= 2.1, 1H), 8.41 (s, 1H), 7.85 (dd, J= 2.1, 8.9, 1H), 7.57 (d, J= 8.9, 1H), 4.22 - 4.12 (m, 1H), 3.74 - 3.65 (m, 4H), 2.66 - 2.55 (m, 4H), 2.36 - 2.25 (m, 1H), 2.19 - 2.09 (m, 2H), 2.09 - 2.00 (m, 2H), 1.54 - 1.38 (m, 4H).

Reference： [1]Patent: WO2015/164374,2015,A1 .Location in patent: Paragraph 00274; 00276; 00277; 00278
[2]Patent: WO2016/53770,2016,A1 .Location in patent: Page/Page column 24
[3]Patent: WO2016/53772,2016,A1 .Location in patent: Page/Page column 40

40
[ 580-16-5 ]
[ 38267-96-8 ]
6-bromo-4-(quinolin-6-yloxy)quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	Stage #1: 6-hydroxyquinoline With caesium carbonate In 1,4-dioxane at 20℃; for 1h; Stage #2: 6-bromo-4-chloroquinozoline In 1,4-dioxane at 20℃;	23 4.1.23. 6-bromo-4-(quinolin-6-yloxy)quinazoline (11g) To a solution of 6-hydroxyquinoline (1.60 g, 0.011 mol) in 20 mL dioxane was added cesium carbonate (7.20 g, 0.022 mol). After stirring at room temperature for 1 h, compound 10 was added. The mixture was stirred at room temperature for a further overnight. The reaction mixture was poured into 200 mL H2O, and pH was adjusted to neutral using aqueous hydrochloric acid. The resulting precipitate was filtered and washed with water and dried overnight under high vacuum to give 11g as white solid (2.10 g, yield, 60%). 1H NMR (400 MHz, DMSO-d6) δ 8.96 (d, J = 2.8 Hz, 1H), 8.79 (s, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.41 (d, J = 8.0 Hz, 1H), 8.22 (dd, J = 2.0, 8.8 Hz, 1H), 8.16 (d, J = 9.2 Hz, 1H), 8.00 (d, J = 9.2 Hz, 2H), 7.82 (dd, J = 2.8, 9.2 Hz, 1H), 7.61 (dd, J = 4.0, 8.4 Hz, 1H). ESI-MS m/z: 354.8 [M+H]+.
60%	With CO₃^(2-)*H₄Se⁽²⁺⁾ In 1,4-dioxane at 20℃; for 1h;	8 Synthesis of 4- (quinoline-6-oxy) -6-bromo-quinazoline (IIB-2) In a 100mL single-necked flask,1.6 g (0.011 mol) of 6-hydroxyquinoline,7.2 g (0.022 mol) of Se2CO3,20 mL of dioxane,After stirring for 1 hour, 2.42 g (0.01 mol) of 4-chloro-6-bromo-quinazoline was added,After stirring at room temperature overnight,The reaction solution was poured into 200mL H2O,Adjusted to neutral with hydrochloric acid,filter,Water washing,dry,A white solid 2.1g,Yield 60%.

Reference： [1]Hou, Ju; Wan, Shanhe; Wang, Guangfa; Zhang, Tingting; Li, Zhonghuang; Tian, Yuanxin; Yu, Yonghuan; Wu, Xiaoyun; Zhang, Jiajie [European Journal of Medicinal Chemistry, 2016, vol. 118, p. 276 - 289]
[2]Current Patent Assignee: SOUTHERN MEDICAL UNIVERSITY CHINA - CN106565684, 2017, A Location in patent: Paragraph 0133; 0134; 0135; 0136

41
[ 38267-96-8 ]
[ 954257-36-4 ]
6-bromo-N-(1-(2,6-dichloro-3-fluorophenyl)ethyl)quinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With potassium carbonate; In 1,4-dioxane; at 20℃;	General procedure: To a solution of compound 10 (2.43 g, 0.01 mol) in 25 mL dioxane was added (3-methoxyphenyl)methanamine (2.06 g, 0.015 mol) and K2CO3 (2.76 g, 0.02 mol), the reaction mixture was stirred at room temperature overnight. After that, the mixture was poured into 150 mL, and then the resulting precipitate was filtered, washed with 50% ethanol, and dried overnight under vacuum to give 11a as white solid (2.33 g, yield, 68%).
71%	In 1,4-dioxane; at 20℃;	In a 100 mL single-necked flask equipped with a stirrer,3.12 g (0.015 mol) of 1- (2,6-dichloro-3-fluorophenyl) ethanamine was added,2.43 g (0.01 mol) of <strong>[38267-96-8]6-bromo-4-chloro-quinazoline</strong>,25 mL of 1,4-dioxane was added,After stirring at room temperature overnight,The reaction solution was poured into 150mLH2O,A solid precipitation,filter,Washed with 50% ethanol,A white solid 3.0g,Yield 71%.

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 118,p. 276 - 289
[2]Patent: CN106565684,2017,A .Location in patent: Paragraph 0107; 0108; 0109; 0110; 0111

42
[ 38267-96-8 ]
[ 756520-66-8 ]
6-bromo-4-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%		In a 100 mL single-necked flask,1- (3-fluoro-2,6-dichlorophenyl) ethanol 2.71g (0.013mol),15 mL of 1,4-dioxane,Ice bath in the cooling,Controlled at 1-5 C,1.2 g of sodium hydride (60% 0.03 mol) was added,About 15min,2.43 g (0.01 mol) of 4-chloro-6-bromo-quinazoline was added,After about 1 h at room temperature, the reaction solution was poured into 100 mL of H2O,With 10% hydrochloric acid transferred to neutral,filter,50% ethanol wash,3.3 g of a white solid,Yield 80%.
79%		To a solution of 1-(2,6-Dichloro-3-fluorophenyl)ethan-1-ol (2.71 g, 0.013 mol) in 15 mL dioxane. The resulting solution was cooled at 0 C and slowly added NaH (2.00 g, 0.03 mol, 60% dispersion in mineral oil) over 15 min. After complete addition, compound 10 was added. The mixture was stirred at 0 C for 1 h and then stirred at room temperature overnight. The reaction mixture was poured into 100 mL H2O, and the pH was adjusted to neutral with 10% aqueous hydrochloric acid. The resulting precipitate was filtered and washed with 50% ethanol, and dried overnight under high vacuum to give 11c as white solid (3.30 g, yield, 79%). 1H NMR (400 MHz, DMSO-d6) delta 8.73 (s, 1H), 8.36 (d, J = 2.0 Hz, 1H), 8.10 (dd, J = 2.0, 8.8 Hz, 1H), 7.86 (d, J = 9.2 Hz, 1H), 7.54 (dd, J = 5.0, 9.2 Hz, 1H), 7.43 (t, J = 8.8 Hz, 1H), 6.90 (q, J = 6.8 Hz, 1H), 1.86 (d, J = 6.8 Hz, 3H). ESI-MS m/z: 417.6 [M+H]+.

Reference： [1]Patent: CN106565684,2017,A .Location in patent: Paragraph 0112; 0113; 0114; 0115
[2]European Journal of Medicinal Chemistry,2016,vol. 118,p. 276 - 289

43
[ 22353-34-0 ]
[ 38267-96-8 ]
6-bromo-N-(5-chloropyridin-3-yl)quinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In isopropyl alcohol; at 80℃;Inert atmosphere;	To a solution consisting of 6-bromo-4-chloroquinazoline (0.448 g, 1.84 mmol) in 2- propanol (10 mL) was added <strong>[22353-34-0]3-amino-5-chloropyridine</strong> (0.248 g, 1.93 mmol). The reaction mixture was heated (80 C) and stirred overnight under a flow of N2. The reaction mixture was cooled to room temperature and then the reaction mixture was filtered over a fritted funnel. Thefiltered solid was rinsed with excess 2-propanol and dried under high vacuum to afford 6-bromo- N-(5-chloropyridin-3-yl)quinazolin-4-amine (3C) as an off-white solid (575 mg, 93% yield, 93% purity). MS (ESI + m/z 336.9, ESI - m/z 334.9). A solution consisting of 6-bromo-N-(5- chloropyridin-3-yl)quinazolin-4-amine (0.136 g, 0.405 mmol) in anhydrous ethanol (3 mL) was placed in a 5 mL microwave reaction vial containing a stir bar. Next, 5-(methylsulfonamido)pyridine-3-yl boronic acid pinacol ester (4, 0.127 g, 0.425 mmol) was added followed by SiliCat DPP-Pd (5 mol %, 0.26mmol/g loading, 0.082 g) and 10% aqueous potassium carbonate solution (2 equivalents, 0.59 mL, 0.81 mmol). The reaction mixture was placed under N2 atmosphere, capped, and then heated at 100 C for 30 minutes in a Biotage Emrys Optimizer microwave. The reaction mixture was allowed to cool to room temperatureand then filtered over a fritted funnel to collect SiliCat DPP-Pd. The filtered solid was rinsed with excess ethanol and the filtrate was concentrated under reduced pressure to afford the crude product. Purification of the crude product by Biotage Isolera flash chromatography using a gradient of 4-100% ethyl acetate in heptane, followed by 0-10% methanol in dichloromethane afforded N-(5 -(4-((5 -chloropyridin-3 -yl)amino)quinazolin-6-yl)pyridin-3-yl)methanesulfonamide (SC, MOL-163, 70 mg, 40% yield, 98% purity) as a white solid; ?HNMR (400MHz, DMSO-d6) oe 10.21 (br. s., 2H), 8.94-9.03 (m, 1H), 8.86-8.88 (d, J=4.65 Hz,2H), 8.73 (s, 1H), 8.59 (s, 1H), 8.50 (d, J=2.01 Hz, 1H), 8.32-8.44 (m, 1H), 8.20 (d, J=8.97 Hz,1H), 7.90-8.04 (m, 2H), 3.15 (s, 3H); MS: (ESI + m/z 427.0, ESI - m/z 425.0); TLC: (90:10:0.5,DCM:MeOH:NH4OH) Rf= 0.47.

Reference： [1]Patent: WO2016/100347,2016,A2 .Location in patent: Page/Page column 68

44
[ 38267-96-8 ]
[ 110598-30-6 ]
6-bromo-N-(3-((trimethylsilyl)ethynyl)phenyl)quinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	In 1,4-dioxane; at 90℃; for 3h;	To a solution consisting of 6-bromo-4-chloroquinazoline (1.2 g, 4.9 mmol) and <strong>[110598-30-6]3-((trimethylsilyl)ethynyl)aniline</strong> (1.1 g, 5.9 mmol, prepared as describe by Ute F. Rohrig, JMC,2012, 55(11), 5270-5290) in 30 mL of 1,4-dioxane was heated at 90 C for 3 hour. The reactionmixture was cooled to room temperature, diluted with diethyl ether and filtered through fritted glass. The solid was triturated under 20 mL of isopropyl alcohol, filtered and dried to give 6- bromo-N-(3-((trimethylsilyl)ethynyl)phenyl)quinazolin-4-amine (3E) as a solid (940 mg, 48%); ?H NMR (400MHz, DMSO-d6) oe 11.8 (br s, 1H), 9.29 (d, J=1.7 Hz, 1H), 9.00 (s, 1H), 8.26 (dd, J=1.7, 8.8 Hz, 1H), 7.95 (d, J=8.9 Hz, 1H), 7.89 (s, 1H), 7.81 (d, J=8.1 Hz,1H), 7.51 (t, J7.9 Hz, 1H), 7.41 (d, J=7.7 Hz, 1H), 0.25 (s, 9H). A solution consisting of 6-bromo-N-(3- ((trimethylsilyl)ethynyl)phenyl)quinazolin-4-amine (0.250 g, 0.63 1 mmol) in anhydrous ethanol(4 mL) was placed in a S mL microwave reaction vial containing a stir bar. Next, 5- (methylsulfonamido)pyridine-3-yl boronic acid pinacol ester (4, 0.200 g, 0.662 mmol) was added followed by SiliCat DPP-Pd (5 mol %, 0.26mmol/g loading, 0.126 g) and 10% aqueous potassium carbonate solution (2 equivalents, 0.9lmL, 1.26 mmol). The reaction mixture was placed under N2 atmosphere, capped, and then heated at 100 C for 5 minutes in a BiotageEmrys Optimizer microwave. The reaction mixture was allowed to cool to room temperature and then filtered over a fritted funnel to collect SiliCat DPP-Pd. The filtered solid was rinsed with excess ethanol and the filtrate was concentrated under reduced pressure to afford the crude product. Purification of the crude product by Biotage Isolera flash chromatography using a gradient of 5-65% ethyl acetate in heptane, followed by 0-10% methanol in dichloromethaneafforded a mixture of SE with TMS-protected SE. This mixture was dissolved in methanol and then treated with excess 10% potassium carbonate (1 mL). The solution was heated to 35 C and the TMS removal was followed by TLC (90:10:0.5, DCM:MeOH:NH4OH). After the reaction was complete, the solution was acidified (iN HC1) to pH 5 and then extracted three times with DCM:MeOH (90:10 mixture, 75 mL). The organic layer was concentrated under reducedpressure to afford the cmde product. Purification of the deprotected crude product by BiotageIsolera flash chromatography using a gradient of 1-13% methanol in dichloromethane affordedN-(S -(4-((3 -ethynylphenyl)amino)quinazolin-6-yl)pyridin-3 -yl)methanesulfonamide (SE, MOL161, 68 mg, 26% yield, 97.5% purity) as a yellow solid. ?H NMR (400MHz, DMSO-d6) oe 10.16(br. s., 1H), 9.97 (s, 1H), 8.75-8.94 (m, 2H), 8.66 (s, 1H), 8.48 (d, J2.38Hz, 1H), 8.16 (dd,J=1.65, 8.60 Hz, 1H), 8.04 (s, 1H), 7.85-7.98 (m, 4H), 7.42 (t, J7.87 Hz, 1H), 7.42 (d, J7.69Hz, 1H), 4.21 (s, 1H), 3.13 (s, 3H); MS: (ESIm/z 416.1, ESIm/z 414.0); TLC: (90:10:0.5, DCM:MeOH:NH4OH) Rf= 0.6.

Reference： [1]Patent: WO2016/100347,2016,A2 .Location in patent: Page/Page column 69; 70

45
[ 38267-96-8 ]
[ 102877-78-1 ]
6-bromo-N-(4-(pyridin-4-yloxy)phenyl)quinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	In isopropyl alcohol; at 80℃;Inert atmosphere;	To a solution consisting of 6-bromo-4-chloroquinazoline (0.448 g, 1.84 mmol) in 2- propanol (10 mL) was added <strong>[102877-78-1]4-(pyridine-4-yloxy)aniline</strong> (0.360 g, 1.93 mmol). The reaction mixture was heated (80 C) and stirred overnight under a flow of N2. The reaction mixture was cooled to room temperature and then the reaction mixture was filtered over a fritted funnel. The filtered solid was rinsed with excess 2-propanol and dried under high vacuum to afford 6-bromo-N-(4-(pyridin-4-yloxy)phenyl)quinazolin-4-amine (3F) as an off-white solid (313 mg, 43% yield,97% purity). MS (ESI + m/z 394.0, ESI - m/z 392.0). Next a solution consisting of 6-bromo-N- (4-(pyridin-4-yloxy)phenyl)quinazolin-4-amine (0.306 g, 0.77 mmol) in anhydrous ethanol (10 mL) was placed in a 20 mL microwave reaction vial containing a stir bar. Next, 3- aminopyridine-5- boronic acid pinacol ester (6, 0.176 g, 0.80 mmol) was added followed bySiliCatDPP-Pd (5 mol %, 0.26mmol/g loading, 0.150 g) and 10% aqueous potassium carbonate solution (2 equivalents, 1.15 mL, 1.6 mmol). The reaction mixture was placed under N2 atmosphere, capped, and then heated at 125 C for one horn in a Biotage Emrys Optimizer microwave. The reaction mixture was allowed to cool to room temperature and then filtered over a fritted funnel to collect SiliCat DPP-Pd. The filtered solid was rinsed with excess ethanoland the filtrate was concentrated under reduced pressure to afford the crude product.Purification of the crude product by Biotage Isolera flash chromatography using a gradient of 4-100% ethyl acetate in heptane, followed by 0-10% methanol in dichloromethane afforded 7F 6-(5-aminopyridin-3-yl)-N-(4-(pyridin-4-yloxy)phenyl)quinazolin-4-amine (50 mg, 15% yield,92% purity) as an off-white solid. MS (ESI + m/z 407.1, ESI m/z 405.1). To a roomtemperature solution of 6-(5 -aminopyridin-3 -yl)-N-(4-(pyridin-4-yloxy)phenyl)quinazolin-4- amine (50 mg, 0.12 mmol) in pyridine (3 mL) was added methanesulfonyl chloride (56 mg, 0.5 mmol). The reaction mixture turned dark red which persisted and was stirred for 15 minutes. The reaction mixture was poured into a saturated solution of sodium bicarbonate and the organic material was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The cmde solid was dissolved in methanol and ?dry loaded? on to a silica column eluted with a gradient of 1/9 to 3/7methanol/ethyl acetate to give N-(5-(4-((4-(pyridin-4-yloxy)phenyl)amino)quinazolin-6- yl)pyridin-3-yl)methanesulfonamide (5F, MOL-166, 20 mg, 33% yield, 96% purity) as a solid. ?H NMR (400MHz, DMSO-d6) oe 10.07 (s, 1H), 8.91 (s, 1H), 8.79 (d, J=1.9 Hz, 1H), 8.62 (s, 1H), 8.4-8.5 (m, 3H), 8.15 (dd,J=1.7, 8.6 Hz, 1H), 7.85-8.0(m, 4H), 7.24 (d,J8.9Hz, 2H),6.94 (d, J=4.7 Hz, 2H), 3.08 (s, 3H); MS: (ESI + m/z 485.1, ESI- m/z 483.0).

Reference： [1]Patent: WO2016/100347,2016,A2 .Location in patent: Page/Page column 71; 72

46
[ 38267-96-8 ]
[ 524955-09-7 ]
6-bromo-N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)quinazolin-4-amine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In 1,4-dioxane; at 80℃;	A mixture consisting of 6-bromo-4-chloroquinazoline (1.0 g, 4.1 mmol) and 3-chloro-4-(pyridin-2-ylmethoxy)aniline (1.15 g, 4.9 mmol) in 40 mL of 1,4-dioxane was heated at 80 C overnight.The reaction mixture was cooled to room temperature, diluted with 20 mL of diethyl ether and filtered. The solids were dried in high vacuum to give 1.98 g (100%, purity 90%) of the title compound; MS (ES-API+) m/z 441.0 (M+1) 443.0 (Cl/Br isotope), (ES-API-) m/z 439.0 (M-1) 441.0 (Cl/Br isotope); ?H NMR (400 MI-Iz, DMSO-d6) oe 11.49 (br s, 1H), 9.15 (d, J1.92 Hz, 1H), 8.91 (s, 1H), 8.61 (d, J=5.03 Hz, 1H), 8.20 (dd, J=2.01, 8.87 Hz, 1H), 7.90-7.96 (m, 2H),7.87 (d, J=8.97 Hz, 1H), 7.59-7.69 (m, 2H), 7.41 (dd, J4.99, 6.54 Hz, 1H), 7.34 (d, J=9.06 Hz,1H), 5.34 (s, 2H).

Reference： [1]Patent: WO2016/100347,2016,A2 .Location in patent: Page/Page column 90

47
[ 38267-96-8 ]
[ 147081-44-5 ]
(S)-tert-butyl 3-((6-bromoquinazolin-4-yl)amino)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 5h;	S)-4-(1-tert-butoxycarbonyl-pyrrolidin-3-yl) amino-6- [...] (intermediate 14-c) weighing 4-chloro-6-bromo-quinoline (1-a, 244 mg, 1mmol) and (S)-1-Boc pyrrolidine-3-amine (14-b, 279 mg, 1mmol) in DMF (10 ml), add DIPEA (516 mg, 4mmol), the temperature is increased to 90 C reaction for 5h, cooling, ice water into 50 ml, stirring, solids are separated out, filtering, drying, to obtain white solid 14-c (308 mg, 78%).
78%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 90℃; for 5h;Inert atmosphere;	To a mixture of <strong>[38267-96-8]6-bromo-4-chloroquinazoline</strong> (8, 244?mg, 1?mmol) and (S)-1-boc-pyrrolidin-3-amine (279?mg, 1?mmol) in DMF (10?mL), was added DIPEA (516?mg, 4?mmol). The mixture was degassed with N2 atmosphere and stirred at 90?C for 5?h. After completed, the reaction mixture was naturally cooled to room temperature, and poured into ice water (50?mL) under vigorously stirring. The mixture was filtered and the solid was collected to give intermediate 9 (308?mg, 78%) as a white solid. 1H NMR (400?M, CDCl3) delta 8.70 (s, 1H, ArH), 7.97 (s, 1H, ArH), 7.84 (d, 1H, J?=?8.9?Hz, ArH), 7.76 (d, 1H, J?=?8.9?Hz, ArH), 6.07-5.95 (m, 1H, NH), 4.97-4.85 (m, 1H, CH), 3.80-3.90 (m, 1H, CH2), 3.68-3.40 (m, 3H, CH2), 2.43-2.30 (m, 1H, CH2), 2.20-2.00 (m, 1H, CH2), 1.49 (s, 9H, 3?*?CH3) ppm. MS (ESI) m/z: [M+H]+?=?393.1, 395.1.
78%	In isopropyl alcohol; for 1h;Reflux;	General procedure: A mixture of <strong>[38267-96-8]6-bromo-4-chloroquinazoline</strong> (2.00 g, 8.20 mmol), 2-morpholinoethan-1-amine (1.28 g, 9.83 mmol) and isopropanol (20 mL)was refluxed for 1 h and then cooled to room temperature. The resultantprecipitate was collected, and then the solid was dried in an infrareddrying oven to afford 15a as white solid in 72% yield.

72.1%

In isopropyl alcohol; for 8h;Reflux; Inert atmosphere;

4-Chloro-6-bromoquinazoline (1-c, 1.00 g, 4.10 mmol) was weighed into isopropanol (15 mL).(S)-1-Bocpyrrolidin-3-amine (0.92 g, 4.92 mmol),The temperature was raised to reflux reaction for 8 h under nitrogen protection.After cooling to room temperature and filtration, a white solid 5-b (1.16 g, 72.1%) was obtained.

Reference： [1]Patent: CN105237484,2016,A .Location in patent: Paragraph 0136; 0137; 0138
[2]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 2028 - 2040
[3]Bioorganic and Medicinal Chemistry,2019,vol. 27
[4]Patent: CN108373462,2018,A .Location in patent: Paragraph 0070; 0072-0073

48
[ 38267-96-8 ]
[ 55121-99-8 ]
2-methoxy-5-(4-((4-(4-methylpiperazine-1-carbonyl)phenyl)amino)-quinazolin-6-yl)benzamide [ No CAS ]

Reference： [1]Patent: CN105237484,2016,A

49
[ 38267-96-8 ]
[ 55121-99-8 ]
(4-((6-bromoquinazolin-4-yl)amino)phenyl)(4-methylpiperazin-1-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	In isopropyl alcohol; for 5h;Reflux; Inert atmosphere;	4-(4-(4-methyl piperazine-1-carbonyl) phenyl) amino-6- [...] (intermediate 1-c) weighing 4-chloro-6- [...] (1-a, 0 . 16g, 0.58mmol) in isopropanol (5 ml), add 4-(4-methyl piperazine-1-carbonyl) aniline (0.14g, 0 . 64mmol), to reflux temperature under nitrogen for 5h, cooling to room temperature, filter, the white solid obtained 1-c (0.18g, 73%).
73%	In isopropyl alcohol; for 4h;Reflux; Inert atmosphere;	General procedure: To a solution of9(0.16g,0.58mmol) ini-PrOH(5mL),substituted phenylamine(0.64mmol)wasadded. The reaction mixture was stirred at reflux for4h under N2atmosphere. After the reaction was completed, the mixture wasnaturally cooled to room temperature.Themixture was filtered and the solid was collectedto giveintermediate12or15. 1.2.1 (4-((6-Bromoquinazolin-4-yl)amino)phenyl)(4-methylpiperazin-1-yl)methanone (12a)Yellow solid; yield:73 %.MS (ESI)m/z: [M+H]+=426.1/428.1.

Reference： [1]Patent: CN105237484,2016,A .Location in patent: Paragraph 0092; 0093; 0094
[2]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1972 - 1977

50
[ 38267-96-8 ]
[ 147081-49-0 ]
(R)-tert-butyl 3-((6-bromoquinazolin-4-yl)amino)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 5h;	R)-4-(1-tert-butoxy-carbonyl pyrrolidine-3-yl) amino-6- [...] (intermediate 29-c) weighing 4-chloro-6-bromo-quinoline (1-a, 2 . 88g, 12mmol) and (R)-1-Boc pyrrolidine-3-amine (29-b, 2 . 2g, 12mmol) dissolved in DMF (40 ml), add DIPEA (6.1g, 47mmol), the temperature is increased to 90 C reaction 5h, cooling, ice water into 50 ml, stirring, solids are separated out, filtering, drying, to obtain white solid 29-c (3.58g, 74%).
74%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 90℃; for 5h;Inert atmosphere;	General procedure: To a mixture of <strong>[38267-96-8]6-bromo-4-chloroquinazoline</strong> (8, 244 mg, 1mmol) and (S)-1-boc-pyrrolidin-3-amine (279 mg, 1 mmol) inDMF (10 mL), was added DIPEA (516 mg, 4 mmol). The mixturewas degassed with N2 atmosphere and stirred at 90 C for 5 h. Aftercompleted, the reaction mixture was naturally cooled to roomtemperature, and poured into ice water (50 mL) under vigorouslystirring. The mixture was filtered and the solid was collected togive intermediate 9 (308 mg, 78%)

Reference： [1]Patent: CN105237484,2016,A .Location in patent: Paragraph 0182; 0183; 0184
[2]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 2028 - 2040

51
[ 38267-96-8 ]
[ 51207-86-4 ]
4-(4-((morpholin-4-yl)carbonyl)phenylamino)-6-bromo-quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	In isopropyl alcohol; for 4h;Reflux; Inert atmosphere;	General procedure: To a solution of9(0.16g,0.58mmol) ini-PrOH(5mL),substituted phenylamine(0.64mmol)wasadded. The reaction mixture was stirred at reflux for4h under N2atmosphere. After the reaction was completed, the mixture wasnaturally cooled to room temperature.Themixture was filtered and the solid was collectedto giveintermediate12or15.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1972 - 1977

52
[ 38267-96-8 ]
[ 4152-90-3 ]
6-bromo-N-(3-chlorobenzyl)quinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With triethylamine; In tetrahydrofuran; at 18 - 25℃; for 3h;	To a mixture of 6-bromo-4-chloroquinazoline (243 mg, 1.0 mmol) and (3- chlorophenyl)methanamine (142 mg, 1.0 mmol) in THF (2 ml) was added Et3N (0.21 ml, 1.5 mmol). The mixture was stirred at RT for 3 h. The mixture was poured into EtOAc/H20 (5 mLI5 mL). The aqueous layer was extracted with EtOAc (3 mL x 2). The combined organic layer wasdried (Na2504) and filtered. After removal of solvent, the product was triturated with hexane and dried to give 6-bromo-N-(3-chlorobenzyl)quinazolin-4-amine (342 mg, 0.98 mmol, 98 percent yield) as a white solid. MS (M+H)= 350.

Reference： [1]Patent: WO2017/91661,2017,A1 .Location in patent: Page/Page column 81; 153

53
[ 582-33-2 ]
[ 38267-96-8 ]
ethyl 3-((6-bromoquinazolin-4-yl)amino)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.7%	In isopropyl alcohol at 90℃; for 4h;	4.1.7. 6-bromo-N-(3-fluorophenyl)quinazolin-4-amine (5a) General procedure: A solution of the 4 (0.48 g, 2 mmol), 3-fluoroaniline (0.24g,2.2 mmol) in isopropanol (30 ml) were stirred at 90 C for 4 h.Isopropanol was removed under reduced pressure and the residuewas purified through a column chromatography on silica withchloroform/methanol (V:V 50:1) as a white solid (0.58 g, 91.8%yield).

Reference： [1]Ding, Huai-Wei; Deng, Cheng-Long; Li, Dan-Dan; Liu, Dan-Dan; Chai, Shao-Meng; Wang, Wei; Zhang, Yan; Chen, Kai; Li, Xin; Wang, Jian; Song, Shao-Jiang; Song, Hong-Rui [European Journal of Medicinal Chemistry, 2018, vol. 146, p. 460 - 470]

54
[ 38267-96-8 ]
[ 56741-34-5 ]
methyl 2‐fluoro‐5‐[6‐(5‐methanesulfonamido‐6‐methoxypyridin‐3‐yl)quinazolin‐4‐yl]amino}benzoate [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 146,p. 460 - 470

55
[ 38267-96-8 ]
[ 56741-34-5 ]
methyl 5-((6-bromoquinazolin-4-yl)amino)-2-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81.6%	In isopropyl alcohol; at 90℃; for 4h;	General procedure: A solution of the 4 (0.48 g, 2 mmol), 3-fluoroaniline (0.24g,2.2 mmol) in isopropanol (30 ml) were stirred at 90 C for 4 h.Isopropanol was removed under reduced pressure and the residuewas purified through a column chromatography on silica withchloroform/methanol (V:V 50:1) as a white solid (0.58 g, 91.8%yield).

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 146,p. 460 - 470

56
[ 38267-96-8 ]
[ 42122-75-8 ]
methyl 2‐chloro‐5‐[6‐(5‐methanesulfonamido‐6‐methoxypyridin‐3‐yl)quinazolin‐4‐yl]amino}benzoate [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 146,p. 460 - 470

57
[ 38267-96-8 ]
[ 42122-75-8 ]
methyl 5-((6-bromoquinazolin-4-yl)amino)-2-chlorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84.3%	In isopropyl alcohol; at 90℃; for 4h;	General procedure: A solution of the 4 (0.48 g, 2 mmol), 3-fluoroaniline (0.24g,2.2 mmol) in isopropanol (30 ml) were stirred at 90 C for 4 h.Isopropanol was removed under reduced pressure and the residuewas purified through a column chromatography on silica withchloroform/methanol (V:V 50:1) as a white solid (0.58 g, 91.8%yield).

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 146,p. 460 - 470

58
[ 38267-96-8 ]
[ 625471-18-3 ]
(S)-tert-butyl 3-((6-bromoquinazolin-4-yl)amino)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 85℃; for 2.5h;	To a solution of (S)-1-Boc-3-aminopiperidine (6.20g, 30.99mmol) in isopropanol (20mL), was slowly added 6-bromo-4-chloroquinazoline (5.00g, 20.66mmol) and DIPEA (5.33g, 41.32mmol). The mixture was stirred at 85C for 2.5h, and cooled to room temperature. After the saturated NaCl solution was added, the reaction mixture was extracted by EtOAc. Dried over anhydrous Na2SO4, the liquid was concentrated and purified by silica gel chromatography (CH2Cl2/CH3OH, 100:1) to produce compound 11 (7.15g, 85%) as a yellow solid. 1H NMR (400MHz, CDCl3) delta 8.66 (s, 1H, ArH), 7.98 (s, 1H, ArH), 7.89-7.79 (m, 2H, ArH), 6.98 (s, 1H, NH), 4.41-4.39 (m, 1H, CH), 3.82-3.32 (m, 4H, 2×CH2), 2.45-2.28 (m, 2H, CH2), 1.98-1.75 (m, 2H, CH2), 1.48 (s, 9H, 3×CH3) ppm. MS (ESI) m/z: [M+H]+=406.9, 408.9.

Reference： [1]Journal of Enzyme Inhibition and Medicinal Chemistry,2018,vol. 33,p. 651 - 656
[2]Bioorganic and Medicinal Chemistry,2019,vol. 27

59
[ 38267-96-8 ]
[ 747413-21-4 ]
6-bromo-4-(4-(4-methylpiperazin-1-yl)phenyl)quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; at 110℃;Inert atmosphere;	Under an argon atmosphere, 6-bromo-4-chloroquinazoline (886 mg, 3.63 mmol),1-methyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-Dioxaborolan-2-yl) phenyl) piperazine(Intermediate 26, 1.0 g, 3.31 mmol) inTetrakis (triphenylphosphine) palladium (382 mg, 0.33 mmol) was added to a solution of 1,4-dioxane (50 mL) and water (5 mL)Sodium carbonate (1.23 g, 11.6 mmol) was added and the mixture was stirred at 110 C. overnight. Saturated multilayer water was added to the reaction solution, and chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off.The resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (628 mg, 56%).Yellow solid.

Reference： [1]Patent: JP6378918,2018,B2 .Location in patent: Paragraph 0203; 0204; 0205; 0206

60
[ 38267-96-8 ]
[ 948571-47-9 ]
2-(4-((6-bromoquinazolin-4-yl)amino)-1H-pyrazol-1-yl)ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	In isopropyl alcohol; at 100℃; for 4h;	In a 50 mL round bottom flask, (2-hydroxyethyl)-1H-pyrazole_4_ammonia 0.26 g (2 mmol), 4_chloro-6-bromoquinozoline 0.48 g (2 mmol), isopropanol 20 ml, stirred at 100 C for 4 hours, cooled, a white solid formed, suction filtered and dried to give 4-((1-(2-hydroxyethyl)-1H-pyrazole. -4-yl)amino)quinazoline 0.55 g, yield 83%.
0.43 g	In isopropyl alcohol; at 90℃; for 4h;	General procedure: 2a (0.32 g, 0.002 mol) was dissolved in 20 ml ethanol in a roundbottomedflask and Pd/C (10%, 0.1 g) was added which reacted at 60 Cfor 12 h under hydrogen atmosphere. The Pd/C was recycled by filtrationand the ethanol was recycled by evaporation to give the amineas purple oil which was retained in the round-bottomed flask. Theamine was used for next reaction without purification, because it was easily oxidized. Then, added 6-bromo-4-chloroquinazoline (0.36 g,0.0015 mol) and isopropanol (30 ml) to the round-bottomed flask aboveand stirred at 90 C for 4 h. The isopropanol was removed under reduced pressure and the residue was purified through a column chromatographyon silica with chloroform/methanol (V:V 10:1) as a white solid (0.43 g, 86.0% yield). mp 178-180 C. 1H NMR (600 MHz,DMSO-d6) delta 12.11 (d, J=18.3 Hz, 1H, NH), 9.28 (d, J=5.8 Hz, 1H,Ar-H), 8.97 (d, J=4.9 Hz, 1H, Ar-H), 8.39 (d, J=4.1 Hz, 1H, Ar-H),8.18 (s, 1H, Ar-H), 8.04 (d, J=3.9 Hz, 1H, Ar-H), 7.91 (s, 1H, Ar-H),4.22 (s, 2H, CH2), 3.77 (s, 2H, CH2). 13C NMR (150 MHz, DMSO-d6) delta155.75, 152.06, 138.50, 132.79, 127.36, 124.55, 120.97, 120.48,115.72, 60.51, 54.97. ESI-MS: m/z 334.0 [M+H]+.

Reference： [1]Patent: CN108929309,2018,A .Location in patent: Paragraph 0063; 0069-0071
[2]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 2729 - 2740

61
[ 38267-96-8 ]
[ 98-02-2 ]
C₁₃H₉BrN₂OS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76.9%	With triethylamine; In isopropyl alcohol; at 80℃; for 1h;	5-chloroquinazoline (5 mmol) was added to a 50 mL round bottom flask, and 20 mL of dry isopropanol was added to stir and dissolve. Then 1.5 equivalents of triethylamine and 1.2 equivalents of 2-furanmethylamine were added, and the reaction was stopped after reacting at 80 C for 1 h. , desolvation, column chromatography (eluent PE: EA = 15:1) gave a white solid.

Reference： [1]Patent: CN109721554,2019,A .Location in patent: Paragraph 0063; 0064; 0067-0071
[2]Journal of Agricultural and Food Chemistry,2019,vol. 67,p. 11005 - 11017

62
[ 38267-96-8 ]
[ 29968-78-3 ]
6-bromo-N-(4-nitrophenethyl)quinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With triethylamine; In isopropyl alcohol; at 20℃; for 15h;	6-Bromo-4-chloroquinazoline (200.0 mg, 0.82 mmol) and 2-(4-nitrophenethyl)ethan-1-amine hydrochloride (182.0 mg, 0.90 mmol) were dissolved in iPrOH (4.0 mL), and Et3N (170.0 muL, 1.23 mmol) was added thereto at room temperature. The reaction mixture was stirred at 20C for 15 hours and distilled under reduced pressure. The residue was extracted with CH2Cl2. The organic layer was washed with brine, dried with Na2SO4, filtered and distilled under reduced pressure. After addition of CH2Cl2and water, the residue was stirred. The obtained solid was filtered and dried to obtain the ivory solid compound, 6-bromo-N-(4-nitrophenethyl)quinazolin-4-amine (210.0 mg, 69%).[616][617]LC/MS ESI (+): 373 (M+1)

Reference： [1]Patent: WO2019/231271,2019,A1 .Location in patent: Paragraph 614-617

63
[ 38267-96-8 ]
[ 29968-78-3 ]
6-(2,4-dichlorophenyl)-N-(4-nitrophenethyl)quinazolin-4-amine [ No CAS ]

Reference： [1]Patent: WO2019/231271,2019,A1

64
[ 38267-96-8 ]
[ 591-27-5 ]
3-((6-bromoquinazolin-4-yl)oxy)aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.3%	With potassium carbonate; In acetonitrile; at 20 - 85℃; for 2.5h;	m-aminophenol 8 (0.38 g, 3.49 mmol) and potassium carbonate (0.96 g, 6.98 mmol) were added to 20 ml of acetonitrile and stirred at room temperature for 30 minutes.Subsequently, <strong>[38267-96-8]6-bromo-4-chloroquinazoline</strong> 3 (0.85 g, 3.49 mmol) was added, and the reaction was heated at 85 C for 2 hours. Distill off the acetonitrile under reduced pressure, add water, extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.04 g of a yellow solid with a yield of 94.30%.

Reference： [1]Patent: CN110357852,2019,A .Location in patent: Paragraph 0103-0105

65
[ 38267-96-8 ]
[ 21419-48-7 ]

Yield	Reaction Conditions	Operation in experiment
88.6%	With ammonium hydroxide; In tetrahydrofuran; at 40℃; for 5.0h;	Add 6-bromo-4-chloroquinazoline (1 g, 5.02 mmol) to a 50 mL round bottom flask,After adding 15mL of tetrahydrofuran to stir and dissolve, add ammonia water (1.7mL, 100mmol) to the system, increase the temperature to 40 C and reflux for 5h. The reaction was monitored by TLC.The reaction was stopped and a solid precipitated in the system. Cool to room temperature, suction filter, wash with water,After drying, 0.8 g of a pale yellow solid was obtained with a yield of 88.6%.

Reference： [1]Patent: CN110627731,2019,A .Location in patent: Paragraph 0072; 0073

66
[ 400899-99-2 ]
[ 38267-96-8 ]
tert-butyl N-[4-(6-bromoquinazolin-4-yl)oxycyclohexyl]-N-(methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium <i>tert</i>-butylate In tetrahydrofuran at 50℃; for 0.5h; Inert atmosphere;	1 Step 1 - Tert-butyl N-[4-(6-bromoquinazolin-4-yl)oxycyclohexyl]-N-methyl- carbamate To a solution of 6-bromo-4-chloro-quinazoline (1.00 g, 4.11 mmol, CAS 38267- 96-8) and tert-butyl N-(4-hydroxycyclohexyl)-N-methyl-carbamate (965 mg, 4.21 mmol, CAS 400899-99-2) in THF (20 mL) was added t-BuOK (1 M in THF, 4.21 mL). The mixture was stirred at 50 °C for 30 minutes. On completion, the mixture was concentrated in vacuo. The residue was diluted with water (50 mL), then extracted with EA (3 X 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (1.50 g, 80% yield) as yellow solid.1H NMR (400 MHz, CDCl3) d 8.79 (s, 1H), 8.32 (d, J = 2.0 Hz, 1H), 7.94 - 7.89 (m, 1H), 7.84 - 7.79 (m, 1H), 5.35 - 5.23 (m, 1H), 2.79 (s, 3H), 2.73 (s, 1H), 2.34 (m, 2H), 1.91 - 1.83 (m, 2H), 1.73 (d, J = 4.0 Hz, 4H), 1.51 (s, 9H), 1.48 (s, 1H).

Reference： [1]Current Patent Assignee: KYMERA THERAPEUTICS INC - WO2020/113233, 2020, A1 Location in patent: Paragraph 00962; 003345-003347

67
[ 400899-99-2 ]
[ 38267-96-8 ]
tert-butyl N-[4-(6-cyanoquinazolin-4-yl)oxycyclohexyl]-N-(methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0.5 h / 50 °C / Inert atmosphere 2: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 1,1'-bis-(diphenylphosphino)ferrocene / N,N-dimethyl-formamide / 16 h / 100 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: KYMERA THERAPEUTICS INC - WO2020/113233, 2020, A1

68
[ 38267-96-8 ]
[ 62257-16-3 ]
3-[(6-bromoquinazolin-4-yl)amino]-4-fluorophenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	In ethanol; for 12h;Reflux;	General procedure: 6-Bromo-4-chloroquinazoline (10, ~5.0 g, 1.0 equiv) and the corresponding3-aminophenol (1.5 equiv) were mixed in EtOH (25 mL).The reaction mixture was heated under reflux for 12 h. The solution wascooled to room temperature and the resulting precipitate was collectedby filtration. The solids were washed with EtOH (20 mL) and air-dried to give the targets 11 and 13a-d as solids in 75-98% yields.

Reference： [1]Bioorganic Chemistry,2021,vol. 109

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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. 38267-96-8 ]

Quality Control of [ 38267-96-8 ]

Related Doc. of [ 38267-96-8 ]

Product Details of [ 38267-96-8 ]

Calculated chemistry of [ 38267-96-8 ]

Physicochemical Properties

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Lipophilicity

Druglikeness

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Medicinal Chemistry

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Application In Synthesis of [ 38267-96-8 ]

[ 38267-96-8 ] Synthesis Path-Upstream 1~6

[ 38267-96-8 ] Synthesis Path-Downstream 1~68

Related Functional Groups of [ 38267-96-8 ]

Bromides

Chlorides

Related Parent Nucleus of [ 38267-96-8 ]

Quinazolines

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[ 38267-96-8 ]

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[ 38267-96-8 ]