Name: 231278-20-9|N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-iodoquinazolin-4-amine|98%
Brand: Ambeed
SKU: A114247
Price: 5.0 USD
Availability: InStock
Rating: 90 (30 reviews)

1
[ 98-01-1 ]
[ 231278-20-9 ]
[ 231278-84-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: furfural With n-butyllithium; N,O-dimethylhydroxylamine*hydrochloride In tetrahydrofuran; hexane at -20℃; for 1.25h; Stage #2: With Triisopropyl borate In tetrahydrofuran; hexane at -15℃; for 0.25h; Stage #3: N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; triethylamine In tetrahydrofuran; ethanol; hexane at 60℃;

Reference： [1]Roschangar, Frank; Brown, Jennifer C; Cooley Jr., Bobby E; Sharp, Matthew J; Matsuoka, Richard T [Tetrahedron, 2002, vol. 58, # 9, p. 1657 - 1666]

2
[ 98556-31-1 ]
[ 202197-26-0 ]
[ 231278-20-9 ]

Yield	Reaction Conditions	Operation in experiment
96%	In isopropyl alcohol; at 70℃; for 3.5h;	4-(3-fluorobenzyloxy)-3-chlorophenyl)-amine (12.3 g, 49 mmol), <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> 14.2 g, 49 mmol) and isopropanol (250 mL) were combined and the reaction mixture was heated to 70 C. for 3.5 hours. The resultant bright yellow solid product was collected by filtration (25.5 g, 96% yield). 1H NMR (DMSO-d6) δ 9.83 (s, 1H); 8.92 (s, 1H); 8.58 (s, 1H); 8.09 (d, 1H); 8.00 (d, 1H); 7.61 (d, 1H); 7.52 (d, 1H); 7.44 (m, 1H); 7.20-7.33 (m, 3H); 7.15 (m, 1H); 5.21 (s, 2H); MS m/z 506 (M+1)
95%	In isopropyl alcohol; at 80℃; for 2h;	General procedure: To a solution of compound 12 (5.8 g, 20 mmol) in i-PrOH was added anilines (22 mmol) at room temperature (RT). Then the reaction mixture was heated to 80 C for 2 h. After the start material was completed, the mixture was filtered through celite, and the cake was washed by i-PrOH, then dried to obtain the desired compound 13a-f.
95%	With triethylamine; In isopropyl alcohol; at 20℃; for 9h;Reflux;	To a round bottle, isopropanol (20 mL), 3-bromoaniline (0.62 g, 3.6 mmol), 4-cholo-6-iodo-quinazoline 15 (0.87 g, 3 mmol) andtriethylamine (0.36 g, 3.6 mmol) was added. The resulting reactionmixture was stirred at room temperature for 6 h and then at refluxfor another 3 h. After cooling to room temperature, the yellow solidwas collected by suck filtration, wash with isopropanol, water andether sequentially, and dried at 50 C to afford compound 12a as ayellow solid (0.74 g, 69% yield)

90 - 95%		Example 1; Preparation of GW572016F; STAGE 1; A stirred suspension of 3H-6-iodoquinazolin-4-one (compound A) in toluene (5 vols) was treated with tri-n-butylamine (1.2 eq.) at 20 to 25C, then heated to 900C. Phosphorous oxychloride (1.1 eq) was added, the reaction mixture was then heated to reflux. The reaction mixture was cooled to 500C and toluene (5vols) added. Compound C (1.03 eq.) was added as a solid, the slurry was warmed back to 900C and stirred for 1 hour. The slurry was transferred to a second vessel; the first vessel was rinsed with toluene (2vol) and combined with the reaction mixture. The reaction mixture was cooled to 700C and 1.0 M aqueous sodium hydroxide solution (16 vols) added dropwise over 1 hour to the stirred slurry maintaining the contents temperature between 68-72C. The mixture was stirred at 65-700C for 1 hour and then cooled to 200C over 1 hour. The suspension was stirred at 200C for 2 hours, the product collected by filtration, and washed successively with water (3 x 5 vols) and ethanol (IMS, 2 x 5 vols), then dried in vacuo at 50-600C. <n="25"/>Volumes are quoted with respect of the quantity of Compound A used. Percent yield range observed: 90 to 95% as white or yellow crystals.
90.72%	In isopropyl alcohol;Reflux;	Compound B2 (5.70 g, 19.70 mmol) and compound B4 (4.90 g, 19.70 mmol) were added to a jar, while isopropanol 150 mm was added and the mixture was heated under reflux overnight. After the reaction is completed, the temperature of the reaction system is lowered to room temperature.The solid product precipitated, was decompressed and filtered to obtain a filter cake. The cake was dried to obtain 9.10 g of a product (a yield of 90.72%). The product was of high purity without purification.
74.2%	In isopropyl alcohol;Heating / reflux;	4-Chloro-6-iodoquinazoline (5.7g, 19.7 mmol) and 3-chloro-4-(3- fluorobenzyloxy)aniline (4.9g, 19.7 mmol) was refluxed in isopropanol (15OmL) overnight. The mixture was cooled to room temperature. The solid product was precipitated, filtrated and dried in vacuum. The product 1405-174 was pure enough and used without further purifcation.(7.4 g, 74.2%): LC-MS: 506 [M+l]+, 1U NMR (DMSO-J6): δ 5.29 (s, 2 H), 7.18 (m, IH), 7.33 (m, 3H), 7.48 (m, IH), 7.66 (m, IH), 7.74 (d, J= 9.0 Hz, 1 H), 7.90 (d, J= 2.2 Hz, 1 H), 8.37 (d, J= 9.0 Hz, 1 H), 8.94 (s, 1 H), 9.29 (s, 1 H).
		Roschangar et al. ,Use of lithium N,O-dimethylhydroxylamide as an efficient in situ protecting agent for aromatic aldehydes. Tertrahedron 2002, 58, 1657-1666). Preparation analogous (Nishino et al.; Process for producing 4-aminoquinazoline compound by chlorination of quinazolin-4-one or its derivative and animation. 2003) as follows: To a mixture of 6-iodo-lH-quinazolin-4-one (10) (6.8Og; 25.0 mmol), toluene (5.0 mL) and POCl3 (27.5 mmol; 2.60 mL) carefully triethylamine (27.5 mmol; 3.81 mL) was added. The mixture was heated to 80 0C for 2 h, cooled to room temperature, a solution of 3-chloro~4-(3- fluorobenzyloxy)phenylamine (15) (27.50 mmol; 6.92 g) in 2~butanone (20.0 mL) added and the mixture stirred at 80 0C for another hour. The mixture was cooled to 00C, the yellow precipitate was filtered off and added to a NaOH solution (IN; 150 mL) by stirring. After 30 min the yellow solid was filtered off, washed with water and a small amount of acetone and dried in vacuo. Yield (8.38 g; 66%) analytical pure sample. 1H-NMR (DMSO-[D6]): δ (ppm) = 5.26 (s, 2H), 7.15-7.22 (m, IH), 7.27 (d, IH, J = 9.1 Hz), 7.29-7.35 (m, 2H), 7.43-7.51 (m, IH), 7.56 (d, IH, J = 8.8 Hz), 7.74 (dd, IH, J = 9.1 Hz, 4J = 2.5 Hz), 8.02 (d, IH5 4J = 2.5 Hz), 8.12 (dd; IH, J = 8.8 Hz, 4J = 1.7 Hz)5 8.62 (s, IH), 8.96 (d, 4J = 1.7 Hz), 9.90 (s, IH, exchangeable).
		4-Chloro-6-iodoquinazoline (1wt) was added to a solution of fluorobenzyloxyaniline (0.894wt, 1.03equiv) in N-methylpyrrolidinone (8.26wt, 8vol) at ca 20C, and after the initial exotherm had subsided, the resulting solution was stirred at 20-25C for at least 30 minutes. The dark solution was treated with triethylamine (0. 58vol, 1.2equiv) and the mixture was stirred for 20-30 minutes. Isopropanol (2. 5vol) was added and the mixture was heated to ca 50C. Water (up to 3vol) was added slowly to the vessel over 10-15 minutes, while keeping the temperature at ca 50C. Once crystallisation had commenced the addition was stopped and the resulting slurry was aged for 30-45 minutes at ca 50C. Any residual water (from the 3vol) was added, then further water (5vol) was added to the vessel over ca 30 minutes while maintaining the temperature at ca 50C. The resulting slurry was cooled to ca 20C over ca 30 minutes and aged at ca 20C for at least 30 minutes. The solid was collected by filtration and washed sequentially with water (2 x 5vol), then isopropanol (5vol). The product was dried in vacuo at ca 60C to give the title compound as a cream crystalline solid.
	at 90℃; for 1h;	A stirred suspension of 3H-6-iodoquinazolin-4-one (compound A) in toluene (5 vols) was treated with tri-n-butylamine (1.2 eq.) at 20 to 25C, then heated to 900C. Phosphorous oxychloride (1.1eq) was added, the reaction mixture was then heated to reflux. The reaction mixture was cooled to 500C and toluene (5vols) added. Compound C (1.03 eq.) was added as a solid, the slurry was warmed back to 900C and stirred for 1 hour. The slurry was transferred to a second vessel; the first vessel was rinsed with toluene (2vol) and combined with the reaction mixture. The reaction mixture was cooled to 7O0C and 1.0 M aqueous sodium hydroxide solution (16 vols) added dropwise over 1 hour to the stirred slurry maintaining the contents temperature between 68-72C. The mixture was stirred at 65-700C for 1 hour and then cooled to 200C over 1 hour. The suspension was stirred at 200C for 2 hours, the product collected by filtration, and washed successively with water (3 x 5 vols) and ethanol (IMS, 2 x 5 vols), then dried in vacuo at 50-600C. Volumes are quoted with respect of the quantity of Compound A used. Percent yield range observed: 90 to 95% as white or yellow crystals.
		A stirred suspension of 3W-6-iodoquinazolin-4-one in toluene (5 vols) is treated with tri-n-butylamine (1.2 equiv.), and then heated to 70-800C. Phosphorous oxychloride (1.1 equiv.) is added and the reaction mixture is then heated to reflux and stirred at this temperature for at least 2 hours. The reaction mixture is then cooled to 55C and toluene (5vol) added followed by 3-chloro-4-[(3-fluorophenyl)rnethyl]oxy}aniline (1.03 equiv.). The reaction mixture is then warmed to 70-900C and stirred for at least 2 hours. The resultant slurry is transferred to a second vessel. The temperature is adjusted to 70-750C and 8 molar aqueous sodium hydroxide solution (2 vols) added over 1 hour, followed by water (6vol.) maintaining the contents at 70-850C. The mixture is stirred at 70-850C for ca. 1 hour and then cooled to 20-250C. The suspension is stirred for ca. 2 hours and the product collected by filtration, and washed successively with water, 0.1 molar aqueous sodium hydroxide, water, and IMS, then dried in vacuo. EPO <DP n="48"/>
		A stirred suspension of 3H-6-iodoquinazolin-4-one (compound A) in toluene (5 vols) was treated with tri-n-butylamine (1.2 eq. ) at 20 to 25C, then heated to 90C. Phosphorous oxychloride (1.1eq) was added, the reaction mixture was then heated to reflux. The reaction mixture was cooled to 50C and toluene (5vols) added. Compound C (1.03 eq. ) was added as a solid, the slurry was warmed back to 90C and stirred for 1 hour. The slurry was transferred to a second vessel; the first vessel was rinsed with toluene (2vol) and combined with the reaction mixture. The reaction mixture was cooled to 70C and 1.0 M aqueous sodium hydroxide solution (16 vols) added dropwise over 1 hour to the stirred slurry maintaining the contents temperature between 68-72C. The mixture was stirred at 65-70C for 1 hour and then cooled to 20C over 1 hour. The suspension was stirred at 20C for 2 hours, the product collected by filtration, and washed successively with water (3 x 5 vols) and ethanol (IMS, 2 x 5 vols), then dried in vacuo at 50-60C. Volumes are quoted with respect of the quantity of Compound A used. Percent yield range observed: 90 to 95% as white or yellow crystals.
		The reaction mixture was cooled to 50C and toluene (5vols) added. Compound C (1.03 eq. ) was added as a solid and the slurry was warmed back to 90C and stirred for 1 hour. The slurry was transferred to a second vessel; the first vessel was rinsed with toluene (2vol) and combined with the reaction mixture. The reaction mixture was cooled to 70C and 1.0 M aqueous sodium hydroxide solution (16 vols) added dropwise over 1 hour to the stirred slurry maintaining the contents temperature between 68-72C. The mixture was stirred at 65-70C for 1 hour and then cooled to 20C over 1 hour. The suspension was stirred at 20C for 2 hours, the product collected by filtration, and washed successively with water (3 x 5 vols) and ethanol (IMS, 2 x 5 vols), then dried in vacuo at 50-60C. Volumes are quoted with respect of the quantity of Compound A used. Percent yield range observed: 90 to 95% as white or yellow crystals.
		4-Chloro-6-iodoquinazoline (1wt) was added to a solution of fluorobenzyloxyaniline (0.894wt, 1.03equiv) in N-methylpyrrolidinone (8.26wt, 8vol) at ca 200C, and after the initial exotherm had subsided, the resulting solution was stirred at 20-25C for at least 30 minutes. The dark solution was treated with triethylamine (0.58vol, 1.2equiv) and the mixture was stirred for 20-30 minutes. lsopropanol (2.5vol) was added and the mixture was heated to ca 500C. Water (up to 3vol) was added slowly to the vessel over 10-15 minutes, while keeping the temperature at ca 500C. Once crystallisation had commenced the addition was stopped and the resulting slurry was aged for 30-45 minutes at ca 500C. Any residual water (from the 3vol) was added, then further water (5vol) was added to the vessel over ca 30 minutes while maintaining the temperature at ca 500C. The resulting slurry was cooled to ca 200C over ca 30 minutes and aged at ca 200C for at least 30 minutes. The solid was collected by filtration and washed sequentially with <n="43"/>water (2 x 5vol), then isopropanol (5vol). The product was dried in vacuo at ca 600C to give the title compound as a cream crystalline solid.

Reference： [1]Patent: US2015/366868,2015,A1 .Location in patent: Paragraph 0159
[2]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 27 - 37
[3]European Journal of Medicinal Chemistry,2017,vol. 127,p. 442 - 458
[4]Patent: WO2008/67144,2008,A2 .Location in patent: Page/Page column 23-24
[5]Patent: CN105085496,2018,B .Location in patent: Paragraph 0044; 0045
[6]Patent: WO2008/33747,2008,A2 .Location in patent: Page/Page column 169
[7]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 637 - 640
[8]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4686 - 4691
[9]Patent: WO2009/63054,2009,A1 .Location in patent: Page/Page column 69
[10]Patent: WO2005/46678,2005,A1 .Location in patent: Page/Page column 67-68
[11]Patent: WO2006/26313,2006,A2 .Location in patent: Page/Page column 23
[12]Patent: WO2006/113649,2006,A1 .Location in patent: Page/Page column 46
[13]Journal of Medicinal Chemistry,2010,vol. 53,p. 8546 - 8555
[14]Patent: WO2005/120512,2005,A2 .Location in patent: Page/Page column 23
[15]Patent: WO2005/120504,2005,A2 .Location in patent: Page/Page column 30
[16]Patent: WO2007/121279,2007,A2 .Location in patent: Page/Page column 25; 40; 41

3
[ 97674-02-7 ]
[ 231278-20-9 ]
[ 320337-22-2 ]

Yield	Reaction Conditions	Operation in experiment
64%	With bis-triphenylphosphine-palladium(II) chloride In acetonitrile for 18h; Reflux;	3.a (a) Preparation of N-(4-(3-fluorobenzyloxy)-chlorophenyl)-6-(1-ethoxyvinylether)-quinazolin-4-yl)-amine To a suspension of the 6-iodo-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-quinazolin-4-yl amine (12.6 g, 24.93 mmol) in acetonitrile (100 mL) was added tributyl(1-ethoxyvinyl)stannane (9 g, 24.93 mmol) and bis(triphenylphosphine) palladium (II) chloride (1.75 g, 2.29 mmol). The reaction mixture was refluxed for 18 hours, then filtered through a plug of silica gel. The resulting solution was poured into 5% aqueous NH4OH (200 mL) and extracted with ethyl acetate (500 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to provide the title compound as a yellow solid (7.2 g, 64% yield). 1H NMR (400 MHz, d6 DMSO) δ 9.92 (s, 1H), 8.76 (s, 1H), 8.58 (s, 1H), 8.08 (m, 1H), 8.01 (m, 1H), 7.76 (m, 2H), 7.48 (m, 1H), 7.32 (m, 3H), 7.22 (m, 1H), 5.28 (s, 2H), 5.02 (s, 1H), 4.56 (s, 1H), 4.01 (q, 2H), 1.42 (t, 3H); ESI-MS m/z 449.9 (M+H)+.
64%	In acetonitrile for 18h; Heating / reflux;	5.a a) Preparation of N-(4-(3-fluorobenzyloxy)-chlorophenyl)-6-(1- ethoxyvinylether)-quinazolin-4-yl)-amine To a suspension of the 6-iodo-(4-(3-fluorobenzyloxy)-3-chlorophenyl)- quinazolin-4-yl amine (12.6 g, 24.93 mmol) in acetonitrile (100 mL) was added tributyl(1-ethoxyvinyl)stannane (9 g, 24.93 mmol) and bis(triphenylphosphine) palladium (II) chloride (1.75 g, 2.29 mmol). The reaction mixture was refluxed for 18 hours, then filtered through a plug of silica gel. The resulting solution was poured into 5% aqueous NH40H (200 mL) and extracted with ethyl acetate (500 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to provide the title compound as a yellow solid (7.2 g, 64% yield).
	With bis-triphenylphosphine-palladium(II) chloride

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US2015/366868, 2015, A1 Location in patent: Paragraph 0175-0176
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC; KUMAR - WO2005/105094, 2005, A2 Location in patent: Page/Page column 51
[3]Gaul, Micheal D.; Guo, Yu; Affleck, Karen; Cockerill, G. Stuart; Gilmer, Tona M.; Griffin, Robert J.; Guntrip, Stephen; Keith, Barry R.; Knight, Wilson B.; Mullin, Robert J.; Murray, Doris M.; Rusnak, David W.; Smith, Kathryn; Tadepalli, Sarva; Wood, Edgar R.; Lackey, Karen [Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 4, p. 637 - 640]

4
[ 27329-70-0 ]
[ 231278-20-9 ]
[ 231278-84-5 ]

Yield	Reaction Conditions	Operation in experiment
98.7%	With potassium carbonate;palladium diacetate; In tetrahydrofuran; ethanol; for 0.666667h;Reflux;Product distribution / selectivity;	Example 13: preparation of crystalline lapatinib aldehyde base[00098] To a 3L reactor lOOg of compound of formula C, 37.35g of 5-fo?nyl-2- furanboronic acid, 1.33g of palladium acetate, 54.66g of potassium carbonate, 750 ml of absolute ethanol and 750ml of THF were added. The suspension was stirred and heated to reflux (T(jacket) = 75C) for 40 minutes. The reaction mixture was cooled to room temperature (T(jacket) = 200C) and diluted with 750 ml of THF and 750 ml of absolute ethanol. The resulting mixture was stirred at 250C for an hour. Inorganic salts were filtered off in vacuum, washed with 100 ml of absolute ethanol, 100 ml of THF and discarded. The filtrate combined with washings was transferred into a 1OL reactor equipped with a mechanical stirrer and a dropping funnel. 3L of water was added dropwise into the solution of lapatinib-aldehyde base in EtOH/THF (1 :1) for an hour (T(jacket) = 200C). The resulting yellow suspension was stirred at RT (T(jacket) = 200C) for 1.5 hour. The yellow solid was filtered in vacuum and washed over the filter with 100 ml of cold absolute ethanol. It was allowed to dry in a vacuum oven at 400C for 16 hours, and additional 24 hours in vacuum oven at 600C to give 92.56g of final product (Yield - 98.7%; Purity - 99.12%)
97.7%	With palladium; triethylamine; In tetrahydrofuran; ethanol; at 65℃; for 7h;Inert atmosphere;	Under the protection of nitrogen, to the 3L joins the type three sequentially in the bottle (IV) compound (100g, 0.198mol), 5-carboxaldehyde furan -2 boric acid (55.4g, 0 . 396mol), triethylamine (60.1g, , 0 . 594mol), thf (1000 ml), ethanol (500 ml), N2deaerization after replacing three times, heating to 65 C, stirring dissolution cleaning. By adding palladium catalyst, temperature control reaction 7h rear, monitoring TLC (developing solvent DCM: MeOH=30:1) to (IV) compound the reaction is complete. The reaction solution is 40g diatomaceous earth filtration, filtrate to room temperature, to its dropping 1000 ml purified water, stirring the mixture at room temperature for 1h, filtering, 45 C drying to obtain pale brown solid, that is, the compound of formula (III) 91.6g, HPLC purity 96.7%, the yield is 97.7%.
96%	With triethylamine;palladium 10% on activated carbon; In methanol; 1,2-dimethoxyethane; at 45 - 50℃; for 15h;Inert atmosphere;	(iii) Preparation of 5-[4-[3-chloro-4-(3-fluorobenzyloxy)-aniIino]-6-quinazolinyl)- furan-2-carbaIdehyde (4)Into a two liter four-necked round bottomed flask, 1000 mL of 1,2-dimethoxyethane, 50.0 g of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodo-quinazolinamine obtained from the previous step(ii), 5-formyl-2-furyl boronicacid (21.5 g), triethylamine (30.5 g), 10% Pd on carbon (wet) (2.5 g) suspended in 500 mL of methanol were charged under stirring. The mass was maintained at 45-50 C for about 15 hours under nitrogen atmosphere and the completion of the reaction was monitored by TLC. The catalyst was filtered and the filtrate was quenched into two liters of water and stirred well. The product was filtered and dried to get 45.0 g (96% of theory) of 5-[4-3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)- fiuran.-2-carbaldehyde as a greenish yellow amorphous powder. Purity: 99.6% by HPLC Melting range: 224-228 C

96%	With triethylamine;palladium 10% on activated carbon; In methanol; 1,2-dimethoxyethane; at 45 - 50℃; for 15h;Inert atmosphere;	(iii) Preparation of 514-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde (4)Into a two liter four-necked round bottomed flask, 1000 mL of 1,2-dimethoxyethane, 50.0 g of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodo-quinazolinamine obtained from the previous step (ii), 5-formyl-2-furyl boronicacid (21.5 g), triethylamine (30.5 g), 10% Pd on carbon (wet) (2.5 g) suspended in 500 mL of methanol were charged under stirring. The mass was maintained at 45-50 C. for about 15 hours under nitrogen atmosphere and the completion of the reaction was monitored by TLC. The catalyst was filtered and the filtrate was quenched into two liters of water and stirred well. The product was filtered and dried to get 45.0 g (96% of theory) of 5-[4-3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan.-2-carbaldehyde as a greenish yellow amorphous powder.Purity: 99.6% by HPLCMelting range: 224-228 C.
92%	With palladium on activated charcoal; triethylamine; In methanol; ethanol; at 60℃; for 3h;	In a 1 L reaction flask, 50 g (10 mmol) of compound II was added in sequence,Compound III 18g (13mmol), ethanol 600ml, triethylamine 50ml,100 ml of methanol and 1 g of palladium carbon, stirred uniformly, and heated to 60 C for 3 hours.After the reaction is completed, palladium carbon is recovered by filtration, the filtrate is desolvated, the desolvation is completed, and 500 ml of water is added.After stirring at room temperature for 1 hour, it was filtered to give 43.1 g of pale yellow solid, Compound IV.Yield 92%, HPLC purity 98.46%
91%	With palladium 10% on activated carbon; triethylamine; In methanol; 1,2-dimethoxyethane; at 50℃; for 14h;	Example 10 - Comparative example in accordance with EPI 7929025-(4-(3-Chloro-4-(3-fluorobenzyloxy)phenylamino)chinazolin-6-yl)furan-2-carbaldehyde (I)Triethylamine (0.2 ml) was added to a mixture of the boronic acid VI (104 mg, 0.74 mmol, 1.5 equiv.), III (250 mg, 0.49 mmol) and 10 % Pd/C (13 mg, 0.012 mmol, 2.5mol. %), DME (4 ml) and methanol (2 ml) and the resulting substance was stirred at the temperature of 50C for 14 hours. After working, 184 mg (78%) of a yellow powdery substance was obtained containing 91% of the title compound I and 8% of the unreacted input substance Ill according to H PLC.
83.4%	With palladium 10% on activated carbon; triethylamine; In methanol; 1,2-dimethoxyethane; at 50℃; for 0.5h;	General procedure: To a 100 mL round bottomed flask, residue C1-4 (0.60 mmol), <strong>[27329-70-0]5-formyl-2-furanboronic acid</strong> (0.90 mmol), Pb/C 10%, triethylamine (2.4 mmol), 1,2-dimethoxyethane (60 mL), methanol (30 mL) were added. The suspension was stirred and heated to 50 C for 0.5 h. The reaction mixture was filtered with diatomite and the filter cake was washed with THF (3 × 10 mL). The filtrate combined with washings was evaporated. The crude product was chromatographed by silica gel, eluted with EtOAc/CHCl3 (1:10) to afford compound D1-4 as orange solid (yield 57.2~83.4%). 4 1.2.1.1 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (D1) Yield 83.4%. 1H NMR (400 MHz, DMSO-d6) delta(ppm): 10.08 (s, 1H), 9.68 (s, 1H), 8.94 (d, J = 1.6 Hz, 1H), 8.60 (s, 1H), 8.33 - 8.25 (m, 1H), 8.00 (d, J = 2.6 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.73 (dd, J = 8.8, 3.1 Hz, 2H), 7.49 (td, J = 8.0, 6.0 Hz, 1H), 7.40 (d, J = 3.8 Hz, 1H), 7.34 (dd, J = 11.9, 5.1 Hz, 2H), 7.29 (d, J = 9.0 Hz, 1H), 7.23 - 7.16 (m, 1H), 5.27 (s, 2H) (Figure S7).
83.4%	With palladium 10% on activated carbon; In methanol; 1,2-dimethoxyethane; at 50℃; for 0.5h;	General procedure: As our previously described,3 to a 100 mL round bottomed flask, residue 13a-13c (0.60 mmol), <strong>[27329-70-0]5-formyl-2-furanboronic acid</strong> (0.90 mmol), Pb/C 10%, triethylamine (2.4 mmol), 1,2-dimethoxyethane (60 mL) and methanol (30 mL) were added. The suspension was stirred and heated to 50 for 0.5 h. The reaction mixture was filtered with diatomite and the filter cake was washed with THF (3 × 10 mL). The filtrate combined with washings was evaporated. The crude product was chromatographed by silica gel, eluted with EtOAc/CHCl3 (1:10) to afford compound 14a-14c as orange solid (yield 65.2% ~ 83.4%). 1.2.1.1 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-formylfuran-2-yl)quinazoline (14a) Orange power, yield: 83.4%.
78%	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; ethanol; water; at 60℃; for 3h;	Preparation analogous to Hosoya et al. (Danthrone Analogues Revisted: General Synthesis and Specific Functions Capable of Discriminating Two Rinds of Ca2+ Release from Sarcoplasmic Rerticulum of Mouse Skeletal Muscle. Bioorg. Med, Chem. 2003, 11, 663-673). A mixture of 16 (5.00 g; 9.88 mmol), the respective arylboronic acid (17a, 17b, 22b: Aldrich; 17c, 17d Alfa Aesar 22a Rare Chemicals ) (13.1 mmol), (PPh3)2PdCl2 (0.35 g; 0.5 mmol), DME (30 mL), ethanol (20 mL) and 2M aqueous Na2CO3 (30 mL) was heated at 60 GC for 3h. After being cooled to room temperature, the crude product precipitated as a yellow solid. It was removed by filtration, washed with water and dried in vacuum over night. Crystallisation from acetone afforded the title compound in sufficient purity for further synthesis. An analytical sample was obtained column chromatography (SiO2; CH2Cl2ZeUIyI acetate = 4:1).; 5-{4-[3-Chloro-4-(3-fluorobenzyloxy)phenylamiDo]-quinazolin-6-yl}furan-2- carbaldehyde (18a) <n="71"/>(Roschangar et al.; Use of lithium N,O~dimethylhydroxylamide as an efficient in situ protecting agent for aromatic aldehydes. Tertrahedron 2002, 55, 1657-1666): Yield (3.65 g, 78%). mp: 229.8-234.1 0C. 1H-NME. (DMSO-[D6]): delta (ppm) = 5.26 (s, 2H), 7.17 (dt, IH, J = 2.5 Hz, J = 8.5), 7.26-7.34 (m, 3H), 7.40 (d, IH, J - 3.6 Hz), 7,43-7.50 (m, IH), 7.68-7.74 (m, 2H), 7.84 (d, IH, J = 8.5 Hz), 7.98 (d, IH, J = 2.5 Hz), 8.28 (dd, IH, J = 1.1 Hz, J = 8.8 Hz), 8.58 (s, IH), 8.95 (d, IH, J = 0.8 Hz), 9.66 (s, IH), 10.10 (s, IH, exchangeable). + p ESI m/z (%): 476 [MH-H+J+' (37); 474 [M+HT (100); - p ESI m/z (%): 474 [M-H+]' (37), 472 [M-H+]" (100). IR (KBr): 3399, 1673 cm"1-
66.2%	With triethylamine;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; ethanol;Heating / reflux;	N-(3-Chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine (387 mg, 0.77 mmol) and 5-formylfuran-2-ylboronic acid (129 mg, 0.92 mmol) were added into the mixture of THF (10 rnL) , ethanol (5 mL) and Et3N (0.3 rnL) under N2 atmosphere. Then PdCl2(dppf) (26 mg, 0.03 mmol) was added into the mixture. The mixture was refluxed overnight. Then the solvent was removed in vacuo, the residue was chromatographed on silica gel with ethyl acetate to give product 1406- 174 (240 mg, 66.2%): LC-MS: 474 [M+l]+, 1H NMR (DMSO-J6): delta 5.20 (s, 2 H), 7.17 (m, IH), 7.29 (m, 3H), 7.41 (m, 2H), 7.74 (m, 2H), 7.86 (d, J= 9.0 Hz, 1 H), 7.97 (s,l H), 8.31 (d, J= 9.0 Hz, 1 H), 8.56 (s, 1 H), 8.96 (s, 1 H), 9.66 (s, 1 H), 10.11 (s, I H).
	With triethylamine;palladium on activated carbon; In methanol; 1,2-dimethoxyethane;	Example 1 Preparation of 5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde To a reaction vessel was added N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodo-4-quinazolinamine (100 mg; 0.198 mmol), 2-formylfuran-5-boronic acid (Frontier Scientific, 42 mg; 0.297 mmol), 10% palladium on activated carbon (5 mg; 0.05 wt), DME (2.0 mL), MeOH (1.0 mL) and triethylamine (83 muL). After heating at 50 C. for 14 h, a HPLC indicated 98.5% clean conversion. 1H NMR (d6-DMSO) delta: 11.44 (s, 1H), 9.38 (s, 2H), 9.11 (s, 1H), 8.90 (s, 1H), 8.39 (dd, 1H, J=8 and 4 Hz), 7.89 (d, 1H, J=12 Hz), 7.84 (d, 1H, J=4 Hz), 7.60 (dd, 1H, J=8 and 4 Hz), 7.47-7.42 (m, 2H), 7.44 (AA'BB', 2H, JAB=8 Hz), 7.35-7.25 (m, 3H), 7.24 (d, 1H, J=4 Hz), 7.16 (dt, 1H, J=8 and 4 Hz), 7.06 (AA'BB', 2H, JAB=8 Hz, 6.84 (d, 1H, J=4 Hz), 5.27 (s, 2H), 4.43 (s, 2H), 3.61-3.50 (m, 2H), 3.47-3.36 (m, 2H), 3.09 (s, 3H), 2.23 (s, 6H).
	With 1,2-dimethoxyethane; triethylamine;palladium 10% on activated carbon; In methanol;Inert atmosphere;	(iv) Preparation of 5-[4-[3-chloro-4-(3-fluorobenzyIoxy)-anilino]-6- quinazolinyl)- furan-2-carbaldehyde (4)Into a two liter four-necked round bottomed flask, 1000 mL of 1,2-dimethoxyethane, 50.0 g of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodo-quinazolinamine obtained from the previous step(iii), 5-formyl-2-furyl boronicacid (21.5 g), triethylamine (30.5 g), 10% Pd on carbon (wet) (2.5 g) suspended in 500 mL of methanol were charged under stirring. The mass was maintained at 45-50 C for about 15 hours under nitrogen atmosphere and the completion of the reaction was monitored by TLC. The catalyst was filtered and the filtrate was quenched into two liters of water and stirred well. The product was filtered and dried to get 45.0 g (96% of theory) of 5-[4-3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-fiuran.-2- carbaldehyde as a greenish yellow amorphous powder.Purity: 99.6% by HPLC Melting range: 224-228 C
7 g	With palladium diacetate; potassium carbonate; In tetrahydrofuran; ethanol; for 1h;Inert atmosphere; Reflux;	A mixture of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine (10.2 g, 20 mmol), 5-formylfuran-2-ylboronic acid (3.8 g, 27 mmol), Pd(OAc)2 (0.4 g, 1.8 mmol) and K2CO3 (11.0 g, 80 mmol) in THF (100ml) and ethanol (100ml) was stirred and heated to reflux for 1 h in a nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with THF (200 ml) and ethanol (200 ml). Solid was filtered off and washed with 100 ml of THF. The combined organic layers were concentrated, diluted with H2O (500 ml) and stirred for 1 h. The yellow solid was collected, washed with ethanol (100 ml) and dried in a vacuum oven for two days at room temperature to give intermediate C (7 g, purity 98%). To a solution of intermediate C (0.47 g, 1 mmol) and morpholine (0.14 ml, 1.6 mmol) in CH2Cl2 (100 ml) and methanol (30 ml) was added NaBH(OAc)3 (0.380 g, 1.80 mmol). After 25 h, the reaction was diluted with H2O (300 mL) and extracted with CH2Cl2 (3 x 250 ml). The organic layers were combined, dried (Na2SO4)and concentrated. Chromatography of the residue (in CH2Cl2/MeOH) gave the title compound as an orange solid (0.21 g, 39%).
	With N-ethyl-N,N-diisopropylamine;palladium 10% on activated carbon; In ethanol; at 70℃; for 3h;	A mixture of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodo-4- quinazolinamine - compound D (1wt), boronic acid - compound E (0.37wt , 1.35equiv), and 10% palladium on charcoal (0.028wt,50% water wet) was slurried in IMS (15vol). The resultant suspension was stirred for 5 minutes, treated with di- isopropylethylamine (0.39vol, 1.15equiv) and then heated to ca 70C for ca 3 hours when the reaction was complete (determined by HPLC analysis). The mixture was diluted with tetrahydrofuran (THF, 15vol) and then hot-filtered to remove the catalyst. The vessel was rinsed with IMS (2vol). A solution of p-toluenesulfonic acid monohydrate (1.5wt, 4 equiv) in water (1.5vol) was added over 5-10 minutes to the filtered solution maintained at 65C. After crystallisation the suspension was stirred at 60-65C for 1 hour, cooled to ca 25C over 1 hour and stirred at this temperature for a further 2 hours. The solid was collected by filtration, washed with IMS (3vol) then dried in vacuo at ca 50C to give the compound F as a yellow-orange crystalline solid (isolated as the ethanol solvate containing approximately 5%w/w EtOH).
	With N-ethyl-N,N-diisopropylamine;palladium 10% on activated carbon; In ethanol; at 70℃; for 3h;	A mixture of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodo-4- quinazolinamine - compound D (1wt), boronic acid - compound E (0.37wt , 1.35equiv), and 10% palladium on charcoal (0.028wt ,50% water wet) was slurried in IMS (15vol). The resultant suspension was stirred for 5 minutes, treated with di- isopropylethylamine (0.39vol, 1.15equiv) and then heated to ca 70C for ca 3 hours when the reaction was complete (determined by HPLC analysis). The mixture was diluted with tetrahydrofuran (THF, 15vol) and then hot-filtered to remove the catalyst. The vessel was rinsed with IMS (2vol).
	With N-ethyl-N,N-diisopropylamine;palladium 10% on activated carbon; In isopropyl methanesulfonate; water; at 70℃; for 3h;Product distribution / selectivity;	A mixture of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodo-4- quinazolinamine (1wt), boronic acid (0.37wt , 1.35equiv), and 10% palladium on charcoal (0.028wt ,50% water wet) was slurried in IMS (15vol). The resultant suspension was stirred for 5 minutes, treated with di-isopropylethylamine (0.39vol, 1.15equiv) and then heated to ca 700C for ca 3 hours when the reaction was complete (determined by HPLC analysis). The mixture was diluted with tetrahydrofuran (THF, 15vol) and then filtered (hot - through GFA filter paper) to remove catalyst. The vessel was rinsed with IMS (2vol).A solution of p-toluenesulfonic acid monohydrate (1.54wt, 4.1equiv) in water (3vol) was added over 5-10 minutes to the filtered solution maintained at 65C. After crystallisation the suspension was stirred at 60-65C for 1 hour, cooled to ca 25C over 1 hour and stirred at this temperature for a further 2 hours. The solid was collected by filtration, washed with IMS (3vol) then dried in vacuo at ca 500C to give the tile compound as a yellow-orange crystalline solid.
		A mixture of lambda/-(3-chloro-4-[(3-fluorophenyl)methyl]oxy}phenyl)-6- iodo-4-quinazolinamine (1 wt), (5-formyl-2-furanyl)boronic acid (0.374 wt, 1.35eq) and 10% Palladium on charcoal (0.028 wt 50% water wet) is slurried in ethanol(industrial methylated spirits, 15 vols) to give a grey suspension. The resultant slurry is stirred for 5 minutes and then treated with lambda/,lambda/-di-isopropylethylamine (0.396 vols,1.15eq.). The reaction slurry is heated to 700C for typically 3 hours when the reaction is complete (by HPLC analysis). The mixture is a thick green slurry at this point which is treated with THF (15 vols) to dissolve the product that has precipitated, leaving only the Pd/C catalyst out of solution. The mixture is then filtered hot throughGFA filter to remove the catalyst. The vessel is rinsed with IMS (1vol) and the wash used to rinse catalyst bed. A solution of p-toluenesulfonic acid monohydrate (1.50wt, 4.0 eq.) in water (1.5 vols) is added to the filtered solution over 5 minutes at 65C.The reaction solution is cooled to 600C, with crystallization observed at 60-650C. <n="47"/>The resultant slurry is then stirred for at least 1 hour at 600C and then cooled to 20- 25C and then held at this temperature for a further 1 hour. The product is isolated by filtration and the cake washed with IMS (3vols). The product may be stored as a wet cake or dried.
		Stage 2: Preparation of 5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6- quinazolinyl)-furan-2-carbaldehyde 4-methylbenzenesulfonate A mixture of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodo-4- quinazolinamine (1wt), boronic acid (0.37wt , 1.35equiv), and 10% palladium on charcoal (0.028wt,50% water wet) was slurried in IMS (15vol). The resultant suspension was stirred for 5 minutes, treated with di- isopropylethylamine (0.39vol, 1.15equiv) and then heated to ca 70C for ca 3 hours when the reaction was complete (determined by HPLC analysis). The mixture was diluted with tetrahydrofuran (THF, 15vol) and then filtered (hot - through GFA filter paper) to remove catalyst. The vessel was rinsed with IMS (2vol).

Reference： [1]Patent: WO2010/17387,2010,A2 .Location in patent: Page/Page column 24
[2]Patent: CN105503839,2016,A .Location in patent: Paragraph 0046; 0047
[3]Patent: WO2010/61400,2010,A1 .Location in patent: Page/Page column 15
[4]Patent: US2011/263852,2011,A1 .Location in patent: Page/Page column 12
[5]Patent: CN109503559,2019,A .Location in patent: Paragraph 0019
[6]Patent: WO2014/59956,2014,A1 .Location in patent: Page/Page column 11; 12
[7]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1584 - 1587
[8]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 4309 - 4313
[9]Journal of Enzyme Inhibition and Medicinal Chemistry,2019,vol. 34,p. 1668 - 1677
[10]Patent: WO2009/63054,2009,A1 .Location in patent: Page/Page column 69-70
[11]Journal of Medicinal Chemistry,2010,vol. 53,p. 8546 - 8555
[12]ChemCatChem,2020,vol. 12,p. 2942 - 2946
[13]Patent: WO2008/33747,2008,A2 .Location in patent: Page/Page column 169-170
[14]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4686 - 4691
[15]Patent: US2003/220354,2003,A1
[16]Patent: WO2011/39759,2011,A1 .Location in patent: Page/Page column 14
[17]European Journal of Medicinal Chemistry,2013,vol. 69,p. 833 - 841
[18]European Journal of Medicinal Chemistry,2014,vol. 87,p. 631 - 642
[19]Patent: WO2005/120512,2005,A2 .Location in patent: Page/Page column 24
[20]Patent: WO2005/120504,2005,A2 .Location in patent: Page/Page column 31
[21]Patent: WO2007/121279,2007,A2 .Location in patent: Page/Page column 41
[22]Patent: WO2007/121279,2007,A2 .Location in patent: Page/Page column 44-45
[23]Patent: WO2005/105094,2005,A2 .Location in patent: Page/Page column 45

5
[ 98556-31-1 ]
[ 202197-25-9 ]
[ 231278-20-9 ]

Yield	Reaction Conditions	Operation in experiment
		Stage 1: Preparation of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6- iodo-4-quinazolinamine 4-Chloro-6-iodoquinazoline (1wt) was added to a solution of fluorobenzyloxyaniline (0.894wt, 1.03equiv) in N-methylpyrrolidinone (8.26wt, 8vol) at ca 20C, and after the initial exotherm had subsided, the resulting solution was stirred at 20-25C for at least 30 minutes. The dark solution was treated with triethylamine (0.58vol, 1.2equiv) and the mixture was stirred for 20-30 minutes. Isopropanol (2.5vol) was added and the mixture was heated to ca 50C. Water (up to 3vol) was added slowly to the vessel over 10-15 minutes, while keeping the temperature at ca 50C. Once crystallisation had commenced the addition was stopped and the resulting slurry was aged for 30-45 minutes at ca 50C. Any residual water (from the 3vol) was added, then further water (5vol) was added to the vessel over ca 30 minutes while maintaining the temperature at ca 50C. The resulting slurry was cooled to ca 20C over ca 30 minutes and aged at ca 20C for at least 30 minutes. The solid was collected by filtration and washed sequentially with water (2 x 5vol), then isopropanol (5vol). The product was dried in vacuo at ca 60C to give the title compound as a cream crystalline solid.

Reference： [1]Patent: WO2005/105094,2005,A2 .Location in patent: Page/Page column 44-45

6
[ 443882-99-3 ]
[ 231278-20-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: H₂ / Pt/C / ethanol; tetrahydrofuran 2: propan-2-ol / 70 °C
	Multi-step reaction with 2 steps 1: platinum/carbon xerogel catalyst; hydrogen / tetrahydrofuran 2: 1 h / Heating; Inert atmosphere
	Multi-step reaction with 2 steps 1: platinum on carbon; hydrogen / ethanol / 0.83 h / 1292.9 Torr / High pressure 2: isopropyl alcohol / 3.5 h / 70 °C

Multi-step reaction with 2 steps 1: zinc; ammonium chloride / ethanol; water / 12 h / 60 °C 2: isopropyl alcohol / Reflux

Reference： [1]Petrov, Kimberly G.; Zhang, Yue-Mei; Carter, Malcolm; Cockerill, G. Stuart; Dickerson, Scott; Gauthier, Cassandra A.; Guo, Yu; Mook Jr., Robert A.; Rusnak, David W.; Walker, Ann L.; Wood, Edgar R.; Lackey, Karen E. [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 17, p. 4686 - 4691]
[2]Mahboobi, Siavosh; Sellmer, Andreas; Winkler, Matthias; Eichhorn, Emerich; Pongratz, Herwig; Ciossek, Thomas; Baer, Thomas; Maier, Thomas; Beckers, Thomas [Journal of Medicinal Chemistry, 2010, vol. 53, # 24, p. 8546 - 8555]
[3]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US2015/366868, 2015, A1
[4]Current Patent Assignee: CHONGQING MEDICAL UNIVERSITY - CN105085496, 2018, B

7
[ 619-08-9 ]
[ 231278-20-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: K₂CO₃ / acetonitrile 2: H₂ / Pt/C / ethanol; tetrahydrofuran 3: propan-2-ol / 70 °C
	Multi-step reaction with 3 steps 1: potassium carbonate / acetonitrile / 2 h / 20 - 60 °C / Inert atmosphere 2: platinum on carbon; hydrogen / ethanol / 0.83 h / 1292.9 Torr / High pressure 3: isopropyl alcohol / 3.5 h / 70 °C
	Multi-step reaction with 3 steps 1: potassium carbonate / acetonitrile / 2 h / 60 °C / Inert atmosphere 2: zinc; ammonium chloride / ethanol; water / 12 h / 60 °C 3: isopropyl alcohol / Reflux

Reference： [1]Petrov, Kimberly G.; Zhang, Yue-Mei; Carter, Malcolm; Cockerill, G. Stuart; Dickerson, Scott; Gauthier, Cassandra A.; Guo, Yu; Mook Jr., Robert A.; Rusnak, David W.; Walker, Ann L.; Wood, Edgar R.; Lackey, Karen E. [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 17, p. 4686 - 4691]
[2]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US2015/366868, 2015, A1
[3]Current Patent Assignee: CHONGQING MEDICAL UNIVERSITY - CN105085496, 2018, B

8
[ 456-41-7 ]
[ 231278-20-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: K₂CO₃ / acetonitrile 2: H₂ / Pt/C / ethanol; tetrahydrofuran 3: propan-2-ol / 70 °C
	Multi-step reaction with 3 steps 1: potassium carbonate / acetonitrile / 2 h / 20 - 60 °C / Inert atmosphere 2: platinum on carbon; hydrogen / ethanol / 0.83 h / 1292.9 Torr / High pressure 3: isopropyl alcohol / 3.5 h / 70 °C
	Multi-step reaction with 3 steps 1: potassium carbonate / acetonitrile / 2 h / 60 °C / Inert atmosphere 2: zinc; ammonium chloride / ethanol; water / 12 h / 60 °C 3: isopropyl alcohol / Reflux

Reference： [1]Petrov, Kimberly G.; Zhang, Yue-Mei; Carter, Malcolm; Cockerill, G. Stuart; Dickerson, Scott; Gauthier, Cassandra A.; Guo, Yu; Mook Jr., Robert A.; Rusnak, David W.; Walker, Ann L.; Wood, Edgar R.; Lackey, Karen E. [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 17, p. 4686 - 4691]
[2]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US2015/366868, 2015, A1
[3]Current Patent Assignee: CHONGQING MEDICAL UNIVERSITY - CN105085496, 2018, B

9
[ 231278-20-9 ]
[ 320337-48-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Pd(OAc)2; PPh₃; Et₃N / dimethylformamide 2: NaBH₄
	Multi-step reaction with 2 steps 1: palladium 10% on activated carbon; triethylamine / methanol; 1,2-dimethoxyethane / 0.5 h / 50 °C 2: sodium tetrahydroborate / methanol; dichloromethane / 4 h / 0 °C

Reference： [1]Petrov, Kimberly G.; Zhang, Yue-Mei; Carter, Malcolm; Cockerill, G. Stuart; Dickerson, Scott; Gauthier, Cassandra A.; Guo, Yu; Mook Jr., Robert A.; Rusnak, David W.; Walker, Ann L.; Wood, Edgar R.; Lackey, Karen E. [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 17, p. 4686 - 4691]
[2]Zhang, Yaling; Zhang, Ying; Liu, Juan; Chen, Li; Zhao, Lijun; Li, Baolin; Wang, Wei [Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 7, p. 1584 - 1587]

10
[ 231278-20-9 ]
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-(5-[2-(methylsulfonyl)ethoxy]methyl}-furan-2-yl)-4-quinazolinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: Pd(OAc)2; PPh₃; Et₃N / dimethylformamide 2: NaBH₄ 3: NaH / dimethylformamide

Reference： [1]Petrov, Kimberly G.; Zhang, Yue-Mei; Carter, Malcolm; Cockerill, G. Stuart; Dickerson, Scott; Gauthier, Cassandra A.; Guo, Yu; Mook Jr., Robert A.; Rusnak, David W.; Walker, Ann L.; Wood, Edgar R.; Lackey, Karen E. [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 17, p. 4686 - 4691]

11
[ 231278-20-9 ]
[ 231277-92-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Pd(OAc)2; PPh₃; Et₃N / dimethylformamide 2: Na(OAc)3BH; HOAc / CH₂Cl₂
	Multi-step reaction with 3 steps 1: triethylamine; 1,2-dimethoxyethane / palladium 10% on activated carbon / methanol / Inert atmosphere 2: triethylamine / methanol / 12 h / Reflux 3: methanol / tetrahydrofuran / 0 - 15 °C
	Multi-step reaction with 3 steps 1: triethylamine / palladium 10% on activated carbon / 1,2-dimethoxyethane; methanol / 15 h / 45 - 50 °C / Inert atmosphere 2: triethylamine / methanol / 12 h / Reflux 3: sodium tetrahydroborate / tetrahydrofuran; methanol / 4 h / 10 - 15 °C

	Multi-step reaction with 2 steps 1.1: n-butyllithium / 1,2-dimethoxyethane / 2.75 h / -40 - -35 °C / Inert atmosphere 1.2: 2.5 h / -40 - -35 °C 2.1: N-ethyl-N,N-diisopropylamine; acetic acid / tetrahydrofuran / 2 h / 30 - 35 °C 2.2: 3 h / 20 - 25 °C
	Multi-step reaction with 3 steps 1.1: bis-triphenylphosphine-palladium(II) chloride; N-ethyl-N,N-diisopropylamine / 1,4-dioxane / Inert atmosphere; Reflux 2.1: hydrogenchloride / 1,4-dioxane; tetrahydrofuran / 20 °C 3.1: triethylamine / tetrahydrofuran; methanol / 3 h 3.2: 20 °C / Cooling with ice
	Multi-step reaction with 2 steps 1.1: triethylamine; palladium / tetrahydrofuran; ethanol / 7 h / 65 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0.33 h / 20 °C 2.2: 2 h / 40 °C 2.3: 3 h / 25 - 40 °C
	Multi-step reaction with 2 steps 1.1: palladium 10% on activated carbon; triethylamine / methanol; 1,2-dimethoxyethane / 0.5 h / 50 °C 2.1: triethylamine; sodium sulfate / methanol / 0.33 h / 0 °C 2.2: 2 h / pH 5 - 6
	Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / palladium 10% on activated carbon / ethanol / 3 h / 70 °C 2.1: tetrahydrofuran; ethanol; water / 4 h / 25 - 65 °C 3.1: acetic acid; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1 h / 30 - 35 °C 3.2: 2.25 h / 22 °C
	Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / palladium 10% on activated carbon / ethanol / 3 h / 70 °C 2.1: ethanol; water / 4 h / 25 - 65 °C 3.1: acetic acid; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1 h / 30 - 35 °C 3.2: 2.25 h / 22 °C
	Multi-step reaction with 3 steps 1.1: palladium 10% on activated carbon / ethanol; water / 0.08 h 1.2: 3 h / 70 °C 2.1: tetrahydrofuran; ethanol; isopropyl methanesulfonate; water / 2.08 h / 20 - 65 °C 3.1: acetic acid; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1 h / 30 - 35 °C 3.2: 2 - 4 h / 22 - 23 °C 3.3: 0.5 h
	Multi-step reaction with 2 steps 1.1: palladium 10% on activated carbon / isopropyl methanesulfonate / 0.08 h 1.2: 3 h / 70 °C
	Multi-step reaction with 3 steps 1.1: palladium 10% on activated carbon / isopropyl methanesulfonate / 0.08 h 1.2: 3 h / 70 °C 2.1: isopropyl methanesulfonate; water / 4.08 - 4.17 h / 25 - 65 °C 3.1: acetic acid; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1 h / 30 - 35 °C 3.2: 2.25 h / 22 - 23 °C 3.3: 0.5 h

Reference： [1]Petrov, Kimberly G.; Zhang, Yue-Mei; Carter, Malcolm; Cockerill, G. Stuart; Dickerson, Scott; Gauthier, Cassandra A.; Guo, Yu; Mook Jr., Robert A.; Rusnak, David W.; Walker, Ann L.; Wood, Edgar R.; Lackey, Karen E. [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 17, p. 4686 - 4691]
[2]Current Patent Assignee: NATCO PHARMA LIMITED - WO2011/39759, 2011, A1
[3]Current Patent Assignee: NATCO PHARMA LIMITED - US2011/263852, 2011, A1
[4]Current Patent Assignee: HETERO DRUGS LIMITED - WO2012/17448, 2012, A2
[5]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US2015/366868, 2015, A1
[6]Current Patent Assignee: SHINEWAY PHARMACEUTICAL GROUP - CN105503839, 2016, A
[7]Zhang, Yaling; Zhang, Ying; Liu, Juan; Chen, Li; Zhao, Lijun; Li, Baolin; Wang, Wei [Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 7, p. 1584 - 1587]
[8]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2005/120512, 2005, A2
[9]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2005/120504, 2005, A2
[10]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2007/121279, 2007, A2
[11]Current Patent Assignee: GLAXOSMITHKLINE PLC; KUMAR - WO2005/105094, 2005, A2
[12]Current Patent Assignee: GLAXOSMITHKLINE PLC; KUMAR - WO2005/105094, 2005, A2

12
[ 231278-20-9 ]
NEU-0000379 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Pd(OAc)2; PPh₃; Et₃N / dimethylformamide 2: Na(OAc)3BH; HOAc / CH₂Cl₂

Reference： [1]Petrov, Kimberly G.; Zhang, Yue-Mei; Carter, Malcolm; Cockerill, G. Stuart; Dickerson, Scott; Gauthier, Cassandra A.; Guo, Yu; Mook Jr., Robert A.; Rusnak, David W.; Walker, Ann L.; Wood, Edgar R.; Lackey, Karen E. [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 17, p. 4686 - 4691]

13
[ 231278-20-9 ]
NEU-0000387 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Pd(OAc)2; PPh₃; Et₃N / dimethylformamide 2: Na(OAc)3BH; HOAc / CH₂Cl₂

Reference： [1]Petrov, Kimberly G.; Zhang, Yue-Mei; Carter, Malcolm; Cockerill, G. Stuart; Dickerson, Scott; Gauthier, Cassandra A.; Guo, Yu; Mook Jr., Robert A.; Rusnak, David W.; Walker, Ann L.; Wood, Edgar R.; Lackey, Karen E. [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 17, p. 4686 - 4691]

14
[ 231278-20-9 ]
NEU-0000380 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: Pd(OAc)2; PPh₃; Et₃N / dimethylformamide 2: NaBH₄ 3: NaH / dimethylformamide

Reference： [1]Petrov, Kimberly G.; Zhang, Yue-Mei; Carter, Malcolm; Cockerill, G. Stuart; Dickerson, Scott; Gauthier, Cassandra A.; Guo, Yu; Mook Jr., Robert A.; Rusnak, David W.; Walker, Ann L.; Wood, Edgar R.; Lackey, Karen E. [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 17, p. 4686 - 4691]

15
[ 231278-20-9 ]
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-(5-[[2-(methylsulfonyl)ethyl](propyl)-amino]methyl}-furan-2-yl)-4-quinazolinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: Pd(OAc)2; PPh₃; Et₃N / dimethylformamide 2: Na(OAc)3BH; HOAc / CH₂Cl₂ 3: iPr₂EtN / dimethylformamide

Reference： [1]Petrov, Kimberly G.; Zhang, Yue-Mei; Carter, Malcolm; Cockerill, G. Stuart; Dickerson, Scott; Gauthier, Cassandra A.; Guo, Yu; Mook Jr., Robert A.; Rusnak, David W.; Walker, Ann L.; Wood, Edgar R.; Lackey, Karen E. [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 17, p. 4686 - 4691]

16
[ 231278-20-9 ]
2-{[5-(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}-6-quinazolinyl)-furan-2-yl]methyl}[2-(methylsulfonyl)ethyl]amino}acetonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: Pd(OAc)2; PPh₃; Et₃N / dimethylformamide 2: Na(OAc)3BH; HOAc / CH₂Cl₂ 3: iPr₂EtN / dimethylformamide

Reference： [1]Petrov, Kimberly G.; Zhang, Yue-Mei; Carter, Malcolm; Cockerill, G. Stuart; Dickerson, Scott; Gauthier, Cassandra A.; Guo, Yu; Mook Jr., Robert A.; Rusnak, David W.; Walker, Ann L.; Wood, Edgar R.; Lackey, Karen E. [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 17, p. 4686 - 4691]

17
[ 231278-20-9 ]
(4-(3-fluorobenzyloxy)-3-chlorophenyl)-(6-(2-((2-(pyridin-2-yl)-sulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Pd(OAc)2; PPh₃; Et₃N / dimethylformamide 2: Na(OAc)3BH; HOAc / CH₂Cl₂

Reference： [1]Petrov, Kimberly G.; Zhang, Yue-Mei; Carter, Malcolm; Cockerill, G. Stuart; Dickerson, Scott; Gauthier, Cassandra A.; Guo, Yu; Mook Jr., Robert A.; Rusnak, David W.; Walker, Ann L.; Wood, Edgar R.; Lackey, Karen E. [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 17, p. 4686 - 4691]

18
[ 231278-20-9 ]
(4-(3-fluorobenzyloxy)-3-chlorophenyl)-(6-(2-((2-phenylsulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Pd(OAc)2; PPh₃; Et₃N / dimethylformamide 2: Na(OAc)3BH; HOAc / CH₂Cl₂

Reference： [1]Petrov, Kimberly G.; Zhang, Yue-Mei; Carter, Malcolm; Cockerill, G. Stuart; Dickerson, Scott; Gauthier, Cassandra A.; Guo, Yu; Mook Jr., Robert A.; Rusnak, David W.; Walker, Ann L.; Wood, Edgar R.; Lackey, Karen E. [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 17, p. 4686 - 4691]

19
[ 231278-20-9 ]
NEU-0000388 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: Pd(OAc)2; PPh₃; Et₃N / dimethylformamide 2: Na(OAc)3BH; HOAc / CH₂Cl₂ 3: iPr₂EtN / dimethylformamide

Reference： [1]Petrov, Kimberly G.; Zhang, Yue-Mei; Carter, Malcolm; Cockerill, G. Stuart; Dickerson, Scott; Gauthier, Cassandra A.; Guo, Yu; Mook Jr., Robert A.; Rusnak, David W.; Walker, Ann L.; Wood, Edgar R.; Lackey, Karen E. [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 17, p. 4686 - 4691]

20
[ 231278-20-9 ]
(4-(3-fluorobenzyloxy)-3-chlorophenyl)-(6-(2-((2-(2-N-methylimidazolyl)-sulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Pd(OAc)2; PPh₃; Et₃N / dimethylformamide 2: Na(OAc)3BH; HOAc / CH₂Cl₂

Reference： [1]Petrov, Kimberly G.; Zhang, Yue-Mei; Carter, Malcolm; Cockerill, G. Stuart; Dickerson, Scott; Gauthier, Cassandra A.; Guo, Yu; Mook Jr., Robert A.; Rusnak, David W.; Walker, Ann L.; Wood, Edgar R.; Lackey, Karen E. [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 17, p. 4686 - 4691]

21
[ 231278-20-9 ]
[ 443883-09-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Pd(PPh₃)2Cl₂ 2: NBS / CH₂Cl₂
	Multi-step reaction with 2 steps 1: bis-triphenylphosphine-palladium(II) chloride / acetonitrile / 18 h / Heating / reflux 2: N-Bromosuccinimide / tetrahydrofuran; water / 0.25 h / 0 °C

Reference： [1]Gaul, Micheal D.; Guo, Yu; Affleck, Karen; Cockerill, G. Stuart; Gilmer, Tona M.; Griffin, Robert J.; Guntrip, Stephen; Keith, Barry R.; Knight, Wilson B.; Mullin, Robert J.; Murray, Doris M.; Rusnak, David W.; Smith, Kathryn; Tadepalli, Sarva; Wood, Edgar R.; Lackey, Karen [Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 4, p. 637 - 640]
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC; KUMAR - WO2005/105094, 2005, A2

22
[ 231278-20-9 ]
[ 388082-81-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: Pd(PPh₃)2Cl₂ 2: NBS / CH₂Cl₂ 3: dimethylformamide / 70 °C 4: NaOH / methanol
	Multi-step reaction with 4 steps 1: bis-triphenylphosphine-palladium(II) chloride / acetonitrile / 18 h / Heating / reflux 2: N-Bromosuccinimide / tetrahydrofuran; water / 0.25 h / 0 °C 3: N,N-dimethyl-formamide / 1 h / 70 °C 4: sodium hydroxide; water / methanol / 2 h / 20 °C

Reference： [1]Gaul, Micheal D.; Guo, Yu; Affleck, Karen; Cockerill, G. Stuart; Gilmer, Tona M.; Griffin, Robert J.; Guntrip, Stephen; Keith, Barry R.; Knight, Wilson B.; Mullin, Robert J.; Murray, Doris M.; Rusnak, David W.; Smith, Kathryn; Tadepalli, Sarva; Wood, Edgar R.; Lackey, Karen [Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 4, p. 637 - 640]
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC; KUMAR - WO2005/105094, 2005, A2

23
[ 231278-20-9 ]
[ 443883-07-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: Pd(PPh₃)2Cl₂ 2: NBS / CH₂Cl₂ 3: dimethylformamide / 70 °C
	Multi-step reaction with 3 steps 1: bis-triphenylphosphine-palladium(II) chloride / acetonitrile / 18 h / Reflux 2: N-Bromosuccinimide / tetrahydrofuran; water / 0.25 h / 0 °C 3: N,N-dimethyl-formamide / 1 h / 70 °C
	Multi-step reaction with 3 steps 1: bis-triphenylphosphine-palladium(II) chloride / acetonitrile / 18 h / Heating / reflux 2: N-Bromosuccinimide / tetrahydrofuran; water / 0.25 h / 0 °C 3: N,N-dimethyl-formamide / 1 h / 70 °C

Reference： [1]Gaul, Micheal D.; Guo, Yu; Affleck, Karen; Cockerill, G. Stuart; Gilmer, Tona M.; Griffin, Robert J.; Guntrip, Stephen; Keith, Barry R.; Knight, Wilson B.; Mullin, Robert J.; Murray, Doris M.; Rusnak, David W.; Smith, Kathryn; Tadepalli, Sarva; Wood, Edgar R.; Lackey, Karen [Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 4, p. 637 - 640]
[2]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US2015/366868, 2015, A1
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC; KUMAR - WO2005/105094, 2005, A2

24
[ 202197-26-0 ]
[ 231278-20-9 ]

Yield	Reaction Conditions	Operation in experiment
98%	Stage #1: 6-iodo-1H-quinazolin-4-one With triethylamine; trichlorophosphate In aqueous sodium hydroxide; toluene at 20 - 80℃; for 3h; Stage #2: 3-chloro-4-(3-fluorobenzyloxy)aniline In toluene; acetonitrile at 20 - 80℃; for 2h;	III.1 [Example III-1]; Preparation of 6-iodo-4-[3-chloro-4-(3-fluorobenzyloxy)anilino]quinazoline In a 200 mL-volume glass vessel equipped with a stirrer, a thermometer and a reflux condenser were placed9.80 g (36 mmol) of 6-iodoquinazolin-4-one, 6.63 g (43 mmol) of phosphorus oxychloride, and 30 mL of toluene in anitrogen atmosphere. While the mixture was stirred at room temperature, 4.41 g (8.8 mmol) of triethylamine was slowlyadded. The resulting mixture was heated to 75C, and then reaction was carried out at 70 - 80C for 3 hours. Subsequently,the mixture was cooled to room temperature, and 40 mL of acetonitrile and 11.8 mg (43 mmol) of 3-chloro-4-(3-fluorobenzyloxy)aniline were added. The resulting mixture was stirred at 70 - 80C for 2 hours. After the reactionwas complete, the reaction mixture was cooled to room temperature, and thus precipitated crystalline product wascollected by filtration and washed with 20 mL of acetonitrile. Subsequently, the crystalline product was placed in 80mL of aqueous sodium hydroxide (1 mol/L), and the aqueous mixture was stirred for 2 hours at room temperature. Thecrystalline product was collected by filtration, washed with 500 mL of water and 20 mL of acetonitrile, and dried underreduced pressure, to give 18.0 g (isolated yield: 98%, purity 100% in terms of area percentage determined by highperformance liquid chromatography) of 6-iodo-4-[3-chloro-4-(3-fluorobenzyloxy)anilino]quinazoline as a yellowish crystallineproduct. 6-Iodo-4-[3-chloro-4-(3-fluorobenzyloxy)anilino]quinazoline had the following physical properties.1H-NMR (DMSO-d6, d (ppm)): 5.26 (2H, s), 7.16-7.22 (1H, m), 7.26-7.35 (3H, m), 7.44-7.51 (1H, m), 7.56 (1H,d, J=8.8Hz), 7.75 (1H, dd, J=9.0, 2.4Hz), 8.03 (1H, s), 8.12 (1H, d, J=8.8Hz), 8.61 (1H, s), 8.96 (1H, s), 9.85 (1H, s)CI-MS (m/e): 506 (M+1)
90%	Stage #1: 6-iodoquinazolin-4(3H)-one With tributyl-amine In toluene at 20 - 25℃; Stage #2: With trichlorophosphate In toluene at 90℃; Heating / reflux; Stage #3: 3-chloro-4-(3-fluorobenzyloxy)aniline With sodium hydroxide more than 3 stages;	1.1 A stirred suspension of 3H-6-iodoquinazolin-4-one (compound A) in toluene (5 vols) was treated with tri-n-butylamine (1.2 eq.) at 20 to 250C, then heated to 900C. Phosphorous oxychloride (1.1eq) was added, the reaction mixture was then heated to reflux. The reaction mixture was cooled to 500C and toluene (5vols) added. Compound C (1.03 eq.) was added as a solid, the slurry was warmed back to 900C and stirred for 1 hour. The slurry was transferred to a second vessel; the first vessel was rinsed with toluene (2vol) and combined with the reaction mixture. The reaction mixture was cooled to 700C and 1.0 M aqueous sodium hydroxide solution (16 vols) added dropwise over 1 hour to the stirred slurry maintaining the contents temperature between 68-72°C. The mixture was stirred at 65-700C for 1 hour and then cooled to 200C over 1 hour. The suspension was stirred at 200C for 2 hours, the product collected by filtration, and washed successively with water (3 x 5 vols) and ethanol (IMS, 2 x 5 vols), then dried in vacuo at 50-600C. Volumes are quoted with respect of the quantity of Compound A used. Percent yield range observed: 90 to 95% as white or yellow crystals.
	Multi-step reaction with 2 steps 1: acetic acid / toluene / 2 h / Reflux 2: acetic acid / xylene / 10 h / Reflux

	Multi-step reaction with 2 steps 1: acetic acid / toluene / 3 h / 80 - 110 °C / Dean-Stark 2: toluene-4-sulfonic acid / toluene / 5 h / 110 °C
	Stage #1: 6-iodoquinazolin-4(3H)-one With tributyl-amine In toluene at 70 - 80℃; Stage #2: With trichlorophosphate In toluene for 2h; Heating / reflux; Stage #3: 3-chloro-4-(3-fluorobenzyloxy)aniline With sodium hydroxide more than 3 stages;	C.1; 2.1 Stage 1- A stirred suspension of 3H-6-iodoquinazolin-4-one in toluene (5 vols) is treated with tri-n-butylamine (1.2 equiv.), and then heated to 70-800C. Phosphorous oxychloride (1.1 equiv.) is added and the reaction mixture is then heated to reflux and stirred at this temperature for at least 2 hours. The reaction mixture is then cooled to 55°C and toluene (5vol) added followed by 3-chloro-4-[(3-fluorophenyl)methyl]oxy}aniline (1.03 equiv.). The reaction mixture is then warmed to 70-900C and stirred for at least 2 hours. The resultant slurry is transferred to a second vessel. The temperature is adjusted to 70-750C and 8 molar aqueous sodium hydroxide solution (2 vols) added over 1 hour, followed by water (6vol.) maintaining the contents at 70-850C. The mixture is stirred at 70-850C for ca. 1 hour and then cooled to 20-250C. The suspension is stirred for ca. 2 hours and the product collected by filtration, and washed successively with water, 0.1 molar aqueous sodium hydroxide, water, and IMS, then dried in vacuo.

Reference： [1]Current Patent Assignee: UBE INDUSTRIES LIMITED - EP1481971, 2004, A1 Location in patent: Page 8-9
[2]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2006/66267, 2006, A2 Location in patent: Page/Page column 22
[3]Current Patent Assignee: NATCO PHARMA LIMITED - US2011/263852, 2011, A1
[4]Current Patent Assignee: YANCHENG TEACHERS UNIVERSITY; INSTITUTE OF DAFENG MARINE INDUSTRY NANJING UNIV O - CN108440420, 2018, A
[5]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2007/121279, 2007, A2 Location in patent: Page/Page column 28; 44

25
[ 97674-02-7 ]
[ 231278-20-9 ]
N-((4-(3-fluorobenzyloxy)-chlorophenyl)-6-(1-ethoxyvinyl)-quinazolin-4-yl)-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	In acetonitrile for 18h; Heating / reflux;	N-(4-(3-fluorobenzyloxy)-chlorophenyl)-6-(1-ethoxyvinylether)-quinazolin-4-yl)-amine N-(4-(3-fluorobenzyloxy)-chlorophenyl)-6-(1-ethoxyvinylether)-quinazolin-4-yl)-amine To a suspension of the 6-iodo-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-quinazolin-4-yl amine (12.6 g, 24.93 mmol) in acetonitrile (100 mL) was added tributyl(1-ethoxyvinyl)stannane (9 g, 24.93 mmol) and bis(triphenylphosphine) palladium (II) chloride (1.75 g, 2.29 mmol). The reaction mixture was refluxed for 18 h, then filtered through a plug of silica gel. The resulting solution was poured into 5% aqueous NH4OH (200 mL) and extracted with ethyl acetate (500 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to provide the title compound as a yellow solid (7.2 g, 64% yield). 1H NMR (400 MHz, d6 DMSO) δ 9.92 (s, 1H), 8.76 (s, 1H), 8.58 (s, 1H), 8.08 (m, 1H), 8.01 (m, 1H), 7.76 (m, 2H), 7.48 (m, 1H), 7.32 (m, 3H), 7.22 (m, 1H), 5.28 (s, 2H), 5.02 (s, 1H), 4.56 (s, 1H), 4.01 (q, 2H), 1.42 (t, 3H); ESI-MS m/z 449.9 (M+H)+.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - US6933299, 2005, B1 Location in patent: Page/Page column 78-79

26
[ 98-01-1 ]
[ 7647-10-1 ]
[ 231278-20-9 ]
5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde 4-methylbenzenesulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.5 g (55%)	With N2; potassium acetate; In 1,2-dimethoxyethane; water; N,N-dimethyl-formamide;	Example 6 Regioselective Preparation of 5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde 4-methylbenzenesulfonate A mixture of 2-furaldehyde (5.7 mL, 69 mmol), potassium acetate (1.4 g, 14 mmol), and palladium(II)chloride (61 mg, 0.35 mmol) in 35 mL of DMF was degassed for 10 minutes by vigorously bubbling N2 through the mixture while stirring. The catalyst mixture was subsequently warmed to 110 C. A solution of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodo-4-quinazolinamine (3.5 g, 6.9 mmol) in 55 mL of DMF was degassed in a similar manner and then added to the catalyst mixture via syringe pump over 10 hours. After the addition was complete, the reaction temperature was maintained at 110 C. for an additional two hours. After cooling to room temperature, the mixture was poured into 125 mL of water. The precipitate was collected on coarse filter paper and washed with water (ca. 7 mL). The solid was re-dissolved in warm (50 C.) DME. To this solution was added (2.0 g; 10.4 mmol) of p-toluenesuflonic acid monohydrate. The temperature was lowered to 35 C. and the mixture was stirred at this temperature overnight Water (60 mL) was added to induce further precipitation. The product was collected on coarse filter paper and subsequently washed with 30-40 mL of DME/water (1:1). The filter cake was dried at 50 C. under house vacuum overnight to provide 2.5 g (55%) of the title compound. 1H NMR (d6-DMSO) delta: 11.44 (s, 1H), 9.38 (s, 2H), 9.11 (s, 1H), 8.90 (s, 1H), 8.39 (dd, 1H, J=8 and 4 Hz), 7.89 (d, 1H, J=12 Hz), 7.84 (d, 1H, J=4 Hz), 7.60 (dd, 1H, J=8 and 4 Hz), 7.47-7.42 (m, 2H), 7.44 (AA'BB', 2H, JAB=8 Hz), 7.35-7.25 (m, 3H), 7.24 (d, 1H. J=4 Hz), 7.16 (dt, 1H, J=8 and 4 Hz), 7.06 (AA'BB', 2H, JAB=8 Hz, 6.84 (d, 1H, J=4 Hz), 5.27 (s, 2H), 4.43 (s, 2H), 3.61-3.50 (m, 2H), 3.47-3.36 (m, 2H), 3.09 (s, 3H), 2.23 (s, 6H).

Reference： [1]Patent: US2003/220354,2003,A1

27
[ 231278-20-9 ]
5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde 4-methylbenzenesulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride In methanol; 1,2-dimethoxyethane; Hg; ethanol; water	2.ii (ii) (ii) Preparation of 5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde 4-methylbenzenesulfonate Using In Situ Prepared 2-diethylacetal-5-boronic Acid To the reaction mixture from above was added 3.4 vol (3.7L) of ethanol over a 5 minute period via vacuum addition. Triethylamine, 0.69 vol (760 mL, 5.45 mol) was added followed by 1 wt (1100 g, 2.18 mol) of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodo-4-quinazolinamine and 3 wt % of 10% Pd/C [Palladium, 10 wt % (dry basis) on Activated Carbon, 500/o Water Wet, Degussa Type E101NE/W]. The reactor, in reactor control mode, was set to 62° C. The internal temperature was observed to rise to 58° C. over ca. 2 hrs. After ca. 14 hours, an aliquot was removed for an in-process check. [Sample preparation: 15 μL was diluted with 1 mL of MeOH and 250 μL of 1 N HCl and subjected to Fast LC at 220 nM.] At this time, the reactor was cooled to 25° C. The dark reaction mixture was transferred to the second reactor through a teflon-lined stainless steel jacketed transfer hose outfitted with an in-line 5.0 μm cartridge filter (Pall part no. R1f050, lot no. FJ0807) and an in-line 0.45 μm filter (Meisner CLMF 0.4-662, lot no. 4087-R-#F). The first reactor was rinsed with 0.5 vol of DME and was passed through the transfer hose so as to wash the solids through the filter cartridges. p-Toluenesulfonic acid monohydrate, 1.55 wt (1700 g, 8.72 mol) was dissolved in 2.27 vol of deionized water and the solution was added to the reaction mixture over 5 minutes. After stirring at 25° C. for 1 hour, the product was collected in a ceramic filter lined with medium filter paper. The reactor and filter cake were rinsed with 0.9 vol of a 1:1 DME/water solution. After suctioning dry for 4 hours, the yellow filter cake was transferred to two glass trays and placed in the drying oven (50-55° C.) under house vacuum (18 in Hg) with a nitrogen bleed. The two glass trays were removed from the oven and allowed to cool to room temperature and sampled accordingly. The isolated yield of the title compound was 1230 grams (1.12 wt., 87% th; 1410 g Th) which existed as a yellowish solid. 1H NMR (d6-DMSO) δ: 11.44 (s, 1H), 9.38 (s, 2H), 9.11 (s, 1H), 8.90 (s, 1H), 8.39 (dd, 1H, J=8 and 4 Hz), 7.89 (d, 1H, J=12 Hz), 7.84 (d, 1H, J=4 Hz), 7.60 (dd, 1H, J=8 and 4 Hz), 7.47-7.42 (m, 2H), 7.44 (M'BB', 2H, JAB=8 Hz), 7.35-7.25 (m, 3H), 7.24 (d, 1H, J=4 Hz), 7.16 (dt, 1H, J=8 and 4 Hz), 7.06 (AA'BB', 2H, JAB=8 Hz, 6.84 (d, 1H, J=4 Hz), 5.27 (s, 2H), 4.43 (s, 2H), 3.61-3.50 (m, 2H), 3.47-3.36 (m, 2H), 3.09 (s, 3H), 2.23 (s, 6H).
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / palladium 10% on activated carbon / ethanol / 3 h / 70 °C 2: tetrahydrofuran; ethanol; water / 4 h / 25 - 65 °C
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / palladium 10% on activated carbon / ethanol / 3 h / 70 °C 2: ethanol; water / 4 h / 25 - 65 °C

	Multi-step reaction with 2 steps 1.1: palladium 10% on activated carbon / ethanol; water / 0.08 h 1.2: 3 h / 70 °C 2.1: tetrahydrofuran; ethanol; isopropyl methanesulfonate; water / 2.08 h / 20 - 65 °C
	Multi-step reaction with 2 steps 1.1: palladium 10% on activated carbon / isopropyl methanesulfonate / 0.08 h 1.2: 3 h / 70 °C 2.1: isopropyl methanesulfonate; water / 4.08 - 4.17 h / 25 - 65 °C

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2003/220354, 2003, A1
[2]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2005/120512, 2005, A2
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2005/120504, 2005, A2
[4]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2007/121279, 2007, A2
[5]Current Patent Assignee: GLAXOSMITHKLINE PLC; KUMAR - WO2005/105094, 2005, A2

28
[ 27329-70-0 ]
[ 104-15-4 ]
[ 231278-20-9 ]
5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde 4-methylbenzenesulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 5-formylfurane-2-boronic acid; N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine In isopropyl methanesulfonate for 0.0833333h; Stage #2: With N-ethyl-N,N-diisopropylamine In isopropyl methanesulfonate at 70℃; for 3h; Stage #3: toluene-4-sulfonic acid In tetrahydrofuran; isopropyl methanesulfonate; water at 25 - 65℃; for 4h;	1.2 STAGE 2; A mixture of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodo-4-quinazolinamine - compound D (1wt), boronic acid - compound E (0.37wt , 1.35equiv), and 10% palladium on charcoal (0.028wt ,50% water wet) was slurried in IMS (15vol). The resultant suspension was stirred for 5 minutes, treated with di-isopropylethylamine (0.39vol, 1.15equiv) and then heated to ca 700C for ca 3 hours when the reaction was complete (determined by HPLC analysis). The mixture was diluted with tetrahydrofuran (THF, 15vol) and then hot-filtered to remove the catalyst. The vessel was rinsed with IMS (2vol).A solution of p-toluenesulfonic acid monohydrate (1.5wt, 4 equiv) in water (1.5vol) was added over 5-10 minutes to the filtered solution maintained at 65°C. After crystallisation the suspension was stirred at 60°-65°C for 1 hour, cooled to ca 25°C over1 hour and stirred at this temperature for a further 2 hours. The solid was collected by filtration, washed with IMS (3vol) then dried in vacuo at ca 500C to give the compound F as a yellow-orange crystalline solid (isolated as the ethanol solvate containing approximately 5%w/w EtOH).
	Stage #1: 5-formylfurane-2-boronic acid; N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine In industrial methylated spirit (IMS); water for 0.0833333h; Stage #2: With N-ethyl-N,N-diisopropylamine In industrial methylated spirit (IMS); water at 70℃; for 3h; Stage #3: toluene-4-sulfonic acid In tetrahydrofuran; industrial methylated spirit (IMS); water at 60 - 65℃; for 3h;	1b.2 A mixture of N- {3-chloro-4- [ (3-fluorobenzyl) oxy] phenyl}-6-iodo-4- quinazolinamine (1wt), boronic acid (0.37wt, 1.35equiv), and 10% palladium on charcoal (0.028wt, 50% water wet) was slurried in IMS (15vol). The resultant suspension was stirred for 5 minutes, treated with di-isopropylethylamine (0. 39vol, 1.15equiv) and then heated to ca 70°C for ca 3 hours when the reaction was complete (determined by HPLC analysis). The mixture was diluted with tetrahydrofuran (THF, 1 5vol) and then filtered (hot-through GFA filter paper) to remove catalyst. The vessel was rinsed with IMS (2vol). A solution of p-toluenesulfonic acid monohydrate (1.54wt, 4. 1equiv) in water (3vol) was added over 5-10 minutes to the filtered solution maintained at 65°C. After crystallisation the suspension was stirred at 60°-65°C for 1 hour, cooled to ca 25°C over 1 hour and stirred at this temperature for a further 2 hours. The solid was collected by filtration, washed with IMS (3vol) then dried in vacuo at ca 50°C to give the tile compound as a yellow-orange crystalline solid.
	Stage #1: 5-formylfurane-2-boronic acid; N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine With potassium carbonate In ethanol for 0.5h; Reflux; Stage #2: toluene-4-sulfonic acid In tetrahydrofuran; ethanol; water at 60℃;	1 Example 1 : Preparation of lapatinib aldehyde monotosylate[00083] In a 500 ml round-bottomed flask were added 1O g of compound ofFormula C, 3.7 g of 5-formyl-2-furanboronic acid, 0.2 g of palladium(II) acetate, 5.5 g of Potassium carbonate and 150 ml of absolute ethanol. The suspension was stirred and heated to reflux for 30 minutes. The reaction mixture was cooled to 250C and diluted with 150 ml of THF. Inorganic salts were filtered off in vacuum and discarded. The filtrate was transferred into 500 ml round-bottomed flask and heated to 600C. The solution of 11.3 gr of p-toluenesulfonic acid in 15 ml of water was added drop-wise. The resulting light- orange suspension was stirred at 600C for an 1 hour. Then, the heating source was removed and the mixture was stirred at 250C for 2 hours, cooled to 5°C and stirred for 0.5 hours. The precipitated yellow solid was filtered in vacuum and washed over the filter with absolute ethanol (3 x 50 ml). It was allowed to dry in a vacuum oven at 25°C for 16 hours to give 15.7 g of the final product, which was identified as lapatinib aldehyde monotosylate. Purity 97.95%

Stage #1: 5-formylfurane-2-boronic acid; N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine In ethanol; water for 0.0833333h; Stage #2: With N-ethyl-N,N-diisopropylamine In ethanol; water at 70℃; for 3h; Stage #3: toluene-4-sulfonic acid In water at 25 - 65℃; for 4.08333 - 4.16667h;

1.2 A mixture of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodo-4- quinazolinamine - compound D (1wt), boronic acid - compound E (0.37wt , 1.35equiv), and 10% palladium on charcoal (0.028wt ,50% water wet) was slurried in IMS (15vol). The resultant suspension was stirred for 5 minutes, treated with di- isopropylethylamine (0.39vol, 1.15equiv) and then heated to ca 700C for ca 3 hours when the reaction was complete (determined by HPLC analysis). The mixture was diluted with tetrahydrofuran (THF, 15vol) and then hot-filtered to remove the catalyst. The vessel was rinsed with IMS (2vol).A solution of p-toluenesulfonic acid monohydrate (1.5wt, 4 equiv) in water (1.5vol) was added over 5-10 minutes to the filtered solution maintained at 65°C. After crystallisation the suspension was stirred at 60°-65°C for 1 hour, cooled to ca 25°C over 1 hour and stirred at this temperature for a further 2 hours. The solid was collected by filtration, washed with IMS (3vol) then dried in vacuo at ca 500C to give the compound F as a yellow-orange crystalline solid (isolated as the ethanol solvate containing approximately 5%w/w EtOH).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2008/67144, 2008, A2 Location in patent: Page/Page column 24
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2005/46678, 2005, A1 Location in patent: Page/Page column 68
[3]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2010/17387, 2010, A2 Location in patent: Page/Page column 19-20
[4]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/26313, 2006, A2 Location in patent: Page/Page column 24

29
[ 443882-99-3 ]
[ 98556-31-1 ]
[ 231278-20-9 ]

Yield	Reaction Conditions	Operation in experiment
		Example 6: N-r3-Chloro-4-(3-Fluorobenzyloxy)-Phenyll-6-Iodoquinazolin-4-amine preparation (one-pot process)[00088] 30.0 g of "Intermediate-A" (compound of Formula A), 17.8 g of iron powder (70 mesh), 51.3 g of ammonium chloride, 432 ml of ethanol and 108 ml of water were refluxed for 5 hours in IL reactor equipped with mechanical stirrer and condenser. The reaction mixture was then cooled to 20-250C and separated from insoluble iron oxide by vacuum filtration. The filtered solids were washed with ethanol (4 x 100 ml). The resulting filtrate was evaporated from reactor under reduced pressure to resulting in a wet orange residue. The residue was dissolved in 350 ml of dichloromethane and 300 ml water. The separated organic phase was washed with water (2 x 300 ml). The obtained organic solution was concentrated to about 150 ml followed by addition of 300 ml iso- propanol. The mixture was concentrated to 300 ml followed by addition 150 ml iso- propanol. The resulting mixture was concentrated to 300 ml. Then iso-propanol was added to obtain a final volume of about 570 ml (purity determined by HPLC: 98.5%).[00089] 23.8 g of <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> were added to the organic solution, heated to reflux, stirred for 30 minutes and then cooled to 20-250C. The slurry was filtered and washed with 110 ml iso-propanol to obtain 53.5 g of wet crude product. Then it was triturated in 830 ml of boiling acetone for an hour, cooled and filtered. The product was triturated twice again each time in 655 ml of boiling acetone for an hour, cooled and filtered. Finally it was dried at 250C in vacuum oven to afford 32.2 g of "Intermediate-C" (Yield: 60%, Purity: 92.62%).

Reference： [1]Patent: WO2010/17387,2010,A2 .Location in patent: Page/Page column 21-22

30
[ 1227853-05-5 ]
[ 132131-24-9 ]
[ 231278-20-9 ]

Yield	Reaction Conditions	Operation in experiment
		(ii) Preparation of N-[3-chloro-4-[(3-fluorobenzyloxy)phenyl]-6-iodo-quinazolin amine (3)Into a one liter four-necked round bottomed flask, 50OmL of xylene, 50.0 g of N'-^-chloro- 4-(3-fluorobenzyloxy)phenyl)-N,N-dimethylformamidine obtained by the process given in example-(l), 40 g of <strong>[132131-24-9]2-amino-5-iodobenzonitrile</strong> obtained by the process given in above step (i) and 25 mL of acetic acid were charged under stirring. The reaction was maintained at reflux condition for 10 hours and the completion of the reaction was monitored by TLC. The solvent was distilled off completely under vacuum and cooled to room temperature. 100 mL of isopropylalcohol was added and adjusted the pH to basic (about 10) with aqueous ammonia solution. The mass was maintained at that temperature for about lhr. The mass was cooled to room temperature and filtered and dried to get 70.0 g of N-[3-chloro-4-[(3- fluorobenzyloxy)phenyl]-6-iodo-quinazolinamine as a pale yellow coloured crystalline powder.Purity: 99.43% by HPLC Melting point range: 222-225 C
	With acetic acid; In xylene; for 10h;Reflux;	(ii) Preparation of N-[3-chloro-4-[(3-fluorobenzyloxy)phenyl]-6-iodo-quinazolin amine (3)Into a one liter four-necked round bottomed flask, 500 mL of xylene, 50.0 g of N1-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-N,N-dimethylformamidine obtained by the process given in example-(1), 40 g of <strong>[132131-24-9]2-amino-5-iodobenzonitrile</strong> obtained by the process given in above step (i) and 25 mL of acetic acid were charged under stirring. The reaction was maintained at reflux condition for 10 hours and the completion of the reaction was monitored by TLC. The solvent was distilled off completely under vacuum and cooled to room temperature. 100 mL of isopropylalcohol was added and adjusted the pH to basic (about 10) with aqueous ammonia solution. The mass was maintained at that temperature for about 1 hr. The mass was cooled to room temperature and filtered and dried to get 70.0 g of N-[3-chloro-4-[(3-fluorobenzyloxy)phenyl]-6-iodo-quinazolinamine as a pale yellow coloured crystalline powder.Purity: 99.43% by HPLCMelting point range: 222-225 C.

Reference： [1]Patent: WO2010/61400,2010,A1 .Location in patent: Page/Page column 14-15
[2]Patent: US2011/263852,2011,A1 .Location in patent: Page/Page column 11-12

31
[ 27329-70-0 ]
[ 104-15-4 ]
[ 231278-20-9 ]
[ 231278-84-5 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 5-formylfurane-2-boronic acid; N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine In ethanol; water for 0.0833333h; Stage #2: With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; ethanol; water at 70℃; for 3h; Stage #3: toluene-4-sulfonic acid In tetrahydrofuran; ethanol; water at 65℃; for 0.0833333h;	2.2 A mixture of /V-(3-chloro-4-[(3-fluorophenyl)methyl]oxy}phenyl)-6- iodo-4-quinazolinamine (1 wt), (5-formyl-2-furanyl)boronic acid (0.374 wt, 1.35eq) and 10% Palladium on charcoal (0.028 wt 50% water wet) is slurried in ethanol (industrial methylated spirits, 15 vols) to give a grey suspension. The resultant slurry is stirred for 5 minutes and then treated with /V,Λ/-di-isopropylethylamine (0.396 vols, 1.15eq.). The reaction slurry is heated to 700C for typically 3 hours when the reaction is complete (by HPLC analysis). The mixture is a thick green slurry at this point which is treated with THF (15 vols ) to dissolve the product that has precipitated, leaving only the Pd/C catalyst out of solution. The mixture is then filtered hot through GFA filter to remove the catalyst. The vessel is rinsed with IMS (1vol) and the wash used to rinse catalyst bed. A solution of p-toluenesulfonic acid monohydrate (1.50wt, 4.0 eq.) in water (1.5 vols) is added to the filtered solution over 5 minutes at 65°C. The reaction solution is cooled to 600C, with crystallization observed at 60-65°C. The resultant slurry is then stirred for at least 1 hour at 600C and then cooled to 20-250C and then held at this temperature for a further 1 hour. The product is isolated by filtration and the cake washed with IMS (3vols). The product may be stored as a wet cake or dried.

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2006/113649, 2006, A1 Location in patent: Page/Page column 47

32
2-carboxythiophene-5-boronic acid [ No CAS ]
[ 231278-20-9 ]
5-{4-[3-chloro-4-(3-fluorobenzyloxy)phenylamino]quinazolin-6-yl}thiophene-2-carboxylic acid dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	Stage #1: 2-carboxythiophene-5-boronic acid; N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine With bis(triphenylphosphine)palladium(II) dichloride; sodium carbonate In 1,2-dimethoxyethane; ethanol; water at 60℃; Inert atmosphere; Stage #2: With hydrogenchloride In water; ethyl acetate Inert atmosphere;

Reference： [1]Mahboobi, Siavosh; Sellmer, Andreas; Winkler, Matthias; Eichhorn, Emerich; Pongratz, Herwig; Ciossek, Thomas; Baer, Thomas; Maier, Thomas; Beckers, Thomas [Journal of Medicinal Chemistry, 2010, vol. 53, # 24, p. 8546 - 8555]

33
[ 852228-11-6 ]
[ 231278-20-9 ]
[ 1152131-73-1 ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 8546 - 8555

34
[ 87199-16-4 ]
[ 231278-20-9 ]
[ 944549-53-5 ]

Yield	Reaction Conditions	Operation in experiment
54%	With bis(triphenylphosphine)palladium(II) dichloride; sodium carbonate In 1,2-dimethoxyethane; ethanol; water at 60℃; Inert atmosphere;

Reference： [1]Mahboobi, Siavosh; Sellmer, Andreas; Winkler, Matthias; Eichhorn, Emerich; Pongratz, Herwig; Ciossek, Thomas; Baer, Thomas; Maier, Thomas; Beckers, Thomas [Journal of Medicinal Chemistry, 2010, vol. 53, # 24, p. 8546 - 8555]

35
[ 87199-17-5 ]
[ 231278-20-9 ]
[ 1152131-72-0 ]

Yield	Reaction Conditions	Operation in experiment
97%	With bis(triphenylphosphine)palladium(II) dichloride; sodium carbonate In 1,2-dimethoxyethane; ethanol; water at 60℃; Inert atmosphere;

Reference： [1]Mahboobi, Siavosh; Sellmer, Andreas; Winkler, Matthias; Eichhorn, Emerich; Pongratz, Herwig; Ciossek, Thomas; Baer, Thomas; Maier, Thomas; Beckers, Thomas [Journal of Medicinal Chemistry, 2010, vol. 53, # 24, p. 8546 - 8555]

36
(5-formylthiophen-2-yl)boronic acid [ No CAS ]
[ 231278-20-9 ]
[ 1152131-71-9 ]

Yield	Reaction Conditions	Operation in experiment
59%	With bis(triphenylphosphine)palladium(II) dichloride; sodium carbonate In 1,2-dimethoxyethane; ethanol; water at 60℃; Inert atmosphere;

Reference： [1]Mahboobi, Siavosh; Sellmer, Andreas; Winkler, Matthias; Eichhorn, Emerich; Pongratz, Herwig; Ciossek, Thomas; Baer, Thomas; Maier, Thomas; Beckers, Thomas [Journal of Medicinal Chemistry, 2010, vol. 53, # 24, p. 8546 - 8555]

37
[ 5326-47-6 ]
[ 231278-20-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: ammonium acetate / Inert atmosphere 1.2: 95 °C / 750.08 - 2250.23 Torr / Inert atmosphere 2.1: triethylamine; trichlorophosphate / toluene / 2 h / Heating; Inert atmosphere 3.1: 1 h / Heating; Inert atmosphere
	Multi-step reaction with 3 steps 1: Reflux 2: thionyl chloride; N,N-dimethyl-formamide / Reflux 3: isopropyl alcohol / 2 h / 80 °C
	Multi-step reaction with 4 steps 1: formamide / 12 h / 180 °C 2: tetraphosphorus decasulfide / pyridine / 0.5 h / 100 °C 3: sodium methylate; sodium hydroxide / 5.5 h / 25 °C 4: isopropyl alcohol / 15 h / 40 °C / Reflux

Reference： [1]Mahboobi, Siavosh; Sellmer, Andreas; Winkler, Matthias; Eichhorn, Emerich; Pongratz, Herwig; Ciossek, Thomas; Baer, Thomas; Maier, Thomas; Beckers, Thomas [Journal of Medicinal Chemistry, 2010, vol. 53, # 24, p. 8546 - 8555]
[2]Ding, Chao; Chen, Shaopeng; Zhang, Cunlong; Hu, Guangnan; Zhang, Wei; Li, Lulu; Chen, Yu Zong; Tan, Chunyan; Jiang, Yuyang [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 1, p. 27 - 37]
[3]Current Patent Assignee: LUOXIN PHARMACEUTICALS GROUP STOCK CO LTD - CN105111193, 2018, B

38
[ 5582-62-7 ]
[ 231278-20-9 ]
[ 1260402-31-0 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: 1-trimethylsilyloxy-2-propyne; N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine With copper(l) iodide; triethylamine In N,N-dimethyl-formamide at 40℃; Stage #2: With hydrogenchloride In methanol; water at 20℃; for 1h; Stage #3: With triethylamine In methanol at 20℃; for 1h;	10.A Step A: 3-(4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)quinazolin-6-yl)prop-2-yn-l -ol (compound 10.1)[0134] To a solution of N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-iodoquinazolin-4-amine (1.52 g), trimethyl(prop-2-ynyloxy)silane (0.7 mL), triethyl amine (0.5 mL) in DMF (10 mL) was added Pd(PPh3)2C12 (106 mg), CuI (114 mg) and the mixture was heated at 40 0C overnight. The solvent was removed, then methanol (10 mL) and 4N HCl (2 mL) were added. The reaction mixture was stirred at room temperature for one hour and the solvent was removed. Another 10 mL methanol and triethyl amine (2 mL) were added and the reaction mixture was stirred at room temperature for one hour. The solvent was removed and the residue was purified by flash chromatography, eluting with EtOAc to give the desired product. LCMS ESI(+) m/z: 434 (M+l). Yield: 86%.

Reference： [1]Current Patent Assignee: KANGYUAN PHARMCEUTICAL; JIANGSU KANION PHARMACEUTICAL CO., LTD. - WO2011/2523, 2011, A1 Location in patent: Page/Page column 54-55

39
[ 231278-20-9 ]
[ 1260402-32-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: triethylamine; copper(l) iodide / bis-triphenylphosphine-palladium(II) chloride / N,N-dimethyl-formamide / 40 °C 1.2: 1 h / 20 °C 1.3: 1 h / 20 °C 2.1: triethylamine / dichloromethane / 0 - 20 °C

Reference： [1]Current Patent Assignee: KANGYUAN PHARMCEUTICAL; JIANGSU KANION PHARMACEUTICAL CO., LTD. - WO2011/2523, 2011, A1

40
[ 231278-20-9 ]
[ 1260401-99-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: triethylamine; copper(l) iodide / bis-triphenylphosphine-palladium(II) chloride / N,N-dimethyl-formamide / 40 °C 1.2: 1 h / 20 °C 1.3: 1 h / 20 °C 2.1: triethylamine / dichloromethane / 0 - 20 °C 3.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 - 20 °C

Reference： [1]Current Patent Assignee: KANGYUAN PHARMCEUTICAL; JIANGSU KANION PHARMACEUTICAL CO., LTD. - WO2011/2523, 2011, A1

41
[ 1260402-34-3 ]
[ 231278-20-9 ]
[ 1260402-00-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In N,N-dimethyl-formamide at 85℃; for 4h; Inert atmosphere;	11.B Step B: N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-((E)-3 -(4-methyl- 1, 4-azaphosphino-l - yl)prop-l-enyl)quinazolin-4-amine (compound 11)[0138] Under nitrogen atmosphere, Pd(dppf)2Cl2 (85 mg) was added to a mixture of 1-allyl- 4-methyl-l,4-azaphosphinane 4-oxide (compound 11.1, 400 mg), -(4-(3-fluorobenzyloxy)- 3-chlorophenyl)-6-iodoquinazolin-4-amine (1.4 g) and triethyl amine (1 mL) in DMF (10 mL). The reaction mixture was heated at 85 0C for 4 h and cooled down to roomtemperature. Ethyl acetate (100 mL ) was added and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with 20% methanol indichloromethane to give the desired product as yellow crystalline solid. LCMS ESI(+) m/z: 551 (M+l). 1H NMR (300 MHz, CDCl3) δ 8.70 (m, 2H), 8.28 (s, IH), 7.86 (m, 2H), 7.63 (m, IH), 7.36 (m, IH), 7.25 (m, 2H), 6.97 (m, IH), 5.62 (s, IH), 5.38 (s, 1H),5.15 (s, 2H), 3.50 (s, 2H), 3.05 (m, 2H), 2.78 (m, 2H), 2.02 (m, 2H), 1.80 (m, 2H), 1.50 (d, 3H).

Reference： [1]Current Patent Assignee: KANGYUAN PHARMCEUTICAL; JIANGSU KANION PHARMACEUTICAL CO., LTD. - WO2011/2523, 2011, A1 Location in patent: Page/Page column 56

42
[ 1885-29-6 ]
[ 231278-20-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: Iodine monochloride; acetic acid / 3 h / 25 - 35 °C 2: 2 h / 70 - 75 °C 3: acetic acid / 2 h / 115 - 120 °C
	Multi-step reaction with 2 steps 1: acetic acid / 3 h / 25 - 35 °C 2: acetic acid / xylene / 10 h / Reflux
	Multi-step reaction with 3 steps 1: ammonium iodide; acetic acid; dihydrogen peroxide / 12 h / 20 °C 2: acetic acid / toluene / 0.5 h / 35 °C 3: acetic acid / 0.25 h / 125 - 130 °C

	Multi-step reaction with 3 steps 1: acetic acid; ammonium iodide; dihydrogen peroxide / 12 h / 20 °C 2: acetic acid / 0.5 h / 35 °C 3: acetic acid / 0.25 h / 130 °C
	Multi-step reaction with 3 steps 1.1: ammonium iodide; acetic acid / 0.5 h / 20 °C 1.2: 12 h / 20 °C 2.1: acetic acid / toluene / 0.5 h / 35 °C 3.1: acetic acid / 125 - 130 °C

Reference： [1]Current Patent Assignee: NATCO PHARMA LIMITED - WO2011/39759, 2011, A1
[2]Current Patent Assignee: NATCO PHARMA LIMITED - US2011/263852, 2011, A1
[3]Zhang, Yaling; Zhang, Ying; Liu, Juan; Chen, Li; Zhao, Lijun; Li, Baolin; Wang, Wei [Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 7, p. 1584 - 1587]
[4]Zhang, Yaling; Gao, Hongliang; Liu, Renjie; Liu, Juan; Chen, Li; Li, Xiabing; Zhao, Lijun; Wang, Wei; Li, Baolin [Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 18, p. 4309 - 4313]
[5]Zhang, Yaling; Chen, Li; Li, Xiabing; Gao, Li; Hao, Yunxia; Li, Baolin; Yan, Yaping [Journal of Enzyme Inhibition and Medicinal Chemistry, 2019, vol. 34, # 1, p. 1668 - 1677]

43
[ 231278-20-9 ]
[ 388082-78-8 ]

Reference： [1]Patent: WO2011/39759,2011,A1
[2]Patent: US2011/263852,2011,A1
[3]Patent: WO2012/17448,2012,A2
[4]Patent: CN105503839,2016,A
[5]Patent: WO2005/120512,2005,A2
[6]Patent: WO2005/120504,2005,A2
[7]Patent: WO2007/121279,2007,A2
[8]Patent: WO2005/105094,2005,A2
[9]Patent: WO2005/105094,2005,A2

44
[ 231278-20-9 ]
[ 1227853-06-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triethylamine; 1,2-dimethoxyethane / palladium 10% on activated carbon / methanol / Inert atmosphere 2: triethylamine / methanol / 12 h / Reflux
	Multi-step reaction with 2 steps 1: triethylamine / palladium 10% on activated carbon / 1,2-dimethoxyethane; methanol / 15 h / 45 - 50 °C / Inert atmosphere 2: triethylamine / methanol / 12 h / Reflux

Reference： [1]Current Patent Assignee: NATCO PHARMA LIMITED - WO2011/39759, 2011, A1
[2]Current Patent Assignee: NATCO PHARMA LIMITED - US2011/263852, 2011, A1

45
[ 132131-24-9 ]
[ 231278-20-9 ]

Reference： [1]Patent: WO2011/39759,2011,A1
[2]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1584 - 1587
[3]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 4309 - 4313
[4]Journal of Enzyme Inhibition and Medicinal Chemistry,2019,vol. 34,p. 1668 - 1677

46
[ 903597-10-4 ]
[ 202197-26-0 ]
[ 231278-20-9 ]

Yield	Reaction Conditions	Operation in experiment
99.3%	With acetic acid In N,N-dimethyl-formamide at 130℃; for 1h;	2.3 Preparation of lapatinib intermediate 4-[3-chloro-4-(3-fluorobenzyloxy)phenylamino]-6-iodoquinazoline N-dimethylformamidine, 0.72 g (6.15 mmol) of N '- [2-cyano-4,5-bis (2-methoxyethoxy) phenyl] ) Of 3-aminophenylacetylene and 8 mL of acetic acid were reacted in a 50 mL reaction flask at 125 ° C for 1 hour and cooled to room temperature.20 mL of ice water was added to the mixture, the pH was adjusted to 10 with aqueous ammonia, and the mixture was stirred for 1 hour, suction filtered and the filter cake washed with water until neutral.The filter cake was dried to obtain 2.15 g of erlotinib in a yield of 91.5%.
92.5%	With acetic acid at 125 - 130℃; for 0.25h;	1.2.3 General method for preparation of 4-arylamino-6-iodoquinazoline (C1-4) General procedure: To B (3.00 mmol) were added acetic acid (3.0 mL) and R2 substituted aniline (3.30 mol). The reaction mixture was heated to 125 - 130 °C and stirred for 15 min. The reaction mixture was then cooled to 25 °C. The acetic acid was evaporated. The reaction mixture was quenched in ice-water (25 mL), and adjusted pH~9 with ammonia solution. The mixture was stirred for 0.5 h. The precipitated product was filtered, and the filter cake was washed with water (3 × 10 mL) to afford crude product. The crude product was chromatographed by silica gel, eluting with EtOAc/PE (1:4) to afford residue C1-4 as white solid (yield 84.3~92.5%). 3 1.2.1.1 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (C1) Yield 92.5%. 1H NMR (300 MHz, DMSO-d6) δ(ppm): 9.85 (s, 1H), 8.95 (d, J = 2.0 Hz, 1H), 8.61 (s, 1H), 8.11 (dd, J = 12.0 Hz, 1H), 8.03 (d, J = 3.6 Hz ,1H), 7.75 (dd, J = 12.0 Hz, 1H), 7.75 (dd, J = 12.0 Hz, 1H), 7.56 (d, J = 12.0 Hz,1H), 7.44-7.51 (m,1H), 7.29-7.35 (m, 3H), 7.15-7.22 (m, 1H), 5.26 (s, 2H) (Figure S1).
92.5%	With acetic acid at 130℃; for 0.25h;	1.2.1 General method for preparation of 4-arylamino-6-iodoquinazoline (13a-13c) General procedure: Followed we described previously, substituted aniline (3.3 mol). The reaction mixture was heated to 130 and stirred for 15 min. The reaction mixture was then cooled to 25 . The acetic acid was evaporated. The reaction mixture was quenched in ice-water (25.0 mL), and adjusted pH~9 with ammonia solution. The mixture was stirred for 0.5 h. The precipitated product was filtered, and the filter cake was washed with water (3 × 10 mL) to afford crude product. The crude product was chromatographed by silica gel, eluting with EtOAc/PE (1:4) to afford residue 13a-13c as white solid (yield 84.3% ~ 92.5%). 1.2.1.1 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-iodoquinazoline (13a) White power, yield: 92.5%.

92.5%	With acetic acid at 125 - 130℃;
	With acetic acid at 115 - 120℃; for 2h;	1.iii (iii) Preparation of N-[3-chIoro-4-[(3-fluorobenzyIoxy)phenyl]-6-iodo- quinazolin amine (3) Into a one liter four-necked round bottomed flask, 500mL of acetic acid, 50.0 g of N'- (2-cyano-4-iodo-phenyl)-N, N-dimethyl formamidine of the formula-(8) obtained according to the process given in the above step (ii) 51.0 g 3-chloro-4-(3'- fluorobenzyloxy)aniline were charged . The reaction mass was maintained at 115- 120° C for about 2 Hrs., the cooled to 25-35° C and quenched into ice cold water. The pH of the reaction mass was adjusted to basic by slow addition of aqueous ammonia solution and the reaction mass was filtered and dried at 70-75° C.Dry weight: 93.0 gPurity: 83.64% by HPLCThe purity of the product is enhanced by adopting the following procedure.

Reference： [1]Current Patent Assignee: SHAANXI NORMAL UNIVERSITY - CN103539702, 2016, B Location in patent: Paragraph 0072-0074
[2]Zhang, Yaling; Zhang, Ying; Liu, Juan; Chen, Li; Zhao, Lijun; Li, Baolin; Wang, Wei [Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 7, p. 1584 - 1587]
[3]Zhang, Yaling; Gao, Hongliang; Liu, Renjie; Liu, Juan; Chen, Li; Li, Xiabing; Zhao, Lijun; Wang, Wei; Li, Baolin [Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 18, p. 4309 - 4313]
[4]Zhang, Yaling; Chen, Li; Li, Xiabing; Gao, Li; Hao, Yunxia; Li, Baolin; Yan, Yaping [Journal of Enzyme Inhibition and Medicinal Chemistry, 2019, vol. 34, # 1, p. 1668 - 1677]
[5]Current Patent Assignee: NATCO PHARMA LIMITED - WO2011/39759, 2011, A1 Location in patent: Page/Page column 14

47
[ 16064-08-7 ]
[ 231278-20-9 ]

Reference： [1]Patent: US2011/281896,2011,A1
[2]Patent: CN105111193,2018,B
[3]Patent: CN105085496,2018,B
[4]Patent: WO2005/120512,2005,A2
[5]Patent: WO2005/120504,2005,A2

48
[ 98556-31-1 ]
[ 944483-37-8 ]
[ 231278-20-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide;Reflux;	Example 1 Preparation of N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-iodine-quinazolin-4-amine 6-Iodine-3H-quinazolin-4-ketone (100 g) was added into a 2000 mL flask, dissolved in a mixed solvent of thionyl chloride (1000 mL) and N,N-dimethylformamide (20 mL), heated to reflux until the reaction solution is clear and transparent. After thionyl chloride was removed, anhydrous toluene was added to the residues and removed under reduced pressure, and the process of the adding and removing of toluene was repeated again to removed the remained thionyl chloride residues. The intermediate was dissolved in isopropyl alcohol (2000 mL), 3-chloro-4-(3-fluoro-benzyloxy)-aniline hydrochloride was added, and anhydrous K2CO3 (150 g) was added with mechanical stirring before the mixture was heated to reflux over night. The reaction solution was cooled to room temperature overnight, the precipitation was filtered and washed with water for multi-times until the pH of washing solution reached neutral. After drying under vacuum, 95 g of the title product was collected in a pale white solid. m/z M+1+: 506

Reference： [1]Patent: US2011/281896,2011,A1 .Location in patent: Page/Page column 7

49
[ 231278-20-9 ]
[ 1235822-68-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: triethylamine / bis-triphenylphosphine-palladium(II) chloride / methanol / 2 h / Reflux 2.1: titanium(IV) isopropylate / tetrahydrofuran / 20 °C 3.1: tetrahydrofuran / 0.17 h / -80 °C 4.1: n-butyllithium / tetrahydrofuran / 0.5 h / -20 °C / Inert atmosphere 4.2: 0.17 h / -80 °C
	Multi-step reaction with 4 steps 1.1: triethylamine; bis-triphenylphosphine-palladium(II) chloride / methanol / 12 h / Reflux 2.1: titanium(IV) isopropylate / tetrahydrofuran / 4 h / Reflux 3.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -40 °C 3.2: 0.5 h / -40 °C 4.1: hydrogenchloride / ethanol / 0.5 h / 20 °C

Reference： [1]Current Patent Assignee: HANSOH PHARMACEUTICAL GROUP CO LTD - US2011/281896, 2011, A1
[2]Lyu, Aifeng; Fang, Lei; Gou, Shaohua [European Journal of Medicinal Chemistry, 2014, vol. 87, p. 631 - 642]

50
[ 231278-20-9 ]
[ 1235820-61-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: triethylamine / bis-triphenylphosphine-palladium(II) chloride / methanol / 2 h / Reflux 2: titanium(IV) isopropylate / tetrahydrofuran / 20 °C 3: tetrahydrofuran / 0.17 h / -80 °C

Reference： [1]Current Patent Assignee: HANSOH PHARMACEUTICAL GROUP CO LTD - US2011/281896, 2011, A1

51
[ 231278-20-9 ]
[ 1235820-63-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: triethylamine / bis-triphenylphosphine-palladium(II) chloride / methanol / 2 h / Reflux 2: titanium(IV) isopropylate / tetrahydrofuran / 20 °C 3: tetrahydrofuran / 0.17 h / -80 °C 4: triethylamine / tetrahydrofuran / 2 h / Reflux
	Multi-step reaction with 4 steps 1: triethylamine / bis-triphenylphosphine-palladium(II) chloride / methanol / 2 h / Reflux 2: titanium(IV) isopropylate / tetrahydrofuran / 20 °C 3: tetrahydrofuran / 0.17 h / -80 °C 4: formic acid / dimethyl sulfoxide / 20 °C

Reference： [1]Current Patent Assignee: HANSOH PHARMACEUTICAL GROUP CO LTD - US2011/281896, 2011, A1
[2]Current Patent Assignee: HANSOH PHARMACEUTICAL GROUP CO LTD - US2011/281896, 2011, A1

52
[ 231278-20-9 ]
[ 1235822-15-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: triethylamine / bis-triphenylphosphine-palladium(II) chloride / methanol / 2 h / Reflux 2.1: titanium(IV) isopropylate / tetrahydrofuran / 20 °C 3.1: n-butyllithium / tetrahydrofuran / 0.17 h / -20 °C / Inert atmosphere 3.2: 0.17 h / -80 °C

Reference： [1]Current Patent Assignee: HANSOH PHARMACEUTICAL GROUP CO LTD - US2011/281896, 2011, A1

53
[ 231278-20-9 ]
[ 1235824-04-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triethylamine / bis-triphenylphosphine-palladium(II) chloride / methanol / 2 h / Reflux 2: titanium(IV) isopropylate / tetrahydrofuran / 20 °C
	Multi-step reaction with 2 steps 1: triethylamine; bis-triphenylphosphine-palladium(II) chloride / methanol / 12 h / Reflux 2: titanium(IV) isopropylate / tetrahydrofuran / 4 h / Reflux

Reference： [1]Current Patent Assignee: HANSOH PHARMACEUTICAL GROUP CO LTD - US2011/281896, 2011, A1
[2]Lyu, Aifeng; Fang, Lei; Gou, Shaohua [European Journal of Medicinal Chemistry, 2014, vol. 87, p. 631 - 642]

54
5-formylfuran-2-boric acid [ No CAS ]
[ 231278-20-9 ]
[ 231278-84-5 ]

Yield	Reaction Conditions	Operation in experiment
95.5%	With palladium 10% on activated carbon; triethylamine In methanol; 1,2-dimethoxyethane; water at 50℃; for 24h;	1 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine Example 1 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine To a reaction flask N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodo-4-quinazolinamine (25.29g, 50mmol), 5-formylfuran-2-boric acid (10.50g, 75mmol), 10% palladium on carbon (1.25g, 54% water content), 1,2-dimethoxyethane (400ml), methanol (200ml) and triethylamine (21ml, 150mmol) were added. The mixture was heated to and kept at 50°C and stirring for 24 h. The resulting reactant is hot filtered under suction and the mixture, and the filtrate is rotary evaporated. Methanol (150ml) and water (50ml) were added in the obtained residue. The mixture was stirred at 50°C in a water bath and then filtered under suction, washed sequentially with water and methanol, and dried under vacuum to afford a orange solid (22.6g, 95.5%), i.e. the target product. m.p.: 225.5-228.4 °C ; 1H NMR(DMSO-d6)δ: 10.04(s, 1H), 9.64(s, 1H), 8.98(s, 1H), 8.56(s, 1H), 8.23(d, J=9.0 Hz, 1H), 7.97(d, J=2.5 Hz, 1H), 7.80(d, J=8.0Hz, 1H), 7.68- 7.72(m, 2H), 7.43- 7.48(m, 1H), 7.35(d, J=9.0 Hz, 1H), 7.24-7.33(m, 3H), 7.17(m, 1H), 5.23(s, 2H); ESI-MS m/z: 474[M+H]+.
95.5%	With palladium 10% on activated carbon; triethylamine In methanol; 1,2-dimethoxyethane at 50℃; for 24h;	1 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine Example 1 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine To a reaction flask N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodo-4-quinazolinamine (25.29 g, 50 mmol), 5-formylfuran-2-boric acid (10.50 g, 75 mmol), 10% palladium on carbon (1.25 g, 54% water content), 1,2-dimethoxyethane (400 ml), methanol (200 ml) and triethylamine (21 ml, 150 mmol) were added. The mixture was heated to and kept at 50° C. and stirring for 24 h. The resulting reactant is hot filtered under suction and the mixture, and the filtrate is rotary evaporated. Methanol (150 ml) and water (50 ml) were added in the obtained residue. The mixture was stirred at 50° C. in a water bath and then filtered under suction, washed sequentially with water and methanol, and dried under vacuum to afford a orange solid (22.6 g, 95.5%), i.e. the target product. m.p.: 225.5-228.4° C.; 1H NMR (DMSO-d6) δ: 10.04 (s, 1H), 9.64 (s, 1H), 8.98 (s, 1H), 8.56 (s, 1H), 8.23 (d, J=9.0 Hz, 1H), 7.97 (d, J=2.5 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.68-7.72 (m, 2H), 7.43-7.48 (m, 1H), 7.35 (d, J=9.0 Hz, 1H), 7.24-7.33 (m, 3H), 7.17 (m, 1H), 5.23 (s, 2H); ESI-MS m/z: 474[M+H]+.
	With triethylamine In methanol for 2h; Reflux;	3 Example 3 Preparation of 5-(4-(4-(3-fluorobenzyl-oxy)-3-chlorophenyl-amino)quinazolin-6-yl)furan-2-aldehyde Product (50 g) of example 1,5-boric acid-2-furfural (21 g), Pd(PPh3)2Cl2(6.2 g) triethylamine (62 mL), and methyl alcohol (1000 mL) were added into a reaction flask. The mixture was refluxed for 2 hours. After the reaction solution was cooled to room temperature, the precipitation was filtered and washed by a small amount of methanol, then dried at 50° C. to obtain the 40 g the subject product in a yellow solid. m/z (M+1)+: 473.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1 Location in patent: Paragraph 0056; 0057
[2]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1 Location in patent: Paragraph 0213
[3]Current Patent Assignee: HANSOH PHARMACEUTICAL GROUP CO LTD - US2011/281896, 2011, A1 Location in patent: Page/Page column 7

55
thiazole-5-carbaldehyde-2-boric acid [ No CAS ]
[ 231278-20-9 ]
[ 1227053-00-0 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In methanol for 2h; Reflux;	5 Example 5 Preparation of 2-(4-(4-(3-fluorobenzyl-oxy)-3-chlorophenyl-amino)quinazolin-6-yl)thiazole-5-aldehyde Product (50 g) of example 1,2-boric acid-5-thiazole aldehyde (21 g), Pd(PPh3)2Cl2(6.2 g), triethylamine (62 mL), and methyl alcohol (1000 mL) were added into a reaction flask. The mixture was refluxed for 2 hours. After the reaction solution was cooled to room temperature, the precipitation was filtered and washed by a small amount of methanol, then dried at 50° C. to obtain 30 g title product. m/z (M+1)+: 490.

Reference： [1]Current Patent Assignee: HANSOH PHARMACEUTICAL GROUP CO LTD - US2011/281896, 2011, A1 Location in patent: Page/Page column 7

56
[ 13529-27-6 ]
[ 104-15-4 ]
[ 231278-20-9 ]
5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde tosylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 1 :Preparation of lapatinib2-Fluraldehyde diethyl acetal (40 gm) was dissolved in dimethoxy ethane (270 ml) at room temperature under nitrogen atmosphere and then cooled to -40C. N-Butyl lithium (180 ml) was added to the solution for 45 minutes and stirred for 2 hours at -40 to -35C. To the reaction mass was added triisopropyl borate (53 gm) for 30 minutes and stirred for 2 hours at -40 to -35C. The temperature of the reaction mass was raised to 0C and then added acetic acid (12 ml), stirred for 30 minutes at 0C. To the reaction mass was added water (15 ml) and stirred for 15 minutes. A mixture of ethanol (200 ml), triethylamine (41 ml) and N-{3-chloro-4-[(3-fluorobenzyl)oxy}phenyl}-6-iodo-4- quinazolinamine (59 gm) was added to the above reaction mass at 20 to 25C and then added palladium carbon (5%, 3.5 gm). The contents were heated to 60 to 65 C and maintained for 4 hours 60 to 65C. The reaction mass was cooled to room temperature and maintained for 30 minutes at room temperature. The reaction mass was filtered through hi-flo bed and the filtrate was cooled to 20 to 25C. To the reaction mass was added p-toluenesulfonic acid (91 gm) and stirred for 1 hour at room temperature. The separated solid was filtered and dried under vacuum at 50 to 55C for 5 hours to obtain 60 gm of 5-[4-({3-chloro-4-{(3-fluorophenyl)methoxy]phenyl)amino)quinazolin-6- yl]furan-2-carbaldehyde p-toluenesulfonic acid.5-[4-({3-Chloro-4-{(3-fluorophenyl)methoxy]phenyl)amino)quinazolin-6- yl]furan-2-carbaldehyde p-toluenesulfonic acidt as obtained above, tetrhydrofuran (1000 ml), 2-(methanesulphonyl)ethylamine (40 gm) and acetic acid (35 ml) were added at room temperature. Diisopropylethylamine (108 ml) was added to the reaction mass and stirred for 2 hours at 30 to 35C, and then cooled to 20C. To the reaction mass was added sodium triacetoxy borohydride (66 gm) and maintained for 3 hours at 20 to 25C, and then added a mixture of sodium hydroxide solution (25%, 310 ml) and water (200 ml). The layers were separated and aqueous layer was extracted with tetrahydrofuran. The combined organic layer was dried over sodium sulfate and the solvent was distilled off under vacuum at below 50C to obtain residual mass. To the residual mass was added isopropyl acetate (300 ml) and stirred for 30 minutes at 55 to 60C. The reaction mass was cooled to room temperature and stirred for 30 minutes at room temperature, filtered. The solid obtained was dried under vacuum at 50 to 55C for 6 hours to obtain 78 gm of crude lapatinib.Crude lapatinib as obtained above was dissolved in methanol (390 ml) and dichloromethane (780 ml) and then treated with carbon (7 gm) at room temperature. The reaction mass was stirred for 20 minutes and filtered through hi-flo bed. The solvent was distilled off under vacuum at 45 to 50C to obtain residual mass. To the residual mass was added methanol (50 ml) and stirred for 1 hour at room temperature. The separated solid was filtered and dried under vacuum at 50 to 55C for 6 hours to obtain 66 gm of lapatinib

Reference： [1]Patent: WO2012/17448,2012,A2 .Location in patent: Page/Page column 7-8

57
[ 27329-70-0 ]
[ 6950-53-4 ]
[ 231278-20-9 ]
C₂₉H₂₄ClFN₄O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; triethylamine In ethanol at 20℃; for 2.5h; Inert atmosphere; Reflux;	4.1.1. 6-(5-((2-(Methylthio)ethylamino)methyl)furan-2-yl)-N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-4-quinazolinamine (L-1) A mixture of 2-(methylthio)ethanamine hydrochloride (3.2 g, 25 mmol), 5-formylfuran-2-ylboronic acid (2.5 g, 18 mmol) and triethylamine (28 ml, 0.2 mol) was stirred under nitrogen in ethanol (200 ml), followed by the addition of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine (5.1 g,10 mmol) and Pd(dppf)2Cl2 (0.6 g, 0.8mmol). The mixture was stirred at room temperature for 1 h, and then heated under reflux for 1.5 h. After cooled to room temperature, NaHB(OAc)3 (2.5 g, 12 mmol) was added, and the mixture was stirred at room temperature for 2 h. The mixture was filtered carefully and washed with EtOH (330ml). The filtrate and washings were combined and concentrated, then diluted with CH2Cl2 (500 ml). The organic phase was washed with H2O (3 x 300 ml), dried (Na2SO4), filtered and concentrated to give the crude product. The crude product was purified on a silica gel column using Ethyl acetate/MeOH to provide the title compound (L-1) as a yellow solid (2.8 g, yield 50%).

Reference： [1]Zhang, Long; Fan, Chuanwen; Guo, Zongru; Li, Ying; Zhao, Shuyong; Yang, Shaobo; Yang, Yingying; Zhu, Jianrong; Lin, Dong [European Journal of Medicinal Chemistry, 2013, vol. 69, p. 833 - 841]

58
[ 231278-20-9 ]
[ 1152131-73-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: palladium diacetate; potassium carbonate / ethanol; tetrahydrofuran / 1 h / Inert atmosphere; Reflux 2: chromium(VI) oxide; sulfuric acid; water / acetone / 2 h / 0 °C
	Multi-step reaction with 2 steps 1: triethylamine; palladium 10% on activated carbon / water; methanol; 1,2-dimethoxyethane / 24 h / 50 °C 2: tetrabutylammomium bromide; potassium permanganate / water; tetrahydrofuran / 24 h / 20 °C / Cooling with ice
	Multi-step reaction with 2 steps 1: triethylamine; palladium 10% on activated carbon / 1,2-dimethoxyethane; methanol / 24 h / 50 °C 2: tetrabutylammomium bromide; potassium permanganate / tetrahydrofuran; water / 24 h / 20 °C / Cooling with ice

Reference： [1]Zhang, Long; Fan, Chuanwen; Guo, Zongru; Li, Ying; Zhao, Shuyong; Yang, Shaobo; Yang, Yingying; Zhu, Jianrong; Lin, Dong [European Journal of Medicinal Chemistry, 2013, vol. 69, p. 833 - 841]
[2]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1
[3]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1

59
[ 27329-70-0 ]
[ 60501-55-5 ]
[ 231278-20-9 ]
C₂₉H₂₄ClFN₄O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; triethylamine; In ethanol; at 20℃; for 2.5h;Inert atmosphere; Reflux;	General procedure: A mixture of 2-(methylthio)ethanamine hydrochloride (3.2 g, 25 mmol), 5-formylfuran-2-ylboronic acid (2.5 g, 18 mmol) and triethylamine (28 ml, 0.2 mol) was stirred under nitrogen in ethanol (200 ml), followed by the addition of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine (5.1 g,10 mmol) and Pd(dppf)2Cl2 (0.6 g, 0.8mmol). The mixture was stirred at room temperature for 1 h, and then heated under reflux for 1.5 h. After cooled to room temperature, NaHB(OAc)3 (2.5 g, 12 mmol) was added, and the mixture was stirred at room temperature for 2 h. The mixture was filtered carefully and washed with EtOH (330ml). The filtrate and washings were combined and concentrated, then diluted with CH2Cl2 (500 ml). The organic phase was washed with H2O (3 x 300 ml), dried (Na2SO4), filtered and concentrated to give the crude product. The crude product was purified on a silica gel column using Ethyl acetate/MeOH to provide the title compound (L-1) as a yellow solid (2.8 g, yield 50%).

Reference： [1]European Journal of Medicinal Chemistry,2013,vol. 69,p. 833 - 841

60
[ 202197-61-3 ]
[ 27329-70-0 ]
[ 231278-20-9 ]
C₂₉H₂₅ClFN₅O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; triethylamine In ethanol at 20℃; for 2.5h; Inert atmosphere; Reflux;	4.1.1. 6-(5-((2-(Methylthio)ethylamino)methyl)furan-2-yl)-N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-4-quinazolinamine (L-1) General procedure: A mixture of 2-(methylthio)ethanamine hydrochloride (3.2 g, 25 mmol), 5-formylfuran-2-ylboronic acid (2.5 g, 18 mmol) and triethylamine (28 ml, 0.2 mol) was stirred under nitrogen in ethanol (200 ml), followed by the addition of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine (5.1 g,10 mmol) and Pd(dppf)2Cl2 (0.6 g, 0.8mmol). The mixture was stirred at room temperature for 1 h, and then heated under reflux for 1.5 h. After cooled to room temperature, NaHB(OAc)3 (2.5 g, 12 mmol) was added, and the mixture was stirred at room temperature for 2 h. The mixture was filtered carefully and washed with EtOH (330ml). The filtrate and washings were combined and concentrated, then diluted with CH2Cl2 (500 ml). The organic phase was washed with H2O (3 x 300 ml), dried (Na2SO4), filtered and concentrated to give the crude product. The crude product was purified on a silica gel column using Ethyl acetate/MeOH to provide the title compound (L-1) as a yellow solid (2.8 g, yield 50%).

Reference： [1]Zhang, Long; Fan, Chuanwen; Guo, Zongru; Li, Ying; Zhao, Shuyong; Yang, Shaobo; Yang, Yingying; Zhu, Jianrong; Lin, Dong [European Journal of Medicinal Chemistry, 2013, vol. 69, p. 833 - 841]

61
[ 27329-70-0 ]
[ 89756-60-5 ]
[ 231278-20-9 ]
C₂₈H₂₃ClFN₅O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; triethylamine; In ethanol; at 20℃; for 2.5h;Inert atmosphere; Reflux;	General procedure: A mixture of 2-(methylthio)ethanamine hydrochloride (3.2 g, 25 mmol), 5-formylfuran-2-ylboronic acid (2.5 g, 18 mmol) and triethylamine (28 ml, 0.2 mol) was stirred under nitrogen in ethanol (200 ml), followed by the addition of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine (5.1 g,10 mmol) and Pd(dppf)2Cl2 (0.6 g, 0.8mmol). The mixture was stirred at room temperature for 1 h, and then heated under reflux for 1.5 h. After cooled to room temperature, NaHB(OAc)3 (2.5 g, 12 mmol) was added, and the mixture was stirred at room temperature for 2 h. The mixture was filtered carefully and washed with EtOH (330ml). The filtrate and washings were combined and concentrated, then diluted with CH2Cl2 (500 ml). The organic phase was washed with H2O (3 x 300 ml), dried (Na2SO4), filtered and concentrated to give the crude product. The crude product was purified on a silica gel column using Ethyl acetate/MeOH to provide the title compound (L-1) as a yellow solid (2.8 g, yield 50%).

Reference： [1]European Journal of Medicinal Chemistry,2013,vol. 69,p. 833 - 841

62
[ 27329-70-0 ]
[ 1275596-05-8 ]
[ 231278-20-9 ]
C₃₀H₂₃ClF₄N₄O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; triethylamine In ethanol at 20℃; for 2.5h; Inert atmosphere; Reflux;	4.1.1. 6-(5-((2-(Methylthio)ethylamino)methyl)furan-2-yl)-N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-4-quinazolinamine (L-1) General procedure: A mixture of 2-(methylthio)ethanamine hydrochloride (3.2 g, 25 mmol), 5-formylfuran-2-ylboronic acid (2.5 g, 18 mmol) and triethylamine (28 ml, 0.2 mol) was stirred under nitrogen in ethanol (200 ml), followed by the addition of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine (5.1 g,10 mmol) and Pd(dppf)2Cl2 (0.6 g, 0.8mmol). The mixture was stirred at room temperature for 1 h, and then heated under reflux for 1.5 h. After cooled to room temperature, NaHB(OAc)3 (2.5 g, 12 mmol) was added, and the mixture was stirred at room temperature for 2 h. The mixture was filtered carefully and washed with EtOH (330ml). The filtrate and washings were combined and concentrated, then diluted with CH2Cl2 (500 ml). The organic phase was washed with H2O (3 x 300 ml), dried (Na2SO4), filtered and concentrated to give the crude product. The crude product was purified on a silica gel column using Ethyl acetate/MeOH to provide the title compound (L-1) as a yellow solid (2.8 g, yield 50%).

Reference： [1]Zhang, Long; Fan, Chuanwen; Guo, Zongru; Li, Ying; Zhao, Shuyong; Yang, Shaobo; Yang, Yingying; Zhu, Jianrong; Lin, Dong [European Journal of Medicinal Chemistry, 2013, vol. 69, p. 833 - 841]

63
[ 1603976-11-9 ]
[ 231278-20-9 ]
[ 231278-84-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	With palladium 10% on activated carbon; N-ethyl-N,N-diisopropylamine In methanol; ethanol at 90℃; for 2.5h;	8 Example 85-(4-(3-Chloro-4-(3-fluorobenzyloxy)phenylam ino)chinazolin-6-yl)furan-2- carbaldehyde (I) Example 85-(4-(3-Chloro-4-(3-fluorobenzyloxy)phenylam ino)chinazolin-6-yl)furan-2- carbaldehyde (I)III (8.0 g, 15.8 mmol, I equiv.), 10 % Pd/C (0,2 g, 0.19 mmol, 1.2 mol. %), kieselguhr(740 mg), a solution of N,N-diisopropylethylamine (5.5 ml, 31.6 mmol, 2 equiv.) in amixture of methanol/ethanol 1: 1.2 (140 ml) were added to the ester VIlc (4.7 g, 21.3mmol, 1.35 equiv.) and the resulting suspension was refluxed (bath temperature 90°C) for 2.5 hours. After cooling to the room temperature the yellow suspension was filtered through kieselguhr and washed with methanol (4 X 90 ml). The product was dissolved directly on the filter by addition of hot THF (2 X 70 ml) and filtered, which,after evaporation of the solvent, provided 6.75 g (90%) of the title compound (I) as ayellow powdery substance. HPLC purity 99%.1H NMR (500 MHz, DMSOd6): 5.27 (s, 2 H), 7.16-7.20 (m, I H), 7.28-7.35 (m, 3H)7.43 (d, J = 3.7 Hz, I H), 7.45-7.48 (m, 1 H), 7.71-7.74 (m, 2 H), 7.46 (d, J = 3.56 Hz,1 H), 7.85 (J= 8.7 Hz, IH), 8.00 (J= 2.4 Hz, 1H), 8.29 (dd, J= 1.8 Hz, J = 8.7 Hz),8.59 (s, IH), 8.99 (d, J= 1.5 Hz, IH), 9.67 (s, IH), 10.14 (s, 1H).

Reference： [1]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2014/59956, 2014, A1 Location in patent: Page/Page column 10; 11

64
[ 273731-82-1 ]
[ 231278-20-9 ]
[ 231278-84-5 ]

Yield	Reaction Conditions	Operation in experiment
87%	With palladium 10% on activated carbon; N-ethyl-N,N-diisopropylamine; In methanol; for 8h;Reflux;	Example 65-(4-(3-Chloro-4-(3-fluorobenzyloxy)phenylam ino)ch inazolin-6-yl)furan-2-carbaldehyde IIII (3.3 g, 6.42 mmol), 10 % Pd/C (78 mg, 0.07 mmol, 1.2 mol. %), methanol (45 ml), N,N-diisopropylethylamine (2.2 ml, 12.85 mmol, 2 equiv.) were added to the ester Vila (1.8 g, 8.35 mmol, 1.3 equiv.) and the resulting suspension was refluxed for 8 hours.After cooling to the room temperature the yellow suspension was filtered and washed with methanol (3 X 20 ml). The product was subsequently dissolved in THF (45 ml) and filtered through a kieselguhr layer, which, after evaporation of the solvent, WO 2014/059956 PCT/CZ2013/000132provided 2.6 g (87 %) of the title compound (I) as a yellow powdery substance. HPLCpurity: 95%1H NMR (500 MHz, DMSOd6): 5.27 (s, 2 H), 7.16-7.20 (m, I H), 7.28-7.35 (m, 3H)7.43 (d, J = 3.7 Hz, 1 H), 7.45-7.48 (m, I H), 7.71-7.74 (m, 2 H), 7.46 (d, J = 3.56 Hz,H), 7.85 (J = 8.7 Hz, 1H), 8.00 (J = 2.4 Hz, 1H), 8.29 (dd, J = 1.8 Hz, J = 8.7 Hz),8.59 (s, 1H), 8.99 (d, J= 1.5 Hz, IH), 9.67 (s, 1H), 10.14 (s, IH).

Reference： [1]Patent: WO2014/59956,2014,A1 .Location in patent: Page/Page column 9; 10

65
[ 1218791-07-1 ]
[ 231278-20-9 ]
[ 231278-84-5 ]

Yield	Reaction Conditions	Operation in experiment
89%	With palladium 10% on activated carbon In methanol for 8h; Reflux;	7 Example 75-(4-(3-Chloro-4-(3-fluorobenzyloxy)phenylamino)chinazolin-6-yl)furan-2- carbaldehyde (I) Example 75-(4-(3-Chloro-4-(3-fluorobenzyloxy)phenylamino)chinazolin-6-yl)furan-2- carbaldehyde (I)III (172 mg, 0.34 mmol), 10 % Pd/C (4.3 mg, 0.004 mmol, 1.2 mol. %), methanol (2.4 ml), N,N-diisopropylethylamine (0.12 ml, 0.68 mmol, 2 equiv.) were added to the esterVllb (92 mg, 0.44 mmol, 1,30equiv.) and the resulting suspension was refluxed for 8 hours. After cooling to the room temperature the yellow suspension was filtered and washed with methanol (3 X 16 ml). The product was dissolved in THE (2.4 ml) and filtered through a kieselguhr layer, which, after evaporation of the solvent, provided 143 mg (89%) of the desired compound (I) as a yellow powdery substance. HPLCpurity: 96%.1H NMR (500 MHz, DMSO-d6): 5.27 (s, 2 H), 7.16-7.20 (m, I H), 7.28-7.35 (m, 3H)7.43 (d, J = 3.7 Hz, 1 H), 7.45-7.48 (m, I H), 7.71-7.74 (m, 2 H), 7.46 (d, J = 3.56 Hz,1 H), 7.85 (J = 8.7 Hz, I H), 8.00 (J = 2.4 Hz, I H), 8.29 (dd, J = 1.8 Hz, J = 8.7 Hz),8.59 (s, IH), 8.99 (d, J= 1.5 Hz, IH), 9.67 (s, IH), 10.14 (s, IH).

Reference： [1]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2014/59956, 2014, A1 Location in patent: Page/Page column 10

66
[ 231278-20-9 ]
[ 1421356-50-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: triethylamine; palladium 10% on activated carbon / water; methanol; 1,2-dimethoxyethane / 24 h / 50 °C 2.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 6 h / 20 °C / Inert atmosphere 2.2: 24 h / 20 °C 2.3: 2 h
	Multi-step reaction with 2 steps 1.1: triethylamine; palladium 10% on activated carbon / 1,2-dimethoxyethane; methanol / 24 h / 50 °C 2.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 6 h / 20 °C / Inert atmosphere 2.2: 24 h / 20 °C 2.3: 2 h