Name: 231278-84-5|5-(4-((3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl)furan-2-carbaldehyde|97%
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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
[ 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).

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3
[ 49773-20-8 ]
[ 231278-84-5 ]
[ 231277-92-2 ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: 2-Methanesulfonyl-ethylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In methanol; dichloromethane at 20℃; Stage #2: With hydrogen In methanol; dichloromethane Inert atmosphere;	8 Example 8:Preparation of /V-(3-chloro-4-[(3-fluorophenyl)methyl]oxy}phenyl)-6-[5-([2- (methylsulfonyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolinamineThe suspension of 5-[4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl]-2-furaldehyde (5g, 10.6 mmoL) in dichloromethane (50 mL) was charged with a solution of 2-aminoethylmethylsulfone (3.2 g, 1 1.7 mmoL) in methanol (25 mL) slowly under constant stirring at room temperature. The reaction mixture was stirred for 2-4 hours until reaction completion and then was charged with 5% Pd-C (750 mg) and stirred under a hydrogen atmosphere using balloon pressure for 12-16 hours until reaction completion. The obtained mixture was filtered through Celite pad and rinsed with methanol (5 mL) and dichloromethane (15 mL) mixture. The filtrate was distilled to low volume and the obtained solution was charged with methanol (25 mL). The reaction mixture was stirred for 2-6 hours and the yellow solid which precipitated out was filtered and washed with methanol (10 mL). The solid obtained was dried under vacuum at 40-45°C to furnish Lapatinib freebase (5 g, Yield = 85%, HPLC purity >99%).
80%	Stage #1: 2-Methanesulfonyl-ethylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine Stage #2: With toluene-4-sulfonic acid
70%	Stage #1: 2-Methanesulfonyl-ethylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With triethylamine In tetrahydrofuran; methanol for 3h; Stage #2: With methanol; sodium tetrahydroborate In tetrahydrofuran at 20℃; Cooling with ice;	D.1.g (g) Preparation of N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-([2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine The title compound was prepared according to Procedure D as follows. The 5-(4-{3-chloro-4-(3-fluorobenzyloxy)-anilino}-6-quinazol inyl)-furan-2-carbaldehyde (12.58 g, 24.7 mmol) was added to a solution of 2-methanesulphonyl-ethylamine (4.55 g, 37.0 mmol) and triethylamine (2.0 ml, 27.2 mmol) in 125 ml of tetrahydrofuran and 125 ml of methanol. After stirring 3 hours, the solution was cooled in an ice bath and sodium borohydride (2.42 g, 64.0 mmol) was added in five portions over a 20 minute period. The reaction mixture was stirred overnight at room temperature and then quenched with the dropwise addition of 250 ml of water. The solution was concentrated in vacuo to remove the organic solvents and the residual oily solution was extracted with 11 of ethyl acetate. The organic solution was washed with 1M sodium hydroxide and brine and then dried with sodium sulfate. The solution was concentrated in vacuo to a very small volume and solid crystallized out. The suspension was filtered with a small volume of ethyl acetate, washed with ether and dried in a vacuum oven at 65 C to give 10.0 g (70%) of free base as an off white solid. 1H NMR 400 MHz (DMSO-d6) δ 9.60 (bs, 1H); 9.32 (bs, 1H); 8.82 (bs, 1H); 8.34 (d, 1H); 8.0 (s, 1H); 7.88 (d, 1H); 7.74 (d, 1H); 7.45 (m, 1H); 7.34-7.23 (m, 4H); 7.17 (m, 1H); 6.83 (d, 1H); 5.27 (s, 2H); 4.42 (s, 2H); 3.59 (m, 2H); 3.40 (m, 2H, obscured by waterpeak); 3.12 (s, 3H); MS m/z 581 (M+H+).

	With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane
		29 N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-([2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine Example 29 N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-([2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine Prepared according to Procedure D from 5-(4-{3-chloro-4-(3-fluorobenzyloxy)-anilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). 1H NMR 400 MHz (DMSO-d6) 9.60 (bs, 1H); 9.32 (bs, 1H); !D 8.82 (bs, 1H); 8.34 (d, 1H); 8.0 (s, 1H); 7.88 (d, 1H); 7.74 (d, 1H); 7.45 (m, 1H); 7.34-7.23 (m, 4H); 7.17 (m, 1H); 6.83 (d, 1H); 5.27 (s, 2H); 4.42 (s, 2H); 3.59 (m, 2H); 3.40 (m, 2H, obscured by waterpeak); 3.12 (s, 3H); MS m/z 581 (M+H+).
10.0 g(70%)	With triethylamine In tetrahydrofuran; methanol; sodium borohydrid; water	1.g (g) (g) Preparation of N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-([2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine The title compound was prepared according to Procedure D as follows. The 5-(4-{3-chloro-4-(3-fluorobenzyloxy)-anilino}-6-quinazolinyl)-furan-2-carbaldehyde (12.58 g, 24.7 mmol) was added to a solution of 2-methanesulphonyl-ethylamine (4.55 g, 37.0 mmol) and triethylamine(2.0 ml, 27.2 mmol) in 125 ml of tetrahydrofuran and 125 ml of methanol. After stirring 3 hours, the solution was cooled in an ice bath and sodium borohydride(2.42 g, 64.0 mmol) was added in five portions over a 20 minute period. The reaction mixture was stirred overnight at room temperature and then quenched with the dropwise addition of 250 ml of water. The solution was concentrated in vacuo to remove the organic solvents and the residual oily solution was extracted with 1 l of ethyl acetate. The organic solution was washed with 1M sodium hydroxide and brine and then dried with sodium sulfate. The solution was concentrated in vacuo to a very small volume and solid crystallized out. The suspension was filtered with a small volume of ethyl acetate, washed with ether and dried in a vacuum oven at 65 C. to give 10.0 g(70%) of free base as an off white solid. 1H NMR 400 MHz (DMSO-d6) δ 9.60 (bs, 1H); 9.32 (bs, 1H); 8.82 (bs, 1H); 8.34 (d, 1H); 8.0 (s, 1H); 7.88 (d, 1H); 7.74 (d 1H); 7.45 (m, 1H); 7.34-7.23 (m, 4H); 7.17 (m, 1H); 6.83 (d, 1H); 5.27 (s, 2H); 4.42 (s, 2H); 3.59 (m, 2H); 3.40 (m, 2H, obscured by waterpeak); 3.12 (s, 3H); MS m/581 (M+H+).
		3.1.a 1 (a) Preparation of N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5- ([2-(methane sulphonyl) ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (free base of compound of formula (II) ) The title compound was prepared according to Procedure D of International Applications WO 02/02552: p. 16, line 19 to p. 17, line 3 and WO 99/35146: p. 56, lines 20-32 and Example 29 p. 100, lines 18-29, from 5-(4-(at)3-chloro-4-(3-fluorobenzyloxy)-anilino}-6-quinazolinyl)-furan-2- carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv).

Reference： [1]Current Patent Assignee: APOTEX INC - WO2012/83440, 2012, A1 Location in patent: Page/Page column 14
[2]Erickson, Greg; Guo, Jiasheng; McClure, Mike; Mitchell, Mark; Salaun, Marie-Catherine; Whitehead, Andrew [Tetrahedron Letters, 2014, vol. 55, # 43, p. 6007 - 6010]
[3]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US2015/366868, 2015, A1 Location in patent: Paragraph 0153; 0161
[4]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]
[5]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2002/147205, 2002, A1
[6]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US2004/53946, 2004, A1
[7]Current Patent Assignee: GLAXOSMITHKLINE PLC; KUMAR - WO2005/105094, 2005, A2 Location in patent: Page/Page column 43

4
[ 231278-84-5 ]
[ 320337-48-2 ]

Yield	Reaction Conditions	Operation in experiment
91.1%	With sodium tetrahydroborate In methanol; dichloromethane at 0℃; for 4h;	1.2.6 General method for preparation of 4-arylamino-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a-2d) General procedure: Residue 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4) (1.0 mmol) was dissolved in methanol (10.0 mL) and dichloromethane (10.0 mL), and then cooled to 0 °C. NaBH4 (1.0 mmol) was added in four portions over 15 min. After 4 h, the solvent was removed under reduced pressure and water (10 mL) was added. The precipitated product was filtered, and the filter cake was washed with water (3 ×10 mL), and dried to afford 2a-2d as a yellow solid (yield 90.3~94.6%). 1.2.1.1 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-hydroxymethylfuran-2-yl)quinazoline (2a) Yield 91.1%. m.p.: 240.7-241.5 °C. 1H NMR (300 MHz, DMSO-d6) δ(ppm): 9.99 (s, 1H), 8.78 (s, 1H), 8.59 (s, 1H), 8.19 (dd, J = 8.8, 1.2 Hz, 1H), 8.05 (d, J = 2.3 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.78 (dd, J = 8.9, 2.3 Hz, 1H), 7.57 - 7.44 (m, 1H), 7.40 - 7.29 (m, 3H), 7.26 - 7.18 (m, 1H), 7.09 (d, J = 3.2 Hz, 1H), 6.55 (d, J = 3.2 Hz, 1H), 5.39 (t, J = 4.5 Hz, 1H), 5.30 (s, 2H), 4.57 (d, J = 4.5 Hz, 2H) (Figure S22). 13C NMR (75 MHz, DMSO-d6) δ(ppm): 162.18 (d, 1JC-F = 243.7 Hz), 157.6, 156.2, 154.2, 151.7, 149.8, 148.8, 139.6 (d, 3JC-F = 7.4 Hz), 133.1, 130.5 (d, 3JC-F = 8.3 Hz), 128.6 (d, 2JC-F = 21.1 Hz), 128.3, 124.4, 123.3 (d, 4JC-F = 2.8 Hz), 122.6, 121.0, 116.4, 115.3, 114.7 (d, 2JC-F = 21.0 Hz), 114.2, 114.1, 113.9, 109.6, 107.8, 69.4, 55.8 (Figure S23). IR νmax(KBr) cm-1: 3314, 3074, 3457, 1608, 2927, 1579, 1504, 1428, 936, 791, 678 (Figure S24). HRMS (C26H19ClFN3O3) m/z [M+H]+: calculated: 476.1177, found: 476.1157 (Figure S25).
	With sodium tetrahydroborate
	With sodium tetrahydroborate In tetrahydrofuran; methanol at 0℃; for 0.5h;	27 Example 27 4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-(5-hydroxym ethyl-furan-2-yl)-quinazoline The 6-bromo-4-amino substituted quinazoline intermediate(3.00g) and 5-formyl-2-furyl boronic acid (1.37g) were dissolved into 1,4-dioxane(150mL). Then Pd(PPh3)4(1.50g) and 20% aqueous Na2CO3 solution(7mL) were added thereto under nitrogen atmosphere. The reaction was heated to 100 and continued for 2h. The solvent was removed under reduced pressure, and the resulting residue was purified by column chromatography to obtain the 6-[2-(5-formylfuryl)]-4-amino substituted quinazoline intermediate. The above intermediate was dissolved into a mixed solvent of THF/MeOH(2: 1). NaBH4 was added thereto at 0 in portions, and the reaction system turned dark gradually. After 30min, most solvent was removed under reduced pressure, and the resulting residue was dissolved into ethyl acetate, washed with saturated saline, dried and purified by silica gel column chromatography to obtain the title compound (2.18g, the total yield of the two steps is 70%). 1H-NMR (400MHz, CDCl3): δ9.29(1H, s), 8.36(1H, s), 8.21(1H, d, J=8.38Hz,), 7.73-7.68(1H, m), 7.60-7.58(1H, m), 7.45-7.35(2H, m), 7.04-6.96(1H, m), 6.92-6.82 (2H, m), 6.70-6.60(2H, m), 6.50-6.47(1H, m), 6.08-6.02(1H, m), 4.80(2H, d, J=6.04Hz), 4.61(1H, t, J=5.63Hz), 4.25(2H, t, J=6.87Hz).

With sodium tetrahydroborate In tetrahydrofuran; methanol at 0℃; for 0.5h;

27 The above intermediate was dissolved into a mixed solvent of THF/MeOH (2:1). NaBH4 was added thereto at 0° C. in portions, and the reaction system turned dark gradually. After 30 min, most solvent was removed under reduced pressure, and the resulting residue was dissolved into ethyl acetate, washed with saturated saline, dried and purified by silica gel column chromatography to obtain the title compound (2.18 g, the total yield of the two steps is 70%). 1H-NMR (400 MHz, CDCl3): δ9.29(1H, s), 8.36 (1H, s), 8.21 (1H, d, J=8.38 Hz,), 7.73-7.68 (1H, m), 7.60-7.58 (1H, m), 7.45-7.35 (2H, m), 7.04-6.96 (1H, m), 6.92-6.82 (2H, m), 6.70-6.60 (2H, m), 6.50-6.47 (1H, m), 6.08-6.02 (1H, m), 4.80 (2H, d, J=6.04 Hz), 4.61 (1H, t, J=5.63 Hz), 4.25 (2H, t, J=6.87 Hz).

Reference： [1]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]
[2]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]
[3]Current Patent Assignee: ALLIST PHARMACEUTICALS INC - EP1990337, 2008, A1 Location in patent: Page/Page column 18-19
[4]Current Patent Assignee: ALLIST PHARMACEUTICALS INC - US2008/300248, 2008, A1 Location in patent: Page/Page column 11

5
[ 851684-46-3 ]
[ 27329-70-0 ]
[ 231278-84-5 ]

Yield	Reaction Conditions	Operation in experiment
94%	With triethylamine In ethanol for 2h; Heating / reflux;	1 5-(4-[3-Chloro-4-(3-fluorobenzyloxy)phenylamino]quinazolin-6-yl}furan-2-carbaldehyde (17). To a suspension of 15 (19.4 g, 35.8 mmol) in ethanol (270 mL) was added triethylamine (24.9 mL, 179 mmol) followed by 5-formylfuran-2-boronic acid (16) (10.0 g, 71.6 mmol). The resulting mixture was purged with nitrogen for 20 min and then Pd(dppf)Cl2-CH2Cl2 (1.18 g, 1.43 mmol) was added. The reaction mixture was refluxed for 2 hours and the volatiles were removed under reduced pressure. The crude residue was taken up in water (500 mL). The precipitate was filtered, washed with water, triturated with methanol (200 mL) and dried at 60° C. to give 17 (16.0 g, 94%) as a tan solid.
	With palladium 10% on activated carbon; triethylamine In 1,4-dioxane; methanol at 25 - 50℃; for 4h;	1-3; 5-7 Stage-02: 5-[4-[3-chloro-4-(3- fluorobenzyloxy)anilino]-6- quinazolinyl)-furan-2-carbaldehyde of formula(Q): Stage-01 wet cake Imole charge in the reactor followed by methanol: dioxane (1:3) lOvol at 25-30°C. Add TEA 0.28mole to the reaction and add 10% palladium on charcoal 5% slurry in dioxane 0.5Vol at 25- 30°C. Allow to heat at 45-50°C for 4.0hrs. Filter the catalyst to use in next batch and clear reaction mass transfer to the clean reactor and cool the reaction mass at 25-30°C. add water lOVol to the reaction mass to get yellowish material and filter to get the material and suck dry well to get wet cake of stage-02 of formula (Q). Yield: 95% HPLC Purity: 99.24%

Reference： [1]Current Patent Assignee: CONCERT PHARMACEUTICALS INC - US2008/51422, 2008, A1 Location in patent: Page/Page column 13-14
[2]Current Patent Assignee: SUMAR BIOTECH LLP - WO2022/29795, 2022, A1 Location in patent: Page/Page column 8-9 13-14

6
[ 4244-84-2 ]
[ 231278-84-5 ]
ethyl 3-((5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-yl)methylamino)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47.9%	Stage #1: ethyl β-alaninate hydrochloride; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With triethylamine In tetrahydrofuran Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran for 1h;	68.68f Compound 1406-174 (240 mg, 0.5 mmol) and ethyl 3-aminopropanoate hydrochloride (77 mg, 0.5 mmol) were dissolved in 10 mL of THF, then Et3N (0.1 mL) was added. The mixture was stirred for 10 min. and then NaBH(AcO)3 (148 mg, 0.7 mmol) was added into the mixture. The mixture was stirred for another 1 hour. The solvent was removed, and the residue was purified by chromatography on silica gel with CH2Cl2/ MeOH (100:5) to give product 1407-174 (140 mg, 47.9%): LC-MS: 575 [M+l]+, 1H NMR (DMSO-J6): δ 1.13 (t, J= 6.9 Hz, 3 H), 2.43 (m, 2 H), 2.80 (t, J= 6.9 Hz, 3 H), 3.76 (s, 2 H), 4.01 (q, J= 6.9 Hz, 2 H), 5.21 (s, 2 H), 6.46 (s, 1 H), 7.03 (m, 1 H), 7.16 (m, 1 H), 7.30 (m, 3 H), 7.46 (m, 1 H), 7.82 (m, 2 H), 8.03 (m, 1 H), 8.14 (m, 1 H), 8.52 (s, 1 H), 8.71 (s, 1 H), 9.90 (s, 1 H)

Reference： [1]Current Patent Assignee: CURIS INC - WO2008/33747, 2008, A2 Location in patent: Page/Page column 170

7
[ 98556-31-1 ]
[ 231278-84-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4686 - 4691
[2]Journal of Medicinal Chemistry,2010,vol. 53,p. 8546 - 8555
[3]Patent: US2011/281896,2011,A1
[4]Patent: CN103772411,2016,B
[5]Patent: CN103772371,2016,B
[6]Patent: WO2007/121279,2007,A2
[7]Patent: WO2005/105094,2005,A2
[8]Patent: WO2022/29795,2022,A1

8
[ 27329-70-0 ]
[ 944549-41-1 ]
[ 231278-84-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate In 1,4-dioxane; water at 100℃; for 2h;	27 Example 27 4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-(5-hydroxym ethyl-furan-2-yl)-quinazoline The 6-bromo-4-amino substituted quinazoline intermediate(3.00g) and 5-formyl-2-furyl boronic acid (1.37g) were dissolved into 1,4-dioxane(150mL). Then Pd(PPh3)4(1.50g) and 20% aqueous Na2CO3 solution(7mL) were added thereto under nitrogen atmosphere. The reaction was heated to 100 and continued for 2h. The solvent was removed under reduced pressure, and the resulting residue was purified by column chromatography to obtain the 6-[2-(5-formylfuryl)]-4-amino substituted quinazoline intermediate. The above intermediate was dissolved into a mixed solvent of THF/MeOH(2: 1). NaBH4 was added thereto at 0 in portions, and the reaction system turned dark gradually. After 30min, most solvent was removed under reduced pressure, and the resulting residue was dissolved into ethyl acetate, washed with saturated saline, dried and purified by silica gel column chromatography to obtain the title compound (2.18g, the total yield of the two steps is 70%). 1H-NMR (400MHz, CDCl3): δ9.29(1H, s), 8.36(1H, s), 8.21(1H, d, J=8.38Hz,), 7.73-7.68(1H, m), 7.60-7.58(1H, m), 7.45-7.35(2H, m), 7.04-6.96(1H, m), 6.92-6.82 (2H, m), 6.70-6.60(2H, m), 6.50-6.47(1H, m), 6.08-6.02(1H, m), 4.80(2H, d, J=6.04Hz), 4.61(1H, t, J=5.63Hz), 4.25(2H, t, J=6.87Hz).
	With sodium carbonate In 1,4-dioxane; water at 100℃; for 2h;	27 Example 27 4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-6-(5-hydroxymethyl-phenyl)-quinazoline ethyl-furan-2-yl)-quinazoline The 6-bromo-4-amino substituted quinazoline intermediate (3.00 g) and 5-formyl-2-furyl boronic acid (1.37 g) were dissolved into 1,4-dioxane (150 mL). Then Pd(PPh3)4(1.50 g) and 20% aqueous Na2CO3 solution (7 mL) were added thereto under nitrogen atmosphere. The reaction was heated to 100° C. and continued for 2 h. The solvent was removed under reduced pressure, and the resulting residue was purified by column chromatography to obtain the 6-[2-(5-formylfuryl)]-4-amino substituted quinazoline intermediate.

Reference： [1]Current Patent Assignee: ALLIST PHARMACEUTICALS INC - EP1990337, 2008, A1 Location in patent: Page/Page column 18-19
[2]Current Patent Assignee: ALLIST PHARMACEUTICALS INC - US2008/300248, 2008, A1 Location in patent: Page/Page column 11

9
[ 35000-37-4 ]
[ 231278-84-5 ]
[ 1152131-75-3 ]

Yield	Reaction Conditions	Operation in experiment
76%	With sodium hydroxide; triethylamine In dichloromethane; water at 20℃;	II A mixture of the respective aryl-2-carbaldehydes 18a-18d (1.0 mmol), (tert- butoxycarbonylmemyl)triphenylphosphonium chloride (0.56 g; 1.02 mmol), NaOH (0.08 g; 2.04 mmol), NEt3 (0.3 g; 3.06 mmol) in CH2Cl2 (100 mL) and water (2.04 mL) was stirred at room temperature over night. The organic layer was separated, subsequently washed with sat. NH4CI solution (3 x 50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM/EE = 1 :1) and precipitated by addition of light petrol.; 3-(5-{4-[3-Chloro-4-(3-fluorobenzyIoxy)phenyI-amino]quinazoliιi'-6-yl}furan~2-yl)acrylic acid tert-butyl ester (19a): Yield (0.43 g, 76%) yellow crystals, mp: 201.3-201.4 0C. 1H-NMR (DMSO-[D6]): δ (ppm) = 1.50 (s, 9H), 5.28 (s, 2H), 6.50 (d, IH, Jtrans = 15.6 Hz), 7.13 (d, IH, J = 3.6 Hz), 7.19 (dt, IH, J = 2.4 Hz, J - 8.6 Hz), 7.28-7.36 (m, 4H), 7.44 (d, IH3 Jtrans = 15.6 Hz), 7.45-7.52 (m, IH), 7.72 (dd, IH, J = 2.5 Hz, J = 8.8 Hz), 7.82 (d, IH3 J = 8.8 Hz), 7.99 (d, IH, J = 2.5 Hz), 8.29 (dd, IH, J = 1.5 Hz, J - 8.6 Hz), 8.57 (s, IH), 8.87 (d, IH, J = 1.1 Hz), 9.97 (s, IH, exchangeable).+ p ESI m/z (%): 574 [MH-H+T (39), 572 [MH-H+T (100 %); - p ESI m/z (%): 572 [M-H+]- (40), 570 [M-H+]". IR (KBr): 2977, 1697 cm".. Anal. (C32H27ClFN3O4): C, H, N.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2009/63054, 2009, A1 Location in patent: Page/Page column 71

10
[ 104458-24-4 ]
[ 104-15-4 ]
[ 231278-84-5 ]
[ 388082-78-8 ]

Yield	Reaction Conditions	Operation in experiment
94.9%		In a 1 L reaction flask, 650 ml of tetrahydrofuran was added in that order.Compound IV 40 g (85 mmol), compound V17.5 g (110 mmol),50 ml of triethylamine and 1.63 g (5 mmol) of tetrabutylammonium bromide were reacted at 30 C for 3 hours. At the end of the reaction, 32.3 g (152 mmol) of sodium triacetoxyborohydride was added in portions.The feeding temperature does not exceed 20 C, the reaction is 4 hours, the reaction is finished, 200 ml of 1 M sodium hydroxide is added dropwise, the pH is adjusted to 8, the dropping temperature does not exceed 30 C, and the dropwise addition is finished.The mixture was allowed to stand for separation, and 56.2 g (296 mmol) of p-toluenesulfonic acid was added to the organic layer.The temperature was raised to 50 C, the reaction was carried out for 1 hour, the temperature was lowered to room temperature, and dried by filtration to obtain 75.8 g of a yellow solid.That is, compound VI, the yield is 94.9%, and the HPLC purity is 99.72%.The largest single impurity is 0.18%.
82.8%		A solution of 5- [4 - [[3-chloro-4 - [(3-fluorophenyl) methoxy] phenyl] amino] -6-quinazoline] -2-furancarboxaldehyde (4 . & Lt; / RTI & gt;2- (amino) ethylmethylsulfone hydrochloride (2. 56 g, 16 mmol),Diisopropylethylamine (5. 17 g, 40 mmol),Acetic acid (2.4 g, 40 mmol) and 50 ml of tetrahydrofuran,Stirring reaction at room temperature 3h,Sodium triacetoxyborohydride (8. 48 g, 40 mmol) was added in portions,Room temperature reaction 12h.30 ml of 20% sodium hydroxide solution was added to the solution,The organic phase was extracted with ethyl acetate.The organic phases were combined,concentrate,The residue was dissolved in 50 ml of tetrahydrofuran,An aqueous solution of p-toluenesulfonic acid (7. 6 g, 40 mmol / 15 ml) was added,Stir at room temperature for 12h,filter,The cake was dried to give a pale yellow solid of 7. 58 g, m.p. 244-246 C, yield 82.8%, and HPLC purity 99.6%.
72%		Example 23: preparation of lapatinib ditosylate.[000121] 100.0 gr (0.211 mol) of lapatinib aldehyde and 54.6 gr (0.342 mol) of methylsulfonylethylamine HCl were mixed with 500 ml THF and 100 ml DMF. 48 ml acetic acid and 147 ml diisopropylethylamine were added. The reaction mixture was heated to 35C and stirred at this temperature for 1 hour and cooled to 20-250C. 111.8 gr (0.528 mol) of sodium triacetoxyborohydride were added and stirred for additional 2 hours to complete the reaction.[000122] 1500 ml ethyl acetate and 300 ml water were added to the reaction mixture.Then 110 ml of 47% sodium hydroxide solution was added. The mixture allowed for the phase separation. The organic phase was washed twice with 500 ml of 25% aqueous ammonium chloride solution. The resulting organic phase was washed twice with 300 ml of water. The resulting organic solution was concentrated to dryness. 350 ml of DMF is added to the evaporation residue to form lapatinib solution in DMF.[000123] The resulting organic solution was heated to about 400C and filtered to remove foreign particles. 263 ml DMF were added to the filtrate and heated again to about 400C. 80.3 g (0.442 mol) of p-toluenesulfonic acid were added to the lapatinib solution in DMF. The solution was seeded with pure lapatinib ditosylate and cooled slowly from 400C to about 00C for 6 hours. The formed slurry was stirred at about 00C for 9 hours, cooled additionally to about (-10)C to complete precipitation and stirred at this temperature during 2 hours. The crude product was filtered and washed with 60 ml of cold DMF to get 248.2 gr of wet lapatinib ditosylate crude.[000124] 244.8 gr of the wet lapatinib ditosylate crude were slurried in 490 ml of DMF at about 400C during 2 hours, cooled to about (-10)C during 2 hours and stirred at this temperature during additional 17 hours. The precipitated product was filtered, washed with 60 ml DMF and dried at 700C under reduced pressure during overnight to give 133.7 gr (72% yield) of the lapatinib ditosylate purity: 99.73%.

5-{4-[(3-Chloro-4-[(3-fluorophenyl)methyl]oxy}phenyl)amino]-6- quinazolinyl}-2-furancarbaldehyde 4-methylbenzenesulfonate (1 wt) and 2-(methylsulfonyl)ethylamine hydrochloride (0.4 wt, 1.60 equiv.) are suspended in THF (10 vols). Sequentially, acetic acid (0.354 vol., 4.00 equiv.) and di- isopropylethylamine (DIPEA, 1.08 vols, 4.00 equiv.) are added. The resulting solution is stirred at 30-35C for ca. 1 hour then cooled to ca. 22C. Sodium tri- acetoxyborohydride (0.66 wt, 2.00 equiv.) is then added. The resulting mixture is stirred at ca. 22C for 2-4 hours then sampled for HPLC analysis. The reaction is quenched by addition of aqueous sodium hydroxide (25% w/w, 3 vols.) followed by water (2 vols.). The aqueous phase is then separated, extracted with THF (2 vols) and the combined THF extracts are then washed twice with 25%w/v aqueous ammonium chloride solution (2 x 5 vols). A solution of p-toluenesulfonic acid monohydrate (p-TSA, 0.74 wt, 2.5 equiv.) in water (1 vol) is prepared, warmed to ca. 6O0C, and N-(3-chloro-4-[(3-fluorophenyl)methyl]oxy}phenyl)-6-[5-([2- (methylsulfonyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolinamine 4- methylbenzenesulfonate hydrate seeds are added. The THF solution of the free base is added to the p-TSA solution over at least 1 hr, maintaining the batch EPO <DP n="49"/>temperature at 60+30C. The resulting suspension is stirred at ca. 600C for 1-2 hours, cooled to 20-250C over an hour and aged at this temperature for ca. 1hr. The solid is collected by filtration, washed with 95:5 THF: Water (3 x 2 vols) and dried in vacuum at ca. 35C to give Lambda/-(3-chloro-4-[(3-fluorophenyl)methyl]oxy}phenyl)-6-[5- ([2-(methylsulfonyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolinamine 4- methylbenzenesulfonate hydrate as a bright yellow crystalline solid.

Reference： [1]Patent: CN109503559,2019,A .Location in patent: Paragraph 0020
[2]Patent: CN103373951,2016,B .Location in patent: Paragraph 0027; 0028
[3]Patent: WO2010/17387,2010,A2 .Location in patent: Page/Page column 29-30
[4]Patent: WO2006/113649,2006,A1 .Location in patent: Page/Page column 47-48

11
[ 104458-24-4 ]
[ 231278-84-5 ]
[ 231277-92-2 ]

Yield	Reaction Conditions	Operation in experiment
100%		To the 3L is sequentially added in three-mouth bottle 2 - (methyl sulfuryl) ethylamine hydrochloride (61.3g, 0 . 384mol), diisopropylethylamine (74.4g, 0 . 576mol), tetrahydrofuran (910 ml), stirring the mixture at room temperature for 20 min, add glacial acetic acid (109.2 ml), the compound of formula (III) (91g, 0.192mol), heating to 40 C, temperature control reaction 2h the rear, to 25-30C, in to the system by adding NaBH (OAC)3(81.4g, 0 . 384mol), heating to 40 C, temperature control reaction 3h rear, monitoring TLC (developing agent PE:EA=2:3) to (III) compound the reaction is complete. System lower the temperature filtering, to the mother liquor the instillment uses 5M sodium hydroxide solution (364 ml), separating, the aqueous phase using 100 ml * 2THF extraction, combined with the phase. Organic reinforced with 25% solution of ammonium chloride to neutral, anhydrous sodium sulfate for drying, filtering, results in the type lapatinib a solution of compound (II), a step directly cast, in order to yield 100% meter.
82.0%		General procedure: To a reaction flask were added 2-(methylsulfonyl)ethylamineHCl (0.75 mmol), methanol (5.0 mL), anhydrous sodium sulfate (2.00 mmol) and triethylamine (0.5 mL) cooled to 0 C. The mixture was stirred 20 min and adjusts pH~5-6 with formic acid. The reactor was added the solution of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (D1-4) (0.50 mmol) resolved in THF (5 mL) and DMF (5 mL). Sodium cyanoborohydride (2.00 mmol) was added in two portions over a 20 min period. After stirring for 2 h, the precipitated product was filtered and the filtrate was evaporated. The crude product was chromatographed by silica gel, eluted with MeOH/CHCl3 (1:15) to afford 1a-1d as pale yellow solid (yield 78.1~82.6%).5, 6 1.2.1.1 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2-(methylsulfonyl)ethyl)aminomethyl)furan-2-yl)quinazoline (lapatinib, 1a) Yield 82.0%. 1H NMR (600 MHz, DMSO-d6) delta(ppm): 9.91 (s, 1H), 8.74 (s, 1H), 8.57 (s, 1H), 8.16 (dd, J = 8.7, 1.5 Hz, 1H), 8.04 (d, J = 2.5 Hz, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.77 (dd, J = 9.0, 2.5 Hz, 1H), 7.48 (dd, J = 14.0, 7.8 Hz, 1H), 7.37 - 7.31 (m, 2H), 7.29 (d, J = 9.0 Hz, 1H), 7.23 - 7.17 (m, 1H), 7.06 (d, J = 3.2 Hz, 1H), 6.51 (d, J = 3.2 Hz, 1H), 5.27 (s, 2H), 3.86 (s, 2H), 3.31 (t, J = 6.7 Hz, 2H), 3.06 (s, 3H), 3.03 (t, J = 6.7 Hz, 2H), 1.93 (s, 1H) (Figure S12).
79%		Example 11 - Synthesis of lapatinibAcetic acid (0.5 ml, 8.44 mmol, 4 equiv.) and N-ethyldiisopropylamine (1.47 ml, 8.44 mmol, 4 equiv.) were added dropwise to a suspension of the aldehyde 1(1 g, 2.11mmol) and <strong>[104458-24-4]2-(methylsulfonyl)ethaneamine hydrochloride</strong> (0.54 g, 3.37 mmol, 1.6equiv.) in THF (10 ml) at the room temperature. The reaction mixture was stirred at40C for I h, cooled to 20C, a solution of NaBH(OAc)3 (0.9 g, 4.25 mmol, 2 equiv.) inTHF (4.2 ml) was added and the resulting mixture was stirred at 20C for 3 h. Then, a1.25M solution of NaOH (16 ml) was added dropwise, the mixture was stirred at 20Cfor 30 mm, the product was extracted to ethyl acetate (3 x 8 ml), the organic layer was dried over MgSO4, filtered and evaporated at a reduced pressure. THF (5 ml) was added to the evaporation product, the resulting suspension was heated to 65C, a solution of PTSA (1622 mg, 8.44 mmol, 4 equiv.) in water (0.6 ml) was added dropwise, the mixture was stirred at 65C for 1 h and at 20C for another 3 h. Thesuspension was aspirated, the product washed with ethanol (20 ml) and dried in a drier (40C) for 3 h, which provided 1.54 g (79%) of the title compound II with the HPLC purity of 97.1%.

51.9%		Example 21 : preparation of lapatinib base.[000117] 10.0 gr of lapatinib-aldehyde base, 5.5 gr of 2-methylsulfonyl-ethylamineHCl, 300 ml of ethyl acetate, 70 ml of DMF, 4.9 ml of acetic acid and 14.6 ml of N,N- diisopropylethylamine were mixed at 250C. The reaction mixture was stirred at 35C for 1 hour and cooled to 25C. Afterwards, 11.2 gr of sodium triacetoxyborohydride were added in one portion. The resulting mixture was stirred at 25C for 1.5 hours. The reaction mixture was quenched with 30 ml of 25% NH4OH and with 70 ml of water and stirred at 25C for 0.5 hours. The resulting phases were separated. The organic phase was washed with 25% NH4Cl aqueous solution (2 x 50 ml) and with 200 ml of water.[000118] To 148 ml of organic phase, 0.11 gr of tetra-butylammonium hydrogen sulfate was added. The mixture was stirred at 250C for 30 min. Then, it was concentrated in vacuum to about 50 ml. The resulting off-white suspension was stirred at 250C in a 100 ml round-bottomed flask for 16 hours. The solid was filtered off in vacuum and washed with 10 ml of fresh ethyl acetate. The solid was dried in a vacuum oven for 16 hours at 500C. 3.18 gr (yield 51.9%). Purity: 99.72%
	With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; water; at 15 - 25℃; for 0.5h;	To 2 - (methyl sulfonyl) ethylamine hydrochloride (1.3 g, 8.1 mmol) of the compound of formula (IV) (3.0 g, 6.3 mmol) of THF (60 ml) suspension is added DIPEA (4.7 ml). Under the ambient temperature stirring 0.5 hours later, to add three acetoxy sodium borohydride (4.0 g, 24.3 mmol) and 20 ± 5 C under (external temperature) and agitating the mixture, until the HPLC display the completion of reaction. In the ice water bath in - H2O (9 ml, 3 P) quenching the reaction mixture, maintaining TInternal4C1 aqueous solution (6 ml) washing the organic phase, filtering, the p - TsOH (4.8 g, 25.2 mmol) is added to the organic phase after filtering, heating the mixture to reflux and keep the 2 hours. Cooling the mixture to ambient temperature, and continuously stirred for 15 hours. The mixtures are filtered, for 1:1 (v/v) THF/H2O (4.5 ml) washing the filter cake, in 80 ± 5 C dried for 6 hours, to obtain pulls the handkerchief thickly for nepal xylene sulfonate (3.4 g, HPLC purity: 95.2%).

Reference： [1]Patent: CN105503839,2016,A .Location in patent: Paragraph 0046; 0048
[2]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1584 - 1587
[3]Patent: WO2014/59956,2014,A1 .Location in patent: Page/Page column 12
[4]Patent: WO2010/17387,2010,A2 .Location in patent: Page/Page column 28
[5]Patent: CN104418845,2017,B .Location in patent: Paragraph 0047-0049

12
5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde 4-methylbenzenesulfonate [ No CAS ]
[ 231278-84-5 ]

Yield	Reaction Conditions	Operation in experiment
82%	With sodium carbonate In water; acetonitrile at 40℃; for 2h;	12 Example 12: preparation of crystalline lapatinib aldehyde base[00097] To a IL reactor, 5Og of lapatinib-aldehyde monotosylate and 300 ml of acetonitrile were added. To the resulting suspension a solution of 12.3g sodium carbonate in 350 ml water was added. The resulting yellow suspension was stirred at 400C for 2 hours, and then cooled to room temperature (T(jacket) = 25°C) for an hour. The product was filtered in vacuum, washed with 50 ml of acetonitrile and dried for 16 hours in a vacuum oven at 400C. Yield - 30 gram (82%); purity - 99.14%.

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2010/17387, 2010, A2 Location in patent: Page/Page column 24

13
[ 104458-24-4 ]
[ 231278-84-5 ]
[ 1227853-06-6 ]

Yield	Reaction Conditions	Operation in experiment
96%	With triethylamine; In methanol; for 12h;Reflux;	(iv) Preparation of N-{3-chloro-4-[(fluorobenzyloxy]phenyl}-6-[5-([2-methane - sulphonyl) ethyl] imino}methyl)-2-furyl]-4-quinazoIinamine (9)Into a two liter four-necked round bottomed flask, 100OmL of methanol, 40.0 g of N-(3- chloro-4-(3-fluorobenzyloxy)anilino)-6- quinazolinyl)-furan-2-carbadehyde, obtained from the previous step(iii), 20.6 g of 2-methanesulfonylethylamine HCl and 13.4 g of triethylamine were charged under stirring . The mass was maintained at reflux temperature for about 12 hours and the reaction was monitored by HPLC. The reaction mass was cooled to room temperature and filtered. The product was dried under vacuum at room temperature to get 47.0 g (96% of theory) of imine as yellow coloured crystalline solid. The product was stored under nitrogen atmosphere. Melting point range: 74 to 76 C Purity: 99.0% by HPLC Mass: 580.1 (M+l)IR (KBr, cm-1): 3339.7, 2928.0, 2362.4, 1637.3, 1608.6, 1593.4, 1572.1, 1539.1, 1497.9, 1445.9, 1425.6, 1394.3, 1371.0, 1330.5, 1294.8, 1216.9, 1198.2, 1171.6, 1123.8, 1061.4, 1026.5, 956.6, 927.8, 888.3, 868.1, 839.9, 789.7, 748.5, 679.9, 643.2, 628.7, 544.4, 517.6, 501.5.1H-NMR (400 MHz, DMSO-D6): delta 3.06(s, 3H); 3.51-3.53 (t, 2H), 3.96-3.98 (t, 2H); 5.27 (s, 2H); 7.19-7.20 (m, 2H); 7.20-7.33 (m, 4 H); 7.47-7.49 (m, IH), 7.71-7.74 (dd, IH), 7.83-7.85 (d, IH); 8.00-8.01 (m, IH); 8.22-8.24 (dd, IH); 8.33 (s, IH); 8.58 (s, IH); 8.86 (s, IH) and 10.03 (s, IH)13C-NMR (400 MHz, DMSO-D6): delta 41.84, 53.92, 54.31, 69.40, 109.25, 113.93, 114.15, 114.32, 114.61, 114.82, 115.35, 117.63, 121.08, 123.33, 124.40, 129.03, 130.62, 132.95, 139.60, 139.68, 149.52, 149.87, 151.17, 151.79, 154.80, 157.73, 161.01, 164.02, 169.05
96%	With triethylamine; In methanol; for 12h;Reflux;	(iv) Preparation of N-{3-chloro-4-[(fluorobenzyloxy]phenyl}-6-[5-([2-methane-sulphonyl)ethyl]imino}methyl)-2-furyl]-4-quinazolinamine (9)Into a two liter four-necked round bottomed flask, 1000 mL of methanol, 40.0 g of N-(3-chloro-4-(3-fluorobenzyloxy)anilino)-6-quinazolinyl)-furan-2-carbadehyde, obtained from the previous step (iii), 20.6 g of 2-methanesulfonylethylamine HCl and 13.4 g of triethylamine were charged under stirring. The mass was maintained at reflux temperature for about 12 hours and the reaction was monitored by HPLC. The reaction mass was cooled to room temperature and filtered. The product was dried under vacuum at room temperature to get 47.0 g (96% of theory) of imine as yellow coloured crystalline solid. The product was stored under nitrogen atmosphere.Melting point range: 74 to 76 C.Purity: 99.0% by HPLCMass: 580.1 (M+1)IR (KBr, cm-1): 3339.7, 2928.0, 2362.4, 1637.3, 1608.6, 1593.4, 1572.1, 1539.1, 1497.9, 1445.9, 1425.6, 1394.3, 1371.0, 1330.5, 1294.8, 1216.9, 1198.2, 1171.6, 1123.8, 1061.4, 1026.5, 956.6, 927.8, 888.3, 868.1, 839.9, 789.7, 748.5, 679.9, 643.2, 628.7, 544.4, 517.6, 501.5.1H-NMR (400 MHz, DMSO-D6): delta 3.06 (s, 3H); 3.51-3.53 (t, 2H), 3.96-3.98 (t, 2H); 5.27 (s, 2H); 7.19-7.20 (m, 2H); 7.20-7.33 (m, 4H); 7.47-7.49 (m, 1H), 7.71-7.74 (dd, 1H), 7.83-7.85 (d, 1H); 8.00-8.01 (m, 1H); 8.22-8.24 (dd, 1H); 8.33 (s, 1H); 8.58 (s, 1H); 8.86 (s, 1H) and 10.03 (s, 1H)13C-NMR (400 MHz, DMSO-D6): delta 41.84, 53.92, 54.31, 69.40, 109.25, 113.93, 114.15, 114.32, 114.61, 114.82, 115.35, 117.63, 121.08, 123.33, 124.40, 129.03, 130.62, 132.95, 139.60, 139.68, 149.52, 149.87, 151.17, 151.79, 154.80, 157.73, 161.01, 164.02, 169.05
	With triethylamine; In methanol; for 12h;Reflux;	(v) Preparation of N-{3-chIoro-4-[(fluoroben2yloxy]phenyl}-6-[5-([2-methane - sulphonyl) ethyl] imino}methyl)-2-furyl]-4-quinazolinamine (9)Into a two liter four-necked round bottomed flask, 1000mL of methanol, 40.0 g of N- (3-chloro-4-(3-fluorobenzyloxy)anilino)-6- quinazolinyl)-furan-2-carbadehyde, obtained from the previous step(iv), 20.6 g of 2-methanesulfonylethylamine HCl and 13.4 g of triethylamine were charged under stirring . The mass was maintained at reflux temperature for about 12 hours and the reaction was monitored by HPLC. The reaction mass was cooled to room temperature and filtered. The product was dried under vacuum at room temperature to get 47.0 g (96% of theory) of imine as yellow coloured crystalline solid. The product was stored under nitrogen atmosphere.Melting point range: 74 to 76 CPurity: 99.0% by HPLCMass: 580.1 (M+1)IR (KBr, cm"1): 3339.7, 2928.0, 2362.4, 1637.3, 1608.6, 1593.4, 1572.1 , 1539.1 , 1497.9, 1445.9, 1425.6, 1394.3, 1371.0, 1330.5, 1294.8, 1216.9, 1 198.2, 1 171.6, 1 123.8, 1061.4, 1026.5, 956.6, 927.8, 888.3, 868.1, 839.9, 789.7, 748.5, 679.9, 643.2, 628.7, 544.4, 517.6, 501.5.-NMR (400 MHz, DMSO-D6): delta 3.06(s, 3H); 3.51-3.53 (t, 2H), 3.96-3.98 (t, 2H); 5.27 (s, 2H); 7.19-7.20 (m, 2H); 7.20-7.33 (m, 4 H); 7.47-7.49 (m, 1 H), 7.71-7.74 (dd, 1H), 7.83-7.85 (d, 1H); 8.00-8.01 (m, 1H); 8.22-8.24 (dd, 1H); 8.33 (s, 1H); 8.58 (s, 1H); 8.86 (s, 1H) and 10.03 (s, 1H),3C-NMR (400 MHz, DMSO-D6): delta 41.84, 53.92, 54.31, 69.40, 109.25, 1 13.93, 1 14.15, 1 14.32, 1 14.61 , 1 14.82, 1 15.35, 1 17.63, 121.08, 123.33, 124.40, 129.03, 130.62, 132.95, 139.60, 139.68, 149.52, 149.87, 151.17, 151.79, 154.80, 157.73, 161.01 , 164.02, 169.05

Reference： [1]Patent: WO2010/61400,2010,A1 .Location in patent: Page/Page column 15-16
[2]Patent: US2011/263852,2011,A1 .Location in patent: Page/Page column 12
[3]Patent: WO2011/39759,2011,A1 .Location in patent: Page/Page column 15

14
[ 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

15
[ 97578-19-3 ]
[ 231278-84-5 ]
[ 1260401-92-0 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: aminomethyl-dimethyl-phosphine oxide; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In dichloromethane Stage #2: With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane at 20℃; Stage #3: With sodium hydroxide In dichloromethane; water	3 Example 36-(5-(((dimethylphosphinoyl)methylamino)methyl)furan-2-yl)-N-(4-(3-fluorobenzyloxy)-3- chlorophenyl)quinazolin-4-amine[0113] 5-(4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)quinazolin-6-yl)furan-2- carbaldehyde (compound 1.7) and (dimethylphosphinoyl)methanamine (preparation:Maier, Ludwig Phosphorus, Sulfur and Silicon and the Related Elements, 53(1-4), 43-67; 1990) were suspended in dichloromethane (20 mL). Sequentially, acetic acid (3 drops) and sodium triacetoxyborohydride (2 equiv.) were added at room temperature. The mixture was stirred at room temperature until the starting material disappeared. The reaction was quenched with 2N NaOH aqueous solution and extracted with dichloromethane. The combined organic layer and extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with 20% methanol in dichloromethane to give the desired product as yellow crystalline solid. LCMS ESI(+) m/z: 566 (M+ 1). 1H NMR (300 MHz, CD3OD) δ 8.65 (s, IH), 8.46 (s, IH), 8.15 (m, IH), 7.91 (d, IH), 7.75 (m, IH), 7.62 (m, IH), 7.40 (m, IH), 7.29 (m, IH), 7.26 (m, IH), 7.13 (m, IH), 7.08 (m, IH), 6.93 (d, IH), 6.47 (d, IH), 5.20 (s, 2H), 3.97 (s, 2H), 3.08 (m, 2H), 2.85 (m, IH), 1.57 (m, 6H).

Reference： [1]Current Patent Assignee: KANGYUAN PHARMCEUTICAL; JIANGSU KANION PHARMACEUTICAL CO., LTD. - WO2011/2523, 2011, A1 Location in patent: Page/Page column 46-47

16
[ 933745-16-5 ]
[ 231278-84-5 ]
[ 1260401-91-9 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-(dimethylphosphinoyl)ethanamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In dichloromethane Stage #2: With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane at 20℃; Stage #3: With sodium hydroxide In dichloromethane; water	2.C Step C : 6-(5 -((2-(dimethylphosphino)ethylaminoyl)methyl)furan-2-yl)-N-(4-(3 - fluorobenzyloxy)-3-chlorophenyl)quinazolin-4-amine (compound 2) [0112] 5-(4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)quinazolin-6-yl)furan-2- carbaldehyde and 2-(dimethylphosphinoyl)ethanamine (compound 2.2) were suspended in dichloromethane (20 mL). Sequentially, acetic acid (3 drops) and sodiumtriacetoxyborohydride (2 equiv.) were added at room temperature. The mixture was stirred at room temperature until the starting material disappeared. The reaction was quenched with 2N NaOH aqueous solution and extracted with dichloromethane. The combined organic layer and extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with 20% methanol in dichloromethane to give the desired product as yellow crystalline solid.LCMS ESI(+) m/z: 580 (M+l). 1H NMR (300 MHz, CD3OD) δ 8.73 (d, IH), 8.50 (s, IH), 8.20 (m, IH), 7.92 (d, IH), 7.80 (m, IH), 7.68 (m, IH), 7.46 (m, IH), 7.36 (m, IH), 7.30 (m, IH), 7.22 (m, IH), 7.11 (m, IH), 7.00 (d, IH), 6.53 (d, IH), 5.25 (s, 2H), 3.94 (s, 2H), 3.08 (m, 2H), 2.15 (m, 2H), 1.57 (s, 3H), 1.53 (s, 3H).

Reference： [1]Current Patent Assignee: KANGYUAN PHARMCEUTICAL; JIANGSU KANION PHARMACEUTICAL CO., LTD. - WO2011/2523, 2011, A1 Location in patent: Page/Page column 45-46

17
[ 1260402-41-2 ]
[ 231278-84-5 ]
[ 1260402-02-5 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-((dimethylphosphinoyl)methyl)piperazine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In dichloromethane Stage #2: With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane at 20℃; Stage #3: With sodium hydroxide In dichloromethane	13.C Step C: N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-(5-((4-((dimethylphosphinoyl)- methyl)piperazin- 1 -yl)methyl)furan-2-yl)quinazolin-4-amine (compound 13)[0146] 5-(4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)quinazolin-6-yl)furan-2- carbaldehyde and 1 -((dimethylphosphinoyl)methyl)piperazine were suspended in dichloromethane (20 mL). Sequentially, acetic acid (3 drops) and sodiumtriacetoxyborohydride (2 equiv.) were added at room temperature. The mixture was stirred at room temperature until the starting material disappeared. The reaction was quenched with 2N NaOH aqueous solution and extracted with dichloromethane. The combined organic layer and extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with 20% methanol in dichloromethane to give the desired product as yellow crystalline solid.LCMS ESI(+) m/z: 635 (M+l). 1H NMR (300 MHz, CD3OD) δ 8.59 (s, IH), 8.44 (s, IH), 8.11 (m, IH), 7.89 (m, IH), 7.72 (m, IH), 7.57 (m, IH), 7.38 (m, IH), 7.26 (m, 2H), 7.08 (m, 2H), 6.90 (d, IH), 6.46 (d, IH), 5.17 (s, 2H), 3.66 (s, 2H), 2.80 (m, 2H), 2.68 (m, 8H), 1.57 (d, 6H).

Reference： [1]Current Patent Assignee: KANGYUAN PHARMCEUTICAL; JIANGSU KANION PHARMACEUTICAL CO., LTD. - WO2011/2523, 2011, A1 Location in patent: Page/Page column 59

18
[ 231278-84-5 ]
[ 388082-78-8 ]

Reference： [1]Patent: WO2011/39759,2011,A1
[2]Patent: US2011/263852,2011,A1
[3]Patent: WO2005/120512,2005,A2
[4]Patent: WO2005/120504,2005,A2
[5]Patent: WO2007/121279,2007,A2
[6]Patent: WO2005/105094,2005,A2
[7]Patent: WO2005/105094,2005,A2

19
[ 132131-24-9 ]
[ 231278-84-5 ]

Reference： [1]Patent: WO2011/39759,2011,A1
[2]Patent: US2011/263852,2011,A1
[3]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1584 - 1587
[4]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 4309 - 4313
[5]Journal of Enzyme Inhibition and Medicinal Chemistry,2019,vol. 34,p. 1668 - 1677

20
[ 16064-08-7 ]
[ 231278-84-5 ]

Reference： [1]Patent: US2011/281896,2011,A1
[2]Patent: CN103772371,2016,B
[3]Patent: CN104418845,2017,B
[4]Patent: WO2005/120512,2005,A2
[5]Patent: WO2005/120504,2005,A2

21
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

22
[ 343338-28-3 ]
[ 231278-84-5 ]
[ 1235824-04-0 ]

Yield	Reaction Conditions	Operation in experiment
	With titanium(IV) isopropylate In tetrahydrofuran at 20℃;	1 Embodiment 1 Preparation of (S)-N-((5-(4-(4-(3-fluorobenzyl-oxy)-3-chlorophenyl-amino)quinazolin-6-yl)furan-2-yl)methylenyl)-2-methylpropane-2-sulfinamide Product of example 3 (47.3 g, 0.1 mol), (S)-(-)-2-methyl-2-propanesulfinamide (14.5 g, 0.12 mol), titanium (IV) isopropoxide (tetra isopropyl titanate) (85 g, 0.3 mol) and anhydrous THF (1000 mL) were added into a reaction flask and reacted at room temperature over night. Then water (50 mL) and ethyl acetate (500 mL) were added with stirring for 10 minutes, followed by a filtration and the precipitation was washed with THF for three times. The combined filtrates were dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to dry to obtain 50 g solid title compound. m/z (M+1)+: 577.
	With titanium(IV) isopropylate In tetrahydrofuran for 4h; Reflux;	4.1.4. General procedure for the synthesis of 9 and 10 General procedure: A mixture of compound 5 (1.0 mmol), (R) or (S)-t-butylsulfinamide (1.2 mmol), titanium(IV) isopropoxide (3 mmol) in THF (15 ml) was refluxed for 4 h. After cooled to the room temperature, the mixture was treated with saturated NaCl aqueous solution and a great amount of deposit was formed. The deposit was filtrated off. The filtrate was then concentrated, diluted by CH2Cl2, and washed by water. Then, the organic phase was separated, dried with anhydrous Na2SO4, and the solvent was removed under vacuum to give the desired product (7 or 8) as yellow oil which was applied in the next reaction without purification.

Reference： [1]Current Patent Assignee: HANSOH PHARMACEUTICAL GROUP CO LTD - US2011/281896, 2011, A1 Location in patent: Page/Page column 8
[2]Lyu, Aifeng; Fang, Lei; Gou, Shaohua [European Journal of Medicinal Chemistry, 2014, vol. 87, p. 631 - 642]

23
[ 49773-20-8 ]
[ 104-15-4 ]
[ 231278-84-5 ]
[ 388082-78-8 ]

Yield	Reaction Conditions	Operation in experiment
93%		Example 7:Preparation of A/-(3-chloro-4-[(3-fluorophenyl)methyl]oxy}phenyl)-6-[5-([2- (methylsulfonyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolinamine bis 4- methylbenzenesulfonate.The suspension of 5-[4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl]-2-furaldehyde (5 g, 10.6 mmoL) in dichloromethane (50ml_) was charged with a solution of 2-aminoethylmethylsulfone (3.2 g, 1 1.7mmoL) in methanol (25ml_) slowly under constant stirring at room temperature. The reaction mixture was stirred for 2-4 hours until reaction completion. The reaction mixture was charged with 5% Pd-C (750mg) and stirred under hydrogen atmosphere using balloon pressure for 12-16 hours until reaction completion. The obtained mixture was filtered through Celite pad and rinsed with methanol (5 mL) and dichloromethane (15 mL) mixture. The filtrate was distilled to low volume and the solution was charged with dichloromethane (25 mL) followed by addition of the solution of p-toluenesulfonic acid monohydrate (4.4 g, 23.3 mmoL) in methanol (10 mL). The yellow solid which precipitated out was filtered after 2- 8 hours and washed with 1 :1 mixture of methanol and dichloromethane (20 mL). The solid obtained was dried under vacuum at 40-45C to provide Lapatinib (1 1.4 g, Yield = 93%, HPLC purity >99%).

Reference： [1]Patent: WO2012/83440,2012,A1 .Location in patent: Page/Page column 13-14

24
[ 104458-24-4 ]
[ 104-15-4 ]
[ 231278-84-5 ]
({5-[4-({3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino)quinazolin-6-yl]furan-2-yl}methyl) [2-(methylsulfonyl)ethyl]azanium 4-methylbenzenesulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%		Example 2:Preparation of A/-(3-chloro-4-[(3-fluorophenyl)methyl]oxy}phenyl)-6-[5-([2- (methylsulfonyl)ethyl]amino}methyl)-2-furanyl]-4- quinazolinamine, 4- methylbenzenesulfonate.The suspension of 5-[4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl]-2-furaldehyde (5 g, 10.6 mmoL) and 2-aminoethylmethylsulfone hydrochloride (3 g, 19 mmoL) in methanol (10 mL) and dichloromethane (25 mL) was charged with N,N-diisopropylethylamine (1.6 g, 12.7 mmoL) slowly under constant stirring at room temperature. The reaction mixture was stirred for 2-4 hours until reaction completion. The reaction mixture was charged with 10% Pt-C (500 mg) and stirred under hydrogen atmosphere (after evacuation) for 16-24 hours until reaction completion. The reaction mixture was further charged with methanol (25 mL) and dichloromethane (25 mL) and stirred for 12-16 hours. The obtained mixture was filtered, washed with 1 :1 mixture of methanol (20 mL) and dichloromethane (20 mL). The yellow filtrate thus obtained was slowly charged with a solution of p-toluenesulfonic acid monohydrate (2 g, 10.6 mmoL) in methanol (5 mL). The yellow solid which precipitated out was filtered and washed with 1 :1 mixture of methanol (20 mL) and dichloromethane (20 mL). The solid obtained was dried under vacuum at 40-45 C to afford the monotosylate salt of Lapatinib (5 g, Yield = 61 %, HPLC purity >99%).

Reference： [1]Patent: WO2012/83440,2012,A1 .Location in patent: Page/Page column 10

25
[ 6950-53-4 ]
[ 231278-84-5 ]
[ 1275595-87-3 ]

Yield	Reaction Conditions	Operation in experiment
56%	Stage #1: 2‐(methylsulfanyl)ethan‐1‐amine hydrochloride; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With triethylamine In methanol; dichloromethane at 20℃; Stage #2: With methanol; sodium tetrahydroborate In dichloromethane Cooling with ice;	3 Example 3: Synthesis of N-(4-(3-fluorobenzyloxy)3-chlorophenyl)-6-(5-((2-(methylthio)ethylamino)methyl)-2-furyl)-quinazolin-4-amine (Compound 3): [Show Image] 10.0g of compound 5-(4-(4-(3-fluorobenzyloxy)-3-chloroanilino)-6-quinazolinyl)furan-2-formaldehyde was dissolved in the mixture of dichloromethane/methanol (3:1). The mixture was added with 4.3g of triethylamine, stirred for 10min, added with 6.9g of 2-methylthioethylamine hydrochloride, and stirred at room temperature. Upon consumption of the starting materials deteced by TLC, 2.4g of sodium borohydride was added in batches under ice-bath. Upon the end of reaction deteced by TLC, dichloromethane (q.s.) was added. The mixture was washed with saturated ammonium chloride and then with saturated sodium chloride, dried over anhydrous sodium sulfate, and subjected to a column chromatography to obtain 6.5g of yellow solid, yield 56%. 1H-NM (600MHz, DMSO-d6, δppm): 9.93 (s, 1H), 8.73 (s, 1H), 8.55 (s, 1H), 8.16 (d, 1H, J = 2.4 Hz), 8.01 (d, 1H, J = 2.4 Hz), 7.80 (d, 1H, J = 7.4 Hz), 7.74 (dd, 1H, J = 2.4 Hz, J = 9 Hz), 7.45 (m, 1H), 7.34 (d, 1H, J = 7.8 Hz), 7.32 (s, 1H), 7.29 (d, 1H, J = 8.4 Hz), 7.19 (t, 1H, J = 8.4 Hz), 7.05 (d, 1H, J = 3.0 Hz), 6.48 (d, 1H, J = 3.0 Hz), 5.25 (s, 2H), 3.83 (s, 2H), 2.77 (t, 2H, J = 7.2 Hz), 2.59 (t, 2H, J = 7.2 Hz), 2.04 (s, 3H). MS (m/z): [M+H]+ 549.5.
56%	Stage #1: 2‐(methylsulfanyl)ethan‐1‐amine hydrochloride; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With triethylamine In methanol; dichloromethane at 20℃; Stage #2: With sodium tetrahydroborate In methanol; dichloromethane Cooling with ice;	3 10.0 g of compound 5-(4-(4-(3-fluorobenzyloxy)-3-chloroanilino)-6-quinazolinyl)furan-2-formaldehyde was dissolved in the mixture of dichloromethane/methanol (3:1). The mixture was added with 4.3 g of triethylamine, stirred for 10 min, added with 6.9 g of 2-methylthioethylamine hydrochloride, and stirred at room temperature. Upon consumption of the starting materials detected by TLC, 2.4 g of sodium borohydride was added in batches under ice-bath. Upon the end of reaction detected by TLC, dichloromethane (q.s.) was added. The mixture was washed with saturated ammonium chloride and then with saturated sodium chloride, dried over anhydrous sodium sulfate, and subjected to a column chromatography to obtain 6.5 g of yellow solid, yield 56%.1H-NM (600 MHz, DMSO-d6, δ ppm): 9.93 (s, 1H), 8.73 (s, 1H), 8.55 (s, 1H), 8.16 (d, 1H, J=2.4 Hz), 8.01 (d, 1H, J=2.4 Hz), 7.80 (d, 1H, J=7.4 Hz), 7.74 (dd, 1H, J=2.4 Hz, J=9 Hz), 7.45 (m, 1H), 7.34 (d, 1H, J=7.8 Hz), 7.32 (s, 1H), 7.29 (d, 1H, J=8.4 Hz), 7.19 (t, 1H, J=8.4 Hz), 7.05 (d, 1H, J=3.0 Hz), 6.48 (d, 1H, J=3.0 Hz), 5.25 (s, 2H), 3.83 (s, 2H), 2.77 (t, 2H, J=7.2 Hz), 2.59 (t, 2H, J=7.2 Hz), 2.04 (s, 3H).MS (m/z): [M+H]+ 549.5.

Reference： [1]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD - EP2484678, 2012, A1 Location in patent: Page/Page column 17-18
[2]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD - US2012/208833, 2012, A1 Location in patent: Page/Page column 12; 13

26
[ 89756-60-5 ]
[ 231278-84-5 ]
[ 1275595-85-1 ]

Yield	Reaction Conditions	Operation in experiment
74%		f. Synthesis of N-(4-(3-fluorobenzyloxy)3-chlorophenyl)-6-(5-((2-(sulfamoyl)ethylamino)methyl)-2-furyl)-auinazolin-4-amine: [Show Image] 2.4g of compound 5-(4-(4-(3-fluorobenzyloxy)-3-chloroanilino)-6-quinazolinyl)furan-2-formaldehyde was dissolved in the mixture of dichloromethane/methanol (3:1). The mixture was added with 1.0g of triethylamine, stirred for 10min, added with 1.6g of 2-aminoethylsulfonamide hydrochloride, and stirred at room temperature. Upon consumption of the starting materials detected by TLC, 0.57g of sodium borohydride was added in batches under ice-bath. Upon the end of reaction detected by TLC, dichloromethane (q.s.) was added. The mixture was washed with saturated ammonium chloride solution and then with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and subjected to a column chromatography to obtain 2.2g of yellow solid, yield 74%. 1H NM (600MHz, DMSO-d6, deltappm): 10.06 (s, 1H), 9.1 (s, 1H), 8.58 (s, 1H), 8.20 (dd, 1H, J = 1.8 Hz, J = 9 Hz), 8.15 (s, 1H), 7.87 (d, 1H, J = 7.8 Hz), 7.82 (d, 1H, J = 8.4 Hz), 7.48 (d, 1H, J = 7.8 Hz), 7.34 (d, 1H, J = 7.8 Hz), 7.32 (s, 1H), 7.29 (d, 1H, J = 9 Hz), 7.21 (d, 1H, J = 2.4 Hz), 7.18 (d, 1H, J = 1.8 Hz), 7.12 (s, 1H), 5.23 (s, 2H), 3.42 (m, 2H), 3.35 (s, 2H), 4.23 (s, 2H), 3.13 (m, 2H). MS (m/z): [M+H]+ 582.1.
74%		2.4 g of compound 5-(4-(4-(3-fluorobenzyloxy)-3-chloroanilino)-6-quinazolinyl)furan-2-formaldehyde was dissolved in the mixture of dichloromethane/methanol (3:1). The mixture was added with 1.0 g of triethylamine, stirred for 10 min, added with 1.6 g of 2-aminoethylsulfonamide hydrochloride, and stirred at room temperature. Upon consumption of the starting materials detected by TLC, 0.57 g of sodium borohydride was added in batches under ice-bath. Upon the end of reaction detected by TLC, dichloromethane (q.s.) was added. The mixture was washed with saturated ammonium chloride solution and then with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and subjected to a column chromatography to obtain 2.2 g of yellow solid, yield 74%.1H NM (600 MHz, DMSO-d6, delta ppm): 10.06 (s, 1H), 9.1 (s, 1H), 8.58 (s, 1H), 8.20 (dd, 1H, J=1.8 Hz, J=9 Hz), 8.15 (s, 1H), 7.87 (d, 1H, J=7.8 Hz), 7.82 (d, 1H, J=8.4 Hz), 7.48 (d, 1H, J=7.8 Hz), 7.34 (d, 1H, J=7.8 Hz), 7.32 (s, 1H), 7.29 (d, 1H, J=9 Hz), 7.21 (d, 1H, J=2.4 Hz), 7.18 (d, 1H, J=1.8 Hz), 7.12 (s, 1H), 5.23 (s, 2H), 3.42 (m, 2H), 3.35 (s, 2H), 4.23 (s, 2H), 3.13 (m, 2H).MS (m/z): [M+H]+ 582.1. Compound 1 was dissolved in tetrahydrofuran, and the solution was slowly added dropwise to a solution of p-toluenesulfonic acid in ethanol. The mixture was heated under reflux for 2 h, precipitated to give a flavo-green deposite, filtrated and dried to obtain a p-tosylate of compound 1.

Reference： [1]Patent: EP2484678,2012,A1 .Location in patent: Page/Page column 15
[2]Patent: US2012/208833,2012,A1 .Location in patent: Page/Page column 10; 11

27
[ 202197-61-3 ]
[ 231278-84-5 ]
[ 1275595-88-4 ]

Yield	Reaction Conditions	Operation in experiment
45%	Stage #1: N-(2-aminoethyl)methanesulfonamide hydrochloride; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With triethylamine In methanol; dichloromethane at 20℃; Stage #2: With methanol; sodium tetrahydroborate In dichloromethane at 20℃; Cooling with ice;	4.d d. Synthesis of N-(4-(3-fluorobenzyloxy)3-chlorophenyl)-6-(5-((2-(methylsulfonamido)ethylamino)methyl)-2-furyl)-quinazolin-4-amine: [Show Image] At room temperature, 10.0g of compound 5-(4-(4-(3-fluorobenzyloxy)-3-chloroanilino)-6-quinazolinyl)furan-2-formaldehyde, 6.5g of compound N-(2-aminoethyl)methanesulfonamide hydrochloride, and 14.6g of triethylamine in the mixture of dichloromethane/methanol (3:1) were stirred overnight, then cooled with ice-bath to 0°C, and 1.4g of sodium borohydride was added at that temperature. The mixture was warmed to room temperature, stirred overnight, saturated sodium bicarbonate was added to quench the reaction, and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and subjected to a column chromatography to obtain 5.7g of the desired product, yield 45.0%. 1H-NMR (300MHz, CDCI3, δppm): 8.65 (s, 1H), 8.62 (s, 1H), 8.28 (s, 1H), 7.84∼7.73 (m, 3H), 7.53 (d, 1H, J = 8.7 Hz), 7.33-7.28 (m, 1H), 7.19∼7.15 (m, 2H), 6.98 (t, 1H, J = 8.4 Hz),6.86 (d, 1H J = 4.5 Hz), 6.57 (d, 1H, J = 1.8 Hz), 6.20 (d, 1H, J = 1.8 Hz), 5.04 (s, 2H), 3.73 (s, 2H), 3.18(t, 2H, J = 8.4 Hz),2.87 (s, 3H),2.78 (t, 2H, J = 8.4); 13C-NMR (75MHz, CDCl3, δppm): 164.4, 161.2, 157.8, 154.4, 153.7, 152.2, 150.7, 148.9, 139.0, 138.9, 132.4, 130.1, 130.0, 124.9, 128.6, 128.5, 124.9, 122.7, 122.4, 122.3, 115.3, 115.1, 114.8, 114.5, 113.9, 113.6, 109.7, 107.1, 70.1, 47.4, 45.2, 42.2, 40.0; HR-MS (m/z): calculated: C29H27ClFN5O4S [M+H]+ 596.1529, measured: 596.1533.
45%	Stage #1: N-(2-aminoethyl)methanesulfonamide hydrochloride; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With triethylamine In methanol; dichloromethane Stage #2: With sodium tetrahydroborate In methanol; dichloromethane at 0 - 20℃;	4.d At room temperature, 10.0 g of compound 5-(4-(4-(3-fluorobenzyloxy)-3-chloroanilino)-6-quinazolinyl)furan-2-formaldehyde, 6.5 g of compound N-(2-aminoethyl)methanesulfonamide hydrochloride, and 14.6 g of triethylamine in the mixture of dichloromethane/methanol (3:1) were stirred overnight, then cooled with ice-bath to 0° C., and 1.4 g of sodium borohydride was added at that temperature. The mixture was warmed to room temperature, stirred overnight, saturated sodium bicarbonate was added to quench the reaction, and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and subjected to a column chromatography to obtain 5.7 g of the desired product, yield 45.0%.1H-NMR (300 MHz, CDCl3, δ ppm): 8.65 (s, 1H), 8.62 (s, 1H), 8.28 (s, 1H), 7.84-7.73 (m, 3H), 7.53 (d, 1H, J=8.7 Hz), 7.33-7.28 (m, 1H), 7.19-7.15 (m, 2H), 6.98 (t, 1H, J=8.4 Hz), 6.86 (d, 1H J=4.5 Hz), 6.57 (d, 1H, J=1.8 Hz), 6.20 (d, 1H, J=1.8 Hz), 5.04 (s, 2H), 3.73 (s, 2H), 3.18 (t, 2H, J=8.4 Hz), 2.87 (s, 3H), 2.78 (t, 2H, J=8.4);13C-NMR (75 MHz, CDCl3, δ ppm): 164.4, 161.2, 157.8, 154.4, 153.7, 152.2, 150.7, 148.9, 139.0, 138.9, 132.4, 130.1, 130.0, 124.9, 128.6, 128.5, 124.9, 122.7, 122.4, 122.3, 115.3, 115.1, 114.8, 114.5, 113.9, 113.6, 109.7, 107.1, 70.1, 47.4, 45.2, 42.2, 40.0;HR-MS (m/z): calculated: C29H27ClFN5O4S [M+H]+ 596.1529, measured: 596.1533.

Reference： [1]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD - EP2484678, 2012, A1 Location in patent: Page/Page column 19
[2]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD - US2012/208833, 2012, A1 Location in patent: Page/Page column 14

28
[ 1275596-06-9 ]
[ 231278-84-5 ]
[ 1275595-90-8 ]

Yield	Reaction Conditions	Operation in experiment
11.1%	Stage #1: 2-trifluoromethylsulfonylethylamine hydrochloride; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With acetic acid; triethylamine In dichloromethane at 20℃; for 4h; Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane at 0 - 20℃; for 12h; Stage #3: With sodium hydrogencarbonate In dichloromethane	6 Example 6: Synthesis of N-(4-(3-fluorobenzyloxy)3-chlorophenyl)-6-(5-((2-(trifluoromethylsulfonyl)ethylamino)methyl)-2-furyl)-quinazolin-4-amine (Compound 6): [Show Image] At room temperature, 240mg of compound 5-(4-(4-(3-fluorobenzyloxy)-3-chloroanilino)-6-quinazolinyl)furan-2-formaldehyde, 120mg of compound 2-trifluoromethylsulfonylethylamine hydrochloride, 0.2ml of triethylamine were mixed in 10ml of dichloromethane, and 0.2ml glacial acetic acid was added. The mixture was stirred for 4h, cooled to 0°C with ice-bath at which temperature 500mg of sodium triacetyloxyborohydride was added, then warmed to room temperature, further stirred for 12h, added with saturated sodium bicarbonate to quench the reaction, and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and subjected to a column chromatography to obtain 35.7mg of yellow solid, yield 11.1%. 1H-NMR(400MHz, CDCI3, δppm): 8.70 (s, 1H), 8.27 (s, 1H), 7.98-7.96 (m, 1H), 7.90-7.88 (m, 2H0, 7.84 (d, J=1.2Hz, 1H), 7.54 (dd, J=2.4Hz, J=8.8Hz, 1H), 7.39-7.34 (m, 1H), 7.24-7.22 (m, 1H), 7.04-6.97 (m, 2H), 6.76 (d, J=1.2Hz, 1H), 6.45 (d, J=1.6Hz, 1H), 5.17 (s, 2H), 3.92 (s, 2H), 3.55-3.49 (m, 2H), 3.37-3.34 (m, 2H); 13C-NMR (100MHz, CDCI3, δppm): 164.20, 161.75, 157.80, 154.97, 153.55, 151.06, 149.77, 49.57, 139.14, 139.07, 132.14, 130.17, 130.09, 129.25, 128.80, 128.18, 125.18, 124.06, 23.40, 123.34, 122.45, 122.43, 122.29, 120.81, 117.56, 115.34, 115.01, 114.95, 114.74, 114.18, 114.08, 113.86, 112.46, 07.11, 70.37, 47.87, 46.12, 45.74; HR-MS (m/z): calculated: C29H23ClF4N4O4S [M+H]+ 635.1137, measured: 635.1142.
11.1%	Stage #1: 2-trifluoromethylsulfonylethylamine hydrochloride; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With acetic acid; triethylamine In dichloromethane for 4h; Stage #2: With sodium tris(acetoxy)borohydride In methanol; dichloromethane at 0 - 20℃; for 12h;	6 At room temperature, 240 mg of compound 5-(4-(4-(3-fluorobenzyloxy)-3-chloroanilino)-6-quinazolinyl)furan-2-formaldehyde, 120 mg of compound 2-trifluoromethylsulfonylethylamine hydrochloride, 0.2 ml of triethylamine were mixed in 10 ml of dichloromethane, and 0.2 ml glacial acetic acid was added. The mixture was stirred for 4 h, cooled to 0° C. with ice-bath at which temperature 500 mg of sodium triacetyloxyborohydride was added, then warmed to room temperature, further stirred for 12 h, added with saturated sodium bicarbonate to quench the reaction, and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and subjected to a column chromatography to obtain 35.7 mg of yellow solid, yield 11.1%.1H-NMR (400 MHz, CDCl3, δ ppm): 8.70 (s, 1H), 8.27 (s, 1H), 7.98-7.96 (m, 1H), 7.90-7.88 (m, 2H0, 7.84 (d, J=1.2 Hz, 1H), 7.54 (dd, J=2.4 Hz, J=8.8 Hz, 1H), 7.39-7.34 (m, 1H), 7.24-7.22 (m, 1H), 7.04-6.97 (m, 2H), 6.76 (d, J=1.2 Hz, 1H), 6.45 (d, J=1.6 Hz, 1H), 5.17 (s, 2H), 3.92 (s, 2H), 3.55-3.49 (m, 2H), 3.37-3.34 (m, 2H);13C-NMR (100 MHz, CDCl3, δ ppm): 164.20, 161.75, 157.80, 154.97, 153.55, 151.06, 149.77, 49.57, 139.14, 139.07, 132.14, 130.17, 130.09, 129.25, 128.80, 128.18, 125.18, 124.06, 23.40, 123.34, 122.45, 122.43, 122.29, 120.81, 117.56, 115.34, 115.01, 114.95, 114.74, 114.18, 114.08, 113.86, 112.46, 07.11, 70.37, 47.87, 46.12, 45.74;HR-MS (m/z): calculated: C29H23ClF4N4O4S [M+H]+ 635.1137, measured: 635.1142. N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-(5-((2-(methylsulfonyl)ethylamino) methyl)-2-furyl)-quinazolin-4-amine (Compound 61) can be readily obtained by using procedures similar to those of the process for preparing Compound 6, except that 2-trifluoromethylsulfonylethylamine hydrochloride was replaced with 2-methylsulfonylethylamine hydrochloride.

Reference： [1]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD - EP2484678, 2012, A1 Location in patent: Page/Page column 22
[2]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD - US2012/208833, 2012, A1 Location in patent: Page/Page column 16; 17

29
[ 231278-84-5 ]
[ 1152131-73-1 ]

Yield	Reaction Conditions	Operation in experiment
0.98 g	With chromium(VI) oxide; sulfuric acid; water In acetone at 0℃; for 2h;	4.1.12. (5-(4-(3-Chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-yl)(4-methylpiperazin-1-yl)methanone (K) To a stirring mixture of intermediate C (1 g) in acetone (100 ml) at 0° C was added dropwise the solution of CrO3-H2SO4 (10 ml) (preparation method: 11 ml of 98% H2SO4 was added into the mixture of CrO3 (10 g) and H2O (50 ml) at 0 °C). The reaction mixture was stirred for 2 h at 0 °C, then diluted with H2O (150 ml).The solid was filtered, washed with saturated aqueous solution of ammonium chloride and dried in a vacuum oven for 10 h at 60 °C to give the intermediate D (0.98 g). A mixture of D (0.98 g) and SOCl2 (0.3 ml) in CH2Cl2 (50 ml) was stirred and heated under reflux for 2 h. After the solvent was removed, the residue was suspended in the solvent of CH2Cl2 (20 ml) and N-methyl piperazine (3 ml). The mixture was heated under reflux for 4 h, then diluted with H2O (150 ml) and concentrated at 35 °C to remove the CH2Cl2 and filtered. The residue was dried, and purified on a silica gel column using ethyl acetate/MeOH to provide the title compound (K) (0.35 g, yield 29%).
4.0 g	With potassium permanganate; tetrabutylammomium bromide In tetrahydrofuran; water at 20℃; for 24h; Cooling with ice;	2.1 Example 2: Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((4-hydroxybutyl)amino)methyl)-2-furyl)-4 -quinazolinamine (MS1) Step 1: Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-carboxy-2-furyl)-4-quinazolinamine (intermediate a) Example 2: Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((4-hydroxybutyl)amino)methyl)-2-furyl)-4 -quinazolinamine (MS1) [0058] In the present invention, the compound of Number MS1 can be synthesized via the following reaction route: in which X is chloro, Y is fluoro, and the specific production steps are as follows: Step 1: Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-carboxy-2-furyl)-4-quinazolinamine (intermediate a) N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (4.71g) produced in Example 1 was added THF (60ml), tetrabutylammonium bromide (0.1g). Then a solution of potassium permanganate dissolved in water (70ml) was slowly added dropwise to the mixture under ice-water cooling. After the addition was complete, the resulting brown suspension was reacted at room temperature for 24 h. The mixture was filtered under suction and the filter cake was washed with warm water of 40°C three times, and methanol three times, and was refined to obtain an intermediate product a, 4.0g; Step 2: Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((4-hydroxybutyl)amino)formyl)-2-furyl)-4-quinazolinamine (intermediate b) To the intermediate a (0.98g, 1mmol) obtained from the above step 1 was added chloroform (50ml), a drop of DMF. Thionyl chloride (0.3 ml) was then added at room temperature. After the mixture was reacted for 6 h, 4-hydroxybutylamine (4 ml) was added. The reaction was kept at room temperature for 24 h. After treatment the intermediate product b was obtained, 0.70g; Step 3: Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((4-hydroxybutyl)amino)methyl)-2-furyl)-4 -quinazolinamine (target product MS1) The intermediate b obtained from the above step 2 was reduced. After reaction the target product of compound MS1 was obtained. The characterization of the related structures can be found in Example 3.
4.0 g	With potassium permanganate; tetrabutylammomium bromide In tetrahydrofuran; water at 20℃; for 24h; Cooling with ice;	2.1 Step 1: Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-carboxy-2-furyl)-4-quinazolinamine (Intermediate a) N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (4.71 g) produced in Example 1 was added THF (60 ml), tetrabutylammonium bromide (0.1 g). Then a solution of potassium permanganate dissolved in water (70 ml) was slowly added dropwise to the mixture under ice-water cooling. After the addition was complete, the resulting brown suspension was reacted at room temperature for 24 h. The mixture was filtered under suction and the filter cake was washed with warm water of 40° C. three times, and methanol three times, and was refined to obtain an intermediate product a, 4.0 g;

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 Location in patent: Paragraph 0057; 0058
[3]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1 Location in patent: Paragraph 0215

30
[ 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

31
[ 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

32
[ 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

33
[ 13529-27-6 ]
[ 231278-84-5 ]

Reference： [1]Patent: WO2014/59956,2014,A1

34
dimethyl glutamate hydrochloride [ No CAS ]
[ 231278-84-5 ]
N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((1,3-dicarboxypropyl)amino)methyl)-2-furyl)-4-quinazolinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61.2%	Stage #1: dimethyl glutamate hydrochloride; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 48h; Stage #3: With water; sodium hydroxide In tetrahydrofuran for 2h;	25 Example 25 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((1,3-dicarboxypropyl)amino)methyl)-2-fur yl)-4-quinazolinamine (MS23) Example 25 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((1,3-dicarboxypropyl)amino)methyl)-2-fur yl)-4-quinazolinamine (MS23) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1mmol) obtained from Example 1 was dissolved in tetrahydrofuran (10ml), followed by the addition of glutamic acid dimethyl ester hydrochloride (0.42g, 2 mmol) and diisopropylethylamine (0.26g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.74g, 3.5mmol) was added, and then the mixture was stirred at room temperature for 48 h. 20% aqueous solution of sodium hydroxide (10 ml) was added and the mixture was stirred for 2 h, and then adjusted to PH ~ 7 with hydrochloric acid. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid (0.37g, 61.2%), i.e. the compound of Number MS23. m.p.: 158- 160°C; 1H NMR(DMSO-d6)δ: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 1H), 7.27- 7.35(m, 3H), 7.18(t, 1H), 7.05(d, J=3.2 Hz, 1H), 6.49(d, J=3.3 Hz, 1H), 5.26(s, 2H), 3.99- 4.04(m, 1H), 3.66(s, 2H), 3.49(t, 1H), 2.33(t, 2H), 1.91(m, 2H); ESI-MS m/z: 605[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1 Location in patent: Paragraph 0082; 0083

35
[ 5619-07-8 ]
[ 231278-84-5 ]
N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((1-carboxy-2-phenyl)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	Stage #1: methyl 2-amino-3-phenylpropanoate hydrochloride; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 48h; Stage #3: With water; sodium hydroxide In tetrahydrofuran for 2h;	26 Example 26 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((1-carboxy-2-phenyl)ethyl)amino)methyl) -2-furyl)-4-quinazolinamine (MS24) Example 26 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((1-carboxy-2-phenyl)ethyl)amino)methyl) -2-furyl)-4-quinazolinamine (MS24) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47g, 1mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10ml), followed by the addition of phenylalanine methyl ester hydrochloride (0.43g, 2 mmol) and diisopropylethylamine (0.26g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.74g, 3.5mmol) was added, and then the mixture was stirred at room temperature for 48 h. 20% aqueous solution of sodium hydroxide (10 ml) was added and the mixture was stirred for 2 h, and then adjusted to PH ~ 7 with hydrochloric acid. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid (0.33g, 53.0%), i.e. the compound of Number MS24. m.p.: 139- 141°C; 1H NMR(DMSO-d6)δ: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 3H), 7.27- 7.35(m, 6H), 7.18(t, 1H), 7.05(d, J=3.2 Hz, 1H), 6.49(d, J=3.3 Hz, 1H), 5.26(s, 2H), 3.99- 4.04(m, 1H), 3.88(t, 1H), 3.66(s, 2H), 3.29(d, 2H); ESI-MS m/z: 623[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1 Location in patent: Paragraph 0083; 0084

36
[ 72-19-5 ]
[ 231278-84-5 ]
N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-carboxypropyl)amino)methyl)-2-furyl)-4-quinazolinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56.8%		Example 27 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-carboxypropyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS25) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1mmol) obtained from Example 1 was dissolved in (0.47g, 1mmol), was dissolved in tetrahydrofuran (10ml), followed by the addition of isopropanol (2ml) and <strong>[72-19-5]threonin</strong>e (0.23g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42 g, 2 mmol) was added, and then the mixture was stirred at room temperature for 48 h. 20% aqueous solution of sodium hydroxide (10 ml) was added and the mixture was stirred for 2 h, and then adjusted to PH ~ 7 with hydrochloric acid. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid (0.32g, 56.8%), i.e. the compound of Number MS25. m.p.: 153- 155C; 1H NMR(DMSO-d6)delta: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 1H), 7.27- 7.35(m, 3H), 7.18(t, 1H), 7.05(d, J=3.2 Hz, 1H), 6.49(d, J=3.3 Hz, 1H), 5.26(s, 2H), 3.99- 4.04(m, 1H), 3.84(s, 2H), 3.75(m, 2H), 3.65(br, 1H), 3.58(t, 1H); ESI-MS m/z: 563[M+H]+.

Reference： [1]Patent: EP2740729,2014,A1 .Location in patent: Paragraph 0084; 0085

37
[ 16118-36-8 ]
[ 231278-84-5 ]
N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((1-carboxy-3-methylthio)propyl)amino)methyl)-2-furyl)-4-quinazolinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49.4%	Stage #1: methionine methyl ester hydrochloride; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 48h; Stage #3: With water; sodium hydroxide In tetrahydrofuran for 2h;	28 Example 28 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((1-carboxy-3-methylthio)propyl)amino)m ethyl)-2-furyl)-4-quinazolinamine (MS26) Example 28 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((1-carboxy-3-methylthio)propyl)amino)m ethyl)-2-furyl)-4-quinazolinamine (MS26) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47g, 1mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10ml), followed by the addition of methionine methyl ester hydrochloride (0.40g, 2 mmol) and diisopropylethylamine (0.26g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.74g, 3.5mmol) was added, and then the mixture was stirred at room temperature for 48 h. 20% aqueous solution of sodium hydroxide (10 ml) was added and the mixture was stirred for 2 h, and then adjusted to PH ~ 7 with hydrochloric acid. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a brown solid (0.30g, 49.4%), i.e. the compound of Number MS26. m.p.: 131- 133°C; 1H NMR(DMSO-d6)δ: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 1H), 7.27- 7.35(m, 3H), 7.18(t, 1H), 7.05(d, J=3.2 Hz, 1H), 6.49(d, J=3.3 Hz, 1H), 5.26(s, 2H), 3.99- 4.04(m, 1H), 3.66(s, 2H), 3.59(t, 1H), 2.60(t, 2H), 2.14(s, 3H), 1.91(m, 2H); ESI-MS m/z: 607[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1 Location in patent: Paragraph 0085; 0086

38
[ 141-43-5 ]
[ 231278-84-5 ]
[ 1421356-63-9 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: ethanolamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 12h;	29 Example 29 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-hydroxyethyl)amino)methyl)-2-furyl)-4 -quinazolinamine (MS27) ·dimethylsulfonate Example 29 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-hydroxyethyl)amino)methyl)-2-furyl)-4 -quinazolinamine (MS27) ·dimethylsulfonate Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (5.69g, 12mmol) obtained from Example 1 was dissolved in tetrahydrofuran (100ml), followed by the addition of ethanolamine (1.53g, 25 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (8.48 g, 40 mmol) was added, and then the mixture was stirred at room temperature for 12 h. A saturated aqueous solution of sodium carbonate (50 ml) was added, and then the mixure was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow powdered solid, i.e. the compound of Number MS27. The yellow powdered solid was dissolved in tetrahydrofuran (50 ml),and a solution of methanesulfonic acid (3.46 g, 36 mmol) in tetrahydrofuran (50 ml) was added dropwise under stirring. After the dropwise addition, the mixture was stirred at room temperature for 12 h. The mixture was filtered under suction and the filter cake was washed with tetrahydrofuran-deionized water (95:5). The product was refined, and dried at 70°C under vacuum to give a yellow solid (7.51g, 88.0%), i.e. the dimethanesulfonate of the compound of Number MS27. m.p.: 263- 265°C; HPLC: > 98.5%, 1H NMR(DMSO-d6) 1H NMR(DMSO-d6)δ: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 1H), 7.277.35(m, 3H), 7.18(t, 1H), 7.05(d, J=3.2 Hz, 1H), 6.49(d, J=3.3 Hz, 1H), 5.26(s, 2H), 3.99- 4.04(m, 1H), 3.84(s, 2H), 3.65(br, 1H), 3.47(m, 2H), 2.73(d, 2H); ESI-MS m/z: 519[M+H]+.
	Stage #1: ethanolamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 12h;	29 Example 29 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-hydroxyethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS27).dimethylsulfonate Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (5.69 g, 12 mmol) obtained from Example 1 was dissolved in tetrahydrofuran (100 ml), followed by the addition of ethanolamine (1.53 g, 25 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (8.48 g, 40 mmol) was added, and then the mixture was stirred at room temperature for 12 h. A saturated aqueous solution of sodium carbonate (50 ml) was added, and then the mixture was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow powdered solid, i.e. the compound of Number MS27. The yellow powdered solid was dissolved in tetrahydrofuran (50 ml), and a solution of methanesulfonic acid (3.46 g, 36 mmol) in tetrahydrofuran (50 ml) was added dropwise under stirring. After the dropwise addition, the mixture was stirred at room temperature for 12 h. The mixture was filtered under suction and the filter cake was washed with tetrahydrofuran-deionized water (95:5). The product was refined, and dried at 70° C. under vacuum to give a yellow solid (7.51 g, 88.0%), i.e. the dimethanesulfonate of the compound of Number MS27. m.p.: 263-265° C.; HPLC: >98.5%, 1H NMR (DMSO-d6) 1H NMR (DMSO-d6) δ: 9.87 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.16 (d, J=8.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.46-7.49 (m, 1H), 7.277.35 (m, 3H), 7.18 (t, 1H), 7.05 (d, J=3.2 Hz, 1H), 6.49 (d, J=3.3 Hz, 1H), 5.26 (s, 2H), 3.99-4.04 (m, 1H), 3.84 (s, 2H), 3.65 (br, 1H), 3.47 (m, 2H), 2.73 (d, 2H); ESI-MS m/z: 519[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1 Location in patent: Paragraph 0086; 0087
[2]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1 Location in patent: Paragraph 0257

39
[ 921-01-7 ]
[ 231278-84-5 ]
N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((1-carboxy-2-mercapto)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56.8%		Example 31 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((1-carboxy-2-mercapto)ethyl)amino)meth yl)-2-furyl)-4-quinazolinamine (MS29) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1mmol) obtained from Example 1 was dissolved in tetrahydrofuran (10ml), followed by the addition of isopropanol (2ml) and cysteine (0.24g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42 g, 2 mmol) was added, and then the mixture was stirred at room temperature for 48 h. 20% aqueous solution of sodium hydroxide (10 ml) was added and the mixture was stirred for 15 min, and then adjusted to PH ~ 7 with hydrochloric acid. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid (0.32g, 56.8%), i.e. the compound of Number MS29. m.p.: 146- 149C; 1H NMR(DMSO-d6)delta: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 1H), 7.27- 7.35(m, 3H), 7.18(t, 1H), 7.05(d, J=3.2 Hz, 1H), 6.49(d, J=3.3 Hz, 1H), 5.26(s, 2H), 3.99-4.04(m, 1H), 3.81(t, 1H), 3.66(s, 2H), 2.79(d, 2H); ESI-MS m/z: 579[M+H]+.

Reference： [1]Patent: EP2740729,2014,A1 .Location in patent: Paragraph 0088; 0089

40
[ 3130-87-8 ]
[ 231278-84-5 ]
N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((1-carboxy-2-aminoformyl)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59.3%	Stage #1: ASPARAGINE; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran; isopropyl alcohol at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran; isopropyl alcohol at 20℃; for 48h; Stage #3: With water; sodium hydroxide In tetrahydrofuran; isopropyl alcohol for 0.25h;	32 Example 32 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((1-carboxy-2-aminoformyl)ethyl)amino) methyl)-2-furyl)-4-quinazolinamine (MS30) Example 32 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((1-carboxy-2-aminoformyl)ethyl)amino) methyl)-2-furyl)-4-quinazolinamine (MS30) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1mmol) obtained from Example 1 was dissolved in tetrahydrofuran (10ml), followed by the addition of isopropanol (2ml) and asparagine (0.27g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42 g, 2 mmol) was added, and then the mixture was stirred at room temperature for 48 h. 20% aqueous solution of sodium hydroxide (10 ml) was added and the mixture was stirred for 15 min, and then adjusted to PH ~ 7 with hydrochloric acid. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid (0.35g, 59.3%), i.e. the compound of Number MS30. m.p.: 152- 154°C; 1H NMR(DMSO-d6)δ: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 1H), 7.27- 7.35(m, 3H), 7.18(t, 1H), 7.16(s, 2H), 7.05(d, J=3.2 Hz, 1H), 6.49(d, J=3.3 Hz, 1H), 5.26(s, 2H), 3.99- 4.04(m, 1H), 3.84(s, 2H), 3.72(t, 1H), 2.65(d, 2H); ESI-MS m/z: 590[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1 Location in patent: Paragraph 0089; 0090

41
[ 13552-31-3 ]
[ 231278-84-5 ]
[ 1421356-68-4 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3-Amino-1,2-propanediol; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 12h;	33 Example 33 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((1-(2,3-dihydroxypropyl)amino)methyl)-2-f uryl)-4-quinazolinamine (MS31) Example 33 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((1-(2,3-dihydroxypropyl)amino)methyl)-2-f uryl)-4-quinazolinamine (MS31) ·dimethylsulfonate Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (5.69g, 12 mmol) obtained from Example 1 was dissolved in tetrahydrofuran (100 ml), followed by the additon of 1-amino-2,3-propanediol (2.28g, 25 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (8.48 g, 40 mmol) was added, and then the mixture was stirred at room temperature for 12 h. A saturated aqueous solution of sodium carbonate (50 ml) was added, and then the mixure was stirred for 15 min to be layered.. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow powdered solid. The yellow powdered solid was dissolved in tetrahydrofuran (50 ml), and a solution of methanesulfonic acid (3.46 g, 36 mmol) in tetrahydrofuran (50 ml) was added dropwise under stirring. After the dropwise addition, the mixture was stirred at room temperature for 12 h. The mixture was filtered under suction and the filter cake was washed with tetrahydrofuran-deionized water (95:5). The product was refined, and dried at 70°C under vacuum to give a yellow solid (7.71g, 86.7%), i.e. the dimethanesulfonate of the compound of Number MS31. HPLC: > 98.5%, m.p.: 206- 210°C; 1H NMR(DMSO-d6) δ: 8.49(s, 1H), 8.22(1H), 8.06(1H), 8.05(1H), 7.43(1H), 7.36(1H), 7.24(d, 1H), 7.17(1H), 7.01(1H), 6.90(m, 1H), 6.7(1H), 6.68(1H), 6.26(1H), 5.16(2H), 4.0(1H), 3.81(2H), 3.66(2H), 3.65(1H), 3.58(1H), 3.54(1H), 3.29(6H), 2.83(2H), 2.0(3H); ESI-MS m/z: 549[M+H]+.
	Stage #1: 3-Amino-1,2-propanediol; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 12h;	33 Example 33 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((1-(2,3-dihydroxypropyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS31).dimethylsulfonate Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (5.69 g, 12 mmol) obtained from Example 1 was dissolved in tetrahydrofuran (100 ml), followed by the addition of 1-amino-2,3-propanediol (2.28 g, 25 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (8.48 g, 40 mmol) was added, and then the mixture was stirred at room temperature for 12 h. A saturated aqueous solution of sodium carbonate (50 ml) was added, and then the mixture was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow powdered solid. The yellow powdered solid was dissolved in tetrahydrofuran (50 ml), and a solution of methanesulfonic acid (3.46 g, 36 mmol) in tetrahydrofuran (50 ml) was added dropwise under stirring. After the dropwise addition, the mixture was stirred at room temperature for 12 h. The mixture was filtered under suction and the filter cake was washed with tetrahydrofuran-deionized water (95:5). The product was refined, and dried at 70° C. under vacuum to give a yellow solid (7.71 g, 86.7%), i.e. the dimethanesulfonate of the compound of Number MS31. HPLC: >98.5%, m.p.: 206-210° C.; 1H NMR (DMSO-d6) δ: 8.49 (s, 1H), 8.22 (1H), 8.06 (1H), 8.05 (1H), 7.43 (1H), 7.36 (1H), 7.24 (d, 1H), 7.17 (1H), 7.01 (1H), 6.90 (m, 1H), 6.7 (1H), 6.68 (1H), 6.26 (1H), 5.16 (2H), 4.0 (1H), 3.81 (2H), 3.66 (2H), 3.65 (1H), 3.58 (1H), 3.54 (1H), 3.29 (6H), 2.83 (2H), 2.0 (3H); ESI-MS m/z: 549[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1 Location in patent: Paragraph 0090; 0091
[2]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1 Location in patent: Paragraph 0261

42
2,5-diaminopentanoic acid [ No CAS ]
[ 231278-84-5 ]
N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((4-carboxy-4-amino)butyl)amino)methyl)-2-furyl)-4-quinazolinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64.4%	Stage #1: 2,5-diaminopentanoic acid; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 48h; Stage #3: With water; sodium hydroxide In tetrahydrofuran for 0.25h;	34 Example 34 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((4-carboxy-4-amino)butyl)amino)methyl) -2-furyl)-4-quinazolinamine (MS32) Example 34 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((4-carboxy-4-amino)butyl)amino)methyl) -2-furyl)-4-quinazolinamine (MS32) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1mmol) obtained from Example 1 was dissolved in tetrahydrofuran (10ml), followed by the addition of isopropyl (2ml) and 2,5-diaminopentanoic acid (0.27g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42 g, 2 mmol) was added, and then the mixture was stirred at room temperature for 48 h. 20% aqueous solution of sodium hydroxide (10 ml) was added and the mixture was stirred for 15 min, and then adjusted to PH ~ 7 with hydrochloric acid. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid (0.38g, 64.4%), i.e. the compound of Number MS32. m.p.: 145- 147°C; 1H NMR(DMSO-d6)δ: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 1H), 7.27- 7.35(m, 3H), 7.18(t, 1H), 7.05(d, J=3.2 Hz, 1H), 6.49(d, J=3.3 Hz, 1H), 5.26(s, 2H), 5.11(s, 2H), 3.99- 4.04(m, 1H), 3.84(s, 2H), 3.49(m, 1H), 2.59(m, 2H), 1.78(m, 2H), 1.41(m, 2H); ESI-MS m/z: 590[M+H]+.
64.4%	Stage #1: 2,5-diaminopentanoic acid; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 48h;	34 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((4-carboxy-4-amino)butyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS32) Example 34 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((4-carboxy-4-amino)butyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS32) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1 mmol) obtained from Example 1 was dissolved in tetrahydrofuran (10 ml), followed by the addition of isopropyl (2 ml) and 2,5-diaminopentanoic acid (0.27 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42 g, 2 mmol) was added, and then the mixture was stirred at room temperature for 48 h. 20% aqueous solution of sodium hydroxide (10 ml) was added and the mixture was stirred for 15 min, and then adjusted to PH˜7 with hydrochloric acid. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid (0.38 g, 64.4%), i.e. the compound of Number MS32. m.p.: 145-147° C.; 1H NMR (DMSO-d6) δ: 9.87 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.16 (d, J=8.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.46-7.49 (m, 1H), 7.27-7.35 (m, 3H), 7.18 (t, 1H), 7.05 (d, J=3.2 Hz, 1H), 6.49 (d, J=3.3 Hz, 1H), 5.26 (s, 2H), 5.11 (s, 2H), 3.99-4.04 (m, 1H), 3.84 (s, 2H), 3.49 (m, 1H), 2.59 (m, 2H), 1.78 (m, 2H), 1.41 (m, 2H); ESI-MS m/z: 590[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1 Location in patent: Paragraph 0091; 0092
[2]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1 Location in patent: Paragraph 0262

43
[ 110-91-8 ]
[ 231278-84-5 ]
N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((morpholin-1-yl)methyl)-2-thienyl)-4-quinazolinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71.5%	Stage #1: morpholine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	35 Example 35 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((morpholinyl)methyl)-2-thienyl)-4-quinazol inamine (MS33) Example 35 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((morpholinyl)methyl)-2-thienyl)-4-quinazol inamine (MS33) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-thienyl)-4-quinazolinamine (0.48g, 1mmol) prepared from Example 1 was dissolved in anhydrous tetrahydrofuran (10ml), followed by the addition of morpholine (0.17g, 2 mmol) and sodium triacetoxy borohydride (0.42 g, 2 mmol), and stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixure was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a solid with a color similar to yellow. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.39g, 71.5%), i.e. the compound of Number MS33. m.p.: 110- 112°C; 1H NMR(DMSO-d6)δ: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 1H), 7.27-7.35(m, 3H), 7.18(t, 1H), 7.05(d, J=3.2 Hz, 1H), 6.49(d, J=3.3 Hz, 1H), 5.26(s, 2H), 3.85(s, 2H), 3.65(t, 4H), 2.50(t, 4H); ESI-MS m/z: 545[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1 Location in patent: Paragraph 0092; 0093

44
[ 13325-10-5 ]
[ 231278-84-5 ]
[ 1421356-24-2 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-Aminobutanol; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 12h;	3 Example 3: Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((4-hydroxybutyl)amino)methyl)-2-furyl)-4 -quinazoiinamine)(MS1)·dimethy)sulfonate Example 3: Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((4-hydroxybutyl)amino)methyl)-2-furyl)-4 -quinazoiinamine)(MS1)·dimethy)sulfonate [0060] N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (5.69g, 12mmol) obtained from Example 1 was dissolved in tetrahydrofuran (100ml), and 4-hydroxy-1-butylamine (2.22g, 25mmol) was added. The mixture was stirred under nitrogen at room temperature for 6 h. Sodium triacetoxy borohydride (8.48 g, 40 mmol) was added, and then the mixture was stirred at room temperature for 12h. To the mixture was added saturated aqueous solution of sodium carbonate (50 ml), and the mixture was stirred for 15 min and then layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow powdered solid, i.e. the compound of Number MS1. The yellow powdered solid was dissolved in tetrahydrofuran (50 ml), and then a solution of methanesulfonic acid (3.46 g, 36 mmol) in tetrahydrofuran (50 ml) was added dropwise under stirring. After addition, the mixture was stirred at room temperature for 12h. The mixture was filtered under suction and the filter cake was washed with tetrahydrofuran-deionized water (95:5). The product was refined, and dried at 70°C under vacuum to afford a yellow solid (7.51g, 88.0%), i.e. the dimethanesolfonate of the compound of Number MS1. m.p.: 257.9-260 °C ; 1H NMR(DMSO-d6) 1H NMR(DMSO-d6)δ: 8.49(s, 1H), 8.22(1H), 8.06(1H),8.05(1H), 7.43(1H), 7.36(1H), 7.24(d, 1H), 7.17(1H), 6.90(m, 1H), 6.7(2H), 6.28(1H), 5.16(2H), 4.0(1H), 3.66(2H), 3.65(1H), 3.50(2H), 3.29(6H), 2.55(2H), 2.0(3H), 1.53(2H), 1.38(2H); ESI-MS m/z: 547[M+H]+. N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((3-phenylpropyl)amino)methyl)-2-fury 1)-4-quinazolinamine can be prepared by the same method, m.p.: 156-160°C;
	Stage #1: 4-Aminobutanol; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 12h;	3 N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (5.69 g, 12 mmol) obtained from Example 1 was dissolved in tetrahydrofuran (100 ml), and 4-hydroxy-1-butylamine (2.22 g, 25 mmol) was added. The mixture was stirred under nitrogen at room temperature for 6 h. Sodium triacetoxy borohydride (8.48 g, 40 mmol) was added, and then the mixture was stirred at room temperature for 12 h. To the mixture was added saturated aqueous solution of sodium carbonate (50 ml), and the mixture was stirred for 15 min and then layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow powdered solid, i.e. the compound of Number MS1. The yellow powdered solid was dissolved in tetrahydrofuran (50 ml), and then a solution of methanesulfonic acid (3.46 g, 36 mmol) in tetrahydrofuran (50 ml) was added dropwise under stirring. After addition, the mixture was stirred at room temperature for 12 h. The mixture was filtered under suction and the filter cake was washed with tetrahydrofuran-deionized water (95:5). The product was refined, and dried at 70° C. under vacuum to afford a yellow solid (7.51 g, 88.0%), i.e. the dimethanesolfonate of the compound of Number MS1. m.p.: 257.9-260° C.; 1H NMR (DMSO-d6) 1H NMR (DMSO-d6) δ: 8.49 (s, 1H), 8.22 (1H), 8.06 (1H), 8.05 (1H), 7.43 (1H), 7.36 (1H), 7.24 (d, 1H), 7.17 (1H), 6.90 (m, 1H), 6.7 (2H), 6.28 (1H), 5.16 (2H), 4.0 (1H), 3.66 (2H), 3.65 (1H), 3.50 (2H), 3.29 (6H), 2.55 (2H), 2.0 (3H), 1.53 (2H), 1.38 (2H); ESI-MS m/z: 547[M+H]+

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1 Location in patent: Paragraph 0059; 0060
[2]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1 Location in patent: Paragraph 0220

45
[ 111-26-2 ]
[ 231278-84-5 ]
[ 1421356-27-5 ]

Yield	Reaction Conditions	Operation in experiment
76.9%	Stage #1: hexan-1-amine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 12h;	4 Example 4: Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((n-hexylamino)methyl)-2-furyl)-4-quinazoli namine (MS2) Example 4: Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((n-hexylamino)methyl)-2-furyl)-4-quinazoli namine (MS2) [0061] Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47g, 1mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10ml), followed by the addition of hexylamine (0.20g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixure was stirred for 15 min to be layered. The organic layer was washed with A saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.43g, 76.9%), i.e. the compound of Number MS2. 1H NMR(DMSO-d6) δ: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 1H), 7.27- 7.35(m, 3H), 7.18(t, 1H), 7.05(d, J=3.2 Hz, 1H), 6.49(d, J=3.3 Hz, 1H), 5.26(s, 2H), 3.99- 4.04(m, 1H), 3.84(s, 2H), 2.56(t, 2H), 1.38(s, 2H), 1.29- 1.31(m, 6H), 1.01(t, 3H); ESI-MS m/z: 559 [M+H]+.
76.9%	Stage #1: hexan-1-amine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	4 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((n-hexylamino)methyl)-2-furyl)-4-quinazolinamine (MS2) Example 4 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((n-hexylamino)methyl)-2-furyl)-4-quinazolinamine (MS2) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1 mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10 ml), followed by the addition of hexylamine (0.20 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42 g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixture was stirred for 15 min to be layered. The organic layer was washed with A saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.43 g, 76.9%), i.e. the compound of Number MS2. 1H NMR (DMSO-d6) δ: 9.87 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.16 (d, J=8.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.46-7.49 (m, 1H), 7.27-7.35 (m, 3H), 7.18 (t, 1H), 7.05 (d, J=3.2 Hz, 1H), 6.49 (d, J=3.3 Hz, 1H), 5.26 (s, 2H), 3.99-4.04 (m, 1H), 3.84 (s, 2H), 2.56 (t, 2H), 1.38 (s, 2H), 1.29-1.31 (m, 6H), 1.01 (t, 3H); ESI-MS m/z: 559[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1 Location in patent: Paragraph 0060; 0061
[2]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1 Location in patent: Paragraph 0222

46
[ 75-04-7 ]
[ 231278-84-5 ]
[ 1421356-28-6 ]

Yield	Reaction Conditions	Operation in experiment
79.5%	Stage #1: ethylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	5 Example 5: Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((ethylamino)methyl)-2-furyl)-4-quinazolina mine (MS3) Example 5: Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((ethylamino)methyl)-2-furyl)-4-quinazolina mine (MS3) [0062] Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47g, 1mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10ml), followed by the addition of ethylamine (0.09 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixure was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.40 g, 79.5%), i.e. the compound of Number MS3. 1H NMR(DMSO-d6)δ: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 1H), 7.27- 7.35(m, 3H), 7.18(t, 1H), 7.05(d, J=3.2 Hz, 1H), 6.49(d, J=3.3 Hz, 1H), 5.26(s, 2H), 3.99- 4.04(m, 1H), 3.84(s, 2H), 2.59(m, 2H), 1.02(t, 3H); ESI-MS m/z: 503[M+H]+.
79.5%	Stage #1: ethylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	5 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((ethylamino)methyl)-2-furyl)-4-quinazolinamine (MS3) Example 5 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((ethylamino)methyl)-2-furyl)-4-quinazolinamine (MS3) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1 mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10 ml), followed by the addition of ethylamine (0.09 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42 g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixture was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.40 g, 79.5%), i.e. the compound of Number MS3. 1H NMR (DMSO-d6) δ: 9.87 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.16 (d, J=8.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.46-7.49 (m, 1H), 7.27-7.35 (m, 3H), 7.18 (t, 1H), 7.05 (d, J=3.2 Hz, 1H), 6.49 (d, J=3.3 Hz, 1H), 5.26 (s, 2H), 3.99-4.04 (m, 1H), 3.84 (s, 2H), 2.59 (m, 2H), 1.02 (t, 3H); ESI-MS m/z: 503 [M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1 Location in patent: Paragraph 0061; 0062
[2]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1 Location in patent: Paragraph 0223

47
[ 109-89-7 ]
[ 231278-84-5 ]
[ 1421356-29-7 ]

Yield	Reaction Conditions	Operation in experiment
73.5%	Stage #1: diethylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	6 Example 6: Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((N,N-diethyl)amino)methyl)-2-furyl)-4-qui nazolinamine (MS4) Example 6: Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((N,N-diethyl)amino)methyl)-2-furyl)-4-qui nazolinamine (MS4) [0063] Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47g, 1mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10ml), followed by the addition of N,N-diethylamine (0.15 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixure was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.38g, 73.5%), i.e. the compound of Number MS4. 1H NMR(DMSO-d6) δ: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 1H), 7.27- 7.35(m, 3H), 7.18(t, 1H), 7.05(d, J=3.2 Hz, 1H), 6.49(d, J=3.3 Hz, 1H), 5.26(s, 4H), 3.76(s, 2H), 2.64(m, 2H), 2.26(s, 3H), 1.02(t, 3H); ESI-MS m/z: 531[M+H]+.
73.5%	Stage #1: diethylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h; Inert atmosphere;	6 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((N,N-diethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS4) Example 6 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((N,N-diethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS4) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1 mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10 ml), followed by the addition of N,N-diethylamine (0.15 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42 g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixture was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.38 g, 73.5%), i.e. the compound of Number MS4. 1H NMR (DMSO-d6) δ: 9.87 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.16 (d, J=8.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.46-7.49 (m, 1H), 7.27-7.35 (m, 3H), 7.18 (t, 1H), 7.05 (d, J=3.2 Hz, 1H), 6.49 (d, J=3.3 Hz, 1H), 5.26 (s, 4H), 3.76 (s, 2H), 2.64 (m, 2H), 2.26 (s, 3H), 1.02 (t, 3H); ESI-MS m/z: 531[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1 Location in patent: Paragraph 0062; 0063
[2]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1 Location in patent: Paragraph 0224

48
[ 534-03-2 ]
[ 231278-84-5 ]
[ 1421356-31-1 ]

Yield	Reaction Conditions	Operation in experiment
86.7%		N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (5.69 g, 12 mmol) obtained from Example 1 was dissolved in tetrahydrofuran (100 ml), followed by the addition of 2-amino-1,3-propanediol (2.28 g, 25 mmol). The mixture was stirred under nitrogen at room temperature for 6 h, followed by the addition of sodium triacetoxy borohydride (8.48 g, 40 mmol), and then stirred at room temperature for 12 h. A saturated aqueous solution of sodium carbonate (50 ml) was added, and then the mixture was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow powdered solid, i.e. the compound of Number MS6. The yellow powdered solid was dissolved in tetrahydrofuran (50 ml), and a solution of methanesulfonic acid (3.46 g, 36 mmol) in tetrahydrofuran (50 ml) was added under stirring. After addition, the mixture was stirred at room temperature for 12 h. The mixture was filtered under suction and the filter cake was washed with tetrahydrofuran-deionized water (95:5). The product was refined, and dried at 70 C. under vacuum to give a yellow solid (7.71 g, 86.7%), i.e. the dimethanesolfonate of the compound of Number MS6. HPLC: >98.5%, m.p.: 234-236 C.; 1H NMR (DMSO-d6) delta: 1H NMR (DMSO-d6) delta: 9.87 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.16 (d, J=8.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.46-7.49 (m, 1H), 7.277.35 (m, 3H), 7.18 (t, 1H), 7.05 (d, J=3.2 Hz, 1H), 6.49 (d, J=3.3 Hz, 1H), 5.26 (s, 2H), 3.99-4.04 (m, 1H), 3.84 (s, 2H), 3.66 (br, 2H), 3.60 (m, 4H), 2.73 (m, 1H); ESI-MS m/z: 549[M+H]+.
		Example 8: Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-((5-(2-(1,3-dihydroxypropyl)amino)methyl)-2-f uryl)-4-quinazolinamine (MS6)·dimethylsulfonate [0065] N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (5.69g, 12mmol) obtained from Example 1 was dissolved in tetrahydrofuran (100ml), followed by the addition of 2-amino-1,3-propanediol (2.28g, 25 mmol). The mixture was stirred under nitrogen at room temperature for 6 h, followed by the addition of sodium triacetoxy borohydride (8.48 g, 40 mmol), and then stirred at room temperature for 12 h. A saturated aqueous solution of sodium carbonate (50 ml) was added, and then the mixure was stirred for 15 min to be layered.. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow powdered solid, i.e. the compound of Number MS6. The yellow powdered solid was dissolved in tetrahydrofuran (50 ml),and a solution of methanesulfonic acid (3.46 g, 36 mmol) in tetrahydrofuran (50 ml) was added under stirring. After addition, the mixture was stirred at room temperature for 12 h. The mixture was filtered under suction and the filter cake was washed with tetrahydrofuran-deionized water (95:5). The product was refined, and dried at 70C under vacuum to give a yellow solid (7.71g, 86.7%), i.e. the dimethanesolfonate of the compound of Number MS6. HPLC: > 98.5%, m.p.: 234-236C; 1H NMR(DMSO-d6)delta: 1H NMR(DMSO-d6)delta: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 1H), 7.277.35(m, 3H), 7.18(t, 1H), 7.05(d, J=3.2 Hz, 1H), 6.49(d, J=3.3 Hz, 1H), 5.26(s, 2H), 3.99- 4.04(m, 1H), 3.84(s, 2H), 3.66(br, 2H), 3.60(m, 4H), 2.73(m, 1H); ESI-MS m/z: 549[M+H]+.

Reference： [1]Patent: US2015/80392,2015,A1 .Location in patent: Paragraph 0226
[2]Patent: EP2740729,2014,A1 .Location in patent: Paragraph 0064; 0065

49
[ 21035-54-1 ]
[ 231278-84-5 ]
[ 1421356-30-0 ]

Yield	Reaction Conditions	Operation in experiment
77.1%	Stage #1: crotylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	7 Example 7 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-butenyl)amino)methyl)-2-furyl)-4-quin azolinamine (MS5) Example 7 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-butenyl)amino)methyl)-2-furyl)-4-quin azolinamine (MS5) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10ml), followed by the addition of 2-butenylamine (0.18 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42 g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixure was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.42g, 77.1%), i.e. the compound of Number MS5. 1H NMR(DMSO-d6) δ: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 1H), 7.27- 7.35(m, 3H), 7.18(t, 1H), 7.05(d, J=3.2 Hz, 1H), 6.49(d, J=3.3 Hz, 1H), 5.26(s, 2H), 3.99- 4.04(m, 1H), 3.76(s, 2H), 2.55(t, 1H), 1.62(m, 1H), 1.39(m, 1H), 0.98(d, 6H); ESI-MS m/z: 543[M+H]+.
77.1%	Stage #1: crotylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	7 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-butenyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS5) Example 7 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-butenyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS5) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1 mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10 ml), followed by the addition of 2-butenylamine (0.18 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42 g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixture was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.42 g, 77.1%), i.e. the compound of Number MS5. 1H NMR (DMSO-d6) δ: 9.87 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.16 (d, J=8.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.46-7.49 (m, 1H), 7.27-7.35 (m, 3H), 7.18 (t, 1H), 7.05 (d, J=3.2 Hz, 1H), 6.49 (d, J=3.3 Hz, 1H), 5.26 (s, 2H), 3.99-4.04 (m, 1H), 3.76 (s, 2H), 2.55 (t, 1H), 1.62 (m, 1H), 1.39 (m, 1H), 0.98 (d, 6H); ESI-MS m/z: 543[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1 Location in patent: Paragraph 0062; 0063
[2]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1 Location in patent: Paragraph 0225

50
[ 3218-02-8 ]
[ 231278-84-5 ]
[ 1421356-33-3 ]

Yield	Reaction Conditions	Operation in experiment
73.5%	Stage #1: cyclohexylmethylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	9 Example 9 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-((5-((cyclohexylmethyl)amino)methyl)-2-furyl) -4-quinazolinamine (MS7) Example 9 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-((5-((cyclohexylmethyl)amino)methyl)-2-furyl) -4-quinazolinamine (MS7) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47g, 1mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10ml), followed by the addition of cyclohexyl-methylamine (0.23g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixure was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.42g, 73.5%), i.e. the compound of Number MS7. 1H NMR(DMSO-d6)δ: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 1H), 7.27- 47.35(m, 3H), 7.18(t, 1H), 7.05(d, J=3.2 Hz, 1H), 6.49(d, J=3.3 Hz, 1H), 5.26(s, 2H), 3.99- 4.04(m, 1H), 3.66(s, 2H), 2.51(d, 2H), 1.49- 1.67(m, 11H); ESI-MS m/z: 571[M+H]+.
73.5%	Stage #1: cyclohexylmethylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	9 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-((5-((cyclohexylmethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS7) Example 9 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-((5-((cyclohexylmethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS7) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1 mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10 ml), followed by the addition of cyclohexyl-methylamine (0.23 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42 g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixture was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.42 g, 73.5%), i.e. the compound of Number MS7. 1H NMR (DMSO-d6) δ: 9.87 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.16 (d, J=8.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.46-7.49 (m, 1H), 7.27-47.35 (m, 3H), 7.18 (t, 1H), 7.05 (d, J=3.2 Hz, 1H), 6.49 (d, J=3.3 Hz, 1H), 5.26 (s, 2H), 3.99-4.04 (m, 1H), 3.66 (s, 2H), 2.51 (d, 2H), 1.49-1.67 (m, 11H); ESI-MS m/z: 571[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1 Location in patent: Paragraph 0065; 0066
[2]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1 Location in patent: Paragraph 0227

51
[ 3399-73-3 ]
[ 231278-84-5 ]
N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(3-cyclohexenyl)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68.8%	Stage #1: 2-(1-cyclohexenyl)ethylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	10 Example 10 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(3-cyclohexenyl)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS8) Example 10 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(3-cyclohexenyl)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS8) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47g, 1mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10ml), followed by the addition of 2-(1-cyclohexenyl)ethylamine (0.23g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixure was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.40g, 68.8%), i.e. the compound of Number MS8. m.p.: 90-92 °C ; 1H NMR(DMSO-d6)δ: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 1H), 7.27- 7.35(m, 3H), 7.18(t, 1H), 7.05(d, J=3.2 Hz, 1H), 6.49(d, J=3.3 Hz, 1H), 5.37(t, 1H), 5.26(s, 2H), 3.99- 4.04(m, 1H), 3.66(s, 2H), 2.59(t, 2H), 2.08(t, 2H), 1.96(t, 4H), 1.74(m, 4H); ESI-MS m/z: 583[M+H]+.
68.8%	Stage #1: 2-(1-cyclohexenyl)ethylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	10 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(3-cyclohexenyl)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS8) Example 10 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(3-cyclohexenyl)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS8) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1 mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10 ml), followed by the addition of 2-(1-cyclohexenyl)ethylamine (0.23 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42 g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixture was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.40 g, 68.8%), i.e. the compound of Number MS8. m.p.: 90-92° C.; 1H NMR (DMSO-d6) δ: 9.87 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.16 (d, J=8.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.46-7.49 (m, 1H), 7.27-7.35 (m, 3H), 7.18 (t, 1H), 7.05 (d, J=3.2 Hz, 1H), 6.49 (d, J=3.3 Hz, 1H), 5.37 (t, 1H), 5.26 (s, 2H), 3.99-4.04 (m, 1H), 3.66 (s, 2H), 2.59 (t, 2H), 2.08 (t, 2H), 1.96 (t, 4H), 1.74 (m, 4H); ESI-MS m/z: 583[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1 Location in patent: Paragraph 0066; 0067
[2]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1 Location in patent: Paragraph 0228

52
[ 114291-27-9 ]
[ 231278-84-5 ]
[ 1421356-35-5 ]

Yield	Reaction Conditions	Operation in experiment
61.1%	Stage #1: 3-chlorocyclohexyl-methylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	11 Example 11 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((3-chlorocyclohexyl)methyl)amino)methy 1)-2-furyl)-4-quinazolinamine (MS9) Example 11 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((3-chlorocyclohexyl)methyl)amino)methy 1)-2-furyl)-4-quinazolinamine (MS9) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47g, 1mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10ml), followed by the addition of 3-chlorocyclohexyl-methylamine (0.30g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixure was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.37g, 61.1%), i.e. the compound of Number MS9. m.p.: 93-96 °C ; 1H NMR(DMSO-d6)δ: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 1H), 7.27- 7.35(m, 3H), 7.18(t, 1H), 7.05(d, J=3.2 Hz, 1H), 6.49(d, J=3.3 Hz, 1H), 5.26(s, 2H), 3.99- 4.04(m, 1H), 3.66(s, 2H), 3.46(s, 1H), 2.66(d, 2H), 1.49- 1.76(m, 9H); ESI-MS m/z: 605[M+H]+.
61.1%	Stage #1: 3-chlorocyclohexyl-methylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	11 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((3-chlorocyclohexyl)methyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS9) Example 11 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((3-chlorocyclohexyl)methyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS9) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1 mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10 ml), followed by the addition of 3-chlorocyclohexyl-methylamine (0.30 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42 g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixture was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.37 g, 61.1%), i.e. the compound of Number MS9. m.p.: 93-96° C.; 1H NMR (DMSO-d6) δ: 9.87 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.16 (d, J=8.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.46-7.49 (m, 1H), 7.27-7.35 (m, 3H), 7.18 (t, 1H), 7.05 (d, J=3.2 Hz, 1H), 6.49 (d, J=3.3 Hz, 1H), 5.26 (s, 2H), 3.99-4.04 (m, 1H), 3.66 (s, 2H), 3.46 (s, 1H), 2.66 (d, 2H), 1.49-1.76 (m, 9H); ESI-MS m/z: 605[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1 Location in patent: Paragraph 006; 0068
[2]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1 Location in patent: Paragraph 0229

53
[ 4152-90-3 ]
[ 231278-84-5 ]
[ 1421356-38-8 ]

Yield	Reaction Conditions	Operation in experiment
63.3%	Stage #1: m-chlorobenzylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	13 Example 13 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((3-chlorobenzyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS11) Example 13 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((3-chlorobenzyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS11) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47g, 1mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10ml), followed by the addition of 3-chlorobenzylamine (0.28g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixure was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.38g, 63.3%), i.e. the compound of Number MS11. m.p.: 103-105°C; 1H NMR(DMSO-d6)δ: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 5H), 7.27- 7.35(m, 3H), 7.18(t, 1H), 7.05(d, J=3.2 Hz, 1H), 6.49(d, J=3.3 Hz, 1H), 5.26(s, 2H), 3.99- 4.04(m, 1H), 3.76- 3.66(s, 4H); ESI-MS m/z: 599[M+H]+.
63.3%	Stage #1: m-chlorobenzylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	13 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((3-chlorobenzyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS11) Example 13 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((3-chlorobenzyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS11) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1 mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10 ml), followed by the addition of 3-chlorobenzylamine (0.28 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42 g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixture was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.38 g, 63.3%), i.e. the compound of Number MS11. m.p.: 103-105° C.; 1H NMR (DMSO-d6) δ: 9.87 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.16 (d, J=8.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.46-7.49 (m, 5H), 7.27-7.35 (m, 3H), 7.18 (t, 1H), 7.05 (d, J=3.2 Hz, 1H), 6.49 (d, J=3.3 Hz, 1H), 5.26 (s, 2H), 3.99-4.04 (m, 1H), 3.76-3.66 (s, 4H); ESI-MS m/z: 599[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1 Location in patent: Paragraph 0069; 0070
[2]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1 Location in patent: Paragraph 0232

54
[ 29968-78-3 ]
[ 231278-84-5 ]
[ 1421356-39-9 ]

Yield	Reaction Conditions	Operation in experiment
49.7%		Example 14 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(4-nitrophenyl)ethyl)amino)methyl)-2-f uryl)-4-quinazolinamine (MS12) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1mmol) obtained from Example 1 was dissolved in tetrahydrofuran (10ml), followed by the addition of 2-(4-nitrophenyl)ethylamine hydrochloride (0.41g, 2 mmol) and diisopropylethylamine (0.26g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.74 g, 3.5 mmol) was added, and the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixure was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow powdered solid (0.31g, 49.7%), i.e. the compound of Number MS12. m.p.: 112- 114C; 1H NMR(DMSO-d6)delta: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.21(s, 2H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 3H), 7.27- 7.35(m, 3H), 7.18(t, 1H), 7.05(d, J=3.2 Hz, 1H), 6.49(d, J=3.3 Hz, 1H), 5.26(s, 2H), 3.99- 4.04(m, 1H), 3.66(s, 2H), 2.84(t, 2H), 2.69(t, 2H); ESI-MS m/z: 624[M+H]+.
49.7%		Example 14 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(4-nitrophenyl)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS12) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1 mmol) obtained from Example 1 was dissolved in tetrahydrofuran (10 ml), followed by the addition of 2-(4-nitrophenyl)ethylamine hydrochloride (0.41 g, 2 mmol) and diisopropylethylamine (0.26 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.74 g, 3.5 mmol) was added, and the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixture was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow powdered solid (0.31 g, 49.7%), i.e. the compound of Number MS12. m.p.: 112-114 C.; 1H NMR (DMSO-d6) delta: 9.87 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.21 (s, 2H), 8.16 (d, J=8.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.46-7.49 (m, 3H), 7.27-7.35 (m, 3H), 7.18 (t, 1H), 7.05 (d, J=3.2 Hz, 1H), 6.49 (d, J=3.3 Hz, 1H), 5.26 (s, 2H), 3.99-4.04 (m, 1H), 3.66 (s, 2H), 2.84 (t, 2H), 2.69 (t, 2H); ESI-MS m/z: 624[M+H]+.

Reference： [1]Patent: EP2740729,2014,A1 .Location in patent: Paragraph 0070; 0071
[2]Patent: US2015/80392,2015,A1 .Location in patent: Paragraph 0233

55
[ 659-34-7 ]
[ 231278-84-5 ]
[ 1421356-40-2 ]

Yield	Reaction Conditions	Operation in experiment
68.9%	Stage #1: (4-hydroxyphenyl)ethylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	15 Example 15 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(4-hydroxyphenyl)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS13) Example 15 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(4-hydroxyphenyl)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS13) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10ml), followed by the addition of p-hydroxy-phenylethylamine (0.28g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixure was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.41g, 68.9%), i.e. the compound of Number MS13. m.p.: 125-127 °C ; 1H NMR(DMSO-d6)δ: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 1H), 7.27- 7.35(m, 3H), 7.12-7.18(m, 3H), 7.05(d, J=3.2 Hz, 1H), 6.70(d, 2H), 6.49(d, J=3.3 Hz, 1H), 5.35(s, 1H), 5.26(s, 2H), 3.99- 4.04(m, 1H), 3.66(s, 2H), 2.84(t, 2H), 2.69(t, 2H); ESI-MS m/z: 595[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1 Location in patent: Paragraph 0071; 0072

56
[ 73674-62-1 ]
[ 231278-84-5 ]
[ 1421356-41-3 ]

Yield	Reaction Conditions	Operation in experiment
70.4%	Stage #1: 3,5-dimethoxy-phenylethylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	16 Example 16 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(3, 5-dimethoxyphenyl)ethylamino)methyl)-2-furyl)-4-quinazolinamine (MS14) Example 16 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(3, 5-dimethoxyphenyl)ethylamino)methyl)-2-furyl)-4-quinazolinamine (MS14) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47g, 1mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10ml), followed by the addition of 3,5-dimethoxy-phenylethylamine (0.36g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixure was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.45g, 70.4%), i.e. the compound of Number MS14. m.p.: 101- 104 °C ; 1H NMR(DMSO-d6)δ: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 1H), 7.27- 7.35(m, 3H), 7.18(t, 1H), 7.05(d, J=3.2 Hz, 1H), 6.63(s, 2H), 6.49(d, J=3.3 Hz, 1H), 6.19(s, 1H), 5.26(s, 2H), 3.99-4.04(m, 1H), 3.82(s, 6H), 3.66(s, 2H), 2.84(t, 2H), 2.69(t, 2H); ESI-MS m/z: 639[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1 Location in patent: Paragraph 0072; 0073

57
[ 1393582-07-4 ]
[ 231278-84-5 ]
[ 1421356-42-4 ]

Yield	Reaction Conditions	Operation in experiment
57.1%	Stage #1: 2-(3-fluoro-5-hydroxyphenyl)ethylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	17 Example 17 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(3-hydroxy-5-fluorophenyl)ethyl)amino )methyl)-2-furyl)-4-quinazolinamine (MS15) Example 17 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(3-hydroxy-5-fluorophenyl)ethyl)amino )methyl)-2-furyl)-4-quinazolinamine (MS15) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47g, 1mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10ml), followed by the addition of 2-(3-fluoro-5-hydroxyphenyl)ethylamine (0.31g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixure was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.35g, 57.1%), i.e. the compound of Number MS15. m.p.: 116- 119 °C ; 1H NMR(DMSO-d6)δ: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 1H), 7.27- 7.35(m, 3H), 7.18(t, 1H), 7.05(d, J=3.2 Hz, 1H), 6.92(s, 1H), 6.80(s, 1H), 6.49(d, J=3.3 Hz, 1H), 6.39(s, 1H), 5.35(s, 1H), 5.26(s, 2H), 3.99- 4.04(m, 1H), 3.84(s, 2H), 2.84(t, 2H), 2.69(t, 2H); ESI-MS m/z: 613[M+H]+.
57.1%	Stage #1: 2-(3-fluoro-5-hydroxyphenyl)ethylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	17 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(3-hydroxy-5-fluorophenyl)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS15) Example 17 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(3-hydroxy-5-fluorophenyl)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS15) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1 mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10 ml), followed by the addition of 2-(3-fluoro-5-hydroxyphenyl)ethylamine (0.31 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42 g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixture was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.35 g, 57.1%), i.e. the compound of Number MS15. m.p.: 116-119° C.; 1H NMR (DMSO-d6) δ: 9.87 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.16 (d, J=8.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.46-7.49 (m, 1H), 7.27-7.35 (m, 3H), 7.18 (t, 1H), 7.05 (d, J=3.2 Hz, 1H), 6.92 (s, 1H), 6.80 (s, 1H), 6.49 (d, J=3.3 Hz, 1H), 6.39 (s, 1H), 5.35 (s, 1H), 5.26 (s, 2H), 3.99-4.04 (m, 1H), 3.84 (s, 2H), 2.84 (t, 2H), 2.69 (t, 2H); ESI-MS m/z: 613[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1 Location in patent: Paragraph 0073; 0074
[2]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1 Location in patent: Paragraph 0236

58
[ 176311-49-2 ]
[ 231278-84-5 ]
[ 1421356-43-5 ]

Yield	Reaction Conditions	Operation in experiment
66.6%	Stage #1: 2-(3-chloro-5-fluorophenyl)ethylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	18 Example 18 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(3-chloro-5-fluorophenyl)ethyl)amino) methyl)-2-furyl)-4-quinazolinamine (MS16) Example 18 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(3-chloro-5-fluorophenyl)ethyl)amino) methyl)-2-furyl)-4-quinazolinamine (MS16) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47g, 1mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10ml), followed by the addition of 2-(3-chloro-5-fluorophenyl)ethylamine (0.35g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixure was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.42g, 66.6%), i.e. the compound of Number MS16. m.p.: 105- 107 °C ; 1H NMR(DMSO-d6)δ: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 1H), 7.27- 7.35(m, 3H), 7.18(t, 1H), 7.05(d, J=3.2 Hz, 1H), 6.63(s, 2H), 6.49(d, J=3.3 Hz, 1H), 6.19(s, 1H), 5.26(s, 2H), 3.99-4.04(m, 1H), 3.66(s, 2H), 2.84(t, 2H), 2.69(t, 2H); ESI-MS m/z: 631 [M+H]+.
66.6%	Stage #1: 2-(3-chloro-5-fluorophenyl)ethylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	18 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(3-chloro-5-fluorophenyl)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS16) Example 18 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(3-chloro-5-fluorophenyl)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS16) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1 mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10 ml), followed by the addition of 2-(3-chloro-5-fluorophenyl)ethylamine (0.35 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42 g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixture was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.42 g, 66.6%), i.e. the compound of Number MS16. m.p.: 105-107° C.; 1H NMR (DMSO-d6) δ: 9.87 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.16 (d, J=8.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.46-7.49 (m, 1H), 7.27-7.35 (m, 3H), 7.18 (t, 1H), 7.05 (d, J=3.2 Hz, 1H), 6.63 (s, 2H), 6.49 (d, J=3.3 Hz, 1H), 6.19 (s, 1H), 5.26 (s, 2H), 3.99-4.04 (m, 1H), 3.66 (s, 2H), 2.84 (t, 2H), 2.69 (t, 2H); ESI-MS m/z: 631[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1 Location in patent: Paragraph 0074; 0075
[2]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1 Location in patent: Paragraph 0237

59
[ 1421356-87-7 ]
[ 231278-84-5 ]
[ 1421356-44-6 ]

Yield	Reaction Conditions	Operation in experiment
67.6%	Stage #1: (±)-6-amino-1,5-hexanediol; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	19 Example 19 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2,6-dihydroxyhexyl)amino)methyl)-2-fur yl)-4-quinazolinamine (MS17) Example 19 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2,6-dihydroxyhexyl)amino)methyl)-2-fur yl)-4-quinazolinamine (MS17) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10ml), followed by the addition of(+-)-6-amino-1,5-hexanediol (0.27g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixure was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.40g, 67.6%), i.e. the compound of Number MS17. m.p.: 123- 125°C; 1H NMR(DMSO-d6)δ: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 1H), 7.277.35(m, 3H), 7.18(t, 1H), 7.05(d, J=3.2 Hz, 1H), 6.49(d, J=3.3 Hz, 1H), 5.26(s, 2H), 3.99- 4.04(m, 1H), 3.84(s, 2H), 3.65(br, 2H), 3.54- 3.58(m, 3H), 2.83(d, 2H), 1.44- 1.48(m, 4H), 1.25(m, 2H); ESI-MS m/z: 591 [M+H]+.
67.6%	Stage #1: (±)-6-amino-1,5-hexanediol; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	19 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2,6-dihydroxyhexyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS17) Example 19 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2,6-dihydroxyhexyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS17) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1 mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10 ml), followed by the addition of (+-)-6-amino-1,5-hexanediol (0.27 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42 g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixture was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.40 g, 67.6%), i.e. the compound of Number MS17. m.p.: 123-125° C.; 1H NMR (DMSO-d6) δ: 9.87 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.16 (d, J=8.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.46-7.49 (m, 1H), 7.277.35 (m, 3H), 7.18 (t, 1H), 7.05 (d, J=3.2 Hz, 1H), 6.49 (d, J=3.3 Hz, 1H), 5.26 (s, 2H), 3.99-4.04 (m, 1H), 3.84 (s, 2H), 3.65 (br, 2H), 3.54-3.58 (m, 3H), 2.83 (d, 2H), 1.44-1.48 (m, 4H), 1.25 (m, 2H); ESI-MS m/z: 591[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1 Location in patent: Paragraph 0075; 0076
[2]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1 Location in patent: Paragraph 0238

60
[ 111-42-2 ]
[ 231278-84-5 ]
[ 1421356-45-7 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2,2'-iminobis[ethanol]; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 12h;	20 Example 20 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((bis(2-hydroxyethyl)amino)methyl)-2-furyl )-4-quinazolinamine (MS18) -dimethylsulfonate Example 20 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((bis(2-hydroxyethyl)amino)methyl)-2-furyl )-4-quinazolinamine (MS18) -dimethylsulfonate Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (5.69g, 12mmol) obtained from Example 1 was dissolved in tetrahydrofuran (100ml), followed by the addition of diethanolamine (1.53g, 25 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (8.48 g, 40mmol) was slowly added in batches, and then the mixture was stirred at room temperature for 12 h. A saturated aqueous solution of sodium carbonate (50ml) was added, and the mixture was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow powdered solid. The yellow powdered solid was dissolved in tetrahydrofuran (50 ml), and a solution of methanesulfonic acid (3.46 g, 36 mmol) in tetrahydrofuran (50 ml) was added dropwise under stirring. After the dropwise addition, the mixture was stirred at room temperature for 12 h. The mixture was filtered under suction and the filter cake was washed with tetrahydrofuran-deionized water (95:5). The product was refined, and dried at 70°C under vacuum to give a yellow solid 6.71g, i.e. the dimethanesulfonate of the compound of Number MS18. HPLC: > 98.5%. 1H NMR(DMSO-d6) δ: 8.49(s, 1H), 8.22(1H), 8.06(2H), 7.36(2H), 7.17(2H), 7.01(1H), 6.09(1H), 6.7(2H), 6.28(1H), 6.68(1H), 6.26(1H), 5.16(2H), 4.0(1H), 3.76(2H), 3.65(2H), 3.45(4H), 3.29(6H), 2.53(3H), 2.21(3H), 2.0(2H) ESI-MS m/z: 563[M+H]+.
	Stage #1: 2,2'-iminobis[ethanol]; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 12h;	20 Example 20 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((bis(2-hydroxyethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS 18).dimethylsulfonate Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (5.69 g, 12 mmol) obtained from Example 1 was dissolved in tetrahydrofuran (100 ml), followed by the addition of diethanolamine (1.53 g, 25 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (8.48 g, 40 mmol) was slowly added in batches, and then the mixture was stirred at room temperature for 12 h. A saturated aqueous solution of sodium carbonate (50 ml) was added, and the mixture was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow powdered solid. The yellow powdered solid was dissolved in tetrahydrofuran (50 ml), and a solution of methanesulfonic acid (3.46 g, 36 mmol) in tetrahydrofuran (50 ml) was added dropwise under stirring. After the dropwise addition, the mixture was stirred at room temperature for 12 h. The mixture was filtered under suction and the filter cake was washed with tetrahydrofuran-deionized water (95:5). The product was refined, and dried at 70° C. under vacuum to give a yellow solid 6.71 g, i.e. the dimethanesulfonate of the compound of Number MS18. HPLC: >98.5%. 1H NMR (DMSO-d6) δ: 8.49 (s, 1H), 8.22 (1H), 8.06 (2H), 7.36 (2H), 7.17 (2H), 7.01 (1H), 6.09 (1H), 6.7 (2H), 6.28 (1H), 6.68 (1H), 6.26 (1H), 5.16 (2H), 4.0 (1H), 3.76 (2H), 3.65 (2H), 3.45 (4H), 3.29 (6H), 2.53 (3H), 2.21 (3H), 2.0 (2H) ESI-MS m/z: 563[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1 Location in patent: Paragraph 0076; 0077
[2]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1 Location in patent: Paragraph 0239

61
[ 29601-98-7 ]
[ 231278-84-5 ]
[ 1421356-47-9 ]

Yield	Reaction Conditions	Operation in experiment
53.3%	Stage #1: N-benzylhydroxylamine hydrochloride; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	21 Example 21 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((benzyloxy)amino)methyl)-2-furyl)-4-quin azolinamine (MS19) Example 21 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((benzyloxy)amino)methyl)-2-furyl)-4-quin azolinamine (MS19) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10ml), followed by the addition of O-benzylhydroxyamine hydrochloride (0.34g, 2 mmol) and diisopropylethylamine (0.26g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.74 g, 3.5 mmol) was added, and the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixure was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.31g, 53.3%), i.e. the compound of Number MS19. m.p.: 117-119°C; 1H NMR(DMSO-d6)δ: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 3H), 7.27- 7.38(m, 6H), 7.18(t, 1H), 7.05(d, J=3.2 Hz, 1H), 6.49(d, J=3.3 Hz, 1H), 5.26(s, 2H), 4.79(s, 2H), 3.99- 4.04(m, 1H), 3.76(s, 2H); ESI-MS m/z: 581[M+H]+.
53.3%	Stage #1: N-benzylhydroxylamine hydrochloride; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	21 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((benzyloxy)amino)methyl)-2-furyl)-4-quinazolinamine (MS19) Example 21 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((benzyloxy)amino)methyl)-2-furyl)-4-quinazolinamine (MS19) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1 mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10 ml), followed by the addition of O-benzylhydroxyamine hydrochloride (0.34 g, 2 mmol) and diisopropylethylamine (0.26 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.74 g, 3.5 mmol) was added, and the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixture was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.31 g, 53.3%), i.e. the compound of Number MS19. m.p.: 117-119° C.; 1H NMR (DMSO-d6) δ: 9.87 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.16 (d, J=8.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.46-7.49 (m, 3H), 7.27-7.38 (m, 6H), 7.18 (t, 1H), 7.05 (d, J=3.2 Hz, 1H), 6.49 (d, J=3.3 Hz, 1H), 5.26 (s, 2H), 4.79 (s, 2H), 3.99-4.04 (m, 1H), 3.76 (s, 2H); ESI-MS m/z: 581[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1 Location in patent: Paragraph 0077; 0078
[2]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1 Location in patent: Paragraph 0240

62
1,3-diaminocyclohexane [ No CAS ]
[ 231278-84-5 ]
[ 1421356-49-1 ]

Yield	Reaction Conditions	Operation in experiment
57.7%	Stage #1: 1,3-diaminocyclohexane; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	23 Example 23 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((3-aminocyclohexyl)amino)methyl)-2-furyl )-4-quinazolinamine (MS21) Example 23 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((3-aminocyclohexyl)amino)methyl)-2-furyl )-4-quinazolinamine (MS21) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47g, 1mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10ml), followed by the addition of 1,3-diaminocyclohexane (0.23g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixure was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a nearly yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.33g, 57.7%), i.e. the compound of Number MS21. m.p.: 122-125°C; 1H NMR(DMSO-d6)δ: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 1H), 7.27- 7.35(m, 3H), 7.18(t, 1H), 7.05(d, J=3.2 Hz, 1H), 6.49(d, J=3.3 Hz, 1H), 5.26(s, 2H), 5.11(d, 2H), 3.99- 4.04(m, 1H), 3.84(s, 2H), 2.80(m, 2H), 1.21- 1.49(m, 8H); ESI-MS m/z: 572 [M+H]+.
57.7%	Stage #1: 1,3-diaminocyclohexane; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	23 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((3-aminocyclohexyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS21) Example 23 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((3-aminocyclohexyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS21) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1 mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10 ml), followed by the addition of 1,3-diaminocyclohexane (0.23 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42 g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixture was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a nearly yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.33 g, 57.7%), i.e. the compound of Number MS21. m.p.: 122-125° C.; 1H NMR (DMSO-d6) δ: 9.87 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.16 (d, J=8.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.46-7.49 (m, 1H), 7.27-7.35 (m, 3H), 7.18 (t, 1H), 7.05 (d, J=3.2 Hz, 1H), 6.49 (d, J=3.3 Hz, 1H), 5.26 (s, 2H), 5.11 (d, 2H), 3.99-4.04 (m, 1H), 3.84 (s, 2H), 2.80 (m, 2H), 1.21-1.49 (m, 8H); ESI-MS m/z: 572[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1 Location in patent: Paragraph 0079; 0080
[2]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1 Location in patent: Paragraph 0242

63
[ 5680-79-5 ]
[ 231278-84-5 ]
[ 1421356-50-4 ]

Yield	Reaction Conditions	Operation in experiment
67.5%	Stage #1: glycine ethyl ester hydrochloride; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h; Stage #3: With water; sodium hydroxide In tetrahydrofuran for 2h;	24 Example 24 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((carboxymethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS22) Example 24 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((carboxymethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS22) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1mmol) obtained from Example 1 was dissolved in tetrahydrofuran (10ml), followed by the addition of glycine methyl ester hydrochloride (0.22g, 2 mmol), added diisopropylethylamine (0.26g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.74 g, 3.5 mmol) was added, and then stirred at room temperature for 24 h. 20% aqueous solution of sodium hydroxide (10 ml) was added and the mixture was stirred for 2 h, and then adjusted to PH ~ 7 with hydrochloric acid. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a brownish yellow solid (0.36g, 67.5%), i.e. the compound of Number MS22. m.p.: 136- 139°C; 1H NMR(DMSO-d6)δ: 9.87(s, 1H), 8.74(s, 1H), 8.56(s, 1H), 8.16(d, J=8.3 Hz, 1H), 8.01(d, J=2.6 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.74(m, 1H), 7.46- 7.49(m, 1H), 7.27- 7.35(m, 3H), 7.18(t, 1H), 7.05(d, J=3.2 Hz, 1H), 6.49(d, J=3.3 Hz, 1H), 5.26(s, 2H), 3.99- 4.04(m, 1H), 3.66(s, 2H), 3.49(s, 2H); ESI-MS m/z: 533 [M+H]+.
67.5%	Stage #1: glycine ethyl ester hydrochloride; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h; Stage #3: With water; sodium hydroxide In tetrahydrofuran for 2h;	24 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((carboxymethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS22) Example 24 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((carboxymethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS22) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1 mmol) obtained from Example 1 was dissolved in tetrahydrofuran (10 ml), followed by the addition of glycine methyl ester hydrochloride (0.22 g, 2 mmol), added diisopropylethylamine (0.26 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.74 g, 3.5 mmol) was added, and then stirred at room temperature for 24 h. 20% aqueous solution of sodium hydroxide (10 ml) was added and the mixture was stirred for 2 h, and then adjusted to PH˜7 with hydrochloric acid. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a brownish yellow solid (0.36 g, 67.5%), i.e. the compound of Number MS22. m.p.: 136-139° C.; 1H NMR (DMSO-d6) δ: 9.87 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.16 (d, J=8.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.46-7.49 (m, 1H), 7.27-7.35 (m, 3H), 7.18 (t, 1H), 7.05 (d, J=3.2 Hz, 1H), 6.49 (d, J=3.3 Hz, 1H), 5.26 (s, 2H), 3.99-4.04 (m, 1H), 3.66 (s, 2H), 3.49 (s, 2H); ESI-MS m/z: 533[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - EP2740729, 2014, A1 Location in patent: Paragraph 0080; 0081
[2]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1 Location in patent: Paragraph 0243

64
[ 67-71-0 ]
[ 231278-84-5 ]
C₂₈H₂₁ClFN₃O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	Stage #1: dimethylsulfone With n-butyllithium In tetrahydrofuran; hexane at 20℃; for 1h; Stage #2: 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran; hexane for 3h; Stage #3: With sulfuric acid In tetrahydrofuran; methanol; hexane for 1h; Reflux;	4.1.2 (E)-N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(2-(methylsulfonyl)vinyl)furan-2-yl)quinazolin-4-amine (6) To a solution of methyl sulfone (3.0g, 32.0mmol) in 50ml of THF was added n-butyllithium-hexane solution (2.5M, 11.4ml). The resulted solution was stirred at room temperature for 1h, then was added to a solution of compound 5 (3.0 g, 6.0 mmol) [9] dissolved in 250 ml of THF and stirred for another 3h. Concentrated sulfuric acid (5ml) was then added and the mixed solution was refluxed for 1h. Thereafter, the reaction solution was neutralized by saturated NaHCO3 aqueous solution and extracted with CH2Cl2 (300 ml×3). The organic phase was then dried with anhydrous Na2SO4, and the solvent was removed under vacuum to give the crude product which was further purified by column chromatography (CH2Cl2/MeOH=60:1) to give the desired product 6 (1.7g) in 50% yield as a yellow solid. m.p. 94-96°C. 1H NMR (400MHz, DMSO-d6) δ: 10.01 (s, 1H, NH), 8.82 (d, J=4.4Hz, 1H, ArH), 8.51 (s, 1H, ArH), 8.20 (dd, J=8.8, 1.6Hz, 1H, ArH), 8.06 (d, J=2.0Hz, 1H, ArH), 7.80 (d, J=8.4Hz, 2H, ArH), 7.50-7.44 (m, 1H, ArH), 7.31-7.26 (m, 3H, ArH), 7.20-7.17 (m, 1H, ArH), 7.11-7.09 (m, 1H, ArH), 6.53 (d, J=3.2Hz, 1H, ArH), 6.20 (d, J=14.2Hz, 1H, ArH), 6.15 (d, J=14.2Hz, 1H, ArH), 5.27 (s, 2H, OCH2), 3.11 (s, 3H, CH3). 13C NMR (100MHz, DMSO-d6)δ: 162.6, 158.1, 157.9, 154.7, 151.9, 150.2, 149.4, 140.1, 133.6, 130.9, 129.1, 128.8, 128.6, 128.1, 124.9, 123.7, 123.1, 121.5, 120.5, 117.2, 115.8, 115.1, 114.8, 114.4, 108.5, 108.3, 69.9, 41.6. MS-ESI (m/z): 550.0 [M+H]+.

Reference： [1]Lyu, Aifeng; Fang, Lei; Gou, Shaohua [European Journal of Medicinal Chemistry, 2014, vol. 87, p. 631 - 642]

65
[ 98-01-1 ]
[ 944549-41-1 ]
C₃₁H₂₀FN₃O₅ [ No CAS ]
[ 231278-84-5 ]

Yield	Reaction Conditions	Operation in experiment
63%	With potassium acetate; palladium diacetate; tricyclohexylphosphine tetrafluoroborate; Trimethylacetic acid at 110 - 115℃; Inert atmosphere; regioselective reaction;	Typical procedure for the synthesis of 5 via direct regioselective arylation offurfural. A reaction vessel was charged with 9 (50 g, 109.0 mmol), Cy3PHBF4(1.606 g, 4.36 mmol), Pd(OAc)2 (0.489 g, 2.18 mmol), KOAc (21.4 g,218.0 mmol), and PivOH (5.57 g, 54.5 mmol). The mixture was purged withnitrogen. Furfural (250 ml) was added. The mixture was purged with nitrogenfor 10 min, then heated to 110-115 C and stirred at 110-115 C until thereaction was complete. The reaction mixture was cooled to 70 C and treatedwith acetone (600 ml). The mixture was further cooled to 30 C and filtered toremove the undesired solids. The filtrate was heated to 55 C. Water (250 ml)was added at a rate maintaining the temperature above 45 C. The mixture wasthen cooled to 40 C. The resultant slurry was stirred at 40 C for 2 h and thencooled to 30 C over 1.5 h. The solids were filtered, washed twice with acetone/water (1:1, 150 ml), and dried at 60 C in a vacuum oven to give 5 as a yellowcrystalline solid (32.5 g, 63% yield). 1H NMR (500 MHz, DMSO-d6) d 5.26 (s, 2H),7.18 (m, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.30-7.36 (m, 2H), 7.38 (d, J = 3.8 Hz, 1 H),7.47 (m, 1H), 7.71 (m, 1H), 7.73 (d, J = 3.8 Hz, 1H), 7.83 (d, J = 8.8, 1H), 7.99 (d,J = 2.5 Hz, 1H), 8.26 (dd, J = 8.8, 1.50 Hz, 1H), 8.58 (s, 1H), 8.93 (s, 1H), 9.67 (s,1H), 10.06 (s, 1H); 13C NMR (125 MHz, DMSO-d6) d 69.4, 109.7, 114.0 (d,J = 21.8 Hz), 114.2, 114.7 (d, J = 20.9 Hz), 115.2, 119.4, 121.1, 122.6, 123.3 (d,J = 2.7 Hz), 124.5, 126.2, 128.7, 129.4, 130.5 (d, J = 8.2 Hz), 132.8, 139.6 (d,J = 7.3 Hz), 149.9, 150.1, 152.0, 155.2, 157.6, 157.7, 162.2 (d, J = 244.3 Hz),177.7. The analytical data are identical to those of an authentic sample.

Reference： [1]Erickson, Greg; Guo, Jiasheng; McClure, Mike; Mitchell, Mark; Salaun, Marie-Catherine; Whitehead, Andrew [Tetrahedron Letters, 2014, vol. 55, # 43, p. 6007 - 6010]

66
[ 23150-65-4 ]
[ 231278-84-5 ]
N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((1,3-dicarboxypropyl)amino)methyl)-2-furyl)-4-quinazolinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61.2%	Stage #1: L-glutamic dimethyl ester hydrochloride; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 48h; Stage #3: With water; sodium hydroxide In tetrahydrofuran for 2h;	25 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((1,3-dicarboxypropyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS23) Example 25 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((1,3-dicarboxypropyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS23) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1 mmol) obtained from Example 1 was dissolved in tetrahydrofuran (10 ml), followed by the addition of glutamic acid dimethyl ester hydrochloride (0.42 g, 2 mmol) and diisopropylethylamine (0.26 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.74 g, 3.5 mmol) was added, and then the mixture was stirred at room temperature for 48 h. 20% aqueous solution of sodium hydroxide (10 ml) was added and the mixture was stirred for 2 h, and then adjusted to PH˜7 with hydrochloric acid. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid (0.37 g, 61.2%), i.e. the compound of Number MS23. m.p.: 158-160° C.; 1H NMR (DMSO-d6) δ: 9.87 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.16 (d, J=8.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.46-7.49 (m, 1H), 7.27-7.35 (m, 3H), 7.18 (t, 1H), 7.05 (d, J=3.2 Hz, 1H), 6.49 (d, J=3.3 Hz, 1H), 5.26 (s, 2H), 3.99-4.04 (m, 1H), 3.66 (s, 2H), 3.49 (t, 1H), 2.33 (t, 2H), 1.91 (m, 2H); ESI-MS m/z: 605[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1 Location in patent: Paragraph 0253

67
[ 7524-50-7 ]
[ 231278-84-5 ]
N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((1-carboxy-2-phenyl)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	Stage #1: methyl (2S)-2-amino-3-phenylpropanoate hydrochloride; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 48h; Stage #3: With water; sodium hydroxide In tetrahydrofuran for 2h;	26 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((1-carboxy-2-phenyl)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS24) Example 26 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((1-carboxy-2-phenyl)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS24) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1 mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10 ml), followed by the addition of phenylalanine methyl ester hydrochloride (0.43 g, 2 mmol) and diisopropylethylamine (0.26 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.74 g, 3.5 mmol) was added, and then the mixture was stirred at room temperature for 48 h. 20% aqueous solution of sodium hydroxide (10 ml) was added and the mixture was stirred for 2 h, and then adjusted to PH˜7 with hydrochloric acid. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid (0.33 g, 53.0%), i.e. the compound of Number MS24. m.p.: 139-141° C.; 1H NMR (DMSO-d6) δ: 9.87 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.16 (d, J=8.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.46-7.49 (m, 3H), 7.27-7.35 (m, 6H), 7.18 (t, 1H), 7.05 (d, J=3.2 Hz, 1H), 6.49 (d, J=3.3 Hz, 1H), 5.26 (s, 2H), 3.99-4.04 (m, 1H), 3.88 (t, 1H), 3.66 (s, 2H), 3.29 (d, 2H); ESI-MS m/z: 623[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1 Location in patent: Paragraph 0254

68
[ 2491-18-1 ]
[ 231278-84-5 ]
N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((1-carboxy-3-methylthio)propyl)amino) methyl)-2-furyl)-4-quinazolinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49.4%	Stage #1: (S)-methyl 2-amino-4-(methylthio)butanoate hydrochloride; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 6h; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 48h; Stage #3: With water; sodium hydroxide In tetrahydrofuran for 2h;	28 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((1-carboxy-3-methylthio)propyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS26) Example 28 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((1-carboxy-3-methylthio)propyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS26) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1 mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10 ml), followed by the addition of methionine methyl ester hydrochloride (0.40 g, 2 mmol) and diisopropylethylamine (0.26 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.74 g, 3.5 mmol) was added, and then the mixture was stirred at room temperature for 48 h. 20% aqueous solution of sodium hydroxide (10 ml) was added and the mixture was stirred for 2 h, and then adjusted to PH˜7 with hydrochloric acid. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a brown solid (0.30 g, 49.4%), i.e. the compound of Number MS26. m.p.: 131-133° C.; 1H NMR (DMSO-d6) δ: 9.87 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.16 (d, J=8.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.46-7.49 (m, 1H), 7.27-7.35 (m, 3H), 7.18 (t, 1H), 7.05 (d, J=3.2 Hz, 1H), 6.49 (d, J=3.3 Hz, 1H), 5.26 (s, 2H), 3.99-4.04 (m, 1H), 3.66 (s, 2H), 3.59 (t, 1H), 2.60 (t, 2H), 2.14 (s, 3H), 1.91 (m, 2H); ESI-MS m/z: 607[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1 Location in patent: Paragraph 0256

69
[ 921-01-7 ]
[ 231278-84-5 ]
N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((1-carboxy-2-mercapto)ethyl)amino)methyl-2-furyl)-4-quinazolinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56.8%	Stage #1: D-cysteine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran; isopropyl alcohol at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran; isopropyl alcohol at 20℃; for 48h;	31 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((1-carboxy-2-mercapto)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS29) Example 31 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((1-carboxy-2-mercapto)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS29) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1 mmol) obtained from Example 1 was dissolved in tetrahydrofuran (10 ml), followed by the addition of isopropanol (2 ml) and cysteine (0.24 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42 g, 2 mmol) was added, and then the mixture was stirred at room temperature for 48 h. 20% aqueous solution of sodium hydroxide (10 ml) was added and the mixture was stirred for 15 min, and then adjusted to PH˜7 with hydrochloric acid. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid (0.32 g, 56.8%), i.e. the compound of Number MS29. m.p.: 146-149° C.; 1H NMR (DMSO-d6) δ: 9.87 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.16 (d, J=8.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.46-7.49 (m, 1H), 7.27-7.35 (m, 3H), 7.18 (t, 1H), 7.05 (d, J=3.2 Hz, 1H), 6.49 (d, J=3.3 Hz, 1H), 5.26 (s, 2H), 3.99-4.04 (m, 1H), 3.81 (t, 1H), 3.66 (s, 2H), 2.79 (d, 2H); ESI-MS m/z: 579[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1 Location in patent: Paragraph 0259

70
[ 70-47-3 ]
[ 231278-84-5 ]
N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((1-carboxy-2-aminoformyl)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59.3%		Example 32 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-((((1-carboxy-2-aminoformyl)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS30) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1 mmol) obtained from Example 1 was dissolved in tetrahydrofuran (10 ml), followed by the addition of isopropanol (2 ml) and asparagine (0.27 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42 g, 2 mmol) was added, and then the mixture was stirred at room temperature for 48 h. 20% aqueous solution of sodium hydroxide (10 ml) was added and the mixture was stirred for 15 min, and then adjusted to PH?7 with hydrochloric acid. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid (0.35 g, 59.3%), i.e. the compound of Number MS30. m.p.: 152-154 C.; 1H NMR (DMSO-d6) delta: 9.87 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.16 (d, J=8.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.46-7.49 (m, 1H), 7.27-7.35 (m, 3H), 7.18 (t, 1H), 7.16 (s, 2H), 7.05 (d, J=3.2 Hz, 1H), 6.49 (d, J=3.3 Hz, 1H), 5.26 (s, 2H), 3.99-4.04 (m, 1H), 3.84 (s, 2H), 3.72 (t, 1H), 2.65 (d, 2H); ESI-MS m/z: 590[M+H]+.

Reference： [1]Patent: US2015/80392,2015,A1 .Location in patent: Paragraph 0260

71
[ 51-67-2 ]
[ 231278-84-5 ]
[ 1421356-40-2 ]

Yield	Reaction Conditions	Operation in experiment
68.9%	Stage #1: tyrosamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	15 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(4-hydroxyphenyl)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS13) Example 15 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(4-hydroxyphenyl)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine (MS13) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1 mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10 ml), followed by the addition of p-hydroxy-phenylethylamine (0.28 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42 g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixture was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.41 g, 68.9%), i.e. the compound of Number MS13. m.p.: 125-127° C.; 1H NMR (DMSO-d6) δ: 9.87 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.16 (d, J=8.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.46-7.49 (m, 1H), 7.27-7.35 (m, 3H), 7.12-7.18 (m, 3H), 7.05 (d, J=3.2 Hz, 1H), 6.70 (d, 2H), 6.49 (d, J=3.3 Hz, 1H), 5.35 (s, 1H), 5.26 (s, 2H), 3.99-4.04 (m, 1H), 3.66 (s, 2H), 2.84 (t, 2H), 2.69 (t, 2H); ESI-MS m/z: 595[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1 Location in patent: Paragraph 0234

72
[ 3213-28-3 ]
[ 231278-84-5 ]
[ 1421356-41-3 ]

Yield	Reaction Conditions	Operation in experiment
70.4%	Stage #1: 3,5-dimethoxyphenethylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	16 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(3,5-dimethoxyphenyl)ethylamino)methyl)-2-furyl)-4-quinazolinamine (MS14) Example 16 Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(3,5-dimethoxyphenyl)ethylamino)methyl)-2-furyl)-4-quinazolinamine (MS14) Under nitrogen, N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-formyl-2-furyl)-4-quinazolinamine (0.47 g, 1 mmol) obtained from Example 1 was dissolved in anhydrous tetrahydrofuran (10 ml), followed by the addition of 3,5-dimethoxy-phenylethylamine (0.36 g, 2 mmol), and stirred at room temperature for 6 h. Sodium triacetoxy borohydride (0.42 g, 2 mmol) was added, and then the mixture was stirred at room temperature for 24 h. A saturated aqueous solution of sodium carbonate (10 ml) was added, and then the mixture was stirred for 15 min to be layered. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give a yellow solid. The solid was separated by column chromatography on silica gel (200-300 mesh) (eluted with a gradient of ethyl acetate/methanol) to give a yellow solid (0.45 g, 70.4%), i.e. the compound of Number MS14. m.p.: 101-104° C.; 1H NMR (DMSO-d6) δ: 9.87 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.16 (d, J=8.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.46-7.49 (m, 1H), 7.27-7.35 (m, 3H), 7.18 (t, 1H), 7.05 (d, J=3.2 Hz, 1H), 6.63 (s, 2H), 6.49 (d, J=3.3 Hz, 1H), 6.19 (s, 1H), 5.26 (s, 2H), 3.99-4.04 (m, 1H), 3.82 (s, 6H), 3.66 (s, 2H), 2.84 (t, 2H), 2.69 (t, 2H); ESI-MS m/z: 639[M+H]+.

Reference： [1]Current Patent Assignee: HANGZHOU MINSHENG PHARMACEUTICAL CO., LTD. - US2015/80392, 2015, A1 Location in patent: Paragraph 0235

73
C₂₈H₂₁ClFN₃O₄ [ No CAS ]
[ 231278-84-5 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride In tetrahydrofuran; 1,4-dioxane at 20℃;	C.1.f (f) Preparation of 5-(4-{3-chloro-4-(3-fluorobenzyloxy)-anilino}-6-quinazolinyl)-furan-2-carbaldehyde General procedure: (C) Removal of a 1,3-dioxolan-2-yl Protecting Group to Liberate an AldehydeThe compound containing the 1,3-dioxolan-2-yl group was suspended in an appropriate solvent, e.g., THF and treated with hydrochloric acid, either as an aqueous solution (e.g. 2N) or as a solution in dioxane (e.g. 4 molar) and stirred at ambient temperature until the reaction was judged complete (e.g. by tlc or LC/MS analysis). Generally the mixture was diluted with water, and the resulting precipitate was collected by filtration, washed with water and dried to give the aldehyde.The title compound was prepared according to Procedure B followed by Procedure C from 6-Iodo-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-quinazolin-4yl)amine (1.0 g, 1.82 mmol) and (1,3 dioxolan-2-yl)-2-(tributylstannyl)furan (11.17 g, 2.73 mmol). 1H NMR 400 MHz (DMSO-d6) δ 12.05 (s, 1H); 9.68 (s, 1H); 9.43 (s, 1H); 8.95 (s, 1H); 8.53 (d, 1H); 7.99 (D, 1H); 7.92 (s, 1H); 7.78 (m, 1H); 7.66 (m, 1H); 7.63 (m, 1H); 7.47 (m, 1H); 7.40-7.30 (M, 3H); 7.19 (m, 1H); 5.31 (s, 2H); MS m/z 472 (M+H).

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US2015/366868, 2015, A1 Location in patent: Paragraph 0152; 0160

74
[ 27329-70-0 ]
N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-iodoquinazolin-4-amine hydrochloride [ No CAS ]
[ 231278-84-5 ]

Yield	Reaction Conditions	Operation in experiment
86%	With 5%-palladium/activated carbon; triethylamine; In methanol; 1,2-dichloro-ethane; at 50℃; for 16h;	To dichloroethane (30ml) and methanol (15ml) was added a mixed solvent of N- [3- chloro-4- (3-fluoro-benzyloxy) -phenyl] -6-iodo - quinazolin-4-amine hydrochloride (1.63g, 3mmol), 5- formyl-furan-2-boronic acid (0.6g, 4.5mmol), palladium on carbon (5%, 0.2g), triethylamine (1.21g, 12mmol), was heated to 50 stirred for 16h. Palladium on carbon was filtered off through celite, and the filtrate was concentrated, the residue was added ethyl acetate (120ml), tetrahydrofuran (60ml), water (20ml) and saturated aqueous sodium bicarbonate (20ml), stirred for 15 minutes. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and dried in vacuo to give an orange solid (1.2g, 86%)
86%	With 5%-palladium/activated carbon; triethylamine; In methanol; dichloromethane; at 50℃; for 16h;	To dichloroethane (30ml) and methanol (15ml) was added a mixed solvent of N-[3-chloro-4-(3-fluorobenzyloxy)phenyl]-6-iodo-quinazolin-4-amine hydrochloride (1.63g, 3mmol), 5-formyl-furan-2-boronic acid (0.6g, 4.5mmol), palladium on carbon (5%, 0.2g), triethylamine (1.21g, 12mmol), was heated to 50 C stirred for 16h. Palladium carbon was filtered off through celite and the filtrate was concentrated, the residue was added ethyl acetate (120ml), tetrahydrofuran (60ml), water (20ml) and saturated aqueous sodium bicarbonate (20ml), stirred for 15 minutes. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and dried in vacuo to give an orange solid (1.2 g of, 86%).

Reference： [1]Patent: CN103772411,2016,B .Location in patent: Paragraph 0017; 0031; 0032
[2]Patent: CN103772371,2016,B .Location in patent: Paragraph 0058; 0059

75
6-thia-2-azaspiro[3.3]heptane oxalate [ No CAS ]
[ 231278-84-5 ]
N-[3-chloro-4-(3-fluorobenzyloxy)phenyl]-6-[5-[(2-thia-6-azaspiro[3,3]heptan-6-yl)methyl]furan-2-yl]quinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 6-thia-2-azaspiro[3.3]heptane oxalate; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With triethylamine In 1,2-dichloro-ethane at 20℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 40℃; for 5h;	1.5 5) Synthesis of N- [3- chloro-4- (3-fluoro-benzyloxy) - phenyl] -6- [5 - [(2-thia-6-aza - spiro [3,3] heptane - 6-yl) methyl] - furan-2-yl] - quinazolin-4-amine N- [3- chloro-4- (3-fluoro-benzyloxy) phenyl] -6 - [(5-formyl) furan-2-yl] -4-quinazolinamine (1eq), 2- Sulfur heteroaryl aza - spiro [3,3] heptane oxalate (1eq, first with triethylamine and 1.5eq into the free form) was dissolved in 1,2-dichloroethane (concentration ~ 0.5mol holding / L), after stirring at room temperature for half an hour,Sodium borohydride was added acetic acid (2.5eq), 40 stirred for 5 hours. Saturated aqueous sodium bicarbonate was added to quench the reaction, methylene chloride was added and the reaction was diluted with water, separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and the residue was purified by column chromatography to give orange solid product.

Reference： [1]Current Patent Assignee: FUDAN UNIVERSITY - CN103772411, 2016, B Location in patent: Paragraph 0017; 0033; 0034

76
(x)C₂H₂O₄*C₅H₉NOS [ No CAS ]
[ 231278-84-5 ]
C₃₁H₂₆ClFN₄O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (x)C₂H₂O₄*C₅H₉NOS; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With triethylamine In 1,2-dichloro-ethane at 20℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 40℃; for 5h;	2 Example 2: Synthesis of Compound 2, N- [3- chloro-4- (3-fluoro-benzyloxy) - phenyl] -6- [5 - [(2-heteroaryl-6-aza sulfoxide - spiro [ 3,3] heptane-6-yl) methyl] - furan-2-yl] - quinazolin-4-amine N- [3- chloro-4- (3-fluoro-benzyloxy) phenyl] -6 - [(5-formyl) furan-2-yl] -4-quinazolinamine (1eq), 2- sulfoxide hetero-6-aza - spiro [3,3] heptane oxalate(1 eq, first with triethylamine and 1.5eq into the free form) was dissolved in 1,2-dichloroethane (maintaining the solution concentration ~ 0.5mol / L), stirred for a half hour at room temperature,Added toAcetate Sodium borohydride (2.5eq), 40 stirred for 5 hours. Saturated aqueous sodium bicarbonate was added to quench the reaction, methylene chloride was added and the reaction was diluted with water, separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and the residue was purified by column chromatography to give orange solid product.

Reference： [1]Current Patent Assignee: FUDAN UNIVERSITY - CN103772411, 2016, B Location in patent: Paragraph 0035; 0036

77
(x)C₂H₂O₄*C₅H₉NO₂S [ No CAS ]
[ 231278-84-5 ]
C₃₁H₂₆ClFN₄O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (x)C₂H₂O₄*C₅H₉NO₂S; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With triethylamine In 1,2-dichloro-ethane at 20℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 40℃; for 5h;	3 Example 3: Synthesis of Compound 3, N-[3-chloro-4-(3-fluoro-benzyloxy)phenyl]-6-[5-[(2-sulfonyl 6-azaspiro [3,3]hept-6-yl)methyl]furan-2-yl]quinazolin-4-amine N- [3- chloro-4- (3-fluoro-benzyloxy) phenyl] -6 - [(5-formyl) furan-2-yl] -4-quinazolinamine (1eq), 2- sulfone heteroaryl aza - spiro [3,3] heptane oxalate (1eq, first with triethylamine and 1.5eq into the free form) was dissolved in 1,2-dichloroethane (concentration ~ 0.5mol holding / L), after stirring at room temperature for half an hour,Added toAcetate Sodium borohydride (2.5eq), 40 stirred for 5 hours. Saturated aqueous sodium bicarbonate Added to to quench the reaction, methylene chloride Added to and the reaction was diluted with water, separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and the residue was purified by column chromatography to give orange solid product.

Reference： [1]Current Patent Assignee: FUDAN UNIVERSITY - CN103772411, 2016, B Location in patent: Paragraph 0037; 0038

78
1-thia-6-azaspiro [3,3]heptane oxalate [ No CAS ]
[ 231278-84-5 ]
N-[3-chloro-4-(3-fluorobenzyloxy)phenyl]-6-[5-[(1-thia-6-azaspiro[3,3]hept-6-yl)methyl]furan-2-yl]quinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-thia-6-azaspiro [3,3]heptane oxalate; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With triethylamine In 1,2-dichloro-ethane at 20℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 40℃; for 5h;	4 Example 4: Synthesis of compound 4, N-[3-chloro-4-(3-fluorobenzyloxy)phenyl]-6-[5-[(1-thia-6-azaspiro[3,3]hept-6-yl)methyl]furan-2-yl]quinazolin-4-amine N- [3- chloro-4- (3-fluoro-benzyloxy) phenyl] -6 - [(5-formyl) furan-2-yl] -4-quinazolinamine (1eq), 1- sulfur heteroaryl aza - spiro [3,3] heptane oxalate (1eq, first with triethylamine and 1.5eq into the free form) was dissolved in 1,2-dichloroethane (concentration ~ 0.5mol holding / L), after stirring at room temperature for half an hour,Sodium borohydride Added to acetic acid (2.5eq), 40 stirred for 5 hours. Saturated aqueous sodium bicarbonate Added to to quench the reaction, methylene chloride Added to and the reaction was diluted with water, separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and the residue was purified by column chromatography to give orange solid product.

Reference： [1]Current Patent Assignee: FUDAN UNIVERSITY - CN103772411, 2016, B Location in patent: Paragraph 0039; 0040

79
(x)C₂H₂O₄*C₅H₉NOS [ No CAS ]
[ 231278-84-5 ]
C₃₁H₂₆ClFN₄O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (x)C₂H₂O₄*C₅H₉NOS; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With triethylamine In 1,2-dichloro-ethane at 20℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 40℃; for 5h;	5 Example 5: Synthesis of Compound 5, N- [3- chloro-4- (3-fluoro-benzyloxy) - phenyl] -6- [5 - [(1-hetero-6-aza sulfoxide - spiro [ 3,3] heptane-6-yl) methyl] - furan-2-yl] - quinazolin-4-amine N- [3- chloro-4- (3-fluoro-benzyloxy) phenyl] -6 - [(5-formyl) furan-2-yl] -4-quinazolinamine (1eq), 1- Asian sulfone heteroaryl aza - spiro [3,3] heptane oxalate (1eq, first with triethylamine and 1.5eq into the free form) was dissolved in 1,2-dichloroethane (maintaining the solution concentration to 0.5 mol / L), after stirring at room temperature for half an hour,Added toAcetate Sodium borohydride (2.5eq), 40 stirred for 5 hours. Saturated aqueous sodium bicarbonate Added to to quench the reaction, methylene chloride Added to and the reaction was diluted with water, separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and the residue was purified by column chromatography to give orange solid product.

Reference： [1]Current Patent Assignee: FUDAN UNIVERSITY - CN103772411, 2016, B Location in patent: Paragraph 0041; 0042

80
[ 104458-24-4 ]
[ 104-15-4 ]
[ 231278-84-5 ]
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-([2-(methylsulphonyl)ethyl]amino}methyl)furan-2-yl]quinazolin-4-amine bis(4-methylbenzenesulphonate) monohydrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82.8%		In 250ml reaction flask 5- [4 - [[3-chloro-4 - [(3-fluorophenyl) methoxy] phenyl] amino] -6- Quinazolin] -2-furaldehyde (4.73g, 10mmol), 2- (amino) ethyl methyl sulfone hydrochloride (2.56g, 16mmol), diisopropylethyl amine (5.17g, 40mmol), acetic acid (2.4g, 40mmol) and 50ml Tetrahydrofuran, at room temperature the reaction mixture was stirred 3h, was added portionwise sodium triacetoxy boron hydride (8.48g, 40mmol), Reaction at room temperature 12h. 30ml 20% aqueous sodium hydroxide solution was added with stirring separated, extracted with ethyl acetate None The organic phase. The combined organic phase was concentrated and the residue was added 50ml of tetrahydrofuran was dissolved, was added p-toluenesulfonic acid Aqueous solution (7.6g, 40mmol / 15ml), stirred at room temperature 12h, filtered, and dried to give a pale yellow cake Solid 7.58g, m.p. 244-246 C, yield 82.8%, HPLC purity: 99.6%.

Reference： [1]Patent: CN103319382,2016,B .Location in patent: Paragraph 0034; 0035

81
1-deoxynojirimycin hydrochloride [ No CAS ]
[ 231278-84-5 ]
4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2R,3R,4R,5S)-2-hydroxymethyl-3,4,5-trihydroxy-1-piperidylmethyl)furan-2-yl)quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31.6%	Stage #1: 1-deoxynojirimycin hydrochloride; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With sodium sulfate; triethylamine In methanol; N,N-dimethyl-formamide at 75℃; for 3h; Cooling with ice; Stage #2: With sodium cyanoborohydride In methanol; N,N-dimethyl-formamide at 20℃; for 48h;	13 Under the condition in the ice bath, taking 0.44g (2.2mmol) 1 - deoxynojirimycin hydrochloride, 1.17g (8.0mmol) anhydrous sodium sulfate, 10.0 ml methanol, 1.5 ml triethylamine is added to the 50 ml single-port in the bottle, the stirring 20 minutes later, using formic acid for adjusting the pH 5 - 6. Under mixing 0.95g (2.0mmol) 4 - [3 - chloro -4 - (3 - fluorobenzyloxy) phenylamino] -6 - (5 - formyl furan -2 - yl) quinazoline (M') and 5.0 ml DMF is added to the mixture in the reaction system. Reaction 3 hours and adding the 0.39g (8.0mmol) cyano sodium borohydride, reaction at room temperature for 2 days. Sodium hydroxide aqueous solution pH adjusted to 9 - 10, filtering, evaporating the filtrate after the silica gel column chromatography separation, to get the yellow powder product M 0.39g, yield 31.6%.
31.6%	Stage #1: 1-deoxynojirimycin hydrochloride With formic acid; sodium sulfate; triethylamine In methanol for 0.333333h; Cooling with ice; Stage #2: 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In N,N-dimethyl-formamide for 3h; Cooling with ice; Stage #3: With sodium cyanoborohydride In N,N-dimethyl-formamide at 20℃; for 48h;	1.2.1 General method for preparation of 4-arylamino-6-(5-((2R,3R,4R,5S)-2-hydroxymethyl-3,4,5-trihydroxy-1-piperidylmethyl)furan-2-yl)quinazoline (15a-15c) General procedure: As described before, 1-DNJHCl (2.2 mmol), anhydrous sodium sulfate (8.0 mmol), methanol (10.0 mL), and triethylamine (1.5 mL) were added to a reaction flask under the condition of ice-bath. The mixture was stirred 20 min and adjusts pH~5-6 with formic acid. The reactor was added the solution of 4-arylamino-6-(5-formylfuran-2-yl)quinazoline (14a-14c) (2.0 mmol) resolved in DMF (5 mL). After 3 h, sodium cyanoborohydride (8.0 mmol) was added, and stirring for 48 h at r.t.. The product was adjusted pH~9-10 with 5% NaOH, and the precipitated product was filtered and the filtrate was evaporated. The crude product was chromatographed by silica gel, eluted with MeOH/CHCl3 (1:15) to afford 15a-15c as yellow solid (yield 30.5% ~ 34.8%). 1.2.1.1 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((2R,3R,4R,5S)-2-hydroxymethyl-3,4,5-trihydroxy-1-piperidylmethyl)furan-2-yl)quinazoline (15a) Yield 31.6%. m.p.: 241.7-242.9 °C; 1H NMR (600 MHz, DMSO-d6) δ(ppm): 9.93 (s, 1H), 8.75 (s, 1H), 8.55 (s, 1H), 8.13 (dd, J = 8.7, 1.5 Hz, 1H), 8.02 (d, J = 2.5 Hz, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.75 (dd, J = 8.9, 2.5 Hz, 1H), 7.48 (dd, J = 14.0, 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.32 (s, 1H), 7.30 (d, J = 8.9 Hz, 1H), 7.23 - 7.16 (m, 1H), 7.07 (d, J = 3.1 Hz, 1H), 6.52 (d, J = 3.1 Hz, 1H), 5.27 (s, 2H), 4.73 (dd, J = 19.7, 4.2 Hz, 2H), 4.42 (s, 1H), 4.01 (d, J = 15.1 Hz, 2H), 3.89 (d, J = 15.1 Hz, 1H), 3.80 - 3.67 (m, 1H), 3.51 (s, 1H), 3.30 - 3.20 (m, 1H), 3.19 - 3.08 (m, 1H), 2.89 (dd, J = 9.6, 3.9 Hz, 2H), 2.10 - 1.95 (m, 2H); 13C NMR (100 MHz, DMSO-d6δ(ppm): 162.2(d, 1JC-F = 243.6 Hz), 157.6, 154.3, 152.9, 151.6, 149.8, 148.8, 139.7(d, 3JC-F = 7.5 Hz), 133.0, 130.6(d, 3JC-F = 8.2 Hz), 128.6, 128.5, 128.4, 124.4, 123.4(d, 4JC-F = 2.7 Hz), 122.6, 121.1, 116.6, 115.4, 114.7(d, 2JC-F = 20.9 Hz), 114.3, 114.1(d, 2JC-F = 21.9 Hz), 111.5, 107.8, 79.1, 70.5, 69.4, 69.3, 66.0, 58.9, 57.3, 48.8; IR νmax(KBr) cm-1: 3412, 2926, 1588, 1470, 1412, 1338, 1235, 1044; 1014, 779; HRMS (C32H30ClFN4O6) m/z [M+H]+: calculated: 621.1916, found: 621.1926.

Reference： [1]Current Patent Assignee: SHAANXI NORMAL UNIVERSITY; SINO BIOPHARMACEUTICAL LIMITED - CN106892898, 2017, A Location in patent: Paragraph 0130-033
[2]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]

82
[ 100-36-7 ]
[ 231278-84-5 ]
4-[3-chloro-4-(3-fluorobenzyloxy)phenylamino]-6-[5-((2-(N,N-diethylamino)ethyl)aminomethyl)furan-2-yl]quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With methanol; formic acid; sodium cyanoborohydride; sodium sulfate In tetrahydrofuran at 20℃; for 2h;	1 Example 1Synthetic compound 1:4-[3-Chloro-4-(3-fluorobenzyloxy)phenylamino]-6-[5-((N,N-diethylaminoethyl)aminomethyl)furan2-yl]quinazoline 0.09 g (0.75 mmol) of N,N-diethylaminoethylamine represented by Formula II-1, 5.0 mL of methanol was added to a 50 mL single-mouth flask, pH was adjusted to 5-6 with formic acid, and then 0.28 g (2.00 mmol) was added. Anhydrous sodium sulfate, 0.06 g (1.00 mmol) of sodium cyanoborohydride, and 0.24 g (0.50 mmol) of the formula I-1 shown with stirringA mixture of 4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-6-(5-formylfuran-2-yl)quinazoline and 5 mL of tetrahydrofuran was added dropwise to the reaction system. After the addition was completed, the reaction was stirred at room temperature for 30 minutes, then 0.06 g (1.00 mmol) of sodium cyanoborohydride was added, and the reaction was continued for 90 minutes. The pH was adjusted to 9-10 with an aqueous sodium hydroxide solution, the mixture was suction filtered, and the filtrate was evaporated to remove the solvent. The residue was subjected to silica gel column chromatography (methanol:chloroform = 1:15, V/V) to give 0.24 g of compound 1 as a pale yellow solid.Yield: 82.0%
82%	Stage #1: N,N-diethylethylenediamine With formic acid In methanol at 0℃; Stage #2: 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With sodium cyanoborohydride; sodium sulfate In tetrahydrofuran; methanol for 2.5h;

Reference： [1]Current Patent Assignee: SHAANXI NORMAL UNIVERSITY - CN107827877, 2018, A Location in patent: Paragraph 0023; 0024; 0025; 0026
[2]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]

83
[ 60501-55-5 ]
[ 231278-84-5 ]
[ 1275595-86-2 ]

Yield	Reaction Conditions	Operation in experiment
93.1%		In a 500 ml reaction flask with a stirring, thermometer, and reflux condenser,120 g of tetrahydrofuran, 23.7 g (0.05 mole) of 6- (5-formylfuran-2-yl) -4- [3-chloro-4- (3-fluorobenzyloxy) phenyl] aminoquinazoline ( I1), 11.5 g (0.08 mol) of <strong>[60501-55-5]2-methylsulfoxide ethylamine hydrochloride</strong>, 7.8 g (0.06 mol) of diisopropylethylamine and 1.5 g of isopropanol.After reacting at 50-60 C for 1 hour, the imine / tetrahydrofuran solution formed by the reaction was added dropwise to the suspension of 21.2 g (0.10 mol) of sodium triacetoxyborohydride in 180 g of tetrahydrofuran at 20 C within 30 minutes. In the liquid. After 90 minutes of reaction at 20 C,Add 70 grams of 5N sodium hydroxide solution, and stir for 15 minutes before turning off the stirring.Most of the tetrahydrofuran was recovered by distillation under reduced pressure. The remaining solution was extracted three times with ethyl acetate.100 g each time, the organic phases were combined, washed once with 40 g of a saturated sodium chloride aqueous solution, and the organic phase was distilled under reduced pressure to recover ethyl acetate. At the same time, 26.3 g of ceratinib solid were obtained, yield 93.1%, and liquid purity 99.9% .

Reference： [1]Patent: CN110698417,2020,A .Location in patent: Paragraph 0112; 0115-0116

84
1,1,2,2-tetramethoxy-4-bromobutane [ No CAS ]
6-cyano-4-[3-chloro-4-(3-fluorobenzyloxy)phenyl]aminoquinazoline [ No CAS ]
[ 231278-84-5 ]

Yield	Reaction Conditions	Operation in experiment
82.8%	Stage #1: 1,1,2,2-tetramethoxy-4-bromobutane With magnesium In tetrahydrofuran; ethylene dibromide at 30 - 45℃; for 4h; Stage #2: 6-cyano-4-[3-chloro-4-(3-fluorobenzyloxy)phenyl]aminoquinazoline In tetrahydrofuran; ethylene dibromide at 15 - 30℃; for 2h; Stage #3: With hydrogenchloride In tetrahydrofuran; water; ethylene dibromide at 50 - 55℃; for 4h;	5.1 Preparation of 6- (5-formylfuran-2-yl) -4- [3-chloro-4- (3-fluorobenzyloxy) phenyl] aminoquinazoline (I1) To the stirring, thermometer,In a 500 ml four-necked flask with constant pressure dropping funnel and reflux condenser,Add 80 grams of tetrahydrofuran, 1.6 grams of magnesium metal powder,0.5 g of 1,2-dibromoethane, 1 milligram of iodine, the reaction is initiated at 30-45 ° C,Then at 35-40 ° C, a mixed solution of 10.5 g (0.06 mol) of 1,1,2,2-tetramethoxy-4-bromobutane and 120 g of tetrahydrofuran was added dropwise, and the addition was completed in about 2 hours. Thereafter, the reaction was stirred at 40-45 ° C for 2 hours. Cool to 20-25 ,Transfer the obtained Grignard reagent liquid to a constant pressure dropping funnel,stand-by. Followed by stirring,A 500 ml four-necked flask with a thermometer and a reflux condenser,Add 100 g of tetrahydrofuran and 20.2 g (0.05 mol) of 6-cyano-4- [3-chloro-4- (3-fluorobenzyloxy) phenyl] aminoquinazoline (IV) at 15-20 ° C. Meanwhile, the obtained Grignard reagent liquid was added dropwise, and the addition was completed in about 2 hours. Thereafter, the reaction was stirred at 25 to 30 ° C for 3 hours, and 50 g of water, 20 g of 30% hydrochloric acid, and 50-55 ° C were stirred for 4 hours. Cool to 20-25 ° C, separate the layers, extract the aqueous phase twice with toluene, 20 g of toluene each time, combine the organic phases, wash once with 30 g of a saturated sodium chloride aqueous solution, distill the organic phase to recover tetrahydrofuran and toluene, and use the residue with Methyl tert-butyl ether was recrystallized to obtain 19.6 g of 6- (5-formylfuran-2-yl) -4- [3-chloro-4- (3-fluorobenzyloxy) phenyl] aminoquinazoline ( I1), yield 82.8%, and liquid phase purity 99.5%

Reference： [1]Current Patent Assignee: XINFA PHARMACEUTICAL CO LTD - CN110698417, 2020, A Location in patent: Paragraph 0107-0109

85
C₈H₁₃BrO₄ [ No CAS ]
6-cyano-4-[3-chloro-4-(3-fluorobenzyloxy)phenyl]aminoquinazoline [ No CAS ]
[ 231278-84-5 ]

Yield	Reaction Conditions	Operation in experiment
84.1%	Stage #1: C₈H₁₃BrO₄ With iodine; magnesium In 2-methyltetrahydrofuran; ethylene dibromide at 30 - 45℃; for 5h; Stage #2: 6-cyano-4-[3-chloro-4-(3-fluorobenzyloxy)phenyl]aminoquinazoline In 2-methyltetrahydrofuran; ethylene dibromide at 20 - 30℃; for 5h; Stage #3: With hydrogenchloride In 2-methyltetrahydrofuran; water; ethylene dibromide at 50 - 55℃; for 4h;	6.1 Preparation of 6- (5-formylfuran-2-yl) -4- [3-chloro-4- (3-fluorobenzyloxy) phenyl] aminoquinazoline (I1) To a 500-ml four-necked flask equipped with a stirring, thermometer, constant-pressure dropping funnel, and reflux condenser, add 150 g of tetrahydrofuran and 1.6 g of magnesium metal powder.0.4 g of 1,2-dibromoethane, 1 milligram of iodine, the reaction is initiated at 30-45 ° C,Then at 40-45 ° C, 10.0 g (0.06 mol) is added dropwise.A mixed solution of 9- (2-bromoethyl) -1,4,5,8-tetrahydrodecahydronaphthalene and 150 g of tetrahydrofuran was added dropwise in about 2 hours.Thereafter, the reaction was stirred at 40-45 ° C for 3 hours. Cool to 20-25 ,The obtained Grignard reagent liquid was transferred to a constant-pressure dropping funnel and was set aside.In another 1000 ml four-necked flask equipped with a stirring, thermometer, and reflux condenser, add 150 g of tetrahydrofuran and 20.2 g (0.05 mol) of 6-cyano-4- [3-chloro-4- (3-fluorobenzyl) Oxy) phenyl] aminoquinazoline (IV), dropwise the obtained Grignard reagent liquid at 20-25 ° C,The addition was completed in about 2 hours. Thereafter, the reaction was stirred at 25 to 30 ° C for 3 hours, and 50 g of water was added.20 grams of 30% hydrochloric acid, stirred at 50-55 ° C for 4 hours, cooled to 20-25 ° C, separated into layers, the aqueous phase was extracted twice with toluene, each time 20 grams of toluene, and the organic phases were combined, and 30 grams of saturated chlorine The sodium chloride aqueous solution was washed once, and the organic phase was distilled to recover 2-methyltetrahydrofuran and toluene. The residue was recrystallized from methyl tert-butyl ether to obtain 19.9 g of 6- (5-formylfuran-2-yl) -4- [3 -Chloro-4- (3-fluorobenzyloxy) phenyl] aminoquinazoline (I1), yield 84.1%, liquid phase purity 99.5%.

Reference： [1]Current Patent Assignee: XINFA PHARMACEUTICAL CO LTD - CN110698417, 2020, A Location in patent: Paragraph 0112-0114

86
[ 76-05-1 ]
[ 57260-71-6 ]
[ 231278-84-5 ]
C₃₀H₂₇ClFN₅O₂*C₂HF₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	Stage #1: 1-t-Butoxycarbonylpiperazine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In methanol; acetic acid at 23℃; for 0.5h; Inert atmosphere; Stage #2: With sodium cyanoborohydride In methanol; acetic acid at 23℃; for 1h; Stage #3: trifluoroacetic acid In dichloromethane at 23℃; for 1h;	5 [0816] A suspension of 5-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]quinazolin-6- yl]furan-2-carbaldehyde (100 mg, 0.211 mmol) in 9: 1 methanol (1.8 mL):acetic acid (0.2 mL) was sonicated until a fine suspension was formed. 1-Boc-Piperazine (79 mg, 0.42 mmol) was added and the resulting mixture was stirred at 23 °C for 30 min. Sodium (1745) cyanoborohydride (20 mg, 0.32 mmol) was added in a single portion at 23 °C. The precipitates dissolved over time to a point with a few speckles left in 1 h. At this point TLC analysis (100% ethyl acetate) showed full consumption of the aldehyde starting material. The reaction mixture was concentrated under reduced pressure. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution (5 mL) and (1746) dichloromethane (5 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 x 5 mL). The combined organic layers were dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (20-100% ethyl acetate-hexanes) to afford the product as a yellow powder. The yellow powder was resuspended in dichloromethane (2.0 mL), and trifluoroacetic acid (2.0 mL) was added dropwise, giving rise to a bright yellow solution. After standing at 23 °C for 1 h, the solution was concentrated under reduced pressure to afford the product as a yellow powder (93 mg, 68%). HRMS (ESI): Calcd for (1747) (C30H27CIFN5O2 + H)+: 544.1910, Found: 544.1882.

Reference： [1]Current Patent Assignee: UNIVERSITY OF CALIFORNIA - WO2020/163598, 2020, A1 Location in patent: Paragraph 0811; 0816

87
C₄₆H₇₆N₂O₁₂S*C₂HF₃O₂ [ No CAS ]
[ 231278-84-5 ]
C₇₂H₉₃ClFN₅O₁₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34%	With sodium tris(acetoxy)borohydride In dichloromethane at 23℃; for 2h; Inert atmosphere;	5 [0858] An oven-dried one-dram vial was charged with 05-011 (10.5 mg, 0.0106 mmol),Lapatinib aldehyde (5.0 mg, 0.0106 mmol) and a magnetic stir bar. DCM (0.11 mL) was added via syringe. The resulting mixture was stirred at 23 °C for 10 min. The aldehyde reactant did not fully dissolve. Sodium triacetoxyborohydride (4.5 mg, 0.0211 mmol) was added as a solid. In about 5 min, all the solids had gone into solution. The reaction mixture was kept stirred for a total of 2 h, at which point no starting material amine could be detected. The reaction solution was concentrated to dryness under vacuum. The residue was diluted with 50% acetonitrile-water to a volume of 3.5 mL, and the solution was filtered through a 0.45 mM PTFE syringe filter. The filtrate was purified by reverse-phase HPLC (Waters XB ridge Cl 8 column 5 pm particle size 30 x 250 mm, 5-95% acetonitrile-water + 0.1% formic acid, 40 min, 20 mL/min) to afford the product as a yellow solid (4.8 mg, 34%).HRMS (ESI): Calcd for (C72H93CIFN5O14S + 2H)2+: 669.8134, Found:669.7951.
34%	Stage #1: C₄₆H₇₆N₂O₁₂S*C₂HF₃O₂; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In dichloromethane at 23℃; for 0.166667h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane for 2.08333h; Inert atmosphere;	6 An oven-dried one-dram vial was charged with ZZY05-011 (10.5 mg, 0.0106 mmol), Lapatinib aldehyde (5.0 mg, 0.0106 mmol) and a magnetic stir bar. DCM (0.11 mL) was added via syringe. The resulting mixture was stirred at 23 °C for 10 min. The aldehyde reactant did not fully dissolve. Sodium triacetoxyborohydride (4.5 mg, 0.0211 mmol) was added as a solid. In about 5 min, all the solids had gone into solution. The reaction mixture was kept stirred for a total of 2 h, at which point no starting material amine could be detected. The reaction solution was concentrated to dryness under vacuum. The residue was diluted with 50% acetonitrile-water to a volume of 3.5 mL, and the solution was filtered through a 0.45 µM PTFE syringe filter. The filtrate was purified by reverse-phase HPLC (Waters XBridge C18 column 5 µm particle size 30 x 250 mm, 5-95% acetonitrile-water + 0.1% formic acid, 40 min, 20 mL/min) to afford the product as a yellow solid (4.8 mg, 34%). HRMS (ESI): Calcd for (C72H93ClFN5O14S + 2H)2+: 669.8134, Found:669.7951

Reference： [1]Current Patent Assignee: UNIVERSITY OF CALIFORNIA - WO2020/163598, 2020, A1 Location in patent: Paragraph 0811; 0858
[2]Current Patent Assignee: UNIVERSITY OF CALIFORNIA - WO2020/163594, 2020, A1 Location in patent: Paragraph 1254; 1421-1422

88
[ 231278-84-5 ]
[ 202197-26-0 ]
C₃₉H₂₆Cl₂F₂N₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87.91%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 25℃; for 4h;	1-8 crafting process: Add 6.0g of compound I to the reaction flask,Compound II 3.5g and tetrahydrofuran 60mL,Under stirring, add 4.1 g of N,N-diisopropylethylamine (DIPEA) dropwise,After dripping,React at 25°C for 4h.Thin layer chromatography (Thin Layer Chromatography, abbreviated as TLC) monitors the reaction (thin layer developing agent: DCM/MeOH=10/1),When the content of compound II drops below 5%,Add 180 mL of purified water dropwise to the reaction system,Crystallize at 25 for 3h,filter,The filter cake was beaten with 30mL isopropanol for 1h,The wet product of the compound of formula III is obtained by suction filtration,After drying under reduced pressure, 7.9g of the compound of formula III was obtained.Yellow powdery solid,The yield was 87.91%,The purity is 97.445%

Reference： [1]Current Patent Assignee: BEIJING XINKAIYUAN PHARMACEUTICALS - CN113321642, 2021, A Location in patent: Paragraph 0041; 0049-0060

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	231278-84-5	MDL No. :	MFCD10565688
Formula :	C₂₆H₁₇ClFN₃O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XQPZOUAAXRXPAM-UHFFFAOYSA-N
M.W :	473.88	Pubchem ID :	11181296
Synonyms :

Num. heavy atoms :	34
Num. arom. heavy atoms :	27
Fraction Csp3 :	0.04
Num. rotatable bonds :	7
Num. H-bond acceptors :	6.0
Num. H-bond donors :	1.0
Molar Refractivity :	128.12
TPSA :	77.25 Å²

GI absorption :	Low
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-4.84 cm/s

Log Po/w (iLOGP) :	3.66
Log Po/w (XLOGP3) :	6.13
Log Po/w (WLOGP) :	7.09
Log Po/w (MLOGP) :	3.7
Log Po/w (SILICOS-IT) :	6.27
Consensus Log Po/w :	5.37

[ CAS No. 231278-84-5 ] {[proInfo.proName]}

Quality Control of [ 231278-84-5 ]

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Product Details of [ 231278-84-5 ]

Calculated chemistry of [ 231278-84-5 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 231278-84-5 ]

Application In Synthesis of [ 231278-84-5 ]

[ 231278-84-5 ] Synthesis Path-Downstream 1~88

Related Functional Groups of
[ 231278-84-5 ]

Fluorinated Building Blocks

Aryls

Chlorides

Ethers

Amines

Related Parent Nucleus of
[ 231278-84-5 ]

Furans

Quinazolines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	1.0
Muegge :	1.0
Bioavailability Score :	0.55

Log S (ESOL) :	-6.77
Solubility :	0.0000813 mg/ml ; 0.000000172 mol/l
Class :	Poorly soluble
Log S (Ali) :	-7.53
Solubility :	0.0000138 mg/ml ; 0.0000000292 mol/l
Class :	Poorly soluble
Log S (SILICOS-IT) :	-10.98
Solubility :	0.0000000049 mg/ml ; 0.0 mol/l
Class :	Insoluble

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	3.44

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

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P378
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