[ CAS No. 574745-97-4 ] {[proInfo.proName]}

Name: 574745-97-4|4-Chloro-7-methoxyquinazolin-6-ol|98%
Brand: Ambeed
SKU: A609190
Rating: 97 (22 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

DV 2D 3D

3d Animation Molecule Structure of 574745-97-4

Structure of 574745-97-4 * Storage: {[proInfo.prStorage]}

Please Login or Create an Account to: See VIP prices and availability

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

* Shipping: {[proInfo.prShipping]}

For Research Only 120K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 574745-97-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 574745-97-4 ]

SDS Specification

Alternatived Products of [ 574745-97-4 ]

Product Details of [ 574745-97-4 ]

CAS No. :	574745-97-4	MDL No. :	MFCD12547341
Formula :	C₉H₇ClN₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZBOFUZBKDHGCAF-UHFFFAOYSA-N
M.W :	210.62	Pubchem ID :	23132475
Synonyms :

Calculated chemistry of [ 574745-97-4 ] Expand+

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	10
Fraction Csp3 :	0.11
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	53.06
TPSA :	55.24 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.08 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.11
Log Po/w (XLOGP3) :	2.12
Log Po/w (WLOGP) :	2.0
Log Po/w (MLOGP) :	0.97
Log Po/w (SILICOS-IT) :	2.05
Consensus Log Po/w :	1.85

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.94
Solubility :	0.24 mg/ml ; 0.00114 mol/l
Class :	Soluble
Log S (Ali) :	-2.91
Solubility :	0.258 mg/ml ; 0.00123 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.5
Solubility :	0.066 mg/ml ; 0.000313 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.57

Safety of [ 574745-97-4 ]

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

Application In Synthesis of [ 574745-97-4 ]

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

Upstream synthesis route of [ 574745-97-4 ]
Downstream synthetic route of [ 574745-97-4 ]

[ 574745-97-4 ] Synthesis Path-Upstream 1~15

1
[ 230955-75-6 ]
[ 574745-97-4 ]

Yield	Reaction Conditions	Operation in experiment
94%	With ammonia In methanol at 20℃; for 1.5 h;	A suspension of 4-chloro-7-methoxyquinazolin-6-yl acetate (prepared as described in Example 25-5 of WO01/66099, 10.1 g, 40 mmol) in 6N methanolic ammonia (200 ml) was stirred at room temperature for 90 minutes. The solvents were evaporated under vacuum. Water was added and the resulting suspension was filtered. The solid obtained was washed with water, ether and dried under high. vacuum in the presence-of phosphorus pentoxide to GIVE 4-CHLORO-7-METHOXYQUINAZOLIN-6-OL (7.9 G, 94percent). NMR SPECTRUM: (DMSOD6) 4.02 (S, 3H), 7.40 (s, 1H), 7.43 (s, 1H), 8. 81 (s, 1H).
86%	With ammonia In methanol at 20℃; for 1.5 h; Inert atmosphere	Under argon, 10 (800 mg, 3.17 mmol) was dissolved in 11.3 mL of NH₃ (7 N in CH₃OH) and the mixture was stirred 1.5 h at room temperature. The solvent was removed under vacuum and a trituration with Et₂O afforded 11 as a beige solid (574 mg, 86percent). Mp: 300 °C (dec.); IR (ATR, ZnSe): ν (cm^-1) 3019, 1555, 1497, 1465, 1350, 1188, 1157, 974, 858, 700; ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 10.78 (s, 1H), 8.81 (s, 1H), 7.43 (s, 1H), 7.40 (s, 1H), 4.01 (s, 3H). ¹³C NMR (126 MHz, DMSO-d₆): δ (ppm) 158.9, 155.3, 155.2, 149.3, 146.4, 120.2, 105.9, 103.9, 56.0; HRMS-ESI calcd for C₉H₈ClN₂O₂ [M+H]⁺ 211.0269 found 211.0257.
84.6%	With ammonium hydroxide In methanol at 20℃; for 3 h;	7-Methoxy-4-hydroxyquinazolin-6-ol acetate (4.68 g, 20 mmol) and DMF (0.4 mL) were added to 25 mL of thionyl chloride and refluxed for 5 hours. The thionyl chloride was distilled off under reduced pressure, and the mixture was steamed with chloroform (10 mL x 3) and toluene (10 mL x 2) The residual thionyl chloride was removed to give 7-methoxy-4-chloroquinazolin-6-ol acetate.Without purification, it was added to concentrated aqueous ammonia (35 mL)In methanol (70 mL) and stirred at room temperature for 3 hours. The filter cake was washed with ether to give 6-hydroxy-7-methoxy 4-chloroquinazoline, 3.61 g as a pale white solid, 84.6percent yield.

78%	With ammonia In methanol at 10℃;	The 10g 4- chloro-7-methoxy-quinazolin-6-yl acetate (Compound 1) was placed in a 250mL three-necked roundFlask in an ice bath was added dropwise with stirring 100mL 7Μ NH3 methanol solution, drip completed within 30 minutes. Below 10 ° C, the reaction was stirred for more than 30min. The reaction solution was filtered under reduced pressure, residue was washed twice with ether, to give 6. 5g (78percent yield) of compound 2,As a pale yellow powder.
78%	With ammonia In methanol at 10℃; Cooling with ice	The 10g4- chloro-7-methoxy-quinazolin-6-yl acetate (Compound 1) was placed in a 250mL three-necked round bottom flask in an ice bath was added dropwise with stirring 100mL7MNH3- methanol solution, more than 30 minutes dropwise. Below 10 , the reaction was stirred for more than 30min. The reaction solution was filtered under reduced pressure, residue was washed with diethyl ether twice to afford 6.5g (78percent yield) of Compound 2 as a pale yellow powder.
78%	at 10℃; for 1 h; Cooling with ice	The 10g4- chloro-7-methoxy-quinazolin-6-yl acetate (Compound 1) was placed in a 250mL three-necked roundBottom flask in an ice bath was added dropwise with stirring 100mL 7MNH3- methanol solution, drip completed within 30 minutes. 10 Hereinafter, the reaction mixture was stirred for more than 30min. The reaction solution was filtered under reduced pressure, residue was washed twice with ether, to give 6.5g(78percent yield) of compound 2 as a pale yellow powder.
78%	With ammonia In methanol at 10℃; for 1 h; Cooling with ice	The 10g4- chloro-7-methoxy-quinazolin-6-yl acetate (Compound 1) was placed in a 250mL three-necked round bottom flask in an ice bath was added dropwise with stirring 100mL7MNH_3-Methanol solution within 30 minutes after dropping below 10 , the reaction was stirred for more than 30min.The reaction solution was filtered under reduced pressure, residue was washed with diethyl ether twice to afford 6.5g (78percent yield) of Compound 2 as a pale yellow powder.
78%	at 10℃; for 1 h;	Chloro-7-methoxyquinazolin-6-yl acetate (Compound 1) was placed in a 250 mL three-necked round bottom flask, 100 mL of 7 M NH3-methanol solution was added dropwise with stirring under ice-30 minutes after the drop finished. Below 10 , the reaction was stirred for more than 30min. The reaction solution was filtered under reduced pressure, and the residue was washed twice with diethyl ether to give 6.5 g (yield 78percent) of Compound 2 as a pale yellow powder.
67.8%	With ammonia In methanol at 10℃; for 1 h;	Example 1 (4S)-4- ({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N- cyclopropyl-1-methyl-D-prolinamide Example 1 HATU (0.23g) was added to an agitated solution of (4Y)-4- ( {4- [ (3-CHLORO-2- fluorophenyl) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-1-METHYL-D-PROLINE (7) (0.18g), cyclopropylamine (34.4mg) and DIPEA (156mg) IN METHYLENE CHLORIDE (5M1). After 16hrs the reaction mixture was reduced in vacuo. The residues were re-dissolved in methylene chloride and washed with sodium hydroxide solution (2M) and water. The organic phase was then purified by column chromatography on silica eluting with increasingly polar mixtures of METHANOL/METHYLENE CHLORIDE (0/100-10/90). THE fractions containing the desired product were combined and evaporated to a foam which was triturated with diethylether to give the title compound as a white solid. (0. 15G). LH NMR Spectrum : (DMSO d6) 0.40-0. 48 (m, 2H), 0.57-0. 64 (M, 2H), 2.05-2. 14 (M, 1H), 2.28 (s, 3H), 2.33-2. 45 (M, 1H), 2.48-2. 56 (M, 1H + DMSO), 2. 61-2. 70 (M, 1H), 3.08 (t, 1H), 3.64 (dd, 1H), 3.94 (s, 3H), 5.06 (M, 1H), 7.20 (s, 1H), 7.28 (t, 1H), 7.44-7. 56 (M, 2H), 7.65 (s, 1H), 7.87 (d, 1H), 8.35 (s, 1H), 9.63 (s, 1H); Mass SPECTRUM : (M+H) + 486. 44 The starting material 1, 2-PYRROLIDINEDICARBOXYLIC acid, 4-hydroxy-, 1- (1, 1-DIMETHYLETHYL) 2- methyl ester, (2R, 4R) (2) was prepared as follows: 1- [3- (DIMETHYLAMINO) PROPYL]-3-ETLIYLCARBODIIMIDE hydrochloride (14.73 g) was added to a stirred suspension of 1, 2-PYRROLIDINEDICARBOXYLIC acid, 4-hydroxy-, l- (l, l-dimethylethyl) ester, (2R, 4R) (1) (13.65 g), DIMETHYLAMINOPYRIDINE (21.65 g) and methanol (5.67 g) in methylene chloride (400 ml) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with citric acid (1.0 M), saturated aqueous sodium bicarbonate solution and saturated brine, dried over MgSO4, filtered and evaporated. The residues were then purified by column chromatography on silica eluting with increasingly polar mixtures of METHANOL/METHYLENE chloride (1/99-5/95). The desired product fractions were combined and evaporated to give 1, 2-PYNOLIDINEDICARBOXYLIC acid, 4-hydroxy-, L- (L, L-DIMETHYLETHYL) 2- methyl ester, (2R, 4R) (2) as a white crystalline solid, (5.9 g). 1H NMR Spectrum : (DMSO d6) 1.32 + 1.38 (2s, 9H), 1.76-1. 87 (M, 1H), 2.24-2. 28 (M, 1H), 3.06-3. 15 (M, 1H), 3.42- 3. 51 (m, 1H), 3.60 + 3.63 (2s, 3H), 4.15-4. 24 (M, 2H), 4.92-5. 00 (M, 1H). Starting material 1, 2-Pyrrolidinedicarboxylic acid, 4-hydroxy-1- (1, 1-dimethylethyl) ester, (2R, 4R), (1), (Boc-D-cis-hyp-OH) is commercially available Starting material (3) was prepared as follows: 6-Acetoxy-4-chloro-7-methoxyquinazoline, (Example 25-5 of in W001/66099 ; 10. 0g, 39.6 MMOLE) was added in portions to a stirred 7N methanolic ammonia solution (220 ML) cooled to 10°C in an ice/water bath. After stirring for one hour the precipitate was filtered, washed with diethylether and dried thoroughly under high vacuum to give 4-chloro-7- METHOXYQUINAZOLIN-6-OL (3) (5.65g, 67.8percent) ; 1H NMR Spectrum : (DMSO d6) 3.96 (s, 3H); 7.25 (s, 1H); 7.31 (s, 1H); 8.68 (s, 1H) ; Mass Spectrum: (M+H) + 211. The starting material (4) was prepared as follows: Di-ethyl azodicarboxylate (5.71g) was added slowly to a stirred suspension of 1,2- PYNOLIDINEDICARBOXYLIC acid, 4-hydroxy-, L- (L, L-DIMETHYLETHYL) 2-methyl ester, (2R, 4R) (2) (5.9g), 4-CHLORO-7-METHOXYQUINAZOLIN-6-OL (3) (4.6g) AND TRIPHENYLPHOSPHINE (8.6g) in methylene chloride (400 ML) at 25°C under an atmosphere of nitrogen and the reaction mixture was stirred for 2 hours. The reaction mixture was then evaporated to 1/2 volume and purified by column chromatography on silica eluting with increasingly polar mixtures of METHANOL/METHYLENE chloride (1/99-3/97). The desired product fractions were combined and evaporated to give 1-tert-butyl 2-methyl (2R, 4S)-4-[(4-chloro-7-methoxyquinazolin-6- yl) oxy] pyrrolidine-1, 2-dicarboxylate (4) as a pale yellow gum. This was used in the preparation of (5) without further purification. The starting material methyl (4S)-4-({4-[(3-CHLORO-2-FLUOROPHENYL) AMINO]-7- METHOXYQUINAZOLIN-6-YL} OXY)-D-PROLINATE HYDROCHLORIDE (5) was prepared as follows: 4. 0M HCl in Dioxane (15 ml) was added to a suspension of 1-tert-butyl 2-methyl (2R, 4S)-4- [(4-chloro-7-methoxyquinazolin-6-yl0 oxy] pyrrolidine-1, 2-dicarboxylate (4) AND 3-CHLORO-2- fluoroaniline (2.89g) in acetonitrile (400 ML) and the reaction mixture was stirred and heated at 70°C for 3 hours. The resulting precipitate was filtered hot and washed with acetonitrile and diethylether and dried under vacuum to give methyl (4S)-4- (14- [ (3-CLILORO-2- FLUOROPHENYL) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-D-PROLINATE HYDROCHLORIDE (S) as an off- white solid, (6. 3G). TH NMR Spectrum : (DMSO D6) 2.46-2. 60 (M, 2H), 3.37-3. 46 (M, 1H), 3.71 (s, 3H), 3.89-3. 98 (m, 4H), 4.53 (t, 1H), 5.42 (M, 1H), 7.29 (t, 1H), 7.38-7. 48 (M, 2H), 7.55 (t, 1H), 8.64 (s, 1H), 8.75 (s, 1H), 12.28 (bs, 1H); Mass Spectrum : (M+H) + 446.96 Compound (6) was prepared as follows: Methyl (4S)-4-({4-[(3-CHLORO-2-FLUOROPHENYL) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-D- PROLINATE HYDROCLULORIDE (S) (6.3g), PARAFORMALDEHYDE (3.9g), sodium cyanoborohydride (3. 28G) and magnesium sulphate (3.13g) were suspended in methanol (50ml) and heated to 45°C for 4 hours under an atmosphere of nitrogen. The reaction mixture was filtered, evaporated and partitioned between ethylacetate and saturated aqueous sodium bicarbonate solution. The organics were then washed with saturated brine, dried over MGS04, filtered and evaporated. The residues were then purified by column chromatography on silica eluting with increasingly polar mixtures of methanol/methylene chloride (2-3percent) to give methyl (4S)-4-({4-[(3-CHLORO-2- FLUOROPHENYL) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-1-METHYL-D-PROLINATE (6) as a yellow foam, (4.19 G). LH NMR Spectrum: (DMSO d6) 2.14-2. 23 (M, 1H), 2.34 (s, 3H), 2.53-2. 60 (M, 2H), 3.36 (t, 1H), 3.61 (dd, 1H), 3.66 (s, 3H), 3.94 (s, 3H), 5.08 (M, 1H), 7.20 (s, 1H), 7.27 (t, 1H), 7.44-7. 54 (M, 2H), 7.68 (s, 1H), 8.36 (s, 1H), 9.62 (s, 1H); Mass Spectrum : (M+H) + 460.9 Compound (7) was prepared as follows: Sodium hydroxide 2M (7 ml) was added to a stirred solution of methyl (4S)-4-({4-[(3-CHLORO- 2-fluorophenyl) AMINO]-7-METHOXYQUINAZO] IN-6-YL} OXY)-1-METHYL-D-PROLINATE (4.18g) in methanol (20 ML) and THF (10 ML) at 25°C and the reaction mixture was stirred for 4 hours. The reaction mixture was evaporated and the residue re-dissolved in water. The pH of this solution was then adjusted to 6 by the dropwise addition OF 2M HC1 (AQ) to give (4S)-4- (F 4- [ (3-CHLORO-2-FLUOROPHENYL) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-1-METHYL-D-PROLINE (7) as a pale yellow solid which was filtered and washed with water and dried, (3.5 G). 1H NMR Spectrum : (DMSO d6) 2. 21-2. 31 (M, 1H), 2.35-2. 49 (M, 1H), 2.50 (s, 3H), 2.78 (dd, 1H), 3.42 (t, 1H), 3.77 (dd, 1H), 3.94 (s, 3H), 5.08 (M, 1H), 7.20 (s, 1H), 7.27 (t, 1H), 7.44-7. 54 (M, 2H), 7.74 (s, 1H), 8.37 (s, 1H), 9.75 (s, 1H) ; Mass Spectrum : (M+H) + 446. 9
67.8%	at 10℃; for 1 h;	6-Acetoxy-4-chloro-7-methoxyquinazoline, (Example 25-5 of in WO01/66099 ; 10. 0g, 39.6 mmole) was added in portions to a stirred 7N methanolic ammonia solution (220 ml) cooled to 10°C in an ice/water bath. After stirring for one hour the precipitate was filtered, washed with diethylether and dried thoroughly under high vacuum to give 4-chloro-6- hydroxy-7-methoxyquinazoline (5.65g, 67. 8percent) ; 1H NMR Spectrum : (DMSO d6) 3.96 (s, 3H); 7.25 (s, 1H); 7.31 (s, 1H); 8.68 (s, 1H) ; Mass Spectrum: (M+H) + 211
67.8%	at 10℃; for 1 h;	Example 1; 4- (3-CHLORO-2-FLUOROANILINO)-6- [1- (HYDROXYACETYL) PIPERIDIN-4-YLOXY]-7- methoxyquinazoline; HATU (28.9 g) was added to a stirred solution of 4- (3-chloro-2-fluoroanilino)-7- METHOXY-6- (PIPERIDIN-4-YLOXY) quinazoline dihydrochloride (30 g), glycolic acid (5.40 g) and di-isopropylethylamine (44.70 ml) in methylene chloride (900 ml). After 1.5 hours the reaction mixture was washed with sodium hydroxide solution (2M), water and saturated brine. The resulting product was then purified by flash chromatography on silica eluting with 3percent MeOH/methylene chloride. The fractions containing the desired product were combined and reduced in vacuo to give the title product as a white solid which was recrystallised from acetonitrile (29.6 g); NMR Spectrum : (DMSO d6) 1.65-1. 81 (m, 2H), 1.99-2. 10 (m, 2H), 3.26- 3.34 (m, 1H), 3.37-3. 47 (m, 1H), 3.60-3. 68 (m, 1H), 3.81-3. 89 (m, 1H), 3.95 (s, 3H), 4.14 (d, 2H), 4.50 (t, 1H), 4.78 (m, 1H), 7.25 (s, 1H), 7.30 (t, 1H), 7.46-7. 55 (m, 2H), 7.88 (s, 1H), 8.40 (s, 1H), 9.55 (s, 1H) ; Mass Spectrum: (M+H) + 460.94. THE 4- (3-CHLORO-2-FLUOROANILINO)-7-METHOXY-6- (PIPERIDIN-4-YLOXY) quinazoline dihydrochloride starting material was prepared as follows: 6-Acetoxy-4-chloro-7-methoxyquinazoline, (Example 25-5 in WO01/66099 ; 10. 0G, 39.6 mmole) was added in portions to a stirred 7N methanolic ammonia solution (220 ml) cooled to 10°C in an ice/water bath. After stirring for one hour the precipitate was filtered, washed with diethylether and dried thoroughly under high vacuum to give 4-chloro-6- hydroxy-7-methoxyquinazoline (5.65 g, 67.8 percent); NMR Spectrum: (DMSO d6) 3.96 (s, 3H); 7.25 (s, 1H); 7.31 (s, 1H); 8.68 (s, 1H); Mass Spectrum : (M+H) + 211 Di-tert-butylazodicarboxylate (9.22 g) in methylene chloride (20 ml) was added slowly to a stirred suspension of 4-chloro-6-hydroxy-7-methoxyquinazoline (5.63 g), 4-hydroxy-1- tert-butoxycarbonylpiperidine (8.06 g) and triphenylphosphine (10.5 g) in methylene chloride (100 ml) at 5°C under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature for 16 hours. The reaction mixture was then evaporated under vacuum and adsorbed onto silica and the product was eluted with isohexane/ethyl acetate/triethylamine (75/24/1 followed by 70/29/1). The fractions containing the desired product were combined and evaporated under vacuum to give tert-butyl 4- [ (4-CHLORO-7-METHOXYQUINAZOLIN-6- yl) oxy] piperidine-l-carboxylate as a white solid (10.3 g) ; IH NMR SPECTRUM : (DMSO d6) 1.40 (s, 9H), 1.56-1. 69 (m, 2H), 1.93-2. 04 (m, 2H), 3.20-3. 31 (m, 2H), 3.60-3. 70 (m, 2H), 4.00 (s, 3H), 4. 89 (m, 1H), 7.45 (s, 1H), 7.50 (s, 1H), 8.86 (s, 1H) ; Mass Spectrum : (M+H) + 394. 4. 0M HC1 in Dioxane (4.0 ml) was added to a suspension of tert-butyl 4- [ (4-chloro-7- methoxyquinazolin-6-yl) oxy] PIPERIDINE-1-CARBOXYLATE (2.62 g) and 3-chloro-2-fluoroaniline (1.08 g) in iso-propanol (50 ml). The reaction mixture was stirred and heated at 100°C for 2 hours. The yellow precipitate was filtered hot and washed with iso-propanol followed by diethylether and dried under vacuum to give 6- (PIPERIDIN-4-YLOXY)-4- (3-CHLORO-2- fluoroanilino) -7-methoxyquinazoline as a di-hydrochloride salt (2.38 g) ; 1H NMR SPECTRUM (DMSO D6) 1.84-1. 99 (m, 2H), 2.22-2. 33 (m, 2H), 3.12-3. 33 (m, 4H), 4.00 (s, 3H), 5. 08 (m, 1H), 7.34 (t, 1H), 7.40 (s, 1H), 7.50 (t, 1H), 7.62 (t, 1H), 8.80 (s, 1H), 8. 84-8. 94 (m, 2H), 8.99-9. 11 (m, 1H); Mass Spectrum: (M+H) + 403.
58%	With ammonia; water In 1,4-dioxane at 0 - 20℃;	Step 6. Product step 5 (8.54 mmol) was converted into 4-chloro-7-hydroxy-6-methoxyquinazoline or 4-chloro-6-hydroxy-7-methoxyquinazoline, respectively, (58-95percent) by reacting them with thionyl chloride (12 mL) and DMF (0.3 mL) at 85° C. for 1.5 h. Excess thionyl chloride was removed by distillation. Traces of thionyl chloride were removed by aceotropic distillation wit toluene (two times). Alternatively the products step 5 can be converted into the chlorides by reacting them with a mixture of POCl₃and PCl₅. The acetyl groups were removed by hydrolysis with ammonium hydroxide (5 mL, 28-30 wt percent) in dioxane/water (100 mL/20 mL) at 0° C. to r.t.

Reference： [1] Patent: WO2005/26151, 2005, A1, . Location in patent: Page/Page column 124
[2] European Journal of Medicinal Chemistry, 2018, vol. 147, p. 130 - 149
[3] Patent: CN106986895, 2017, A, . Location in patent: Paragraph 0072; 0073; 0074; 0075; 0076
[4] Patent: CN105384699, 2016, A, . Location in patent: Paragraph 0032; 0033
[5] Patent: CN105418517, 2016, A, . Location in patent: Paragraph 0026; 0030; 0031
[6] Patent: CN105503747, 2016, A, . Location in patent: Paragraph 0032; 0033
[7] Patent: CN105461642, 2016, A, . Location in patent: Paragraph 0028; 0029
[8] Patent: CN105399689, 2016, A, . Location in patent: Paragraph 0029; 0030
[9] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 8, p. 742 - 746
[10] Patent: WO2005/30757, 2005, A1, . Location in patent: Page/Page column 102-105
[11] Patent: WO2003/82831, 2003, A1, . Location in patent: Page/Page column 109
[12] Patent: WO2005/12290, 2005, A1, . Location in patent: Page/Page column 36-37
[13] Patent: US2007/149523, 2007, A1, . Location in patent: Page/Page column 13-14
[14] Patent: EP1785420, 2007, A1, . Location in patent: Page/Page column 18-19
[15] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 18, p. 6728 - 6737

2
[ 179688-53-0 ]
[ 574745-97-4 ]

Reference： [1] Patent: WO2004/41829, 2004, A1, . Location in patent: Page 88
[2] Patent: CN105384699, 2016, A,
[3] Patent: CN105418517, 2016, A,
[4] Patent: CN105503747, 2016, A,
[5] Patent: CN105461642, 2016, A,
[6] Patent: CN105399689, 2016, A,
[7] European Journal of Medicinal Chemistry, 2018, vol. 147, p. 130 - 149
[8] Patent: US2007/149523, 2007, A1,
[9] Patent: WO2008/150118, 2008, A2,

3
[ 1276184-25-8 ]
[ 574745-97-4 ]
[ 1276184-26-9 ]

Yield	Reaction Conditions	Operation in experiment
35%	With tetrachloromethane; triphenylphosphine In 1,2-dichloro-ethane at 80℃;	Compound 12 was obtained using the same procedure as for 11. Depropargylated 4-chloro-6-hydroxy-7-methoxy quinazoline (0.032g, 0.15 mmol, 25percent) was eluted first, followed by 12 (0.059g, 0.22 mmol, 35percent). The product was recrystallized from iso-propanol to give colorless needles. Mp 196-198 °C, ¹H-NMR (CDCl₃): 8.920 (s, 1H, C₂-H); 8.622 (s, 1H, C₅-H); 7.344 (s, 1H, C₈-H); 4.963 (d, 2H, J = 2.5 Hz); 4.054 (s, 3H); 2.604 (t, 1H, J= 2.5 Hz).

Reference： [1] Tetrahedron Letters, 2011, vol. 52, # 10, p. 1053 - 1056

4
[ 179688-52-9 ]
[ 574745-97-4 ]

Reference： [1] Patent: CN105399688, 2016, A, . Location in patent: Paragraph 0038
[2] Patent: US2007/149523, 2007, A1,
[3] Patent: WO2008/150118, 2008, A2,

5
[ 6702-50-7 ]
[ 574745-97-4 ]

Reference： [1] Tetrahedron Letters, 2011, vol. 52, # 10, p. 1053 - 1056
[2] Patent: US2007/149523, 2007, A1,

6
[ 164161-49-3 ]
[ 574745-97-4 ]

Reference： [1] Patent: US2007/149523, 2007, A1,

7
[ 57535-57-6 ]
[ 574745-97-4 ]

Reference： [1] Patent: US2007/149523, 2007, A1,

8
[ 1276184-22-5 ]
[ 574745-97-4 ]

Reference： [1] Tetrahedron Letters, 2011, vol. 52, # 10, p. 1053 - 1056

9
[ 1276184-23-6 ]
[ 574745-97-4 ]

Reference： [1] Tetrahedron Letters, 2011, vol. 52, # 10, p. 1053 - 1056

10
[ 1276184-24-7 ]
[ 574745-97-4 ]

Reference： [1] Tetrahedron Letters, 2011, vol. 52, # 10, p. 1053 - 1056

11
[ 13794-72-4 ]
[ 574745-97-4 ]

Reference： [1] European Journal of Medicinal Chemistry, 2018, vol. 147, p. 130 - 149
[2] Patent: WO2008/150118, 2008, A2,

12
[ 179688-53-0 ]
[ 574745-97-4 ]

Reference： [1] Patent: CN106986895, 2017, A,

13
[ 13790-39-1 ]
[ 574745-97-4 ]

Reference： [1] European Journal of Medicinal Chemistry, 2018, vol. 147, p. 130 - 149

14
[ 50413-44-0 ]
[ 574745-97-4 ]

Reference： [1] Patent: US2007/149523, 2007, A1,

15
[ 5653-40-7 ]
[ 574745-97-4 ]

Reference： [1] Patent: WO2008/150118, 2008, A2,

[ 574745-97-4 ] Synthesis Path-Downstream 1~102

1
[ 574745-97-4 ]
[ 69610-40-8 ]
4-chloro-7-methoxy-6-[(2S)-1-tert-butoxycarbonylpyrrolidin-2-yl]methoxy}quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In dichloromethane; at 0 - 10℃; for 3h;	The 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{ [(2S)-pyrrolidin-2- yl] methoxy} quinazoline hydrochloride starting material was prepared as described below: 4-Chloro-6-hydroxy-7-methoxyquinazoline (prepared as described in the preparation of starting materials for Example 16; 2.75g, 13 mmol) was mixed with triphenylphosphine (5.13g, 19.6 mmole) and (2S)-l-tert-butoxycarbonyl)-2- (hydroxymethyl) pyrrolidine (3.94g, 19.6 mmole). Methylene chloride (85ml) was added and the mixture cooled under nitrogen in an ice/water bath. Di-tert-butyl azodicarboxylate (4. 51g, 19.6 mmole) was dissolved in methylene chloride (35ml) and added dropwise such that the internal temperature remained less than 10C. Once the addition was complete the cooling bath was removed and the reaction mixture stirred for 3 hours. The solvent was removed under vacuum and the residue purified by column chromatography eluting with methylene chloride/ethyl acetate (saturated with ammonia) (70/30) to give 4-chloro-7-methoxy-6-{ [(2S)-l-tert-butoxycarbonylpyrrolidin- 2-yl] methoxy} quinazoline as a gum (6.15g) ; Mass Spectrum : (M+H) + 394.

Reference： [1]Patent: WO2003/82831,2003,A1 .Location in patent: Page/Page column 127

2
[ 574745-97-4 ]
[ 85275-45-2 ]
[ 612501-69-6 ]

Yield	Reaction Conditions	Operation in experiment
53%	With triphenylphosphine; diethylazodicarboxylate; In dichloromethane; toluene; at 20 - 40℃;	The4-chloro-7-methoxy-6-[1- (tert-butoxycarbonyl) piperidin-3-yloxy) ] quinazoline starting material was prepared as follows: Diethyl azodicarboxylate (9. 41ml, 40% solution in toluene) was added to a mixture of <strong>[574745-97-4]4-chloro-6-hydroxy-7-methoxyquinazoline</strong> (2.90g ; prepared as described in Example 16- preparation of starting materials), triphenylphosphine (5.43g) and tert-butoxycarbonyl-3- hydroxypiperidine (4.15g) in dichloromethane (75ml). The resulting solution was heated to 40C for 6 hours, and then allowed to stand overnight at room temperature. This was purified by flash column chromatography eluting with isohexane (79%), acetone (20%), and triethylamine (1%) to give 4-chloro-7-methoxy-6- [l- tert-butoxycarbonyl) piperidin-3- yloxy] quinazoline as a white solid (2.47g, 53%) ; 1H NMR Spectrum : (CDC13) 1. 5 (m, 9H) ; 1.6 (m, 1H); 1.9 (m, 2H) ; 2.1 (m, 1H); 3.5 (m, 1H); 3.6 (m, 1H); 4.0 (s, 3H); 4.2-3. 9 (m, 2H) ; 4.5 (m, 1H); 7.3 (s, 1H) ; 7.4 (s, 1H); 8.9 (s, lH) ; Mass Spectrum : (M+H) : 394.

Reference： [1]Patent: WO2003/82831,2003,A1 .Location in patent: Page/Page column 138
[2]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 742 - 746

3
[ 574745-97-4 ]
[ 143900-43-0 ]
[ 612501-77-6 ]

Yield	Reaction Conditions	Operation in experiment
48%	With triphenylphosphine; diethylazodicarboxylate; In dichloromethane; at 20℃;	The 4-chloro-7-methoxy-6-[(3S)-l-(t-butoxycarbonyl) piperidin-3-yloxy] quinazoline starting material was prepared as follows: Diethyl azodicarboxylate (2. 76ml, 40% solution in toluene) was added to 4-chloro-6- hydroxy-7-methoxyquinazoline (0.89g ; prepared as described in Example 16), triphenylphosphine (1.66g) and (3R)-l-tert-butoxycarbonyl)-3-hydroxypiperidine (CAS Registry No 143900-43-0) (1.28g) in dichloromethane (25ml). The resulting solution was allowed to stir overnight at room temperature. This was purified by flash column chromatography eluting with an increasingly polar mixture of acetone/isohexane/triethylamine (79/20/1 to 64/35/1) to give 4-chloro-7-methoxy-6- [ (3S)-l- (tert-butoxycarbonyl) piperidin-3-yloxy) ] quinazoline as a white solid (0.794g, 48%) ; Mass Spectrum : (M+H) + 394.

Reference： [1]Patent: WO2003/82831,2003,A1 .Location in patent: Page/Page column 145

4
[ 574745-97-4 ]
[ 107-07-3 ]
[ 692059-26-0 ]

Yield	Reaction Conditions	Operation in experiment
	With 2,2'-azobis(isobutyronitrile); triphenylphosphine; In dichloromethane; at 20℃; for 2h;	Di-tert-butyl azodicarboxylate (1.53 ml) was added portionwise over a few minutes to a stirred mixture of <strong>[574745-97-4]4-chloro-6-hydroxy-7-methoxyquinazoline</strong> (1 g), 2-chloroethanol (0.382 ml), triphenylphosphine (1.74 g) and methylene chloride (30 ml) and the reaction mixture was stirred at ambient temperature for 2 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained 4-chloro- 6- (2-chloroethoxy)-7-methoxyquinazoline as a white solid (1.06 g); NMR Spectrum : (CDC13) 3.95 (t, 2H), 4.05 (s, 3H), 4.45 (t, 2H), 7.35 (s, 1H), 7.4 (s, 1H), 8.9 (s, 1H)

Reference： [1]Patent: WO2004/41829,2004,A1 .Location in patent: Page 88

5
[ 179688-53-0 ]
[ 574745-97-4 ]

Yield	Reaction Conditions	Operation in experiment
		A mixture OF 6-ACETOXY-7-METHOXY-3, 4-dihydroquinazolin-4-one (International Patent Application WO 96/15118, Example 39 thereof; 8 g), thionyl chloride (80 ml) and DMF (0.8 ml) was stirred and heated to 80C for 1.5 hours. The mixture was cooled to ambient temperature and the thionyl chloride was evaporated. The material so obtained was suspended in toluene and evaporated to dryness (twice). The resultant residue was diluted with methylene chloride (5 ml) and a 10: 1 mixture (290 ml) of methanol and a saturated aqueous ammonium hydroxide solution was added. The resultant mixture was stirred and heated to 80C for 5 minutes. The solvent was evaporated and the solid residue was suspended in water. The basicity of the mixture was adjusted to pH7 by the addition of dilute aqueous hydrochloric acid solution. The resultant solid was collected by filtration, washed with water and dried under vacuum over phosphorus pentoxide. There was thus obtained 4-chloro-6-hydroxy-7-methoxyquinazoline (6.08 g) which was used without further purification; NMR Spectrum: (DMSOD6) 4.05 (s, 3H), 7.4 (s, 1H), 7.45 (s, 1H), 8.8 (s, 1H)

Reference： [1]Patent: WO2004/41829,2004,A1 .Location in patent: Page 88
[2]Patent: CN105384699,2016,A
[3]Patent: CN105418517,2016,A
[4]Patent: CN105503747,2016,A
[5]Patent: CN105461642,2016,A
[6]Patent: CN105399689,2016,A
[7]European Journal of Medicinal Chemistry,2018,vol. 147,p. 130 - 149
[8]Patent: US2007/149523,2007,A1
[9]Patent: WO2008/150118,2008,A2
[10]Journal of Medicinal Chemistry,2019,vol. 62,p. 2099 - 2111

6
[ 574745-97-4 ]
[ 627-30-5 ]
[ 692059-41-9 ]

Yield	Reaction Conditions	Operation in experiment
	With 2,2'-azobis(isobutyronitrile); triphenylphosphine; In dichloromethane; at 20℃; for 3h;	Di-tert-butyl azodicarboxylate (1.84 g) was added portionwise over a few minutes to a stirred mixture of <strong>[574745-97-4]4-chloro-6-hydroxy-7-methoxyquinazoline</strong> (1.2 g), 3-chloropropanol (0.572 ml), triphenylphosphine (2.1 g) and methylene chloride (30 ml) and the reaction mixture was stirred at ambient temperature for 3 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. The material so obtained was triturated under diethyl ether. The resultant solid was isolated and dried under vacuum. There was thus obtained 4-CHLORO-6- (3-CHLOROPROPOXY)-7-METHOXYQUINAZOLINE as a white solid (0.84 g); NMR Spectrum: (CDCl3) 2.4 (m, 2H), 3.8 (t, 2H), 4.05 (s, 3H), 4.35 (t, 2H), 7.35 (s, 1H), 7.45 (s, 1H), 8.9 (s, 1H)

Reference： [1]Patent: WO2004/41829,2004,A1 .Location in patent: Page 88-89

7
[ 622-40-2 ]
[ 574745-97-4 ]
4-chloro-7-methoxy-6-(2-morpholin-4-yl-ethoxy)-quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In dichloromethane; at 20℃; for 2h;	a) Di-tert-butyl azodicarboxylate (1.44g, 6. 26mmol) was added portionwise at room temperature to a stirred suspension of <strong>[574745-97-4]4-chloro-7-methoxyquinazolin-6-ol</strong> (1.20 g, 5.70 mmol), 2-morpholin-4-ylethanol (0.82 g, 6.2 6mmol) and triphenylphosphine (1.8 g, 6.87 mmol) in dichloromethane (25 ml). The reaction mixture was stirred for 2 hour and then the resulting orange solution was purified directly by silica gel chromatography eluting with a mixture of 3% methanol in dichloromethane and then purified further by chromatography on neutral alumina eluting with a 3% mixture of methanol in dichloromethane to give 4-chloro-7- METHOXY-6- (2-MORPHOLIN-4-YLETHOXY) quinazoline (1.40 g, 76% yield) as a pale yellow solid: 1H-NMR (CDC13) : 8.86 (s, 1H), 7.42 (s, 1H), 7.33 (s, 1H), 4.34 (t, 2H), 4.04 (s, 3H), 3.75 (m, 4H), 2.94 (t, 2H), 2.64 (m, 4H).

Reference： [1]Patent: WO2004/94410,2004,A1 .Location in patent: Page 238

8
[ 13220-33-2 ]
[ 574745-97-4 ]
4-chloro-7-methoxy-6-[(1-methylpyrrolidin-3-yl)oxy]quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%	With triphenylphosphine; diethylazodicarboxylate; In dichloromethane; at 20℃; for 2h;	a) Diethyl azodicarboxylate (793 mg, 4.56 mmol) was added portionwise at room temperature to a stirred suspension of <strong>[574745-97-4]4-chloro-7-methoxyquinazolin-6-ol</strong> (800 mg, 3.80 mmol), 1-methylpyrrolidin-3-ol (422 mg, 4.18 mmol) and triphenylphosphine (1.3 g, 4.96 mmol) in dichloromethane (16 ml). The reaction mixture was stirred for LHOUR and then a further portion of diethyl azodicarboxylate (360 ul) and triphenylphosphine (0.65 mg) were added. The mixture was stirred for LHOUR and the resulting orange solution was purified directly by silica gel chromatography eluting with a 0-10percent mixture of methanol in dichloromethane to 4-CHLORO-7-METHOXY-6- [ (1-METHYLPYRROLIDIN-3-YL) oxy] quinazoline (330 mg, 28percent yield) as a tan coloured solid: 1H-NMR (DMSO d6) : 8. 87 (s, 1H), 7.45 (s, 1H), 7.30 (s, 1H), 5.14 (m, 1H), 4.01 (S, 3H), 2.80 (m, 3H), 2.40 (m, 2H), 2.29 (s, 3H), 1.88 (m, 1H) ; MS (+ve ESI): 294 (M+H) +.

Reference： [1]Patent: WO2004/94410,2004,A1 .Location in patent: Page 237

9
[ 574745-97-4 ]
[ 786681-59-2 ]
N-(3-fluorophenyl)-2-{4-[(6-hydroxy-7-methoxyquinazolin-4-yl)amino]-1H-pyrazol-1-yl}acetamide hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	In ISOPROPYLAMIDE; at 90 - 120℃; for 5h;	A solution of <strong>[574745-97-4]4-chloro-7-methoxyquinazolin-6-ol</strong> (see W003/064413, 0.119 g, 0.57 mmol) and 2-(4-AMINO-LH-PYRAZOL-L-YL)-N-(3-FLUOROPHENYL) acetamide (0.132 g, 0.56 mmol) in dimethylacetamide (5 ml) was heated at 90C for 2 hours and then at 120C for 3 hours. The mixture was cooled to room temperature and diluted with diethyl ether (25 ml) and then filtered to yield compound 233 in table 9 as the hydrochloride salt (0.119 g, 48% yield) as a yellow solid. H-NMR (DMSO D6) : 11.27 (br s, 1H), 10.74 (br s, 1H), 8. 86 (s, 1H), 8.36 (s, 1H), 8. 00 (s, 1H), 7.95 (s, 1H), 7.58 (m, 1H), 7.34 (m, 3H), 6.93 (m, 1H), 5.12 (s, 2H), 4.01 (s, 3H); MS (+ve ESI) : 409 (M+H) +.

Reference： [1]Patent: WO2004/94410,2004,A1 .Location in patent: Page 239

10
[ 4441-30-9 ]
[ 574745-97-4 ]
[ 199327-59-8 ]

Yield	Reaction Conditions	Operation in experiment
67%	With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In dichloromethane; for 2h;	a) DI-TERT-BUTYL azodicarboxylate (1.44 g, 6.26 mmol) was added portionwise at room temperature to a stirred suspension of <strong>[574745-97-4]4-chloro-7-methoxyquinazolin-6-ol</strong> (1.20 g, 5.70 mmol), 3-MORPHOLIN-4-YLPROPAN-1-OL (0.91 g, 6.27 mmol) and triphenylphosphine (1.8 g, 6. 87 mmol) in dichloromethane (25 ml). The reaction mixture was stirred for 2 hours and then the resulting orange solution was purified directly by silica gel chromatography eluting with a mixture of 5% methanol in dichloromethane to give 4-CHLORO-7-METHOXY-6- (3-MORPHOLIN-4- ylpropoxy) quinazoline (1. 28 g, 67% yield) as a pale yellow solid: 1H-NMR (CDC13) : 8. 86 (s, 1H), 7.40 (s, 1H), 7.31 (s, 1H), 4.28 (t, 2H), 4.05 (s, 3H), 3.73 (m, 4H), 2.60 (t, 2H), 2.50 (m, 4H), 2.13 (quintet, 2H); MS (+ve ESI) : 338 (M+H) +.

Reference： [1]Patent: WO2004/94410,2004,A1 .Location in patent: Page 236

11
[ 574745-97-4 ]
[ 114676-69-6 ]
1-tert-butyl 2-methyl (2R,4S)-4-[(4-chloro-7-methoxyquinazolin-6-yl)oxy]pyrrolidine-1,2-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triphenylphosphine; diethylazodicarboxylate; In dichloromethane; at 25℃; for 2h;	Example 1 (4S)-4- ({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N- cyclopropyl-1-methyl-D-prolinamide Example 1 HATU (0.23g) was added to an agitated solution of (4Y)-4- ( {4- [ (3-CHLORO-2- fluorophenyl) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-1-METHYL-D-PROLINE (7) (0.18g), cyclopropylamine (34.4mg) and DIPEA (156mg) IN METHYLENE CHLORIDE (5M1). After 16hrs the reaction mixture was reduced in vacuo. The residues were re-dissolved in methylene chloride and washed with sodium hydroxide solution (2M) and water. The organic phase was then purified by column chromatography on silica eluting with increasingly polar mixtures of METHANOL/METHYLENE CHLORIDE (0/100-10/90). THE fractions containing the desired product were combined and evaporated to a foam which was triturated with diethylether to give the title compound as a white solid. (0. 15G). LH NMR Spectrum : (DMSO d6) 0.40-0. 48 (m, 2H), 0.57-0. 64 (M, 2H), 2.05-2. 14 (M, 1H), 2.28 (s, 3H), 2.33-2. 45 (M, 1H), 2.48-2. 56 (M, 1H + DMSO), 2. 61-2. 70 (M, 1H), 3.08 (t, 1H), 3.64 (dd, 1H), 3.94 (s, 3H), 5.06 (M, 1H), 7.20 (s, 1H), 7.28 (t, 1H), 7.44-7. 56 (M, 2H), 7.65 (s, 1H), 7.87 (d, 1H), 8.35 (s, 1H), 9.63 (s, 1H); Mass SPECTRUM : (M+H) + 486. 44 The starting material 1, 2-PYRROLIDINEDICARBOXYLIC acid, 4-hydroxy-, 1- (1, 1-DIMETHYLETHYL) 2- methyl ester, (2R, 4R) (2) was prepared as follows: 1- [3- (DIMETHYLAMINO) PROPYL]-3-ETLIYLCARBODIIMIDE hydrochloride (14.73 g) was added to a stirred suspension of 1, 2-PYRROLIDINEDICARBOXYLIC acid, 4-hydroxy-, l- (l, l-dimethylethyl) ester, (2R, 4R) (1) (13.65 g), DIMETHYLAMINOPYRIDINE (21.65 g) and methanol (5.67 g) in methylene chloride (400 ml) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with citric acid (1.0 M), saturated aqueous sodium bicarbonate solution and saturated brine, dried over MgSO4, filtered and evaporated. The residues were then purified by column chromatography on silica eluting with increasingly polar mixtures of METHANOL/METHYLENE chloride (1/99-5/95). The desired product fractions were combined and evaporated to give 1, 2-PYNOLIDINEDICARBOXYLIC acid, 4-hydroxy-, L- (L, L-DIMETHYLETHYL) 2- methyl ester, (2R, 4R) (2) as a white crystalline solid, (5.9 g). 1H NMR Spectrum : (DMSO d6) 1.32 + 1.38 (2s, 9H), 1.76-1. 87 (M, 1H), 2.24-2. 28 (M, 1H), 3.06-3. 15 (M, 1H), 3.42- 3. 51 (m, 1H), 3.60 + 3.63 (2s, 3H), 4.15-4. 24 (M, 2H), 4.92-5. 00 (M, 1H). Starting material 1, 2-Pyrrolidinedicarboxylic acid, 4-hydroxy-1- (1, 1-dimethylethyl) ester, (2R, 4R), (1), (Boc-D-cis-hyp-OH) is commercially available Starting material (3) was prepared as follows: 6-Acetoxy-4-chloro-7-methoxyquinazoline, (Example 25-5 of in W001/66099 ; 10. 0g, 39.6 MMOLE) was added in portions to a stirred 7N methanolic ammonia solution (220 ML) cooled to 10C in an ice/water bath. After stirring for one hour the precipitate was filtered, washed with diethylether and dried thoroughly under high vacuum to give 4-chloro-7- METHOXYQUINAZOLIN-6-OL (3) (5.65g, 67.8%) ; 1H NMR Spectrum : (DMSO d6) 3.96 (s, 3H); 7.25 (s, 1H); 7.31 (s, 1H); 8.68 (s, 1H) ; Mass Spectrum: (M+H) + 211. The starting material (4) was prepared as follows: Di-ethyl azodicarboxylate (5.71g) was added slowly to a stirred suspension of 1,2- PYNOLIDINEDICARBOXYLIC acid, 4-hydroxy-, L- (L, L-DIMETHYLETHYL) 2-methyl ester, (2R, 4R) (2) (5.9g), 4-CHLORO-7-METHOXYQUINAZOLIN-6-OL (3) (4.6g) AND TRIPHENYLPHOSPHINE (8.6g) in methylene chloride (400 ML) at 25C under an atmosphere of nitrogen and the reaction mixture was stirred for 2 hours. The reaction mixture was then evaporated to ½ volume and purified by column chromatography on silica eluting with increasingly polar mixtures of METHANOL/METHYLENE chloride (1/99-3/97). The desired product fractions were combined and evaporated to give 1-tert-butyl 2-methyl (2R, 4S)-4-[(4-chloro-7-methoxyquinazolin-6- yl) oxy] pyrrolidine-1, 2-dicarboxylate (4) as a pale yellow gum. This was used in the preparation of (5) without further purification. The starting material methyl (4S)-4-({4-[(3-CHLORO-2-FLUOROPHENYL) AMINO]-7- METHOXYQUINAZOLIN-6-YL} OXY)-D-PROLINATE HYDROCHLORIDE (5) was prepared as follows: 4. 0M HCl in Dioxane (15 ml) was added to a suspension of 1-tert-butyl 2-methyl (2R, 4S)-4- [(4-chloro-7-methoxyquinazolin-6-yl0 oxy] pyrrolidine-1, 2-dicarboxylate (4) AND 3-CHLORO-2- fluoroaniline (2.89g) in acetonitrile (400 ML) and the reaction mixture was stirred and heated at 70C for 3 hours. The resulting precipitate was filtered hot and washed with acetonitrile and diethylether and dried under vacuum to give methyl (4S)-4- (14- [ (3-CLILORO-2- FLUOROPHENYL) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-D-PROLINATE HYDROCHLORIDE (S) as an off- white solid, (6. 3G). TH NMR Spectrum : (DMSO D6) 2.46-2. 60 (M, 2H), 3.37-3. 46 (M, 1H), 3.71 (s, 3H), 3.89-3. 98 (m, 4H), 4.53 (t, 1H), 5.42 (M, 1H), 7.29 (t, 1H), 7.38-7. 48 (M, 2H), 7.55 (t, 1H), 8.64 (s, 1H), 8.75 (s, 1H)...

Reference： [1]Patent: WO2005/30757,2005,A1 .Location in patent: Page/Page column 102-105

12
[ 574745-97-4 ]
[ 74844-91-0 ]
[ 849345-89-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triphenylphosphine; diethylazodicarboxylate; In dichloromethane; at 25℃; for 1h;	Example 12 (4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-1-methyl-N- PROP-2-VN-1-VL-L-PROLINAMIDE Example 12 HATU (0.34g) was added to an agitated solution of (4R)-4-({4-[(3-CHLORO-2- fluorophenyl) amino]-7-methoxyquinazolin-6-yl} oxy)-1-methyl-L-proline (0.2g), propargylamine (49.3mg) and DIPEA (231mg) in DIMETHYLACETAMIDE (10ML). THE MIXTURE was stirred at 50C for 10 minutes then allowed to stand at room temperature overnight. The reaction mixture was reduced in vacuo. The residues were re-dissolved in methylene chloride and washed with sodium hydroxide solution (2M) and water. The organic phase was then purified by column chromatography on silica eluting with increasingly polar mixtures of METHANOL/METHYLENE chloride (0/100-12/88). The fractions containing the desired product were combined and evaporated to a foam which was triturated with diethylether to give the title compound as a white solid. (0. 067G). LH NMR Spectrum (DMSO D6) 2.08-2. 22 (M, 1H), 2.25-2. 62 (M, 2H + DMSO), 2.31 (s, 3H), 3.06 (s, 1H), 3.15 (t, 1H), 3.62-3. 72 (M, 1H), 3.78-4. 02 (M, 2H), 3.93 (s, 3H), 5.06 (M, 1H), 7.16-7. 32 (M, 1H), 7.21 (s, 1H), 7.43- 7.56 (M, 2H), 7.67 (s, 1H), 8.28 (M, 1H), 8.36 (s, 1H), 9.63 (s, 1H); Mass Spectrum : (M+H) + 484. The starting material was prepared as follows: 1-TERT-BUTYL 2-methyl (2S, 4S)-4-HYDROXYPYRROLIDINE-1, 2-dicarboxylate (1), (Boc-cis- Hyp-OMe) is commercially available. Di-ethyl azodicarboxylate (12.4g) was added slowly to a stirred suspension of 1-TEST- butyl 2-methyl (2S, 4S)-4-HYDROXYPYRROLIDINE-1, 2-dicarboxylate (1) (17.46g), 4-chloro-7- methoxyquinazolin-6-ol (2) (10g) [prepared as described in Example 1 above (compound 3)] and TRIPHENYLPHOSPHINE (L8. 67G) INMETHYLENE chloride (300 ML) at 25C under an atmosphere of nitrogen and the reaction mixture was stirred for 1 hours. The reaction mixture was then evaporated to ½ volume and purified by column chromatography on silica eluting with increasingly polar mixtures of METHANOL/METHYLENE chloride (0/100-3.5/96. 5). The desired product fractions were combined and evaporated to give 1-TERT-BUTYL 2-methyl (2S, 4R)-4- [ (4- CHLORO-7-METHOXYQUINAZOLIN-6-YL) oxy] pyrrolidine-1, 2-dicarboxylate (3) as a pale yellow foam Mass Spectrum : (M+H) + 438. This was used in the preparation of (4) without further purification. The starting material (4) was prepared as follows: 4. 0M HCl in Dioxane (39.2 ML) was added to a suspension of 1-tert-butyl 2-methyl (2S, 4R)-4- [ (4-chloro-7-methoxyquinazolin-6-yl) oxy] pyrrolidine-1, 2-dicarboxylate (3) and 3- CHLORO-2-FLUOROANILINE (7.61g) in acetonitrile (300 ML) and the reaction mixture was stirred and heated at 50C for 1 hours. The resulting precipitate was filtered hot and washed with acetonitrile and diethylether and dried under vacuum to give methyl (4R)-4-({4-[(3-CHLORO-2- fluorophenyl) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-L-PROLINATE HYDROCHLORIDE (4) as an off- white solid, (23. 05G). 1H NMR Spectrum : (DMSO D6) 2.46-2. 74 (M, 2H), 3.24-3. 68 (m, 1H), 3.78 (s, 3H), 3.95-4. 07 (M, 1H), 4.00 (s, 3H), 4.61 (t, 1H), 5.50 (M, 1H), 7.35 (t, 1H), 7.47-7. 57 (M, 1H), 7.49 (s, 1H), 7.63 (t, 1H), 8.73 (s, 1H), 8.83 (s, 1H), 12.38 (bs, LH)-, MASS SPECTRUM : (M+H) + 447. Methyl (4R)-4-({4-[(3-CLZLORO-2-FLUOROPHENYL) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)- L-PROLINATE HYDROCHLORIDE (4) (22.9g), paraformaldehyde (14.25g), sodium cyanoborohydride (11.97g) and magnesium sulphate (11.4g) were suspended in methanol (600ML) and heated at 45C for 3 hours under an atmosphere of nitrogen. The reaction mixture was filtered, evaporated and partitioned between ethylacetate and saturated aqueous sodium bicarbonate solution. The organics were then washed with saturated brine, dried over MgS04, filtered and evaporated. The residues were then purified by column chromatography on silica eluting with increasingly polar mixtures of methanol/methylene chloride (0/100-10/90) to give methyl (4R)- 4-({4-[(3-CHLORO-2-FLUOROPHENYL) AMINO] -7-METHOXYQUINAZOLIN-6-YL} OXY)-L-METHYL-L-PROLINATE (5) as a yellow solid, (14. 87 G). LH NMR SPECTRUM : (DMSO d6) 2.13-2. 25 (M, 1H), 2.34 (s, 3H), 2.46-2. 61 (M, 2H + DMSO), 3.37 (t, 1H), 3.57-3. 69 (M, 1H), 3.66 (s, 3H), 3.93 (s, 3H), 5.08 (M, 1H), 7.21 (s, 1H), 7.23-7. 31 (t, 1H), 7.43-7. 58 (M, 2H), 7.69 (s, 1H), 8.37 (s, 1H), 9.62 (s, 1H) ; Mass Spectrum : (M+H) + 461. Sodium hydroxide 2M (24.2 ml) was added to a stirred solution of methyl (4R)-4- ( {4- [(3-CHLORO-2-FLUOROPHENYL) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-1-METHYL-L-PROLINATE (5) (14.87g) in methanol (100 ml) at 25C and the reaction mixture was stirred for 1 hour. The reaction mixture was evaporated and the residue re-dissolved in water. The pH of this solution was then adjusted to 6 by the dropwise addition of 2M HCl (aq) to give (4R0-4-({4-[(3-chloro- 2-fluorophenyl) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-L-METHYL-L-PROLINE (6) as a pale yellow solid which was filtered and washed with water and dried, (1...

Reference： [1]Patent: WO2005/30757,2005,A1 .Location in patent: Page/Page column 147-149

13
[ 230955-75-6 ]
[ 574745-97-4 ]

Yield	Reaction Conditions	Operation in experiment
94%	With ammonia; In methanol; at 20℃; for 1.5h;	A suspension of 4-chloro-7-methoxyquinazolin-6-yl acetate (prepared as described in Example 25-5 of WO01/66099, 10.1 g, 40 mmol) in 6N methanolic ammonia (200 ml) was stirred at room temperature for 90 minutes. The solvents were evaporated under vacuum. Water was added and the resulting suspension was filtered. The solid obtained was washed with water, ether and dried under high. vacuum in the presence-of phosphorus pentoxide to GIVE 4-CHLORO-7-METHOXYQUINAZOLIN-6-OL (7.9 G, 94%). NMR SPECTRUM: (DMSOD6) 4.02 (S, 3H), 7.40 (s, 1H), 7.43 (s, 1H), 8. 81 (s, 1H).
86%	With ammonia; In methanol; at 20℃; for 1.5h;Inert atmosphere;	Under argon, 10 (800?mg, 3.17?mmol) was dissolved in 11.3?mL of NH3 (7?N in CH3OH) and the mixture was stirred 1.5?h?at room temperature. The solvent was removed under vacuum and a trituration with Et2O afforded 11 as a beige solid (574?mg, 86%). Mp: 300?C (dec.); IR (ATR, ZnSe): nu (cm-1) 3019, 1555, 1497, 1465, 1350, 1188, 1157, 974, 858, 700; 1H NMR (400?MHz, DMSO-d6): delta (ppm) 10.78 (s, 1H), 8.81 (s, 1H), 7.43 (s, 1H), 7.40 (s, 1H), 4.01 (s, 3H). 13C NMR (126?MHz, DMSO-d6): delta (ppm) 158.9, 155.3, 155.2, 149.3, 146.4, 120.2, 105.9, 103.9, 56.0; HRMS-ESI calcd for C9H8ClN2O2 [M+H]+ 211.0269 found 211.0257.
84.6%	With ammonium hydroxide; In methanol; at 20℃; for 3h;	7-Methoxy-4-hydroxyquinazolin-6-ol acetate (4.68 g, 20 mmol) and DMF (0.4 mL) were added to 25 mL of thionyl chloride and refluxed for 5 hours. The thionyl chloride was distilled off under reduced pressure, and the mixture was steamed with chloroform (10 mL x 3) and toluene (10 mL x 2) The residual thionyl chloride was removed to give 7-methoxy-4-chloroquinazolin-6-ol acetate.Without purification, it was added to concentrated aqueous ammonia (35 mL)In methanol (70 mL) and stirred at room temperature for 3 hours. The filter cake was washed with ether to give 6-hydroxy-7-methoxy 4-chloroquinazoline, 3.61 g as a pale white solid, 84.6% yield.

78%	With ammonia; In methanol; at 10℃;	The 10g 4- chloro-7-methoxy-quinazolin-6-yl acetate (Compound 1) was placed in a 250mL three-necked roundFlask in an ice bath was added dropwise with stirring 100mL 7Mu NH3 methanol solution, drip completed within 30 minutes. Below 10 C, the reaction was stirred for more than 30min. The reaction solution was filtered under reduced pressure, residue was washed twice with ether, to give 6. 5g (78% yield) of compound 2,As a pale yellow powder.
78%	With ammonia; In methanol; at 10℃;Cooling with ice;	The 10g4- chloro-7-methoxy-quinazolin-6-yl acetate (Compound 1) was placed in a 250mL three-necked round bottom flask in an ice bath was added dropwise with stirring 100mL7MNH3- methanol solution, more than 30 minutes dropwise. Below 10 , the reaction was stirred for more than 30min. The reaction solution was filtered under reduced pressure, residue was washed with diethyl ether twice to afford 6.5g (78% yield) of Compound 2 as a pale yellow powder.
78%	With methanol; ammonia; at 10℃; for 1h;Cooling with ice;	The 10g4- chloro-7-methoxy-quinazolin-6-yl acetate (Compound 1) was placed in a 250mL three-necked roundBottom flask in an ice bath was added dropwise with stirring 100mL 7MNH3- methanol solution, drip completed within 30 minutes. 10 Hereinafter, the reaction mixture was stirred for more than 30min. The reaction solution was filtered under reduced pressure, residue was washed twice with ether, to give 6.5g(78% yield) of compound 2 as a pale yellow powder.
78%	With ammonia; In methanol; at 10℃; for 1h;Cooling with ice;	The 10g4- chloro-7-methoxy-quinazolin-6-yl acetate (Compound 1) was placed in a 250mL three-necked round bottom flask in an ice bath was added dropwise with stirring 100mL7MNH3-Methanol solution within 30 minutes after dropping below 10 , the reaction was stirred for more than 30min.The reaction solution was filtered under reduced pressure, residue was washed with diethyl ether twice to afford 6.5g (78% yield) of Compound 2 as a pale yellow powder.
78%	With methanol; ammonia; at 10℃; for 1h;	Chloro-7-methoxyquinazolin-6-yl acetate (Compound 1) was placed in a 250 mL three-necked round bottom flask, 100 mL of 7 M NH3-methanol solution was added dropwise with stirring under ice-30 minutes after the drop finished. Below 10 , the reaction was stirred for more than 30min. The reaction solution was filtered under reduced pressure, and the residue was washed twice with diethyl ether to give 6.5 g (yield 78%) of Compound 2 as a pale yellow powder.
67.8%	With ammonia; In methanol; at 10℃; for 1h;	Example 1 (4S)-4- ({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N- cyclopropyl-1-methyl-D-prolinamide Example 1 HATU (0.23g) was added to an agitated solution of (4Y)-4- ( {4- [ (3-CHLORO-2- fluorophenyl) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-1-METHYL-D-PROLINE (7) (0.18g), cyclopropylamine (34.4mg) and DIPEA (156mg) IN METHYLENE CHLORIDE (5M1). After 16hrs the reaction mixture was reduced in vacuo. The residues were re-dissolved in methylene chloride and washed with sodium hydroxide solution (2M) and water. The organic phase was then purified by column chromatography on silica eluting with increasingly polar mixtures of METHANOL/METHYLENE CHLORIDE (0/100-10/90). THE fractions containing the desired product were combined and evaporated to a foam which was triturated with diethylether to give the title compound as a white solid. (0. 15G). LH NMR Spectrum : (DMSO d6) 0.40-0. 48 (m, 2H), 0.57-0. 64 (M, 2H), 2.05-2. 14 (M, 1H), 2.28 (s, 3H), 2.33-2. 45 (M, 1H), 2.48-2. 56 (M, 1H + DMSO), 2. 61-2. 70 (M, 1H), 3.08 (t, 1H), 3.64 (dd, 1H), 3.94 (s, 3H), 5.06 (M, 1H), 7.20 (s, 1H), 7.28 (t, 1H), 7.44-7. 56 (M, 2H), 7.65 (s, 1H), 7.87 (d, 1H), 8.35 (s, 1H), 9.63 (s, 1H); Mass SPECTRUM : (M+H) + 486. 44 The starting material 1, 2-PYRROLIDINEDICARBOXYLIC acid, 4-hydroxy-, 1- (1, 1-DIMETHYLETHYL) 2- methyl ester, (2R, 4R) (2) was prepared as follows: 1- [3- (DIMETHYLAMINO) PROPYL]-3-ETLIYLCARBODIIMIDE hydrochloride (14.73 g) was added to a stirred suspension of 1, 2-PYRROLIDINEDICARBOXYLIC acid, 4-hydroxy-, l- (l, l-dimethylethyl) ester, (2R, 4R) (1) (13.65 g), DIMETHYLAMINOPYRIDINE (21.65 g) and methanol (5.67 g) in methylene chloride (400 ml) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with citric acid (1.0 M), saturated aqueous sodium bicarbonate solution and saturated brine, dried over MgSO4, filtered and evaporated. The residues were then purified by column chromatography on silica eluting with increasingly polar mixtures of METHANOL/METHYLENE chloride (1/99-5/95). The desired product fractions were combined and evaporated to give 1, 2-PYNOLIDINEDICARBOXYLIC acid, 4-hydroxy-, L- (L, L-DIMETHYLETHYL) 2- methyl ester, (2R, 4R) (2) as a white crystalline solid, (5.9 g). 1H NMR Spectrum : (DMSO d6) 1.32 + 1.38 (2s, 9H), 1.76-1. 87 (M, 1H), 2.24-2. 28 (M, 1H), 3.06-3. 15 (M, 1H), 3.42- 3. 51 (m, 1H), 3.60 + 3.63 (2s, 3H), 4.15-4. 24 (M, 2H), 4.92-5. 00 (M, 1H). Starting material 1, 2-Pyrrolidinedicarboxylic acid, 4-hydroxy-1- (1, 1-dimethylethyl) ester, (2R, 4R), (1), (Boc-D-cis-hyp-OH) is commercially available Starting material (3) was prepared as follows: 6-Acetoxy-4-chloro-7-methoxyquinazoline, (Example 25-5 of in W001/66099 ; 10. 0g, 39.6 MMOLE) was added in portions to a stirred 7N methanolic ammonia solution (220 ML) cooled to 10C in an ice/water bath. After stirring for one hour the precipitate was filtered, washed with diethylether and dried thoroughly under high vacuum to give 4-chloro-7- METHOXYQUINAZOLIN-6-OL (3) (5.65g, 67.8%) ; 1H NMR Spectrum : (DMSO d6) 3.96 (s, 3H); 7.25 (s, 1H); 7.31 (s, 1H); 8.68 (s, 1H) ; Mass Spectrum: (M+H) + 211. The starting material (4) was prepared as follows: Di-ethyl azodicarboxylate (5.71g) was added slowly to a stirred suspension of 1,2- PYNOLIDINEDICARBOXYLIC acid, 4-hydroxy-, L- (L, L-DIMETHYLETHYL) 2-methyl ester, (2R, 4R) (2) (5.9g), 4-CHLORO-7-METHOXYQUINAZOLIN-6-OL (3) (4.6g) AND TRIPHENYLPHOSPHINE (8.6g) in methylene chloride (400 ML) at 25C under an atmosphere of nitrogen and the reaction mixture was stirred for 2 hours. The reaction mixture was then evaporated to ½ volume and purified by column chromatography on silica eluting with increasingly polar mixtures of METHANOL/METHYLENE chloride (1/99-3/97). The desired product fractions were combined and evaporated to give 1-tert-butyl 2-methyl (2R, 4S)-4-[(4-chloro-7-methoxyquinazolin-6- yl) oxy] pyrrolidine-1, 2-dicarboxylate (4) as a pale yellow gum. This was used in the preparation of (5) without further purification. The starting material methyl (4S)-4-({4-[(3-CHLORO-2-FLUOROPHENYL) AMINO]-7- METHOXYQUINAZOLIN-6-YL} OXY)-D-PROLINATE HYDROCHLORIDE (5) was prepared as follows: 4. 0M HCl in Dioxane (15 ml) was added to a suspension of 1-tert-butyl 2-methyl (2R, 4S)-4- [(4-chloro-7-methoxyquinazolin-6-yl0 oxy] pyrrolidine-1, 2-dicarboxylate (4) AND 3-CHLORO-2- fluoroaniline (2.89g) in acetonitrile (400 ML) and the reaction mixture was stirred and heated at 70C for 3 hours. The resulting precipitate was filtered hot and washed with acetonitrile and diethylether and dried under vacuum to give methyl (4S)-4- (14- [ (3-CLILORO-2- FLUOROPHENYL) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-D-PROLINATE HYDROCHLORIDE (S) as an off- white solid, (6. 3G). TH NMR Spectrum : (DMSO D6) 2.46-2. 60 (M, 2H), 3.37-3. 46 (M, 1H), 3.71 (s, 3H), 3.89-3. 98 (m, 4H), 4.53 (t, 1H), 5.42 (M, 1H), 7.29 (t, 1H), 7.38-7. 48 (M, 2H), 7.55 (t, 1H), 8.64 (s, 1H), 8.75 (s, 1H)...
67.8%	With methanol; ammonia; at 10℃; for 1h;	6-Acetoxy-4-chloro-7-methoxyquinazoline, (Example 25-5 of in WO01/66099 ; 10. 0g, 39.6 mmole) was added in portions to a stirred 7N methanolic ammonia solution (220 ml) cooled to 10C in an ice/water bath. After stirring for one hour the precipitate was filtered, washed with diethylether and dried thoroughly under high vacuum to give 4-chloro-6- hydroxy-7-methoxyquinazoline (5.65g, 67. 8%) ; 1H NMR Spectrum : (DMSO d6) 3.96 (s, 3H); 7.25 (s, 1H); 7.31 (s, 1H); 8.68 (s, 1H) ; Mass Spectrum: (M+H) + 211
67.8%	With methanol; ammonia; at 10℃; for 1h;	Example 1; 4- (3-CHLORO-2-FLUOROANILINO)-6- [1- (HYDROXYACETYL) PIPERIDIN-4-YLOXY]-7- methoxyquinazoline; HATU (28.9 g) was added to a stirred solution of 4- (3-chloro-2-fluoroanilino)-7- METHOXY-6- (PIPERIDIN-4-YLOXY) quinazoline dihydrochloride (30 g), glycolic acid (5.40 g) and di-isopropylethylamine (44.70 ml) in methylene chloride (900 ml). After 1.5 hours the reaction mixture was washed with sodium hydroxide solution (2M), water and saturated brine. The resulting product was then purified by flash chromatography on silica eluting with 3% MeOH/methylene chloride. The fractions containing the desired product were combined and reduced in vacuo to give the title product as a white solid which was recrystallised from acetonitrile (29.6 g); NMR Spectrum : (DMSO d6) 1.65-1. 81 (m, 2H), 1.99-2. 10 (m, 2H), 3.26- 3.34 (m, 1H), 3.37-3. 47 (m, 1H), 3.60-3. 68 (m, 1H), 3.81-3. 89 (m, 1H), 3.95 (s, 3H), 4.14 (d, 2H), 4.50 (t, 1H), 4.78 (m, 1H), 7.25 (s, 1H), 7.30 (t, 1H), 7.46-7. 55 (m, 2H), 7.88 (s, 1H), 8.40 (s, 1H), 9.55 (s, 1H) ; Mass Spectrum: (M+H) + 460.94. THE 4- (3-CHLORO-2-FLUOROANILINO)-7-METHOXY-6- (PIPERIDIN-4-YLOXY) quinazoline dihydrochloride starting material was prepared as follows: 6-Acetoxy-4-chloro-7-methoxyquinazoline, (Example 25-5 in WO01/66099 ; 10. 0G, 39.6 mmole) was added in portions to a stirred 7N methanolic ammonia solution (220 ml) cooled to 10C in an ice/water bath. After stirring for one hour the precipitate was filtered, washed with diethylether and dried thoroughly under high vacuum to give 4-chloro-6- hydroxy-7-methoxyquinazoline (5.65 g, 67.8 %); NMR Spectrum: (DMSO d6) 3.96 (s, 3H); 7.25 (s, 1H); 7.31 (s, 1H); 8.68 (s, 1H); Mass Spectrum : (M+H) + 211 Di-tert-butylazodicarboxylate (9.22 g) in methylene chloride (20 ml) was added slowly to a stirred suspension of 4-chloro-6-hydroxy-7-methoxyquinazoline (5.63 g), 4-hydroxy-1- tert-butoxycarbonylpiperidine (8.06 g) and triphenylphosphine (10.5 g) in methylene chloride (100 ml) at 5C under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature for 16 hours. The reaction mixture was then evaporated under vacuum and adsorbed onto silica and the product was eluted with isohexane/ethyl acetate/triethylamine (75/24/1 followed by 70/29/1). The fractions containing the desired product were combined and evaporated under vacuum to give tert-butyl 4- [ (4-CHLORO-7-METHOXYQUINAZOLIN-6- yl) oxy] piperidine-l-carboxylate as a white solid (10.3 g) ; IH NMR SPECTRUM : (DMSO d6) 1.40 (s, 9H), 1.56-1. 69 (m, 2H), 1.93-2. 04 (m, 2H), 3.20-3. 31 (m, 2H), 3.60-3. 70 (m, 2H), 4.00 (s, 3H), 4. 89 (m, 1H), 7.45 (s, 1H), 7.50 (s, 1H), 8.86 (s, 1H) ; Mass Spectrum : (M+H) + 394. 4. 0M HC1 in Dioxane (4.0 ml) was added to a suspension of tert-butyl 4- [ (4-chloro-7- methoxyquinazolin-6-yl) oxy] PIPERIDINE-1-CARBOXYLATE (2.62 g) and 3-chloro-2-fluoroaniline (1.08 g) in iso-propanol (50 ml). The reaction mixture was stirred and heated at 100C for 2 hours. The yellow precipitate was filtered hot and washed with iso-propanol followed by diethylether and dried under vacuum to give 6- (PIPERIDIN-4-YLOXY)-4- (3-CHLORO-2- fluoroanilino) -7-methoxyquinazoline as a di-hydrochloride salt (2.38 g) ; 1H NMR SPECTRUM (DMSO D6) 1.84-1. 99 (m, 2H), 2.22-2. 33 (m, 2H), 3.12-3. 33 (m, 4H), 4.00 (s, 3H), 5. 08 (m, 1H), 7.34 (t, 1H), 7.40 (s, 1H), 7.50 (t, 1H), 7.62 (t, 1H), 8.80 (s, 1H), 8. 84-8. 94 (m, 2H), 8.99-9. 11 (m, 1H); Mass Spectrum: (M+H) + 403.
58 - 95%	With ammonia; water; In 1,4-dioxane; at 0 - 20℃;	Step 6. Product step 5 (8.54 mmol) was converted into 4-chloro-7-hydroxy-6-methoxyquinazoline or 4-chloro-6-hydroxy-7-methoxyquinazoline, respectively, (58-95%) by reacting them with thionyl chloride (12 mL) and DMF (0.3 mL) at 85 C. for 1.5 h. Excess thionyl chloride was removed by distillation. Traces of thionyl chloride were removed by aceotropic distillation wit toluene (two times). Alternatively the products step 5 can be converted into the chlorides by reacting them with a mixture of POCl3 and PCl5. The acetyl groups were removed by hydrolysis with ammonium hydroxide (5 mL, 28-30 wt %) in dioxane/water (100 mL/20 mL) at 0 C. to r.t.
	With ammonia; water; In 1,4-dioxane; at 0 - 20℃;	Step 6. Product step 5 (8.54 mmol) was converted into 4-chloro-7-hydroxy-6-methoxyquinazoline or 4-chloro-6-hydroxy-7-methoxyquinazoline, respectively, (58-95%) by reacting them with thionyl chloride (12 mL) and DMF (0.3 mL) at 85 C for 1.5 h. Excess thionyl chloride was removed by distillation. Traces of thionyl chloride were removed by aceotropic distillation wit toluene (two times). Alternatively the products step 5 can be converted into the chlorides by reacting them with a mixture of POCl3 and PCl5. The acetyl groups were removed by hydrolysis with ammonium hydroxide (5 mL, 28-30 wt%) in dioxane / water (100 mL / 20 mL) at 0 C to r.t.

Reference： [1]Patent: WO2005/26151,2005,A1 .Location in patent: Page/Page column 124
[2]European Journal of Medicinal Chemistry,2018,vol. 147,p. 130 - 149
[3]Patent: CN106986895,2017,A .Location in patent: Paragraph 0072; 0073; 0074; 0075; 0076
[4]Patent: CN105384699,2016,A .Location in patent: Paragraph 0032; 0033
[5]Patent: CN105418517,2016,A .Location in patent: Paragraph 0026; 0030; 0031
[6]Patent: CN105503747,2016,A .Location in patent: Paragraph 0032; 0033
[7]Patent: CN105461642,2016,A .Location in patent: Paragraph 0028; 0029
[8]Patent: CN105399689,2016,A .Location in patent: Paragraph 0029; 0030
[9]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 742 - 746
[10]Patent: WO2005/30757,2005,A1 .Location in patent: Page/Page column 102-105
[11]Patent: WO2003/82831,2003,A1 .Location in patent: Page/Page column 109
[12]Patent: WO2005/12290,2005,A1 .Location in patent: Page/Page column 36-37
[13]Patent: US2007/149523,2007,A1 .Location in patent: Page/Page column 13-14
[14]Patent: EP1785420,2007,A1 .Location in patent: Page/Page column 18-19
[15]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 6728 - 6737
[16]Journal of Medicinal Chemistry,2019,vol. 62,p. 2099 - 2111

14
[ 574745-97-4 ]
[ 109384-19-2 ]
[ 612501-45-8 ]

Yield	Reaction Conditions	Operation in experiment
	With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In dichloromethane; at 5 - 20℃; for 16h;	Di-tert-butylazodicarboxylate (9.22 g) in methylene chloride (20 ml) was added slowly to a stirred suspension of <strong>[574745-97-4]4-chloro-6-hydroxy-7-methoxyquinazoline</strong> (5.63 g), 4-hydroxy-1- tert-butoxycarbonylpiperidine (8. 06 g) and triphenylphosphine (10.5 g) in methylene chloride (100 ml) at 5C under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature for 16 hours. The reaction mixture was then evaporated under vacuum and adsorbed onto silica and the product was eluted with isohexane/ethyl acetate/triethylamine (75/24/1 followed by 70/29/1). The fractions containing the desired product were combined and evaporated under vacuum to give tert-butyl 4- [ (4-chloro-7-methoxyquinazolin-6- yl) oxy] piperidine-l-carboxylate as a white solid (10.3g) ; 1H NMR Spectrum: (DMSO d6) 1.40 (s, 9H), 1.56-1. 69 (m, 2H), 1.93-2. 04 (m, 2H), 3.20-3. 31 (m, 2H), 3.60-3. 70 (m, 2H), 4.00 (s, 3H), 4.89 (m, 1H), 7.45 (s, 1H), 7.50 (s, 1H), 8. 86 (s, 1H); Mass Spectrum: (M+H) + 394.
	With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In dichloromethane; at 5 - 20℃; for 16h;	Example 1; 4- (3-CHLORO-2-FLUOROANILINO)-6- [1- (HYDROXYACETYL) PIPERIDIN-4-YLOXY]-7- methoxyquinazoline; HATU (28.9 g) was added to a stirred solution of 4- (3-chloro-2-fluoroanilino)-7- METHOXY-6- (PIPERIDIN-4-YLOXY) quinazoline dihydrochloride (30 g), glycolic acid (5.40 g) and di-isopropylethylamine (44.70 ml) in methylene chloride (900 ml). After 1.5 hours the reaction mixture was washed with sodium hydroxide solution (2M), water and saturated brine. The resulting product was then purified by flash chromatography on silica eluting with 3% MeOH/methylene chloride. The fractions containing the desired product were combined and reduced in vacuo to give the title product as a white solid which was recrystallised from acetonitrile (29.6 g); NMR Spectrum : (DMSO d6) 1.65-1. 81 (m, 2H), 1.99-2. 10 (m, 2H), 3.26- 3.34 (m, 1H), 3.37-3. 47 (m, 1H), 3.60-3. 68 (m, 1H), 3.81-3. 89 (m, 1H), 3.95 (s, 3H), 4.14 (d, 2H), 4.50 (t, 1H), 4.78 (m, 1H), 7.25 (s, 1H), 7.30 (t, 1H), 7.46-7. 55 (m, 2H), 7.88 (s, 1H), 8.40 (s, 1H), 9.55 (s, 1H) ; Mass Spectrum: (M+H) + 460.94. THE 4- (3-CHLORO-2-FLUOROANILINO)-7-METHOXY-6- (PIPERIDIN-4-YLOXY) quinazoline dihydrochloride starting material was prepared as follows: 6-Acetoxy-4-chloro-7-methoxyquinazoline, (Example 25-5 in WO01/66099 ; 10. 0G, 39.6 mmole) was added in portions to a stirred 7N methanolic ammonia solution (220 ml) cooled to 10C in an ice/water bath. After stirring for one hour the precipitate was filtered, washed with diethylether and dried thoroughly under high vacuum to give 4-chloro-6- hydroxy-7-methoxyquinazoline (5.65 g, 67.8 %); NMR Spectrum: (DMSO d6) 3.96 (s, 3H); 7.25 (s, 1H); 7.31 (s, 1H); 8.68 (s, 1H); Mass Spectrum : (M+H) + 211 Di-tert-butylazodicarboxylate (9.22 g) in methylene chloride (20 ml) was added slowly to a stirred suspension of <strong>[574745-97-4]4-chloro-6-hydroxy-7-methoxyquinazoline</strong> (5.63 g), 4-hydroxy-1- tert-butoxycarbonylpiperidine (8.06 g) and triphenylphosphine (10.5 g) in methylene chloride (100 ml) at 5C under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature for 16 hours. The reaction mixture was then evaporated under vacuum and adsorbed onto silica and the product was eluted with isohexane/ethyl acetate/triethylamine (75/24/1 followed by 70/29/1). The fractions containing the desired product were combined and evaporated under vacuum to give tert-butyl 4- [ (4-CHLORO-7-METHOXYQUINAZOLIN-6- yl) oxy] piperidine-l-carboxylate as a white solid (10.3 g) ; IH NMR SPECTRUM : (DMSO d6) 1.40 (s, 9H), 1.56-1. 69 (m, 2H), 1.93-2. 04 (m, 2H), 3.20-3. 31 (m, 2H), 3.60-3. 70 (m, 2H), 4.00 (s, 3H), 4. 89 (m, 1H), 7.45 (s, 1H), 7.50 (s, 1H), 8.86 (s, 1H) ; Mass Spectrum : (M+H) + 394. 4. 0M HC1 in Dioxane (4.0 ml) was added to a suspension of tert-butyl 4- [ (4-chloro-7- methoxyquinazolin-6-yl) oxy] PIPERIDINE-1-CARBOXYLATE (2.62 g) and 3-chloro-2-fluoroaniline (1.08 g) in iso-propanol (50 ml). The reaction mixture was stirred and heated at 100C for 2 hours. The yellow precipitate was filtered hot and washed with iso-propanol followed by diethylether and dried under vacuum to give 6- (PIPERIDIN-4-YLOXY)-4- (3-CHLORO-2- fluoroanilino) -7-methoxyquinazoline as a di-hydrochloride salt (2.38 g) ; 1H NMR SPECTRUM (DMSO D6) 1.84-1. 99 (m, 2H), 2.22-2. 33 (m, 2H), 3.12-3. 33 (m, 4H), 4.00 (s, 3H), 5. 08 (m, 1H), 7.34 (t, 1H), 7.40 (s, 1H), 7.50 (t, 1H), 7.62 (t, 1H), 8.80 (s, 1H), 8. 84-8. 94 (m, 2H), 8.99-9. 11 (m, 1H); Mass Spectrum: (M+H) + 403.

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 742 - 746
[2]Patent: WO2003/82831,2003,A1 .Location in patent: Page/Page column 109-110
[3]Patent: WO2005/12290,2005,A1 .Location in patent: Page/Page column 36-37

15
[ 574745-97-4 ]
[ 129999-45-7 ]
[ 848438-63-1 ]

Yield	Reaction Conditions	Operation in experiment
94%	With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In dichloromethane; at 0 - 20℃; for 1h;	DI-TE7ZT-BUTYLAZADICARBOXYLATE (759 mg, 3.3 mmol) was added portionwise to an ice- cooled solution of <strong>[574745-97-4]4-chloro-7-methoxyquinazolin-6-ol</strong> (462 mg, 2.2 mmol), 1- dimethylaminoacetyl-4-hydroxypiperidine (490 mg, 2.6 mmol, prepared as described in example 9, preparation of starting materials) and triphenylphosphine (865 mg, 3.3 mmol) in dichloromethane (20 ml). The mixture was stirred at room temperature for 1 hour. After evaporation of the solvent under vacuum, the residue was purified by chromatography on silica gel (eluant: 0% to 2% 7N methanolic ammonia in dichloromethane) to give 4-chloro-6- ({1-[(DIMETHYLAMINO) acetyl] piperidin-4-yl} oxy)-7-methoxyquinazoline (804 mg, 94%). NMR Spectrum : (CDC13) 1.90-2. 15 (m, 4H), 2.29 (s, 6H), 3.15 (s, 2H), 3.60-3. 70 (m, 2H), 3.90 (M, 2H), 4.05 (s, 3H), 4.81 (m, 1H), 7.36 (s, 1H), 7.45 (s, 1H), 8.87 (s, 1H) ; Mass spectrum: MH+ 379.

Reference： [1]Patent: WO2005/26151,2005,A1 .Location in patent: Page/Page column 124

16
[ 574745-97-4 ]
[ 849345-18-2 ]
[ 849345-19-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triphenylphosphine; diethylazodicarboxylate; In dichloromethane; at 25℃; for 2h;	Example 4 HCl in Dioxan (4. 0M, 0. 4ml) was added to a stirred solution of (13) (200 mg) 4- amino-3-fluorobenzonitrile (83 mg) in acetonitrile (10 RRA) and the reaction mixture was heated at 65C for 3 hours. The resulting precipitate was filtered, washed with acetonitrile then diethyl ether and dried under vacuum to give the title compound as a beige powder solid HCl salt, (210 MG). LH NMR Spectrum : (DMSO D6 + CD3CO2D) 2.55-2. 69 (M, 1H), 2.75-2. 88 (M, 1H), 2.92 (s, 3H), 2.95 (s, 3H), 2.98 (s, 3H), 3.50-3. 57 (M, 1H), 4.01 (s, 3H), 4.29 (dd, 1H), 4.94 (dd, 1H), 5.47 (M, 1H), 7.47 (s, 1H), 7.74-7. 86 (M, 2H), 8.04 (d, 1H), 8.66 (M, 1H), 8.86 (s, 1H) Mass Spectrum : (M+H) +465. The starting material L-PYRROLIDINECARBOXYLIC acid, 2-[(DIMETHYLAMINO) CARBONYL]-4- hydroxy-, 1, 1-dimethylethyl ester, (2R, 4R)- (9) was prepared as follows : 1- [3- (DIMETHYLAMINO) PROPYL]-3-ETHYLCARBODIIMIDE HYDROCHLORIDE (25.53 g) was added to a stirred suspension of BOC-D-CIS-HYP-OH, 1, 2-PYRROLIDINEDICARBOXYLIC acid, 4-hydroxy-1- (1, 1-dimethylethyl) ester, (2R, 4R) (1) (22.0 g), DIMETHYLAMINOPYRIDINE (58. 11 g) and DIMETHYLAMINE hydrochloride (15.3 g) in methylene chloride (600 ML) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with citric acid (1.0 M), saturated aqueous sodium bicarbonate solution and saturated brine, dried over magnesium sulphate and filtered. The organic phase was then purified by column chromatography on silica eluting with increasingly polar mixtures OF METHANOL/METHYLENE chloride (1/99-5/95). The desired product fractions were combined and evaporated to give (9) as a white crystalline solid, (16.95 G). LH NMR Spectrum : (DMSO D6) 1.30 + 1.38 (2s, 9H), 1.50-1. 61 (M, 1H), 2. 31-2. 42 (m, 1H), 2.83 + 3.02 (2M, 6H), 3.08-3. 15 (M, 1H), 3.46- 3.58 (M, 1H), 4.09-4. 18 (M, 1H), 4.53-4. 61 (M, 1H), 5.15-5. 22 (M, 1H). Starting material Boc-D-cis-hyp-OH (1), 1, 2-PYNOLIDINEDICARBOXYLIC acid, 4-hydroxy- 1- (1, 1-DIMETHYLETHYL) ester, (2R, 4R) is commercially available The starting material (10) was prepared as follows: TFA (20 ML) was added to a stirred solution of L-PYRROLIDINECARBOXYLIC acid, 2- [ (DIMETHYLAMINO) CARBONYL] -4-HYDROXY-, 1, 1-DIMETHYLETHYL ESTER, (2R, 4R)- (9) (SG) IN METHYLENE chloride (20 ML) at 25C under an atmosphere of nitrogen and the reaction mixture was stirred for 1.5 hours. The reaction mixture was then reduced in vacuo and triturated with diethyl ether to give the TFA salt of (4R)-4-HYDROXY-N, N-DIMETHYL-D-PROLINAMIDE (10) as a white solid. (4.83 G) 1H NMR Spectrum : (DMSO D6) 1.68-1. 77 (M, 1H), 2.56-2. 67 (M, 1H), 2.90 (s, 3H), 2.95 (s, 3H), 3.16-3. 20 (m, 2H), 4.37 (M, 1H), 4.52-4. 58 (M, 1H), 5.32 (M, 1H). The starting material (4R)-4-HYDROXY-N, N, L-TRIMETHYL-D-PROLINAMIDE (4) was prepared as follows: Platinum oxide was added to a solution of (4R)-4-HYDROXY-N, N-DIMETHYL-D- prolinamide (10) (4.83g) in formaldehyde (37 wt % solution in water) (3g), water (16 ML) and acetic acid (30 ML) under an atmosphere of nitrogen. The reaction was then purged with hydrogen and stirred vigorously for 16 hours. The reaction mixture was filtered through celite and reduced in vacuo. The residue was dissolved in methylene chloride and dried over magnesium sulphate. Potassium carbonate (7g) was added and the mixture stirred for one hour. The crudes were filtered and purified by column chromatography on silica eluting with increasingly polar mixtures of methanol (saturated with AMMONIA)/METHYLENE chloride (5/95- 15/85). The fractions containing the desired product were combined and reduced in vacuo to give (4R)-4-hydroxy-N, N, l-trimethyl-D-prolinamide (11) as a colourless oil. (2. 57G). 1H NMR Spectrum : (DMSO D6) 1. 51-1. 60 (M, 1H), 2.17 (s, 3H), 2.28-2. 39 (m, 2H), 2.79-2. 86 (M, 4H), 3.06 (s, 3H), 3.17 (t, 1H), 4.10-4. 19 (M, 1H), 4.80 (d, 1H). The starting material (45)-4- [ (4-CHLORO-7-METHOXYQUINAZOLIN-6-YL) OXY]-N, N, 1- trimethyl-D-prolinamide (13) was prepared as follows: Di-ethyl azodicarboxylate (1.38g) was added slowly to a stirred suspension of (4R)-4- hydroxy-N, N, L-TRIMETHYL-D-PROLINAMIDE (11) (1. OG), 4-CHLORO-7-METHOXYQUINAZOLIN-6-OL (3) (1. 1 LG) AND TRIPHENYLPHOSPHINE (2.07g) IN METHYLENE CHLORIDE (60 ML) AT 25C under an atmosphere of nitrogen and the reaction mixture was stirred for 2 hours. The reaction mixture was then reduced in vacuo to 1/2 volume, applied to a silica flash column and eluted with increasingly polar mixtures OF METHANOL/METHYLENE chloride (5/95-10/90). The fractions containing the desired product were combined and evaporated to give (4S)-4-[(4-CHLORO-7- METHOXYQUINAZOLIN-6-YL) oxy]-N, N, L-TRIMETHYL-D-PROLINAMIDE (13) as a colourless foam. (1.6g). H NMR Spectrum : (DMSO d6) 2.09-2. 20 (M, 1H), 2.25 (s, 3H), 2.28-2. 40 (M, 1H), 2.60 (M, 1H), 2.81 (s, 3H), 3.02 (s, 3H), 3.52 (M, 1H), 3.74 (m, 1H), 3.98 (s, 3H), 5.12-5. 20 (M, 1H), 7.28 (s, 1H), 7.41 (s, 1H), 8.83 (s, 1H) ; Mass SPECTRUM : (M+H) + 365.

Reference： [1]Patent: WO2005/30757,2005,A1 .Location in patent: Page/Page column 110-112

18
[ 574745-97-4 ]
[ 254882-14-9 ]
[ 908294-19-9 ]

Yield	Reaction Conditions	Operation in experiment
79%	With triphenylphosphine; diethylazodicarboxylate; In dichloromethane; at 30℃;	Example 7; (2S,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N,l- dimethylpiperidine-2-carboxamide; The title compound was prepared as shown in Scheme DExample 7 (15)Scheme D (25,42?)-4-({4-[(3-cMoro-2-fluorophenyl)amiQo]-7-methoxyquinazolin~6-yl}oxy)-l- methylpiperidine-2-carboxylic acid (15) (145mg, 0.32mmol) was dissolved in DMF (10ml) under nitrogen. Triethylamine (0.13ml, 0.95mmol) was added, followed by DEPEA (0.055ml, 0.32mmol) and methylamine hydrocMoride (0.043g, 0.63mmol). The mixture was cooled in an ice/water bath and HATU (180mg, 0.47mmol) was then added portionwise such that the temperature remained < 1O0C. The reaction mixture was stirred at room temperature overnight and evaporated to dryness. The residues were dissolved in EtOAc, washed with water (10ml), brine (10ml), dried over MgSO4, filtered and evaporated. The crudes were purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0-90/10). Fractions containing the desired product were combined and evaporated. The resulting solids were dissolved in methanol, loaded onto an SCX column and eluted with MeOH (20ml) followed by 7N NH3 in MeOH. Appropriate fractions were combined and evaporated to give the title product as a white solid (69mg, 40%): 1H NMR Spectrum: (DMSO-dg) deltal.63 - 1.69 (2H, m), 2.15 - 2.21 (6H, m), 2.55 - 2.62 (4H, m), 2.93 - 2.98 (IH, m), 3.94 (3H, s), 4.43 - 4.51 (IH, m), 7.23 (IH, s), 7.28 - 7.33 (IH, m), 7.49 - 7.56 (2H, m), 7.68 - 7.72 (IH, m), 7.86 (IH, s), 8.39 (IH, s), 9.57 (IH, s); Mass Spectrum: (M+H)+ 474.The starting material (25,4i?)-4-({4-[(3-cMoro-2-fluorophenyl)arnino]-7- methoxyquinazoHn-6-yl}oxy)-l-methylpiperidine-2-carboxync acid (15) was prepared as follows:(2S, 4S)-N Boc-4-hydroxy pirhoeridine-2 carboxylic acid benyzlamine salt (0.5g) was dissolved in methanol and loaded onto a SCX column. This was eluted with methanol (20ml). The combined filtrates were evaporated in vacuo to give a gum (405mg). This was dissolved in DMF (5ml). Iodomethane (0.107ml, 1.7mmol) was added and the resulting mixture cooled to 00C. Cesium carbonate (647mg, 1.98mmol) was added in one portion and the mixture stirred overnight at room temperature. The reaction mixture was partitioned between water (10ml) and DCM (3xlthetaml). The combined organics were washed with brine (10ml), dried over MgSO4, filtered and evaporated to give 1-tert-bntyl 2-methyl (IS, AS)A- hydroxypiperidine-l,2-dicarboxylate (11) as a clear gum (347mg, 81%): 1H NMR Spectrum: (CDCl3) 51.39 - 1.50 (1OH, m), 1.60 - 1.66 (IH, m), 1.86 - 1.96 (2H, m), 2.40 - 2.49 (IH, m), 2.96 - 3.10 (IH, m), 3.65 (IH, t), 3.73 (3H, s), 3.95 - 4.18 (IH, m), 4.82 - 5.06 (IH, m). A solution of DEAD (0.329ml, 2.08mmol) in DCM (2ml) was added to as stirred suspension of 4-chloro-7-methoxyquinazohn-6-ol (283mg, 1.74mmol prepared as described in Example 16 of WO03/082831), 1-te/t-butyl 2-methyl (2S,4S)~4-hydroxypirhoeridine-l,2- dicarboxylate (11) (450mg, 2.08mmol) and triphenylphosphine (547mg, 2.098mmol) in DCM (10ml), such that the internal temperature remained < 3O0C. The reaction mixture was stirred overnight and evaporated to dryness. The residues were purified by column chromatography on SiO2 eluting with increasingly polar mixtures of DCM/methanol (100/0-95/5). The fractions containing the desired product were combined and evaporated to give 1-fetaut-butyl 2- methyl (25,4i?)-4-[(4-chloro-7-methoxyquinazohn-6-yl)oxy]piperidine-l,2-dicarboxylate (12) as a gum (478mg, 79%): 1H NMR Spectrum: (DMSO-d6) deltal.39 - 1.46 (1OH, m), 1.73 - 1.84 (IH, m), 1.92 - 2.03 (IH, m), 2.10 - 2.18 (IH, m), 2.60 - 2.69 (IH, m), 3.15 - 3.40 (3H, m), 3.74 - 3.85 (IH, m), 4.01 (3H, s), 4.61 - 4.73 (IH, m), 5.06 (IH, s), 7.43 (IH, s), 7.47 (IH, s), 8.89 (IH, s), 8.97 (IH, s); Mass Spectrum: (M+H)+452. l-te^butyl 2-methyl (25',4i2)-4-[(4-cliloro-7-metlioxyquinazolialpha-6-yl)oxy]piperidiiie- 1,2-dicarboxylate (12) (0.45g, l.Ommol) was dissolved in MeCN (11ml) under nitrogen. 3- Chloro-2-fluoro aniline (153mg, 1.05mmol) was then added followed by 4M HCl in dioxane (1.2ml). The resulting mixture was heated overnight at 6O0C. The reaction mixture was cooled to -80C and the resulting solids collected "by filtration and washed with diethylether. The solids were dissolved in methanol, loaded onto an SCX column and eluted with methanol followed by 7N NH3 in MeOH. Appropriate fractions were combined and evaporated. The residues were purified by column chromatography on SiO2 eluting with increasingly polar mixtures of DCM/methanol (100/0-95/5). The fractions containing the desired product were combined and evaporated to give methyl (25r,4i?)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7- methoxyquinazonn-6-yl}oxy)piperidine-2-carboxylate (13) as a clear gum (316mg, 69%): 1H NMR Spectrum: (DMSO-d6) 51.45 - 1.58 (2H, m), 2.02 - 2.11 (IH, m), 2.32 - 2.40 (IH, m), 2.57 - 2.67 (IH, m), 3.08 - 3.13 (IH, m), 3.42 - 3.48 (IH, m), 3.64 (3H, s),...

Reference： [1]Patent: WO2006/90163,2006,A1 .Location in patent: Page/Page column 79-82

19
4-chloro-7-methoxyquinazolin-6-yl acetate hydrochloride salt [ No CAS ]
[ 574745-97-4 ]

Yield	Reaction Conditions	Operation in experiment
98%	With methanol; ammonia; at 20℃; for 1h;	(1-5) 4-chloro-7-methoxyquinazolin-6-ol; 2 g of the compound obtained in (1-4) was added to 25 ml of 7 N ammonia methanol solution. The mixture was stirred at room temperature for 1 hour, the solid formed in the reacting mixture was filtered, washed with diethylether, and dried to obtain the title compound (1.43 g, 98%).1H-NMR (300MHz, DMSO-d6) delta 8.78 (s, IH), 7.41 (s, IH), 7.37 (s, IH), 4.00 (s, 3H).
98%	With ammonia; In methanol; at 20℃; for 1h;	2 g of the compound obtained in (1-4) was added to 25 ml of 7 N ammonia methanol solution. The mixture was stirred at room temperature for 1 hour, the solid formed in the reacting mixture was filtered, washed with diethylether, and dried toobtain the title compound (1 .43 g, 98%). 1H-NMR (300MHz, DMSO-d6) O 8.78 (s, 1 H), 7.41 (s, 1 H), 7.37 (s, 1 H), 4.00 (s, 3H).

Reference： [1]Patent: WO2008/150118,2008,A2 .Location in patent: Page/Page column 22
[2]Patent: WO2019/79599,2019,A1 .Location in patent: Paragraph 0083; 0084; 0085

20
[ 574745-97-4 ]
[ 83220-73-9 ]
[ 612501-62-9 ]

Yield	Reaction Conditions	Operation in experiment
	With di-isopropyl azodicarboxylate; triphenylphosphine; In dichloromethane; at 20℃; for 1h;	(1-6) N-(3-chloro-2,4-difluorophenyl)-7-methoxy-6-((3S)-pyrrolidin-3- yloxy)quinazolin-4-amine; 1.43 g of the compound obtained in (1-5), 1.91 g of (R)-(-)-N-Boc-3- pyrrolidinol and 1.96 g of triphenylphosphine were added to 20 mi of methylene chloride, and 2.01 m£ of diisopropylazodicarboxylate was added thereto dropwise. The resulting mixture was stirred at room temperature for 1 hour and distilled under a reduced pressure, and the residue was briefly purified by column chromatography (ethylacetate : methylenechloride : methanol - 20 : 20 : 1). The partially purified residue was then dissolved in 60 mi of 2-propanol, 1.17 g of 3- chloro-2,4-difluoroaniline was thereto, and the mixture was stirred at 100 C for 3 hours. The resulting mixture was distilled under a reduced pressure to remove the solvent, and the residue was dissolved in 60 mi of methylenechloride. 60 mi of trifluoroacetic acid was added thereto and the mixture was stirred at room temperature for 1 hour. The resulting mixture was distilled under a reduced pressure to remove the solvent. Saturated sodium bicarbonate solution was added to the resulting residue to make it basic, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and distilled under a reduced pressure. The resulting residue was subjected to <n="24"/>column chromatography (chloroform : methanol = 1 : 2) to obtain the title compound (2 g, 73%).1H-NMR (300MHz, CDCl3) delta 8.68 (s, IH), 8.35 (m, IH), 7.29 (s, IH), 7.09 (s, IH), 7.08 (m, IH), 5.03 (bm, IH), 4.02 (s, 3H), 3.37 (m, IH), 3.27 (m, IH), 3.11 (m, IH), 3.00 (m, IH), 2.24 (m, IH), 2.12 (m, IH); MS (ESI+): m/z = 407.19 [M+H]+.

Reference： [1]Patent: WO2008/150118,2008,A2 .Location in patent: Page/Page column 22-23

21
[ 5317-33-9 ]
[ 574745-97-4 ]
[ 894426-67-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 6728 - 6737

23
[ 1276184-25-8 ]
[ 574745-97-4 ]
[ 1276184-26-9 ]

Yield	Reaction Conditions	Operation in experiment
25%; 35%	With tetrachloromethane; triphenylphosphine; In 1,2-dichloro-ethane; at 80℃;	Compound 12 was obtained using the same procedure as for 11. Depropargylated 4-chloro-6-hydroxy-7-methoxy quinazoline (0.032g, 0.15 mmol, 25%) was eluted first, followed by 12 (0.059g, 0.22 mmol, 35%). The product was recrystallized from iso-propanol to give colorless needles. Mp 196-198 C, 1H-NMR (CDCl3): 8.920 (s, 1H, C2-H); 8.622 (s, 1H, C5-H); 7.344 (s, 1H, C8-H); 4.963 (d, 2H, J = 2.5 Hz); 4.054 (s, 3H); 2.604 (t, 1H, J= 2.5 Hz).

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 1053 - 1056

24
[ 1276184-22-5 ]
[ 574745-97-4 ]

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 1053 - 1056

25
[ 1276184-23-6 ]
[ 574745-97-4 ]

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 1053 - 1056

26
[ 1276184-24-7 ]
[ 574745-97-4 ]

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 1053 - 1056

27
[ 6702-50-7 ]
[ 574745-97-4 ]

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 1053 - 1056
[2]Patent: US2007/149523,2007,A1

28
[ 3040-44-6 ]
[ 574745-97-4 ]
[ 1355221-54-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 262 - 266

29
[ 3040-44-6 ]
[ 574745-97-4 ]
[ 1355221-14-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 262 - 266

30
[ 574745-97-4 ]
[ 1355221-13-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 262 - 266

31
[ 574745-97-4 ]
[ 109-86-4 ]
[ 1188906-86-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 262 - 266

32
[ 574745-97-4 ]
[ 1441145-40-9 ]