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Quality Control of [ 449811-29-4 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 449811-29-4 ]

CAS No. :	449811-29-4	MDL No. :	MFCD14706814
Formula :	C₇H₇ClN₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	170.60	Pubchem ID :	-
Synonyms :

Safety of [ 449811-29-4 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P264-P270-P301+P312-P330-P501	UN#:
Hazard Statements:	H302	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 449811-29-4 ]

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

Downstream synthetic route of [ 449811-29-4 ]

[ 449811-29-4 ] Synthesis Path-Downstream 1~10

1
[ 449811-30-7 ]
[ 449811-29-4 ]

Yield	Reaction Conditions	Operation in experiment
93%	With manganese(IV) oxide In dichloromethane at 20℃; Inert atmosphere;	1 6-chloro-4-(methylamino)nicotinaldehyde (54) To a solution of 53 (495 mg, 2.86 mmol) in DCM (10 mL), was added Mn02 (1496 mg, 17.20 mmol) and the mixture was allowed to stir overnight at room temperature. The reaction mixture was then filtered, concentrated to remove DCM and purified by column chromatography using silica gel (2 % MeOH/DCM) to afford 54 (453 mg, 93%) as white solid. lH NMR (400 MHz, CDC13) δ (ppm) 9.70 (s, 1H), 8.43 (brs, 1H), 8.16 (s, 1H), 6.43 (s, 1H), 2.83 (d, / = 5.6 Hz, 3H).
93%	With manganese(IV) oxide In dichloromethane at 20℃; Inert atmosphere;	6-chloro-4-(methylamino)nicotinaldehyde (D4): To a solution of D3 (495 mg, 2.86 mmol) in DCM (10 mL), was added MnO2 (1496 mg, 17.20 mmol) and the mixture was stir overnight at rt under argon. The reaction mixture was then filtered, concentrated to remove DCM and purified by column chromatography on silica gel (5 % MeOH/DCM) to afford D4 (453 mg, 93%) as white solid. 1H NMR (400 MHz, CDCl3) d (ppm) 9.70 (s, 1H), 8.43 (brs, 1H), 8.16 (s, 1H), 6.43 (s, 1H), 2.83 (d, J = 5.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) d (ppm) 192.5, 157.9, 156.5, 155.8, 114.9, 104.3, 29.0.
87%	With manganese(IV) oxide In dichloromethane at 30℃; for 6h;	A24 A mixture of (6-chtoro-4-(methyIamino)pyridm-3-yl)methanoI (2.9 g, 16.7 mmol) and MnO2 (11.7 g, 133.6 mmol) in anhydrous DCM (25 mL) was stirred at 30 0C for 6 h. The reaction mixture was cooled to RT, filtered and concentrated in vacuo to give 6-chloro-4- (methylamino)nicotinaldehyde (2.5 g, 87% yield). 1H NMR (400 MHz, OMSO-d6): δ 9.83 (s, 1 H), 8.52 (br s, 1 H), 8.40 (s, 1 H), 6.75 (s, 1 H), 2.87 (d, J= 5.8 Hz, 3 H); MS (ESI) m/z: 171.0

87%	With manganese(IV) oxide In dichloromethane at 30℃; for 6h;	B3 A mixture of (6-chloro-4-(methylamino)pyridin-3-yl)methanol (2.9 g, 16.7 mmol)and Mn02 (11.7 g, 133.6 mmol) in anhydrous DCM (25 mL) was stirred at 30°C for 6 h. Thereaction mixture was cooled to RT and filtered. The filtrate was concentrated in vacuo togive 6-chloro-4-(methylamino)nicotinaldehyde (2.5 g, 87% yield). 1H NMR (400 MHz,DMSO-d6): 8 9.83 (s, 1 H), 8.52 (br s, 1 H), 8.40 (s, 1 H), 6.75 (s, 1 H), 2.87 (d, J = 5.8 Hz, 3H); MS (ESI) m/z: 171.0 [M+Ht.71
	With manganese(IV) oxide In dichloromethane at 20℃; for 2h;	1 Compound 5 (20 g, 116 mmol) is dissolved in DCM (250 mL) and MnO2 (100 g, 1.16 mol) is added. The reaction is stirred at rt overnight, then filtered through a celite plug and washed using ethyl acetate. After removing the solvent in vacuo, 6 is obtained and is used in the next step without further purification. 1H NMR (300MHz, CDCl3) δ 9.85 (s, IH), 8.59 (bs, IH), 8.31 (s, IH), 6.59 (s, IH), 2.96 (d, J = 5.1 Hz, 3H).
	With manganese(IV) oxide In dichloromethane at 20℃;	5.5 (6-Chloro-4-(methylamino)pyridin-3-yl)methanol (20 g, 116 mmol) was dissolved in DCM (250 mL) and Mn02 (100 g, 1.16 mol) was added. The reaction mixture was stirred at rt overnight, then filtered through a celite plug and washed with ethyl acetate. The filtrate was concentrated to obtain the title compound. ]H NMR (300MHz, CDC13) δ 9.85 (s, 1H), 8.59 (bs, 1H), 8.31 (s, 1H), 6.59 (s, 1H), 2.96 (d, / = 5.1 Hz, 3H).
	With manganese(IV) oxide In dichloromethane at 30℃; for 6h;	B3 Example B3 A mixture of (6-chloro-4-(methylamino)pyridin-3-yl)methanol (2.9 g, 16.7 mmol) and MnO2 (11.7 g, 133.6 mmol) in anhydrous DCM (25 mL) was stirred at 30° C. for 6 h. The reaction mixture was cooled to RT and filtered. The filtrate was concentrated in vacuo to give 6-chloro-4-(methylamino)nicotinaldehyde (2.5 g, 87% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.83 (s, 1H), 8.52 (br s, 1H), 8.40 (s, 1H), 6.75 (s, 1H), 2.87 (d, J=5.8 Hz, 3H); MS (ESI) m/z: 171.0 [M+H]+.
	With manganese(IV) oxide In tetrahydrofuran; dichloromethane at 20℃;	5 Synthesis of 6-chloro-4-(methylamino)nicotinaldehyde Synthesis of 6-chloro-4-(methylamino)nicotinaldehyde. A mixture of (6-chloro-4-(methylamino)pyridin-3-yl)methanol (4.2 g, 24.7 mmol) andmanganese(IV) oxide (active, 25.8 g, 296.6 mmol) in dichloromethane (50 mL) and THF (50mL) was stuffed at RT overnight. LCMS showed the reaction was completed. The solid was filtered off, and the filtrate was concentrated to afford the title compound (3.7 g, crude) as a light yellow solid, which was directly used in the next step without further purification. MS (ES+) C7H7C1N2O requires: 170, 172, found: 171, 173 [M + H].
3.51 g	With manganese(IV) oxide In dichloromethane at 20℃; for 2h;
6.2 g	With sodium hydrogencarbonate; Dess-Martin periodane In dichloromethane for 1h;	1.2 6-chloro-4-(methylamino)nicotinaldehyde Step 2: 6-chloro-4-(methylamino)nicotinaldehyde To a solution of ethyl 6-chloro-4-(methylamino)nicotinate (11.0 g, 50.2 mmol) in methylene chloride (400 mL) was added 1.0 M diisobutylaluminum hydride in THF (150 mL, 150 mmol). The resulting mixture was stirred at room temperature for 6 h before it was quenched by a solution of Rochelle's salt. After stirring for 12 h, the aqueous solution was extracted with EtOAc (3150 mL) and the organic layer was dried over Na2SO4 and concentrated in vacuo to afford the crude alcohol. LC-MS calculated for C7H10ClN2O [M+H]+ m/z: 173.0. found 173.0. To the solution of crude alcohol in methylene chloride (300 mL) were added sodium bicarbonate (42 g, 500 mmol) and Dess-Martin periodinane (42 g, 100 mmol). The resulting mixture was stirred for 1 h before it was quenched with Na2S2O3 (sat. aq, 100 mL) and NaHCO3 (sat. aq, 100 mL). The aqueous phase was extracted with EtOAc (3100 mL) and the organic layer was dried over Na2SO4 and concentrated in vacuo. Purified by flash column chromatography to afford the the aldehyde (6.2 g, 80% yield over two steps). LC-MS calculated for C7H8ClN2O [M+H]+ m/z: 171.0. found 171.0.
	With manganese(IV) oxide In tetrahydrofuran; dichloromethane at 20℃;	2.3 Synthesis of 6-chloro-4-(methylamino)nicotinaldehyde A mixture of (6-chloro-4-(methylamino)pyridin-3-yl)methanol (4.2 g, 24.7 mmol) and manganese(IV) oxide (active, 25.8 g, 296.6 mmol) in dichloromethane (50 mL) and THF (50 mL) was stirred at RT overnight. LCMS showed the reaction was completed. The solid was filtered off, and the filtrate was concentrated to afford the title compound (3.7 g, crude) as a light yellow solid, which was directly used in the next step without further purification. MS (ES+) C7H7ClN2O requires: 170, 172, found: 171, 173 [M+H]+.
3.51 g	With manganese(IV) oxide In dichloromethane at 20℃; for 2h;
	With manganese(IV) oxide In tetrahydrofuran; dichloromethane at 20℃;	2.3 Step 3: Synthesis of 6-chloro-4-(methylamino)nicotinaldehyde A mixture of (6-chloro-4-(methylamino)pyridin-3-yl)methanol (4.2 g, 24.7 mmol) and manganese(IV) oxide (active, 25.8 g, 296.6 mmol) in dichloromethane (50 mL) and THF (50 mL) was stirred at RT overnight. LCMS showed the reaction was completed. The solid was filtered off, and the filtrate was concentrated to afford the title compound (3.7 g, crude) as a light yellow solid, which was directly used in the next step without further purification. MS (ES+) C7H7ClN2O requires: 170, 172, found: 171, 173 [M+H]+.
	With manganese(IV) oxide In dichloromethane at 20℃;	Compound 5 (20 g, 116 mmol) was dissolved in DCM (250 mL) and MnO2(100 g, 1.16 mol) was added. The reaction was stirred at rt overnight, then filtered through a celite plug and washed using ethyl acetate. After removal of the solvent in vacuo, 6 was obtained and used in the next step without further purification. 1H NMR (300MHz, CDCl3) δ 9.85 (s, IH), 8.59 (bs, IH), 8.31 (s, IH), 6.59 (s, IH), 2.96 (d, J = 5.1 Hz, 3H).
	With manganese(IV) oxide In dichloromethane at 20℃; for 2h;	8 (6-chloro-4-methylamino-pyridin-3-yl)-methanol (1.40g, 8. 1mmol) is dissolved in 40mL DCM and 7. 0g Mn02 (81mmol) is added. The reaction is stirred in RT for 2 hours. Then the reaction solution goes through a celite plug and washed by EA. After removing the solvent under the vacuum, the crude product is purified by flash chromatography using EA/Hexane (3: 7). The final compound (6) 6-chloro-4-methylamino- pyridine-3-carbaldehyde is the white solid, 1.30g

Reference： [1]Current Patent Assignee: THE UNIVERSITY OF HOUSTON SYSTEM; TRUSTEES OF TUFTS COLLEGE, INC. - WO2018/213219, 2018, A1 Location in patent: Paragraph 0267-0268; 0021
[2]Current Patent Assignee: INSTITUTE FOR CANCER RES D B A THE RES INTITUTE OF FOX CHASE CANCER CENTER; FOX CHASE CANCER CENTER; TRUSTEES OF TUFTS COLLEGE, INC.; THE UNIVERSITY OF HOUSTON SYSTEM - WO2020/232190, 2020, A1 Location in patent: Paragraph 0087; 0092; 0093; 0323; 0327; 0328
[3]Current Patent Assignee: DECIPHERA PHARMACEUTICALS LLC - WO2008/33999, 2008, A2 Location in patent: Page/Page column 76
[4]Current Patent Assignee: DECIPHERA PHARMACEUTICALS LLC - WO2013/184119, 2013, A1 Location in patent: Paragraph 0196
[5]Current Patent Assignee: IRM LLC - WO2008/51757, 2008, A1 Location in patent: Page/Page column 31; 32
[6]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2011/97526, 2011, A1 Location in patent: Page/Page column 31
[7]Current Patent Assignee: DECIPHERA PHARMACEUTICALS LLC - US8461179, 2013, B1 Location in patent: Page/Page column 64
[8]Current Patent Assignee: BLUEPRINT MEDICINES CORP - WO2014/11900, 2014, A2 Location in patent: Page/Page column 53; 54
[9]Montoir, David; Tonnerre, Alain; Duflos, Muriel; Bazin, Marc-Antoine [European Journal of Organic Chemistry, 2014, vol. 2014, # 7, p. 1487 - 1495]
[10]Current Patent Assignee: INCYTE CORP - US2014/315902, 2014, A1 Location in patent: Paragraph 0265; 0266
[11]Current Patent Assignee: BLUEPRINT MEDICINES CORP - US2015/197519, 2015, A1 Location in patent: Paragraph 0141; 0142
[12]Montoir, David; Tonnerre, Alain; Duflos, Muriel; Bazin, Marc-Antoine [European Journal of Organic Chemistry, 2014, vol. 2014, # 7, p. 1487 - 1495]
[13]Current Patent Assignee: BLUEPRINT MEDICINES CORP - US9695165, 2017, B2 Location in patent: Page/Page column 41
[14]Current Patent Assignee: IRM LLC - WO2009/105712, 2009, A1 Location in patent: Page/Page column 35; 37
[15]Current Patent Assignee: IRM LLC - WO2005/34869, 2005, A2 Location in patent: Page/Page column 40

2
[ 449811-29-4 ]
[ 446-18-4 ]
[ 1011464-19-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium tris(acetoxy)borohydride; In acetic acid; at 20℃;	To a solution of 6-chloro-4-(metlrylamino)nicotinaldehyde (1.00 g, 5.88 mmol) and Example Dl (1.00 g, 5.88 mmol) in glacial acetic acid (7.5 mL) was added sodium triacetoxy borohydride (2.49 g, 11.7 mmol). The mixture was stirred overnight at RT. Another portion of sodium triacetoxy borohydride (1.30 g, 6.11 mmol) was added and the mixture was stirred another 24 h. The reaction was diluted with ice water and basified (pH ~ 7-8) with NaOH. The yellow precipitate was collected by filtration, washed with H2O and dried under vacuum to give <n="78"/>crude 2-chloro-5-((4-fluoro-2-methyl-5"nitrophenylamino)methyl)-N-methylpyridin-4-amine (2.04 g, 107 % yield), which was used without further purification. MS (ESI) m/z: 325.0 [M+H]+.

Reference： [1]Patent: WO2008/33999,2008,A2 .Location in patent: Page/Page column 76-77

3
[ 449811-29-4 ]
[ 850449-93-3 ]
[ 850451-77-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16.0h;	6-Chloro-4-methylamino-pyridine-3-carbaldehyde 6 (19.8 g, 116 mmol) is mixed with <strong>[850449-93-3]2-(5-amino-2-methyl-phenyl)acetic acid methyl ester</strong> 7 (27 g, 151 mmol) and potassium carbonate (48.1 g, 348 mmol) in DMF (1 L). The mixture is heated to 100 0C for 16 h. After cooling to rt and removing solvent in vacuo, the crude product is purified using flash EPO <DP n="34"/>P A T E N TGNF Patent No.: P1274PC10 chromatography (ethyl acetate : petroleum ether = 1 : 1). The title compound 8 is obtained as a pale solid. 1H NMR (300MHz, CDCl3) delta 8.56 (s, IH), 7.63 (s, IH), 7.27 (s, IH), 7.06 (d, J = 8.1 Hz, IH), 6.74 (dd, J = 2.4, 8.1 Hz, IH), 6.58 (d, J = 2.4 Hz, IH), 3.71 (s, 2H), 2.10 (s, 3H).
	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16.0h;	[00120] 6-Chloro-4-methylamino-pyridine-3-carbaldehyde 6 (19.8 g, 116 mmol) was mixed with <strong>[850449-93-3]2-(5-amino-2-methyl-phenyl)acetic acid methyl ester</strong> 7 (27 g, 151 mmol) and potassium carbonate (48.1 g, 348 mmol) in DMF (1 L). The mixture was heated to 100 0C for 16 h. After cooling to rt and removing solvent in vacuo, the crude product was purified using flash chromatography (ethyl acetate : petroleum ether = 1:1). The title compound 8 was obtained as a pale solid. 1H NMR (300MHz, CDCl3) delta 8.56 (s, IH), 7.63 (s, IH), 7.27 (s, IH), 7.06 (d, J = 8.1 Hz, IH), 6.74 (dd, 7 = 2.4, 8.1 Hz, IH), 6.58 (d, J = 2.4 Hz, IH), 3.71 (s, 2H), 2.10 (s, 3H).

Reference： [1]Patent: WO2008/51757,2008,A1 .Location in patent: Page/Page column 32-33
[2]Patent: WO2009/105712,2009,A1 .Location in patent: Page/Page column 35; 37

4
[ 449811-29-4 ]
[ 850449-93-3 ]
3-(4-amino-2-methyl-phenyl)-7-chloro-1-methyl-1H-[1,6]naphthyridin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16.0h;	6-chloro-4-methylamino-pyridine-3-carbaldehyde (850mg, 5mmol) is mixed with 2- <strong>[850449-93-3](5-amino-2-methyl-phenyl)-acetic acid methyl ester</strong> (compound 7,1. 35g, 7. 5mmol) and potassium carbonate (2.07g, 15mmol) in 15mL DMF, heat up to 100C for 16 hours. After cooling down and removing solvent under the vacuum, the crude product is purified by flash chromatography using EA/Hexane (6: 4). The final compound (8) 3- (4- amino-2-methyl-phenyl)-7-chloro-1-methyl-lH- [1, 6] naphthyridin-2-one is the pale solid, 1.30g.

Reference： [1]Patent: WO2005/34869,2005,A2 .Location in patent: Page/Page column 42

5
[ 449811-28-3 ]
[ 449811-29-4 ]

Yield	Reaction Conditions	Operation in experiment
84%	Stage #1: ethyl 6-chloro-4-(methylamino)pyridine-3-carboxylate With lithium aluminium tetrahydride In tetrahydrofuran at -78℃; for 3h; Stage #2: With manganese(IV) oxide In dichloromethane at 20℃; for 2h;
	Multi-step reaction with 2 steps 1.1: lithium aluminium tetrahydride / tetrahydrofuran / -78 °C 1.2: 20 °C 2.1: manganese(IV) oxide / dichloromethane / 20 °C
	Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0.33 h / 0 °C / Inert atmosphere 2: manganese(IV) oxide / dichloromethane / 6 h / 30 °C

	Multi-step reaction with 2 steps 1: lithium borohydride / methanol; tetrahydrofuran / 55 °C 2: manganese(IV) oxide / tetrahydrofuran; dichloromethane / 20 °C
	Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 3 h / -78 °C 2: manganese(IV) oxide / dichloromethane / 2 h / 20 °C
	Multi-step reaction with 2 steps 1: diisobutylaluminium hydride / dichloromethane; tetrahydrofuran / 6 h / 20 °C 2: sodium hydrogencarbonate; Dess-Martin periodane / dichloromethane / 1 h
	Multi-step reaction with 2 steps 1: lithium borohydride / tetrahydrofuran; methanol / 55 °C 2: manganese(IV) oxide / tetrahydrofuran; dichloromethane / 20 °C
	Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 3 h / -78 °C 2: manganese(IV) oxide / dichloromethane / 2 h / 20 °C
	Multi-step reaction with 2 steps 1: methanol; lithium borohydride / tetrahydrofuran / 55 °C 2: manganese(IV) oxide / tetrahydrofuran; dichloromethane / 20 °C
	Multi-step reaction with 2 steps 1.1: lithium aluminium tetrahydride / tetrahydrofuran / -78 °C 1.2: 20 °C 2.1: manganese(IV) oxide / dichloromethane / 20 °C
	Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 3 h / 78 °C 2: manganese(IV) oxide / dichloromethane / 2 h / 20 °C
	Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0.5 h / 20 °C / Inert atmosphere 2: manganese(IV) oxide / dichloromethane / 20 °C / Inert atmosphere

Reference： [1]Montoir, David; Barillé-Nion, Sophie; Tonnerre, Alain; Juin, Philippe; Duflos, Muriel; Bazin, Marc-Antoine [European Journal of Medicinal Chemistry, 2016, vol. 119, p. 17 - 33]
[2]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2011/97526, 2011, A1
[3]Current Patent Assignee: DECIPHERA PHARMACEUTICALS LLC - US8461179, 2013, B1 Current Patent Assignee: DECIPHERA PHARMACEUTICALS LLC - WO2013/184119, 2013, A1
[4]Current Patent Assignee: BLUEPRINT MEDICINES CORP - WO2014/11900, 2014, A2
[5]Montoir, David; Tonnerre, Alain; Duflos, Muriel; Bazin, Marc-Antoine [European Journal of Organic Chemistry, 2014, vol. 2014, # 7, p. 1487 - 1495]
[6]Current Patent Assignee: INCYTE CORP - US2014/315902, 2014, A1
[7]Current Patent Assignee: BLUEPRINT MEDICINES CORP - US2015/197519, 2015, A1
[8]Montoir, David; Tonnerre, Alain; Duflos, Muriel; Bazin, Marc-Antoine [European Journal of Organic Chemistry, 2014, vol. 2014, # 7, p. 1487 - 1495]
[9]Current Patent Assignee: BLUEPRINT MEDICINES CORP - US9695165, 2017, B2
[10]Current Patent Assignee: IRM LLC - WO2009/105712, 2009, A1
[11]Current Patent Assignee: IRM LLC - WO2005/34869, 2005, A2
[12]Current Patent Assignee: FOX CHASE CANCER CENTER; TRUSTEES OF TUFTS COLLEGE, INC.; INSTITUTE FOR CANCER RES D B A THE RES INTITUTE OF FOX CHASE CANCER CENTER; THE UNIVERSITY OF HOUSTON SYSTEM - WO2020/232190, 2020, A1

6
[ 449811-29-4 ]
[ 1442471-26-2 ]
[ 1442470-77-0 ]

Yield	Reaction Conditions	Operation in experiment
67%	With aluminum oxide; potassium fluoride In N,N-dimethyl acetamide at 20℃; for 0.166667h;	A37 Example A37 To a solution of Example B3 (1 g, 5.5 mmol) and Example C5 (1.53 g, 5.5 mmol) in DMA (10 mL) was added KF/Al2O3 (3 g), and the mixture was stirred at RT for 10 min. The reaction mixture was filtered, the filtrate concentrated and the residue poured into water. The resulting solid was collected via filtration, washed with water, dried under vacuum and washed with MTBE to give 3-(5-amino-2-bromo-4-fluoro-phenyl)-7-chloro-1-methyl-1H-[1,6]naphthyridin-2-one (1.5 g, 67% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.76 (s, 1H), 7.99 (s, 1H), 7.66 (s, 1H), 7.37 (d, J=11.2, 1H), 6.75 (d, J=9.6 Hz, 1H), 5.44 (s, 2H), 3.62 (s, 3H).
67%	With potassium fluoride on basic alumina In N,N-dimethyl acetamide at 20℃; for 0.166667h;	A37 Example A37: To a solution of Example B3 (1 g, 5.5 mmol) and Example C5(1.53 g, 5.5 mmol) in DMA (10 mL) was added KF/Ab03 (3 g), and the mixture was stirredat R T for 10 min. The reaction mixture was filtered, the filtrate concentrated and the residuepoured into water. The resulting solid was collected via filtration, washed with water, driedunder vacuum and washed with MTBE to give 3-(5-amino-2-bromo-4-fluoro-phenyl)-7-chloro-1-methyl-1H-[1,6]naphthyridin-2-one (1.5 g, 67% yield). 1H NMR (400 MHz,DMSO-d6): 8 8.76 (s, 1 H), 7.99 (s, 1 H), 7.66 (s, 1 H), 7.37 (d, J = 11.2, 1 H), 6.75 (d, J = 9.6Hz, 1 H), 5.44 (s, 2 H), 3.62 (s, 3 H).

Reference： [1]Current Patent Assignee: DECIPHERA PHARMACEUTICALS LLC - US8461179, 2013, B1 Location in patent: Page/Page column 51
[2]Current Patent Assignee: DECIPHERA PHARMACEUTICALS LLC - WO2013/184119, 2013, A1 Location in patent: Paragraph 0151

7
[ 449811-29-4 ]
[ 6512-32-9 ]
[ 1538605-20-7 ]

Yield	Reaction Conditions	Operation in experiment
5.8 g	With potassium carbonate In N,N-dimethyl-formamide at 105℃; for 5h;	5 Synthesis of 7-chloro-3-(3 ,5-dimethoxyphenyl)- 1-methyl-i ,6-naphthyridin-2( 1 H)-one A mixture of 6-chloro-4-(methylamino)nicotinaldehyde (3.7 g, 21.7 mmol), methyl 2-(3,5- dimethoxyphenyl)acetate (4.5 g, 21.7 mmol) and potassium carbonate (9.0 g, 65.1 mmol) in N,Ndimethylformamide (30 mL) was heated at 105 °C for 5 h. LCMS showed the reaction wascompleted. The reaction was cooled to RT, quenched with water (200 mL), and filtered. The filtration cake was washed by petroleum ether (50 mL) and ethyl acetate (50 mL) to afford the title compound (5.8 g, 77%) as a yellow solid. MS (ES+) C18H19C1N203 requires: 346, 348, found: 347, 349 [M + H].
5.8 g	With potassium carbonate In N,N-dimethyl-formamide at 105℃; for 5h;	2.4 Synthesis of 7-chloro-3-(3,5-dimethoxyphenyl)-1-methyl-1,6-naphthyridin-2(1H)-one A mixture of 6-chloro-4-(methylamino)nicotinaldehyde (3.7 g, 21.7 mmol), methyl 2-(3,5-dimethoxyphenyl)acetate (4.5 g, 21.7 mmol) and potassium carbonate (9.0 g, 65.1 mmol) in N,N-dimethylformamide (30 mL) was heated at 105° C. for 5 h. LCMS showed the reaction was completed. The reaction was cooled to RT, quenched with water (200 mL), and filtered. The filtration cake was washed by petroleum ether (50 mL) and ethyl acetate (50 mL) to afford the title compound (5.8 g, 77%) as a yellow solid. MS (ES+) C18H19ClN2O3 requires: 346, 348, found: 347, 349 [M+H]+.
5.8 g	With potassium carbonate at 105℃; for 5h;	2.4 Step 4: Synthesis of 7-chloro-3-(3,5-dimethoxyphenyl)-1-methyl-1,6-naphthyridin-2(1H)-one A mixture of 6-chloro-4-(methylamino)nicotinaldehyde (3.7 g, 21.7 mmol), methyl 2-(3,5-dimethoxyphenyl)acetate (4.5 g, 21.7 mmol) and potassium carbonate (9.0 g, 65.1 mmol) in N,N-dimethylformamide (30 mL) was heated at 105° C. for 5 h. LCMS showed the reaction was completed. The reaction was cooled to RT, quenched with water (200 mL), and filtered. The filtration cake was washed by petroleum ether (50 mL) and ethyl acetate (50 mL) to afford the title compound (5.8 g, 77%) as a yellow solid. MS (ES+) C18H19ClN2O3 requires: 346, 348, found: 347, 349 [M+H]+.

Reference： [1]Current Patent Assignee: BLUEPRINT MEDICINES CORP - WO2014/11900, 2014, A2 Location in patent: Page/Page column 53; 54; 55
[2]Current Patent Assignee: BLUEPRINT MEDICINES CORP - US2015/197519, 2015, A1 Location in patent: Paragraph 0143; 0145
[3]Current Patent Assignee: BLUEPRINT MEDICINES CORP - US9695165, 2017, B2 Location in patent: Page/Page column 41; 42

8
[ 651734-54-2 ]
[ 449811-29-4 ]
2-chloro-5-[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-N-methylpyridin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%		Step 3: 2-chloro-5-[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-N-methylpyridin-4-amine To a mixture of <strong>[651734-54-2]2,6-difluoro-3,5-dimethoxyaniline</strong> (CAS No.651734-54-2, LakeStar Tech, LSP-210C, Lot: 132-110-05: 1.07 g, 5.68 mmol) in trifluoroacetic acid (7.9 mL, 0.1 mol) was added sodium triacetoxyborohydride (3.6 g, 17.0 mmol). The mixture was stirred at 0 C. for 2 minutes before a solution of 6-chloro-4-(methylamino)-nicotinaldehyde (0.97 g, 5.7 mmol) in methylene chloride (8.0 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight before it was concentrated in vacuo to remove the excess trifluoroacetic acid. The residue was neutralized by NaHCO3 solution. The aqueous phase was extracted with EtOAc (3*10 mL) and the organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography to afford the aniline (1.36 g, 68%). LC-MS calculated for C15H17ClF2N3O2 [M+H]+ m/z: 344.1. found 344.1.

Reference： [1]Patent: US2014/315902,2014,A1 .Location in patent: Paragraph 0267; 0268

9
[ 449811-29-4 ]
[ 57486-68-7 ]
7-chloro-3-(2-chlorophenyl)-1-methyl-1,6-naphthyridin-2(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With aluminum oxide; potassium fluoride; In N,N-dimethyl acetamide; at 20℃; for 2h;Inert atmosphere;	To a stirred solution of 54 (300 mg, 1.75 mmol) and methyl 2-(2- chlorophenyl)acetate 55 (325 mg, 1.75 mmol) in dry DMA (4 mL), KF/AI2O3 (1800 mg, 40 wt %) was added and the reaction mixture was stirred at room temperature for 2 h. After completion the reaction mixture was filtered through celite and the residual solid was washed with DCM and filtrate was concentrated. The residue was purified by column chromatography using silica gel (20 % EtOAc/Hexane) to give 56 (400 mg, 75%) as white solid. lH NMR (400 MHz, CDCb) delta (ppm) 8.54 (s, 1H), 7.72 (s, 1H), 7.44-7.39 (m, 1H), 7.34-7.26 (m, 4H), 3.65 (s, 3H).

Reference： [1]Patent: WO2018/213219,2018,A1 .Location in patent: Paragraph 0269-0270

10
[ 73998-95-5 ]
[ 449811-29-4 ]

Reference： [1]Patent: CN110272415,2019,A

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P378
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P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
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P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
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P401
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Physical hazards
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H200	Unstable explosive
H201	Explosive; mass explosion hazard
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H204	Fire or projection hazard
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H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
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H242	Heating may cause a fire
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H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
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Health hazards
Code	Phrase
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H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
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H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
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H319	Causes serious eye irritation
H320	Causes eye irritation
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H332	Harmful if inhaled
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H361d	Suspected of damaging the unborn child
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H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 449811-29-4 ] {[proInfo.proName]}

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[ 449811-29-4 ] Synthesis Path-Downstream 1~10

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