[ CAS No. 1151665-15-4 ] {[proInfo.proName]}

Name: 1151665-15-4|tert-Butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate|95%
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Product Details of [ 1151665-15-4 ]

CAS No. :	1151665-15-4	MDL No. :	MFCD10565958
Formula :	C₁₃H₁₇ClN₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	268.74	Pubchem ID :	-
Synonyms :

Safety of [ 1151665-15-4 ]

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

Application In Synthesis of [ 1151665-15-4 ]

* 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 [ 1151665-15-4 ]
Downstream synthetic route of [ 1151665-15-4 ]

[ 1151665-15-4 ] Synthesis Path-Upstream 1~3

1
[ 766545-20-4 ]
[ 24424-99-5 ]
[ 1151665-15-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2 h;	To a slurry of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride (106.1 g, 517 mmol, commercially available from D-L Chiral Chemicals, ST-0143) and N,N-diisopropylethylamine (80 g, 108 mL, 621 mmol, 1.2 eq) in DCM (1 L) was added a solution of di-tert-butyl dicarbonate (119 g, 543 mmol, 1.05 eq) in DCM (100 mL) via an addition funnel within 1 hr. The reaction mixture became a clean solution and the solution thus obtained was stirred at room temperature for an additional hour and monitored using LCMS. Upon completion, the reaction mixture was concentrated. The residue was dissolved in EtOAc (1 L) and washed with water (3*300 mL), washed with brine (300 mL) and dried over Mg50₄. The solvent was evaporated under vacuum to give the title compound as an off-white solid (139 g, yield: 100percent). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.49 (9H, s), 2.97 (2H, t, J=5.9 Hz), 3.73 (2H, t, J=6.0 Hz), 4.57 (2H, s), 7.17 (1H, d, J=8.0 Hz), 7.38 (1H, d, J=8.0 Hz) ppm; LCMS m/z: 269 (M+1).
95.41%	With triethylamine In dichloromethane at 15℃; for 12 h; Inert atmosphere	2-Chloro-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride (2.00 g, 9.75 mmol, 1.00 eq) was dissolved in DCM (20.00 mL) and triethylamine (2.47 g, 24.38 mmol, 2.50 eq) and di-tert-butyl dicarbonate (3.19 g, 14.63 mmol, 1.50 eq) were added at 15 °C under the nitrogen gas atmosphere. The mixture was stirred at 15 °C for 12 hours. The mixture was poured into water (30 mL) and the aqueous phase was extracted with dichloromethane (100 mL * 4). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to deliver tert-butyl 2-chloro-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate (2.50 g, 9.30 mmol, 95.41percent yield) as a white solid. LCMS (ESI) m / z: 269 (M + 1).
89%	With triethylamine In dichloromethane at 0 - 20℃;	Di-tert-butyl dicarbonate (2.40 g, 11 mmol) was added to a solution of 2-chloro-5,6,7,8- tetrahydro-l,6-naphthyridine hydrochloride (available from Activate Scientific) (2.05 g, 10 mmol) and Et₃N (3.33 g, 4.59 mL, 33 mmol) in DCM at 0⁰C. DMAP (0.12 g, 1.00 mmol) was added and the reaction was stirred at RT for 3 days. The reaction was diluted with DCM and washed successively with 10percent w/v citric acid (aq.), saturated NaHCO₃ (aq.), water, dried (Na₂SO₄), filtered and concentrated at reduced pressure. The residue (2.8g) was purified by FCC (SiO₂, eluting with 9:1 to 3:1 heptane / EtOAc) to give the title compound (2.63 g, 89percent). LCMS data: Calculated MH⁺ (269); Found 100percent (MH⁺) m/z 269, Rt = 1.33 min. 1H NMR (250 MHz, CHLOROFORM-J) δ ppm 1.49 (8 H, s) 2.97 (2 H, t, J=5.86 Hz) 3.73 (2 H, t, J=5.94 Hz) 4.57 (2 H, s) 7.17 (1 H, d, J=8.07 Hz) 7.38 (1 H, d, J=8.07 Hz).

Reference： [1] Patent: US2012/244110, 2012, A1, . Location in patent: Page/Page column 61
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 8, p. 3430 - 3449
[3] Patent: EP3252059, 2017, A1, . Location in patent: Paragraph 0335; 0338; 0339
[4] Patent: WO2009/121812, 2009, A1, . Location in patent: Page/Page column 78
[5] Patent: WO2013/79452, 2013, A1, . Location in patent: Page/Page column 138; 139

2
[ 24424-99-5 ]
[ 1151665-15-4 ]

Yield	Reaction Conditions	Operation in experiment
89.75%	With sodium hydrogencarbonate In dichloromethane; water at 15℃; for 2 h;	2-Chloro-5,6,7,8-tetrahydro-1,6-naphthyridine (850.00 mg, 4.14 mmol, 1.00 eq) and Di-tert-butyl dicarbonate (1.36 g, 6.22 mmol, 1.50 eq) were dissolved in a mixed solution of dichloromethane (15.00 mL) and water (15.00 mL), sodium bicarbonate (1.04 g, 12.43 mmol, 3.00 eq) was added at 15 °C. The mixture was stirred at 15 °C for 2 hours. The mixture was poured into water (30 mL) and the aqueous phase was extracted with ethyl acetate (50 mL * 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 50/1, 30/1) to deliver tert-butyl-2-chloro-7,8-dihydro-1,6-naphthyridin-6(5H)-carboxylate (1.00 g, 3.72 mmol, 89.75percent yield) as a white solid.
87%	Stage #1: With sodium hydrogencarbonate In 1,4-dioxane; water at 20℃; for 0.166667 h; Stage #2: for 16 h;	Example 22-Oxo-3-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)indoline-5-carbonitrile2.1 tert-Butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylateTo a solution of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine (500 mg, 2.97 mmol) in dioxane (7.4 mL) and water (7.4 mL) was added sodium bicarbonate in as a solid in one portion (498 mg, 5.93 mmol). After stirring the resulting suspension for 10 min at RT Boc₂O (777 mg, 3.56 mmol) was added and the mixture was stirred for 16 h. The mixture was diluted with ethyl acetate and the organic layer was washed with water and brine. The organic phase was dried over sodium sulfate, filtered, and evaporated to dryness. Amount 693 mg. Yield 87percent.¹H-NMR (CDCl₃, 400 MHz) δ 1.52 (s, 9H), 2.99 (t, 2H), 3.75 (t, 2H), 4.58 (s, 2H), 7.17 (d, 1H), 7.39 (d, 1H)MS (ES-API) m/z 369.1 (M+H⁺, 100percent).
85.44%	With triethylamine In tetrahydrofuran at 0 - 20℃; for 3.16667 h;	In a 100mL one-neck flask, 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine (170mg, 1.0mmol) (25mL) was dissolved in tetrahydrofuran,At 0 was added triethylamine (0.35mL, 2.5mmol), (Boc) 2O (240mg, 1.1mmol), stirred for 10min, then the reaction mixture was slowly raised toRoom temperature for 3h.The solvent was distilled off under reduced pressure, to the residue was added methylene chloride (100 mL) and water (100 mL), the organic layer was washed with saturated brineWash (80mL × 3), the organic layer was dried over anhydrous sodium sulfate and concentrated.The crude product was purified by column chromatography (petroleum ether / ethyl acetate(V / V) = 5/1), a pale yellow solid (229mg, 85.44percent).

Reference： [1] Patent: EP3252059, 2017, A1, . Location in patent: Paragraph 0279-0281
[2] Patent: US2012/77840, 2012, A1, . Location in patent: Page/Page column 74
[3] Patent: CN105294737, 2016, A, . Location in patent: Paragraph 0215; 0265; 0266

3
[ 210539-04-1 ]
[ 24424-99-5 ]
[ 1151665-15-4 ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: With carbonochloridic acid 1-chloro-ethyl ester In 1,2-dichloro-ethane at 90℃; for 2 h; Stage #2: for 1 h; Reflux Stage #3: With sodium hydroxide In tetrahydrofuran; water at 20℃; for 16 h;	Example 26 2-(3-Furyl)-5,6,7,8-tetrahydro-1,6-naphthyridine dihydrochloride (step 1) To a solution of the compound (2.00 g) obtained in Example 6, step 2 in dichloroethane (30 mL) was added 1-chloroethyl chloroformate (0.917 mL), and the mixture was stirred at 90°C for 2 hr. The reaction mixture was cooled to room temperature, and concentrated. To the obtained residue was added methanol (20 mL), and the mixture was stirred under reflux for 1 hr. To the reaction mixture was added diisopropyl ether (30 mL), and the precipitate was collected by filtration. A mixed solution of the obtained solid (1.55 g) and (Boc)₂O (1.69 g) in THF/1N aqueous sodium hydroxide solution (23 mL/23 mL) was stirred at room temperature for 16 hr. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (1.56 g, 75percent) as a white powder. ¹H-NMR(CDCl₃):δ1.49(9H,s), 2.97(2H,t,J=6.0Hz), 3.73(2H,d,J=6.0Hz), 4.56(2H,s), 7.17(1H,d,J=8.2Hz), 7.38(1H,d,J=8.2Hz)

Reference： [1] Patent: EP2216023, 2010, A1, . Location in patent: Page/Page column 103

[ 1151665-15-4 ] Synthesis Path-Downstream 1~88

1
[ 766545-20-4 ]
[ 24424-99-5 ]
[ 1151665-15-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h;	To a slurry of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride (106.1 g, 517 mmol, commercially available from D-L Chiral Chemicals, ST-0143) and N,N-diisopropylethylamine (80 g, 108 mL, 621 mmol, 1.2 eq) in DCM (1 L) was added a solution of di-tert-butyl dicarbonate (119 g, 543 mmol, 1.05 eq) in DCM (100 mL) via an addition funnel within 1 hr. The reaction mixture became a clean solution and the solution thus obtained was stirred at room temperature for an additional hour and monitored using LCMS. Upon completion, the reaction mixture was concentrated. The residue was dissolved in EtOAc (1 L) and washed with water (3*300 mL), washed with brine (300 mL) and dried over Mg504. The solvent was evaporated under vacuum to give the title compound as an off-white solid (139 g, yield: 100%). 1H NMR (400 MHz, CDCl3) delta ppm 1.49 (9H, s), 2.97 (2H, t, J=5.9 Hz), 3.73 (2H, t, J=6.0 Hz), 4.57 (2H, s), 7.17 (1H, d, J=8.0 Hz), 7.38 (1H, d, J=8.0 Hz) ppm; LCMS m/z: 269 (M+1).
95.41%	With triethylamine; In dichloromethane; at 15℃; for 12h;Inert atmosphere;	2-Chloro-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride (2.00 g, 9.75 mmol, 1.00 eq) was dissolved in DCM (20.00 mL) and triethylamine (2.47 g, 24.38 mmol, 2.50 eq) and di-tert-butyl dicarbonate (3.19 g, 14.63 mmol, 1.50 eq) were added at 15 C under the nitrogen gas atmosphere. The mixture was stirred at 15 C for 12 hours. The mixture was poured into water (30 mL) and the aqueous phase was extracted with dichloromethane (100 mL * 4). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to deliver tert-butyl 2-chloro-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate (2.50 g, 9.30 mmol, 95.41% yield) as a white solid. LCMS (ESI) m / z: 269 (M + 1).
92%		To a solution of compound 36 (5 g, 24.4 mmol, 1 eq) in DCM (40 mL) was added DIEA (9.45 g, 73.1 mmol, 3 eq) and stirred for 20 mins, B0C2O (6.5 g, 29.3 mmol, 1.2 eq) in DCM (30 mL) was added drop wise and then stirred for lh. After LCMS and TLC indicated completion, the mixture was concentrated and the residue was dissolved in EA (200 mL), washed with water (100 mL X 3) and brine (100 mL), dried over sodium sulfate, concentrated and purified by silica column to give the desired product as white solid (6 g, 92%). *H NMR (300 MHz, CDCb-de): delta 7.39 (d, J= 8.1 Hz, 1 H), 7.18 (d, J= 8.1 Hz, 1 H), 4.57 (s, 2 H), 3.74 (t, J= 6.0 Hz, 2 H), 2.98 (t, J= 5.4 Hz 2 H), 1.53 (s, 9 H). LCMS: (M+H)+: 268.9.

89%	With triethylamine;dmap; In dichloromethane; at 0 - 20℃;	Di-tert-butyl dicarbonate (2.40 g, 11 mmol) was added to a solution of 2-chloro-5,6,7,8- tetrahydro-l,6-naphthyridine hydrochloride (available from Activate Scientific) (2.05 g, 10 mmol) and Et3N (3.33 g, 4.59 mL, 33 mmol) in DCM at 00C. DMAP (0.12 g, 1.00 mmol) was added and the reaction was stirred at RT for 3 days. The reaction was diluted with DCM and washed successively with 10% w/v citric acid (aq.), saturated NaHCO3 (aq.), water, dried (Na2SO4), filtered and concentrated at reduced pressure. The residue (2.8g) was purified by FCC (SiO2, eluting with 9:1 to 3:1 heptane / EtOAc) to give the title compound (2.63 g, 89%). LCMS data: Calculated MH+ (269); Found 100% (MH+) m/z 269, Rt = 1.33 min. 1H NMR (250 MHz, CHLOROFORM-J) delta ppm 1.49 (8 H, s) 2.97 (2 H, t, J=5.86 Hz) 3.73 (2 H, t, J=5.94 Hz) 4.57 (2 H, s) 7.17 (1 H, d, J=8.07 Hz) 7.38 (1 H, d, J=8.07 Hz).
	With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere;	To a solution of 2-chloro-5,6,7,8-tetrahydro-[l,6]naphthyridine hydrochloride (1.54 g, 7.5 mmol) in DCM (25 mL) was added EtsN (2 mL, 15 mmol). After the addition and stirring - 139 -at room temperature for 5 min, the solution was cooled to 0 C, followed by the addition of (Boc)20 (1.88 g, 8.63 mmol). The resulting reaction mixture was then allowed to stir at room temperature for 2 hours. It was then washed with H20 and brine. The organic layer was dried over anhy. Na2S04, filtered and concentrated in vacuo to give the title compound (1.87 g, 93%) as a white solid. MS: 269.1 (M+H+). It was used directly in the next step without further purification.

Reference： [1]Patent: US2012/244110,2012,A1 .Location in patent: Page/Page column 61
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 3430 - 3449
[3]Patent: EP3252059,2017,A1 .Location in patent: Paragraph 0335; 0338; 0339
[4]Patent: WO2019/35008,2019,A1 .Location in patent: Paragraph 666-668
[5]Patent: WO2009/121812,2009,A1 .Location in patent: Page/Page column 78
[6]Patent: WO2013/79452,2013,A1 .Location in patent: Page/Page column 138; 139

2
[ 869224-62-4 ]
[ 1151665-15-4 ]
[ 1190440-42-6 ]

Yield	Reaction Conditions	Operation in experiment
55%	With potassium tert-butylate; In 1,4-dioxane; at 115℃; for 0.666667h;Inert atmosphere; Microwave irradiation;	A mixture of tert-butyl 2-chloro-7,8-dihydro-l,6-naphthyridine-6(5H)-carboxylate ( 0.59 g, 2.20 mmol), l-cyclobutylpiperidin-4-ol (0.52 g, 3.30 mmol) and potassium tert-butoxide (0.62 g, 5.50 mmol) in dioxane (20 volumes) was heated at 115C for 40 min in a CEM microwave reactor (150W) under N2 (g) atmosphere. The reaction mixture was diluted with EtOAc, <n="80"/>washed with brine, dried (Na2SO4), filtered and concentrated at reduced pressure. The residue (0.9 g) was purified by FCC (SiO2, eluting with DCM/MeOH/NH3, 90:10:1) to give the title compound (0.47 g, 55%).LCMS data: Calculated MH+ (387); Found 100% (M+) m/z 387, Rt = 5.78 min. 1H NMR (250 MHz, CHLOROFORM-J) delta ppm 1.38 - 2.15 (21 H, m) 2.47 - 2.81 (5 H, m) 3.63 (2 H, t, J=5.86 Hz) 4.40 (2 H, s) 4.97 (1 H, br. s.) 6.47 (1 H, d, J=8.38 Hz) 7.06 (1 H, d, J=8.38 Hz).

Reference： [1]Patent: WO2009/121812,2009,A1 .Location in patent: Page/Page column 78-79

3
[ 55552-70-0 ]
[ 1151665-15-4 ]
[ 1151665-16-5 ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 150℃; for 0.333333h;Inert atmosphere; Microwave irradiation;	(step 2) To a mixed solution of the compound (0.300 g) obtained in step 1, 3-furylboronic acid (0.187 g) and potassium carbonate (0.154 g) in DME/water (6 mL)/0.6 mL) was added under an argon atmosphere tetrakis(triphenylphosphine)palladium (0) (Pd(PPh3)4) (0.129 g), and the reaction vessel was irradiated in a microwave reaction apparatus at 150C for 20 min. To the reaction solution was added water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (solvent gradient: 0?30% ethyl acetate/hexane) to give tert-butyl 2-(3-furyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (0.310 g, 92%) as an oil. 1H-NMR(CDCl3):delta1.50(9H,s), 2.95-3.05(2H,m), 3.73-3.77(2H,m), 4.58(2H,s), 6.87(1H,dd,J=1.7Hz,0.7Hz), 7.29(1H,d,J=8.2Hz), 7.39(1H,d,J=8.2Hz), 7.47(1H,dd,J=1.7Hz,1.7Hz), 7.99(1H,s)

Reference： [1]Patent: EP2216023,2010,A1 .Location in patent: Page/Page column 103-104

4
[ 210539-04-1 ]
[ 24424-99-5 ]
[ 1151665-15-4 ]

Yield	Reaction Conditions	Operation in experiment
75%		Example 26 2-(3-Furyl)-5,6,7,8-tetrahydro-1,6-naphthyridine dihydrochloride (step 1) To a solution of the compound (2.00 g) obtained in Example 6, step 2 in dichloroethane (30 mL) was added 1-chloroethyl chloroformate (0.917 mL), and the mixture was stirred at 90C for 2 hr. The reaction mixture was cooled to room temperature, and concentrated. To the obtained residue was added methanol (20 mL), and the mixture was stirred under reflux for 1 hr. To the reaction mixture was added diisopropyl ether (30 mL), and the precipitate was collected by filtration. A mixed solution of the obtained solid (1.55 g) and (Boc)2O (1.69 g) in THF/1N aqueous sodium hydroxide solution (23 mL/23 mL) was stirred at room temperature for 16 hr. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (1.56 g, 75%) as a white powder. 1H-NMR(CDCl3):delta1.49(9H,s), 2.97(2H,t,J=6.0Hz), 3.73(2H,d,J=6.0Hz), 4.56(2H,s), 7.17(1H,d,J=8.2Hz), 7.38(1H,d,J=8.2Hz)

Reference： [1]Patent: EP2216023,2010,A1 .Location in patent: Page/Page column 103

5
[ 1013-88-3 ]
[ 1151665-15-4 ]
[ 1346673-94-6 ]

Yield	Reaction Conditions	Operation in experiment
33%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃; for 3.08333h;Inert atmosphere;	Nitrogen was bubbled into a solution of compound 37 (1.0 g, 3.7 mmol, 1.0 eq), compound 38 (742 mg, 4.1 mmol, 1.1 eq), Pd2(dba)3 (340 mg, 0.37 mmol, 0.1 eq), Xantphos (454 mg, 0.78 mmol, 0.21 eq) and CS2CO3 (2.4 g, 7.4 mmol, 2 eq) in dioxane (20 mL) for 5 mins. The mixture was stirred at 110 C for 3 h. After completion, the mixture was cooled down to RT, diluted with DCM (50 mL) and filtered through a pad of Celite, rinsed with DCM (20 mL). The filtrate was dried over sodium sulfate, concentrated and purified by silica column to give the desired product as a yellow solid (0.5 g, 33%). NMR (300 MHz, CDCb): delta 7.36-7.25 (m, 10 H), 7.17 (d, J= 8.1 Hz, 1 H), 6.35 (d, J= 8.4 Hz, 1 H), 4.48 (s, 2 H), 3.70 (t, J= 6.0 Hz, 2 H), 2.92 (s, J= 6.0 Hz, 2 H), 1.50 (s, 9 H). LCMS: (M+H)+:413.9.
	With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 110℃; for 48h;	To a round-bottomed flask equipped with a stirring bar, tert-butyl 2-chloro-7,8- dihydro-l,6-naphthyridine-6(5H)-carboxylate (1.09 g, 4.05 mmol), diphenyl-methanimine 26 (2.20 g, 12.14 mmol), Pd(OAc)2 (181.6 mg, 0.809 mmol), BINAP (503.8 mg, 0.809 mmol), CS2CO3 (6.59 g, 20.23 mmol) and toluene (16 mL) were added. The reaction mixture was heated at 110 C for 2 days. The reaction mixture was filtered and removed solvent in vacuo. The residue 158a was directly used in the next step.
	With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate;	Intermediate W-1 was synthesized through the reaction of <strong>[1151665-15-4]tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate</strong> with benzophenone imine and tert-butoxysodium in the presence of a Pd catalyst and deprotection.

Reference： [1]Patent: WO2019/35008,2019,A1 .Location in patent: Paragraph 666; 669; 670
[2]Patent: WO2011/140488,2011,A1 .Location in patent: Page/Page column 228; 229
[3]Patent: EP3305785,2018,A1 .Location in patent: Paragraph 0237

6
[ 1151665-15-4 ]
[ 1149333-40-3 ]

Reference： [1]Patent: WO2011/140488,2011,A1
[2]Patent: CN105294737,2016,A
[3]Patent: EP3305785,2018,A1
[4]Patent: WO2019/35008,2019,A1

7
[ 1151665-15-4 ]
[ 1346673-95-7 ]

Reference： [1]Patent: WO2011/140488,2011,A1

8
[ 1151665-15-4 ]
[ 1346673-96-8 ]

Reference： [1]Patent: WO2011/140488,2011,A1

9
[ 1151665-15-4 ]
[ 1346670-07-2 ]

Reference： [1]Patent: WO2011/140488,2011,A1

10
2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine [ No CAS ]
[ 24424-99-5 ]
[ 1151665-15-4 ]

Yield	Reaction Conditions	Operation in experiment
97%	With triethylamine; In dichloromethane; at 20℃; for 1h;Cooling with ice;	1) In a 250mL single-mouth bottle,will2-chloro-5,6,7,8-tetrahydronaphthyridine 20.0g and 14.0gTriethylamine was dissolved in 50 mL of dichloromethane.The solution was stirred and cooled in an ice salt bath.27.2g Boc2O was added dropwise,After the addition was completed, the reaction was carried out at room temperature for 1 h.Dilute with 50 mL of dichloromethane.Wash twice with 1 mol/L of dilute hydrochloric acid,Wash once with saturated sodium bicarbonate and once with saturated brine.The organic phase was dried over anhydrous magnesium sulfate.filter,The filtrate was spun dry to give 30.9 g of a pale yellow color.which is2-chloro-6-tert-butoxycarbonyl-5,7,8-trihydro-1,6-naphthyridine, yield 97%,
89.75%	With sodium hydrogencarbonate; In dichloromethane; water; at 15℃; for 2h;	2-Chloro-5,6,7,8-tetrahydro-1,6-naphthyridine (850.00 mg, 4.14 mmol, 1.00 eq) and Di-tert-butyl dicarbonate (1.36 g, 6.22 mmol, 1.50 eq) were dissolved in a mixed solution of dichloromethane (15.00 mL) and water (15.00 mL), sodium bicarbonate (1.04 g, 12.43 mmol, 3.00 eq) was added at 15 C. The mixture was stirred at 15 C for 2 hours. The mixture was poured into water (30 mL) and the aqueous phase was extracted with ethyl acetate (50 mL * 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 50/1, 30/1) to deliver tert-butyl-2-chloro-7,8-dihydro-1,6-naphthyridin-6(5H)-carboxylate (1.00 g, 3.72 mmol, 89.75% yield) as a white solid.
87%		Example 22-Oxo-3-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)indoline-5-carbonitrile2.1 tert-Butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylateTo a solution of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine (500 mg, 2.97 mmol) in dioxane (7.4 mL) and water (7.4 mL) was added sodium bicarbonate in as a solid in one portion (498 mg, 5.93 mmol). After stirring the resulting suspension for 10 min at RT Boc2O (777 mg, 3.56 mmol) was added and the mixture was stirred for 16 h. The mixture was diluted with ethyl acetate and the organic layer was washed with water and brine. The organic phase was dried over sodium sulfate, filtered, and evaporated to dryness. Amount 693 mg. Yield 87%.1H-NMR (CDCl3, 400 MHz) delta 1.52 (s, 9H), 2.99 (t, 2H), 3.75 (t, 2H), 4.58 (s, 2H), 7.17 (d, 1H), 7.39 (d, 1H)MS (ES-API) m/z 369.1 (M+H+, 100%).

85.44%

With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 3.16667h;

In a 100mL one-neck flask, 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine (170mg, 1.0mmol) (25mL) was dissolved in tetrahydrofuran,At 0 was added triethylamine (0.35mL, 2.5mmol), (Boc) 2O (240mg, 1.1mmol), stirred for 10min, then the reaction mixture was slowly raised toRoom temperature for 3h.The solvent was distilled off under reduced pressure, to the residue was added methylene chloride (100 mL) and water (100 mL), the organic layer was washed with saturated brineWash (80mL × 3), the organic layer was dried over anhydrous sodium sulfate and concentrated.The crude product was purified by column chromatography (petroleum ether / ethyl acetate(V / V) = 5/1), a pale yellow solid (229mg, 85.44%).

Reference： [1]Patent: CN107021965,2019,B .Location in patent: Paragraph 0021; 0023
[2]Patent: EP3252059,2017,A1 .Location in patent: Paragraph 0279-0281
[3]Patent: US2012/77840,2012,A1 .Location in patent: Page/Page column 74
[4]Patent: CN105294737,2016,A .Location in patent: Paragraph 0215; 0265; 0266

11
[ 1151665-15-4 ]
[ 1401034-54-5 ]

Reference： [1]Patent: US2012/244110,2012,A1

12
[ 1151665-15-4 ]
[ 1401034-02-3 ]

Reference： [1]Patent: US2012/244110,2012,A1

13
[ 1151665-15-4 ]
[ 1401034-03-4 ]

Reference： [1]Patent: US2012/244110,2012,A1

14
[ 1169698-48-9 ]
[ 1151665-15-4 ]
[ 1401034-58-9 ]

Yield	Reaction Conditions	Operation in experiment
72%	With 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 150℃; for 1h;Microwave radiation;	To a solution of 9-cyclopentyl-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-amine (prepared as described in WO 2009/085185) (152 mg, 0.6 mmol) in dioxane (6 mL) were added <strong>[1151665-15-4]tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate</strong> (177 mg, 0.66 mmol), tris(dibenzylideneacetone)dipalladium (0) (28 mg, 0.030 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (52 mg, 0.090 mmol), and sodium t-butoxide (86 mg, 0.9 mmol). The reaction mixture thus obtained was heated at 150 C. under microwave irradiation for 1 hour. The reaction mixture was diluted with DCM, washed with brine, and then dried. The solvent was evaporated and the residue was purified by flash chromatography on silica gel eluting with 10% to 50% solvent A (DCM/MeOH/NH4OH, 100:10:1) in DCM to give the title compound as a light yellow solid (211 mg, 72% yield). 1H NMR (500 MHz, CDCl3) delta 1.52 (9H, s), 1.88-1.90 (2H, m), 2.14-2.21 (4H, m), 2.45-2.47 (2H, m), 2.92-2.94 (2H, m), 3.76-3.79 (2H, m), 4.59 (2H, m), 5.37 (1H, m), 7.49 (1H, d, J=10.0 Hz), 7.85 (1H, d, J=5.0 Hz), 8.14 (1H, br. s), 8.37 (1H, d, J=10.0 Hz), 8.52 (1H, d, J=5.0 Hz), 8.92 (1H, s), 9.11 (1H, s) ppm; LCMS m/z: 486 (M+1).

Reference： [1]Patent: US2012/244110,2012,A1 .Location in patent: Page/Page column 83

15
[ 1151665-15-4 ]
[ 1401034-53-4 ]

Yield	Reaction Conditions	Operation in experiment
78.52%	With 3-chloro-benzenecarboperoxoic acid; In chloroform; at 0 - 25℃; for 12h;	tert-Butyl-2-chloro-7,8-dihydro-1,6-naphthyridin-6(5H)-carboxylate (1.20 g, 4.47 mmol, 1.00 eq) was dissolved in chloroform (20.00 mL) and m-chloroperbenzoic acid (1.45 g, 6.71 mmol, 1.50 eq) was added to the mixture at 0 C. The mixture was stirred at 25 C for 12 hours. The mixture was then quenched with a saturated sodium sulfate solution (20 mL) and extracted with dichloromethane (40 ml * 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to deliver tert-butyl-2-chloro-1-oxo-7,8-dihydro-5H-1,6-naphthyridin-1-onium-6-carboxylate (1.00 g, 3.51 mmol, 78.52% yield) as a yellow solid which was used directly in the next step. LCMS (ESI) m / z: 285 (M + 1).
56.6%	With 3-chloro-benzenecarboperoxoic acid; In chloroform; at 0 - 20℃;	3-Chlorobenzoperoxoic acid (241 mg, 1.4 mmol) was added to a solution at 0 C. of <strong>[1151665-15-4]tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate</strong> (250 mg, 0.93 mmol, see Example 1 procedure) in CHCl3 (3 mL). The reaction mixture thus obtained was warmed to room temperature and stirred overnight. After concentration, the residue was purified by flash chromatography on silica gel eluting with 0% to 80% EtOAc in hexane to give the title compound (150 mg, 56.6% yield). 1H NMR (400 MHz, CDCl3) delta ppm 1.51 (9H, s), 3.11 (2H, m), 3.77 (2H, t, J=6.16 Hz), 4.60 (2H, s), 6.99 (1H, d, J=8.41 Hz), 7.40 (1H, d, J=8.41 Hz) ppm; LC/MS m/z: 285 (M+1).

Reference： [1]Patent: EP3252059,2017,A1 .Location in patent: Paragraph 0279; 0282; 0283
[2]Patent: US2012/244110,2012,A1 .Location in patent: Page/Page column 77

16
[ 1151665-15-4 ]
[ 1401033-82-6 ]

Reference： [1]Patent: US2012/244110,2012,A1
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 3430 - 3449
[3]Organic Process Research and Development,2015,vol. 19,p. 476 - 485

17
[ 1151665-15-4 ]
1-[2-({9-[(1r,4r)-4-methylcyclohexyl]-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-yl}amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]ethanone [ No CAS ]

Reference： [1]Patent: US2012/244110,2012,A1

18
[ 1151665-15-4 ]
[ 1401033-84-8 ]

Reference： [1]Patent: US2012/244110,2012,A1

19
[ 1151665-15-4 ]
[ 1401034-47-6 ]

Reference： [1]Patent: US2012/244110,2012,A1
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 3430 - 3449

20
[ 1151665-15-4 ]
[ 1401033-86-0 ]

Reference： [1]Patent: US2012/244110,2012,A1
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 3430 - 3449
[3]Organic Process Research and Development,2015,vol. 19,p. 476 - 485

21
[ 1151665-15-4 ]
[ 1401034-19-2 ]

Reference： [1]Patent: US2012/244110,2012,A1
[2]Organic Process Research and Development,2015,vol. 19,p. 476 - 485

22
[ 1151665-15-4 ]
[ 1401033-87-1 ]

Reference： [1]Patent: US2012/244110,2012,A1

23
[ 1151665-15-4 ]
[ 1401034-48-7 ]

Reference： [1]Patent: US2012/244110,2012,A1

24
[ 1151665-15-4 ]
[ 1401033-88-2 ]

Reference： [1]Patent: US2012/244110,2012,A1

25
[ 1151665-15-4 ]
[ 1401033-90-6 ]

Reference： [1]Patent: US2012/244110,2012,A1

26
[ 1151665-15-4 ]
[ 1401033-91-7 ]

Reference： [1]Patent: US2012/244110,2012,A1

27
[ 1151665-15-4 ]
[ 1401034-13-6 ]

Reference： [1]Patent: US2012/244110,2012,A1

28
[ 1151665-15-4 ]
C₂₆H₂₉N₇O₂*(x)H₃O₄P [ No CAS ]

Reference： [1]Patent: US2012/244110,2012,A1

29
[ 1151665-15-4 ]
(x)C₆H₈O₇*C₂₆H₂₉N₇O₂ [ No CAS ]

Reference： [1]Patent: US2012/244110,2012,A1

30
[ 1151665-15-4 ]
(x)C₄H₆O₆*C₂₆H₂₉N₇O₂ [ No CAS ]

Reference： [1]Patent: US2012/244110,2012,A1

31
[ 1151665-15-4 ]
(x)C₇H₆O₃*C₂₆H₂₉N₇O₂ [ No CAS ]

Reference： [1]Patent: US2012/244110,2012,A1

32
[ 1151665-15-4 ]
(x)C₆H₆O₃S*C₂₆H₂₉N₇O₂ [ No CAS ]

Reference： [1]Patent: US2012/244110,2012,A1

33
[ 1151665-15-4 ]
(x)C₇H₈O₃S*C₂₆H₂₉N₇O₂ [ No CAS ]

Reference： [1]Patent: US2012/244110,2012,A1

34
[ 1151665-15-4 ]
C₂₆H₂₉N₇O₂*(x)H₂O₄S [ No CAS ]

Reference： [1]Patent: US2012/244110,2012,A1

35
[ 1151665-15-4 ]
[ 1412895-86-3 ]

Reference： [1]Patent: US2012/244110,2012,A1

36
[ 1151665-15-4 ]
(x)C₂H₆O₃S*C₂₆H₂₉N₇O₂ [ No CAS ]

Reference： [1]Patent: US2012/244110,2012,A1

37
[ 1151665-15-4 ]
(x)C₂H₆O₆S₂*C₂₆H₂₉N₇O₂ [ No CAS ]

Reference： [1]Patent: US2012/244110,2012,A1

38
[ 1151665-15-4 ]
[ 1401034-45-4 ]
[ 1401034-46-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 100℃; for 3h;Inert atmosphere;	To a solution of 9-((1r,4r)-4-methylcyclohexyl)-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-amine (2.81 g, 10 mmol) in 1,4-dioxane (45 mL) were added <strong>[1151665-15-4]tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate</strong> (2.57 g, 9.55 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanene (231 mg, 0.40 mmol), and sodium t-butoxide (1.44 g, 15 mmol). Argon was bubbled through the mixture for 10 minutes. Tris(dibenzylideneacetone)dipalladium (0)(183 mg, 0.20 mmol) was added, and argon was again bubbled through the mixture for 5 minutes. The reaction mixture thus obtained was stirred at 100 C. for 3 hours whereupon HPLC-MS analysis indicated that the reaction was complete. The reaction mixture was cooled to 40 C. and diluted with DCM (90 mL) and treated with Si-triamine (functionalized silica gel, from Silicycle, FR31017TR130B) (2.8 g) overnight at room temperature. Celite brand filter aid 545 (6 g) was added, and the mixture was filtered with a sintered glass funnel and the solid phase was rinsed with DCM (100 mL). The filtrate was concentrated to 25 mL on a rotary evaporator and diluted with a mixture of EtOAc and hexane (20 mL, 4:1). The resulting slurry was stirred at room temperature for 5 hours. The solid was collected by filtration, washed with a mixture of EtOAc and hexane (20 mL, 1:1) and air dried for a few hours to provide the title compound as an off-white solid (4.90 g, 100% yield). 1H NMR (500 MHz, CD2Cl2) delta ppm 1.06 (3H, d, J=6.4 Hz), 1.34-1.22 (2H, m), 1.48 (9H, s), 1.67 (1H, br. s), 2.02-1.93 (4H, m), 2.63 (2H, dq, J=3.1, 12.8 Hz), 2.88 (2H, t, J=5.7 Hz), 3.74 (2H, t, J=6.0 Hz), 4.57 (2H, s), 7.51 (1H, d, J=8.6 Hz), 7.85 (1H, d, J=5.1 Hz), 8.10 (1H, br. s), 8.42 (1H, d, J=8.3 Hz), 8.46 (1H, d, J=4.9 Hz), 8.97 (1H, s), 9.10 (1H, s) ppm; LCMS m/z: 514(M+1).

Reference： [1]Patent: US2012/244110,2012,A1 .Location in patent: Page/Page column 62
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 3430 - 3449
[3]Organic Process Research and Development,2015,vol. 19,p. 476 - 485

39
[ 1151665-15-4 ]
6-acetyl-8-cyclopentyl-5-methyl-2-((5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one [ No CAS ]

Reference： [1]Patent: WO2016/15598,2016,A1

40
[ 1151665-15-4 ]
[ 1226898-92-5 ]

Yield	Reaction Conditions	Operation in experiment
85.73%	With ruthenium trichloride; sodium periodate; In tetrachloromethane; at 20℃;	Step 1) tert-butyl 2-chloro-5-oxo-7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylate [0606]To a 100 mL of dry one-neck flask were added tert-butyl 2-chloro-7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylate (500 mg, 1.86 mmol) , a solution of ruthenium (III) chloride (100 mg, 0.48 mmol) in tetrachloromethane (16 mL) in turn, and then sodium periodate (1.2 g, 5.6 mmol) was added, the reaction mixture was stirred at rt The reaction was monitored by TLC and LC-MS until the reaction was completed. The reaction mixture was concentrated in vacuo. The residue was diluted with water (100 mL) , and extracted with DCM (100 mL × 2) . The combined organic layers were washed with saturated aqueous NaCl (100 mL × 1) and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with DCM/MeOH (V/V) 10/1 to give a yellow solid product (451 mg, 85.73) .[0607]MS-ESI: (ESI, pos. ion) m/z: 283.6 [M+1]+
74.38%	With ruthenium trichloride; sodium periodate; In tetrachloromethane; water; acetonitrile; at 15℃; for 12h;Inert atmosphere;	Sodium pentachlorate (5.49 g, 25.68 mmol, 3.00 eq) and RuCl3 (532.58 mg, 2.57 mmol, 0.30 eq) were added to a mixed solution of <strong>[1151665-15-4]tert-butyl 2-chloro-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate</strong> (2.30 g, 8.56 mmol, 1.00 eq) in acetonitrile (740.00 muL) and carbon tetrachloride (37.00 mL) and water (14.80 mL) at 15 C under the nitrogen gas atmosphere. The mixture was stirred at 15 C for 12 hours. The mixture was poured into water (20 mL) and then extracted with dichloromethane (100 mL * 4). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100 to 200 mesh silica gel, petroleum ether / ethyl acetate = 20/1 to 10/1) to deliver tert-butyl 2-chloro-5-oxo-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (1.80 g, 6.37 mmol, 74.38% yield) as a white solid. 1H NMR (400MHz, CDCl3): delta 8.38 (d, J = 8.3 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 4.13-4.04 (m, 2H), 3.24-3.12 (m, 2H), 1.60 (s, 9H). LCMS (ESI) m/z: 283 (M+1).

Reference： [1]Patent: WO2016/15598,2016,A1 .Location in patent: Paragraph 00309
[2]Patent: EP3252059,2017,A1 .Location in patent: Paragraph 0335; 0340; 0341

41
[ 1151665-15-4 ]
tert-butyl 2-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-5-oxo-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate [ No CAS ]

Reference： [1]Patent: WO2016/15598,2016,A1

42
[ 1151665-15-4 ]
[ 100-51-6 ]
tert-butyl 2-benzyloxy-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1 g		To a solution of tert-butyl 2-chloro-7 ,8-dihydro-5H- 1 ,6-naphthyridine-6-carboxylate (1.0 g,3.7 mmol) in toluene (10 mL) was added KOH (0.6 g, 11.1 mmol) at 0 C and the mixture was stirred for 0.5 hr. To the resulting mixture was added a solution of BnOH (0.34 g, 5.6 mmol) in toluene (10 mL) followed by 18-crown-6 (100 mg) at 0C. The resulting mixture was heated with stirring at 130 C for 2 hrs and then filtered. The filtrate was concentrated in vacuo. Theresidue was purified by flash column to give tert-butyl 2-benzyloxy-7,8-dihydro-5H-1,6- naphthyridine-6-carboxylate (1 g).

Reference： [1]Patent: WO2016/107832,2016,A1 .Location in patent: Page/Page column 161

43
[ 1151665-15-4 ]
2-(pyridin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine [ No CAS ]

Reference： [1]Patent: WO2016/107832,2016,A1

44
[ 1151665-15-4 ]
2-benzyloxy-5,6,7,8-tetrahydro-1,6-naphthyridine [ No CAS ]

Reference： [1]Patent: WO2016/107832,2016,A1

45
[ 1151665-15-4 ]
2-benzyloxy-6-(3,4-difluoro-5-methoxyphenyl)-7,8-dihydro-5H-1,6-naphthyridine [ No CAS ]

Reference： [1]Patent: WO2016/107832,2016,A1

46
[ 1151665-15-4 ]
6-(3,4-difluoro-5-methoxyphenyl)-7,8-dihydro-5H-1,6-naphthyridin-2-ol [ No CAS ]

Reference： [1]Patent: WO2016/107832,2016,A1

47
[ 1151665-15-4 ]
[6-(3,4-difluoro-5-methoxyphenyl)-7,8-dihydro-5H-1,6-naphthyridin-2-yl] trifluoromethanesulfonate [ No CAS ]

Reference： [1]Patent: WO2016/107832,2016,A1

48
[ 1151665-15-4 ]
6-(4-methylsulfonylphenyl)-2-(2-pyridyl)-7,8-dihydro-5H-1,6-naphthyridine [ No CAS ]

Reference： [1]Patent: WO2016/107832,2016,A1

49
[ 1151665-15-4 ]
6-(3,4-difluoro-5-methoxyphenyl)-2-pyrimidin-2-yl-7,8-dihydro-5H-1,6-naphthyridine [ No CAS ]

Reference： [1]Patent: WO2016/107832,2016,A1

50
[ 1151665-15-4 ]
[ 17997-47-6 ]
tert-butyl 2-(2-pyridyl)-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.1 g	With bis-triphenylphosphine-palladium(II) chloride; In 1-methyl-pyrrolidin-2-one; at 150℃; for 0.5h;Inert atmosphere; Sealed tube; Microwave irradiation;	To a reaction vessel containing a solution of tert-butyl 2-chloro-7,8-dihydro-5H-1,6- naphthyridine-6-carboxylate (1.0 g, 3.72 mmol) in NMP (5 mL) was added tributyl(2- pyridyl)stannane (2.06 g, 5.58 mmol) and Pd2C12(PPh3)2 (260 mg, 0.37 mmol) under an argonatmosphere. The reaction vessel was sealed and heated at 150 C for 30 minutes in a microwave reactor. After being cooled to rt, the resulting reaction mixture was diluted with water (10 mL) and extracted with DCM (20 mL) for three times. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column to afford tert-butyl 2-(2-pyridyl)-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate (1.1 g) as a white solid.

Reference： [1]Patent: WO2016/107832,2016,A1 .Location in patent: Page/Page column 146

51
[ 1151665-15-4 ]
tert-butyl 2-[7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carboxylate [ No CAS ]

Reference： [1]Patent: CN105294737,2016,A

52
[ 1151665-15-4 ]
7-cyclopentyl-N,N-dimethyl-2-[(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide [ No CAS ]

Reference： [1]Patent: CN105294737,2016,A

53
[ 1151665-15-4 ]
7-cyclopentyl-2-[6-(2-hydroxyacetyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl]amino}-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide [ No CAS ]

Reference： [1]Patent: CN105294737,2016,A

54
[ 1151665-15-4 ]
7-cyclopentyl-N,N-dimethyl-2-[6-(3,3,3-trifluoropropyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide [ No CAS ]

Reference： [1]Patent: CN105294737,2016,A

55
[ 1151665-15-4 ]
2-[(6-acetyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino]-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide [ No CAS ]

Reference： [1]Patent: CN105294737,2016,A

56
[ 1151665-15-4 ]
C₂₄H₃₁N₇O [ No CAS ]

Reference： [1]Patent: CN105294737,2016,A

57
[ 1151665-15-4 ]
benzophenoneimine [ No CAS ]
[ 1346673-94-6 ]

Yield	Reaction Conditions	Operation in experiment
69.56%	With 4,5-bis-(di-tert-butyl-phosphanyl)-9,9-dimethyl-9H-xanthene; tris(dibenzylideneacetone)dipalladium(0) chloroform complex; caesium carbonate; In 1,4-dioxane; at 110℃; for 3h;Inert atmosphere;	Under nitrogen, benzophenone imine (200mg,1.1mmol), 2- chloro-7,8-tetrahydro-1,6-naphthyridin--6 (5H) - carboxylate (220mg, 1.0mmol), cesium carbonate (652mg,2.0mmol), 4,5- dimethyl-9,9-bis diphenylphosphino xanthene (58mg, 0.1mmol) andtris (dimethyleneBenzyl) dipalladium (92mg, 0.1mmol) wasdissolved in 1,4-dioxane (25mL) was stirred and heated to 110 , the reaction 3h. Cooled to room temperature,Dichloromethane (100 mL) was diluted,filtered through Celite, and the filtrate was concentrated under reducedpressure and the solvent was evaporated, residue was separated by columnchromatography (methylene chloride / AAlcohol (V / V) = 10/1) to give a paleyellow solid (288mg, 69.56%).

Reference： [1]Patent: CN105294737,2016,A .Location in patent: Paragraph 0215; 0268; 0269

58
[ 1151665-15-4 ]
potassium (4-(benzyloxy)phenyl)trifluoroborate [ No CAS ]
tert-butyl 2-(4-(benzyloxy)phenyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In N,N-dimethyl-formamide; at 120℃; for 1h;Inert atmosphere;	Compound IXa was prepared in accordance with scheme 1 starting from tert-butyl2-cMoro- 7,8- dihydro- 1, 6-naphthyridine- 6(5H) -carboxylate instead of compound III.To a solution of tert-butyl 2-chloro- 7,8- dihydro- 1,6- naphthyridine- 6(5H) -carboxylate (500 mg; 1.86 mmol, 1 eq) in 15 mL DMF was added potassium (4-benzyloxyphenyl)-trifluoroborate (648 mg; 2.23 mmol; 1.2 eq) and sodium carbonate (493 mg; 4.65 mmol; 2.5 eq). The mixture was degassed with argon for 10 mm. Tetrakis(triphenylphosphine)-palladium(0) (107 mg; 0.093 mmol; 0.05 eq) was added and the mixture was stirred for lh at 120C. The reaction mixture wasevaporated, the residue was dissolved in DCM/water. After phase separation, the organic phase was washed once with a saturated NaC1 solution, dried with MgSO4, filtered and evaporated. The residue was purified by flash chromatography (silica gel, 0-5% MeOH in DCM) giving tert-butyl 2-(4-(benzyloxy)phenyl)-7,8-dihydro-1,6- naphthyridine-6(5H)-carboxyate with a yieffl of 600 mg (1.441 mmo 77%).

Reference： [1]Patent: WO2017/36978,2017,A1 .Location in patent: Page/Page column 81

59
[ 1151665-15-4 ]
3-(2-(4-(benzyloxy)phenyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-methylpropanoic acid [ No CAS ]