[ CAS No. 59514-89-5 ] {[proInfo.proName]}

Name: 59514-89-5|2,4-Dichloro-1,8-naphthyridine|97%
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SKU: A190384
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Quality Control of [ 59514-89-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 59514-89-5 ]

Product Details of [ 59514-89-5 ]

CAS No. :	59514-89-5	MDL No. :	MFCD00234380
Formula :	C₈H₄Cl₂N₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CCQHBZIXZFQYSO-UHFFFAOYSA-N
M.W :	199.04	Pubchem ID :	18449302
Synonyms :

Calculated chemistry of [ 59514-89-5 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	10
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	49.56
TPSA :	25.78 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) :	-5.36 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.85
Log Po/w (XLOGP3) :	3.04
Log Po/w (WLOGP) :	2.94
Log Po/w (MLOGP) :	2.43
Log Po/w (SILICOS-IT) :	3.21
Consensus Log Po/w :	2.69

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.61
Solubility :	0.0493 mg/ml ; 0.000248 mol/l
Class :	Soluble
Log S (Ali) :	-3.25
Solubility :	0.113 mg/ml ; 0.000566 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.57
Solubility :	0.00542 mg/ml ; 0.0000272 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.62

Safety of [ 59514-89-5 ]

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 [ 59514-89-5 ]

* 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 [ 59514-89-5 ]
Downstream synthetic route of [ 59514-89-5 ]

[ 59514-89-5 ] Synthesis Path-Upstream 1~7

1
[ 59514-89-5 ]
[ 13623-87-5 ]

Reference： [1] Monatshefte fuer Chemie, 1931, vol. 58, p. 234

2
[ 59514-86-2 ]
[ 59514-89-5 ]

Reference： [1] Patent: WO2012/595, 2012, A1, . Location in patent: Page/Page column 74
[2] Patent: US2013/102603, 2013, A1, . Location in patent: Paragraph 0271; 0278; 0279

3
[ 219775-95-8 ]
[ 59514-89-5 ]
[ 583031-57-6 ]

Yield	Reaction Conditions	Operation in experiment
47%	for 2 h; Heating / reflux	A mixture of l-benzyl-4-hydroxy-lH-[l,8]naphthyridin-2-one (2.52 g, 10 mmol) in POCU (100 mL) was heated under reflux for 2h. After cooling down, the reaction mixture was dropped to crashed ice while shaking. The solution was neutralized with NaOH followed by extraction with EtOAc. The organic layer was separated, washed with brine and dried over Na₂SCv The products were purified on column after removal of solvent under vacuum to give 1 - benzyl-4-chloro-lH-[l,8]naphthyridin-2-one (1.26 g, yield: 47percent) and 2,4-dichloro- [l,8]naphthyridine (556 mg, 28percent). l-Benzyl-4-chloro-lH-[l,8]naphthyridin-2-one: ¹H NMR (500 MHz, CDCl₃) δ 8.64 (d, J = 3.0 Hz, IH), 8.22 (d, J = 7.0 Hz, IH), 7.49 (d, J = 7.0 Hz, 2H), 7.21-7.28 (m, 4H), 6.94 (s, IH), 5.73 (s, 2H); ¹³C NMR (125MHz, CDCl₃) 161.62, 151.31, 149.38, 143.20, 137.49, 134.57, 128.92, 128.55, 127.58, 122.40, 118.80, 115.00, 44.56; LCMS (EI) m/z 270.9 (M⁺), 273.0. 2,4-Dichloro-[l,8]naphthyridine: ¹H NMR (500 MHz, CDCl₃) δ 9.10 (d, J = 3.0 Hz, IH), 8.51 (d, J = 8.5 Hz, IH), 7.57 (dd, J 8.5, 3.0 Hz, IH), 7.54 (s, IH); ¹³C NMR (125MHz, CDCl₃) 155.63, 155.39, 153.62, 144.70, 133.97, 123.38, 123.36, 120.69; LCMS (EI) m/z 198.9 (M⁺), 200.7, 203.0.
28%	for 2 h; Heating / reflux	Example 7 1-Benzyl-4-chloro-1H-[1,8]naphthyridin-2-one and 2,4-Dichloro-[1,8]naphthyridine A mixture of 1-benzyl-4-hydroxy-1H-[1,8]naphthyridin-2-one (2.52 g, 10 mmol) in POCl₃ (100 mL) was heated under reflux for 2 h. After cooling down, the reaction mixture was dropped to crashed ice while shaking. The solution was neutralized with NaOH followed by extraction with EtOAc. The organic layer was separated, washed with brine and dried over Na₂SO₄. The products were purified on column after removal of solvent under vacuum to give 1-benzyl-4-chloro-1H-[1,8]naphthyridin-2-one (1.26 g, yield: 47percent) and 2,4-dichloro-[1,8]naphthyridine (556 mg, 28percent). 1-Benzyl-4-chloro-1H-[1,8]naphthyridin-2-one: ¹H NMR (500 MHz, CDCl₃) δ 8.64 (d, J=3.0 Hz, 1H), 8.22 (d, J=7.0 Hz, 1H), 7.49 (d, J=7.0 Hz, 2H), 7.21-7.28 (m, 4H), 6.94 (s, 1H), 5.73 (s, 2H); ¹³C NMR (125 MHz, CDCl₃) 161.62, 151.31, 149.38, 143.20, 137.49, 134.57, 128.92, 128.55, 127.58, 122.40, 118.80, 115.00, 44.56; LCMS (EI) m/z 270.9 (M⁺), 273.0. 2,4-Dichloro-[1,8]naphthyridine: ¹H NMR (500 MHz, CDCl₃) δ 9.10 (d, J=3.0 Hz, 1H), 8.51 (d, J=8.5 Hz, 1H), 7.57 (dd, J=8.5, 3.0 Hz, 1H), 7.54 (s, 1H); ¹³C NMR (125 MHz, CDCl₃) 155.63, 155.39, 153.62, 144.70, 133.97, 123.38, 123.36, 120.69; LCMS (EI) m/z 198.9 (M⁺), 200.7, 203.0.

Reference： [1] Patent: WO2008/24423, 2008, A2, . Location in patent: Page/Page column 43
[2] Patent: US2009/54477, 2009, A1, . Location in patent: Page/Page column 18

4
[ 5345-47-1 ]
[ 59514-89-5 ]

Reference： [1] Patent: WO2012/595, 2012, A1,
[2] Patent: US2013/102603, 2013, A1,

5
[ 13362-26-0 ]
[ 59514-89-5 ]

Reference： [1] Patent: WO2012/595, 2012, A1,
[2] Patent: US2013/102603, 2013, A1,

6
[ 504-29-0 ]
[ 1663-67-8 ]
[ 59514-89-5 ]

Reference： [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 12, p. 5419 - 5434

7
[ 59514-89-5 ]
[ 59514-93-1 ]

Reference： [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 12, p. 5419 - 5434
[2] Patent: WO2008/24423, 2008, A2, . Location in patent: Page/Page column 45
[3] Patent: US2009/54477, 2009, A1, . Location in patent: Page/Page column 19

[ 59514-89-5 ] Synthesis Path-Downstream 1~87

1
[ 59514-89-5 ]
[ 1756-68-9 ]

Reference： [1]Monatshefte fur Chemie,1931,vol. 58,p. 234

3
2.4-dioxy-1.8-naphthyridine [ No CAS ]
[ 59514-89-5 ]

Reference： [1]Chemische Berichte,1927,vol. 60,p. 408

4
[ 219775-95-8 ]
[ 59514-89-5 ]
[ 583031-57-6 ]

Yield	Reaction Conditions	Operation in experiment
28%; 47%	With trichlorophosphate; for 2h;Heating / reflux;	A mixture of l-benzyl-4-hydroxy-lH-[l,8]naphthyridin-2-one (2.52 g, 10 mmol) in POCU (100 mL) was heated under reflux for 2h. After cooling down, the reaction mixture was dropped to crashed ice while shaking. The solution was neutralized with NaOH followed by extraction with EtOAc. The organic layer was separated, washed with brine and dried over Na2SCv The products were purified on column after removal of solvent under vacuum to give 1 - benzyl-4-chloro-lH-[l,8]naphthyridin-2-one (1.26 g, yield: 47%) and 2,4-dichloro- [l,8]naphthyridine (556 mg, 28%). l-Benzyl-4-chloro-lH-[l,8]naphthyridin-2-one: 1H NMR (500 MHz, CDCl3) delta 8.64 (d, J = 3.0 Hz, IH), 8.22 (d, J = 7.0 Hz, IH), 7.49 (d, J = 7.0 Hz, 2H), 7.21-7.28 (m, 4H), 6.94 (s, IH), 5.73 (s, 2H); 13C NMR (125MHz, CDCl3) 161.62, 151.31, 149.38, 143.20, 137.49, 134.57, 128.92, 128.55, 127.58, 122.40, 118.80, 115.00, 44.56; LCMS (EI) m/z 270.9 (M+), 273.0. 2,4-Dichloro-[l,8]naphthyridine: 1H NMR (500 MHz, CDCl3) delta 9.10 (d, J = 3.0 Hz, IH), 8.51 (d, J = 8.5 Hz, IH), 7.57 (dd, J » 8.5, 3.0 Hz, IH), 7.54 (s, IH); 13C NMR (125MHz, CDCl3) 155.63, 155.39, 153.62, 144.70, 133.97, 123.38, 123.36, 120.69; LCMS (EI) m/z 198.9 (M+), 200.7, 203.0.
28%; 47%	With trichlorophosphate; for 2h;Heating / reflux;	Example 7 1-Benzyl-4-chloro-1H-[1,8]naphthyridin-2-one and 2,4-Dichloro-[1,8]naphthyridine A mixture of 1-benzyl-4-hydroxy-1H-[1,8]naphthyridin-2-one (2.52 g, 10 mmol) in POCl3 (100 mL) was heated under reflux for 2 h. After cooling down, the reaction mixture was dropped to crashed ice while shaking. The solution was neutralized with NaOH followed by extraction with EtOAc. The organic layer was separated, washed with brine and dried over Na2SO4. The products were purified on column after removal of solvent under vacuum to give 1-benzyl-4-chloro-1H-[1,8]naphthyridin-2-one (1.26 g, yield: 47%) and 2,4-dichloro-[1,8]naphthyridine (556 mg, 28%). 1-Benzyl-4-chloro-1H-[1,8]naphthyridin-2-one: 1H NMR (500 MHz, CDCl3) delta 8.64 (d, J=3.0 Hz, 1H), 8.22 (d, J=7.0 Hz, 1H), 7.49 (d, J=7.0 Hz, 2H), 7.21-7.28 (m, 4H), 6.94 (s, 1H), 5.73 (s, 2H); 13C NMR (125 MHz, CDCl3) 161.62, 151.31, 149.38, 143.20, 137.49, 134.57, 128.92, 128.55, 127.58, 122.40, 118.80, 115.00, 44.56; LCMS (EI) m/z 270.9 (M+), 273.0. 2,4-Dichloro-[1,8]naphthyridine: 1H NMR (500 MHz, CDCl3) delta 9.10 (d, J=3.0 Hz, 1H), 8.51 (d, J=8.5 Hz, 1H), 7.57 (dd, J=8.5, 3.0 Hz, 1H), 7.54 (s, 1H); 13C NMR (125 MHz, CDCl3) 155.63, 155.39, 153.62, 144.70, 133.97, 123.38, 123.36, 120.69; LCMS (EI) m/z 198.9 (M+), 200.7, 203.0.

Reference： [1]Patent: WO2008/24423,2008,A2 .Location in patent: Page/Page column 43
[2]Patent: US2009/54477,2009,A1 .Location in patent: Page/Page column 18

5
[ 59514-89-5 ]
[ 59514-93-1 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In 1,4-dioxane; water;Heating / reflux;	A solution of 2,4-dichloro-[l ,8]naphthyridine (556 mg, 2.79 mmol) in 1 ,4- dioxane (20 mL) and HCl (6N, 20 mL) was heated under reflux overnight. After cooling down, the reaction was neutralized with NaOH solution. The precipitate was collected by filtration and washed with water for several times. The product was air dried to give 400 mg of product and it was used for the next step without further purification. To a suspension of 4-chloro-li/- [l,8]naphthyridin-2-one obtained above in DMF (20 mL) was added NaH (64 mg) in portion at rt. After 20 min, MeI (0.27 mL, 4.4 mmol) was added and stirred overnight at rt. The reaction was quenched by adding water, extracting with EtOAc. The organic layer was washed once again with brine and dried over Na2SO^ The product (300 mg, 55% for 2 steps) was purified by column chromatography after being concentrated under vacuum. 1H NMR (500 MHz, CDCI3) delta 8.67 (d, J = 4.5 Hz, IH), 8.27 (d, J = 8.0 Hz, IH), 7.28 (dd, J = 8.0, 4.5 Hz, IH), 6.94 (s, IH); 13C NMR (125MHz, CDCl3) 161.94, 151.23, 149.80, 142.96, 134.55, 122.16, 118.57, 115.04, 28.84; LCMS (EI) m/z 198.9 (M+), 200.7, 203.0.
		Example 10 4-Chloro-1-methyl-1H-[1,8]naphthyridin-2-one A solution of 2,4-dichloro-[1,8]naphthyridine (556 mg, 2.79 mmol) in 1,4-dioxane (20 mL) and HCl (6N, 20 mL) was heated under reflux overnight. After cooling down, the reaction was neutralized with NaOH solution. The precipitate was collected by filtration and washed with water for several times. The product was air dried to give 400 mg of product and it was used for the next step without further purification.

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 5419 - 5434
[2]Patent: WO2008/24423,2008,A2 .Location in patent: Page/Page column 45
[3]Patent: US2009/54477,2009,A1 .Location in patent: Page/Page column 19

6
[ 59514-89-5 ]
[ 13623-87-5 ]

Reference： [1]Monatshefte fur Chemie,1931,vol. 58,p. 234

7
[ 59514-89-5 ]
[ 138642-62-3 ]
[ 1323919-38-5 ]

Reference： [1]Patent: WO2011/95196,2011,A1
[2]Patent: US2012/295902,2012,A1

8
[ 59514-89-5 ]
[ 138642-62-3 ]
[ 1323919-42-1 ]

Yield	Reaction Conditions	Operation in experiment
	With water; sodium hydrogencarbonate;bis-triphenylphosphine-palladium(II) chloride; In N,N-dimethyl-formamide; at 80℃; for 16h;Inert atmosphere;	E -(4-chloro-[1 ,8]naphthyridin-2-yl)-benzonitrileA solution of 1.99 g (10.0 mmol) <strong>[59514-89-5]2,4-dichloro-[1,8]naphthyridine</strong>, 1.47 g (10.0 mmol) 2- cyanobenzeneboronic acid and 1.01 g (120.0 mmol) sodium bicarbonate in 100 ml DMF and 50 ml water was heated to 80C under nitrogen. 140 mg (0.20 mmol) bis-(triphenyl- phosphine)-palladium(ll)-chloride were added and the mixture was stirred for 16 hrs at 80C. Water was added to the reaction mixture and the resulting precipitate was filtered off and washed well with water. The residue was dried in vacuum yielding 2-(4-chloro- [1 ,8]naphthyridin-2-yl)-benzamide as yellow crystals; HPLC-MS: 1.55 min, [M+H] 284.
	With bis-triphenylphosphine-palladium(II) chloride; sodium hydrogencarbonate; In water; N,N-dimethyl-formamide; at 80℃; for 16h;	A solution of 1.99 g (10.0 mmol) <strong>[59514-89-5]2,4-dichloro-[1,8]naphthyridine</strong>, 1.47 g (10.0 mmol) 2-cyanobenzeneboronic acid and 1.01 g (120.0 mmol) sodium bicarbonate in 100 ml DMF and 50 ml water was heated to 80 C. under nitrogen. 140 mg (0.20 mmol) bis-(triphenyl-phosphine)-palladium(II)-chloride were added and the mixture was stirred for 16 hrs at 80 C. Water was added to the reaction mixture and the resulting precipitate was filtered off and washed well with water. The residue was dried in vacuum yielding 2-(4-chloro-[1,8]naphthyridin-2-yl)-benzamide as yellow crystals; HPLC-MS: 1.55 min, [M+H] 284.

Reference： [1]Patent: WO2011/95196,2011,A1 .Location in patent: Page/Page column 84
[2]Patent: US2012/295902,2012,A1 .Location in patent: Paragraph 0254; 0255

9
[ 59514-89-5 ]
[ 259807-95-9 ]
[ 1323919-44-3 ]

Yield	Reaction Conditions	Operation in experiment
	bis-triphenylphosphine-palladium(II) chloride; In toluene; at 80℃; for 16h;Inert atmosphere;	EXAMPLE 3: S nthesis of 4-chloro-2-(6-methylpyridin-2-yl)-[1,8]naphthyridineA solution of 1.69 g (8.47 mmol) <strong>[59514-89-5]2,4-dichloro-[1,8]naphthyridine</strong> and 3.24 g (8.47 mmol) 6-methyl-2-(tributylstannyl)-pyridine in 8.5 ml toluene under nitrogen was heated to 80C. Then 178 mg (0.254 mmol) bis-(triphenylphosphine)-palladium(ll)-chloride were added. The mixture was stirred for 16 hrs at 80C and then cooled to 0C in an ice bath. The precipitate was filtered off, washed with ice cold toluene and petrolether and dried in vacuum. This yielded 4-chloro-2-(6-methylpyridin-2-yl)-[1,8]naphthyridine as gray felted needles; HPLC- MS: 2.25 min, [M+H] 256.H-NMR (CDCI3): delta [ppm] = 2.71 (s, 3H), 7.29 (d, J=7.3 Hz, 1 H), 7.61 (dd, ^=8.3 Hz, J2= 4.1 Hz, 1 H), 7.80 (t, J=7.7 Hz, 1 H), 8.66 (dd, ^=8.1 Hz, J2=2.0 Hz, 1 H), 8.67 (d, J=7.8 Hz, 1H), 8.9 (s, 1 H), 9.2 (dd, =4.1 Hz, J2=1.9 Hz, 1H).
	In toluene; at 80℃; for 16h;	A solution of 1.69 g (8.47 mmol) <strong>[59514-89-5]2,4-dichloro-[1,8]naphthyridine</strong> and 3.24 g (8.47 mmol) 6-methyl-2-(tributylstannyl)-pyridine in 8.5 ml toluene under nitrogen was heated to 80C. Then 178 mg (0.254 mmol) bis-(triphenylphosphine)-palladium(ll)-chloride were added. The mixture was stirred for 16 hrs at 80C and then cooled to 0C in an ice bath. The precipitate is filtered off, washed with ice cold toluene and petrolether and dried in vacuum. This yielded 4-chloro-2-(6-methylpyridin-2-yl)-[1 ,8]naphthyridine as gray felted needles; HPLC- MS: 2.25 min, [M+H] 256.1H-NMR (CDCIs): delta [ppm] = 2.71 (s, 3H), 7.29 (d, J=7.3 Hz, 1H), 7.61 (dd, ^=8.3 Hz, J2= 4.1 Hz, 1 H), 7.80 (t, J=7.7 Hz, 1 H), 8.66 (dd, ^=8.1 Hz, J2=2.0 Hz, 1 H), 8.67 (d, J=7.8 Hz, 1H), 8.9 (s, 1H), 9.2 (dd, J,=4.1 Hz, J2=1.9 Hz, 1 H).
	bis-triphenylphosphine-palladium(II) chloride; In toluene; at 80℃; for 16h;Inert atmosphere;	Example 3 - Synthesis of 4-chloro-2-(6-methylpyridin-2-yl)-[1 ,8]naphthyridine; A solution of 1.69 g (8.47 mmol) 2,4-dichloro-[1 ,8]naphthyridine and 3.24 g (8.47 mmol) 6-methyl-2-(tributylstannyl)-pyridine in 8.5 ml toluene was heated to 80 C under nitrogen. Then 178 mg (0.254 mmol) bis-(triphenylphosphine)-palladium(ll)- chloride were added. The mixture was stirred for 16 hrs at 80 C and then cooled to 0 C in an ice bath. The precipitate was filtered off, washed with ice-cold toluene and petrolether and dried in vacuum. This yields 4-chloro-2-(6-methylpyridin-2-yl)- [1 ,8]naphthyridine as gray felt-like needles; HPLC-MS: 2.25 min, [M+H] 256.1H-NMR (CDCI3): delta [ppm] = 2.71 (s, 3H), 7.29 (d, J = 7.3 Hz, 1 H), 7.61 (dd, ^ = 8.3 Hz, J2 = 4.1 Hz, 1 H), 7.80 (t, J = 7.7 Hz, 1 H), 8.66 (dd, J, = 8.1 Hz, J2 = 2.0 Hz, 1 H), 8.67 (d, J = 7.8 Hz, 1 H), 8.9 (s, 1 H), 9.2 (dd, Jn = 4.1 Hz, J2 = 1.9 Hz, 1 H).

	bis-triphenylphosphine-palladium(II) chloride; In toluene; at 80℃; for 16h;Inert atmosphere;	EXAMPLE 2Synthesis of 4-chloro-2-(6-methylpyridin-2-yl)-[1,8]naphthyridine A solution of 1.69 g (8.47 mmol) <strong>[59514-89-5]2,4-dichloro-[1,8]naphthyridine</strong> and 3.24 g (8.47 mmol) 6-methyl-2-(tributylstannyl)-pyridine in 8.5 ml toluene under nitrogen was heated to 80 C.Then 178 mg (0.254 mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added. The mixture was stirred for 16 hrs at 80 C. and then cooled to 0 C. in an ice bath. The precipitate is filtered off, washed with ice cold toluene and petrolether and dried in vacuum. This yielded 4-chloro-2-(6-methylpyridin-2-yl)-[1,8]naphthyridine as gray felted needles; HPLC-MS: 2.25 min, [M+H] 256.1H-NMR (CDC3): delta [ppm]=2.71 (s, 3H), 7.29 (d, J=7.3 Hz, 1H), 7.61 (dd, J1=8.3 Hz, J2=4.1 Hz, 1H), 7.80 (t, J=7.7 Hz, 1H), 8.66 (dd, J1=8.1 Hz, J2=2.0 Hz, 1H), 8.67 (d, J=7.8 Hz, 1H), 8.9 (s, 1H), 9.2 (dd, J1=4.1 Hz, J2=1.9 Hz, 1H).
	With bis-triphenylphosphine-palladium(II) chloride; In toluene; at 80℃; for 16h;Inert atmosphere;	A solution of 1.69 g (8.47 mmol) <strong>[59514-89-5]2,4-dichloro-[1,8]naphthyridine</strong> and 3.24 g (8.47 mmol) 6-methyl-2-(tributylstannyl)-pyridine in 8.5 ml toluene under nitrogen was heated to 80 C. Then 178 mg (0.254 mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added. The mixture was stirred for 16 hrs at 80 C. and then cooled to 0 C. in an ice bath. The precipitate was filtered off, washed with ice cold toluene and petrolether and dried in vacuum. This yielded 4-chloro-2-(6-methylpyridin-2-yl)-[18]naphthyridine as gray felted needles; HPLC-MS: 2.25 min, [M+H] 256. [0259] 1H-NMR (CDCl3): delta [ppm]=2.71 (s, 3H), 7.29 (d, J=7.3 Hz, 1H), 7.61 (dd, J1=8.3 Hz, J2=4.1 Hz, 1H), 7.80 (t, J=7.7 Hz, 1H), 8.66 (dd, J1=8.1 Hz, J2=2.0 Hz, 1H), 8.67 (d, J=7.8 Hz, 1H), 8.9 (s, 1H), 9.2 (dd, J1=4.1 Hz, J2=1.9 Hz, 1H).
	With bis-triphenylphosphine-palladium(II) chloride; In toluene; at 80℃; for 16h;Inert atmosphere;	Example 3 Synthesis of 4-chloro-2-(6-methylpyridin-2-yl)-[1,8]naphthyridine A solution of 1.69 g (8.47 mmol) <strong>[59514-89-5]2,4-dichloro-[1,8]naphthyridine</strong> and 3.24 g (8.47 mmol) 6-methyl-2-(tributylstannyl)-pyridine in 8.5 ml toluene was heated to 80 C. under nitrogen. Then 178 mg (0.254 mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added. The mixture was stirred for 16 hrs at 80 C. and then cooled to 0 C. in an ice bath. The precipitate was filtered off, washed with ice-cold toluene and petrolether and dried in vacuum. This yields 4-chloro-2-(6-methylpyridin-2-yl)-[1,8]naphthyridine as gray felt-like needles; HPLC-MS: 2.25 min, [M+H] 256. 1H-NMR (CDCl3): delta [ppm]=2.71 (s, 3H), 7.29 (d, J=7.3 Hz, 1H), 7.61 (dd, J1=8.3 Hz, J2=4.1 Hz, 1H), 7.80 (t, J=7.7 Hz, 1H), 8.66 (dd, J1=8.1 Hz, J2=2.0 Hz, 1H), 8.67 (d, J=7.8 Hz, 1H), 8.9 (s, 1H), 9.2 (dd, J1=4.1 Hz, J2=1.9 Hz, 1H).

Reference： [1]Patent: WO2011/95196,2011,A1 .Location in patent: Page/Page column 84-85
[2]Patent: WO2011/101069,2011,A2 .Location in patent: Page/Page column 83
[3]Patent: WO2012/595,2012,A1 .Location in patent: Page/Page column 76
[4]Patent: US2012/316166,2012,A1 .Location in patent: Page/Page column 68
[5]Patent: US2012/295902,2012,A1 .Location in patent: Paragraph 0257; 0258; 0259
[6]Patent: US2013/102603,2013,A1 .Location in patent: Paragraph 0291; 0292; 0293

10
[ 59514-89-5 ]
[ 259807-95-9 ]
[ 1323916-59-1 ]

Reference： [1]Patent: WO2011/95196,2011,A1
[2]Patent: US2012/295902,2012,A1

11
[ 59514-89-5 ]
5-chloro-2-fluorophenylboronic acid [ No CAS ]
[ 1323919-28-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate;bis-triphenylphosphine-palladium(II) chloride; In water; N,N-dimethyl-formamide; at 80℃; for 16h;Inert atmosphere;	EXAMPLE 1 : Synthesis of 4-chloro-2-(5-chloro-2-fluoro-phenyl)-[1 ,8]naphthyridineA solution of 9.95 g (50.0 mmol) <strong>[59514-89-5]2,4-dichloro-[1,8]naphthyridine</strong> (described by Koller, Chemische Berichte 60: 407 (1927)), 8.72 g (50.0 mmol) 5-chloro-2-fluorophenylboronic acid und 5.04 g (60.0 mmol) sodium hydrogencarbonate in 100 ml DMF und 50 ml water was heated to 80C under nitrogen. 701 mg (1.0 mmol) bis-(triphenylphosphine)- palladium(ll)-chloride were added and the mixture was stirred for 16 hrs at 80C. Water was added to the reaction mixture and the precipitate was filtered off, dried in vacuum and recrystallized from 2-propanol. This yielded 4-chloro-2-(5-chloro-2-fluoro-phenyl)- [1 ,8]naphthyridine as yellowish crystals; HPLC-MS: 2.49 min, [M+H] 293.1H NMR (400 MHz, CDCI3) delta [ppm] = 9.14 (dd, J=4.2, 1.9, 1H), 8.56 (dd, J=8.3, 1.9, 1H), 8.37 (dd, J=6.8, 2.7, 1 H), 8.10 (d, J=1.6, 1H), 7.56 (dd, J=8.4, 4.2, 1 H), 7.36 (ddd, J=8.7, 4.2, 2.8, 1H), 7.10 (dd, J=10.9, 8.8, 1H).
		A solution of 9.95 g (50.0 mmol) 2,4-dichloro-[1 ,8]naphthyridine (described by Koller, Chemische Berichte 60: 407 (1927)), 8.72 g (50.0 mmol) 5-chloro-2-fluorophenylboronic acid und 5.04 g (60.0 mmol) sodium hydrogencarbonate in 100 ml DMF und 50 ml water was heated to 80C under nitrogen. 701 mg (1.0 mmol) bis-(triphenylphosphine)- palladium(ll)-chloride were added and the mixture was stirred for 16 hrs at 80C. Water was added to the reaction mixture and the precipitate was filtered off, dried in vacuum and re- crystallized from 2-propanole. This yielded 4-chloro-2-(5-chloro-2-fluoro-phenyl)- [1,8]naphthyridine as yellowish crystals; HPLC-MS: 2.49 min, [M+H] 293.1H NMR (400 MHz, CDCI3) delta [ppm] = 9.14 (dd, J=4.2, 1.9, 1H), 8.56 (dd, J=8.3, 1.9, 1 H), 8.37 (dd, J=6.8, 2.7, 1 H), 8.10 (d, J=1.6, 1 H), 7.56 (dd, J=8.4, 4.2, 1 H), 7.36 (ddd, J=8.7, 4.2, 2.8, 1H), 7.10 (dd, J=10.9, 8.8, 1 H).
	With sodium hydrogencarbonate;bis-triphenylphosphine-palladium(II) chloride; In water; N,N-dimethyl-formamide; at 80℃; for 16h;Inert atmosphere;	Example 2 - Synthesis of 4-chloro-2-(5-chloro-2-fluoro-phenyl)-[1 ,8]naphthyridine; A solution of 9.95 g (50.0 mmol) 2,4-dichloro-[1 ,8]naphthyridine, 8.72 g (50.0 mmol) 5-chloro-2-fluorophenylboronic acid and 5.04 g (60.0 mmol) sodium bicarbonate in 100 ml DMF and 50 ml water was heated to 80 C under nitrogen. 701 mg (1.0 mmol) bis-(triphenylphosphine)-palladium(ll)-chloride were added and the mixture was stirred for 16 hrs at 80 C. Water was added to the reaction mixture and the precipitate was filtered off, dried in vacuum and recrystallized from 2-propanol: 4-chloro-2-(5-chloro-2-fluoro-phenyl)-[1 ,8]naphthyridine as slightly yellow crystals; HPLC-MS: 2.49 min, [M+H] 293.1H NMR (400 MHz, CDCI3) delta [ppm] = 9.14 (dd, J=4.2, 1.9, 1 H), 8.56 (dd, J=8.3, 1.9, 1 H), 8.37 (dd, J=6.8, 2.7, 1 H), 8.10 (d, J=1.6, 1 H), 7.56 (dd, J=8.4, 4.2, 1 H), 7.36 (ddd, J=8.7, 4.2, 2.8, 1 H), 7.10 (dd, J=10.9, 8.8, 1 H).

	With sodium hydrogencarbonate;bis-triphenylphosphine-palladium(II) chloride; In water; N,N-dimethyl-formamide; at 80℃; for 16h;Inert atmosphere;	EXAMPLE 1Synthesis of 4-chloro-2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine A solution of 9.95 g (50.0 mmol) <strong>[59514-89-5]2,4-dichloro-[1,8]naphthyridine</strong> (described by Koller, Chemische Berichte 60: 407 (1927)), 8.72 g (50.0 mmol) 5-chloro-2-fluorophenylboronic acid und 5.04 g (60.0 mmol) sodium hydrogencarbonate in 100 ml DMF und 50 ml water was heated to 80 C. under nitrogen. 701 mg (1.0 mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added and the mixture was stirred for 16 hrs at 80 C. Water was added to the reaction mixture and the precipitate was filtered off, dried in vacuum and re-crystallized from 2-propanole. This yielded 4-chloro-2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine as yellowish crystals; HPLC-MS: 2.49 min, [M+H] 293. 1H NMR (400 MHz, CDCl3) delta [ppm]=9.14 (dd, J=4.2, 1.9, 1H), 8.56 (dd, J=8.3, 1.9, 1H), 8.37 (dd, J=6.8, 2.7, 1H), 8.10 (d, J=1.6, 1H), 7.56 (dd, J=8.4, 4.2, 1H), 7.36 (ddd, J=8.7, 4.2, 2.8, 1H), 7.10 (dd, J=10.9, 8.8, 1H).
	With bis-triphenylphosphine-palladium(II) chloride; sodium hydrogencarbonate; In water; N,N-dimethyl-formamide; at 80℃; for 16h;Inert atmosphere;	A solution of 9.95 g (50.0 mmol) <strong>[59514-89-5]2,4-dichloro-[1,8]naphthyridine</strong> (described by Koller, Chemische Berichte 60: 407 (1927)), 8.72 g (50.0 mmol) 5-chloro-2-fluorophenylboronic acid und 5.04 g (60.0 mmol) sodium hydrogencarbonate in 100 ml DMF und 50 ml water was heated to 80 C. under nitrogen. 701 mg (1.0 mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added and the mixture was stirred for 16 hrs at 80 C. Water was added to the reaction mixture and the precipitate was filtered off, dried in vacuum and recrystallized from 2-propanol. This yielded 4-chloro-2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine as yellowish crystals; HPLC-MS: 2.49 min, [M+H] 293. [0244] 1H NMR (400 MHz, CDCl3) delta [ppm]=9.14 (dd, J=4.2, 1.9, 1H), 8.56 (dd, J=8.3, 1.9, 1H), 8.37 (dd, J=6.8, 2.7, 1H), 8.10 (d, J=1.6, 1H), 7.56 (dd, J=8.4, 4.2, 1H), 7.36 (ddd, J=8.7, 4.2, 2.8, 1H), 7.10 (dd, J=10.9, 8.8, 1H).
	With bis-triphenylphosphine-palladium(II) chloride; sodium hydrogencarbonate; In water; N,N-dimethyl-formamide; at 80℃; for 16h;	Example 2 Synthesis of 4-chloro-2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine A solution of 9.95 g (50.0 mmol) <strong>[59514-89-5]2,4-dichloro-[1,8]naphthyridine</strong>, 8.72 g (50.0 mmol) 5-chloro-2-fluorophenylboronic acid and 5.04 g (60.0 mmol) sodium bicarbonate in 100 ml DMF and 50 ml water was heated to 80 C. under nitrogen. 701 mg (1.0 mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added and the mixture was stirred for 16 hrs at 80 C. Water was added to the reaction mixture and the precipitate was filtered off, dried in vacuum and recrystallized from 2-propanol: 4-chloro-2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine as slightly yellow crystals; HPLC-MS: 2.49 min, [M+H] 293. 1H NMR (400 MHz, CDCl3) delta [ppm]=9.14 (dd, J=4.2, 1.9, 1H), 8.56 (dd, J=8.3, 1.9, 1H), 8.37 (dd, J=6.8, 2.7, 1H), 8.10 (d, J=1.6, 1H), 7.56 (dd, J=8.4, 4.2, 1H), 7.36 (ddd, J=8.7, 4.2, 2.8, 1H), 7.10 (dd, J=10.9, 8.8, 1H).

Reference： [1]Patent: WO2011/95196,2011,A1 .Location in patent: Page/Page column 21
[2]Patent: WO2011/101069,2011,A2 .Location in patent: Page/Page column 82
[3]Patent: WO2012/595,2012,A1 .Location in patent: Page/Page column 75
[4]Patent: US2012/316166,2012,A1 .Location in patent: Page/Page column 67
[5]Patent: US2012/295902,2012,A1 .Location in patent: Paragraph 0242; 0243; 0244
[6]Patent: US2013/102603,2013,A1 .Location in patent: Paragraph 0280; 0281; 0282

12
[ 59514-89-5 ]
2-(5-chloro-2-fluoro-phenyl)-4-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-3-yl]-[1,8]naphthyridine dihydrochloride [ No CAS ]

Reference： [1]Patent: WO2011/95196,2011,A1
[2]Patent: WO2011/95196,2011,A1
[3]Patent: US2012/295902,2012,A1
[4]Patent: US2012/295902,2012,A1

13
[ 59514-89-5 ]
[ 1323919-45-4 ]

Reference： [1]Patent: WO2011/95196,2011,A1
[2]Patent: WO2012/595,2012,A1
[3]Patent: US2012/295902,2012,A1
[4]Patent: US2013/102603,2013,A1

14
[ 59514-89-5 ]
[ 1323919-53-4 ]

Reference： [1]Patent: WO2011/95196,2011,A1
[2]Patent: US2012/295902,2012,A1

15
[ 59514-89-5 ]
[ 1323919-54-5 ]

Reference： [1]Patent: WO2011/95196,2011,A1
[2]Patent: US2012/295902,2012,A1

16
[ 59514-89-5 ]
[ 1323919-55-6 ]

Reference： [1]Patent: WO2011/95196,2011,A1
[2]Patent: US2012/295902,2012,A1

17
[ 59514-89-5 ]
[ 1323919-56-7 ]

Reference： [1]Patent: WO2011/95196,2011,A1
[2]Patent: US2012/295902,2012,A1

18
[ 59514-89-5 ]
[ 1323919-58-9 ]

Reference： [1]Patent: WO2011/95196,2011,A1
[2]Patent: WO2011/95196,2011,A1
[3]Patent: US2012/295902,2012,A1
[4]Patent: US2012/295902,2012,A1

19
[ 59514-89-5 ]
[ 1323916-90-0 ]

Reference： [1]Patent: WO2011/95196,2011,A1
[2]Patent: US2012/295902,2012,A1

20
[ 59514-89-5 ]
[ 1323916-91-1 ]

Reference： [1]Patent: WO2011/95196,2011,A1
[2]Patent: US2012/295902,2012,A1

21
[ 59514-89-5 ]
[ 1323916-92-2 ]

Reference： [1]Patent: WO2011/95196,2011,A1
[2]Patent: US2012/295902,2012,A1

22
[ 59514-89-5 ]
[ 1323919-73-8 ]

Reference： [1]Patent: WO2011/95196,2011,A1
[2]Patent: US2012/295902,2012,A1

23
[ 59514-89-5 ]
[ 1323919-74-9 ]

Reference： [1]Patent: WO2011/95196,2011,A1
[2]Patent: US2012/295902,2012,A1

24
[ 59514-89-5 ]
2-(5-chloro-2-fluoro-phenyl)-4-(6'-piperazin-1-yl-[3,3']bipyridinyl-5-yl)-[1,8]naphthyridine hydrochloride [ No CAS ]

Reference： [1]Patent: WO2011/95196,2011,A1
[2]Patent: US2012/295902,2012,A1

25
[ 59514-89-5 ]
2-(5-chloro-2-fluoro-phenyl)-4-{5-[1-(1-methyl-piperidin-4-yl)-1H-pyrazol-4-yl]-pyridin-3-yl}-[1,8]naphthyridine formate [ No CAS ]

Reference： [1]Patent: WO2011/95196,2011,A1
[2]Patent: US2012/295902,2012,A1

26
[ 59514-89-5 ]
[ 1323917-03-8 ]

Reference： [1]Patent: WO2011/95196,2011,A1
[2]Patent: US2012/295902,2012,A1

27
[ 59514-89-5 ]
[ 1323917-09-4 ]

Reference： [1]Patent: WO2011/95196,2011,A1
[2]Patent: US2012/295902,2012,A1

28
[ 59514-89-5 ]
[ 1323917-17-4 ]

Reference： [1]Patent: WO2011/95196,2011,A1
[2]Patent: US2012/295902,2012,A1

29
[ 59514-89-5 ]
[ 1323917-28-7 ]

Reference： [1]Patent: WO2011/95196,2011,A1
[2]Patent: US2012/295902,2012,A1

30
[ 59514-89-5 ]
[ 1323917-29-8 ]

Reference： [1]Patent: WO2011/95196,2011,A1
[2]Patent: US2012/295902,2012,A1

31
[ 59514-89-5 ]
[ 1323916-58-0 ]

Reference： [1]Patent: WO2011/95196,2011,A1
[2]Patent: US2012/295902,2012,A1

32
[ 59514-89-5 ]
[ 1323917-48-1 ]

Reference： [1]Patent: WO2011/95196,2011,A1
[2]Patent: US2012/295902,2012,A1

33
[ 59514-89-5 ]
[ 1323916-60-4 ]

Reference： [1]Patent: WO2011/95196,2011,A1
[2]Patent: US2012/295902,2012,A1

34
[ 59514-89-5 ]
[ 1323916-65-9 ]

Reference： [1]Patent: WO2011/95196,2011,A1
[2]Patent: US2012/295902,2012,A1

35
[ 59514-89-5 ]
[ 844501-71-9 ]
[ 74-88-4 ]
[ 1330532-96-1 ]
[ 1330532-97-2 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 10.6 g (54.7 mmol) 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1 H- pyrazole in 100 ml acetonitrile, 17.8 g (54.7 mmol) caesium carbonate were added and the mixture stirred at ambient temperature for 70 hrs. The reaction mixture was filtered and the residue washed with acetonitrile. The combined filtrates were evaporated and taken into tert.butylmethylether. Undissolved material was filtered off; the filtrate was dried over sodium sulfate and evaporated. One got a mixture of 1-methyl-3-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-1H-pyrazole und 1-methyl-5-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazole as colorless, slowly crystallizing oil. A solution of 2.99 g (15.0 mmol) 2,4-dichloro-[1,8]naphthyridine, 3.12 g (15.0 mmol) of the product mixture from step 1 and 1.51 g (18.0 mmol) sodium hydrogen carbonate in30 ml D F and 15 ml water were heated to 80C under nitrogen. Then 526 mg (0.75 mmol) bis-(triphenylphosphine)-palladium(ll)-chloride were added and the mixture stirred at 80C for 16 hrs. The reaction mixture was distributed between dichloromethane and water. The organic phase was dried over sodium sulfate and the product chromatographed on a silica column in dichloromethane/methanol. One obtained the two isomers:4-chloro-2-(1-methyl-1 H-pyrazol-3-yl)-[1 ,8]naphthyridine as pale yellow powder (HPLC-MS: [M+H] 245)1H NMR (400 MHz, d6-DMSO): delta [ppm] = 9.15 (dd, J=4.2, 1.9, 1 H), 8.62 (dd, J=8.3, 1.9, 1 H), 8.28 (s, 1 H), 7.91 (d, J=2.2, 1 H), 7.73 (dd, J=8.3, 4.2, 1 H), 7.05 (d, J=2.3, 1 H), 4.00 (s, 3H)4-chloro-2-(2-methyl-2H-pyrazol-3-yl)-[1 ,8]naphthyridine as pale yellow powder (HPLC-MS: [M+H] 245).1H NMR (400 MHz, d6-DMSO): delta [ppm] = 9.19 (dd, J=4.2, 1.8, 1H), 8.65 (dd, J=8.3, 1.8, 1H), 8.37 (s, 1 H), 7.79 (dd, J=8.3, 4.2, H), 7.61 (d, J=2.0, 1 H), 7.27 (d, J=2.0, 1 H), 4.38 (s, 3H).
		EXAMPLE 7Synthesis of Obtained [2-(1-methyl-1H-pyrazol-3-yl)-[1,8]naphthyridin-4-yl]-pyridin-4-yl-amine (no. 35) and [2-(2-Methyl-2H-pyrazol-3-yl)-[1,8]naphthyridin-4-yl]-pyridin-4-yl-amine (no. 36) To a solution of 10.6 g (54.7 mmol) <strong>[844501-71-9]3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole</strong> in 100 ml acetonitrile, 17.8 g (54.7 mmol) caesium carbonate were added and the mixture stirred at ambient temperature for 70 hrs. The reaction mixture was filtered and the residue washed with acetonitrile. The combined filtrates were evaporated and taken into tert.butylmethylether. Undissolved material was filtered off; the filtrate was dried over sodium sulfate and evaporated. One got a mixture of 1-methyl-<strong>[844501-71-9]3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole</strong> und 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole as colorless, slowly crystallizing oil.A solution of 2.99 g (15.0 mmol) 2,4-dichloro-[1,8]naphthyridine, 3.12 g (15.0 mmol) of the product mixture from step 1 and 1.51 g (18.0 mmol) sodium hydrogen carbonate in ml DMF and 15 ml water were heated to 80 C. under nitrogen. Then 526 mg (0.75 mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added and the mixture stirred at 80 C. for 16 hrs. The reaction mixture was distributed between dichloromethane and water. The organic phase was dried over sodium sulfate and the product chromatographed on a silica column in dichloromethane/methanol. One obtained the two isomers:4-chloro-2-(1-methyl-1H-pyrazol-3-yl)-[1,8]naphthyridine as pale yellow powder (HPLC-MS: [M+H] 245)1H NMR (400 MHz, d6-DMSO): delta [ppm]=9.15 (dd, J=4.2, 1.9, 1H), 8.62 (dd, J=8.3, 1.9, 1H), 8.28 (s, 1H), 7.91 (d, J=2.2, 1H), 7.73 (dd, J=8.3, 4.2, 1H), 7.05 (d, J=2.3, 1H), 4.00 (s, 3H)4-chloro-2-(2-methyl-2H-pyrazol-3-yl)-[1,8]naphthyridine as pale yellow powder (HPLC-MS: [M+H] 245).1H NMR (400 MHz, d6-DMSO): delta [ppm]=9.19 (dd, J=4.2, 1.8, 1H), 8.65 (dd, J=8.3, 1.8, 1H), 8.37 (s, 1H), 7.79 (dd, J=8.3, 4.2, 1H), 7.61 (d, J=2.0, 1H), 7.27 (d, J=2.0, 1H), 4.38 (s, 3H).

Reference： [1]Patent: WO2011/101069,2011,A2 .Location in patent: Page/Page column 89-90
[2]Patent: US2012/316166,2012,A1 .Location in patent: Page/Page column 71

36
[ 59514-89-5 ]
[ 1330531-36-6 ]

Reference： [1]Patent: WO2011/101069,2011,A2
[2]Patent: US2012/316166,2012,A1

37
[ 59514-89-5 ]
[2-(6-methylpyridin-2-yl)-[1,8]naphthyridin-4-yl]-pyridin-4-yl-amine dihydrochloride [ No CAS ]

Reference： [1]Patent: WO2011/101069,2011,A2
[2]Patent: US2012/316166,2012,A1

38
[ 59514-89-5 ]
[ 1330531-68-4 ]

Reference： [1]Patent: WO2011/101069,2011,A2
[2]Patent: US2012/316166,2012,A1

39
[ 59514-89-5 ]
[ 1330531-69-5 ]

Reference： [1]Patent: WO2011/101069,2011,A2
[2]Patent: US2012/316166,2012,A1

40
[ 59514-89-5 ]
[ 1330531-85-5 ]

Reference： [1]Patent: WO2011/101069,2011,A2
[2]Patent: US2012/316166,2012,A1

41
[ 59514-89-5 ]
N₄-[2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-pyrimidine-2,4-diamine hydrochloride [ No CAS ]

Reference： [1]Patent: WO2011/101069,2011,A2

42
[ 59514-89-5 ]
[ 1330531-74-2 ]

Reference： [1]Patent: WO2011/101069,2011,A2
[2]Patent: US2012/316166,2012,A1

43
[ 59514-89-5 ]
[ 1330531-76-4 ]

Reference： [1]Patent: WO2011/101069,2011,A2
[2]Patent: US2012/316166,2012,A1

44
[ 59514-89-5 ]
[ 1453-58-3 ]
[ 1353970-79-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In water; N,N-dimethyl-formamide;	Example 48 - Synthesis of Compound 118

Reference： [1]Patent: WO2012/595,2012,A1 .Location in patent: Page/Page column 123
[2]Patent: US2013/102603,2013,A1 .Location in patent: Paragraph 0545

45
[ 5345-47-1 ]
[ 59514-89-5 ]

Reference： [1]Patent: WO2012/595,2012,A1
[2]Patent: US2013/102603,2013,A1

46
[ 59514-86-2 ]
[ 59514-89-5 ]

Yield	Reaction Conditions	Operation in experiment
76%	With trichlorophosphate; at 90℃;	A mixture of <strong>[59514-86-2]1,8-naphthyridine-2,4-diol</strong> (2.02 g, 12.47 mmol) and in POd3 (100 mL) was stirred at 90 C for overnight. Then the solvent was removed under reduce pressure in vacuum, the mixture was dissolved in 100 mL DCM and adjusted to pH= 5-6 with NaHCO3 saturated aqueous solution. Extracted with DCM (100 mL), washed with brine, dried over Na2SO4. Evaporation of the organic phase provides a yellow solid (1.9 g) for use in the next step without further purification. Yield:76%; LC-MS (ESI): 198, 200 (M + 1)
		slurry of 3.24 g (20.0 mmol) [1 ,8]naphthyridine-2,4-diol in 28 ml toluene was treated with 5.51 ml (60.0 mmol) phosphorus oxychloride and stirred at 100 C for 4 hours. The resulting two-phase solution was cooled to room temperature and ice was added. Then 15 ml aqueous sodium hydroxide (50% by weight) was added slowly to reach a basic pH, while the temperature was kept below 20 C by adding more ice. The mixture was extracted with dichloromethane. The organic phase was dried over sodium sulphate, evaporated and dried under vacuum to yield 2,4-dichloro- [1 ,8]naphthyridine as slightly yellow crystals; HPLC/MS: 1.82 min, [M+H] 199.1H NMR (400 MHz, CDCI3) delta = 9.18 (dd, J=4.3, 1.9, 1 H), 8.59 (dd, J=8A, 1.9, 1 H), 7.63 (m, 2H).
	With trichlorophosphate; In toluene; at 100℃; for 4h;Large scale;	4. A slurry of 3.24 g (20.0 mmol) <strong>[59514-86-2][1,8]naphthyridine-2,4-diol</strong> in 28 ml toluene was treated with 5.51 ml (60.0 mmol) phosphorus oxychloride and stirred at 100 C. for 4 hours. The resulting two-phase solution was cooled to room temperature and ice was added. Then 15 ml aqueous sodium hydroxide (50% by weight) was added slowly to reach a basic pH, while the temperature was kept below 20 C. by adding more ice. The mixture was extracted with dichloromethane. The organic phase was dried over sodium sulphate, evaporated and dried under vacuum to yield 2,4-dichloro-[1,8]naphthyridine as slightly yellow crystals; HPLC/MS: 1.82 min, [M+H] 199. 1H NMR (400 MHz, CDCl3) delta=9.18 (dd, J=4.3, 1.9, 1H), 8.59 (dd, J=8.4, 1.9, 1H), 7.63 (m, 2H).

Reference： [1]Patent: WO2018/204176,2018,A1 .Location in patent: Paragraph 00306
[2]Patent: WO2012/595,2012,A1 .Location in patent: Page/Page column 74
[3]Patent: US2013/102603,2013,A1 .Location in patent: Paragraph 0271; 0278; 0279

47
[ 13362-26-0 ]
[ 59514-89-5 ]

Reference： [1]Patent: WO2012/595,2012,A1
[2]Patent: US2013/102603,2013,A1
[3]Patent: WO2018/204176,2018,A1

48
[ 59514-89-5 ]
[ 1353968-26-9 ]

Reference： [1]Patent: WO2012/595,2012,A1
[2]Patent: US2013/102603,2013,A1

49
[ 59514-89-5 ]
[ 1353968-39-4 ]

Reference： [1]Patent: WO2012/595,2012,A1
[2]Patent: US2013/102603,2013,A1

50
[ 59514-89-5 ]
[ 1353968-43-0 ]

Reference： [1]Patent: WO2012/595,2012,A1
[2]Patent: US2013/102603,2013,A1

51
[ 59514-89-5 ]
[ 1353968-55-4 ]

Reference： [1]Patent: WO2012/595,2012,A1
[2]Patent: US2013/102603,2013,A1

52
[ 59514-89-5 ]
[ 1353968-79-2 ]

Reference： [1]Patent: WO2012/595,2012,A1
[2]Patent: US2013/102603,2013,A1

53
[ 59514-89-5 ]
[ 1353969-27-3 ]

Reference： [1]Patent: WO2012/595,2012,A1
[2]Patent: US2013/102603,2013,A1

54
[ 59514-89-5 ]
[ 1353969-32-0 ]

Reference： [1]Patent: WO2012/595,2012,A1
[2]Patent: US2013/102603,2013,A1

55
[ 59514-89-5 ]
[ 1353969-48-8 ]

Reference： [1]Patent: WO2012/595,2012,A1
[2]Patent: US2013/102603,2013,A1

56
[ 59514-89-5 ]
[ 1353967-13-1 ]

Reference： [1]Patent: WO2012/595,2012,A1

57
[ 59514-89-5 ]
[ 1353969-93-3 ]

Reference： [1]Patent: WO2012/595,2012,A1
[2]Patent: US2013/102603,2013,A1

58
[ 59514-89-5 ]
[ 1353969-96-6 ]

Reference： [1]Patent: WO2012/595,2012,A1
[2]Patent: US2013/102603,2013,A1

59
[ 59514-89-5 ]
[ 1353970-81-6 ]

Reference： [1]Patent: WO2012/595,2012,A1
[2]Patent: US2013/102603,2013,A1

60
[ 59514-89-5 ]
[ 1353967-23-3 ]

Reference： [1]Patent: WO2012/595,2012,A1

61
[ 59514-89-5 ]
[ 1353967-14-2 ]

Reference： [1]Patent: WO2012/595,2012,A1
[2]Patent: US2013/102603,2013,A1

62
[ 59514-89-5 ]
[ 1353967-21-1 ]

Reference： [1]Patent: WO2012/595,2012,A1
[2]Patent: US2013/102603,2013,A1

63
[ 59514-89-5 ]
[ 1353967-93-7 ]
[ 1353967-21-1 ]

Reference： [1]Patent: WO2012/595,2012,A1
[2]Patent: US2013/102603,2013,A1

64
[ 59514-89-5 ]
[ 1353967-36-8 ]

Reference： [1]Patent: WO2012/595,2012,A1
[2]Patent: US2013/102603,2013,A1

65
2,4-dihydroxy-[1,8]naphthyridine-3-carboxylic acid ethyl ester disodium salt [ No CAS ]
[ 59514-89-5 ]

Reference： [1]Patent: WO2012/595,2012,A1
[2]Patent: US2013/102603,2013,A1

66
[ 59514-89-5 ]
N₄-[2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-pyrimidine-2,4-diamine hydrochloride [ No CAS ]

Reference： [1]Patent: US2012/316166,2012,A1

67
[ 59514-89-5 ]
C₂₁H₁₁ClFN₃ [ No CAS ]

Reference： [1]Patent: US2012/295902,2012,A1

68
[ 59514-89-5 ]
2-(5-chloro-2-fluoro-phenyl)-4-(1H-pyrrolo[2,3-c]pyridin-3-yl)-[1,8]naphthyridine formate [ No CAS ]

Reference： [1]Patent: US2013/102603,2013,A1

69
[ 59514-89-5 ]
2-(5-chloro-2-fluoro-phenyl)-4-[1-(2-methoxy-ethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-[1,8]naphthyridine formate [ No CAS ]

Reference： [1]Patent: US2013/102603,2013,A1

70
[ 504-29-0 ]
[ 1663-67-8 ]
[ 59514-89-5 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 5419 - 5434

71
[ 59514-89-5 ]
[ 1009360-86-4 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 5419 - 5434

72
[ 59514-89-5 ]
(1R,3r,5S)-tert-butyl 3-((1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 5419 - 5434

73
[ 59514-89-5 ]
4-((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-ylamino)-1-methyl-1,8-naphthyridin-2(1H)-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 5419 - 5434

74
[ 59514-89-5 ]
2-(2-methoxy-1,8-naphthyridin-4-yloxy)-N-methyl-N-phenylpropanamide [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 124,p. 677 - 688

75
[ 59514-89-5 ]
[ 124-41-4 ]
4-chloro-2-methoxy-1,8-naphthyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
4.12 g	In toluene; at 20 - 32℃; for 17h;	Method A: A slurry of <strong>[59514-89-5]2,4-dichloro-1,8-naphthyridine</strong> (4.95 g, 24.9 mmol) in dry toluene (50 mL) was added to a slurry of NaOMe (5.0 g, 93 mmol) in toluene (50 mL) at rt. The temperature rose to 32 C as the yellow solid dissolved to give a brown solution [Note-NaOMe should be broken up periodically if needed]. After 17 h, the mixture was filtered through diatomaceous earth, and washed with toluene. The solvent was removed and the residue recrystallized (aq EtOH) to give 26 as fine, light yellow needles (3.87 g). Concentration of the mother liquor yielded more product (250 mg; 4.12 g total, 85%). mp 134-135 C. HRMS-ESI (m/z): [M+H]+ calcd for C9H8ClN2O, 195.0325; found, 195.0327. 1H NMR (CDCl3): delta 8.99 (dd, J = 4.4, 2.0 Hz, 1H), 8.48 (dd, J = 8.0, 2.0 Hz, 1H), 7.45 (dd, J = 8.0, 4.4 Hz, 1H), 7.12 (s, 1H), 4.16 (s, 3H). 13C NMR (CDCl3): delta 164.5, 155.4, 153.6, 143.7, 133.6, 120.5, 118.2, 114.0, 54.5.

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 124,p. 677 - 688

76
[ 59514-89-5 ]
[ 75-31-0 ]
4-chloro-N-isopropyl-1,8-naphthyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With triethylamine; In 1,4-dioxane; at 90℃; for 16h;	To a solution of 2,4-dichloro-1 ,8-naphthyridine (50 mg, 251 umol, 1 eq) and propan-2-amine (22 mg, 377 umol, 32 uL, 1 ,5 eq) in dioxane (6 ml_) was added TEA (51 mg, 502 umol, 69 uL, 2 eq). The mixture was stirred at 90 C for 16 hours. TLC (Petroleum ether: EtOAc=1 : 1 ) showed that 2,4-dichloro-1 ,8-naphthyridine was consumed completely and several new spots. LCMS showed that a major peak of desired product's MS was detected. The mixture was concentrated directly. The residue was purified by trituration from (H2O: Petroleum ether: EtOAc=10: 10: 1) to obtain compound 4-chloro-N-isopropyl-1 ,8- naphthyridin-2-amine (35 mg, 158 umol, 63% yield) as a light brown solid. 1 H NMR (400MHz, CDCl3-d) delta ppm 8.83 (dd, J=4.4, 1.6 Hz, 1 H), 8,28 (dd, J=8.0, 19 Hz, 1 H), 7.20 (dd, J=8.0, 4.5 Hz, 1 H), 6.76 (s, 1 H), 4.95 (br. s., 1 H), 4.44 (d, J=5.6 Hz, 1 H), 1.29 (d, J=6.5 Hz, 6H).

Reference： [1]Patent: WO2018/134685,2018,A2 .Location in patent: Paragraph 00165; 00166; 00167

77
[ 59514-89-5 ]
N<SUP>2</SUP>-isopropyl-N -((2-(trifluoromethyl)pyridin-3-yl)methyl)-1,8-naphthyridine-2,4-diamine [ No CAS ]

Reference： [1]Patent: WO2018/134685,2018,A2

78
[ 3529-08-6 ]
[ 59514-89-5 ]
4-chloro-N-(3-(piperidin-1-yl)propyl)-1,8-naphthyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
200 mg	With potassium carbonate; In acetonitrile; at 90℃; for 2h;	A mixture of <strong>[59514-89-5]2,4-dichloro-1,8-naphthyridine</strong> (1.0 g, 5 mmol) and 3-(piperidin-1-yl)propan-1- amine (0.71 g, 5 mmol) in CH3CN (50 mL) and was stirred at 90 C for 2hours. Filtered and the mixture was evaporated and the residue was purified by Prep-TLC to give the desired compound (200 mg). LCMS (ESI): 305 (M + 1).

Reference： [1]Patent: WO2018/204176,2018,A1 .Location in patent: Paragraph 00302

79
[ 3529-08-6 ]
[ 59514-89-5 ]
N,N-diethyl-4-(2-(3-(piperidin-1-yl)propylamino)-1,8-naphthyridin-4-yl)benzamide [ No CAS ]

Reference： [1]Patent: WO2018/204176,2018,A1

80
[ 3529-08-6 ]
[ 59514-89-5 ]
2-chloro-N-(3-(piperidin-1-yl)propyl)-1,8-naphthyridin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40 mg	With potassium carbonate; In acetonitrile; at 90℃; for 2h;	A mixture of <strong>[59514-89-5]2,4-dichloro-1,8-naphthyridine</strong> (1.0 g, 5 mmol) and 3-(piperidin-1-yl)propan-1- amine (0.71 g, 5 mmol) in CH3CN (50 mL) and was stirred at 90 C for 2hours. Filtered and the mixture was evaporated and the residue was purified by-TLC to give desired compound (400 mg). LC-MS (ESI):305 (M + 1).

Reference： [1]Patent: WO2018/204176,2018,A1 .Location in patent: Paragraph 00307

81
[ 59514-89-5 ]
N,N-diethyl-4-(4-(3-(piperidin-1-yl)propylamino)-1,8-naphthyridin-2-yl)benzamide [ No CAS ]

Reference： [1]Patent: WO2018/204176,2018,A1

82
ethyl 2,4-dihydroxy-1,8-naphthyridine-3-carboxylate [ No CAS ]
[ 59514-89-5 ]

Reference： [1]Patent: WO2018/204176,2018,A1

83
[ 59514-89-5 ]
(R)-tert-butyl 3-(but-3-enyloxy)pyrrolidine-1-carboxylate [ No CAS ]
(R)-tert-butyl 3-(4-(4-chloro-1,8-naphthyridin-2-yl)butoxy)pyrrolidine-1- carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%		To a solution of tert-butyl (R)-tert-butyl 3-(but-3-enyloxy)pyrrolidine-l-carboxylate (486 mg, 1.8 mmol) in THF (dry, 2 mL) under Ar was added 9-BBN (0.5M solution in THF, 7.2 mL, 3.6 mmol). The reaction was stirred at 50 C for 2 hours, then cooled to room temperature. This solution was added to a mixture of 2,4-dichloro-l,8-naphthyridine (360 mg, 1.8 mmol), cesium carbonate (1730 mg, 5.4 mmol) and Pd(PPh3)4 (208 mg, 0.18 mmol) in l,4-dioxane (7 mL). The reaction was stirred at 90 C for 1.5 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 1 : 1 to 1 : 10) to give the desired product (R)-tert-butyl 3-(4-(4-chloro-l,8- naphthyridin-2-yl)butoxy)pyrrolidine-l-carboxylate as a yellow oil (300 mg). Yield 41% (ESI 406 (M+H) +).
41%		[0088] To a solution of tert-butyl (R)-tert-butyl 3-(but-3-enyloxy)pyrrolidine-1-carboxylate (486 mg, 1.8 mmol) in THF (dry, 2 mL) under Ar was added 9-BBN (0.5 M solution in THF, 7.2 mL, 3.6 mmol). The reaction was stirred at 50 C for 2 hours, then cooled to room temperature. This solution was added to a mixture of <strong>[59514-89-5]2,4-dichloro-1,8-naphthyridine</strong> (360 mg, 1.8 mmol), cesium carbonate (1730 mg, 5.4 mmol) and Pd(PPh3)4 (208 mg, 0.18 mmol) in 1,4-dioxane (7 mL). The reaction was stirred at 90 C for 1.5 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 1:1 to 1:10) to give the desired product (R)-tert-butyl 3-(4-(4-chloro-1,8-naphthyridin-2-yl)butoxy)pyrrolidine-1-carboxylate as a yellow oil (300 mg). Yield 41% (ESI 406 (M+H)+).
41%		To a solution of tert-butyl (R)-tert-butyl 3-(but-3-enyloxy)pyrrolidine-l-carboxylate (486 mg, 1.8 mmol) in THF (dry, 2 mL) under Ar was added 9-BBN (0.5M solution in THF, 7.2 mL, 3.6 mmol). The reaction was stirred at 50 C for 2 hours, then cooled to room temperature. This solution was added to a mixture of 2,4-dichloro-l,8-naphthyridine (360 mg, 1.8 mmol), cesium carbonate (1730 mg, 5.4 mmol) and Pd(PPh3)4 (208 mg, 0.18 mmol) in l,4-dioxane (7 mL). The reaction was stirred at 90 C for 1.5 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 1 : 1 to 1 : 10) to give the desired product (R)-tert-butyl 3-(4-(4-chloro-l,8- naphthyridin-2-yl)butoxy)pyrrolidine-l-carboxylate as a yellow oil (300 mg). Yield 41% (ESI 406 (M+H) +).

Reference： [1]Patent: WO2020/47208,2020,A1 .Location in patent: Page/Page column 53
[2]Patent: EP3617206,2020,A1 .Location in patent: Paragraph 0087-0088
[3]Patent: WO2020/47207,2020,A1 .Location in patent: Page/Page column 63

84
[ 59514-89-5 ]
(S)-tert-butyl 3-(1,1-difluoropent-4-enyl)pyrrolidine-1-carboxylate [ No CAS ]
(R)-tert-butyl 3-(5-(4-chloro-1,8-naphthyridin-2-yl)-1,1-difluoropentyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%		To a solution of (S)-tert-butyl 3-(l,l-difluoropent-4-enyl)pyrrolidine-l-carboxylate (l.4g, 5.1 mmol) in THF (dry, 5 mL) under Ar, was added 9-BBN (0.5M solution in THF, 20.4 mL, 10.2 mmol). The reaction was stirred at 50 C for 2 hours, then cooled to room temperature and added to a mixture of 2,4-dichloro-l,8-naphthyridine (l.Olg, 5.1 mmol), cesium carbonate (4.98g, 15.3 mmol) and Pd(PPh3)4 (295mg, 0.255 mmol) in 1,4- Dioxane (10 mL). The reaction was stirred at 90 C for 2 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (DCM:MeOH 30: 1) to give the desired product as a yellow oil (0.95 g). Yield 42% (ESI 440 (M+H) +).

Reference： [1]Patent: WO2020/47208,2020,A1 .Location in patent: Page/Page column 57

85
[ 59514-89-5 ]
(S)-tert-butyl 3-(1,1-difluoropent-4-enyl)pyrrolidine-1-carboxylate [ No CAS ]
(R)-tert-butyl 3-(1,1-difluoro-5-(4-methoxy-1,8-naphthyridin-2-yl)pentyl)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2020/47208,2020,A1

86
[ 59514-89-5 ]
(3R)-tert-butyl 3-(1-fluoropent-4-enyl)pyrrolidine-1-carboxylate [ No CAS ]
tert-butyl (3R)-3-(5-(4-chloro-1,8-naphthyridin-2-yl)-1-fluoropentyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%		To a solution of (3R)-tert-butyl 3-(l-fluoropent-4-enyl)pyrrolidine-l-carboxylate stereoisomer A (1.3 g, 5.0 mmol) in THF (dry, 5 mL) under Ar, was added 9-BBN (0.5M solution in THF, 20 mL, 10.0 mmol). The reaction was stirred at 50 C for 2 hours, then cooled to room temperature. This solution was added to a mixture of 2,4-dichloro-l,8- naphthyridine (1.01 g, 5.1 mmol), cesium carbonate (4.98 g, 15.3 mmol) and Pd(PPh3)4 (295 mg, 0.255 mmol) in l,4-dioxane (10 mL). The reaction was stirred at 90 C for 2 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (DCM:MeOH 30: 1) to give the desired product tert-butyl (3R)-3-(5-(4-chloro-l,8- naphthyridin-2-yl)-l-fluoropentyl)pyrrolidine-l -carboxylate stereoisomer A as a yellow oil (0.95 g). Yield 45% (ESI 422 (M+H) +).
45%		To a solution of (3R)-tert-butyl 3-(l-fluoropent-4-enyl)pyrrolidine-l-carboxylate stereoisomer A (1.3 g, 5.0 mmol) in THF (dry, 5 mL) under Ar, was added 9-BBN (0.5M solution in THF, 20 mL, 10.0 mmol). The reaction was stirred at 50 C for 2 hours, then cooled to room temperature. This solution was added to a mixture of 2,4-dichloro-l,8- naphthyridine (1.01 g, 5.1 mmol), cesium carbonate (4.98 g, 15.3 mmol) and Pd(PPh3)4 (295 mg, 0.255 mmol) in l,4-dioxane (10 mL). The reaction was stirred at 90 C for 2 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (DGVTMeOH 30: 1) to give the desired product tert-butyl (3R)-3-(5-(4-chloro-l,8- naphthyridin-2-yl)-l-fluoropentyl)pyrrolidine-l-carboxylate stereoisomer A as a yellow oil (0.95 g). Yield 45% (ESI 422 (M+H) +).
45%		To a solution of (3R)-tert-butyl 3-(1-fluoropent-4-enyl)pyrrolidine-1-carboxylate stereoisomer A (1.3 g, 5.0 mmol) in THF (dry, 5 mL) under Ar, was added 9-BBN (0.5M solution in THF, 20 mL, 10.0 mmol). The reaction was stirred at 50 C for 2 hours, then cooled to room temperature. This solution was added to a mixture of 2,4-dichloro-1,8- naphthyridine (1.01 g, 5.1 mmol), cesium carbonate (4.98 g, 15.3 mmol) and Pd(PPh3)4 (295 mg, 0.255 mmol) in 1,4-dioxane (10 mL). The reaction was stirred at 90 C for 2 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (DCM:MeOH 30:1) to give the desired product tert-butyl (3R)-3-(5-(4-chloro-1,8- naphthyridin-2-yl)-1-fluoropentyl)pyrrolidine-1-carboxylate stereoisomer A as a yellow oil (0.95 g). Yield 45% (ESI 422 (M+H) +).

Reference： [1]Patent: WO2020/47208,2020,A1 .Location in patent: Page/Page column 60; 61
[2]Patent: WO2020/47207,2020,A1 .Location in patent: Page/Page column 70
[3]Patent: WO2020/81154,2020,A1 .Location in patent: Page/Page column 58; 70-71

87
[ 59514-89-5 ]
(R)-tert-butyl 3-(1,1-difluoropent-4-enyl)pyrrolidine-1-carboxylate [ No CAS ]
(R)-tert-butyl 3-(5-(4-chloro-1,8-naphthyridin-2-yl)-1,1-difluoropentyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%		To a solution of (S)-tert-butyl 3-(l,l-difluoropent-4-enyl)pyrrolidine-l-carboxylate (l.4g, 5.1 mmol) in THF (dry, 5 mL) under Ar, was added 9-BBN (0.5M solution in THF, 20.4 mL, 10.2 mmol). The reaction was stirred at 50 C for 2 hours, then cooled to room temperature and added to a mixture of 2,4-dichloro-l,8-naphthyridine (l.Olg, 5.1 mmol), cesium carbonate (4.98g, 15.3 mmol) and Pd(PPh3)4 (295 mg, 0.255 mmol) in 1,4- Dioxane (10 mL). The reaction was stirred at 90 C for 2 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (DCM:MeOH 30: 1) to give the desired product as a yellow oil (0.95 g). Yield 42% (ESI 440 (M+H) +).
42%		To a solution of (S)-tert-butyl 3-(1,1-difluoropent-4-enyl)pyrrolidine-1-carboxylate (1.4g, 5.1 mmol) in THF (dry, 5 mL) under Ar, was added 9-BBN (0.5M solution in THF, 20.4 mL, 10.2 mmol). The reaction was stirred at 50 C for 2 hours, then cooled to room temperature and added to a mixture of <strong>[59514-89-5]2,4-dichloro-1,8-naphthyridine</strong> (1.01g, 5.1 mmol), cesium carbonate (4.98g, 15.3 mmol) and Pd(PPh3)4 (295mg, 0.255 mmol) in 1,4- Dioxane (10 mL). The reaction was stirred at 90 C for 2 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (DCM:MeOH 30:1) to give the desired product as a yellow oil (0.95 g). Yield 42% (ESI 440 (M+H) +).

Reference： [1]Patent: WO2020/47207,2020,A1 .Location in patent: Page/Page column 67
[2]Patent: WO2020/81154,2020,A1 .Location in patent: Page/Page column 58; 67

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[ 59514-89-5 ]

Chlorides

[ 35170-94-6 ]

4-Chloro-1,8-naphthyridine

Similarity: 0.89

[ 15936-10-4 ]

2-Chloro-1,8-naphthyridine

Similarity: 0.88

[ 91870-15-4 ]

2,5-Dichloro-1,8-naphthyridine

Similarity: 0.87

[ 3740-92-9 ]

4,6-Dichloro-2-phenylpyrimidine

Similarity: 0.80

[ 35170-93-5 ]

3-Chloro-1,8-naphthyridine

Similarity: 0.77

Related Parent Nucleus of
[ 59514-89-5 ]

Naphthyridines

[ 35170-94-6 ]

4-Chloro-1,8-naphthyridine

Similarity: 0.89

[ 15936-10-4 ]

2-Chloro-1,8-naphthyridine

Similarity: 0.88

[ 91870-15-4 ]

2,5-Dichloro-1,8-naphthyridine

Similarity: 0.87

[ 35170-93-5 ]

3-Chloro-1,8-naphthyridine

Similarity: 0.77

[ 15944-34-0 ]

7-Chloro-1,8-naphthyridin-2-ol

Similarity: 0.77

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Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
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.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
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
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
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
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
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. 59514-89-5 ] {[proInfo.proName]}

Quality Control of [ 59514-89-5 ]

Related Doc. of [ 59514-89-5 ]

Product Details of [ 59514-89-5 ]

Calculated chemistry of [ 59514-89-5 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 59514-89-5 ]

Application In Synthesis of [ 59514-89-5 ]

[ 59514-89-5 ] Synthesis Path-Upstream 1~7

[ 59514-89-5 ] Synthesis Path-Downstream 1~87

Related Functional Groups of [ 59514-89-5 ]

Chlorides

Related Parent Nucleus of [ 59514-89-5 ]

Naphthyridines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 59514-89-5 ]

Related Parent Nucleus of
[ 59514-89-5 ]