[ CAS No. 286947-03-3 ] {[proInfo.proName]}

Name: 286947-03-3|5-Bromo-2-chloro-3-methoxypyridine|98%
Brand: Ambeed
SKU: A134273
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Quality Control of [ 286947-03-3 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 286947-03-3 ]

CAS No. :	286947-03-3	MDL No. :	MFCD08234976
Formula :	C₆H₅BrClNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GFJMOZYIDADKLJ-UHFFFAOYSA-N
M.W :	222.47	Pubchem ID :	16748108
Synonyms :

Calculated chemistry of [ 286947-03-3 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	43.44
TPSA :	22.12 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) :	-5.9 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.2
Log Po/w (XLOGP3) :	2.48
Log Po/w (WLOGP) :	2.51
Log Po/w (MLOGP) :	1.52
Log Po/w (SILICOS-IT) :	2.67
Consensus Log Po/w :	2.27

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.16
Solubility :	0.154 mg/ml ; 0.000692 mol/l
Class :	Soluble
Log S (Ali) :	-2.59
Solubility :	0.573 mg/ml ; 0.00258 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.63
Solubility :	0.0524 mg/ml ; 0.000236 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.04

Safety of [ 286947-03-3 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P280-P305+P351+P338	UN#:
Hazard Statements:	H317-H319	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 286947-03-3 ]

* 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 [ 286947-03-3 ]
Downstream synthetic route of [ 286947-03-3 ]

[ 286947-03-3 ] Synthesis Path-Upstream 1~14

1
[ 286947-03-3 ]
[ 141-52-6 ]
[ 52605-98-8 ]

Yield	Reaction Conditions	Operation in experiment
97%	at 60℃; for 16 h; Inert atmosphere	To a 25ml flask containing (63.8mg, 1.2mmol) of sodium ethoxide was added 3ml dry ethanol. The mixture was stirred for 30min. 2-Chloro-3-methoxy-5-bromopyridine (230mg, 1.04mmol) was added to the mixture and heated to 60°C for 16h. The reaction was allowed to cool and the solvent was removed. Ethyl acetate (50ml) was added to the residue. The ethyl acetate solution was washed with water and then brine. The organic solvent was dried and concentrated under reduced pressure, and purified by ISCO flash chromatography using 10percent ethyl acetate in hexane to give 220mg (97percent yield) of the desired product. ¹H NMR (300MHz, CDCl₃) δ: 7.71 (s, 1H), 7.09 (s, 1H), 4.37 (qt, 2H), 3.82 (s, 3H), 1.38 (t, 3H).

Reference： [1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 21, p. 6435 - 6446

2
[ 67-56-1 ]
[ 286947-03-3 ]
[ 124-41-4 ]
[ 52605-98-8 ]

Reference： [1] Patent: EP2426135, 2012, A1, . Location in patent: Page/Page column 108-109

3
[ 286947-03-3 ]
[ 286946-77-8 ]

Yield	Reaction Conditions	Operation in experiment
52.9%	at 100℃; for 48 h;	A mixture of 5-bromo-2-chloro-3-methoxypyridine (36 g 162 mmol) in hydrobromic acid (200 mL 3683 mmol) was stirred at 100 for 48 hrs. Then the mixture was concentrated basified with saturated NaHCO₃solution and extracted with EtOAc (600 mL x 2) . The combined organic extract was washed with brine dried over Na₂SO₄ filtered and concentrated. The crude material was purified by silica column chromatography (PE/EtOAc1021) . All fractions found to contain product by TLC (PE/EtOAc21 R_f0.6) were combined and concentrated to yield a light yellow oil of 5-bromo-2-chloropyridin-3-ol (21 g 86 mmol 52.9yield) ¹HNMR(400 MHz METHANOL-d₄) δ7.96 (t J2.0 Hz 1H) 7.47 (d J2.4 Hz 1H) ES-LCMS m/z 208.0 210.0 (M+H)

Reference： [1] Patent: WO2016/37578, 2016, A1, . Location in patent: Page/Page column 103

4
[ 286946-77-8 ]
[ 74-88-4 ]
[ 286947-03-3 ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium carbonate In acetonitrile at 80℃; for 4 h;	Step 3: 5-bromo-2-chloro-3-methoxypyridine 5-Bromo-2-chloro-3-hydroxypyridine (1.88 g, 9 mmol), iodomethane (1.42g, 10 mmol), and K₂CO₃ (2.76g, 20 mmol) were added to acetonitrile. The solution was stirred at 80°C for 4 hours. The solvent was evaporated, and the residue was dissolved by adding CH₂Cl₂. The solution was washed by water, dried, concentrated, and purified by silica gel column chromatography to give 5-bromo-2-chloro-3-methoxypyridine (1.62 g, 81percent yield). MS m/z [ESI]: 223.9 [M+1].
25%	Stage #1: With sodium hydride In diethyl ether; N,N-dimethyl-formamide at 20℃; for 0.5 h; Stage #2: at 20℃; for 0.5 h;	Example 51A 5-bromo-2-chloro-3-methoxypyridine The product from Example 40B (1.2 g, 5.8 mmol) in diethyl ether (5 mL) was added to a suspension of NaH (181 mg, 7.5 mmol) in dry DMF (30 mL) and diethyl ether (6 mL). After stirring at ambient temperature for 30 minutes, the mixture was treated with a solution of iodomethane (1.06 g, 7.5 mmol) in diethyl ether (3 mL) and stirring was continued for an additional 30 minutes. The reaction mixture was quenched with water (20 mL), extracted with diethyl ether (100 mL), dried (MgSO₄), and concentrated under reduced pressure. The residue was purified on SiO₂ (ethyl acetate/hexane, 1/4) to provide the title compound (0.32 g, 25percent) as a colorless oil. MS(DCI/NH₃) m/z 222/224/226 (M+H)⁺.
25%	Stage #1: With sodium hydride In DMF (N,N-dimethyl-formamide); diethyl ether for 0.5 h; Stage #2: for 0.5 h;	The product from Example 40B (1.2 g, 5.8 mmol) in diethyl ether (5 mL) was added to a suspension of NaH (181 mg, 7.5 mmol) in dry DMF (30 mL) and diethyl ether (6 mL). After stirring at ambient temperature for 30 minutes, the mixture was treated with a solution of iodomethane (1.06 g, 7.5 mmol) in diethyl ether (3 mL) and stirring was continued for an additional 30 minutes. The reaction mixture was quenched with water (20 mL), extracted with diethyl ether (100 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified on SiO2 (ethyl acetate/hexane, 1/4) to provide the title compound (0.32 g, 25percent) as a colorless oil. MS (DCI/NH3) m/z 222/224/226 (M+H)+.

25%

Stage #1: With sodium hydride In DMF (N,N-dimethyl-formamide); diethyl ether at 20℃; for 0.5 h;
Stage #2: for 0.5 h;

A suspension of NaH (0.181 g, 7.5 mmol) in dry DMF (30 mL) and diethyl ether (6 mL) was treated with the product from Example 23B (1.2 g, 5.8 mmol) in diethyl ether (5 mL). After stirring at ambient temperature for 30 minutes, the mixture was treated with a solution of iodomethane (1.06 g, 7.5 mmol) in diethyl ether (3 mL). After stirring for 30 minutes, the mixture was quenched with water (20 mL), extracted with diethyl ether (100 mL), dried (MgSO4) and concentrated under reduced pressure. The crude was purified on SiO2 (ethyl acetate:hexane, 1:4) to provide the title compound as a colorless oil (0.32 g, 25percentprovide). MS(DCI/NH3) m/z 222/224/226 (M+H)+.

Reference： [1] Patent: EP2952510, 2015, A1, . Location in patent: Paragraph 0148
[2] Patent: US2002/19388, 2002, A1,
[3] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3627 - 3644
[4] Patent: EP1147112, 2003, B1, . Location in patent: Page/Page column 35
[5] Patent: US2003/225268, 2003, A1, . Location in patent: Page 31-32
[6] Patent: EP1428824, 2004, A1, . Location in patent: Page 38
[7] Patent: EP2848622, 2015, A1, . Location in patent: Paragraph 0339

5
[ 78156-39-5 ]
[ 286947-03-3 ]

Yield	Reaction Conditions	Operation in experiment
62%	With trichlorophosphate In dichloromethane at 20℃; Inert atmosphere	Phosphoryl chloride (POCl₃) (4.8ml, 52.9mmol) was added to a solution of 5-bromo-3-methoxypyridine oxide (540mg, 2.6mmol) in 15ml DCM. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with saturated NaHCO₃ and brine. The organic layer was dried, concentrated under reduced pressure and purified using ISCO flash chromatography using 50percent ethyl acetate in hexane to provide 369mg product (62percent yield). ¹H NMR (300MHz, CDCl₃) δ: 8.05 (s, 1H), 7.34 (s, 1H), 3.93 (s, 3H).
62%	With trichlorophosphate In dichloromethane at 20℃;	b. Preparation of Compound Phosphoryl chloride (POCl₃) (4.8 mL, 52.9 mmol) was added to a solution of 5-bromo-3- methoxy-pyridine oxide (540 mg, 2.6 mmol) in 15 ml CH₂C1₂. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with sat. sodium bicarbonate and brine. The organic layer was dried, concentrated and purified using ISCO flash chromatography using 50percent ethyl acetate in hexane to provide 369 mg product (62percent yield). ^lH NMR (300 MHz, CDC1₃) δ: 8.05 (s, IH), 7.34 (s, IH), 3.93 (s, 3H).
43.6%	With trichlorophosphate In dichloromethane at 40℃; for 16 h;	To a mixture of 3-bromo-5-methoxypyridine 1-oxide (2 g 9.80 mmol) in DCM (40 mL) was added POCl₃(18.27 mL 196 mmol) . The mixture was stirred at 40 for 16 h. The mixture was evaporated and distributed between EA (100 mL x 2) and saturated NaHCO₃solution (200 mL) . The combined organic extract was washed with brine dried over MgSO₄ filtered and concentrated. The residue was purified by silica column chromatography (PE/EA 101) . All fractions found to contain product by TLC (PE/EA 101 R_f 0.6) were combined and concentrated to yield a light yellow oil of 5-bromo-2-chloro-3-methoxypyridine (1 g 4.27 mmol 43.6 yield) ¹HNMR(400 MHz CDCl₃) δ 8.05 (d J 2.0 Hz 1H) 7.33 (d J 2.0 Hz 1H) 3.93 (s 3H) ES-LCMS m/z 222.0 224.0 (M+H)

Reference： [1] Tetrahedron, 2009, vol. 65, # 4, p. 757 - 764
[2] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 21, p. 6435 - 6446
[3] Patent: WO2014/43252, 2014, A2, . Location in patent: Page/Page column 24; 35-36
[4] Patent: WO2016/37578, 2016, A1, . Location in patent: Page/Page column 150; 151
[5] Patent: EP2426135, 2012, A1, . Location in patent: Page/Page column 108

6
[ 74115-13-2 ]
[ 286947-03-3 ]

Reference： [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3627 - 3644
[2] Patent: EP2848622, 2015, A1,

7
[ 130722-95-1 ]
[ 286947-03-3 ]

Reference： [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3627 - 3644

8
[ 74115-13-2 ]
[ 74-88-4 ]
[ 286947-03-3 ]

Reference： [1] Tetrahedron, 2009, vol. 65, # 4, p. 757 - 764

9
[ 50720-12-2 ]
[ 286947-03-3 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 21, p. 6435 - 6446
[2] Patent: WO2016/37578, 2016, A1,
[3] Patent: WO2014/43252, 2014, A2,

10
[ 2402-99-5 ]
[ 286947-03-3 ]

Reference： [1] Patent: EP2426135, 2012, A1,

11
[ 286947-03-3 ]
[ 141-52-6 ]
[ 1241752-31-7 ]

Yield	Reaction Conditions	Operation in experiment
97%	at 60℃; for 16 h;	c. Preparation of Compound To a 25 mL flask containing (63.8 mg, 1.2 mmol) of sodium ethoxide was added 3 mL dry ethanol. The mixture was stirred for 30 minutes. 2-Chloro-3-methoxy-5-bromopyridine (230 mg, 1.04 mmol) was added to the mixture and heated to 60 °C for 16 hours. The reaction was allowed to cool and the solvent was removed. Ethyl acetate was added (50 ml) was added to the residue. The ethyl acetate solution was washed with water and then brine. The organic solvent was dried and concentrated, purified by ISCO flash chromatography using 10percent ethyl acetate in hexane to give 220 mg (97percent yield) of the desired product. NMR (300 MHz, CDC1₃) δ: 7.71 (s, IH), 7.09 (s, IH), 4.37 (qt, 2H), 3.82 (s, 3H), 1.38 (t, 3H).

Reference： [1] Patent: WO2014/43252, 2014, A2, . Location in patent: Page/Page column 24; 36

12
[ 286947-03-3 ]
[ 248939-25-5 ]
[ 1241752-31-7 ]

Yield	Reaction Conditions	Operation in experiment
69%	at 100℃; for 0.333333 h; microwave irradiation	As shown in step 5-i of Scheme 5,5-bromo-2-chloro-3-methoxypyridine (1.0 g, 4.5 mmol, prepared in the same manner as Compound 1003 in Example 2 starting with 3- bromo-5-methoxypyridine) was treated with a sodium ethoxide/ethanol solution (5.05 mL, 21percent w/v, 13.5 mmol) and the reaction mixture microwave irradiated at 100⁰C for 20 minutes. Water was added and the ethanol evaporated under reduced pressure. The resulting aqueous solution was extracted with DCM and ether, followed by drying the combined extracts over MgSO4. After filtration, removal of the volatiles under reduced pressure provided 5-bromo-2-ethoxy-3-methoxypyridine (Compound 1016), 0.72 g, 69percent yield): ESMS (M+H) 232.32/234.23.

Reference： [1] Patent: WO2010/135014, 2010, A1, . Location in patent: Page/Page column 52

13
[ 286947-03-3 ]
[ 64-17-5 ]
[ 141-52-6 ]
[ 1241752-31-7 ]

Yield	Reaction Conditions	Operation in experiment
69%	at 100℃; for 0.333333 h; Microwave irradiation	As shown in step 3(b)-i of Scheme 3(b), 5-bromo-2-chloro-3-methoxypyridine (1.0 g, 4.5 mmol, prepared in the same manner as Compound 2003 in Example 2 starting with 3- bromo-5-methoxypyridine) was treated with a sodium ethoxide/ethanol solution (5.05 mL, 21percent w/v, 13.5 mmol) and the reaction mixture microwave irradiated at 100°C for 20 minutes. Water was added and the ethanol evaporated under reduced pressure. The resulting aqueous solution was extracted with DCM and ether, followed by drying the combined extracts over MgS04. After filtration, removal of the volatiles under reduced pressure provided 5-bromo- 2-ethoxy-3-methoxypyridine (Compound 2011), 0.72 g, 69percent yield): ESMS (M+H)

Reference： [1] Patent: WO2011/87776, 2011, A1, . Location in patent: Page/Page column 53-54

14
[ 286947-03-3 ]
[ 64-17-5 ]
[ 1241752-31-7 ]

Reference： [1] Patent: WO2018/81167, 2018, A1, . Location in patent: Page/Page column 256

[ 286947-03-3 ] Synthesis Path-Downstream 1~88

1
[ 134003-84-2 ]
[ 286947-03-3 ]
[ 286947-05-5 ]

Yield	Reaction Conditions	Operation in experiment
74%		The product from Example 15B and the product from Example 51A were processed as described in Example 15C to provide the title compound (74percent yield). MS (DCI/NH3) m/z 340 (M+H)+.

Reference： [1]Patent: US2003/225268,2003,A1 .Location in patent: Page 32
[2]Journal of Medicinal Chemistry,2007,vol. 50,p. 3627 - 3644

2
[ 286946-77-8 ]
[ 74-88-4 ]
[ 286947-03-3 ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium carbonate; In acetonitrile; at 80℃; for 4h;	Step 3: 5-bromo-2-chloro-3-methoxypyridine 5-Bromo-2-chloro-3-hydroxypyridine (1.88 g, 9 mmol), iodomethane (1.42g, 10 mmol), and K2CO3 (2.76g, 20 mmol) were added to acetonitrile. The solution was stirred at 80C for 4 hours. The solvent was evaporated, and the residue was dissolved by adding CH2Cl2. The solution was washed by water, dried, concentrated, and purified by silica gel column chromatography to give 5-bromo-2-chloro-3-methoxypyridine (1.62 g, 81% yield). MS m/z [ESI]: 223.9 [M+1].
65%	In diethyl ether; N,N-dimethyl-formamide;	EXAMPLE 10C 5-bromo-2-chloro-3-methoxypyridine A suspension of sodium hydride (181 mg, 7.5 mmol) in dry DMF (30 mL) and diethyl ether (6 mL) was treated with the product from Example 10B (1.2 g, 5.8 mmol) in diethyl ether (5 mL). After stirring at ambient temperature for 30 minutes, the reaction mixture was treated with a solution of iodomethane (1.06 g, 7.5 mmol) in diethyl ether (3 mL) and stirring was continued for 30 minutes longer. The mixture was quenched with water (20 mL), extracted with diethyl ether (100 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified on SiO2 (ethyl acetate:hexane, 1:4) to provide the title compound as a colorless oil (0.83 g, 65% yield). MS(DCI/NH3) m/z 222/224/226 (M+H)+.
25%		Example 51A 5-bromo-2-chloro-3-methoxypyridine The product from Example 40B (1.2 g, 5.8 mmol) in diethyl ether (5 mL) was added to a suspension of NaH (181 mg, 7.5 mmol) in dry DMF (30 mL) and diethyl ether (6 mL). After stirring at ambient temperature for 30 minutes, the mixture was treated with a solution of iodomethane (1.06 g, 7.5 mmol) in diethyl ether (3 mL) and stirring was continued for an additional 30 minutes. The reaction mixture was quenched with water (20 mL), extracted with diethyl ether (100 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified on SiO2 (ethyl acetate/hexane, 1/4) to provide the title compound (0.32 g, 25%) as a colorless oil. MS(DCI/NH3) m/z 222/224/226 (M+H)+.

25%		The product from Example 40B (1.2 g, 5.8 mmol) in diethyl ether (5 mL) was added to a suspension of NaH (181 mg, 7.5 mmol) in dry DMF (30 mL) and diethyl ether (6 mL). After stirring at ambient temperature for 30 minutes, the mixture was treated with a solution of iodomethane (1.06 g, 7.5 mmol) in diethyl ether (3 mL) and stirring was continued for an additional 30 minutes. The reaction mixture was quenched with water (20 mL), extracted with diethyl ether (100 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified on SiO2 (ethyl acetate/hexane, 1/4) to provide the title compound (0.32 g, 25%) as a colorless oil. MS (DCI/NH3) m/z 222/224/226 (M+H)+.
25%		A suspension of NaH (0.181 g, 7.5 mmol) in dry DMF (30 mL) and diethyl ether (6 mL) was treated with the product from Example 23B (1.2 g, 5.8 mmol) in diethyl ether (5 mL). After stirring at ambient temperature for 30 minutes, the mixture was treated with a solution of iodomethane (1.06 g, 7.5 mmol) in diethyl ether (3 mL). After stirring for 30 minutes, the mixture was quenched with water (20 mL), extracted with diethyl ether (100 mL), dried (MgSO4) and concentrated under reduced pressure. The crude was purified on SiO2 (ethyl acetate:hexane, 1:4) to provide the title compound as a colorless oil (0.32 g, 25%provide). MS(DCI/NH3) m/z 222/224/226 (M+H)+.
	With potassium carbonate; In tetrahydrofuran; N,N-dimethyl-formamide; at 1 - 30℃;	Potassium carbonate (1.0 g) was added to a mixture of 5-bromo-2-chloropyridin-3-ol (1.0 g), iodomethane (0.45 mL), THF (20 mL) and DMF (5.0 mL) at room temperature, and the mixture was stirred overnight. To the reaction mixture was added brine, and the mixture was extracted with ethyl acetate twice. The resulting organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.80 g) as a pale yellow solid, which included 5-bromo-2,4-dichloro-3-methoxypyridine as a byproduct. The solid was subjected to the next reaction without further purification. 1H NMR (400 MHz, CHLOROFORM-d) delta 3.93 (3H, s), 7.33 (1H, s), 8.07 (1H, s).

Reference： [1]Patent: EP2952510,2015,A1 .Location in patent: Paragraph 0148
[2]Patent: US2002/19388,2002,A1
[3]Journal of Medicinal Chemistry,2007,vol. 50,p. 3627 - 3644
[4]Patent: EP1147112,2003,B1 .Location in patent: Page/Page column 35
[5]Patent: US2003/225268,2003,A1 .Location in patent: Page 31-32
[6]Patent: EP1428824,2004,A1 .Location in patent: Page 38
[7]Patent: EP2848622,2015,A1 .Location in patent: Paragraph 0339

3
[ 74115-13-2 ]
[ 286947-03-3 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3627 - 3644
[2]Patent: EP2848622,2015,A1

4
[ 286947-03-3 ]
(1R,4R)-2-(6-chloro-5-methoxy-3-pyridinyl)-2,5-diazabicyclo[2.2.1]heptane p-toluenesulfonate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3627 - 3644

5
[ 130722-95-1 ]
[ 286947-03-3 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3627 - 3644

6
[ 286947-03-3 ]
[ 75-05-8 ]
[ 947688-87-1 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium hexamethyldisilazane; In tetrahydrofuran; at 18 - 25℃;	The 2-[5-(6,7-dimethoxyquinazolin-4-yloxy)-3-methoxypyridin-2-yl]acetic acid used as a starting material was prepared as follows :-Under an atmosphere of argon, a IM solution of lithium hexamethyldisilazane in THF (80 ml) was added dropwise to a stirred mixture of <strong>[286947-03-3]5-bromo-2-chloro-3-methoxypyridine</strong> (International Patent Application WO 01/81347, within Example 10 thereof; 8 g), acetonitrile (4.1 ml) and THF (80 ml) that had been cooled to 18C. Additional acetonitrile (4.1 ml) and IM lithium hexamethyldisilazane solution (80 ml) were added in turn. The reaction mixture was allowed to warm to ambient temperature and poured into a stirred mixture of water (300 ml) and diethyl ether (300 ml). The aqueous phase was extracted with diethyl ether. The <n="111"/>organic phases were combined, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a solvent gradient of 4: 1 to 1 : 1 petroleum ether and diethyl ether as eluent. There was thus obtained 2-(5-bromo- 3-methoxypyridin-2-yl)acetonitrile (4.8 g); 1H NMR: (CDCl3) 3.85 (s, 2H), 3.91 (s, 3H), 7.35 (d, IH), 8.25 (d, IH); Mass Spectrum: M+H+ 227 and 229.
		Under an atmosphere of argon, a 1M solution of lithium hexamethyldisilazane in THF (80 ml) was added dropwise to a stirred mixture of <strong>[286947-03-3]5-bromo-2-chloro-3-methoxypyridine</strong> (International Patent Application WO 01/81347, within Example 10 thereof; 8 g), acetonitrile (4.1 ml) and THF (80 ml) that had been cooled to 18 C. Additional acetonitrile (4.1 ml) and 1M lithium hexamethyldisilazane solution (80 ml) were added in turn. The reaction mixture was allowed to warm to ambient temperature and poured into a stirred mixture of water (300 ml) and diethyl ether (300 ml). The aqueous phase was extracted with diethyl ether. The organic phases were combined, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a solvent gradient of 4:1 to 1:1 petroleum ether and diethyl ether as eluent. There was thus obtained 2-(5-bromo-3-methoxypyridin-2-yl)acetonitrile (4.8 g); 1H NMR: (CDCl3) 3.85 (s, 2H), 3.91 (s, 3H), 7.35 (d, 1H), 8.25 (d, 1H); Mass Spectrum: M+H+ 227 and 229.
	With lithium hexamethyldisilazane; In tetrahydrofuran; at 18 - 20℃;	The 2-[3-methoxy-5-(6-methoxy-l,5-naphthyridin-4-yloxy)pyridin-2-yl]acetic acid used as a starting material was prepared as follows :; -Under an atmosphere of argon, a IM solution of lithium hexamethyldisilazane in THF (80 ml) was added dropwise to a stirred mixture of <strong>[286947-03-3]5-bromo-2-chloro-3-methoxypyridine</strong> (International Patent Application WO 01/81347, within Example 10 thereof; 8 g), acetonitrile (4.1 ml) and THF (80 ml) that had been cooled to 18C. Additional acetonitrile (4.1 ml) and IM lithium hexamethyldisilazane solution (80 ml) were added in turn. The reaction mixture was allowed to warm to ambient temperature and poured into a stirred mixture of water (300 ml) and diethyl ether (300 ml). The aqueous phase was extracted with diethyl ether. The organic phases were combined, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a solvent gradient of 4:1 to 1 :1 petroleum ether and diethyl ether as eluent. There was thus obtained 2-(5-bromo- 3-methoxypyridin-2-yl)acetonitrile (4.8 g); 1H NMR Spectrum: (CDCl3) 3.85 (s, 2H)3 3.91 (s, 3H), 7.35 (d, IH), 8.25 (d, IH); Mass Spectrum: M+H" 227 and 229.

With lithium hexamethyldisilazane; In tetrahydrofuran; at 18 - 20℃;

The 2-[3-methoxy-5-(l,6-naphthyridin-4-yloxy)pyridin-2-yl]acetic acid used as a starting material was prepared as follows :-; Under an atmosphere of argon, a IM solution of lithium hexamethyldisilazane in THF (80 ml) was added dropwise to a stirred mixture of <strong>[286947-03-3]5-bromo-2-chloro-3-methoxypyridine</strong>(International Patent Application WO 01/81347, within Example 10 thereof; 8 g), acetonitrile (4.1 ml) and THF (80 ml) that had been cooled to 180C. Additional acetonitrile (4.1 ml) and IM lithium hexamethyldisilazane solution (80 ml) were added in turn. The reaction mixture was allowed to warm to ambient temperature and poured into a stirred mixture of water (300 ml) and diethyl ether (300 ml). The aqueous phase was extracted with diethyl ether. The organic phases were combined, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a solvent gradient of 4:1 to 1:1 <n="114"/>petroleum ether and diethyl ether as eluent. There was thus obtained 2-(5-bromo- 3-methoxypyridin-2-yl)acetonitrile (4.8 g); 1H NMR Spectrum: (CDCl3) 3.85 (s, 2H), 3.91 (s, 3H), 7.35 (d, IH)5 8.25 (d, IH); Mass Spectrum: M+H+ 227 and 229.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3050 - 3055
[2]Tetrahedron,2009,vol. 65,p. 757 - 764
[3]Patent: WO2007/99317,2007,A1 .Location in patent: Page/Page column 109-110
[4]Patent: US2009/76075,2009,A1 .Location in patent: Page/Page column 38
[5]Patent: WO2007/113548,2007,A1 .Location in patent: Page/Page column 169
[6]Patent: WO2007/113565,2007,A1 .Location in patent: Page/Page column 112-113

7
[ 74115-13-2 ]
[ 74-88-4 ]
[ 286947-03-3 ]
3-bromo-2,6-dichloro-5-methoxypyridine [ No CAS ]

Reference： [1]Tetrahedron,2009,vol. 65,p. 757 - 764

8
[ 78156-39-5 ]
[ 286947-03-3 ]

Yield	Reaction Conditions	Operation in experiment
62%	With trichlorophosphate; In dichloromethane; at 20℃;Inert atmosphere;	Phosphoryl chloride (POCl3) (4.8ml, 52.9mmol) was added to a solution of 5-bromo-3-methoxypyridine oxide (540mg, 2.6mmol) in 15ml DCM. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with saturated NaHCO3 and brine. The organic layer was dried, concentrated under reduced pressure and purified using ISCO flash chromatography using 50% ethyl acetate in hexane to provide 369mg product (62% yield). 1H NMR (300MHz, CDCl3) delta: 8.05 (s, 1H), 7.34 (s, 1H), 3.93 (s, 3H).
62%	With trichlorophosphate; In dichloromethane; at 20℃;	b. Preparation of Compound Phosphoryl chloride (POCl3) (4.8 mL, 52.9 mmol) was added to a solution of 5-bromo-3- methoxy-pyridine oxide (540 mg, 2.6 mmol) in 15 ml CH2C12. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with sat. sodium bicarbonate and brine. The organic layer was dried, concentrated and purified using ISCO flash chromatography using 50% ethyl acetate in hexane to provide 369 mg product (62% yield). lH NMR (300 MHz, CDC13) delta: 8.05 (s, IH), 7.34 (s, IH), 3.93 (s, 3H).
43.6%	With trichlorophosphate; In dichloromethane; at 40℃; for 16h;	To a mixture of 3-bromo-5-methoxypyridine 1-oxide (2 g 9.80 mmol) in DCM (40 mL) was added POCl3(18.27 mL 196 mmol) . The mixture was stirred at 40 for 16 h. The mixture was evaporated and distributed between EA (100 mL x 2) and saturated NaHCO3solution (200 mL) . The combined organic extract was washed with brine dried over MgSO4 filtered and concentrated. The residue was purified by silica column chromatography (PE/EA 101) . All fractions found to contain product by TLC (PE/EA 101 Rf 0.6) were combined and concentrated to yield a light yellow oil of 5-bromo-2-chloro-3-methoxypyridine (1 g 4.27 mmol 43.6 yield) 1HNMR(400 MHz CDCl3) delta 8.05 (d J 2.0 Hz 1H) 7.33 (d J 2.0 Hz 1H) 3.93 (s 3H) ES-LCMS m/z 222.0 224.0 (M+H)

With trichlorophosphate; In chloroform; for 7h;Reflux; Inert atmosphere; Cooling with ice;

Step 2; To Compound 37 (8.87 g), under flow of nitrogen, chloroform (166 mL) was added. Under icebath-cooling, phosphorus oxychloride was then added thereto. The reaction mixture was stirred under reflux for 7 hours. The reaction mixture was cooled, and then aqueous sodium hydrogen carbonate solution and aqueous potassium carbonate solution were added thereto, followed by extraction with dichloromethane. The extract was washed with water, dried over anhydrous magnesium sulfate, and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 1:0 ? 9:1) to yield Compound 38 (7.07 g). 1H-NMR (CDCl3) delta: 8.06 (1H, d, J = 1.85 Hz), 7.33 (1H, d, J = 1.85 Hz), 3.93 (3H, s).

Reference： [1]Tetrahedron,2009,vol. 65,p. 757 - 764
[2]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 6435 - 6446
[3]Patent: WO2014/43252,2014,A2 .Location in patent: Page/Page column 24; 35-36
[4]Patent: WO2016/37578,2016,A1 .Location in patent: Page/Page column 150; 151
[5]Patent: EP2426135,2012,A1 .Location in patent: Page/Page column 108

9
[ 286947-03-3 ]
[ 105-13-5 ]
[ 1219956-62-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 1543 - 1547
[2]Patent: WO2019/174601,2019,A1 .Location in patent: Page/Page column 89-90

11
[ 286947-03-3 ]
[ 248939-25-5 ]
[ 1241752-31-7 ]

Yield	Reaction Conditions	Operation in experiment
69%	In ethanol; at 100℃; for 0.333333h;microwave irradiation;	As shown in step 5-i of Scheme 5,5-bromo-2-chloro-3-methoxypyridine (1.0 g, 4.5 mmol, prepared in the same manner as Compound 1003 in Example 2 starting with 3- bromo-5-methoxypyridine) was treated with a sodium ethoxide/ethanol solution (5.05 mL, 21% w/v, 13.5 mmol) and the reaction mixture microwave irradiated at 1000C for 20 minutes. Water was added and the ethanol evaporated under reduced pressure. The resulting aqueous solution was extracted with DCM and ether, followed by drying the combined extracts over MgSO4. After filtration, removal of the volatiles under reduced pressure provided 5-bromo-2-ethoxy-3-methoxypyridine (Compound 1016), 0.72 g, 69% yield): ESMS (M+H) 232.32/234.23.

Reference： [1]Patent: WO2010/135014,2010,A1 .Location in patent: Page/Page column 52

12
[ 286947-03-3 ]
[ 64-17-5 ]
[ 141-52-6 ]
[ 1241752-31-7 ]

Yield	Reaction Conditions	Operation in experiment
69%	at 100℃; for 0.333333h;Microwave irradiation;	As shown in step 3(b)-i of Scheme 3(b), 5-bromo-2-chloro-3-methoxypyridine (1.0 g, 4.5 mmol, prepared in the same manner as Compound 2003 in Example 2 starting with 3- bromo-5-methoxypyridine) was treated with a sodium ethoxide/ethanol solution (5.05 mL, 21% w/v, 13.5 mmol) and the reaction mixture microwave irradiated at 100C for 20 minutes. Water was added and the ethanol evaporated under reduced pressure. The resulting aqueous solution was extracted with DCM and ether, followed by drying the combined extracts over MgS04. After filtration, removal of the volatiles under reduced pressure provided 5-bromo- 2-ethoxy-3-methoxypyridine (Compound 2011), 0.72 g, 69% yield): ESMS (M+H)

Reference： [1]Patent: WO2011/87776,2011,A1 .Location in patent: Page/Page column 53-54

13
[ 67-56-1 ]
[ 286947-03-3 ]
[ 124-41-4 ]
[ 52605-98-8 ]

Yield	Reaction Conditions	Operation in experiment
	for 7h;Inert atmosphere; Reflux;	Step 3; To Compound 38 (11.30 g), under flow of nitrogen, methanol (25 mL) and 28% sodium methoxide/methanol solution (41.75 g) were added. The solution was then stirred under reflux for 7 hours. The reaction mixture was cooled and then concentrated. Water was then added thereto, followed by extraction with ethyl acetate. The extract was washed with saturated brine, then dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 1:0 ? 9:1) to yield Compound 39 (10.48 g). 1H-NMR (CDCl3) delta: 7.78 (1H, d, J = 2.01 Hz), 7.14 (1H, d, J = 2.01 Hz), 3.99 (3H, s), 3.87 (3H, s).

Reference： [1]Patent: EP2426135,2012,A1 .Location in patent: Page/Page column 108-109

14
[ 286947-03-3 ]
[ 1253408-56-8 ]

Reference： [1]Patent: EP2426135,2012,A1

15
[ 286947-03-3 ]
[ 1253415-38-1 ]

Reference： [1]Patent: EP2426135,2012,A1

16
[ 286947-03-3 ]
[ 1253415-39-2 ]

Reference： [1]Patent: EP2426135,2012,A1

17
[ 286947-03-3 ]
[ 1253415-40-5 ]

Reference： [1]Patent: EP2426135,2012,A1

18
[ 286947-03-3 ]
[ 1253415-41-6 ]

Reference： [1]Patent: EP2426135,2012,A1

19
[ 2402-99-5 ]
[ 286947-03-3 ]

Reference： [1]Patent: EP2426135,2012,A1

20
[ 286947-03-3 ]
[ 947688-90-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3050 - 3055
[2]Patent: WO2007/113548,2007,A1

21
[ 286947-03-3 ]
[ 947688-88-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3050 - 3055
[2]Patent: WO2007/113548,2007,A1

22
[ 286947-03-3 ]
[ 947688-89-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3050 - 3055
[2]Patent: WO2007/113548,2007,A1

23
[ 286947-03-3 ]
methyl 2-[5-(6,7-dimethoxyquinolin-4-yloxy)-3-methoxypyridin-2-yl]acetate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3050 - 3055

24
[ 286947-03-3 ]
[ 947763-36-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3050 - 3055

25
[ 286947-03-3 ]
[ 947763-55-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3050 - 3055

26
[ 286947-03-3 ]
[ 909135-34-8 ]
7-(6-chloro-5-methoxypyridin-3-yl)-3-azabicyclo[3.3.1]non-7-ene trifluoroacetate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 9929 - 9945

27
[ 286947-03-3 ]
[ 909135-34-8 ]
C₁₉H₂₅ClN₂O₃ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 9929 - 9945

28
[ 286947-03-3 ]
[ 141-52-6 ]
[ 52605-98-8 ]

Yield	Reaction Conditions	Operation in experiment
97%	In ethanol; at 60℃; for 16h;Inert atmosphere;	To a 25ml flask containing (63.8mg, 1.2mmol) of sodium ethoxide was added 3ml dry ethanol. The mixture was stirred for 30min. 2-Chloro-3-methoxy-5-bromopyridine (230mg, 1.04mmol) was added to the mixture and heated to 60C for 16h. The reaction was allowed to cool and the solvent was removed. Ethyl acetate (50ml) was added to the residue. The ethyl acetate solution was washed with water and then brine. The organic solvent was dried and concentrated under reduced pressure, and purified by ISCO flash chromatography using 10% ethyl acetate in hexane to give 220mg (97% yield) of the desired product. 1H NMR (300MHz, CDCl3) delta: 7.71 (s, 1H), 7.09 (s, 1H), 4.37 (qt, 2H), 3.82 (s, 3H), 1.38 (t, 3H).

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 6435 - 6446

29
[ 50720-12-2 ]
[ 286947-03-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 6435 - 6446
[2]Patent: WO2016/37578,2016,A1
[3]Patent: WO2014/43252,2014,A2

30
[ 286947-03-3 ]
[ 141-52-6 ]
[ 1241752-31-7 ]

Yield	Reaction Conditions	Operation in experiment
97%	In ethanol; at 60℃; for 16h;	c. Preparation of Compound To a 25 mL flask containing (63.8 mg, 1.2 mmol) of sodium ethoxide was added 3 mL dry ethanol. The mixture was stirred for 30 minutes. 2-Chloro-3-methoxy-5-bromopyridine (230 mg, 1.04 mmol) was added to the mixture and heated to 60 C for 16 hours. The reaction was allowed to cool and the solvent was removed. Ethyl acetate was added (50 ml) was added to the residue. The ethyl acetate solution was washed with water and then brine. The organic solvent was dried and concentrated, purified by ISCO flash chromatography using 10% ethyl acetate in hexane to give 220 mg (97% yield) of the desired product. NMR (300 MHz, CDC13) delta: 7.71 (s, IH), 7.09 (s, IH), 4.37 (qt, 2H), 3.82 (s, 3H), 1.38 (t, 3H).

Reference： [1]Patent: WO2014/43252,2014,A2 .Location in patent: Page/Page column 24; 36

31
[ 286947-03-3 ]
2-ethoxy-3-methoxy-5-cyclohexylpyridinepyridine [ No CAS ]

Reference： [1]Patent: WO2014/43252,2014,A2

32
[ 286947-03-3 ]
[ 1581767-17-0 ]

Reference： [1]Patent: WO2014/43252,2014,A2

33
[ 286947-03-3 ]
[ 1581767-61-4 ]

Reference： [1]Patent: WO2014/43252,2014,A2

34
[ 286947-03-3 ]
[ 1581767-18-1 ]

Reference： [1]Patent: WO2014/43252,2014,A2

35
[ 286947-03-3 ]
[ 1333146-11-4 ]

Reference： [1]Patent: WO2014/43252,2014,A2

36
[ 286947-03-3 ]
[ 1454909-34-2 ]

Reference： [1]Patent: WO2014/43252,2014,A2

37
[ 286947-03-3 ]
[ 1581767-30-7 ]

Reference： [1]Patent: WO2014/43252,2014,A2

38
[ 286947-03-3 ]
3-Hydroxy-5-methyl-2-pyridon [ No CAS ]

Reference： [1]Patent: WO2014/43252,2014,A2

39
[ 286947-03-3 ]
[ 1581767-04-5 ]

Reference： [1]Patent: WO2014/43252,2014,A2

40
[ 286947-03-3 ]
5-(4-fluorophenyl)-3-hydroxypyridin-2(1H)-one [ No CAS ]

Reference： [1]Patent: WO2014/43252,2014,A2

41
[ 286947-03-3 ]
[ 1469896-37-4 ]

Reference： [1]Patent: WO2014/43252,2014,A2

42
[ 286947-03-3 ]
[ 1581767-46-5 ]

Reference： [1]Patent: WO2014/43252,2014,A2

43
[ 286947-03-3 ]
1-(((5-(2-(4-chlorophenyl)-4-oxofuro[3,2-c]pyridin-5(4H)-yl)-3-methoxypyridin-2-yl)oxy)methyl)cyclopropanecarbonitrile [ No CAS ]

Reference： [1]Patent: EP2848622,2015,A1

44
[ 286947-03-3 ]
[ 98730-77-9 ]
1-(((5-bromo-3-methoxypyridin-2-yl)oxy)methyl)cyclopropanecarbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Sodium hydride (60% oil dispersion, 76 mg) was added to a solution of <strong>[98730-77-9]1-(hydroxymethyl)cyclopropanecarbonitrile</strong> (170 mg) in THF (5 mL) at 0C, and the mixture was stirred under nitrogen atomsphere for 10 min. A solution of 5-bromo-2-chloro-3-methoxypyridine (300 mg) in DMF (1.0 mL) was added to the mixture at 0C. The resulting mixture was stirred at 40C under nitrogen atomsphere overnight. To the reaction mixture was added brine, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (155 mg) as a white solid, which included 1-(((5-bromo-4-chloro-3-methoxypyridin-2-yl)oxy)methyl)cyclopropanecarbonitrile as a byproduct. The solid was subjected to the next reaction without further purification. 1H NMR (400 MHz, CHLOROFORM-d) delta 1.14-1.23 (2H, m), 1.36-1.45 (2H, m), 3.88 (3H, s), 4.35 (2H, s), 7.18 (1H, s), 7.72 (1H, s).

Reference： [1]Patent: EP2848622,2015,A1 .Location in patent: Paragraph 0340

45
[ 286947-03-3 ]
N-[(1S,2S)-2-aminocyclopentyl]-2-(2H-1,2_,3-triazol-2-yl)benzamide hydrochloride [ No CAS ]
N-[(1S,2S)-2-[(5-bromo-3-methoxypyridin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 85 - 100℃;	Example 118 N-[(1S,2S)-2-[(5-Bromopyridin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide A mixture of N-[(1S,2S)-2-aminocyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 4; 300 mg, 0.98 mmol), 5-bromo-2-chloropyridine (CAS number 53939-30-3; 225 mg, 1.17 mmol), sodium tert-butoxide (150 mg, 1.56 mmol), BINAP (24 mg, 0.039 mmol) and tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.019 mmol) in toluene (4 ml) was heated at 85 C. overnight. The mixture was partitioned between ethyl acetate (10 ml) and water (10 ml). The aqueous layer was further extracted with ethyl acetate (320 ml). The combined organics were washed with water (220 ml), filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound. 1H NMR (300 MHz, DCM-d2) delta ppm 1.40-1.52 (m, 2H), 1.66-1.88 (m, 2H), 2.08-2.30 (m, 2H), 3.72-3.90 (m, 1H), 3.94-4.12 (m, 1H), 5.00-5.19 (m, 1H), 6.34-6.45 (m, 1H), 6.59-6.79 (m, 1H), 7.39-7.61 (m, 4H), 7.66 (s, 2H), 7.73-7.79 (m, 1H), 7.92-7.96 (m, 1H). MS ES+: 427, 429 Example 119 N-[(1S,2S)-2-[(5-Bromo-3-methoxypyridin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide Prepared according to the procedure for N-[(1S,2S)-2-[(5-bromopyridin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 118) from N-[(1S,2S)-2-amino cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 4; 300 mg, 0.98 mmol) and <strong>[286947-03-3]5-bromo-2-chloro-3-methoxypyridine</strong> (CAS number 286947-03-3; 260 mg, 1.17 mmol) except after heating overnight, to this was then added further <strong>[286947-03-3]5-bromo-2-chloro-3-methoxypyridine</strong> (CAS number 286947-03-3; 260 mg, 1.17 mmol), sodium tert-butoxide (150 mg, 1.56 mmol), BINAP (24 mg, 0.039 mmol) and tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.019 mmol) and the reaction was heated at 100 C. for 3 hours. The mixture was partitioned between ethyl acetate (10 ml) and water (10 ml). The aqueous layer was further extracted with ethyl acetate (3×10 ml). The combined organics were washed with brine, filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound. 1H NMR (400 MHz, DCM-d2) delta ppm 1.43-1.52 (m, 1H), 1.55-1.60 (m, 1H), 1.73-1.84 (m, 2H), 2.12-2.23 (m, 1H), 2.29-2.40 (m, 1H), 3.82 (s, 3H), 3.84-3.94 (m, 1H), 3.97-4.09 (m, 1H), 5.23-5.30 (m, 1H), 6.90-6.94 (m, 1H), 7.25-7.35 (m, 1H), 7.41-7.49 (m, 3H), 7.51-7.59 (m, 1H), 7.65 (s, 2H), 7.73-7.78 (m, 1H) MS ES+: 457, 459

Reference： [1]Patent: US2015/232460,2015,A1 .Location in patent: Paragraph 1276-1279; 1280-1283

46
[ 286947-03-3 ]
[ 177-11-7 ]
1-(6-chloro-5-methoxypyridin-3-yl)piperidin-4-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 5684 - 5688

47
[ 286947-03-3 ]
5-(6-chloro-5-methoxypyridin-3-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-amine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 5684 - 5688

48
[ 286947-03-3 ]
N-(5-(6-chloro-5-methoxypyridin-3-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)acetamide hydrochloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 5684 - 5688

49
[ 286947-03-3 ]
C₁₆H₁₅ClN₆O₂S [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 5684 - 5688

50
[ 286947-03-3 ]
[ 877399-49-0 ]
(R)-6'-chloro-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5'-methoxy-[3,3'-bipyridin]-6-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃;Inert atmosphere;	Step 1: (R)-6'-chloro-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5'-methoxy-[3,3'-bipyridin]-6-amine 5-Bromo-2-chloro-3-methoxypyridine (244 mg, 1.1 mmol), (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (427 mg, 1.0 mmol), Pd(PPh3)4 (116 mg, 0.1 mmol), and Cs2CO3 (652 mg, 2.0 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1.5 mL), purged with nitrogen, and the resultant was stirred at 100C overnight. After the resultant was cooled, it was purified by silica gel column chromatography to give (R)-6'-chloro-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5'-methoxy-[3,3'-bipyridin]-6-amine (252 mg, 57% yield). MS m/z[ESI]:442.0[M+1].

Reference： [1]Patent: EP2952510,2015,A1 .Location in patent: Paragraph 0318

51
[ 286947-03-3 ]
[ 536-60-7 ]
C₁₄H₁₃BrClNO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 110℃; for 2.33333h;Inert atmosphere; Sealed tube; Microwave irradiation;	a- Synthesis of Int. 47 : NaH 60% (0.275 g, 6.87 mmol) was added to a stirred suspension of 6 (0.967 g, 6.44 mmol) and <strong>[286947-03-3]5-bromo-2-chloro-3-methoxypyridine</strong> (0.955 g, 4.29 mmol) in dry THF (16 mL) at 0C under N2. The mixture was stirred 10 min at 0C under N2, and the vial was sealed. Then the r.m. was stirred at 110 C using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W for 140 min. [fixed hold time]. The crude mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgS04, filtered and concentrated in vacuo. The solid residue was purified by trituration with MeOH, filtration and washing with MeOH, t give 0.785g of Int. 47, white solid (54%).

Reference： [1]Patent: WO2015/144799,2015,A1 .Location in patent: Page/Page column 102

52
[ 286947-03-3 ]
C₂₀H₂₅BClNO₃ [ No CAS ]

Reference： [1]Patent: WO2015/144799,2015,A1

53
[ 286947-03-3 ]
C₂₅H₂₂ClN₅O₂ [ No CAS ]

Reference： [1]Patent: WO2015/144799,2015,A1

54
[ 286947-03-3 ]
[ 877399-49-0 ]
(R)-tert-butyl 6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5'-methoxy-5",6"-dihydro-[3,3':6',4"-terpyridine]-1"(2"H)-carboxylate [ No CAS ]

Reference： [1]Patent: EP2952510,2015,A1

55
[ 286947-03-3 ]
3-(2-(benzyloxy)ethoxy)-5-bromo-2-chloropyridine [ No CAS ]