[ CAS No. 80650-45-9 ] {[proInfo.proName]}

Name: 80650-45-9|4-(Pyridin-3-yloxy)aniline|95%
Brand: Ambeed
SKU: A181990
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Quality Control of [ 80650-45-9 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 80650-45-9 ]

SDS Specification

Alternatived Products of [ 80650-45-9 ]

Product Details of [ 80650-45-9 ]

CAS No. :	80650-45-9	MDL No. :	MFCD07186369
Formula :	C₁₁H₁₀N₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZSLIXJKSPVCNHZ-UHFFFAOYSA-N
M.W :	186.21	Pubchem ID :	3159631
Synonyms :

Calculated chemistry of [ 80650-45-9 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.0
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	55.16
TPSA :	48.14 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 :	Yes
Log Kp (skin permeation) :	-6.11 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.8
Log Po/w (XLOGP3) :	1.87
Log Po/w (WLOGP) :	2.46
Log Po/w (MLOGP) :	1.13
Log Po/w (SILICOS-IT) :	1.8
Consensus Log Po/w :	1.81

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.67
Solubility :	0.394 mg/ml ; 0.00211 mol/l
Class :	Soluble
Log S (Ali) :	-2.5
Solubility :	0.585 mg/ml ; 0.00314 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.92
Solubility :	0.0222 mg/ml ; 0.000119 mol/l
Class :	Soluble

Medicinal Chemistry

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

Safety of [ 80650-45-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280	UN#:	N/A
Hazard Statements:	H302-H317	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 80650-45-9 ]

* 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 [ 80650-45-9 ]
Downstream synthetic route of [ 80650-45-9 ]

[ 80650-45-9 ] Synthesis Path-Upstream 1~6

1
[ 28232-53-3 ]
[ 80650-45-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	With palladium 10% on activated carbon; hydrogen In methanol at 20℃;	Synthesis of compound 34-2 (0476) To the solution of 34-1 (2.0 g, 9.259 mmol) in MeOH (20 mL) was added 10percent Pd/C (0.2 g) purged with N₂. Then H₂was added to remove N₂. The mixture was stirred at room temperature overnight. After filtrated, the filtrate was concentrated to dryness affording 34-2 (1.7 g, 99percent) as brown solid.
98%	With palladium 10% on activated carbon; hydrogen In methanol at 20℃;	Step 4. 4-(Pyridin-3-yloxy) aniline. 3-(4-nitrophenoxy)pyridine (10.2 g, 47.18 mmol) was dissolved in 100 mL MeOH, followed by addition of Pd/C powder (10percentwt, 1.1 g). The reaction mixture was stirred at r.t. under H₂ atmosphere overnight and filtered through Celite. The filtrate was concentrated to afford 4-(pyridin-3-yloxy)aniline (17.45 g, 98percent yield) as grey solid. LC-MS: m/z: 187 (M+H)⁺.
95%	With hydrogen In tetrahydrofuran; methanol at 20℃;	b) Compound 5 was hydrogenated at room temperature using PD/C in MEOH/THF. The reaction solution was filtered through kieselguhr and rinsed with MEOH, and the filtrate was subsequently evaporated. The residue was digested with diethyl ether, filtered off with suction, rinsed with diethyl ether and dried overnight at 40'C under reduced pressure. Yield : 37. 14 G (95percent) OF 6, PALE-BROWN CRYSTALS

95%	With hydrogen In tetrahydrofuran; methanol at 20℃;	The thus obtained nitro comound was hydrogenated at room temperature using Pd/C in MeOH/THF. The reaction solution was filtered through kieselguhr and rinsed with MeOH, and the filtrate was subsequently evaporated. The residue was digested with diethyl ether, filtered off with suction, rinsed with diethyl, ether and dried overnight at 40°C under reduced pressure. Yield : 37.14 g (95percent) of 5b, pale-brown crystals
95%	With hydrogen In tetrahydrofuran; methanol at 20℃;	Compound 5 is hydrogenated with Pd/C in [METHANOL/TETRAHYDROFURANE] at room temperature. The reaction mixture is filtered over kieselguhr, the residue washed with methanol and the filtrate evaporated. The residue is digested with diethyl ether, filtered by suction, washed with diethyl ether and dried in vacuum at 40 [°C] overnight to yield 37.14 g (95 percent) light brownish crystals of 6.
95%	With hydrogen In tetrahydrofuran; methanol at 20℃;	b) Compound 5 is hydrogenated at room temperature using Pd/C in MeOH/THF. The reaction solution is filtered through kieselguhr and rinsed with MeOH, and the filtrate is subsequently evaporated. The residue is digested with diethyl ether, filtered off with suction, rinsed with diethyl ether and dried overnight at 40°C under reduced pressure. Yield : 37.14 g (95percent) of 6, pale-brown crystals
95%	With hydrogen In ethyl acetate for 3.5 h;	A solution of 3- (4-nitrophenoxy)pyridine g, 23.13 mmol) in EtOAc (100 mL) in a 250 ml Parr bottle was purged with nitrogen. To this solution was added EtOAc-moistened 10percent Pd/C catalyst (500 mg, 10percent by weight). The reaction flask was placed in a Parr hygrogenation apparatus, purged with nitrogen (5x), evacuated, and then pressurized to 40 psi with hydrogen and shaken for 3.5 h. The reaction mixture was then purged with nitrogen, and filtered through a pad of Celite , rinsing with ethyl acetate (3x) and ethanol (3x). The filtrate was evaporated at reduced pressure to give a brown crystalline residue. The residue was stirred in diethyl ether at room temperature for 16 h and then filtered to provide 4.11 g (95percent) of the desired product as light brown crystals. (at)H-NMR (DMSO-d6) No. 8.21 (m, 2H), 7.30 (ddd, J = 8.4,4.6, 0.7 Hz, 1 H), 7.18 (ddd, J = 8.4, 2.9, 1.4 Hz, 1 H), 6.79 (d, J = 8.8 Hz, 2H), 6.58 (d, J = 9.0 Hz, 2H), 5.05 (br s, 2H) ; MS LC-MS [M+H]+ = 187, RT = 1.03 min.
36%	With iron; ammonium chloride In tetrahydrofuran; methanol; water at 80℃; for 3 h;	4-(Pyridin-3-yl)oxy-l -nitrobenzene prepared in Step A was dissolved in the mixture of water (100 mL), tetrahydrofuran (100 mL) and methanol (100 mL). Iron powder (103 g, 1.84 mol) and ammonium chloride (99 g, 1.84 mol) were added thereto, and the mixture was stirred for 3 h at 80 ^°C using a mechanical stirrer. After completion of the reaction, the reaction mixture was filtered through a cellite, washed with methanol, and concentrated under reduced pressure. The solid thus obtained was filtered, washed with ether, and dried to give the title compound (17 g, Yield 36percent). Mass[M+H] : 186 (M+l)
36%	With iron; ammonium chloride In tetrahydrofuran; methanol at 80℃; for 3 h;	The compound thus obtained was dissolved using water (100ml), tetrahydrofuran (100ml) and methanol (100ml). Iron powder (103g, 1.84 mol) and ammonium chloride (99g, 1.84 mol) were added thereto, and the mixture was stirred using a mechanical stirrer for 3 h at 80 "C . After completion of the reaction, the reaction solution was filtered through a celite, washed with methanol, and concentrated.The resulting solid was filtered, washed with ether, and dried to give 4-(pyridin-3- yloxy)-phenylamine ( 17g, Yield 36percent).
36%	With water; iron; ammonium chloride In tetrahydrofuran; methanol at 80℃; for 3 h;	4-(Pyridin-3-yl)oxy-1-nitrobenzene prepared in Step A was dissolved in the mixture of water (100 mL), tetrahydrofuran (100 mL) and methanol (100 mL). Iron powder (103 g, 1.84 mol) and ammonium chloride (99 g, 1.84 mol) were added thereto, and the mixture was stirred for 3 h at 80° C. using a mechanical stirrer. After completion of the reaction, the reaction mixture was filtered through a cellite, washed with methanol, and concentrated under reduced pressure. The solid thus obtained was filtered, washed with ether, and dried to give the title compound (17 g, Yield 36percent).

Reference： [1] Patent: US9138427, 2015, B2, . Location in patent: Page/Page column 309
[2] Patent: WO2014/176258, 2014, A1, . Location in patent: Page/Page column 30
[3] Patent: WO2004/85399, 2004, A1, . Location in patent: Page 168
[4] Patent: WO2005/4863, 2005, A1, . Location in patent: Page/Page column 128
[5] Patent: WO2004/19941, 2004, A1, . Location in patent: Page/Page column 154
[6] Patent: WO2005/5389, 2005, A2, . Location in patent: Page 165
[7] Patent: WO2005/110994, 2005, A2, . Location in patent: Page/Page column 81
[8] Organic Letters, 2015, vol. 17, # 3, p. 426 - 429
[9] Chemical Communications, 2017, vol. 53, # 95, p. 12814 - 12817
[10] Patent: WO2009/25477, 2009, A1, . Location in patent: Page/Page column 57
[11] Patent: WO2009/82152, 2009, A2, . Location in patent: Page/Page column 74
[12] Patent: US2010/210647, 2010, A1, . Location in patent: Page/Page column 17
[13] Yakugaku Zasshi, 1957, vol. 77, p. 944[14] Chem.Abstr., 1958, p. 2855
[15] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 11, p. 1253 - 1256
[16] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 22, p. 5473 - 5476
[17] Patent: US2010/267708, 2010, A1, . Location in patent: Page/Page column 22
[18] Patent: US2010/291533, 2010, A1, . Location in patent: Page/Page column 21
[19] Patent: WO2009/117421, 2009, A2, . Location in patent: Page/Page column 207-208

2
[ 109-00-2 ]
[ 80650-45-9 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 22, p. 5473 - 5476
[2] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 11, p. 1253 - 1256
[3] Patent: WO2014/176258, 2014, A1,
[4] Organic Letters, 2015, vol. 17, # 3, p. 426 - 429
[5] Chemical Communications, 2017, vol. 53, # 95, p. 12814 - 12817
[6] Patent: WO2009/117421, 2009, A2,

3
[ 350-46-9 ]
[ 80650-45-9 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 22, p. 5473 - 5476
[2] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 11, p. 1253 - 1256
[3] Patent: WO2014/176258, 2014, A1,
[4] Chemical Communications, 2017, vol. 53, # 95, p. 12814 - 12817

4
[ 636-98-6 ]
[ 80650-45-9 ]

Reference： [1] Organic Letters, 2015, vol. 17, # 3, p. 426 - 429

5
[ 109-00-2 ]
[ 350-46-9 ]
[ 80650-45-9 ]

Reference： [1] Patent: US9138427, 2015, B2,

6
[ 100-00-5 ]
[ 80650-45-9 ]

Reference： [1] Yakugaku Zasshi, 1957, vol. 77, p. 944[2] Chem.Abstr., 1958, p. 2855

[ 80650-45-9 ] Synthesis Path-Downstream 1~62

1
[ 28232-53-3 ]
[ 80650-45-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃;	Synthesis of compound 34-2 (0476) To the solution of 34-1 (2.0 g, 9.259 mmol) in MeOH (20 mL) was added 10% Pd/C (0.2 g) purged with N2. Then H2 was added to remove N2. The mixture was stirred at room temperature overnight. After filtrated, the filtrate was concentrated to dryness affording 34-2 (1.7 g, 99%) as brown solid.
98%	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃;	Step 4. 4-(Pyridin-3-yloxy) aniline. 3-(4-nitrophenoxy)pyridine (10.2 g, 47.18 mmol) was dissolved in 100 mL MeOH, followed by addition of Pd/C powder (10%wt, 1.1 g). The reaction mixture was stirred at r.t. under H2 atmosphere overnight and filtered through Celite. The filtrate was concentrated to afford 4-(pyridin-3-yloxy)aniline (17.45 g, 98% yield) as grey solid. LC-MS: m/z: 187 (M+H)+.
95%	With hydrogen;palladium on activated charcoal; In tetrahydrofuran; methanol; at 20℃;	b) Compound 5 was hydrogenated at room temperature using PD/C in MEOH/THF. The reaction solution was filtered through kieselguhr and rinsed with MEOH, and the filtrate was subsequently evaporated. The residue was digested with diethyl ether, filtered off with suction, rinsed with diethyl ether and dried overnight at 40'C under reduced pressure. Yield : 37. 14 G (95%) OF 6, PALE-BROWN CRYSTALS

95%	With hydrogen;palladium on activated charcoal; In tetrahydrofuran; methanol; at 20℃;	The thus obtained nitro comound was hydrogenated at room temperature using Pd/C in MeOH/THF. The reaction solution was filtered through kieselguhr and rinsed with MeOH, and the filtrate was subsequently evaporated. The residue was digested with diethyl ether, filtered off with suction, rinsed with diethyl, ether and dried overnight at 40C under reduced pressure. Yield : 37.14 g (95%) of 5b, pale-brown crystals
95%	With hydrogen;palladium on activated charcoal; In tetrahydrofuran; methanol; at 20℃;	Compound 5 is hydrogenated with Pd/C in [METHANOL/TETRAHYDROFURANE] at room temperature. The reaction mixture is filtered over kieselguhr, the residue washed with methanol and the filtrate evaporated. The residue is digested with diethyl ether, filtered by suction, washed with diethyl ether and dried in vacuum at 40 [C] overnight to yield 37.14 g (95 %) light brownish crystals of 6.
95%	With hydrogen;palladium on activated charcoal; In tetrahydrofuran; methanol; at 20℃;	b) Compound 5 is hydrogenated at room temperature using Pd/C in MeOH/THF. The reaction solution is filtered through kieselguhr and rinsed with MeOH, and the filtrate is subsequently evaporated. The residue is digested with diethyl ether, filtered off with suction, rinsed with diethyl ether and dried overnight at 40C under reduced pressure. Yield : 37.14 g (95%) of 6, pale-brown crystals
95%	With hydrogen;palladium 10% on activated carbon; In ethyl acetate; under 2068.65 Torr; for 3.5h;	A solution of 3- (4-nitrophenoxy)pyridine g, 23.13 mmol) in EtOAc (100 mL) in a 250 ml Parr bottle was purged with nitrogen. To this solution was added EtOAc-moistened 10% Pd/C catalyst (500 mg, 10% by weight). The reaction flask was placed in a Parr hygrogenation apparatus, purged with nitrogen (5x), evacuated, and then pressurized to 40 psi with hydrogen and shaken for 3.5 h. The reaction mixture was then purged with nitrogen, and filtered through a pad of Celite , rinsing with ethyl acetate (3x) and ethanol (3x). The filtrate was evaporated at reduced pressure to give a brown crystalline residue. The residue was stirred in diethyl ether at room temperature for 16 h and then filtered to provide 4.11 g (95%) of the desired product as light brown crystals. (at)H-NMR (DMSO-d6) No. 8.21 (m, 2H), 7.30 (ddd, J = 8.4,4.6, 0.7 Hz, 1 H), 7.18 (ddd, J = 8.4, 2.9, 1.4 Hz, 1 H), 6.79 (d, J = 8.8 Hz, 2H), 6.58 (d, J = 9.0 Hz, 2H), 5.05 (br s, 2H) ; MS LC-MS [M+H]+ = 187, RT = 1.03 min.
36%	With iron; ammonium chloride; In tetrahydrofuran; methanol; water; at 80℃; for 3h;	4-(Pyridin-3-yl)oxy-l -nitrobenzene prepared in Step A was dissolved in the mixture of water (100 mL), tetrahydrofuran (100 mL) and methanol (100 mL). Iron powder (103 g, 1.84 mol) and ammonium chloride (99 g, 1.84 mol) were added thereto, and the mixture was stirred for 3 h at 80 C using a mechanical stirrer. After completion of the reaction, the reaction mixture was filtered through a cellite, washed with methanol, and concentrated under reduced pressure. The solid thus obtained was filtered, washed with ether, and dried to give the title compound (17 g, Yield 36%). Mass[M+H] : 186 (M+l)
36%	With iron; ammonium chloride; In tetrahydrofuran; methanol; at 80℃; for 3h;	The compound thus obtained was dissolved using water (100ml), tetrahydrofuran (100ml) and methanol (100ml). Iron powder (103g, 1.84 mol) and ammonium chloride (99g, 1.84 mol) were added thereto, and the mixture was stirred using a mechanical stirrer for 3 h at 80 "C . After completion of the reaction, the reaction solution was filtered through a celite, washed with methanol, and concentrated.The resulting solid was filtered, washed with ether, and dried to give 4-(pyridin-3- yloxy)-phenylamine ( 17g, Yield 36%).
36%	With water; iron; ammonium chloride; In tetrahydrofuran; methanol; at 80℃; for 3h;	4-(Pyridin-3-yl)oxy-1-nitrobenzene prepared in Step A was dissolved in the mixture of water (100 mL), tetrahydrofuran (100 mL) and methanol (100 mL). Iron powder (103 g, 1.84 mol) and ammonium chloride (99 g, 1.84 mol) were added thereto, and the mixture was stirred for 3 h at 80 C. using a mechanical stirrer. After completion of the reaction, the reaction mixture was filtered through a cellite, washed with methanol, and concentrated under reduced pressure. The solid thus obtained was filtered, washed with ether, and dried to give the title compound (17 g, Yield 36%).
	With iron; ammonium chloride; In tetrahydrofuran; water; at 80℃; for 3h;	1-Chloro-4-nitrobenzene (40 g, 0.25 mol) and 3-hydroxypyridine (36 g, 0.38 mol) were dissolved in N,N-dimethylformamide (100 ml). Potassium carbonate (52.6 g, 0.38 mol) was added thereto, and the mixture was stirred for 20 h at 100 C. Water was added to the reaction solution, which was then extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate to give 3-(4-nitro-phenoxy)-pyridine.The compound thus obtained was dissolved using water (100 ml), tetrahydrofuran (100 ml) and methanol (100 ml). Iron powder (103 g, 1.84 mol) and ammonium chloride (99 g, 1.84 mol) were added thereto, and the mixture was stirred using a mechanical stirrer for 3 h at 80 C. After completion of the reaction, the reaction solution was filtered through a celite, washed with methanol, and concentrated. The resulting solid was filtered, washed with ether, and dried to give 4-(pyridin-3-yloxy)-phenylamine (17 g, Yield 36%).
	With iron; ammonium chloride; In tetrahydrofuran; methanol; water; at 80℃; for 3h;	(Step 1)1-Chloro-4-nitrobenzene (40 g, 0.25 mol) and 3-hydroxypyridine (36 g, 0.38 mol) were dissolved in N,N-dimethylformamide (100 ml). Potassium carbonate (52.6 g, 0.38 mol) was added, and the mixture was stirred for 20 h at 100. Water was added, and the resulting mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate to give 3-(4-nitro-phenoxy)-pyridine.Thus obtained compound was dissolved using water (100 ml), tetrahydrofuran (100 ml) and methanol (100 ml). Iron dust (103 g, 1.84 mol) and ammonium chloride (99 g, 1.84 mol) were added, and the mixture was stirred using a mechanical stirrer for 3 h at 80. After completion of the reaction, the reaction mixture was filtered through celite, washed with methanol and concentrated. The resulting solid was filtered, washed with ether and dried to give 4-(pyridin-3-yloxy)-phenylamine (17 g, Yield 36%).
	With hydrogen;palladium on activated charcoal; In methanol; for 2.5h;	3-(4-nitrophenoxy)pyridine (4.1 g, 18.9 mmol) was dissolved in MeOH (50 mL) and hydrogenated in the presence of a catalytic amount of Pd/C with a balloon of Hydrogen for 2.5 h. Pd/C was removed by filtration and the filtrate was evaporated to dryness under reduced pressure to afford 4-(pyridin-3-yloxy)aniline as a grey solid.

Reference： [1]Patent: US9138427,2015,B2 .Location in patent: Page/Page column 309
[2]Patent: WO2014/176258,2014,A1 .Location in patent: Page/Page column 30
[3]Patent: WO2004/85399,2004,A1 .Location in patent: Page 168
[4]Patent: WO2005/4863,2005,A1 .Location in patent: Page/Page column 128
[5]Patent: WO2004/19941,2004,A1 .Location in patent: Page/Page column 154
[6]Patent: WO2005/5389,2005,A2 .Location in patent: Page 165
[7]Patent: WO2005/110994,2005,A2 .Location in patent: Page/Page column 81
[8]Organic Letters,2015,vol. 17,p. 426 - 429
[9]Chemical Communications,2017,vol. 53,p. 12814 - 12817
[10]Patent: WO2009/25477,2009,A1 .Location in patent: Page/Page column 57
[11]Patent: WO2009/82152,2009,A2 .Location in patent: Page/Page column 74
[12]Patent: US2010/210647,2010,A1 .Location in patent: Page/Page column 17
[13]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1957,vol. 77,p. 944
Chem.Abstr.,1958,p. 2855
[14]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 1253 - 1256
[15]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5473 - 5476
[16]Patent: US2010/267708,2010,A1 .Location in patent: Page/Page column 22
[17]Patent: US2010/291533,2010,A1 .Location in patent: Page/Page column 21
[18]Patent: WO2009/117421,2009,A2 .Location in patent: Page/Page column 207-208

2
[ 80650-45-9 ]
4-methyl-N'-[(1E)-pyridin-2-ylmethylene]benzenesulfonohydrazide [ No CAS ]
C₁₇H₁₂N₆O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5473 - 5476

3
[ 36082-50-5 ]
[ 80650-45-9 ]
(5-bromo-2-chloro-pyrimidin-4-yl)-[4-(pyridin-3-yloxy)-phenyl]-amine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 1973 - 1977

4
[ 852357-08-5 ]
[ 80650-45-9 ]
N⁴-(1H-benzoimidazol-5-yl)-5-bromo-N²-[4-(pyridin-3-yloxy)-phenyl]-pyrimidine-2,4-diamine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 1973 - 1977

5
[ 80650-45-9 ]
N²-(1H-benzoimidazol-5-yl)-5-bromo-N⁴-[4-(pyridin-3-yloxy)-phenyl]-pyrimidine-2,4-diamine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 1973 - 1977

6
[ 109-00-2 ]
[ 80650-45-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5473 - 5476
[2]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 1253 - 1256
[3]Patent: WO2014/176258,2014,A1
[4]Organic Letters,2015,vol. 17,p. 426 - 429
[5]Chemical Communications,2017,vol. 53,p. 12814 - 12817
[6]Patent: WO2009/117421,2009,A2

7
[ 350-46-9 ]
[ 80650-45-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5473 - 5476
[2]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 1253 - 1256
[3]Patent: WO2014/176258,2014,A1
[4]Chemical Communications,2017,vol. 53,p. 12814 - 12817

8
[ 100-00-5 ]
[ 80650-45-9 ]

Reference： [1]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1957,vol. 77,p. 944
Chem.Abstr.,1958,p. 2855

9
[ 80650-45-9 ]
[ 17738-61-3 ]
N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-[4-(3-pyridinyloxy)phenyl]ethanediamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52.5%	With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃;	27 mg (0.10 MMOL) of 10,17. 1 mg (0.09 MMOL) of 6,39 mg of TBTU (0.12 MMOL) and 4.3 mg (0.03 MMOL) of HOBT were dissolved in DIMETHYLFORMAMIDE, 0.06 mi (0.37 MMOL) of N-ethyldiisopropylamine was added at room temperature, and the mixture was stirred overnight. Water was added to the reaction mixture, and the deposited crystals were filtered off with suction, washed with diethyl ether and dried. Yield : 21 mg (52.5%), beige solid

Reference： [1]Patent: WO2004/85399,2004,A1 .Location in patent: Page 171; 172

10
[ 2849-93-6 ]
[ 80650-45-9 ]
N-[4-(pyridine-3-yloxy)phenyl]-1H-benzimidazole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%		0.064 mmol of benzimidazolecarboxylic acid 41 was dissolved in DMF together with 0.064 mmol of the amine 5b, a solution of TBTU (0.096 MMOL) in DMF, HOBT (0.026 MMOL) in DMF and 0.32 mmol of DIPEA were added successively, and the mixture was stirred at room temperature. After 2.5 hours, 0.2 eq. of acid was added, and the mixture was stirred overnight. The reaction mixture was diluted with water and extracted a number of times with ethyl acetate. The combined organic phases were washed 2 x with water, dried, filtered and evaporated. Yield : 92%, pale-beige solid

Reference： [1]Patent: WO2005/4863,2005,A1 .Location in patent: Page/Page column 145-146

11
[ 39811-14-8 ]
[ 80650-45-9 ]
N-[4-(pyridine-3-yloxy)phenyl]-5-chloro-1H-benzimidazole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%		0.064 mmol of benzimidazolecarboxylic acid 4a was dissolved in DMF together with 0.064 MMOL of the amine 5B, A solution of TBTU (0. 096 MMOL) in DMF, HOBT (0.026 mmol) in DMF and 0. 32 mmol of DIPEA were added successively, and the mixture was stirred at room temperature. After 2.5 hours, 0.2 EQ. of acid was added, and the mixture was stirred overnight. The reaction mixture was diluted with water, and the resulting precipitate was filtered off with suction, washed with water and digested with diethyl ether. Yield : 69%, pale-brown solid

Reference： [1]Patent: WO2005/4863,2005,A1 .Location in patent: Page/Page column 141

12
[ 827029-04-9 ]
[ 80650-45-9 ]
N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-[4-(pyridine-3-yloxy)phenyl]-malonamid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With O-benzotriazol-1-yl-N,N,N',N'-bis(tetramethylene)uronium tetrafluoroborate; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃;	30 MG (0. 107 MMOL) OF 21, 18. 1 mg (0. 097 MMOL) OF 6, 41 mg of TBTU (0.127 MMOL) and 4.5 mg (0.029 MMOL) of HOBT are dissolved in 3 mi DIMETHYLFORMAMIDE, 0.07 ml (0. 39 MMOL) of N-ethyldiisopropylamine is added at room temperature, and the mixture is stirred overnight. The reaction mixture is diluted with water and extracted several times with ethyl acetate. The combined organic phases are washed with water, dried over NA2SO4, filtered and evaporated. The residue is put on silica gel and purified by column chromatography (4 g silica gel, eluent : ethyl acetate/n- heptane). Yield : 24 mg (55%), colourless solid.

Reference： [1]Patent: WO2005/5389,2005,A2 .Location in patent: Page 173; 174

13
[ 80650-45-9 ]
[ 2107-39-3 ]
N-[4-(pyridine-3-yloxy)phenyl]-5-trifluoromethyl-1H-benzimidazole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%		0.064 MMOL of BENZIMIDAZOLECARBOXYLIC acid 4b was dissolved in DMF together with 0.064 MMOL of the amine 5b, a solution of TBTU (0.096 MMOL) in DMF, HOBT (0.026 MMOL) in DMF and 0.32 mmol of DIPEA were added successively, and the mixture was stirred at room temperature. After 2 hours, a further 0.4 eq. of acid was added, and the mixture was stirred for 2 hours. The reaction mixture was diluted with water, and the resulting precipitate was filtered off with suction, washed with water and digested with diethyl ether. Yield : 57%, colourless solid

Reference： [1]Patent: WO2005/4863,2005,A1 .Location in patent: Page/Page column 141-142

14
[ 80650-45-9 ]
[ 827042-59-1 ]
N-[4-(pyridine-3-yloxy)phenyl]-5-chloro-4-methyl-1H-benzimidazole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%		0.064 mmol of benzimidazolecarboxylic acid 4c was dissolved in DMF together with 0.064 MMOL of the amine 5b, A solution of TBTU (0.096 MMOL) in DMF, HOBT (0. 026 mmol) in DMF and 0. 32 mmol of DIPEA were added successively, and the mixture was stirred at room temperature. After 2 hours, a further 0.3 EQ. of acid was added, and the mixture was stirred for 2 hours. The reaction mixture was diluted with water, and the resulting precipitate was filtered off with suction, washed with water and digested with diethyl ether and ethyl acetate. Yield: 95%, yellow solid

Reference： [1]Patent: WO2005/4863,2005,A1 .Location in patent: Page/Page column 142

15
[ 80650-45-9 ]
[ 827042-60-4 ]
N-[4-(pyridine-3-yloxy)phenyl]-4-bromo-6-trifluoromethyl-1H-benzimidazole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%		0.064 MMOL of benzimidazolecarboxylic acid 4d was dissolved in DMF together with 0.064 mmol of the amine 5b, a solution of TBTU (0.096 MMOL) in DMF, HOBT (0. 026 MMOL) in DMF and 0.32 mmol of DIPEA were added successively, and the mixture was stirred at room temperature. After 2 hours, a further 0.2 eq. of acid was added, and the mixture was stirred for 2 hours. The reaction mixture was diluted with water, and the resulting precipitate was filtered off with suction and washed with water. Yield : 93%, pale-beige solid

Reference： [1]Patent: WO2005/4863,2005,A1 .Location in patent: Page/Page column 142-143

16
[ 80650-45-9 ]
[ 827042-61-5 ]
N-[4-(pyridine-3-yloxy)phenyl]-5-chloro-6-trifluoromethyl-1H-benzimidazole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75.5%		0.064 mmol of benzimidazolecarboxylic acid 4e was dissolved in DMF together with 0.064 mmol of the amine 5b, a solution of TBTU (0.096 mmol) in DMF, HOBT (0.026 MMOL) in DMF and 0. 32 MMOL of DIPEA were added successively, and the mixture was stirred at room temperature. After 2 hours, a further 0.1 eq. of acid was added, and the mixture was stirred for 2 hours. The reaction mixture was diluted with water, and the resulting precipitate was filtered off with suction and washed with water. Yield : 75.5%, colourless solid

Reference： [1]Patent: WO2005/4863,2005,A1 .Location in patent: Page/Page column 143

17
[ 80650-45-9 ]
[ 673487-32-6 ]
N-[4-(pyridine-3-yloxy)phenyl]-4-methyl-1H-benzimidazole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73.5%		0.064 mmol of BENZIMIDAZOLECARBOXYLIC acid 4f was dissolved in DMF together with 0. 064 mmol of the amine 5b, a solution of TBTU (0. 096 MMOL) in DMF, HOBT (0.026 MMOL) in DMF and 0. 32 MMOL of DIPEA were added successively, and the mixture was stirred at room temperature. After 3 hours, a further 0.3 eq. of acid was added, and the mixture was stirred for 2 hours. The reaction mixture was diluted with water, and the resulting precipitate was filtered off with suction and washed with water. Yield : 73.5%, beige solid

Reference： [1]Patent: WO2005/4863,2005,A1 .Location in patent: Page/Page column 143

18
[ 80650-45-9 ]
[ 827042-62-6 ]
N-[4-(pyridine-3-yloxy)phenyl]-4-chloro-6-trifluoromethyl-1H-benzimidazole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 4h;	0.064 mmol of benzimidazolecarboxylic acid 4g was dissolved in DMF together with 0.064 mmol of the amine 5b, a solution of TBTU (0.096 MMOL) in DMF, HOBT (0.026 MMOL) in DMF and 0.32 MMOL of DIPEA were added successively, and the mixture was stirred for 4 hours at room temperature. The reaction mixture was diluted with water, and the resulting precipitate was filtered off with suction and washed with water. Yield : 73%, pale-beige solid

Reference： [1]Patent: WO2005/4863,2005,A1 .Location in patent: Page/Page column 143-144

19
[ 80650-45-9 ]
[ 827042-63-7 ]
N-[4-(pyridine-3-yloxy)phenyl]-5-chloro-6-methyl-1H-benzimidazole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃;	0.064 mmol of BENZIMIDAZOLECARBOXYLIC acid 4h was dissolved in DMF together with 0.064 mmol of the amine 5b, a solution of TBTU (0.096 MMOL) in DMF, HOBT (0. 026 mmol) in DMF and 0.32 mmol of DIPEA were added successively, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, and the resulting precipitate was filtered off with suction and washed with water. The resulting solid was digested a number of times with ethyl acetate, and the combined filtrates were evaporated. Yield: 36%, brown solid

Reference： [1]Patent: WO2005/4863,2005,A1 .Location in patent: Page/Page column 144

20
[ 80650-45-9 ]
[ 827042-64-8 ]
N-[4-(pyridine-3-yloxy)phenyl]-4,6-bis(tifluoromethyl)-1H-benzimidazole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃;	0.064 mmol of benzimidazolecarboxylic acid 4i was dissolved in DMF together with 0.064 mmol of the amine 5b, a solution of TBTU (0.096 MMOL) in DMF, HOBT (0.026 MMOL) in DMF and 0.32 mmol of DIPEA were added successively, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, and the resulting precipitate was filtered off with suction and washed with water. Yield : 67%, pale-beige solid

Reference： [1]Patent: WO2005/4863,2005,A1 .Location in patent: Page/Page column 144

21
[ 80650-45-9 ]
[ 287730-14-7 ]
N-[4-(pyridine-3-yloxy)phenyl]-5,6-dichloro-1H-benzimidazole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃;	0.064 mmol of benzimidazolecarboxylic acid 4j was suspended in DMF together with 0.064 mmol of the amine 5b, a solution of TBTU (0.096 MMOL) in DMF, HOBT (0.026 MMOL) in DMF and 0.32 mmol of DIPEA were added successively, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, and the resulting precipitate was filtered off with suction and washed with water. Yield : 46%, pale-brown solid

Reference： [1]Patent: WO2005/4863,2005,A1 .Location in patent: Page/Page column 145

22
[ 80650-45-9 ]
[ 99459-47-9 ]
N-[4-(pyridine-3-yloxy)phenyl]-5-methyl-1H-benzimidazole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%		0.064 mmol of benzimidazolecarboxylic acid 4k was dissolved in DMF together with 0. 064 mmol of the amine 5B, A solution of TBTU (0.096 MMOL) in DMF, HOBT (0.026 MMOL) in DMF and 0.32 mmol of DIPEA were added successively, and the mixture was stirred at room temperature. After 4 hours, 0.3 eq. of acid was added, and the mixture was stirred overnight. After further addition of 0.3 eq. of acid, the reaction mixture was diluted with water after 2 hours, and the resulting precipitate was filtered off with suction and washed with water. The resulting crude product was purified by chromatography (ethyl ACETATE/N-HEPTANE : 6/4). Yield : 57%, pale-orange solid

Reference： [1]Patent: WO2005/4863,2005,A1 .Location in patent: Page/Page column 145

23
[ 80650-45-9 ]
[ 351-33-7 ]
N-(4-chloro-3-trifluoromethylphenyl)-2-[4-(3-pyridinyloxy)phenylamino]acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9%	With N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 100℃; for 4h;	A solution of 146.1 mg (0.54 [MMOL)] of compound 9 in dimethylformamide (DMF) is given to a solution of 100 mg (0.54 [MMOL)] of compound 6 and 0.1 ml (0.59 [MMOL)] N-Ethyl-diisopropylamine in DMF. The reaction mixture is heated to 100 [C] for 4 h, then evaporated and the residue is purified by preparative HPLC to yield 20 mg (9 %) colourless solid.

Reference： [1]Patent: WO2004/19941,2004,A1 .Location in patent: Page/Page column 157

Yield	Reaction Conditions	Operation in experiment
	With palladium 10% on activated carbon; hydrogen; In ethanol; for 12h;	General procedure: General Procedure B: Reduction of the Nitro Group10% Palladium on carbon (10% by weight) was added to a stilTed solution of the nitro compound in ethanol under nitrogen atmosphere. The reaction mixture was stilTed under a hydrogenatmosphere for 12 h, filtered through sintered funnel and evaporated under reduced pressure to get the corresponding amine. Step 2)3-Fluoro-4-phenoxy-phenylamine 2-Fluoro-4-nitro-1-phenoxy-benzene was reduced using the conditions outlined in GeneralProcedure B to give 3-fluoro-4-phenoxy-phenylamine.
	With iron; ammonium chloride; In tetrahydrofuran; methanol; water; at 50℃; for 18h;	General procedure: Intermediate H (808 mg,3.52 mmol) was dissolved in a mixture of THF (10 ml_) and MeOH (5 ml_). Ammonium chloride (566 mg,10.6 mmol) was dissolved in water (2 ml_) and added to the reaction mixture along with iron (591 mg,10.6 mmol). The reaction mixture was heated to 50 C for 18h. After cooling to r.t.,the mixture was filtered through Dicalite,washing with EtOAc. The filtrate was washed with water,and the aqueous layer extracted with EtOAc. The combined organics were washed (brine),dried (MgS04) and concentrated in vacuo to yield the title compound as a yellow solid (609 mg,87%). NMR dH(500 MHz,DMSO-d6) 7.45 - 7.35 (m,4H),7.34 - 7.27 (m,1 H),6.75 - 6.69 (m,2H),6.53 - 6.47 (m,2H),4.94 (s,2H),4.62 (br s,2H); LCMS: (Method A) 3.32 min,(200.2,MH+).

25
ethyl (4-{3-tert-butyl-5-[(phenoxycarbonyl)amino]-1H-pyrazol-1-yl}phenyl)acetate [ No CAS ]
[ 80650-45-9 ]
ethyl (4-{3-tert-butyl-5-[([4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	In tetrahydrofuran; at 60℃;	A mixture of ethyl (4-{3-tert-butyl-5-[(phenoxycarbonyl)amino]-1 H-pyrazol-1- yl}phenyl)acetate (3.0 g, 7.12 mmol) and 4-(pyridin-4-yloxy)aniline (1.26 g, 6.78 mmol) in THF (50 mL) was heated at 60C overnight. The reaction mixture was cooled to room temperature and then evaporated at reduced pressure to afford a brown syrup, which was purified by MPLC (25: 75 to 70:30 EtOAc/hexane). The desired product was obtained as a white solid (2.42 g) in 70% yield. 'H-NMR (CD2Cl2-d2) No. 8.35 (m, 2H), 8.06 (s, 1 H), 7.42 (m, 4H), 7.33 (s, 1 H), 7.28 (d, J = 8.3 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 5.8 Hz, 2H), 6.35 (s, 1 H), 4.12 (q, J = 7.1 Hz, 2H), 3.63 (s, 2H), 1.31 (s, 9H), 1.27 (t, J = 7.1 Hz, 3H) ; MS LC-MS [M+H]+ = 514.2, RT = 2.66 min.

Reference： [1]Patent: WO2005/110994,2005,A2 .Location in patent: Page/Page column 105

26
[ 80650-45-9 ]
[ 1188476-09-6 ]

Yield	Reaction Conditions	Operation in experiment
		4-(Pyridin-3-yloxy)aniline (1 g, 5.4 mmol) was suspended in HCl (cone, 10 niL) and cooled to O0C in an ice bath. Sodium nitrite (373 mg, 5.40 mmol) in H2O (2 mL) was then added dropwise and the resulting dark blue mixture was stirred at O0C for 30 min. Any insoluble particles were removed by filtration and tin dichloride dihydrate (3.6 g, 16.2 mmol) in HCl (cone, 10 mL) was added dropwise while the temperature was maintained at O0C. The yellowish precipitate was filtered, washed with H2O, and dried overnight. It afforded 3-(4-hydrazinylphenoxy)pyridine hydrochloride as a yellow solid. 1H NMR (400 MHz, DMSO-d6) delta 10.37 (bs, 3H), 8.52 (m, 2H), 7.82 (m, 2H), 7.15 (d, 2H), 7.09 (d, 2H).

Reference： [1]Patent: WO2009/117421,2009,A2 .Location in patent: Page/Page column 208

27
[ 80650-45-9 ]
[ 333-20-0 ]
[ 1325724-10-4 ]

Yield	Reaction Conditions	Operation in experiment
		6-(Pyridin-3-yloxy)-benzothiazol-2-ylamine (2.1 g) was prepared using <strong>[80650-45-9]4-(pyridin-3-yloxy)-phenylamine</strong> (2.0 g) and KCNS (3.3 g) in acetic acid (45.0 ml). The reaction was stirred at room temperature for 20 min. Bromine (0.3 mL) in 3.0 ml acetic acid was added slowly and the reaction was stirred at room temperature for 8-10 h. The reaction mixture was diluted with water (100.0 ml), and the precipitate was filtered and dried. The precipitate was washed with saturated sodium bicarbonate solution and the crude product was used in the next step without further purification.

Reference： [1]Patent: US2011/201604,2011,A1 .Location in patent: Page/Page column 144

28
[ 80650-45-9 ]
[ 1362703-30-7 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 2388 - 2405

29
[ 80650-45-9 ]
1-isopentyl-4-[4-(pyridin-3-yloxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carbonitrile [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 2388 - 2405

30
[ 80650-45-9 ]
[ 18085-61-5 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 2388 - 2405

31
[ 80650-45-9 ]
3-(5-chloro-1H-benzo[d]imidazol-2-yl)-N-(4-(pyridin-3-yloxy)phenyl)propanamide [ No CAS ]

Reference： [1]Patent: WO2014/176258,2014,A1

32
[ 80650-45-9 ]
4-oxo-4-(4-(pyridin-3-yloxy)phenylamino)butanoic acid [ No CAS ]

Reference： [1]Patent: WO2014/176258,2014,A1

33
[ 80650-45-9 ]
N1-(2-amino-4-chlorophenyl)-N4-(4-(pyridin-3-yloxy)phenyl)succinamide [ No CAS ]

Reference： [1]Patent: WO2014/176258,2014,A1

34
[ 80650-45-9 ]
2-amino-N-(4-(pyridin-3-yloxy)phenyl)acetamide [ No CAS ]

Reference： [1]Patent: WO2014/176258,2014,A1

35
[ 80650-45-9 ]
2-(5-chlorobenzo[d]thiazol-2-ylamino)-N-(4-(pyridin-3-yloxy)phenyl)acetamide [ No CAS ]

Reference： [1]Patent: WO2014/176258,2014,A1

36
[ 80650-45-9 ]
2-(5-chlorobenzo[d]oxazol-2-ylamino)-N-(4-(pyridin-3-yloxy)phenyl)acetamide [ No CAS ]

Reference： [1]Patent: WO2014/176258,2014,A1

37
[ 80650-45-9 ]
1-((5-chloro-1H-benzo[d]imidazol-2-yl)thio)-N-(4-(pyridin-3-yloxy)phenyl)methanesulfonamide [ No CAS ]

Reference： [1]Patent: WO2014/176258,2014,A1

38
[ 4530-20-5 ]
[ 80650-45-9 ]
tert-butyl (2-oxo-2-(4-(pyridin-3-yloxy)phenylamino)ethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;	Step 5. Tert-butyl 2-oxo-2-(4-(pyridin-3-yloxy)phenylamino)ethyl carbamate. To a reaction mixture of <strong>[80650-45-9]4-(pyridin-3-yloxy)aniline</strong> (1.0 g, 5.37 mmol), 2-(tert-butoxycarbonylamino)acetic acid (1.13 g, 6.45 mmol), EDCI (1.03 g, 5.37 mmol), HOBT (1.45 g, 10.74 mmol) in DMF (15 mL) was added TEA (2.2 mL, 16.12 mmol). The mixture was stirred at r.t. overnight, diluted with water, and extracted with EtOAc. Combined organic layers were dried over anhydrous Na2S04 and concentrated. The residue was purified by column chromatography to give tert-butyl 2-oxo-2-(4-(pyridin-3-yloxy)phenylamino)ethyl carbamate (1.5 g, 82% yield) as a yellow foam solid. LC-MS: m/z: 344 (M+H)+.

Reference： [1]Patent: WO2014/176258,2014,A1 .Location in patent: Page/Page column 30

39
[ 80650-45-9 ]
(S)-6-chloro-3-hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-1-one [ No CAS ]
(S)-3-(6-chloro-1H-benzo[d]imidazol-2-yl)-3-hydroxy-N-(4-(pyridin-3-yloxy)phenyl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10 mg	In 1,4-dioxane; at 120℃; for 4h;	Step 3. (S)-3-(6-chloro-lH-benzo[d]imidazol-2-yl)-3-hydroxy-N-(4-(pyridin-3-yloxy^ phenyl)propanamide. The above crude product was dissolved in dioxane (4 mL) followed by addition of <strong>[80650-45-9]4-(pyridin-3-yloxy)aniline</strong> (231 mg, 1.25 mmol). The reaction mixture was heated to 120C for 4 hr and cooled to r.t. The resulting mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC to afford (S)-3-(6-chloro-lH-benzo[d]imidazol-2-yl)-3-hydroxy-N-(4-(pyridin-3-yloxy) phenyl)propanamide (10.0 mg, 3% yield over two steps) as grey solid. LC-MS: m/z 409(M+H)+. *H NMR (400 MHz, DMSO-d6) delta 12.59 (s, 1H), 10.15 (s, 1H), 8.42 - 8.28 (m, 2H), 7.67 (d, J= 9.0 Hz, 2H), 7.50 (s, 2H), 7.43 - 7.34 (m, 2H), 7.17 (d, J= 8.5 Hz, 1H), 7.06 (d, J= 9.0 Hz, 2H), 6.16 (s, 1H), 5.29 (s, lH), 3.03 (dd, J= 14.8, 4.3 Hz, 1H), 2.82 (dd, J= 14.8, 8.8 Hz, 1H).

Reference： [1]Patent: WO2014/176258,2014,A1 .Location in patent: Page/Page column 63

40
[ 80650-45-9 ]
3-(5-chlorobenzo[d]thiazol-2-yl)propanoic acid [ No CAS ]
3-(5-chlorobenzo[d]thiazol-2-yl)-N-(4-(pyridin-3-yloxy)phenyl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;	Step 2. 3-(5-ChlorobenzofdJthiazol-2-yl)-N-(4-(pyridin-3-yloxy)phenyl)propanamide. To a solution of 3-(5-chlorobenzo[d]thiazol-2-yl)propanoic acid (120 mg, 0.5 mmol) in DMF (10 mL) were added EDCI (1 15 mg, 0.6 mmol), HOBT (135 mg, 1 mmol), <strong>[80650-45-9]4-(pyridin-3-yloxy)aniline</strong> (111 mg, 0.6 mmol) and Et3N (200 mg, 2 mmol) at r.t. The mixture was stirred at r.t. for 4 hr until LCMS showed the reaction completed. The resulting mixture was poured into S. aq. NaHC03 (30 mL) and extracted with DCM (2x20 mL). Combined organic layers were washed with S. aq. LiCl (30 mL), dried over anhydrous Na2S04 and concentrated reduced pressure. The residue was purified by prep. HPLC to give 3-(5- chlorobenzo[d]thiazol-2-yl)-N-(4-(pyridin-3-yloxy)phenyl)propanamide (60 mg, 29%) as a white solid. LC-MS: m/z: 410 (M+H)+. NMR (400 MHz, DMSO-i/6) delta 10.12 (s, 1H), 8.32-8.34 (m, 2H), 8.10 (d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 7.63 (d, J= 8.8 Hz, 2H), 7.36-7.48 (m, 3H), 7.05 (d, J= 8.8 Hz, 2H), 3.44 (t, J= 7.2 Hz, 2H), 2.95 (t, J= 7.2 Hz, 2H).

Reference： [1]Patent: WO2014/176258,2014,A1 .Location in patent: Page/Page column 35; 36

41
[ 80650-45-9 ]
[ 3518-65-8 ]
1-chloro-N-(4-(pyridin-3-yloxy)phenyl)methanesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%	With triethylamine; In dichloromethane; at 0 - 20℃;	Step 1. l-Chloro-N-(4-(pyridin-3-ylox )phenyl)methanesulfonamide. To a stirred solution of 4- (pyridin-3-yloxy)aniline (500 mg, 5.4 mmol) in DCM (10 mL) at 0C was added TEA (1.5 mL, 10.8 mmol), followed by dropwise addition of a solution of chloromethanesulfonyl chloride (947 mg, 6.4 mmol) in DCM (2 mL). After addition, the reaction mixture was stirred at 10C for 0.5 hr then at r.t. overnight. The resulting mixture was concentrated under reduced pressure to dryness. The residue was purified by column chromatography to afford the desired product (300 mg, 37% yield). MS: 299(M+H)+.

Reference： [1]Patent: WO2014/176258,2014,A1 .Location in patent: Page/Page column 39

42
[ 80650-45-9 ]
[ 14794-31-1 ]
ethyl 4-oxo-4-(4-(pyridin-3-yloxy)phenylamino)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In dichloromethane; at 0 - 20℃;	Step 1. Ethyl 4-oxo-4-(4-(pyridin-3-yloxy)phenylamino)butanoate. To a solution of 4-(pyridin- 3- yloxy)aniline (1.0 g, 5.37 mmol) in anhydrous DCM (10 mL) at 0 C were added ethyl 4-chloro-4- oxobutanoate (0.92 mL, 6.44 mmol) and pyridine (0.65 mL, 8.06 mmol). The reaction mixture was stirred at r.t. till the reaction was complete. The resulting mixture was washed in sequence with diluted HCl and brine. The organic layer was separated, dried over anhydrous Na2SC>4 and concentrated to afford the crude product which was used directly without further purification. LC-MS : m/z 315 (M+H)+.

Reference： [1]Patent: WO2014/176258,2014,A1 .Location in patent: Page/Page column 57

43
[ 80650-45-9 ]
3-(6-chlorobenzo[d]oxazol-2-yl)propanoic acid [ No CAS ]
3-(6-chlorobenzo[d]oxazol-2-yl)-N-(4-(pyridin-3-yloxy)phenyl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30 mg	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 3h;	Step 4. 3-(6-chlorobenzo[d]oxazol-2-yl)-N-(4-(pyridin-3-yloxy)phenyl)propanamide. To a mixture of 3-(6-chlorobenzo[d]oxazol-2-yl)propanoic acid (100 mg, 0.44 mmol), 4-(pyridin-3- yloxy)benzenamine (90 mg, 0.48 mmol), EDCI (102 mg, 0.53 mmol), HOBT (72 mg, 0.53 mmol) in DMF (10 mL) was added DIPEA (114 mg, 0.88 mmol). The mixture was stirred at r.t. for 3 hr, then diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by flash column chromatography to give 3-(6-chlorobenzo[d]oxazol-2-yl)-N-(4-(pyridin-3-yloxy) phenyl)propanamide (30 mg, 18% yield) as a white foamy solid. LC-MS: m/z: 394 (M+H)+. NMR (400 MHz, DMSO-d6) delta 10.19(s, 1H), 8.32 (m, 2H), 7.90(s, 1H), 7.70-7.61(m, 3H), 7.40-7.34 (m, 3H), 7.03 (m, 2H), 3.34-2.94 (d, J= 5.7 Hz, 4H).

Reference： [1]Patent: WO2014/176258,2014,A1 .Location in patent: Page/Page column 40; 41

44
[ 636-98-6 ]
[ 80650-45-9 ]

Reference： [1]Organic Letters,2015,vol. 17,p. 426 - 429

45
[ 80650-45-9 ]
8-benzamidobenzofuro[3,2-b]pyridine 1-oxide [ No CAS ]

Reference： [1]Organic Letters,2015,vol. 17,p. 426 - 429

46
[ 80650-45-9 ]
8-benzamidobenzofuro[3,2-b]pyridine [ No CAS ]

Reference： [1]Organic Letters,2015,vol. 17,p. 426 - 429

47
[ 80650-45-9 ]
3-(4-benzamidophenoxy)pyridine 1-oxide [ No CAS ]

Reference： [1]Organic Letters,2015,vol. 17,p. 426 - 429

48
[ 80650-45-9 ]
[ 98-88-4 ]
N-(4-(pyridin-3-yloxy)phenyl)benzamide [ No CAS ]

Reference： [1]Organic Letters,2015,vol. 17,p. 426 - 429

49
[ 109-00-2 ]
[ 350-46-9 ]
[ 80650-45-9 ]

Reference： [1]Patent: US9138427,2015,B2

50
[ 80650-45-9 ]
N-(4-chloro-7-methoxy-6-quinazolinyl)propanamide [ No CAS ]
N-{7-methoxy-4-[4-(3-pyridinyloxy)anilino]-6-quinazolinyl}-propanamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 8103 - 8124

51
[ 80650-45-9 ]
4-{(1,3-benzodioxol-5-ylmethyl)[4-(3-pyridinyloxy)phenyl]amino}-5-fluoropyrimidine-2-carbonitrile [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 2485 - 2497

52
[ 80650-45-9 ]
N-(1,3-benzodioxol-5-ylmethyl)-2-chloro-5-fluoro-N-[4-(3-pyridinyloxy)phenyl]pyrimidin-4-amine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 2485 - 2497

53
[ 120-57-0 ]
[ 80650-45-9 ]
N-(1,3-benzodioxol-5-ylmethyl)-4-(pyridin-3-yloxy)aniline [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 2485 - 2497

54
[ 80650-45-9 ]
[ 56044-12-3 ]
[ 1214468-35-5 ]