[ CAS No. 3621-82-7 ] {[proInfo.proName]}

Name: 3621-82-7|2,6-Dichlorobenzoxazole|98%
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SKU: A228495
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Quality Control of [ 3621-82-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 3621-82-7 ]

Product Details of [ 3621-82-7 ]

CAS No. :	3621-82-7	MDL No. :	MFCD07368635
Formula :	C₇H₃Cl₂NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LVVQTPZQNHQLOM-UHFFFAOYSA-N
M.W :	188.01	Pubchem ID :	77175
Synonyms :

Calculated chemistry of [ 3621-82-7 ] Expand+

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	44.03
TPSA :	26.03 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) :	-4.77 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.35
Log Po/w (XLOGP3) :	3.77
Log Po/w (WLOGP) :	3.13
Log Po/w (MLOGP) :	2.17
Log Po/w (SILICOS-IT) :	3.18
Consensus Log Po/w :	2.92

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.99
Solubility :	0.0194 mg/ml ; 0.000103 mol/l
Class :	Soluble
Log S (Ali) :	-4.01
Solubility :	0.0184 mg/ml ; 0.0000977 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-4.15
Solubility :	0.0134 mg/ml ; 0.0000711 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	2.26

Safety of [ 3621-82-7 ]

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

Application In Synthesis of [ 3621-82-7 ]

* 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 [ 3621-82-7 ]
Downstream synthetic route of [ 3621-82-7 ]

[ 3621-82-7 ] Synthesis Path-Upstream 1~4

1
[ 273-53-0 ]
[ 3621-82-7 ]
[ 615-18-9 ]

Reference： [1] Patent: US6274739, 2001, B1,

2
[ 22876-20-6 ]
[ 3621-82-7 ]

Yield	Reaction Conditions	Operation in experiment
98.4%	With bis(trichloromethyl) carbonate In toluene at 50 - 105℃;	In a 500 ml four-necked reaction flask, 50 g (folds hundred) of 2-mercapto-6-chlorobenzoxazole and 300 ml of toluene and 40 g tris(trichloromethyl)carbonate were placed, The temperature was raised to 50 °C and the temperature was raised at a rate of 0.5 °C/min, Each heating temperature 10 °C, holding 10 minutes, when the temperature to 105 °C, reaction insulation for 1 hour, After the end of the incubation reaction, the solvent was distilled off under reduced pressure (the vacuum was maintained at -0.07 MPa when the distillation was started. when the temperature reaches 100 °C - 110 °C time, vacuum to -0.095 MPa, evaporating the solvent), solvent after evaporation to dryness, taken out when it is hot, the cooling crystallization 2,6-dichlorobenzoxazole, weight 50.82 g, content 98.1percent, molar yield 98.4percent.
41%	With phosphorus pentachloride In toluene at 120℃; for 16 h;	To a solution of 6-chlorobenzo[d]oxazole-2-thiol (5.Og, 27.lmmol) in toluene (l5OmL) was added PCI5 (28.2g, l36mmol) portion wise at rt. The reaction mixture was heated at 120°C for 16h. TLC showed the reaction to be complete. The reaction mixture was concentrated under reduced pressure to dryness. The residue was dissolved in Et20 (lOOmL). The insoluble solid was filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography using silica gel (100-200 mesh), eluting with hexane to 3percent EtOAc in hexane to afford 2,6-dichlorobenzo[d]oxazole as an orange solid. Yield: 2.lg(41percent); 1H NMR (400 MHz, DMSO-d6): O 8.01 (d, J= 1.6Hz, 1H), 7.78 (d, J= 8.6Hz, 1H), 7.49 (dd, J= 1.6, 8.6Hz, 1H).

Reference： [1] Patent: CN102432559, 2016, B, . Location in patent: Paragraph 0020; 0037; 0038
[2] Patent: WO2018/37223, 2018, A1, . Location in patent: Page/Page column 197; 198
[3] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 7, p. 1975 - 1980
[4] Journal of Organic Chemistry, 2009, vol. 74, # 8, p. 3229 - 3231
[5] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 9, p. 3044 - 3049
[6] Journal of Fluorine Chemistry, 2013, vol. 156, p. 120 - 123

3
[ 19932-84-4 ]
[ 95-50-1 ]
[ 3621-82-7 ]

Reference： [1] Patent: US4714766, 1987, A,

4
[ 28443-50-7 ]
[ 3621-82-7 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 7, p. 1975 - 1980
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 9, p. 3044 - 3049
[3] Journal of Fluorine Chemistry, 2013, vol. 156, p. 120 - 123
[4] Patent: WO2018/37223, 2018, A1,

[ 3621-82-7 ] Synthesis Path-Downstream 1~109

1
[ 3621-82-7 ]
[ 108-95-2 ]
[ 160254-72-8 ]

Reference： [1]Synthesis,1994,p. 1124 - 1126

2
[ 3621-82-7 ]
[ 17193-39-4 ]
(S)-2-(6-Chloro-benzooxazol-2-ylamino)-3-cyclohexyl-propionic acid methyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 1975 - 1980

3
[ 22876-20-6 ]
[ 3621-82-7 ]

Yield	Reaction Conditions	Operation in experiment
98.4%	With bis(trichloromethyl) carbonate; In toluene; at 50 - 105℃;	In a 500 ml four-necked reaction flask, 50 g (folds hundred) of 2-mercapto-6-chlorobenzoxazole and 300 ml of toluene and 40 g tris(trichloromethyl)carbonate were placed, The temperature was raised to 50 °C and the temperature was raised at a rate of 0.5 °C/min, Each heating temperature 10 °C, holding 10 minutes, when the temperature to 105 °C, reaction insulation for 1 hour, After the end of the incubation reaction, the solvent was distilled off under reduced pressure (the vacuum was maintained at -0.07 MPa when the distillation was started. when the temperature reaches 100 °C - 110 °C time, vacuum to -0.095 MPa, evaporating the solvent), solvent after evaporation to dryness, taken out when it is hot, the cooling crystallization 2,6-dichlorobenzoxazole, weight 50.82 g, content 98.1percent, molar yield 98.4percent.
96.1%	With bis(trichloromethyl) carbonate; In N,N-dimethyl-formamide; at 110℃; for 2h;	2) :Using 6-chloro-2-mercaptobenzoxazole and bis(trichloromethyl) carbonate as raw materials,N,N-dimethylformamide was used as a catalyst to synthesize 2,6-dichlorobenzoxazole.The molar ratio of bis(trichloromethyl)carbonate to 6-chloro-2-mercaptobenzoxazole is 1.2:3.0,Reaction at 110 ° C for 2 hours,Product purity is 98.3percent,Yield 96.1percent,1H NMR,LC/MS,The IR spectrum confirmed that the product was 2,6-dichlorobenzoxazole;
78%	With bis(trichloromethyl) carbonate; In toluene; at 50 - 105℃; for 1.33333h;	Step 5,2mmol 2-mercapto-6-chlorobenzoxazole was placed in the flask,Add 10 ml of toluene as a solvent.4 mmol of solid triphosgene was added to the flask.Stir the temperature to 50 ° C, keep warm for 10 min,Slowly heat up again, each temperature is raised by 10 ° C10 min, when the temperature rose to 105 ° C, kept for 1 h; after extraction with sodium bicarbonate solution,Taking the organic phase and steaming it, after drying,The obtained 2,6-dichlorobenzoxazole was 0.293 g, and the yield was 78percent.

41%	With phosphorus pentachloride; In toluene; at 120℃; for 16h;	To a solution of 6-chlorobenzo[d]oxazole-2-thiol (5.Og, 27.lmmol) in toluene (l5OmL) was added PCI5 (28.2g, l36mmol) portion wise at rt. The reaction mixture was heated at 120°C for 16h. TLC showed the reaction to be complete. The reaction mixture was concentrated under reduced pressure to dryness. The residue was dissolved in Et20 (lOOmL). The insoluble solid was filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography using silica gel (100-200 mesh), eluting with hexane to 3percent EtOAc in hexane to afford 2,6-dichlorobenzo[d]oxazole as an orange solid. Yield: 2.lg(41percent); 1H NMR (400 MHz, DMSO-d6): O 8.01 (d, J= 1.6Hz, 1H), 7.78 (d, J= 8.6Hz, 1H), 7.49 (dd, J= 1.6, 8.6Hz, 1H).
	With phosphorus pentachloride; In toluene; for 2h;Reflux;	General procedure: The substituted 2-aminophenol (1eq.) in water and 95percent ethanol was added potassium carbonate (1eq.) and CS2 (1eq.).The mixture was heated under reflux for 3 hours. After cooling, the solution was neutralized with 15 mL of acetic acid in 30 mL water. The precipitate was collected to give 2-thiolbenzoxazoles. Then, the substituted 2-thiolbenzoxazoles (1eq.) dissolved in toluene, PCl5 (1.5eq) was added dropwise. The mixture was heated to reflux for 2 hours. After the solvent was evaporated, the crude product was purified by silica gel column chromatography using PE-EA as an eluent.
	With thionyl chloride; for 2h;Reflux;	General procedure: Potassium hydroxide (46 mmol), ethanol (25 mL) and water (10 mL) were added to a dried round-bottomed flask sequentially, followed by the dropwise addition of CS2 (25 mmol), after 15 min, (un)substituted 2-aminophenol (23 mmol) was added, then the resulting solution was heated to reflux for 4 h. The reaction solution was acidified to pH~4 with dilute hydrochloric acid and then poured into water, extracted with ethyl acetate, the organic phase was washed with brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and the residue was purified via silica gel column chromatography to obtain the intermediate the (un)substituted 2-mercaptobenzoxazole as a yellow solid. Then, the (un)substituted 2-mercaptobenzoxazole (5.5 mmol) was refluxed in SOCl2 (15 mL) for 2 h, excessive SOCl2 was removed under reduced pressure to give (un)substituted 2-chlorobenzoxazole as a yellow solid which was used in next reaction without further purification. Finally, 60 percent of NaH (1.0 mmol) was added into a solution of 3,3-dichloroallyloxyphe-noxy intermediates (1.0 mmol) in THF (5 mL), after 2 h, (un)substituted 2-chloro-benzoxazole (1.0 mmol) was added, the reaction mixture was stirred for another 5 h at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate, the organic phase was washed with saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, concentrated and the residue was purified via silica gel column chromatography to afford the title compounds.

Reference： [1]Patent: CN102432559,2016,B .Location in patent: Paragraph 0020; 0037; 0038
[2]Patent: CN109362744,2019,A .Location in patent: Paragraph 0024; 0027; 0036; 0042; 0055
[3]Patent: CN108794421,2018,A .Location in patent: Paragraph 0032-0034; 0037
[4]Patent: WO2018/37223,2018,A1 .Location in patent: Page/Page column 197; 198
[5]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 1975 - 1980
[6]Journal of Organic Chemistry,2009,vol. 74,p. 3229 - 3231
[7]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3044 - 3049
[8]Journal of Fluorine Chemistry,2013,vol. 156,p. 120 - 123

4
[ 3621-82-7 ]
(S)-2-(6-Chloro-benzooxazol-2-ylamino)-3-cyclohexyl-propionic acid [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 1975 - 1980

5
[ 3621-82-7 ]
2-(6-chloro-benzooxazol-2-ylamino)-3-cyclohexyl-<i>N</i>-[2-(4-fluoro-phenylamino)-ethyl]-propionamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 1975 - 1980

6
[ 3621-82-7 ]
(S)-2-(6-Chloro-benzooxazol-2-ylamino)-3-cyclohexyl-N-[(S)-2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-methyl-ethyl]-propionamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 1975 - 1980

7
[ 3621-82-7 ]
[ 819075-95-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 1975 - 1980

8
[ 3621-82-7 ]
(S)-3-[(S)-2-(6-Chloro-benzooxazol-2-ylamino)-3-cyclohexyl-propionylamino]-4-(5-fluoro-2,3-dihydro-indol-1-yl)-butyric acid ethyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 1975 - 1980

9
[ 3621-82-7 ]
(S)-2-(6-Chloro-benzooxazol-2-ylamino)-3-cyclohexyl-N-[(S)-1-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-3-methanesulfonyl-propyl]-propionamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 1975 - 1980

10
[ 3621-82-7 ]
[ 819075-99-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 1975 - 1980

11
[ 28443-50-7 ]
[ 3621-82-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 1975 - 1980
[2]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3044 - 3049
[3]Journal of Fluorine Chemistry,2013,vol. 156,p. 120 - 123
[4]Patent: WO2018/37223,2018,A1

12
[ 3621-82-7 ]
[ 73519-55-8 ]

Reference： [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 3130 - 3137

13
[ 3621-82-7 ]
ethyl 2-{4-[N-methyl-N-(6-chloro-2-benzoxazolyl)amino]phenoxy}propionate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1997,vol. 7,p. 1489 - 1492

14
[ 3621-82-7 ]
[ 78096-48-7 ]

Reference： [1]Synthesis,1994,p. 1124 - 1126

15
[ 3621-82-7 ]
6-chloro-2-(isopropylamino)benzoxazole [ No CAS ]

Reference： [1]Synthesis,1994,p. 1124 - 1126

16
[ 3621-82-7 ]
Allyl-(6-chloro-benzooxazol-2-yl)-amine [ No CAS ]

Reference： [1]Synthesis,1994,p. 1124 - 1126

17
[ 3621-82-7 ]
(6-Chloro-benzooxazol-2-yl)-cyclopropyl-amine [ No CAS ]

Reference： [1]Synthesis,1994,p. 1124 - 1126

18
[ 3621-82-7 ]
(6-Chloro-benzooxazol-2-yl)-cyclopropylmethyl-amine [ No CAS ]

Reference： [1]Synthesis,1994,p. 1124 - 1126

19
[ 3621-82-7 ]
N-benzyl-6-chloro-1,3-benzoxazol-2-amine [ No CAS ]

Reference： [1]Synthesis,1994,p. 1124 - 1126

20
[ 3621-82-7 ]
(6-Chloro-benzooxazol-2-yl)-pyridin-2-ylmethyl-amine [ No CAS ]

Reference： [1]Synthesis,1994,p. 1124 - 1126

21
[ 3621-82-7 ]
(6-Chloro-benzooxazol-2-yl)-pyridin-3-ylmethyl-amine [ No CAS ]

Reference： [1]Synthesis,1994,p. 1124 - 1126

22
[ 3621-82-7 ]
(6-Chloro-benzooxazol-2-yl)-pyridin-4-ylmethyl-amine [ No CAS ]

Reference： [1]Synthesis,1994,p. 1124 - 1126

23
[ 3621-82-7 ]
Benzo[1,3]dioxol-5-ylmethyl-(6-chloro-benzooxazol-2-yl)-amine [ No CAS ]

Reference： [1]Synthesis,1994,p. 1124 - 1126

24
[ 3621-82-7 ]
[ 71301-98-9 ]
[ 66441-23-4 ]

Reference： [1]Patent: WO2004/2925,2004,A2 .Location in patent: Page 19

25
[ 3621-82-7 ]
[ 71301-98-9 ]
(-)-ethyl (2S)-2-[4-[(6-chloro-2-benzoxazolyl)oxy]phenoxy]propanoate [ No CAS ]
[ 66441-23-4 ]

Reference： [1]Patent: WO2004/2925,2004,A2 .Location in patent: Page 19
[2]Patent: WO2004/2925,2004,A2 .Location in patent: Page 19
[3]Patent: WO2004/2925,2004,A2 .Location in patent: Page 19
[4]Patent: WO2004/2925,2004,A2 .Location in patent: Page 19

26
[ 3621-82-7 ]
[ 42404-09-1 ]
2-(6-chlorobenzoxazol-2-yl)-N-methyloxyacetanilide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In isopropyl alcohol;	EXAMPLE 2 STR55 A solution of 9.4 g (0.05 mole) of <strong>[3621-82-7]2,6-dichlorobenzoxazole</strong> in 20 ml of isopropanol is added dropwise to a mixture of 8.2 g (0.05 mole) of glycolic acid N-methylanilide and 3.1 g (0.05 mole) of powdered potassium hydroxide in 80 ml of isopropanol at -10° C., with stirring, and, when the addition has ended, the mixture is stirred at -5° C. for a further 15 hours. For working up, the reaction mixture is poured into water and the solid precipitate is filtered off with suction, rinsed with water and dried. 13 g (82percent of theory) of 2-(6-chlorobenzoxazol-2-yl)-N-methyloxyacetanilide of melting point 139° C. are obtained. The following compounds of the general formula (I) are obtained in a corresponding manner and in accordance with the general preparation statements.

Reference： [1]Patent: US4784682,1988,A

27
[ 19932-84-4 ]
[ 95-50-1 ]
[ 3621-82-7 ]

Yield	Reaction Conditions	Operation in experiment
99.7%.	With phosphorus pentachloride;	EXAMPLE 1 1 litre of o-dichlorobenzene and 625 g (3 moles) of phosphorus pentachloride are heated to 160° C., then 169.5 g (1 mole) of solid 6-chlorobenzoxazolin-2-one are introduced in small portions over the course of 60 minutes, vigorous evolution of hydrogen chloride occuring for a short time after each portion. The mixture is then stirred for a further 15 minutes at 150°-160° C., and then cooled to 0° C., whereupon the major part of the excess pCl5 crystallises out. The phosphorus pentachloride precipitate is filtered off with suction, Washed with a little cold o-dichlorobenzene, and the filtrate is fractionated under reduced pressure. phosphorus oxychloride distils over first, then o-dichlorobenzene together with the remainder of the excess phosphorus pentachloride, and last, at about 110° C. and 17.3 mbar, 2,6-dichlorobenzoxazole. About 136 g of 2,6-dichlorobenzoxazole of melting point 48-49° C. are obtained. GC purity 99.7percent. yield: 72percent of theory. The recovered phosphorus pentachloride and o-dichlorobenzene can be used again for the next batch.

Reference： [1]Patent: US4714766,1987,A

28
[ 273-53-0 ]
[ 3621-82-7 ]
[ 615-18-9 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 2 Using the method of Example 1, 11.9 g (0.1 mol) of 1,3-benzoxazole were reacted under the same conditions to give 2-chlorobenzoxazole.

Reference： [1]Patent: US6274739,2001,B1

29
6-chlorobenzo[d]oxazole [ No CAS ]
[ 3621-82-7 ]

Yield	Reaction Conditions	Operation in experiment
94%	With aluminium trichloride; chlorine; In trichlorophosphate;	EXAMPLE 4 10 g (0.065 mol) of 6-chlorobenzoxazole (>99percent pure) were dissolved in 70 ml of phosphorus oxychloride and admixed with 0.26 g of dry aluminum trichloride. The mixture was heated to 90° C., chlorine gas was then introduced, with efficient stirring, under the surface of the liquid, and the progress of the reaction was monitored by gas chromatography (GC analysis). After approximately 6 hours, the starting material had been consumed. The batch was cooled and the reaction mixture was transferred into a distillation apparatus fitted with a short Vigreux column. Excess POCl3 was separated off in a forerun. A fraction of pure 2,6-dichlorobenzoxazole was subsequently distilled off under reduced pressure. This gave 11.6 g of 2,6-dichlorobenzoxazole having a purity by GC of more than 99percent; this corresponds to a yield of more than 94percent of theory.

Reference： [1]Patent: US6274739,2001,B1

30
iron (III) chloride (FeCl₃) [ No CAS ]
6-chlorobenzo[d]oxazole [ No CAS ]
[ 3621-82-7 ]

Yield	Reaction Conditions	Operation in experiment
	With chlorine; In chlorobenzene;	EXAMPLE 1 In a stirred flask fitted with gas inlet tube and dry-ice cooler, 20 g (0.1302 mol) of 6-chlorobenzoxazole and 50 ml of chlorobenzene were, after addition of 0.1 g of iron (III) chloride (FeCl3), heated to 100° C. With efficient stirring, a total of 11.0 g (0.155 mol) of chlorine gas was introduced slowly under the surface of the liquid over a period of approximately 4 hours. The progress of the reaction was monitored by gas chromatography (GC analysis). After the starting material had been consumed, the batch was allowed to cool. According to GC analysis, 95percent of the starting material was converted into 2,6-dichlorobenzoxazole. After stripping off the solvent, the crude product could be distilled under reduced pressure. This gave 23.07 g (0.122 mol) of 2,6-dichlorobenzoxazole, purity by GC: 99.5percent=93.8percent of theory.

Reference： [1]Patent: US6274739,2001,B1

31
iron(III) chloride [ No CAS ]
6-chlorobenzo[d]oxazole [ No CAS ]
[ 3621-82-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With phosphorus pentachloride; In chlorobenzene;	EXAMPLE 5 10 g (0.065 mol) of 6-chlorobenzoxazole (>99percent pure) and 100 ml of chlorobenzene, together with 13.54 g (0.065 mol) of phosphorus pentachloride and 0.05 g of iron (III) chloride (dry), were heated with stirring to 130-133° C. After approximately 6 hours, the reaction had ended. The reaction mixture was cooled and filtered through a layer of silica gel 60. Elution with methylene chloride and stripping off of the low-boilers gives a product which solidifies in the cold and which, according to GC, contains no other components; yield 12.25 g of 2,6-dichlorobenzoxazole (100percent of theory).

Reference： [1]Patent: US6274739,2001,B1

32
[ 3621-82-7 ]
C₁₂H₁₉NO₂ [ No CAS ]
2-(6-chloro-benzoxazol-2-yloxy)-N-methyl-N-(3,3,5-trimethylcyclohexa-1,5-dienyl)-acetamide [ No CAS ]

Reference： [1]Patent: US6339042,2002,B1 .Location in patent: Table 2

33
[ 3621-82-7 ]
C₁₄H₂₃NO₂ [ No CAS ]
2-(6-chloro-benzoxazol-2-yloxy)-N-isopropyl-N-(3,5,5-trimethylcyclohexa-1,3-dienyl)-acetamide [ No CAS ]

Reference： [1]Patent: US6339042,2002,B1 .Location in patent: Table 2

34
[ 3621-82-7 ]
[ 35626-68-7 ]
2-(6-chloro-benzoxazol-2-yloxy)-N-ethyl-N-(3,3,5-trimethylcyclohexa-1,5-dienyl)-acetamide [ No CAS ]

Reference： [1]Patent: US6339042,2002,B1 .Location in patent: Table 2

35
[ 3621-82-7 ]
C₁₄H₂₃NO₃ [ No CAS ]
2-(6-chloro-benzoxazol-2-yloxy)-N-(2-methoxyethyl)-N-(3,3,5-trimethylcyclohexa-1,5-dienyl)-acetamide [ No CAS ]

Reference： [1]Patent: US6339042,2002,B1 .Location in patent: Table 2

36
[ 3621-82-7 ]
[ 1163123-31-6 ]
[ 1163121-05-8 ]

Yield	Reaction Conditions	Operation in experiment
35%	With triethylamine; In dichloromethane; at 20℃;	Step 2: A mixture of 22 mg (0.083 mmol) ((R)-3-Amino-piperidin-1-yl)-(2,6-dimethoxy-phenyl)-methanone, 15.6 mg (0.083 mmol) <strong>[3621-82-7]2,6-dichlorobenzoxazole</strong> and 12.6 mg (0.125 mmol) NEt3 in 3 mL DCM was stirred at room temperature over night. The mixture was evaporated to dryness and the residue was purified by preparative HPLC on reversed phase eluding with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to yield 12 mg (35percent) of the title compound as colourless oil. (MH+) 416.2.

Reference： [1]Patent: US2009/163485,2009,A1 .Location in patent: Page/Page column 11

37
[ 3621-82-7 ]
[ 186550-13-0 ]
[ 1163123-30-5 ]

Yield	Reaction Conditions	Operation in experiment
		Step 1: (6-Chloro-benzooxazol-2-yl)-pyrrolidin-3-yl-amine; hydrochloride A mixture of 470 mg (2.5 mmol) <strong>[3621-82-7]2,6-dichloro-benzooxazole</strong> (commercially available), 511 mg (2.75 mmol) 3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (commercially available) and 328 mg (3.25 mmol) NEt3 in 8 mL DCM was stirred at room temperature over night. KHSO4 aq (1N) was added and the organic layer was evaporated under reduced pressure. The residue was taken up in 10 mL HCl in dioxane (4N) and concentrated under reduced pressure to yield the crude title compound which was used without further purification in the consecutive step. (MH+) 238.0.

Reference： [1]Patent: US2009/163485,2009,A1 .Location in patent: Page/Page column 8

38
[ 3621-82-7 ]
[ 144043-17-4 ]
[ 1163123-42-9 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 20℃;	Step 1: ((R)-1-Benzyl-pyrrolidin-3-yl)-(6-chloro-benzooxazol-2-yl)-methyl-amine A mixture of 0.5 g (2.6 mmol) 2,6-dichloro benzoxazole, 0.68 g (3.58 mmol) ((R)-1-benzyl-pyrrolidin-3-yl)-methyl-amine and 0.4 g (4 mmol) NEt3 in 12 mL DCM was stirred over night at room temperature. DCM was added and the mixture was washed with NaHCO3 aq., dried with MgSO4 and evaporated to dryness to yield the title compound as yellow oil which was used in the consecutive step without further purification. (MH+) 342.1

Reference： [1]Patent: US2009/163485,2009,A1 .Location in patent: Page/Page column 13-14

39
[ 3621-82-7 ]
[ 1097632-40-0 ]
[ 1097631-47-4 ]

Yield	Reaction Conditions	Operation in experiment
80.9%	With potassium carbonate; In acetonitrile; for 7h;Heating / reflux;	A mixture of 1.6g (4.8mmol) of the compound obtained in (1-1), l.lOg (5.7mmol) of <strong>[3621-82-7]2,6-dichlorobenzoxazole</strong>, and 0.72g (5.7mmol) of potassium carbonate was added in 80ml of acetonitrile, and the mixture was reflexed for 7 hours. The resulting mixture was cooled to room temperature and filtered to remove unreacted solid therefrom, and the filtrate was distilled under a reduced pressure. The resulting residue was subjected to column chromatography (ethyl acetate: n-hexane = 1 : 4) to obtain the title compound (1.88g, 80.9 percent). 1H-NMR(CDCl3) : deltal.70(3H, d), 4.91(1H, q), 7.02 ~7.60(10H, m), 9.19(1H, s)
80.9%	With potassium carbonate; In acetonitrile; for 7h;Reflux;	A mixture of 1.6 g (4.8 mmol) of the compound obtained in (1-1), 1.10 g (5.7 mmol) of <strong>[3621-82-7]2,6-dichlorobenzoxazole</strong>, and 0.72 g (5.7 mmol) of potassium carbonate was added in 80 ml of acetonitrile, and the mixture was reflexed for 7 hours. The resulting mixture was cooled to room temperature and filtered to remove unreacted solid therefrom, and the filtrate was distilled under a reduced pressure. The resulting residue was subjected to column chromatography (ethyl acetate: n-hexane=1:4) to obtain the title compound (1.88 g, 80.9percent).1H-NMR(CDCl3): delta1.70(3H, d), 4.91(1H, q), 7.027.60(10H, m), 9.19(1H, s)

Reference： [1]Patent: WO2009/5297,2009,A2 .Location in patent: Page/Page column 13
[2]Patent: US2010/279871,2010,A1 .Location in patent: Page/Page column 4-5

40
[ 3621-82-7 ]
[ 1258933-04-8 ]
[ 1258934-25-6 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; at 85℃; for 0.75h;microwave irradiation;	Example 112 4-(6-chloro-1,3-benzoxazol-2-yl)-1,4-diazatricyclo[4.3.1.13,8]undecane A mixture of the product of Example 2 (40 mg, 0.26 mmol) and <strong>[3621-82-7]2,6-dichloro-1,3-benzoxazole</strong> (30 mg, 0.16 mmol) in ethanol (6 mL) was stirred at 85° C. for 45 minutes under microwave irradiation (Biotage Initiator.(TM). Sixty EXP, 375 W maximum). After removal of the solvent, the residue was purified by prep-TLC(CHCl3-CH3OH=20:1) to afford the title compound: LC-MS Method A (ESI+) m/z 304.0 (M+H)+, retention time 1.23 minutes.

Reference： [1]Patent: US2010/324027,2010,A1 .Location in patent: Page/Page column 33

41
[ 3621-82-7 ]
[ 52-67-5 ]
[ 1334386-05-8 ]

Yield	Reaction Conditions	Operation in experiment
58%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 3h;	Compound 15 (693 mg, 3.7 mmol) and D-penicillamine (550 mg, 3.7 mmol) were dissolved in 4 mL of DMF. Subsequently DIPEA (960 mg, 7.5 mmol) was added. The reaction was stirred at r.t. for 3 h. The resultant mixture was concentrated and the crude product was purified by preparative HPLC eluting with an H2O/CH3CN gradient containing 0.05percent TFA, giving compound 28 as a pink solid (652 mg, yield 58percent). 1H NMR (DMSO-d6, 500 MHz): delta 7.17 (brs, 1H), 6.81-6.75 (m, 2H), 4.37 (s, 1H), 1.62 (s, 3H), 1.39 (s, 3H); 13C NMR (DMSO-d6, 125 MHz): delta 170.7, 159.4, 149.4, 127.2, 122.4, 118.7, 116.5, 28.3, 25.5; ESI-MS (m/z): 301.1 [M+1]+

Reference： [1]Patent: US2011/224269,2011,A1 .Location in patent: Page/Page column 24

42
[ 3621-82-7 ]
[ 64-18-6 ]
[ 924643-90-3 ]
N-{2-[4-(aminosulfonyl)phenyl]ethyl}-1-(6-chloro-1,3-benzoxazol-2-yl)-3-piperidinecarboxamide formate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2%		Example 7 : yV-{2-[4-(Aminosulfonyl)phenyl]ethyl}-1 -(6-chloro-1 ,3-benzoxazol-2- -3-piperidinecarboxamide formate (E7)A mixture of 2,6-dichloro-1 ,3-benzoxazole (for a method of preparation see, for example, Description 4) (53mg, 0.28mmol) and /V-{2-[4-(aminosulfonyl)phenyl]ethyl}- 3-piperidinecarboxamide (for a method of preparation see, for example, Description 2 B) (60mg, 0.19mmol) in 2-pentanol:acetonitrile (4:1 v/v, 2ml) was heated in the microwave at 200°C a total of 45 minutes on normal absorbance.The solvent of the mixture was then removed in vacuo and the resulting residue was purified using MDAP. Fractions containing product were combined and the solvent was removed in vacuo to give the title compound as a brown-beige solid (2mg, 2percent). 1 H NMR (400 MHz, DMSO): delta 1 .47-1 .63 (2H, m), 1 .74-1 .85 (2H, m), 2.39 (1 H, m), 2.80 (2H, t, J=6.8), 3.09-3.20 (2H, m), -3.33 (assumed 2H underneath solvent signal), 4.04-4.07 (2H, m), 7.19 (1 H, m), 7.26 (1 H, m), 7.30 (2H, s), 7.39 (2H, d, J=8.0), 7.57 (1 H, m), 7.75 (2H, d, J=8.4), 8.08 (1 H, m).LCMS m/z (ES): 463 [M+H]+.

Reference： [1]Patent: WO2011/131975,2011,A1 .Location in patent: Page/Page column 34-35

43
[ 3621-82-7 ]
[ 1374820-38-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3044 - 3049

44
[ 3621-82-7 ]
C₁₇H₁₄Cl₃N₃O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3044 - 3049

45
[ 3621-82-7 ]
[ 1374820-07-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3044 - 3049

46
[ 3621-82-7 ]
[ 75178-96-0 ]
[ 1374820-33-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;	General procedure: The mono Boc-protected diamines (1eq.) in DMF were added potassium carbonate (2eq.) and intermediates 2 or 3 (2eq). The mixture was heated at 120 oC for 2h. After cooling, the solution was taken up in ethyl acetate and washed with 1M HCl,1 M NaHCO3 and brine each for twice. The organic layer was dried and evaporated to give the crude final product. The product compound 5 was purified by silica gel column chromatography using PE-EA as an eluent.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3044 - 3049

47
[ 3621-82-7 ]
[ 1401241-38-0 ]
[ 1401241-89-1 ]

Yield	Reaction Conditions	Operation in experiment
44%	With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; water; at 85℃; for 64h;Inert atmosphere;	A dried pressure tube was consecutively charged with [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-5-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl}-amine (intermediate B10.1) (100 mg, 127 mumol), tetrahydrofuran (3 ml), <strong>[3621-82-7]2,6-dichlorobenzo[d]oxazole</strong> (31.6 mg, 165 mumol), cesium carbonate (165 mg, 507 mumol) and water (1.5 ml).The tube was flushed with argon, thereafter [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (11 mg, 12.7 mumol) was added, the tube was sealed and the reaction mixture heated at 85° C. for 64 hours.For the workup, the reaction mixture was evaporated at reduced pressure and the residue directly purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 80:20 as the eluent.The [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-5-[5-(6-chloro-benzo oxazol-2-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl}-amine (41 mg, 44percent yield) was obtained as a white solid. MS (ISP): m/z=740.4 [M+H]+ and 742.3 [M+2+H]+.
44%	With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 85℃; for 64h;Inert atmosphere; Sealed tube;	Example 19 (R)-5-[5-(6-Chloro-benzooxazol-2-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-2,5,6,7- tetrahydro-[l,4]oxazepin-3-ylamine hydrochloride a) [Bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-5-[5-(6-chloro-benzooxazol-2-yl)-2- fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[l,4]oxazepin-3-yl}-amineA dried pressure tube was consecutively charged with [bis-(4-methoxy-phenyl)-phenyl- methyl]-{(R)-5-[5-(5,5-dimethyl-[l,3,2]dioxaborinan-2-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7- trimethyl-2,5,6,7-tetrahydro-[l,4]oxazepin-3-yl}-amine (intermediate B 10.1) (100 mg, 127 muiotaetaomicron), tetrahydrofuran (3 ml), <strong>[3621-82-7]2,6-dichlorobenzo[d]oxazole</strong> (31.6 mg, 165 muiotaetaomicron), cesium carbonate (165 mg, 507 muiotaetaomicron) and water (1.5 ml). The tube was flushed with argon, thereafter [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (11 mg, 12.7 muiotaetaomicron) was added, the tube was sealed and the reaction mixture heated at 85 °C for 64 hours. For the workup, the reaction mixture was evaporated at reduced pressure and the residue directly purified by chromatography on silica gel using a gradient of heptane/ethyl acetate = 100:0 to 80:20 as the eluent. The [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-5-[5-(6-chloro- benzooxazol-2-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro- [l,4]oxazepin-3-yl}-amine (41 mg, 44percent yield) was obtained as a white solid. MS (ISP): m/z = 740.4 [M+H]+ and 742.3 [M+2+H]+.

Reference： [1]Patent: US2012/253035,2012,A1 .Location in patent: Page/Page column 42-43
[2]Patent: WO2012/136603,2012,A1 .Location in patent: Page/Page column 83-84

48
[ 3621-82-7 ]
[ 1414877-50-1 ]
[ 1414919-25-7 ]

Yield	Reaction Conditions	Operation in experiment
50%	With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; at 80℃; for 16h;Inert atmosphere; Sealed tube;	Example 15(R)-4-[5-(6-Chloro-benzooxazol-2-yl)-2,4-difluoro-phenyl]-5,5-difluoro-4-methyl-5,6- dihydro-4H- [ 1 ,3] oxazin-2-ylamine Hydrochloride a) [Bis-(4-methoxy-phenyl)-phenyl-methyl]-{ (R)-4-[5-(6-chloro-benzooxazol-2-yl)-2,4- difluoro-phenyl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[l,3]oxazin-2-yl}-amineIn a tube a mixture of [bis-(4-methoxy-phenyl)-phenyl-methyl]-{ (R)-4-[5-(5,5-dimethyl- [l,3,2]dioxaborinan-2-yl)-2,4-difluoro-phenyl]-5,5-difluoro-4-methyl-5,6-dihydro-4H- [l,3]oxazin-2-yl}-amine (intermediate Dl.l) (130 mg, 144 muiotaetaomicron), <strong>[3621-82-7]2,6-dichlorobenzo[d]oxazole</strong> (30.4 mg, 159 muiotaetaomicron), and cesium carbonate (188 mg, 576 muiotaetaomicron) in tetrahydrofuran (4 ml) and water (2 ml) was purged with argon for 5 minutes. Thereafter, [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (5.88 mg, 7.21 muiotaetaomicron) was added, the tube was sealed and the mixture heated at 80 °C for 16 hours. After evaporation, the residue was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate = 100:0 to 70:30 as the eluent. The [bis-(4-methoxy-phenyl)-phenyl- methyl]-{ (R)-4-[5-(6-chloro-benzooxazol-2-yl)-2,4-difluoro-phenyl]-5,5-difluoro-4-methyl-5,6- dihydro-4H-[l,3]oxazin-2-yl}-amine (52 mg, 50percent yield) was obtained as a pale yellow solid. MS (ISP): m/z = 716.1 [M+H]+.
50%	With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; dichloromethane; water; at 80℃; for 16h;Inert atmosphere; Sealed tube;	a)[Bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-4-[5-(6-chloro-benzooxazol-2-yl)-2,4-difluoro-phenyl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl}-amineIn a tube a mixture of [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-4-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2,4-difluoro-phenyl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl}-amine (intermediate D1.1) (130 mg, 144 mumol), <strong>[3621-82-7]2,6-dichlorobenzo[d]oxazole</strong> (30.4 mg, 159 mumol), and cesium carbonate (188 mg, 576 mumol) in tetrahydrofuran (4 ml) and water (2 ml) was purged with argon for 5 minutes.Thereafter, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (5.88 mg, 7.21 mumol) was added, the tube was sealed and the mixture heated at 80° C. for 16 hours.After evaporation, the residue was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 70:30 as the eluent.The [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-4-[5-(6-chloro-benzooxazol-2-yl)-2,4-difluoro-phenyl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl}-amine (52 mg, 50percent yield) was obtained as a pale yellow solid. MS (ISP): m/z=716.1 [M+H]+.

Reference： [1]Patent: WO2012/156284,2012,A1 .Location in patent: Page/Page column 124
[2]Patent: US2012/295900,2012,A1 .Location in patent: Page/Page column 65-66

49
[ 3621-82-7 ]
[ 172975-69-8 ]
[ 1421278-26-3 ]