[ CAS No. 862599-47-1 ] {[proInfo.proName]}

Name: 862599-47-1|Ethyl 2-chlorooxazole-5-carboxylate|95%
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Quality Control of [ 862599-47-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 862599-47-1 ]

CAS No. :	862599-47-1	MDL No. :	MFCD09475866
Formula :	C₆H₆ClNO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZFLDTEIDAGWEEI-UHFFFAOYSA-N
M.W :	175.57	Pubchem ID :	26369855
Synonyms :

Calculated chemistry of [ 862599-47-1 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.33
Num. rotatable bonds :	3
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	37.6
TPSA :	52.33 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) :	-6.06 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.13
Log Po/w (XLOGP3) :	1.85
Log Po/w (WLOGP) :	1.5
Log Po/w (MLOGP) :	0.19
Log Po/w (SILICOS-IT) :	1.61
Consensus Log Po/w :	1.46

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.23
Solubility :	1.03 mg/ml ; 0.00586 mol/l
Class :	Soluble
Log S (Ali) :	-2.57
Solubility :	0.473 mg/ml ; 0.00269 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.33
Solubility :	0.816 mg/ml ; 0.00465 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.29

Safety of [ 862599-47-1 ]

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

Application In Synthesis of [ 862599-47-1 ]

* 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 [ 862599-47-1 ]
Downstream synthetic route of [ 862599-47-1 ]

[ 862599-47-1 ] Synthesis Path-Upstream 1~3

1
[ 118994-89-1 ]
[ 862599-47-1 ]

Yield	Reaction Conditions	Operation in experiment
56%	Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -60 - -50℃; for 1 h; Stage #2: With hexachloroethane In tetrahydrofuran at 25℃; for 12 h;	To a solution of compound 6A (15.0 g, 106 mmol) in THF (150 mL) was added dropwise lithium hexamethyl disilazide (178 mL, 170 mmol) at -60 °C. The solution was stirred at -50 °C for 1 h. Then hexachloroethane (37,8 g, 160 mmol) was added to the solution. The solution was stirred at room temperature for 12 h. The reaction was quenched by saturated aq. NH₄C1 solution (50 mL) and extracted with EtOAc (50 mL). The organic layer was separated, dried over Na₂S0₄, concentrated under vacuum and the residue was purified with column chromatography to give compound 6B (10 g, 56percent) as colorless oil. 1H NMR (400 MHz, CDCI₃) δ 7.71 (s, IH), 3.39 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H).

Reference： [1] Organic Letters, 2005, vol. 7, # 15, p. 3351 - 3354
[2] Patent: WO2015/116663, 2015, A1, . Location in patent: Paragraph 0116

2
[ 113853-16-0 ]
[ 862599-47-1 ]

Yield	Reaction Conditions	Operation in experiment
40%	at 60 - 80℃; for 2 h; Inert atmosphere	A mixture of 1.19 g (8.8 mmol, 1.50 mol eq) of CuCl₂ abs and 1.05 mL (8.8 mmol, 1.50 mol eq) of ^tBuONO in 30 mL of AN abs under Ar was heated to 60 °C. By this temperature 920.0 mg (5.9 mmol, 1.00 mol eq) of ethyl 2-aminooxazole-5-carboxylate (14) was added portion wise. Then the temperature was raised to 80 °C and the reaction mixture was stirred for 2 h. After the consumption of starting material 14 (TLC analysis) the reaction mixture was cooled down to RT and 15 mL of water and 8 mL of 2M HCl were added. The aqueous solution was extracted with EA (3 x 20 mL) and the combined organic layers were washed with brine, dried by Na₂SO₄, filtered and concentrated under reduced pressure yielding 850 mg (4.8 mmol, 83 percent) of ethyl 2-chlorooxazole-5-carboxylate (15) as light yellow oil. The obtained crude product 15 was sufficiently pure to be used for the further synthesis. Purification of 15 can be done by FLC (SiO₂, H / EA; 1 / 1), however because of instability of 15 on silica, the yield is lowered to approximately 40 percent.

Reference： [1] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 754 - 761

3
[ 862599-47-1 ]
[ 7486-35-3 ]
[ 1257266-93-5 ]

Reference： [1] Patent: WO2010/136474, 2010, A2, . Location in patent: Page/Page column 194
[2] Patent: WO2010/136493, 2010, A1, . Location in patent: Page/Page column 235

[ 862599-47-1 ] Synthesis Path-Downstream 1~26

1
[ 862599-47-1 ]
[ 38622-91-2 ]
2-[isocyano-(toluene-4-sulfonyl)-methyl]-oxazole-5-carboxylic acid ethyl ester [ No CAS ]

Reference： [1]Organic Letters,2005,vol. 7,p. 3351 - 3354

2
[ 118994-89-1 ]
[ 862599-47-1 ]

Yield	Reaction Conditions	Operation in experiment
56%		To a solution of compound 6A (15.0 g, 106 mmol) in THF (150 mL) was added dropwise lithium hexamethyl disilazide (178 mL, 170 mmol) at -60 C. The solution was stirred at -50 C for 1 h. Then hexachloroethane (37,8 g, 160 mmol) was added to the solution. The solution was stirred at room temperature for 12 h. The reaction was quenched by saturated aq. NH4C1 solution (50 mL) and extracted with EtOAc (50 mL). The organic layer was separated, dried over Na2S04, concentrated under vacuum and the residue was purified with column chromatography to give compound 6B (10 g, 56%) as colorless oil. 1H NMR (400 MHz, CDCI3) delta 7.71 (s, IH), 3.39 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H).

Reference： [1]Organic Letters,2005,vol. 7,p. 3351 - 3354
[2]Patent: WO2015/116663,2015,A1 .Location in patent: Paragraph 0116

3
[ 862599-47-1 ]
5-ethoxycarbonyl-[2,4']bisoxazole [ No CAS ]

Reference： [1]Organic Letters,2005,vol. 7,p. 3351 - 3354

4
[ 862599-47-1 ]
[ 1160065-00-8 ]
[ 1160064-99-2 ]

Yield	Reaction Conditions	Operation in experiment
46%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃; for 3h;	Example 15: Synthesis of 2-((2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-(1-methy]- 1 H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-oxazole-4-carboxylic acid ethyl ester; A solution of [3,5-bis(trifluoromethyl)benzyl]-(5-ethyl-pyrrolidin-3-yl)-[5-(1-methyl-1H-pyrazol- 4-yl)-pyrimidin-2-yl]-amine (0.025 mmol, 12.5 mg), <strong>[862599-47-1]2-chloro-oxazole-5-carboxylic acid ethyl ester</strong> (0.03 mmol, 5 mg) and lambda/;lambda/-diisopropylethylamine (0.03 mmol, 5 uL) in DMF (0.1 mL) is allowed to warm to 12O0C and stirred for 3 hours. The mixture is cooled to room temperature, then added with water. The mixture is extracted with CH2CI2. The combined organic layer is dried over Na2SO4, filtrated, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane / EtOAc) to give 2-((2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-(1-methyl-1 H-pyrazol-4-yl)-pyrimidin- 2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-oxazole-4-carboxylic acid ethyl ester (7.4 mg, 46%); ESI- MS m/z: 638 [M+1]+, Retention time 2.20 min (condition A).

Reference： [1]Patent: WO2009/71509,2009,A1 .Location in patent: Page/Page column 81-82

5
[ 862599-47-1 ]
4-(2-methylimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-amine [ No CAS ]
[ 1204527-68-3 ]

Yield	Reaction Conditions	Operation in experiment
18.5%	With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;palladium diacetate; In benzene; at 95℃;	To a stirred solution of Int-1 (0.5 g, 2.2 mmol) in benzene (25 mL) were added Int-2 (0.38 g, 2.2 mmol), Pd(OAc)2 (0.05 g, 0.2 mmol), xanthpos (0.128 g, 0.2 mmol) and Cs2CO3 (1.08 g, 3.3 mmol). The reaction mixture was purged with N2 for 10 minutes and stirred at 95 C. for 24 hours. The volatiles were concentrated under reduced pressure and the residue was diluted with water (35 mL), the precipitated solid was filtered and dried under reduced pressure to obtain crude compound which was purified by column chromatography and eluting with pure compound with 5% MeOH/DCM to afford Int-3 (0.15 g, 18.5% yield) as a solid. 1H NMR (200 MHz, dmso-d6): delta 10.6 (brs, 1H), 8.61 (d, J=5.6 Hz, 1H), 8.03 (s, 1H), 7.17-7.65 (m, 5H), 4.3 (q, J=7.0 Hz, 2H), 2.7 (s, 3H), 1.29 (t, J=7.0 Hz, 3H). To a stirred solution of Int-3 (0.6 g, 1.6 mmol) in MeOH:THF (21 mL, 1:20) was added a solution of LiOH (0.207 g, 4.94 mmol) in water (10 mL) and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was acidified to about pH 5 using 2 N HCl. The precipitated solid was filtered and dried under reduced pressure to afford Int-4 (0.25 g, 45% yield) as a solid. 1H NMR (200 MHz, dmso-d6): delta 11.65 (s, 1H), 10.6 (brs, 1H), 8.66 (d, J=5.4 Hz, 1H), 7.94 (t, J=4.0 Hz, 1H), 7.66 (d, J=9.0 Hz, 1H), 7.48-7.56 (m, 1H), 7.35 (d, J=5.4 Hz, 1H) 7.23 (t, J=7.0 Hz, 1H), 2.7 (s, 3H). To a stirred solution of Int-4 (0.25 g, 0.74 mmol) in DMF (4 mL) were added HOBt (0.1 g, 0.74 mmol), EDCI (0.35 g, 1.86 mmol) and DIPEA (0.3 mL, 1.86 mmol) at 0 C. under inert atmosphere. After being stirred for 5 minutes, added NH2OTHP (0.13 g, 1.1 mmol) to the reaction mixture at 0 C. and stirred at room temperature for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (2×25 mL). The combined organic extract was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain crude compound which was purified by column chromatography and eluting pure compound with 5% MeOH/DCM to afford Int-5 (0.1 g, 31% yield) as a solid. 1H NMR (200 MHz, dmso-d6): delta 11.6 (brs, 1H), 11.42 (brs, 1H), 10.42 (d, J=6.2 Hz, 1H), 8.62 (d, J=4.2 Hz, 1H), 7.72 (s, 1H), 7.62 (d, J=7.2 Hz, 1H), 7.51 (t, J=4.2 Hz, 1H), 7.3 (d, J=5.0 Hz, 1H), 7.1 (d, J=6.5 Hz, 1H), 4.95 (s, 1H), 4.07 (brs, 1H), 3.57 (d, J=10 Hz, 1H), 2.7 (s, 3H), 1.75 (brs, 3H), 1.53 (brs, 3H).

Reference： [1]Patent: US2010/29638,2010,A1 .Location in patent: Page/Page column 121

6
[ 862599-47-1 ]
[ 5188-07-8 ]
2-ethylsulfanyl-oxazole-5-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; at 50℃; for 18h;	To a solution of <strong>[862599-47-1]2-chloro-oxazole-5-carboxylic acid ethyl ester</strong> (4 g, 22 mmol) in DMF (75 mL) was added sodium thiomethoxide (1.8 g, 25.7 mmol). The mixture was heated to 5O0C to afford a yellow solution. After 18 hours, the mixture was diluted with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuo to afford 2-ethylsulfanyl-oxazole-5-carboxylic acid ethyl ester.

Reference： [1]Patent: WO2010/36632,2010,A1 .Location in patent: Page/Page column 174

7
[ 862599-47-1 ]
[ 1254036-80-0 ]
[ 1254036-81-1 ]

Yield	Reaction Conditions	Operation in experiment
	copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 100℃; for 0.5h;Microwave irradiation;	Intermediate 3a-[6-chloro-1-(phenylsulfonyl)-1 H-indazol-4-yl]-1,3-oxazole-5-carboxylateIn 4 batches, tetrakis(triphenylphosphine)palladium(0) (3.37 g, 2.92 mmol), ethyl 2-chloro- 1 ,3-oxazole-5-carboxylate (6.65 g, 37.9 mmol, available from Apollo Scientific) and copper(l) iodide (1.11 g, 5.83 mmol) were added to a solution of 6-chloro-1- (phenylsulfonyl)-4-(trimethylstannanyl)-1/-/-indazole (13.28 g, 29.2 mmol) in N,N- dimethylformamide (52 ml). In 3 of the batches, tetrakis(triphenylphosphine)palladium(0) (1.03 g, 0.89 mmol), ethyl 2-chloro-1 ,3-oxazole-5-carboxylate (2.03 g, 1 1.59 mmol) and copper(l) iodide (0.34 g, 1.78 mmol) were added to a solution of 6-chloro-1- (phenylsulfonyl)-4-(trimethylstannanyl)-1/-/-indazole (4.06 g, 8.91 mmol) in N,N- dimethylformamide (16 ml). In the fourth batch, tetrakis(triphenylphosphine)palladium(0) (0.28 g, 0.24 mmol), ethyl 2-chloro-1 ,3-oxazole-5-carboxylate (0.55 g, 3.14 mmol) and copper(l) iodide (0.09 g, 0.48 mmol) were added to a solution of 6-chloro-1- (phenylsulfonyl)-4-(trimethylstannanyl)-1/-/-indazole (1.10 g, 2.42 mmol) in N,N- dimethylformamide (4 ml). Each batch was heated and stirred at 100C under microwave irradiation for 30 min. The mixtures were allowed to cool to RT and the combined precipitated product suspended in diethyl ether and collected by filtration, washing with further diethyl ether then drying in a vacuum oven for 72 h. Approximately 5.2 g of the resultant solid was dissolved in dichloromethane and passed through Celite, eluting with further dichloromethane. The solvent was evaporated in vacuo to give the title compound as a pale orange solid (4.95 g).
	copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 100℃; for 0.5h;microwave irradiation;	Intermediate 3a-[6-chloro-1 -(phenylsulfonyl)-l H-indazol-4-yl]-1 ,3-oxazole-5-carboxylateIn 4 batches, tetrakis(triphenylphosphine)palladium(0) (3.37 g, 2.92 mmol), ethyl 2-chloro- 1 ,3-oxazole-5-carboxylate (6.65 g, 37.9 mmol, available from Apollo Scientific) and copper(l) iodide (1.1 1 g, 5.83 mmol) were added to a solution of 6-chloro-1- (phenylsulfonyl)-4-(trimethylstannanyl)-1 H-indazole (13.28 g, 29.2 mmol) in N,N- dimethylformamide (52 ml). In 3 of the batches, tetrakis(triphenylphosphine)palladium(0) (1.03 g, 0.89 mmol), ethyl 2-chloro-1 ,3-oxazole-5-carboxylate (2.03 g, 1 1.59 mmol) and copper(l) iodide (0.34 g, 1.78 mmol) were added to a solution of 6-chloro-1- (phenylsulfonyl)-4-(trimethylstannanyl)-1 H-indazole (4.06 g, 8.91 mmol) in N,N- dimethylformamide (16 ml). In the fourth batch, tetrakis(triphenylphosphine)palladium(0) (0.28 g, 0.24 mmol), ethyl 2-chloro-1 ,3-oxazole-5-carboxylate (0.55 g, 3.14 mmol) and copper(l) iodide (0.09 g, 0.48 mmol) were added to a solution of 6-chloro-1- (phenylsulfonyl)-4-(trimethylstannanyl)-1 H-indazole (1 .10 g, 2.42 mmol) in N,N- dimethylformamide (4 ml). Each batch was heated and stirred at 100C under microwave irradiation for 30 min. The mixtures were allowed to cool to RT and the combined precipitated product suspended in diethyl ether and collected by filtration, washing with further diethyl ether then drying in a vacuum oven for 72 h. Approximately 5.2 g of the resultant solid was dissolved in dichloromethane and passed through Celite, eluting with further dichloromethane. The solvent was evaporated in vacuo to give the title compound as a pale orange solid (4.95 g).LCMS (Method A): Rt 1.38 mins, MH+ 432.
4.95 g	With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 100℃; for 2h;Microwave irradiation;	In 4 batches, tetrakis(triphenylphosphine)palladium(0) (3.37 g, 2.92 mmol), <strong>[862599-47-1]ethyl 2-chloro-1,3-oxazole-5-carboxylate</strong> (6.65 g, 37.9 mmol, available from Apollo Scientific) and copper(I) iodide (1.11 g, 5.83 mmol) were added to a solution of 6-chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole (13.28 g, 29.2 mmol) in N,N-dimethylformamide (52 ml). In 3 of the batches, tetrakis(triphenylphosphine)palladium(0) (1.03 g, 0.89 mmol), <strong>[862599-47-1]ethyl 2-chloro-1,3-oxazole-5-carboxylate</strong> (2.03 g, 11.59 mmol) and copper(I) iodide (0.34 g, 1.78 mmol) were added to a solution of 6-chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole (4.06 g, 8.91 mmol) in N,N-dimethylformamide (16 ml). In the fourth batch, tetrakis(triphenylphosphine)palladium(0) (0.28 g, 0.24 mmol), <strong>[862599-47-1]ethyl 2-chloro-1,3-oxazole-5-carboxylate</strong> (0.55 g, 3.14 mmol) and copper(I) iodide (0.09 g, 0.48 mmol) were added to a solution of 6-chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole (1.10 g, 2.42 mmol) in N,N-dimethylformamide (4 ml). Each batch was heated and stirred at 100 C. under microwave irradiation for 30 min. The mixtures were allowed to cool to RT and the combined precipitated product suspended in diethyl ether and collected by filtration, washing with further diethyl ether then drying in a vacuum oven for 72 h. Approximately 5.2 g of the resultant solid was dissolved in dichloromethane and passed through Celite, eluting with further dichloromethane. The solvent was evaporated in vacuo to give the title compound as a pale orange solid (4.95 g).LCMS (Method A): Rt 1.38 mins, MH+ 432.

4.95 g	With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 100℃; for 0.05h;Microwave irradiation;	Ethyl 2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazole-5-carboxylate In 4 batches, tetrakis(triphenylphosphine)palladium(0) (3.37 g, 2.92 mmol), <strong>[862599-47-1]ethyl 2-chloro-1,3-oxazole-5-carboxylate</strong> (6.65 g, 37.9 mmol, available from Apollo Scientific) and copper(I) iodide (1.11 g, 5.83 mmol) were added to a solution of 6-chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole (13.28 g, 29.2 mmol) in N,N-dimethylformamide (52 ml). In 3 of the batches, tetrakis(triphenylphosphine)palladium(0) (1.03 g, 0.89 mmol), <strong>[862599-47-1]ethyl 2-chloro-1,3-oxazole-5-carboxylate</strong> (2.03 g, 11.59 mmol) and copper(I) iodide (0.34 g, 1.78 mmol) were added to a solution of 6-chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole (4.06 g, 8.91 mmol) in N,N-dimethylformamide (16 ml). In the fourth batch, tetrakis(triphenylphosphine)palladium(0) (0.28 g, 0.24 mmol), <strong>[862599-47-1]ethyl 2-chloro-1,3-oxazole-5-carboxylate</strong> (0.55 g, 3.14 mmol) and copper(I) iodide (0.09 g, 0.48 mmol) were added to a solution of 6-chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole (1.10 g, 2.42 mmol) in N,N-dimethylformamide (4 ml). Each batch was heated and stirred at 100 C. under microwave irradiation for 30 min. The mixtures were allowed to cool to RT and the combined precipitated product suspended in diethyl ether and collected by filtration, washing with further diethyl ether then drying in a vacuum oven for 72 h. Approximately 5.2 g of the resultant solid was dissolved in dichloromethane and passed through Celite, eluting with further dichloromethane. The solvent was evaporated in vacuo to give the title compound as a pale orange solid (4.95 g).
	copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 100℃; for 0.5h;Microwave irradiation;	Intermediate 3a Ethyl 2-[6-chloro-1 -(phenylsulfonyl)-i H-indazol-4-yl]-1 ,3-oxazole-5-carboxylateIn 4 batches, tetrakis(triphenylphosphine)palladium(0) (3.37 g, 2.92 mmol), ethyl 2-chloro- 1 ,3-oxazole-5-carboxylate (6.65 g, 37.9 mmol, available from Apollo Scientific) and copper(l) iodide (1.11 g, 5.83 mmol) were added to a solution of 6-chloro-1- (phenylsulfonyl)-4-(trimethylstannanyl)-1 H-indazole (13.28 g, 29.2 mmol) in N, N- dimethylformamide (52 ml). In 3 of the batches, tetrakis(triphenylphosphine)palladium(0) (1.03 g, 0.89 mmol), ethyl 2-chloro-1 ,3-oxazole-5-carboxylate (2.03 g, 1 1.59 mmol) and copper(l) iodide (0.34 g, 1.78 mmol) were added to a solution of 6-chloro-1- (phenylsulfonyl)-4-(trimethylstannanyl)-1 H-indazole (4.06 g, 8.91 mmol) in N, N- dimethylformamide (16 ml). In the fourth batch, tetrakis(triphenylphosphine)palladium(0) (0.28 g, 0.24 mmol), ethyl 2-chloro-1 ,3-oxazole-5-carboxylate (0.55 g, 3.14 mmol) and copper(l) iodide (0.09 g, 0.48 mmol) were added to a solution of 6-chloro-1- (phenylsulfonyl)-4-(trimethylstannanyl)-1 H-indazole (1.10 g, 2.42 mmol) in N, N- dimethylformamide (4 ml). Each batch washeated and stirred at 1000C under microwave irradiation for 30 min. The mixtures were allowed to cool to RT and the combined precipitated product suspended in diethyl ether and collected by filtration, washing with further diethyl ether then drying in a vacuum oven for 72 h. Approximately 5.2 g of the resultant solid was dissolved in dichloromethane and passed through Celite, eluting with further dichloromethane. The solvent was evaporated in vacuo to give the title compound as a pale orange solid (4.95 g).LCMS (Method A): Rt 1.38 mins, MH+ 432.

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 7381 - 7399
[2]Patent: WO2012/32067,2012,A1 .Location in patent: Page/Page column 47-48
[3]Patent: WO2012/55846,2012,A1 .Location in patent: Page/Page column 46-47
[4]Patent: US2013/203772,2013,A1 .Location in patent: Paragraph 0283; 0284; 0285
[5]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 125; 126
[6]Patent: WO2010/125082,2010,A1 .Location in patent: Page/Page column 69-70

8
[ 862599-47-1 ]
[ 7486-35-3 ]
[ 1257266-93-5 ]

Yield	Reaction Conditions	Operation in experiment
	bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; at 100.0℃; for 4.0h;Inert atmosphere;	lntermediate 46: ethyl 2-vinyloxazole-5-carboxylate; To a solution of tributyl(vinyl)stannane (1 .1 mL, 3.83 mmol) and ethyl 2-chlorooxazole-5- carboxylate (546 mg, 3.1 1 mmol) in dioxane (37 mL) is added Pd(PPh3)2CI2 (222 mg, 0.32 mmol) at room temperature. After stirring at 100 0C under nitrogen for 4 hours, the solution is cooled to ambient temperature and then quenched with H2O. The crude is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography (eluent: heptane/EtOAc = 90:10 to 80:20) to give ethyl 2-vinyloxazole-5-carboxylate (470 mg). HPLC retention time = 0.39 minutes (condition B); MS (m+1 ) = 168.2; 1 H NMR (400 MHz, CD3OD) delta ppm 1 .38 (t, J=7.1 Hz, 3 H) 4.38 (q, J=7.2 Hz, 2 H) 5.88 (d, J= 1 1 .4 Hz, 1 H) 6.39 (d, J= 17.7 Hz, 1 H) 6.69 (dd, J= 17.6, 1 1 .2 Hz, 1 H) 7.83 (s, 1 H)
	bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; at 100.0℃; for 4.0h;Inert atmosphere;	lntermediate 37: ethyl 2-vtnyloxazole-5-carboxylate; To a solution of tributyl{vinyl)stannane (1.1 mL, 3.83 mmol) and ethyl 2-cNorooxazole-5- carboxylate (546 mg, 3.11 mmol) in dioxane (37 mL) is added Pd(PPh3J2CI2 (222 mg, 0.32 mmol) at room temperature. After stirring at 100 C under nitrogen for 4 hours, the solution is cooled to ambient temperature and then quenched with H2O. The crude is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography (eluent: heptane/EtOAc = 90:10 to 80:20) to give ethyl 2-vinyloxazote-delta-carboxylate (470 mg). HPLC retention time - 0.39 minutes (condition B); MS (m+1) = 168.2; 1H NMR (400 MHz, CD3OD) delta ppm 1.38 (t, ./=7.1 Hz, 3 H) 4.38 (q, J=7.2 Hz, 2 H) 5.88 (d, J=11.4 Hz, 1 H) 6.39 (d, J=17.7 Hz, 1 H) 6.69 (dd, J=17,6, 11.2 Hz1 1 H) 7.83 (s, 1 H)

Reference： [1]Patent: WO2010/136474,2010,A2 .Location in patent: Page/Page column 194
[2]Patent: WO2010/136493,2010,A1 .Location in patent: Page/Page column 235

9
[ 862599-47-1 ]
[ 67-56-1 ]
[ 124-41-4 ]
2-oxo-2,3-dihydrooxazole-4-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 41 : 2-methoxyoxazole-5-carboxylic acid; To a solution of <strong>[862599-47-1]ethyl 2-chlorooxazole-5-carboxylate</strong> (510 mg, 2.90 mmol) in anhdryous MeCN (10 ml_) and anhydrous MeOH (10 ml_) is added NaOMe (628 mg, 1 1.62 mmol). The crude is stirred at reflux for 2 hrs. To this crude is added additional MeOH. The crude is refluxed for another 4 hrs. The crude is cooled and then concentrated and is redissolved in MeOH (10 ml_). To this crude is added 1 N NaOH (10 ml, 10 mmol). The crude is stirred at room temperature for 3 hrs. The crude is quenched with concentrated HCI, PH adjusted to 7 via pH paper indicator. The crude is concentrated to remove MeOH. The crude is diluted in water. The aq. layer is acidified with concentrated HCI and diluted in EtOAc. The organic layer is washed with water, brine, dried over MgSO4, filtered, and concentrated to give 2- methoxyoxazole-5-carboxylic acid (290 mg). This acid is used without further purification. HPLC retention time = 0.58 minutes (condition B); MS 144.0 (M+1 ).

Reference： [1]Patent: WO2010/136474,2010,A2 .Location in patent: Page/Page column 191

10
[ 862599-47-1 ]
[ 124-41-4 ]
C₇H₉NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; acetonitrile; for 4h;Reflux;	Intermediate 32: 2>;methoxyoxazoie~5-carboxylic acid; To a solution of <strong>[862599-47-1]ethyl 2-chlorooxazole-5-carboxylate</strong> (510 mg, 2.90 mmol) in anhdryous MeCN (10 mL) and anhydrous MeOH (10 mL) is added NaOMe (628 mg, 11.62 mmol), The crude is stirred at reflux for 2 hrs. To this crude is added additional MeOH. The crude is refluxed for another 4 hrs. The crude is concentrated and is redissolved in MeOH (10 mL). To this crude is added 1 N NaOH (10 ml). The crude is stirred at room temperature for 3 hrs. The crude is quenched with concentrated HCI, PH adjusted to 7 via PH paper indicator. The crude is concentrated and diluted in water. The aq. layer is acidified with concentrated HCI and diluted in EtOAc. The organic layer is washed with water, brine, dried over MgSO4, filtered, and concentrated to give2-methoxyoxazoie-5-carboxylic acid (290 mg). HPLC retention time ~ 0.58 minutes (condition D); MS (m+1) - 144.0.

Reference： [1]Patent: WO2010/136493,2010,A1 .Location in patent: Page/Page column 233

11
[ 862599-47-1 ]
[ 1407858-88-1 ]

Yield	Reaction Conditions	Operation in experiment
43%	With sodium methylate; In methanol; acetonitrile;Reflux;	<strong>[862599-47-1]Ethyl 2-chlorooxazole-5-carboxylate</strong> (1.82 g, 10.3 mmol) was dissolved in MeCN (20 ml) and MeOH (20 ml). Sodiummethoxide (9 ml, 25% solution in MeOH, 41 mmol) was added and the reaction mixture heated at reflux overnight.The solvent was removed under reduced pressure and the crude product dissolved in MeOH (20 ml). 2M aqueousNaOH solution (20 ml) was added and the mixture stirred overnight. The resulting mixture was acidified with 1Maqueous HCl and evaporated under reduced pressure. The residue was triturated with a minimal volume of 5Maqueous HCl and filtered. The solid was slurried with ice chips (~10 ml), filtered and dried under vacuum to give theacid as a tan solid (570 mg, 4.4 mmol, 43% yield).
	With hydrogenchloride; sodium methylate;	Step 1: 2-Oxo-2,3-dihydrooxazole-5-carboxylic acid <strong>[862599-47-1]Ethyl 2-chlorooxazole-5-carboxylate</strong> (1.816 g, 10.34 mmol) was solubilised in MeCN (20 ml) and MeOH (20 ml). Sodium methoxide (9 ml, 25% solution in MeOH, 41.4 mmol) was added and the reaction mixture was heated at reflux overnight. The solvent was removed under reduced pressure and the crude product was dissolved in MeOH (20 ml) and 2M NaOH(aq) (20 ml) and stirred at RT overnight. The resulting mixture was acidified with 1M HCl and evaporated under reduced pressure. The residue was triturated with a minimal volume of 5M HCl and filtered. The solid was slurried with ice chips (approx. 10 ml), filtered, washed with water and dried under high vacuum to afford the title compound; LCMS: Rt 0.26 mins MS m/z 127.8 [M-H]- Method 2minLowpHv01

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 2279 - 2284
[2]Patent: US2014/171403,2014,A1 .Location in patent: Page/Page column

12
[ 862599-47-1 ]
[ 109-01-3 ]
C₁₁H₁₇N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium carbonate; In acetonitrile; at 80℃; for 2h;Reflux;	A mixture of compound 6B (5.5 g, 31.3 mmol), N-methylpiperazine (9.4 g, 94 mmol), and K2CO3 (17.3 g, 125.2 mmol) in acetonitrile (80 mL) was heated at reflux at 80 C for 2 h. The mixture was diluted with H20 and extracted with EtOAc. The organic layer was separated, dried over Na2S04, and concentrated under vacuum to give compound 6C (7 g, 94%) as a brown oil. 1H NMR (400 MHz, CDC13) delta 7.52 (s, 1H), 4.32 (q, J = 7.2 Hz, 2H), 3.66 (t, J = 4.8 Hz, 4H), 2.48 (q, J = 4.8 Hz, 4H), 2.34 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H).

Reference： [1]Patent: WO2015/116663,2015,A1 .Location in patent: Paragraph 0117

13
[ 862599-47-1 ]
4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine hydrochloride [ No CAS ]
ethyl 2-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)oxazole-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In dimethyl sulfoxide; at 130℃; for 0.5h;Inert atmosphere; Microwave irradiation;	Preparation 136 Ethyl 2-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)oxazole-5-carboxylate A mixture of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine hydrochloride (Preparation 19, 300 mg, 0.614 mmol), ethyl-2-chloro-1,3-oxazole-5-carboxylate (300 mg, 1.71 mmol), potassium phosphate (163 mg, 0.613 mmol), X-phos (60 mg, 0.126 mmol) and Pd2(dba)3 (60 mg, 0.065 mmol) in DMSO (20 mL) was purged with nitrogen for 1 minutes. The reaction was heated to 130 C. for 30 minutes under microwave irradiation. The reaction was filtered, concentrated in vacuo and purified by silica gel column chromatography 0-20% MeOH in DCM to afford the title compound (200 mg, 76%). MS m/z 425 [M+H]+

Reference： [1]Patent: US2016/52930,2016,A1 .Location in patent: Paragraph 0738

14
[ 862599-47-1 ]
C₄H₄ClNO₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 5444 - 5449

15
[ 113853-16-0 ]
[ 862599-47-1 ]

Yield	Reaction Conditions	Operation in experiment
Ca. 40%	With tert.-butylnitrite; copper dichloride; at 60 - 80℃; for 2.0h;Inert atmosphere;	A mixture of 1.19 g (8.8 mmol, 1.50 mol eq) of CuCl2 abs and 1.05 mL (8.8 mmol, 1.50 mol eq) of tBuONO in 30 mL of AN abs under Ar was heated to 60 C. By this temperature 920.0 mg (5.9 mmol, 1.00 mol eq) of ethyl 2-aminooxazole-5-carboxylate (14) was added portion wise. Then the temperature was raised to 80 C and the reaction mixture was stirred for 2 h. After the consumption of starting material 14 (TLC analysis) the reaction mixture was cooled down to RT and 15 mL of water and 8 mL of 2M HCl were added. The aqueous solution was extracted with EA (3 x 20 mL) and the combined organic layers were washed with brine, dried by Na2SO4, filtered and concentrated under reduced pressure yielding 850 mg (4.8 mmol, 83 %) of ethyl 2-chlorooxazole-5-carboxylate (15) as light yellow oil. The obtained crude product 15 was sufficiently pure to be used for the further synthesis. Purification of 15 can be done by FLC (SiO2, H / EA; 1 / 1), however because of instability of 15 on silica, the yield is lowered to approximately 40 %.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 126,p. 754 - 761

16
[ 862599-47-1 ]
3-amino-4-methoxyphenylethyl sulfone [ No CAS ]
ethyl 2-(5-(ethylsulfonyl)-2-methoxyphenylamino)oxazole-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	In isopropyl alcohol; at 20℃; for 120h;Inert atmosphere;	To the suspension of 1.41 g (6.5 mmol, 1.00 mol eq) of aniline 1 in 40 mL iPrOH abs 2.29 g (13.1 mmol, 2.00 mol eq) of <strong>[862599-47-1]ethyl 2-chlorooxazole-5-carboxylate</strong> (15) in 20 mL iPrOH abs was added dropwise and the reaction mixture was stirred for 5 days at RT under Ar. After the consumption of the starting material 1 was completed (TLC analysis) the solvent was evaporated under reduced pressure. The obtained solid was dissolved in 80 mL EA and washed with saturated aqueous solution of NaHCO3 and water. The separated organic layer was dried by Na2SO4, filtrated and concentrated under reduced pressure. The crude product was purified by FLC (H / EA; from 1 / 2 to 1 / 3) yielding 1.50 g (4.2 mmol, 65 %) of ethyl 2-(5-(ethylsulfonyl)-2-methoxyphenylamino)oxazole-5-carboxylate (16).

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 126,p. 754 - 761

17
[ 862599-47-1 ]
(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0²,⁷]icosa-1⁽²⁰⁾,16,18-trien-8-one hydrochloride [ No CAS ]
[ 76-05-1 ]
ethyl 2-[(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0²,⁷]icosa-1⁽²⁰⁾,16,18-trien-5-yl]-1,3-oxazole-5-carboxylate trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29.5%		To a RBF was added (7R,15S)-15-{4-[5-chloro-2-(4-chloro-lH-l,2,3-triazol-l- yl)phenyl]-6-oxo-l,6-dihydropyrimidin-l-yl}-2,5,9-triazatricyclo[14.3.1.02,7]icosa- l(20),16,18-trien-8-one hydrochloride prepared as described in Example 9 (12 mg, 0.019 mmol), DMF (0.2 mL), EtsN (0.013 mL, 0.095 mmol) and ethyl 2-chlorooxazole-5- carboxylate (6.69 mg, 0.038 mmol). The reaction was stirred at 80 C overnight. The reaction was purified using RP prep-HPLC to give ethyl 2-[(7R,15S)-15-{4-[5-chloro-2-(4- chloro-lH-1, 2,3 riazol-l-yl)phenyl]-6-oxo-l,6-dihydropyrimidin-l-yl} -8-0X0-2,5,9- triazatricyclo[14.3.1.02,7]icosa-l(20),16,18-trien-5-yl]-l,3-oxazole-5-carboxylate trifluoromethyl acetate (5 mg, 5.61 muiotatauiotaomicron, 29.5 % yield) as a light brown solid. (ESI) m/z:732.2 (M+H)+ NMR (400MHz, CD3OD) delta 8.69 (s, 1H), 8.36 (s, 1H), 8.31 (d, J=8.1 Hz, 1H), 7.90 (d, J=2.2 Hz, 1H), 7.77 - 7.73 (m, 1H), 7.69 - 7.65 (m, 1H), 7.64 - 7.59 (m, 1H), 7.32 (t, J=7.8 Hz, 1H), 7.12 - 7.03 (m, 2H), 6.62 (d, J=7.7 Hz, 1H), 6.42 (s, 1H), 5.71 (dd, J=13.0, 2.4 Hz, 1H), 4.33 (q, J=7.2 Hz, 3H), 4.29 - 4.23 (m, 1H), 4.09 - 4.01 (m, 1H), 3.97 - 3.82 (m, 3H), 3.73 - 3.63 (m, 1H), 3.55 - 3.44 (m, 1H), 2.94 - 2.84 (m, 1H), 2.38 - 2.27 (m, 1H), 2.00 - 1.90 (m, 1H), 1.84 - 1.71 (m, 2H), 1.63 - 1.54 (m, 1H), 1.36 (t, J=7.2 Hz, 5H), 1.23 (d, J=6.8 Hz, 1H), 1.12 (d, J=12.3 Hz, 1H). Analytical HPLC (Method A) RT = 12.214 min, purity = 95%. Factor XIa Ki = 16 nM, Plasma Kallikrein Ki = 1218 nM.

Reference： [1]Patent: WO2017/19821,2017,A1 .Location in patent: Page/Page column 67-68; 105-106

18
[ 862599-47-1 ]
(S)-4-(3-amino-5-chloro-2-methylbenzyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester [ No CAS ]
ethyl 2-[3-[[(3S)-4-tert-butoxycarbonyl-3-methylpiperazin-1-yl]methyl]-5-chloro-2-methylanilino]oxazole-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18.7%	In isopropyl alcohol; at 160℃; for 0.5h;Microwave irradiation;	<strong>[862599-47-1]Ethyl 2-chlorooxazole-5-carboxylate</strong> (372 mg, 2.12 mmol) was added to a solution oftert-butyl (25)-4- [ (3-a mi no-5-chloro-2 -methyl-phenyl) methyl] -2-methyl-piperazi ne-tcarboxylatefrom Preparation 5 (500 mg, 1.41 mmol) in propan-2-ol (5.0 mL) and stirred under microwave irradiation at 160C for 30 min. The solvent was removed underreduced pressure and the obtained residue was purified by silica gel (100-200 mesh)column chromatography eluting with a gradient of 10-70% ethyl acetate in heptane.Clean fractions were evaporated under reduced pressure to give title compound ascolourless oil. (130 mg, 18. 7%) LCM5 Method 4: m/z 493.3 [M+H+]; RT = 0.94 min.

Reference： [1]Patent: WO2018/11201,2018,A1 .Location in patent: Page/Page column 61; 62

19
[ 862599-47-1 ]
(trans)-N-(azetidin-3-yl)-3-(benzo[d]thiazol-4-yloxy)cyclobutanecarboxamide hydrochloride [ No CAS ]
ethyl 2-(3-((trans)-3-(benzo[d]thiazol-4-yloxy)cyclobutanecarboxamido)azetidin-1-yl)oxazole-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 125℃; for 2h;Microwave irradiation;	To (frans)-/V-(azetidin-3-yl)-3-(benzo[d]thiazol-4-yloxy)cyclobutanecarboxamide hydrochloride (Intermediate 32) (100 mg, 0.27 mmol) and /V,/V-diisopropylethylamine (0.14 mL, 0.80 mmol) in acetonitrile (15 mL), <strong>[862599-47-1]ethyl 2-chlorooxazole-5-carboxylate</strong> (56 mg, 0.34 mmol) was added. The mixture was heated in a microwave at 125 C for 2 h, concentrated, and the residue was purified on silica gel, eluting with a 5%-20% MePH in DCM gradient to give the title compound (96 mg, 82%). 1H NMR (400 MHz, CD3OD) delta 1 .35 (t, J = 7 Hz, 3 H), 2.49-2.66 (m, 2 H), 2.71 -2.87 (m, 2 H), 3.18-3.29 (m, 1 H), 4.14 (dd, J = 8, 6 Hz, 2 H), 4.14 (dd, J = 8, 6 Hz, 2 H), 4.32 (q, J = 7 Hz, 2 H), 4.54 (t, J = 8 Hz, 2 H), 5.1 1 -5.21 (m, 1 H), 6.89 (d, J = 8 Hz, 1 H), 7.42 (t, J = 8 Hz, 1 H), 7.53-7.72 (m, 2 H), 9.16 (s, 1 H); LC-MS (LC-ES) M+H = 443.

Reference： [1]Patent: WO2018/69863,2018,A1 .Location in patent: Page/Page column 304-305

20
[ 862599-47-1 ]
[ 22050-10-8 ]
ethyl 2-(2-oxo-5-phenylpyrrolidin-1-yl)oxazole-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In tetrahydrofuran; at 0 - 15℃; for 17h;	<strong>[862599-47-1]Ethyl 2-chlorooxazole-5-carboxylate</strong> (457 mg, 2.61 mmol) was added to a mixture of 5- phenylpyrrolidin-2-one (350 mg, 2.17 mmol) and sodium hydride (100mg, 2.61 mmol) in THF (10 mL) at 0 C, and the resulting mixture was stirred at 15 C for 17 h. The mixture wasdiluted with saturated aqueous NH4C1 solution (20 mL) at 0 C, then extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (saturated, 30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by prepTLC (Si02, PE: EA= 2:1) to give ethyl 2-(2-oxo-5-phenylpyrrolidin-1-yl)oxazole-5-carboxylate as a solid. ESI-MS m/z [M+Hf?: 301.0.

Reference： [1]Patent: WO2017/222950,2017,A1 .Location in patent: Page/Page column 66

21
[ 862599-47-1 ]
(S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperidin-4-yl)methanone 1R-(-)-camphor-10-sulphonic acid salt [ No CAS ]
(S)-ethyl 2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperidin- 1-yl)oxazole-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3h;	To a solution of (S)-(5 -(3,5 -difluorophenyl)-4,5-dihydro- 1H-pyrazol- 1 -yl)(piperidin-4- yl)methanone, (1R)-10-camphorsulphonate salt (500 mg, 1.7 mmol) and cesium carbonate (1.11 g, 3.4 mmol) in DMF (2 mL) was added <strong>[862599-47-1]ethyl 2-chlorooxazole-5-carboxylate</strong> (359 mg, 2.1 mmol). The reaction minxture was stirred 60 C for 3 h and concentrated in vacuo. The residue was dissolved in EtOAc (20 mL) which was then washd with water (10 mL). Afterseparation, the organic layer was washed with brine (10 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was precipitated in hexanes to afford (S)-ethyl 2-(4-(5- (3,5 -difluorophenyl)-4,5 -dihydro- 1H-pyrazole- 1 -carbonyl)piperidin- 1 -yl)oxazole-5 - carboxylate (477 mg, 1.1 mmol, purity: 100 %, recovery: 65 %) as a white solid. LCMS (mlz) 433 (M+H), retention time: 2.53 min LC/MS Method 1.

Reference： [1]Patent: WO2018/92089,2018,A1 .Location in patent: Page/Page column 168

22
[ 862599-47-1 ]
2-methylpropyl zinc bromide [ No CAS ]
ethyl 2-(2-methylpropyl)-1,3-oxazole-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%	With copper(l) iodide; In tetrahydrofuran; at -5 - 20℃; for 3h;Inert atmosphere;	Ethyl 2-(2-methylpropyl)-1,3-oxazole-5-carboxylate To a solution of <strong>[862599-47-1]ethyl 2-chloro-1,3-oxazole-5-carboxylate</strong> (3 g, 17.09 mmol, 1.00 equiv) in THF (45 mL), under N2, was added copper(I) iodide (1.5 g, 7.88 mmol, 0.50 equiv). This was followed by the addition of bromo(2-methylpropyl)zinc (15 mL, 2.00 equiv) at -5 C. The resulting solution was stirred for 3 h at room temperature. The reaction was then quenched by the addition of aq 1 M HCl. The resulting solution was extracted with 2×100 mL of EtOAc, and the organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column with EtOAc/petroleum ether (1:5). This resulted in the title compound as a red oil (1.3 g, 39%).

Reference： [1]Patent: US2018/162822,2018,A1 .Location in patent: Paragraph 0532

23
[ 862599-47-1 ]
2-hydroxy-1,3-oxazole-5-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With water; lithium hydroxide; In tetrahydrofuran; at 30℃; for 16h;	2-Hydroxy-1,3-oxazole-5-carboxylic acid A solution of 48 <strong>[862599-47-1]ethyl 2-chloro-1,3-oxazole-5-carboxylate</strong> (3 g, 17.09 mmol, 1.00 equiv) and 49 LiOH (1.7 g, 70.98 mmol, 4.00 equiv) in 50 THF/51 H2O (60/15 mL) was stirred for 16 h at 30 C. The pH was then adjusted to 4 with 1 M HCl, and the resulting solution was extracted with 4×50 mL of EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum to afford 2 g (91%) of the title compound as a yellow solid. LC-MS: (ES, m/z): 129.

Reference： [1]Patent: US2018/162822,2018,A1 .Location in patent: Paragraph 0517

24
[ 862599-47-1 ]
[ 57260-71-6 ]
ethyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)oxazole-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 100℃; for 2h;	Tert-butyl piperazine-1-carboxylate (744 mg, 4 mmol), <strong>[862599-47-1]ethyl 2-chlorooxazole-5-carboxylate</strong> (700 mg, 4 mmol) and DIPEA (1032 mg, 8 mmol) were added into 1 ,4-dioxane (15 ml). The mixture was stirred for 2 h at 1000 C. When the reaction finished, it was cooled and water was added. The precipitate was collected to afford the yellow solid as product (1.45 g, crude).

Reference： [1]Patent: US2018/141923,2018,A1 .Location in patent: Paragraph 0608; 0609; 0610

25
[ 862599-47-1 ]
methyl 2-(4-((2-oxopyridin-1(2H)-yl)methyl)phenyl)acetate [ No CAS ]
ethyl 2-(2-methoxy-2-oxo-1-(4-((2-oxopyridin-1(2H)-yl)methyl)phenyl)ethyl)oxazole-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0℃; for 1h;Inert atmosphere;	To a mixture of methyl 2-(4-((2-oxopyridin-l(2H)-yl)methyl)phenyl)acetate (1.0 g, 3.9 mmol, 1.0 eq) and <strong>[862599-47-1]ethyl 2-chlorooxazole-5-carboxylate</strong> (684 mg, 3.9 mmol, 1.0 eq) in DMF (50 mL) was added NaH (312 mg, 7.8 mmol, 2.0 eq) at 0 C. The reaction mixture was stirred at this temperature for 1 h under N2. Water (20 mL) was added and the mixture was extracted with EA (50 mL x3). The combined organic layers were washed with brine (50 mL), dried over Na2S04 and concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 1/1, v/v) to give ethyl 2-(2-methoxy-2-oxo-l-(4-((2-oxopyridin- l(2H)-yl)methyl)phenyl)ethyl)oxazole-5-carboxylate (1.0 g, 65%). (0854)

Reference： [1]Patent: WO2019/142053,2019,A2 .Location in patent: Paragraph 00322; 00324

26
[ 862599-47-1 ]
[ 1449661-84-0 ]
ethyl 2-(4-((benzyloxy)carbonyl)cyclohex-1-en-1-yl)oxazole-5-carboxylate [ No CAS ]

Reference： [1]Patent: WO2020/1448,2020,A1 .Location in patent: Page/Page column 39; 65-66

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[ 862599-47-1 ]

Chlorides

[ 934236-41-6 ]

Methyl 2-chlorooxazole-5-carboxylate

Similarity: 0.97

[ 78451-11-3 ]

Ethyl 2-chloro-4-methyloxazole-5-carboxylate

Similarity: 0.83

[ 460081-18-9 ]

Ethyl 2-chlorooxazole-4-carboxylate

Similarity: 0.64

[ 934236-35-8 ]

Methyl 2-chlorooxazole-4-carboxylate

Similarity: 0.61

[ 706789-07-3 ]

2-Chlorooxazole-4-carboxylic acid

Similarity: 0.60

Esters

[ 934236-41-6 ]

Methyl 2-chlorooxazole-5-carboxylate

Similarity: 0.97

[ 78451-11-3 ]

Ethyl 2-chloro-4-methyloxazole-5-carboxylate

Similarity: 0.83

[ 118994-89-1 ]

Ethyl oxazole-5-carboxylate

Similarity: 0.81

[ 121432-12-0 ]

Methyl 5-oxazolecarboxylate

Similarity: 0.78

[ 651059-70-0 ]

Methyl 2-methyloxazole-5-carboxylate

Similarity: 0.72

Related Parent Nucleus of
[ 862599-47-1 ]

Oxazoles

[ 934236-41-6 ]

Methyl 2-chlorooxazole-5-carboxylate

Similarity: 0.97

[ 78451-11-3 ]

Ethyl 2-chloro-4-methyloxazole-5-carboxylate

Similarity: 0.83

[ 118994-89-1 ]

Ethyl oxazole-5-carboxylate

Similarity: 0.81

[ 121432-12-0 ]

Methyl 5-oxazolecarboxylate

Similarity: 0.78

[ 118994-90-4 ]

Oxazole-5-carboxylic acid

Similarity: 0.76

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

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 862599-47-1 ] {[proInfo.proName]}

Quality Control of [ 862599-47-1 ]

Related Doc. of [ 862599-47-1 ]

Product Details of [ 862599-47-1 ]

Calculated chemistry of [ 862599-47-1 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 862599-47-1 ]

Application In Synthesis of [ 862599-47-1 ]

[ 862599-47-1 ] Synthesis Path-Upstream 1~3

[ 862599-47-1 ] Synthesis Path-Downstream 1~26

Related Functional Groups of [ 862599-47-1 ]

Chlorides

Esters

Related Parent Nucleus of [ 862599-47-1 ]

Oxazoles

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 862599-47-1 ]

Related Parent Nucleus of
[ 862599-47-1 ]