[ CAS No. 460081-18-9 ] {[proInfo.proName]}

Name: 460081-18-9|Ethyl 2-chlorooxazole-4-carboxylate|97%
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Quality Control of [ 460081-18-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 460081-18-9 ]

Product Details of [ 460081-18-9 ]

CAS No. :	460081-18-9	MDL No. :	MFCD06660120
Formula :	C₆H₆ClNO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SYWQOPRAPDMWMC-UHFFFAOYSA-N
M.W :	175.57	Pubchem ID :	2763184
Synonyms :

Calculated chemistry of [ 460081-18-9 ]

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) :	2.11
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 :	2.45

Safety of [ 460081-18-9 ]

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 [ 460081-18-9 ]

* 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 [ 460081-18-9 ]
Downstream synthetic route of [ 460081-18-9 ]

[ 460081-18-9 ] Synthesis Path-Upstream 1~4

1
[ 177760-52-0 ]
[ 460081-18-9 ]

Yield	Reaction Conditions	Operation in experiment
71%	With tert.-butylnitrite; copper dichloride In acetonitrile at 75℃; for 0.833333 h;	Under a nitrogen atmosphere, 1. 70 ML (14.3 mmol) of tert-butyl nitrite was added to a suspension OF 1. 65 g (12.3 mmol) OF COPPER (II) CHLORIDE in 50 ML of acetonitrile. The resulting suspension was heated to 75 °C, then 1.60 g (10.2 mmol) of ethyl 2-aminooxazole-4- carboxylate (G Crank MJ Foulis, J Med Chem 1971,14 : 1075-1077) was added in portions over 20 min (gas evolution). After stirring for an additional 30 min, the reaction was allowed to cool to ambient temperature, diluted with 50 ML of EtOAc, and extracted with water (2 x 25 ml). The organic layer was dried over MgS04 and concentrated in vacuo to a dark oily solid. Flash chromatography through neutral silica gel using a 3: 1 mixture of hexane and EtOAc gave 1.27 g (71 percent) OF THE TITLE compound, which crystallized from hexane as white needles. m/z (ES+): 176/177. 1H NMR (CDCL3) No.: 1. 47 (t, 3H, J = 7.16) ; 4.48 (q, 2H, J = 7.16) ; 6.92 8.28 (s, 1H).
56%	With tert.-butylnitrite; copper dichloride In acetonitrile at 20 - 80℃; for 2.5 h;	A stirred solution of tert-butyl nitrite (1.0 g, 9.61 mmol) and copper (II) chloride (1.29 g, 9.61 mmol) in CH₃CN was treated with ethyl 2-amino-1,3-oxazole-4-carboxylate (1.0 g, 6.4 mmol) stirred 2 hours at room temperature, heated to 80° C. for 30 minutes and concentrated under reduced pressure. The resultant residue was dissolved in EtOAc and water. The layers were separated and the organic layer washed with saturated sodium chloride, dried over Mg₂SO₄ and concentrated under reduced pressure to give the title product in 56percent yield, identified by NMR and mass spectral analyses. LCMS (ESI⁺) 175 (MH⁺).
1.9 g	With tert-butyl nitrate; copper dichloride In acetonitrile at 60 - 80℃; for 3 h;	To a mixture of tert-butyl nitrate (2.86 mL), copper(II) chloride (3.23 g) and acetonitrile (64 mL) was added ethyl 2-amino-1,3-oxazole-4-carboxylate obtained in Step A (2.50 g) at 60°C. The reaction mixture was heated at 80°C for 3 hr, and cooled to room temperature. The reaction mixture was poured into 1 M hydrochloric acid, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.90 g). ¹H NMR (400 MHz, CDCl₃) δ 1.39 (3H, t, J = 7.2 Hz), 4.40 (2H, q, J = 7.2 Hz), 8.19 (1H, s).

Reference： [1] Organic Letters, 2003, vol. 5, # 16, p. 2911 - 2914
[2] Organic Letters, 2002, vol. 4, # 17, p. 2905 - 2907
[3] European Journal of Medicinal Chemistry, 2019, p. 80 - 108
[4] Patent: WO2005/26149, 2005, A1, . Location in patent: Page/Page column 111
[5] Journal of Medicinal Chemistry, 2010, vol. 53, # 9, p. 3814 - 3830
[6] Patent: US2009/23707, 2009, A1, . Location in patent: Page/Page column 34
[7] Organic and Biomolecular Chemistry, 2012, vol. 10, # 30, p. 5764 - 5768
[8] Patent: WO2007/146066, 2007, A2, . Location in patent: Page/Page column 157
[9] Patent: WO2008/57336, 2008, A2, . Location in patent: Page/Page column 43
[10] Patent: US2010/16609, 2010, A1, . Location in patent: Page/Page column 10
[11] Patent: WO2012/143599, 2012, A1, . Location in patent: Page/Page column 26
[12] Patent: EP2818473, 2014, A1, . Location in patent: Paragraph 0602
[13] Patent: WO2018/35005, 2018, A1, . Location in patent: Page/Page column 40
[14] Patent: WO2009/158374, 2009, A2, . Location in patent: Page/Page column 34; 35

2
[ 70-23-5 ]
[ 460081-18-9 ]

Reference： [1] Organic Letters, 2002, vol. 4, # 17, p. 2905 - 2907
[2] Organic and Biomolecular Chemistry, 2012, vol. 10, # 30, p. 5764 - 5768
[3] Patent: EP2818473, 2014, A1,
[4] European Journal of Medicinal Chemistry, 2019, p. 80 - 108

3
[ 540-80-7 ]
[ 177760-52-0 ]
[ 7447-39-4 ]
[ 460081-18-9 ]

Reference： [1] Patent: US2014/94474, 2014, A1, . Location in patent: Page/Page column

4
[ 460081-18-9 ]
[ 706789-07-3 ]

Reference： [1] Tetrahedron Letters, 2004, vol. 45, # 19, p. 3797 - 3801
[2] Tetrahedron Letters, 2007, vol. 48, # 21, p. 3713 - 3717
[3] Patent: WO2007/146066, 2007, A2, . Location in patent: Page/Page column 157

[ 460081-18-9 ] Synthesis Path-Downstream 1~75

1
[ 7486-35-3 ]
[ 460081-18-9 ]
[ 460081-24-7 ]

Reference： [1]Organic Letters,2002,vol. 4,p. 2905 - 2907

2
[ 177760-52-0 ]
[ 460081-18-9 ]

Yield	Reaction Conditions	Operation in experiment
71%	With tert.-butylnitrite; copper dichloride; In acetonitrile; at 75℃; for 0.833333h;	Under a nitrogen atmosphere, 1. 70 ML (14.3 mmol) of tert-butyl nitrite was added to a suspension OF 1. 65 g (12.3 mmol) OF COPPER (II) CHLORIDE in 50 ML of acetonitrile. The resulting suspension was heated to 75 C, then 1.60 g (10.2 mmol) of ethyl 2-aminooxazole-4- carboxylate (G Crank & MJ Foulis, J Med Chem 1971,14 : 1075-1077) was added in portions over 20 min (gas evolution). After stirring for an additional 30 min, the reaction was allowed to cool to ambient temperature, diluted with 50 ML of EtOAc, and extracted with water (2 x 25 ml). The organic layer was dried over MgS04 and concentrated in vacuo to a dark oily solid. Flash chromatography through neutral silica gel using a 3: 1 mixture of hexane and EtOAc gave 1.27 g (71 %) OF THE TITLE compound, which crystallized from hexane as white needles. m/z (ES+): 176/177. 1H NMR (CDCL3) No.: 1. 47 (t, 3H, J = 7.16) ; 4.48 (q, 2H, J = 7.16) ; 6.92 & 8.28 (s, 1H).
56%	With tert.-butylnitrite; copper dichloride; In acetonitrile; at 20 - 80℃; for 2.5h;	A stirred solution of tert-butyl nitrite (1.0 g, 9.61 mmol) and copper (II) chloride (1.29 g, 9.61 mmol) in CH3CN was treated with <strong>[177760-52-0]ethyl 2-amino-1,3-oxazole-4-carboxylate</strong> (1.0 g, 6.4 mmol) stirred 2 hours at room temperature, heated to 80 C. for 30 minutes and concentrated under reduced pressure. The resultant residue was dissolved in EtOAc and water. The layers were separated and the organic layer washed with saturated sodium chloride, dried over Mg2SO4 and concentrated under reduced pressure to give the title product in 56% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 175 (MH+).
	With tert.-butylnitrite; copper dichloride; In acetonitrile; at 60 - 80℃; for 1h;	The solid (3.16 g, 20.2 mmol) was added portionwise to a 60 0C solution of Copper(II) chloride (3.40 g, 25.3 mmol) and t-butyl nitrite (3.13 mL, 25.3 mmol) in acetonitrile (100 mL) while maintaining the reaction temperature between 60 and 65 0C. After complete addition, the reaction mixture was heated to 80 C for 1 h. Upon cooling to rt, the reaction mixture was poured into a mixture Of CH2Cl2 (150 mL), water (150 mL), and HCl (cone, 10 mL). The organics were separated and the aqueous layer was extracted with CH2Cl2 (2 x 100 mL). The combined organics were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting material was dissolved in EtOH (50 mL) and water (25 mL), and NaOH (0.972 g, 24.3 mmol) was added. After stirring overnight at rt, the ethanol was removed under reduced pressure and the reaction mixture was diluted with water (100 mL). The mixture was washed with Et2O (50 mL, discarded) and brought to pH ~2 with cone. HCl. The aqueous solution was extracted with EtOAc (3 x 150 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. This gave 2.12 g (31%) of the title compound as a yellow solid. LC-MS: RT = 3.51 min, [M+H]+ = 147.9.

	With tert.-butylnitrite; copper dichloride; In acetonitrile; at 60 - 75℃; for 2h;	Intermediate 39 (3g, 19.2mmol) was added portionwise to a mixture of tert-butyl nitrite (93.4ml, 28.8mmol) and copper (II) chloride (3.87g, 28.8mmol) in acetonitrile (100 ml) warmed at 6O0C. After complete addition the mixture was heated at 750C for 2 hours. The mixture was 30 cooled and poured into IN HCl (300ml), and extracted with CH2Cl2 (3 x 120ml). The combined CH2Cl2 extracts were dried over Na2SO4, filtered and evaporated to give of the title compound. 1HNMR (500 MHz, CDCl3) delta: 8.20 (s, IH), 4.39 (q, J = 7.3, 2H), 1.39 (t, J = 7.3, 3H).
	With tert.-butylnitrite; copper dichloride; In acetonitrile; at 20 - 80℃; for 2.5h;	Step 2: Preparation of ethyl 2-chloro-1,3-oxazole-4-carboxylate; A stirred solution of tert-butyl nitrite (1.0 g, 9.61 mmol) and copper (II) chloride (1.29 g, 9.61 mmol) in CH3CN is treated with <strong>[177760-52-0]ethyl 2-amino-1,3-oxazole-4-carboxylate</strong> (1.0 g, 6.4 mmol) stirred 2 hours at room temperature, heated to 80 C. for 30 minutes and concentrated under reduced pressure. The resultant residue is dissolved in EtOAc and water. The layers are separated and the organic layer washed with saturated sodium chloride, dried over Mg2SO4 and concentrated under reduced pressure to give the title product.
		a) Ethyl 2rchlorooxazole-4-carboxylateEthyl 2-aminooxazole-4-carboxylate (20 g, 128 mmol) was added to a solution of cupric chloride (32.8 g, 192 mmol) and t-butylnitrite (23 ml, 192 mmol) in ACN (500 ml) at 80 C and the resulting mixture was refluxed for 4 h. The reaction mixture was concentrated and treated with concentrated HC1 and extracted with EtOAc. The product was purified with flash chromatography. Yield 10.5 g. 1H- NMR (400MHz; CDC13): delta 1.36 (t, 3H), 4.39 (q, 2H), 8.47 (s, 1H).
1.9 g	With tert-butyl nitrate; copper dichloride; In acetonitrile; at 60 - 80℃; for 3h;	To a mixture of tert-butyl nitrate (2.86 mL), copper(II) chloride (3.23 g) and acetonitrile (64 mL) was added <strong>[177760-52-0]ethyl 2-amino-1,3-oxazole-4-carboxylate</strong> obtained in Step A (2.50 g) at 60C. The reaction mixture was heated at 80C for 3 hr, and cooled to room temperature. The reaction mixture was poured into 1 M hydrochloric acid, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.90 g). 1H NMR (400 MHz, CDCl3) delta 1.39 (3H, t, J = 7.2 Hz), 4.40 (2H, q, J = 7.2 Hz), 8.19 (1H, s).
	With tert.-butylnitrite; copper dichloride; In acetonitrile; at 60 - 80℃; for 2h;	Compound 7A was added in portions to a stirred solution of tert-butyl nitrite (6.92 g, 67.12 mmol) and copper (II) chloride (9.02 g, 67.12 mmol) in MeCN(200 mL) at 60C. The mixture was heated at 80C and allowed to stir at this temperature for 2 hours, then the reaction mixture was cooled and patitioned between dichloromethane (250 mL), water (130 mL), and concentrated hydrochloric acid (13 mL). The aqueous layer was further extracted with dichlormethane, and the combined organics were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue obtained was purified using flash column chromatography on silica gel (petroleum ether/ethyl acetate 100: 1?50: 1) to provide compound 7B as a solid. MS (ESI) m/z (M+H)+: 176.
	With tert.-butylnitrite; copper dichloride; In acetonitrile; at 65℃; for 1h;	Preparation of Lambda/-{(1 S)-2-amino-1-r(3-fluorophenyl)methyllethyl}-2-(1-methyl-1 H-pyrazol-5- yl)-1 ,3-oxazole-4-carboxamidea) ethyl 2-chloro-1 ,3-oxazole-4-carboxylate To a solution of ethyl 2-amino-1 ,3-oxazole-4-carboxylate (5.0 g, 32.0 mmol) in acetonitrile (100 ml.) and copper (II) chloride (6.46 g, 48.0 mmol) was added f-butyl nitrite (6.39 ml_, 48.0 mmol) slowly. After stirring at 65 0C 1 h, the solution was concentrated and purified using a silica gel column eluting with chloroform to afford a light- yellow solid as the desired product: LC-MS (ES) m/z 176 (M+H)+.

Reference： [1]Organic Letters,2003,vol. 5,p. 2911 - 2914
[2]Organic Letters,2002,vol. 4,p. 2905 - 2907
[3]European Journal of Medicinal Chemistry,2019,vol. 162,p. 80 - 108
[4]Patent: WO2005/26149,2005,A1 .Location in patent: Page/Page column 111
[5]Journal of Medicinal Chemistry,2010,vol. 53,p. 3814 - 3830
[6]Patent: US2009/23707,2009,A1 .Location in patent: Page/Page column 34
[7]Organic and Biomolecular Chemistry,2012,vol. 10,p. 5764 - 5768
[8]Patent: WO2007/146066,2007,A2 .Location in patent: Page/Page column 157
[9]Patent: WO2008/57336,2008,A2 .Location in patent: Page/Page column 43
[10]Patent: US2010/16609,2010,A1 .Location in patent: Page/Page column 10
[11]Patent: WO2012/143599,2012,A1 .Location in patent: Page/Page column 26
[12]Patent: EP2818473,2014,A1 .Location in patent: Paragraph 0602
[13]Patent: WO2018/35005,2018,A1 .Location in patent: Page/Page column 40
[14]Patent: WO2009/158374,2009,A2 .Location in patent: Page/Page column 34; 35

3
pyridin-2-ylzinc(II) bromide [ No CAS ]
[ 460081-18-9 ]
[ 460081-26-9 ]

Reference： [1]Organic Letters,2002,vol. 4,p. 2905 - 2907

4
[ 460081-18-9 ]
[ 98-80-6 ]
[ 39819-39-1 ]

Yield	Reaction Conditions	Operation in experiment
83%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 90℃;	Preparation of 5-chloro-2-phenyl-oxazole-4-carboxylic acid A mixture of phenylboronic acid (729 mg, 5.98 mmol), <strong>[460081-18-9]2-chloro-oxazole-4-carboxylic acid ethyl ester</strong> (prepared according to the procedures described in Org. Lett. 2002, 4 (17), 2905 and J. Med. Chem. 1971, 14, 1075) (1.0 g, 5.70 mmol), Pd[PPh3]4 (329 mg, 0.285 mmol), and sodium carbonate (2M, 2 mL) in ethylene glycol dimethyl ether (10 mL) were heated at 90 degrees overnight. After cooling the reaction, solvent was removed to give the crude residue. Flash chromatography (Merck silica gel 60, 230-400 mesh, 5-45% ethyl acetate in hexane for 35 min) gave 2-phenyl-oxazole-4-carboxylic acid ethyl ester (1.03 g, 83%) as colorless oil. LCMS calcd for C12H11NO3 (m/e) 217, obsd 218 (M+H).

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 162,p. 80 - 108
[2]Organic Letters,2003,vol. 5,p. 2911 - 2914
[3]Organic Letters,2002,vol. 4,p. 2905 - 2907
[4]Patent: US2007/123504,2007,A1 .Location in patent: Page/Page column 23
[5]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 7205 - 7209

5
[ 460081-18-9 ]
[ 155742-48-6 ]
[ 706789-06-2 ]

Reference： [1]Tetrahedron Letters,2004,vol. 45,p. 3797 - 3801

6
[ 460081-18-9 ]
[ 706789-06-2 ]

Reference： [1]Tetrahedron Letters,2004,vol. 45,p. 3797 - 3801

7
[ 460081-18-9 ]
[ 706789-07-3 ]

Yield	Reaction Conditions	Operation in experiment
		The solid (3.16 g, 20.2 mmol) was added portionwise to a 60 0C solution of Copper(II) chloride (3.40 g, 25.3 mmol) and t-butyl nitrite (3.13 mL, 25.3 mmol) in acetonitrile (100 mL) while maintaining the reaction temperature between 60 and 65 0C. After complete addition, the reaction mixture was heated to 80 C for 1 h. Upon cooling to rt, the reaction mixture was poured into a mixture Of CH2Cl2 (150 mL), water (150 mL), and HCl (cone, 10 mL). The organics were separated and the aqueous layer was extracted with CH2Cl2 (2 x 100 mL). The combined organics were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting material was dissolved in EtOH (50 mL) and water (25 mL), and NaOH (0.972 g, 24.3 mmol) was added. After stirring overnight at rt, the ethanol was removed under reduced pressure and the reaction mixture was diluted with water (100 mL). The mixture was washed with Et2O (50 mL, discarded) and brought to pH ~2 with cone. HCl. The aqueous solution was extracted with EtOAc (3 x 150 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. This gave 2.12 g (31%) of the title compound as a yellow solid. LC-MS: RT = 3.51 min, [M+H]+ = 147.9.

Reference： [1]Tetrahedron Letters,2004,vol. 45,p. 3797 - 3801
[2]Tetrahedron Letters,2007,vol. 48,p. 3713 - 3717
[3]Patent: WO2007/146066,2007,A2 .Location in patent: Page/Page column 157

8
[ 460081-18-9 ]
2-ethoxy-oxazole-4-carboxylic acid [ No CAS ]

Reference： [1]Tetrahedron Letters,2004,vol. 45,p. 3797 - 3801

9
[ 885669-16-9 ]
[ 460081-18-9 ]
2'-phenyl-[2,4']bioxazolyl-4-carboxylic acid ethyl ester [ No CAS ]

Reference： [1]Synlett,2006,p. 555 - 558

10
[ 885669-17-0 ]
[ 460081-18-9 ]
5'-methyl-2'-phenyl-[2,4']bioxazolyl-4-carboxylic acid ethyl ester [ No CAS ]

Reference： [1]Synlett,2006,p. 555 - 558

11
[ 1003846-78-3 ]
[ 460081-18-9 ]
C₂₅H₃₅N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 24h;	31). Synthesis of 2-benzyl-4-(4-ethoxycarbonyl-oxazol-2-ylamino)-6-ethyl-piperidine-1- carboxylic acid tert-butyl ester; <n="188"/>A solution of 4-amino-2-benzyl-6-ethyl-piperidine-1-carboxylic acid tert-butyl ester (1 mmol, 318 mg), <strong>[460081-18-9]2-chloro-oxazole-4-carboxylic acid ethyl ester</strong> (3 mmol, 527 mg) and lambda/,/V-diotasopropylethylamine (2 mmol, 348 uL) in DMF (4 ml) is allowed to warm to 110 0C and stirred for 24 hours. The mixture is cooled to room temperature, then added with water. The mixture is extracted with EtOAc. 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: hexane / EtOAc) to give 2-benzyl-4-(4-ethoxycarbonyl- oxazol-2-ylamino)-6-ethyl-piperidine-1-carboxylic acid tert-butyl ester (288 mg, 63%); ESI- MS m/z: 458 [M+1]+, Retention time 2.46 min (condition A).

Reference： [1]Patent: WO2008/9435,2008,A1 .Location in patent: Page/Page column 185-186

12
[ 941306-35-0 ]
[ 460081-18-9 ]
[ 941306-37-2 ]

Reference： [1]Tetrahedron Letters,2007,vol. 48,p. 3713 - 3717

13
[ 460081-18-9 ]
[ 942502-74-1 ]

Reference： [1]Tetrahedron Letters,2007,vol. 48,p. 3713 - 3717

14
[ 460081-18-9 ]
C₂₄H₂₅N₅O₇Si [ No CAS ]

Reference： [1]Tetrahedron Letters,2007,vol. 48,p. 3713 - 3717

15
[ 460081-18-9 ]
[ 460081-28-1 ]

Reference： [1]Organic Letters,2003,vol. 5,p. 2911 - 2914
[2]Organic Letters,2002,vol. 4,p. 2905 - 2907
[3]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 7205 - 7209

16
[ 460081-18-9 ]
[ 587884-71-7 ]

Reference： [1]Organic Letters,2003,vol. 5,p. 2911 - 2914
[2]Organic Letters,2003,vol. 5,p. 2911 - 2914
[3]Organic Letters,2003,vol. 5,p. 2911 - 2914

17
[ 460081-18-9 ]
[ 587884-70-6 ]

Reference： [1]Organic Letters,2003,vol. 5,p. 2911 - 2914
[2]Organic Letters,2003,vol. 5,p. 2911 - 2914
[3]Organic Letters,2003,vol. 5,p. 2911 - 2914

18
[ 70-23-5 ]
[ 460081-18-9 ]

Reference： [1]Organic Letters,2002,vol. 4,p. 2905 - 2907
[2]Organic and Biomolecular Chemistry,2012,vol. 10,p. 5764 - 5768
[3]Patent: EP2818473,2014,A1
[4]European Journal of Medicinal Chemistry,2019,vol. 162,p. 80 - 108

19
[ 460081-18-9 ]
[ 93729-29-4 ]

Reference： [1]Organic Letters,2002,vol. 4,p. 2905 - 2907

20
[ 460081-18-9 ]
ethyl 2-phenyl-5-vinyloxazole-4-carboxylate [ No CAS ]

Reference： [1]Organic Letters,2002,vol. 4,p. 2905 - 2907

21
[ 460081-18-9 ]
ethyl 2-phenyl-5-(pyridin-2-yl)oxazole-4-carboxylate [ No CAS ]

Reference： [1]Organic Letters,2002,vol. 4,p. 2905 - 2907

22
[ 460081-18-9 ]
2-phenyl-5-phenylethynyl-oxazole-4-carboxylic acid ethyl ester [ No CAS ]

Reference： [1]Organic Letters,2002,vol. 4,p. 2905 - 2907

23
[ 460081-18-9 ]
[ 460081-31-6 ]

Reference： [1]Organic Letters,2002,vol. 4,p. 2905 - 2907

24
[ 261947-64-2 ]
[ 460081-18-9 ]
(2R,4S)-4-(4-ethoxycarbonyloxazol-2-yl)amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 130℃;	(2R, 4S)-4-Amino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H- quinoline-l-carboxylic acid ethyl ester (1.28 g), <strong>[460081-18-9]2-chloroxazole-4-carboxylic acid ethyl ester</strong> (1. 44 g) and diisopropylethylamine (1. 42 ml) are dissolved in 1, 4-dioxane (10 ml), and the mixture is stirred at 130C overnight. The reaction solution is cooled to room temperature, and water and ethyl acetate are added thereto. The organic layer is washed with a saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate = 4: 1No.1 : 1) to give (2R, 4S)-4- (4-ethoxycarbonyloxazol- 2-yl) amino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-l- carboxylic acid ethyl ester (1.13 g). MS (m/z): 456 [M+H] +

Reference： [1]Patent: WO2005/95409,2005,A2 .Location in patent: Page/Page column 166-167

25
[ 58425-32-4 ]
[ 460081-18-9 ]
[ 918444-58-3 ]

Yield	Reaction Conditions	Operation in experiment
	In dimethyl sulfoxide; at 85℃; for 16h;	To a solution of 3-ferf-butyl phenol (1.00 g, 6.65 mmol) in dry THF (25 ml) was added potassium tert-butoxide (747 mg, 6.65 mmol) and the mixture was heated to reflux for 1 h. Upon cooling, the volatiles were removed in vacuo before the residue was taken up into DMSO (20 ml). Ethyl 2- chlorooxazole-4-carboxylate (prepared according to the procedure of K. J. Hodgetts and M. T. Kershaw, Organic Letters, 2002, 4, 2905-2907; 993 mg, 5.65 mmol) was then added before the mixture was heated to 85 C for 16 h. Upon cooling the reaction mixture was partitioned between ethyl acetate (25 ml) and water (25 ml) and after rigorous shaking the aqueous layer was separated and extracted further with ethyl acetate (3 x 25 ml). The combined organic phase was washed with brine (50 ml) and dried (MgSO4) before being concentrated in vacuo. The crude product was then purified by column chromatography (SiO2; 19:1 light petroleum-ethyl acetate to 9:1) to afford the title compound as a pale yellow oil (1.43 g, 87 %). 1H NMR delta 7.84 (1 H, s), 7.20-7.30 (3 H, m), 7.10-7.15 (1 H, m), 4.27 (2 H, q), 1.27 (3 H, t) and 1.26 (9 H, s).

Reference： [1]Patent: WO2007/582,2007,A1 .Location in patent: Page/Page column 46

26
C₁₁H₁₃O^(1-)*K⁽¹⁺⁾ [ No CAS ]
[ 460081-18-9 ]
[ 918444-62-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	In dimethyl sulfoxide; at 85℃; for 16h;	To a solution of 3,3-dimethyl-2,3-dihydro-1 H-inden-5-ol (Intermediate 5; 430 mg, 2.63 mmol) in dry THF (10 ml) was added potassium tert-butoxide (295 mg, 2.63 mmol) and the mixture was heated to 70 0C for 1 h. Upon cooling, the volatiles were removed in vacuo before the residue was taken up into DMSO (10 ml). Ethyl 2-chlorooxazole-4-carboxylate (prepared according to the procedure of K. J. Hodgetts and M. T. Kershaw, Organic Letters, 2002, 4, 2905-2907; 400 mg, 2.27 mmol) was then added before the mixture was heated to 85 0C for 16 h. Upon cooling the reaction mixture was partitioned between ethyl acetate (25 ml) and water (25 ml) and after rigorous shaking the aqueous layer was separated and extracted further with ethyl acetate (3 x 25 ml). The combined organic phase was washed with brine (50 ml) and dried (MgSO4) before being concentrated in vacuo. The crude product was then purified by column chromatography (SiO2; 19:1 pentane-ethyl acetate) to afford the title compound as a yellow oil (quantitative yield). 1H NMR (DMSO) 8.55 (1 H, s), 7.27-7.29 (1 H, m), 7.14-7.2 (2 H1 m), 4.24 (2 H, 4.24), 2.87 (2 H, t), 1.93 (2 H, t), 1.25 (3 H, t), 1.23 (6 H, s).

Reference： [1]Patent: WO2007/582,2007,A1 .Location in patent: Page/Page column 48-49

27
[ 943313-30-2 ]
[ 460081-18-9 ]
[ 943314-75-8 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrabutyl ammonium fluoride; bis(tri-n-butyltin);tetrakis(triphenylphosphine) palladium(0); In toluene; at 110℃; for 3.5h;	Step 1 Preparation of compound 81a: 2-[6-(3-tert-Butoxycarbonylamino-phenoxy)-pyrimidin-4-yl]-oxazole-4-carboxylic acid ethyl ester A mixture of 2a (5.00 g, 15.5 mmol), <strong>[460081-18-9]ethyl 2-chlorooxazole-4-carboxylate</strong> (5.00 g, 28.5 mmol), tetrabutylammonium fluoride (25.0 g, 95.6 mmol) and toluene (100 mL) was stirred for 5 minutes at room temperature under nitrogen prior to the addition of hexabutyldistannane (10.0 g, 17.2 mmol). The reaction mixture was purged with nitrogen gas, then tetrakis(triphenylphosphine)palladium(0) (1.50 g, 1.30 mmol) was added. The solution was heated to 110 C. for 3.5 h prior to cooling to room temperature. Ethyl acetate (100 mL) was added and the mixture filtered through a 5 cm plug of silica gel. The filtrate was concentrated under vacuum and the product was purified using column chromatography (hexanes to 3:1 hexanes/ethyl acetate) to give 250 mg of 2-[6-(3-tert-butoxycarbonylamino-phenoxy)-pyrimidin-4-yl]-oxazole-4-carboxylic acid ethyl ester as a yellow solid. [M+H]+ 427.04.

Reference： [1]Patent: US2007/155764,2007,A1 .Location in patent: Page/Page column 82

28
[ 916971-27-2 ]
[ 460081-18-9 ]
[ 1030613-60-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In ethanol; at 20℃; for 5h;	Step 1: Ethyl-2-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3-oxazole-4-carboxylate To a solution of 4-(2-bromo-5-fluorophenoxy)piperidine (3.281 g, 11.97 mmol) in EtOH (28.5 mL) was added <strong>[460081-18-9]ethyl 2-chlorooxazole-4-carboxylate</strong> (1 g, 5.70 mmol) and DIPEA (1.990 mL, 11.39 mmol). The reaction mixture was stirred at rt for 5 h. The solvent was evaporated under reduced pressure. The residue was diluted with 1N HCl and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure to give the title compound. 1H NMR (500 MHz, acetone-d6): delta8.02 (s, 1H), 7.59 (dd, 1H), 7.08 (dd, 1H), 6.73 (td, 1 H), 4.89-4.85 (m, 1H), 4.25 (q, 2 H), 3.79-3.72 (m, 2 H), 3.64-3.57 (m, 2 H), 2.12-2.06 (m, 2 H), 1.94-1.86 (m, 2 H), 1.28 (t, 3 H). MS (+ESI) m/z 413 (MH+)

Reference： [1]Patent: US2008/132542,2008,A1 .Location in patent: Page/Page column 32

29
[ 59016-93-2 ]
[ 460081-18-9 ]
[ 1104735-59-2 ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium carbonate;tris-(dibenzylideneacetone)dipalladium(0); tri tert-butylphosphoniumtetrafluoroborate; In 1,4-dioxane; at 80 - 90℃;Product distribution / selectivity;	A solution of <strong>[460081-18-9]ethyl 2-chloro-1,3-oxazole-4-carboxylate</strong> (0.59 g, 3.36 mmol) in dioxane was treated with 4-(hydroxymethyl)phenyl boronic acid (0.766 g, 5.04 mmol), K2CO3 (0.929 g, 6.72 mmol), t-Bu3PhBF4 (0.049 g, 0.168 mmol) heated to 80 C. then treated with Pd2(dba)3 (0.154 g 0.168 mmol) and stirred overnight at 90 C. The reaction mixture was diluted with EtOAc, washed with water, saturated sodium chloride, dried over MgSO4 and concentrated in in vacuo. The resultant residue was purified by flash chromatography (silica, EtOAc:hexanes 20?50%) to give the title product in 70% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 248 (MH+).
68%	With potassium carbonate;tris-(dibenzylideneacetone)dipalladium(0); tri tert-butylphosphoniumtetrafluoroborate; In 1,4-dioxane; water; at 86℃; for 2h;Product distribution / selectivity;	To a suspension of tris(dibenzylideneacetone)dipalladium (0) (0.025 eq) and tri-tert-butylphosphonium tetrafluoroborate (0.05 eq) a mixture of dioxane and 1N aqueous potassium carbonate (3:1) degassed with nitrogen was added chlorooxazole carboxylate (1 eq) followed by a suspension of 4-hydroxymethylphenylboronic acid (1 eq) in a mixture of dioxane and 1N aqueous potassium carbonate (8:1) continuing to degas with nitrogen and the resulting reaction mixture was stirred at 86 C. (reflux) until determined complete by HPLC (about 2 h). The reaction mixture was allowed to cool to room temperature and filtered through celite, the organic layer separated, and the aqueous layer extracted with ethyl acetate. The dioxane layer was concentrated (avoiding total evaporation to dryness) and combined with the ethyl acetate extract and washed with aq. sodium bicarbonate, brine, dried over sodium sulphate, filtered, evaporated, and triturated with MTBE. The isolated yield of the target compound was 68%. m. p. 99-101 C.; 1H NMR (300 MHz, CDCl3, delta): 8.27 (s, 1H), 8.10 (d, 2H, J=8.2 Hz), 7.47 (d, 2H, J=8.2 Hz), 4.77 (s, 2H), 4.43 (m, 2H, J=7.4 Hz), 1.41 (t, 3H, J=7.4 Hz).
68%	With potassium carbonate;tris-(dibenzylideneacetone)dipalladium(0); tri tert-butylphosphoniumtetrafluoroborate; In 1,4-dioxane; water; at 86℃;Inert atmosphere;	Example 2; Step 1: Preparation of ethyl 2-[4-(hydroxymethyl)phenyl]-1,3-oxazole-4-carboxylate; To a suspension of tris(dibenzylideneacetone)dipalladium (0) (3.1 g, 3.36 mmol) and tri-tert-butylphosphonium tetrafluoroborate (1.95 g, 6.7 mmol) in a mixture of dioxane (500 ml) and 1N aqueous potassium carbonate (150 ml) degassed with nitrogen was added chlorooxazole carboxylate (23.5. g, 135 mmol) followed by a suspension of 4-hydroxymethylphenylboronic acid (21.3 g, 135 mmol) in a mixture of dioxane (200 ml, +50 ml wash) and 1N aqueous potassium carbonate (30 ml) continuing to degas with nitrogen and the resulting reaction mixture was stirred at 86 C. (reflux) until determined complete by HPLC (about 2 h). The reaction mixture was allowed to cool to room temperature and filtered through celite, the organic layer separated, and the aqueous layer extracted with ethyl acetate. The dioxane layer was concentrated (avoiding total evaporation to dryness) and combined with the ethyl acetate extract and washed with aq. sodium bicarbonate, brine, dried over sodium sulphate, filtered, evaporated, and triturated with MTBE. The isolated yield of the target compound 22.7 g (68%). m.p. 99-101 C.; 1H NMR (300 MHz, CDCl3, delta): 8.27 (s, 1H), 8.10 (d, 2H, J=8.2 Hz), 7.47 (d, 2H, J=8.2 Hz), 4.77 (s, 2H), 4.43 (m, 2H, J=7.4 Hz), 1.41 (t, 3H, J=7.4 Hz).

Reference： [1]Patent: US2009/23707,2009,A1 .Location in patent: Page/Page column 34
[2]Patent: US2009/23707,2009,A1 .Location in patent: Page/Page column 15
[3]Patent: US2010/16609,2010,A1 .Location in patent: Page/Page column 9

30
[ 945627-36-1 ]
[ 460081-18-9 ]
[ 1127234-43-8 ]

Yield	Reaction Conditions	Operation in experiment
	bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; at 100℃; for 22h;	tert-butyl 1 S-cyclohexyl--ft-fethoxycarbonyl)-. ,3-oxazol-2-yl)-3-methoxy- 7H-indolo[2,l-a] [2]benzazepine-10-carboxylate.; 1,1 -dimethylethyl 13 -cyclohexyl-3 -(methyloxy)-6-(tributylstannanyl)-7H- indolo[2,l-alpha][2]benzazepine-10-carboxylate (266mg, 0.36mMol) was dissolved in 3.4mL of 1,4-dioxane in a 2 dram vial. Ethyl 2-chlorooxazole-4-carboxylate (83.4mg, 0.47mMol) was dissolved in the reaction followed by the addition of bis(triphenylphosphine)palladium(II) chloride (17.7mg, 0.025mMol). The reaction was capped under nitrogen and heated in an oil bath at 100 C for 17hrs, after which the reaction was cooled and the reaction progress was measured by LC-MS. To the reaction mixture was added bis(triphenylphosphine)palladium(II) chloride (lOmg, 0.014mMol). The reaction was capped under nitrogen and heated for an additional 5hrs at lOOC. The reaction was concentrated in vacuuo and the residue adsorbed onto silica gel purified by silica gel chromatography eluting with a gradient of dichloromethane to 2% ethyl acetate in dichloromethane to yield 233mg of a yellow solid product. 1eta NMR (500 MHz, CHLOROFORM-D) delta ppm 1.13 - 1.37 (m, 4 H) 1.37 - 1.44 (m, 4 H) 1.46 - 1.55 (m, 1 H) 1.64 (s, 9 H) 1.68 - 1.81 (m, 2 H) 1.83 - 1.98 (m, 3 H) 1.98 - 2.13 (m, 3 H) 2.74 - 2.88 (m, 1 H) 3.91 (s, 3 H) 4.34 - 4.48 (m, 3 H) 5.84 - 6.00 (m, 1 H) 7.00 (d, J=2.44 Hz, 1 H) 7.08 (dd, J=8.55, 2.75 Hz, 1 H) 7.53 (d, J=8.85 Hz, 1 H) 7.69 (dd, J=8.55, 1.22 Hz, 1 H) 7.74 (s, 1 H) 7.82 (d, J=8.24 Hz, 1 H) 8.21 (s, 1 H) 8.30 (s, 1 H); LC-MS: Shimadzu Analytical HPLC using Discovery VP software: %A= 10% methanol, 90% water, 0.1% trifluoroacetic acid %B= 90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial %B= 0; Final % B=IOO; Gradient= 3 min; Runtime= 5 min; Flow rate= 5 ml/min; Wavelength= 220nm; <n="23"/>Column= Phenomenex Luna 3.0mm x 50mm SlO; Retention Time= 3.4 min, MS m/z 583(MH+).
	bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; at 100℃; for 22h;Inert atmosphere;	tert-butyl 13-cyclohexyl-6-(4-(ethoxycarbonyl)-l,3-oxazol-2-yl)-3-methoxy- 7H-indolo[2,l-a][2]benzazepine-10-carboxylate.1 , 1 -dimethylethyl 13 -cyclohexyl-3 -(methyloxy)-6-(tributylstannanyl)-7H- indolo[2,l-alpha][2]benzazepine-10-carboxylate (266mg, 0.36mMol) was dissolved in 3.4mL of 1,4-dioxane in a 2 dram vial. Ethyl 2-chlorooxazole-4-carboxylate (83.4mg, 0.47mMol) was dissolved in the reaction followed by the addition of bis(triphenylphosphine)palladium(II) chloride (17.7mg, 0.025mMol). The reaction was capped under nitrogen and heated in an oil bath at 100 C for 17hrs, after which the reaction was cooled and the reaction progress was measured by LC-MS. To the reaction mixture was added bis(triphenylphosphine)palladium(II) chloride (lOmg, 0.014mMol). The reaction was capped under nitrogen and heated for an additional 5hrs at lOOC. The reaction was concentrated in vacuuo and the residue adsorbed onto silica gel purified by silica gel chromatography eluting with a gradient of dichloromethane to 2% ethyl acetate in dichloromethane to yield 233mg of a yellow solid product. 1 Eta NMR (500 MHz, CHLOROFORM-D) delta ppm 1.13 - 1.37 (m, 4 H) 1.37 - 1.44 (m, 4 H) 1.46 - 1.55 (m, 1 H) 1.64 (s, 9 H) 1.68 - 1.81 (m, 2 H) 1.83 - 1.98 (m, 3 H) 1.98 - 2.13 (m, 3 H) 2.74 - 2.88 (m, 1 H) 3.91 (s, 3 H) 4.34 - 4.48 (m, 3 H) 5.84 - 6.00 (m, 1 H) 7.00 (d, J=2.44 Hz, 1 H) 7.08 (dd, J=8.55, 2.75 Hz, 1 H) 7.53 (d, J=8.85 Hz, 1 H) 7.69 (dd, J=8.55, 1.22 Hz, 1 H) 7.74 (s, 1 H) 7.82 (d, J=8.24 Hz, 1 H) 8.21 (s, 1 H) 8.30 (s, 1 H); LC-MS: Shimadzu Analytical HPLC using Discovery VP software: %A= 10% methanol, 90% water, 0.1% trifluoroacetic acid %B= 90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial %B= 0; Final % B=IOO; Gradient= 3 min; Runtime= 5 min; Flow rate= 5 ml/min; Wavelength= 220nm; Column= Phenomenex Luna 3.0mm x 50mm SlO; Retention Time= 3.4 min, MS m/z 583(MH+).

Reference： [1]Patent: WO2009/29384,2009,A2 .Location in patent: Page/Page column 21-22
[2]Patent: WO2010/93359,2010,A1 .Location in patent: Page/Page column 21

31
[ 1135871-91-8 ]
[ 460081-18-9 ]
[ 1135872-20-6 ]

Yield	Reaction Conditions	Operation in experiment
54%	With tetrabutylammomium bromide;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 100℃; for 1h;Microwave irradiation;	a) 2-(8-Oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-oxazole-4-carboxylic acid ethyl ester<strong>[460081-18-9]2-Chloro-oxazole-4-carboxylic acid ethyl ester</strong> (50mg, 0.28 mmol), prepared according to Hodgetts and Kershaw, 2002, 7-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-3,4- dihydro-2H-naphthalen-l-one (94mg, 0.36 mmol), tetrabutylammonium bromide (lOmg, 0.04 mmol) and Pd(PPh3)2Cl2 (13mg, 0.02 mmol) in dioxane:water (1.2 mL/0.6 mL) were heated at 1000C in a microwave reactor for 1 hour. After this time, water and ethyl acetate were added and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with water and brine and dried over Na2SO4. Concentration afforded a brown solid which was triturated with Et2O. The product was obtained as an off-white solid (43mg, 54%). NMR 1H (CDCl3, ppm): 8.72 (s, IH), 8.31 (s, IH), 8.28 (dd, IH), 7.41 (d, IH), 4.45 (q, 2H), 3.07-3.03 (m, 2H), 2.75-2.71 (m, 2H), 2.25-2.16 (m, 2H), 1.44 (t, IH).

Reference： [1]Patent: WO2009/39553,2009,A1 .Location in patent: Page/Page column 107

32
[ 121882-41-5 ]
[ 460081-18-9 ]
[ 1168207-97-3 ]

Reference： [1]Organic Letters,2009,vol. 11,p. 2756 - 2759

33
[ 460081-18-9 ]
[ 847818-74-0 ]
[ 1202248-04-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;bis(tri-t-butylphosphine)palladium(0); In 1,4-dioxane; water; at 100℃; for 0.333333h;Microwave irradiation; Sealed tube;	b) ethyl 2-(1-methyl-1 H-pyrazol-5-yl)-1 ,3-oxazole-4-carboxylate To a solution of ethyl 2-chloro-1 ,3-oxazole-4-carboxylate (2.00 g, 11.39 mmol), 1- methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazole(2.65 g, 13.67 mmol)[prepared in Preparation 2] and potassium carbonate (4.72 g, 34.2 mmol) in 1 ,4-dioxane (16 ml.) and water (4.00 ml.) in a microwave tube was added bis(tri- t-butylphosphine)palladium (0) (0.58 g, 1.14 mmol). The tube was sealed and heated in the microwave reactor at 100 0C for 20 minutes. The mixture was concentrated and purified by column chromatography (silica, 0-40% ethyl acetate / hexane) to generate a yellow solid as the desired product: LC-MS (ES) m/z 222 (M+H)+.

Reference： [1]Patent: WO2009/158374,2009,A2 .Location in patent: Page/Page column 35

34
[ 1204654-52-3 ]
[ 460081-18-9 ]
ethyl 2-(4-((1H-benzo[d]imidazol-1-yl)methyl)phenyl)oxazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%		Step 3: Preparation of Ethyl 2-[4-(1H-benzimidazol-1-ylmethyl)phenyl]-1,3-oxazole-4-carboxylate; To a suspension of tris(dibenzylideneacetone)dipalladium (0) (230 mg, 0.25 mmol) and tri-tert-butylphosphonium tetrafluoroborate (150 mg, 0.5 mmol) in dioxane (50 ml) and 1N aqueous potassium carbonate (10 ml) degassed with nitrogen was added chlorooxazole carboxylate (1.75. g, 10 mmol) and the reaction mixture allowed to stir for 10 min. A solution of [4-(1H-benzimidazol-1-ylmethyl)phenyl]boronic acid (2.8 g, 11 mmol) in 1N aqueous potassium carbonate (7 mL) was added and the reaction mixture was heated to 86 C. (reflux) for 2 h. The reaction mixture was cooled to room temperature, filtered, diluted with ethyl acetate (50 mL) and washed with conc.aq. ammonium chloride (30 ml). The combined aqueous layers were washed with ethyl acetate and the combined organic layers washed with aqueous sodium bicarbonate, brine, dried over sodium sulphate, filtered, evaporated, and the crude product crystallized from MTBE to give 2.6 g (75%) of the target compound. m.p. 99-101 C.; 1H NMR (300 MHz, DMSO-D6, delta): 8.92 (s, 1H), 8.45 (d, 2H, J=8.5 Hz), 7.99 (d, 2H, J=8.5 Hz), 7.68 (m, 1H), 7.51 (m, 1H), 7.46 (d, 2H, J=8.5 Hz), 7.21 (m, 2H), 5.61 (s, 2H), 4.31(m, 2H, J=7.2 Hz), 3.32 (s, 2H), 130 (t, 3H, J=7.2 Hz).

Reference： [1]Patent: US2010/16609,2010,A1 .Location in patent: Page/Page column 8-9

35
[ 509083-73-2 ]
[ 460081-18-9 ]
[ 1224465-34-2 ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 3814 - 3830

36
N₂'-(trans-4-aminocyclohexyl)-5'-chloro-N₆-(3-fluorobenzyl)-2,4'-bipyridine-2',6-diamine [ No CAS ]
[ 460081-18-9 ]
ethyl 2-(trans-4-(5'-chloro-6-(3-fluorobenzylamino)-2,4'-bipyridin-2'-yl-amino)cyclohexylamino)oxazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In 1,4-dioxane; at 80℃; for 20h;	Example 26Compound 155Ethyl 2-(trans-4-(5'-chloro-6-(3-fluorobenzylamino)-2,4'-bipyridin-2'-yl-amino)cyclohexylamino)oxazole-4-carboxylate; A mixture of N2'-(trans-4-aminocyclohexyl)-5'-chloro-N6-(3-fluorobenzyl)-2,4'-bipyridine-2',6-diamine (25 mg, 0.059 mmol), <strong>[460081-18-9]ethyl 2-chlorooxazole-4-carboxylate</strong> (12.88 mg, 0.073 mmol), triethylamine (0.041 mL, 0.293 mmol) in dioxane (1 mL) was heated at 80 C. for 20 hr. The mixture was concentrated in vacuo. The resulting residue was dissolved in DMSO and purified by HPLC providing ethyl 2-(trans-4-(5'-chloro-6-(3-fluorobenzylamino)-2,4'-bipyridin-2'-yl-amino)cyclohexylamino)oxazole-4-carboxylate as its trifluoroacetic acid salt. Yield: 7.1 mg. LCMS (m/z): 565.2 [M+H]+; Retention time=0.85 min.

Reference： [1]Patent: US2011/28492,2011,A1 .Location in patent: Page/Page column 44

37
[ 460081-18-9 ]
[ 855405-24-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 7205 - 7209

38
N₂'-(trans-4-aminocyclohexyl)-5'-chloro-N₆-(3-fluorobenzyl)-2,4'-bipyridine-2',6-diamine [ No CAS ]
[ 76-05-1 ]
[ 460081-18-9 ]
ethyl 2-(trans-4-(5'-chloro-6-(3-fluorobenzylamino)-2,4'-bipyridin-2'-ylamino)cyclohexylamino)oxazole-4-carboxylate trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of N2'-(trans-4-aminocyclohexyl)-5'-chloro-N6-(3-fluorobenzyl)-2,4'- bipyridine-2',6-diamine (25 mg, 0.059 mmol), <strong>[460081-18-9]ethyl 2-chlorooxazole-4-carboxylate</strong> (12.88 mg, 0.073 mmol), triethylamine (0.041 mL, 0.293 mmol) in dioxane (1 mL) was heated at 80 C for -20 hr. The mixture was concentrated in vacuo. The resulting residue was dissolved in DMSO and purified by HPLC providing ethyl 2-(trans-4-(5'-chloro-6-(3- fluorobenzylamino)-2,4'-bipyridin-2'-yl-amino)cyclohexylamino)oxazole-4-carboxylate as its trifluoroacetic acid salt. Yield: 7.1 mg. LCMS (m/z): 565.2 [M+H]+; Retention time = 0.85 min

Reference： [1]Patent: WO2012/101065,2012,A2 .Location in patent: Page/Page column 176-177

39
N₂'-(trans-4-aminocyclohexyl)-5'-chloro-N₆-(3-fluorobenzyl)-2,4'-bipyridine-2',6-diamine [ No CAS ]
[ 76-05-1 ]
[ 460081-18-9 ]
ethyl 2-(trans-4-(5'-chloro-6-(3-fluorobenzylamino)-2,4'-bipyridin-2'-yl-amino)cyclohexylamino)oxazole-4-carboxylate trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 26 (Compound 155) Ethyl 2-(trans-4-(5'-chloro-6-(3-fluorobenzylamino)-2,4'-bipyridin-2'-yl- amino)cyclohexylamino)oxazole-4-carboxylateA mixture of N2'-(trans-4-aminocyclohexyl)-5'-chloro-N6-(3-fluorobenzyl)-2,4'- bipyridine-2',6-diamine (25 mg, 0.059 mmol), <strong>[460081-18-9]ethyl 2-chlorooxazole-4-carboxylate</strong> (12.88 mg, 0.073 mmol), triethylamine (0.041 mL, 0.293 mmol) in dioxane (1 mL) was heated at 80 C for -20 hr. The mixture was concentrated in vacuo. The resulting residue was dissolved in DMSO and purified by HPLC providing ethyl 2-(trans-4-(5'-chloro-6-(3- fluorobenzylamino)-2,4'-bipyridin-2'-yl-amino)cyclohexylamino)oxazole-4-carboxylate as its trifluoroacetic acid salt. Yield: 7.1 mg. LCMS (m/z): 565.2 [M+H]+; Retention time = 0.85 min.

Reference： [1]Patent: WO2012/101066,2012,A1 .Location in patent: Page/Page column 159-160

40
[ 227017-79-0 ]
[ 460081-18-9 ]
[ 1392426-91-3 ]

Reference： [1]Organic and Biomolecular Chemistry,2012,vol. 10,p. 5764 - 5768

41
[ 17953-46-7 ]
[ 460081-18-9 ]
C₂₂H₁₉N₃O₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6569 - 6576

42
[ 227305-69-3 ]
[ 460081-18-9 ]
[ 1528744-84-4 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 6h;	<strong>[460081-18-9]2-Chloro-oxazole-4-carboxylic acid ethyl ester</strong> (1.5 g, 8.5 mmol, 1 eq.) and 2,3-Dihydro-l- benzofuran-5-ylboronic acid (2.1 g, 12.8 mmol, 1.5 eq.) were suspended in DME (170 ml). Tetrakis(triphenylphosphine)palladium(0) (987 mg, 0.85 mmol, 0.1 eq.) and an aqueous 2M sodium carbonate solution (17.1 ml, 34.2 mmol, 4 eq.) were added. The reaction mixture was stirred at 90C for 6 h. DME was then removed under reduced pressure. The obtained residue was dissolved inEtOAc and was washed three times with water. The organic layer was dried over MgS04, filtered and concentrated in vacuo. The obtained crude product was purified by - - flash column chromatography on silica gel (PE/EtOAc 9:1 to 8:2). The fractions containing the product were collected and concentrated in vacuo. The product was obtained as a yellow oil (472 mg, Purity: ca. 50%). LC/MS [M+H]+: 259.10

Reference： [1]Patent: WO2014/1464,2014,A1 .Location in patent: Page/Page column 58; 59

43
[ 1150114-77-4 ]
[ 460081-18-9 ]
[ 1557037-79-2 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 150℃;Inert atmosphere; Microwave irradiation;	2-(4-Cyano-2-fluoro-phenyl)-oxazole-4-carboxylic acid ethyl ester A mixture of <strong>[460081-18-9]2-chloro-oxazole-4-carboxylic acid ethyl ester</strong> (250 mg), 4-cyano-2-fluorophenylboronic acid (277 mg), tetrakis-(triphenylphosphine)-palladium (115 mg), and aqueous Na2CO3 solution (2 M; 1.84 mL) in 1,4-dioxane (10 mL) is heated to 150 C. under an argon atmosphere in a microwave oven. The reaction mixture is concentrated in vacuo. The residue is stirred in methanol for two days, filtered off and dried to give the title product. LC (method 8): tR=1.41 min; Mass spectrum (ESI+): m/z=261 [M+H]+.
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 150℃;Inert atmosphere; Microwave irradiation;	Intermediate 272-(4-Cyano-2-fluoro-henyl)-oxazole-4-carboxylic acid ethyl ester: A mixture of <strong>[460081-18-9]2-chloro-oxazole-4-carboxylic acid ethyl ester</strong> (250 mg), 4-cyano-2- fluorophenylboronic acid (277 mg), tetrakis-(triphenylphosphine)-palladium (115 mg), and aqueous Na2003 solution (2 M; 1 .84 mL) in 1 ,4-dioxane (10 mL) is heated to150C under an argon atmosphere in a microwave oven. The reaction mixture is concentrated in vacuo. The residue is stirred in methanol for two days, filtered off and dried to give the title product. LC (method 8): tR = 1 .41 mm; Mass spectrum (ESI):mlz = 261 [M+H]

Reference： [1]Patent: US2014/45823,2014,A1 .Location in patent: Paragraph 0320; 0321
[2]Patent: WO2014/19967,2014,A1 .Location in patent: Page/Page column 82

44
[ 1186127-11-6 ]
[ 460081-18-9 ]
[ 1557037-95-2 ]

Yield	Reaction Conditions	Operation in experiment
		[2,5']Bioxazolyl-4-carboxylic acid ethyl ester A mixture of 2-chloro-4-oxazolecarboxylic acid ethyl ester (200 mg), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-triisopropylsilanyl-oxazole (596 mg) and aqueous Na2CO3 solution (2 M; 1.49 mL) in N,N-dimethylformamide (8 mL) is sparged with argon for 10 minutes prior to the addition of PdCl2[1,1'-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex (93 mg). The reaction mixture is stirred overnight at 80 C. under an argon atmosphere. After cooling to room temperature, water and ethyl acetate are added and the organic phase is separated, washed with brine, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 6:4?3:7) to afford the title compound. LC (method 8): tR=1.09 min; Mass spectrum (ESI+): m/z=209 [M+H]+.
		Intermediate 35[2.59 Bioxazolyl -4-carboxyl ic acid ethyl ester: A mixture of 2-chloro-4-oxazolecarboxylic acid ethyl ester (200 mg), 5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-2-triisopropylsilanyl-oxazole (596 mg) andaqueous Na2003 solution (2 M; 1.49 mL) in N,N-dimethylformamide (8 mL) is sparged with argon for 10 minutes prior to the addition of PdCI2[1,1?- bis(diphenylphosphino)ferrocene]CH2Cl2 complex (93 mg). The reaction mixture is stirred overnight at 80C under an argon atmosphere. After cooling to roomtemperature, water and ethyl acetate are added and the organic phase is separated, washed with brine, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 6:4 - 3:7) to afford the title compound. LC (method 8): tR = 1 .09 mm; Mass spectrum (ESI): mlz = 209 [M+H]

Reference： [1]Patent: US2014/45823,2014,A1 .Location in patent: Paragraph 0336; 0337
[2]Patent: WO2014/19967,2014,A1 .Location in patent: Page/Page column 85

45
[ 540-80-7 ]
[ 177760-52-0 ]
[ 7447-39-4 ]
[ 460081-18-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride;	a) Ethyl 2-chlorooxazole-4-carboxylate Ethyl 2-aminooxazole-4-carboxylate (20 g, 128 mmol) was added to a solution of cupric chloride (32.8 g, 192 mmol) and t-butylnitrite (23 ml, 192 mmol) in ACN (500 ml) at 80 C. and the resulting mixture was refluxed for 4 h. The reaction mixture was concentrated and treated with concentrated HCl and extracted with EtOAc. The product was purified with flash chromatography. Yield 10.5 g. 1H-NMR (400 MHz; CDCl3): delta 1.36 (t, 3H), 4.39 (q, 2H), 8.47 (s, 1H).

Reference： [1]Patent: US2014/94474,2014,A1 .Location in patent: Page/Page column

46
[ 460081-18-9 ]
[ 1256276-24-0 ]

Reference： [1]Patent: US2014/94474,2014,A1

47
[ 460081-18-9 ]
[ 1403332-46-6 ]

Reference： [1]Patent: US2014/94474,2014,A1

48
[ 460081-18-9 ]
[ 1403335-21-6 ]

Reference： [1]Patent: US2014/94474,2014,A1

49
[ 97674-02-7 ]
[ 460081-18-9 ]
[ 1403332-43-3 ]

Yield	Reaction Conditions	Operation in experiment
		b) Ethyl 2-(1-ethoxyvinyl)oxazole-4-carboxylate Ethyl 2-(1-ethoxyvinyl)oxazole-4-carboxylate was prepared using the procedure described in Example 33(a), starting from <strong>[460081-18-9]ethyl 2-chlorooxazole-4-carboxylate</strong> (10.5 g, 59.8 mmol) and tributyl(1-ethoxyvinyl)stannane (24 ml, 65.8 mmol), The product was purified with flash-chromatography. Yield 10.3 g. 1H-NMR (400 MHz; CDCl3): delta ppm 1.23-1.46 (m, 6H), 3.94-3.99 (m, 2H), 4.36-4.42 (m, 2H), 4.8 (d, 1H), 5.33 (s, 1H), 8.19 (s, 1H).

Reference： [1]Patent: US2014/94474,2014,A1 .Location in patent: Page/Page column

50
[ 16419-60-6 ]
[ 460081-18-9 ]
[ 885274-61-3 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In toluene; at 90℃; for 1h;Inert atmosphere;	A flask was charged with <strong>[460081-18-9]ethyl 2-chlorooxazole-4-carboxylate</strong> (500 mg, 2.85 mmol), 2-methylbenzeneboronic acid (387 mg, 2.85 mmol), Pd(PPh3)4 (132 mg, 0.114 mmol), K2CO3 (787 mg, 5.7 mmol), and toluene (29 mL).The reaction mixture was degassed under a stream of N2, and was then heated to 90 C. for 1 h. The reaction was thendiluted with EtOAc and washed with 1M aqueous NaOH. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified on via flash chromatography on silica gel (hexanes:EtOAc) to give a 2:1 mixture of product to <strong>[460081-18-9]ethyl 2-chlorooxazole-4-carboxylate</strong> (360 mg) that was carried on without further purification.

Reference： [1]Patent: US2014/154179,2014,A1 .Location in patent: Paragraph 0466; 0467

51
[ 122536-76-9 ]
[ 460081-18-9 ]
ethyl (S)-2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)oxazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91.89%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃; for 2h;	Step 1: Preparation of ethyl (S)-2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-l-yl)oxazole- 4-carboxylate The mixture of <strong>[460081-18-9]ethyl 2-chlorooxazole-4-carboxylate</strong> (lOOmg, 0.5698 mmol), tert-butyl (S)-pyrrolidin-3-ylcarbamate (127mg, 0.6837 mmol), DIPEA (0.284mL, 1.4245 mmol) and DMF (5mL) were heated at 120C for 2h. The reaction mass was quenched with ice water and extracted with DCM. The solvent was distilled out to get the title compound (170mg, 91.89%). LCMS: m/z = 270.1 (M - t-butyl +1)+.
91.89%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃; for 2h;	The mixture of <strong>[460081-18-9]ethyl 2-chlorooxazole-4-carboxylate</strong> (100mg, 0.5698mmo1), tert-butyl (S)-pynolidin-3-ylcarbamate (127mg, 0.6837mmo1), DIPEA (0.284mL, 1.4245mmo1) and DMF (5mL) were heated at 120C for 2h. The reaction mass was quenched with ice water and extracted with DCM. The solvent was distilled out to get the title compound (170mg, 9 1.89%).LCMS: mlz = 270.1 (M-t-butyl+1).
91.89%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃; for 2h;	Step 1:Preparation of ethyl (S)-2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)oxazole- 4-carboxylate The mixture of <strong>[460081-18-9]ethyl 2-chlorooxazole-4-carboxylate</strong> (lOOmg, 0.5698mmol), tert-butyl (S)-pyrrolidin-3-ylcarbamate (127mg, 0.6837mmol), DIPEA (0.284mL, 1.4245mmol) and DMF (5mL) were heated at 120C for 2h. The reaction mass was quenched with ice water and extracted with DCM. The solvent was removed under reduced pressure to get the title compound (170mg, 91.89%). LCMS: %, m/z = 270.1 (M - t-butyl +1).

91.89%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃; for 2h;	Preparation of ethyl (S)-2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)oxazole-4-carboxylate The mixture of <strong>[460081-18-9]ethyl 2-chlorooxazole-4-carboxylate</strong> (100 mg, 0.5698 mmol), tert-butyl (S)-pyrrolidin-3-ylcarbamate (127 mg, 0.6837 mmol), DIPEA (0.284 mL, 1.4245 mmol) and DMF (5 mL) were heated at 120 C. for 2 h. The reaction mass was quenched with ice water and extracted with DCM. The solvent was distilled out to get the title compound (170 mg, 91.89%). LCMS: m/z=270.1 (M-t-butyl+1)+.
91.89%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃; for 2h;	The mixture of <strong>[460081-18-9]ethyl 2-chlorooxazole-4-carboxylate</strong> (100 mg, 0.5698 mmol), tert-butyl (S)-pyrrolidin-3-ylcarbamate (127 mg, 0.6837 mmol), DIPEA (0.284 mL, 1.4245 mmol) and DMF (5 mL) were heated at 120 C. for 2 h. The reaction mass was quenched with ice water and extracted with DCM. The solvent was distilled out to get the title compound (170 mg, 91.89%). LCMS: m/z=270.1 (M-t-butyl+1)+.
91.89%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃; for 2h;	The mixture of <strong>[460081-18-9]ethyl 2-chlorooxazole-4-carboxylate</strong> (100mg, 0.5698mmo1), tert-butyl (S)-pynolidin-3-ylcarbamate (127mg, 0.6837mmo1), DIPEA (0.284mL, 1.4245mmo1) and DMF (5mL) was heated at 120C for 2h. The reaction mass was quenched with ice water and extractedwith DCM. The solvent was distilled out to get the title product (170mg, 9 1.89%). LCMS: mlz =270.1 (M - t-butyl +1).

Reference： [1]Patent: WO2015/104688,2015,A1 .Location in patent: Page/Page column 30
[2]Patent: WO2015/104662,2015,A1 .Location in patent: Page/Page column 28; 29
[3]Patent: WO2015/193846,A1 .Location in patent: Page/Page column 39
Patent: ,2015, .Location in patent: Page/Page column 39
[4]Patent: US2016/326151,2016,A1 .Location in patent: Paragraph 0159
[5]Patent: US2016/340366,2016,A1 .Location in patent: Paragraph 0173
[6]Patent: WO2017/9798,2017,A1 .Location in patent: Page/Page column 71

52
[ 100243-39-8 ]
[ 460081-18-9 ]
ethyl (S)-2-(3-hydroxypyrrolidin-1-yl)oxazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83.07%	With sodium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;	General procedure: Step l:Preparation of ethyl (S)-2-(3-hydroxypyrrolidin-l-yl)oxazole-4-carboxylate Using the same reaction conditions as described in step 1 of intermediate 14, ethyl 2- chlorooxazole-4-carboxylate (500mg, 2.8490 mmol) was reacted with (S)-pyrrolidin-3-ol (298mg, 3.4188 mmol) using, sodium carbonate (453mg, 4.2735 mmol) in DMF (lOmL) to get the title compound (535mg, 83.07%). LCMS: m/z = 227.1 (M+l)+.
83.07%	With sodium carbonate; In N,N-dimethyl-formamide;	Using the same reaction conditions as described in step 1 of intermediate 7, ethyl 2- chlorooxazole-4-carboxylate (500mg, 2.8490mmo1), was reacted with (S)-pynolidin-3-ol(298mg, 3.4188mmo1), sodium carbonate (453mg, 4.2735mmo1) in DMF (l0mL) to get the desired product (535mg, 83.07%). LCMS: mlz = 227.1 (M+1) .
83.07%	With sodium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;	Preparation of ethyl (S)-2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)oxazole-4-carboxylate The mixture of <strong>[460081-18-9]ethyl 2-chlorooxazole-4-carboxylate</strong> (100 mg, 0.5698 mmol), tert-butyl (S)-pyrrolidin-3-ylcarbamate (127 mg, 0.6837 mmol), DIPEA (0.284 mL, 1.4245 mmol) and DMF (5 mL) were heated at 120 C. for 2 h. The reaction mass was quenched with ice water and extracted with DCM. The solvent was distilled out to get the title compound (170 mg, 91.89%). LCMS: m/z=270.1 (M-t-butyl+1)+.; Using the same reaction conditions as described in step 1 of intermediate 7, <strong>[460081-18-9]ethyl 2-chlorooxazole-4-carboxylate</strong> (500 mg, 2.8490 mmol), was reacted with (S)-pyrrolidin-3-ol (298 mg, 3.4188 mmol), sodium carbonate (453 mg, 4.2735 mmol) in DMF (10 mL) to get the desired product (535 mg, 83.07%). LCMS: m/z=227.1 (M+1)+.

83.07%	With sodium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;	The mixture of <strong>[460081-18-9]ethyl 2-chlorooxazole-4-carboxylate</strong> (100 mg, 0.5698 mmol), tert-butyl (S)-pyrrolidin-3-ylcarbamate (127 mg, 0.6837 mmol), DIPEA (0.284 mL, 1.4245 mmol) and DMF (5 mL) were heated at 120 C. for 2 h. The reaction mass was quenched with ice water and extracted with DCM. The solvent was distilled out to get the title compound (170 mg, 91.89%). Using the same reaction conditions as described in step 1 of intermediate 14, <strong>[460081-18-9]ethyl 2-chlorooxazole-4-carboxylate</strong> (500 mg, 2.8490 mmol) was reacted with (S)-pyrrolidin-3-ol (298 mg, 3.4188 mmol) using, sodium carbonate (453 mg, 4.2735 mmol) in DMF (10 mL) to get the title compound (535 mg, 83.07%). LCMS: m/z=227.1 (M+1)+.
83.07%	With sodium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;	The mixture of <strong>[460081-18-9]ethyl 2-chlorooxazole-4-carboxylate</strong> (100mg, 0.5698mmo1), tert-butyl (S)-pynolidin-3-ylcarbamate (127mg, 0.6837mmo1), DIPEA (0.284mL, 1.4245mmo1) and DMF (5mL) was heated at 120C for 2h. The reaction mass was quenched with ice water and extractedwith DCM. The solvent was distilled out to get the title product (170mg, 9 1.89%); Using the same reaction conditions as described in step 1 of Example 17, ethyl 2- chlorooxazole-4-carboxylate (500mg, 2.849mmol) was reacted with (S)-pyrrolidin-3-ol (298mg, 3.4188mmo1) and sodium carbonate (453mg, 4.2735mmo1) in DMF (lOmL) to get the titlecompound (535mg, 83.07%). LCMS: mlz = 227.1 (M+1).

Reference： [1]Patent: WO2015/104688,2015,A1 .Location in patent: Page/Page column 30-31
[2]Patent: WO2015/104662,2015,A1 .Location in patent: Page/Page column 28; 30
[3]Patent: US2016/326151,2016,A1 .Location in patent: Paragraph 0159; 0165
[4]Patent: US2016/340366,2016,A1 .Location in patent: Paragraph 0173; 0176
[5]Patent: WO2017/9798,2017,A1 .Location in patent: Page/Page column 72; 71

53
[ 444120-95-0 ]
[ 460081-18-9 ]
ethyl 2-(6-fluoropyridin-3-yl)oxazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59.8%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 95℃;Inert atmosphere;	General procedure: Step 1: Preparation of ethyl 2-(6-fluoropyridin-3-yl)oxazole-4-carboxylate Using the same reaction conditions as described in step 7 of example 1, 2-fluoro-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (200mg, 1.41 mmol) was coupled with ethyl 2-chlorooxazole-4-carboxylate (298mg, 1.70 mmol) using sodium carbonate (451 mg, 4.25 mmol) and Pd(PPh3)4 (289mg, 0.332 mmol) in 1 ,2-dimethoxyethane/water (15/3mL) to get the crude product. The resultant crude was purified by 60-120 silica gel column chromatography using 20% ethyl acetate in hexane as eluent to obtain the title compound (200mg, 59.8%).
59.8%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; tricyclohexylphosphine; In 1,2-dimethoxyethane; water; at 90℃; for 12.0h;Inert atmosphere; Sealed tube;	A solution of 6-bromo-2-cyclopentyl-5-nitro-2H-indazole (0.300 g, 0.967 mmol) (product of step 3 in example 5) in toluene:H20 (12 mL, 3:1), cyclopropyl boronic acid (0.124 g, 1.45 mmol), Pd2(dba)3 (10 mg, 0.009 mmol), potassium carbonate (0.300 g, 2.901 mmol) andtricyclohexyl phosphine (16 mg, 0.058 mmol) were taken in a sealed tube under nitrogen atmosphere. The contents were heated at 90 C for 12 h, cooled to room temperature and filtered through Celite. The filtrate was diluted with ethyl acetate and the organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude compound. The residue was purified by column chromatography (n-hexane:EtOAc;7:3) to give the title compound (0.160 g, 61 %) as a light brown solid.?H NMR (400 MHz, DMSO-d6):oe8.69 (s, 1H), 8.43 (s, 1H), 7.50 (s, 1H), 5.12-5.05 (m, 1H), 2.33-2.20 (m, 3H), 2.19-2.01 (m, 2H), 1.93-1.83 (m, 2H), 1.75-1.65 (m, 2H), 0.94-0.79 (m, 2H),0.73-0.69 (m, 2H). LCMS: mlz: 272 (M+1).Using the same reaction conditions as described in step 1 of example 6, 2-fluoro-5- (4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyridine (200mg, 1.41 mmol) was coupled with ethyl 2-chlorooxazole-4-carboxylate (29 8mg, 1 .7Ommol) using sodium carbonate (451mg, 4.2Smmol) and Pd(PPh3)4 (289mg, 0.332mmo1) in 1,2-dimethoxyethane/water (15/3mL) to get the crude product. The obtained crude was purified by 60-120 silica gel column chromatographyusing 20% ethyl acetate in hexane as eluent to obtain the title compound (200mg, 59.8%).
59.8%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 12.0h;Inert atmosphere; Sealed tube;	A solution of 6-bromo-2-cyclopentyl-5-nitro-2H-indazole (0.300 g, 0.967 mmol) (product of step 3 in example 5) in toluene:H2O (12 mL, 3:1), cyclopropyl boronic acid (0.124 g, 1.45 mmol), Pd2(dba)3 (10 mg, 0.009 mmol), potassium carbonate (0.300 g, 2.901 mmol) and tricyclohexyl phosphine (16 mg, 0.058 mmol) were taken in a sealed tube under nitrogen atmosphere. The contents were heated at 90 C. for 12 h, cooled to room temperature and filtered through Celite. The filtrate was diluted with ethyl acetate and the organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude compound. The residue was purified by column chromatography (n-hexane:EtOAc; 7:3) to give the title compound (0.160 g, 61%) as a light brown solid. ; Preparation of ethyl 2-(6-fluoropyridin-3-yl)oxazole-4-carboxylate Using the same reaction conditions as described in step 1 of example 6, <strong>[444120-95-0]2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (200 mg, 1.41 mmol) was coupled with ethyl 2-chlorooxazole-4-carboxylate (298 mg, 1.70 mmol) using sodium carbonate (451 mg, 4.25 mmol) and Pd(PPh3)4 (289 mg, 0.332 mmol) in 1,2-dimethoxyethane/water (15/3 mL) to get the crude product. The obtained crude was purified by 60-120 silica gel column chromatography using 20% ethyl acetate in hexane as eluent to obtain the title compound (200 mg, 59.8%).

59.8%

With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 95℃;Sealed tube; Inert atmosphere;

To a sealed tube 6-bromo-N-(2-morpholinooxazolo [4,5-b]pyridin-6-yl)picolinamide (350 mg, 0.866 mmol), tert-butyl (5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl) pyridin-2-yl)carbamate (360 mg, 1.126 mmol) (intermediate 1), sodium carbonate (275 mg, 2.598 mmol) in 1,2-dime- thoxyethane (10 mL) and water (2 mL) were added. The reaction mixture was purged with argon for 10 mm, added Pd(PPh3)2C12 (31 mg, 0.043 mmol) and heated at 95 C. overnight. The solvent was distilled out. The resultant crude was purified by 60-120 silica gel column chromatography using 5% methanol in DCM as eluent to obtain the title compound (300 mg, 67.11%). Using the same reaction conditions as described in step 7 of example 1, 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (200 mg, 1.41 mmol) was coupled with ethyl 2-chlorooxazole-4-carboxylate (298 mg, 1.70 mmol) using sodium carbonate (451 mg, 4.25 mmol) and Pd(PPh3)4 (289 mg, 0.332 mmol) in 1,2-dimethoxy- ethane/water (15/3 mE) to get the crude product. The resultant crude was purified by 60-120 silica gel colunm chromatography using 20% ethyl acetate in hexane as eluent to obtain the title compound (200 mg, 59.8%).

Reference： [1]Patent: WO2015/104688,2015,A1 .Location in patent: Page/Page column 27
[2]Patent: WO2015/104662,2015,A1 .Location in patent: Page/Page column 26; 46
[3]Patent: US2016/326151,2016,A1 .Location in patent: Paragraph 0143; 0251; 0252
[4]Patent: US2016/340366,2016,A1 .Location in patent: Paragraph 0154; 0216

54
[ 1012084-56-8 ]
[ 460081-18-9 ]
ethyl 2-(2-methylpyridin-3-yl)oxazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59.8%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 95℃;Inert atmosphere;	General procedure: Step 1: Preparation of ethyl 2-(2-methylpyridin-3-yl)oxazole-4-carboxylate Using the same reaction conditions as described in step 7 of example 1, 2-methyl-3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (lg, 7.09 mmol) was coupled with ethyl 2- chlorooxazole-4-carboxylate (1.86g, 0.851 mmol) using sodium carbonate (2.25g, 21.2 mmol) and Pd(dppf)Cl2 (289mg, 0.332 mmol) in 1 ,2-dimethoxyethane/water (30/6mL) to get the crude product. The resultant crude was purified by 60-120 silica gel column chromatography using 20% ethyl acetate in hexane as eluent to obtain the title compound (lg, 59.8%).
59.8%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; tricyclohexylphosphine; In 1,2-dimethoxyethane; water; at 90℃; for 12h;Sealed tube; Inert atmosphere;	A solution of 6-bromo-2-cyclopentyl-5-nitro-2H-indazole (0.300 g, 0.967 mmol) (product of step 3 in example 5) in toluene:H20 (12 mL, 3:1), cyclopropyl boronic acid (0.124 g, 1.45 mmol), Pd2(dba)3 (10 mg, 0.009 mmol), potassium carbonate (0.300 g, 2.901 mmol) andtricyclohexyl phosphine (16 mg, 0.058 mmol) were taken in a sealed tube under nitrogen atmosphere. The contents were heated at 90 C for 12 h, cooled to room temperature and filtered through Celite. The filtrate was diluted with ethyl acetate and the organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude compound. The residue was purified by column chromatography (n-hexane:EtOAc;7:3) to give the title compound (0.160 g, 61 %) as a light brown solid.?H NMR (400 MHz, DMSO-d6):oe8.69 (s, 1H), 8.43 (s, 1H), 7.50 (s, 1H), 5.12-5.05 (m, 1H), 2.33-2.20 (m, 3H), 2.19-2.01 (m, 2H), 1.93-1.83 (m, 2H), 1.75-1.65 (m, 2H), 0.94-0.79 (m, 2H),0.73-0.69 (m, 2H). LCMS: mlz: 272 (M+1).Using the same reaction conditions as described in step 1 of example 6, 2-methyl-3- (4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyridine (1 g, 7.O9mmol) was coupled with ethyl 2- chlorooxazole-4-carboxylate (1.86g, 0.85 immol) using sodium carbonate (2.25g, 21.2mmol) and Pd(dppf)C12 (289mg, 0.332mmo1) in 1,2-dimethoxyethane/water (30I6mL) to get the crudeproduct. The obtained crude was purified by 60-120 silica gel column chromatography using20% ethyl acetate in hexane as eluent to obtain the title compound (ig, 59.8%).
59.8%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 12h;Inert atmosphere; Sealed tube;	A solution of 6-bromo-2-cyclopentyl-5-nitro-2H-indazole (0.300 g, 0.967 mmol) (product of step 3 in example 5) in toluene:H2O (12 mL, 3:1), cyclopropyl boronic acid (0.124 g, 1.45 mmol), Pd2(dba)3 (10 mg, 0.009 mmol), potassium carbonate (0.300 g, 2.901 mmol) and tricyclohexyl phosphine (16 mg, 0.058 mmol) were taken in a sealed tube under nitrogen atmosphere. The contents were heated at 90 C. for 12 h, cooled to room temperature and filtered through Celite. The filtrate was diluted with ethyl acetate and the organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude compound. The residue was purified by column chromatography (n-hexane:EtOAc; 7:3) to give the title compound (0.160 g, 61%) as a light brown solid. ; Preparation of ethyl 2-(6-fluoropyridin-3-yl)oxazole-4-carboxylate Preparation of ethyl 2-(2-methylpyridin-3-yl)oxazole-4-carboxylate Using the same reaction conditions as described in step 1 of example 6, <strong>[1012084-56-8]2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (1 g, 7.09 mmol) was coupled with ethyl 2-chlorooxazole-4-carboxylate (1.86 g, 0.851 mmol) using sodium carbonate (2.25 g, 21.2 mmol) and Pd(dppf)Cl2 (289 mg, 0.332 mmol) in 1,2-dimethoxyethane/water (30/6 mL) to get the crude product. The obtained crude was purified by 60-120 silica gel column chromatography using 20% ethyl acetate in hexane as eluent to obtain the title compound (1 g, 59.8%).

59.8%

With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 95℃;Sealed tube; Inert atmosphere;

Using the same reaction conditions as described in step 7 of example 1, 2-methyl-3-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)pyridine (1 g, 7.09 mmol) was coupled with ethyl 2-chlorooxazole-4-carboxylate (1.86 g, 0.851 mmol) using sodium carbonate (2.25 g, 21.2 mmol) and Pd(dppf)C12 (289 mg, 0.332 mmol) in 1,2-dimethoxyethane/ water (3 0/6 mE) to get the crude product. The resultant crude was purified by 60-120 silica gel column chromatography using 20% ethyl acetate in hexane as eluent to obtain the title compound (1 g, 59.8%). To a sealed tube 6-bromo-N-(2-morpholinooxazolo [4,5-b]pyridin-6-yl)picolinamide (350 mg, 0.866 mmol), tert-butyl (5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl) pyridin-2-yl)carbamate (360 mg, 1.126 mmol) (intermediate 1), sodium carbonate (275 mg, 2.598 mmol) in 1,2-dime- thoxyethane (10 mL) and water (2 mL) were added. The reaction mixture was purged with argon for 10 mm, added Pd(PPh3)2C12 (31 mg, 0.043 mmol) and heated at 95 C. overnight. The solvent was distilled out. The resultant crude was purified by 60-120 silica gel column chromatography using 5% methanol in DCM as eluent to obtain the title compound (300 mg, 67.11%).

Reference： [1]Patent: WO2015/104688,2015,A1 .Location in patent: Page/Page column 28
[2]Patent: WO2015/104662,2015,A1 .Location in patent: Page/Page column 26; 27; 46
[3]Patent: US2016/326151,2016,A1 .Location in patent: Paragraph 0147; 0251; 0252
[4]Patent: US2016/340366,2016,A1 .Location in patent: Paragraph 0158; 0216

55
[ 460081-18-9 ]
ethyl (S)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)oxazole-4-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/104662,2015,A1
[2]Patent: US2016/326151,2016,A1

56
[ 174669-73-9 ]
[ 460081-18-9 ]
ethyl 2-(2-fluoropyridin-3-yl)oxazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60.6%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; water;	Using the same reaction conditions as described in step 1 of example 6, (2-fluoropyridin- 3-yl)boronic acid (400mg, 2.83mmol) was coupled with <strong>[460081-18-9]ethyl 2-chlorooxazole-4-carboxylate</strong>(596mg, 3.4Ommol) using sodium carbonate (902mg, 8.Slmmol) and Pd(dppf)C12 (115mg,0.l4lmmol) in 1,2-dimethoxyethane/water (25/4mL) to get the crude product. The obtained crude was purified by 60-120 silica gel column chromatography using 30% ethyl acetate in hexane as eluent to obtain the title compound (400mg, 60.6%).?HNMR (400MHz, DMSO-d6): oe 9.11 (s, 1H), 8.64-8.59 (m, 1H), 8.48-8.47 (d, 1H),7.62-7.59 (m, 1H), 4.3 8-4.33 (q, 2H), 1.35-1.32 (t, 3H).
60.6%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 12h;Inert atmosphere; Sealed tube;	A solution of 6-bromo-2-cyclopentyl-5-nitro-2H-indazole (0.300 g, 0.967 mmol) (product of step 3 in example 5) in toluene:H2O (12 mL, 3:1), cyclopropyl boronic acid (0.124 g, 1.45 mmol), Pd2(dba)3 (10 mg, 0.009 mmol), potassium carbonate (0.300 g, 2.901 mmol) and tricyclohexyl phosphine (16 mg, 0.058 mmol) were taken in a sealed tube under nitrogen atmosphere. The contents were heated at 90 C. for 12 h, cooled to room temperature and filtered through Celite. The filtrate was diluted with ethyl acetate and the organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude compound. The residue was purified by column chromatography (n-hexane:EtOAc; 7:3) to give the title compound (0.160 g, 61%) as a light brown solid. ; Preparation of ethyl 2-(6-fluoropyridin-3-yl)oxazole-4-carboxylate Preparation of ethyl 2-(2-methylpyridin-3-yl)oxazole-4-carboxylate ; Preparation of ethyl 2-(2-fluoropyridin-3-yl)oxazole-4-carboxylate Using the same reaction conditions as described in step 1 of example 6, (2-fluoropyridin-3-yl)boronic acid (400 mg, 2.83 mmol) was coupled with <strong>[460081-18-9]ethyl 2-chlorooxazole-4-carboxylate</strong> (596 mg, 3.40 mmol) using sodium carbonate (902 mg, 8.51 mmol) and Pd(dppf)Cl2 (115 mg, 0.141 mmol) in 1,2-dimethoxyethane/water (25/4 mL) to get the crude product. The obtained crude was purified by 60-120 silica gel column chromatography using 30% ethyl acetate in hexane as eluent to obtain the title compound (400 mg, 60.6%). 1HNMR (400 MHz, DMSO-d6): delta 9.11 (s, 1H), 8.64-8.59 (m, 1H), 8.48-8.47 (d, 1H), 7.62-7.59 (m, 1H), 4.38-4.33 (q, 2H), 1.35-1.32 (t, 3H).

Reference： [1]Patent: WO2015/104662,2015,A1 .Location in patent: Page/Page column 27
[2]Patent: US2016/326151,2016,A1 .Location in patent: Paragraph 0151; 0251; 0252

57
6-{1-[(1,1-dimethylethyl)(dimethyl)silyl]-1H-indol-4-yl}-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole [ No CAS ]
[ 460081-18-9 ]
ethyl 2-[6-{1-[(1,1-dimethylethyl)(dimethyl)silyl]-1H-indol-4-yl}-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazole-4-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 7381 - 7399

58
[ 1236146-96-5 ]
[ 460081-18-9 ]
[ 1236146-98-7 ]

Reference： [1]Journal of the American Chemical Society,2015,vol. 137,p. 15426 - 15429

59
[ 1220220-21-2 ]
[ 460081-18-9 ]
ethyl 2-(2-acetamidopyridin-4-yl)oxazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 4h;Inert atmosphere;	Step 1: Preparation of ethyl 2-(2-acetamidopyridin-4-yl)oxazole-4-carboxylate To a solution of N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (2.78g, 10.04mmol) in 1,2-dimethoxyethane (30ml) under nitrogen was added ethyl 2-chlorooxazole-4-carboxylate (1g, 7.09mmol), sodium carbonate (106mg, 21.2mmol) in water (5ml) and Pd(DPPF)Cl2 (259mg, 0.354mmol) and heated to 90C for 4h to get the crude compound which was purifiedby 60-120 silica gel column chromatography using 50% ethyl acetate in hexane as eluent to obtain the title compound (680mg, 36%). LCMS: 276.3 (M+1)+.

Reference： [1]Patent: WO2015/193846,A1 .Location in patent: Page/Page column 41
Patent: ,2015, .Location in patent: Page/Page column 41

60
[ 57260-71-6 ]
[ 460081-18-9 ]
ethyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)oxazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 5h;	Step 1: Preparation of ethyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)oxazole-4-carboxylate To a solution of tert-butyl piperazine-1-carboxylate (637mg, 3.42mmol) and ethyl 2- chlorooxazole-4-carboxylate (500mg, 2.85mmol) in DMF (10ml), K2CO3 (771mg 5.714mmol) was added and stirred at RT for 5h. The reaction mixture was quenched by water, the compound was extracted with ethyl acetate and concentrated to obtain the title compound (380mg, 41%). LCMS: 98.04%, m/z = 277.2 (M-tert-butyl).

Reference： [1]Patent: WO2015/193846,A1 .Location in patent: Page/Page column 44
Patent: ,2015, .Location in patent: Page/Page column 44

61
[ 109-01-3 ]
[ 460081-18-9 ]
ethyl 2-(4-methylpiperazin-1-yl)oxazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 5h;	Step 1: Preparation of ethyl 2-(4-methylpiperazin-1-yl)oxazole-4-carboxylate To a solution of 1-methylpiperazine (1g, 5.71mmol) and ethyl 2-chlorooxazole-4- carboxylate (0.7g, 6.85mmol) in DMF (15ml) K2CO3 (1.5g, 11.42mmol) was added and stirred at RT for 5h. The reaction mixture was quenched by water, the compound was extracted with ethyl acetate and concentrated to obtain the title compound (450mg, 33%). LCMS: 93.9%, m/z = 240.3(M+1)

Reference： [1]Patent: WO2015/193846,A1 .Location in patent: Page/Page column 45
Patent: ,2015, .Location in patent: Page/Page column 45

62
[ 460081-18-9 ]
[ 411235-57-9 ]
C₉H₁₁NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With palladium diacetate; caesium carbonate; In water; toluene; at 100℃;Inert atmosphere;	To a solution of compound 7B (3.5 g, 19.89 mmol) in toluene/H20 (10: 1, 165 mL) was added cyclopropylboronic acid (5.13 g, 59.66 mmol), Pd(OAc)2 (0.45 g, 1.99 mmol), n- BuPACl2 (1.42 g, 3.98 mmol) and Cs2C03 (19.45 g, 59.66 mmol). The reaction was heated to 100C and allowed to stir under N2 at this temperature overnight. The reaction mixture was filtered, the filtrate was washed with water (50 mL) and extracted with ethyl acetate (200 mL). The organics were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo, and the residue obtained was purified using flash column chromatography on silica gel (petroleum ether / ethyl acetate = 100: 1?50: 1?20: 1) to provide compound 7C. MS (ESI) m/z (M+H)+: 182.1.

Reference： [1]Patent: WO2018/35005,2018,A1 .Location in patent: Page/Page column 40

63
methyl 4-((4S,5R)-2,2-dimethyl-5-((E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-1,3-dioxolan-4-yl)butanoate [ No CAS ]
[ 693-25-4 ]
[ 460081-18-9 ]
methyl 4-((4S,5R)-5-((E)-2-(4-hexanoyloxazol-2-yl)vinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.12 g		In a 100 mL round bottom flask, Chlorooxazole Ox_3 (0.5 g, 2.848 mmol) was dissolved in dry toluene(25 mL). The reaction was cooled to - 78 CC and DIBAL-H (2.35 mL of 25wt % in toluene) was slowlyadded. A magnesium n-pentane bromide solution (24 mL, 0.36M) was slowly added to the reaction at - 78 C. The reaction was stirred for 2 h prior quenching by adding water (5mL). The layers were separatedand the aqueous layer was extracted with EtOAc (2 x 50 mL). The organic layers were combined, dried over MgSO4 and concentrated in vacuo. The crude mixture was dissolved in toluene (20 mL) in a 50 mL flame dried round bottom flask with boronic ester (0.56 g, 1.57 mmol) and Pd(PPh3)4 (0.083 g, 0.0718 mmol). 2 M K2C03 (1.4 mL) was added to the reaction flask and the reaction mixture was heated to reflux for 16 h. The solution was left to cool to r.t, then water (15 mL) and EtOAc (10 mL) were added. Thelayers were separated, the aqueous layer was extracted with EtOAc (2 x 30 mL) and dried over MgSO4.Concentration in vacuo and filtration with a silica plug (3:2 cyclohexane : EtOAc) to give a crude mixture.The off yellow crude mixture (0.156 g) was dissolved in CH2CI2 (30 mL), Dess-Martin reagent (0.198 g,0.468 mmol) was added and the reaction was stirred at room temperature for 2 h. A saturated solution ofNa2S2O3(l5mL) was added. The solution was vigorously stirred for 0.5 h. The layers were separated andthe aqueous layer was extracted with CH2CI2 (2 x 20 mL). The organic layers were combined, dried over MgSO4 and concentrated in vacuo. The product was purified by column chromatography using silica gel(3:2 Cyclohexane: EtOAc) yielding the product Ox_12 as a white wax (0.120 g, 10.1 % over 4 steps) Rf:0.67 (3:2 Pentane : EtOAc); HRMS calculated for C21H33N06 : 394.2230 found : 394.2235. IR (vmax) =862.14, 882.62, 949.30, 982.05. 1052.95, 1082.05, 1116.23, 1216.51, 1372.13, 1437.72, 1457.88,1559.77, 1691.06, 1734.91, 2009.08, 2259.46, 2871.37, 2932.89, 2954.37, 2984.79, 3141.62, 3248.56,3367.79 cm1 1H NMR (400 MHz, CDCI3) oe 8.11 (s, 1H), 6.69 (dd, J = 15.9, 6.3 Hz, 1H), 6.56 (dd, J =16.0, 0.9 Hz, 1H), 4.70 (td, J = 6.3, 0.9 Hz, 1H), 4.25 (ddd, J = 8.9, 6.3, 4.7 Hz, 1H), 3.64 (s, 3H), 2.91 -2.83 (m, 2H), 2.41 - 2.30 (m, 2H), 1.83 (m, 2H), 1.70 (m, 4H), 1.51 (s, 3H), 1.50 - 1.43 (m, 2H), 1.38 (s,3H), 1.36- 1.29 (m, 4H), 0.89 (dd, J = 9.6, 4.5 Hz, 3H). 13C NMR (101 MHz, CDCI3) oe 195.36, 173.63,160.46, 141.55, 141.49, 136.53, 117.71, 108.93, 78.05, 77.77, 51.51, 39.83, 33.59, 31.35, 29.94, 28.04,25.49, 23.43, 22.42, 21.78, i3.89 [a]D=O.34 (c= 1 inCHCI3).

Reference： [1]Patent: WO2018/33642,2018,A1 .Location in patent: Page/Page column 72; 73

64
C₆H₁₁IO [ No CAS ]
[ 460081-18-9 ]
C₁₂H₁₇NO₄ [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2018,vol. 83,p. 6110 - 6126

65
[ 74067-97-3 ]
[ 460081-18-9 ]
ethyl 2-((4-cyclohexylbenzyl)amino)oxazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 55℃; for 22h;Inert atmosphere;	To a solution of (4-cyclohexylphenyl)methanamine (827 mg, 4.4 mmol) in THF (18 mL) under nitrogen was added <strong>[460081-18-9]ethyl 2-chlorooxazole-4-carboxylate</strong> (1.08 g, 6.16 mmol) followed by DIPEA (0.92 mL, 5.28 mmol) and the resultant mixture was heated with stirring at 55 C for 22 h. After cooling to room temperature, water was added and the mixture was extracted with EtOAc (2X). The combined extract was washed with brine and concentrated under reduced pressure. The resultant crude product was triturated with ether to provide ethyl 2-((4-cyclohexylbenzyl)amino)oxazole-4-carboxylate (998 mg, 69 % yield). NMR (300 MHz, Chloroform-i ) delta 7.76 (s, 1H), 7.27 (d, J = 8.2 Hz, 2H), 7.21 (d, J= 8.2 Hz, 2H), 5.13 - 4.94 (m, 1H), 4.55 (d, J= 5.8 Hz, 2H), 4.37 (q, J= 7.1 Hz, 2H), 2.60 - 2.38 (m, 1H), 1.97 - 1.70 (m, 6H), 1.51 - 1.10 (m and overlapping t, J = 7.1 Hz, 7H).

Reference： [1]Patent: WO2018/136935,2018,A1 .Location in patent: Paragraph 00602

66
[ 6165-69-1 ]
[ 460081-18-9 ]
ethyl 2-(thiophen-3-yl)oxazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; at 90℃; for 12h;Inert atmosphere;	To a degassed solution of the oxazole (0.175g, 1 mmol), boronic acid (0.134g, 1.05 mmol) and potassium carbonate (0.278g, 2 mmol) in dimethoxy ethane (4 mL) was added Pd(PPH3)4 (0.058g, 0.005 mmol). The resulting mixture was heated to 90 C for 12h. The reaction was then cooled to rt and the reaction mixture was diluted with ethyl acetate and filtered through a pad of celite. The celite was washed with additional ethyl acetate. The resulting organics were combined, dried over sodium sulfate and concentrated under vacuum. The crude product was then purified by flash chromatography (1 : 1 to 1 :2 Hex:EtOAc). Product was isolated a pink solid in 32% yield (0.075 mg). LC-MS m/z calcd for (CioH9N03S)H+ 224.2, found 224.2.

Reference： [1]Patent: WO2019/36562,2019,A1 .Location in patent: Page/Page column 69

67
[ 460081-18-9 ]
C₁₀H₁₁NO₄ [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2019,vol. 2019,p. 2884 - 2898

68
[ 460081-18-9 ]
C₁₁H₁₂N₂O₃S [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2019,vol. 2019,p. 2884 - 2898

69
[ 460081-18-9 ]
C₁₅H₁₅N₃O₃ [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2019,vol. 2019,p. 2884 - 2898

70
[ 460081-18-9 ]
C₁₂H₁₂N₂O₄ [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2019,vol. 2019,p. 2884 - 2898

71
[ 460081-18-9 ]
C₁₁H₁₃N₃O₃ [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2019,vol. 2019,p. 2884 - 2898

72
[ 460081-18-9 ]
[ 460081-20-3 ]

Reference： [1]European Journal of Organic Chemistry,2019,vol. 2019,p. 2884 - 2898

73
1'-benzyloxycarbonyl-1-tert-butyloxycarbonyl-6-(4,4,5,5-tet ramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4'-piperidine] [ No CAS ]
[ 460081-18-9 ]
1'-benzyloxycarbonyl-1-tert-butyloxycarbonyl-6-(4-ethoxycarbonyloxazol-2-yl)spiro[indoline-3,4'-piperidine] [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
110 mg	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 1h;	<Step 2> The 1'-benzyloxycarbonyl-1-tert-butyloxycarbonyl-6-(4,4,5,5-tet ramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4'-piperi dine] (109 mg) was dissolved in dioxane (2 mL) and water (0.5 mL), then 2-chlorooxazol-4-ethyl carboxylate (52 mg), sodium carbonate (41 mg), and tetrakis(triphenylphosphine)palladium (11 mg) were added thereto, and the mixture was stirred at 90 ºC for 1 hour. Brine was added to the reaction solution, followed by two times of extraction with ethyl acetate. The organic layer was washed with brine, was dried with anhydrous magnesium sulfate, and was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/chloroform = 5/95) to obtain 1'-benzyloxycarbonyl-1-tert-butyloxycarbonyl-6-(4-ethoxycar bonyloxazol-2-yl)spiro[indoline-3,4'-piperidine] (110 mg). 1H-NMR (400MHz, CDCl3) delta: 1.40 (t, J=7.2Hz, 3H), 1.50-1.95 (m, 13H), 2.90-3.05 (m, 2H), 3.85-4. 00 (m, 2H), 4.10-4.35 (m, 2H), 4.42 (q, J=7.2Hz, 2H), 5.17 (s, 2H), 7.16 (d, J=8.0Hz, 1H), 7.30-7.45 (m, 5H), 7.80-7.90 (m, 1H), 8.24 (s, 1H), 8 .25-8.60 (m, 1H).

Reference： [1]Patent: EP3480198,2019,A1 .Location in patent: Paragraph 0295; 0297

74
[ 460081-18-9 ]
[ 761446-44-0 ]
ethyl 2-(1-methylpyrazol-4-yl)oxazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 4h;Inert atmosphere;	To a solution of <strong>[460081-18-9]ethyl 2-chlorooxazole-4-carboxylate</strong> (1.87 g, 10.7 mmol, CAS4600081-18-9) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (2.22 g, 10.7 mmol, CAS761446-44-0) in a mixed solvent of H2O (6 mL) and dioxane (30 mL) was added K2CO3 (2.94 g, 21.3 mmol) and Pd(dppf)Cl2.CH2Cl2 (870 mg, 1.07 mmol). The reaction mixture was stirred at 80 C. for 4 hours under nitrogen. On completion, the reaction mixture was diluted with EA (100 mL) and filtered. The organic layers were dried with anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica column chromatography (SiO2) to give the title compound (1.50 g, 64% yield) as a white solid. LC-MS (ESI+) m/z 222.1 (M+H)+.

Reference： [1]Patent: US2019/192668,2019,A1 .Location in patent: Paragraph 2991; 2992

75
[ 460081-18-9 ]
ethyl 2-(6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)oxazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; triethylamine;	Step 1: ethyl 2-(6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)oxazole-4-carboxylate (35b) To a solution of <strong>[460081-18-9]ethyl 2-chlorooxazole-4-carboxylate</strong> (5.0 g, 28.00 mmol) in DMF (50 ml) was added 9a (12.0 g, 43.0 mmol), K2CO3 (12.0 g, 85.0 mmol), triethylamine (5.8 g, 57.0 mmol). The mixture was stirred for 2 h at 120 C. After cooling to room temperature, then the reaction mixture was partitioned between ethyl acetate (100 ml) and water (150 ml). The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure, the residue was directly used for the next step without purification. 1H NMR (400 MHz, CDCl3) delta 7.77 (s, 1H), 4.35 (q, 2H), 4.27 (d, 4H), 4.08 (d, 4H), 1.44 (s, 9H), 1.35 (m, 3H). LC-MS (ESI): m/z=338.2 [M+H]+

Reference： [1]Patent: US2019/367515,2019,A1

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[ CAS No. 460081-18-9 ] {[proInfo.proName]}

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[ 460081-18-9 ] Synthesis Path-Upstream 1~4

[ 460081-18-9 ] Synthesis Path-Downstream 1~75

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Chlorides

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Oxazoles

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