[ CAS No. 288-14-2 ] {[proInfo.proName]}

Name: 288-14-2|Isoxazole|98%
Brand: Ambeed
SKU: A448611
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Quality Control of [ 288-14-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 288-14-2 ]

CAS No. :	288-14-2	MDL No. :	MFCD00003149
Formula :	C₃H₃NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CTAPFRYPJLPFDF-UHFFFAOYSA-N
M.W :	69.06	Pubchem ID :	9254
Synonyms :

Calculated chemistry of [ 288-14-2 ]

Physicochemical Properties

Num. heavy atoms :	5
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	16.5
TPSA :	26.03 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.66 cm/s

Lipophilicity

Log Po/w (iLOGP) :	-1.73
Log Po/w (XLOGP3) :	0.08
Log Po/w (WLOGP) :	0.67
Log Po/w (MLOGP) :	-0.52
Log Po/w (SILICOS-IT) :	1.23
Consensus Log Po/w :	-0.05

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.06
Solubility :	6.03 mg/ml ; 0.0874 mol/l
Class :	Very soluble
Log S (Ali) :	-0.18
Solubility :	45.5 mg/ml ; 0.659 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.09
Solubility :	5.6 mg/ml ; 0.0811 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.18

Safety of [ 288-14-2 ]

Signal Word:	Danger	Class:	3
Precautionary Statements:	P501-P210-P233-P370+P378-P303+P361+P353-P403+P235	UN#:	1993
Hazard Statements:	H225	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 288-14-2 ]

* 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 [ 288-14-2 ]
Downstream synthetic route of [ 288-14-2 ]

[ 288-14-2 ] Synthesis Path-Upstream 1~7

1
[ 288-14-2 ]
[ 1750-42-1 ]

Reference： [1] Patent: US2003/130246, 2003, A1,

2
[ 288-14-2 ]
[ 97925-43-4 ]

Reference： [1] Zhurnal Obshchei Khimii, 1959, vol. 29, p. 535,538; engl. Ausg. S. 533

3
[ 288-14-2 ]
[ 124-38-9 ]
[ 21169-71-1 ]

Reference： [1] Journal of the American Chemical Society, 2010, vol. 132, # 26, p. 8858 - 8859

4
[ 288-14-2 ]
[ 1121-13-7 ]

Yield	Reaction Conditions	Operation in experiment
44%	at 25 - 30℃;	To the solution of 4a (Ig, 14.5mmol) in trifluoroacetic anhydride (7mL, 50.7mmol) was added ammonium nitrate (1.8g, 22.5mmol) in 0.3g each portion, keeping the reaction temperature between 25-3O⁰C. After the addition was complete, the mixture was poured into ice water and extracted with DCM (15mLx4). The extract was washed with water and the aqueous layer was extracted with DCM. The combined DCM extract was dried over MgSO₄, filtered and concentrated to give a yellow green oil. The oil was triturated by hexane (cooled to 5⁰C) to provide a solid which was filtered to provide 4b (0.72g, 44percent).

Reference： [1] Journal of Organic Chemistry, 1987, vol. 52, # 13, p. 2714 - 2726
[2] Helvetica Chimica Acta, 1989, vol. 72, p. 556 - 569
[3] Patent: WO2009/154769, 2009, A1, . Location in patent: Page/Page column 37-38
[4] Zhurnal Obshchei Khimii, 1959, vol. 29, p. 535,538; engl. Ausg. S. 533
[5] Patent: WO2011/38572, 2011, A1, . Location in patent: Page/Page column 76

5
[ 288-14-2 ]
[ 124-38-9 ]
[ 74-88-4 ]
[ 15055-81-9 ]

Reference： [1] Journal of the American Chemical Society, 2010, vol. 132, # 26, p. 8858 - 8859

6
[ 288-14-2 ]
[ 13433-00-6 ]
[ 252932-48-2 ]

Yield	Reaction Conditions	Operation in experiment
20%	Stage #1: With sodium ethanolate In ethanol at 0 - 5℃; for 0.5 h; Stage #2: With sodium acetate; acetic acid In ethanol at 20℃; for 18 h; Stage #3: With sodium ethanolate In ethanol at 0 - 20℃; for 18 h;	To asolution of isoxazole (30 g, 0.43 mol) in anhydrous ethanol(120 mL) was added drop-wise sodium ethoxide (21 percent, inethanol) (0.45 mol) at 0-5 °C. After stirring for 30 min, aceticacid (0.43 mol), diethyl amino malonate hydrochloride (0.30mol), anhydrous sodium acetate (0.33 mol) were added. Afterstirring at room temperature for 18 h, the reaction mixturewas concentrated under reduced pressure. The residue wasdiluted with chloroform (1.5 L) and water (500 mL), the organiclayer was dried over Na2SO4, filtered and concentrated underreduced pressure. The residue was dissolved in anhydrousethanol (450 mL), sodium ethoxide (21 percent, in ethanol) (0.45mol) was added drop-wise at 0-5 °C. The reaction mixturewas warmed to room temperature slowly, stirred for 18 h, wasquenched with acetic acid (0.45 mol) and basified with aq. Na2CO3 pH range for 8. The mixture was extracted with chloroform(1 L) and washed water (500 mL), dried over anhydrousmagnesium sulfate, filtered and concentrated under reducedpressure. The residue was purified by silica gel column chromatograph(25 percent ethyl acetate in hexane). Yield (20 percent). 1HNMR (500 MHz, CDCl3): δ 8.14 (s, 1H), 6.71 (s, 1H), 5.75 (t,1H, J = 2.8 Hz), 4.33 (m, 4H, J = 6.9 Hz), 1.37 (t, 3H, J = 7.0Hz); EI-MS m/z: (M++1) 154; Anal. calcd. (percent) for C7H10N2O2:C, 54.54; H, 6.54; N18.17. Found (percent): C, 54.78; H, 6.57; N,16.88.

Reference： [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 19, p. 6734 - 6750
[2] Asian Journal of Chemistry, 2017, vol. 29, # 6, p. 1199 - 1205
[3] Patent: EP1956009, 2008, A1, . Location in patent: Page/Page column 37
[4] Patent: EP1970373, 2008, A1, . Location in patent: Page/Page column 93

7
[ 288-14-2 ]
[ 847490-69-1 ]

Yield	Reaction Conditions	Operation in experiment
7%	at 20℃; for 18 h;	[00458] Intermediate 46 : Synthesis of 3-(isoxazol-4-yl)benzaldehyde: [00459] Step 1: Synthesis of 4-iodoisoxazole: To a solution of NIS (23.0 g, 100 mmol) in TFA (200 mL) was added isoxazole (6.9 g, 100 mmol) in one portion at room temperature and the resultant mixture was stirred for 18 h. The mixture was partitioned between PE (200 mL) and water (1000 mL). The organic phase was separated and washed with saturated sodium bisulfate, dried with anhydrous Na₂S0₄, filtered and concentrated to give a yellow solid (1.2 g, 7percent).

Reference： [1] Angewandte Chemie - International Edition, 2016, vol. 55, # 43, p. 13580 - 13584[2] Angew. Chem., 2016, vol. 128, p. 13778 - 13782,5
[3] Patent: US2006/46991, 2006, A1, . Location in patent: Page/Page column 50
[4] Patent: WO2006/21886, 2006, A1, . Location in patent: Page/Page column 83
[5] Patent: WO2011/38204, 2011, A1, . Location in patent: Page/Page column 150

[ 288-14-2 ] Synthesis Path-Downstream 1~88

1
[ 288-14-2 ]
[ 50-00-0 ]
[ 98020-14-5 ]

Reference： [1]Zhurnal Obshchei Khimii,1958,vol. 28,p. 2736,2743; engl. Ausg. S. 2762, 2768

2
[ 288-14-2 ]
[ 64-67-5 ]
[ 61310-53-0 ]
[ 2032-34-0 ]

Reference： [1]Journal of Organic Chemistry,1957,vol. 22,p. 192

3
[ 288-14-2 ]
[ 97925-43-4 ]

Reference： [1]Zhurnal Obshchei Khimii,1959,vol. 29,p. 535,538; engl. Ausg. S. 533

4
[ 288-14-2 ]
[ 98026-52-9 ]

Reference： [1]Zhurnal Obshchei Khimii,1959,vol. 29,p. 535,538; engl. Ausg. S. 533

5
[ 288-14-2 ]
[ 3463-30-7 ]

Reference： [1]Gazzetta Chimica Italiana,1950,vol. 80,p. 441,446

6
[ 288-14-2 ]
[ 6162-76-1 ]

Reference： [1]Chemische Berichte,1903,vol. 36,p. 3671
[2]Bulletin de la Societe Chimique de France,1975,p. 188 - 195
[3]Journal of Organic Chemistry,1999,vol. 64,p. 8411 - 8412
[4]Journal of Organic Chemistry,2012,vol. 77,p. 8723 - 8732,10

7
[ 108-05-4 ]
[ 15736-98-8 ]
[ 288-14-2 ]

Reference： [1]Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti,1951,vol. <8> 10,p. 52,54

8
[ 122-31-6 ]
[ 288-14-2 ]

Reference： [1]Beilstein Journal of Organic Chemistry,2011,vol. 7,p. 127 - 134
[2]Journal of Organic Chemistry,1957,vol. 22,p. 192
[3]Zhurnal Obshchei Khimii,1957,vol. 27,p. 1276,1279; engl. Ausg. S. 1360, 1362
[4]Journal of Organic Chemistry,1966,vol. 31,p. 1565 - 1569

9
[ 4643-13-4 ]
[ 288-14-2 ]

Reference： [1]Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti,1956,vol. <8> 21,p. 253,256

10
[ 98021-69-3 ]
[ 288-14-2 ]

Reference： [1]Zhurnal Obshchei Khimii,1956,vol. 26,p. 3355,3359;engl.Ausg.S.3733,3736
Zhurnal Obshchei Khimii,1957,vol. 27,p. 1276,1278;engl.Ausg.S.1360,1361
[2]Zhurnal Obshchei Khimii,1956,vol. 26,p. 3355,3359;engl.Ausg.S.3733,3736
Zhurnal Obshchei Khimii,1957,vol. 27,p. 1276,1278;engl.Ausg.S.1360,1361

11
[ 86046-91-5 ]
[ 288-14-2 ]

12
[ 288-14-2 ]
[ 98-01-1 ]
[ 148840-19-1 ]

Reference： [1]Collection of Czechoslovak Chemical Communications,1993,vol. 58,p. 555 - 564

13
[ 288-14-2 ]
[ 38443-19-5 ]
(E)-2-formyl-3-(5-<²H>-2-furyl)propenenitrile [ No CAS ]

Reference： [1]Collection of Czechoslovak Chemical Communications,1993,vol. 58,p. 555 - 564

14
[ 288-14-2 ]
[ 104-87-0 ]
[ 65430-29-7 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1985,p. 2581 - 2584

15
[ 288-14-2 ]
[ 100-52-7 ]
[ 56069-64-8 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1985,p. 2581 - 2584

16
[ 288-14-2 ]
[ 42220-86-0 ]
(E)-2-formyl-α-<²H>-3-(2-furyl)propenenitrile [ No CAS ]

Reference： [1]Collection of Czechoslovak Chemical Communications,1993,vol. 58,p. 555 - 564

17
[ 288-14-2 ]
[ 73028-29-2 ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1990,vol. 29,p. 61 - 63

18
[ 288-14-2 ]
C₃H₄NO₂ [ No CAS ]
[ 124855-46-5 ]
[ 124855-47-6 ]

Reference： [1]Journal of Physical Chemistry,1990,vol. 94,p. 1887 - 1894

19
[ 288-14-2 ]
C₃H₃NO₅S^(1-) [ No CAS ]

Reference： [1]Journal of Physical Chemistry,1990,vol. 94,p. 1887 - 1894

20
[ 288-14-2 ]
[ 847490-69-1 ]

Yield	Reaction Conditions	Operation in experiment
11%	With N-iodo-succinimide; trifluoroacetic acid;	General Procedure 49 Isoxazole (0.64 mL, 10 mmol) was added to a solution of N-iodosuccinimide (2.3 g, 10 mmol) in trifluoroacetic acid (20 mL). After stirring overnight, water (50 mL), hexanes (50 mL) and sodium bisulfite were added to the reaction. The phases were separated and the organic phase was dried over Na2SO4, filtered and concentrated by rotary evaporation to give 4-iodo-isoxazole (218 mg, 11%).
11%	With N-iodo-succinimide; trifluoroacetic acid;	Isoxazole (0.64 mL, 10 mmol) was added to a solution of N-iodosuccinimide (2.3 g, 10 mmol) in trifluoroacetic acid (20 mL). After stirring overnight, water (50 mL), hexanes (50 mL) and sodium bisulfite were added to the reaction. The phases were separated and the organic phase was dried over Na2S04, filtered and concentrated by rotary evaporation to give 4-iodo-isoxazole (218 mg, 11%).
7%	With N-iodo-succinimide; trifluoroacetic acid; at 20℃; for 18h;	[00458] Intermediate 46 : Synthesis of 3-(isoxazol-4-yl)benzaldehyde: [00459] Step 1: Synthesis of 4-iodoisoxazole: To a solution of NIS (23.0 g, 100 mmol) in TFA (200 mL) was added isoxazole (6.9 g, 100 mmol) in one portion at room temperature and the resultant mixture was stirred for 18 h. The mixture was partitioned between PE (200 mL) and water (1000 mL). The organic phase was separated and washed with saturated sodium bisulfate, dried with anhydrous Na2S04, filtered and concentrated to give a yellow solid (1.2 g, 7%).

Reference： [1]Angewandte Chemie - International Edition,2016,vol. 55,p. 13580 - 13584
Angew. Chem.,2016,vol. 128,p. 13778 - 13782,5
[2]Patent: US2006/46991,2006,A1 .Location in patent: Page/Page column 50
[3]Patent: WO2006/21886,2006,A1 .Location in patent: Page/Page column 83
[4]Patent: WO2011/38204,2011,A1 .Location in patent: Page/Page column 150

Yield	Reaction Conditions	Operation in experiment
0.75 g (50%)		Purification of the crude by flash column chromatography [20% (ether/triethylamine 9:1) in hexane] gave 0.75 g (50%) of pure isoxazole RTI-177 which was further purified by crystallizing from ether/petroleum ether: 1H NMR (CDCl3) delta 1.74 (m, 3H), 2.22 (m, 3H), 2.27 (s, 3H), 3.24 (m, 2H), 3.36 (m, 2H), 6.80 (s, 1 H), 6.94 (m, 2H), 7.12 (m, 2H), 7.40 (m, 3H), 7.76 (m, 2 H); IR (CHCl3) 2940, 1600, 1590, 1490, 1450, 1405, 1350 cm-1. The isoxazole was crystallized as the hydrochloride salt: 1H NMR (MeOD) delta 2.35 (m, 6H), 2.84 (s, 3H), 3.73 (m, 1 H;, 4.09 (m, 1H), 4.21 (m, 1H), 6.12 (s, 1H), 7.14 (m, 4H), 7.34 (m, 3H), 7.57 (m, 2H); mp 287 C.; Anal calcd for C23H24Cl2IN2O.0.25H2O C=65.79, H=5.88, N 6.67, Cl=16.89; found C=65.94, H=5.79, N=6.68, Cl=17.00; [alpha]D-97.5 (c=0.28, MeOH).
0.75 g (50%)		Purification of the crude by flash column chromatography [20% (ether/triethylamine 9:1) in hexane] gave 0.75 g (50%) of pure isoxazole RTI-177 which was further purified by crystallizing from ether/petroleum ether: 1H NMR (CDCl3) delta 1.74 (m, 3H), 2.22 (m, 3H), 2.27 (s, 3H), 3.24 (m, 2H), 3.36 (m, 2H), 6.80 (s, 1H), 6.94 (m, 2H), 7.12 (m, 2H), 7.40 (m, 3H), 7.76 (m, 2H); IR (CHCl3) 2940, 1600, 1590, 1490, 1450, 1405, 1350 cm-1. The isoxazole was crystallized as the hydrochloride salt: 1H NMR (MeOD) delta 2.35 (m, 6H), 2.84 (s, 3H), 3.73 (m, 1H), 4.09 (m, 1H), 4.21 (m, 1H), 6.12 (s, 1H), 7.14 (m, 4H), 7.34 (m, 3H), 7.57 (m, 2H); mp 287 C.; Anal calcd for C23H24Cl2IN2O.0.25H2O C=65.79, H=5.88, N, 6.67, Cl=16.89; found C=65.94, H=5.79, N=6.68, Cl=17.00; [alpha]D -97.5 (c=0.28, MeOH).
0.75 g (50%)		Purification of the crude by flash column chromatography ?20% (ether/triethylamine 9:1) in hexane! gave 0.75 g (50%) of pure isoxazole RTI-177 which was further purified by crystallizing from ether/petroleum ether: 6 H NMR (CDCl3) delta 1.74 (m, 3 H), 2.22 (m, 3 H), 2.27 (s, 3 H), 3.24 (m, 2 H), 3.36 (m, 2 H), 6.80 (s, 1 H), 6.94 (m, 2 H), 7.12 (m,2 H), 7.40 (m, 3 H), 7.76 (m, 2 H); IR (CHCl3) 2940, 1600, 1590, 1490, 1450, 1405, 1350 cm-1. The isoxazole was crystallized as the hydrochloride salt: 1 H NMR (MeOD) delta 2.35 (m, 6 H), 2.84 (s, 3 H), 3.73 (m, 1 H), 4.09 (m, 1 H), 4.21 (m, 1 H), 6.12 (s, 1 H), 7.14 (m, 4 H), 7.34 (m, 3 H), 7.57 (m, 2 H); mp 287 C.; Anal calcd for C23 H24 Cl2 IN2 O.0.25H2 O C=65.79, H=5.88, N 6.67, Cl=16.89; found C=65.94, H=5.79, N=6.68, Cl=17.00; [alpha]D -97.5 (c=0.28, MeOH).

0.75 g (50%)

Purification of the crude by flash column chromatography [20% (ether/triethylamine 9:1) in hexane] gave 0.75 g (50%) of pure isoxazole RTI-177 which was further purified by crystallizing from ether/petroleum ether: 1H NMR (CDCl3) delta1.74 (m, 3 H), 2.22 (m, 3 H), 2.27 (s, 3 H), 3.24 (m, 2 H), 3.36 (m, 2 H), 6.80 (s, 1 H), 6.94 (m, 2 H), 7.12 (m,2 H), 7.40 (m, 3 H), 7.76 (m, 2 H); IR (CHCl3) 2940, 1600, 1590, 1490, 1450, 1405, 1350 cm-1. The isoxazole was crystallized as the hydrochloride salt: 1H NMR (MeOD) delta2.35 (m, 6 H), 2.84 (s, 3 H), 3.73 (m, 1 H), 4.09 (m, 1 H), 4.21 (m, 1 H), 6.12 (s, 1 H), 7.14 (m, 4 H), 7.34 (m, 3 H), 7.57 (m, 2 H); mp 287 C.; Anal calcd for C23H24Cl2IN2O.0.25H2O C=65.79, H=5.88, N 6.67, Cl=16.89; found C=65.94, H=5.79, N=6.68, Cl=17.00; [alpha]D-97.5 (c=0.28, MeOH).

22
[ 288-14-2 ]
[ 3717-23-5 ]
[ 70-55-3 ]
[ 536-74-3 ]
[ 130966-62-0 ]

Yield	Reaction Conditions	Operation in experiment
82%	With chloroamine-T; In methanol; water;	Example 1 Preparation of 3-(4-Chlorophenyl)-4-Phenyl Isoxazole (Compound of the Formula I wherein R1=H, Y=4-phenyl and Z=4-chlorophenyl). A solution of phenylacetylene (10 mmol), 4-chlorobenzaldoxime (10 mmol) and chloramine-T (10 mmol, N-chloro-p-toluenesulfoneamide, sodium salt) were dissolved in methanol (40 mL) and refluxed for 6 h. The contents of the flask were cooled and the precipitated material, which was a mixture of isoxazole and 4-toluenesulfonamide, was filtered and washed with water. The solid material on boiling in hot water kept the sulfonamide in solution while precipitating the isoxazole. The precipitated isoxazole was filtered and recrystallized from ethanol, yield (82%), m.p.: 178-180 C.; 1H NMR (DMSO-d6) 6.75(s, 1H), 7.49-7.55(m, 5H), 7.77-7.82 (m, 4H).

Reference： [1]Patent: US2003/162813,2003,A1

23
[ 288-14-2 ]
[ 1056189-40-2 ]
[ 326818-04-6 ]
[ 326818-05-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In ethanol; dichloromethane;	EXAMPLE 12 4-[5-Benzyloxymethyl-3-(4-fluoro-phenyl)-isoxazol-4-yl]-2-methylsulfanyl-pyrimidine (Compound 8). To a stirred solution of the above compound 7 (13.75 g, 47.7 mmol) and Et3N (14.6 mL, 105 mmol) in EtOH (200 mL), was added a solution of 4-fluoro-benzoylchloride oxime (56 mmol) in EtOH (50 mL) over 30 min. The solution was stirred at 25 C. for 15 min. Then, the solution was heated to reflux for 90 min. The solution was cooled to 25 C. Additional Et3N (7.3 mL, 52 mmol) was added followed by dropwise addition of a solution of 4-fluoro-benzoylchloride oxime (38.5 mmol) in EtOH (50 mL) over 1 h. to drive the reaction to completion. The solution was refluxed for 1 h. until TLC indicated that all of the starting isoxazole was consumed. The solution was cooled to 25 C. and concentrated. The crude material was picked up in CH2Cl2 (50 mL) and poured into saturated aqueous NaHCO3 (150 mL), extracted with CH2Cl2 (3*150 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (SiO2, 20% EtOAc-hexanes) provided the title compound (14.2 g, 34.8 mmol, 60%) in sufficient purity (>85%) for use in the next reaction.

Reference： [1]Patent: US2003/149051,2003,A1

Yield	Reaction Conditions	Operation in experiment
		PREPARATION 157 5-(2-Chloro-6-fluorophenyl)-3-methylisoxazole-4-carboxylic acid Hydrolysis of the ethyl ester was accomplished by dissolving the crude ester (7.5 g, approx. 0.027 mol) in THF (250 mL), and adding aq. LiOH (1.344 g in 100 mL, 2 eq). After stirring overnight at r.t., the solution was concentrated to 2/3rd volume, diluted with EtOAc (200 mL) and 50 mL water, transferred to a separatory funnel, and the aqueous phase collected. The organic phase was washed twice, and the combined aqueous phase was then acidified with 5N HCl. Back extraction with three washings of EtOAc was then followed with a brine wash of the combined organics. After drying over Na2SO4, filtration and concentration, clean isoxazole acid was obtained (2.94 g). NMR (CDCl3) delta7.13, 7.32 7.46 (3 m, 3H), 2.58 (s, CH3). MS (-ES) m/z 253.8, 255.8 (M-H)-.

25
[ 288-14-2 ]
[ 1750-42-1 ]

Yield	Reaction Conditions	Operation in experiment
	With 3-chloro-benzenecarboperoxoic acid; In tetrahydrofuran; N,N-dimethyl-formamide;	The appropriate isoxazole 56 (3 mmol) is treated with m-chloroperbenzoic acid (7 mmol) in THF (25 mL) at room temperature for 12-24 h (monitored by TLC or LC/MS). The reaction mixture is filtered, the filtrate is diluted with water (25 mL) and extracted with ethyl acetate (25 mL3). The combined extract is washed with saturated sodium bicarbonate (15 mL2), water (25 mL), dried over anhydrous sodium sulfate, and cautiously evaporated under reduced pressure. Then, a solution the crude sulfone and the appropriate amine 14 (3 mmol) is heated at ~70 C. in DMF (25 mL) for 12-24 h (monitored by TLC). The solvent is evaporated under reduced pressure and the residue is chromatographed on silica gel column using a gradient of ethyl acetate and hexane as eluents to give the corresponding pure aminoisoxazole 57 (Scheme 29).

Reference： [1]Patent: US2003/130246,2003,A1

Yield	Reaction Conditions	Operation in experiment
0.74 g (46%)		Purification of the crude residue by flash column chromatography (10% CMA in methylene chloride) gave 0.74 g (46%) of pure isoxazole RTI-165 which was further purified by crystallization from methylene chloride/hexane: 1H NMR (CDCl3) delta 1.71 (m, 3H), 2.10 (m, 3H), 2.18 (s, 3H), 2.24 (s, 3H), 3.20 (m, 2H), 3.32 (m, 2H), 6.18 (s, 1H), 6.9 (d, J=8 Hz, 2H), 7.14 (d, J=8, Hz, 2H); IR (CCl4) 2950, 1590, 1490, 1420, 1350, 1020, 910 cm-1; mp 154-156 C.; Anal calcd for C18H21N2OCl; C=68.28, H=6.68, N=8.84, Cl=11.19; found C=68.22, H=6.69, N=8.87, Cl=11.19; [alpha]D -125.58 (c=0.43, MeOH). The isoxazole was crystallized as the hydrochloride salt: 1H NMR (MeOD) delta 2.04 (s, 3H), 2.19 (m, 1H), 2.30 (m, 1H), 2.48 (m, 2H), 2.60 (m, 1H), 2.70 (m, 1H), 2.90 (s, 3H), 3.68 (m, 1H), 3.81 (m, 1H), 4.04 (m, 1H), 4.15 (m, 1H), 5.55 (s, 1H), 7.04 (d, J=8 Hz, 2H), 7.14 (d, J=8 Hz, 2H); mp>235 C. (dec); Anal calcd for C18H22Cl2N2O; C=61.19, H=6.28, N=7.93, Cl=20.07; found c=60.98, H=6.38, N=7.91, Cl=19.96; [alpha]D -102.890 (c=0.46, MeOH).
0.74 g (46%)		Purification of the crude residue by flash column chromatography (10% CMA in methylene chloride) gave 0.74 g (46%) of pure isoxazole RTI-165 which was further purified by crystallization from methylene chloride/hexane: 1 H NMR (CDCl3) delta 1.71 (m, 3 H), 2.10 (m, 3 H), 2.18 (s, 3 H), 2.24 (s, 3 H), 3.20 (m, 2 H), 3.32 (m, 2 H), 6.18 (s, 1 H), 6.9 (d, J=8 Hz, 2 H),7.14 (d, J=8, Hz, 2 H); IR (CCl4) 2950, 1590, 1490, 1420, 1350, 1020, 910 cm-1; mp 154-156 C.; Anal calcd for C18 H21 N2 OCl; C=68.28, H=6.68, N=8.84, Cl=11.19; found C=68.22, H=6.69, N=8.87, Cl=11.19; [alpha]D -125.58 (c=0.43, MeOH). The isoxazole was crystallized as the hydrochloride salt: 1 H NMR (MeOD) delta0 2.04 (s, 3 H), 2.19 (m, 1 H), 2.30 (m, 1 H), 2.48 (m, 2 H), 2.60 (m, 1 H), 2.70 (m, 1 H), 2.90 (s, 3 H), 3.68 (m, 1 H), 3.81 (m, 1 H), 4.04 (m, 1 H), 4.15 (m, 1 H), 5.55 (s, 1 H), 7.04 (d, J=8 Hz, 2 H), 7.14 (d, J=8 Hz, 2 H); mp>235 C. (dec); Anal calcd for C18 H22 Cl2 N2 O; C=61.19, H=6.28, N=7.93, Cl=20.07; found c=60.98, H=6.38, N=7.91, Cl=19.96; [alpha]D -102.89 (c=0.46, MeOH).
0.74 g (46%)		Purification of the crude residue by flash column chromatography (10% CMA in methylene chloride) gave 0.74 g (46%) of pure isoxazole RTI-165 which was further purified by crystallization from methylene chloride/hexane: 1H NMR (CDCl3) delta1.71 (m, 3 H), 2.10 (m, 3 H), 2.18 (s, 3 H), 2.24 (s, 3 H), 3.20 (m, 2 H), 3.32 (m, 2 H), 6.18 (s, 1 H), 6.9 (d, J=8 Hz, 2 H),7.14 (d, J=8, Hz, 2 H); IR (CCl4) 2950, 1590, 1490, 1420, 1350, 1020, 910 cm-1; mp 154-156 C.; Anal calcd for C18H21N2OCl; C=68.28, H=6.68, N=8.84, Cl=11.19; found C =68.22, H=6.69, N=8.87, Cl=11.19; [alpha]D-125.58 (c=0.43, MeOH). The isoxazole was crystallized as the hydrochloride salt: 1H NMR (MeOD) delta2.04 (s, 3 H), 2.19 (m, 1 H), 2.30 (m, 1 H), 2.48 (m, 2 H), 2.60 (m, 1 H), 2.70 (m, 1 H), 2.90 (s, 3 H), 3.68 (m, 1 H), 3.81 (m, 1 H), 4.04 (m, 1 H), 4.15 (m, 1 H), 5.55 (s, 1 H), 7.04 (d, J=8 Hz, 2 H), 7.14 (d, J=8 Hz, 2 H); mp>235 C. (dec); Anal calcd for C18H22Cl2N2O; C=61.19, H=6.28, N=7.93, Cl=20.07; found c=60.98, H=6.38, N=7.91, Cl=19.96; [alpha]D-102.89 (c=0.46, MeOH).

27
[ 288-14-2 ]
[ 124-58-3 ]
[ 130342-81-3 ]
RTI-4229-165 [ No CAS ]
RTI-4229-171 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane;	Example 16 3beta-(4-Methylphenyl)-2beta-(3-methylisoxazol-5-yl)tropane Hydrochloride (RTI-171) Reaction of 1.09 g (4 mmol) of 3beta-(4-Methylphenyl)-2beta-(carbomethoxy)tropane as described above for RTI-165 gave after workup 1.21 g crude isoxazole. Purification of the crude by flash column chromatography (15% CMA in methylene chloride) gave 0.73 g (62%) pure isoxazole (RTI-171): 1H NMR (CDCl3) delta 1.73 (m, 3H), 2.11 (m, 3H), 2.17 (s, 3H), 2.23 (s, 3H), 2.25 (s, 3H), 3.20 (m, 2H), 3.32 (m, 2H), 6.13 (s, 1H), 6.97 (m, 4H); IR (CCl4) 2935,.2785, 1590, 1510, 1460, 1421, 1350, 1125,1010, 910 cm-1. The isoxazole was crystallized as the hydrochloride salt: 1H NMR (MeOD) delta 2.01 (s, 3H), 2.24 (s, 3H), 2.32 (m, 2H), 2.42 (m, 4H), 2.81 (s, 3H), 3.61 (m, 1H), 3.78 (m, 1H), 4.03 (m, 1H), 4.15 (m, 1H), 5.45 (s, 1H), 6.96 (m, 4H); mp 277 C.; Anal calcd for C19H25CIN2O; C=68.55, H=7.57, N=8.42, Cl=10.65; found C=68.65, H=7.62, N=8.42, Cl=10.56; [alpha]D -107.28 (c-0.71, MEOH).
	In dichloromethane;	Example 18 3beta-(4-Methylphenyl)-2beta-(3-methylisoxazol-5-yl)tropane Hydrochloride (RTI-171) Reaction of 1.09 g (4 mmol) of 3beta-(4-Methylphenyl)-2beta-(carbomethoxy)tropane as described above for RTI-165 gave after workup 1.21 g crude isoxazole. Purification of the crude by flash column chromatography (15% CMA in methylene chloride) gave 0.73 g (62%) pure isoxazole (RTI-171): 1 H NMR (CDCl3) delta 1.73 (m, 3 H), 2.11 (m, 3 H), 2.17 (s, 3 H), 2.23 (s, 3 H), 2.25 (s, 3 H), 3.20 (m, 2 H), 3.32 (m, 2 H), 6.13 (s, 1 H), 6.97 (m, 4 H); IR (CCl4) 2935, 2785, 1590, 1510, 1460, 1421, 1350, 1125,1010, 910 cm-1. The isoxazole was crystallized as the hydrochloride salt: 1 H NMR (MeOD) delta 2.01 (s, 3 H), 2.24 (s, 3 H), 2.32 (m, 2 H), 2.42 (m, 4 H), 2.81 (s, 3 H), 3.61 (m, 1 H), 3.78 (m, 1 H), 4.03 (m, 1 H), 4.15 (m, 1 H), 5.45 (s, 1 H), 6.96 (m, 4 H); mp 277 C.; Anal calcd for C19 H25 CIN2 O; C=68.55, H=7.57, N=8.42, Cl=10.65; found C=68.65, H=7.62, N=8.42, Cl=10.56; [alpha]D -107.28 (c=0.71, MEOH).
	In dichloromethane;	Example 16 3beta-(4-Methylphenyl)-2beta-(3-methylisoxazol-5-yl)tropane Hydrochloride (RTI-171) Reaction of 1.09 g (4 mmol) of 3beta-(4-Methylphenyl)-2beta-(carbomethoxy)tropane as described above for RTI-165 gave after workup 1.21 g crude isoxazole. Purification of the crude by flash column chromatography (15% CMA in methylene chloride) gave 0.73 g (62%) pure isoxazole (RTI-171): 1H NMR (CDCl3) delta1.73 (m, 3 H), 2.11 (m, 3 H), 2.17 (s, 3 H), 2.23 (s, 3 H), 2.25 (s, 3 H), 3.20 (m, 2 H), 3.32 (m, 2 H), 6.13 (s, 1 H), 6.97 (m, 4 H); IR (CCl4) 2935, 2785, 1590, 1510, 1460, 1421, 1350, 1125,1010, 910 cm-1. The isoxazole was crystallized as the hydrochloride salt: 1H NMR (MeOD) delta2.01 (s, 3 H), 2.24 (s, 3 H), 2.32 (m, 2 H), 2.42 (m, 4 H), 2.81 (s, 3 H), 3.61 (m, 1 H), 3.78 (m, 1 H), 4.03 (m, 1 H), 4.15 (m, 1 H), 5.45 (s, 1 H), 6.96 (m, 4 H); mp 277 C.; Anal calcd for C19H25CIN2O; C=68.55, H=7.57, N=8.42, Cl=10.65; found C=68.65, H=7.62, N=8.42, Cl=10.56; [alpha]D-107.28 (c=0.71, MEOH).

Reference： [1]Patent: US6531483,2003,B1
[2]Patent: US5935953,1999,A
[3]Patent: US6329520,2001,B1

Yield	Reaction Conditions	Operation in experiment
96%		Step 3. Preparation of 5-(4-methylthio-phenyl)-4-phenyl-3-methylisoxazole Following the procedure of Step 2 of Example 13, the oxime from Step 2 (500 mg, 1.7 mmol) was reacted with iodine (450 mg, 1.7 mmol) and potassium iodide (1 g, 6 mmol) in the presence of sodium bicarbonate (600 mg, 7 mmol) in tetrahydrofuran (10 mL) and water (10 mL). The crude material was chromatographed on silica gel using toluene as the eluent. The material isolated was recrystallized from ethyl acetate and hexane to give the desired isoxazole (460 mg, 96%): mp 88-90 C. Anal. Calc'd. for C17 H15 NOS (281.38): C, 72.57; H, 5.37; N, 4.98; S, 11.40. Found: C, 72.19; H, 5.49; N, 4.66; S, 11.79.

Yield	Reaction Conditions	Operation in experiment
2.1 g (96%)		Step 5. Preparation of 3-ethyl-4-(4-methylthiophenyl)-5-phenylisoxazole To a solution of the oxime from Step 4 (2.21 g, 0.0074 mol) in 25 mL of tetrahydrofuran was added a solution of sodium bicarbonate (2.62 g, 0.031 mol) in 20 mL of water, followed by a solution of potassium iodide (4.56 g, 0.028 mol) and iodine (2.07 g, 0.0082 mol) in 30 mL of water. The reaction mixture was heated to reflux for 3 hours. After cooling, the mixture was treated with 100 mL of saturated aqueous potassium bisulfate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by chromatography on silica gel (ethyl acetate/hexane, 5:95) to afford 2.1 g (96%) of the isoxazole as a brownish solid: mp (DSC) 85-87 0 C. Anal. Calc'd. for C18 H17 NOS: C, 73.19; H, 5.80; N, 4.74; S, 10.85. Found: C, 73.03; H, 5.49; N, 4.55; S, 10.86.

Yield	Reaction Conditions	Operation in experiment
35%		Step 4. Preparation of 5-difluoromethyl-4-(4-methylthiophenyl)-3-phenylisoxazole The oxime from Step 3 (14.13 g, 54.9 mmol) was dissolved in tetrahydrofuran (150 mL), cooled to -78 C., and treated with 2.1 equivalents of n-butyllithium. The reaction was warmed to 10 C. over 1.9 hours, treated with ethyl difluoroacetate (7.03 g, 56.7 mmol) and stirred at room temperature for 3.2 hours. The reaction was quenched with water, extracted with ethyl acetate, washed with saturated NaHCO3, and brine, dried over MgSO4, and concentrated in vacuo to give a brown oil (12.17 g). The oil was dissolved in tetrahydrofuran (50 mL) along with triethylamine (8.02 g, 79.2 mmol), dimethylaminopyridine (1.13 g, 9.2 mmol), and toluenesulfonyl chloride (7.72 g, 40.5 mnmol). The solution was heated to reflux for 1.8 hours, ethyl acetate was added and the reaction mixture was washed with 3N HCl, saturated NaHCO3, and brine, dried over MgSO4, and concentrated in vacuo. The material was purified (silica gel eluding with 25% ethyl acetate/hexane) to give the isoxazole as a brown oil (6.12 g, 35%): 1 H NMR (CDCl3) 300 MHz 7.32-7.45 (m, 5H) 7.24 (d, J=-8.5 Hz, 2H) 7.16 (d, J=8.5 Hz, 2H) 6.63 (t, J=52.4 Hz, 1H) 2.51 (s, 3H). 19 F NMR (acetone-d6) 282 MHz -116.26 (d). Mass spectrum: M+=317.

Yield	Reaction Conditions	Operation in experiment
95%		Step 1. Preparation of 3-ethyl-5-(4-fluorophenyl)-4-phenylisoxazole By substituting 4-fluorobenzaldehyde for benzaldehyde, and 1-phenyl-2-butanone for 1-(4-methylthiophenyl)-2-butanone in the method of Example 29 (Steps 3-5), the isoxazole was obtained as a yellow solid (9.5 g, 95%): mp 61-63 C. Anal. Calc'd. for C17 H14 FNO: C, 76.39; H, 5.28; N, 5.24. Found: C, 75.75; H, 4.98; N, 5.06.

Yield	Reaction Conditions	Operation in experiment
290 mg (57%)		Step 2. Preparation of 3,4-diphenyl-5-methylisoxazole To a solution of oxime from Step 1 (450 mg, 1.9 mmol) and sodium bicarbonate (650 mg, 7.7 mmol) in tetrahydrofuran (6 mL) and water (6 mL) in a vessel wrapped in aluminum foil was added a solution of potassium iodide (1.1 g, 6.6 mmol) and iodine (525 mg, 2 mmol) in water (4 mL). The reaction was heated to reflux for 7 hours and stirred at room temperature overnight. Saturated aqueous sodium bisulfite solution (5 mL) was added and the reaction mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and the crude material was isolated after filtration and concentration of the filtrate. Chromatography on silica gel using toluene as the eluant gave 290 mg (57%) of the isoxazole as an oil which crystallized on standing: mp 92-94 C. Anal. Calc'd for C16 H13 NO: C, 81.31; H, 5.57; N, 5.95. Found: C, 81.31, H, 5.71; N, 6.18.

33
[ 288-14-2 ]
[ 219679-74-0 ]
[ 181695-95-4 ]

Yield	Reaction Conditions	Operation in experiment
	With chlorosulfonic acid;	Step 4. Preparation of 4-[3-methyl-5-(3-chlorophenyl)isoxazol-4-yl]benzenesulfonamide Following the procedure of Example 14, Step 4, the isoxazole from Step 3 (2 g, 7.4 mmol) was reacted with chlorosulfonic acid (8 mL) and quenched with ammonium hydroxide. The crude product was recrystallized from ethyl acetate to give pure sulfonamide (220 mg): mp 176-178 C. Anal. Calc'd. for C16 H13 ClN2 O3 S (348.81): C, 55.10; H, 3.76; N, 8.03; S, 9.19. Found: C, 54.60; H, 3.63; N, 7.77; S, 9.21.

Reference： [1]Patent: US5859257,1999,A

34
[ 288-14-2 ]
Oxone [ No CAS ]
[ 219679-74-0 ]
[ 181695-93-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	In tetrahydrofuran; methanol; water;	Step 4. Preparation of 3-methyl-5-(4-methylsulfonylphenyl)-4-phenylisoxazole To a solution of the isoxazole from Step 3 (450 mg, 1.6 mmol) in tetrahydrofuran (6 mL) and methanol (12 mL), was added dropwise a solution of Oxone (1.6 g) in water (6 mL) at room temperature. The reaction was stirred for 2 hours, diluted with water and filtered. The crude product was recrystallized from ethyl acetate and hexane to give pure sulfone (475 mg, 95%): mp 183-185 C. Anal. Calc'd. for C17 H15 NO3 S (313.38): C, 65.16; H, 4.82; N, 4.47; S, 10.23. Found: C, 65.06; H, 4.93; N, 4.31; S, 10.37.

Reference： [1]Patent: US5859257,1999,A

Yield	Reaction Conditions	Operation in experiment
75%		Step 4 (4,4-Dimethyl-8-ethoxy-4,5-dihydrothieno[3,4-g]-1,2-benzisoxazol-6-yl)(pyrrolidin-1-yl)methanone In the same way as described in Example 1, Step 3, using 6,6-dimethyl-3-et hoxy-5-hydroxymethylene-1-(pyrrolidin-1-ylcarbonyl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the isoxazole (73 mg, 75%) was isolated as a yellow solid. mp 123-126 C. C18 H22 N2 O3 S requires C, 62.40; H, 6.40; N, 8.09%. Found: C, 62.06; H, 6.25; N, 7.90%. 1 H NMR (250 MHz, CDCl3) delta1.25 (6H, s), 1.54 (3H, t, J=7.0 Hz), 1.92-1.98 (4H, m), 2.90 (2H, s), 3.58-3.64 (4H, m), 4.28 (2H, q), 8.15 (1H, s). MS (ES+) 347 (M+1).

Yield	Reaction Conditions	Operation in experiment
73%		Step 3 (4,4-Dimethyl-8-methylthio-4,5-dihydrothieno[3,4-g]-1,2-benzisoxazol-6-yl)(morpholin-4-yl)methanone In the same way as described in Example 1, Step 3, using 6,6-dimethyl-5-hydroxymethylene-3-methylthio-1-(morpholin-4-ylcarbonyl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the isoxazole (65 mg, 73%) was isolated as a colourless solid. mp 175-177 C. C17 H20 N2 O3 S2 requires: C, 56.02; H, 5.53; N, 7.69%. Found: C, 56.18; H, 5.84; N, 7.77%. 1 H NMR (250 MHz, CDCl3) delta1.27 (6H, s), 2.64 (3H, s), 2.74 (2H, s), 3.64-3.75 (8H, m), 8.20 (1H, s). MS (ES+) 365 (M+1).

Yield	Reaction Conditions	Operation in experiment
52%		Step 3 (4,4-Dimethyl-8-phenylthio-4,5-dihydrothieno[3,4-g]-1,2-benzisoxazol-6-yl)(pyrrolidin-1-yl)methanone In the same way as described in Example 1, Step 3, using 6,6-dimethyl-5-hydroxymethylene-3-phenylthio-1-(pyrrolidin-1-ylcarbonyl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the isoxazole (33 mg, 52%) was isolated as a colourless solid. mp 49-52 C. C22 H22 N2 O2 S2 requires: C, 64.36; H, 5.40; N, 6.82% Found: C, 64.22; H, 5.60; N, 6.46%. 1 H NMR (360 MHz, (CDCl3) delta1.28 (6H, s), 1.92-1.96 (4H, m), 2.91 (2H, s), 3.41-3.64 (4H, m), 7.25-7.34 (3H, m), 7.44-7.47 (2H, m), 8.19 (1H, s). MS (ES+) 411 (M+1).

Yield	Reaction Conditions	Operation in experiment
47%		Step 3 (4,4-Dimethyl-8-ethylthio-4,5-dihydrothieno[3,4-g]-1,2-benzisoxazol-6-yl)(pyrrolidin-1-yl)methanone In the same way as described in Example 1, Step 3, using 6,6-dimethyl-3-ethylthio-5-hydroxymethylene-1-(pyrrolidin-1-ylcarbonyl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the isoxazole (80 mg, 47%) was isolated as a yellow solid. mp 91-93 C. C18 H22 N2 O2 S2 requires: C, 59.64; H, 6.12; N, 7.73%. Found: C, 59.94; H, 5.86; N, 7.69%. 1 H NMR (360 MHz, CDCl3) delta1.19 (6H, s), 1.28 (3H, t, J=7.4 Hz), 1.87-1.92 (4H, m), 2.83 (2H, s), 2.98 (2H, q, J=7.4 Hz), 3.45-3.59 (4H, m), 8.13 (1H, s). MS (ES+) 363 (M+1).

Yield	Reaction Conditions	Operation in experiment
10%		Step 3 (4,4-Dimethyl-8-propylthio-4,5-dihydrothieno[3,4-g]-1,2-benzisoxazol-6-yl)(pyrrolidin-1-yl)methanone In the same way as described in Example 1, Step 3, using 6,6-dimethyl-5-hydroxymethylene-3-propylthio-1-(pyrrolidin-1-ylcarbonyl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the isoxazole (14 mg, 10%) was isolated as a colourless solid. mp 72-76 C. C19 H24 N2 O2 S2 requires: C, 60.61; H, 6.42; N, 7.44%. Found: C, 60.82; H, 6.15; N, 7.01%. 1 H NMR (360 MHz, CDCl3) delta1.04 (3H, t, J=7.4 Hz), 1.26 (6H, s), 1.72 (2H, sextet, J=7.4 Hz), 1.94-1.98 (4H, m), 2.89 (2H, s), 3.00 (2H, t, J=7.4 Hz), 3.51-3.65 (4H, m), 8.20 (1H, s). MS (ES+) 377 (M+1).

Yield	Reaction Conditions	Operation in experiment
16%		Step 4 4,4-Dimethyl-8-methylthio-6-(1-methyl-1,2,4-triazol-3-yl)-4,5-dihydrothieno[3,4-g]-1,2-benzisoxazole In the same way as described in Example 1, Step 3, using 6,6-dimethyl-5-hydroxymethylene -3-methylthio-1-(1-methyl-1,2,4-triazol-3-yl) -4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the isoxazole (8 mg, 16%) was isolated as a colourless solid. 1 H NMR (360 MHz, CDCl3) delta1.27 (6H, s), 2.68 (3H, s), 2.87 (2H, s), 3.99 (3H, s), 7.98 (1H, s), 8.22 (1H, s). MS (ES+) 333 (M+1).

Yield	Reaction Conditions	Operation in experiment
8%		Step 3: (4,4-Dimethyl-8-methylthio-4,5-dihydro[2-15 N]-thieno[3,4-g]-1,2-benzisoxazol-6-yl)(4-methylpiperazin-1-yl)methanone In the same way as described in Example 1, Step 3, using 6,6-dimethyl-5-hydroxymethylene-1-(4-methylpiperazin-1-ylcarbonyl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one and 15 N-hydroxylamine hydrochloride, the isoxazole (10 mg, 8%) was isolated as a colourless solid. 1 H NMR (360 MHz, CDCl3) delta1.26 (6H, s), 2.33 (3H, s), 2.42-2.46 (4H, m), 2.64 (3H, s), 2.73 (2H, s), 3.64-3.67 (4H, m), 8.19 (1H, d, J=14.4 Hz). MS (ES+) 379 (M+1).

Yield	Reaction Conditions	Operation in experiment
70%		Step 3 4,4-Dimethyl-8-methylthio-6-(pyrid-2-yl)-4,5-dihydrothieno[3,4-g]-1,2-benzisoxazole In the same way as described in Example 1, Step 3, using 6,6-dimethyl-5-hydroxymethylene-3-methylthio-1-(pyrid-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the isoxazole (60 mg, 70%) was isolated as a yellow solid. mp 153-155 C. C17 H16 N2 OS2.0.1(H2 O) requires: C, 61.83; H, 4.94; N, 8.48%. Found: C, 61.69; H, 4.84; N 8.13%. 1 H NMR (360 MHz, CDCl3) delta1.28 (6H, s), 2.68 (3H, s), 3.05 (2H, s), 7.19-7.23 (1H, m), 7.46 (1H, d, J=8.0 Hz), 7.75 (1H, d of t, J=7.7 and 1.8 Hz), 8.20 (1H, s), 8.62-8.66 (1H, m). MS (ES+) 329 (M+1).

Yield	Reaction Conditions	Operation in experiment
53%		Step 3 4,4-Dimethyl-8-methylthio-6-(pyrid-3-yl)-4,5-dihydrothieno[3,4-g ]-1,2-benzisoxazole In the same way as described in Example 13, Step 3, using 6,6-dimethyl-5-hydroxymethylene-3-methylthio-1-(pyrid-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the isoxazole (42 mg, 53%) was isolated as a yellow solid. mp 123-125 C. C17 H16 N2 OS2.0.4(H2 O) requires: C, 60.83; H, 5.05; N, 8.36% Found: C, 60.55; H, 4.73; N, 8.03%. 1 H NMR (360 MHz, CDCl3) delta1.22 (6H, s), 2.67 (3H, s), 2.80 (2H, s), 7.38 (1H, dd, J=7.7 and 4.9 Hz), 7.71 (1H, d of t, J=7.9 and 1.9 Hz), 8.21 (1H, s), 8.59-8.64 (1H, m), 8.70 (1H, d, J=1.9 Hz). MS (ES+) 329 (M+1).

Yield	Reaction Conditions	Operation in experiment
67%		Step 3 (4,4-Dimethyl-8-methylthio-4,5-dihydrothieno[3,4-g]-1,2-benzisoxazol-6-yl)(homopiperidin-1-yl)methanone In the same way as described in Example 1, Step 3, using 6,6-dimethyl-1-(homopiperidin-1-ylcarbonyl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the isoxazole (205 mg, 67%) was isolated as a colourless solid. mp 99-101 C. C19 H24 N2 O2 S2 requires: C, 61.50; H, 7.17; N, 3.98%. found: C, 61.81; H, 7.17; N. 3.83%. 1 H NMR (360 MHz, CDCl3) delta1.26 (6H, s), 1.59-1.90 (8H, m), 2.63 (3H, s), 2.73 (2H, s), 3.52-3.68 (4H, m), 8.19 (1H, s). MS (ES+) 377 (M+1).

45
[ 504-73-4 ]
[ 288-14-2 ]

Yield	Reaction Conditions	Operation in experiment
	With toluene-4-sulfonic acid;	A solution of the crude isoxazoline and p-toluenesulfonic acid (2 g) was refluxed for 36 h. After that the solvent was removed in vacuo and the residue was chromatographed to give 2.86 g of crude isoxazole.

Reference： [1]Patent: US5260262,1993,A

Yield	Reaction Conditions	Operation in experiment
41%		32 a. 3-trifluoromethyl 5-(1'-t-butyloxycarbonyl-2'(S)-pyrrolidinyl)-isoxazole To a solution of the product of Example 1c (200 mg, 1.02 mmoL) in toluene (10 mL) was added solid K2 CO3 (414 mg, 3.00 mmoL) followed by freshly prepared (trifluoroacetyl) hydroximoyl chloride [W. J. Middleton, J. Org. Chem., (1984), 49, 919-922] (295 mg, 2.00 mmoL), and the reaction mixture brought to reflux. After refluxing for ~20 hours a second aliquot of K2 CO3 (~450 mg) and (trifluoroacetyl)hydroximoyl chloride (592 mg, 4.01 mmoL) were added and refluxing was continued for an additional 7 hours. The reaction mixture was then diluted with Et2 O (50 mL) and washed with 20-mL portions of sat aq. NaHCO3, 10% aq. citric acid and brine, then dried (MgSO4) and concentrated to afford the crude product as an oil. Chromatographic purification (silica, EtOAc/Hex 1:6) afforded the pure isoxazole as a pale yellow oil (130 mg, 41% yield). 1 H-NMR (CDCl3) delta: 6.35,6.29 (two br s, 1H); 5.11, 4.99 (two br s, 1H); 3.66-3.37 (br m, 2); 2.43-1.94 (br m, 4H); 1.47, 1.34 (s, 9H). MS(Cl) m/e 307 (M+H)+, 324 (M+NH4)+.

47
[ 288-14-2 ]
[ 138251-24-8 ]
[ 464917-76-8 ]
propyl 3-cyano-6-methyl-4-(3-phenylquinolin-5-yl)-1,4-dihydropyridine-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium; acetic acid; In propan-1-ol; water; ethyl acetate; toluene;	EXAMPLE 1 Propyl 3-cyano-6-methyl-4-(3-phenylquinolin-5-yl)-1,4-dihydropyridine-5-carboxylate STR16 2.33 g (10 mmol) of 3-phenylquinoline-5-carbaldehyde are treated in 20 ml of n-propanol with 0.69 g (10 mmol) of isoxazole. A solution of 0.23 g (10 mmol) of sodium in 6 ml of n-propanol is added dropwise to this suspension. The mixture is stirred at 40 C. for 4 hours, treated with 1.43 g (10 mmol) of propyl 3-aminocrotonate and 0.6 ml (10 mmol) of acetic acid and heated to reflux for 24 h. It is cooled and concentrated, and the residue is taken up in ethyl acetate/water. The aqueous phase is separated off, and the ethyl acetate phase is washed with water, dried and concentrated. The crude product obtained is purified by flash chromatography using toluene/ethyl acetate mixtures. After crystallization with acetonitrile, 1.4 g of colourless crystals of melting point 217-218 C. are obtained.

Reference： [1]Patent: US5514803,1996,A

Yield	Reaction Conditions	Operation in experiment
		b Methyl alpha-keto-alpha-(5-phenylisoxazol-3-yl)-acetate O-methyloxime (Table 3, No. 47) 50 ml of hypochlorite solution are added dropwise to a solution of 2 g (12.5 mmol) of the aldoxime from Example 21a and 2.55 g (25 mmol) of phenylacetylene 2 in 50 ml of methylene chloride while cooling. After 30 minutes at room temperature, the organic phase is separated off and the aqueous phase is extracted with methylene chloride. The organic phase is dried and evaporated down. Chromatography over silica gel with hexane/ethyl acetate gives 1.1 g (35%) of isoxazole 2 as a yellow oil. 1 H--NMR (CDCl3; delta in ppm): 7.4-7.9 (m, 5 H, phenyl); 6.9 (s, 1 H, isoxazolyl); 4.2 (s, 3 H, O--CH3); 3.95 (s, 3 H, O--CH3)

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 2 3-(3-Thienyl)isoxazole To a solution of 88.6 g of the dihydroisoxazole in 300 mL of methylene chloride was added 88 g of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) whereupon an exotherm caused the solvent to reflux. The solution was washed with aqueous HCl and with brine then was dried (Na2 SO4), concentrated, and distilled to afford 52 g of the isoxazole, bp 75-80 C./1 mm.

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 26 3-(4-CHLOROPHENYL)-5-AMINOISOXAZOLE 4-Chlorobenzoylacetonitrile (20 grams), sodium acetate (38 grams), hydroxylamine.HCl (29 grams), 350 ml. ethanol, and 350 ml. water were placed in a reaction vessel and heated to reflux for 3 hours. The final product can be collected either by removing the solvent and filtering directly or by extracting with chloroform, washing with 2 N NaOH, water, brine, and then drying with sodium sulfate. A yield of 5 grams of isoxazole was obtained and the structure was confirmed by NMR, m.p. 174-175 C.

51
[ 288-14-2 ]
2-cyano-4,4,17α-trimethylandrosta-2,5-diene-3,17β-diol [ No CAS ]
[ 87425-82-9 ]
[ 4248-66-2 ]
3-(acetyloxy)-17β-hydroxy-4,4,17α-trimethylandrosta-2,5-diene-2-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydroxylamine hydrochloride; sodium methylate; sodium acetate; pyridine hydrochloride; acetic anhydride; In tetrahydrofuran; pyridine; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; ethanol; water;	EXAMPLE 1 Preparation of 3-(acetyloxy)-17beta-hydroxy-4,4,17alpha-trimethylandrosta-2,5-diene-2-carbonitrile. STR2 A mixture of 12 g of (I), 250 ml of 95% ethanol, 2.8 g of hydroxylamine hydrochloride, and 2.8 g of sodium acetate was stirred and heated under reflux for 2 hr. Then 1.0 g of pyridine hydrochloride was added to the mixture, which contained the oxime (III) as well as the isoxazole (II). The mixture was stirred and heated under reflux for an additional 20 minutes, after which approximately 100 ml of solvent was removed by distillation under reduced pressure. The residue was poured into 2 liters of ice water. After ca. 1 hr. the solid, II, was collected by filtration, washed with water, and dried. STR3 To a solution of 10 g of (II) in 80 ml of tetrahydrofuran was added 3.5 g of sodium methoxide. The reaction mixture was stirred at 25 C. for 1 hr. after which it was diluted with 1 liter of water. The resultant mixture was extracted with ether, and the ether extract was set aside. The aqueous solution was acidified with 6 N HCl. The solid which formed was collected by filtration, washed with water, and dried. Crystallization from ethyl acetate gave a product melting at 224-226 C. NMR indicated it was a mixture of 2alpha-cyano-17beta-hydroxy-4,4,17alpha-trimethylandrost-5-en-3-one, 2beta-cyano-17beta-hydroxy-4,4,17alpha-trimethylandrost-5-en-3-one, and 2-cyano-4,4,17alpha-trimethylandrosta-2,5-diene-3,17beta-diol. STR4 A mixture of 5.0 g of 2alpha-cyano-17beta-hydroxy-4,4,17alpha-trimethylandrost-5-en-3-one, 2beta-cyano-17beta-hydroxy-4,4,17alpha-trimethylandrost-5-en-3-one, and 2-cyano-4,4,17beta-trimethylandrosta-2,5-diene-3,17beta-diol was dissolved in 40 ml of pyridine. After the addition of 30 ml of acetic anhydride, the reaction mixture was allowed to stand at 25 C. for 18 hr. The mixture was then diluted with a large volume (ca. 1 liter) of ice water. The mixture was allowed to stand for 0.5 hr. after which the solid product was collected by filtration, washed with water, and dried. Crystallization from ether-hexane afforded 4.5 g of the title compound, (IV), mp 159-161. Concentration of the mother liquor gave additional quantity of the title compound, mp 158-161.

Reference： [1]Patent: US4388311,1983,A

Yield	Reaction Conditions	Operation in experiment
55%		(a) 5-Bromomethyl-3-phenylisoxazole To a solution of propargyl bromide (1.51 ml, 20 mmol) in dichloromethane (15 ml) and aqueous sodium hyopchlorite (22.4 ml, 10%, 30 mmol) at 0 C. was added dropwise with stirring benzaldoxime (2.42 g, 20 mmol) in dichloromethane (15 ml). When addition was complete the ice bath was removed and the reaction stirred for a further 2 h. The organic layer was separated and the aqueous layer washed with dichloromethane (2*20 ml) then the combined organic layers dried (MgSO4). Solvent removal under reduced pressure gave a solid which was recrystallized from 40-60 C. petroleum ether fraction to give the desired isoxazole (2.64 g, 11.1 mmol, 55%); mp 82-3 C., deltaH (CDCl3) 4.40 (2H, s, CH2 --Br), 6.50 (1H, s, CH-4), 7.3-7.9 (5H, m, C6 H5).

Yield	Reaction Conditions	Operation in experiment
91%		EXAMPLE 3 3-Methyl-5-[2,6,6-trimethyl-cyclohex-1-en-1-yl]-isoxazole A solution of sodium hydrogenocarbonate (136 g) in 1300 ml of water was added, while stirring, to a solution of beta-ionone oxime (85 g; 0.410 mole) in 1500 ml of tetrahydrofuran. The process was then carried on in the absence of light, and a solution of potassium iodide (235 g; 1.41 moles) and iodine (109 g; 0.43 mole) in 1000 ml of water was added. After having been refluxed for 4 hours, the solution was allowed to stand overnight. After dilution with 1500 ml of a concentrated solution of sodium bisulphite in water the reaction mixture was extracted with ether (3 litres) and the combined organic extracts were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The fractional distillation of the thus obtained residue yielded 77.2 g of isoxazole (yield 91%), b.p. 70-71/0.03 Torr. Ir (chcl3): 2930, 1655, 1585, 1410 cm-1 Nmr (cdcl3): 1.00 (6H, s); 1.50 (3H, s); 2.27 (3H, s); 5.86 (1H, s); 1.5 - 2.2 (6H, multiplets) delta ppm Uv (95% ethanol): nm max 209, 224 Ms (70 eV): M+ = 205.

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 7 3-Methyl-5-[2-methylene-6,6-dimethyl-cyclohexyl]-isoxazole A solution of sodium hydrogenocarbonate (13.6 g in 230 ml of water was added to a solution of gamma-ionone oxime (8.5 g) in 150 ml of tetrahydrofuran. The process was then carried on as indicated in Example 1 by adding to the above mentioned solution a solution of potassium iodide (23.5 g) and iodine (10.9 g), whereupon the solution was refluxed for 4 hours. After cooling, the solution was extracted with petroleum-ether. After the usual treatment of drying and evaporation of the volatile portions the combined organic extracts yielded 8.4 g of crude product which, by fractional distillation, gave 6.0 g of the desired isoxazole in the form of a yellowish oil. B.p. 130/0.001 Torr. The analysis carried out by means of a sample obtained by vapour phase chromatography ("Carbowax" column, 3 m, 180) showed that the obtained product was constituted by two substances in a ratio by weight of 80:20, the main product being the desired isoxazole. nD = 1.5025; d420 = 1.005. Ir: 3080, 1640, 1590, 890 cm-1 Nmr: 0.92 (6h, 2s); 2.21 (3H, s); 3.3 (1H, s); 4.58 and 4.76 (2H, 2m); 5.75 (1H, s) delta ppm Ms: m+ = 205 (23); m/e: 190 (13); 177 (25); 162 (8); 149 (10); 137 (100); 122 (10); 108 (15); 97 (13); 82 (15); 69 (63); 55 (13); 41 (50); 27 (38).

Yield	Reaction Conditions	Operation in experiment
57%		EXAMPLE 5 3,4-Dimethyl-5-[2,6,6-trimethyl-cyclohex-2-en-1-yl]-isoxazole A solution of sodium hydrogenocarbonate (4.50 g) in 25 ml of water was added, while stirring, to a solution of alpha-isomethyl ionone oxime (2.42 g; 0.011 mole) in 30 ml of tetrahydrofuran. The process was then carried on in the absence of light, and a solution of potassium iodide (5.80 g) and iodine (2.84 g; 0.011 mole) in 15 ml of water was added. After having been refluxed for 18 hours, the reaction mixture was poured into a concentrated solution of sodium bisulphite (130 ml), extracted with ether (150 ml), and the organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The fractional distillation of the obtained residue yielded 1.380 g of the desired isoxazole (yield 57%): b.p. 72-74/0.04 Torr. Ir (chcl3): 2910, 1620, 1440, 1414 cm-1 Nmr (cdcl3): 0.72 (3H, s); 1.00 (3H, s); 1.50 (3H, m); 1.90 (3H, s); 2.14 (3H, s); 2.96 (1H, broad band, s); 5.63 (1H, m); 1.2 - 2.2 (4H, multiplets) delta ppm Uv (95% ethanol): nm max 225 (epsilon 8150) Ms (70 eV): M+ = 219.

Yield	Reaction Conditions	Operation in experiment
		b. A solution of sodium hydrogenocarbonate (13.6 g) in 230 ml of water was added to a solution of gamma-ionone oxime (8.5 g) in 150 ml of tetrahydrofuran. The process was then carried on as indicated in Example 1 by adding to the above mentioned solution a solution of potassium iodide (23.5 g) and iodine (10.9 g), whereupon the solution was refluxed for 4 hours. After cooling the solution was extracted with petroleum-ether. After the usual treatment of drying and evaporation of the volatile portions the combined organic extracts yielded 8.4 g of crude product which, by fractional distillation, gave 6.0 g of the desired isoxazole in the form of a yellowish oil. B.p. 130/0.001 Torr. The analysis carried out by means of a sample obtained by vapour phase chromatography ("Carbowax" column, 3 m, 180) showed that the obtained product was constituted by two substances in a ratio by weight of 80:20, the main product being 3-methyl-5-[2-methylene-6,6-dimethyl-cyclohexyl]-isoxazole.

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 10 The general procedure described in Example 2, Step E was repeated except tert-butylamine used therein was replaced by methlamine to provide 5-cyclopropylisoxazole-4-(N-methyl)-carboxamide, m.p. 77-80 C. he isoxazole thus obtained may be subjected to treatment with NaOH using the procedue of Example 2, Step F to provide the product of Example 1.

58
[ 288-14-2 ]
[ 86-81-7 ]
α-cyano-trimethoxycinnamaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; water; acetic acid;	EXAMPLE 1 1,235 parts of an about 31 percent strength solution of isoxazole in methanol are added dropwise to 1,980 parts of about 30 percent strength sodium methylate solution and 750 parts of methanol, whilst cooling and stirring. During this addition the temperature may rise sufficiently to cause the contents of the reaction vessel to boil, and reflux cooling is therefore necessary. The mixture is stirred for a further 30 minutes under reflux and is then cooled to 40 C., and 980 parts of 97 percent pure 3,4,5-trimethoxy-benzaldehyde are added. The reaction mixture is then stirred for 2 hours at 40 C. and poured into 7,500 parts of water whilst stirring, glacial acetic acid is added until the pH is 5, and the precipitate is filtered off whilst the mixture is hot, and is washed with water and dried in a drying oven. Yield of alpha-cyanotrimethoxycinnamaldehyde, 1,009 parts=84.2% of theory; melting point 185-188 C. The product is in the form of yellow needles. After recrystallization from ethyl acetate, the pure compound melts at 191-192 C.

Reference： [1]Patent: US4172090,1979,A

Yield	Reaction Conditions	Operation in experiment
		c) 3-Methyl-5-[1-(tetrahydropyran-2-yl)-oxy]-ethyl isoxazole-4-carboxylic acid methyl ester A solution of 0.68g of nitroethane and 0.1g of triethylamine in 20ml of benzene was added dropwise over a period of 2 hours to a solution of 0.83g of the compound prepared in b) above and 1.96g of phenyl isocyanate in 25ml of dry benzene. The reaction mixture was stirred at room temperature for 20 hours, then diluted with 50ml of a 1:1 (by volume) mixture of diethyl ether and petroleum ether, filtered and the solvent removed. Following silica gel chromatography using diethyl ether/hexane (1:4 by volume) as eluant, 0.81g of the isoxazole was obtained as a colourless oil. Analysis (%): Calc. C 57.9 H 7.1 N 5.2 Found C 58.2 H 7.2 N 5.6

Yield	Reaction Conditions	Operation in experiment
20%		Step 2: 6,6-Dimethyl-1-(isoxazol-5-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one A solution of 6,6-dimethyl-1-(3-hydroxy-1-oxoprop-2-enyl)-3-methylthio-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one (200 mg, 0.68 mmol) in ethanol (14 mL) and water (1.6 mL) was heated to 80 C., after which hydroxylamine hydrochloride (52 mg, 0.74 mmol) was added. The mixture was heated at reflux for 4 h, after which time the solvent was removed in vacuo and the residue triturated in hexane/ether. The isoxazole (50 mg, 20%) was isolated as a colourless solid. mp 143-145 C. 1H NMR (360 MHz, CDCl3) delta 1.09 (6H, s), 2.45 (2H, s), 2.64 (3H, s), 2.90 (2H, s), 6.28 (1H, d, J=1.9 Hz), 8.29 (1H, d, J=1.9 Hz). MS (ES+) 294 (M+1).

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 50 4-(5-Furan-2-yl-isoxazol-3-yl)-phenol To a mixture of 3-furan-2-yl-1-(4-hydroxy-phenyl)-propenone (0.4 g, 1.9 mmol) and hydroxylamine hydrochloride (0.2 g, 2.85 mmol) was added sodium hydroxide (0.15 g, 2.8 mmol). The reaction mixture was heated to reflux for 3 days. The mixture was then concentrated, and neutralized with diluted HCl. Ethyl acetate and water were then added, and the mixture was shaken. The organic layer was separated and dried over sodium sulfate. The solvent was removed and the residue was purified by column chromatography (eluted with 20% ethyl acetate/hexanes) to give the desired isoxazole in poor yield (50 mg). 1H NMR (400 MHz, DMSO) delta=6.65 (d, 1H), 6.85 (d, 2H), 7.05 (d, 1H), 7.15 (s, 1H), 7.75 (d, 2H), 7.85 (d, 1H). MS calculated=m/e 227, found=m/e 227.

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 51 5-Furan-2-yl-3-(4-methoxy-phenyl)-isoxazole To a mixture of 3-furan-2-yl-1-(4-methoxy-phenyl)-propenone (0.4 g, 1.75 mmol) and hydroxylamine hydrochloride (0.18 g, 2.6 mmol), was added sodium hydroxide (0.14 g, 3.5 mmol). The reaction mixture was heated to reflux for 3 days. The mixture was then concentrated, and neutralized with diluted HCl. Then ethyl acetate and water were added. The organic layer was separated and dried over sodium sulfate. The solvent was removed and the residue was purified by column chromatography (silica, eluted with 20% ethyl acetate/hexanes) to give the desired isoxazole in poor yield (10 mg).

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 52 5-Furan-2-yl-3-(4-phenoxy-phenyl)-isoxazole To a mixture of 3-furan-2-yl-1-(4-phenoxy-phenyl)-propenone (0.4 g, 1.4 mmol) and hydroxylamine hydrochloride (0.14 g, 2.1 mmol), was added sodium hydroxide (0.11 g, 2.8 mmol). The reaction mixture was heated to reflux for 3 days. The mixture was then concentrated, and neutralized with diluted HCl. Ethyl acetate and water were added. The organic layer was separated and dried over sodium sulfate. The solvent was removed and the residue was purified by column chromatography (silica, eluted with 20% ethyl acetate/hexanes) to give the desired isoxazole in poor yield (10 mg).

Yield	Reaction Conditions	Operation in experiment
		Example 108 Compound 131 The phenyllithium intermediate was reacted with N-methoxy-N-methylacetamide and the resulting acetophenone was reacted with dimethylformamide dimethylacetal and hydroxylamine-O-sulfonic acid in methanol in presence of pyridine to give the isoxazole. LRMS (ESI+) m/z: 347.0 (M-H+ C14H13Cl2N2O3 requires 347.0)

65
[ 288-14-2 ]
[ 110-18-9 ]
[ 7637-07-2 ]
[ 10294-34-5 ]
[ 71963-95-6 ]
[ 256389-18-1 ]
[ 256389-14-7 ]
(N,N,N',N'-tetramethylethylenediamine)BF₂^(1-), chloride salt [ No CAS ]
(N,N,N',N'-tetramethylethylenediamine)BFCl^(1-) [ No CAS ]

Reference： [1]Canadian Journal of Chemistry,1999,vol. 77,p. 1856 - 1868

66
[ 288-14-2 ]
[ 110-18-9 ]
[ 7637-07-2 ]
[ 10294-34-5 ]
[ 71963-95-6 ]
[ 256389-13-6 ]

Reference： [1]Canadian Journal of Chemistry,1999,vol. 77,p. 1856 - 1868

67
[ 288-14-2 ]
[ 25327-03-1 ]
Mn⁽²⁺⁾*2C₃H₃NO*2NCS^(1-)=Mn(C₃H₃NO)2(NCS)2 [ No CAS ]

Reference： [1]Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy,1980,vol. 36,p. 143 - 150

68
[ 288-14-2 ]
manganese(II) bromide [ No CAS ]
Mn⁽²⁺⁾*2C₃H₃NO*2Br^(1-)=Mn(C₃H₃NO)2Br₂ [ No CAS ]

Reference： [1]Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy,1980,vol. 36,p. 143 - 150

69
[ 288-14-2 ]
manganese(ll) chloride [ No CAS ]
Mn⁽²⁺⁾*2C₃H₃NO*2Cl^(1-)=Mn(C₃H₃NO)2Cl₂ [ No CAS ]

Reference： [1]Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy,1980,vol. 36,p. 143 - 150

70
[ 288-14-2 ]
manganese(II) iodide [ No CAS ]
Mn⁽²⁺⁾*2C₃H₃NO*2I^(1-)*H₂O=Mn(C₃H₃NO)2I₂*H₂O [ No CAS ]

Reference： [1]Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy,1980,vol. 36,p. 143 - 150

71
[ 288-14-2 ]
[ 115245-01-7 ]
[ 13820-81-0 ]
[ 80679-88-5 ]

Reference： [1]Inorganic Chemistry,1982,vol. 21,p. 2089 - 2091

72
[ 288-14-2 ]
[ 150-77-6 ]
[ 7637-07-2 ]
[ 10294-34-5 ]
[ 352516-05-3 ]
(N,N,N',N'-tetraethylethylenediamine)BFCl⁽¹⁺⁾ [ No CAS ]
[ 352516-02-0 ]
N,N,N',N'-tetraethylethylenediamine boron trichloride adduct [ No CAS ]
N,N,N',N'-tetraethylethylenediamine BFCl₂ adduct [ No CAS ]

Reference： [1]Canadian Journal of Chemistry,2001,vol. 79,p. 426 - 436

73
[ 288-14-2 ]
iron(II) perchlorate hexahydrate [ No CAS ]
[ 64-19-7 ]
[ 606968-00-7 ]

Reference： [1]Inorganic Chemistry,2003,vol. 42,p. 5645 - 5653

74
[ 288-14-2 ]
iron(II) perchlorate hexahydrate [ No CAS ]
[ 127-09-3 ]
[ 606968-00-7 ]

Reference： [1]Inorganic Chemistry,2003,vol. 42,p. 5645 - 5653

75
[ 288-14-2 ]
iron(II) perchlorate hexahydrate [ No CAS ]
[ 108-24-7 ]
[Fe(isoxazole)6](ClO₄)2 [ No CAS ]
[ 606968-00-7 ]

Reference： [1]Inorganic Chemistry,2003,vol. 42,p. 5645 - 5653

76
[ 288-14-2 ]
ferrous perchlorate [ No CAS ]
[Fe(isoxazole)6](ClO₄)2 [ No CAS ]

Reference： [1]Inorganica Chimica Acta,1977,vol. 21,p. 217 - 222

77
[ 288-14-2 ]
[ 7550-45-0 ]
TiCl₄C₃H₃NO [ No CAS ]

Reference： [1]Synthesis and Reactivity in Inorganic and Metal-Organic Chemistry,1995,vol. 25,p. 115 - 126

78
[ 288-14-2 ]
[ 7550-45-0 ]
[ 161645-55-2 ]

Reference： [1]Synthesis and Reactivity in Inorganic and Metal-Organic Chemistry,1995,vol. 25,p. 115 - 126

79
[ 288-14-2 ]
[ 7789-68-6 ]
[ 161645-56-3 ]

Reference： [1]Synthesis and Reactivity in Inorganic and Metal-Organic Chemistry,1995,vol. 25,p. 115 - 126

80
[ 288-14-2 ]
hexaaquairon(II) tetrafluoroborate [ No CAS ]
[Fe(isoxazole)6](BF₄)2 [ No CAS ]

Reference： [1]Inorganica Chimica Acta,1977,vol. 21,p. 217 - 222

81
[ 288-14-2 ]
iron(II) tetrafluoroborate hexahydrate [ No CAS ]
[Fe(isoxazole)6](BF₄)2 [ No CAS ]

Reference： [1]Inorganic Chemistry,2003,vol. 42,p. 5645 - 5653

82
[ 288-14-2 ]
[ 3030-47-5 ]
[ 7637-07-2 ]
[ 10294-34-5 ]
[ 256389-16-9 ]
[ 256389-03-4 ]
(N,N,N',N'',N''-pentamethyldiethylenetriamine) * BCl₃ [ No CAS ]
(N,N,N',N''N''-pentamethyldiethylenetriamine)BF₂^(1-) [ No CAS ]
(N,N,N',N'',N''-pentamethyldiethylenetriamine)BFCl^(1-) [ No CAS ]

Reference： [1]Canadian Journal of Chemistry,1999,vol. 77,p. 1856 - 1868

83
[ 288-14-2 ]
[ 110-18-9 ]
[ 7637-07-2 ]
[ 10294-33-4 ]
(N,N,N',N'-tetramethylethylenediamine)BFBr₂ [ No CAS ]
(N,N,N',N'-tetramethylethylenediamine)BFBr⁽¹⁺⁾ [ No CAS ]
[ 256388-94-0 ]

Reference： [1]Canadian Journal of Chemistry,1999,vol. 77,p. 1856 - 1868

84
[ 288-14-2 ]
[ 3030-47-5 ]
[ 7637-07-2 ]
[ 10294-33-4 ]
[ 256389-03-4 ]
(N,N,N',N''N'''-pentametnyldiethylenetriamine)BFBr⁽¹⁺⁾ [ No CAS ]
(N,N,N',N''N''-pentamethyldiethylenetriamine)BF₂^(1-) [ No CAS ]

Reference： [1]Canadian Journal of Chemistry,1999,vol. 77,p. 1856 - 1868

85
[ 288-14-2 ]
hexakis(aquo)cadmium(II) fluoroborate [ No CAS ]
[Cd(isoxazole)6](BF₄)2 [ No CAS ]

Reference： [1]Inorganica Chimica Acta,1977,vol. 21,p. 217 - 222

86
[ 288-14-2 ]
hexakis(aquo)manganese(II) fluoroborate [ No CAS ]
[Mn(isoxazole)6](BF₄)2 [ No CAS ]

Reference： [1]Inorganica Chimica Acta,1977,vol. 21,p. 217 - 222

87
[ 288-14-2 ]
zinc tetrafluoroborate hexahydrate [ No CAS ]
[Zn(isoxazole)6](BF₄)2 [ No CAS ]

Reference： [1]Inorganica Chimica Acta,1977,vol. 21,p. 217 - 222

88
[ 288-14-2 ]
{Ph3P(benzyl)}2{Pt2(μ-Cl)2Cl4} [ No CAS ]
[ 216388-88-4 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1998,p. 3139 - 3140

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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. 288-14-2 ] {[proInfo.proName]}

Quality Control of [ 288-14-2 ]

Related Doc. of [ 288-14-2 ]

Product Details of [ 288-14-2 ]

Calculated chemistry of [ 288-14-2 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 288-14-2 ]

Application In Synthesis of [ 288-14-2 ]

[ 288-14-2 ] Synthesis Path-Upstream 1~7

[ 288-14-2 ] Synthesis Path-Downstream 1~88

Related Parent Nucleus of [ 288-14-2 ]

Isoxazoles

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Parent Nucleus of
[ 288-14-2 ]