[ CAS No. 5735-53-5 ] {[proInfo.proName]}

Name: 5735-53-5|Benzomorpholine|97%
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Quality Control of [ 5735-53-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 5735-53-5 ]

CAS No. :	5735-53-5	MDL No. :	MFCD02181098
Formula :	C₈H₉NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YRLORWPBJZEGBX-UHFFFAOYSA-N
M.W :	135.16	Pubchem ID :	585096
Synonyms :

Calculated chemistry of [ 5735-53-5 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.25
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	43.06
TPSA :	21.26 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) :	-5.95 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.66
Log Po/w (XLOGP3) :	1.65
Log Po/w (WLOGP) :	0.92
Log Po/w (MLOGP) :	1.09
Log Po/w (SILICOS-IT) :	1.93
Consensus Log Po/w :	1.45

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.16
Solubility :	0.932 mg/ml ; 0.00689 mol/l
Class :	Soluble
Log S (Ali) :	-1.71
Solubility :	2.64 mg/ml ; 0.0195 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.71
Solubility :	0.265 mg/ml ; 0.00196 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.82

Safety of [ 5735-53-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 5735-53-5 ]

* 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 [ 5735-53-5 ]
Downstream synthetic route of [ 5735-53-5 ]

[ 5735-53-5 ] Synthesis Path-Upstream 1~22

1
[ 106-93-4 ]
[ 95-55-6 ]
[ 5735-53-5 ]

Yield	Reaction Conditions	Operation in experiment
65%	With potassium carbonate In N,N-dimethyl-formamide at 125℃; for 15 h;	To a suspension of 2-aminophenol (1.0 g, 9.2 mmol) and potassium carbonate (6.36 g, 46 mmol) in dry DMF (10 mL) was added 1, 2-dibromoethane (2.59 g, 13.8 mmol). The mixture was then heated at 125'C for 15 hours. After cooling, the mixture was treated with crushed ice and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum ether 1:10 (v:v) as eluent to give 3,4- dihydro-2H-benzo[b][1,4]oxazine as reddish oil (0.81 g, 65percent). LC-MS (ES-API); rt 7.51 min; m/z calculated for C₈H₉NO [M+Hf 136.1, found 136.1.
29%	With potassium carbonate In water; acetone for 24 h; Reflux	1 , 2-Dibromoethane (1.51 g, 13.87 mmol) was dissolved in 100 mL of acetone and a solution of 3.19 g of K₂CO₃ in 30 mL of water was added. A solution of 2-aminophenol in 10 mL of acetone suspension was added slowly to the suspension. The solution was heated to reflux for 24 hours. The acetone was evaporated to dryness. The residue was dissolved in water and extracted with dichloromethane . The combined organic layer was washed with brine, dried over Na₂SO₄ and evaporated to dryness. The residue was purified by chromatography eluted with petroleum ether :ether acetate=50:l to 10:1 to obtain 450 mg of the target product as brown oil (yield: 29percent, ) .

Reference： [1] Tetrahedron Letters, 2006, vol. 47, # 44, p. 7823 - 7826
[2] Patent: WO2011/47432, 2011, A1, . Location in patent: Page/Page column 88
[3] Heterocyclic Communications, 2012, vol. 18, # 3, p. 143 - 146
[4] Patent: WO2010/51374, 2010, A1, . Location in patent: Page/Page column 132
[5] Patent: EP2172453, 2010, A1, . Location in patent: Page/Page column 13
[6] Patent: WO2011/103460, 2011, A1, . Location in patent: Page/Page column 240

2
[ 70801-52-4 ]
[ 82756-78-3 ]
[ 5735-53-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	With triethyl borane; Triethoxysilane; sodium hydroxide In hexane at 80℃; for 6 h; Inert atmosphere; Sealed tube	Under argon atmosphere, NaOH and triethyl boron were first stirred at room temperature to form a clear clear solution at a concentration of 1 M / L;Subsequently, 10 mol (2 molpercent) of the above-mentioned triethylboron solution, 5 mmol of amide substrate, 15 mmol of silane, 2 mL of solventInto a 10 mL sealed tube and placed in an oil bath at 80 ° C for 6 hours with heating. The reaction was completed and the reaction was exposed to air quenching, followed byThe yield was determined by column chromatography and gas chromatography and a pure product was obtained. When using polymethylhydrogensiloxane (PMHS) andWhen the tetrahydrofuran was used as the silane and the solvent, the yields of the products A and B were 81percent and 3percent, respectively. When the triethoxysilaneAnd n-hexane as silane and solvent, respectively, the yield of products A, B were: 90percent, 7percent

Reference： [1] Patent: CN107235845, 2017, A, . Location in patent: Paragraph 0102; 0103; 0104; 0105

3
[ 87762-20-7 ]
[ 5735-53-5 ]

Reference： [1] Journal of the American Chemical Society, 2001, vol. 123, # 49, p. 12202 - 12206
[2] Journal of the American Chemical Society, 2000, vol. 122, # 51, p. 12907 - 12908

4
[ 95-55-6 ]
[ 5735-53-5 ]

Yield	Reaction Conditions	Operation in experiment
68%	Stage #1: With sodium hydride In dichloromethane at 0℃; for 0.0833333 h; Inert atmosphere Stage #2: at 25 - 30℃; for 15 h; Inert atmosphere	General procedure: A stifling solution of the requisite phenol derivative, (10 mmol) in CH₂Cl₂(20 mL) was treated with NaH (35 mmol) at 0° C. under argon. After 5 minutes, 2-bromoethyldiphenylsulfonium salt (12 mmol) was added and the reaction was stirred for 5 hours at RT. The reaction was then quenched with saturated ammonium chloride solution (10 mL), and extraction was performed with CH₂Cl₂(3×25 mL), washed with brine (20 mL), the resultant was dried over MgSO₄, filtered and concentrated under vacuum. The targeted compound was then purified using chromatography on silica.

Reference： [1] Patent: US2014/323720, 2014, A1, . Location in patent: Paragraph 0063; 0064; 0083; 0084

5
[ 5466-88-6 ]
[ 5735-53-5 ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: With lithium aluminium tetrahydride In tetrahydrofuranHeating / reflux Stage #2: With sodium hydroxide; water In tetrahydrofuran	Synthesis of 3,4-dihydro-2H-benzo[b][1,4]oxazine Into a 250 mL 3-necked round-bottom flask, was placed a solution of lithium aluminum hydride (3.6 g, 94.74 mmol) in THF (80 mL). The mixture was stirred for 15 min. This was followed by the addition of a solution of 2H-benzo[b][1,4]oxazin-3(4H)-one (5.7 g, 38.22 mmol) in THF (21 mL), which was added dropwise with stirring. The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at reflux in a bath of oil. The reaction progress was monitored by TLC (EtOAc/PE=1:1). The reaction mixture was then quenched by the adding 3.6 mL of H₂O and 10.8 mL 15percent NaOH. A filtration was performed. The filter cake was washed 1 time with 30 mL of THF. The resulting solution was extracted two times with 100 mL of EtOAc and the organic layers combined and dried over Na₂SO₄ and concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 4.8 g (79percent) of 3,4-dihydro-2H-benzo[b][1,4]oxazine as a red oil.
79%	Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran for 16 h; Heating / reflux Stage #2: With sodium hydroxide In tetrahydrofuran; water	A solution of 2H-benzo[b][1,4]oxazin-3(4H)-one (38.2 mmol) in tetrahydrofuran (21 mL) was slowly added to a suspension of lithium aluminum hydride (94.7 mmol) in tetrahydrofuran (80 mL) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was diluted with water (3.6 mL) and 15percentsodium hydroxide (10.8 mL) and the insoluble solids were removed by filtration. The aqueous layer was extracted with ethyl acetate (2 x 100 mL) and the combined organic layers were dried (sodium sulfate) and concentrated to provide 3,4-dihydro-2H-benzo[b][1,4]oxazine in 79percent yield as red oil.
79%	Stage #1: With lithium aluminium tetrahydride In tetrahydrofuranHeating / reflux Stage #2: With sodium hydroxide In water	Synthesis of 3,4-dihydro-2H-benzo[b][1,4]oxazine Into a 250 mL 3-necked round-bottom flask, was placed a solution of lithium aluminum hydride (3.6 g, 94.74 mmol) in THE (80 mL). The mixture was stirred for 15 minutes. This was followed by the addition of a solution of 2H-benzo[b][1,4]oxazin-3(4H)-one (5.7 g, 38.22 mmol) in THF (21 mL), which was added dropwise with stirring. The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at reflux in a bath of oil. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:1). The reaction mixture was then quenched by the adding 3.6 mL of H₂O and 10.8 mL 15percentNaOH. A filtration was performed. The filter cake was washed 1 time with 30 mL of THF. The resulting solution was extracted two times with 100 mL of ethyl acetate and the organic layers combined and dried over Na₂SO₄ and concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 4.8 g (79percent) of 3,4-dihydro-2H-benzo[b][1,4]oxazine as red oil.

79%	Stage #1: With lithium aluminium tetrahydride In tetrahydrofuranReflux Stage #2: With water; sodium hydroxide In tetrahydrofuran	Intermediate 31: Synthesis of 4-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-6-sulfonyl chloride.1. Synthesis of 3,4-dihydro-2H-benzo\|^"b^"\|\|^"l,4^"\|oxazine.A solution of 2H-benzo[b][l,4]oxazin-3(4H)-one (38.2 mmol) in tetrahydrofuran (21 mL) was slowly added to a suspension of lithium aluminum hydride (94.7 mmol) in tetrahydrofuran (80 mL) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was diluted with water (3.6 mL) and 15percentsodium hydroxide (10.8 mL) and the insoluble solids were removed by filtration. The aqueous layer was extracted with ethyl acetate (2 x 100 mL) and the combined organic layers were dried (sodium sulfate) and concentrated to provide 3,4-dihydro-2H- benzo[b][l,4]oxazine in 79percent yield as red oil.
79%	With lithium aluminium tetrahydride In tetrahydrofuran for 16 h; Reflux	A solution of 2H-benzo[b][1,4]oxazin-3(4H)-one (38.2 mmol) in tetrahydrofuran (21 mL) was slowly added to a suspension of lithium aluminum hydride (94.7 mmol) in tetrahydrofuran (80 mL) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was diluted with water (3.6 mL) and 15percent sodium hydroxide (10.8 mL) and the insoluble solids were removed by filtration. The aqueous layer was extracted with ethyl acetate (2.x.100 mL) and the combined organic layers were dried (sodium sulfate) and concentrated to provide 3,4-dihydro-2H-benzo[b][1,4]oxazine in 79percent yield as red oil.
79%	Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran for 16 h; Reflux Stage #2: With water In tetrahydrofuran	Intermediate 31: Synthesis of 4-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-6-sulfonyl chloride.1. Synthesis of 3,4-dihvdro-2i/-benzo\|^'b][l,4^"\|oxazine.A solution of 2H-benzo[b][l,4]oxazin-3(4H)-one (38.2 mmol) in tetrahydrofuran (21 mL) was slowly added to a suspension of lithium aluminum hydride (94.7 mmol) in tetrahydrofuran (80 mL) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was diluted with water (3.6 mL) and 15percentsodium hydroxide (10.8 mL) and the insoluble solids were removed by filtration. The aqueous layer was extracted with ethyl acetate (2 x 100 mL) and the combined organic layers were dried (sodium sulfate) and concentrated to provide 3,4-dihydro-2H- benzo[b][l,4]oxazine in 79percent yield as red oil.
79%	With lithium aluminium tetrahydride In tetrahydrofuran for 16 h; Reflux	A solution of 2H-benzo[b][1,4]oxazin-3(4H)-one (38.2 mmol) in tetrahydrofuran (21 mL) was slowly added to a suspension of lithium aluminum hydride (94.7 mmol) in tetrahydrofuran (80 mL) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was diluted with water (3.6 mL) and 15percent sodium hydroxide (10.8 mL) and the insoluble solids were removed by filtration. The aqueous layer was extracted with ethyl acetate (2*100 mL) and the combined organic layers were dried (sodium sulfate) and concentrated to provide 3,4-dihydro-2H-benzo[b][1,4]oxazine in 79percent yield as red oil.
79%	Stage #1: With lithium aluminium tetrahydride In tetrahydrofuranHeating / reflux Stage #2: With sodium hydroxide; water In tetrahydrofuran	Into a 250 mL 3-necked round bottom flask was placed a solution of lithium aluminum hydride (3.6 g, 94.74 mmol) in tetrahydrofuran (80 mL). The mixture was stirred for 15 minutes. This was followed by the addition of a solution of 2H-benzo[b][l,4]oxazin-3(4H)-one (5.7 g, 38.22 mmol) in tetrahydrofuran (21 mL), which was added drop wise with stirring. The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at reflux in a bath of <n="132"/>oil. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether = 1:1). The reaction mixture was then quenched by the adding 3.6 mL of H₂O and 10.8 mL 15percentNaOH. A filtration was performed. The filter cake was washed with 30 mL of tetrahydrofuran. The resulting solution was extracted two times with 100 mL of ethyl acetate and the organic layers combined and dried over Na₂SO₄ and concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 4.8 g (79percent) of 3,4-dihydro-2H-benzo[b]fl,4]oxazine as red oil.
72%	With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 16 h;	General procedure: LAH (2 equiv.) in THF (100 mL) was cooled to 0oC inan ice bath under nitrogen. A solution of 4 (1 equiv.) in THF (20 mL) was added dropwise, and the resulting solution was stirred at RT for 16 hrs. The reaction mixture was cooled to 0oC andcarefully quenched with water (2 mL), 2 N NaOH (2 mL) and water (8 mL). The resulting slurrywas stirred at RT for 1 h and filtered through Celite. The filter cake was washed with ethylacetate and discarded. The filtrate was dried (Na2SO4), separated and concentrated to afford 5 asa colorless oil.
50%	Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; Reflux Stage #2: With water; sodium hydroxide In tetrahydrofuran at 0℃;	Step B: 3,4-Dihydro-2H-benzo[l,4]oxazine. To a mixture of LAH (3.6 g, 94.74 mmol) in THF (80 ml) was added a solution of 4H-Benzo[l,4]oxazin-3-one (5.7 g, 38.22 mmol) in THF (21 ml) dropwise at room temperature. The reaction mixture was refluxed overnight. The resulting mixture was cooled to 0°C and then quenched by the adding 3.6 ml of H₂0, followed by 10.8 ml 15percent NaOH solution. The precipitate was filtered off and the solvent was extracted with EtOAc (2x50 ml). The organic layer was washed with brine, dried over Na2S04, filtered and concentrated to give the 3,4-dihydro-2H-benzo[b][l,4]oxazine as red oil which was pure enough to be used directly (1.5 g , 50percent yield). 1H NMR (300 MHz, DMSO-d6): δ 6.67-6.41 (m, 4H), 5.68 (s, 1H), 4.11-4.07 (m, 2H), 3.27-3.24 (m, 2H).
4.3 g	With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 16 h; Inert atmosphere; Reflux	Synthesis of 3,4-dihydro-2H-1,4-benzoxazine (Intermediate-29) A solution of Starting Material-13(5 g, 33.5 mmol) in tetrahydrofuran (50 mL) was slowly added to a suspension of lithium aluminum hydride (3.18 g, 83.8 mmol) under N₂ atmosphere at 0° C. The reaction mixture was refluxed for 16 h. The reaction mixture was diluted with EtOAc, quenched with 15percent aqueous sodium hydroxide solution at 0° C., and extracted with ether, and concentrated to give Intermediate-29 as brown liquid (4.3 g).

Reference： [1] Archiv der Pharmazie, 2018, vol. 351, # 5,
[2] Patent: US2008/318941, 2008, A1, . Location in patent: Page/Page column 24
[3] Patent: WO2009/23844, 2009, A2, . Location in patent: Page/Page column 121
[4] Patent: US2008/200471, 2008, A1, . Location in patent: Page/Page column 47
[5] Patent: WO2010/21797, 2010, A1, . Location in patent: Page/Page column 86
[6] Patent: US2010/29629, 2010, A1, . Location in patent: Page/Page column 58
[7] Patent: WO2010/24980, 2010, A1, . Location in patent: Page/Page column 104
[8] Patent: US2010/22581, 2010, A1, . Location in patent: Page/Page column 37; 41
[9] Patent: WO2007/98418, 2007, A1, . Location in patent: Page/Page column 130-131; 141
[10] Synthesis (Germany), 2014, vol. 46,
[11] Patent: WO2012/9678, 2012, A1, . Location in patent: Page/Page column 222-223
[12] Australian Journal of Chemistry, 1956, vol. 9, p. 397,402
[13] Patent: US4721784, 1988, A,
[14] Patent: US6248739, 2001, B1,
[15] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 17, p. 7956 - 7967
[16] Patent: US2008/305169, 2008, A1,
[17] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 16, p. 4700 - 4704
[18] Patent: US2010/16297, 2010, A1, . Location in patent: Page/Page column 26
[19] Patent: US2007/10670, 2007, A1, . Location in patent: Page/Page column 79-80
[20] Patent: US2007/197512, 2007, A1, . Location in patent: Page/Page column 49
[21] Patent: WO2011/26085, 2011, A2, . Location in patent: Page/Page column 58
[22] Patent: WO2011/48148, 2011, A2, . Location in patent: Page/Page column 60
[23] Patent: WO2011/48112, 2011, A1, . Location in patent: Page/Page column 79-80; 90
[24] Patent: US2011/171159, 2011, A1, . Location in patent: Page/Page column 33
[25] Patent: US2012/196813, 2012, A1, . Location in patent: Page/Page column 25
[26] Patent: WO2013/128465, 2013, A1, . Location in patent: Page/Page column 98
[27] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2670 - 2682
[28] Patent: US2015/158860, 2015, A1, . Location in patent: Paragraph 0345
[29] Patent: US2008/64871, 2008, A1, . Location in patent: Page/Page column 43
[30] Patent: US2008/64871, 2008, A1, . Location in patent: Page/Page column 87; 88; 89; 89-90

6
[ 55339-51-0 ]
[ 5735-53-5 ]
[ 77901-22-5 ]

Reference： [1] Journal of Heterocyclic Chemistry, 2003, vol. 40, # 6, p. 1031 - 1039

7
[ 82415-84-7 ]
[ 5735-53-5 ]

Reference： [1] Heterocycles, 2009, vol. 78, # 5, p. 1183 - 1190
[2] Journal of Organic Chemistry, 2010, vol. 75, # 3, p. 627 - 636
[3] Chemical and Pharmaceutical Bulletin, 2014, vol. 62, # 4, p. 354 - 363

8
[ 31507-30-9 ]
[ 5735-53-5 ]

Reference： [1] Tetrahedron Letters, 2007, vol. 48, # 15, p. 2765 - 2768

9
[ 70801-52-4 ]
[ 5735-53-5 ]

Reference： [1] Archiv der Pharmazie, 1982, vol. 315, # 6, p. 538 - 545

10
[ 438013-84-4 ]
[ 5735-53-5 ]

Reference： [1] Tetrahedron Letters, 2010, vol. 51, # 2, p. 435 - 438

11
[ 19202-00-7 ]
[ 5735-53-5 ]
[ 100-52-7 ]

Reference： [1] Archiv der Pharmazie, 1982, vol. 315, # 6, p. 538 - 545

12
[ 212180-23-9 ]
[ 5735-53-5 ]

Reference： [1] Journal of Heterocyclic Chemistry, 2006, vol. 43, # 4, p. 1125 - 1127
[2] Organic Letters, 2010, vol. 12, # 6, p. 1160 - 1163

13
[ 325147-53-3 ]
[ 5735-53-5 ]

Reference： [1] Journal of the American Chemical Society, 2000, vol. 122, # 51, p. 12907 - 12908
[2] Journal of the American Chemical Society, 2001, vol. 123, # 49, p. 12202 - 12206

14
[ 26378-53-0 ]
[ 5735-53-5 ]

Reference： [1] Synthesis, 2004, # 15, p. 2527 - 2534

15
[ 18800-26-5 ]
[ 5735-53-5 ]

Reference： [1] Synthesis, 2004, # 15, p. 2527 - 2534

16
[ 66443-61-6 ]
[ 5735-53-5 ]

Reference： [1] Synthesis, 2004, # 15, p. 2527 - 2534

17
[ 95-55-6 ]
[ 5735-53-5 ]

Reference： [1] Patent: WO2012/9678, 2012, A1,
[2] Synthesis (Germany), 2014, vol. 46,
[3] Archiv der Pharmazie, 2018, vol. 351, # 5,

18
[ 106-93-4 ]
[ 95-55-6 ]
[ 5735-53-5 ]

Reference： [1] Russian Journal of Organic Chemistry, 2004, vol. 40, # 2, p. 284 - 285

19
[ 70801-51-3 ]
[ 82756-78-3 ]
[ 5735-53-5 ]

Reference： [1] Archiv der Pharmazie, 1982, vol. 315, # 6, p. 561 - 563

20
[ 7169-34-8 ]
[ 5735-53-5 ]

Reference： [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2670 - 2682

21
[ 10147-68-9 ]
[ 5735-53-5 ]

Reference： [1] Synthesis (Germany), 2014, vol. 46,

22
[ 88-75-5 ]
[ 5735-53-5 ]

Reference： [1] Archiv der Pharmazie, 2018, vol. 351, # 5,

[ 5735-53-5 ] Synthesis Path-Downstream 1~42

1
[ 5466-88-6 ]
[ 5735-53-5 ]

Yield	Reaction Conditions	Operation in experiment
79%		Synthesis of 3,4-dihydro-2H-benzo[b][1,4]oxazine Into a 250 mL 3-necked round-bottom flask, was placed a solution of lithium aluminum hydride (3.6 g, 94.74 mmol) in THF (80 mL). The mixture was stirred for 15 min. This was followed by the addition of a solution of 2H-benzo[b][1,4]oxazin-3(4H)-one (5.7 g, 38.22 mmol) in THF (21 mL), which was added dropwise with stirring. The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at reflux in a bath of oil. The reaction progress was monitored by TLC (EtOAc/PE=1:1). The reaction mixture was then quenched by the adding 3.6 mL of H2O and 10.8 mL 15% NaOH. A filtration was performed. The filter cake was washed 1 time with 30 mL of THF. The resulting solution was extracted two times with 100 mL of EtOAc and the organic layers combined and dried over Na2SO4 and concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 4.8 g (79%) of 3,4-dihydro-2H-benzo[b][1,4]oxazine as a red oil.
79%		A solution of 2H-benzo[b][1,4]oxazin-3(4H)-one (38.2 mmol) in tetrahydrofuran (21 mL) was slowly added to a suspension of lithium aluminum hydride (94.7 mmol) in tetrahydrofuran (80 mL) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was diluted with water (3.6 mL) and 15%sodium hydroxide (10.8 mL) and the insoluble solids were removed by filtration. The aqueous layer was extracted with ethyl acetate (2 x 100 mL) and the combined organic layers were dried (sodium sulfate) and concentrated to provide 3,4-dihydro-2H-benzo[b][1,4]oxazine in 79% yield as red oil.
79%		Synthesis of 3,4-dihydro-2H-benzo[b][1,4]oxazine Into a 250 mL 3-necked round-bottom flask, was placed a solution of lithium aluminum hydride (3.6 g, 94.74 mmol) in THE (80 mL). The mixture was stirred for 15 minutes. This was followed by the addition of a solution of 2H-benzo[b][1,4]oxazin-3(4H)-one (5.7 g, 38.22 mmol) in THF (21 mL), which was added dropwise with stirring. The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at reflux in a bath of oil. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:1). The reaction mixture was then quenched by the adding 3.6 mL of H2O and 10.8 mL 15%NaOH. A filtration was performed. The filter cake was washed 1 time with 30 mL of THF. The resulting solution was extracted two times with 100 mL of ethyl acetate and the organic layers combined and dried over Na2SO4 and concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 4.8 g (79%) of 3,4-dihydro-2H-benzo[b][1,4]oxazine as red oil.

79%		Intermediate 31: Synthesis of 4-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-6-sulfonyl chloride.1. Synthesis of 3,4-dihydro-2H-benzo\|"b"\|\|"l,4"\|oxazine.A solution of 2H-benzo[b][l,4]oxazin-3(4H)-one (38.2 mmol) in tetrahydrofuran (21 mL) was slowly added to a suspension of lithium aluminum hydride (94.7 mmol) in tetrahydrofuran (80 mL) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was diluted with water (3.6 mL) and 15%sodium hydroxide (10.8 mL) and the insoluble solids were removed by filtration. The aqueous layer was extracted with ethyl acetate (2 x 100 mL) and the combined organic layers were dried (sodium sulfate) and concentrated to provide 3,4-dihydro-2H- benzo[b][l,4]oxazine in 79% yield as red oil.
79%	With lithium aluminium tetrahydride; In tetrahydrofuran; for 16h;Reflux;	A solution of 2H-benzo[b][1,4]oxazin-3(4H)-one (38.2 mmol) in tetrahydrofuran (21 mL) was slowly added to a suspension of lithium aluminum hydride (94.7 mmol) in tetrahydrofuran (80 mL) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was diluted with water (3.6 mL) and 15% sodium hydroxide (10.8 mL) and the insoluble solids were removed by filtration. The aqueous layer was extracted with ethyl acetate (2×100 mL) and the combined organic layers were dried (sodium sulfate) and concentrated to provide 3,4-dihydro-2H-benzo[b][1,4]oxazine in 79% yield as red oil.
79%		Intermediate 31: Synthesis of 4-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-6-sulfonyl chloride.1. Synthesis of 3,4-dihvdro-2i/-benzo\|'b][l,4"\|oxazine.A solution of 2H-benzo[b][l,4]oxazin-3(4H)-one (38.2 mmol) in tetrahydrofuran (21 mL) was slowly added to a suspension of lithium aluminum hydride (94.7 mmol) in tetrahydrofuran (80 mL) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was diluted with water (3.6 mL) and 15%sodium hydroxide (10.8 mL) and the insoluble solids were removed by filtration. The aqueous layer was extracted with ethyl acetate (2 x 100 mL) and the combined organic layers were dried (sodium sulfate) and concentrated to provide 3,4-dihydro-2H- benzo[b][l,4]oxazine in 79% yield as red oil.
79%	With lithium aluminium tetrahydride; In tetrahydrofuran; for 16h;Reflux;	A solution of 2H-benzo[b][1,4]oxazin-3(4H)-one (38.2 mmol) in tetrahydrofuran (21 mL) was slowly added to a suspension of lithium aluminum hydride (94.7 mmol) in tetrahydrofuran (80 mL) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was diluted with water (3.6 mL) and 15% sodium hydroxide (10.8 mL) and the insoluble solids were removed by filtration. The aqueous layer was extracted with ethyl acetate (2*100 mL) and the combined organic layers were dried (sodium sulfate) and concentrated to provide 3,4-dihydro-2H-benzo[b][1,4]oxazine in 79% yield as red oil.
79%		Into a 250 mL 3-necked round bottom flask was placed a solution of lithium aluminum hydride (3.6 g, 94.74 mmol) in tetrahydrofuran (80 mL). The mixture was stirred for 15 minutes. This was followed by the addition of a solution of 2H-benzo[b][l,4]oxazin-3(4H)-one (5.7 g, 38.22 mmol) in tetrahydrofuran (21 mL), which was added drop wise with stirring. The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at reflux in a bath of <n="132"/>oil. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether = 1:1). The reaction mixture was then quenched by the adding 3.6 mL of H2O and 10.8 mL 15%NaOH. A filtration was performed. The filter cake was washed with 30 mL of tetrahydrofuran. The resulting solution was extracted two times with 100 mL of ethyl acetate and the organic layers combined and dried over Na2SO4 and concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 4.8 g (79%) of 3,4-dihydro-2H-benzo[b]fl,4]oxazine as red oil.
72%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 16h;	General procedure: LAH (2 equiv.) in THF (100 mL) was cooled to 0oC inan ice bath under nitrogen. A solution of 4 (1 equiv.) in THF (20 mL) was added dropwise, and the resulting solution was stirred at RT for 16 hrs. The reaction mixture was cooled to 0oC andcarefully quenched with water (2 mL), 2 N NaOH (2 mL) and water (8 mL). The resulting slurrywas stirred at RT for 1 h and filtered through Celite. The filter cake was washed with ethylacetate and discarded. The filtrate was dried (Na2SO4), separated and concentrated to afford 5 asa colorless oil.
50%		Step B: 3,4-Dihydro-2H-benzo[l,4]oxazine. To a mixture of LAH (3.6 g, 94.74 mmol) in THF (80 ml) was added a solution of 4H-Benzo[l,4]oxazin-3-one (5.7 g, 38.22 mmol) in THF (21 ml) dropwise at room temperature. The reaction mixture was refluxed overnight. The resulting mixture was cooled to 0C and then quenched by the adding 3.6 ml of H20, followed by 10.8 ml 15% NaOH solution. The precipitate was filtered off and the solvent was extracted with EtOAc (2x50 ml). The organic layer was washed with brine, dried over Na2S04, filtered and concentrated to give the 3,4-dihydro-2H-benzo[b][l,4]oxazine as red oil which was pure enough to be used directly (1.5 g , 50% yield). 1H NMR (300 MHz, DMSO-d6): delta 6.67-6.41 (m, 4H), 5.68 (s, 1H), 4.11-4.07 (m, 2H), 3.27-3.24 (m, 2H).
	In tetrahydrofuran; diborane;	EXAMPLE 2 3,4-Dihydro-1,4(2H)-benzoxazine 3,4-Dihydro-3-oxo-1,4(2H)-benzoxazine was refluxed for several hours in one equivalent of diborane in tetrahydrofuran. Excess sodium hydroxide solution was added, the product was extracted with ether and the solvent was evaporated to give the title compound as an oil.
	With sodium hydroxide; LiAlH4; In tetrahydrofuran; dichloromethane; water;	Example 49 N-(4-Chlorobenzyl)-6-(2,3-dihydro-4H-1,4-benzoxazin-4-ylmethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide A solution of LiAlH4 (34 mL, 1M in THF) is added dropwise via addition funnel to a cold (0 C.) solution of (2H)1,4-benzoxazin-3(4H)-one (5.04 g) in freshly distilled THF (110 mL). The LiAlH4 is added at such a rate to keep the reaction temperature below 10 C. The mixture is stirred at room temperature for 2 h and then is quenched successively with water (5 mL), 15% NaOH (5 mL), and water (5 mL) again. The resulting precipitate is filtered and the filtrate is concentrated in vacuo. The residue is dissolved in CH2Cl2 and dried (Na2SO4), filtered, and concentrated to afford the product benzomorpholine as a yellow oil which was used without further purification in the next step.
	With sodium hydroxide; In tetrahydrofuran; water;	Step 2 Production of 3,4-dihydro-2H-benzo[1,4]oxazine Synthesis was performed in reference to Australian journal of chemistry, 9, 397-405 (1956). To be specific, lithium aluminum hydride (3 g) was suspended in tetrahydrofuran (120 mL), and 2H-1,4-benzoxazin-3(4H)-one (6 g) was added by small portions under ice-cooling. After heating under reflux for 10 hrs, water (3 mL), 15% aqueous sodium hydroxide (3 mL) and water (9 mL) were successively added under ice-cooling, and the mixture was stirred at room temperature. The mixture was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate=4:1) to give the title compound (4.9239 g) as an orange oil.
		Intermediate 14: Synthesis of 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl chloride; 1. Synthesis of 3,4-dihydro-2H-benzo[b][1,4]oxazine; A solution of 2H-benzo[b][1,4]oxazin-3(4H)-one (38.2 mmol) in tetrahydrofuran (21 mL) was slowly added to a suspension of lithium aluminum hydride (94.7 mmol) in tetrahydrofuran (80 mL) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was diluted with water (3.6 mL) and 15% sodium hydroxide (10.8 mL) and the insoluble solids were removed by filtration. The aqueous layer was extracted with ethyl acetate (2×100 mL) and the combined organic layers were dried (sodium sulfate) and concentrated to provide 3,4-dihydro-2H-benzo[b][1,4]oxazine in 79% yield as red oil.
		Step 2 Production of 3,4-dihydro-2H-benzo[1,4]oxazine Synthesis was performed in reference to Australian journal of chemistry, 9, 397-405 (1956). To be specific, lithium aluminum hydride (3 g) was suspended in tetrahydrofuran (120 mL), and 2H-1,4-benzoxazin-3(4H)-one (6 g) was added by small portions under ice-cooling. After heating under reflux for 10 hrs, water (3 mL), 15% aqueous sodium.hydroxide (3 mL) and water (9 mL) were successively added under ice-cooling, and the mixture was stirred at room temperature. The mixture was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate=4:1) to give the title compound (4.9239 g) as an orange oil.
		step 1 Production of 3,4-dihydro-2H-benzo[1,4]oxazine Lithium aluminum hydride (3 g) was suspended in tetrahydrofuran (120 mL), and 2H-1,4-benzoxazin-3(4H)-one (6 g) was added by small portions under ice-cooling. After heating under reflux for 10 hr, water (3 mL), 15% aqueous sodium hydroxide solution (3 mL) and water (9 mL) were successively added under ice-cooling, and the mixture was stirred at room temperature. Anhydrous sodium sulfate was added, and the mixture was dried and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate=4:1) to give the title compound (4.9239 g) as an orange oil.
		[00192] 3,4-Dihydro-2H-benzo[b] [l,4]oxazine (2). A solution of LAH (970 mg, 25.6 mmol) was refluxed in THF 50 mL under nitrogen atmosphere. A solution of 2H-1,4-Benzoaxin-3(4H)- one (1.88g, 12.6 mmol) was added dropwise over 10 minutes. After 1 hour, the reaction was cooled in an ice bath and slowly quenched with a solution of Roche lie's salt, triturated with EtOAc and filtered through a plug of celite. The solvent was evaporated and the crude product purified by column chromatography on silica (1 :1 heptane : EtOAc) to give 1.2 g of the desired product. 1H-NMR (300 MHz, CD2Cl2) delta: 6.76 (m, 2H), 6.61 (m, 2H), 4.22 (m, 2H), 3.80 (bs, NH), 3.39 (m, 2H); MS m/z calculated for C8Hi0NO (M+H) 136.08. Found 136.1 (M+H, ESI+).
	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 4h;	To a stirred suspension LiAIH4 (7.6 g, 201 mmol) in THF at 0 C was added 4H- benzo[1 ,4]oxazin-3-one (15 g, 100 mmol) in 30 ml of THF and stirred for 4h at room temperature. After cooling, excess of LiAIH4 was quenched by the addition of EtOAc followed by aq. NH4CI solution. The residue was filtered through a celite bed and usual work up followed by evaporation of the solvent resulted in 3,4-dihydro-2H- benzo[1 ,4]oxazine (12 g) which was used as such for the next step.MS (ES) m/z 136 (M+1)
		To a stirred suspension UAIH4 (7.6 g, 201 mmol) in THF at 0 C was added 4H- benzo[1 ,4]oxazin-3-one (15 g, 100 mmol) in 30 mL of THF and stirred for 4h at room temperature. After cooling, excess of LiAIH4 was quenched by the addition of EtOAc followed by aq. NH4CI solution. The residue was filtered through a celite bed and filtrate was concentrated. The residue was diluted with water and extracted with ethylacetate (200 ml_X 2), combined organic layer was washed with water (100 mL) and brine (100 mL). Evaporation of the solvent resulted in 3,4-dihydro-2H-benzo[1>4]oxazine (12 g) which was used as such for the next step.MS (ES) m/z 136 (M+1)
	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 4h;Product distribution / selectivity;	Step I. To a stirred suspension LiAlH4 (7.6 g, 201 mmol) in THF at 0 C. was added 4H-benzo[1,4]oxazin-3-one (15 g, 100 mmol) in 30 mL of THF and stirred for 4 h at room temperature. After cooling, excess of LiAlH4 was quenched by the addition of EtOAc followed by aq. NH4Cl solution. The residue was filtered through a celite bed and filtrate was concentrated. The residue was diluted with water and extracted with ethylacetate (200 mL*2), combined organic layer was washed with water (100 mL) and brine (100 mL). Evaporation of the solvent resulted in 3,4-dihydro-2H-benzo[1,4]oxazine (12 g) which was used as such for the next step. MS (ES) m/z 136 (M+1)
	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 4h;	To a stirred suspension LiAlH4 (7.6 g, 201 mmol) in THF at 0 C. was added 4H-benzo[1,4]oxazin-3-one (15 g, 100 mmol) in 30 ml of THF and stirred for 4 h at room temperature. After cooling, excess of LiAlH4 was quenched by the addition of EtOAc followed by aq. NH4Cl solution. The residue was filtered through a celite bed and usual work up followed by evaporation of the solvent resulted in 3,4-dihydro-2H-benzo[1,4]oxazine (12 g) which was used as such for the next step. MS (ES) m/z 136 (M+1)
4.3 g	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 16h;Inert atmosphere; Reflux;	Synthesis of 3,4-dihydro-2H-1,4-benzoxazine (Intermediate-29) A solution of Starting Material-13(5 g, 33.5 mmol) in tetrahydrofuran (50 mL) was slowly added to a suspension of lithium aluminum hydride (3.18 g, 83.8 mmol) under N2 atmosphere at 0 C. The reaction mixture was refluxed for 16 h. The reaction mixture was diluted with EtOAc, quenched with 15% aqueous sodium hydroxide solution at 0 C., and extracted with ether, and concentrated to give Intermediate-29 as brown liquid (4.3 g).
		Step 2 Production of 3,4-dihydro-2H-benzo[1,4]oxazine Synthesis was performed in reference to Australian journal of chemistry, 9, 397-405 (1956). To be specific, lithium aluminum hydride (3 g) was suspended in tetrahydrofuran (120 mL), and 2H-1,4-benzoxazin-3(4H)-one (6 g) was added by small portions under ice-cooling. After heating under reflux for 10 hrs, water (3 mL), 15% aqueous sodium hydroxide (3 mL) and water (9 mL) were successively added under ice-cooling, and the mixture was stirred at room temperature. The mixture was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate=4:1) to give the title compound (4.9239 g) as an orange oil.
		Example A Production of (3-chloro-4-hydroxyphenyl)-(2,3-dihydrobenzo[1,4]oxazin-4-yl)-methanone (example using 1-butanol as recrystallization solvent) Step 1 Production of 3,4-dihydro-2H-benzo[1,4]oxazine Under nitrogen atmosphere, 2H-1,4-benzoxazin-3(4H)-one (100 g) is suspended in toluene (1 L), and a 65 (w/w) % solution (376 g) of sodium bis(2-methoxyethoxy)aluminum hydride in toluene is added dropwise at 3-14 C. over 2 hrs. After the completion of the dropwise addition, the mixture is stirred at 20-26 C. for 19 hrs. The obtained reaction mixture is added dropwise to 30 (w/w) % sodium potassium tartarate solution (1.3 L) at 5-8 C. over 1.5 hrs. After the completion of the dropwise addition, the mixture is stirred at 15-30 C. for 2 hrs, and partitioned. The organic layer is washed once with 30% (w/w) sodium potassium tartarate solution (0.9 L) and twice with water (0.65 L), concentrated under reduced pressure, and distilled under reduced pressure (85-90 C./1.3 Torr) to give the title compound as a pale-yellow oil. Example C Production of (3-chloro-4-hydroxyphenyl)-(2,3-dihydrobenzo[1,4]oxazin-4-yl)-methanone (example using 1-butanol as recrystallization solvent) Step 1 Production of 3,4-dihydro-2H-benzo[1,4]oxazine Under nitrogen atmosphere, 2H-1,4-benzoxazin-3(4H)-one (116 kg) is suspended in toluene (1.2 kL), and a 70 (w/w) % solution (408 kg) of sodium bis(2-methoxyethoxy)aluminum hydride in toluene is added dropwise at 8-10 C. After the completion of the dropwise addition, the mixture is stirred at 15-23 C. for 18 hrs. The obtained reaction mixture is added dropwise to 30 (w/w) % sodium potassium tartarate solution (1.7 Mg) at 8-23 C. After the completion of the dropwise addition, the mixture is stirred at 23 C. for 2 hrs, and partitioned. The organic layer is washed once with 30% (w/w) sodium potassium tartarate solution (1.2 Mg) and twice with water (0.76 kL), concentrated under reduced pressure, and distilled under reduced pressure to give the title compound as a pale-yellow oil.

Reference： [1]Organic Letters,2019,vol. 21,p. 9954 - 9959
[2]Archiv der Pharmazie,2018,vol. 351
[3]Patent: US2008/318941,2008,A1 .Location in patent: Page/Page column 24
[4]Patent: WO2009/23844,2009,A2 .Location in patent: Page/Page column 121
[5]Patent: US2008/200471,2008,A1 .Location in patent: Page/Page column 47
[6]Patent: WO2010/21797,2010,A1 .Location in patent: Page/Page column 86
[7]Patent: US2010/29629,2010,A1 .Location in patent: Page/Page column 58
[8]Patent: WO2010/24980,2010,A1 .Location in patent: Page/Page column 104
[9]Patent: US2010/22581,2010,A1 .Location in patent: Page/Page column 37; 41
[10]Patent: WO2007/98418,2007,A1 .Location in patent: Page/Page column 130-131; 141
[11]Synthesis,2014,vol. 46
[12]Journal of Organic Chemistry,2019
[13]Journal of Organic Chemistry,2019,vol. 84,p. 6084 - 6093
[14]Patent: WO2012/9678,2012,A1 .Location in patent: Page/Page column 222-223
[15]Australian Journal of Chemistry,1956,vol. 9,p. 397,402
[16]Patent: US4721784,1988,A
[17]Patent: US6248739,2001,B1
[18]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 7956 - 7967
[19]Patent: US2008/305169,2008,A1
[20]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4700 - 4704
[21]Patent: US2010/16297,2010,A1 .Location in patent: Page/Page column 26
[22]Patent: US2007/10670,2007,A1 .Location in patent: Page/Page column 79-80
[23]Patent: US2007/197512,2007,A1 .Location in patent: Page/Page column 49
[24]Patent: WO2011/26085,2011,A2 .Location in patent: Page/Page column 58
[25]Patent: WO2011/48148,2011,A2 .Location in patent: Page/Page column 60
[26]Patent: WO2011/48112,2011,A1 .Location in patent: Page/Page column 79-80; 90
[27]Patent: US2011/171159,2011,A1 .Location in patent: Page/Page column 33
[28]Patent: US2012/196813,2012,A1 .Location in patent: Page/Page column 25
[29]Patent: WO2013/128465,2013,A1 .Location in patent: Page/Page column 98
[30]Journal of Medicinal Chemistry,2014,vol. 57,p. 2670 - 2682
[31]Patent: US2015/158860,2015,A1 .Location in patent: Paragraph 0345
[32]Patent: US2008/64871,2008,A1 .Location in patent: Page/Page column 43
[33]Patent: US2008/64871,2008,A1 .Location in patent: Page/Page column 87; 88; 89; 89-90

2
[ 5735-53-5 ]
[ 63169-10-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium nitrite; In water; at 0℃; for 1.08333h;	3,4-Dihydro-2H-benzo[l,4]oxazine (425 mg, 3.148 mmol) was dissolved in HC1 (3N) at 0 C, and stirred for 5 min. at 0 C. A solution of sodium nitrite (217 mg, 3.148 mmol) in water was added at the same temperature, and the reaction mixture stirred at 0 C for lh. After completion of reaction, water was added and the mixture extracted with DCM. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure, to give 400 mg desired product.

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 3693 - 3699
[2]Patent: WO2011/103460,2011,A1 .Location in patent: Page/Page column 240
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 2670 - 2682

3
[ 87762-20-7 ]
[ 5735-53-5 ]

Reference： [1]Journal of the American Chemical Society,2001,vol. 123,p. 12202 - 12206
[2]Journal of the American Chemical Society,2000,vol. 122,p. 12907 - 12908

4
[ 106-93-4 ]
[ 95-55-6 ]
[ 5735-53-5 ]

Yield	Reaction Conditions	Operation in experiment
65%	With potassium carbonate; In N,N-dimethyl-formamide; at 125℃; for 15h;	To a suspension of 2-aminophenol (1.0 g, 9.2 mmol) and potassium carbonate (6.36 g, 46 mmol) in dry DMF (10 mL) was added 1, 2-dibromoethane (2.59 g, 13.8 mmol). The mixture was then heated at 125'C for 15 hours. After cooling, the mixture was treated with crushed ice and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum ether 1:10 (v:v) as eluent to give 3,4- dihydro-2H-benzo[b][1,4]oxazine as reddish oil (0.81 g, 65%). LC-MS (ES-API); rt 7.51 min; m/z calculated for C8H9NO [M+Hf 136.1, found 136.1.
29%	With potassium carbonate; In water; acetone; for 24h;Reflux;	1 , 2-Dibromoethane (1.51 g, 13.87 mmol) was dissolved in 100 mL of acetone and a solution of 3.19 g of K2CO3 in 30 mL of water was added. A solution of 2-aminophenol in 10 mL of acetone suspension was added slowly to the suspension. The solution was heated to reflux for 24 hours. The acetone was evaporated to dryness. The residue was dissolved in water and extracted with dichloromethane . The combined organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by chromatography eluted with petroleum ether :ether acetate=50:l to 10:1 to obtain 450 mg of the target product as brown oil (yield: 29%, ) .
	With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 130℃; for 85.5h;	To a solution of 2-aminophenol (8.01 g) in N,N-dimethylformamide (70 ml), potassium carbonate (51.0 g) and 1,2-dibromoethane (9.5 ml) were added and stirred at 130C for 7.5 hours and then at room temperature for 3 days. After addition of additional 1,2-dibromoethane (9.5 ml), the reaction mixture was stirred at 130C for 6 hours. The reaction mixture was diluted with ice-cold water and extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluting solvent: n=hexane:ethyl acetate = 20:1 to 5:1) to give the titled compound, i.e., 3,4-dihydro-2H-1,4-benzoxazine (3.77 g) as a brown oil. 1H NMR (300 MHz, CHLOROFORM-D) delta 3.40-3.45 (m, 2 H), 3.72 (brs, 1 H), 4.23-4.28 (m, 2 H), 6.57-6.81 (m, 4 H).

With potassium carbonate; In tetrahydrofuran; at 100℃; for 16h;

A mixture of 2-aminophenol (5 g, 45.87 mmol), 1,2-dibromoethane (4.3 g, 22.93 mmol), and K2C03 (15.8 g, 114.67 mmol) in THF (30 mL) was heated at 100 C for 16h. After completion of reaction, water was added and extracted with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The reaction mixture was purified by column chromatography (using 100-200 mesh size silica, the desired product was eluted at 15% EtOAc in hexane) to obtained 1 g of desired product.

Reference： [1]Tetrahedron Letters,2006,vol. 47,p. 7823 - 7826
[2]Patent: WO2011/47432,2011,A1 .Location in patent: Page/Page column 88
[3]Heterocyclic Communications,2012,vol. 18,p. 143 - 146
[4]Patent: WO2010/51374,2010,A1 .Location in patent: Page/Page column 132
[5]Patent: EP2172453,2010,A1 .Location in patent: Page/Page column 13
[6]Patent: WO2011/103460,2011,A1 .Location in patent: Page/Page column 240
[7]Biomolecules,2019,vol. 9

5
[ 31507-30-9 ]
[ 5735-53-5 ]

Yield	Reaction Conditions	Operation in experiment
88%	With palladium 10% on activated carbon; hydrogen; toluene-4-sulfonic acid; In ethanol; at 50℃; under 37503.8 Torr; for 2h;	In step (ii), intermediate c was reduced and cyclised to give the following fuel additive e Specifically, 2-(2-nitrophenoxy)acetonitrile (2.0 g, 11 mmol), //TSA (50 mg), 10 % Pd/C (100 mg) were stirred in ethanol (35 ml) under 50 bar at 50 C for 2 hours. The reaction mixture was filtered, the solvent was evaporated, the residue was taken up into diethyl ether and filtered to remove solids. The solvent was removed in vacuo to give 1.34 g (88 % yield) of fuel additive e as a clear brown oil.

Reference： [1]Patent: WO2019/129591,2019,A1 .Location in patent: Page/Page column 33
[2]Tetrahedron Letters,2007,vol. 48,p. 2765 - 2768

6
[ 10513-26-5 ]
[ 5735-53-5 ]
2-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	hydrogenchloride; In 1-ethoxyethanol; water; at 160℃; for 0.333333h;Microwave;	EXAMPLE 232-(2,3-Dihvdro-4H-l,4-benzoxazin-4-ylV5,5-dimethyl-5,6-dihydro-l,3-benzothiazol- To a solution of 3,4-dihydro-2H-l,4-benzoxazine (0.19 g, 1.27 mmol) in ethoxyethanol (5 mL) with one drop of cone. HCl was added Intermediate 15 (0.30 g, 1.15 mmol) and the reaction mixture was heated under microwave irradiation in a sealed tube to 1600C for 20 minutes. The reaction mixture was then poured into EtOAc (25 mL) and washed with brine (25 mL). The organic fraction was dried over MgSO4 and concentrated in vacuo to give the title compound (0.26 g, 64%) as a colourless solid, delta? (CDCl3) 7.83 (1Eta, dd, J8.8 and 1.8 Hz), 7.01 (IH, m), 6.89 (2H, m), 4.27 (2H, m), 4.13 (2H, m), 2.69 (2H, s), 2.35 (2H, m), 1.07 (6H, s). LCMS (ES+) 315.0 (M+H)+.

Reference： [1]Patent: WO2006/114606,2006,A1 .Location in patent: Page/Page column 90
[2]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4700 - 4704

7
[ 1486-51-7 ]
[ 5735-53-5 ]
(4-benzyloxyphenyl)-(2,3-dihydrobenzo[1,4]oxazin-4-yl)-methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In chloroform at 0 - 20℃;	88.1 Production of (2,3-dihydrobenzo[1,4]oxazin-4-yl)-(4-hydroxyphenyl)-methanone Step 1 Production of (4-benzyloxyphenyl)-(2,3-dihydrobenzo[1,4]oxazin-4-yl)-methanone 3,4-Dihydro-2H-benzo[1,4]oxazine (270 mg) obtained in Step 2 of Example 1, 4-benzyloxybenzoic acid (457 mg) and 4-dimethylaminopyridine (269 mg) were dissolved in chloroform (7 mL), and WSC.HCl (422 mg) was added under ice-cooling. After stirring overnight at room temperature, the reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate=3:1) to give the title compound (636.2 mg) as an orange oil.
	With dmap In chloroform at 0 - 40℃;	88.1 Step 1 Production of (4-benzyloxyphenyl)-(2,3-dihydrobenzo[1,4]oxazin-4-yl)-methanone 3,4-Dihydro-2H-benzo[1,4]oxazine (270 mg) obtained in Step 2 of Example 1, 4-benzyloxybenzoic acid (457 mg) and 4-dimethylaminopyridine (269 mg) were dissolved in chloroform (7 mL), and WSC.HCl (422 mg) was added under ice-cooling. After stirring overnight at room temperature, the reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate=3:1) to give the title compound (636.2 mg) as an orange oil.

Reference： [1]Current Patent Assignee: JAPAN TOBACCO INC - US2007/10670, 2007, A1 Location in patent: Page/Page column 103
[2]Current Patent Assignee: JAPAN TOBACCO INC - US2008/64871, 2008, A1 Location in patent: Page/Page column 66

8
[ 56961-25-2 ]
[ 5735-53-5 ]
[ 888730-73-2 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In chloroform; at 0 - 20℃;	Example 28 Production of (4-amino-3,5-dichlorophenyl)-(2,3-dihydrobenzo[1,4]oxazin-4-yl)-methanone 3,4-Dihydro-2H-benzo[1,4]oxazine (270 mg) obtained in Step 2 of Example 1,<strong>[56961-25-2]4-amino-3,5-dichlorobenzoic acid</strong> (412 mg) and N,N-dimethylaminopyridine (269 mg) were dissolved in chloroform (8 mL), and WSC.HCl (422 mg) was added under ice-cooling. After stirring overnight at room temperature, the reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate=5:1) to give the title compound (412.5 mg) as bright yellow crystals.

Reference： [1]Patent: US2007/10670,2007,A1 .Location in patent: Page/Page column 89

9
[ 6964-21-2 ]
[ 5735-53-5 ]
[ 928117-99-1 ]

Yield	Reaction Conditions	Operation in experiment
55%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl-formamide; at 70℃;	A solution of 3,4-dihydro-2H-<strong>[5735-53-5]1,4-benzoxazine</strong> (0.52 g, 3.8 mmol) and thiophene-3-acetic acid (0.82 g, 5.7 mmol) in 1:1 CH2Cl2:DMF (20 mL) was treated with DIPEA (2.6 ml, 15 mmol), HOBt (1.29 g, 9.5 mmol), and EDCI (1.83 g, 9.5 mmol) and stirred at 70 C. overnight. The reaction was then diluted with CH2Cl2, washed with saturated aqueous NaHCO3, dried over Na2SO4, and concentrated. Chromatography (0-10% 1 N NH3-MeOH/EtOAc) provided 2A as a red solid (0.54 g, 55%)

Reference： [1]Patent: US2007/93477,2007,A1 .Location in patent: Page/Page column 20

10
[ 5735-53-5 ]
[ 74-88-4 ]
[ 77901-22-5 ]

Yield	Reaction Conditions	Operation in experiment
50%		Synthesis of 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine Into a 250 mL 3-necked round-bottom flask, was placed a solution of 3,4-dihydro-2H-benzo[b][1,4]oxazine (4.8 g, 35.51 mmol) in THF (50 mL). To the above was added NaH (2.3 g, 57.50 mmol) in several batches, while cooling to a temperature of 0-5 C. The mixture was stirred for 30 min at 0-5 C. To the above was added iodomethane (9.0 g, 63.41 mmol) dropwise with stirring, while cooling to a temperature of 0-5 C. The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (EtOAc/PE=1:2). A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. The residue was purified by eluding through a column with a 1:1100 EtOAc/PE solvent system. This resulted in 3.0 g (50%) of 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine as a yellow oil.
50%		Sodium hydride (57.5 mmol) was added in several batches to a solution of 3,4-dihydro-2H- benzo[b][1,4]oxazine (35.5 mmol) in tetrahydrofuran (50 mL) at 0 C and the reaction mixture was maintained for 30 min. Iodomethane (63.4 mmol) was added dropwise and the reaction mixture was allowed to warm to rt and was maintained for 16 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was purified by Flash chromatography (1/100 ethyl acetate/petroleum ether) to provide 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine in 50% yield as yellow oil.
50%		Into a 250 mL 3-necked round-bottom flask was placed a solution of 3,4-dihydro-2H-benzo[b[1,4]oxazine (4.8 g, 35.51 mmol) in THF (50 mL). To the above was added NaH (2.3 g, 57.50 mmol) in several batches, while cooling to a temperature of 0-5 C. The mixture was stirred for 30 minutes at 0-5 C. To the above was added iodomethane (9.0 g, 63.41 mmol) dropwise with stirring, while cooling to a temperature of 0-5 C. The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:2). A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. The residue was purified by eluding through a column with a 1:100 ethyl acetate/petroleum ether solvent system. This resulted in 3.0 g (50%)of 4-metliyl-3,4-dihydro-2H-benzo[b][1,4]oxazine as yellow oil.

50%		2. Synthesis of 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine; Sodium hydride (57.5 mmol) was added in several batches to a solution of 3,4-dihydro-2H-benzo[b][1,4]oxazine (35.5 mmol) in tetrahydrofuran (50 mL) at 0 C. and the reaction mixture was maintained for 30 min. Iodomethane (63.4 mmol) was added dropwise and the reaction mixture was allowed to warm to rt and was maintained for 16 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was purified by Flash chromatography (1/100 ethyl acetate/petroleum ether) to provide 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine in 50% yield as yellow oil.
50%		2. Synthesis of 4-methyl-3,4-dihydro-2//-benzo\|"b1\|"l,41oxazine.Sodium hydride (57.5 mmol) was added in several batches to a solution of 3,4-dihydro- 2H-benzo[b][l,4]oxazine (35.5 mmol) in tetrahydrofuran (50 mL) at 0 0C and the reaction mixture was maintained for 30 min. Iodomethane (63.4 mmol) was added dropwise and the reaction mixture was allowed to warm to rt and was maintained for 16 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was purified by Flash chromatography (1/100 ethyl acetate/petroleum ether) to provide 4-methyl-3,4-dihydro-2H- benzo[b][l,4]oxazine in 50% yield as yellow oil.
50%	With sodium hydride; In tetrahydrofuran; at 0 - 20℃;	Sodium hydride (57.5 mmol) was added in several batches to a solution of 3,4-dihydro-2H-benzo[b][1,4]oxazine (35.5 mmol) in tetrahydrofuran (50 mL) at 0 C. and the reaction mixture was maintained for 30 min. Iodomethane (63.4 mmol) was added dropwise and the reaction mixture was allowed to warm to rt and was maintained for 16 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was purified by Flash chromatography (1/100 ethyl acetate/petroleum ether) to provide 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine in 50% yield as yellow oil.
50%		2. Synthesis of 4-methyl-3,4-dmvdro-2H-benzorb~l[l,4"loxazine.Sodium hydride (57.5 mmol) was added in several batches to a solution of 3,4-dihydro- 2i/-benzo[b][l,4]oxazine (35.5 mmol) in tetrahydrofuran (50 mL) at 0 0C and the reaction mixture was maintained for 30 min. Iodomethane (63.4 mmol) was added dropwise and the reaction mixture was allowed to warm to rt and was maintained for 16 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was purified by Flash chromatography (1/100 ethyl acetate/petroleum ether) to provide 4-methyl-3,4-dihydro-2H- benzo[b][l,4]oxazine in 50% yield as yellow oil.
50%		Sodium hydride (57.5 mmol) was added in several batches to a solution of 3,4-dihydro-2H-benzo[b][1,4]oxazine (35.5 mmol) in tetrahydrofuran (50 mL) at 0 C. and the reaction mixture was maintained for 30 min. Iodomethane (63.4 mmol) was added dropwise and the reaction mixture was allowed to warm to rt and was maintained for 16 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was purified by Flash chromatography (1/100 ethyl acetate/petroleum ether) to provide 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine in 50% yield as yellow oil.
50%		Into a 250 mL 3-necked round bottom flask was placed a solution of 3,4-dihydro-2H- benzo[b][l,4]oxazine (4.8 g, 35.51 mmol) in tetrahydrofuran (50 mL). To the above was added NaH (2.3 g, 57.50 mmol) in several batches, while cooling to a temperature of 0-5 0C. The mixture was stirred for 30 minutes at 0-5 0C. To the above was added iodomethane (9.0 g, 63.41 mmol) dropwise with stirring, while cooling to a temperature of 0-5 0C. The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether = 1:2). A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. The residue was purified by eluting through a column with a 1:100 ethyl acetate/petroleum ether solvent system. This resulted in 3.0 g (50%) of 4-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine as yellow oil.

Reference： [1]Patent: US2008/318941,2008,A1 .Location in patent: Page/Page column 24
[2]Patent: WO2009/23844,2009,A2 .Location in patent: Page/Page column 121-122
[3]Patent: US2008/200471,2008,A1 .Location in patent: Page/Page column 47
[4]Patent: US2010/16297,2010,A1 .Location in patent: Page/Page column 26
[5]Patent: WO2010/21797,2010,A1 .Location in patent: Page/Page column 86
[6]Patent: US2010/29629,2010,A1 .Location in patent: Page/Page column 58
[7]Patent: WO2010/24980,2010,A1 .Location in patent: Page/Page column 104; 105
[8]Patent: US2010/22581,2010,A1 .Location in patent: Page/Page column 37; 41-42
[9]Patent: WO2007/98418,2007,A1 .Location in patent: Page/Page column 130; 131; 141-142

11
[ 913718-58-8 ]
[ 5735-53-5 ]
[ 1027133-62-5 ]

Yield	Reaction Conditions	Operation in experiment
22%	With johnphos; sodium t-butanolate;palladium diacetate; In toluene; at 100℃;Inert atmosphere;	Example 6 Method I: 5,6,7,8-tetrahydro-2-(2,3-dihydrobenzo[b][1,4]oxazin-4-yl)-7,7-dimethylthiazolo[5,4-c]azepin-4-one (I-6) 2-bromo-5,6,7,8-tetrahydro-7,7-dimethylthiazolo[5,4-c]azepin-4-one (200 mg, 1 Eq.), 3,4-dihydro-2H-benzo[b][1,4]oxazine (118 mg, 1.2 Eq.), NaOtBu (196 mg, 2.8 Eq.), Pd(OAc)2 (6 mg, 0.04 Eq.), were suspended/dissolved in dry toluene (3 mL). The reaction mixture was degassed (vacuum/N2 cycles5). 2-(Di-tert-butylphosphino)biphenyl (18 mg, 0.08 Eq.) was added and the reaction mixture heated to 100 C. overnight. The reaction mixture was allowed to cool to room temperature, partitioned in EtOAc/sat. aq. NH4Cl, extracted with EtOAc (320 ml). The combined extracts were washed with brine (1*200 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification was achieved using column chromatography (70/30 EtOAc/Hexanes), titration with ether followed by filtration. The product was then washed with ether, pentane, and dried under vacuum at 50 C. overnight. 5,6,7,8-tetrahydro-2-(2,3-dihydrobenzo[b][1,4]oxazin-4-yl)-7,7-dimethylthiazolo[5,4-c]azepin-4-one was isolated as a light yellow powder in 22% yield; 1H NMR (DMSO D6) 1.0 (6H, s), 2.8 (2H, 2), 2.9-3.0 (2H, d), 4.0 (2H, m), 4.3 (2H, m), 6.9-7.0 (2H, m), 7.0-7.1 (1H, m), 7.8-7.9 (1H, br m), 8.0-8.1 (1H, d); LC/MS M+1 (obs.) 330.20; LC/MS M-1 (obs.) 328.50.

Reference： [1]Patent: US2009/281082,2009,A1 .Location in patent: Page/Page column 17

12
[ 1722-12-9 ]
[ 5735-53-5 ]
[ 1255145-29-9 ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium acetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In tetrahydrofuran; at 110℃; for 0.166667h;microwave irradiation; Inert atmosphere;	Description 244-pyrimidin-2-yl-3,4-dihydro-2H-benzo[1,4]oxazine (D24)A nitrogen stream was bubbled through a mixture of 2-chloropyrimidine (1 g, 8.731 mmol), and potassium acetate (0.098 g, 0.437 mmol), racemic-2,2'- bis(diphenylphosphino)-1,1'-binaphthyl (0.407 g, 0.655 mmol) and Cs2CO3 (5.689 g, 17.462 mmol). Then, 3,4-dihydro-2H-l,4-benzoxazino [CA.S. 5735-53-5] (1.77 g, 13.097 mmol) in TEtaF (0.5 ml) was added. The reaction mixture was heated at 110 0C under microwave irradiation for 10 min. After cooling to room temperature, the reaction mixture was washed with EtOAc. The organic layer was separated, washed with water, dried (Na2SO4), and the solvent was evaporated in vacuo. The residue was purified by column chromatography (silica gel; eluent: DCM/Etaeptane up to 20% as eluent). The desired fractions were collected and the solvent was evaporated in vacuo to yield intermediate compound D24 (1.9 g, 81 %).

Reference： [1]Patent: WO2010/130422,2010,A1 .Location in patent: Page/Page column 62
[2]Organic Letters,2018,vol. 20,p. 6799 - 6803

13
[ 3430-13-5 ]
[ 5735-53-5 ]
[ 1255145-33-5 ]

Yield	Reaction Conditions	Operation in experiment
75%	With sodium t-butanolate;1,1'-bis-(diphenylphosphino)ferrocene; bis(dibenzylideneacetone)-palladium(0); In toluene; at 80℃;	Description 294-(6-methyl-pyridin-3-yl)-3,4-dihydro-2H-benzo[1,4]oxazine (D29)A nitrogen stream was bubbled through a mixture of 5-bromo-2-methylpyridine (3.818 g, 22.195 mmol) in toluene (28 ml), then, tBuONa (6.186 g, 64.365 mmol), 1,1'- bis(diphenylphosphino)ferrocene (0.615 g, 1.11 mmol), bis(dibenzylideneacetonato)palladium (0.383 g, 0.666 mmol) and 3,4-dihydro-2H-l,4- benzoxazino [CA.S. 5735-53-5] (1.77 g, 13.097 mmol) were added. The reaction mixture was heated at 80 0C overnight. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth and washed with EtOAc. The solvent was evaporated in vacuo. The residue was purified by column chromatography (silica gel; eluent: DCM/EtOAc from 100/0 to 80/10 as eluent). The desired fractions were collected and the solvent was evaporated in vacuo to yield intermediate compound D29 (3.812 g, 75 %) as a yellow oil.

Reference： [1]Patent: WO2010/130422,2010,A1 .Location in patent: Page/Page column 65

14
[ 1258399-08-4 ]
[ 5735-53-5 ]
[ 1258400-07-5 ]

Yield	Reaction Conditions	Operation in experiment
82%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 100℃; for 16h;Inert atmosphere;	Reference Example 67 methyl [ (3S) -6-{ [ (3S) -7- (2, 3-dihydro-4H-l, 4-benzooxazin-4-yl) - 2, 3-dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3- dihydro-l-benzofuran-3-yl] acetate; [0395]A solution of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3-dihydro- l-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3-dihydro-l- benzofuran-3-yl] acetate (200 mg, 0.400 mmol), 3, 4-dihydro-2H- 1, 4-benzooxazine (64.8 mg, 0.480 mmol) and cesium carbonate (390 mg, 1.20 mmol) in toluene (4 mL) was substituted with argon, and tris (dibenzylideneacetone) dipalladium (0) (14.6 mg, 0.0160 mmol) and 4, 5-bis (diphenylphosphino) -9, 9- dimethylxanthene (18.5 mg, 0.0320 mmol) were added. The reaction mixture was stirred under an argon atmosphere at 1000C for 16 hr. The reaction mixture was cooled, and the insoluble material was filtered off, and washed with toluene. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 60:40) to give the title compound (181 ing, yield 82%) as a yellow oil.MS m/z 555 (M + H)+.

Reference： [1]Patent: WO2010/143733,2010,A1 .Location in patent: Page/Page column 159-160

15
[ 4333-56-6 ]
[ 5735-53-5 ]
[ 1290630-76-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In N,N-dimethyl-formamide; at 0 - 20℃; for 4.08333h;	To a stirred solution of 3,4-dihydro-2H-benzo[1,4]oxazine (5 g, 37.0 mmol) in DMF (20 mL) was added potassium tert-butoxide (6.22 g, 55.55 mmol) at 0 C. After stirring for 5 min, bromo-cyclopropane (4.44 ml, 55.55 mmol) was added and the reaction mixture was stirred for another 4h at room temperature. The reaction was quenched by addition of water and extracted with ethyl acetate (50 x 2 ml). The organic layer was washed with water (20 mL), concentrated and purified by silica gel column chromatoghraphy to furnish 4-Cyclopropyl-3,4-dihydro-2H-benzo[1 ,4]oxazine (4.42 g).MS (ES) m/z 176 (M+1).
		To a stirred solution of 3,4-dihydro-2H-benzo[1 ,4]oxazine (5 g, 37.0 mmol) in DMF (20 mL) was added potassium tert-butoxide (6.22 g, 55.55 mmol) at 0 C. After stirring for 5 min, bromo-cyclopropane (4.44 mL, 55.55 mmol) was added and the reaction mixture was stirred for another 4h at room temperature. The reaction was quenched by addition of water and extracted with ethyl acetate (50 x 2 mL). The organic layer was washed with water (20 mL), concentrated and purified by silica gel column chromatoghraphy to furnish 4-Cyclopropyl-3,4-dihydro-2H-benzo[1 ,4]oxazine (4.42 g).MS (ES) m z 176 (M+1).
		Intermediate 3; Step I. To a stirred solution of 3,4-dihydro-2H-benzo[1,4]oxazine (5 g, 37.0 mmol) in DMF (20 mL) was added potassium tert-butoxide (6.22 g, 55.55 mmol) at 0 C. After stirring for 5 min, bromo-cyclopropane (4.44 mL, 55.55 mmol) was added and the reaction mixture was stirred for another 4 h at room temperature. The reaction was quenched by addition of water and extracted with ethyl acetate (50×2 mL). The organic layer was washed with water (20 mL), concentrated and purified by silica gel column chromatoghraphy to furnish 4-Cyclopropyl-3,4-dihydro-2H-benzo[1,4]oxazine (4.42 g).MS (ES) m/z 176 (M+1).

To a stirred solution of 3,4-dihydro-2H-benzo[1,4]oxazine (5 g, 37.0 mmol) in DMF (20 mL) was added potassium tert-butoxide (6.22 g, 55.55 mmol) at 0 C. After stirring for 5 min, bromo-cyclopropane (4.44 ml, 55.55 mmol) was added and the reaction mixture was stirred for another 4 h at room temperature. The reaction was quenched by addition of water and extracted with ethyl acetate (50×2 ml). The organic layer was washed with water (20 mL), concentrated and purified by silica gel column chromatography to furnish 4-Cyclopropyl-3,4-dihydro-2H-benzo[1,4]oxazine (4.42 g).MS (ES) m/z 176 (M+1).

Reference： [1]Patent: WO2011/48148,2011,A2 .Location in patent: Page/Page column 61
[2]Patent: WO2011/48112,2011,A1 .Location in patent: Page/Page column 80
[3]Patent: US2011/171159,2011,A1 .Location in patent: Page/Page column 34
[4]Patent: US2012/196813,2012,A1 .Location in patent: Page/Page column 25

16
[ 5735-53-5 ]
[ 75-03-6 ]
[ 82756-78-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃;	To a stirred solution of 3,4-dihydro-2H-benzo[1 ,4]oxazine (4.0 g, 29.6 mmol) in DMF (20 ml) was added potassium carbonate (10.22 g, 74.0 mmol). After stirring for five min. lodo-ethane (3.5 ml, 44.4 mmol) was added and heated to 60 C for overnight. Reaction mixture was cooled to room temperature, quenched by the addition of water (20 ml), extracted with ethyl acetate (3 X 25 ml). The organic layer was washed with water (30 ml), brine (30 ml), dried over sodium sulfate, concentrated and purified by silica gel column chromatoghraphy to furnish 4-ethyl-3,4-dihydro-2H-benzo[1 ,4]oxazine(2.7 g ).1H NMR (400 MHz, CD3OD): delta 1.10 (t, J = 6.8 Hz, 3H), 3.26-3.33 (m, 4H), 4.16 (t, J = 4.4 Hz, 2H), 4.40 (s, 2H), 6.52-6.58 (m, 1 H), 6.60-6.80 (m, 3H).MS (ES) m/z 163.2 (M+1 )
		To a stirred solution of 3,4-dihydro-2H-benzo[1 ,4]oxazine (4.0 g, 29.6 mmol) in DMF (20 mL) was added potassium carbonate (10.22 g, 74.0 mmol). After stirring for five min. lodo-ethane (3.5 mL, 44.4 mmol) was added and heated to 60 C for overnight. Reaction mixture was cooled to room temperature, quenched by the addition of water (20 mL), extracted with ethyl acetate (3 X 25 mL). The organic layer was washed with water (30 mL), brine (30 mL), dried over sodium sulfate, concentrated and purified by silica gel column chromatoghraphy to furnish 4-ethyl-3,4-dihydro-2H- benzo[1,4]oxazine (2.7 g ).1H NMR (400 MHz, CD3OD): delta 1.10 (t, J = 6.8 Hz, 3H), 3.26-3.33 (m, 4H), 4.16 (t, J - 4.4 Hz, 2H), 4.40 (s, 2H), 6.52-6.58 (m, 1 H), 6.60-6.80 (m, 3H). MS (ES) m z 163.2 (M+1)
		Step II: To a stirred solution of 3,4-dihydro-2H-benzo[1,4]oxazine (4.0 g, 29.6 mmol) in DMF (20 mL) was added potassium carbonate (10.22 g, 74.0 mmol). After stirring for five min. Iodo-ethane (3.5 mL, 44.4 mmol) was added and heated to 60 C. for overnight. Reaction mixture was cooled to room temperature, quenched by the addition of water (20 mL), extracted with ethyl acetate (3×25 mL). The organic layer was washed with water (30 mL), brine (30 mL), dried over sodium sulfate, concentrated and purified by silica gel column chromatoghraphy to furnish 4-ethyl-3,4-dihydro-2H-benzo[1,4]oxazine (2.7 g).1H NMR (400 MHz, CD3OD): delta 1.10 (t, J=6.8 Hz, 3H), 3.26-3.33 (m, 4H), 4.16 (t, J=4.4 Hz, 2H), 4.40 (s, 2H), 6.52-6.58 (m, 1H), 6.60-6.80 (m, 3H).

To a stirred solution of 3,4-dihydro-2H-benzo[1,4]oxazine (4.0 g, 29.6 mmol) in DMF (20 ml) was added potassium carbonate (10.22 g, 74.0 mmol). After stirring for five min. Iodo-ethane (3.5 ml, 44.4 mmol) was added and heated to 60 C. for overnight. Reaction mixture was cooled to room temperature, quenched by the addition of water (20 ml), extracted with ethyl acetate (3×25 ml). The organic layer was washed with water (30 ml), brine (30 ml), dried over sodium sulfate, concentrated and purified by silica gel column chromatography to furnish 4-ethyl-3,4-dihydro-2H-benzo[1,4]oxazine (2.7 g).1H NMR (400 MHz, CD3OD): delta 1.10 (t, J=6.8 Hz, 3H), 3.26-3.33 (m, 4H), 4.16 (t, J=4.4 Hz, 2H), 4.40 (s, 2H), 6.52-6.58 (m, 1H), 6.60-6.80 (m, 3H).MS (ES) m/z 163.2 (M+1)

Reference： [1]Patent: WO2011/48148,2011,A2 .Location in patent: Page/Page column 60
[2]Patent: WO2011/48112,2011,A1 .Location in patent: Page/Page column 80
[3]Patent: US2011/171159,2011,A1 .Location in patent: Page/Page column 33-34
[4]Patent: US2012/196813,2012,A1 .Location in patent: Page/Page column 25

17
[ 1323407-86-8 ]
[ 5735-53-5 ]
[ 1323403-40-2 ]

Yield	Reaction Conditions	Operation in experiment
53%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20 - 40℃; for 42h;	5.68 3-{4-[4-(2,3-DIHYDRO-BENZO[1,4]OXAZIN-4-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE To the stirred solution of 3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (350 mg, 0.79 mmol) in Acetonitrile (8 mL) was added solution of 3,4-dihydro-2H-benzo[b][1,4]oxazine (128 mg, 0.9 mmol) in acetonitrile (2 mL) and DIPEA (0.21 ml, 1.2 mmol) at room temperature. The resulting light yellow solution was stirred at room temperature for 18 hrs and stirred at 40 C. for 24 hrs. The product was purified by prep HPLC to give 3-{4-[4-(2,3-Dihydro-benzo[1,4]oxazin-4-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dione as a white solid (208 mg, 53% yield). HPLC: Waters Symmetry C-18, 3.9*150 mm, 5 mum, 1 mL/min, 240 nm, 55/45, (CH3CN/0.1% H3PO4), 4.50 min (99.0%); mp: 145-147 C.; 1H NMR (DMSO-d6) delta 1.91-2.04 (m, 1H, CHH), 2.33-2.47 (m, 1H, CHH), 2.53-2.65 (m, 1H, CHH), 2.80-3.01 (m, 1H, CHH), 3.35-3.43 (m, 2H, CH2), 4.14-4.45 (m, 4H, CHH, CHH, CH2), 4.47 (s, 2H, CH2), 5.10 (dd, J=5.1, 13.2 Hz, 1H, CHH), 5.21 (s, 2H, CH2), 6.44-6.56 (m, 1H, Ar), 6.57-6.76 (m, 3H, Ar), 7.22-7.39 (m, 4H, Ar), 7.39-7.59 (m, 3H, Ar), 10.96 (s, 1H, NHH); 13C NMR (DMSO-d6) delta 22.31, 31.16, 45.06, 47.06, 51.55, 53.57, 64.03, 69.32, 112.27, 114.91, 115.20, 115.77, 116.91, 121.24, 127.20, 127.96, 129.78, 129.95, 133.28, 135.17, 135.21, 138.23, 143.46, 153.45, 167.99, 170.95, 172.81; LCMS MH=498; Anal. Calcd for C29H27N3O5+0.3H2O: C, 69.25; H, 5.53; N, 8.35; Found: C, 69.01; H, 5.29; N, 8.25.

Reference： [1]Patent: US2011/196150,2011,A1 .Location in patent: Page/Page column 95

18
[ 90841-55-7 ]
[ 5735-53-5 ]
C₁₈H₁₉NO₃ [ No CAS ]

Reference： [1]Journal of Heterocyclic Chemistry,2011,vol. 48,p. 1187 - 1191

19
[ 5735-53-5 ]
[ 62336-24-7 ]
[ 1350654-31-7 ]

Yield	Reaction Conditions	Operation in experiment
44%	With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 100℃; for 24h;	General procedure: BDPP (341 mg, 1 mmol), NaOtBu (114 mg, 1.5 mmol), piperazine (129 mg, 1.5 mmol), Pd2(dba)3 (9 mg, 0.01 mmol), L7 (31 mg, 0.06 mmol), and toluene (2.5 mL) were mixed in a Schlenk reactor. After the reaction mixture was placed in a pre-heated oil bath at 100 C for 24 h, H2O (20 mL) was added at room temperature. The product was extracted with ether (10 mL × 3) and was dried over Na2SO4. The solvent was evaporated in vacuo. The remaining solid was purified by chromatography (5:100 methanol/dichloromethane) to give L3 (249 mg, 72% yield) as a yellow crystal along with a debrominated product (PPh3, 25%).

Reference： [1]Journal of Organometallic Chemistry,2012,vol. 696,p. 4309 - 4314

20
[ 98556-31-1 ]
[ 5735-53-5 ]
[ 1373622-12-8 ]

Yield	Reaction Conditions	Operation in experiment
40%	With triethylamine; In 1,4-dioxane; at 80℃; for 24h;	11.1 Preparation of 4-(6-iodoquinazolin-4-yl)-3,4-dihydro-2H-benzo-1,4-oxazine 0.75 g of <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong>, 0.39 g of 3,4-dihydro-2H-benzo-1,4-oxazine and 0.50 ml of triethylamine in 5 ml of dioxane are heated at 80 C. in a flask until the quinazoline has reacted completely (HPLC check, about 24 hours). The cooled reaction solution is evaporated to dryness. The residue is washed by stirring with EA and filtered off with suction, giving 0.35 g of 4-(6-iodoquinazolin-4-yl)-3,4-dihydro-2H-benzo-1,4-oxazine as yellowish solid (yield 40%, content 96%); MS-FAB (M+H+)=390.0; Rf (polar method): 2.36 min.

Reference： [1]Patent: US2013/210819,2013,A1 .Location in patent: Paragraph 0304-0305

21
[ 68322-84-9 ]
[ 5735-53-5 ]
[ 1450923-15-5 ]

Yield	Reaction Conditions	Operation in experiment
1.73 g		To a flask under nitrogen, 3,4-dihydro-2H-benzo[b][1,4]oxazine (Tyger Scientific Inc., Ewing, NJ, 0.457 mL, 3.70 mmol) was dissolved in DMF (18.50 mL) and at room temperature, NaH (60% dispersion in mineral oil) (0.326 g, 8.14 mmol) was added, and the reaction was stirred for 15 minutes. 2-Bromo-1-fluoro-4-(trifluoromethyl)benzene (Alfa Aesar, Ward Hill, MA, 0.790 mL, 5.55 mmol) was then added, and the reaction was stirred overnight at room temperature until complete conversion to the desired product. The reaction was then quenched with saturated aqueous ammonium chloride solution, and extracted with EtOAc (x2). The combined organics were washed with brine, dried over sodium sulfate, and concentrated to give material, which was purified via silica gel MPLC (Biotage Isolera One; PuriFlash HP, 15mu, 25 g (Biotage, Uppsala, Sweden)), eluting with 0 to 100% ethyl acetate in heptanes. Fractions containing clean product were collected and concentrated under a vacuum to yield 1.73 g of 4-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (INTERMEDIATE B) as an orange oil. 1H NMR (400 MHz, DMSO-d6) delta ppm 3.62 - 3.69 (m, 2 H) 4.28 (t, J=4.21 Hz, 2 H) 6.30 (dd, J=7.87, 1.71 Hz, 1 H) 6.71 (dtd, J=18.67, 7.42, 7.42, 1.71 Hz, 2 H) 6.85 (dd, J=7.78, 1.81 Hz, 1 H) 7.59 (d, J=8.41 Hz, 1 H) 7.81 (dd, J=8.41, 1.56 Hz, 1 H) 8.13 (d, J=1.66 Hz, 1 H). m/z (ESI) 357.0 (M+H)+
1.7 g		To a flask under nitrogen, 3,4-dihydro-2H-benzo[b][1,4]oxazine (Tyger Scientific Inc., Ewing, NJ, 0.46 mL, 3.7 mmol) was dissolved in DMF (19 mL) and at room temperature, NaH (60% dispersion in mineral oil) (0.33 g, 8.1 mmol) was added, and the reaction was stirred for 15 minutes. 2-Bromo-1-fluoro-4-(trifluoromethyl)benzene (Alfa Aesar, Ward Hill, MA, 0.790 mL, 5.6 mmol) was then added, and the reaction was stirred overnight at room temperature until complete conversion to the desired product. The reaction was then quenched with saturated aqueous ammonium chloride solution, and extracted with EtOAc (x2). The combined organics were washed with brine, dried over sodium sulfate, and concentrated to give material, which was purified via silica gel MPLC (Biotage Isolera One; PuriFlash HP, 15mu, 25 g (Biotage, Uppsala, Sweden)), eluting with 0 to 100% ethyl acetate in heptanes. Fractions containing clean product were collected and concentrated under a vacuum to yield 1.7 g of 4-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine as an orange oil. 1H NMR (400 MHz, DMSO-d6) d ppm 3.62 - 3.69 (m, 2 H) 4.28 (t, J=4.21 Hz, 2 H) 6.30 (dd, J=7.87, 1.71 Hz, 1 H) 6.71 (dtd, J=18.67, 7.42, 7.42, 1.71 Hz, 2 H) 6.85 (dd, J=7.78, 1.81 Hz, 1 H) 7.59 (d, J=8.41 Hz, 1 H) 7.81 (dd, J=8.41, 1.56 Hz, 1 H) 8.13 (d, J=1.66 Hz, 1 H). m/z (ESI) 357.0 (M+H)+.

Reference： [1]Patent: WO2013/122897,2013,A1 .Location in patent: Page/Page column 64; 65
[2]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 3477 - 3485

22
[ 5735-53-5 ]
[ 51997-51-4 ]
[ 1479050-46-8 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 8626 - 8655
[2]Patent: WO2015/31914,2015,A1 .Location in patent: Sheet 6/7

23
[ 5735-53-5 ]
[ 620-22-4 ]
[ 1582184-94-8 ]

Yield	Reaction Conditions	Operation in experiment
68%		A dried 200 mL round bottom was charged with boron trichloride (1.0 M PhMe) (4.67 mL, 4.67 mmol) and cooled to 0 C for 15 min. Next, 3,4-dihydro-2H-benzo[b][l,4]oxazine (574 mg, 4.25 mmol) in toluene (Volume: 9.4 mL) was added drop wise over about 5 min, and then the solution was stirred for 10 minutes. Aluminum chloride (623 mg, 4.67 mmol) was added and the solution was stirred for 5 minutes. Then, 3-methylbenzonitrile (0.605 mL, 5.10 mmol) was added. The reaction mixture was stirred at 0 C, for about 1 h, then allowed to warm to room temperature and heated to reflux for 8 h. HC1 (1.5 M) (28.3 mL, 42.5 mmol) was added, and the reaction mixture was heated to reflux for 2 h. The reaction mixture was cooled to room temperature, basified to pH 9 with 1 M NaOH, and extracted three times with CH2CI2. The organic layers were dried with MgSC^ and evaporated. The residue was purified via ISCO (40g column; hex/EtOAc; 2 min, 0%, 27 min, 40%, 30 min 40%;) to afford (3,4-dihydro-2H- benzo[b][l,4]oxazin-5-yl)(m-tolyl)methanone, Intermediate C-1A (0.73g, 2.9 mmol, 68%) 1H NMR (400MHz, chloroform-d) delta 8.31 (br. s., 1H), 7.47-7.39 (m, 2H), 7.37-7.33 (m, 2H), 7.12 (dd, J=8.1, 1.5 Hz, 1H), 6.99-6.88 (m, 1H), 6.48 (t, J=7.9 Hz, 1H), 4.29 (t, J=4.5 Hz, 2H), 3.63 (td, J=4.6, 2.8 Hz, 2H), 2.43 (s, 3H).

Reference： [1]Patent: WO2014/47390,2014,A1 .Location in patent: Paragraph 00223; 00224

24
[ 95-55-6 ]
(2-bromoethyl)(diphenyl)sulfonium trifluoromethanesulfonate [ No CAS ]
[ 5735-53-5 ]

Yield	Reaction Conditions	Operation in experiment
68%		General procedure: A stifling solution of the requisite phenol derivative, (10 mmol) in CH2Cl2 (20 mL) was treated with NaH (35 mmol) at 0 C. under argon. After 5 minutes, 2-bromoethyldiphenylsulfonium salt (12 mmol) was added and the reaction was stirred for 5 hours at RT. The reaction was then quenched with saturated ammonium chloride solution (10 mL), and extraction was performed with CH2Cl2 (3×25 mL), washed with brine (20 mL), the resultant was dried over MgSO4, filtered and concentrated under vacuum. The targeted compound was then purified using chromatography on silica.

Reference： [1]Patent: US2014/323720,2014,A1 .Location in patent: Paragraph 0063; 0064; 0083; 0084

25
[ 17249-80-8 ]
[ 5735-53-5 ]
4-(thiophen-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With 2-dicyclohexylphosphino-2?,6?-diisopropoxybiphenyl; potassium carbonate; ruphos; In tert-Amyl alcohol; at 110℃; for 20h;Inert atmosphere;	4-(thiophen-3-yl)-3,4-dihydro-2H-benzo[bl[1 ,41oxazine The general procedure is followed with the following modifications: a mixture of 3-chlorothiophene (93 muIota_, 1 .00 mmol), benzomorpholine (140 muIota_, 1 .20 mmol), K2C03 (194 mg, 1 .40 mmol), (7i-crotyl)Pd(RuPhos)CI (6.6 mg, 0.01 mmol), RuPhos (4.7 mg, 0.01 mmol), and 2 mL f-AmOH are stirred at 1 10 C for 20 hour. The crude material is chromatographed on silica gel with a gradient of 0 - 5 % EtOAc/hexanes as the eluent to give 212 mg (0.98 mmol, 98 %) of 4-(thiophen-3-yl)-3,4- dihydro-2H-benzo[b][1 ,4]oxazine as a yellow oil. H NMR (400 MHz, CDCI3, delta): 7.30 (dd, J = 3.2 Hz, 5.2 Hz, 1 H), 7.07 (dd, J = 1 .4 Hz, 5.2 Hz, 1 H), 6.92 - 6.98 (m, 1 H), 6.85 - 6.91 (m, 1 H), 6.81 (dd, J = 1 .4Hz, 3.2 Hz, 1 H), 6.73 - 6.81 (m, 2H), 4.33 (t, J = 4.5 Hz, 2H), 3.69 (t, J = 4.4 Hz, 2H). 3C NMR (100 MHz, CDCI3, delta): 146.1 , 144.5, 133.1 , 125.4, 124.1 , 121 .2, 120.1 , 1 17.0, 1 16.3, 1 12.3, 64.5, 49.0. Anal. Calcd. for C12H NOS: C, 66.33; H, 5.10; N, 6.45. Found: C, 66.42; H, 5.24; N, 6.42.

Reference： [1]Journal of Organic Chemistry,2015,vol. 80,p. 6794 - 6813
[2]Patent: WO2015/189554,2015,A1 .Location in patent: Page/Page column 48; 50

26
[ 5735-53-5 ]
[ 105-36-2 ]
[ 903161-55-7 ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 125℃;	[00481] Intermediate 43a: ethyl 2-(2,3-dihydro-1 ,4-benzoxazin-4-yI)acetate[00482] A flask containing 3,4-dihydro-2H-1 ,4-benzoxazine (200mg, 1 .48mmol), ethyl bromoacetate (0.23mL, 2.O7mmol), potassium carbonate (409mg, 2.g6mmol) and sodium iodide(333mg, 2.22mmol) in DMF (2mL) was heated to 125 C and left to stir overnight. The reaction mixture was quenched with water (5OmL) and extracted using EtOAc (3 x 5OmL). The combined organic layers were dried over Na2504, filtered and solvent removed in vacuo to give ethyl 2-(2,3- dihydro-1 ,4-benzoxazin-4-yl)acetate (325mg,1 .47mmol, 99% yield) as a yellow oil which was used in next step without further purification.1H NMR (CDCI3, 400MHz) O/ppm: 6.84 - 6.79 (2H, m), 6.69-6.64 (1 H, m), 6.55-6.51 (1 H, m), 4.38-4.28 (2H, m), 4.20 (2H, q, J = 7.1 Hz), 4.02 (2H, 5), 3.53 - 3.49 (2H, m), 1.26 (3H, t, J = 7.1 Hz). MS Method 2: RT: 1.63 mi m/z 222.1 [M+H]

Reference： [1]Patent: WO2016/51193,2016,A1 .Location in patent: Paragraph 00480; 00481; 00482

27
4-(2-cyclopropyloxazol-5-yl)phenylsulfonyl chloride [ No CAS ]
[ 5735-53-5 ]
4-(4-(2-cyclopropyloxazol-5-yl)phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With pyridine; In dichloromethane; at 20℃; for 2h;	General procedure: The precursor compound BA-1 was synthesized according to the reference methods [22], illustrated above in Chemistry section. Then BA-1(1.0 mmol) was added with compounds BA-2(1.2 mmol) and pyridine (2.0 mmol) in CH2Cl2 (5 mL), the reaction was stirred at room temperature for 2 h, and then purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain compounds BA-3(a-m), BA-3o and BA-4(a-b). 4.1.20 4-(4-(2-cyclopropyloxazol-5-yl)phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (BA-4a) Yellow solid, yield: 88%. M.p. 114-115 C. 1H NMR (400 MHz, CDCl3)delta7.86 (dd, J = 8.2, 1.5 Hz, 1H), 7.67-7.57 (m, 4H), 7.30 (s, 1H), 7.08 (ddd, J = 8.2, 7.4, 1.5 Hz, 1H), 6.95 (ddd, J = 8.2, 7.4, 1.5 Hz, 1H), 6.80 (dd, J = 8.2, 1.5 Hz, 1H),4.01-3.83 (m, 2H), 3.83-3.62 (m, 2H), 2.16-2.06 (m, J = 8.1, 5.3 Hz, 1H), 1.18-1.07 (m, 4H). 13C NMR (100 MHz, CDCl3) delta 146.85, 137.25, 132.68, 127.89, 126.52, 124.90, 124.87, 124.07, 123.67, 120.98, 117.58, 62.63, 44.39, 9.09, 8.75. HR-ESI-MS: Calcd C20H18N2O4S [M+H]+: 383.10655; found: 383.10545.

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 122,p. 488 - 496

28
4-Bromo-2-methyl indene [ No CAS ]
[ 5735-53-5 ]
C₁₈H₁₇NO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%		Well dried 2-neck round bottom flask to 500ml 4-bromo-2-methylindene 5g (23.9mmol), 3,4-dihydro-2Hbenzo [b] [1,4] oxazine 3ml (1.05equiv.) were placed,And vacuum-dried at room temperature for 1 hour.Within the glove box,Insert the lithium tert-butoxide 5.8g (3equiv.), Bis (tri- (tert-butyl) phosphine) palladium (0),Again it brought out into the hood.In an Ar-purge state, 106 ml of anhydrous toluene was added,and after mounting Water-cooled condenser, and placed in an oil bath at 130 C for one day.After confirming the completion of the reaction conversion by TLC analysis, the reaction mixture was cooled to room temperature,and 100ml of distilled water was added to complete the reaction.The organic layer was separated and the aqueous layer was extracted with diethyl ether (50 ml, twice).The organic layer was collected, dried with Na-2SO4,and Filtered and evaporated to give a crude product in the form of a brown solid.Purification by, Flashcolumn chromatography (10 MC:: Hx = n-1),5.1 g of pure product (19.4 mmol, 81% yield) was obtained as a white solid.Anhydrous methyl tert-butyl ether (44 ml) was added to the resultant product (16.8 mmol),and 7.4 ml (2.5 M in n-hexane, 1.1 equiv.) Of n-butyl lithium was added at -78 C.The mixture was warmed to room temperature and stirred overnight.After removing the solvent by vacuum drying, anhydrous n-hexane (50 ml) was added,and After stirring for 10 minutes at room temperature and filtering, 4.4 g of white solid product was obtained (16.2 mmol, 97% yield).Then in the glove box,Well dried 100ml in Schlenk flask,insert [2-Me-4-DBO-Ind] Li 2.95g (10.9mmol), Me2Si [2-Me-4-Naph-Ind] Cl 3.6g (1equiv.), copper cyanide 40mg (0.04 equiv.) ,and Taken in a hood, and vacuum-dried at -78 C for 10 minutes.70 ml of anhydrous diethyl ether was added in an Ar-purge state at -78 C,and After stirring for 10 minutes, the mixture was warmed to room temperature and stirred for 1 day. After a certain period of time, distilled water (50 ml) was added to terminate the reaction.After separating the organic layer, the water layer was extracted twice with diethylether (20 ml).The organic layer was collected, washed with brine,and After drying with MgSO4, filtered and evaporated to give a yellow solid product of 6.17g (10.7mmol, 98% yield).
5.1 g	With bis(tri-t-butylphosphine)palladium(0); lithium tert-butoxide; In toluene; at 130℃; for 24h;Glovebox; Inert atmosphere;	4-bromo-2-methylindene 5 g (23.9mmol), 3,4-dihydro-2H- benzo [b] [1,4] oxazine 3 ml (1.05equiv.) was put into well rolled 500ml 2-neck round bottom flask and it vacuumed dry at at a room temperature for 1 hour. The lithium tert-butoxide 5.8 g (3equiv.), and the bis (tri-(tert-butyl)phosphime) palladium (0) were put in the Glove box and it had and it again came out to the hood. In the Ar-purge state, the anhydrous toluene 106 ml was added and the water-cooled condenser was put in 130 oil bath after doing the installation and it refluxed to 1 days. It cooled after doing the confirmation in a room temperature that the reaction conversion was completed to the TLC analysis and the distilled water 100ml was added and reaction was terminated. The organic layer was separated and the layer of water extracted in diethyl ethers (50ml, and two times). The organic layer was dried to more, and the Na -2SO4and after it filtered it evaporated and the crude product of the brown solid form was obtained. It was refined to the Flash column chromatography (MC:n-Hx=1:10) and the pure outcome 5.1 g of the white colour solid was obtained (19.4mmol, 81% yield). In this way, the anhydrous methyl tert-butyl ether (44ml) was added to the synthesized outcome (16.8mmol) and it melted and n-butyl lithium 7.4mls (2.5M in n-hexane, 1.1 equiv.) were added at -78. In a room temperature, it was stirred for one night after it heated. After it vacuumed dry and the solvent was removed the anhydrous n-hexane (50ml) was added and it at a room temperature was stirred in for 10 minutes and the white solid result material 4.4g was obtained after doing the filtering (16.2mmol, 97% yield). Next, [2-Me-4-DBO-Ind] Li 2.95g (10.9mmol), the Me2 Si [2-Me-4-Naph-Ind] Cl 3.6g (1 equiv.), and the copper cyanide 40mg (0.04 equiv.) were put into 100ml Schlenk flask well rolled in the Glove box and it brought with the hood and it vacuum dried for 10 minutes at -78. In -78, and the Ar-purge state, the anhydrous diethyl ether 70ml was added and it heated to a room temperature and it was stirred in 1 days after doing for 10 minutes mixing. The distilled water (50ml) was added after preset time and reaction was terminated. After the organic layer was separated the layer of water extracted in the diethyl ether (20ml). The organic layer was collected and it washed with brine and after it dried to the MgSO4it filtered and it evaporated and outcome 6.17 gs (10.7mmol, 98% yield) of the yellow solid were obtained.

Reference： [1]Patent: KR2015/16827,2015,A .Location in patent: Paragraph 0175-0179
[2]Patent: KR2015/16828,2015,A .Location in patent: Paragraph 0162; 0163

29
tert-butyl (2-phenoxyethyl)(tosyloxy)carbamate [ No CAS ]
[ 5735-53-5 ]

Yield	Reaction Conditions	Operation in experiment
82%	With Rh2(esp)2; trifluoroacetic acid; In 2,2,2-trifluoroethanol; at 20℃; for 17h;Inert atmosphere;	Following the general intramolecular aza-annulation procedure, 147 tert-butyl (2-phenoxyethyl)(tosyloxy)carbamate (10g: 0.102 g, 0.25 mmol), 45 TFA (38 muL, 0.5 mmol), and Du Bois' catalyst (3.8 mg, 5 mumol) were stirred at rt in TFE (2.5 mL) for 17 h. Chromatographic purification of the crude product afforded 149 3,4-dihydro-2H-benzo[b][1,4]oxazine (11g) as an oil (28 mg, 82%) whose spectral data were in agreement with literature values in Dugar, et al., 2015. TLC: Rf?0.4 (30% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) delta 6.82-6.74 (m, 2H), 6.70-6.63 (m, 1H), 6.60 (dd, J=7.7, 1.6 Hz, 1H), 4.26 (app t, J=4.5 Hz, 2H), 3.74 (br s, 1H), 3.42 (app t, J=4.5, 2H); 13C NMR (101 MHz, CDCl3) delta 144.11, 133.64, 121.28, 118.85, 116.73, 115.63, 65.22, 40.99.

Reference： [1]Science,2016,vol. 353,p. 1144 - 1147
[2]Patent: US2019/152892,2019,A1 .Location in patent: Paragraph 0132; 0227

30
[ 32315-10-9 ]
[ 5735-53-5 ]
2,3-dihydro-4H-benzo[b]-[1,4]oxazine-4-carbonyl chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With pyridine; In dichloromethane; at -78 - 20℃;Inert atmosphere;	Synthesis of 2,3-dihydro-4H-benzo[b]-[1,4]oxazine-4-carbonyl chloride: to a solution of 44 triphosgene (3.4g, 12mmol, 0.46equiv) in anhydrous 45 CH2Cl2 (17mL, 0.7M) under a N2 atmosphere was added 46 pyridine (2.0mL, 25mmol, 1.0equiv) dropwise at -78C. A solution of 29 3,4-dihydro-2H-benz-[b]-[1,4]oxazine (3.5g, 26mmol, 1.0equiv) in anhydrous CH2Cl2 (2mL) was added dropwise at -78C before warming to room temperature. After completion, the reaction was quenched with 47 HCl (1.0M) and extracted three times with CH2Cl2. The combined organic layers were washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and the resulting filtrate was concentrated under vacuum. The resulting residue was purified on a short pad of silica (eluting with 20% EtOAc/n-pentane) to give the 48 carbamoyl chloride. Preparation of 16 18: to a dried Schlenk flask under a N2 atmosphere was added a solution of 50 (S)-N-methyl-1-phenylethanamine (0.75mL, 3.9mmol, 1.3equiv) and 51 triethylamine (0.66mL, 4.8mmol, 1.6equiv) in anhydrous 52 acetonitrile (10mL, 0.4M). A solution of the 48 carbamoyl chloride (0.79g, 4.0mmol, 1.0equiv) in anhydrous acetonitrile (1mL) was added dropwise to the mixture and stirred at room temperature until completion (followed by TLC). The reaction was quenched with saturated 53 aqueous NaHCO3, extracted three times with CH2Cl2 and the combined organic layers were dried over MgSO4, filtered and the resulting filtrate was concentrated under vacuum. The crude urea was purified by flash column chromatography (eluting with 7-60% Et2O/petrol on a ZIP Sphere 30g column over 14 column volumes) to give the title compound 18; 1.07g, 90% yield; light yellow solid; Rf 0.18 (30% Et2O/n-pentane); mp 79-80C (CH2Cl2/n-pentane); numax (film)/cm-1 1642, 1601, 1584, 1496, 1431, 1391, 1338, 1306, 1282, 1217, 1178, 1061, 1050, 770; [alpha]21D [alpha]D21 =-43 (c 1.0, CHCl3); deltaH (400MHz, CDCl3) 7.37-7.28 (m, 5H, ArH), 6.96-6.93 (m, 1H, ArH), 6.87-6.86 (m, 1H, ArH), 6.81-6.77 (m, 1H, ArH), 5.59 (q, J=7.1Hz, 1H, NCHPh), 4.35-4.31 (m, 2H, CH2), 3.72-3.68 (m, 2H, CH2), 2.60 (s, 3H, NCH3), 1.61 (d, J=7.0Hz, 3H, CH3); deltaC (101MHz, CDCl3) 159.5 (C=O), 145.0 (C), 140.7 (C), 128.7 (CH), 128.4 (C), 127.6 (CH), 127.6 (CH), 123.1 (CH), 120.7 (CH), 119.5 (CH), 117.3 (CH), 66.4 (CH2), 54.4 (CH), 44.0 (CH2), 31.0 (CH3), 16.2 (CH3); HRMS (ESI+) [M+H]+ C18H21N2O2+ requires 297.1598; found 297.1607. Chiral supercritical fluid chromatography ((S,S)-Whelk-01, 5/100 Kromasil, 25cm×4.6mm ID), 125bar CO2, 40C, 4mL/min, 20% co-solvent (MeOH); tR 3.8min (major), 5.2min (minor) 99:1 er. Racemic sample was prepared by making a 1:1 mixture of (-)-18 and (+)-18, which was prepared in an analogous manner.

Reference： [1]Comptes Rendus Chimie,2017,vol. 20,p. 634 - 642
[2]Angewandte Chemie - International Edition,2016,vol. 55,p. 11153 - 11157
Angew. Chem.,2016,vol. 128,p. 11319 - 11323,5

31
[ 68322-84-9 ]
[ 5735-53-5 ]
[ 1450923-16-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 3477 - 3485

32
[ 70801-52-4 ]
[ 82756-78-3 ]
[ 5735-53-5 ]

Yield	Reaction Conditions	Operation in experiment
7%; 90%	With triethyl borane; Triethoxysilane; sodium hydroxide; In hexane; at 80℃; for 6h;Inert atmosphere; Sealed tube;	Under argon atmosphere, NaOH and triethyl boron were first stirred at room temperature to form a clear clear solution at a concentration of 1 M / L;Subsequently, 10 mol (2 mol%) of the above-mentioned triethylboron solution, 5 mmol of amide substrate, 15 mmol of silane, 2 mL of solventInto a 10 mL sealed tube and placed in an oil bath at 80 C for 6 hours with heating. The reaction was completed and the reaction was exposed to air quenching, followed byThe yield was determined by column chromatography and gas chromatography and a pure product was obtained. When using polymethylhydrogensiloxane (PMHS) andWhen the tetrahydrofuran was used as the silane and the solvent, the yields of the products A and B were 81% and 3%, respectively. When the triethoxysilaneAnd n-hexane as silane and solvent, respectively, the yield of products A, B were: 90%, 7%

Reference： [1]Patent: CN107235845,2017,A .Location in patent: Paragraph 0102; 0103; 0104; 0105
[2]Journal of Organic Chemistry,2019
[3]Journal of Organic Chemistry,2019,vol. 84,p. 14627 - 14635

33
ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate [ No CAS ]
[ 5735-53-5 ]
N-[5-(3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%		To a solution of 192 mg (0.43 5 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the same way as in Reference Example 4 in 2 ml of 1,4-dioxane, 0.24 ml (1.4 mmol) of DIPEA and 180 mg (1.33 mmol) of 3,4-dihydro-2H-<strong>[5735-53-5]1,4-benzoxazine</strong> [purchased from Combi-Blocks Inc.] were added at room temperature in an argon atmosphere and then reacted at 100 C. for 3 hours with stirring. The reaction solution was cooled, and 0.24 ml (2.2 mmol) of N,N-dimethylethane-1,2-diamine was added thereto at room temperature and then reacted at room temperature for 1.5 hours with stirring. After completion of the reaction, the reaction solution was separated into an organic layer and an aqueous layer by the addition of ethyl acetate and a 5% aqueous potassium bisulfate solution. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to preparative column chromatography (apparatus 1, DIOL silica gel, n-hexane:ethyl acetate=41:59?20:80 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in aqueous acetonitrile and freeze-dried to obtain 150 mg of the title compound (yield: 74%) as a pale yellow solid. Mass spectrum (CI, m/z): 468 [M+1]+. 1H-NMR spectrum (400 MHz, DMSO-d6) delta: 12.30 & 11.99 (br s, total 1H), 9.90-9.41 (m, 1H), 6.83-6.74 (m, 4H), 4.53-4.42 (m, 2H), 4.34-4.26 (m, 2H), 3.50-3.46 (m, 2H), 2.43-2.33 (m, 2H), 2.19-2.07 (m, 2H), 1.83-1.66 (m, 8H), 0.09-0.09 (m, 9H).

Reference： [1]Patent: US2018/186818,2018,A1 .Location in patent: Paragraph 1066; 1067; 1068; 1069; 1070

34
C₁₄H₁₃ClO₂ [ No CAS ]
[ 5735-53-5 ]
(E)-1-(2H-benzo[b][1,4]oxazin-4(3H)-yl)-3-(3-ethyl-4-(prop-2-yn-1-yloxy)phenyl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With dmap; triethylamine; In dichloromethane; at 25℃; for 12h;	To a stirred solution of (E)-3-(3-ethyl-4-(prop-2-yn-l-yloxy)phenyl)acrylic acid (0.28 g, 1.22 mmol, 1.0 equiv.) in dichloromethane (5 mL) at 0C was added oxalyl chloride (0.463 g, 3.65 mmol, 3.0 equiv.) and the mixture stirred at 25C for 10 minutes. The reaction mixture was concentrated under reduced pressure to give a yellow solid and the residue was dissolved in dichloromethane (4 mL). 3,4-Dihydro-2H-l,4-benzoxazine (0.197g, 1.46mmol, 1.2 equiv.), triethylamine (0.057 g, 0.563 mmol, 2.0 equiv.) and dimethylaminopyridine (0.003 g, 0.028 mmol, 0.1 equiv.) were added at 25C and the resultant mixture was stirred at 25C for 12 hours. The reaction was diluted with water (30 mL) and extracted with dichloromethane (4 x 10 mL). The combined organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford the desired product as a white solid (48 mg, 47%); 1H NMR (CDC13, 400 MHz) delta 7.74 (d, = 15.6 Hz, 1H), 7.34 - 7.32 (m, 2H), 7.21 (d, = 6.8 Hz, 1H), 7.14 - 7.10 (m, 1H), 6.98 - 6.92 (m, 4H), 4.75 (d, = 2.4 Hz, 2H), 4.37 (t, = 4.4 Hz, 2H), 4.08 (t, = 4.8 Hz, 2H), 2.65 (q, = 7.6 Hz, 2H), 2.52 (t, = 2.4 Hz, 1H), 1.20 (t, = 7.6 Hz, 3H); MS (ESI+) m/z 348.1 (M+H)+; 100% purity, RT 2.42 min (Method 10).

Reference： [1]Patent: WO2018/144620,2018,A1 .Location in patent: Paragraph 00418

35
[ 667-27-6 ]
[ 5735-53-5 ]
2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With copper (I) acetate; caesium carbonate; XPhos; In N,N-dimethyl-formamide; at 110℃; for 12h;	27.0 mg (0.2 mmol) of benzomorpholine,81.2 mg of ethyl bromodifluoroacetate (0.4 mmol),2.5 mg (0.02 mmol) of cuprous acetate, 19.1 mg (0.04 mmol) of X-phos, 32.7 mg (0.2 mmol) of cesium carbonate were added to 2 mL of DMF solvent.The reaction was carried out at 110 C for 12 hours, after the reaction was completed, it was cooled, filtered, and the filtrate was evaporated.The solvent was removed and the residue was chromatographed on silica gel.It was washed with a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 8:1.The effluent was collected according to the actual gradient, detected by TLC, and the effluent containing the product was combined.The solvent was distilled off by a rotary evaporator. Vacuum drying to give a yellow liquid 2H benzo[b][1,4]oxazin-4(3H)-formaldehyde26.1 mg, yield 80%.
72%	With water; In N,N-dimethyl-formamide; at 110℃; for 6h;Schlenk technique;	General procedure: A 25 mL oven-dried Schlenk tube was sequentially added N-methylaniline 1 or aniline 4 (0.2 mmol), Ethyl Bromodifluoroacetate 2a (81.2 mg, 0.4 mmol), DMF (1ml) and H2O (1 mL) was added under air. The reaction mixture was stirred for 6 h at 110. The solution was then diluted with ethyl acetate (20 mL), washed with brine (10 mL), extracted with ethyl acetate (3*5 mL), dried over anhydrous Na2SO4, filtered and evaporated under vacuum. The crude reaction mixture was purified by column chromatography (silica gel, ethyl acetate/petroleum ether) yielded the desired product 3 or 5.

Reference： [1]Patent: CN108774147,2018,A .Location in patent: Paragraph 0046
[2]Journal of Organic Chemistry,2018,vol. 83,p. 12815 - 12821
[3]Tetrahedron Letters,2019,vol. 60,p. 1254 - 1258

36
[ 134997-87-8 ]
[ 5735-53-5 ]
6-(3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 1385 - 1406

37
[ 102236-25-9 ]
[ 5735-53-5 ]

Yield	Reaction Conditions	Operation in experiment
37%		In step (ii), intermediate c was reduced and cyclised to give the following fuel additive e In a first experiment, intermediate c in which L is Cl (6.0 g, 30 mmol), Pt02 (50 mg) and sodium acetate (1 eq) in ethyl acetate (100 ml) was hydrogenated at 10 bar and 25 C for 2 hours. The reaction mixture was filtered and the resulting red oil was extracted in ethyl acetate, Et3N (1 eq) and Nal (200 mg) were added and the mixture was refluxed for 16 hours, to afford fuel additive e in 37 % yield.

Reference： [1]Patent: WO2019/129591,2019,A1 .Location in patent: Page/Page column 35; 36

38
[ 18800-37-8 ]
[ 5735-53-5 ]

Yield	Reaction Conditions	Operation in experiment
		In a second experiment, intermediate c in which L is Br (3.0 g, 12.2 mmol), sodium acetate (1 eq) and Pt20 (10 mg) in ethyl acetate (30 ml) was hydrogenated at 10 bar and 25 C for 18 hours. The mixture was filtered, and the brown oil was taken up into ethyl acetate (25 ml) and Et3N (2 ml) and refluxed 6 hours, to give a product which comprises 80 % of fuel additive e (measured using 1H-NMR).

Reference： [1]Patent: WO2019/129591,2019,A1 .Location in patent: Page/Page column 35; 36

39
[ 61144-93-2 ]
[ 5735-53-5 ]

Yield	Reaction Conditions	Operation in experiment
		In step (ii), intermediate c was reduced and cyclised to give the following fuel additive e Specifically, intermediate c (2.0 g, 8 mmol), 10 % Pd/C (100 mg), and pTSA (50 mg) hydrogenated at 30 bar in dioxane (30 ml) at 25 C for 2 hours and then the temperature raised to 100 C and maintained at this temp overnight. TLC analysis of the reaction mixture confirmed the reduction of the nitro group to an amino group, but minimal cyclisation was observed. 1 ml of concentrated HC1 was added and hydrogenated at 50 C and 40 bar for 2 hours. Sampling confirmed that no acetal was left in the reaction, which was consequently filtered and diluted with water to give a pinkish solid. TLC analysis showed an impure mixture containing fuel additive e.

Reference： [1]Patent: WO2019/129591,2019,A1 .Location in patent: Page/Page column 38; 39

40
[ 42876-07-3 ]
[ 5735-53-5 ]

Reference： [1]Organic Letters,2019,vol. 21,p. 9954 - 9959

41
[ 16883-16-2 ]
[ 5735-53-5 ]
C₁₉H₁₆N₂O₃ [ No CAS ]

Reference： [1]Journal of Agricultural and Food Chemistry,2020,vol. 68,p. 10550 - 10559

42
[ 1878-87-1 ]
[ 5735-53-5 ]

Yield	Reaction Conditions	Operation in experiment
62%	Stage #1: 2-nitrophenoxyacetic acid With phenylsilane; potassium-t-butoxide; C₂₂H₃₀ClN₂RuS₂⁽¹⁺⁾*Cl^(1-) In tetrahydrofuran; 1,4-dioxane at 100℃; for 18h; Inert atmosphere; Stage #2: With water monomer; caesium fluoride In tert-butyl methyl ether at 20℃; for 3h; Inert atmosphere;	3,4-Dihydro-2H-benzo[1,4]oxazine (6): To a stirred suspension of (2-nitro-phenoxy)-aceticacid (3f) (500 mg, 2.5105 mmol,1equiv.) in degassed 1,4-dioxane (10 V) was added ARP-03 (26.3 mg, 0.0502 mmol,2 mol%) and again degassed for 10 minutes. After 10 minutes of degassing, PhSiH3(1.56 mL, 12.5525 mmol, 5 equiv.) and t-BuOK (1 M in THF) (0.25 mL,0.2510 mmol, 10 mol%) were added dropwise to reaction mixture at RT. Thereaction mixture was heated to 100°C and stirred for 18 h. The reaction mixturewas then evaporated to remove volatiles, then suspended in MTBE and stirred withaq. CsF solution (10%, 10 V) for 3 h. The organic layer was then separated andconcentrated in vacuum to furnish the crude, which was purified by columnchromatography on silica gel (eluent: Ethyl acetate / n-hexane = 1 /4) to afford 3,4-dihydro-2H-benzo[1,4]oxazine (6) (213 mg, 62%) as a brown oil.1HNMR (400 MHz, CDCl3): δ 6.85 - 6.70 (m, 2H), 6.70 - 6.50 (m, 2H), 4.35 - 4.20 (m,2H), 3.50 - 3.40 (m, 2H).13CNMR (100 MHz, DEPT - 135, CDCl3): δ 144.22 (C), 133.72 (C),121.39 (CH), 118.98 (CH), 116.84 (CH), 115.75 (CH), 65.31 (CH2),41.08 (CH2).LCMS (EI, m/z) calcd for C8H9NO [M + H]: 136.17 Found: 136.11.

Reference： [1]Abhilash, Vishwanathan; Gadakh, Amol V.; Ganesh, Sambasivam; Hegde, Shivaprasad N.; Jacob, Anand; Karthik, C. S.; Lamees, Thundianandi; Mathivanan, Namachivayam; Sathiyanarayanan, Arumugam Murugan [Journal of Organometallic Chemistry, 2022, vol. 963]

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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. 5735-53-5 ] {[proInfo.proName]}

Quality Control of [ 5735-53-5 ]

Related Doc. of [ 5735-53-5 ]

Product Details of [ 5735-53-5 ]

Calculated chemistry of [ 5735-53-5 ]

Physicochemical Properties

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Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 5735-53-5 ]

Application In Synthesis of [ 5735-53-5 ]

[ 5735-53-5 ] Synthesis Path-Upstream 1~22

[ 5735-53-5 ] Synthesis Path-Downstream 1~42

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Other Aromatic Heterocycles

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[ 5735-53-5 ]