105655-01-4|6-Bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine| Ambeed

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Quality Control of [ 105655-01-4 ] Purity: 98% SDS Specification

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Product Details of [ 105655-01-4 ]

CAS No. :	105655-01-4
Formula :	C₈H₈BrNO
M.W :	214.06
SMILES Code :	BrC1=CC=C2OCCNC2=C1
MDL No. :	MFCD08544341
InChI Key :	RWKBNMSHIJBNAO-UHFFFAOYSA-N
Pubchem ID :	10727336

Safety of [ 105655-01-4 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 105655-01-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
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	50.76
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	21.26 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.08
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.34
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.68
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.83
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	2.53
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.09

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.05
Solubility	0.193 mg/ml ; 0.000902 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.43
Solubility	0.803 mg/ml ; 0.00375 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-3.6
Solubility	0.0539 mg/ml ; 0.000252 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.94 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.13

Application In Synthesis of [ 105655-01-4 ]

* 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.

Downstream synthetic route of [ 105655-01-4 ]

[ 105655-01-4 ] Synthesis Path-Downstream 1~35

1
[ 50-00-0 ]
[ 105655-01-4 ]
[ 188947-79-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium cyanoborohydride; acetic acid; In tetrahydrofuran; at 70℃;	Into a 20-mL microwave tube, were placed a solution of <strong>[105655-01-4]6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine</strong> (400 mg, 1.869 mmol, 1.0 equiv.) in THF (5 mL). Then, CH2O (5 mL), CH3COOH (1 mL), NaBH3CN (450 mg, 7.258 mmol, 4.0 equiv.) was added. The resulting solution was stirred overnight at 70 C. in an oil bath. The reaction was monitored by TLC (PE/EA=4/1). Water (5 ml) was added to the mixture and the mixture was stirred for 10 minutes at room temperature. The resulting mixture was evaporated under reduced pressure. The residue was applied onto a silica gel column with PE/EA (95/5) to 6-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine obtained as a yellow oil. Mass spectrum (EI, m/z): Calcd for C9H10BrNO, 228.0 (M+H), found, 229.7.
	With sodium cyanoborohydride; acetic acid; In tetrahydrofuran; at 70℃;	Into a 20-mL microwave tube, were placed a solution of <strong>[105655-01-4]6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine</strong> (400 mg, 1.869 mmol, 1.0 equiv.) in THF (5 mL). Then, CH2O (5 mL), CH3COOH (1 mL), NaBH3CN (450 mg, 7.258 mmol, 4.0 equiv.) was added. The resulting solution was stirred overnight at 70 C. in an oil bath. The reaction was monitored by TLC (PE/EA=4/1). Water (5 ml) was added to the mixture and the mixture was stirred for 10 minutes at room temperature. The resulting mixture was evaporated under reduced pressure. The residue was applied onto a silica gel column with PE/EA (95/5) to 6-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine obtained as a yellow oil. Mass spectrum (EI, m/z): Calcd for C9H10BrNO, 228.0 (M+H), found, 229.7.

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 1465 - 1474.
[2]Patent: US2019/47960,2019,A1 .Location in patent: Paragraph 0644; 0645; 0646; 0647.
[3]Patent: US2019/47961,2019,A1 .Location in patent: Paragraph 0643-0644.

2
[ 188947-78-6 ]
[ 105655-01-4 ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 1465 - 1474.

3
[ 24036-52-0 ]
[ 105655-01-4 ]

Yield	Reaction Conditions	Operation in experiment
100%		INTERMEDIATE 13; 6-Bromo-3,4-dihydro-2H-benzo[l.,4]oxazine; Borane-TetaF ( 13.2 mL of a 1 M solution in TetaF, 13.2 mmol) was added portionwise to Intermediate 6 (2.0 g, 8.0 mmol) in TetaF (50 mL) at r.t. The resulting solution was stirred at r.t. for 10 min, heated to reflux for 1 h and then allowed to cool to r.t. The reaction was cooled in an ice bath and quenched with water (20 mL) and 2N aqueous sodium hydroxide solution (2OmL). The solvent was removed in vacuo and the resulting mixture diluted with water (100 mL). It was extracted with EtOAc (10OmL), washed with brine (10OmL), dried (MgSO4), filtered and concentrated in vacuo to yield the title compound as a brown oil (2 g, quant). deltaeta (DMSO-d6) 3.36-3.44 (2H, m), 3.81 (IH, br s), 4.18-4.25 (2H, m), 6.68 (3H, m).
100%	With borane-THF; In tetrahydrofuran; at 20℃; for 1.16667h;Heating / reflux;	Borane-TetaF (13.2 mL, IM solution in TetaF, 13.2 mmol) was added portionwise to Intermediate 37 (2.0 g, 8.0 mmol) in TetaF (50 mL) at r.t. The resulting mixture was stirred at r.t. for 10 minutes, heated to reflux for 1 h and then allowed to cool to r.t. The reaction mixture was cooled to 00C and quenched with water (20 mL) and aqueous 2N NaOH (20 mL). The solvent was removed in vacuo and the resulting mixture diluted with water (100 mL). The aqueous fraction was extracted with EtOAc (100 mL), washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to yield the title <n="52"/>compound (2 g, quantitative) as a brown oil. deltaH (DMSOd6) 6.68 (3H, m), 4.25-4.18 (2H, m), 3.81 (IH, br. s), 3.44-3.36 (2H, m).
100%		INTERMEDIATE 106-Bromo-3,4-dihvdro-2H-benzo[ 1 ,4]oxazineBorane-THF (13.2 mL of a IM solution in THF, 13.2 mmol) was added portionwise to Intermediate 8 (2.0 g, 8.0 mmol) in THF (50 mL) at r.t. The resulting solution was stirred at r.t. for 10 minutes, heated to reflux for 1 h and then allowed to cool to r.t. The reaction was cooled in an ice bath and quenched with water (20 mL) and 2N aqueous sodium hydroxide solution (20 mL). The solvent was removed in vacuo and the resulting mixture diluted with water (100 mL). It was extracted with EtOAc (100 mL), <n="99"/>washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to yield the title compound (2 g, quantitative) as a brown oil. deltaH (DMSO-d6) 6.68 (3H, m), 4.18- 4.25 (2H, m), 3.81 (IH, br s), 3.36-3.44 (2H, m).

100%		Borane-THF (13.2 mL, IM solution in THF, 13.2 mmol) was added portionwise to Intermediate 5 (2.0 g, 8.0 mmol) in THF (50 mL) at r.t. The resulting solution was stirred at r.t. for 10 minutes, heated to reflux for 1 h and then allowed to cool to r.t. The reaction mixture was cooled to 00C and quenched with water (20 mL) and aqueous 2N NaOH (20 mL). The solvent was removed in vacuo and the resulting mixture diluted with water (100 mL). The aqueous fraction was extracted with EtOAc (100 mL), washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to yield the title compound (2 g, quantitative) as a brown oil. deltaH (DMSO-d6) 6.68 (3H, m), 4.25-4.18 (2H, m), 3.81 (IH, br. s), 3.44-3.36 (2H, m).
100%		To a stirred solution of Intermediate 32 (2.0 g, 8.0 mmol) in TetaF (50 mL) was added borane-TetaF (13.2 mL, IM solution in TetaF, 13.2 mmol) portionwise. The reaction mixture was stirred at r.t. for 10 minutes, then heated to reflux for 1 h and allowed to cool to r.t. The reaction mixture was cooled to 00C and quenched with water (20 mL), then 2M aqueous NaOH (20 mL), and concentrated in vacuo. Water (100 mL) and EtOAc (100 mL) were added and the layers separated. The organic fraction was washed with <n="105"/>brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (2 g, quantitative) as a brown oil. deltaH (DMSOd6) 6.68 (3 H, m), 4.25-4.18 (2H, m), 3.81 (IH, br. s), 3.44-3.36 (2H, m).
93%	With dimethylsulfide borane complex; In tetrahydrofuran; for 3h;Inert atmosphere; Reflux;	To a solution of 6-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (400 mg, 1.75 mmol) in anhydrous tetrahydrofuran (3 mL) under a nitrogen atmosphere was added a 1M solution of borane dimethyl sulfide complex in tetrahydrofuran (7.0 mL, 7.0 mmol) slowly. The resulting solution was refluxed for 3 hours. Then, the reaction mixture was cooled to ambient temperature and carefully quenched with the addition of methanol (10 mL). Next, the reaction mixture was heated to reflux for 10 minutes, and then the reaction mixture was cooled and concentrated in vacuo to provide a residue. The residue was redissolved in ethyl acetate, washed with water, brine, dried with sodium sulfate, filtered and concentrated in vacuo to yield title compound. The title compound was used in Part IV below without purification. (350 mg, 93% yield) ESI m/z 214.03, 216.0 (M+H).
88%		Example 48; lambda/-{2-chloro-5-[4-(phenylmethyl)-3,4-dihydro-2H-l,4-benzoxazin-6-yl]-3- pyridinyl}benzenesulfonamide; a) 6-bromo-3 ,4-dihy dro-2H- 1 ,4-benzoxazine; 6-Bromo-2H-l,4-benzoxazin-3(4H)-one (2.085 g, 9.143 mmol) was suspended in dry TetaF (20 mL) and placed under nitrogen with stirring and to this was added 1 M BH3-THF complex (3.143 g, 36.572 mmol, 36.52 mL) over 5 minutes. Addition causes the reaction to become homogeneous. After 70 minutes, the reaction was cooled to O0C and made acidic by addition of 3N HCl (109 mL). Addition of acid causes vigorous bubbling. After the addition was completed, the reaction was refluxed for 10 minutes and then cooled and made basic by addition of 6N NaOH. The basified reaction was extracted with EtOAc (3 x 100 mL), dried over Na2SO4, filtered, and the concentrated filtrate was purified by flash chromatography on silica gel (.00% CH2Cl2) to give the title compound (1.713 g, 88%) as a pale yellow oil. MS(ES)+ m/e 214 [M+H].
87%	With borane-THF; In tetrahydrofuran;Inert atmosphere; Cooling with ice; Reflux;	[Synthesis of Compound E4] (0133) Compound E3 (1.0 g, 4.4 mmol, 1 Eq) was dissolved in THF (20 mL) in an argon atmosphere, and placed on an ice bath. A THF solution of 1 M borane-THF complex (7.0 mL, 7.0 mmol, 1.6 Eq) was added and the combination was stirred overnight while heating and refluxing. The reaction system was returned to room temperature, methanol was added in small amounts, and the solvent was removed under reduced pressure. The reaction system was then diluted by ethyl acetate, and the organic layer was washed by saturated sodium hydrogen carbonate aqueous solution and saturated saline, dried by anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue obtained was purified by medium-pressure silica gel chromatography (eluent: dichloromethane/methanol=98/2), and the target compound E4 (817 mg, 87%) was obtained as a colorless liquid. (0134) 1H NMR (CDCl3): delta 6.71 (dd, J=2.3 Hz, 8.4 Hz, 1H), 6.68 (d, J=2.3 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 4.20 (t, J=4.4 Hz, 2H), 3.80 (br s, 1H), 3.38 (t, J=4.4 Hz, 2H).; 13C NMR (CDCl3): delta 143.1 (C), 135.2 (C), 121.2 (CH), 118.1 (CH), 117.7 (CH), 113.2 (C), 65.1 (CH2), 40.6 (CH2).; HRMS-ESI (m/z): [M+H]+ calcd for C8H9BrNO: 213.98620. found: 213.98626 (-0.1 mDa, -0.3 ppm).
	With borane-THF; In tetrahydrofuran; for 14h;Reflux;	Step II: To a stirred solution of 6-bromo-2H-1,4-benzoxazin-3(4H)-one (10 g, 43.85 mmol) in THF (25 ml) was added 1.0 M borane-tetrahydrofuran complex in THF (153.5 ml, 153.48 mmol) and refluxed for 14 h. The reaction mixture was cooled to room temperature, quenched with methanol (50 ml) and concentrated under reduced pressure. The resulting residue was taken in ethyl acetate (100 ml), washed with aqueous saturated sodium bicarbonate solution (100 ml), water (100 ml), brine (100 ml), dried over sodium sulphate, concentrated and purified by silica gel column chromatography (5% ethyl acetate in hexane) to provide 6-bromo-3,4-dihydro-2H- benzop^oxazine (8.5 g).
3.2 g	With borane-THF; In tetrahydrofuran; at 0℃; for 3h;Reflux;	6-bromo-3,4-dihydro-2H-benzo[6] [l,4]oxazine (2): To a stirred solution of 6- bromo-2H-benzo[6][l,4]oxazin-3(4H)-one (7 g, 30.8 mmol) in THF (20 mL) was added 1M borane in THF (15.41 mL) at 0 C and stirred for 3 h at reflux temperature. After completion of the reaction, methanol (2 mL) was added to the reaction mixture at 0 C and stirred for 2 h at reflux. After completion of the reaction, cone. HC1 (2 mL) was added to reaction mixture at 0 C and again stirred for 2 h at reflux. The reaction mixture was then neutralized with 2N NaOH solution at 0 C and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by column chromatography (100-200 mesh silica gel, 15% ethyl acetate in pet. ether as eluent) to afford 2 (3.2 g, 49% yield) as a brown solid. MS m/z (M+H): 214.4
	With borane-THF; In tetrahydrofuran; at 0℃;Reflux;	Compound 7-2 (22 g, 0.1 mol) was dissolved in tetrahydrofuran (200 ml) and a solution of BH3 / tetrahydrofuran (1.0 M, 200 ml) was added dropwise at 0 C. The mixture was then stirred under reflux overnight. Then slowly at 0 reaction was quenched with methanol. The mixture was concentrated to give a crude product was used directly in the next step.

References: [1]Patent: WO2008/44022,2008,A1 .Location in patent: Page/Page column 29.
[2]Patent: WO2008/47109,2008,A1 .Location in patent: Page/Page column 50-51.
[3]Patent: WO2009/71895,2009,A1 .Location in patent: Page/Page column 97-98.
[4]Patent: WO2009/71888,2009,A1 .Location in patent: Page/Page column 73.
[5]Patent: WO2009/71890,2009,A1 .Location in patent: Page/Page column 103-104.
[6]Patent: US9512111,2016,B2 .Location in patent: Page/Page column 233; 234.
[7]Patent: WO2009/55418,2009,A1 .Location in patent: Page/Page column 69-70.
[8]Patent: US2017/45525,2017,A1 .Location in patent: Paragraph 0132; 0133; 0134.
[9]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4700 - 4704.
[10]Patent: WO2010/128152,2010,A1 .Location in patent: Page/Page column 52.
[11]Patent: WO2014/149164,2014,A1 .Location in patent: Paragraph 00945.
[12]Patent: CN106146482,2016,A .Location in patent: Paragraph 0118; 0119; 0120.

4
[ 24424-99-5 ]
[ 105655-01-4 ]
[ 719310-31-3 ]

Yield	Reaction Conditions	Operation in experiment
65%	With dmap; triethylamine; In tetrahydrofuran; at 20℃;	A mixture of the product 6-bromo-3,4-dihydro-2H-benzo[£][l,4]oxazine (1.37 g, 6.4 mmol), Boc20 (1.676 g, 7.68 mmol), Et3N (970 mg, 9.6 mmol), DMAP (78 mg, 0.64 mmol) in THF (27 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL) and brine, dried over Na2S04 and concentrated to give compound 0601-182 (1.3 g, 65%) as a yellow oil. LCMS: 258 [M-55]+. 1H NMR (400 MHz, OMSO-de) delta 1.49 (s, 9H), 3.78 (t, J= 4.8 Hz, 2H), 4.21 (t, J= 4.4 Hz, 2H), 6.83 (d, J = 4.4 Hz, 1H), 7.12 (dd, J; = 2.0 Hz, J2 = 8.4 Hz, 2H), 8.01 (s, 1H).
65%	With dmap; triethylamine; In tetrahydrofuran; at 20℃;	A mixture of the product <strong>[105655-01-4]6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine</strong> (1.37 g, 6.4 mmol), Boc2O (1.676 g, 7.68 mmol), Et3N (970 mg, 9.6 mmol), DMAP (78 mg, 0.64 mmol) in THF (27 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL) and brine, dried over Na2SO4 and concentrated to give compound 0601-182 (1.3 g, 65%) as a yellow oil. LCMS: 258 [M-55]+. 1H NMR (400 MHz, DMSO-d6) delta 1.49 (s, 9H), 3.78 (t, J=4.8 Hz, 2H), 4.21 (t, J=4.4 Hz, 2H), 6.83 (d, J=4.4 Hz, 1H), 7.12 (dd, J1=2.0 Hz, J2=8.4 Hz, 2H), 8.01 (s, 1H).
65%	With dmap; triethylamine; In tetrahydrofuran; at 20℃;	The product 6-bromo-3,4-dihydro--2H- benzo [b] [1,4] oxazine (1.37g, 6.4mmol), Boc2O (1.676g, 7.68mmol), Et3N (970mg, 9.6mmol), DMAP (78mg, 0.64mmol) a mixture of in THF (27mL), and stirred at room temperature overnight. The reaction mixture was diluted with water (200 mL), and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL) and brine, dried and concentrated in Na2SO4, to give the compound 0601-182 as a yellow oil (1.3g, 65%).

60%	With triethylamine;dmap; In tetrahydrofuran;Heating / reflux;	INTERMEDIATE 25; 6-Bromo-2,3-dihvdrobenzo[l,41oxazine-4-carboxylic acid fe/t-butyl ester; A mixture of Intermediate 13 (4.0 g, 18.6 mmol), di-fert-butyl dicarbonate (4.9 g, 22.4 mmol), 4-(dimethylamino)pyridine (50 mg, catalytic) and triethylamine (2.6 mL, 18.6 mmol) in THF (50 mL) was heated to reflux overnight. After cooling to r.t. the reaction mixture was concentrated in vacuo. The crude material was purified by column chromatography (SiO2, linear gradient elution: 0-100% EtOAc in heptane) to give the title compound as an off-white solid (3.5g, 60%). deltaH (DMSO-d6) 1.56 (9H, s), 3.80-3.89 (2H, m), 4.19-4.26 (2H, m), 6.77 (IH, d, J 8.9 Hz), 7.08 (IH, dd, J8.7, 2.4 Hz), 8.02 (IH, s).
	With dmap; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 15 - 25℃; for 48h;Inert atmosphere;	Step 1: To a solution of <strong>[105655-01-4]6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine</strong> (12-a) (1.00 g, 4.67 mmol) in CH2Cl2 (30 mL) was added di-tert-butyl dicarbonate ((Boc)2O) (1.63 mL, 7.01 mmol), DIPEA (1.63 ml, 9.34 mmol) and DMAP (57 mg, 0.47 mmol) at rt. The resulting mixture was stirred at rt for 2 days under a nitrogen atmosphere. To the reaction mixture was added water (20 mL) and the mixture was stirred for 5 min. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (× 2). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0-100% EtOAc/hexanes to afford tert-butyl 6-bromo-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate.1H NMR (400 MHz, CDCl3) G 8.01 (br s, 1H), 7.06 (dd, J = 8.8 Hz, J = 2.2 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 4.24-4.18 (m, 2H), 3.86-3.81 (m, 2H), 1.55 (s, 9H).

References: [1]Patent: WO2011/130628,2011,A1 .Location in patent: Page/Page column 227.
[2]Patent: US2013/102595,2013,A1 .Location in patent: Paragraph 0575.
[3]Patent: JP2015/187145,2015,A .Location in patent: Paragraph 0488.
[4]Patent: WO2008/44022,2008,A1 .Location in patent: Page/Page column 32.
[5]Patent: WO2019/182886,2019,A1 .Location in patent: Page/Page column 76.

5
[ 6160-65-2 ]
[ 105655-01-4 ]
[ 1000801-20-6 ]

Yield	Reaction Conditions	Operation in experiment
58%		INTERMEDIATE 30; 6-Bromo-2,3-dihvdro-benzo[l,4]oxazine-4-carbothioic acid amide; A solution of Intermediate 13 (11.68 g, 54.6 mmol) in THF (120 mL) was added to thiocarbonyldiimidazole (19.45 g, 109.12 mmol) and the mixture divided between 8 microwave vials. The reactions were each heated to 12O0C under microwave irradiation for 15 minutes, then cooled to r.t., combined and poured into methanolic ammonia (10OmL of a 7M solution, 0.7 mol) and stirred at r.t. overnight. The mixture was concentrated in vacuo, and the residue partitioned between water (200 mL), 2M HCl (50 mL) and then hexane and ether. The resulting solid was collected by filtration and washed with methanol/water to give the title compound (8.72 g, 58%) as a brown solid. 5H (CDCl3) 4.33-4.40 (2H, m), 4.45-4.52 (2H, m), 6.41 (2H, br.s), 6.88 (IH, d, J 8.7 Hz), 7.25 (IH, dd, J 8.7, 2.1 Hz), 7.51 (IH, d, J 2.1 Hz). LCMS (ES+) 275 (M+H)+.; EXAMPLE 1 (METHOD A); 2-(6-Bromo-2.3-dihvdrobenzori,41oxazin-4-yl)-5,5-dimethyl-5,6-dihydro-4H- benzothiazol-7-one; Intermediate 13 (2 g, 9.4 mmol) and l,l'-thiocarbonyldiimidazole (3.3 g, 18.8 mmol) were combined in THF (16 ml) and heated to 125C under microwave irradiation <n="42"/>for 15 min. The mixture was cooled to r.t, reduced in vacuo, and ammonia (50 ml of a 7N solution in methanol, 0.35 mol) was added. It was stirred for 2 h, then concentrated in vacuo. The residue was partitioned between EtOAc (100 ml) and 2N HCl (100 ml). The organics were washed with brine (100 ml), dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated with Et2O and heptane to give a yellow solid. Of this material, 0.5 g (1.8 mmol) was combined with Intermediate 1 (0.69 g, 3.1 mmol) and DIPEA (0.6 mL, 3.4 mmol) in THF (18 mL) and heated to 140C under microwave irradiation for 30 min. After cooling to r.t. the mixture was partitioned between EtOAc (130 mL) and water (130 mL). The organics were washed with water (150 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting crude material was purified by prep HPLC to yield the title compound as an off-white solid (166 mg, 23%). deltaH (CDCl3) 1.16 (6H, s), 2.44 (2H, s), 2.79 (2H, s), 4.07-4.17 (2H, m), 4.27- 4.38 (2H, m), 6.84 (IH, d, J 8.7 Hz), 7.17 (IH, dd, J 8.7, 2.3 Hz), 8.22 (IH, d, J2.3 Hz). LCMS (ES+) 393 (M+H)+.
23%		INTERMEDIATE 136-Bromo-3,4-dihvdro-2H-benzo[l,41oxazine-4-carbothioic acid amideIntermediate 10 (1.7 g, 8.0 mmol) and l,r-thiocarbonyldiimidazole (2.84 g, 16 mmol) were combined in TetaF (15 mL) and heated to 1200C under microwave irradiation for 15 minutes. After cooling to r.t., NH3 (40 mL of a 7N solution in MeOH, 280 mmol) was added, and the mixture stirred at r.t. for 3 h. The reaction mixture was concentrated in vacuo and then partitioned between EtOAc (100 mL) and water (100 mL). The organic fraction was washed with water (100 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated with ether and heptane to give the title compound (0.5 g, 23%) as a white solid. deltaH (DMSO-de) 8.20 (2H, br s), 7.60 (IH, d, J2.3 Hz), 7.21 (IH, dd, J 8.7, 2.3 Hz), 6.88 (IH, d, J 8.9 Hz), 4.30-4.16 (4H, m).
23%		Intermediate 6 (1.7 g, 8 mmol) and lj'-thiocarbonyldiimidazole (2.84 g, 16 mmol) were combined in THF (15 mL) and heated to 12O0C under microwave irradiation for 15 minutes. After cooling to r.t., NH3 (40 mL, 7N solution in MeOH, 280 mmol) was added, and the mixture stirred at r.t. for 3 h. The reaction mixture was concentrated in vacuo and then partitioned between EtOAc (100 mL) and water (100 mL). The organic fraction was washed with water (100 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated with Et2O and heptane to give the title compound (0.5 g, 23%) as a white solid. deltaH (DMSO-d6) 8.20 (2H, br. s), 7.60 (IH, d, J2.3 Hz), 7.21 (IH, dd, J 8.7 and 2.3 Hz), 6.88 (IH, d, J8.9 Hz), 4.30-4.16 (4H, m).

23%		A solution of Intermediate 33 (1.7 g, 8 mmol) and l,r-thiocarbonyldiimidazole (2.84 g, 16 mmol) in TetaF (15 mL) was heated to 1200C under microwave irradiation, in a sealed tube, for 15 minutes. After cooling to r.t., NH3 (40 mL, 7N solution in MeOH, 280 mmol) was added. The reaction mixture was stirred at r.t. for 3 h, concentrated in vacuo, and then partitioned between EtOAc (100 mL) and water (100 mL). The organic fraction was washed with water (100 mL), then brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. Trituration with Et2O and heptane gave the title compound (0.5 g, 23%) as a white solid. deltaH (DMSO-d6) 8.20 (2H, br. s), 7.60 (IH, d, J 2.3 Hz), 7.21 (IH, dd, J 8.7 and 2.3 Hz), 6.88 (IH, d, J 8.9 Hz), 4.30-4.16 (4H, m).
		INTERMEDIATE 312-(6-Bromo-2J-dihvdrobenzo("l,41oxazin-4-yl)-5,5-dimethyl-5,6-dihvdro-4H- benzothiazol-7-one Intermediate 10 (2.0 g, 9.4 mmol) and l,r-thiocarbonyldiimidazole (3.3 g, 18.8 mmol) were combined in TetaF (16 mL) and heated to 125C under microwave irradiation for 15 minutes. The mixture was cooled to r.t., concentrated in vacuo, and NH3 (50 mL of a 7N solution in methanol, 0.35 mol) was added. It was stirred for 2 h, then <n="109"/>concentrated in vacuo. The residue was partitioned between EtOAc (100 mL) and 2N HCl (IUO mL). The organic fraction was washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated with ether and heptane to give a yellow solid. Of this material, 0.5 g (1.8 mmol) was combined with Intermediate 5 (0.69 g, 3.1 mmol) and DIPEA (0.6 mL, 3.4 mmol) in THF (18 mL) and heated to 1400C under microwave irradiation for 30 minutes. After cooling to r.t. the mixture was partitioned between EtOAc (130 mL) and water (130 mL). The organic fraction was washed with water (150 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting crude material was purified by preparative HPLC (Method 6) to yield the title compound (166 mg, 23%) as an off-white solid. deltaH (CDCl3) 8.22 (IH, d, J2.3 Hz), 7.17 (IH, dd, J8.7, 2.3 Hz), 6.84 (IH, d, J8.7 Hz), 4.27-4.38 (2H, m), 4.07-4.17 (2H, m), 2.79 (2H, s), 2.44 (2H, s), 1.16 (6H, s).

References: [1]Patent: WO2008/44022,2008,A1 .Location in patent: Page/Page column 34; 40-41.
[2]Patent: WO2009/71895,2009,A1 .Location in patent: Page/Page column 99.
[3]Patent: WO2009/71888,2009,A1 .Location in patent: Page/Page column 73.
[4]Patent: WO2009/71890,2009,A1 .Location in patent: Page/Page column 104.
[5]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4700 - 4704.
[6]Patent: WO2009/71895,2009,A1 .Location in patent: Page/Page column 107-108.

6
[ 106-41-2 ]
isobutyl halide [ No CAS ]
[ 105655-01-4 ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 1465 - 1474.

7
[ 7693-52-9 ]
[ 105655-01-4 ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 1465 - 1474.
[2]Patent: WO2011/130628,2011,A1 .
[3]Patent: JP2015/187145,2015,A .
[4]Patent: US9512111,2016,B2 .
[5]Patent: CN106146482,2016,A .
[6]Patent: US2017/45525,2017,A1 .
[7]Patent: US2013/102595,2013,A1 .

8
[ 36749-01-6 ]
[ 105655-01-4 ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 1465 - 1474.

9
[ 40925-68-6 ]
[ 105655-01-4 ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 1465 - 1474.
[2]Patent: WO2011/130628,2011,A1 .
[3]Patent: JP2015/187145,2015,A .
[4]Patent: WO2014/149164,2014,A1 .

10
[ 107986-49-2 ]
[ 105655-01-4 ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 1465 - 1474.

11
[ 105655-01-4 ]
[ 1053719-61-1 ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 1465 - 1474.

12
[ 105655-01-4 ]
[ 1053742-77-0 ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 1465 - 1474.

13
[ 105655-01-4 ]
(3aS,4R,8R,8aS)-2,2-Dimethyl-4,8-bis-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-hexahydro-1,3-dioxa-5,7-diaza-azulen-6-one [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 1465 - 1474.

14
[ 105655-01-4 ]
[ 1053247-90-7 ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 1465 - 1474.

15
[ 105655-01-4 ]
(4R,5S,6S,7R)-1,3-Dibenzyl-5,6-dihydroxy-4,7-bis-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-[1,3]diazepan-2-one [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 1465 - 1474.

16
[ 105655-01-4 ]
(3aS,4R,8R,8aS)-5,7-Dibenzyl-2,2-dimethyl-4,8-bis-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-hexahydro-1,3-dioxa-5,7-diaza-azulen-6-one [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 1465 - 1474.

17
[ 105655-01-4 ]
(4R,5S,6S,7R)-1,3-Bis-(3-acetyl-benzyl)-5,6-dihydroxy-4,7-bis-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-[1,3]diazepan-2-one [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 1465 - 1474.

18
[ 105655-01-4 ]
C₄₄H₄₆N₆O₅ [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 1465 - 1474.

19
[ 105655-01-4 ]
[ 1053733-51-9 ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 1465 - 1474.

20
[ 544-92-3 ]
[ 105655-01-4 ]
[ 928118-07-4 ]

Yield	Reaction Conditions	Operation in experiment
94%		A mixture of <strong>[105655-01-4]6-bromo-3,4-dihydro-2H-benzo[1,4]oxazine</strong> (9D, 1.5 g, 7.05 mmol) and CuCN (1.58 g, 17.61 mmol) in anhydrous DMF (15 mL) was stirred at 130 C. for 3 h and then at 150 C. overnight. Then the mixture was cooled to RT, quenched with water and concentrated under vacuum. The residue was taken up in 2N NaOH and EtOAc (100 mL) and then agitated in a sonicator for 1 h. The precipitate was filtered off and washed with EtOAc. The filtrate and washings were combined and extracted with EtOAc (2×80 mL). The organic layer was dried (MgSO4), filtered and concentrated under vacuum to give compound 12A (1.062 g, 94%).

References: [1]Patent: US2007/93477,2007,A1 .Location in patent: Page/Page column 27-28.

21
[ 6160-65-2 ]
[ 105655-01-4 ]
C₁₂H₁₀BrN₃OS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at 120℃; for 0.25h;Microwave irradiation;	Intermediate 38 (1.7 g, 8 mmol) and l,l '-thiocarbonyldiimidazole (2.84 g, 16 mmol) were dissolved in THF (15 mL) and heated to 1200C under microwave irradiation for 15 minutes. After cooling to r.t., NH3 (40 mL, 7N solution in MeOH, 280 mmol) was added, and the mixture stirred at r.t. for 3 h. The reaction mixture was concentrated in vacuo and then partitioned between EtOAc (100 mL) and water (100 mL). The organic fraction was washed with water (100 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated with Et2O and heptane to give the title compound (0.5 g, 23%) as a white solid. deltaH (DMSO-d6) 8.20 (2H, br. s), 7.60 (IH, d, J2.3 Hz), 7.21 (IH, dd, J 8.7 Hz and J2.3 Hz), 6.88 (IH, d, J 8.9 Hz), 4.30-4.16 (4H, m).

References: [1]Patent: WO2008/47109,2008,A1 .Location in patent: Page/Page column 51.

22
[ 100-39-0 ]
[ 105655-01-4 ]
[ 1148008-74-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	b) 6-bromo-4-(phenylmethyl)-3,4-dihydro-2H-l,4-benzoxazine; A suspension of 6-bromo-3,4-dihydro-2H-l,4-benzoxazine (0.150 g, 0.70 mmol), potassium carbonate (0.242 g, 1.75 mmol), and benzyl bromide (0.179 g, 1.049 mmol) in dry DMF (1.5 mL) was stirred overnight at room temperature. The reaction was diluted with water and EtOAc and transferred to a separatory funnel. The layers were separated and the water was extracted twice with EtOAc. The combined EtOAc layers were washed with water and saturated NaCl, dried over Na2SO4, filtered and concentrated to give the title compound (0.203 g, 95%) as a slightly pink crystalline solid. MS(ES)+ m/e 305 [M+eta].

References: [1]Patent: WO2009/55418,2009,A1 .Location in patent: Page/Page column 70.

23
[ 98-09-9 ]
[ 105655-01-4 ]
[ 1185265-47-7 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine;	1-[2-(4-Benzenesulfonyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one. Substituting 4-benzenesulfonyl-<strong>[105655-01-4]6-bromo-3,4-dihydro-2H-benzo[1,4]oxazine</strong> (prepared by treatment of <strong>[105655-01-4]6-bromo-3,4-dihydro-2H-benzo[1,4]oxazine</strong>(Bioorg. Med. Chem., 15 (2007), 5912) with benzene sulfonyl chloride in pyridine) for 6-bromo-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one. MP=217-219 C, (M+H)+=477.

References: [1]Patent: US2009/215724,2009,A1 .Location in patent: Page/Page column 27.

24
[ 121-60-8 ]
[ 105655-01-4 ]
[ 1185265-49-9 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine;	N-(4-{6-[7-(2,2-Dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-2,3-dihydrobenzo[1,4]oxazine-4-sulfonyl}-phenyl)-acetamide. Substituting N-[4-(6-bromo-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-phenyl]-acetamide (prepared by treatment of <strong>[105655-01-4]6-bromo-3,4-dihydro-2H-benzo[1,4]oxazine</strong>(Bioorg. Med. Chem., 15 (2007), 5912) with 4-acetylamino-benzenesulfonyl chloride in pyridine) for 6-bromo-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one. MP=273-274 C, (M+H)+=534.

References: [1]Patent: US2009/215724,2009,A1 .Location in patent: Page/Page column 27.

25
[ 18162-48-6 ]
[ 105655-01-4 ]
C₁₄H₂₂BrNOSi [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		2H-3,4-Dihydro-6-bromo-1,4-benzoxazine (600 mg; 2.8 mmol) is dissolved in absolute tetrahydrofuran (30 ml), and sodium hydride (202 mg; 55%; 4.2 mmol) is added at 0 C. After stirring for one hour at this temperature, tert-butyl-dimethyl-chlorosilane (465 mg; 3.08 mmol) is added and stirring of the entire mixture is continued for half an hour at room temperature. The reaction mixture is then cooled to -78 C., tert-butyllithium (5.61 ml of a 1.5 M solution; 5.6 mmol) is added and stirring is continued for a quarter of an hour at -78 C. (cooling bath). Trimethoxy-borate (0.625 ml; 5.6 mmol) is then added and the cooling bath is removed. As soon as the reaction mixture has reached room temperature, aqueous hydrochloric acid (10 ml of a 2 M solution; 20 mmol) is added and stirring of the entire mixture is continued for one hour at room temperature. The reaction mixture is then poured on to ice-water and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulphate and filtered with suction and the solvent is evaporated off. The residue is recrystallized from a 1/1 n-hexane/ethyl acetate mixture. Yield: 163 mg (32%) 2H-1,4-benzoxazine-3,4-dihydro-6-boron acid as a brown powder. NMR (1H, 250 MHz in DMSO): ppm: 3.1 (broad singlet, 2H); 4.0 (broad singlet, 2H); 5.47 (broad singlet, 1H); 6.47 (d, 1H); 6.85 (d, 1H); 6.93 (s, 1H)

References: [1]Patent: US6821980,2004,B1 .Location in patent: Page column 24-25.

26
[ 824-94-2 ]
[ 105655-01-4 ]
[ 1254333-03-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 60℃; for 20h;	Step I: To a stirred solution of 6-bromo-3,4-dthydro-2H-benzo(1,4}oxa2tne (1.5 g, 7.0 mmol) in DMF (10 ml) was added 4-methoxybenzyl chloride (1.43 ml, 10.5 mmol), sodium iodide (105 mg, 0.7 mmol), and potassium carbonate (1.93 g. 14.0 mmol). The reaction mixture was heated at 60 C for 20 h, quenched with water (40 ml). After usual work up, compound was purified by silica gel column chromatography to furnish 6- bromo-4-(4-methoxy-benzyl)-3,4-dihydro-2H-benzo(1 ,4]oxazine (2.2 g). 1H NMR (400 MHz, CDCI3): delta 3.28 (t, J = 4.4 Hz1 2H), 3-8 (s, 3H), 4.20 (t, J * 4.4 Hz. 2H), 4.34 (s, 2H), 6.64 (d, J * 8.4 Hz1 1H)1 6.70 (dds J * 8>;4, 2.0 Hz1 1H), 6.80 (d, J - 2.0 Hz, 1H). 6.87 (d. J « 8.4 Hz, 2H). 7 17 (d, J « 8.4 Hz, 2H). MS (ES) m/z 336.1 (M+2)
11 g	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;	To the mixture of 6-bromo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazine (10g, 47mmol) and K2CO3 (13g, 94mmol) in DMF (100 mL) . was added 1- (chloromethyl) -4-methoxybenzene (8.8g, 56mmol) . The mixture was stirred at r.t. for 16h. The mixture was poured into water (30 mL) and extracted with EA (30Ml X 3) . The combined organic layers were dried, concentrated and purified by silica gel column (PE: EA5: 1) to give the desired product (11g) as a white solid. [0990] 1H NMR (CHLOROFORM-d) : delta 7.12 -7.20 (m, J 8.5 Hz, 2H) , 6.84 -6.90 (m, 2H) , 6.80 (d, J 2.1 Hz, 1H) , 6.61 -6.73 (m, 2H) , 4.32 (s, 2H) , 4.15 -4.20 (m, 2H) , 3.76 -3.80 (m, 3H) , 3.22 -3.30 (m, 2H) . LC-MS: m/z 334.5 (M+H) +.

References: [1]Patent: WO2010/128152,2010,A1 .Location in patent: Page/Page column 61.
[2]Patent: WO2018/39972,2018,A1 .Location in patent: Page/Page column 157-158.

27
[ 104-01-8 ]
[ 105655-01-4 ]
[ 1254333-57-7 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; at 0 - 70℃;	Step I: To a stirred solution of 6-bromo-3,4-dihydro-2H-benzo(1,4Joxazine (1.5 g, 7.0 mmol) in dichloromethane - dimethylforrnamide (1:1 mixture. 40 ml) was added 4- methoxyphenyl acetic acid (1.8 g, 10.5 mmol), HOBt (2.4 g, 17.5 mmol), diisopropyiethylamine (4.8 ml, 28 mmol ). EDCI.HCI (3.4 g . 17.5 mmol) at 0 C After 15 rnin, reaction mixture was heated to 70 C for 15 h. quenched by the addition of water. After usual work up, the compound was purified by silica gel column chromatography (10% ethyl acetate in hexane) to furnish 1-(6-bromo-2,3-dihydro-benzo[1.4]oxazin-4-yl)- 2-(4-methoxy-phenyl)-ethanone (1.8 g).1H NMR (400 MHz, CDCI3): delta 3.79 (s, 3H), 3.86 (bs, 4H), 4.14 (bs. 2H): 6.76 (ds J * 8.4 Hz, 1H), 6.86 (d. J « 8.8 Hz. 2H)1 7,16 (d, J * 8.4 Hz: 4H). MS (ES) iWz 364.0 (M+2).

References: [1]Patent: WO2010/128152,2010,A1 .Location in patent: Page/Page column 83.

28
[ 1467-05-6 ]
[ 105655-01-4 ]
[ 1254332-85-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 60℃; for 20h;	Step III: To a stirred solution of 6-bromo-3,4-dihydro~2H-benzo{1,4]oxazine (2.0 g, 9.34 mmol) in DMF (10 ml) was added 4-ethylbenzyl chloride (2.0 ml, 14,01 mmol), sodium iodide (250 mg, 0.93 mmol), potassium carbonate (2.58 g, 18.68 mmol) and heated at 6OC for 20 h, quenched with water (40 ml). After usual work up, compound was purified by silica gel column chromatography (3% ethyl acetate n hexane) to furnish 6-bromo-4- (4-ethyl-benzyl)-3)4-dihydro-2H-ben2o[1,4]oxa2:ine (2.2 g).1H NMR (400 MHz, CDCIS): 6 1.25 (t, J * 8.0 Hz, 3H), 2.65 (q, J - 8.0 Hz1 2H), 3.35 (t, J « 4.4 Hz, 2H)t 4.24 (t, J = 4.4 Hz, 2H), 4.41 (s, 2H), 6.89 (d, J = 8.4 Hz, 1H). 6.76 (dd, J * 8.4, 2.4 Hz, 1H), 6.85 (d, J * 2.0 Hz, 1H), 7.20-7.33 (m, 4H). MS (ES) m/z 334.0 (M+2)

References: [1]Patent: WO2010/128152,2010,A1 .Location in patent: Page/Page column 52.

29
[ 1000800-88-3 ]
[ 105655-01-4 ]
[ 1000793-42-9 ]

Yield	Reaction Conditions	Operation in experiment
80%	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In acetonitrile; at 85℃; for 16h;Inert atmosphere;	2-(6-bromo-2,3-dihydrobenzo[b][1,4]oxazin-4-yl)-6,7-dihydro-6,6-dimethylthiazolo[5,4-c]pyridin-4(5H)-one (11-III)To a solution of compound 11-I (2.7 g, 10.3 mmol) in acetonitrile (100 mL) were added Cs2CO3 (6.71 g, 20.6 mmol), Xanthophos (476 mg, 0.82 mmol) and Pd(OAc)2 (139 mg, 0.61 mmol) at room temperature. The reaction mixture was degassed by purging with argon and <strong>[105655-01-4]6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine</strong> (2.31 g, 10.3 mmol) in acetonitrile was added. The reaction mixture was degassed for 45 minutes at RT and at 85 C. for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of celite, washed with 5% MeOH/DCM and the filtrate was concentrated in vacuo. The crude compound was purified by washing with diethyl ether to afford compound 11-III (3.24 g, 80%) as brown solid. TLC: EtOAc (Rf: 0.4); 1H-NMR (CDCl3, 200 MHz): delta 8.24 (d, J=2.2 Hz, 1H), 7.14 (dd, J=2.4, 8.8 Hz, 1H), 6.83 (d, J=9.0 Hz, 1H), 5.29 (bs, NH), 4.38-4.30 (m, 2H), 4.10-4.02 (m, 2H), 2.90 (s, 2H), 1.40 (s, 6H); Mass: 394.5 [M++1]; MP: 154.7 C.

References: [1]Patent: US2011/230476,2011,A1 .Location in patent: Page/Page column 293.

30
[ 1235451-65-6 ]
[ 105655-01-4 ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 4h;	A mixture of the product 5-bromo-2-(2-bromoethoxy)benzenamine (250 mg, 0.848 mmol) and K2C03 (234 mg, 1.695 mmol) in DMF (5 mL) was stirred at 60 C for 4 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (3 x 50 mL) and brine (50 mL), concentrated to give 6-bromo-3,4-dihydro-2H-benzo[6][l,4]oxazine (170 mg, 94%) as a yellow oil. LCMS: 214 [M+l]+. 1H NMR (400 MHz, DMSO-<¾) delta 3.26 (m, 2H), 4.08 (t, J= 4.8 Hz, 2H), 6.06 (s, 1H), 6.56 (m, 2H), 6.69 (d, J= 1.6 Hz, 1H).
94%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 4h;	A mixture of the product 5-bromo-2-(2-bromoethoxy)benzenamine (250 mg, 0.848 mmol) and K2CO3 (234 mg, 1.695 mmol) in DMF (5 mL) was stirred at 60 C. for 4 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (3×50 mL) and brine (50 mL), concentrated to give 6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine (170 mg, 94%) as a yellow oil. LCMS: 214 [M+1]+. 1H NMR (400 MHz, DMSO-d6) delta 3.26 (m, 2H), 4.08 (t, J=4.8 Hz, 2H), 6.06 (s, 1H), 6.56 (m, 2H), 6.69 (d, J=1.6 Hz, 1H)
94%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 4h;	The product 5-bromo-2- (2-bromoethoxy) benzene amine (250mg, 0.848mmol) and K2CO3 (234mg, 1.695mmol) A mixture of in DMF (5 mL), and stirred for 4 hours at 60 C.. The mixture was diluted with water (100 mL), and extracted with ethyl acetate (100 mL). The organic layer was washed with water (3 × 50 mL) and brine (50 mL), concentrated to give 6-bromo-3,4-dihydro -2H- benzo [b] [1,4] oxazine as a yellow oil (170 mg , 94%).

References: [1]Patent: WO2011/130628,2011,A1 .Location in patent: Page/Page column 227.
[2]Patent: US2013/102595,2013,A1 .Location in patent: Paragraph 0574.
[3]Patent: JP2015/187145,2015,A .Location in patent: Paragraph 0487.

31
[ 79-36-7 ]
[ 105655-01-4 ]
[ 1405679-49-3 ]

References: [1]Heterocyclic Communications,2012,vol. 18,p. 143 - 146.

32
[ 40925-68-6 ]
[ 106-93-4 ]
[ 105655-01-4 ]

Yield	Reaction Conditions	Operation in experiment
19%	With potassium carbonate; In N,N-dimethyl-formamide; at 125℃; for 15h;Inert atmosphere;	To a solution of 2-amino-4-bromophenol (4e) (200.0 mg, 1.06 mmol) and K2C03 (735.3 mg, 5.32 mmol) in anhydrous DMF (3 mL) was added 1,2-dibromoethane (0.14 mL, 1.60 mmol) under argon. The resulting mixture was stirred at 125 C for 15 h. After being quenched with H20 (5 mL), the aqueous layer was extracted with EtOAc (2 x 15 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (EtOAc/hexane, 10:90 to 20:80) to afford 3e (44.0 mg, 19%) as a brown oil; ?H NMR (CDC13, 400 MHz) 6.74-6.69 (2 H, m), 6.64 (1 H, d, J = 8.7 Hz), 4.22-4.20 (2 H, m), 3.89 (2 H, br),3.04-3.38 (2 H, m); ?3C NMR (CDC13, 100 MHz) 142.9, 135.0, 121.0, 118.0, 117.6, 113.1,64.9, 40.5.

References: [1]Heterocyclic Communications,2012,vol. 18,p. 143 - 146.
[2]Patent: WO2018/183633,2018,A1 .Location in patent: Paragraph 0006; 0008; 0017;0106; 0107.

33
[ 105655-01-4 ]
[ 1000793-42-9 ]

Yield	Reaction Conditions	Operation in experiment
80%	With palladium diacetate; In acetonitrile;	2-(6-bromo-2,3-dihydrobenzo[b][1,4]oxazin-4-yl)-6,7-dihydro-6,6-dimethylthiazolo[5,4-c]pyridin-4(5H)-one (5-III-1) To a solution of compound 5-I (2.7 g, 10.3 mmol) in acetonitrile (100 mL) were added Cs2CO3 (6.71 g, 20.6 mmol), Xanthophos (476 mg, 0.82 mmol) and Pd(OAc)2 (139 mg, 0.61 mmol) at room temperature. The reaction mixture was degassed by purging with argon and <strong>[105655-01-4]6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine</strong> (2.31 g, 10.3 mmol) in acetonitrile was added. The reaction mixture was degassed for 45 minutes at RT and at 85 C. for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of celite, washed with 5% MeOH/DCM and the filtrate was concentrated in vacuo. The crude compound was purified by washing with diethyl ether to afford compound 5-III-1 (3.24 g, 80%) as brown solid. TLC: EtOAc (Rf: 0.4); 1H-NMR (CDCl3, 200 MHz): delta 8.24 (d, J=2.2 Hz, 1H), 7.14 (dd, J=2.4, 8.8 Hz, 1H), 6.83 (d, J=9.0 Hz, 1H), 5.29 (bs, NH), 4.38-4.30 (m, 2H), 4.10-4.02 (m, 2H), 2.90 (s, 2H), 1.40 (s, 6H); Mass: 394.5 [M++1]; MP: 154.7 C.

References: [1]Patent: US2011/269244,2011,A1 .Location in patent: Page/Page column.

34
[ 1446002-31-8 ]
[ 105655-01-4 ]
[ 1446002-32-9 ]

Yield	Reaction Conditions	Operation in experiment
52%	With bis(tri-t-butylphosphine)palladium(0); sodium t-butanolate; In toluene; at 110℃; for 18h;Inert atmosphere;	b) 5-(6-Bromo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-2-methoxy-nicotinonitrile A mixture of <strong>[105655-01-4]6-bromo-3,4-dihydro-2H-benzo[1,4]oxazine</strong> (CAS registry 105655-01-4) (5.0 g, 23.36 mmol), 5-iodo-2-methoxy-nicotinonitrile (12.2 g, 46.7 mmol) and NaOtBu (2.69 g, 28.0 mmol) in toluene (50 ml) was degassed with argon for 10 min, then bis(tri-tert-butylphosphine)-palladium(0) (0.36 g, 0.70 mmol) was added. The reaction mixture stirred at 110 C. for 18 h under argon. After cooling to rt, the reaction mixture was filtered through celite, rinsed with EtOAc and the filtrates were washed with sat. aq. NaHCO3 soln. The organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography on silica gel (cyclohexane/EtOAc, 100:0 to 50:50) to yield the title compound (4.2 g, 52% yield). UPLC RtM14=1.55 min; ESIMS: 348 [(M+H)+]. 1H NMR (400 MHz, CDCl3): delta 8.31 (d, 1H), 7.80 (d, 1H), 6.89 (dd, 1H), 6.78 (d, 1H), 6.67 (d, 1H), 4.30-4.35 (m, 2H), 4.10 (s, 3H), 3.61-3.66 (m, 2H).

References: [1]Patent: US2013/165436,2013,A1 .Location in patent: Paragraph 0702; 0703; 0704.

35
[ 103-71-9 ]
[ 105655-01-4 ]
[ 1578241-58-3 ]

References: [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 544 - 549.

Historical Records

Technical Information

• Alkyl Halide Occurrence • General Reactivity • Grignard Reaction • Hiyama Cross-Coupling Reaction • Kinetics of Alkyl Halides • Kumada Cross-Coupling Reaction • Reactions of Alkyl Halides with Reducing Metals • Reactions of Amines • Reactions of Dihalides • Stille Coupling • Substitution and Elimination Reactions of Alkyl Halides • Suzuki Coupling

Related Functional Groups of
[ 105655-01-4 ]

Bromides

A171016 [625394-65-2]

8-Bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine

Similarity: 0.95

A369541 [154264-95-6]

7-Bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine

Similarity: 0.94

A116061 [105679-22-9]

7-Bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine

Similarity: 0.89

A379336 [1350738-87-2]

7-Bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine hydrochloride

Similarity: 0.87

A281836 [321436-06-0]

7-Bromo-2H-benzo[b][1,4]oxazin-3(4H)-one

Similarity: 0.84

Related Parent Nucleus of
[ 105655-01-4 ]

Other Aromatic Heterocycles

A171016 [625394-65-2]

8-Bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine

Similarity: 0.95

A369541 [154264-95-6]

7-Bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine

Similarity: 0.94

A116061 [105679-22-9]

7-Bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine

Similarity: 0.89

A379336 [1350738-87-2]

7-Bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine hydrochloride

Similarity: 0.87

A281836 [321436-06-0]

7-Bromo-2H-benzo[b][1,4]oxazin-3(4H)-one

Similarity: 0.84

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H420	Harms public health and the environment by destroying ozone in the upper atmosphere

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CAS No.: 105655-01-4

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