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Quality Control of [ 187235-08-1 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 187235-08-1 ]

SDS Specification

Alternatived Products of [ 187235-08-1 ]

Product Details of [ 187235-08-1 ]

CAS No. :	187235-08-1	MDL No. :	MFCD08436173
Formula :	C₆H₇N₃O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HMFPMGBWSFUHEN-BYPYZUCNSA-N
M.W :	185.14	Pubchem ID :	10130259
Synonyms :

Calculated chemistry of [ 187235-08-1 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.5
Num. rotatable bonds :	1
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	42.66
TPSA :	93.1 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.73 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.63
Log Po/w (XLOGP3) :	-0.43
Log Po/w (WLOGP) :	-0.46
Log Po/w (MLOGP) :	-0.91
Log Po/w (SILICOS-IT) :	-2.26
Consensus Log Po/w :	-0.69

Druglikeness

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

Water Solubility

Log S (ESOL) :	-0.94
Solubility :	21.5 mg/ml ; 0.116 mol/l
Class :	Very soluble
Log S (Ali) :	-1.06
Solubility :	16.1 mg/ml ; 0.0871 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	0.44
Solubility :	513.0 mg/ml ; 2.77 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.25

Safety of [ 187235-08-1 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P261-P280-P305+P351+P338-P304+P340	UN#:
Hazard Statements:	H302	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 187235-08-1 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 187235-08-1 ]

[ 187235-08-1 ] Synthesis Path-Downstream 1~33

1
[ 187235-08-1 ]
[ 112257-12-2 ]
4-[2-(6S-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxy)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With sodium hydride; In N,N-dimethyl-formamide; at -60 - 20℃; for 2h;	A solution of 4-(2-bromo- acetyl)-piperazine-l-carboxylic acid tert-butyl ester (0.39 g, 1.3 mmol) and 2-nitro-6,7- dihydro-5H-imidazo[2,l-b][l,3]oxazin-6.Sr-ol (0.2 g, 1.08 mmol) in DMF (9 ml) was cooled to -60 0C and treated with sodium hydride (50 mg, 1.3 mmol) and warmed to room temperature over 2 h. The mixture was diluted with ethyl acetate, washed with water dried over sodium sulfate and concentrated. The residue is purified by silica gel chromatography (5% methanol in dichloromethane) to give 4-[2-(2-nit?>-6,7-dihydro-5H- imidazo[2,l-b][l,3]oxazin-6S-yloxy)-acetyl]-piperazine-l-carboxylic acid tert-butyl ester as a yellow oil (314 mg, 77%). ESI MS m/z 434 (M + Na+); 1H NMR (400 MHz, CDCl3) delta 7.48 (s, IH), 4.48-4.40 (m, IH), 4.40-4.22 (m, 4H), 3.38-3.44 (s, 2H), 3.42-3.30 (m, 8H), 1.42 (s, 9H).

Reference： [1]Patent: WO2008/8480,2008,A2 .Location in patent: Page/Page column 63-64

2
[ 187235-08-1 ]
[ 21101-63-3 ]
(S)-2-nitro-6-((4-((trifluoromethyl)thio)benzyl)oxy)-6,7-dihydro-5Himidazo[2,1-b][1,3]oxazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (S)‐2‐nitro‐6,7‐dihydro‐5H‐imidazo[2,1‐b][1,3]oxazin‐6‐ol; 4-(trifluoromethylthio)benzyl bromide With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; Stage #2: With water In N,N-dimethyl-formamide at 0℃;	48 Example 48(S)-2-Nitro-6-(4-trifluoromethylsulfanyl-benzyloxy)-6,7-dihvdro-5H-imidazof2.1- b]f1.31oxazine (521)52At 0 'C under Ar, NaH (60% in mineral oil, 150 mol%) is added to stirred solution of (S)-2- Nitro-6,7-dihydro-5H-imidazo[2,1-b][1 ,3]oxazin-6-ol (100 mol%), 1-bromomethyl-4- trifluoromethylsulfanyl-benzene (120 mo.%), and tetrabutylammonium iodide (5 mol%) in anhydrous DMF. The mixture is allowed to warm to room temperature and stirred for overnight. The reaction is cooled to 0 'C and quenched with iced cold water. Product is extracted two times with 250 mL EtOAc, dried over MgSO4 and concentrated under vacuo to give crude brown oil, which is purified using reverse phase preparative LC to yield (S)-2- Nitro-6-(4-trifluoromethylsulfanyl-ben2yloxy)-6,7-dihydro-5H-imidazo[2,1-b][1 ,3]oxazine, 52. Mass: M* 376.3.

Reference： [1]Current Patent Assignee: GOVERNMENT OF THE UNITED STATES; Novartis (w/o Sandoz); NOVARTIS AG - WO2007/75872, 2007, A2 Location in patent: Page/Page column 64-65

3
[ 187235-08-1 ]
[ 589-15-1 ]
[ 1188331-12-5 ]

Yield	Reaction Conditions	Operation in experiment
88%	With sodium hydride In N,N-dimethyl-formamide; mineral oil at 5 - 20℃;
88%	With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2h;	2.J Reaction of oxazine alcohol 41 (5.00 g, 27.0 mmol) with 4-bromobenzyl bromide (60) (7.62 g, 30.5 mmol) and NaH (60% w/w, 1.40 g, 35.0 mmol) in DMF (100 mL) for 2 h at room temperature gave (65)-6-[(4-bromobenzyl)oxy]-2-nitro-6,7-dihydro-5/f-imidazo[2,l- 6][l,3]oxazine (61) (8.368 g, 88%) as a light yellow solid: mp (Et2O) 188-190 °C; 1H NMR [(CDs)2SO] δ 8.01 (s, 1 H), 7.54 (dt, J = 8.4, 2.2 Hz, 2 H), 7.13 (dt, J = 8.5, 2.2 Hz, 2 H), 4.67- 4.62 (m, 2 H), 4.61 (d, J = 12.2 Hz, 1 H), 4.46 (d, J = 12.0 Hz, 1 H), 4.28-4.19 (m, 3 H). Anal. (C13H12BrN3O4) C, H, N.
88%	With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2h;	2.J J. Synthesis of (6S)-2-nitro-6-({4-[5-(trifluoromethyl)-2-pyridinyl]benzyl}oxy)-6,7-dihydro-5H-imidazo[2,1-6][1,3]oxazine (8) by the method of Scheme 6 Reaction of oxazine alcohol 41 (5.00 g, 27.0 mmol) with 4-bromobenzyl bromide (60) (7.62 g, 30.5 mmol) and NaH (60% w/w, 1.40 g, 35.0 mmol) in DMF (100 mL) for 2 h at room temperature gave (6S)-6-[(4-bromobenzyl)oxy]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (61) (8.368 g, 88%) as a light yellow solid: mp (Et2O) 188-190° C.; 1H NMR [(CD3)2SO] δ 8.01 (s, 1H), 7.54 (dt, J=8.4, 2.2 Hz, 2H), 7.13 (dt, J=8.5, 2.2 Hz, 2H), 4.67-4.62 (m, 2H), 4.61 (d, J=12.2 Hz, 1H), 4.46 (d, J=12.0 Hz, 1H), 4.28-4.19 (m, 3H). Anal. (C13H12BrN3O4) C, H, N.

	With sodium hydride In N,N-dimethyl-formamide at 20℃; for 4h;	31.1 A solution of 2-nitro-6,7-dmydro-5H-imidazo[2,l-b][l,3]oxazin-6(S)-ol (0.5 g, 2.7 mmol) and 4-bromobenzylbromide (0.81 g, 3.24 mmol) was dissolved in DMF (50 ml) and treated with NaH (0.13 g, 3.24 mmol). The mixture was stirred for 4 hours at room temperature and diluted with water (100 ml) and extracted with EtOAc. The organic layer was separated and washed with water (2X), dried over Na2SO4 and concentrated. The resulting gum was washed with hexanes to remove unreacted benzyl bromide. The mixture was purified by preparative TLC. ESI MS m/z 356 (M + H+); 1H NMR (400 MHz, CDCl3) δ 7.56-7.42 (m, 2H), 7.40 (s, IH), 7.24-7.18 (m, 2H), 4.73-4.50 (m, 4H), 4.39-4.30 (m, IH), 4.28-4.03 (m, 2H).
	With sodium hydride In N,N-dimethyl-formamide

Reference： [1]Location in patent: experimental part Palmer, Brian D.; Thompson, Andrew M.; Sutherland, Hamish S.; Blaser, Adrian; Kmentova, Iveta; Franzblau, Scott G.; Wan, Baojie; Wang, Yuehong; Ma, Zhenkun; Denny, William A. [Journal of Medicinal Chemistry, 2010, vol. 53, # 1, p. 282 - 294]
[2]Current Patent Assignee: TB ALLIANCE INC - WO2011/14774, 2011, A1 Location in patent: Page/Page column 30
[3]Current Patent Assignee: TB ALLIANCE INC - US2012/28973, 2012, A1 Location in patent: Page/Page column 12
[4]Current Patent Assignee: TENNOR THERAPEUTICS LTD. - WO2009/120789, 2009, A1 Location in patent: Page/Page column 61
[5]Cooper, Christopher B.; Denny, William A.; Ding, Charles Z.; Ding, Jun; He, Shijie; Lu, Yu; Lynch, Anthony Simon; Ma, Zhenkun; Upton, Anna M.; Wan, Dawei; Wang, Xiaomei; Yuan, Ying; Zhang, Qian; Zhuang, Zhijun [Molecules, 2020, vol. 25, # 10]

4
[ 187235-08-1 ]
[ 138500-85-3 ]
[ 1188329-66-9 ]

Yield	Reaction Conditions	Operation in experiment
89%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at -60 - 20℃;	To a solution of 2-nitro-6,7- dihydro-5H-imidazo[2,l-b][l,3]oxazin-6-ol (420 nig, 2.28 mniol) and 2-(4-bromomethyl- phenyl)-4,4,5,5-tetramethyl-[l,3,2]dioxaborolane (339 mg, 1.14 mmol) in DMF (10.0 mL) at - 60 0C under nitrogen was added NaH (137 mg, 3.42 mmol, 60% dispersion in mineral oil). The mixture was slowly warmed to room temperature and stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc, washed with brine and concentrated in vacuo to give the title compound as a yellow solid (0.460 g, 89%). ESI MS m/z 402.4 (M + H+).

Reference： [1]Patent: WO2009/120789,2009,A1 .Location in patent: Page/Page column 55

5
[ 187235-08-1 ]
[ 76283-09-5 ]
[ 1188335-21-8 ]

Yield	Reaction Conditions	Operation in experiment
93%	With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃;Inert atmosphere;	A solution of alcohol 41 (1.403 g, 7.58 mmol) and 4-bromo- 1 -(bromomethyl)- 2-fluorobenzene (74) (2.66 g, 9.93 mmol) in anhydrous DMF (30 mL) under N2 at 0 0C was treated with 60% NaH (427 mg, 10.7 mmol), then quickly degassed and resealed under N2. After stirring at room temperature for 3 h, the reaction was cooled (CO2/acetone), quenched with ice/aqueous NaHCO3 (20 mL), added to brine (150 mL) and extracted with CH2Cl2 (4x 80 mL). The combined extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-2% EtOAcZCH2Cl2 firstly gave foreruns, and then elution with 3-5% EtO Ac/CH2C12 gave (65)-6-[(4-bromo-2-fluorobenzyl)oxy]-2-nitro-6,7-dihydro-5/f-imidazo[2,l- Z>][l,3]oxazine (75) (2.633 g, 93%) as a pale yellow solid: mp (MeOH/CH2Cl2/hexane) 171-173 0C; 1H NMR [(CD3)2SO] delta 8.01 (s, 1 H), 7.54 (dd, J = 9.7, 1.8 Hz, 1 H), 7.42 (dd, J = 8.2, 1.8 Hz, 1 H), 7.37 (dd, J = 8.1, 7.7 Hz, 1 H), 4.72-4.62 (m, 3 H), 4.47 (br d, J = 11.9 Hz, 1 H), 4.30- 4.19 (m, 3 H). Anal. (C13HnBrFN3O4) C, H, N.
93%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 3h;Inert atmosphere;	N. Synthesis of (6S)-6-[3-fluoro-4?-(trifluoromethoxy)[1,1'-biphenyl]-4-yl]methoxy}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (12) by the method of Scheme 9 A solution of alcohol 41 (1.403 g, 7.58 mmol) and 4-bromo-1-(bromomethyl)-2-fluorobenzene (74) (2.66 g, 9.93 mmol) in anhydrous DMF (30 mL) under N2 at 0 C. was treated with 60% NaH (427 mg, 10.7 mmol), then quickly degassed and resealed under N2. After stirring at room temperature for 3 h, the reaction was cooled (CO2/acetone), quenched with ice/aqueous NaHCO3 (20 mL), added to brine (150 mL) and extracted with CH2Cl2 (4×80 mL). The combined extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-2% EtOAc/CH2Cl2 firstly gave foreruns, and then elution with 3-5% EtOAc/CH2Cl2 gave (6S)-6-[(4-bromo-2-fluorobenzyl)oxy]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (75) (2.633 g, 93%) as a pale yellow solid: mp (MeOH/CH2Cl2/hexane) 171-173 C.; 1H NMR [(CD3)2SO]delta 8.01 (s, 1H), 7.54 (dd, J=9.7, 1.8 Hz, 1H), 7.42 (dd, J=8.2, 1.8 Hz, 1H), 7.37 (dd, J=8.1, 7.7 Hz, 1H), 4.72-4.62 (m, 3H), 4.47 (br d, J=11.9 Hz, 1H), 4.30-4.19 (m, 3H). Anal. (C13H11BrEN3O4) C, H, N.
93%	With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃;	To a solution of 2-nitro-6,7-dihydro-5H-imidazo[2,l- b][l,3]oxazin-6(S)-ol (1.40 g, 7.58 mmol) and 4-bromo-l-(bromomethyl)-2-fluorobenzene (2.66 g, 9.93 mmol) in anhydrous DMF (30 mL) under N2 at 0 0C was added 60% NaH (427 mg, 10.70 mmol) then quickly degassed and resealed under N2. The mixture was slowly warmed to room temperature and stirred at room temperature for 3 h. The reaction mixture was cooled (solid CO2/acetone), quenched with ice/aqueous NaHCO3 (20 mL), added to brine (150 mL) and extracted with CH2Cl2 (4 x 80 mL). The combined extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-2% EtOAc/CH2Cl2 firstly gave foreruns, and then elution with 3-5% EtOAc/CH2Cl2 gave the title compound as a <n="89"/>pale yellow solid (2.63 g, 93%); APCI MS m/z 372, 374 (bromine isotope pattern, M + H+); 1H NMR (400 MHz, (CD3)2SO) delta 8.01 (s, 1 H), 7.54 (dd, J = 9.7, 1.8 Hz, 1 H), 7.42 (dd, J = 8.2, 1.8 Hz, 1 H), 7.37 (dd, J= 8.1, 7.7 Hz, 1 H), 4.72-4.62 (m, 3 H), 4.47 ( br d, J = 11.9 Hz, 1 H), 4.30-4.19 (m, 3 H).

Reference： [1]Patent: WO2011/14774,2011,A1 .Location in patent: Page/Page column 35
[2]Patent: US2012/28973,2012,A1 .Location in patent: Page/Page column 14
[3]Patent: WO2009/120789,2009,A1 .Location in patent: Page/Page column 86; 87
[4]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 3804 - 3809

6
[ 187235-08-1 ]
[ 39741-46-3 ]
[ 1188334-67-9 ]

Yield	Reaction Conditions	Operation in experiment
30%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃;	A solution of (S)-2-nitro-6,7-dihydro-5H-imidazo[2,l-b][l,3]oxa- zin-6-ol ( 3.63 g, 19.6 mmol) and <strong>[39741-46-3]3-bromo-5-(chloromethyl)pyridine hydrochloride</strong> (4.78 g, 19.6 mmol, 1 eq ) in dry DMF (80 mL) was treated with NaH (1.88 g, 47 mmol, 2.4 eq, 60 % in mineral oil) at 0-5 0C, then stirred at room temperature overnight (16 h), quenched with water (150 mL), and extracted into EtOAc. Chromatography of the crude product on silica gel, eluting with MeOH/CH2Cl2 (1:19), gave the title product (2.10 g, 30%) as white solid. APCI MS m/z 355.7, 357.7 (M + H). 1H NMR (400 MHz, (CD3)2SO) δ 8.64 (d, J = 2.3 Hz, IH), 8.52 (d, J= 1.7 Hz, IH), 8.03 (s, IH), 7.97 (br t, J= 2.1 Hz, IH), 4.73 (d, J=12.6 Hz, IH), 4.70-4.65 (m, 2H), 4.48 (d, J=12 Hz, IH), 4.31-4.20 (m, 3H).

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 8421 - 8439
[2]Patent: WO2009/120789,2009,A1 .Location in patent: Page/Page column 77

7
[ 59311-27-2 ]
[ 187235-08-1 ]
[ 1188335-23-0 ]

Yield	Reaction Conditions	Operation in experiment
77%	With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 2h;
77%	With sodium hydride In N,N-dimethyl-formamide at 0℃; for 2h;	60.1 NaH (60% w/w, 0.60 g, 15 mmol) was added to a solution of (65)-2-nitro-6,7-dihydro-5H-imidazo[2,l-Z>][l,3]oxazin-6-ol (2.00 g, 10.8 mmol) and 2- bromo-5-(bromomethyl)thiophene (prepared by the method of Mamane et al, Synthesis, 3; 2003; 455 - 467) (3.20 g, 12.5 mmol) in DMF (40 mL) at 0 0C. The mixture was stirred at 0 0C for 2 h, then poured onto ice and extracted with EtOAc (2 x 200 mL). The organic layer was dried and evaporated. Column chromatography (hexanes/EtOAc, gradient elution) gave the titled compound (2.985 g, 77%) as a white solid. APCI MS m/z 360, 362 (M + H). 1H NMR (400 MHz, DMSO-^6) δ 8.00 (s, IH), 7.11 (d, J= 3.7 Hz, IH), 6.95 (d,J= 3.7 Hz, IH), 4.79 (d,J= 13.2 Hz, IH), 4.76 (d,J= 13.2 Hz, IH), 4.60 (dt,J= 12.0, 1.6 Hz, IH), 4.44 (d,J = 12.0 Hz, IH), 4.19-4.25 (m, 3H).

Reference： [1]Location in patent: experimental part Sutherland, Hamish S.; Blaser, Adrian; Kmentova, Iveta; Franzblau, Scott G.; Wan, Baojie; Wang, Yuehong; Ma, Zhenkun; Palmer, Brian D.; Denny, William A.; Thompson, Andrew M. [Journal of Medicinal Chemistry, 2010, vol. 53, # 2, p. 855 - 866]
[2]Current Patent Assignee: TENNOR THERAPEUTICS LTD. - WO2009/120789, 2009, A1 Location in patent: Page/Page column 87; 88

8
[ 187235-08-1 ]
[ 49617-83-6 ]
[ 1198422-66-0 ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 282 - 294

9
[ 727356-19-6 ]
[ 187235-08-1 ]
[ 1188334-77-1 ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 8421 - 8439

10
[ 187235-08-1 ]
[ 32938-44-6 ]
[ 1188334-71-5 ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 8421 - 8439

11
[ 187235-08-1 ]
[ 1193116-74-3 ]
[ 1257426-62-2 ]

Yield	Reaction Conditions	Operation in experiment
51%	With sodium hydride In N,N-dimethyl-formamide at -78 - 0℃;
51%	With sodium hydride In N,N-dimethyl-formamide at -78 - 0℃;	2.CC NaH (60% w/w, 0.170 g, 4.25 mmol) was added to a solution of bromide 120 (0.879 g, 3.49 mmol) and alcohol 41 (0.520 g, 2.81 mmol) in anhydrous DMF (10 mL) at -78 0C. The mixture was stirred at 0 °C for 0.5 h and then quenched with ice and extracted with EtOAc (200 mL). The organic layer was dried (MgSO4) and evaporated, and then column chromatography of the residue using gradient elution (0-5% MeOH/EtOAc) gave (65)-6-[(5- bromo-2-pyrimidinyl)methoxy]-2-nitro-6,7-dihydro-5H-imidazo[2,l -/>][l,3]oxazine (121) (0.510 g, 51%) as a light brown solid: mp >290 0C; 1H NMR [(CD3)2SO] δ 8.98 (s, 2 H), 8.03 (s, 1 H), 4.83 (d, J = 13.2 Hz, 1 H), 4.80 (d, J = 13.2 Hz, 1 H), 4.68 (dt, J - 12.0, 2.6 Hz, 1 H)3 4.48 (br d, J = 11.9 Hz, 1 H), 4.40-4.36 (m, 1 H), 4.31 (dt, J = 13.5, 2.1 Hz, 1 H), 4.23 (dd, J = 13.5, 3.3 Hz, 1 H). Anal. (C1 ,H10BrN5O4) C, H. N: calcd, 19.67; found, 19.17.
51%	With sodium hydride In N,N-dimethyl-formamide; mineral oil at -78 - 0℃; for 0.5h;	2.CC NaH (60% w/w, 0.170 g, 4.25 mmol) was added to a solution of bromide 120 (0.879 g, 3.49 mmol) and alcohol 41 (0.520 g, 2.81 mmol) in anhydrous DMF (10 mL) at -78° C. The mixture was stirred at 0° C. for 0.5 h and then quenched with ice and extracted with EtOAc (200 mL). The organic layer was dried (MgSO4) and evaporated, and then column chromatography of the residue using gradient elution (0-5% MeOH/EtOAc) gave (6S)-6-[(5-bromo-2-pyrimidinyl)methoxy]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (121) (0.510 g, 51%) as a light brown solid: mp>290° C.; 1H NMR [(CD3)2SO] δ 8.98 (s, 2H), 8.03 (s, 1H), 4.83 (d, J=13.2 Hz, 1H), 4.80 (d, J=13.2 Hz, 1H), 4.68 (dt, J=12.0, 2.6 Hz, 1H), 4.48 (br d, J=11.9 Hz, 1H), 4.40-4.36 (m, 1H), 4.31 (dt, J=13.5, 2.1 Hz, 1H), 4.23 (dd, J=13.5, 3.3 Hz, 1H). Anal. (C11H10BrN5O4) C, H, N: calcd, 19.67; found, 19.17.

Reference： [1]Location in patent: experimental part Kmentova, Iveta; Sutherland, Hamish S.; Palmer, Brian D.; Blaser, Adrian; Franzblau, Scott G.; Wan, Baojie; Wang, Yuehong; Ma, Zhenkun; Denny, William A.; Thompson, Andrew M. [Journal of Medicinal Chemistry, 2010, vol. 53, # 23, p. 8421 - 8439]
[2]Current Patent Assignee: TB ALLIANCE INC - WO2011/14774, 2011, A1 Location in patent: Page/Page column 55
[3]Current Patent Assignee: TB ALLIANCE INC - US2012/28973, 2012, A1 Location in patent: Page/Page column 22

12
[ 187235-08-1 ]
[ 70258-18-3 ]
[ 1257426-57-5 ]

Yield	Reaction Conditions	Operation in experiment
97%	With sodium hydride; In N,N-dimethyl-formamide; at 5 - 20℃;	NaH (60% w/w, 0.584 g, 14.6 mmol) was added to a solution of oxazine alcohol 41 (2.073 g, 1 1.2 mmol) and <strong>[70258-18-3]2-chloro-5-(chloromethyl)pyridine</strong> (48) (2.0 g, 12.3 mmol) in anhydrous DMF (40 mL) at 5 0C. The resulting mixture was stirred at room temperature for 16 h and then quenched with water (150 mL). The precipitate was filtered off, washed with water and dried to give (65)-6-[(6-chloro-3-pyridinyl)methoxy]-2-nitro-6,7-dihydro-5//-imidazo[2,l- ft][l,3]oxazine (49) (3.39 g, 97%) as a light yellow solid: mp 191-193 0C; 1H NMR [(CD3)2SO] delta 8.37 (d, J- 2.3 Hz, 1 H), 8.02 (s, 1 H), 7.79 (dd, J = 8.3, 2.4 Hz, 1 H), 7.51 (br d, J = 8.2 Hz, 1 H), 4.74 (d, J= 12.4 Hz, 1 H), 4.69-4.64 (m, 2 H), 4.47 (d, J= 1 1.8 Hz, 1 H), 4.29-4.21 (m, 3 H). HRESIMS calcd for C12Hi2ClN4O4 mlz [M + H]+ 313.0513, 311.0542, found 313.0518, 311.0545.
97%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 5 - 20℃; for 16h;	E. Synthesis of (6S)-2-nitro-6-({6-[4-(trifluoromethoxy)phenyl]-3-pyridinyl}methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (6) by the method of Scheme 4 NaH (60% w/w, 0.584 g, 14.6 mmol) was added to a solution of oxazine alcohol 41 (2.073 g, 11.2 mmol) and <strong>[70258-18-3]2-chloro-5-(chloromethyl)pyridine</strong> (48) (2.0 g, 12.3 mmol) in anhydrous DMF (40 mL) at 5 C. The resulting mixture was stirred at room temperature for 16 h and then quenched with water (150 mL). The precipitate was filtered off, washed with water and dried to give (6S)-6-[(6-chloro-3-pyridinyl)methoxy]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (49) (3.39 g, 97%) as a light yellow solid: mp 191-193 C.; 1H NMR [(CD3)2SO] delta 8.37 (d, 1-2.3 Hz, 1H), 8.02 (s, 1H), 7.79 (dd, J=8.3, 2.4 Hz, 1H), 7.51 (br d, J=8.2 Hz, 1 H), 4.74 (d, J=12.4 Hz, 1H), 4.69-4.64 (m, 2H), 4.47 (d, J=11.8 Hz, 1H), 4.29-4.21 (m, 3H). HRESIMS calcd for C12H12ClN4O4m/z [M+H]+ 313.0513, 311.0542, found 313.0518, 311.0545.

Reference： [1]Patent: WO2011/14774,2011,A1 .Location in patent: Page/Page column 24
[2]Patent: US2012/28973,2012,A1 .Location in patent: Page/Page column 9-10
[3]Journal of Medicinal Chemistry,2010,vol. 53,p. 8421 - 8439

13
[ 187235-08-1 ]
[ 101990-45-8 ]
[ 1188329-26-1 ]

Yield	Reaction Conditions	Operation in experiment
88%	With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃;	A solution of oxazine alcohol 41 (2.224 g, 12.0 mmol) and bromide 51 (3.045 g, 12.1 mmol) in anhydrous DMF (46 mL) under N2 at 0 0C was treated with 60% NaH (639 mg, 16.0 mmol) then quickly degassed and resealed under N2. After stirring at room temperature for 2.5 h, the reaction was cooled (CO2/acetone), quenched with ice/aqueous NaHCO3 (50 mL), added to brine (250 mL) and extracted with CH2Cl2 (12x 200 mL). The combined extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-1% MeOH/CH2Cl2 firstly gave foreruns, and then further elution with 1-1.5% MeOH/CH2Cl2 gave (65')-6-[(6-bromo-3-pyridinyl)methoxy]-2-nitro-6,7-dihydro-5H-imidazo[2,l-δ][l,3]oxazine (52) (3.739 g, 88%) as a cream solid: mp (MeOΗ/CΗ2Cl2/hexane) 200-203 0C; 1H NMR [(CD3)2SO] δ 8.35 (dd, J- 2.3, 0.4 Hz, 1 H), 8.02 (s, 1 H), 7.69 (dd, J= 8.2, 2.5 Hz, 1 H), 7.63 (dd, J= 8.1, 0.5 Hz, 1 H), 4.72-4.62 (m, 3 H), 4.47 (br d, J = 11.8 Hz, 1 H), 4.31 -4.19 (m, 3 H). Anal. (Ci2HnBrN4O4) C, H, N. HPLC purity: 100%.
88%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 2.5h;Inert atmosphere;	A solution of oxazine alcohol 41 (2.224 g, 12.0 mmol) and bromide 51 (3.045 g, 12.1 mmol) in anhydrous DMF (46 mL) under N2 at 0 C. was treated with 60% NaH (639 mg, 16.0 mmol) then quickly degassed and resealed under N2. After stirring at room temperature for 2.5 h, the reaction was cooled (CO2/acetone), quenched with ice/aqueous NaHCO3 (50 mL), added to brine (250 mL) and extracted with CH2Cl2 (12*200 mL). The combined extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-1% MeOH/CH2Cl2 firstly gave foreruns, and then further elution with 1-1.5% MeOH/CH2Cl2 gave (6S)-6-[(6-bromo-3-pyridinyl)methoxy]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (52) (3.739 g, 88%) as a cream solid: mp (MeOH/CH2Cl2/hexane) 200-203 C.; 1H NMR [(CD3)2SO] δ 8.35 (dd, J=2.3, 0.4 Hz, 1H), 8.02 (s, 1H), 7.69 (dd, J=8.2, 2.5 Hz, 1H), 7.63 (dd, J=8.1, 0.5 Hz, 1H), 4.72-4.62 (m, 3H), 4.47 (br d, J=11.8 Hz, 1H), 4.31-4.19 (m, 3H). Anal. (C12H1lBrN4O4) C, H, N. HPLC purity: 100%.

Reference： [1]Patent: WO2011/14774,2011,A1 .Location in patent: Page/Page column 25; 26
[2]Patent: US2012/28973,2012,A1 .Location in patent: Page/Page column 10
[3]Journal of Medicinal Chemistry,2010,vol. 53,p. 8421 - 8439

14
[ 187235-08-1 ]
[ 168823-76-5 ]
[ 1188329-32-9 ]

Yield	Reaction Conditions	Operation in experiment
86%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 5 - 20℃;	NaH (0.525 g, 13.1 mmol, 60% in mineral oil) was added to a solution of alcohol 41 (1.872, 10.1 mmol) and <strong>[168823-76-5]5-bromo-2-(chloromethyl)pyridine</strong> (58) (prepared by chlorination of (5-bromo-2-pyridinyl)methanol, as reported by van den Heuvel et al., 2004) (2.5 g, 12.1 mmol) in anhydrous DMF (40 rnL) at 5 0C. The resulting mixture was stirred at room temperature for 2 h and then quenched with water (300 mL). The precipitate was filtered off, washed with water and dried to give (6S)-6-[(5-bromo-2-pyridinyl)methoxy]-2-nitro-6,7- dihydro-5H-imidazo[2,l-6][l,3]oxazine (59) (3.087 g, 86%) as a light brown solid: mp 171-173 0C; 1H NMR [(CD3)2SO] delta 8.65 (dd, J= 2.3, 0.4 Hz, 1 H), 8.04 (dd, J = 8.4, 2.4 Hz, 1 H), 8.02 (s, 1 H), 7.35 (dd, J = 8.4, 0.4 Hz, 1 H), 4.72-4.66 (m, 3 H), 4.49 (br d, J= 12.0 Hz, 1 H), 4.35- 4.21 (m, 3 H). Anal. (Ci2HnBrN4O4) C, H, N. HPLC purity: 99.4%.
86%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 5 - 20℃; for 2h;	I. Synthesis of (6S)-2-nitro-6-({5-[4-(trifluoromethoxy)phenyl]-2-pyridinyl}methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (7) by the method of Scheme 5 NaH (0.525 g, 13.1 mmol, 60% in mineral oil) was added to a solution of alcohol 41 (1.872, 10.1 mmol) and <strong>[168823-76-5]5-bromo-2-(chloromethyl)pyridine</strong> (58) (prepared by chlorination of (5-bromo-2-pyridinyl)methanol, as reported by van den Fleuvel et al., 2004) (2.5 g, 12.1 mmol) in anhydrous DMF (40 mL) at 5 C. The resulting mixture was stirred at room temperature for 2 h and then quenched with water (300 mL). The precipitate was filtered off, washed with water and dried to give (6S)-6-[(5-bromo-2-pyridinyl)methoxy]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (59) (3.087 g, 86%) as a light brown solid: mp 171-173 C.; 1H NMR [(CD3)2SO] delta 8.65 (dd, J=2.3, 0.4 Hz, 1H), 8.04 (dd, J=8.4, 2.4 Hz, 1H), 8.02 (s, 1H), 7.35 (dd, J=8.4, 0.4 Hz, 1H), 4.72-4.66 (m, 3H), 4.49 (br d, J=12.0 Hz, 1H), 4.35-4.21 (m, 3H). Anal. (C12H11BrN4O4) C, H, N. HPLC purity: 99.4%.

Reference： [1]Patent: WO2011/14774,2011,A1 .Location in patent: Page/Page column 29
[2]Patent: US2012/28973,2012,A1 .Location in patent: Page/Page column 11
[3]Journal of Medicinal Chemistry,2010,vol. 53,p. 8421 - 8439

15
[ 187235-08-1 ]
[ 386715-33-9 ]
[ 1333170-18-5 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 6563 - 6585

16
[ 187235-08-1 ]
[ 82994-41-0 ]
[ 100366-75-4 ]
[ 1333170-29-8 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 6563 - 6585

17
[ 187235-08-1 ]
[ 137100-52-8 ]
[ 187235-52-5 ]

Yield	Reaction Conditions	Operation in experiment
48%	With copper(l) chloride In N,N-dimethyl-formamide at 20℃; for 3.7h;

Reference： [1]Blaser, Adrian; Palmer, Brian D.; Sutherland, Hamish S.; Kmentova, Iveta; Franzblau, Scott G.; Wan, Baojie; Wang, Yuehong; Ma, Zhenkun; Thompson, Andrew M.; Denny, William A. [Journal of Medicinal Chemistry, 2012, vol. 55, # 1, p. 312 - 326]

18
[ 187235-08-1 ]
[ 23138-56-9 ]
[ 1353754-76-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	With copper(l) chloride In N,N-dimethyl-formamide at 20℃; for 2h;

19
[ 187235-08-1 ]
[ 1160430-95-4 ]
(6S)-2-nitro-6-[(4-[5-(trifluoromethyl)pyridin-2-yl]-oxy}benzyl)oxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 2.5h; Inert atmosphere;

Reference： [1]Palmer, Brian D.; Sutherland, Hamish S.; Blaser, Adrian; Kmentova, Iveta; Franzblau, Scott G.; Wan, Baojie; Wang, Yuehong; Ma, Zhenkun; Denny, William A.; Thompson, Andrew M. [Journal of Medicinal Chemistry, 2015, vol. 58, # 7, p. 3036 - 3059]

20
[ 127425-73-4 ]
[ 187235-08-1 ]
[ 1263417-27-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 3804 - 3809

21
[ 187235-08-1 ]
[ 335013-18-8 ]
C₁₄H₁₁BrF₃N₃O₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 3804 - 3809

22
[ 187235-08-1 ]
[ 335013-18-8 ]
C₂₁H₁₅F₆N₃O₅ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 3804 - 3809

23
[ 187235-08-1 ]
[ 89720-77-4 ]
C₁₃H₁₁BrClN₃O₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 3804 - 3809

24
[ 187235-08-1 ]
[ 89720-77-4 ]
C₂₀H₁₅ClF₃N₃O₅ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 3804 - 3809

25
[ 187235-08-1 ]
[ 23611-75-8 ]
C₁₁H₁₀N₆O₅ [ No CAS ]

Reference： [1]Medicinal Chemistry Research,2015,vol. 24,p. 2986 - 2992

26
[ 187235-08-1 ]
[ 23611-75-8 ]
C₁₂H₁₁N₅O₆ [ No CAS ]

Reference： [1]Medicinal Chemistry Research,2015,vol. 24,p. 2986 - 2992

27
[ 187235-08-1 ]
[ 62802-38-4 ]
[ 1188328-31-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20 - 60℃; for 3h;Inert atmosphere;	In -60 C, Ar under protection, NaH (60%, 130 mg, 5.4mmol) adding (S)-2 - nitro - 6, 7 - dihydro - 5H - imidazole [2,1 - the b] [1, 3] oxazine -6 - alcohol (500 mg, 2 . 7mmol) and 5 - bromo -2 - fluoro pyrimidine (570 mg, 3 . 2mmol) of DMF (5 ml) solution. The solution stirring at room temperature 3 hours, inverted water (50 ml) in. Filtering, solid dissolved in EtOAc, salt water washing, drying (Na2SO4). Evaporate the solvent to obtain the white solid product.

Reference： [1]Patent: CN106317072,2017,A .Location in patent: Paragraph 0071; 0072

28
[ 187235-08-1 ]
[ 94446-97-6 ]
(6S)-6-[(2-bromopyridin-3-yl)methoxy]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine [ No CAS ]