[ CAS No. 928664-98-6 ] {[proInfo.proName]}

Name: 928664-98-6|4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole|98%
Brand: Ambeed
SKU: A281292
Price: 7.0 USD
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Quality Control of [ 928664-98-6 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 928664-98-6 ]

SDS Specification

Alternatived Products of [ 928664-98-6 ]

Product Details of [ 928664-98-6 ]

CAS No. :	928664-98-6	MDL No. :	MFCD06657891
Formula :	C₉H₁₄BNO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LXCICYRNWIGDQA-UHFFFAOYSA-N
M.W :	195.02	Pubchem ID :	16414180
Synonyms :

Calculated chemistry of [ 928664-98-6 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.67
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	52.98
TPSA :	44.49 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.52 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	1.36
Log Po/w (WLOGP) :	0.97
Log Po/w (MLOGP) :	0.0
Log Po/w (SILICOS-IT) :	0.74
Consensus Log Po/w :	0.61

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.1
Solubility :	1.53 mg/ml ; 0.00787 mol/l
Class :	Soluble
Log S (Ali) :	-1.9
Solubility :	2.47 mg/ml ; 0.0127 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.84
Solubility :	0.281 mg/ml ; 0.00144 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.21

Safety of [ 928664-98-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280	UN#:	N/A
Hazard Statements:	H302+H312+H332	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 928664-98-6 ]

* 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 [ 928664-98-6 ]
Downstream synthetic route of [ 928664-98-6 ]

[ 928664-98-6 ] Synthesis Path-Upstream 1~9

1
[ 109-04-6 ]
[ 928664-98-6 ]
[ 2739-97-1 ]

Reference： [1] Journal of the American Chemical Society, 2011, vol. 133, # 18, p. 6948 - 6951

2
[ 928664-98-6 ]
[ 95-46-5 ]
[ 22364-68-7 ]

Reference： [1] Journal of the American Chemical Society, 2011, vol. 133, # 18, p. 6948 - 6951

3
[ 928664-98-6 ]
[ 402-43-7 ]
[ 2338-75-2 ]

Reference： [1] Journal of the American Chemical Society, 2011, vol. 133, # 18, p. 6948 - 6951

4
[ 928664-98-6 ]
[ 106-40-1 ]
[ 3544-25-0 ]

Reference： [1] Journal of the American Chemical Society, 2011, vol. 133, # 18, p. 6948 - 6951

5
[ 928664-98-6 ]
[ 460-00-4 ]
[ 459-22-3 ]

Reference： [1] Journal of the American Chemical Society, 2011, vol. 133, # 18, p. 6948 - 6951

6
[ 928664-98-6 ]
[ 623-00-7 ]
[ 876-31-3 ]

Reference： [1] Journal of the American Chemical Society, 2011, vol. 133, # 18, p. 6948 - 6951

7
[ 928664-98-6 ]
[ 618-89-3 ]
[ 68432-92-8 ]

Yield	Reaction Conditions	Operation in experiment
69%	With potassium fluoride; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ In dimethyl sulfoxide at 130℃; for 18 h; Inert atmosphere; Sealed tube	Step 1: To a vial with a stir bar was added methyl 3-bromobenzoate (1.0 equiv.) 4-isoxazoleboronic acid (1.2 equiv.), PdCl₂(dppf).CH₂Cl₂adduct (0.1 equiv.), 1M KF (2.0) and DMSO (0.10 M). The reaction mixture was degassed with bubbling nitrogen and the vial capped and heated at 130° C. for 18 hr. LCMS analysis indicated the formation of the desired product (MH⁺-176, Rt—0.62 min). The reaction mixture was diluted with a saturated solution of NH₄Cl and extracted with EtOAc (2×). The combined organics were washed with water and brine, dried over MgSO₄, filtered and concentrated. The crude material was purified via flash chromatography over silica gel eluting with heptanes and 0-100percent ethyl acetate gradient. Isolated methyl 3-(cyanomethyl)benzoate in 69percent yield. LCMS (m/z) (M+H)=176.1, Rt=0.62). ¹H NMR (400 MHz, ) δ ppm 3.92 (s, 3H), 3.99 (s, 2H), 7.49-7.55 (m, 1H), 7.62 (d, J=7.83 Hz, 1H), 7.99 (d, J=7.83 Hz, 1H), 8.04 (s, 1H).

Reference： [1] Patent: US2014/275003, 2014, A1, . Location in patent: Paragraph 0182

8
[ 847490-69-1 ]
[ 61676-62-8 ]
[ 928664-98-6 ]

Reference： [1] Angewandte Chemie - International Edition, 2016, vol. 55, # 43, p. 13580 - 13584[2] Angew. Chem., 2016, vol. 128, p. 13778 - 13782,5

9
[ 76-09-5 ]
[ 928664-98-6 ]

Reference： [1] Journal of the American Chemical Society, 2011, vol. 133, # 18, p. 6948 - 6951

[ 928664-98-6 ] Synthesis Path-Downstream 1~87

1
[ 928664-98-6 ]
[ 1033805-92-3 ]
[ 1033805-99-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; acetonitrile; at 150℃; for 0.0833333h;Microwave irradiation;	6.33. Synthesis of (S)-2-Amino-3-(4-{2-amino-6-[(S)-2,2,2-trifluoro-1-(4-isoxazol-4-yl-phenyl)-ethoxy]-pyrimidin-4-yl}-phenyl)-propionic acid A microwave vial (2 ml) was charged with (S)-3-(4-{2-amino-6-[(S)-1-(4-bromo-phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidin-4-yl}-phenyl)-2-tert-butoxycarbonylamino-propionic acid (139 mg, 0.23 mmol), <strong>[928664-98-6]4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-isoxazole</strong> (57.5 mg, 0.3 mmol), 1 ml of acetonitrile, and 0.7 ml of water. To this mixture was added 0.4 ml of aqueous sodium carbonate (1M), followed by 14 mg of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150 C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness, the residue was dissolved in 2.5 ml of methanol and was purified by preparative HPLC to give 20 mg of (S)-3-(4-{2-amino-6-[(S)-2,2,2-trifluoro-1-(4-isoxazol-4-yl-phenyl)-ethoxy]-pyrimidin-4-yl}-phenyl)-2-tert-butoxycarbonylamino propionic acid. The above product (20 mg) was dissolved in 5 ml of 30% TFA in DCM. The mixture was stirred at r.t. overnight. Removal of solvent gave a crude product, which was purified by preparative HPLC to give 10 mg of (S)-2-amino-3-(4-{2-amino-6-[(S)-2,2,2-trifluoro-1-(4-isoxazol-4-yl-phenyl)-ethoxy]-pyrimidin-4-yl}-phenyl)-propionic acid. 1H NMR (300 MHz, CD3OD) delta (ppm) 9.03 (s, 1H), 8.77 (s, 1H), 7.84 (m, 2H), 7.63 (d, J=8.2, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.50 (m, 1H), 7.37 (m, 3H), 6.70 (m, 2H), 4.20 (t, 1H), 3.22 (m, 2H).
20 mg	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In water; acetonitrile; at 150℃; for 0.0833333h;Sealed tube; Microwave irradiation;	A microwave vial (2 ml) was charged with (S) -3- (4- {2-amino-6 - [(S) -1- (4-bromo-phenyl) -2,2,2-Yl) -phenyl) -2-tert-butoxycarbonylamino-propionic acid (139 mg, 0.23 mmol)4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -isoxazole(57.5 mg, 0.3 mmol), 1 ml of acetonitrile, and 0.7 ml of water. To the mixWas added 0.4 ml of aqueous sodium carbonate solution (1 M) followed by 14 mg of dichlorobis (triphenylphosphine) -palladium (II). Sealed reaction capacityAnd heated to 150 C with microwave irradiation for 5 minutes. After cooling, the reaction mixture was evaporated to dryness and the residue was dissolved2.5 ml of methanol and purified by preparative HPLC to give 20 mg(S) -3- (4- {2-amino-6 - [(S) -2,2,2)- trifluoro-1- (4-isoxazol-4-yl-phenyl) -ethoxy] -pyrimidin-4-yl} -phenyl) -2-tert-butoxycarbonylaminopropionic acid.

Reference： [1]Patent: US2008/153852,2008,A1 .Location in patent: Page/Page column 27
[2]Patent: CN104045626,2017,B .Location in patent: Paragraph 0314

2
[ 928664-98-6 ]
[ 1041205-02-0 ]
[ 1041205-17-7 ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate;palladium diacetate; In tetrahydrofuran; at 85℃;	Methyl 4-bromo-3,5-diethoxybenzoate (456 mg) and 4-(4,4,5,5-Tetramethyl- [l,3,2]dioxaborolan-2-yl)-isoxazole (438 mg) were dissolved in THF in a nitrogen atmosphere, and potassium phosphate (954 mg), palladium acetate (33 mg) and dicyclohexyl-(2',6'- dimethoxy-biphenyl-2-yl)-phosphane (62 mg) were added to it, and degassed. The reaction liquid was stirred overnight at 85C, then cooled to room temperature, water was added to it, and filtered through Celite. The filtrate was extracted with chloroform, washed with saturated saline water, and the organic layer was dried with sodium sulfate. Sodium sulfate was removed through filtration, the filtrate was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate = 100/0 to 80/20) to obtain the title compound as a pale yellow solid.

Reference： [1]Patent: WO2008/88692,2008,A2 .Location in patent: Page/Page column 143

3
[ 928664-98-6 ]
[ 1138473-16-1 ]
[ 1138473-20-7 ]

Yield	Reaction Conditions	Operation in experiment
15%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 160℃; for 0.333333h;sealed tube; microwave irradiation;	[0200] To a microwave reaction tube was charged with 11 (70 mg, 0.15 mmol), 4-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-isoxazole (40 mg, 0.21 mmol) and Pd(PPlIs)4 (15 mg, 0.013 mmol). DMF (3 mL) was added to the above mixture followed by aqueous sodium carbonate (2 M; 0.3 mL, 0.6 mmol). The reaction tube was sealed and the suspension irradiated with microwave at 160 0C for 20 min. After cooling to room temperature, the resulting mixture was filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a brown solid (10 mg, 15%). 1H NMR (500 MHz, DMSO-d6): delta 1.75-1.85 (m, 4H), 2.33 (s, 3H), 2.42 (s, 3H), 2.80-3.00 (m, 4H), 3.10-3.20 (m, 2H), 4.10- 4.20 (m, 2H), 6.65 (d, J = 4.1 Hz, IH), 6.90 (d, J = 9.0 Hz, 2H), 7.53 (d, J = 4.2 Hz, IH), 7.77 (d, J = 9.0 Hz, 2H), 8.10 (s, IH), 8.71 (s, IH), 9.07 (s, IH) MS (ES+): m/z 448 (M+H)+

Reference： [1]Patent: WO2009/46416,2009,A1 .Location in patent: Page/Page column 62-63

4
[ 928664-98-6 ]
[ 1156499-31-8 ]
[ 1156500-64-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water;	Following the General Experimental for Suzuki Coupling as shown in Scheme 11, the above named compound was obtained as an off-white powder. [M+H]+ 268.1 (ESI).

Reference： [1]Patent: US2009/143361,2009,A1 .Location in patent: Page/Page column 48

5
[ 928664-98-6 ]
[ 1055880-27-7 ]
[ 1055880-80-2 ]

Yield	Reaction Conditions	Operation in experiment
62.2%	With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 85℃; for 12h;Inert atmosphere;	Example 46; 9-isoxazol-4-yl-2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride; (1) tert-butyl 9-isoxazol-4-yl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate; A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), 4-isooxazolylboronic acid pinacol ester (119 mg, 0.609 mmol), tripotassium phosphate (194 mg, 0.914 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane complex (24.9 mg, 0.0305 mmol) in dioxane (2 ml) was stirred at 85C for 12 hr under a nitrogen atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (120 mg, 62.2%) as an oil. 1H-NMR (CDCl3) delta; 1.41 (9H, s), 3.84-3.87 (2H, m), 4.04-4.07 (2H, m), 4.45-4.51 (2H, m), 7.05-7.53 (3H, m), 8.62 (1H, s), 8.84 (1H, s).

Reference： [1]Patent: EP2123644,2009,A1 .Location in patent: Page/Page column 67-68

6
[ 928664-98-6 ]
[ 1067185-55-0 ]
[ 1067184-89-7 ]

Yield	Reaction Conditions	Operation in experiment
12%	With potassium phosphate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; for 4h;Inert atmosphere; Reflux;	Example 11 Preparation of 3-t-butyl-5-(4-isoxazol-4-ylphenyl)-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one To a mixture of 5-(4-bromophenyl)-3-t-butyl-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (0.10 g, 0.23 mmol), <strong>[928664-98-6]4-(4,4,5,5-tetramethyl-1,3-2-dioxaborolan-2-yl)isoxazole</strong> (0.066 g, 0.34 mmol), tripotassium phosphate (0.145 g, 0.68 mmol), ethylene glycol dimethylether (3 mL) and water (0.6 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (0.018 g, 0.023 mmol) was added under a nitrogen atmosphere, and the mixture was stirred under reflux for 4 hr. The mixture was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give 3-t-butyl-5-(4-isoxazol-4-ylphenyl)-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (0.012 g, 12%) as colorless crystals. 1H-NMR (delta ppm TMS/DMSO-d6) 1.05 (9H, s), 3.91 (3H, s), 6.22-7.61 (9H, m), 9.09 (1H, s), 9.36 (1H, s), 13.34 (1H, s).

Reference： [1]Patent: EP2143713,2010,A1 .Location in patent: Page/Page column 85

7
[ 928664-98-6 ]
[ 1036757-02-4 ]
[ 1036756-92-9 ]

Yield	Reaction Conditions	Operation in experiment
50%	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; at 120℃; for 0.166667h;Irradiation with microwave;	A mixture of tert-butyl-4- (6-bromo-2- (3-fluorophenylamino) quinazolin-7- yloxy) piperidine-1 -carboxylate (leq, see example 11 for synthesis), 4-isoxazole boronic ester (3eq), l,l'-bis(diphenylphosphino)ferrocenedichloro palladium(II) (O.leq), sodium carbonate (0.5ml of 2M aqueous solution) in DME (2ml) was heated in microwave at 120C for 1 Omin. The reaction mixture was partitioned between ethylacetate and water. Ethylacetate layer was separated and washed with water, brine and dried over sodium sulfate. Filtered, evaporated and purified by semi-prep HPLC to provide pure product in 50%yield ES/MS m/z 506.1 (MH+).

Reference： [1]Patent: WO2009/153313,2009,A1 .Location in patent: Page/Page column 316

8
[ 928664-98-6 ]
[ 1208249-95-9 ]
N-(6-(difluoro(6-(isoxazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12%		A mixture of N-(6-((6-bromo-[l ,2,4]triazolo[4,3-a]pyridin-3- yl)difluoromethyl)imidazo[ 1 ,2-b]pyridazin-2-yl)-N(cyclopropanecarbonyl)cyclopropanecarboxamide (45N, 0.200 g, 0.38 mmol), 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)isoxazole (0.1 g, 0.5 mmol) and PdCl2(dppf): CH2Cl2 (5 mg, 0.006 mmol) in Na2CO3 (2N, 1 mL)/dioxane (2 mL) was heated at HO0C in a microwave for 30 min. The reaction mixture was filtered and the solids washed with EtOAc. The filtrate was then washed with saturated NaCl, dried with MgSO4, filtered, and concentrated to dryness via rotary evaporation. The resulting residue was purified by preparative LCMS. The collected fractions were combined and the resulting mixture was treated with two drops of concentrated HCl. The solution was lyophilized to provide the HCl salt of the title compound, N-(6-(difluoro(6-(isoxazol-4-yl)-[l,2,4]triazolo[4,3-a]pyridin-3- yl)methyl)imidazo[l,2-b]pyridazin-2-yl)cyclopropanecarboxamide (20 mg, 0.04 mmol, 12%). 1H NMR (400 MHz, DMSO-J6) delta ppm 0.82 (d, J=6.32 Hz, 4 H) 1.91 - 2.01 (m, 1 H) 7.67 (dd, J=9.47, 5.43 Hz, 1 H) 7.75 (dd, J=9.73, 1.64 Hz, 1 H) 7.84 (dd, J=9.85, 1.77 Hz, 1 H) 7.98 - 8.07 (m, 1 H) 8.23 - 8.34 (m, 2 H) 8.46 (s, 1 H) 9.02 (s, 1 H) 11.36 (d, J=2.27 Hz, 1 H). ESI-MS :m/z 437.2 (M+H)+.

Reference： [1]Patent: WO2010/19899,2010,A1 .Location in patent: Page/Page column 175-176

9
[ 928664-98-6 ]
(4s)-4-(5-bromothiazol-2-yloxy)-1-azatricyclo[3.3.1.13,7]decane N-borane complex [ No CAS ]
(4s)-4-[(5-isoxazol-4-yl-1,3-thiazol-2-yl)oxy]-1-azatricyclo[3.3.1.13,7]decane trihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of the product of Example 20A (100 mg, 0.304 mmol) in 2- propanol (2.0 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoxazole (71.1 mg, 0.365 mmol), bis(triphenylphosphine)-palladium(II) chloride (10.7 mg, 0.015 mmol) and aqueous sodium carbonate (1 0M, 0.76 mL). The reaction mixture was degassed with nitrogen and heated with stirring at 100 C for 2 hours. After cooling to room temperature, the reaction mixture was passed through a glass microfiber frit, concentrated, dissolved in MeOH (2.0 mL), and purified by preparative HPLC [Waters XTerra RP18 5 mum column, 30x100 mm, flow rate 40 <n="168"/>itiL/minute, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 22 minutes, with UV detection at 254 nra]. Fractions containing both the desired free base and the N- borane complex were pooled, concentrated under vacuum, and processed as described in Method C. The resulting material was taken into 3 N HCl, was concentrated to dryness and sti?ed in 10:1 diethyl ether/MeOH. The precipitate was filtered and dried under vacuum to afford the titled compound as the trihydrochloride salt: 1H NMR (400 MHz, methanol-D4) delta ppm 1.90 - 2.02 (m, 2 H), 2,20 (br s, 1 H), 2.25 - 2.39 (m, 2 H), 2.64 (br s, 2 H), 3.58 (br s, 2 H), 3.60 - 3.75 (m, 4 H), 5.36 (t, J=3.3 Hz, 1 H), 7.19 (s, 1 H), 7.43 (s, 1 H). MS (ESI) m/z - 304 (M+H)+. Anal. Calcd. for C15H17N3O2S' 2.95HCl-0.45NH4C1: C, 41.42; H, 5.04; N, 11.11; Found: C, 41.35; H, 4.99; N, 11.05.

Reference： [1]Patent: WO2008/58096,2008,A2 .Location in patent: Page/Page column 166-167

10
[ 928664-98-6 ]
[ 1141877-97-5 ]
[ 1141878-05-8 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 7289 - 7300

11
[ 928664-98-6 ]
trans-4-[4-[(6-bromo-1,3-benzothiazol-2-yl)amino]-6-(phenylmethyl)-2-pyrimidinyl]amino}cyclohexanol [ No CAS ]
trans-4-[4-[6-(4-isoxazolyl)-1,3-benzothiazol-2-yl]amino}-6-(phenylmethyl)-2-pyrimidinyl]amino}cyclohexanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.2%	With potassium phosphate;2'-(dimethylamino)-2-biphenyl-palladium(ll) chloride dinorbornylphosphine; In 1,4-dioxane; water; at 100 - 135℃;Anton Parr microwave; CEM "Discover" microwave;	Example 176: trans-4-[4-[6-(4-isoxazolyl)-1,3-benzothiazol-2-yl]amino}-6-(phenylmethyl)-2-pyrimidinyl]amino}cyclohexanolA mixture of trans-4-[4-[(6-bromo-1,3-benzothiazol-2-yl)amino]-6-(phenylmethyl)-2-pyrimidinyl]amino}cyclohexanol (50mg, O.i mmol), <strong>[928664-98-6]4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole</strong> (39mg, 0.2mmol), 2'-(dimethylamiono)-2-biphenyl-palladium(ll) chloride dinorbornylphosphine complex (2.2mg, 0.004mmol) and potassium phosphate (42mg, 0.2mmol) in 1 ,4-dioxane (0.8mL) and water (0.2mL) was sealed and heated in an Anton Parr microwave at 1000C for 20 minutes. After cooling additional 2'- (dimethylamiono)-2-biphenyl-palladium(ii) chloride dinorbornylphosphine complex (2.2mg, 0.004mmol) and 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)isoxazole (39mg, 0.2mmol) were added and the mixture was heated in a CEM "Discover" microwave at 135C for an additional 5 minutes. The reaction mixture was then loaded onto a C18 solid- phase extraction cartridge (pre-conditioned with acetonitrile/0.1% trifluoroacetic acid) and the cartridge was eluted with acetonitrile/0.1% trifluoroacetic acid. The product-containing fractions were evaporated to dryness and the product was purified using mass-directed automated preparative HPLC (ammonium bicarbonate modifier) to afford the title compound (1.15mg, 0.002mmol, 2.2% yield). LCMS (Method A): Rt 0.79 minutes; m/z 499 (MH+).

Reference： [1]Patent: WO2010/106016,2010,A1 .Location in patent: Page/Page column 189-190

12
[ 928664-98-6 ]
[ 558469-71-9 ]
4-dedimethylamino-9-(isoxazol-4-yl)-minocycline hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%		To 9-iodo-4-dedimethylaminominocycline (2.0 g) was added a DMF (15 mL) previously purged with argon to remove any oxygen, a previously prepared solution of Na2CO3 (784 mg) in water (5.0 mL), dichloro(1,1' bis-diphenylphosphine) (Ferrocene)Pd(0) complexed with DCM (541 mg) and <strong>[928664-98-6]4-<strong>[928664-98-6]isoxazoleboronic acid pinacol ester</strong></strong> (1.08 g). The reaction was subject to microwave irradiation for duration of 1 minute at temperature of 100 C. Following, the reaction was added to an aqueous solution containing acetonitrile (20%) and TFA (0.2%). The solution was then filtered through celite to remove the catalyst, loaded onto a C18 reverse phase column and the crude product was purified by reverse phase HPLC (C18, linear gradient 20-40% MeCN in water with 0.1% TFA). The fractions containing the final product were loaded onto DVB plug, washed with aqueous HCl (1.0 L, 0.01 N) and eluted with methanol to give the HCl salt of 4-dedimethylamino-9-(isoxazol-4-yl)-minocycline (1000 mg, 1.93 mmol, 51%). 1H-NMR (Bruker DPX300 300 MHz spectrometer, chemical shifts in ppm with TMS as internal reference at 0 ppm) delta 1.6-1.8 (m, 1H), 2.1-2.25 (m, 1H), 2.35-2.7 (m, 3H), 2.9-3.1 (m, 1H), 3.18-3.3 (m, 2H), 3.35-3.45 (m, 6H), 8.3 (s, 1H), 9.15 (s, 1H), 9.35 (s, 1H). MW calcd for C24H23N3O8 481.47, ESIMS found m/z 482 (MH+). Compounds CI, CK, EP, EQ, ER, ES, ET, EU, EV, EW and EX were prepared in this manner.

Reference： [1]Patent: US2010/305072,2010,A1 .Location in patent: Page/Page column 109

13
8-(6-iodo-benzo[1,3]dioxol-5-ylsulfanyl)-9-(3-isopropylamino-propyl)adenine [ No CAS ]
[ 928664-98-6 ]
[ 1289543-88-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate;bis-triphenylphosphine-palladium(II) chloride; In water; N,N-dimethyl-formamide; at 90℃; for 4h;Inert atmosphere;	2-(6-(6-amino-9-(3-(isopropylamino)propyl)-9H-purin-8-ylthio)benzo [d j [1,3] dioxol-5- yl)acetonitrile [DZ3-39].; 4-Isoxazoleboronic acid pinacol ester (20.5 mg, 0.1053 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHC03 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh3)2Cl2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 90C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC(hexane:CH2Cl2:EtOAc:MeOH-NH3 (7N), 2:2: 1 :0.5) to give 10.3 mg (%) of DZ3-39. 1H NMR (500 MHz, CDCl3/MeOH-^) delta 8.17 (s, 1H), 7.14 (s, lH), 7.12 (s, lH), 6.10 (s, 2H), 4.35 (t, J= 6.9 Hz, 2H), 3.99 (s, 2H), 3.08 (septet, J= 6.5 Hz, 1H), 2.82 (t, J= 7.0 Hz, 2H), 2.25 (m, 2H), 1.27 (d, J= 6.5 Hz, 6H); 13C NMR (125 MHz, CDCl3/MeOH-<¾) delta 154.2, 152.1, 152.0, 151.5, 150.8, 148.6, 147.7, 129.5, 119.2, 117.6, 116.2, 110.3, 102.7, 49.8, 42.5, 40.7, 27.7, 22.9, 20.4; HRMS (ESI) m/z [M+H]+ calcd. for C2oH24N702S, 426.1712; found 426.1712; HPLC: method A Rt = 5.69, method B Rt = 4.57.

Reference： [1]Patent: WO2011/44394,2011,A1 .Location in patent: Page/Page column 85-86

14
8-(6-iodo-benzo[1,3]dioxol-5-ylsulfanyl)-9-(3-isopropylamino-propyl)adenine [ No CAS ]
[ 928664-98-6 ]
[ 1289543-88-9 ]
[ 1289543-92-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate;bis-triphenylphosphine-palladium(II) chloride; In water; N,N-dimethyl-formamide; at 60℃; for 4h;Inert atmosphere;	9- (3-(isopropylamino)propyl)-8-(6-(isoxazol-4-yl)benzo [d \| [1,3] dioxol-5-ylthio)-9H- purin-6-amine [DZ3-49].; 4-Isoxazoleboronic acid pinacol ester (20.5 mg, 0.1053 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHC03 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh3)2Cl2 (8 mg, 0.01 17 mmol) were added and the reaction mixture was heated under nitrogen at 60C for 4 h. Solvent was removed under reduced pressure and the resulting residue was attempted to be purified by preparatory TLC (hexane:CH2Cl2:EtOAc:MeOH-NH3 (7N), 4:7:2: 1) to give 7.4 mg (28%) of an inseparable mixture of DZ3-49 and DZ3-39 in a ratio of approximately 71 :29, respectively, as determined by HPLC. 1H NMR (500 MHz, CDCl3/MeOH-<¾ delta 8.66 (s, 1H), 8.45 (s, 1H), 8.17 (s, 1H), 7.18 (s, 1H), 7.01 (s, 1H), 6.13 (s, 2H), 4.37 (t, J= 7.0 Hz, 2H), 3.27 (septet, J= 7.1 Hz, 1H), 2.89 (t, J= 7.1 Hz, 2H), 2.22 (m, 2H), 1.38 (d, J= 6.5 Hz, 6H); MS (ESI) m/z [M+H]+ 454.1 ; HPLC: method ARt = 5.67 (DZ3-39, 29%) and 5.87 (DZ3-49, 71%); method B Rt = 4.58 (DZ3-39, 34%) and 5.57 (DZ3-49, 66%).

Reference： [1]Patent: WO2011/44394,2011,A1 .Location in patent: Page/Page column 87-88

15
PU-DZ₁₃ [ No CAS ]
[ 928664-98-6 ]
[ 1289544-03-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate;bis-triphenylphosphine-palladium(II) chloride; In water; N,N-dimethyl-formamide; at 90℃; for 4h;Inert atmosphere;	2-(6-((6-amino-2-fluoro-9-(2-(isobutylamino)ethyI)-9H-purin-8- yl)methyl)benzo[d][l,3]dioxol-5-yl)acetonitrile [DZ3-40].; 4-Isoxazoleboronic acid pinacol ester (20.5 mg, 0.1053 mmol) was added to PU-DZ13 (30 mg, 0.0585 mmol) and NaHC03 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh3)2Cl2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 90C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH2Cl2:EtOAc:MeOH-NH3 (7N), 4:7:2:1) to give 8.3 mg (%) of DZ3-40. 1H NMR (500 MHz, CDCl3/MeOH-^) delta 6.94 (s, 1H), 6.70 (s, 1H), 6.00 (s, 2H), 4.39 (t, J= 6.7 Hz, 2H), 4.31 (s, 2H), 3.84 (s, 2H), 3.18 (t, J= 6.6 Hz, 2H), 2.65 (d, J= 7.1 Hz, 2H), 1.94 (m, 1H), 0.99 (d, J= 6.7 Hz, 6H); 13C NMR (125 MHz, CDC13/ MeOH-^) delta 158.7 (d, J= 210.4 Hz), 156.6 (d, J= 20.1 Hz), 152.1 (d, J= 18.2 Hz), 150.5, 148.1, 147.7, 126.7, 122.4, 117.9, 116.1, 110.6, 109.9, 101.8, 56.5, 47.4, 41.2, 31.3, 27.1, 21.5, 20.0;HRMS (ESI) m/z [M+H]+ calcd. for C21H25FN702, 426.2054; found 426.2048; HPLC:method A Rt = 6.48, method B Rt = 7.10.

Reference： [1]Patent: WO2011/44394,2011,A1 .Location in patent: Page/Page column 94

16
PU-DZ₁₃ [ No CAS ]
[ 928664-98-6 ]
[ 1289544-03-1 ]
[ 1289544-07-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate;bis-triphenylphosphine-palladium(II) chloride; In water; N,N-dimethyl-formamide; at 60℃; for 4h;Inert atmosphere;	2-fluoro-9-(2-(isobutylamino)ethyl)-8-((6-(isoxazol-4-yl)benzo[d][l,3]dioxol-5- yl)methyl)-9H-purin-6-amine [DZ3-51].; 4-Isoxazoleboronic acid pinacol ester (20.5 mg, 0.1053 mmol) was added to PU-DZ13 (30 mg, 0.0585 mmol) and NaHC03 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh3)2Cl2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 60C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH2Cl2:EtOAc:MeOH-NH3 (7N), 2:2:1:0.5) to give 7.8 mg (29%) of an inseparable mixture of DZ3-51 and DZ3-40 in a ratio of approximately 44:56, respectively, asdetermined by HPLC. MS (ESI) m/z [M+H]+ 454.4; HPLC: method A Rt = 6.46 (DZ3-40, 56%) and 6.65 (DZ3-51, 44%); method B Rt = 7.08 (DZ3-40, 65%) and 7.52 (DZ3-51, 35%).

Reference： [1]Patent: WO2011/44394,2011,A1 .Location in patent: Page/Page column 94

17
[ 109-04-6 ]
[ 928664-98-6 ]
[ 2739-97-1 ]