[ CAS No. 905273-91-8 ] {[proInfo.proName]}

Name: 905273-91-8|tert-Butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate|97%
Brand: Ambeed
SKU: A267611
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Quality Control of [ 905273-91-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 905273-91-8 ]

Product Details of [ 905273-91-8 ]

CAS No. :	905273-91-8	MDL No. :	MFCD11226842
Formula :	C₁₉H₂₈BNO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GVNKCVZBPCUBLS-UHFFFAOYSA-N
M.W :	345.24	Pubchem ID :	16102684
Synonyms :

Calculated chemistry of [ 905273-91-8 ]

Physicochemical Properties

Num. heavy atoms :	25
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.63
Num. rotatable bonds :	4
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	103.29
TPSA :	48.0 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.16 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	3.16
Log Po/w (WLOGP) :	2.55
Log Po/w (MLOGP) :	2.07
Log Po/w (SILICOS-IT) :	2.27
Consensus Log Po/w :	2.01

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.88
Solubility :	0.045 mg/ml ; 0.00013 mol/l
Class :	Soluble
Log S (Ali) :	-3.84
Solubility :	0.0501 mg/ml ; 0.000145 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.75
Solubility :	0.00618 mg/ml ; 0.0000179 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	3.38

Safety of [ 905273-91-8 ]

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

Application In Synthesis of [ 905273-91-8 ]

* 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 [ 905273-91-8 ]
Downstream synthetic route of [ 905273-91-8 ]

[ 905273-91-8 ] Synthesis Path-Upstream 1~4

1
[ 201940-08-1 ]
[ 73183-34-3 ]
[ 905273-91-8 ]

Yield	Reaction Conditions	Operation in experiment
73%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate In dimethyl sulfoxide at 90℃; for 12 h; Inert atmosphere	To a suspension of tert-butyl 5-bromo-2-(tert-butoxycarbonyl)isoindoline (1.2 g, 4 mmol) and bis(pinacolato)diboron (2 g, 8 mmol) in DMSO (20 mL) was added AcOK (1.6 g, 16 mmol), followed by Pd(dppf)Cl₂-CH₂Cl₂ (327 mg, 0.4 mmol) under N₂ atmosphere. The reaction was heated at 90 °C for 12 h, then cooled to rt and poured into EtOAc/H₂0 (300 mL/100 mL). The separatedorganic phase was washed with brine (100 mL), dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) =20/1) to give the title compound as yellow oil (1 g, 73percent). MS (ESI, pos. ion) m/z: 290.2 [M-56+l ; NMR (400 MHz, CDC1₃) δ (ppm): 7.68-7.74 (m, 2H), 7.23-7.30 (m, 1H), 4.64-4.70 (m, 4H), 1.53 (s, 9H), 1.36 (s, 12H).
73%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ In dimethyl sulfoxide at 90℃; for 12 h; Inert atmosphere	Under nitrogen protection,A solution of 5-bromo-2- (tert-butoxycarbonyl) isoindoline (1.2 g, 4 mmol)And boronic acid pinacol ester (2 g, 8 mmol)Was dissolved in dimethylsulfoxide (20 mL)To this was added potassium acetate (1.6 g, 16 mmol) andPd (dppf) Cl2CH2Cl2 (327 mg, 0.4 mmol).The reaction solution was heated and stirred at 90 ° C for 12 hours,Cool to room temperature and pour into acetic acidEthyl acetate / water (300 mL / 100 mL), the separated organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate,Filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 20/1)The title compound was obtained as a yellow oil (1 g, 73percent).
72%	With potassium acetate In N,N-dimethyl-formamide at 85℃; for 4 h;	Step 2: tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-isoindole-2-carboxylate A solution of tert-butyl 5-bromo-1,3-dihydro-2H-isoindole-2-carboxylate (0.80 mmol), bis(pinacolato)diboron (0.96 mmol) and potassium acetate (2.5 mmol) in DMF (4 mL) was degassed. To this solution was added PdCl₂dppf (1:1 complex with DCM, 0.04 mmol). The reaction mixture was heated at 85° C. for 4 hr and then allowed to cool to rt and diluted with EtOAc. The solution was washed with water and brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (10-30percent EtOAc in hexane) to give tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-isoindole-2-carboxylate (0.57 mmol, 72percent) as a white solid. LCMS: (FA) ES+346.

Reference： [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 2, p. 199 - 210
[2] Patent: WO2014/89324, 2014, A1, . Location in patent: Paragraph 0237
[3] Patent: CN104016979, 2017, B, . Location in patent: Paragraph 0606; 0607; 0608; 0609
[4] Patent: US2008/171754, 2008, A1, . Location in patent: Page/Page column 103
[5] Patent: WO2010/10186, 2010, A1, . Location in patent: Page/Page column 58
[6] Patent: WO2010/145202, 2010, A1, . Location in patent: Page/Page column 59
[7] Patent: WO2015/112441, 2015, A1, . Location in patent: Page/Page column 56
[8] Patent: US2016/333021, 2016, A1, . Location in patent: Paragraph 0345

2
[ 6941-75-9 ]
[ 905273-91-8 ]

Reference： [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 2, p. 199 - 210
[2] Patent: WO2014/89324, 2014, A1,
[3] Patent: CN104016979, 2017, B,

3
[ 127168-84-7 ]
[ 905273-91-8 ]

Reference： [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 2, p. 199 - 210
[2] Patent: WO2014/89324, 2014, A1,
[3] Patent: CN104016979, 2017, B,

4
[ 86-90-8 ]
[ 905273-91-8 ]

Reference： [1] Patent: WO2014/89324, 2014, A1,
[2] Patent: CN104016979, 2017, B,

[ 905273-91-8 ] Synthesis Path-Downstream 1~41

1
[ 846563-95-9 ]
[ 905273-91-8 ]
[ 846566-17-4 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 199 - 210

2
[ 905273-91-8 ]
[ 922718-28-3 ]
5-(9-cyclopropyl-8-methoxy-3,4-dioxo-2,3,4,9-tetrahydro-isothiazolo[5,4-b]quinolin-7-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 199 - 210

3
[ 905273-91-8 ]
[ 922718-28-3 ]
5-(9-cyclopropyl-6-fluoro-8-methoxy-3,4-dioxo-2,3,4,9-tetrahydro-isothiazolo[5,4-b]quinolin-7-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 199 - 210

4
[ 201940-08-1 ]
[ 73183-34-3 ]
[ 905273-91-8 ]

Yield	Reaction Conditions	Operation in experiment
99.3%		Tert-butyl-5-bromisoindoline-2-carboxylate (20.0 g, 67.09 mmol) was dissolved in Dioxane (200 ml.) and the solution was purged with Argon gas for 10 min. Bispinacalato diborane (34.07 g, 134.18 mmol), KOAc (26.34 g, 268.36 mmol) and Pd(PPh3)4 (7.75 g, 6.70 mmol) were added and the reaction mixture was stirred at 80C for 12 h. Reaction mixture was diluted with water, extracted with EtOAc (1 Ltr. X 2) twice The combined organic layers were washed with water (500 ml_), brine (300 ml_), dried over sodium sulphate and concentrated under vacuo. Crude compound was purified by Combiflash chromatography using 40 g Column and 10% EtOAc in n-Hexane to afford title compound as a White solid 23.0 g (99.30 %). Rf = 0.50 (10% EtOAc in n-Hexane); 1 H NMR (300 MHz, CDCI3): d 7.72-7.65 (m, 2H), 7.31 -7.20 (m, 1 H), 4.70-4.60 (m, 4H), 1 .40 (s, 9 H), 1 .37 (s, 12H).
73%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In dimethyl sulfoxide; at 90℃; for 12h;Inert atmosphere;	To a suspension of tert-butyl 5-bromo-2-(tert-butoxycarbonyl)isoindoline (1.2 g, 4 mmol) and bis(pinacolato)diboron (2 g, 8 mmol) in DMSO (20 mL) was added AcOK (1.6 g, 16 mmol), followed by Pd(dppf)Cl2-CH2Cl2 (327 mg, 0.4 mmol) under N2 atmosphere. The reaction was heated at 90 C for 12 h, then cooled to rt and poured into EtOAc/H20 (300 mL/100 mL). The separatedorganic phase was washed with brine (100 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) =20/1) to give the title compound as yellow oil (1 g, 73%). MS (ESI, pos. ion) m/z: 290.2 [M-56+l ; NMR (400 MHz, CDC13) delta (ppm): 7.68-7.74 (m, 2H), 7.23-7.30 (m, 1H), 4.64-4.70 (m, 4H), 1.53 (s, 9H), 1.36 (s, 12H).
73%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In dimethyl sulfoxide; at 90℃; for 12h;Inert atmosphere;	Under nitrogen protection,A solution of 5-bromo-2- (tert-butoxycarbonyl) isoindoline (1.2 g, 4 mmol)And boronic acid pinacol ester (2 g, 8 mmol)Was dissolved in dimethylsulfoxide (20 mL)To this was added potassium acetate (1.6 g, 16 mmol) andPd (dppf) Cl2CH2Cl2 (327 mg, 0.4 mmol).The reaction solution was heated and stirred at 90 C for 12 hours,Cool to room temperature and pour into acetic acidEthyl acetate / water (300 mL / 100 mL), the separated organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate,Filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 20/1)The title compound was obtained as a yellow oil (1 g, 73%).

72%	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 85℃; for 4h;	Step 2: tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-isoindole-2-carboxylate A solution of tert-butyl 5-bromo-1,3-dihydro-2H-isoindole-2-carboxylate (0.80 mmol), bis(pinacolato)diboron (0.96 mmol) and potassium acetate (2.5 mmol) in DMF (4 mL) was degassed. To this solution was added PdCl2dppf (1:1 complex with DCM, 0.04 mmol). The reaction mixture was heated at 85 C. for 4 hr and then allowed to cool to rt and diluted with EtOAc. The solution was washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (10-30% EtOAc in hexane) to give tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-isoindole-2-carboxylate (0.57 mmol, 72%) as a white solid. LCMS: (FA) ES+346.
36%	With tetrakis(triphenylphosphine) palladium(0); potassium acetate; In dimethyl sulfoxide; at 80℃; for 16h;Inert atmosphere;	To a solution of tert-butyl 5-bromoisoindoline-2-carboxylate (1.20 g, 4.02 mmol, CAS201940-08-1), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.12 g, 4.43 mmol) in DMSO (20.0 mL) was added KOAc (1.18 g, 12.0 mmol) and Pd(PPh3)4 (139 mg, 120 umol). The mixture was stirred at 80 C. for 16 hours under N2. On completion, the mixture was diluted with H2O (50 mL), and extracted with EA (3×30 mL). The organic layers were washed with brine (3×30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The mixture was purified by prep-HPLC (reserve phase (0.1% FA)) to give the title compound (500 mg, 36% yield) as yellow solid. 1H NMR (400 MHz, CDCl3) delta 7.75 (s, 1H), 7.32-7.29 (m, 1H), 7.25 (d, J=7.6 Hz, 1H), 4.74-4.66 (m, 4H), 1.54 (s, 9H), 1.37 (s, 12H).
	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 90℃; for 20h;Inert atmosphere;	In a microwave vessel, a solution of 5-bromo-l,3-dihydro-isoindole-2-carboxylic acid tert- butyl ester (1.5 equiv.), di(pinacolato)diborane (2.0 equiv.), potassium acetate (2.0 equiv.) in 1,4-dioxane (2.0 mL) is flushed with nitrogen. [l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 equiv.) was then added and the reaction mixture was flushed again with argon (and heated up to 900C for 20 hours until the reaction is complete on TLC. No purification was carried out.
	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; at 120℃; for 1h;Microwave irradiation;Product distribution / selectivity;	A flask was charged with 1,1-dimethylethyl 5-bromo-1 ,3-dihydro-2H-isoindole-2- carboxylate (CASNo. 201940-08-1, commercially available from AB chemical, 53.6 mg, 0.180 mmol), potassium acetate (52.9 mg, 0.540 mmol), 4,4,4',4',5,5,5',S'- octamethyl-2,2'-bi-1,3,2-dioxaborolane (45.7 mg, 0.180 mmol) and 1,1'- bis(diphenylphosphino)ferrocenedichloro palladium(ll) (13.16 mg, 0.018 mmol) then filled with DME (2 ml) and the resulting mixture was stirred at 1200C for 60 minutes under microwave irradiation. 2-Bromo-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}- 1,3,4-thiadiazole (Preparation 11) (60.0 mg, 0.180 mmol) was added along with a saturated NaHCO3 aqueous solution (0.2 ml). The resulting mixture was stirred at 120C for 60 minutes under microwave irradiation then at 1400C for 30 minutes, still under microwave irradiation. The insoluble material was filtered off via a pad of silica gel and rinsed with DCM and AcOEt. The combined organic phases were concentrated in vacuo and the residue dissolved in DCM (5 ml) and trifluoroacetic acid (3 ml, 38.9 mmol). The resulting mixture was stirred at room temperature for 2 hours then concentrated in vacuo. The residue was loaded on a SCX cartridge and eluted with MeOH then with a 2N NH3 solution in MeOH. The combined ammonia fractions were combined and concentrated in vacuo. Purification of the residue by MDAP gave 5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1 ,3,4-thiadiazol-2-yl)-2,3- dihydro-1 H-isoindole trifluoroacetic acid salt (15.1 mg, 17.3 % yield) as a white foam. LCMS: retention time 1.07 min; [M+H]+ = 372.2
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 80℃;	Commercially available tert-butyl 5-bromoisoindoline-2-carboxylate (i.e., Matric Scientific, catalog 74109) (20 g, 0.0671 mol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (17 g, 0.0671 mol), KAc (8.5 g, 0.087 mol) and PdCfedppf (1.8 g, 0.00221 mol) in 200 mL 1,4-dioxane was heated to 80C overnight. The mixture was cooled, water was added, the mixture was extacted with EA, dried and concentrated. The residue was purified by chromatography on silica gel to afford the title compound. 1HNMR (300MHz,DMSO)5: 1.2-1.3 (s, 12H), 1.4-1.5 (s, 9H), 4.5-4.6 (s, 4H), 7.2-7.3(m,lH), 7.5-7.6 (M,2H); LC-MS: m/z=246 (M+l-100)+.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 80℃;	Reference Example 17 tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate (0344) tert-butyl 5-bromoisoindoline-2-carboxylate (i.e., Matric Scientific, catalog 74109) (20 g, 0.0671 mol), 4,4,4?,4?,5,5,5?,5?-octamethyl-2,2?-bi(1,3,2-dioxaborolane) (17 g, 0.0671 mol), KAc (8.5 g, 0.087 mol) and PdCl2dppf (1.8 g, 0.00221 mol) in 200 mL 1,4-dioxane was heated to 80 C. overnight. The mixture was cooled, water was added, the mixture was extracted with EA, dried and concentrated. The residue was purified by chromatography on silica gel to afford the title compound. 1HNMR (300 MHz, DMSO) delta: 1.2-1.3 (s, 12H), 1.4-1.5 (s, 9H), 4.5-4.6 (s, 4H), 7.2-7.3 (m, 1H), 7.5-7.6 (M, 2H); LC-MS: m/z=246 (M+1-100)+.

Reference： [1]Patent: WO2019/244049,2019,A1 .Location in patent: Paragraph 00180; 00212; 00214
[2]Journal of Medicinal Chemistry,2007,vol. 50,p. 199 - 210
[3]Patent: WO2014/89324,2014,A1 .Location in patent: Paragraph 0237
[4]Patent: CN104016979,2017,B .Location in patent: Paragraph 0606; 0607; 0608; 0609
[5]Patent: US2008/171754,2008,A1 .Location in patent: Page/Page column 103
[6]Patent: US2019/192668,2019,A1 .Location in patent: Paragraph 2685; 2686
[7]Patent: WO2010/10186,2010,A1 .Location in patent: Page/Page column 58
[8]Patent: WO2010/145202,2010,A1 .Location in patent: Page/Page column 59
[9]Patent: WO2015/112441,2015,A1 .Location in patent: Page/Page column 56
[10]Patent: US2016/333021,2016,A1 .Location in patent: Paragraph 0345

5
[ 905273-91-8 ]
9-cyclopropyl-7-(2,3-dihydro-1H-isoindol-5-yl)-8-methoxy-9H-isothiazolo[5,4-b]quinoline-3,4-dione [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 199 - 210

6
[ 905273-91-8 ]
9-cyclopropyl-7-(2,3-dihydro-1H-isoindol-5-yl)-6-fiuoro-9H-isothiazolo[5,4-b]quinoline-3,4-dione [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 199 - 210

7
[ 905273-91-8 ]
9-cyclopropyl-6-fluoro-7-(isoindol-5-yl)-8-methoxyisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 199 - 210

8
[ 6941-75-9 ]
[ 905273-91-8 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 199 - 210
[2]Patent: WO2014/89324,2014,A1
[3]Patent: CN104016979,2017,B

9
[ 127168-84-7 ]
[ 905273-91-8 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 199 - 210
[2]Patent: WO2014/89324,2014,A1
[3]Patent: CN104016979,2017,B

10
[ 905273-91-8 ]
[ 1205683-27-7 ]
[ 1205683-30-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 90℃; for 20h;Inert atmosphere;	Cyclopropanecarboxylic acid (8-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)-amide (1.0 equiv.),K2CO3 (2.0 equiv.), [l,r-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 equiv.) and 1,4- dioxane/water 4:1 (1.5 mL) were added to the mixture. The reaction mixture was heated at 900C for 16 h until complete consumption of the starting material. The precipitate was fitered, washed with H2O, dried under vacuum. The product was obtained which was used in the next step without further purification.

Reference： [1]Patent: WO2010/10186,2010,A1 .Location in patent: Page/Page column 58

11
[ 905273-91-8 ]
[ 1258440-64-0 ]
C₂₄H₂₆ClN₃O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 120 - 140℃; for 1.5h;Microwave irradiation;Product distribution / selectivity;	A flask was charged with 1,1-dimethylethyl 5-bromo-1 ,3-dihydro-2H-isoindole-2- carboxylate (CASNo. 201940-08-1, commercially available from AB chemical, 53.6 mg, 0.180 mmol), potassium acetate (52.9 mg, 0.540 mmol), 4,4,4',4',5,5,5',S'- octamethyl-2,2'-bi-1,3,2-dioxaborolane (45.7 mg, 0.180 mmol) and 1,1'- bis(diphenylphosphino)ferrocenedichloro palladium(ll) (13.16 mg, 0.018 mmol) then filled with DME (2 ml) and the resulting mixture was stirred at 1200C for 60 minutes under microwave irradiation. 2-Bromo-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}- 1,3,4-thiadiazole (Preparation 11) (60.0 mg, 0.180 mmol) was added along with a saturated NaHCO3 aqueous solution (0.2 ml). The resulting mixture was stirred at 120C for 60 minutes under microwave irradiation then at 1400C for 30 minutes, still under microwave irradiation. The insoluble material was filtered off via a pad of silica gel and rinsed with DCM and AcOEt. The combined organic phases were concentrated in vacuo and the residue dissolved in DCM (5 ml) and trifluoroacetic acid (3 ml, 38.9 mmol). The resulting mixture was stirred at room temperature for 2 hours then concentrated in vacuo. The residue was loaded on a SCX cartridge and eluted with MeOH then with a 2N NH3 solution in MeOH. The combined ammonia fractions were combined and concentrated in vacuo. Purification of the residue by MDAP gave 5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1 ,3,4-thiadiazol-2-yl)-2,3- dihydro-1 H-isoindole trifluoroacetic acid salt (15.1 mg, 17.3 % yield) as a white foam. LCMS: retention time 1.07 min; [M+H]+ = 372.2

Reference： [1]Patent: WO2010/145202,2010,A1 .Location in patent: Page/Page column 59

12
[ 86-90-8 ]
[ 905273-91-8 ]

Reference： [1]Patent: WO2014/89324,2014,A1
[2]Patent: CN104016979,2017,B

13
[ 905273-91-8 ]
5-bromo-3-[1 (R)-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine [ No CAS ]
[ 1613147-74-2 ]

Yield	Reaction Conditions	Operation in experiment
71%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 12h;Inert atmosphere;	To a suspension of (R)-5-bromo-3-(l-(2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-2-amine (731 mg, 1.92 mmol) and 2-(tert-butoxycarbonyl)-5- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoindoline (0.93 g, 2.7 mmol) in DME (25 mL) was added a solution of Cs2C03 (1.88 g, 5.76 mmol) in H20 (5 mL), followed by Pd(dppf)Cl2-CH2Ci2 (156 mg, 0.19 mmol) under 2 atmosphere. The reaction was stirred at 90 C for 12 h, then cooled to rt, diluted with H20 (20 mL) and extracted with DCM (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous a2S04, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as a pale yellow solid (0.71 g, 71%). MS (ESI, pos. ion) m/z: 518.15[M + H]+; NMR (400 MHz, CDC13) delta (ppm): 7.87 (s, 1H), 7.23-7.33 (m, 4H), 7.05-7.09 (m, 1H), 6.99 (s, 1H), 6.12-6.16 (m, 1H), 4.94 (s, 2H), 4.68-4.73 (m, 4H), 1.88-1.89 (d, J= 6.7 Hz, 3H), 1.55 (s, 9H).

Reference： [1]Patent: WO2014/89324,2014,A1 .Location in patent: Paragraph 0238

14
[ 905273-91-8 ]
5-bromo-3-[1 (R)-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine [ No CAS ]
(R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(isoindolin-5-yl)pyridin-2-amine hydrochloride [ No CAS ]

Reference： [1]Patent: WO2014/89324,2014,A1

15
[ 905273-91-8 ]
(S)-tert-butyl 2-((S)-2-(6-bromopyridin-3-yl)-1-(1H-tetrazol-5-yl)ethyl)pent-4-enoate [ No CAS ]
tert-butyl 5-(5-((2S,3S)-3-(tert-butoxycarbonyl)-2-(1H-tetrazol-5-yl)hex-5-en-1-yl)pyridin-2-yl)isoindoline-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; dichloro[1,1?-bis[bis(1,1-dimethylethyl)phosphino]ferrocene-P,P?]palladium; In ethanol; water; at 120℃; for 0.5h;Inert atmosphere; Microwave irradiation;	In a 5 ml microwave tube, (S)-tert-butyl 2-((S)-2-(6-bromopyridin-3-yl)-1-(1H-tetrazol-5-yl)ethyl)pent-4-enoate (90 mg, 0.22 mmol) was dissolved in ethanol (2 ml)/water (1ml) and to which was added tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindoline-2-carboxylate, potassium phosphate tribasic (190 mg, 0.88 mmol). The tube was capped and degassed by vacuum and purged with N2. The tube was uncapped and 1,1?-bis(di- tert-butylphosphino)ferrocene palladium dichloride (14 mg, 0.022 mmol) was added then thetube was recapped and degassed again. The tube was microwaved at 100C for 1/2 hr. The reaction was filtered and concentrated. The residue was purified by reverse phase HPLC with ACN and water buffered with 0.05% TFA. LC-MS [M+1]: 547.39.

Reference： [1]Patent: WO2015/171474,2015,A1 .Location in patent: Page/Page column 112

16
[ 905273-91-8 ]
tert-butyl 5-(5-((2S,3S)-3-(tert-butoxycarbonyl)-2-(1H-tetrazol-5-yl)hexyl)pyridin-2-yl)isoindoline-2-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/171474,2015,A1

17
[ 905273-91-8 ]
5-(5-((2S,3S)-3-carboxy-2-(1H-tetrazol-5-yl)hexyl)pyridin-2-yl)isoindolin-2-ium 2,2,2-trifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2015/171474,2015,A1

18
[ 905273-91-8 ]
tert-butyl 5-(6-(((methylsulfonyl)oxy)methyl)pyridin-3-yl)isoindoline-2-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/171474,2015,A1

19
[ 905273-91-8 ]
tert-butyl 5-(6-(chloromethyl)pyridin-3-yl)isoindoline-2-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/171474,2015,A1

20
[ 905273-91-8 ]
(S)-2-((S)-2-(5-(2-(tert-butoxycarbonyl)isoindolin-5-yl)pyridin-2-yl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-tetrazol-5-yl)ethyl)-4-methylpentanoic acid [ No CAS ]

Reference： [1]Patent: WO2015/171474,2015,A1

21
[ 905273-91-8 ]
(S)-2-((S)-2-(5-(isoindolin-5-yl)pyridin-2-yl)-1-(1H-tetrazol-5-yl)ethyl)-4-methylpentanoic acid [ No CAS ]

Reference： [1]Patent: WO2015/171474,2015,A1

22
[ 905273-91-8 ]
[ 88139-91-7 ]
tert-butyl 5-(6-(hydroxymethyl)pyridin-3-yl)isoindoline-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; dichloro[1,1?-bis[bis(1,1-dimethylethyl)phosphino]ferrocene-P,P?]palladium; In ethanol; water; at 100℃; for 0.5h;Sealed tube; Inert atmosphere;	To a 25 mL microwave vial with a stir bar was added tert-butyl 5-(4,4,5,5- tetramethyl- 1,3 ,2-dioxaborolan-2-yl)isoindoline-2-carboxylate (260 mg, 0.75 mmol), (5- bromopyridin-2-yl)methanol (212 mg, 1.13 mmol), 1,1 ?-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (49 mg, 0.075 mmol), and K3P04 (480 mg, 2.3 mmol). The vial was sealed, and then EtOH (4 ml) and water (2 ml) were added. The mixture was flushed with nitrogen, and then heated to 100C for 30 minutes. LC showed very good reaction. The reaction was diluted with 1 mL of water, and the organic layer was diluted with EtOAc (5 mL). The crude solution was sucked out with a syringe. The solution was evaporated on a rotavapor, andthe residue was dissolved in DCM and injected onto a 24G ISCO column. The desired productwas isolated by MPLC with hexane and EtOAc gradient. The product was eluted at about 100%EtOAc. It was a yellow solid. LC-MS [M+1]: 327.2

Reference： [1]Patent: WO2015/171474,2015,A1 .Location in patent: Page/Page column 115

23
[ 905273-91-8 ]
7-bromo-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one [ No CAS ]
tert-butyl 5-(5-cyclopropyl-2,6-dimethyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)isoindoline-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,2-dimethoxyethane; water; at 60℃; for 1.5h;Inert atmosphere; Microwave irradiation;	7-Bromo-5-cyclopropyl-2,6-dimethyl-oxazolo[4,5-c]quinolin-4-one (Intermediate A) (41 mg, 0.12 mmol), Cs2C03 (120 mg, 0.37 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-isoindoline-2-carboxylate (68 mg, 0.20 mmol) and [1 , T- bis(diphenylphosphino)ferrocene]-palladium(ll) chloride dichloromethane complex (10.05 mg, 0.01 mmol) were dissolved in dimethoxyethane (1 mL)/H20 (0.25 mL) under N2. The mixture was then heated in a microwave reactor at 60C for 1.5 h. The organic phase of the reaction mixture was then dry loaded onto silica and purified by column chromatography, eluting with a gradient of 0-100% EtOAc in heptane and evaporated to give tert-butyl 5-(5- cyclopropyl-2,6-dimethyl-4-oxo-oxazolo[4,5-c]quinolin-7-yl)isoindoline-2-carboxylate (40 mg, 69 %) as a solid. LC-MS (Method D) 472.4 [M+H]+; RT 1.98 min

Reference： [1]Patent: WO2017/46605,2017,A1 .Location in patent: Page/Page column 73-74

24
[ 905273-91-8 ]
[ 407-14-7 ]
C₁₅H₁₂F₃NO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%		5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindole-2-carboxylic acid tert-butyl ester (690 mg, 2.0 mmol, Reference: J. Med. Chem. 2007, 50 (2) 199-210) was dissolved in tetrahydrofuran (20 mL). 1-bromo-4-trifluoromethoxybenzene (578 mg, 2.4 mmol) and water (5 mL) were added. Sodium carbonate (424 mg, 4.0 mmol) was added, purged with argon, tetrakis(triphenylphosphine)palladium (114 mg, 0.1 mmol) was added, reacted overnight at 80 C, diluted with water (50 mL), extracted with ethyl acetate (30 mL * 3). The ethyl acetate layers were combined, washed with saturated brine (50 mL), dried over sodium sulfate, dried solvent, column chromatographed (CH2Cl2 / CH3OH = 100/1) and the resulting intermediate product was directly charged to the next step. The intermediate was added to methylene chloride (20 mL). The ice salt was cooled and trifluoroacetic acid (20 mL) was added. The reaction was carried out at room temperature for 3h. The residue was dissolved in dichloromethane (100 mL) and saturated sodium bicarbonate solution (50 mL), washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and the solvent was dried to give the intermediate TH-8 (312 mg, 56% in two steps).

Reference： [1]Patent: CN103450220,2017,B .Location in patent: Paragraph 0123; 0124; 0125; 0126; 0127

25
[ 905273-91-8 ]
[ 172976-00-0 ]
tert-butyl 5-(2-methylbiphenyl-3-yl)isoindoline-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 120℃;Inert atmosphere;	A mixture of 3-bromo-2-methylbiphenyl (Example 2, Step 1: 40 mg, 0.2 mmol), <strong>[905273-91-8]tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-isoindole-2-carboxylate</strong> (67 mg, 0.19 mmol), [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (7 mg, 0.008 mmol) and potassium carbonate (67 mg, 0.48 mmol) in 1,4-dioxane (20 mL) and water (1 mL) was degassed and recharged with nitrogen three times. The mixture was then heated and stirred at 120 C. overnight. The reaction mixture was quenched with water, and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the crude product.

Reference： [1]Patent: US2018/177784,2018,A1 .Location in patent: Paragraph 0510-0511

26
[ 905273-91-8 ]
2-(chloromethyl)-N-(2,4-dimethoxybenzyl)-7-fluoroimidazo[1,2-c]quinazolin-5-amine [ No CAS ]
tert-butyl 5-((5-((2,4-dimethoxybenzyl)amino)-7-fluoroimidazo[1,2-c]quinazolin-2-yl)methyl)isoindoline-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
106.4 mg	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; for 3h;	To a stirred solution of 2-(chloromethyl)-N-(2,4-dimethoxybenzyl)-7-fluoroimidazo[1,2- c]quinazolin-5-amine prepared in accordance with the procedures of Example 1, steps 1 to 9 (100 mg, 0.249 mmol) in Dioxane (3742 mul) was added Int A (the 5- [4,4,5,5-pentamethyl-1,3,2- dioxaborolane] salt of tert-butyl isoindoline-2-carboxylate (172 mg, 0.499 mmol), K2CO3 (103 mg, 0.748 mmol), and Pd(Cl)2(dppf) complex (50.9 mg, 0.062 mmol). The reaction mixture was heated to 87 C for 3hrs, then the solvent was evaporated and the mixture worked-up with EtOAc/NaHCO3 (aqueous). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by ISCO (EtOAc/Hex = 1/1) to afford tert- butyl 5-((5-((2,4-dimethoxybenzyl)amino)-7-fluoroimidazo[1,2-c]quinazolin-2- yl)methyl)isoindoline-2-carboxylate (106.4 mg). LC/MS = 584 [M+1].

Reference： [1]Patent: WO2019/118313,2019,A1 .Location in patent: Paragraph 0069

27
[ 905273-91-8 ]
2-((2-benzylisoindolin-5-yl)methyl)-7-fluoroimidazo[1,2-c]quinazolin-5-amine [ No CAS ]

Reference： [1]Patent: WO2019/118313,2019,A1

28
[ 905273-91-8 ]
7-fluoro-2-(isoindolin-5-ylmethyl)imidazo[1,2-c]quinazolin-5-amine [ No CAS ]

Reference： [1]Patent: WO2019/118313,2019,A1

29
[ 905273-91-8 ]
(5-((5-amino-7-fluoroimidazo[1,2-c]quinazolin-2-yl)methyl)isoindolin-2-yl)(phenyl)methanone [ No CAS ]

Reference： [1]Patent: WO2019/118313,2019,A1

30
[ 905273-91-8 ]
(2-(tert-butoxycarbonyl)isoindolin-5-yl)boronic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%		To a solution of <strong>[905273-91-8]tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate</strong> (500 mg, 1.45 mmol, Intermediate FL) in a mixed solvent of THF (20.0 mL) and H2O (4.00 mL) was added NaIO4 (929 mg, 4.34 mmol). The mixture was stirred at 25 C. for 0.5 hr. HCl (3 M, 965 uL) was added to the mixture; and the mixture was stirred at 25 C. for 1.5 hrs. On completion, the mixture was diluted with H2O (30 mL), and extracted with EA (3×30 mL). The organic layers were washed with brine (3×20 mL), the organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The mixture was purified by prep-HPLC (reverse phase (0.1% FA)) to give the title compound (260 mg, 68% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) delta 8.05 (s, 2H), 7.72 (s, 1H), 7.70 (s, 1H), 7.29 (t, J=6.4 Hz, 1H), 4.64-4.53 (m, 4H), 1.46 (s, 9H).

Reference： [1]Patent: US2019/192668,2019,A1 .Location in patent: Paragraph 2687; 2688

31
[ 905273-91-8 ]
tert-butyl 5-[4-nitro-3-(trifluoromethyl) pyrazol-1-yl]isoindoline-2-carboxylate [ No CAS ]

Reference： [1]Patent: US2019/192668,2019,A1

32
[ 905273-91-8 ]
tert-butyl 5-[4-amino-3-(trifluoromethyl)pyrazol-1-yl]isoindoline-2-carboxylate [ No CAS ]

Reference： [1]Patent: US2019/192668,2019,A1

33
[ 905273-91-8 ]
[ 659731-48-3 ]
tert-butyl 5-(5-chloro-2-fluoropyridin-4-yl)isoindoline-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59.26%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 6h;Sealed tube;	General procedure: To a sealed tube containing aryl bromide (1 .0 equiv.) in 7:3 1 ,4-dioxane/H20 was added Na2C03 (1 .5- 3.0 equiv.), arylboronic acid/ ester (1 .5 equiv.) and Pd(dppf)Cl2*CH2Cl2 (5 mol%). The reaction mixture was heated at 100 C for 6 hours before it was diluted with H20 and extracted with EtOAc (twice). The combined organic layers were washed with H20, then brine, dried over Na2S04, filtered and concentrated under vacuo to give crude material which was purified by silica gel chromatography to provide the desired product.

Reference： [1]Patent: WO2019/244049,2019,A1 .Location in patent: Paragraph 00163; 00194

34
[ 905273-91-8 ]
[ 147460-41-1 ]
tert-butyl 5-(4-fluoro-2-hydroxyphenyl)isoindoline-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58.04%	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In water; N,N-dimethyl-formamide; at 60℃; for 5h;	General procedure: To a sealed tube containing aryl bromide (1 .0 equiv.) in 1 :1 DMF/H2O was added K2CO3 (3.0 equiv.), arylboronic acid/ ester (1 .2 equiv.) and Pd(PPh3)2Cl2 (5 mol%). The reaction mixture was heated at 60 C for 5 hours before it was diluted with H2O and extracted with EtOAc (twice). The combined organic layers were washed with H2O, then brine, dried over Na2S04, filtered and concentrated under vacuo to give crude material which was purified by silica gel chromatography to provide the desired product. Suzuki Coupling Procedure I: Pd(dtbpf)CI2, K3P04, Dioxane/H20

Reference： [1]Patent: WO2019/244049,2019,A1 .Location in patent: Paragraph 00164; 00305

35
[ 905273-91-8 ]
3-bromo-5-fluoro-2-(trifluoromethyl)pyridine [ No CAS ]
tert-butyl 5-(5-fluoro-2-(trifluoromethyl)pyridin-3-yl)isoindoline-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47.86%		Tert-butyl 5-(4, 4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl) isoindoline-2- carboxylate (5.6 g, 16.39 mmol) was dissolved in Dioxane:H20 (8:2) (100 ml_), purged with Argon gas for 10 min., K3PO4 (8.67 g, 40.98 mmol), 3-bromo-5-fluoro-2- (trifluoromethyl)pyridine (4.0 g, 16.39 mmol) and Pd(dppf)Cl2.DCM (1 .34 g, 1 .63 mmol) were added and the reaction mixture was stirred at 100C for 3 h. Reaction mixture was diluted with water, extracted with EtOAc (500 ml. X 2) twice. The combined organic layers were washed with water (300 ml_), brine (300 ml_), dried over sodium sulphate and concentrated invacuo. Crude compound was purified by Combiflash chromatography using 40 g Column and 25% EtOAc in n-Hexane to afford title compound as a brownish semisolid 3.0 g (47.86%). Rf = 0.50 (20% EtOAc in n-Hexane); 1 H NMR (300 MHz, CDCI3): d 8.56 (d, J = 2.4 Hz, 1 H), 7.50-7.32 (m, 2H), 7.32-7.15 (m, 2H), 4.75(s, 2H), 4.71 (s,2H), 1 .52(s,9H). LC-MS: [M-Boc]+1 =282.8.

Reference： [1]Patent: WO2019/244049,2019,A1 .Location in patent: Paragraph 00212; 00215

36
[ 905273-91-8 ]
1-(2-bromo-5-fluorophenyl)pyrrolidine [ No CAS ]
tert-butyl 5-(4-fluoro-2-(pyrrolidin-1-yl)phenyl)isoindoline-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38.35%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 6h;Sealed tube;	General procedure: To a sealed tube containing aryl bromide (1 .0 equiv.) in 4:1 1 ,4-dioxane/H20 was added K2C03 / K3P04 (1 .5 equiv.), arylboronic acid/ ester (1 .5 equiv.) and Pd(PPh3)4 (5 mol%). The reaction mixture was heated at 100 C for 6 hours before it was diluted with H2O and extracted with EtOAc (twice). The combined organic layers were washed with H20, then brine, dried over Na2S04, filtered and concentrated under vacuo to give crude material which was purified by silica gel chromatography to provide the desired product.

Reference： [1]Patent: WO2019/244049,2019,A1 .Location in patent: Paragraph 00167; 00224-00225

37
[ 905273-91-8 ]
tert-butyl 5-(4-fluoro-2-(2-methoxyethoxy)phenyl)isoindoline-2-carboxylate [ No CAS ]

Reference： [1]Patent: WO2019/244049,2019,A1

38
[ 905273-91-8 ]
5-(5-fluoro-2-(trifluoromethyl)pyridin-3-yl)isoindoline trifluoroacetic acid salt [ No CAS ]

Reference： [1]Patent: WO2019/244049,2019,A1

39
[ 905273-91-8 ]
1-(2-(5-(5-fluoro-2-(trifluoromethyl)pyridin-3-yl)isoindolin-2-yl)-2-oxoethyl)-1H-1,2,4-triazole-3-carbonitrile [ No CAS ]

Reference： [1]Patent: WO2019/244049,2019,A1

40
[ 905273-91-8 ]
1-(3-bromopyridin-2-yl)-2,2,2-trifluoroethyl methanesulfonate [ No CAS ]
tert-butyl 5-(2-(2,2,2-trifluoroethyl)pyridin-3-yl)isoindoline-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28.1%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine; In methanol; at 100℃; for 10h;Sealed tube;	General procedure: To a sealed tube containing aryl bromide (1 .0 equiv.) in MeOH (40 vol) was added TEA (2.5 equiv.) arylboronic acid/ ester (1 .0 equiv.) and Pd(dppf)Cl2*CH2Cl2 (10 mol%). The reaction mixture was heated at 100 C for 10 hours before it was diluted with H2O and extracted with EtOAc (twice). The combined organic layers were washed with H20, then brine, dried over Na2S04, filtered and concentrated under vacuo to give crude material which was purified by silica gel chromatography to provide the desired product. Suzuki Coupling Procedure K: Pd(PPh3)4, K2C03, 1 ,4-dioxane/H20

Reference： [1]Patent: WO2019/244049,2019,A1 .Location in patent: Paragraph 00166; 00258; 00260

41
[ 905273-91-8 ]
3-bromo-2-(difluoromethyl)pyridine [ No CAS ]
tert-butyl 5-(2-(difluoromethyl)pyridin-3-yl)isoindoline-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59.8%	With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 6h;Sealed tube;	General procedure: To a sealed tube containing aryl bromide (1 .0 equiv.) in 7:3 1 ,4-dioxane/H20 (0.23 molar) was added K3P04 (1.5 equiv.), arylboronic acid (1.5 equiv.) and Pd(dppf)CI2*CH2Cl2 (5 mol%). The reaction mixture was heated at 100 C for 6 hours before it was diluted with H20 and extracted with EtOAc (twice). The combined organic layers were washed with H20, then brine, dried over Na2S04, filtered and concentrated under vacuo to give crude material which was purified by silica gel chromatography to provide the desired product.

Reference： [1]Patent: WO2019/244049,2019,A1 .Location in patent: Paragraph 00162; 00182-00183

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[ 1004294-80-7 ]

6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one

Similarity: 0.78

[ 1221239-09-3 ]

2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one

Similarity: 0.76

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Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 905273-91-8 ] {[proInfo.proName]}

Quality Control of [ 905273-91-8 ]

Related Doc. of [ 905273-91-8 ]

Product Details of [ 905273-91-8 ]

Calculated chemistry of [ 905273-91-8 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 905273-91-8 ]

Application In Synthesis of [ 905273-91-8 ]

[ 905273-91-8 ] Synthesis Path-Upstream 1~4

[ 905273-91-8 ] Synthesis Path-Downstream 1~41

Related Functional Groups of [ 905273-91-8 ]

Organoboron

Amides

Related Parent Nucleus of [ 905273-91-8 ]

Indolines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 905273-91-8 ]

Related Parent Nucleus of
[ 905273-91-8 ]