1047644-76-7|1,4-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole| Ambeed

Structure of 1047644-76-7

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Quality Control of [ 1047644-76-7 ] Purity: 95% SDS Specification

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Product Details of [ 1047644-76-7 ]

CAS No. :	1047644-76-7
Formula :	C₁₁H₁₉BN₂O₂
M.W :	222.09
SMILES Code :	CC1(C)C(C)(C)OB(C2=C(C)C=NN2C)O1
MDL No. :	MFCD12400853
InChI Key :	NOZSCXDKBYFTBH-UHFFFAOYSA-N
Pubchem ID :	57826676

Safety of [ 1047644-76-7 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 1047644-76-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	16
Num. arom. heavy atoms	5
Fraction Csp3	0.73
Num. rotatable bonds	1
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	64.93
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	36.28 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.0
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.62
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.03
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.59
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	0.76
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.8

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.4
Solubility	0.878 mg/ml ; 0.00396 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.99
Solubility	2.25 mg/ml ; 0.0101 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-2.79
Solubility	0.359 mg/ml ; 0.00162 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	Yes
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.5 cm/s

Druglikeness

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

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	1.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	3.17

Application In Synthesis of [ 1047644-76-7 ]

* 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 [ 1047644-76-7 ]

[ 1047644-76-7 ] Synthesis Path-Downstream 1~35

1
[ 1072-68-0 ]
[ 61676-62-8 ]
[ 1047644-76-7 ]

Yield	Reaction Conditions	Operation in experiment
		To a suspension of NaH (60% in mineral oil, 3.5 g, 146 mmol, washed with 200 mL of hexane) in THF (200 mL) was added 4-methyl-1 H-pyrazole (10 g, 122 mmol) at 0 0C dropwise. After stirring at RT for 1 h, to above suspension was added MeI (7.3 mL, 117 mmol) dropwise at 0 0C. The reaction mixture was stirred overnight. The NaI by-product was removed by filtration and the filtrate solution was used directly in the next step.At 00C, to above THF solution of 1 ,4-dimethyl pyrazole was added n-BuLi (2.5M in hexane, 58.5 mL, 146 mmole). The reaction solution was stirred for 2 hour at RT and then cooled to -78C [J. Heterocyclic Chem. 41 , 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (27.2 g, 146 mmole). After 15 min at -78C, the reaction was allowed to warm to 00C and stir for 3h. The reaction was diluted with saturated NH4CI solution and extracted with DCM. The organics were dried over Na2SO4 and concentrated under vacuum to afford the title compound as a brown solid (21 g, 78%) which was used directly without further purification: LC-MS: 141 (M-C6H12)"1", 223 (M+H)+. 1H NMR (CDCI3): delta 7.28 (s, 1 H), 4.03 (s, 3H), 2.22 (s, 3H), and 1.32 (s, 12H).
142 mg		1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole A solution of 1,4-dimethyl-1H-pyrazole (480.0 mg, 4.993 mol) in tetrahydrofuran (20 mL, 300 mmol) at 0 C. was added 1.6 M n-butyllithium in hexane (4.7 mL, 7.5 mmol). The solution was stirred at room temperature for 1 h and then cooled to -78 C. To the solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.63 mL, 7.99 mmol). The reaction mixture was stirred at -78 C. for 0.5 h, then warmed up to 0 C. (taking 0.5 h). The reaction was quenched with brine and extracted with EtOAc (3*). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by combi-flash chromatography and eluted with EtOAc/hexane (0-60%). The purification gave 142 mg of product as white solid.
		Step 1. 1, 4-Dimethyl-5-( 4, 4, 5, 5-tetrame orolan-2-yl)-lH-pyrazole l,4-Dimethyl-7H-pyrazole (50 mg, 0.5 mmol) was stirred in THF (2 mL) and cooled to 0 C. A solution of 1.6 M w-butyllithium in hexanes (390 mL) was added dropwise by syringe and the mixture was allowed to warm to room temperature for 2 h. The mixture was cooled to -78 C and 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane(110 mL, 0.52 mmol) was added dropwise by syringe. The mixture was stirred at -78 C for 15 min. and at 0 C for 3 h. The mixture was diluted with EtOAc and washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography on silica gel using EtOAc in hexanes gave the sub-title compound. LCMS calc. for CnH2oB 202 (M+H)+: m/z = 223.2; found: 223.0.

With n-butyllithium;

Step 1 To a solution of 1,4-dimethyl-1H-pyrazole (2.5 g, 26.0 mmol, 1 equiv) in tetrahydrofuran (50 mL) was added n-butyllithium in hexane solution (2.5 M in hexane, 78.0 mmol, 31 mL, 3 equiv) dropwise at 0 C. under nitrogen atmosphere. The resulting solution was stirred at room temperature for 1 h and then cooled to -78 C. 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (14.52 g, 78.017 mmol, 3 equiv) was added and the reaction mixture was stirred at -78 C. for 0.5 hour, then slowly warmed up to 0 C. The reaction was quenched with brine and extracted with EtOAc (250 mL*3). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (1:5). This resulted in 2.6 g (45%) of 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a white solid.

References: [1]Patent: WO2008/98104,2008,A1 .Location in patent: Page/Page column 90.
[2]Patent: US2013/96144,2013,A1 .Location in patent: Paragraph 0171; 0172.
[3]Patent: WO2014/143768,2014,A1 .Location in patent: Page/Page column 109; 110.
[4]Patent: US2019/300521,2019,A1 .

2
[ 1047644-76-7 ]
[ 1047645-01-1 ]
[ 1047645-51-1 ]

Yield	Reaction Conditions	Operation in experiment
73.4%	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; at 75℃; for 8h;	To a solution of 4-bromo-5-chloro-lambda/-((1 S)-2-(1 ,3-dioxo-1 ,3-dihydro-2/-/- isoindol-2-yl)-1-[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (260 mg, 0.46 mmol) in THF (5 ml.) was added Na2CO3 (2N, 0.7 ml_, 1.4 mmol), Pd(dppf)CI2 (40 mg, 48 mumol) and 1 ,4-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (303 mg, 1.38 mmol). The reaction mixture was heated to 75 0C in a sealed tube under N2. After 8h, the reaction mixture was concentrated under vacuum and purified on silica (10:1 CHCI3/MeOH) to afford the title compound (196 mg, 73.4percent): LC-MS (ES) m/z = 587 (M+H)+.

References: [1]Patent: WO2008/98104,2008,A1 .Location in patent: Page/Page column 180-181.

3
[ 1047644-76-7 ]
[ 1047645-41-9 ]
[ 1047645-42-0 ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80℃; for 2h;	To a solution of 4-bromo-lambda/-((1 S)-2-(1 ,3-dioxo-1 ,3-dihydro-2H-isoindol-2-yl)- 1-[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (200 mg, 0.37 mmol) in dioxane/H2O (5:1 , 6 ml.) was added K2CO3 (0.17g, 1.23 mmol), tetrakistriphenylphosphine Pd(O) (42 mg, 0.036mmol) and 1 ,4-dimethyl-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (413 mg, 1.86 mmol) [from Preparation 17] . The reaction mixture was heated to 80° C in a sealed tube for 2h. The reaction solution was concentrated under vacuum, and purified on silica gel (10-50percent EtOAc/Hex) to give the title compound (192 mg, 94percent) as a white solid: LC-MS (ES) m/z 553 (M+H)+.

References: [1]Patent: WO2008/98104,2008,A1 .Location in patent: Page/Page column 175.

4
[ 1047644-76-7 ]
[ 1609259-43-9 ]
[ 1609259-44-0 ]

Yield	Reaction Conditions	Operation in experiment
48%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 20 - 120℃; for 1h;	Step 2. Synthesis of 4-[4-(1,4-dimethyl-1H-pyrazol-5-yl)-3-methylphenoxy]-1-[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-c]pyridine (C16) To a mixture of C15 (100 mg, 0.231 mmol), 1,4-dioxane (2 mL) and water (0.5 mL) was added <strong>[1047644-76-7]1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (56 mg, 0.25 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (25.6 mg, 0.0350 mmol) and potassium carbonate (97 mg, 0.70 mmol) at room temperature. The reaction mixture was stirred at 120° C. for 1 hour; after cooling to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. Purification via preparative thin layer chromatography on silica gel (Eluent: 1:1 petroleum ether/ethyl acetate) provided the product as a red oil. Yield: 51 mg, 0.11 mmol, 48percent. 1H NMR (400 MHz, CD3OD) delta 7.80 (d, J=6.0 Hz, 1H), 7.43 (d, J=3.3 Hz, 1H), 7.37-7.40 (m, 2H), 7.21 (d, J=8.3 Hz, 1H), 7.16 (br d, J=2.0 Hz, 1H), 7.08 (br dd, J=8.3, 2.5 Hz, 1H), 6.61 (d, J=3.3 Hz, 1H), 5.60 (s, 2H), 3.61 (s, 3H), 3.51-3.57 (m, 2H), 2.09 (s, 3H), 1.91 (s, 3H), 0.85-0.91 (m, 2H), -0.06 (s, 9H).

References: [1]Patent: US2014/128374,2014,A1 .Location in patent: Paragraph 0345; 0347.

5
[ 1047644-76-7 ]
[ 1616290-48-2 ]
[ 1616286-89-5 ]

Yield	Reaction Conditions	Operation in experiment
19%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; at 100℃; for 2h;Inert atmosphere; Microwave irradiation;	A suspension of 7-bromo-4-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-6-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (126d, 36 mg), <strong>[1047644-76-7]1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (34 mg, 0.092 mmol), and sodium carbonate (2M aq, 32 mg, 0.30 mmol) in 1,4-dioxane (3 mL) was degassed with N2 for 10 minutes. The reaction mixture was treated with PdCl2(DPPF)-DCM (8.2 mg, 0.010 mmol) and heated at 100° C. in the microwave for 1 hour, then at 120° C. in the microwave for an additional 1 hour. The reaction mixture was poured into DCM (25 mL) and washed with water (3*25 mL). The organic layer was concentrated under vacuum and the residue was purified by preparative HPLC to give the title compound (Example 126, 7 mg, 19percent yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) delta 7.33 (s, 1H), 7.23 (d, J=8.07 Hz, 1H), 6.99 (d, J=8.19 Hz, 1H), 5.93 (s, 1H), 4.66 (s, 2H), 4.09 (t, J=5.44 Hz, 2H), 3.48 (s, 3H), 3.42-3.46 (m, 2H), 2.23 (s, 3H), 2.14 (s, 3H), 2.03 (s, 3H), 1.79 (s, 3H); MS 407.1 [M+1].

References: [1]Patent: US2014/179667,2014,A1 .Location in patent: Paragraph 0956; 0961.

6
[ 1047644-76-7 ]
7-bromo-4-(pyridin-2-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one [ No CAS ]
7-(1,4-dimethyl-1H-pyrazol-5-yl)-4-(pyridin-2-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); In 1,4-dioxane; water; at 90℃; for 2h;Inert atmosphere;	Step 2. 7-(l, 4-dimethyl-lH-pyrazol-5-yl)-4-pyridin-2-yl-4, 5-dihydroimidazo[ 1, 5, 4- dejf 1 ,4] benzoxazin-2( lH)-one 7-Bromo-4-pyridin-2-y 1-4,5 -dihydroimidazo [ 1 ,5 ,4-de] [ 1 ,4]benzoxazin-2( 1 H)-one (28 mg, 0.084 mmol) was dissolved in 1, 4-dioxane (0.67 mL). l,4-Dimethyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (28 mg, 0.13 mmol) and potassium phosphate (40 mg, 0.2 mmol) in water (0.17 mL) was added. The reaction mixture was deoxygenated with nitrogen. Dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine-(2'- aminobiphenyl-2-yl)(chloro)palladium (1 : 1) (2 mg, 0.002 mmol) was added and the mixture was again deoxygenated with nitrogen. The reaction mixture was then stirred at 90 °C under nitrogen for 2 h. Product was purified using preparative LCMS (pH 10) to give the title compound. LCMS calc. for CigHn jOz (M+H)+: m/z = 348.1 ; found: 348.0.

References: [1]Patent: WO2014/143768,2014,A1 .Location in patent: Page/Page column 110.

7
[ 1047644-76-7 ]
4-(2-cyclopropyl-7-iodo-1-methyl-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole [ No CAS ]
4-(2-cyclopropyl-7-(1,4-dimethyl-1H-pyrazol-5-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride; caesium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 1h;Microwave irradiation;	To a microwave vial containing 4-(2-cyclopropyl-7-iodo-1-methyl-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole (22 mg, 0.056 mmol, 1 equiv.) was added <strong>[1047644-76-7]1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (31 mg, 0.14 mmol, 2.5 equiv.), Cs2CO3 (72 mg, 0.22 mmol, 4 equiv.) and PEPPSI?-IPr catalyst (4 mg, 0.006 mmol, 0.1 equiv.) and dissolved in DME-H2O (4 mL, 0.2 M, 2/1, v/v). The mixture was heated to 120° C. After 1 hr, the reaction was complete. The reaction was concentrated in vacuo and purification was then carried out by reverse phase HPLC to furnish 4-(2-cyclopropyl-7-(1,4-dimethyl-1H-pyrazol-5-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole. LCMS (m/z+1) 362.24. 1H NMR (400 MHz, cd3od) delta 7.57 (d, J=1.6 Hz, 1H), 7.46 (s, 1H), 7.02 (d, J=1.6 Hz, 1H), 3.70-3.58 (m, 3H), 3.40 (s, 3H), 2.42 (s, 3H), 2.26 (s, 3H), 2.24-2.12 (m, 1H), 1.93 (s, 3H), 1.20-1.04 (m, 4H)

References: [1]Patent: US2014/336190,2014,A1 .Location in patent: Paragraph 0525; 0526; 0527.

8
[ 1047644-76-7 ]
3,5-dimethyl-4-(4-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-6-yl)isoxazole [ No CAS ]
4-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride; caesium carbonate; In 1,4-dioxane; water; at 130℃; for 0.5h;Inert atmosphere; Microwave irradiation;	4-(4-Iodo-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole (0.1 g, 0.3 mmol) was reacted with (6-methylquinolin-5-yl)boronic acid (0.275 g, 1.47 mmol), PEPPSI-IPr catalyst (0.02 g, 0.03 mmol) and Cs2CO3 (0.3 g, 0.9 mmol) in dioxane/water (4/2 ml, degassed with Argon) at 130° C. for 30 min in a microwave reactor. The aqueous layer was discarded, volatiles were removed and the residue was purified via preparatory HPLC (5-100percent, H2O-MeCN, 0.1percent HCl) to afford 3,5-dimethyl-4-(4-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-6-yl)isoxazole. C22H18N4O. 355.1 (M+1). 1H NMR (400 MHz, dmso) delta 9.41 (s, 1H), 9.07 (d, J=3.7 Hz, 1H), 8.32 (d, J=8.8 Hz, 1H), 8.04 (d, J=8.8 Hz, 1H), 7.96 (d, J=1.4 Hz, 1H), 7.65 (dd, J=8.5, 4.8 Hz, 1H), 7.50 (d, J=1.2 Hz, 1H), 2.46 (s, 3H), 2.28 (d, J=3.0 Hz, 6H). Compound (1020-85) was synthesized in a similar manner as that of Example 83, Step 2, using (1,4-dimethyl-1H-pyrazol-5-yl)boronic acid, pinacol ester. C17H17N5O. 308.1 (M+1) 1H NMR (400 MHz, dmso) delta 9.09 (s, 1H), 9.09 (s, 1H), 7.83 (s, 1H), 7.83 (s, 1H), 7.45 (s, 1H), 7.45 (s, 1H), 7.40 (s, 1H), 7.40 (s, 1H), 3.70 (s, 3H), 2.47 (s, 3H), 2.29 (s, 3H), 1.95 (s, 3H)

References: [1]Patent: US2014/336190,2014,A1 .Location in patent: Paragraph 0558; 0559; 0563; 0564; 0565.

9
[ 1047644-76-7 ]
(S)-3-bromo-7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indole [ No CAS ]
5-{7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In water; dimethyl sulfoxide; at 150℃; for 0.25h;Inert atmosphere; Sonication; Microwave irradiation;	Step 4: 5- {7-Methanesulfonyl-5- [(S)-oxan-4-yl(phenyl)methylj -5H-pyrido [3,2- bj indol-3-yl}-1 ,4-dimethyl- 1H-pyrazole(S)-3 -Bromo-7-(methylsulfonyl)-5 -(phenyl(tetrahydro-2H-pyran-4-yl)methyl)- 5H-pyrido[3 ,2-b]indole (80.0 mg, 0.0800 mmol) and 1 ,4-dimethyl-5-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (35.6 mg, 0.160 mmol) were dissolved in 2 mL of DMSO. To this was added sodium carbonate (25.5 mg, 0.240 mmol) and 0.1 mL of water. Argon was bubbled through this mixture for 5 mm before adding PdC12(dppf)- CH2C12 adduct (6.54 mg, 8.01 jimol), and then bubbled in argon while sonicating for 30 seconds. The vial was capped and heated in the microwave at 150 °C for 15 mm. Thecrude material was purified via preparative LC/MS (Preparative HPLC Method 1):Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.1 mg (33percent), and its estimated purity by LCMS analysis was 98percent. Two analytical LC/MS injections were used to determine the final purity. Injection 1 conditions LC/MS Method 3; HPLC RT = 1.67 mm. Injection 2conditions: LC/MS Method 4; HPLC RT = 2.51 mm. ?H NMR (500MHz, DMSO-d6) oe8.74 (br. s., 1H), 8.60 (s, 1H), 8.48 (d, J=8.4 Hz, 2H), 7.96 (s, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.69 (d, J=7.7 Hz, 3H), 7.46 (s, 1H), 7.38-7.30 (m, 3H), 7.30-7.21 (m, 1H), 6.03 (d, J=11.0 Hz, 1H), 3.95-3.86 (m, 2H), 3.73 (d,J=8.4 Hz, 1H), 3.57-3.43 (m, 2H), 3.37 (br. s., 1H), 3.27 (t,J=12.1 Hz, 1H), 2.90 (s, 3H), 2.74 (s, 3H), 2.03 (s, 3H), 1.81-1.69 (m,1H), 1.68-1.54 (m, 1H), 1.45-1.28 (m, 1H).
33%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In dimethyl sulfoxide; at 150℃; for 0.25h;Inert atmosphere; Sealed tube;	(S)-3-Bromo-7-(methylsulfonyl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole (80.0 mg, 0.0800 mmol) and <strong>[1047644-76-7]1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (35.6 mg, 0.160 mmol) were dissolved in 2 mL of DMSO. To this was added sodium carbonate (25.5 mg, 0.240 mmol) and 0.1 mL of water. Argon was bubbled through this mixture for 5 min before adding PdCl2(dppf)-CH2Cl2 adduct (6.54 mg, 8.01 mumol), and then bubbled in argon while sonicating for 30 seconds. The vial was capped and heated in the microwave at 150° C. for 15 min. The crude material was purified via preparative LC/MS (Preparative HPLC Method 1): Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.1 mg (33percent), and its estimated purity by LCMS analysis was 98percent. Two analytical LC/MS injections were used to determine the final purity. Injection 1 conditions LC/MS Method 3; HPLC RT=1.67 min. Injection 2 conditions: LC/MS Method 4; HPLC RT=2.51 min. 1H NMR (500 MHz, DMSO-d6) delta 8.74 (br. s., 1H), 8.60 (s, 1H), 8.48 (d, J=8.4 Hz, 2H), 7.96 (s, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.69 (d, J=7.7 Hz, 3H), 7.46 (s, 1H), 7.38-7.30 (m, 3H), 7.30-7.21 (m, 1H), 6.03 (d, J=11.0 Hz, 1H), 3.95-3.86 (m, 2H), 3.73 (d, J=8.4 Hz, 1H), 3.57-3.43 (m, 2H), 3.37 (br. s., 1H), 3.27 (t, J=12.1 Hz, 1H), 2.90 (s, 3H), 2.74 (s, 3H), 2.03 (s, 3H), 1.81-1.69 (m, 1H), 1.68-1.54 (m, 1H), 1.45-1.28 (m, 1H).

References: [1]Patent: WO2015/100282,2015,A1 .Location in patent: Page/Page column 427; 429.
[2]Patent: US2016/176864,2016,A1 .Location in patent: Paragraph 1092.

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[ 1047644-76-7 ]
ethyl 2-bromo-6-methoxybenzoate [ No CAS ]
ethyl 2-(1,4-dimethyl-1H-pyrazol-5-yl)-6-methoxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 1h;Microwave irradiation; Inert atmosphere;	10314] In a microwave vial was dissolved ethyl 2-bromo-6-methoxybenzoate (500 g, 1.54 mmol) and 1,4-dimethyl-5- (4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (377 g, 1.70 mmol) in DME (10 mE) and water (2 mE). Na2CO3 (259 g, 3.09 mmol) was then added followed by Pd(PPh3)4 (89 mg, 0.077 mmol) and the reaction mixture was degassed with N2 for 10 minutes. The reaction mixture was then heated at 1000 C. for h in the microwave. The mixture was cooled to room temperature, filtered through Celite and washed with EtOAc and DCM. The crude solution was concentrated in vacuo and directly purified via silica gel chromatography (10-80percent EtOAc in hexanes) to afford the title compound (402 g, 95percent). MS (ESI) mass calcd. for C,5H,8N203, 274.1; mlz found 275.2 [M+H]. 1H NMR (400 MHz, Chloroform-d) 7.45 (dd, J=8.4, 7.6 Hz, 1H), 7.29 (s, 1H), 7.04 (dd, J=8.5, 0.9 Hz, 1H), 6.84 (dd, J=7.6, 0.9 Hz, 1H), 4.07 (qd, J=7.2, 1.5 Hz, 2H), 3.90 (s, 3H), 3.61 (s, 3H), 1.86 (s, 3H), 1.01 (t, J=7.1 Hz, 3H).

References: [1]Patent: US2016/46640,2016,A1 .Location in patent: Paragraph 0314.

11
[ 1047644-76-7 ]
methyl 2-(2-(3-((R)-3-(tert-butoxycarbonyl(methyl)amino)-2-(tert-butyldimethylsilyloxy)propoxy)phenyl)-6-chloro-5-methylpyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate [ No CAS ]
methyl 2-(2-(3-((R)-3-(tert-butoxycarbonyl(methyl)amino)-2-(tert-butyldimethylsilyloxy)propoxy)phenyl)-6-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methylpyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 90℃; for 3h;Inert atmosphere;	To a solution of methyl 2-(2-(3- ((R)-3-(tert-butoxycarbonyl(methyl)amino)-2-(tert- butyldimethylsilyloxy)propoxy)phenyl)- 6-chloro-5-methylpyrimidin-4-yl)-2,7-diaza- spiro[3.5] nonane-7-carboxylate (160 mg, 0.23 mmol) in degassed dioxane:H20 (5: 1, 6 mL) was added l,4-dimethyl-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazole (78 mg, 0.35 mmol), Pd(dppf)Cl2 (16 mg, 0.02mmol) and Na2C03 (73 mg, 0.69 mmol) at room temperature. The system was purged with N2 and the mixture was stirred at 90°C for 3h. After being cooled down to room temperature the mixture was filtered through a pad of celite. The filtrate was concentrated and the resulting residue was purified by preparative-TLC on silicagel eluting with petroleum ether/EtOAc = 2/1 to give methyl 2-(2-(3- ((R)-3-(tert-butoxycarbonyl (methyl)amino)-2-(tert- butyldimethylsilyloxy)propoxy) phenyl)-6-(l,4-dimethyl-lH-pyrazol-5-yl)-5- methylpyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (130 mg, 74percent yield) as a white solid. ESI-LCMS (m/z): 764.1 found for [M+l]+.

References: [1]Patent: WO2016/44604,2016,A1 .Location in patent: Paragraph 00424.

12
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(2R)-1-(4-chloro-3-(4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-6-(6-(2,2,2-trifluoroethyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-2-yl)phenoxy)-3-(methylamino)propan-2-ol [ No CAS ]