894807-98-8|4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole| Ambeed

Structure of 894807-98-8

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Quality Control of [ 894807-98-8 ] Purity: 95% SDS Specification

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Product Details of [ 894807-98-8 ]

CAS No. :	894807-98-8
Formula :	C₁₅H₂₉BN₂O₃Si
M.W :	324.30
SMILES Code :	C[Si](CCOCN1N=CC(B2OC(C)(C)C(C)(C)O2)=C1)(C)C
MDL No. :	MFCD20486100
Boiling Point :	No data available
InChI Key :	FERKWUXUTFCIFW-UHFFFAOYSA-N
Pubchem ID :	57477666

Safety of [ 894807-98-8 ]

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

Computational Chemistry of [ 894807-98-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	22
Num. arom. heavy atoms	5
Fraction Csp3	0.8
Num. rotatable bonds	6
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	92.95
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	45.51 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	3.3
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.34
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.24
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	0.23
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.42

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.7
Solubility	0.0644 mg/ml ; 0.000199 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.	-3.93
Solubility	0.038 mg/ml ; 0.000117 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-4.21
Solubility	0.0202 mg/ml ; 0.0000622 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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	Yes
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	Yes
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.94 cm/s

Druglikeness

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

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	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<0.0
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)	3.89

Application In Synthesis of [ 894807-98-8 ]

* 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.

Downstream synthetic route of [ 894807-98-8 ]

[ 894807-98-8 ] Synthesis Path-Downstream 1~35

1
[ 76513-69-4 ]
[ 894807-98-8 ]

Yield	Reaction Conditions	Operation in experiment
61%		4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (348 mg, 1.8 mmol) was dissolved in DMF (5 mL) and sodium hydride (60percent dispersion, 86 mg, 2.15 mmol) added. The mixture heated to 60° C. for 5 min. Upon cooling and stirring for an additional 15 min, trimethylsilylethoxymethyl chloride (358 mg, 2.15 mmol, 381 muL) was added dropwise over 5 min and mixture stirred for 16 h. The reaction mixture was diluted with ethyl acetate (25 mL), washed with 5percent lithium chloride (5.x.), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (40 g ISCO column eluting with hexanes and ethyl acetate; gradient 100percent hexanes to 50percent hexanes over 30 min at 30 mL/min) to provide the SEM-protected pyrazole (360 mg, 61percent) as a colorless oil; 1H NMR (500 MHz, CDCl3) delta 7.84 (s, 1H), 7.80 (s, 1H), 5.42 (s, 2H), 3.56-3.53 (t, J=8.3 Hz, 2H), 1.31 (s, 12H), 0.91-0.87 (t, J=8.3 Hz, 2H), -0.03 (s, 9H).

References: [1]Patent: US2006/142307,2006,A1 .Location in patent: Page/Page column 7.

2
[ 894807-97-7 ]
[ 894807-98-8 ]
3-(4-methyl-1,4-diazepan-1-yl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; N,N-dimethyl-formamide; at 100℃; for 18h;	Aryl bromide 5/6 (0.699 mmol), boronic acid (2.10 mmol, 3 eq.) and K2CO3 (3.50 mmol, 5 eq.) were stirred in DMF (7 mL) and water (3 mL) and the resulting mixture was degassed with a nitrogen stream as the temperature was increased to 100° C. After degassing at this temperature for 10 min, Pd(dppf)Cl2 (0.07 mmol, 0.1 equiv) was added and the reaction was stirred at 100° C. under a nitrogen atmosphere for 18 h. Upon cooling the mixture was poured into water (100 mL) and stirred for 10 min. The mixture was extracted with ethyl acetate and the combined organic extracts washed with 5percent lithium chloride (5.x.), dried over sodium sulfate and concentrated to provide the coupled product 7/8. ; Step B: 3-(4-Methyl-1,4-diazepan-1-yl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazin-2-amine The product from Step A was reacted with the product from Step A in example 1 according to general procedure 6 (method 2) and the product purified by column chromatography (12 g ISCO column eluting with methylene chloride and methanol/ammonia mixture (10:1); gradient 100percent methylene chloride to 80percent methylene chloride over 30 min at 25 mL/min) providing the coupled product (137 mg, 81percent) as a brown oil; 1H NMR (500 MHz, CDCl3) delta 7.94 (s, 1H), 7.91 (s, 1H), 7.84 (s, 1H), 5.46 (s, 2H), 4.50-4.49 (m, 2H), 3.62-3.53 (m, 6H), 2.79-2.72 (m, 4H), 2.45 (s, 3H), 2.02-1.99 (m, 2H), 0.95-0.92 (t, J=8.2 Hz, 2H), -0.03 (s, 9H).

References: [1]Patent: US2006/142307,2006,A1 .Location in patent: Page/Page column 6-7.

3
[ 269410-08-4 ]
[ 76513-69-4 ]
[ 894807-98-8 ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 20℃; for 16h;Inert atmosphere;	Synthesis of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2~yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1 t-15a)lnt-15aTo a solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- H- pyrazole (8.2 g, 41 mmol) in NMP (60 mL) was added K2C03 (12 g, 82 mmoi) and 2-(trimethylsilyi)ethoxymethy. chloride (7.8 mL, 43 mmol) in sequence. The reaction mixture was stirred at r.t. under N2 for 16 h. Then, the reaction mixture was diluted and filtered, and then the filtrate was diluted with EtOAc (300 mL). The resulting solution was washed with sat. NaHC03 (aq) (3 x 200 mL), H20 (4 x 200 mL), brine (1 x 200 mL), dried over Na2S04, filtered, concentrated and dried in vacuo to yield intermediate .nt-15a (11.4 g, 86 %) as a clear yellowish oil.
86%		[96] SEM-pyrazolo-4-boronic acid pinacol ester was prepared according the procedure from WO2011/130146, page 84. A solution of pyrazolboronic acid pinacolester (20 g, 103 mmol) in DMF (180 mL) was cooled to 0 C and treated with sodium hydride (60 % dispersion in oil) (6.2 g, 150 mmol) in nitrogen athmosphere. [97] The reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was then cooled to 0 C and (2-(chloromethoxy)ethyl)trimethylsilane (23.65 ml, 134 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. [98] The reaction mixture was poured into aqueous saturated ammonium chloride (200 mL) containing ice (approximately 200 mL) and stirred until the ice melted. The cold mixture was extracted with ethyl acetate twice. The combined organic extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to afford SEM-pyrazolo-4-boronic acid pinacol ester (27.6 g, 86 % yield).
72%	With sodium hydride; In tetrahydrofuran; at 20℃;Inert atmosphere;	Compound 280.1. 4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazole. Into a 250-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-(tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (5.82 g, 30.0 mmol) in tetrahydrofuran (80 mL). This was followed by the addition of NaH (70%) (2.05 g, 85.4 mmol) in portions at 0 C. To this was added SEMC1 (6.4 mL, 36.1 mmol) dropwise. The reaction mixture was stirred overnight at room temperature, then quenched with 50 mL of NH4CI (sat). The aqueous phase was extracted with 2 x 100 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 7 g (72%) of the title compound as colorless oil.

65.94%	With caesium carbonate; In tetrahydrofuran; acetonitrile; at 20℃; for 2h;	13.2 4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl- ethoxymethyl)-1 H-p razole To a solution of 1H-pyrazole-4-boronic acid pinacol ester (0.5 g, 2.57 mmol), in tetrahydrofuran/acetonitrile (3:2, 20ml), 2-(chloromethoxylethyl)trimethyl- silane (0.51 g, 3.09 mmol) and cesium carbonate (1.67 g, 5.15 mmol) are added and stirred for 2 hours at room temperature. The reaction mixture is filtered through celite, and concentrated, the crude mass is taken in ethylacetate (30 ml), washed with water, brine solution, dried over anhydrous MgS04 and concentrated to get the product as brown oil (0.55 g, 65.94 %); TLC: Pet ether/ethyl acetate(8/2) R - 0.5; 1H NMR: 400 MHz, DMSO-d6: delta [ppm] 8.08 (s, 1H), 7.64 (s, 1 H), 5.40 (s, 2H), 3.48-3.54 (m, 2H), 1.24 (s, 12H), 0.81-0.85 (m, 2H), -0.049(s, 9H);
61%		4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (348 mg, 1.8 mmol) was dissolved in DMF (5 mL) and sodium hydride (60% dispersion, 86 mg, 2.15 mmol) added and the mixture heated to 60 C. for 5 min. Upon cooling and stirring for an additional 15 min, trimethylsilylethoxymethyl chloride (358 mg, 2.15 mmol, 381 muL) was added dropwise over 5 min and mixture stirred for 16 h. The reaction mixture was diluted with ethyl acetate (25 mL), washed with 5% lithium chloride (5×), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (40 g ISCO column eluting with hexanes and ethyl acetate; gradient 100% hexanes to 50% hexanes over 30 min at 30 mL/min) to provide the SEM-protected pyrazole (360 mg, 61%) as a colorless oil; 1H NMR (500 MHz, CDCl3) delta 7.84 (s, 1H), 7.80 (s, 1H), 5.42 (s, 2H), 3.56-3.53 (t, J=8.3 Hz, 2H), 1.31 (s, 12H), 0.91-0.87 (t, J=8.3 Hz, 2H), -0.03 (s, 9H).
56%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h;	To a solution of methyl 4-(tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-1H-pyrazole (1 .238 g, 6.316 mmol) in DMF (20 mL) was added potassium carbonate (2.62 g, 18.95 mmol) and [2-(chloromethoxy)ethyl](trimethyl)silane (1 .68 mL, 9.48 mmol) at room temperature. The mixture was stirred for 3 hours and then partitioned between TBME (100 ml.) and water (50 ml_). The organic layer was separated, washed with water (2 x 30 mL) and brine (30 ml_), dried (Na2S04) and concentrated at reduced pressure. The residue was purified by Biotage Isolera chromatography [Biotage SNAP Cartridge KP-Sil 50 g; using a gradient of eluents, 0-50% EtOAc in heptane]. The product containing fractions were combined, concentrated in vacuo to give the title compound (1 .20 g, 56% yield) as colourless oil. 1H NMR (500 MHz, chloroform-d) delta [ppm] 7.88 (s, 1 H), 7.84 (s, 1 H), 5.46 (s, 2H), 3.61- 3.55 (m, 2H), 1 .35 (s, 12H), 0.96 - 0.90 (m, 2H), 0.00 (s, 9H). LCMS (Analytical Method A): Rt = 1 .34 mins; MS (ESIPos) m/z = 324.95 (M+H)
46%		32-(a) 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilylethoxymethyl)-1H-pyrazole; Under argon atmosphere, to 20 ml of tetrahydrofuran solution containing 1.09 g (5.62 mmol) of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole was added 443 mg (11.1 mmol) of 60% sodium hydride under ice-cooling, and the mixture was stirred for 5 minutes. Then, 3 ml (17.0 mmol) of (2-trimethylsilylethoxy)methyl chloride was added dropwise to the mixture, and the mixture was reacted at room temperature for 2 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, and the solutions were washed successively with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 832 mg of the title compound as a colorless oil. (46%) Mass Spectrum (CI, m/z): 325 (M++1). 1H-NMR Spectrum (CDCl3, delta ppm): -0.03 (s, 9H), 0.86-0.94 (m, 2H), 1.32 (s, 12H), 3.51-3.59 (m, 2H), 5.43 (s, 2H), 7.81 (d, J=0.5 Hz, 1H), 7.86 (d, J=0.5 Hz, 1H).
44%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h;	To a stirred solution of 4-(4 , 4,5 , 5-tetra methyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (2 g, 10.3 mmol) in DMF (30 mL), (2-(chloromethoxy)ethyl)trimethylsilane (2 g, 12.3 mmol), and CS2CO3 (10 g, 30.9 mmol) were added. The resulting mixturen was stirred at rt for 3 h. Solvents were evaporated and the crude residue was diluted with ice cold water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SC>4 and filtered. The filtered solution was concentrated under reduced pressure and the resulting crude compound was purified by flash column chromatography using 20-30% EtOAc/Pet ether to get the title compound (1.5 g, 44%) as pale yellow gummy.LC-MS (method 14): R, = 3.08 min; m/z = 325.2 (M+H?).
	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 25℃; for 0.75h;	Preparative Example 1; To a suspension of potassium carbonate (5.85 g, 1.5 equiv) and 4- (4,4,5,5-tetramethyM ,3,2-dioxaborolan-2-yl)-1 h-pyrazole (5.48 g, 1.0 equiv) in NMP (50 mL) at rt was added SEMCI (5.2 mL, 1.05 equiv) dropwise (mildly exothermic). The resulting mixture was allowed to stir an additional 45 min at rt. The reaction was diluted with ethyl acetate, rinsed with water (2x), brine and dried (sodium sulfate). Filtration and concentration afforded the title compound that was used without purification. MH+ = 325.
	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; for 1h;	A mixture of 4,4,5,5-tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (5.48 g), SEMCl (5.2 mL), and K2CO3 (5.85 g) in NMP (50 mL) was stirred under N2 for 1 hr. The reaction mixture was diluted with EtOAc, rinsed with H2O, brine, and dried over Na2SO4. The mixture was filtered, the solvents were evaporated and the residue was used directly in the next step.
	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 20℃; for 0.75h;	To a suspension of potassium carbonate (5.85 g, 1.5 equiv) and 1H-pyrazole-4-boronate (5.48 g, 1.0 equiv) in NMP (50 mL) at room temperature was added SEMCI (5.2 mL, 1.05 equiv) dropwise (mildly exothermic). The resulting mixture was allowed to stir for an additional 45 min at room temperature. The reaction was diluted with ethyl acetate, rinsed with water (×2), brine and dried (sodium sulfate). Filtration and concentration afforded the title compound (270) that used directly in the next step.
	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 20℃; for 0.75h;	Example 270; To a suspension of potassium carbonate (5.85 g, 1.5 equiv) and 1H-pyrazole-4-boronate (5.48 g, 1.0 equiv) in NMP (50 mL) at room temperature was added SEMCl (5.2 mL, 1.05 equiv) dropwise (mildly exothermic). The resulting mixture was allowed to stir for an additional 45 min at room temperature. The reaction was diluted with ethyl acetate, rinsed with water (×2), brine and dried (sodium sulfate). Filtration and concentration afforded the title compound (270) that used directly in the next step.
		Preparation E4-(4A5 -tetramethyl-l ,3,2-dioxaborolan-2-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrazole [00624] A solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole(10.00 g, 51.54 mmol) in DMF (100 mL) was cooled to 0 C in an ice bath and treated with sodium hydride (60% dispersion in oil) (3.092 g, 77.30 mmol) in one portion. The reaction mixture was stirred at 0 C for 2 minutes, then at ambient temperature for 30 minutes. The reaction mixture was cooled to 0 C and (2-(chloromethoxy)ethyl)trimethylsilane (11.82 mL, 67.00 mmol) was added. The reaction mixture was warmed to ambient temperature and allowed to stir overnight. The reaction mixture was poured into aqueous saturated ammonium chloride (100 mL) containing ice (approximately 100 mL) and stirred until the ice melted. After the ice melted, the cold mixture was extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over MgS04, and concentrated under reduced pressure to afford the title compound (14.45 g, 44.56 mmol, 86.46% yield). MS (apci) m/z = 325.0 (M+H).
	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 20℃; for 16h;Inert atmosphere;	To a solution of 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (8.2 g, 41 mmol) in NMP (60 mL) were added K2C03 (12 g, 82 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (7.8 mL, 43 mmol) in sequence. The reaction mixture was stirred at RT under N2 for 16 h. Then, the reaction mixture was diluted filtered and the filtrate was diluted with EtOAc (300 mL), The resulting solution was washed with sat NaHC03(aq) (3 x 200 mL), ¾0 (4 x 200 mL), brine (1 x 200 mL), dried over Na2S0 , filtered, concentrated and dried in vacuo to yield Int-37 as clear yellowish oil
0.9 g		A) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole [1064] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (770 mg) in DMF (10 mL) was added sodium hydride (60%, 114 mg) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr. To the reaction mixture was added dropwise (2-(chloromethoxy)ethyl)(trimethyl)silane (990 mg) at room temperature, and the mixture was stirred for 15 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 5% aqueous lithium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.90 g). MS(ESI+): [M+H]+ 325.2. MS(ESI+), found: 325.2.
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;	To a solution of 4-(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazole (1.00 g, 5.15 mmol) in DMF (20 mL) was added K2C03 (1.07 g, 7.73 mmol) and (2-(chloromethoxy)ethyl)trimethylsilane (1.03 g, 6.18 mmol). The reaction was stirred at ambient temperature for 16 h and then diluted with water (20 mL). The mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-pyrazole (1.00 g, 60% yield) as ayellow oil.A mixture of 2-(3-bromophenyl)- 1,1,1 -trifluorobut-3 -yn-2-ol (500 mg, 1.79 mmol), 4-(4,4,5,5- tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-pyrazole (872 mg, 2.69 mmol), Cs2CO3 (1.17 g, 3.58 mmol) and 1,1?-Bis(diphenylphosphion) ferrocene dichloride palladium(II) (66 mg, 0.09 mmol) in dioxane/H20 (5 mL/1 mL) was heated at 110 Cfor 0.5 h under microwave conditions. The solvent was removed and the crude residue was purified by column chromatography (petroleum ether: EtOAc = 4:1) to give the title compound (300 mg, 42% yield) as a colorless oil.

References: [1]Patent: WO2011/149874,2011,A2 .Location in patent: Page/Page column 81-82.
[2]Patent: WO2016/25918,2016,A1 .Location in patent: Paragraph 96-98.
[3]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 3075 - 3080.
[4]Patent: WO2015/95767,2015,A1 .Location in patent: Page/Page column 325.
[5]Patent: WO2013/131609,2013,A1 .Location in patent: Page/Page column 112.
[6]Patent: US2008/153813,2008,A1 .Location in patent: Page/Page column 7.
[7]Patent: WO2018/114786,2018,A1 .Location in patent: Page/Page column 141-142.
[8]Patent: EP1982986,2008,A1 .Location in patent: Page/Page column 233.
[9]Patent: WO2019/110663,2019,A1 .Location in patent: Page/Page column 58.
[10]Patent: WO2008/57512,2008,A2 .Location in patent: Page/Page column 97.
[11]Patent: US2007/82900,2007,A1 .Location in patent: Page/Page column 153.
[12]Patent: US2007/105864,2007,A1 .Location in patent: Page/Page column 205.
[13]Patent: US2007/117804,2007,A1 .Location in patent: Page/Page column 137-138.
[14]Patent: WO2011/130146,2011,A1 .Location in patent: Page/Page column 83-84.
[15]Patent: WO2012/58174,2012,A1 .Location in patent: Page/Page column 43; 44.
[16]Patent: EP2857400,2015,A1 .Location in patent: Paragraph 315.A.
[17]Patent: WO2016/123391,2016,A1 .Location in patent: Page/Page column 87; 88.

4
[ 894807-98-8 ]
[ 930596-28-4 ]
[ 930596-29-5 ]

Yield	Reaction Conditions	Operation in experiment
58%	With potassium phosphate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; for 5h;Heating / reflux;	A mixture of the product from Preparative Example X-850-C (774 mg, 1.23 mmol), the boronate from Preparative Example X-1650 (520 mg, 1.60 mmol), PdCl2dppf.CH2Cl2 (100 mg, 0.123 mmol), and K3PO4 (1.04 g, 4.92 mmol) in 1,2-dimethoxyethane (18 mL) and H2O (6 mL) was stirred and refluxed under N2 for 5 hr. The solvents were evaporated and the residue was purified by column chromatography on silica gel with 4:1 hexane/EtOAc as eluent. Yellow wax (528 mg, 58percent) was obtained. LC-MS: 744 [M+H].

References: [1]Patent: US2007/82900,2007,A1 .Location in patent: Page/Page column 154.

5
[ 894807-98-8 ]
[ 936360-80-4 ]
[ 936360-81-5 ]

Yield	Reaction Conditions	Operation in experiment
46%	With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 40℃; for 23h;	Part B; A flask was charged with iodide from Part A (1.83 g, 1.00 equiv), boronate from Preparative Example 1 (2.08 g, 1.3 equiv), PdCfe(dppf) (0.4 g, 0.1 equiv) and potassium phosphate monohydrate (3.4 g, 3.0 equiv). After purging the flask with argon, 1 ,4-dioxane (50 ml_) and water (5 ml. ) were added and the resulting mixture was heated at 4O0C overnight (23 h). The reaction was cooled to rt. EtOAc was added to the reaction mixture and filtered through Celite. After concentration the residue was purified by column chromatography (silica gel, 25percent EtOAc/hexane) to give the title compound (46percent).
46%	With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 40℃;	A flask was charged with iodo-compound 273 (1.83 g, 1.00 equiv), Bpin-compound 270 (2.08 g, 1.3 equiv), PdCl2(dppf) (0.4 g, 0.1 equiv) and potassium phosphate monohydrate (3.4 g, 3.0 equiv). After purging the flask with argon, 1,4-dioxane (50 mL) and water (5 mL ) were added and the resulting mixture was heated at 40 0C overnight (23 hr). The reaction was cooled to rt. EtOAc was added to the reaction mixture and filtered through Celite. After concentration the residue was purified by column chromatography (silica gel, 25percent EtOAc/hexane) to give the title compound 274 (46percent).
46%	With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 40℃; for 23h;	Example 274; A flask was charged with iodo-compound 273 (1.83 g, 1.00 equiv), Bpin-compound 270 (2.08 g, 1.3 equiv), PdCl2(dppf) (0.4 g, 0.1 equiv) and potassium phosphate monohydrate (3.4 g, 3.0 equiv). After purging the flask with argon, 1,4-dioxane (50 mL) and water (5 mL) were added and the resulting mixture was heated at 40° C. overnight (23 hr). The reaction was cooled to rt. EtOAc was added to the reaction mixture and filtered through Celite. After concentration the residue was purified by column chromatography (silica gel, 25percent EtOAc/hexane) to give the title compound 274 (46percent).

References: [1]Patent: WO2008/57512,2008,A2 .Location in patent: Page/Page column 98.
[2]Patent: US2007/105864,2007,A1 .Location in patent: Page/Page column 206.
[3]Patent: US2007/117804,2007,A1 .Location in patent: Page/Page column 139.

6
[ 894807-98-8 ]
[ 887475-39-0 ]
[ 936360-79-1 ]

Yield	Reaction Conditions	Operation in experiment
46%	With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 40℃; for 23h;	A flask was charged with compound 103 (1.83 g, 1.00 equiv), Bpin-compound 270 (2.08 g, 1.3 equiv), PdCl2(dppf) (0.4 g, 0.1 equiv) and potassium phosphate monohydrate (3.4 g, 3.0 equiv). After purging the flask with argon, 1,4-dioxane (50 mL) and water (5 mL ) were added and the resulting mixture was heated at 40° C. overnight (23 hr). The reaction was cooled to room temperature. EtOAc was added to the reaction mixture and filtered through Celite. After concentration the residue was purified by column chromatography (silica gel, 25percent EtOAc/hexane) to give the title compound 271 (46percent).
46%	With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 140℃;	Example 271; A flask was charged with compound 103 (1.83 g, 1.00 equiv), Bpin-compound 270 (2.08 g, 1.3 equiv), PdCl2(dppf) (0.4 g, 0.1 equiv) and potassium phosphate monohydrate (3.4 g, 3.0 equiv). After purging the flask with argon, 1,4-dioxane (50 mL) and water (5 mL) were added and the resulting mixture was heated at 40° C. overnight (23 hr). The reaction was cooled to room temperature. EtOAc was added to the reaction mixture and filtered through Celite. After concentration the residue was purified by column chromatography (silica gel, 25percent EtOAc/hexane) to give the title compound 271 (46percent).

References: [1]Patent: US2007/105864,2007,A1 .Location in patent: Page/Page column 205.
[2]Patent: US2007/117804,2007,A1 .Location in patent: Page/Page column 138.

7
[ 141-30-0 ]
[ 894807-98-8 ]
[ 1022151-61-6 ]

Yield	Reaction Conditions	Operation in experiment
66%	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 100℃; for 4h;	Example 9: 6-[6-(l/-r-Pyrazol-4-yl)-[l,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl]- quinoline (compound 39); Step 1 : 3-Chloro-6- [ 1 -(2-trimethy Isilanyl-ethoxymethyl)-li7-py razol-4-yl] -py ridazine; [0365] A mixture of 3,6-dichloropyridazine (505 mg, 3.4 mmol), 4-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-l-(2-trimethylsilanyl-ethoxymethyl)-l//-pyrazole (l g, 3.1 mmol) and K2CO3 (1.3 g, 9.3 mmol) in 10 mL of dioxane and 4 mL of H2O was degassed with nitrogen. To this mixture was added dichloro[ 1 , 1 '-bis(diphenylphosphino)ferrocene] palladium(II) dichloromethane adduct (45 mg, 0.06 mmol) and the resulting mixture was bubbled with nitrogen for another 15 min. The reaction mixture was heated at 1000C for 4h, then after cooling to room temperature the aqueous phase was removed via pipette. The organic phase was concentrated onto silica gel and purified by flash column chromatography eluting with hexanes:ethyl acetate 100:0 to 60:40 returning title compound as a white solid (640 mg, 2.06 mmol, 66% yield): 1H NMR(CDCl3) delta 0.02 (9H, s), 0.96 (2H, t), 3.64 (2H, t), 5.52 (2H, s), 7.52 (IH, d), 7.62 (IH, d), 8.10 (IH, s), 8.34 (IH, s); MS (m/z) 311 [M+H+]+.

References: [1]Patent: WO2008/51808,2008,A2 .Location in patent: Page/Page column 104.

8
[ 894807-98-8 ]
[ 1022150-99-7 ]
[ 1022151-71-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 130℃; for 0.5h;Microwave irradiation;	Example 20: 6-(6-Methyl-[l,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-3-(lH-pyrazol- 4-yl)-quinoline (Compound 59); [0393] A microwave vessel was charged with 3-bromo-6-(6-methyl-[l ,2,4]triazolo[4,3- b]pyridazin-3-ylsulfanyl)-quinoline (970 mg, 2.606 mmol), 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-l-(2-trimethylsilanyl-ethoxymethyl)-l//-pyrazole (930 mg, 2.866 mmol), and dichlorobis(triphenylphosphine) palladium(O) (92 mg, 0.13 mmol). 1,4-Dioxane (10 mL) and a 2 M aqueous solution of sodium carbonate (5 mL) were added. The vessel was capped and micro waved at 13O0C for 30 min. The reaction mixture was partitioned between water and 10percent methanol/dichloromethane. The aqueous layer was extracted with 10percent methanol/dichloromethane, and the combined organics were adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-8percent methanol/dichloromethane afforded 1.073 g of the crude coupling product as a light brown oil. The oil was treated with TFA (10 mL). The reaction mixture was stirred at room temperature for 2 h, before concentrating in vacuo. The residue was treated with 1 N aqueous NaOH, and the precipitate was filtered, washed sequentially with water and ethyl acetate. The resulting yellow solid was dissolved in 10percent methanol/dichloromethane and adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-10percent methanol/dichloromethane afforded 417 mg of impure 6-(6-methyl- [l,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-3-(lH-pyrazol-4-yl)-quinoline. Purification of EPO <DP n="118"/>30 mg of material by mass-triggered HPLC (5 - 95percent CH3CN/H2O, 0.1percent HCOOH modifier) provided 12 mg of pure 6-(6-methyl-[l,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-3-(lH- pyrazol-4-yl)-quinoline.

References: [1]Patent: WO2008/51808,2008,A2 .Location in patent: Page/Page column 116-117.

9
[ 894807-98-8 ]
[ 1238323-79-9 ]
[ 1238324-01-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃;	A mixture of tert-butyl 5-chloro-3-(2-fluorophenyl)-2-oxo-l,6-naphthyridine- l(2H)-carboxylate (30-1, 300 mg), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-[2- (trimethylsilyl)ethoxy]methyl}-lH-pyrazole (286 mg), Pd(PPh3)4 (92 mg) and 3M Na2CO3 (0.800 mL) in 1,4-dioxane (8 mL) was stirred at 1000C overnight. The reaction mixture was diluted with EtOAc, washed with water, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography to give 3-(2-fluorophenyl)-5-(l-[2- (trimethylsilyl)ethoxy]methyl}-lH-pyrazol-4-yl)-l,6-naphthyridin-2(lH)-one (30-2) as a colorless solid.

References: [1]Patent: WO2010/88177,2010,A1 .Location in patent: Page/Page column 133-134.

10
[ 894807-98-8 ]
C₇H₆IN₃S [ No CAS ]
C₁₀H₉N₅S [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5870 - 5875.

11
[ 894807-98-8 ]
C₉H₁₀IN₃S [ No CAS ]
C₁₂H₁₃N₅S [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5870 - 5875.

12
[ 894807-98-8 ]
C₁₀H₁₀IN₃S [ No CAS ]
C₁₃H₁₃N₅S [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5870 - 5875.

13
[ 894807-98-8 ]
C₁₀H₁₂IN₃S [ No CAS ]
C₁₃H₁₅N₅S [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5870 - 5875.

14
[ 894807-98-8 ]
[ 1094070-47-9 ]
C₁₁H₁₁N₅S [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5870 - 5875.

15
[ 10132-07-7 ]
[ 894807-98-8 ]
[ 1339891-08-5 ]

Yield	Reaction Conditions	Operation in experiment
25.2%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 50℃;Inert atmosphere; sealed;	Preparation of 6-chloro-2-( 1 -((2-(trimethylsilyl ethoxy)methyl - 1 H- pyrazol-4-yl pyrimidin-4-amine: A flask was charged with 2,6-dichloropyrimidin-4-amine (10.0 g, 61.0 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazole (Preparation E; 29.7 g, 91.5 mmol), and K2CO3 (25.3 g, 183 mmol) in dioxane (40 mL) before 300 mL of dioxane and 11 mL of water were added to the reaction mixture. The reaction mixture was then purged with argon for 30 minutes before tetrakis(triphenylphosphine)palladium (0) (3.52 g, 3.05 mmol) was added in one portion to the reaction which was then purged with argon for another 30 minutes. The reaction mixture was then sealed and heated at 50 °C overnight. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate (300 mL) and aqueous saturated sodium bicarbonate (300 mL). The aqueous layer was then extracted with ethyl acetate twice more and separated. The organic layers were combined, dried over MgSO t, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with 20-100percent ethyl acetate in hexanes to afford 6- chloro-2-( 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-pyrazol-4-yl)pyrimidin-4-amine (5.00 g, 15.3 mmol, 25.2percent yield). MS (apci) m/z = 326.1 (M+H). Structure and regioisomer confirmed by observed nOe.

References: [1]Patent: WO2011/130146,2011,A1 .Location in patent: Page/Page column 85-86.

16
[ 10132-07-7 ]
[ 894807-98-8 ]
[ 1339891-08-5 ]
[ 1339891-21-2 ]

Yield	Reaction Conditions	Operation in experiment
50.3%; 37.2%	With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 50℃; for 15h;Inert atmosphere;	(Method 2)[00634] Preparation of 6-chloro-2-( 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H- pyrazol-4-yl)pyrimidin-4-amine and 2-chloro-6-( 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H- pyrazol-4-yl)pyrimidin-4-amine : 2,6-Dichloropyrimidin-4-amine (4.00 g, 24.4 mmol), 4- (4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-l -((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrazole (Preparation E; 14.0 g, 36.6 mmol) and K3PO4 (15.5 g, 73.2 mmol) were suspended in dioxane (120 mL, 24.4 mmol) and H20 (4.39 mL, 244 mmol). After degassing under nitrogen, Pd(PPh3)4 (1.41 g, 1.22 mmol) was added and the reaction sealed and stirred at 50 °C for 15 hours. After cooling, the reaction mixture was partitioned between saturated aqueous NaHCC>3 and EtOAc. The organics were washed with water, brine , dried with MgSC>4, filtered and concentrated under reduced pressure to afford the crude material as a thick yellow orange oil. The crude mixture was purified by silica chromatography using a 20- 100percent EtOAc/Hexanes gradient to afford 6-chloro-2-(l-((2-(trimethylsilyl)ethoxy)methyl)- lH-pyrazol-4-yl)pyrimidin-4-amine (4.00 g, 50.3percent) and 2-chloro-6-(l -((2- (trimethylsilyl)ethoxy)methyl)- lH-pyrazol-4-yl)pyrimidin-4-amine (2.96 g, 37.2percent yield). MS (apci) m/z = 326.1 (M+H). The structure and regioisomer of products were confirmed by observed nOe.
50.3%; 37.2%	With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 50℃; for 15h;Inert atmosphere;	Preparation of 6-chloro-2-( 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H- pyrazol-4-yl)pyrimidin-4-amine and 2-chloro-6-( 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H- pyrazol-4-yl)pyrimidin-4-amine : 2,6-Dichloropyrimidin-4-amine (4.00 g, 24.4 mmol), 4- (4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H- pyrazole (14.0 g, 36.6 mmol) and K3PO4 (15.5 g, 73.2 mmol) were suspended in dioxane (120 mL, 24.4 mmol) and H20 (4.39 mL, 244 mmol). After degassing under nitrogen, Pd(PPh3)4 (1.41 g, 1.22 mmol) was added and the reaction sealed and stirred at 50 °C for 15 hours. After cooling, the reaction mixture was partitioned between saturated aqueous NaHC03 and EtOAc. The combined organic layers were washed with water and brine, dried with MgS04, filtered and concentrated under reduced pressure to afford the crude material as a thick yellow orange oil. The crude mixture was purified by silica chromatography, eluting with a 20-100percent EtOAc/Hexanes gradient to afford 6-chloro-2-(l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-yl)pyrimidin-4-amine (4.00 g, 50.3percent) and 2- chloro-6-( 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-pyrazol-4-yl)pyrimidin-4-amine (2.96 g, 37.2percent) yield). MS (apci) m/z = 326.1 (M+H). The structure and regioisomer of products were confirmed by observed nOe.

References: [1]Patent: WO2011/130146,2011,A1 .Location in patent: Page/Page column 89.
[2]Patent: WO2013/55645,2013,A1 .Location in patent: Paragraph 00364.

17
[ 894807-98-8 ]
[ 1339891-25-6 ]

References: [1]Patent: WO2011/130146,2011,A1 .
[2]Patent: WO2011/130146,2011,A1 .
[3]Patent: WO2013/55645,2013,A1 .

18
[ 894807-98-8 ]
[ 1339891-68-7 ]