847818-71-7|1-(2-Methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole| Ambeed

Structure of 847818-71-7

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Quality Control of [ 847818-71-7 ] Purity: 97% SDS Specification

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Product Details of [ 847818-71-7 ]

CAS No. :	847818-71-7
Formula :	C₁₂H₂₁BN₂O₃
M.W :	252.12
SMILES Code :	COCC[N]1C=C(C=N1)B2OC(C(O2)(C)C)(C)C
MDL No. :	MFCD12405649
InChI Key :	NZMICYAXDXTDJV-UHFFFAOYSA-N
Pubchem ID :	11230491

Safety of [ 847818-71-7 ]

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

Computational Chemistry of [ 847818-71-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	18
Num. arom. heavy atoms	5
Fraction Csp3	0.75
Num. rotatable bonds	4
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	70.66
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	1.01
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.83
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.	0.04
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	0.54
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.48

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.98
Solubility	2.63 mg/ml ; 0.0104 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.55
Solubility	7.02 mg/ml ; 0.0279 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	-2.95
Solubility	0.282 mg/ml ; 0.00112 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.	-7.12 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)	3.2

Application In Synthesis of [ 847818-71-7 ]

* 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 [ 847818-71-7 ]

[ 847818-71-7 ] Synthesis Path-Downstream 1~35

1
[ 76-09-5 ]
1-(2-methoxyethyl)-1H-pyrazol-4-ylboronic acid [ No CAS ]
[ 847818-71-7 ]

References: [1]Journal of Heterocyclic Chemistry,2004,vol. 41,p. 931 - 939.

Yield	Reaction Conditions	Operation in experiment
55.54%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In dimethyl sulfoxide; at 105℃; for 17h;Inert atmosphere;	General procedure: Under nitrogen, DMSO (12 mL) was added to a solution of 4-iodo-N- (2- (methylsulfonyl) ethyl) amine (78 mg,0.24 mmol),Pinacol ester (75mg, 0.30mmol) with boronic acid,Potassium acetate (75 mg, 0.76 mmol)Pd (dppf) Cl2 (9 mg, 0.01 mmol)105 ° C for 17 h, the reaction solution was cooled to room temperature, extracted with ethyl acetate (50 mL x 3)The organic phase was concentrated and chromatographed (petroleum ether / ethyl acetate (v / v) = 1/2) to give 58 mg of a colorless oil, yield:74.4percent.
	With caesium carbonate; In acetonitrile; at 80℃; for 6h;	General procedure: Reference example 14 1-(2-[tert-Butyl(diphenyl)silyl]oxy}ethyl)-4-(4,4,5,5-te tramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [0123] 8.7 g of (2-bromoethoxy)(tert-butyl)diphenylsilane and 12 g of cesium carbonate were added to 3.3 g of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazo le in 33 mL of acetonitrile, and the mixture was stirred at 80°C for 6 hours. The reaction solution was diluted with ethyl acetate, and the obtained organic layer was washed with water and brine sequentially, and was dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 5.96 g of the objective compound as a pale yellow oil.
		General procedure: To 1-methyl-4-iodopyrazole (1.0 g) and 10 mL of THF,Under the protection of nitrogen, slowly add isopropylmagnesium chloride/lithium chloride solution (3.97mL), the temperature during the dropwise addition does not exceed 0 °C,After the addition, stir for 1 h, then at 0 ° C,Slowly add isopropyl pinacol borate (1.11g) to control the temperature not to exceed 0 ° C, and then stir at room temperature for 1.5 h after the addition.After the reaction was completed, 10 mL of a saturated ammonium chloride solution was added dropwise.Quenched.Then add 50 mL of ethyl acetate and 10 mL of saturated ammonium chloride solution.The organic layer was separated, and the aqueous layer was extracted twice with 50 mL of ethyl acetate. The organic layer was combined and dried over anhydrous Na2SO?Dry under reduced pressure,The title product (1 g) was obtained.

3
[ 847818-49-9 ]
[ 847818-71-7 ]

References: [1]Journal of Heterocyclic Chemistry,2004,vol. 41,p. 931 - 939.

4
[ 73183-34-3 ]
[ 847818-49-9 ]
[ 847818-71-7 ]

Yield	Reaction Conditions	Operation in experiment
45%		To the solution of 23b (0.61g, 2.97mmol) and bis(pinacolato)diboron (0.91g, 3.57mmol) in DMF (2OmL), was added KOAc (0.87g, 8.91mmol). The mixture was degassed with N2, stirred for 1 Omin and added Pd(dppf)Cl2. CH2Cl2 (73mg, 0.089mmol). The mixture was degassed with N2 and stirred at 8O0C overnight. After the reaction was complete, DMF was evaporated and the residue was purified by column chromatography (EA:PE=1 :7) to afford 23c (0.34g, 45percent yield) as oil.

References: [1]Patent: WO2008/88881,2008,A1 .Location in patent: Page/Page column 48.

5
[ 1040376-44-0 ]
[ 847818-71-7 ]
[ 1040376-75-7 ]

Yield	Reaction Conditions	Operation in experiment
36.6%		To the solution of 23c (99mg, 0.39mmol) and D (lOOmg, 0.26mmol) in DMF (15mL) was added Pd(Ph3P)2Cl2 (18mg, 0.026mmol) under the protection of N2. The mixture was degassed with N2, stirred for lOmin and added IN Na2CO3 aq. dropwise. The mixture was degassed with N2 and stirred overnight at 8O0C. After the reaction was complete, DMF was evaporated and the residue was purified by FC (EA:PE=1 : 1) and Prep-TLC subsequently to give the title compound (41mg, 36.6percent yield) as white solid. 1H-NMR (300MHz, CDCl3): 5=8.15-8.16 (d, IH), 7.64 (s, 2H), 7.26-7.31 (m, IH), 7.00-7.06 (dd, IH), 6.95-6.96 (d, IH), 5.99-6.06 (m, IH), 4.27-4.31 (t, 2H), 3.74- 3.77 (t, 2H), 3.35 (s, 3H), 2.55 (s, 3H), 1.84-1.86 (d, 3H). LC/MS [M+H]+ : 424.0.

References: [1]Patent: WO2008/88881,2008,A1 .Location in patent: Page/Page column 48.

6
[ 269410-08-4 ]
[ 6482-24-2 ]
[ 847818-71-7 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate; In N,N-dimethyl-formamide; at 160℃; for 2h;Microwave irradiation;	A mixture of 4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1H-pyrazole (1.94 g, 10 mmol), 2-bromoethyl methyl ether (1.68 g, 12 mmol) and K2C03 (2.76 g, 20 mmol) in DMF (16 mL) was stirred at 160 °C for 2 h in the microwave. The reaction mixture was concentrated and purified by silica gel chromatography (30percent EA:PE) to give 2.2 g (90percent) of the title compound as yellow oil. ?H NMR (400 MHz, CDC13): oe 1.32 (12H, s), 3.32 (3H, s), 3.75 (2H, t, J= 5.2 Hz), 4.30 (2H, t, J= 5.2 Hz), 7.77 (1H, s), 7.79 (1H, s). [M+H] Calc?d for C,2H2,BN203, 253; Found, 253.
68%	With caesium carbonate; In N,N-dimethyl-formamide; at 150℃; for 0.5h;Microwave irradiation;	Example A68Preparation of intermediate 68: l-(2-Methoxy-ethyl)-4-(4,4,5,5-tetramethyl- [l,3,21dioxaborolan-2-yl)-7H-pyrazoleA mixture of 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-7H-pyrazole (1 g, 5.15 mmol), 2-bromoethyl methyl ether (0.63 ml, 6.7 mmol) and cesium carbonate (2.52 g, 7.73 mmol) in N,N-dimethylformamide (7 ml) was stirred at 150 °C for 30 min. under microwave irradiation. The mixture was partitioned between water and diethyl ether. The organic layer was separated, dried (Na2S04), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; ethyl acetate in heptane 30/70). The desired fractions were collected and concentrated in vacuo to yield intermediate 68 (0.88 g, 68percent) as a pale yellow oil.
68%	With caesium carbonate; In N,N-dimethyl-formamide; at 150℃; for 0.5h;microwave irradiation;	Example A68Preparation of intermediate 68: 1-(2-Methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazoleA mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1 g, 5.15 mmol), 2-bromoethyl methyl ether (0.63 ml, 6.7 mmol) and cesium carbonate (2.52 g, 7.73 mmol) in N,N-dimethylformamide (7 ml) was stirred at 150° C. for 30 min. under microwave irradiation.The mixture was partitioned between water and diethyl ether.The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo.The crude product was purified by flash column chromatography (silica; ethyl acetate in heptane 30/70).The desired fractions were collected and concentrated in vacuo to yield intermediate 68 (0.88 g, 68percent) as a pale yellow oil.

57%	With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃;	2-Bromoethyl methyl ether (0.93 g, 6.70 mmol, 0.64 mL) was added to a mixture of 4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1 .00 g, 5.15 mmol) and caesium carbonate (3.49 mg, 10.72 mmol) in dry N,N-dimethylformamide (20 mL) at 0°O. After stirring for 30 mm the ice-water bath was removed. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with brine(3x100 mL). The organic layer was dried with sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (Method L7; 12 g; heptane, 10percent-30percent ethyl acetate) afforded 0.74 g (2.92 mmol; 57percent of theory) of the title compound.GO-MS (Method L9): R1 = 4.21 mm; m/z = 251 MH NMR (300 MHz, Ohloroform-d, Method M2) 6 7.79 (s, 1 H), 7.76 (s, 1 H), 4.29 (t, J = 5.3 Hz,2H), 3.75 (t, J = 5.3 Hz, 2H), 3.32 (s, 3H), 1.31 (s, 12H).
56%		General procedure: Preparation 122: 1 -(2-Methoxyethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- Method H NaH (60percent, 83 mg) was added to a solution of 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 - -pyrazole (204 mg, 1 .05 mmol) in DMF (4 mL). After stirring for 15 minutes, 1 -bromo-2-methoxyethane (175 mg, 1 .26 mmol) in DMF (1 mL) was added. The resulting solution was stirred at 80°C under microwave irradiation for 60 minutes. The reaction mixture was diluted with brine and extracted with EtOAc. The combined organic layers were washed with water, dried with Na2S04j and concentrated in vacuo to afford the title compound as a yellow oil that was used directly in the next step (148 mg, 56percent). 1 H NMR (500 MHz, CDCI3): delta 7.80 (d, J = 0.7 Hz, 1 H), 7.77 (d, J = 0.7 Hz, 1 H), 4.31 (t, = 5.3 Hz, 2H), 3.76 (t, J = 5.3 Hz, 2H), 3.33 (s, 3H), 1.32 (s, 12H). LCMS (ESI) Rt = 2.17 minutes MS m/z 253 [M+H]+
26%		To a solution of 4-(tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-1H-pyrazole (1 .00 g, 5.1 mmol) in DMF (5 mL) was added sodium hydride (245 mg of a 60percent dispersion in mineral oil, 6.1 mmol) at room temperature. The mixture was then stirred at room temperature for 60 minutes. The mixture was cooled to 0 ° C and 2-bromoethyl methyl ether (0.72 mL, 7.7 mmol) was added drop wise via syringe. After complete addition, the mixture was allowed to warm to room temperature and stirred for an hour prior to addition of ethyl acetate (70 mL) and water (30 mL). The organic layer was separated, washed with water (2 x 30 mL) and brine (30 mL), dried (Na2S04), filtered 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, 0-50percent EtOAc in heptane] to give the title compound (333 mg, 26percent yield) as a colourless oil. 1H NMR (250 MHz, DMSO-d6) delta [ppm] 7.88 (s, 1 H), 7.57 (s, 1 H), 4.32 - 4.20 (m, 2H), 3.73 - 3.60 (m, 2H), 3.21 (s, 3H), 1 .25 (s, 12H). LCMS (Analytical Method A): Rt = 1 .01 mins, MS (ESIPos): m/z = 253 (M+H)\
20%	With potassium hydroxide; In ethanol; at 50℃; for 76h;	Intermediate 1171 -[2-(Methyloxy)ethyl]-4-(4,4,5,5-tetrameth l-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazolA solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (10 g, 51 .5 mmol) in ethanol (50 mL) was treated with KOH (3.47 g, 61 .8 mmol) and 1 -bromo-2- (methyloxy)ethane (5.81 mL, 61.8 mmol) at room temperature and the resulting mixture was stirred at 50°C under nitrogen for 16 h then cooled to room temeprature. 1 -Bromo-2- (methyloxy)ethane (2 ml_, 21 .3 mmol) was added and the resulting mixture was stirred at 50°C for 60 h then cooled to room temperature. The mixture was filtered through celite and the insoluble were washed with ethanol. The combined filtrate and washings were concentrated in vacuo. Purification of the residue on SP4 using a 100 G silica cartridge (gradient: 0 to 100percent AcOEt in Hexanes) gave 1 -[2-(methyloxy)ethyl]-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazole (2.72 g, 10.25 mmol, 20percent) as a yellow oil. LCMS (method G): Retention time 0.87 min, [M+H]+ = 252.9
20%	With potassium hydroxide; In ethanol; at 50℃; for 66h;Inert atmosphere;	A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10 g, 51.5 mmol) in ethanol (50 mL) was treated with KOH (3.47 g, 61.8 mmol) and 1-bromo-2-(methyloxy)ethane (5.81 mL, 61.8 mmol) at room temperature and the resulting mixture was stirred at 50° C. under nitrogen for 16 h then cooled to room temperature. 1-Bromo-2-(methyloxy)ethane (2 mL, 21.3 mmol) was added and the resulting mixture was stirred at 50° C. for 60 h then cooled to room temperature. The mixture was filtered through celite and the insoluble were washed with ethanol. The combined filtrate and washings were concentrated in vacuo. Purification of the residue on SP4 using a 100 G silica cartridge (gradient: 0 to 100percent AcOEt in Hexanes) gave 1-[2-(methyloxy)ethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.72 g, 10.25 mmol, 20percent) as a yellow oil. LCMS (method G): Retention time 0.87 min, [M+H]+=252.9
	With caesium carbonate; In N,N-dimethyl-formamide; at 90℃; for 2h;microwave irradiation;	A solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.8 g, 4.1 mmol), cesium carbonate (2.0 g, 6.2 mmol), and l-bromo-2-methoxyethane (0.41 rnL, 4.3 mmol) in DMF (14 rnL) was heated in a microwave at 900C for 1 hr. After the initial heating, additional l-bromo-2-methoxyethane (0.41 rnL) was added to the reaction. Heating was repeated for an additional 1 hr. The crude reaction mixtures were then diluted with water (250 mL) and extracted with ethyl acetate (3 x 50 mL). Product was purified by silica gel column using DCM/EtOAc/MeOH (8/1.5/0.5) as eluent to give l-(2-methoxyethyl)-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (1.2 g) as a light yellow oil. ESI- MS :m/z 253.2 (M+H)+.
	With caesium carbonate; In acetonitrile; at 90℃;	Step I : l-(2-methoxyethyl)-4-(4, 4, 5, 5-tetramethyl-L 3, 2-dioxaborolan-2-yl)-W-pyrazoIe; A mixture of [A] 4-(4,4,5s5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l H-pyrazole ( 100 mg, 0.5 mmol), 2-bromoethyl methyl ether (58 uL, 0.62 mmol, Aldrich, Cat. No. 238155), and cesium carbonate (500.0 mg, 1.5 mmol) in acetonitrile (1 mL) was stirred at 90 0C overnight. After cooling it was quenched with water, extracted with ethyl acetate. The extract was washed with water twice, brine once; dried over Na2SO4. After filtration the filtrate was concentrated to yield 90 mg of the product. LCMS (M+H)+: m/z = 253.1
	With sodium hydride; In tetrahydrofuran; mineral oil; for 24h;Reflux;	ntermediate 1 1 1 -(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole[094] A mixture of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (200 mg, 1 .03 mmol),1 -bromo-2-methoxyethane (280 mg, 2.01 mmol), and NaH (200 mg, 4 mmol) in THF (15 mL) was stirred at reflux for 24 hours, cooled to the ambient temperature, and concentrated in vacuo. The residue was treated with HCI(aq) and extracted with EtOAc. The insoluble solid was removed by filtration, and the organic solution was concentrated to give the title compound. MS (m/z): 253 (M.bul.H)+.
25.4 g	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃;	4-(4,4,5,5-Tetramethyl-[1 ,3,2]clioxaborolan-2-yl)-1 H-pyrazole (19.4 g, 0.10 mol), 1- bromo-2-methoxy-ethane (14.18 ml, 0.15 mol), and caesium carbonate (32.58 g, 0.1 mol) are dissolved in DMF (200 ml). The suspension is stirred for 16 h at 80°C, filtered and the solvent is removed in vacuum. The residue is treated with tert-butyl methyl ether (200 ml), filtered over Celite and then the solvent is removed in vacuum; yield: 25.4 g 1-(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxa- borolan-2-yl)-1H-pyrazole; HPLC/MS: 1.82 min, [M+H] = 253.
	With sodium hydride; In tetrahydrofuran; for 24h;Reflux;	A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (200 mg, 1.03 mmol), 1-bromo-2-methoxyethane (280 mg, 2.01 mmol), and NaH (200 mg, 4 mmol) in THF (15 mL) was stirred at reflux for 24 hours, cooled to the ambient temperature, and concentrated in vacuo. The residue was treated with HCl(aq) and extracted with EtOAc. The insoluble solid was removed by filtration, and the organic solution was concentrated to give the title compound. MS (m/z): 253 (M+H)+.
1.31 g	With caesium carbonate; In acetonitrile; at 50℃;Inert atmosphere;	1H-pyrazole-4-boronic acid pinacol ester (1.0 g, 5.155 mmol),2-Bromoethyl methyl ether (0.788 g, 5.669 mmol)And cesium carbonate (5.04 g, 15.469 mmol) were dissolved in acetonitrile (20 mL),The mixture was stirred under nitrogen at 50 ° C overnight,filter,Concentrate to dryness to give 1- (2-methoxyethyl) -1H-pyrazole-4-boronic acid pinacol ester (1.310 g).

References: [1]Patent: WO2014/151106,2014,A1 .Location in patent: Paragraph 00179.
[2]Patent: WO2011/51342,2011,A1 .Location in patent: Page/Page column 95.
[3]Patent: US2011/269752,2011,A1 .Location in patent: Page/Page column 42.
[4]Patent: WO2017/178416,2017,A1 .Location in patent: Page/Page column 115.
[5]Patent: WO2014/37751,2014,A1 .Location in patent: Paragraph 00416-00418.
[6]Patent: WO2018/114786,2018,A1 .Location in patent: Page/Page column 142.
[7]Patent: WO2011/54841,2011,A1 .Location in patent: Page/Page column 106-107.
[8]Patent: US2012/208798,2012,A1 .Location in patent: Page/Page column 48.
[9]Patent: WO2010/19899,2010,A1 .Location in patent: Page/Page column 154.
[10]Patent: WO2010/75270,2010,A1 .Location in patent: Page/Page column 169.
[11]Patent: WO2012/167423,2012,A1 .Location in patent: Page/Page column 35-36.
[12]Patent: WO2013/117285,2013,A1 .Location in patent: Page/Page column 82; 83.
[13]Patent: US2014/121200,2014,A1 .Location in patent: Paragraph 0166; 0167.
[14]Patent: CN107312005,2017,A .Location in patent: Paragraph 0474; 0475; 0476; 0477.

7
[ 1208247-67-9 ]
[ 76-05-1 ]
[ 847818-71-7 ]
N-(6-(6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5.43%		A mixture of N-(6-(6-bromo-[l,2,4]triazolo[4,3-a]pyridin-3-ylthio)imidazo[l,2- b]pyridazin-2-yl)cyclopropanecarboxamide (100 mg, 0.232 mmol), l-(2-methoxyethyl)-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (410 mg, 1.627 mmol), pdcl2(dppf) (8.50 mg, 0.012 mmol), and cesium carbonate (0.232 mL, 0.697 mmol) inDioxane (Volume: 1.0 mL) was heated in a microwave on high absorbance for 1 hr at 1000C. The reaction mixture was then concentrated to dryness via rotary evaporation. The resulting crude material was reconstituted in DMSO (Volume: 1.0 mL) and purified via preparative mass trigger LCMS using a gradient eluant of 15-40percent ACN:0.05percent TFA (aq). The collected fractions were combined and the ACN was removed via rotary evaporation. The resulting mixture was lyophilized to provide the TFA salt of the title compound (6.0 mg, 0.013 mmol, 5.43 percent yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) delta ppm 0.69 - 0.86 (m, 4 H) 1.90 (m, 1 H) 3.20 (m, 3 H) 3.63 - 3.70 (m, 2 H) 4.22 - 4.27 (m, 2 H) 7.00 (m, 1 H) 7.57 (m, 1 H) 7.86 - 7.95 (m, 3 H) 8.04 (m, 1 H) 8.08 (m, 1 H) 8.37 (m, 1 H), 11.16 (s, 1 H). ESI- MS :m/z 476.3 (M+H)+.

References: [1]Patent: WO2010/19899,2010,A1 .Location in patent: Page/Page column 154-155.

8
4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine [ No CAS ]
[ 847818-71-7 ]
4-[7-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 90℃; for 2h;	Step 2: 4-[7-[l-(2-methoxyethyl)-lHpsiyrazol-4-yl]-3-methyl-3J-dihydroisoquinolm-2(lH)-yl]-6-(4- methylpiperazin-l-yl)pyrimidin-2-amine; A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(l H)-yl)-6-(4-methylpiperazin-l- yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), l-(2-methoxyethyl)-4-(4,4,5,5- teframethyl-l ,3,2-dioxarx)rolan-2-yl)-l H-pyrazole (9.1 mg, 0.036 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in 1,4-dioxane (0.2 mL) and water (0.1 mL) was stirred at 90 0C for 2 h. After cooling, it was diluted with methanol, and purified with RP-HPLC (pH = 10) . to afford the desired product (4.7 mg). LCMS (M+H)+: m/z = 463.3.

References: [1]Patent: WO2010/75270,2010,A1 .Location in patent: Page/Page column 169.

9
[ 1257993-77-3 ]
[ 847818-71-7 ]
[ 1257994-16-3 ]

Yield	Reaction Conditions	Operation in experiment
19.6%	With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 0.5h;Microwave irradiation; Inert atmosphere;	A mixture of diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1 H-isoindol-4-yl)amino]-5- (trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate (10.0 mg, 0.0159 mmol), 1-(2- methoxyethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (8.02 mg, 0.0318 mmol), potassium carbonate (6.60 mg, 0.0477 mmol), 1 ,4-dioxane (0.4 ml_), H2O (0.1 ml.) and [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll),complex with dichloromethane (1 :1 ) (1.30 mg, 0.00159 mmol) was evacuated and purged with N2. The mixture was irradiated in a microwave reactor at 100 0C for 30 minutes. The crude mixture was passed through a Thiol-SPE column to remove Pd and purified by MDP to obtain the title compound (2.1 mg, 19.6percent yield). 1H NMR (400 MHz, CD3OD) delta = 1.25 (t, J = 7.1 Hz, 6 H), 3.21 (s, 3 H), 3.30 (d, J = 22.7 Hz), 3.35 (s, 3 H), 3.79 (t, J = 5.2 Hz, 2 H), 4.01 - 4.13 (m, 4 H), 4.37 (t, J = 5.2 Hz, 2 H), 4.60 (s, 2 H), 7.37 (dd, J = 8.6, 2.3 Hz, 2 H), 7.57 (d, J = 8.6 Hz, 2 H), 7.72 (d, J = 8.8 Hz, 1 H), 7.94 (s, 1 H), 8.08 (s, 1 H), 8.36 (s, 1 H), 8.68 (br. s., 1 H). MS (ES+): m/z 674.34 (100) [MH+]; HPLC: tR = 1.05 min (UPLC, purity).

References: [1]Patent: WO2010/141406,2010,A2 .Location in patent: Page/Page column 86-87.

10
[ 1300031-98-4 ]
[ 847818-71-7 ]
[ 1301197-83-0 ]

Yield	Reaction Conditions	Operation in experiment
37%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 80℃; for 18h;Inert atmosphere;	Example 1071 -Methylethyl ((2S,4 ?)-1 -acetyl-2-methyl-6-{1 -[2-(methyloxy)ethyl]-1 H-pyrazol-4-yl}- 1 ,2,3,4-tetrahydro-4-quinolinyl)carbamateA flask was charged with 1 -methylethyl [(2S,4/?)-1 -acetyl-6-bromo-2-methyl-1 ,2,3,4- tetrahydro-4-quinolinyl]carbamate (for a preparation see Example 4) (0.185 g, 0.500 mmol), 1 -[2-(methyloxy)ethyl]-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (for a preparation see Intermediate 1 17) (151 mg, 0.600 mmol), K2C03 (90 mg, 0.650 mmol) and tetrakis(triphenylphosphine)palladium(0) (28.9 mg, 0.025 mmol) then filled with EtOH (1 mL) and toluene (1 mL) and the resulting mixture was stirred at 80°C for 18 h then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt (10 mL) and water (10 mL) and the layers were separated. The aqueous layer was extracted with AcOEt and the combined organic phases were washed with brine (25 mL), dried over Na2S04 and concentrated in vacuo. Purification of the residue using MDAP (modifier: formic acid) gave an oil which was dissolved in 1 ,4- dioxane, freezed using an acetone bath cooled with solid C02 and left on a freeze drier for 16 h to give 1 -methylethyl ((2S,4R)-1 -acetyl-2-methyl-6-{1 -[2-(methyloxy)ethyl]-1 H- pyrazol-4-yl}-1 ,2,3,4-tetrahydro-4-quinolinyl)carbamate (84.7 mg, 0.204 mmol, 37percent) as a white solid. LCMS (method A): Retention time 0.84 min, [M+H]+ = 415.15
37%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 80℃; for 18h;	A flask was charged with 1-methylethyl [(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Example 4) (0.185 g, 0.500 mmol), <strong>[847818-71-7]<strong>[847818-71-7]1-[2-(methyloxy)ethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol</strong>e</strong> (for a preparation see Intermediate 117) (151 mg, 0.600 mmol), K2CO3 (90 mg, 0.650 mmol) and tetrakis(triphenylphosphine)palladium(0) (28.9 mg, 0.025 mmol) then filled with EtOH (1 mL) and toluene (1 mL) and the resulting mixture was stirred at 80° C. for 18 h then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt (10 mL) and water (10 mL) and the layers were separated. The aqueous layer was extracted with AcOEt and the combined organic phases were washed with brine (25 mL), dried over Na2SO4 and concentrated in vacuo. Purification of the residue using MDAP (modifier: formic acid) gave an oil which was dissolved in 1,4-dioxane, freezed using an acetone bath cooled with solid CO2 and left on a freeze drier for 16 h to give 1-methylethyl ((2S,4R)-1-acetyl-2-methyl-6-{1-[2-(methyloxy)ethyl]-1H-pyrazol-4-yl}-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (84.7 mg, 0.204 mmol, 37percent) as a white solid. LCMS (method A): Retention time 0.84 min, [M+H]+=415.15
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 80℃; for 18h;Inert atmosphere;	Example 11-methylethyl ((2S,4R)-l-acetyl-2-methyl-6-{l-[2-(methyloxy)ethyl]-lH-pyrazol- 4-y I }- 1, 2,3,4-tetra hy d ro-4-qu i nol i ny l)ca rba mate1-Methylethyl [(25,4/?)-l-acetyl-6-bromo-2-methyl-l,2,3,4-tetrahydro-4- quinolinyl]carbamate (for preparation see Intermediate l)(185mg), l-[2-(methyloxy)ethyl]-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l pyrazole (for a preparation see Journal of Heterocyclic Chemistry, 41(6), 931-939; 2004) (151mg), potassium carbonate (90mg) and tetrakis(triphenylphosphine)palladium (0) (28.9mg) were combined in ethanol and toluene under nitrogen and heated to 80°C for 18h. The reaction was concentrated, the residue partioned between ethyl acetate (10ml) and water (10ml) and the aqueous layer was extracted with ethyl acetate (10ml). The combined organics were washed with brine (25ml), dried with sodium sulphate, filtered and concentrated. The residue was purified by MDAP (formate x2) and the collected product dissolved in 1,4-dioxane (0.5ml) and cooled in a C02 bath then left on a freeze dryer overnight. The resulting white solid was dried at 40°C under vacuum overnight to give 1-methylethyl ((2S,4R)-l-acetyl-2-methyl-6-{l-[2- (methyloxy)ethyl]-lH-pyrazol-4-yl}-l,2,3,4-tetrahydro-4-quinolinyl)carbamate (84.7mg). LCMS (formate), Rt 0.84min, MH+ 415

84.7 mg

With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; toluene; at 80℃; for 18h;Inert atmosphere;

EXAMPLE 1 1-methylethyl((2S,4R)-1-acetyl-2-methyl-6-{1-[2-(methyloxy)ethyl]-1H-pyrazol-4-yl}-1,2,3,4-tetrahydro-4-quinolinyl)carbamate 1-Methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for preparation see Intermediate 1) (185 mg), <strong>[847818-71-7]<strong>[847818-71-7]1-[2-(methyloxy)ethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol</strong>e</strong> (for a preparation see Journal of Heterocyclic Chemistry, 41(6), 931-939; 2004) (151 mg), potassium carbonate (90 mg) and tetrakis(triphenylphosphine)palladium(0) (28.9 mg) were combined in ethanol and toluene under nitrogen and heated to 80° C. for 18 h. The reaction was concentrated, the residue partioned between ethyl acetate (10 ml) and water (10 ml) and the aqueous layer was extracted with ethyl acetate (10 ml). The combined organics were washed with brine (25 ml), dried with sodium sulphate, filtered and concentrated. The residue was purified by MDAP (formate *2) and the collected product dissolved in 1,4-dioxane (0.5 ml) and cooled in a CO2 bath then left on a freeze dryer overnight. The resulting white solid was dried at 40° C. under vacuum overnight to give 1-methylethyl((2S,4R)-1-acetyl-2-methyl-6-{1-[2-(methyloxy)ethyl]-1H-pyrazol-4-yl}-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (84.7 mg). LCMS (formate), Rt 0.84 min, MH+415

References: [1]Patent: WO2011/54841,2011,A1 .Location in patent: Page/Page column 176.
[2]Patent: US2012/208798,2012,A1 .Location in patent: Page/Page column 82.
[3]Patent: WO2012/150234,2012,A1 .Location in patent: Page/Page column 34.
[4]Patent: US2014/66459,2014,A1 .Location in patent: Paragraph 0267-0268.

11
[ 269410-08-4 ]
[ 627-42-9 ]
[ 847818-71-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With caesium carbonate; In N,N-dimethyl-formamide; at 160℃; for 0.5h;Microwave irradiation;	4-( 4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 00 mg, 0.52mmol), 1-chloro-2-methoxyethane (0.056 mL, 0.62 mmol) and cesium carbonate (252mg, 0.73 mmol) in DMF (1 mL) were heated in microwave reactor at 160 °C for 30 min.The reaction mixture was concentrated under reduced pressure and purified by silica gelchromatography (ISCO, hexanes/ethyl acetate 0-100percent over 15 min) to isolate CompoundB162a (130 mg, 100percent yield). HPLC: RT = 1.0 min (LCMS Method M). MS (ES): m/z= 253.0 [M+H( 1H NMR (500MHz, CHLOROFORM-d) 8 8.04 (s, 1H), 7.83 (d,J=18.4 Hz, 1H), 4.37 (t, J=5.2 Hz, 1H), 3.78 (t, J=5.2 Hz, 1H), 3.38-3.31 (m, 2H), 2.98(s, 3H), 2.90 (s, 3H), 1.34 (s, 6H), 1.26 (s, 3H).
72%	With caesium carbonate; In N,N-dimethyl-formamide; at 160℃; for 0.5h;microwave irradiation;	2-Chloroethyl methyl ether (0.050 ml, 0.63 mmol) was added to a stirred solution of 4- (4,4,5, 5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-pyrazole (5.0 g, 25.77 mmol) and cesium carbonate (12.59 g, 38.65 mmol) in DMF (27 ml). The mixture was stirred at 160 °C for 30 min. under microwave irradiation and then the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; MeOH in DCM 2/98). The desired fractions were collected and evaporated in vacuo to yield intermediate 67 (4.6 g, 72percent) as a pale yellow oil.
72%	With caesium carbonate; In N,N-dimethyl-formamide; at 160℃; for 0.5h;Microwave irradiation;	Example A671-(2-Methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole2-Chloroethyl methyl ether (0.050 ml, 0.63 mmol) was added to a stirred solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (5.0 g, 25.77 mmol) and cesium carbonate (12.59 g, 38.65 mmol) in DMF (27 ml).The mixture was stirred at 160° C. for 30 min. under microwave irradiation and then the solvent was evaporated in vacuo.The crude product was purified by flash column chromatography (silica; MeOH in DCM 2/98).The desired fractions were collected and evaporated in vacuo to yield intermediate 67 (4.6 g, 72percent) as a pale yellow oil.

References: [1]Patent: WO2014/15088,2014,A1 .Location in patent: Paragraph 00223.
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 4196 - 4212.
[3]Patent: WO2011/110545,2011,A1 .Location in patent: Page/Page column 95-96.
[4]Patent: US2012/329792,2012,A1 .Location in patent: Page/Page column 46.

12
[ 847818-71-7 ]
[ 1334168-01-2 ]

References: [1]Patent: WO2011/110545,2011,A1 .
[2]Patent: US2012/329792,2012,A1 .
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 4196 - 4212.

13
[ 847818-71-7 ]
[ 1334166-13-0 ]

References: [1]Patent: WO2011/110545,2011,A1 .
[2]Patent: US2012/329792,2012,A1 .
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 4196 - 4212.

14
[ 1334167-32-6 ]
[ 847818-71-7 ]
[ 1334166-07-2 ]

Yield	Reaction Conditions	Operation in experiment
48%		Palladium (II) acetate (0.016 g, 0.073 mmol) was added to a stirred solution of intermediate 22 (0.3 g, 1.04 mmol), intermediate 67 (0.52 g, 2.08 mmol) and triphenylphosphine (0.027 g, 0.1 mmol) in a mixture of 1,4-dioxane (10 ml) and a 1.5 M solution of potassium carbonate (2.6 ml, 3.9 mmol). The mixture was stirred at 80 °C for 16 h. and then the solvents were evaporated in vacuo. The crude product was partitioned between water and DCM and the organic layer was separated, dried (Na2S04), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7 M solution of ammonia in MeOH in DCM 10/90). The desired fractions were collected and evaporated in vacuo to yield compound 34 (0.168 g, 48percent) as a white solid.
48%	With potassium carbonate;palladium diacetate; triphenylphosphine; In 1,4-dioxane; at 80℃; for 16h;	Example B343-[1-(2-Methoxy-ethyl)-1H-pyrazol-4-yl]-2-methyl-8-pyridin-4-yl-imidazo[1,2-a]pyrazinePalladium (II) acetate (0.016 g, 0.073 mmol) was added to a stirred solution of intermediate 22 (0.3 g, 1.04 mmol), intermediate 67 (0.52 g, 2.08 mmol) and triphenylphosphine (0.027 g, 0.1 mmol) in a mixture of 1,4-dioxane (10 ml) and a 1.5 M solution of potassium carbonate (2.6 ml, 3.9 mmol).The mixture was stirred at 80° C. for 16 h. and then the solvents were evaporated in vacuo.The crude product was partitioned between water and DCM and the organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo.The crude product was purified by flash column chromatography (silica; 7 M solution of ammonia in MeOH in DCM 10/90).The desired fractions were collected and evaporated in vacuo to yield compound 34 (0.168 g, 48percent) as a white solid.

References: [1]Patent: WO2011/110545,2011,A1 .Location in patent: Page/Page column 114.
[2]Patent: US2012/329792,2012,A1 .Location in patent: Page/Page column 56.
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 4196 - 4212.

15
[ 1334167-52-0 ]
[ 847818-71-7 ]
[ 1334168-00-1 ]

Yield	Reaction Conditions	Operation in experiment
28%	palladium diacetate; In 1,4-dioxane; at 80℃; for 18h;Inert atmosphere;	Palladium acetate (0) (0.043 g, 0.189 mmol) was added to a stirred solution of intermediate 31 (0.96 g, 2.7 mmol) and intermediate 67 (1.36 g, 5.40 mmol) in 1,4- dioxane (48 ml). The mixture was stirred at 80 °C for 18 h. under nitrogen and then the solvent was evaporated in vacuo. The crude product was partitioned between water and DCM and the organic layer was separated, dried (Na2S04), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 10/90). The desired fractions were collected and evaporated in vacuo and the crude product purified by RP HPLC (0.1percent solution of ammonium formate/ammonium hydroxide buffer pH 9 in ACN 80/20 to 0/100) to yield intermediate 79 (0.31 g, 28percent) as a white solid.
28%	With ammonium formate;palladium diacetate; In 1,4-dioxane; at 80℃; for 18h;Inert atmosphere;	Example A793-[1-(2-Methoxy-ethyl)-1H-pyrazol-4-yl]-8-morpholin-4-yl-imidazo[1,2-c]pyrazine-2-carboxylic acid ethyl esterPalladium acetate (0) (0.043 g, 0.189 mmol) was added to a stirred solution of intermediate 31 (0.96 g, 2.7 mmol) and intermediate 67 (1.36 g, 5.40 mmol) in 1,4-dioxane (48 ml).The mixture was stirred at 80° C. for 18 h. under nitrogen and then the solvent was evaporated in vacuo.The crude product was partitioned between water and DCM and the organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo.The crude product was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 10/90).The desired fractions were collected and evaporated in vacuo and the crude product purified by RP HPLC (0.1percent solution of ammonium formate/ammonium hydroxide buffer pH 9 in ACN 80/20 to 0/100) to yield intermediate 79 (0.31 g, 28percent) as a white solid.

References: [1]Patent: WO2011/110545,2011,A1 .Location in patent: Page/Page column 99.
[2]Patent: US2012/329792,2012,A1 .Location in patent: Page/Page column 48.
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 4196 - 4212.

16
[ 1334167-75-7 ]
[ 847818-71-7 ]
[ 1334166-12-9 ]

Yield	Reaction Conditions	Operation in experiment
37%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 150℃; for 0.25h;Inert atmosphere; microwave irradiation; sealed tube;	Tetrakis(triphenylphosphine)palladium (0) (0.005 g, 0.0045 mmol) was added to a stirred solution of intermediate 38 (0.070 g, 0.18 mmol) and intermediate 67 (0.054 mg, 0.21 mmol) in a mixture of 1,4-dioxane (1.5 ml) and a saturated solution of sodium carbonate (0.5 ml). The mixture was stirred at 150 °C for 15 min. in a sealed tube under nitrogen and under microwave irradiation. The mixture was partitioned between water and DCM and the organic layer was separated, extracted with brine, dried (Na2S04), filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in heptane 0/100 to 100/0). The desired fractions were collected and evaporated in vacuo and the crude product purified again by flash column chromatography (silica; EtOAc in DCM 0/100 to 50/50). The desired fractions were collected and evaporated in vacuo and the residue triturated with diisopropyl ether to yield compound 39 (0.029 g, 37percent) as a white solid.
37%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 150℃; for 0.25h;Sealed tube; Microwave irradiation; Inert atmosphere;	Example B393-[1-(2-Methoxy-ethyl)-1H-pyrazol-4-yl]-2-methyl-8-morpholin-4-yl-6-(3,3,3-trifluoro-propyl)-imidazo[1,2-a]pyrazineTetrakis(triphenylphosphine)palladium (0) (0.005 g, 0.0045 mmol) was added to a stirred solution of intermediate 38 (0.070 g, 0.18 mmol) and intermediate 67 (0.054 mg, 0.21 mmol) in a mixture of 1,4-dioxane (1.5 ml) and a saturated solution of sodium carbonate (0.5 ml).The mixture was stirred at 150° C. for 15 min. in a sealed tube under nitrogen and under microwave irradiation.The mixture was partitioned between water and DCM and the organic layer was separated, extracted with brine, dried (Na2SO4), filtered and the solvent evaporated in vacuo.The crude product was purified by flash column chromatography (silica; EtOAc in heptane 0/100 to 100/0).The desired fractions were collected and evaporated in vacuo and the crude product purified again by flash column chromatography (silica; EtOAc in DCM 0/100 to 50/50).The desired fractions were collected and evaporated in vacuo and the residue triturated with diisopropyl ether to yield compound 39 (0.029 g, 37percent) as a white solid.

References: [1]Patent: WO2011/110545,2011,A1 .Location in patent: Page/Page column 116.
[2]Patent: US2012/329792,2012,A1 .Location in patent: Page/Page column 57.

17
[ 1352151-91-7 ]
[ 847818-71-7 ]
[ 1352152-58-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; acetonitrile; at 80℃; for 36h;Inert atmosphere;	(i) (S)-terf-Butyl l-(l-amino-3-(4-(l-(2-methoxyethyl)-lH-pyrazol-4-yl)phoxopropan-2-ylcarbamoyl)cyclohexylcarbamatePotassium acetate (76 mg) in water (0.5 mL) was added to (S)-tert-butyl l-(l-amino-3-(4- iodophenyl)-l-oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (Example 6, step (i), 200 mg) and l-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (98 mg) in degassed acetonitrile (4 mL) at 20°C under an atmosphere of nitrogen. 1 , 1 bis(di-tert- butylphosphino)ferrocene palladium dichloride (5 mg) was added. The resulting mixture was stirred at 80°C for 18 h. Further additions of l-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (33mg), potassium acetate (25mg) and 1,1 bis(di-tert- butylphosphino)ferrocene palladium dichloride (5 mg) were made, with stirring at 80°C for 18 h. The reaction was repeated using {S)-tert- vXy\\ l-(l-amino-3-(4-iodophenyl)-l- oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (100 mg). The combined, cooled products were purified by chromatography on silica, eluting with ethyl acetate. Pure fractions were evaporated to dryness to afford the sub-titled compound (111 mg). m/e (APCI+) 414 [M+H]+

References: [1]Patent: WO2011/154677,2011,A1 .Location in patent: Page/Page column 138-139.

18
[ 1300695-47-9 ]
[ 847818-71-7 ]
[ 1407544-52-8 ]

Yield	Reaction Conditions	Operation in experiment
68%	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 110℃; for 2.16667h;Microwave irradiation;	Intermediate 11l-((2S,4R)-4-amino-6-(l-(2-methoxyethyl)-lH-pyrazol-4-yl)-2-methyl-3,4- dihydroquinolin-l(2H)-yl)ethanone(2S,4R)-l-Acetyl-6-bromo-2-methyl-l,2,3,4-tetrahydro-4-quinolinamine (for a preparation see Intermediate 7) (900 mg, 2.82 mmol),l-(2-methoxyethyl)-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (852mg, 3.38 mmol), [Iota, - bis(diphenylphosphino)ferrocene]dichloropalladium(II) (309mg, 0.422 mmol) and K2C03 (895mg, 6.48 mmol) were combined in 1,4-dioxane (12ml) and water (4.0ml) and heated at 110°C for 60min (microwave). The reaction was heated for a further lOmin and then, for a further 30min under the same conditions. PdCI2(dppf) (309mg, 0.422 mmol), K2C03 (895mg, 6.48 mmol) and water (1.5ml) were added and the mixture heated at 110°C for 30min (microwave). The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate (150ml) and DCM (3x150ml). The organics were combined, dried (hydrophobic frit) and evaporated under vacuum. The residue was dissolved in DCM, the solution applied to a silica cartridge (lOOg) and purified the cartridge eluted with an ethyl acetate / cyclohexane gradient (0-100percent over 10CV followed by 100percent ethyl acetate for 5CV). The cartridge was washed using a methanol / DCM gradient (0-20percent over 10CV, followed by holding at 20percent methanol / DCM for 5CV). The cartridge was further washed using a gradient 2M ammonia in methanol / DCM (0-20percent over 10CV, followed by 2M ammonia in methanol / DCM 20percent for 5CV). The appropriate fractions were combined and evaporated under vacuum to leave l-((2S,4R)-4-amino-6-(l-(2-methoxyethyl)-lH-pyrazol-4-yl)-2-methyl-3,4- dihydroquinolin-l(2H)-yl)ethanone (631mg, 1.921 mmol, 68 percent yield) as a brown glass. LCMS (HpH), Rt 0.68min, MH+ 329
68%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 110℃; for 2.16667h;Microwave irradiation;	Intermediate 11 1-((2S,4R)-4-amino-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (2S,4R)-1-Acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see Intermediate 7) (900 mg, 2.82 mmol), <strong>[847818-71-7]1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (852 mg, 3.38 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (309 mg, 0.422 mmol) and K2CO3 (895 mg, 6.48 mmol) were combined in 1,4-dioxane (12 ml) and water (4.0 ml) and heated at 110° C. for 60 min (microwave). The reaction was heated for a further 10 min and then, for a further 30 min under the same conditions. PdCl2(dppf) (309 mg, 0.422 mmol), K2CO3 (895 mg, 6.48 mmol) and water (1.5 ml) were added and the mixture heated at 110° C. for 30 min (microwave). The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate (150 ml) and DCM (3*150 ml). The organics were combined, dried (hydrophobic frit) and evaporated under vacuum. The residue was dissolved in DCM, the solution applied to a silica cartridge (100 g) and purified the cartridge eluted with an ethyl acetate/cyclohexane gradient (0-100percent over 10 CV followed by 100percent ethyl acetate for 5 CV). The cartridge was washed using a methanol/DCM gradient (0-20percent over 10 CV, followed by holding at 20percent methanol/DCM for 5 CV). The cartridge was further washed using a gradient 2M ammonia in methanol/DCM (0-20percent over 10 CV, followed by 2M ammonia in methanol/DCM 20percent for 5 CV). The appropriate fractions were combined and evaporated under vacuum to leave 1-((2S,4R)-4-amino-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (631 mg, 1.921 mmol, 68percent yield) as a brown glass. LCMS (HpH), Rt 0.68 min, MH+329

References: [1]Patent: WO2012/150234,2012,A1 .Location in patent: Page/Page column 33-34.
[2]Patent: US2014/66459,2014,A1 .Location in patent: Paragraph 0265-0266.

19
[ 1403384-74-6 ]
[ 847818-71-7 ]
[ 1407544-33-5 ]

Yield	Reaction Conditions	Operation in experiment
	[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride; In ethanol; water; toluene; for 6h;Reflux; Inert atmosphere;Product distribution / selectivity;	Example 2, alternative preparation6-(((25,4/?)-l-acetyl-6-(l-(2-methoxyethyl)-l -pyrazol-4-yl)-2-methyl-l,2,3,4- tetrahydroquinolin-4-yl)amino)nicotinonitrile6-(((25,4/?)-l-acetyl-6-bromo-2-methyl-l,2,3,4-tetrahydroquinolin-4- yl)amino)nicotinonitrile (Intermediate 6) (lOg, 26.0 mmol), PEPPSI.(TM). (1.764 g, 2.60 mmol), KOH (4.37 g, 78 mmol) and l-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-lH-pyrazole (CAS No. 847818-71-7 available from Milestone PharmTech USA Inc.)(11.78 g, 46.7 mmol) were combined in a mixture of toluene (80 ml_), EtOH (40 ml.) and water (50 ml_). The mixture was degassed and then heated at reflux under a nitrogen atmosphere for 6 h. The solution was cooled, diluted with EtOAc (200 ml.) and washed with water (200 ml_). The organic layer was dried over sodium sulphate and concentrated in vacuo to give a pale yellow gum. This yellow gum was purified by silica gel column chromatography (330 g column, eluting with 0-100percent EtOAC/cyclohexane followed by 10percent MeOH/EtOAc). The appropriate fractions were collected and the solvent evaporated in vacuo to give the crude product which was further purified by preparative HPLC (Method HpH) and then dried overnight in a vacuum oven at 55°C to give 6-(((25,4/?)-l-acetyl-6-(l-(2-methoxyethyl)-l pyrazol-4-yl)-2-methyl-l,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (4.62 g).LCMS (formate): Rt 0.82 min, MH+ 431.*H NMR (DMSO-d6): 8.42 (d, J = 2.6 Hz, 1H), 8.02 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.79 (dd, J = 8.8, 2.6 Hz, 1H), 7.76 (s, 1H), 7.48 (dd, J = 8.1, 2.2 Etazeta,IotaEta), 7.33 (d, J = 8.1 Hz, 1H), 7.27 (s, 1H), 6.79 (d, J = 8.8 Hz, 1H), 4.99 (br. s., 1H), 4.62 - 4.77 (m, 1H), 4.26 (t, J = 5.3 Hz, 2H), 3.63 - 3.71 (m, 2H), 3.21 (s,3H), 2.56 (ddd, J = 12.7, 8.3, 4.6 Hz, 1H), 2.09 (s, 3H), 1.24 - 1.38 (m, 1H), 1.08 (d, J = 6.2 Hz, 3H)
40 mg	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 120℃; for 0.5h;Sealed tube; Microwave irradiation;	EXAMPLE 2 6-(((2S,4R)-1-acetyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile A microwaveable vial was charged with 6-(((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (for a preparation see Intermediate 6) (74 mg, 0.192 mmol), <strong>[847818-71-7]1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (CAS No. 847818-71-7 available from Milestone PharmTech USA Inc.) (63 mg, 0.250 mmol), [1,1T-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (21 mg, 0.029 mmol), potassium carbonate (56 mg, 0.405 mmol), water (0.5 ml), and 1,4-dioxane (1.5 ml). The vial was sealed and heated at 120° C. for 30 min (microwave). The reaction solution was diluted with water (10 ml), extracted with ethyl acetate (3*15 ml). The organics were combined, dried (hydrophobic frit). The solvent was evaporated in vacuo. The residue was dissolved in methanol/DMSO (1:1, 1 ml) and purified by MDAP (TFA). The solvent was evaporated under a stream of nitrogen, the residue was redissolved in methanol and filtered through an aminopropyl SPE (2 g). The solvent was evaporated in vacuo, to give 6-(((2S,4R)-1-acetyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (40 mg) as a white solid. LCMS (formate): Rt 0.82 min, MH+431. EXAMPLE 2, ALTERNATIVE PREPARATION [0272] 6-(((2S,4R)-1-acetyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile [0273] 6-(((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (Intermediate 6) (10 g, 26.0 mmol), PEPPSI? (1.764 g, 2.60 mmol), KOH (4.37 g, 78 mmol) and <strong>[847818-71-7]1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (CAS No. 847818-71-7 available from Milestone PharmTech USA Inc.) (11.78 g, 46.7 mmol) were combined in a mixture of toluene (80 mL), EtOH (40 mL) and water (50 mL). The mixture was degassed and then heated at reflux under a nitrogen atmosphere for 6 h. The solution was cooled, diluted with EtOAc (200 mL) and washed with water (200 mL). The organic layer was dried over sodium sulphate and concentrated in vacuo to give a pale yellow gum. This yellow gum was purified by silica gel column chromatography (330 g column, eluting with 0-100percent EtOAC/cyclohexane followed by 10percent MeOH/ EtOAc). The appropriate fractions were collected and the solvent evaporated in vacuo to give the crude product which was further purified by preparative HPLC (Method HpH) and then dried overnight in a vacuum oven at 55° C. to give 6-(((2S,4R)-1-acetyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (4.62 g). [0274] LCMS (formate): Rt 0.82 min, MH+431. [0275] 1H NMR (DMSO-d6): 8.42 (d, J=2.6 Hz, 1H), 8.02 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.79 (dd, J=8.8, 2.6 Hz, 1H), 7.76 (s, 1H), 7.48 (dd, J=8.1, 2.2 Hz,1H), 7.33 (d, J=8.1 Hz, 1H), 7.27 (s, 1H), 6.79 (d, J=8.8 Hz, 1H), 4.99 (br. s., 1H), 4.62-4.77 (m, 1H), 4.26 (t, J=5.3 Hz, 2H), 3.63-3.71 (m, 2H), 3.21 (s,3H), 2.56 (ddd, J=12.7, 8.3, 4.6 Hz, 1H), 2.09 (s, 3H), 1.24-1.38 (m, 1H), 1.08 (d, J=6.2 Hz, 3H)

References: [1]Patent: WO2012/150234,2012,A1 .Location in patent: Page/Page column 35.
[2]Patent: US2014/66459,2014,A1 .Location in patent: Paragraph 0269-0275.

20
[ 1334167-38-2 ]
[ 847818-71-7 ]
[ 1334167-17-7 ]