1002309-48-9|1-Cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole| Ambeed

Structure of 1002309-48-9

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Quality Control of [ 1002309-48-9 ] Purity: 97% SDS Specification

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Product Details of [ 1002309-48-9 ]

CAS No. :	1002309-48-9
Formula :	C₁₃H₂₁BN₂O₂
M.W :	248.13
SMILES Code :	C1(CCC1)[N]2C=C(C=N2)B3OC(C(O3)(C)C)(C)C
MDL No. :	MFCD16659010
InChI Key :	OBCTWWFLJFCNPC-UHFFFAOYSA-N
Pubchem ID :	56965732

Safety of [ 1002309-48-9 ]

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

Computational Chemistry of [ 1002309-48-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	18
Num. arom. heavy atoms	5
Fraction Csp3	0.77
Num. rotatable bonds	2
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	72.27
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	36.28 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.0
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.03
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.91
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.	1.14
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	1.01
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.22

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.73
Solubility	0.461 mg/ml ; 0.00186 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.	-2.42
Solubility	0.944 mg/ml ; 0.00381 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	-2.89
Solubility	0.317 mg/ml ; 0.00128 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	Yes
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.37 cm/s

Druglikeness

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

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	1.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	3.19

Application In Synthesis of [ 1002309-48-9 ]

* 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 [ 1002309-48-9 ]

[ 1002309-48-9 ] Synthesis Path-Downstream 1~28

2
[ 1002309-48-9 ]
[ 1339891-40-5 ]
[ 1339892-02-2 ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; at 20 - 75℃;Inert atmosphere;	Step A: Preparation of tert-butyl 3 -(cyanomethyl)-3-(4-(7-(l -cyclobutyl- 1H- pyrazol-4-yl)imidazo[ 1 ,2-c]pyrimidin-5-yl)- lH-pyrazol- 1 -yl)azetidine- 1 -carboxylate: The tert-butyl 3 -(4-(7-chloroimidazo [ 1 ,2-c]pyrimidin-5-yl)- 1 H-pyrazol- 1 -yl)-3 -(cyanomethyl) azetidine-1 -carboxylate (0.080 g, 0.19 mmol) (Preparation N), l-cyclobutyl-4-(4,4,5,5- tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (Table 2, compound e; 0.072 g, 0.29 mmol), and potassium phosphate (0.29 mL, 0.58 mmol) were combined in 3 mL of dioxane and argon was bubbled through for 10 minutes before dicyclohexyl(2',4',6'- triisopropylbiphenyl-2-yl)phosphine (0.018 g, 0.039 mmol) and Pd2dba3 (0.018 g, 0.019 mmol) were added. Argon was bubbled through the reaction for 1 minutes. The reaction flask was sealed and heated to 75 C with stirring for 2.5 hours and then at ambient temperature overnight. The reaction was concentrated under reduced pressure and the crude was purified by silica gel chromatography eluting with EtOAc containing 0.5% NH4OH to afford tert-butyl 3 -(cyanomethyl)-3-(4-(7-( 1 -cyclobutyl- 1 H-pyrazol-4-yl)imidazo [ 1 ,2- c]pyrimidin-5-yl)-l H-pyrazol- l-yl)azetidine-l -carboxylate (0.094 g, 0.19 mmol, 97% yield). MS (apci) m/z = 500.3 (M+H).

References: [1]Patent: WO2011/130146,2011,A1 .Location in patent: Page/Page column 143.

3
[ 1002309-48-9 ]
tert-butyl (3R)-3-([5-chloro-6-(4-cyanophenyl)imidazo[1,5-a]pyridin-8-yl]oxy}-methyl)pyrrolidine-1-carboxylate [ No CAS ]
[ 76-05-1 ]
4-{5-(1-cyclobutyl-1H-pyrazol-4-yl)-8-[(3R)-pyrrolidin-3-ylmethoxy]imidazo[1,5-a]pyridin-6-yl}benzonitrile trifluoroacetic acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: A mixture of tert-butyl (3R)-3-([5-chloro-6-(4-cyanophenyl)imidazo[1,5-a]pyridin-8-yl]oxy}methyl)pyrrolidine-1-carboxylate (Example 6, Step 5: 10 mg, 0.02 mmol), <strong>[1002309-48-9]1-cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (8.2 mg, 0.033 mmol), dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (0.2 mg, 0.0002 mmol) and cesium fluoride (9.0 mg, 0.060 mmol) in tert-butyl alcohol (0.8 mL) and water (0.2 mL) was evacuated and filled with nitrogen. The mixture was stirred at 90 C. for 2 h then cooled to room temperature and filtered. The filtrate was concentrated and the residue was dissolved in methylene chloride (1 mL) then trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at room temperature for 1 h then concentrated. The residue was dissolved in methanol then purified by prep HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C26H27N6O (M+H)+: m/z=439.2. found 439.2

References: [1]Patent: US2016/9712,2016,A1 .Location in patent: Paragraph 0316.

4
[ 1002309-48-9 ]
7-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)benzo[d]thiazol-5-yl trifluoromethanesulfonate [ No CAS ]
(R)-4-((R)-1-((5-(1-cyclobutyl-1H-pyrazol-4-yl)benzo[d]thiazol-7-yl)oxy)ethyl)pyrrolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; palladium diacetate; XPhos; In tetrahydrofuran; at 65℃;Inert atmosphere;	General procedure: To an appropriate-sized vial was added 7-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)benzo[d]thiazol-5-yl trifluoromethanesulfonate (4.04) (1 eq.), boronic acid or pinacol ester (2 eq.), Pd(OAc)2 (3-15 mol %), 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos) (2-3 eq. vs. Pd(OAc)2), and K3PO4 (3 eq.). The vessel was purged with Ar, and the reagents were taken up in THF (ca. 25 volumes versus triflate) and water (75-100 eq.). The resulting mixture was stirred at 65 C. until the reaction was judged complete by HPLC, LC/MS or TLC. In certain cases where incomplete conversion was observed, additional boronic acid/ester, Pd(OAc)2, and XPhos were added. The mixture was diluted with EtOAc, water and brine, and the phases were separated. The aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography to provide Examples 4.07-4.17, summarized in Table B below.

References: [1]Patent: KR2016/37198,2016,A .Location in patent: Paragraph 2559-2562.

5
[ 1002309-48-9 ]
(R)-4-[(R)-1-(6-bromo-3-fluoro-2-methyl-2H-indazol-4-yloxy)ethyl]pyrrolidin-2-one [ No CAS ]
(R)-4-{(R)-1-[6-(1-cyclobutyl-1H-pyrazol-4-yl)-3-fluoro-2-methyl-2H-indazol-4-yloxy]ethyl}pyrrolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43 mg	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 70℃; for 0.75h;	To 8.3 (70 mg) in dioxan (1 mL) and 2M aqueous Na2003 (295 pL) was added borolane 4.8 (48.7 mg) and 1,V-Bis(diphenylphosphino)ferrocenedichloropalladium(ll) (A), 7.2 mg) and the mixture was stirred for 45 mins at 7000. The mixture was filtered via Agilent StratoSpheres PL-Thiol MP SPE using MeOH as eluent and purified via prep HPLC to yield after lyophilisation 43 mg of Example 1.Analysis: HPLC-MS: R1 = 0.68 mm (001_CAO2), M+H = 3981H NMR (DMSO, 400 MHz) 61.31 (3H, d, J=6.1 Hz), 1.78-1.85 (2H, m), 2.17-2.32 (2H, m),2.38-2.44 (3H, m), 2.75-2.77 (1H, m), 3.09-3.13 (1H, m), 3.37 (1H, t, J=9.0 Hz), 3.92 (3H, s),4.73-4.85 (2H, m), 6.66 (1H, s), 7.18 (1H, s), 7.53 (1H, s), 7.96 (1H, s), 8.33 (1H, s)

References: [1]Patent: WO2017/42100,2017,A1 .Location in patent: Page/Page column 59; 60.

6
[ 269410-08-4 ]
[ 4399-47-7 ]
[ 1002309-48-9 ]

Yield	Reaction Conditions	Operation in experiment
5.21%		4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (300 mg, 1.55 mmol) was dissolved in DMF (5 mL) at 0 C under Ar. NaH (60% in oil, 40.8 mg, 1.70 mmol) was added portionwise, and the reaction mixture was then stirred for 20 minutes at rt. A solution of bromocyclobutane (209 mg, 1.55 mmol) in 1 mL of DMF was added, and stirring was continued 2 h at rt. The reaction mixture was quenched with saturated aq. NH4Cl, and then extracted 3x with EtOAc, washed with brine, dried with Na2SO4, filtered and concentrated. The product was purified by silica gel chromatography to provide pyrazole boronate 20A (40 mg, 5.21 %) . MS (ESI): m/z 249.0 (M+H).
		4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CAS 269410-08-4, 1.20 g, 6.18 mmol) was dissolved in DMF (23 mL) and sodium hydride (0.81 g, 18.6 mmol) was added at room temperature (rt). After 10 min, cyclobutyl bromide (2.51 g, 18.6 mmol) was added and the mixture stirred for 2 g at 50 C and further 16 h at rt. The mixture was partitioned between water and ethyl acetate, extracted with ethyl acetate, and the combined organic layers washed with water, dried (Na2SC>4) and concentrated. The crude product (1.14 g, 87% purity, 64% yield) was used without further purification.

References: [1]Patent: WO2017/160632,2017,A1 .Location in patent: Page/Page column 96.
[2]Patent: WO2018/114786,2018,A1 .Location in patent: Page/Page column 152-153.

7
[ 1002309-48-9 ]
[ 6942-37-6 ]
methyl 5-amino-2-(1-cyclobutyl-1H-pyrazol-4-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With dichlorobis(triphenylphosphine)palladium(II); potassium carbonate; In 1,2-dimethoxyethane; water; at 90℃;Inert atmosphere;	methyl 5-amino-2-bromobenzoate (Int 1A, 4.21 g, 18.3 mmol), <strong>[1002309-48-9]1-cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (5.00 g, 20.2 mmol) and potassium carbonate (8.36 g, 60.5 mmol) were dissolved in 1 ,2-dimethoxyethane (67 mL) and water (33 mL) under an atmosphere of nitrogen. Pd(PPh3)2Cl2 (155 mg, 0.22 mmol) was added and the reaction mixture heated at 90 C until completion. The reaction was cooled to RT, diluted with water (100 mL) and extracted with ethyl acetate (75 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried (Na2S04), filtered and concentrated at reduced pressure. The crude product was purified by Biotage Isolera chromatography to give the title compound (4.34 g, 87% yield) as a yellow oil. 1H NMR (500 MHz, DMSO-d6) delta [ppm] 7.73 (d, J = 0.7 Hz, 1 H), 7.37 (d, J = 0.6 Hz, 1 H), 7.11 (d, J = 8.3 Hz, 1 H), 6.80 (d, J = 2.5 Hz, 1 H), 6.70 (dd, J = 8.3, 2.5 Hz, 1 H), 5.31 (s, 2H), 4.86 - 4.73 (m, 1 H), 3.69 (s, 3H), 2.48 -2.31 (m, 4H), 1.83 - 1.71 (m, 2H). LCMS (method 4): Rt = 0.94 min, MS (ESIpos) m/z = 272 (M+H)
9.61 g	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In 1,2-dimethoxyethane; water; at 90℃;Inert atmosphere;	Under an atmosphere of nitrogen to a mixture of methyl 5-amino-2-bromobenzoate (Int. 1A, 11.5 g, 50.38 mmol), <strong>[1002309-48-9]1-cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (15.0 g, 60.45 mmol) and potassium carbonate (22.98 g, 166.24 mmol) in 1,2-dimethoxyethane (183 mL) and water (91 mL) was added Pd(PPh3)2Cl2 (425 mg, 0.61 mmol) and the reaction mixture heated at 90 C. until completion. The reaction was cooled to RT, diluted with water (200 mL) and extracted with ethyl acetate (150 mL). The organic layer was washed with water (100 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated at reduced pressure. The residue was purified by Biotage Isolera chromatography (using a gradient of eluents; 0-40% EE in heptane) to give the title compound (9.61 g, 70% yield) as a golden oil. 1H NMR (500 MHz, DMSO-d6) delta [ppm] 7.73 (d, J=0.7 Hz, 1H), 7.37 (d, J=0.6 Hz, 1H), 7.11 (d, J=8.3 Hz, 1H), 6.80 (d, J=2.5 Hz, 1H), 6.70 (dd, J=8.3, 2.5 Hz, 1H), 5.31 (s, 2H), 4.86-4.73 (m, 1H), 3.69 (s, 3H), 2.48-2.31 (m, 4H), 1.83-1.71 (m, 2H). LCMS (method 3): Rt=0.88 min; MS (ESIPos) m/z=272.8 (M+H)+.

References: [1]Patent: WO2018/114786,2018,A1 .Location in patent: Page/Page column 152.
[2]Patent: US2019/177279,2019,A1 .Location in patent: Paragraph 0786-0789.

8
[ 1002309-48-9 ]
2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoic acid [ No CAS ]

References: [1]Patent: WO2018/114786,2018,A1 .
[2]Patent: WO2018/114786,2018,A1 .

9
[ 1002309-48-9 ]
methyl 5-amino-2-(1-cyclobutyl-1H-pyrazol-4-yl)benzoate [ No CAS ]

References: [1]Patent: WO2018/114786,2018,A1 .
[2]Patent: US2019/177279,2019,A1 .

10
[ 1002309-48-9 ]
ethyl 5-amino-2-(1-cyclobutyl-1H-pyrazol-4-yl)-3-fluorobenzoate [ No CAS ]

References: [1]Patent: WO2018/114786,2018,A1 .

11
[ 1002309-48-9 ]
methyl 5-([1-(3-chlorophenyl)cyclopropyl]carbonyl}amino)-2-(1-cyclobutyl-1H-pyrazol-4-yl)benzoate [ No CAS ]

References: [1]Patent: WO2018/114786,2018,A1 .
[2]Patent: WO2018/114786,2018,A1 .

12
[ 1002309-48-9 ]
methyl 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-[({1-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)amino]benzoate [ No CAS ]

References: [1]Patent: WO2018/114786,2018,A1 .
[2]Patent: WO2018/114786,2018,A1 .

13
[ 1002309-48-9 ]
ethyl 5-([1-(4-chlorophenyl)cyclopropyl]carbonyl}amino)-2-(1-cyclobutyl-1H-pyrazol-4-yl)-3-fluorobenzoate [ No CAS ]

References: [1]Patent: WO2018/114786,2018,A1 .

14
[ 1002309-48-9 ]
ethyl 5-amino-2-bromo-3-fluorobenzoate [ No CAS ]
ethyl 5-amino-2-(1-cyclobutyl-1H-pyrazol-4-yl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; In tetrahydrofuran; water; at 60℃; for 16h;Inert atmosphere; Sealed tube;	A mixture of <strong>[1002309-48-9]1-cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (440 mg, 1 .77 mmol), ethyl 5-amino-2-bromo-3-fluorobenzoate (310 mg, 1 .18 mmol), palladium(ll) acetate (13 mg, 0.06 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (48 mg, 0.12 mmol) and potassium phosphate (752 mg, 3.55 mmol) in tetrahydrofuran/water (7: 1 v/v/; 5.9 mL) in a pressure tube was degassed with nitrogen for 5 minutes. After this time the tube was sealed and the reaction mixture warmed to 60 C for 16 h. The reaction mixture was allowed to cool to room temperature and was partitioned between EtOAc and saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was removed and the organic layer was washed with saturated aqueous sodium chloride solution, dried (MgS04), filtered and concentrated at reduced pressure. The residue was purified by Biotage Isolera chromatography (eluting with a gradient of eluents; 100% heptane to 6:4 heptane/ EtOAc) giving the title compound (470 mg, 86% yield) as a pale yellow solid. 1H NMR (250 MHz, DMSO-d6) delta [ppm] 7.70 (s, 1 H), 7.33 (s, 1 H), 6.66 (d, J = 2.3 Hz, 1 H), 6.53 (dd, J = 12.6, 2.3 Hz, 1 H), 5.67 (s, 2H), 4.83 (m, 1 H), 4.11 (q, J = 7.1 Hz, 2H), 2.45 -2.28 (m, 4H), 1.87 - 1.69 (m, 2H), 1.07 (t, J = 7.1 Hz, 3H). LCMS (Analytical Method A) Rt = 1.11 min, MS (ESIPos): m/z = 304.05 (M+H)

References: [1]Patent: WO2018/114786,2018,A1 .Location in patent: Page/Page column 200-201.

15
[ 1002309-48-9 ]
ethyl 5-amino-2-bromo-3-fluorobenzoate [ No CAS ]
ethyl 5-([1-(4-chlorophenyl)cyclopropyl]carbonyl}amino)-2-(1-cyclobutyl-1H-pyrazol-4-yl)-3-fluorobenzoate [ No CAS ]

References: [1]Patent: WO2018/114786,2018,A1 .

16
[ 1002309-48-9 ]
ethyl 3-fluoro-5-nitro-2-[(trifluoromethyl)sulfonyl]oxy}-benzoate [ No CAS ]
ethyl 2-(1-cyclobutyl-1H-pyrazol-4-yl)-3-fluoro-5-nitrobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With dichlorobis(triphenylphosphine)palladium(II); potassium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 1h;Inert atmosphere;	A mixture of <strong>[1002309-48-9]1-cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (7.56 g, 30.45 mmol), Pd(PPh3)2Cl2 (388 mg, 0.55 mmol), K2C03 (7.65 g, 55.37 mmol) and ethyl 3-fluoro-5-nitro-2-[(trifluoromethyl)sulfonyl]oxy}benzoate (Int 100A, 10.00 g, 27.68 mmol) was split equally between 8 pressure tubes and dissolved in DME/water (10:1 , 8 x 17.3 mL) and the resulting solutions were degassed with nitrogen for 5 minutes. The reaction vessels were sealed and heated to 100 C for 1 hour. The reaction mixtures were then cooled to room temperature, combined and diluted with ethyl acetate and washed with 1M aqueous sodium hydroxide solution, then saturated aqueous sodium chloride solution, dried (MgS04), filtered and concentrated at reduced pressure. The residue was purified by Biotage Isolera chromatography (eluting with a gradient of eluents; 100% heptane to 85:15 heptane/ EtOAc) giving the desired product (8.65 g, 94% yield) as a pale yellow oil. 1H NMR (250 MHz, chloroform-d) delta [ppm] 8.34 (dd, J = 2.3, 1.2 Hz, 1 H), 8.10 (dd, J = 9.6, 2.4 Hz, 1 H), 7.77 (d, J = 2.2 Hz, 1 H), 7.68 (s, 1 H), 4.84 (m, 1 H), 4.35 (q, J = 7.1 Hz, 2H), 2.71-2.47 (m, 4H), 2.04 - 1.84 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H). LCMS (Analytical Method A): Rt = 1.30 mins; MS (ESIPos): m/z = 334.0 (M+H)+.
94%	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 1h;Inert atmosphere; Sealed tube;	A biphasic mixture of <strong>[1002309-48-9]1-cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (7.56 g, 30.45 mmol), Pd(PPh3)2Cl2 (388 mg, 0.55 mmol), K2CO3 (7.65 g, 55.37 mmol) and ethyl 3-fluoro-5-nitro-2-[(trifluoromethyl)sulfonyl]oxy}benzoate (10.00 g, 27.68 mmol) was split equally between 8 pressure tubes and dissolved in DME/water (10:1, 8*17.3 mL) and the resulting solutions were degassed with nitrogen for 5 minutes. The reaction vessels were sealed and heated to 100 C. for 1 hour. The reaction mixtures were then cooled to room temperature, combined and diluted with ethyl acetate and washed with 1M aqueous sodium hydroxide solution, then saturated aqueous sodium chloride solution, dried (MgSO4), filtered and concentrated at reduced pressure. The residue was purified by Biotage Isolera chromatography (using a gradient of eluents; 0-15% EE in heptane) giving the title compound (8.65 g, 94% yield) as a pale yellow oil. 1H NMR (250 MHz, Chloroform-d) delta [ppm] 8.34 (dd, J=2.3, 1.2 Hz, 1H), 8.10 (dd, J=9.6, 2.4 Hz, 1H), 7.77 (d, J=2.2 Hz, 1H), 7.68 (s, 1H), 4.84 (m, 1H), 4.35 (q, J=7.1 Hz, 2H), 2.71-2.47 (m, 4H), 2.04-1.84 (m, 2H), 1.30 (t, J=7.1 Hz, 3H). LCMS (Analytical Method A): Rt=1.30 min; MS (ESIPos) m/z=334.0 (M+H)+.

References: [1]Patent: WO2018/114786,2018,A1 .Location in patent: Page/Page column 193.
[2]Patent: US2019/177279,2019,A1 .Location in patent: Paragraph 0853-0856.

17
[ 1002309-48-9 ]
[ 1103234-34-9 ]
ethyl 3-amino-6-(1-cyclobutyl-1H-pyrazol-4-yl)-2-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; In tetrahydrofuran; water; at 80℃; for 16h;Inert atmosphere;	A mixture of 1-cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole (934 mg, 3.76 mmol), ethyl 3-amino-6-chloro-2-fluorobenzoate (Int 125A, 700 mg, 2.51 mmol), palladium(ll) acetate (28 mg, 0.13 mmol), 2- dicyclohexylphosphino-2',6'-dimethoxybiphenyl (103 mg, 0.25 mmol) and potassium phosphate (1.60 g, 3.55 mmol) in tetrahydrofuran /water (7:1 v/v; 12.5 mL) in a pressure tube was degassed with nitrogen for 5 minutes. After this time the reaction mixture heated at 80 C for 16 h. The reaction mixture was allowed to cool to room temperature and was then partitioned between EtOAc and saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was removed and the organic layer was washed with saturated aqueous sodium chloride solution, dried (MgS04), filtered and concentrated at reduced pressure. The residue was purified by Biotage Isolera chromatography (eluting with a gradient of eluents; 100% heptane to 6:4 heptane/ EtOAc) giving the title compound (733 mg, 94% yield) as a dark yellow oil. 1H NMR (250 MHz, DMSO-d6) delta [ppm] 7.65 (d, J = 0.6 Hz, 1 H), 7.34 - 7.28 (m, 1 H), 6.91 (dd, J = 8.3, 0.7 Hz, 1 H), 6.73 (dd, J = 9.3, 8.4 Hz, 1 H), 5.24 (s, 2H), 4.71 (m, 1 H), 4.15 (q, J = 7.1 Hz, 2H), 2.36 -2.19 (m, 4H), 1.75 - 1.59 (m, 2H), 1.08 (t, J = 7.1 Hz, 3H). LCMS (Analytical Method A) Rt = 1.11 min, MS (ESIpos): m/z = 304.55 (M+H)+.

References: [1]Patent: WO2018/114786,2018,A1 .Location in patent: Page/Page column 208.

18
[ 1002309-48-9 ]
ethyl 2-bromo-3-chloro-5-nitrobenzoate [ No CAS ]
ethyl 3-chloro-2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-nitrobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With dichlorobis(triphenylphosphine)palladium(II); potassium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 2.5h;Inert atmosphere; Sealed tube;	In a sealed tube, <strong>[1002309-48-9]1-cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (500 mg, 2.02 mmol) and ethyl 2-bromo-3-chloro-5-nitrobenzoate (Int 128A, 478 mg, 1.55 mmol) in DME (8 mL) and water (1.5 mL) was degassed with nitrogen for 5 minutes. Pd(PPh3)2Cl2 (22 mg, 0.03 mmol) and potassium carbonate (643 mg, 4.65 mmol) were then added and the reaction was heated to 100 C for 2.5 hours. The reaction was then cooled to room temperature and diluted with water and EtOAc. The layers were separated and the aqueous was extracted twice with EtOAc. Combined organic extracts were dried over MgS04, filtered, concentrated under reduced pressure and the residue obtained was purified by Biotage Isolera chromatography (eluting with a gradient of eluents, 0-25% EtOAc in heptane) to afford the title compound (385 mg, 52% yield) as a viscous pale yellow oil. 1H NMR (250 MHz, chloroform-d) delta [ppm] 8.44 (d, J = 2.4 Hz, 1 H), 8.40 (d, J = 2.4 Hz, 1 H), 7.65 (m, 1 H), 7.60 (m, 1 H), 4.84 (m, 1 H), 4.24 (q, J = 7.1 Hz, 2H), 2.69 -2.48 (m, 4H), 2.06 - 1 .81 (m, 2H), 1 .18 (t, J = 7.1 Hz, 3H). LCMS (Analytical Method A) Rt = 1 .29 min, MS (ESIpos): m/z = 350.0 (M+H)

References: [1]Patent: WO2018/114786,2018,A1 .Location in patent: Page/Page column 209-210.

19
[ 1002309-48-9 ]
ethyl 2-bromo-3-chloro-5-nitrobenzoate [ No CAS ]
ethyl 5-amino-3-chloro-2-(1-cyclobutyl-1H-pyrazol-4-yl)benzoate [ No CAS ]

References: [1]Patent: WO2018/114786,2018,A1 .

20
[ 1002309-48-9 ]
ethyl 2-bromo-3-methyl-5-nitrobenzoate [ No CAS ]
ethyl 2-(1-cyclobutyl-1H-pyrazol-4-yl)-3-methyl-5-nitrobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With dichlorobis(triphenylphosphine)palladium(II); potassium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 16h;Inert atmosphere;	A mixture of ethyl 2-bromo-3-methyl-5-nitrobenzoate (Int 138A, 0.576 g, 2.00 mmol), <strong>[1002309-48-9]1-cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (0.744 g, 3.00 mmol), potassium carbonate (0.829 g, 6.00 mmol) and dichlorobis(triphenylphosphine)palladium(ll) (28 mg, 0.04 mmol) in dimethoxyethane/water (10 mL; 2: 1 v/v) was degassed by bubbling nitrogen through the mixture for 5 minutes and then heated at 100 C for 16 hours. The mixture was then allowed to cool to room temperature and filtered through Celite (washing with EtOAc). The organic layer was washed with saturated aqueous sodium chloride solution, dried (MgS04), filtered and concentrated at reduced pressure. The residue purified by Biotage Isolera chromatography (eluting with a gradient of eluents; 100% heptane to 8:2 heptane/ EtOAc) giving the title compound (0.56 g, 84% yield) as a pale yellow oil. 1H NMR (250 MHz, chloroform-d) delta [ppm] 8.35 (d, J = 2.2 Hz, 1 H), 8.22 (d, J = 1 .9 Hz, 1 H), 7.49 (m, 1 H), 7.46 (m, 1 H), 4.83 (m, 1 H), 4.18 (q, J = 7.1 Hz, 2H), 2.66 -2.50 (m, 4H), 2.39 (s, 3H), 2.02 - 1 .86 (m, 2H), 1 .14 (t, J = 7.1 Hz, 3H). LCMS (Analytical Method A): Rt = 1 .35 min, MS (ESIPos): m/z = 330.05 (M+H)

References: [1]Patent: WO2018/114786,2018,A1 .Location in patent: Page/Page column 214-215.

21
[ 1002309-48-9 ]
ethyl 2-bromo-3-methyl-5-nitrobenzoate [ No CAS ]
ethyl 5-amino-2-(1-cyclobutyl-1H-pyrazol-4-yl)-3-methylbenzoate [ No CAS ]

References: [1]Patent: WO2018/114786,2018,A1 .

22
[ 1002309-48-9 ]
[ 6942-36-5 ]
methyl 2-(1-cyclobutyl-1H-pyrazol-4-yl)-5-nitrobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With dichlorobis(triphenylphosphine)palladium(II); potassium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 2h;Inert atmosphere;	<strong>[1002309-48-9]1-cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (1.5 g, 6.0 mmol) and methyl 2-bromo-5-nitrobenzoate (1.66 g, 6.0 mmol) in DME (30 mL) and water (15 mL) was degassed with nitrogen for 5 minutes. Bis(triphenylphosphine)-palladium(ll) dichloride (127 mg, 0.18 mmol) and potassium carbonate (2.5 g, 18.1 mmol) were added and the reaction heated with stirring at 100 C for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine (2 x 30 mL), dried (Na2S04), filtered and concentrated at reduced pressure. The residue was purified by Biotage Isolera chromatography (silica gel; using a gradient of eluents; 0-50% EtOAc in heptane) to give the title compound (1.72 g, 72% yield) as a yellow oil. 1H NMR (500 MHz, DMSO-d6) delta [ppm] 8.43 (d, J = 2.5 Hz, 1 H), 8.33 (dd, J = 8.7, 2.6 Hz, 1 H), 8.20 (s, 1 H), 7.83 (d, J = 8.7 Hz, 1 H), 7.72 (s, 1 H), 4.97 - 4.81 (m, 1 H), 3.85 (s, 3H), 2.45 -2.33 (m, 2H), 1.87 - 1.76 (m, 2H). LCMS (Analytical Method A): R t= 1.19 mins, MS (ESIPos): m/z = 302 (M+H)
72%	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 2h;Inert atmosphere;	1-Cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.50 g, 6.0 mmol) and methyl 2-bromo-5-nitrobenzoate (1.66 g, 6.0 mmol) in DME (30 mL) and water (15 mL) was degassed with nitrogen for 5 minutes. Pd(PPh3)2Cl2 (127 mg, 0.18 mmol) and K2CO3 (2.5 g, 18.1 mmol) were then added and the reaction was heated to 100 C. for 2 hours. The reaction was then cooled to RT and diluted with water (30 mL) and extracted with EE (50 mL). The organic layer was then washed with brine (2*30 mL), dried (Na2SO4), filtered and concentrated at reduced pressure. The residue was purified by Biotage Isolera chromatography (using a gradient of eluents; 0-50% EE in heptane) to afford the title compound (1.72 g, 72% yield) as a yellow oil. 1H NMR (500 MHz, DMSO-d6) delta 8.43 (d, J=2.5 Hz, 1H), 8.33 (dd, J=8.7, 2.6 Hz, 1H), 8.20 (s, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.72 (s, 1H), 4.97-4.81 (m, 1H), 3.85 (s, 3H), 2.45-2.33 (m, 4H), 1.87-1.76 (m, 2H). LCMS (Analytical Method A): Rt=1.19 min; MS (ESIPos) m/z=302 (M+H)+.

References: [1]Patent: WO2018/114786,2018,A1 .Location in patent: Page/Page column 155.
[2]Patent: US2019/177279,2019,A1 .Location in patent: Paragraph 0810-0813.

23
[ 1002309-48-9 ]
methyl 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate [ No CAS ]
C₁₉H₁₇ClN₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With [2,2]bipyridinyl; copper diacetate; sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 20℃; for 96h;	Methyl 6-(4-chlorophenyl)-3-oxo-2,3-di hydropyridazi ne-4-carboxylate (0.5 g, 1 .89 mmcl) was dissolved in DMF (15 mL). 1 -Cyclobutyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1H-pyrazole (1406 mg, 5.67 mmol), 2,2?-bipyridine (737.7 mg, 4.72 mmol), sodium hydrogen carbonate (318 mg, 3.78 mmol), and anhydrous copper diacetate (429 mg, 3.79 mmol) wereadded. It was stirred for 96 h at rt. Water was added and the pH was adjusted to 3 with 2N HCI. The precipitate was filtered, washed three times with water, and dried at 50C under vacuum to afford 370 mg (36%) of the methyl ester which was used in the successive step without further purification.

References: [1]Patent: WO2018/146010,2018,A1 .Location in patent: Page/Page column 73.

24
[ 1002309-48-9 ]
55-bromo-14H-6-oxa-3-aza-2(2,6)-pyridina-1(3,4)-triazola-5(1,2)-benzenacyclodecaphan-4-one [ No CAS ]
55-(1-cyclobutyl-1H-pyrazol-4-yl)-14H-6-oxa-3-aza-2(2,6)-pyridina-1(3,4)-triazola-5(1,2)-benzenacyclodecaphan-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In dimethyl sulfoxide; at 80℃; for 2h;Inert atmosphere;	A reaction vial was charged with l-cyclobutyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)- lH-pyrazole (49 mg, 0.20 mmol), 55-bromo- l4H-6-oxa-3-aza-2(2,6)-pyridina- 1(3,4)- triazola-5(l,2)-benzenacyclodecaphan-4-one (75 mg, 0.18 mmol), Pd(dppf)Cl2 (13 mg, 0.02 mmol) and K3P04 (80 mg, 0.38 mmol). The vial was purged with N2 for 10 min. DMSO (1 mL) was added and the resulting mixture was heated to 80 C for 2 h. After this time, the reaction mixture was allowed to reach room temperature and the solids were removed by filtration. The filtrate was subjected to HPLC purification (using an XTerra Prep RP18 OBD, 10 muiotaeta 50x250mm column and using water (containing 0.1% TFA)/CH3CN from 90/10 to 40/60 as the mobile phase at a flow rate of 50 mL/min) to give the title compound (57 mg, 56%) as a white solid. 1H NMR (400 MHz, DMSO-i) delta ppm 11.30 (s, IH), 8.77 (s, IH), 8.34 (d, 7=0.8 Hz, IH), 8.16 (d, 7=2.5 Hz, IH), 8.05 - 8.12 (m, IH), 7.90 - 7.94 (m, 2H), 7.87 (dd, 7=0.8, 7.8 Hz, IH), 7.81 (dd, 7=2.5, 8.5 Hz, IH), 7.31 (d, 7=8.8 Hz, IH), 4.84 (quin, 7=8.5 Hz, IH), 4.35 (br t, 7=5.0 Hz, 2H), 4.25 - 4.32 (m, 2H), 2.35 - 2.56 (m, 6H), 1.97 (br d, 7=6.0 Hz, 2H), 1.75 - 1.86 (m, 2H). MS (ESI): 456.2 [M + H]+.

References: [1]Patent: WO2018/148204,2018,A1 .Location in patent: Page/Page column 57-58.

25
[ 1002309-48-9 ]
N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-chloro-2-methoxybenzenesulfonamide [ No CAS ]
4-chloro-N-((1S,2R)-2-(3-(1-cyclobutyl-1H-pyrazol-4-yl)-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-methoxybenzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 1h;	General procedure: To a 1,4-dioxane (1.0 mL) solution of N-((1S,2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-chloro-2-methoxybenzenesulfonamide (11 mg), 4-methoxyphenylboronic acid (5.0 mg),[1,1?-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct (4.0 mg), and a sodium carbonateaqueous solution (2 M, 100 mL) was added sequentially at room temperature, and the reaction solution wasstirred at 100 C for 1 hour. The reaction solution was allowed to cool to room temperature, insoluble matter was removedby CELITE filtration, and the residue was washed with hexane / ethyl acetate = 1/1 (10 mL). The combined filtrate wasconcentrated under reduced pressure, and the obtained residue was purified by reverse phase HPLC (water / acetonitrile)to give the title compound.

References: [1]Patent: EP3466934,2019,A1 .Location in patent: Paragraph 0496; 0497.

26
[ 1002309-48-9 ]
methyl 5-([2-(3-chlorophenyl)cyclopropyl]carbonyl}amino)-2-(1-cyclobutyl-1H-pyrazol-4-yl)benzoate [ No CAS ]

References: [1]Patent: US2019/177279,2019,A1 .

27
[ 1002309-48-9 ]
5-([trans-2-(3-chlorophenyl)cyclopropyl]carbonyl}amino)-2-(1-cyclobutyl-1H-pyrazol-4-yl)benzoic acid [ No CAS ]

References: [1]Patent: US2019/177279,2019,A1 .

28
[ 1002309-48-9 ]
(R)-N-(1-(2,5-difluorophenyl)ethyl)-3-iodopyrazolo[1,5-a]pyrimidin-5-amine [ No CAS ]
C₂₁H₂₀F₂N₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 2h;Inert atmosphere;	General procedure: Add N- (2,5-difluorobenzyl) -3-iodopyrazolo [1,5-a] pyrimidin-5-amine (0.52 mmol), 1-Boc-pyrazole-4-boronic acid pinacol Ester (0.78 mmol), anhydrous potassium carbonate (2.08 mmol), tetrakis (triphenylphosphine) palladium (0.052 mmol) were added to a 100 ml reaction tube, replaced with argon 3 times, and 10 ml of anhydrous DMF and 2 ml of water were added.The reaction was performed at 100 C for 2 h under an argon atmosphere, and monitored by TLC (petroleum ether: acetone = 2: 1).After the reaction was completed, it was cooled to 50 C, filtered through celite, and the filtrate was added with water and extracted with ethyl acetate.The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude oily black product. The crude product was purified by column chromatography (TLC, petroleum ether: acetone = 2: 1) to obtain a pale yellow solid.

References: [1]Patent: CN110734437,2020,A .Location in patent: Paragraph 0092-0093; 0098-0099; 0236-0237; 0240; 0265-0266.

Historical Records

Related Functional Groups of
[ 1002309-48-9 ]

Organoborons

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Pyrazoles

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P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

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

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CAS No.: 1002309-48-9

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