313735-62-5|4-Bromo-1-isopropylpyrazole| Ambeed

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Quality Control of [ 313735-62-5 ] Purity: 97% SDS Specification

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Product Details of [ 313735-62-5 ]

CAS No. :	313735-62-5
Formula :	C₆H₉BrN₂
M.W :	189.05
SMILES Code :	CC(N1N=CC(Br)=C1)C
MDL No. :	MFCD09801021
InChI Key :	HYWPFIXULAMLRZ-UHFFFAOYSA-N
Pubchem ID :	22329200

Safety of [ 313735-62-5 ]

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

Computational Chemistry of [ 313735-62-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	9
Num. arom. heavy atoms	5
Fraction Csp3	0.5
Num. rotatable bonds	1
Num. H-bond acceptors	1.0
Num. H-bond donors	0.0
Molar Refractivity	40.8
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	17.82 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.16
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	1.63
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.23
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.	1.51
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	1.44
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.79

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.38
Solubility	0.781 mg/ml ; 0.00413 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.62
Solubility	4.57 mg/ml ; 0.0242 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	-2.09
Solubility	1.55 mg/ml ; 0.00818 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	No
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.	-6.3 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	1.0
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	0.0 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)	1.53

Application In Synthesis of [ 313735-62-5 ]

* 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 [ 313735-62-5 ]

[ 313735-62-5 ] Synthesis Path-Downstream 1~36

1
[ 2075-45-8 ]
[ 75-30-9 ]
[ 313735-62-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;	A sealable vessel was charged with potassium carbonate (3.76 g, 27.2 mmol), 4-bromo- lH-pyrazole (4.00 g, 27.2 mmol), and 10 mL DMF. To this mixture, 2-iodopropane (3.27 ml, 32.7 mmol) was added and the <n="115"/>vessel sealed. The mixture was heated at 80 C for 16 h and allowed to cool to rt . The mixture was diluted with EtOAc, extracted with water, water, sat NaHCO3, and the organic layer dried over Na2SO4, filtered and evaporated. The mixture was purified via flash chromatography using a EtOAc in CH2C12 gradient. The desired compound (as determined by TLC, 12 stain) was collected as a colorless liquid.
		To a solution of 4-bromo-1H-pyrazole (20 g, 0.137 mol)in DMF (60 mL) was added NaH (60 wtin oil, 8.2 g, 0.203 mol) at 0 .The resulting mixture was stirred for 30 mins at 0 ,then a solution of 2-iodopropane (25.6 g, 0.15 mol) indioxane (10 mL) was added dropwise at 0 . Theresulting mixture was stirred at RT overnight, quenched with water (50 mL) ,and extracted with EtOAc (30 mL x 3) . The combined organic layers were washedwith brine, dried over Na2SO4, filtered, and concentratedin vacuo. The residue was purified by silica gel column chromatography (7EtOAc in petroleum ether) to give the title compound as a solid.LRMS m/z (M+H) 189.1, 191.1 found, 189.2, 191.2 required.

References: [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 529 - 541.
[2]Patent: WO2008/8539,2008,A2 .Location in patent: Page/Page column 113-114.
[3]Journal of Medicinal Chemistry,2011,vol. 54,p. 6342 - 6363.
[4]Patent: WO2016/65587,2016,A1 .Location in patent: Page/Page column 33-34.

2
[ 313735-62-5 ]
1-(propan-2-yl)-1H-pyrazole-4-carbaldehyde [ No CAS ]

References: [1]Patent: EP1186604,2002,A1 .Location in patent: Page 116.

3
[ 2075-45-8 ]
[ 75-03-6 ]
[ 313735-62-5 ]

References: [1]Patent: EP1186604,2002,A1 .Location in patent: Page 115-116.

4
[ 313735-62-5 ]
[ 1461-22-9 ]
[ 1200131-52-7 ]

Yield	Reaction Conditions	Operation in experiment
94%		n--Butyllithium (2.5M in hexanes, 1.38 mL, 3.45 mmol) was added over 15 min to a solution of <strong>[313735-62-5]4-bromo-1-isopropyl-1H-pyrazole</strong> (500 mg, 2.65 mmol) in diethyl ether (10 mL) at -78 C. After 30 min, a solution of tri-n-butylstannane chloride (920 muL, 3.45 mmol) in diethyl ether (1 mL) was added and the resultant reaction mixture was left to stir at -78 C for 1 h, then allowed to warm to ambient temperature. The reaction mixture was diluted with diethyl ether (40 mL) and washed with water (20 mL), then brine (20 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford the title product as a colourless oil (98 mg, 94%) which was used without further purification. 1H-NMR (CDCl3, 400MHz): 7.46- 7.42 (m, 1 H); 7.28 (t, J = 4.2Hz, 1 H); 4.59-4.43 (m, 1 H); 1.58-1.42 (m, 12 H); 1.39-1.24 (m, 6 H); 1.02-0.77 (m, 15 H).

References: [1]Patent: WO2009/151598,2009,A1 .Location in patent: Page/Page column 163.

5
[ 313735-62-5 ]
3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-amine [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 6342 - 6363.

6
[ 313735-62-5 ]
[ 73183-34-3 ]
[ 879487-10-2 ]

Yield	Reaction Conditions	Operation in experiment
67%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 100℃; for 12h;Inert atmosphere; Sealed tube;	b) l-Isopropyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole To a degassed (N2 bubbling) solution of the compound of Intermediate Example 12(a) 4-bromo-l-isopropyl-lH-pyrazole (1.5 g, 7.9 mmol) in 1,4-dioxane (30 ml) were added 4,4,4',4,,5,5,5',5'-octamethyl-2,2*-bi(l,3,2-dioxaborolane) (3 g, 1 1.84 mmol, 1.5 eq.), Pd(dppf)Cl2 (0.64 g, 0.79 mmol, 0.1 eq.) and potassium acetate (1.93 g, 19.74 mmol, 2.5 eq.) using the procedure of Intermediate Example 1(b). The solvent was distilled off to afford the product in 67 % yield (1.2 g). LC-MS (ESI): Calculated mass: 236.12; Observed mass: 237.1 [M+H]+ (rt: 1.41 min).
67%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 100℃; for 12h;Sealed tube; Inert atmosphere;	To a degassed (N2 bubbling) solution of the compound of Intermediate Example 12(a) <strong>[313735-62-5]4-bromo-1-isopropyl-1H-pyrazole</strong> (1.5 g, 7.9 mmol) in 1,4-dioxane (30 ml) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3 g, 11.84 mmol, 1.5 eq.), Pd(dppf)Cl2 (0.64 g, 0.79 mmol, 0.1 eq.) and potassium acetate (1.93 g, 19.74 mmol, 2.5 eq.) using the procedure of Intermediate Example 1(b). The solvent was distilled off to afford the product in 67% yield (1.2 g). LC-MS (ESI): Calculated mass: 236.12; Observed mass: 237.1 [M+H]+ (rt: 1.41 min).
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,2-dimethoxyethane; water; at 95℃;Inert atmosphere;	To a solution of the product from Step 1 (4.2 g, 0.02 mol) , 4, 4, 4', 4',5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (11.3 g, 0.04 mol) ,and KOAc (4.38 g, 0.04 mol) in DME/H2O (3: 1, 15 mL) was added Pd(dppf) Cl2 (0.8 g, 1.0 mmol) . The resulting mixture was heated at95 under N2overnight. After cooling to RT, the mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography (5EtOAc in petroleum ether) to give thetitle compound as an oil. LRMS m/z (M+H) 237.2 found, 237.2 required.

References: [1]Patent: WO2013/53983,2013,A1 .Location in patent: Page/Page column 35; 36.
[2]Patent: US2015/11548,2015,A1 .Location in patent: Paragraph 0149.
[3]Journal of Medicinal Chemistry,2011,vol. 54,p. 6342 - 6363.
[4]Patent: WO2016/65587,2016,A1 .Location in patent: Page/Page column 33-34.

7
[ 313735-62-5 ]
methyl 7-(4-butoxyethoxyphenyl)-1-[(1-isopropylpyrazol-4-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylate [ No CAS ]

References: [1]Patent: EP1186604,2002,A1 .

8
[ 313735-62-5 ]
C₃₀H₃₆ClN₃O₃ [ No CAS ]

References: [1]Patent: EP1186604,2002,A1 .

9
[ 313735-62-5 ]
7-(4-butoxyethoxyphenyl)-1-[(1-isopropylpyrazol-4-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid [ No CAS ]

References: [1]Patent: EP1186604,2002,A1 .

10
[ 313735-62-5 ]
7-(4-butoxyethoxyphenyl)-1-[(1-isopropylpyrazol-4-yl)methyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide [ No CAS ]

References: [1]Patent: EP1186604,2002,A1 .

11
[ 2075-45-8 ]
[ 75-26-3 ]
[ 313735-62-5 ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;	a) 4-Bromo- 1 -isopropyl- 1 H-pyrazoleTo a solution of 4-bromo-l H-pyrazole (5 g, 34 mmol) in DMF (70 ml) were added 2C03 (11.83 g, 85.6 mmol, 2.5 eq.) and 2-bromopropane (6.3 g, 51.36 mmol, 1.5 eq.) and the mixture was stirred at RT for 12 h. The mixture was quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off and the crude residue was purified by column chromatography (60-120 silica gel, 20 % ethyl acetate in hexane) to afford the product in 89 % yield (5.8 g). 1H NMR (300 MHz, DMSO-i¾): delta 8.01 (s, 1H), 7.50 (s, 1H), 4.49-4.43 (m, 1H), 1.38 (d, 6H).
89%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;	To a solution of 4-bromo-1H-pyrazole (5 g, 34 mmol) in DMF (70 ml) were added K2CO3 (11.83 g, 85.6 mmol, 2.5 eq.) and 2-bromopropane (6.3 g, 51.36 mmol, 1.5 eq.) and the mixture was stirred at RT for 12 h. The mixture was quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off and the crude residue was purified by column chromatography (60-120 silica gel, 20% ethyl acetate in hexane) to afford the product in 89% yield (5.8 g). 1H NMR (300 MHz, DMSO-d6): delta 8.01 (s, 1H), 7.50 (s, 1H), 4.49-4.43 (m, 1H), 1.38 (d, 6H).
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 10h;	[0001187] To a solution of 4-bromo-lH-pyrazole (2.92 g, 20.0 mmol) in anhydrous DMF (50 mL) was added 2-bromopropane (3.69 g, 30.0 mmol) and potassium carbonate (6.90 g, 50 mmol) at room temperature. The reaction mixture was stirred for 10 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic extracts were washed with brine (150 mL x 2) and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo and the residue was purified with flash column chromatography on silica gel to give Compound 330A.

References: [1]Patent: WO2013/53983,2013,A1 .Location in patent: Page/Page column 35.
[2]Patent: US2015/11548,2015,A1 .Location in patent: Paragraph 0148.
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 770 - 792.
[4]Patent: WO2015/42397,2015,A1 .Location in patent: Paragraph 0001187.
[5]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 4405 - 4411.

12
[ 313735-62-5 ]
[ 350-46-9 ]
[ 1609560-82-8 ]

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 770 - 792.

13
[ 313735-62-5 ]
[ 1541194-15-3 ]

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 770 - 792.
[2]Patent: WO2014/74715,2014,A1 .

14
[ 313735-62-5 ]
trans-N-(4-((1-isopropyl-1H-pyrazol-4-yl)sulfonyl)phenyl)-2-(pyridin-3-yl)cyclopropanecarboxamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 770 - 792.

15
[ 313735-62-5 ]
[ 1541194-03-9 ]

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 770 - 792.

16
[ 313735-62-5 ]
[ 1541194-04-0 ]

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 770 - 792.

17
[ 313735-62-5 ]
trans-N-[4-[1-(propan-2-yl)-1H-pyrazole-4-sulfonyl]phenyl]-2-(pyridin-3-yl)cyclopropane-1-carboxamide [ No CAS ]

References: [1]Patent: WO2014/74715,2014,A1 .

18
[ 313735-62-5 ]
[ 1609560-81-7 ]

Yield	Reaction Conditions	Operation in experiment
47%		To a solution of 4-bromo-l- (propan-2-yl)-lH-pyrazole (2 g, 10.58 mmol, 1.00 equiv) in Et20 (20 mL) maintained under nitrogen at -78 C was added dropwise a 2.5 M n-butyllithium solution (4.6 mL) in hexane. The reaction mixture was stirred at -78 C for 1 h. Sulfur dioxide gas was then bubbled in for 30 min. The reaction mixture was stirred at -78 C for 30 min and then warmed to rt. The solid was collected by filtration, washed with Et20 and dried in a vacuum to give 0.9 g (47%) of the title compound as a white solid. LCMS (Method G, ESI): RT =1.03 min, m/z = 191.0.

References: [1]Patent: WO2014/74715,2014,A1 .Location in patent: Paragraph 0204.
[2]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 529 - 541.

19
[ 313735-62-5 ]
[ 1609560-82-8 ]

References: [1]Patent: WO2014/74715,2014,A1 .

20
[ 313735-62-5 ]
ethyl 2-oxo-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate [ No CAS ]
C₁₄H₁₄N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 110℃; for 2h;Inert atmosphere;	[0001188] To a solution of Compound 330A (189 mg, 1.0 mmol) in 1,4-dioxane (10 mL) was added Intermediate 175B (304 mg, 1.0 mmol), Pd(dppf)Cl2 (35 mg, 0.05 mmol), sodium carbonate (318 mg, 3.0 mmol), and water (1 mL) under nitrogen. The reaction mixture was stirred at 110 C for 2 hours. The resulting mixture was cooled to 25 C. The precipitated solid was filtered and dried to afford Compound 330B.

References: [1]Patent: WO2015/42397,2015,A1 .Location in patent: Paragraph 0001188.

21
[ 313735-62-5 ]
ethyl 2-oxo-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate [ No CAS ]
N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(4-(1-isopropyl-1H-pyrazol-4-yl)phenyl)-2-oxoacetamide [ No CAS ]

References: [1]Patent: WO2015/42397,2015,A1 .

22
[ 313735-62-5 ]
[ 431-47-0 ]
2,2,2-trifluoro-1-(1-isopropyl-1H-pyrazol-4-yl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%		A standard literature procedure for TFK synthesis was followed.5 <strong>[313735-62-5]4-bromo-1-isopropyl-1H-pyrazole</strong> (1.3 g,7.1 mmol) 11d was dissolved in dry THF (15 mL) at -78 C under nitrogen and was stirred for 10min. n-BuLi (2.5 M in hexanes, 2.96 mL, 7.4 mmol) was added drop wise to the solution was stirred for 2 h at -78 C. After two hours, methyl trifluoroacetate (0.85 mL, 8.5 mmol) was added drop wise and stirred for 30 min at -78 C. The solution was then allowed to warm up to room temperature and let stir for overnight. The mixture was then quenched with NH4Cl (20mL) and extracted with ether (50 mL), and dried over MgSO4. After concentration in vacuo(note: remove shortly after the ether is removed, because the compound is quite volatile), the residue was purified with flash chromatography over silica gel (hexane: ether = 98:2) to yield the product as a liquid.

References: [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 4405 - 4411.

23
[ 313735-62-5 ]
[ 454-31-9 ]
2,2-difluoro-1-(1-isopropyl-1H-pyrazol-4-yl)ethan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%		4-bromo-1-(isopropyl)-1H-pyrazole 11d (200 mg, 1.06 mmol) was dissolved in dry THF (6 mL) at -78 Cunder nitrogen and was stirred for 10 min. n-BuLi (2.5 M in hexanes, 0.44 mL, 1.11 mmol) was added drop wise to the solution was stirred for 2 h at -78 C. After two hours, ethyl difluoroacetate (0.11 mL, 1.27 mmol) was added drop wise and stirred for 10 min at -78 C uponwhich the mixture was then quenched with NH4Cl (20 mL) and warmed to room temp. Themixture was then extracted with ether (50 mL), and dried over MgSO4. After concentration invacuo (note: remove shortly after the ether is removed, because the compound is quite volatile),the residue was purified with flash chromatography over silica gel (hexane: ethyl acetate =80:20) to yield the product as a clear oil in 48% yield (0.1 g).

References: [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 4405 - 4411.

24
[ 313735-62-5 ]
[ 459-72-3 ]
2-fluoro-1-(1-(isopropyl)-1H-pyrazol-4-yl)ethan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%		4-bromo-1-(isopropyl)-1H-pyrazole (551 mg, 2.91 mmol) was dissolved in dry THF (7 mL) at -78 C under nitrogen and was stirred for 10 min. n-BuLi (2.5 M in hexanes, 1.45 mL, 3.06 mmol) was added drop wise to the solution was stirred for 2 h at -78 C. After two hours, ethyl fluoroacetate (0.33mL, 3.49 mmol) was added drop wise and stirred for 1 min at -78 C upon which the mixture was then quenched with NH4Cl (20 mL) and warmed to room temp. The mixture was then extracted with ether (50 mL), and dried over MgSO4. After concentration in vacuo (note: removeshortly after the ether is removed, because the compound is quite volatile), the residue waspurified with flash chromatography over silica gel (hexane: ethyl acetate = 80:20) to yield theproduct as a yellow solid in 20% yield (0.10 g)

References: [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 4405 - 4411.

25
[ 313735-62-5 ]
[ 1244041-62-0 ]
C₁₃H₁₄N₄S [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 3189 - 3193.

26
[ 313735-62-5 ]
(2R,5S)-2-methyl-5-[1-(1-methylethyl)-1H-pyrazol-4-yl]-1-[2-(2H-1,2,3-triazol-2-yl)thiophen-3-yl]carbonyl}piperidine [ No CAS ]

References: [1]Patent: WO2016/65587,2016,A1 .

27
[ 313735-62-5 ]
5-(1-isopropyl-1H-pyrazol-4-yl)-2-methylpyridine [ No CAS ]

References: [1]Patent: WO2016/65587,2016,A1 .

28
[ 313735-62-5 ]
5-(1-isopropyl-1H-pyrazol-4-yl)-2-methylpiperidine [ No CAS ]

References: [1]Patent: WO2016/65587,2016,A1 .

29
[ 313735-62-5 ]
(2R,5S)-5-(1-isopropyl-1H-pyrazol-4-yl)-2-methylpiperidine [ No CAS ]

References: [1]Patent: WO2016/65587,2016,A1 .

30
[ 313735-62-5 ]
[ 581060-27-7 ]
tert-butyl 4-(((1-isopropyl-1H-pyrazol-4-yl)thio)methyl)piperidine-1-carboxylate [ No CAS ]