610796-21-9|4-Bromo-5-isopropyl-1H-indazole| Ambeed

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Quality Control of [ 610796-21-9 ] Purity: 97% SDS Specification

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Product Details of [ 610796-21-9 ]

CAS No. :	610796-21-9
Formula :	C₁₀H₁₁BrN₂
M.W :	239.11
SMILES Code :	CC(C1=C(Br)C2=C(NN=C2)C=C1)C
MDL No. :	MFCD11044106
InChI Key :	YKZRMRNUPRUYCW-UHFFFAOYSA-N
Pubchem ID :	22566916

Safety of [ 610796-21-9 ]

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

Computational Chemistry of [ 610796-21-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	9
Fraction Csp3	0.3
Num. rotatable bonds	1
Num. H-bond acceptors	1.0
Num. H-bond donors	1.0
Molar Refractivity	58.37
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	28.68 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.91
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	3.37
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.45
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.	2.78
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	3.61
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.02

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.89
Solubility	0.0307 mg/ml ; 0.000128 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-3.65
Solubility	0.0535 mg/ml ; 0.000224 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-4.59
Solubility	0.0061 mg/ml ; 0.0000255 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	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	Yes
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.	-5.37 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	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)	1.66

Application In Synthesis of [ 610796-21-9 ]

* 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.

Upstream synthesis route of [ 610796-21-9 ]
Downstream synthetic route of [ 610796-21-9 ]

[ 610796-21-9 ] Synthesis Path-Upstream 1~5

1
[ 693285-68-6 ]
[ 610796-21-9 ]

References: [1] Patent: WO2005/110416, 2005, A2, . Location in patent: Page/Page column 58-59.
[2] Patent: WO2005/110991, 2005, A1, .

2
[ 1252572-35-2 ]
[ 610796-21-9 ]

References: [1] Patent: WO2005/110416, 2005, A2, .
[2] Patent: WO2005/110991, 2005, A1, .

3
[ 1006-39-9 ]
[ 610796-21-9 ]

References: [1] Patent: WO2017/201161, 2017, A1, .

4
[ 51788-83-1 ]
[ 610796-21-9 ]

References: [1] Patent: WO2017/201161, 2017, A1, .

5
[ 112611-88-8 ]
[ 610796-21-9 ]

References: [1] Patent: WO2017/201161, 2017, A1, .

[ 610796-21-9 ] Synthesis Path-Downstream 1~23

1
[ 693285-68-6 ]
[ 610796-21-9 ]

Yield	Reaction Conditions	Operation in experiment
		Nitric acid (30 mL, fuming) is added slowly to an ice-cold solution of 2-isopropyl-6-methyl- bromobenzene (10 g, 213 mmol) in HOAc (60 mL). The mixture is heated hour at 90 C and cooled to room temperature. The reaction mixture is poured into 200 mL ice-water and extracted with CH2Cl2 (3 x 60 mL). The combined extracts are washed with 1 N NaOH (3 x 40 mL) and then water (40 mL), dried (Na2S04), and concentrated to yield crude 2-isopropyl-6-methyl-5-nitro-bromobenzene which is dissolved in HOAc (75 mL)/EtOH (75 mL). To this is added Fe powder (5.3 g, 95 mmol) and the mixture is refluxed for 2 h. The mixture is cooled to room temperature, diluted with water, and neutralized with solid Na2C03. The mixture is extracted with EtOAc, dried (Na2S04), and concentrated in vacuo. The residue is purified by flash chromatography (elution with Hex/EtOAc 4:1) to yield 3-bromo-4-isopropyl-2-methyl-aniline. A solution of NaN02 (798 mg, 12 mmol) in H20 (10 mL) is added dropwise at 0 C to a slurry of 3-bromo-4-isopropyl-2-methyl-aniline (2.4 g, 11 mmol) in HBF4 (15 mL)-H20 (15 mL), and the mixture is stirred for 1 hour at 0 C. The resulting solid is filtered, washed with cold water and then Et2O, and dried under reduced pressure to yield the diazonium salt as a beige solid. The diazonium salt is added in one portion to mixture of KOAc (1.5 g, 15 mmol) and 18-C-6 (98 mg, 0.37 mmol) in ethanol-free CHCI3 (70 mL) at room temperature. The mixture is stirred for 1 hour and the resulting solid is removed by filtration. The filtrate is washed with water, dried (Na2SO4), and concentrated in vacuo. The residue is purified by flash chromatography (elution with Hex/EtOAc 4:1) to yield 4-bromo-5-isopropyl-1H indazole. 'H NMR (CDC13) 8.03 (br s, 1H), 7.41 (d, 1H), 7.35 (d, 1H), 3.55 (m, 1H), 1.24 (d, 6H).

References: [1]Patent: WO2005/110416,2005,A2 .Location in patent: Page/Page column 58-59.
[2]Patent: WO2005/110991,2005,A1 .

2
[ 610796-21-9 ]
[ 693285-67-5 ]

Yield	Reaction Conditions	Operation in experiment
		A solution OF 4-BROMO-5-ISOPROPYL-LH-INDAZOLE (1.6 g, 6.9 mmol) in Et2O (4 mL) is added slowly to a suspension OF KH (1.0 g of 30 % dispersion in mineral oil, 7.7 mmol) in Et20 (20 ML) at 0 C and the mixture is stirred for 20 minutes. After cooling TO-78 C, T- BuLi (8.9 mL of 1.7 M in Hex, 15 mmol) is added and the resulting mixture is stirred for 40 minutes AT-78 C. To this is added B (ON-BU) 3 (5.6 mL, 21 mmol) and the mixture is stirred for 24 hours at room temperature. The reaction mixture is quenched with IN H3P04 and extracted with Et2O. The combined Et20 layers are back-extracted with IN NAOH (3 * 10 mL). The combined NAOH extracts are acidified with IN H3P04 and extracted with EtOAc. The EtOAc extracts are washed with saturated brine, dried (MgS04), and concentrated to yield 5-ISOPROPYL-LH-INDAZOLE-4-BORONIC ACID. 1H NMR (CDCI3) 7. 85 (s, 1H), 7.42 (d, 1H), 7. 37 (d, 1H), 3.6 (br s, 2H), 2.88 (m, 1H), 1.32 (d, 6H).
		A solution of 4-bromo-5-isopropyl-l/J-indazole (1.6 g, 6.9 mmol) in Et2O (4 mL) is added slowly to a suspension of KH (1.0 g of 30 % dispersion in mineral oil, 7.7 mmol) in Et2O (20 mL) at 0 C and the mixture is stirred for 20 min. After cooling to -78 C, /-BuLi (8.9 mL of 1.7 M in Hex, 15 mmol) is added and the resulting mixture is stirred for 40 min at -78 C. To this is added B(O«-Bu)3 (5.6 mL, 21 mmol) and the mixture is stirred for 24 h at room temperature. The reaction mixture is quenched with IN H3PO4 and extracted with Et2O. The combined Et2O layers are back-extracted with IN NaOH (3x10 mL). The combined NaOH extracts are acidified with IN H3PO4 and extracted with EtOAc. The EtOAc extracts are washed with saturated brine, dried (MgSO4), and concentrated to yield 5-isopropyl-lNo.-indazole-4-boronic acid. 'H NMR (CDC13) 7.85 (s, 1H), 7.42 (d, 1H), 7.37 (d, 1H), 3.6 (br s, 2H), 2.88 (m, 1H), 1.32 (d, 6H).
		A solution of 4-bromo-5-isopropyl-IH-indazole (1.6 g, 6.9 mmol) in EtzO (4 mL) is added slowly to a suspension of KH (1.0 g of 30 % dispersion in mineral oil, 7.7 mmol) in Et2O (20 mL) at 0 C and the mixture is stirred for 20 min. After cooling to -78 C, t-BuLi (8.9 mL of 1.7 M in Hex, 15 mmol) is added and the resulting mixture is stirred for 40 min at -78 C. To this is added B(On-Bu)3 (5.6 mL, 21 mmol) and the mixture is stirred for 24 h at room temperature. The reaction mixture is quenched with IN H3P04 and extracted with Et2O. The combined Et2O layers are back-extracted with IN NaOH (3 x 10 mL). The combined NaOH extracts are acidified with IN H3P04 and extracted with EtOAc. The EtOAc extracts are washed with saturated brine, dried (MgS04), and concentrated to yield 5-isopropyl-IH-indazole-4-boronic acid. 'H NMR (CDC13) 7.85 (s, 1H), 7.42 (d, 1H), 7.37 (d, 1H), 3.6 (br s, 2H), 2.88 (m, 1H), 1.32 (d, 6H).

A solution of <strong>[610796-21-9]4-bromo-5-isopropyl-1H-indazole</strong> (1.6 g, 6.9 mmol) in Et2O (4 mL) is added slowly to a suspension of KH (1.0 g of 30 % dispersion in mineral oil, 7.7 mmol) in Et2O (20 mL) at 0 C and the mixture is stirred for 20 min. After cooling to -78 C, t-BuLi (8.9 mL of 1.7 M in Hex, 15 mmol) is added and the resulting mixture is stirred for 40 min at -78 C. To this is added B(On-Bu)3 (5.6 mL, 21 mmol) and the mixture is stirred for 24 h at room temperature. The reaction mixture is quenched with IN H3PO4 and extracted with Et2O. The combined Et2O layers are back-extracted with 1N NaOH (3 x 10 mL). The combined NaOH extracts are acidified with IN H3P04 and extracted with EtOAc. The EtOAc extracts are washed with saturated brine, dried (MgSO4), and concentrated to yield 5-isopropyl-1H-indazole-4-boronic acid. 1H NMR (CDCl3) 7.85 (s, 1H), 7.42 (d, 1H), 7.37 (d, 1H), 3.6 (br s, 2H), 2.88 (m, 1H), 1.32 (d, 6H).

References: [1]Patent: WO2004/43925,2004,A2 .Location in patent: Page 71.
[2]Patent: WO2006/4589,2006,A2 .Location in patent: Page/Page column 55.
[3]Patent: WO2005/110416,2005,A2 .Location in patent: Page/Page column 59.
[4]Patent: WO2005/110991,2005,A1 .Location in patent: Page/Page column 52.

3
BF₄^(1-)*C₁₀H₁₂BrN₂⁽¹⁺⁾ [ No CAS ]
[ 610796-21-9 ]

Yield	Reaction Conditions	Operation in experiment
	With 18-crown-6 ether; potassium ethoxide; In chloroform; at 20℃; for 1h;	Nitric acid (30 ML, fuming) is added slowly to an ice-cold solution of 2-isopropyl-6- methyl-bromobenzene (10 g, 213 mmol) in acetic acid (60 mL). The mixture is heated 1 hour at 90 C and cooled to room temperature. The reaction mixture is poured into 200 mL ice- water and extracted with CH2C12 (3 * 60 mL). The combined extracts are washed with 1 N NAOH (3 * 40 mL) and then water (40 mL), dried (NA2SO4), and concentrated to yield crude 2-isopropyl-6-methyl-5-nitro-bromobenzene which is dissolved in ACOH (75 ML)/ETOH (75 mL). To this is added Fe power (5.3 g, 95 mmol) and the mixture is refluxed for 2 hours. The mixture is cooled to room temperature, diluted with water, and neutralized with solid NazC03. The mixture is extracted with EtOAc, dried (NA2SO4), and concentrated in vacuo. The residue is purified by flash chromatography (elution with HEX/ETOAC 4: 1) to yield 3- bromo-4-isopropyl-2-methyl-aniline. A solution of NaNO2 (798 mg, 12 mmol) in H20 (10 mL) is added dropwise at 0 C to a slurry of 3-bromo-4-isopropyl-2-methyl-aniline (2.4 g, 11 mmol) in HBF4 (15 mL)-H20 (15 mL), and the mixture is stirred for 1 hour at 0 C. THE resulting solid is filtered, washed with cold water and then ET20, and dried under reduced pressure to yield the diazonium salt as a beige solid. The diazonium salt is added in one portion to mixture OF KOAC (1.5 g, 15 mmol) and 18-C-6 (98 mg, 0.37 mmol) in ethanol-free CHC13 (70 mL) at room temperature. The mixture is stirred for 1 hour and the resulting solid is removed by filtration. The filtrate is washed with water, dried (NA2SO4), and concentrated in vacuo. The residue is purified by flash chromatography (elution with Hex/EtOAc 4: 1) to yield 4-BROMO-5-ISOPROPYL-LH-INDAZOLE. LH NMR (CDCl3) 8.03 (br s, 1H), 7.41 (d, 1H), 7. 35 (d, 1H), 3.55 (m, 1H), 1.24 (d, 6H).
	With potassium acetate;18-crown-6 ether; In chloroform; at 20℃; for 1h;	Nitric acid (30 mL, fuming) is added slowly to an ice-cold solution of 2-isopropyl-6-methyl-bromobenzene (10 g, 213 mmol) in acetic acid (60 mL). The mixture is heated 1 h at 90 C and cooled to room temperature. The reaction mixture is poured into 200 mL ice-water and extracted with CH2C12 (3 x 60 mL). The combined extracts are washed with 1 N NaOH (3 x 40 mL) and then water(40 mL), dried (Na2SO4), and concentrated to yield crude 2-isopropyI-6-methyl-5-nitro-bromobenzene which is dissolved in AcOH (75 mL)/EtOH (75 mL). To this is added Fe power (5.3 g, 95 mmol) and the mixture is refluxed for 2 h. The mixture is cooled to room temperature, diluted with water, and neutralized with solid Na2CO3. The mixture is extracted with EtOAc, dried (Na2SO4), and concentrated in vacua. The residue is purified by flash chromatography (elution with Hex/EtOAc 4:1) to yield 3-bromo-4-isopropyl-2-methyl-aniline. A solution of NaNO2 (798 mg, 12 mmol) in H2O (10 mL) is added dropwise at 0 C to a slurry of 3-bromo-4-isopropyl-2-methyl-aniline (2.4 g, 11 mmol) in HBF4 (15 mL>H2O (15 mL), and the mixture is stirred for 1 h at 0 C. The resulting solid is filtered, washed with cold water and then Et2O, and dried under reduced pressure to yield the diazonium salt as a beige solid. The diazonium salt is added in one portion to mixture of KOAc (1.5 g, 15 mmol) and 18-C-6 (98 mg, 0.37 mmol) in ethanol-free CHC13 (70 mL) at room temperature. The mixture is stirred for 1 h and the resulting solid is removed by filtration. The filtrate is washed with water, dried (Na2SO4), and concentrated in vacua. The residue is purified by flash chromatography (elution with Hex/EtOAc 4:1) to yield 4-bromo-5-isopropyl-l//-indazole. 'H NMR (CDC13) 8.03 (br s, 1H), 7.41 (d, 1H), 7.35 (d , 1H), 3.55 (m, 1H), 1.24 (d, 6H).
	With 18-crown-6 ether; potassium acetate; In chloroform; at 20℃; for 1h;	Nitric acid (30 mL, fuming) is added slowly to an ice-cold solution of 2-isopropyl-6-methyl- bromobenzene (10 g, 213 mmol) in acetic acid (60 mL). The mixture is heated 1 h at 90 C and cooled to room temperature. The reaction mixture is poured into 200 mL ice-water and extracted with CH2Cl2 (3 x 60 mL). The combined extracts are washed with 1 N NaOH (3 x 40 mL) and then water (40 mL), dried (Na2SO4), and concentrated to yield crude 2-isopropyl-6-methyl-5-nitro-bromobenzene which is dissolved in AcOH (75 mL) /EtOH (75 mL). To this is added Fe power (5.3 g, 95 mmol) and the mixture is refluxed for 2 h. The mixture is cooled to room temperature, diluted.with water, and neutralized with solid Na2CO3. The mixture is extracted with EtOAc, dried (Na2SO4), and concentrated in vacuo. The residue is purified by flash chromatography (elution with Hex/EtOAc 4:1) to yield 3-bromo-4-isopropyl-2-methyl-aniline. A solution of NaNO2 (798 mg, 12 mmol) in H20 (10 mL) is added dropwise at 0 C to a slurry of 3-bromo-4-isopropyl-2-methyl-aniline (2.4 g, 11 mmol) in HBF4 (15 mL)-H2O (15 mL), and the mixture is stirred for 1 h at 0 C. The resulting solid is filtered, washed with cold water and then Et2O, and dried under reduced pressure to yield the diazonium salt as a beige solid. The diazonium salt is added in one portion to mixture of KOAc (1.5 g, 15 mmol) and 18-C-6 (98 mg, 0.37 mmol) in ethanol-free CHCl3 (70 mL) at room temperature. The mixture is stirred for 1 h and the resulting solid is removed by filtration. The filtrate is washed with water, dried (Na2SO4), and concentrated in vacuo. The residue is purified by flash chromatography (elution with Hex/EtOAc 4:1) to yield 4-bromo-5-isopropyl-lH-indazole. 1H NMR (CDCl3) 8.03 (br s, 1H), 7.41 (d, 1H), 7.35 (d , 1H), 3.55 (m, 1H), 1.24 (d, 6H).

References: [1]Patent: WO2004/43925,2004,A2 .Location in patent: Page 70-71.
[2]Patent: WO2006/4589,2006,A2 .Location in patent: Page/Page column 54-55.
[3]Patent: WO2005/110991,2005,A1 .Location in patent: Page/Page column 51-52.

4
[ 610796-21-9 ]
[ 74-88-4 ]
[ 610794-18-8 ]

Yield	Reaction Conditions	Operation in experiment
		STEP A. PREPARATION OF 4-BROMO-5-ISOPROPYL-1-METHYLINDAZOLE (28) A solution of <strong>[610796-21-9]4-bromo-5-isopropylindazole</strong> (27) (488mg, 2.04 mmol) in 5 ml of anhydrous DMF is added to a suspension of sodium hydride (122 mg, 60% in mineral oil, 3. 06mmol, 1.5 eq. ) in 5 ml of DMF under nitrogen at 0 C. The resulting mixture is stirred at 0 C for 30 minutes, then warmed to room temperature. After stirring at room temperature for an additional 2 hours, the reaction mixture is cooled to 0 C, and iodomethane (318 mg, 2.24 mmol, 1.1 eq. ) is added dropwise, the mixture is stirred at 0 C for 2 hours, then warmed to room temperature, and stirred overnight. The reaction mixture is poured into 30 ml of ice- water, extracted with ethyl acetate (30 ml x 3), washed with water and brine, and dried over anhydrous sodium sulfate. The solvent is evaporated and the product is purified via flash chromatography to give 340 mg of 4-bromo-5-isopropyl-1-methylindazole lH NMR (400 MHz, CDC13) 7.95 (1H, s), 7.31 (2H, S), 4.05 (3H, S), 3.55 (1H, m), 1.27 (6H, d, J = 6.8Hz). MS (+VE) m/z 253 (M+). 165 mg of 4-bromo-5-isopropyl-2-methylindazole (28). 'H NMR (400 MHz, CDC13) 8 7.82 (1H, s), 7.59 (1H, d, J = 9.2 Hz), 7.21 (1H, d, J = 8.8 Hz), 4.16 (3H, s), 3.50 (1H, m), 1.21 (6H, d, J = 6.8 Hz). MS (+VE) m/z 253 (M+).

References: [1]Patent: WO2003/82826,2003,A1 .Location in patent: Page/Page column 56.

5
[ 610796-21-9 ]
[ 98-59-9 ]
[ 1421252-93-8 ]

Yield	Reaction Conditions	Operation in experiment
		Example 44-A. 4-Bromo-5-isopropyl-l-tosyl-lH-indazole.NaH (60% dispersion in mineral oil, 241 mg, 6.02 mmol) was added to a solution of 4-bromo-5- isopropyl-lH-indazole (720 mg, 3.01 mmol) in THF (15 mL) at 0 C. After 10 min, TsCl (861 mg, 4.52 mmol) was added and the resulting mixture was stirred at 0 C for 1 h, then at room temperature overnight. Saturated aqueous NH4C1 was added and the mixture was extracted with EtOAc (2X). The combined organics were washed with brine, dried (Na2S04) and concentrated. Ther residue was purified by silica gel chromatography (0-30%o EtO Ac/heptanes) to provide 4-bromo-5-isopropyl-l-tosyl-lH- indazole. MS (ESI+) m/z 394.8 (M+H)+.

References: [1]Patent: WO2013/16197,2013,A1 .Location in patent: Page/Page column 79.

6
[ 610796-21-9 ]
[ 98-59-9 ]
[ 1421252-94-9 ]

References: [1]Patent: WO2013/16197,2013,A1 .

7
[ 610796-21-9 ]
[ 1421251-59-3 ]

References: [1]Patent: WO2013/16197,2013,A1 .

8
[ 610796-21-9 ]
[ 1421251-60-6 ]

References: [1]Patent: WO2013/16197,2013,A1 .

9
[ 610796-21-9 ]
[ 73183-34-3 ]
[ 1421252-95-0 ]

Yield	Reaction Conditions	Operation in experiment
345 mg		Example 55-Isopropyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazole.A suspension of 4-bromo-5-isopropyl-l//-indazole (396 mg, 1.656 mmol), bis(pinacolato)diboron (841 mg, 3.31 mmol), KOAc (488 mg, 4.97 mmol), PdCl2(CH3CN)2 (21.48 mg, 0.083 mmol) and S-Phos (136 mg, 0.331 mmol) in DMSO (6 mL) was allowed to stir at 110 C for 23 h under nitrogen. The reaction mixture was cooled to rt, and diluted with EtOAc and half-saturated brine. The products were extracted three times with EtOAc. The combined organic layer was washed with brine, and concentrated. After the residue was diluted with THF (10 mL) and MeOH (1.5 mL), 1 M aq LiOH (4.5 mL) was added. After stirring for 0.5 h, the reaction was quenched with sat aq NH4C1, and diluted with EtOAc and brine. The mixture was extracted twice with EtOAc. The combined organic layer were washed with a 1 : 1 solution of sat aq NH4C1 and saturated brine, dried over Na2S04, filtered, and concentrated. The residue was purified by flash column chromatography on 40 g of silica gel (0-20% EtO Ac/heptane) to give 5-isopropyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazole along with 20 mol% of debromonated product (345 mg) as a yellow solid. lH NMR (400 MHz, CDC13, the desired boronic ester) delta ppm 9.93 (br s, 1 H), 8.39 (d, J= 1.01 Hz, 1 H), 7.50 - 7.52 (m, 1 H), 7.41 (d, J= 8.84 Hz, 1 H), 3.75 - 3.85 (m, 1 H), 1.42 (s, 12 H), 1.28 (d, J= 6.82 Hz, 6 H); MS (ESI+) m/z 287.30 (M+H)+. The obtained material was used without further purification.

References: [1]Patent: WO2013/16197,2013,A1 .Location in patent: Page/Page column 80.

10
[ 110-87-2 ]
[ 610796-21-9 ]
4-bromo-5-isopropyl-1-tetrahydropyran-2-yl-indazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With toluene-4-sulfonic acid; In dichloromethane; at 20℃; for 3h;	To a solution of 3,4- dihydro-2H-pyran (457 mg, 5.44 mmol, 497 uL, 2 eq) in dichloromethane (15 mL) was added TsOH H20 (51.7 mg, 271 umol) and 4-bromo-5-isopropyl-lH-indazole (650 mg, 2.72 mmol). The mixture was stirred at 20 C for 3 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL chi 2). The combined organic layers were washed with brine (20 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 1/0 to 5/1) and further purificated by reversed phase flash [water (0.1% formic acid)/acetonitrile] to give 4-bromo-5-isopropyl-l-tetrahydropyran-2-yl-indazole (170 mg, 494 umol, 18.2% yield, 94% purity) as a yellow oil. ESI MS m/z 323.0 [M+H]+.

References: [1]Patent: WO2017/201161,2017,A1 .Location in patent: Paragraph 0916.

11
[ 1006-39-9 ]
[ 610796-21-9 ]