465529-56-0|5-Bromo-2-methyl-2H-indazole| Ambeed

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Quality Control of [ 465529-56-0 ] Purity: 97% SDS Specification

COA

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NMR

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Product Details of [ 465529-56-0 ]

CAS No. :	465529-56-0
Formula :	C₈H₇BrN₂
M.W :	211.06
SMILES Code :	CN1N=C2C=CC(Br)=CC2=C1
MDL No. :	MFCD09870047
InChI Key :	QFZOHVHNTZTZMJ-UHFFFAOYSA-N
Pubchem ID :	11514007

Safety of [ 465529-56-0 ]

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

Computational Chemistry of [ 465529-56-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	9
Fraction Csp3	0.12
Num. rotatable bonds	0
Num. H-bond acceptors	1.0
Num. H-bond donors	0.0
Molar Refractivity	48.7
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.	2.12
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	2.26
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.34
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	2.19
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	2.11
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.2

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.18
Solubility	0.14 mg/ml ; 0.000664 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.	-2.27
Solubility	1.13 mg/ml ; 0.00536 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	-3.33
Solubility	0.0985 mg/ml ; 0.000467 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	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.	-5.98 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)	1.54

Application In Synthesis of [ 465529-56-0 ]

* 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 [ 465529-56-0 ]

[ 465529-56-0 ] Synthesis Path-Downstream 1~35

1
[ 53857-57-1 ]
[ 74-88-4 ]
[ 465529-56-0 ]
[ 465529-57-1 ]

Yield	Reaction Conditions	Operation in experiment
36%; 52%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium hydride; In tetrahydrofuran; at 20℃; for 3h;	The A14-1 (590mg, 2.99mmol) was dissolved in tetrahydrofuran (10mL), was added NaH in the case of an ice bath with stirring (180mg80%, 6.00mmol),After stirring for 30 minutes was added CH3I (468mg, 3.30mmol), stirring was continued for 3 hours, raised to room temperature, water (20 mL), ethyl acetate (20mL × 3)Extraction, the organic phase was washed with saturated brine (50mL × 3), dried over anhydrous sodium sulfate, and spin dry solvent, the residue was purified by column chromatography (petroleum ether: ethyl acetate= 10:1-3:1) to give A14-2 (230mg, 36%) and A14-3 (330mg, 52%).A14-2: off-white solid. 1HNMR (400MHz, DMSO) delta8.33 (s, 1H), 7.96-7.95 (m, 1H), 7.57 (d, J = 9.2Hz,1H), 7.31-7.28 (m, 1H), 4.16 (s, 3H).A14-3: white solid.
29%; 42.5%		5-Bromo-1-methyl-1 H-indazole (ii) and 5-Bromo-2-methyl-2H-indazole (iii)To a solution of 5-bromo-1 H-indazole (0.19 g, 0.94 mmol) in 3 mL THF at 0 0C was added NaH (0.04 g, 1.03 mmol). The reaction solution was stirred at this temperature for 1 hour before methyl iodide (0.09 mL, 1.41 mmol) was added at 0 0C. The reaction was allowed to warm to room temperature slowly and stirred for 2 hours, quenched with water and concentrated in vacuo. The residue was diluted with water and extracted with DCM twice. The organic layers were combined, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (hexane:EtOAc = 10:1 ) to give the title compound ii (88.7 mg, 42.5 %) and iii (60.9 mg, 29 %) as two white solids, ii: 1H-NMR (400MHz, DMSO- Cf6) delta ppm 8.02 (d, 1 H), 7.99 (d, 1 H), 7.64 (d, 1 H), 7.50 (dd, 1 H), 4.04 (s, 3H). LCMS(method A): [MH]+ = 21 1/213, tR = 5.19 min. iii: 1H-NMR (400MHz, DMSO-Cf6) delta ppm 8.33 (s, 1 H), 7.95 (d, 1 H), 7.57 (d, 1 H), 7.30 (dd, 1 H), 4.16 (s, 3H). LCMS (method A): [MH]+ = 21 1/213, tR = 4.95 min.
29%; 42.5%		To a solution of 5-bromo-1 H-indazole (0.19 g, 0.94 mmol) in 3 ml_ of THF at 0 QC was added NaH (0.04 g, 1 .03 mmol). The reaction mixture was stirred at this temperature for 1 h before the addition of methyl iodide (0.09 ml_, 1 .41 mmol) at 0 QC. The reaction was allowed to warm to rt slowly and stirred for 2 h, quenched with water and concentrated in vacuo. The residue was diluted with water and extracted with DCM twice. The organic layers were combined, dried over Na2SO4 and concentrated. The crude products were purified by flash chromatography (hexane:EtOAc = 10:1 ) to give the title compound ii (88.7 mg, 42.5 %) and iii (60.9 mg, 29 %) as white solid, ii: 1H-NMR (400MHz, DMSO-d6) Dppm 8.02 (d, 1 H), 7.99 (d, 1 H), 7.64 (d, 1 H), 7.50 (dd, 1 H), 4.04 (s, 3H). LCMS (method A): [MH]+ = 21 1/213, tR = 5.19 min. iii: 1H-NMR (400MHz, DMSO-Cf6) deltappm 8.33 (s, 1 H), 7.95 (d, 1 H), 7.57 (d, 1 H),7.30 (dd, 1 H), 4.16 (s, 3H). LCMS (method A): [MH]+ = 21 1/213, tR = 4.95 min.

		Scheme 5:F G R Me HI R Et JK R Pr LM R iPr N Sodium hydride (60% in oil, 1.5 g, 37.5 mmol, 1.2 equiv) was added to a solution of 5- bromoindazole F (6 g, 30.6 mmol, 1 equiv) in DMF (60 mL) at RT. After stirring for 30 min, methyl iodide (2.83 mL, 45.9 mmol, 1.5 equiv) was added and the reaction stirred for another 2 h at RT. The reaction was quenched with sat. NaHC03, extracted with EtOAc (lx), dried over MgS04, filtered, and concentrated under reduced pressure to give a mixture of JV-l and N-2 methylated 5-bromoindazoles G and H, which were separated by silica-gel chromatography using 0?30 % EtOAc/hexanes as eluent. The Nl -alkylated regioisomer G elutes first, followed by the N2-methyl regioisomer H. Other N-l -alkylated 5-bromoindazoles (I, , M) were prepared by the same procedure, substituting the appropriate electrophile for methyl iodide (ethyl iodide, i-propyl iodide, n-propyi iodide).
		[000842] To a solution of 5-bromo-lH-indazole, 202A, (4.92 g, 25.0 mmol) in THF (300 mL) at 0 C was added NaH (1.10 g, 27.5 mmol). The reaction solution was stirred at this temperature for 1 hour before methyl iodide (5.32 g, 37.5 mmol) was added at 0 C. The reaction was allowed to warm to room temperature slowly, stirred for 2 hours, and quenched with water and concentrated in vacuo. The residue was diluted with water and extracted with dichloromethane (80 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to give Compound 202B and Compound 202C.
		[000791j To a solution of Compound 125A (4.92 g, 25.0 mmol) in THF (300 mL) was added NaH (1.10 g, 27.5 mmol) at 0 C. The reaction solution was stirred at this temperature for 1 h before methyl iodide (5.32 g, 37.5 mmol) was added at 0 C. The reaction was allowed to warm to room temperature slowly, stirred for 2 h, and quenched with water and concentrated in vacuo. The residue was diluted with water and extracted with dichloromethane (80 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to give Compound 125B and Compound 125C. For Compound 125B: LC-MS (ESI) mlz: 211 [M+H] ?H-NMR (CDC13, 400 MHz): (5(ppm) 4.06 (s, 3H), 7.26-7.28 (m, 1H), 7.44-7.48 (m, 1H), 7.86-7.87 (m, 1H), 7.91 (s, 1H). For Compound 125C: LC-MS (ESI) mlz: 211 [M+H] ?H-NMR (CDC13, 400 MHz) (5(ppm) 4.20 (s, 3H), 7.3 1-7.34 (m, 1H), 7.56-7.58 (m, 1H), 7.79-7.80 (m,1H), 7.84 (s, 1H).
		Sodium hydride (60% in oil, 1.5 g, 37.5 mmol) was added to a solution of 5-bromoindazole D (6 g, 30.6 mmol) in DMF (60 mL) at RT. After stirring for 30 min, methyl iodide (2.83 mL, 45.9 mmol) was added and the reaction stirred for another 2 h at RT. The reaction was quenched with sat. NaHCO3 (aq), extracted with EtOAc (1×), dried over MgSO4, filtered, and concentrated under reduced pressure to give a mixture of N-1 and N-2 methylated 5-bromoindazoles E and F, which were separated by silica-gel chromatography using 0?30% EtOAc/hexanes.

References: [1]Patent: CN105254613,2016,A .Location in patent: Paragraph 0131; 0132; 0133; 0134; 0135.
[2]Journal of Organic Chemistry,2018,vol. 83,p. 6334 - 6353.
[3]Patent: WO2011/18454,2011,A1 .Location in patent: Page/Page column 60-61.
[4]Patent: WO2011/20861,2011,A1 .Location in patent: Page/Page column 59.
[5]Chemische Berichte,1922,vol. 55,p. 1141,1157.
[6]Patent: WO2011/44187,2011,A1 .Location in patent: Page/Page column 88-89.
[7]Patent: WO2015/42397,2015,A1 .Location in patent: Paragraph 000842.
[8]Patent: WO2015/65937,2015,A1 .Location in patent: Paragraph 000791.
[9]Patent: US2015/307465,2015,A1 .Location in patent: Paragraph 0512.

2
[ 465529-56-0 ]
[ 74-88-4 ]
5-bromo-2,3-dimethyl-2H-indazole [ No CAS ]

References: [1]Synthetic Communications,2006,vol. 36,p. 285 - 293.

3
[ 74-88-4 ]
[ 465529-56-0 ]
[ 465529-57-1 ]

Yield	Reaction Conditions	Operation in experiment
42%; 44%		Example 2004 Compound 2004A (1 g, 5.07 mmol) was dissolved in 20 mL of THF and reacted with sodium methoxide (10 mL, 5.07 mmol). After 30 min, iodomethane (1.3 mL, 20.3 mmol) was added. Reaction mixture was stirred for 5 hours at room temp, then it was added to ethyl acetate and water. The aqueous layer was extracted with ethyl acetate twice. All the organic layers were combined, washed with brine solution and dried over sodium sulfate. The solvent was removed by rotary evaporator and further purified by SiO2 column chromatography to give 2004B (470 mg, 44% yield) and 2004C (450 mg, 42% yield).

References: [1]Patent: WO2007/84451,2007,A1 .Location in patent: Page/Page column 167.

4
[ 24106-05-6 ]
[ 465529-56-0 ]

References: [1]Chemische Berichte,1922,vol. 55,p. 1141,1157.

5
[ 861796-22-7 ]
[ 465529-56-0 ]

References: [1]Chemische Berichte,1922,vol. 55,p. 1141,1157.

6
[ 40598-94-5 ]
[ 465529-56-0 ]

References: [1]Chemische Berichte,1922,vol. 55,p. 1141,1157.

7
[ 40598-76-3 ]
[ 465529-56-0 ]

References: [1]Chemische Berichte,1922,vol. 55,p. 1141,1157.

Yield	Reaction Conditions	Operation in experiment
38.6%		General procedure: NaH 60% in oil (100.92 mg; 2.52 mmol; 1.10 eqf.) is added portionwise to a solution of 6-chloro-1 H-pyrrolo[2,3-b]pyridine (350.00 mg; 2.29 mmol; 1.00 eq.) in anhydrous DMF (5.00 mL) at 0~5C. After stirring for 30 minutes CH3I (0.10 mL; 1.61 mmol; 0.70 eqf.) is added dropwise. After addition, RM is stirred at 0-5C for 30 min and then at rt for 1 h. Reaction is quenched with water and extracted with EtOAc. Organic phase is washed with water, brine, dried over Na2SO4, filtered and concentrated to afford 6-chloro-1 -methyl-1 H- pyrrolo[2,3- 3]pyridine (332.00 mg; yield 85 %; 98 % by UPLC) as a brown oil. The crude product is used in the next step
		Preparation 112 3-(1-Methyl-1H-indazol-5-yl)-2-propenenitrile The 1-methyl isomer from Preparation 111(100 mg, 0.47 mmol) was taken up in dioxan (6 ml), and potassium carbonate (72 mg, 0.52 mmol), acrylonitrile (0.035 ml, 0.52 mmol), Pd2(dba)3 (43 mg, 0.047 mmol) and PtertBu3 (0,038 ml, 0.16 mmol) were added in sequence.
	In ethyl acetate; at 20℃; for 20h;	General procedure: To a suspension of 5-bromo-4-chloro-1H-indazole (10.0 g, 43.2 mmol) in EtOAc (200 mL) was added trimethyloxonium tetrafluoroborate (9.58 g, 64.8 mmol) at RT. The mixture was stirred at RT for 20 h, quenched with sat. NaHCO 3, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na 2SO 4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution, 0 - 50% EtOAc/hexane) to give the title compound (9.16 g). MS: [M+H] + = 245, 247.

10
[ 53857-57-1 ]
[ 420-37-1 ]
[ 465529-56-0 ]

Yield	Reaction Conditions	Operation in experiment
70%		Preparation 1 Synthesis of 5-bromo-2-methyl-2H-indazole Add at room temperature under nitrogen, trimethyloxonium tetrafluoroborate (229.34 g, 1.52 mol) portion wise to a mixture of 5-bromo-1H-indazole (199.6 g, 1.01 mol) in ethyl acetate (3.04 L, 31.06 mol), stir 2.5 h and filter to give a white solid. Wash the recovered solid twice with ethyl acetate (500 mL) and then add it portion wise to a cooled aqueous solution of 2 M sodium hydroxide (3.80 L, 7.60 mol) in an ice bath. Stir the mixture for 1 h, sonicate for 15 min., filter and wash the recovered solid twice with water (200 mL). Dry the solid overnight under vacuum, slurry in dichloromethane (1 L) and filter. Concentrate the filtrate and purify by silica gel chromatography eluding with dichloromethane to give the title compound as a yellow solid (149.77 g, 70%). MS (m/z): 211, 213 (M+1).

References: [1]Patent: US2009/253750,2009,A1 .Location in patent: Page/Page column 6.

11
[ 465529-56-0 ]
[ 73183-34-3 ]
[ 1189746-27-7 ]

Yield	Reaction Conditions	Operation in experiment
76%	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 100℃; for 1.5h;Inert atmosphere;	Preparation 3 Synthesis of 2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazole Add potassium acetate (207.16 g, 2.11 mol) in one portion to a stirring solution of <strong>[465529-56-0]5-bromo-2-methyl-2H-indazole</strong> (148.5 g, 0.703 mol) and bis(pinacolato)diboron (196.54 g, 0.77 mol) in 1,4-dioxane (1.62 L). Bubble nitrogen through the suspension for 20 min, add (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) chloride:dichloromethane (17.24 g, 21.11 mmol) in one portion and heat at 100 C. for 1.5 h. Cool, filter through Celite using ethyl acetate (1 L) and concentrate. Purify the residue by silica gel chromatography, gradient eluding from 50:50 to 20:80 using n-hexane:methyl t-butyl ether to give the title compound as a yellow solid (124.79 g, 64%) which is used without further purification. Concentrate impure fractions and triturate the recovered solid with n-heptane to give additional amounts of the title compound as a white solid (32.36 g, 12%). 1H-NMR (DMSO-d6): delta1.30 (s, 12H), 4.17 (s, 3H), 7.43 (dd, 1H), 7.53 (dd, 1H), 8.14 (t, 1H), 8.39 (s, 1H).
410 mg	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In dimethyl sulfoxide; at 90℃;Inert atmosphere;	The A14-2 (190mg, 0.90mmol) was dissolved in DMSO (10mL), was added bis (pinacolato) borate (274mg, 1.08mmol), KOAc(265mg, 2.70mmol), Pd (dppf) 2Cl2 (37mg, 0.045mmol), purged with nitrogen, stirred overnight at 90 deg.] C, cooled to room temperature, celiteSoil filtration, the filtrate was diluted with ethyl acetate (20 mL), saturated brine (20mL × 3), dried over anhydrous sodium sulfate, and sodium sulfate was filtered, the solvent was spin-dryTo a black oil (410mg), was used directly in the next step.

References: [1]Patent: US2009/253750,2009,A1 .Location in patent: Page/Page column 6.
[2]Patent: CN105254613,2016,A .Location in patent: Paragraph 0131; 0136; 0137;.

12
[ 465529-56-0 ]
[ 661-69-8 ]
[ 1189746-28-8 ]

Yield	Reaction Conditions	Operation in experiment
41%	tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 110℃; for 0.25h;Inert atmosphere;	Preparation 4 Synthesis of 2-methyl-5-trimethylstannanyl-2H-indazole Add tetrakis(triphenylphosphine)palladium (0.26 g, 0.22 mmol) to a mixture of <strong>[465529-56-0]5-bromo-2-methyl-2H-indazole</strong> (0.94 g, 4.43 mmol) and hexamethylditin (1.02 mL, 4.88 mmol) in 1,4-dioxane (5 mL). Flush with nitrogen and heat in a microwave at 110 C. for 15 min. Prepare similarly two other batches from respectively tetrakis(triphenyl-phosphine)palladium (0.29 g, 0.25 mmol), <strong>[465529-56-0]5-bromo-2-methyl-2H-indazole</strong> (1.07 g, 5.07 mmol), hexamethylditin (1.16 mL, 5.58 mmol) in 1,4-dioxane (5 mL) and tetrakis(triphenylphosphine)palladium (0.25 g, 0.22 mmol), <strong>[465529-56-0]5-bromo-2-methyl-2H-indazole</strong> (0.92 g, 4.36 mmol), hexamethylditin (1.00 mL, 4.80 mmol) in 1,4-dioxane (5 mL). Combine the three batches and purify by silica gel chromatography gradient eluding from 15:85 to 80:20 using ethyl acetate:iso-hexane, and then further purify with a second silica gel chromatography, gradient eluding from 15:85 to 30:70 using ethyl acetate:iso-hexane to give the title compound as an oil which crystallizes on standing (1.68 g, 41%). MS (m/z): 293-301 cluster (M+1).

References: [1]Patent: US2009/253750,2009,A1 .Location in patent: Page/Page column 6.

13
[ 93777-26-5 ]
[ 465529-56-0 ]

References: [1]Patent: WO2011/18454,2011,A1 .
[2]Patent: WO2011/20861,2011,A1 .
[3]Patent: EP3269715,2018,A1 .
[4]Patent: US2019/194168,2019,A1 .

14
5-bromo-2-fluoro-benzaldehyde <i>O</i>-methyl-oxime [ No CAS ]
[ 465529-56-0 ]

References: [1]Patent: WO2011/18454,2011,A1 .
[2]Patent: WO2011/20861,2011,A1 .

15
[ 465529-56-0 ]
[ 67-64-1 ]
2‐(5‐bromo‐2‐methyl‐2H‐indazol‐3‐yl)propan‐2‐ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With sodium hydride; In tetrahydrofuran; at -10 - 20℃;	5-Bromo-2-methyl-2H-indazole (210.0 g, 1.0 mol, 1.0 eq)Dissolve NaH (60%, 40.0 g, 1.0 mol, 1.0 eq) in tetrahydrofuran (3.0 L).Acetone (220.0 mL, 3.0 mol, 3.0 eq) was slowly added dropwise to the reaction solution.The dropping temperature was controlled below -10C, the addition was complete, the temperature was raised to room temperature, and the reaction was stirred overnight.The reaction was completed by TLC until the reaction was complete. The reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The crude product was concentrated by column chromatography (PE/EA= 10/1-1/2)Compound 2-(5-bromo-2-methyl-2H-indazol-3-yl)propan-2-ol was obtained as a brown solid (234.5 g, yield: 87%, purity: 99.8%).
31%		To a stirred solution of <strong>[465529-56-0]5-bromo-2-methyl-2H-indazole</strong> (30a) (300 mg, 1.42 mmol) in THF (10.0 mL) was added LDA (2.0 M in THF, 2.13 mL, 4.26 mmol) at -78 C. The reaction mixture was stirred at 0 C. for 10 min and then cooled to -78 C. Acetone (124 mg, 2.14 mmol) was added to the reaction mixture at -78 C. The reaction was then allowed to warm to ambient temperature and stirred for 18 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The reaction was quenched with saturated aqueous NaHCO3 (10 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (3*10 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (ISCO, 20 g SiO2, 0-100% EtOAc/petroleum ether) to provide 2-(5-bromo-2-methyl-2H-indazol-3-yl)propan-2-ol (Int-61) (120 mg, 31% yield) as a colorless oil. m/z (ESI+) for (C11H13BrN2O), 270.9 (M+H)+.
20 g		Into a 1 L 3 -necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen were placed <strong>[465529-56-0]5-bromo-2-methyl-2H-indazole</strong> A (32.0 g, 128.9 mmol, 1.0 equiv., 85%) in tetrahydrofuran (300 mL). To the solution was added LDA (97.5 mL, 1.5 equiv., 2 M) at -78C. The solution was stirred at 0-5C for 10 min, then cooled to -78C. To the solution was added propan-2-one (11.3 g, 194.7 mmol, 1.5 equiv.). The resulting solution was stirred for 12 h at 25C. The reaction was then quenched with 100 mL of aqueous sodium bicarbonate. The resulting solution was extracted with 3x500 mL of ethyl acetate and the organic layers combined, dried with anhydrous Na2S04, and filtered. The filtrate was concentrated under vacuum, and the residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1 : 10 to 1 :2). This resulted in 20 g (58%) of 2-(5-bromo-2-methyl-2H-indazol-3-yl)propan-2-ol B as a yellow oil: MS m/z M += 269

References: [1]Patent: CN105111191,2018,B .Location in patent: Paragraph 0065; 0066; 0067; 0070; 0071.
[2]Patent: US2019/330196,2019,A1 .Location in patent: Paragraph 1125-1126.
[3]Patent: WO2016/14904,2016,A1 .Location in patent: Page/Page column 21; 22.

16
[ 20357-20-4 ]
[ 74-89-5 ]
[ 465529-56-0 ]

Yield	Reaction Conditions	Operation in experiment
		Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen were placed 5-bromo-2-nitrobenzaldehyde (30.0 g, 130.4 mmol, 1.0 equiv.), methanamine (71.5 mL, 1.1 equiv.), and propan-2-ol (300 mL). The resulting solution was stirred for 4 h at 80C. The mixture was cooled to rt and tributylphosphine (98 mL, 3.0 equiv.) was added. The resulting solution was stirred for 12 h at 80C and then extracted with 500 mL of ethyl acetate. The resulting mixture was washed sequentially with 300 mL of NH4CI (aq.) and 300 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1 :4). This resulted in 32 g (crude) of 5- bromo-2-methyl-2H-indazole A as a red oil: MS m/z MH+= 211

References: [1]Patent: WO2016/14904,2016,A1 .Location in patent: Page/Page column 21; 22.

17
[ 465529-56-0 ]
5-bromo-2-methyl-3-(propan-2-yl)-2H-indazole [ No CAS ]

References: [1]Patent: WO2016/14904,2016,A1 .
[2]Patent: CN105111191,2018,B .
[3]Patent: US2019/330196,2019,A1 .

18
[ 465529-56-0 ]
3-isopropyl-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole [ No CAS ]

References: [1]Patent: WO2016/14904,2016,A1 .
[2]Patent: CN105111191,2018,B .

19
[ 465529-56-0 ]
5-(2-chloro-5-fluoropyrimidin-4-yl)-2-methyl-3-(propan-2-yl)-2H-indazole [ No CAS ]

References: [1]Patent: WO2016/14904,2016,A1 .
[2]Patent: EP3269715,2018,A1 .

20
[ 465529-56-0 ]
N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-amine [ No CAS ]

References: [1]Patent: WO2016/14904,2016,A1 .
[2]Patent: US2019/194168,2019,A1 .

21
[ 465529-56-0 ]
5-methoxy-2-methyl-3-(5-methylthien-2-yl)-2H-indazole [ No CAS ]