[ CAS No. 861881-02-9 ] {[proInfo.proName]}

Name: 861881-02-9|4-Iodo-1H-pyrazolo[3,4-b]pyridine|98%
Brand: Ambeed
SKU: A290011
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Quality Control of [ 861881-02-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 861881-02-9 ]

CAS No. :	861881-02-9	MDL No. :	MFCD11846314
Formula :	C₆H₄IN₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PEHWWSPOLYSDBW-UHFFFAOYSA-N
M.W :	245.02	Pubchem ID :	57642801
Synonyms :

Calculated chemistry of [ 861881-02-9 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	46.61
TPSA :	41.57 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.75 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.08
Log Po/w (XLOGP3) :	1.47
Log Po/w (WLOGP) :	1.56
Log Po/w (MLOGP) :	1.52
Log Po/w (SILICOS-IT) :	2.57
Consensus Log Po/w :	1.64

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.95
Solubility :	0.274 mg/ml ; 0.00112 mol/l
Class :	Soluble
Log S (Ali) :	-1.95
Solubility :	2.75 mg/ml ; 0.0112 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.5
Solubility :	0.0784 mg/ml ; 0.00032 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.8

Safety of [ 861881-02-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 861881-02-9 ]

* 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 [ 861881-02-9 ]

[ 861881-02-9 ] Synthesis Path-Downstream 1~61

1
[ 861881-02-9 ]
[ 151-50-8 ]
[ 1378652-03-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium 4-methylbenzenesulfinate; In dimethyl sulfoxide; at 100℃; for 18h;	4-Iodo-lH-pyrazolo[3,4-]pyridine (802 mg, 3.27 mmol) was dissolved in DMSO (10 mL) then added p-toluenesulfinic acid, sodium salt (583 mg, 3.27 mmol) and KCN (319 mg, 4.90 mmol). The reaction was heated at 100 0C for 18 h. The mixture was diluted EPO <DP n="130"/>with water and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4 to yield lH-pyrazolo[3,4-]pyridme-4-carbonitrile as a light orange solid.

Reference： [1]Patent: WO2007/48070,2007,A2 .Location in patent: Page/Page column 128-129

2
[ 153034-82-3 ]
[ 861881-02-9 ]

Yield	Reaction Conditions	Operation in experiment
92%	With hydrazine; In tetrahydrofuran; at 10 - 90℃; for 2.08333h;	To a cooled solution of <strong>[153034-82-3]2-fluoro-4-iodonicotinaldehyde</strong> (19.75g, 78.7 mmol) in anhydrous tetrahydrofuran (100 ml) at 100C was carefully added IM hydrazine in tetrahydrofuran (100 ml, 100 mmol) at such a rate that the temperature of the reaction mixture remained below 300C. After complete addition a precipitate started to form and this was allowed to stir for a few minutes and then the vessel was sealed and heated to 900C for 2 hours behind a blast shield. After this time, the reaction mixture was allowed to cool down to room temperature and concentrated to dryness. The resulting yellow solid was triturated with a small amount of ethyl acetate to give the product as a pale yellow powder (17.68 g, 92% yield).1H NMR (DMSO-d6, 400 MHz) delta 7.7 (IH, d), 8.0 (IH, s), 8.2 (IH, d) and 12.0 (IH, br s); MS (ES+) 246, (ES") 244.
82%	With hydrazine hydrate; In isopropyl alcohol; at 60℃; for 2h;	a) Hydrazine monohydrate (0.78 mL, 15.94 mmol) was added dropwise to a suspension of <strong>[153034-82-3]2-fluoro-4-iodonicotinaldehyde</strong> (2.00 g, 7.97 mmol) in 2-propanol (20 mL) and heated at 60 C. After 2 h, the solvent was removed by rotatory evaporation and the residue dissolved in EtAcO (40 mL) and washed with water (30 mL). The organic layer was dried over anhydrous Na2S04 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (10D40% EtAcO/hexanes), affording 1 .62 g of 4-iodo-1 H-pyrazolo[3,4-b]pyridine, [Rf= 0.30 (20% EtAcO/hexanes), white solid, 82% yield].LC-MS ESI+ m/z: 246 (M+1 , 99%) (Method 5).1 H-NMR (CDCI3, 250 MHz, ?) : 12.45 (br s, 1 H); 8.23 (d, J= 5.0 Hz, 1 H, ArH); 7.98 (s, 1 H, ArH); 7.61 (d, J= 5.0 Hz, 1 H, ArH).
77%	With hydrazine hydrate; In isopropyl alcohol; at 60℃; for 3h;	To a solution of <strong>[153034-82-3]2-fluoro-4-iodonicotinaldehyde</strong> (0.2 g, 0.797 mmol) in 2- propanol (2 mL) was added hydrazine monohydrate (0.2 mL, 6.37 mmol) and the reaction mixture was heated to 60 C for 3 h. The reaction mixture was concentrated under reduced pressure .To the residue was added water and ethyl acetate (8 mL). The ethyl acetate layer was separated. The aqueous layer was washed ethyl acetate(2x6 mL). The combined The ethyl acetate layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 4-iodo-1H- pyrazolo[3,4-bjpyridine (0.150 g, 0.612 mmol, 77% yield) as a off white solid which was taken to next step without purification. LCMS (ESI) m/e 246.0 [(M+H), calcd for C6H51N3 246.01; LC/MS retention time (method A2): tR = 1.65 mm.

	With hydrazine hydrate; In ethanol; at 120℃;	Compound 16A: To a solution of <strong>[153034-82-3]2-fluoro-4-iodonicotinaldehyde</strong> (3.0 g, 11.95 mmol) in ethanol (45 ml) was added hydrazine monohydrate (1.12 g, 14.34 mmol) and the reaction mixture was heated at 120 C. in a sealed vial overnight. The reaction mixture was cooled to room temperature, and then was concentrated under reduced pressure. The residue was treated with water (30 ml) and 1 N NaOH (20 ml) and extracted with CHCl3 (40×4 ml). The organic layer was separated, dried over MgSO4 and concentrated to yield crude compound 16A as solid (2.74 g). [M+H] calc'd for C6H41N3 246; found 246.
	With toluene-4-sulfonic acid; hydrazine; at 130℃; for 0.0555556h;microwave irradiation;	To a mixture of <strong>[153034-82-3]2-fluoro-4-iodopyridine-3-carboxaldehyde</strong> (0.25 g, 0.1 mmol) and p- toluenesulfonic acid monohydrate (0.1 g) was added hydrazine hydrate (0.3 mL) in a microwave vial. The reaction was heated at 130 0C for 200 sec. Precipitate was washed with water and Et2O resulting in white solid and 4-Iodo-lH-pyrazolo[3,4-]pyridine was used for the next step without further purification.
	With hydrazine; for 0.25h;	To 3 mL N2H4 (anhydrous) was added 1.0 g of 2-fluoro-4-iodoiiicotinaldehyde (over -5 minutes). After stirring at room temperature for ~10 minutes solid precipitated. Water was added (10 rnL) and the solid was filtered. The solid was washed further with cold water and dried overnight. To 385 nig of the dried solid in ~5 mL DMF was added 256 mg K2CO3 and 0.1 mL CH3I. The reaction was stirred at room temperature for 1.5 hours. Solid precipitated and 15 mL water was added to the mixture. The solid was filtered, further washed with water and dried to give 203 mg of pure product
	With hydrazine hydrate; at 20℃; for 5.08333h;	Intermediate 1014-lodo-1H-pyrazolo[3,4-fe]pyridine 2-Fluoro-4-iodo-3-pyridinecarbaldehyde (from Asymchem) (0.97g) was added portionwise over 5min to hydrazine hydrate (5ml). The resulting suspension was stirred at room temperature for 5h. Water (10ml) was added and the solid was filtered and washed with further water to give title compound, 664mg. LC/MS R1 0.84min m/z 246 [MH+]. Method B.

Reference： [1]Patent: WO2009/73300,2009,A1 .Location in patent: Page/Page column 108
[2]Patent: WO2013/37960,2013,A1 .Location in patent: Page/Page column 170
[3]Patent: WO2017/59080,2017,A1 .Location in patent: Page/Page column 96; 107
[4]Patent: US2009/286800,2009,A1 .Location in patent: Page/Page column 111-112
[5]Patent: WO2007/48070,2007,A2 .Location in patent: Page/Page column 128
[6]Patent: WO2013/192049,2013,A2 .Location in patent: Paragraph 0252
[7]Patent: WO2009/147188,2009,A1 .Location in patent: Page/Page column 134

3
[ 214210-21-6 ]
[ 64-18-6 ]
[ 861881-02-9 ]
[ 1075699-17-0 ]

Yield	Reaction Conditions	Operation in experiment
		A microwave tube was charged with 4-iodo-1 H-pyrazolo[3,4-b]pyridine (Intermediate 3; for a synthesis see Potashman, M. et al, Int. Patent Appl. WO 2005/070891 A2), (154 mg, 0.63 mmol), <strong>[214210-21-6](3-cyano-4-fluorophenyl)boronic acid</strong> (155 mg, 0.94 mmol), potassium carbonate (0.63 ml. of a 2M aqueous solution, 1.26 mmol), dichloro(1 ,1'- bis(diphenylphosphino)ferrocene)palladium(ll) (46 mg, 0.06 mmol), 1 ,4-dioxane (2.0 ml.) and water (0.37 ml_). The reaction was heated in a microwave reactor for 10 minutes at 15O0C. The crude reaction mixture was loaded onto a 1 g SiO2 SPE cartridge (which had been wetted with methanol, 1 column volume), the reaction vial was rinsed with methanol (2 ml.) and this was loaded onto the SPE cartridge. The cartridge was eluted with methanol (3 column volumes) and the combined eluants were concentrated in vacuo. Purification by reverse phase flash chromatography on a 43g C18 column, eluting with Solvent A - water + 0.1% formic acid; Solvent B - acetonitrile + 0.1% formic acid (step 1 : 5% B in A for 1 min; step 2: a gradient of 20% B in A to 50% B in A over 20 min; step 3: 100%B in A for 2 min) yielded 2-fluoro-5- (1H-pyrazolo[3,4-b]pyridin-4-yl)benzonitrile formate (Intermediate 4, 180 mg, 0.63 mmol) as an off-white solid.1H NMR (d6-DMSO) 13.90 (br. s, 1 H), 8.63 (d, 1 H), 8.50 (s, 1 H), 8.45 (dd, 1 H), 8.41 (s, 1 H), 8.31 (ddd, 1 H), 7.75 (t, 1 H), 7.45 (d, 1 H). m/z: 239.0 [M+H]+.

Reference： [1]Patent: WO2008/132121,2008,A1 .Location in patent: Page/Page column 31; 33-34

4
[ 861881-02-9 ]
[ 76-83-5 ]
[ 1160502-12-4 ]

Yield	Reaction Conditions	Operation in experiment
46%		Example 1 : 2-(2-(lH-pyrazolo[3,4-Z>;]pyridin-4-yl)thiazol-4-yl)ethanenitrile (CompoundMethod A :Step 1 : 4-iodo-l-trityl-lH-pyrazolo[3,4-Z>;]pyridine4-iodo-lΗ-pyrazolo[3,4-b]pyridine (15 g, 61.22 mmol) was dissolved in DMF (300 mL) and the solution was cooled down in an ice bath to 5C. Sodium hydride (60%, 2.938 g, 73.46 mmol) was added portionwise and left to stir at this temperature for 2 hours. After this time a solution of trityl chloride (18.77 g, 67.34 mmol) in DMF (150 mL) was added dropwise over 30 minutes. After an additonal 2 hours of stirring, the solvent was removed by evaporation, and the residue was partitioned between ethyl acetate and saturated bicarbonate (2 x 100 ml). The organic layer was further washed with brine (100 ml), dried (MgSO4) and concentrated in vacuo to give a brown oil. This residue was purified on silica gel by flash column chromatography to afford the title compound as a white solid (13.71 g, 46% Yield). 1H NMR (DMSOd6, 400 MHz) δ 7.16-7.31 (15H, m), 7.59 (IH, d), 7.89 (IH, d), 8.10 (IH, s); MS (ES+) 488.
27%		4-iodo-lH-pyrazolo[3,4-b]pyridine (15 g, 61.22 mmol) was dissolved in dimethylformamide (300 mL) and the solution was cooled down in an ice bath to 5C. Sodium hydride (60%, 2.938 g, 73.46 mmol) was added portionwise and left to stir at this temperature for 2 hours. After this time a solution of trityl chloride (18.77 g, 67.34 mmol) in dimethylformamide (150 mL) was added dropwise over 30 minutes. After an additonal 2 hours of stirring, the solvent was removed by evaporation, and the residue was partitioned between ethyl acetate and saturated bicarbonate (2 x 100 ml). The organic layer was further washed with brine (100 ml), dried over magnesium sulfate and concentrated in vacuo to give a brown oil. This residue was purified on silica gel by flash column chromatography to afford the title compound as a white solid (less polar fraction: 2- regioisomer, 13.71 g, 46% yield; more polar fraction: 3-regioisomer, pale yellow solid, 8.06 g, 27% yield).1H NMR (DMSO-d6, 400 MHz) δ 7.16-7.31 (15H, m), 7.59 (IH, d), 7.89 (IH, d), 8.10 (IH, s); MS (ES+) 488.4-iodo-lH-pyrazolo[3,4-b]pyridine (15 g, 61.22 mmol) was dissolved in dimethylformamide (300 mL) and the solution was cooled down in an ice bath to 5C. Sodium hydride (60%, 2.938 g, 73.46 mmol) was added portionwise and left to stir at this temperature for 2 hours. After this time a solution of trityl chloride (18.77 g, 67.34 <n="175"/>mmol) in dimethylformamide (150 mL) was added dropwise over 30 minutes. After an additonal 2 hours of stirring, the solvent was removed by evaporation, and the residue was partitioned between ethyl acetate and saturated bicarbonate (2 x 100 ml). The organic layer was further washed with brine (100 ml), dried over magnesium sulfate and concentrated in vacuo to give a brown oil. This residue was purified on silica gel by flash column chromatography to afford the title compound as a white solid (less polar fraction: 2-regioisomer, 13.71 g, 46% yield; more polar fraction: 3-regioisomer, pale yellow solid, 8.06 g, 27% yield).1H NMR (DMSO-d6, 400 MHz) δ 7.16-7.31 (15H, m), 7.59 (IH, d), 7.89 (IH, d) and 8.10 (IH, s) ppm; MS (ES+) 488.

Reference： [1]Patent: WO2010/129668,2010,A1 .Location in patent: Page/Page column 47
[2]Patent: WO2009/73300,2009,A1 .Location in patent: Page/Page column 122; 172

5
[ 861881-02-9 ]
[ 1160502-23-7 ]

Yield	Reaction Conditions	Operation in experiment
56%	With N-chloro-succinimide; In acetonitrile;Heating / reflux;	4-iodo-lH-pyrazolo[3,4-b]pyridine (1 g, 4.081 mmol) and NCS (653.9 mg, 4.897 mmol) were dissolved/suspended in dry CH3CN (20 mL) and refluxed overnight (material dissolves as temperature reaches reflux point to give slightly cloudy solution). The reaction mixture was allowed to cool to RT and concentrated under reduced pressure to give a dark yellow solid. This material was partitioned between EtOAc (~300mL) and brine. The organic layer was washed with brine (I x 5OmL), saturated Na2S2O3 (1 x 5OmL) and brine (1 x 5OmL) and then dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow solid. The resulting solid was purified by column chromatography (25% EtOAc in DCM, -10OmL silica) to give a white solid (641mg, 56% Yield). IH NMR (400.0 MHz, DMSO: 7.88 (IH, d), 8.23 (IH, d).

Reference： [1]Patent: WO2009/73300,2009,A1 .Location in patent: Page/Page column 143
[2]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1134 - 1139

6
[ 861881-02-9 ]
[ 915402-06-1 ]
[ 1160498-53-2 ]

Yield	Reaction Conditions	Operation in experiment
56%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 150℃; for 1.5h;Microwave irradiation;	To a mixture of 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3- dihydro-lH-inden-1-one (3 g, 11.6 mmol) and 4-iodo-lH-pyrazolo[3,4-b]pyridine (3.13 g, 12.8 mmol) in DME (20 mL) was added aq. sodium carbonate (2M, 11.62 mL, 23.2 mmol) followed by tetrakistriphenylphosphine palladium (978 mg, 0.846 mmol). The mixture was microwaved for 90 min at 150 0C. The reaction mixture was diluted with ethyl acetate and water and the layers separated. The organic layer was filtered off since it contained a yellow precipitate (desired prod ca. 85% pure) and then it was washed with water and then dried (MgSO4), filtered and concentrated and added to the precipitate above. The solids were recrystallised from boiling MeOH-THF to provide the pure ketone (1.62 g, 56%) as a yellow solid.IH NMR (400 MHz, DMSO): 2.74 (2H, br s), 3.21 (2H, br s), 7.43 (IH, d), 7.82 (IH, d), 8.01 (IH, s), 8.18 (IH, d), 8.29 (IH, s), 8.60 (IH, d), 13.87 (IH, br s).

Reference： [1]Patent: WO2009/73300,2009,A1 .Location in patent: Page/Page column 140

7
[ 861881-02-9 ]
[ 1160502-11-3 ]
[ 1160498-32-7 ]

Yield	Reaction Conditions	Operation in experiment
77%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 150℃; for 0.5h;Microwave irradiation;	2-(3-bromo-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2- methylpropanenitrile (137 mg, 0.39 mmol), 2 M aqueous solution of sodium carbonate (0.79 ml, 1.58 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mol %, 23 mg, 0.02 mmol), in ethylene glycol dimethyl ether (4 ml) was heated under microwave irradiation at <n="122"/>1500C for 30 minutes. The mixture was cooled down to room temperature, filtered through a path of celite and evaporated to dryness. The residue was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as a white solid (102.5 mg, 77% yield). 1H NMR (CDCl3, 400 MHz) δ 1.84 (6H, s), 7.35 (IH, d), 7.79 (IH, s), 7.85 (IH, s), 7.90 (IH, s), 8.29 (IH, s), 8.72 (IH, d); MS (ES+) 341.

Reference： [1]Patent: WO2009/73300,2009,A1 .Location in patent: Page/Page column 119-120

8
[ 861881-02-9 ]
[ 1160502-10-2 ]
[ 1160498-05-4 ]

Yield	Reaction Conditions	Operation in experiment
53%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 150℃; for 0.5h;Microwave irradiation;	2-methyl-2-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanenitrile (66 mg, 0.245 mmol), 2 M aqueous solution of sodium carbonate (0.31 ml, 0.612 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mol %, 12 mg, 0.01 mmol), in ethylene glycol dimethyl ether (2.5 ml) was heated under microwave irradiation at 1500C for 30 minutes. The mixture was cooled down to room temperature, filtered through a path of celite and evaporated to dryness. The residue was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as a white solid (28.4 mg, 53% yield).1H NMR (CDCl3, 400 MHz) δ 1.79 (6H, s), 7.42 (IH, d), 7.67-7.72 (2H, m), 7.86 (IH, d), 7.95 (IH, s), 8.31 (IH, s), 8.61 (IH, d), 13.85 (IH, br s); MS (ES+) 263

Reference： [1]Patent: WO2009/73300,2009,A1 .Location in patent: Page/Page column 109
[2]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1134 - 1139

9
[ 861881-02-9 ]
[ 910209-21-1 ]
[ 1196875-94-1 ]

Yield	Reaction Conditions	Operation in experiment
9%	With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In dimethyl sulfoxide; at 100℃; for 16h;Inert atmosphere;	Reference Example 20 4-(cyclopropylsulfonyl)-1H-pyrazolo[3,4-b]pyridine [Show Image] To a solution of 4-iodo-1H-pyrazolo[3,4-b]pyridine (5.2 g) in dimethyl sulfoxide (70 mL) were added N,N'-dimethylethylenediamine (114 muL), copper (I) iodide (202 mg), <strong>[910209-21-1]sodium cyclopropanesulfinate</strong> (8.16 g) and potassium carbonate (5.06 g) at room temperature under argon atmosphere, and the mixture was stirred at 100C for 16 hr. The reaction mixture was filtered, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (0.42 g, yield 9%) as yellow crystals from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS:224(MH+).
	In N,N-dimethyl-formamide; at 120℃; for 4h;	Compound 16B: To a solution of 16A (1.00 g, 4.02 mmol) in DMF (12 ml) was added <strong>[910209-21-1]sodium cyclopropanesulfinate</strong> (1.57 g, 12.2 mmol) and the reaction was heated at 120 C. for 4 hours. After cooling to room temperature, the reaction mixture was concentrated and the residue was treated with water, followed by extracted into ethyl acetate. The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure to yield crude 16B (0.98 g). [M+H] calc'd for C9H9N3O2S 224; found 224.

Reference： [1]Patent: EP2266983,2010,A1 .Location in patent: Page/Page column 50
[2]Patent: US2009/286800,2009,A1 .Location in patent: Page/Page column 111-113

10
[ 861881-02-9 ]
[ 98-09-9 ]
[ 1198437-88-5 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 102 4-lodo-1-(phenylsulfonyl)-1H-pyrazolo[3,4-fe]pyridine To a stirring suspension of NaH (0.9g) in anhydrous THF (25ml) at -5C was added 4- iodo-1 H-pyrazolo[3,4-b]pyridine (5g) in anhydrous THF (75ml) and DMF (25ml). Triethylamine (3ml) was added and the reaction was stirred for 30min at 00C. Benzenesulfonyl choride (2.9ml) in anhydrous THF (25ml) was added dropwise over 10 min and the reaction was stirred for 1 h at 00C then quenched with water. The layers were separated and the aqueous was re-extracted with ethyl acetate. The combined organics <n="137"/>were washed with brine, dried over magnesium sulfate, filtered and then evaporated to yield a solid residue that was triturated with methanol to give title compound, 4.1g. LC/MS R1 1.04min m/z 386 [MH+]. Method D.

Reference： [1]Patent: WO2009/147188,2009,A1 .Location in patent: Page/Page column 134-135

11
[ 861881-02-9 ]
[ 1192004-56-0 ]
[ 1192004-70-8 ]

Yield	Reaction Conditions	Operation in experiment
53%		Reference Example 21 ethyl 2-(4-iodo-1H-pyrazolo[3,4-b]pyridin-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanoate [Show Image] A mixture of <strong>[861881-02-9]4-iodo-1H-pyrazolo[3,4-b]pyridine</strong> (1.72 g), a 1:1 mixture (3.1 g) of ethyl 2-bromo-3-(tetrahydro-2H-pyran-4-yl)propanoate and ethyl 3-(tetrahydro-2H-pyran-4-yl)-2-propenoate, potassium carbonate (1.0 g) and N,N-dimethylformamide (15 mL) was stirred overnight at room temperature. To the reaction mixture was added aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (1.6 g, yield 53%) as a colorless oil from the fraction eluted with ethyl acetate-hexane (35:75, volume ratio). MS:430(MH+).

Reference： [1]Patent: EP2266983,2010,A1 .Location in patent: Page/Page column 50-51

12
[ 861881-02-9 ]
C₂₄H₃₃N₉O₄ [ No CAS ]

Reference： [1]Patent: WO2013/192049,2013,A2

13
[ 861881-02-9 ]
[ 74-88-4 ]
4-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%		A solution of 4-iodo- 1H-pyrazolo [3,4-bj pyridine, prepared as described in Example 284 (0.050 g, 0.204 mmol) in DMF (0.5 mL) was cooled to 0 C and NaH (8.16 mg, 0.204 mmol) was added. The reaction mixture was stirred for 30 mm at 0C and iodomethane (0.029 g, 0.204 mmol) was added. The reaction mixture was stirred for 10 mm at 0 C and at room temperature for 1 h. The reaction mixture was quenched with ice and diluted with ethyl acetate (5 mL). The organic layer was separated. The aqueous layer was again extracted with ethyl acetate (2x5 mL). The ethyl acetate layer was washed with brine, dried over Na2SO4, filtered, andconcentrated under reduced pressure. The cmde material was purified via silica gel chromatography (30% ethyl acetate in hexanes) to afford 4-iodo-i-methyl-1H- pyrazolo[3,4-bjpyridine (0.030 g, 0.114 mmol, 56% yield) as a brown solid. LCMS (ESI) m/e 259.9 [(M+H) , calcd for C7H71N3 259.91; LC/MS retention time (Method C): tR=0.87min.
47%	With ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)(pyrazolo[1,5-a]pyrimidin-3-yl)methanone; In N,N-dimethyl-formamide; mineral oil; at 0℃; for 0.25h;Inert atmosphere;	To a solution of <strong>[861881-02-9]4-iodo-1H-pyrazolo[3,4-b]pyridine</strong> (405 mg, 1.65 mmol) in N,N-dimethylformamide (4 mL) was added sodium hydride (60% in mineral oil, 80 mg, 2.0 mmol) at 0 C. and the reaction was stirred at 0 C. for 15 min. To the reaction mixture was added iodomethane (115 μL, 1.85 mmol, 2.28 g/mL) and the reaction was stirred at 0 C. for 45 min. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (3*15 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography eluting with n-heptane:ethyl acetate (9:1) to afford the title compound (200 mg, 0.772 mmol, 47%) as a white powder. MS (ESI): mass calcd. for C7H6IN3, 259.0; m/z found, 260.0 [M+H]+.
203 mg	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 1.5h;	] To 3 mL N2H4 (anhydrous) was added 1.0 g of 2-fluoro-4-iodoiiicotinaldehyde (over -5 minutes). After stirring at room temperature for ~10 minutes solid precipitated. Water was added (10 rnL) and the solid was filtered. The solid was washed further with cold water and dried overnight. To 385 nig of the dried solid in ~5 mL DMF was added 256 mg K2CO3 and 0.1 mL CH3I. The reaction was stirred at room temperature for 1.5 hours. Solid precipitated and 15 mL water was added to the mixture. The solid was filtered, further washed with water and dried to give 203 mg of pure

Reference： [1]Patent: WO2017/59080,2017,A1 .Location in patent: Page/Page column 102; 103
[2]Patent: US2020/102311,2020,A1 .Location in patent: Paragraph 0410; 0669
[3]Patent: WO2013/192049,2013,A2 .Location in patent: Paragraph 0252

14
[ 861881-02-9 ]
(S)-tert-butyl (1-(2-fluoro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate [ No CAS ]

Reference： [1]Patent: WO2017/59080,2017,A1

15
[ 861881-02-9 ]
(S)-1-(2-fluoro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine [ No CAS ]

Reference： [1]Patent: WO2017/59080,2017,A1

16
[ 861881-02-9 ]
(S)-tert-butyl (1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate [ No CAS ]
(S)-1-(2-fluoro-4-(1H-pyrazolo[3,4-b]pyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine [ No CAS ]

Reference： [1]Patent: WO2017/59080,2017,A1

17
[ 861881-02-9 ]
(S)-tert-butyl (1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate [ No CAS ]
(S)-tert-butyl (1-(2-fluoro-4-(1H-pyrazolo[3,4-b]pyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With dipotassium hydrogenphosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 60℃; for 3h;Inert atmosphere;	To a solution of 4-iodo-1H-pyrazolo[3,4-bjpyridine (prepared as described in Example 284) (0.030 g, 0.122 mmol) in 1,4-dioxane (6 mL) and water (2 mL) wasadded (5)-tert-butyl (1 -(2-fluoro-4-(4,4,5,5 -tetramethyl- 1,3 ,2-dioxaborolan-2- yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate (prepared as in Example 253, Part B) (0.055 g, 0.122 mmol) and potassium phosphate, dibasic (0.043 g, 0.245 mmol). The reaction mixture was purged with argon for 10 mm and PdC12(dppf)-CH2C12 adduct (10.00 mg, 0.012 mmol) was added. The reaction mixture was again purgedwith argon for 10 mm and heated for 3 h at 60 C. The reaction mixture was diluted with ethyl acetate and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (2x5 mL). The ethyl acetate layer was washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The cmde product was purified by Preparative TLC using 40% EtOAc in hexane.The required spot was collected, dissolved in 10% MeOH in DCM(20 mL), filtered and concentrated under reduced pressure to afford (S)-tert-butyl (1-(2-fluoro-4-(1H- pyrazolo[3 ,4-bj pyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate (0.038 g, 0.086 mmol, 70% yield) as a pale yellow solid. LCMS (ESI) m/e 443.2 [(M+H), calcd for C24H32FN403 443.21; LC/MS retention time (method D): tR = 2.13 mm.

Reference： [1]Patent: WO2017/59080,2017,A1 .Location in patent: Page/Page column 100; 101

18
[ 861881-02-9 ]
(S)-tert-butyl (2,4-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)pentan-2-yl)carbamate [ No CAS ]
(S)-tert-butyl (1-(4-(1H-pyrazolo[3,4-b]pyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 60℃; for 4h;Inert atmosphere;	To a solution of 4-iodo-1H-pyrazolo[3,4-bjpyridine (0.030 g, 0.122 mmol) in 1,4-dioxane (6 mL) and water (2 mL), (S)-tert-butyl (2,4-dimethyl-l-(4-(4,4,5,5- tetramethyl- 1,3 ,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)pentan-2-yl)carbamate (prepared as described in Example 255, Parts A and B) (0.061 g, 0.122 mmol) and potassium phosphate, dibasic (0.043 g, 0.244 mmol) was added. The reaction mixture was purged with argon for 10 mm and PdC12(dppf)-CH2C12 adduct (9.98 mg, 0.012 mmol) was added. The reaction mixture was again purged with argon for 10 mm and heated for 4 h at 60C. The reaction mixture was diluted withethyl acetate (10 mL) and the aqueous layer was washed with ethyl acetate (2x8 mL). The ethyl acetate layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The reaction mixture was purified by Preparative TLC by 70% ethyl acetate in hexanes. The required spot was collected, dissolved 15% MeOH in DCM(20 mL), filtered and concentrated under reduced pressure to afford (5)-tert-butyl (1 -(4-( 1H-pyrazolo [3 ,4-bj pyridin-4-yl)-2- (trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate (0.031 g, 0.058 mmol,47% yield) as an off-white solid .LCMS (ESI) m/e 493.2 [(M+H) , calcd for C25H32F3N403 493.21; LC/MS retention time (method B): tR = 1.11 mm.

Reference： [1]Patent: WO2017/59080,2017,A1 .Location in patent: Page/Page column 107; 108

19
[ 861881-02-9 ]
(S)-tert-butyl (2,4-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)pentan-2-yl)carbamate [ No CAS ]
(S)-1-(4-(1H-pyrazolo[3,4-b]pyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine [ No CAS ]

Reference： [1]Patent: WO2017/59080,2017,A1

20
[ 861881-02-9 ]
(S)-tert-butyl (1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate [ No CAS ]
(S)-tert-butyl (1-(2-chloro-4-(1H-pyrazolo[3,4-b]pyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 60℃; for 3h;Inert atmosphere;	A solution of 4-iodo-1H-pyrazolo[3,4-bjpyridine (0.030 g, 0.122 mmol),(5)-tert-butyl (1 -(2-chloro-4-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate (prepared as described in Example 260, Part A and B) (0.057 g, 0.122 mmol) and potassium phosphate, dibasic (0.043 g, 0.245 mmol) in 1 ,4-dioxane (6 mL) and water (2 mL) was purged with argon for 10 mm. PdC12(dppf)-CH2C12 adduct (10.00 mg, 0.012 mmol) was added to the reaction mixture under argon and heated to 60 C for 3 h. The reaction mixture was diluted with ethyl acetate and the organic layer was separated. The aqueous layer wasextracted with ethyl acetate (2x5 mL). The ethyl acetate layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The cmde product was purified by Prep TLC using 40% ethyl acetate in hexane. The required spot was collected, dissolved in 10% methanol in dichloromethane (20 mL), filtered and concentrated under reduced pressure to afford (5)-tert-butyl (1-(2-chloro-4-( 1H-pyrazolo[3,4-bj pyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate(0.032 g, 0.063 mmol, 52% yield) as a pale yellow solid. LCMS (ESI) m/e 459.2[(M+H), calcd for C24H32C1N403 459.2j; LC/MS retention time (method A2): tR =2.16 mm.

Reference： [1]Patent: WO2017/59080,2017,A1 .Location in patent: Page/Page column 96; 97

21
[ 861881-02-9 ]
(S)-tert-butyl (1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate [ No CAS ]
(S)-1-(2-chloro-4-(1H-pyrazolo[3,4-b]pyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine hemihydrochloride [ No CAS ]

Reference： [1]Patent: WO2017/59080,2017,A1

22
[ 214210-21-6 ]
[ 861881-02-9 ]
[ 1075699-15-8 ]

Reference： [1]Patent: WO2008/132121,2008,A1

23
[ 861881-02-9 ]
[ 1198433-13-4 ]

Reference： [1]Patent: WO2009/147188,2009,A1

24
[ 861881-02-9 ]
C₃₂H₂₆N₈O₅S₂ [ No CAS ]

Reference： [1]Patent: WO2009/147188,2009,A1

25
[ 861881-02-9 ]
4-iodo-7-oxido-1H-pyrazolo[3,4-b]pyridin-7-ium [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With 3-chloro-benzenecarboperoxoic acid; In 1-methyl-pyrrolidin-2-one; at 0 - 25℃;	4-Iodo-lH-pyrazolo[3,4-b]pyridine (1 g, 4.08 mmol) was dissolved in NMP (5 ml) at rt and then cooled to 0 C. mCPBA (1.2 g, 5.22 mmol) was added portion wise and the resulting mixture was stirred at rt overnight. More mCPBA (200 mg, 0.87 mmol) was added and the mixture stirred at rt for 1 h. MTBE (10 ml) was added and the mixture stirred vigorously for 30 min. The formed precipitate was filtered off, washed with pentane and dried to give the product as a solid (820 mg, 77%). MS ES+ m/z 262 [M+H]+.

Reference： [1]Patent: WO2019/126733,2019,A1 .Location in patent: Paragraph 0280; 0364

26
[ 861881-02-9 ]
6-chloro-4-iodo-1H-pyrazolo[3,4-b]pyridine [ No CAS ]

Reference： [1]Patent: WO2019/126733,2019,A1

27
[ 861881-02-9 ]
[ 76-83-5 ]
[ 1160502-12-4 ]
C₂₅H₁₈IN₃ [ No CAS ]