[ CAS No. 875781-17-2 ] {[proInfo.proName]}

Name: 875781-17-2|5-Bromo-1H-pyrazolo[3,4-b]pyridine|97%
Brand: Ambeed
SKU: A217103
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Quality Control of [ 875781-17-2 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 875781-17-2 ]

SDS Specification

Alternatived Products of [ 875781-17-2 ]

Product Details of [ 875781-17-2 ]

CAS No. :	875781-17-2	MDL No. :	MFCD05663982
Formula :	C₆H₄BrN₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BASYLPMLKGQZOG-UHFFFAOYSA-N
M.W :	198.02	Pubchem ID :	40427454
Synonyms :

Calculated chemistry of [ 875781-17-2 ]

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 :	41.59
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) :	-6.44 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.13
Log Po/w (XLOGP3) :	1.51
Log Po/w (WLOGP) :	1.72
Log Po/w (MLOGP) :	1.35
Log Po/w (SILICOS-IT) :	2.28
Consensus Log Po/w :	1.6

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.69
Solubility :	0.409 mg/ml ; 0.00207 mol/l
Class :	Soluble
Log S (Ali) :	-1.99
Solubility :	2.02 mg/ml ; 0.0102 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.4
Solubility :	0.0797 mg/ml ; 0.000403 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.68

Safety of [ 875781-17-2 ]

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 [ 875781-17-2 ]

* 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 [ 875781-17-2 ]
Downstream synthetic route of [ 875781-17-2 ]

[ 875781-17-2 ] Synthesis Path-Upstream 1~14

1
[ 875781-17-2 ]
[ 875781-18-3 ]

Yield	Reaction Conditions	Operation in experiment
97%	Stage #1: With iodine; potassium hydroxide In N,N-dimethyl-formamide for 3.5 h; Stage #2: With iodine; sodium hydroxide In 1,4-dioxane at 40℃; for 23 h;	5-bromo-3 -iodo- 1 H-pyrazolo [3 ,4-bipyridine ( IV-A-I); To a stirred solution of the bromo-diazaindole III- A-I (1 g, 5.05 mmol) in DMF (14 mL) was added crushed KOH pellets (1.06 g, 19.03 mmol) in one portion. After 11 min, I₂ (1.15 g, 4.54 mmol) was added and the mixture stirred vigorously for 3.5 h. The mixture was then partially concentrated in vacuo, diluted with EtOAc (40 mL): saturated NaHCO₃ solution (20 mL) and partitioned. The aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were dried (MgSO₄), filtered and concentrated to afford a 1 :1 mixture of III-A-1 and IV-A-I (1.377 g). This mixture was re-dissolved in 1,4-dioxane (14 mL) and treated with solid NaOH (0.7 g). The mixture was stirred for 5 min at RT and I₂ (0.7 g) was added. The mixture was stirred at 40 ⁰C for 23 h, diluted with EtOAc (50 mL) and washed with saturated aqueous Na₂S₂O₃ solution (30 mL). The aqueous layer was extracted with EtOAc (2 x 30 mL) and the combined organic extracts were dried (MgSO₄), filtered and concentrated to afford azaindazole IV-A-I (1.585 g, 97percent). ¹H NMR (400 MHz; CDCl₃) δ 7.94 (d, J2.1, IH), 8.55 (d, J2.1, IH), 10.85 (brs, NH).
91%	With iodine; sodium hydroxide In 1,4-dioxane; water at 60℃;	To a solution of 5-bromo-lH-pyrazolo[3,4-b]pyridine (I) (5 g, 25.25 mmol, 1 eq) in 1,4- dioxane (100 mL) and 4 N aqueous NaOH (100 mL) was added iodine (64.1 g, 252.5 mmol, 10 eq). The mixture was stirred at 60 °C overnight, and TLC showed the reaction was complete. The reaction mixture was extracted with EtOAc (100 ml x 2). The combined organic extracts were washed with saturated aqueous NaHS0₃ solution (100 mL x 3) and brine (50 mL), dried over Na₂S0₄, filtered, and concentrated to give the title compound 5-bromo-3-iodo-lH- pyrazolo[3,4-b]pyridine as an off-white solid (7.5 g , yield:91percent).
91%	With iodine; sodium hydroxide In 1,4-dioxane; water at 60℃;	[0116] To a solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine (I) (5 g, 25.25 mmol, 1 eq) in a mixture of 1 ,4-dioxane (100 mL) and 4 N aqueous NaOH (100 mL) was added iodine (64.1 g, 252.5 mmol, 10 eq). The resulting mixture was stirred at 60 °C overnight, and TLC showed the reaction was complete. The resulting mixture was extracted with EtOAc (100 ml x 2). The combined organic layers were washed with saturated aqueous NaHSO3 (100 mL x 3) and brine (50 mL), dried over Na2504, and concentrated to give the title compound 5-bromo-3-iodo-JH- pyrazolo[3,4-b]pyridine (II) as an off-white solid (7.5 g , yield:91percent), which was used in the next step without any further purification.

91%	With iodine; sodium hydroxide In 1,4-dioxane; water at 60℃;	To a solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine (I) (5 g, 25.25 mmol, 1 eq) in 1,4-dioxane (100 mL) and 4 N aqueous NaOH (100 mL) was added iodine (64.1 g, 252.5 mmol, 10 eq). The mixture was stirred at 60 °C overnight, and TLC showed the reaction was complete. The reaction mixture was extracted with EtOAc (100 ml x 2). The combined organics were washed with saturated aqueous NaHSO3 (100 mL x 3) and brine (50 mL), dried over Na2SO4, and concentrated to give the title compound 5-bromo-3-iodo-JH-pyrazolo[3,4- b]pyridine (II) as an off-white solid (7.5 g , yield:91percent), which was used in the next step without any further purification.
85.6%	Stage #1: With potassium hydroxide In N,N-dimethyl-formamide at 25℃; for 0.166667 h; Inert atmosphere Stage #2: With iodine In N,N-dimethyl-formamide at 25℃; for 4 h; Inert atmosphere	To a solution of 5-Bromo-1H-pyrazolo[3,4-b]pyridine (2.0 g, 10.1 mmol) in DMF (20 mL) Potassium hydroxide (KOH, 1.2 g, 21.4 mmol) was added at 25 °C. After stirring for 10 min, Iodine (2.8 g, 11.1 mmol) was added and stirred at 25 °C for 4 h. The resulting mixture was diluted with water (30 mL), extracted with EtOAc (20 mL * 3). The organic phase was washed with sat. Na₂S₂O₃ solution (30 mL * 2), brine (30 mL * 2), dried over Na₂SO₄, and concentrated to give compound 39 as a brown solid (2.8 g, 85.6percent yield). ¹H NMR (400 MHz, DMSO-d₆) δ 14.30 (s, 1H, NH), 8.65 (s, 1H, Ar-H), 8.21 (s, 1H, Ar-H).
85.6%	Stage #1: With potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 0.166667 h; Stage #2: With iodine In N,N-dimethyl-formamide at 20℃; for 4 h;	The 5-bromo -1H-pyrazolo [3,4-b] pyridine (2.0g, 10 . 1mmol) adding 20mLN, in N-dimethyl formamide, stirring to dissolve, then adding flaky potassium hydroxide (1.2g, 21 . 4mmol), stir at room temperature the reaction 10 minutes, and then added with the solid iodine (2.8g, 11 . 1mmol), stir at room temperature the reaction 4 experimental, then water (30 ml) dilution, ethyl acetate (3×20 ml) extraction, then with saturated sodium thiosulfate solution (2×30 ml) and saturated salt water (2×30 ml) washing, the organic phase is dried with anhydrous sodium sulfate, concentrated. Then the solid plus dioxane (30 ml) is dissolved, add potassium hydroxide (1.2g, 21 . 4mmol), stir to react under room temperature for 10 minutes, then adding solid iodine (2.8g, 11 . 1mmol), stir at room temperature reaction sleepovers, water reaction is ended (30 ml) dilution, ethyl acetate (3×20 ml) extraction, then with saturated sodium thiosulfate solution (2×30 ml) and saturated salt water (2×30 ml) washing, the organic phase is dried with anhydrous sodium sulfate, concentrated to obtain pale brown solid (2.8g, 85.6percent).
77%	With N-iodo-succinimide In 1,2-dichloro-ethane for 6 h; Heating / reflux	Step 4: Synthesis of 5-bromo-3-iodo-lH-pyrazolo[3,4-b]pyridine.[0220] 5-bromo-17J-pyrazolo[3,4-b]pyridine (3.00 g, 15.2 mmol) and A'-iodosuccinimide(3.60 g, 16.0 mmol) were dissolved in anhydrous dichloroethane (100 mL). The resultingmixture was stirred under reflux conditions for 6 h, cooled to room temperature and dilutedwith THF (300 mL). The resulting solution was washed with a saturated aqueous solutionof sodium thiosulfate (100 mL) and brine, then dried over magnesium sulfate, filtered andconcentrated. The residue was titurated with a 1:1 mixture of dichloromethane and etherand then ether before being dried in vacuum to afford 5-bromo-3-iodo-l//-pyrazolo[3,4-bjpyridine (3.795 g, 77percent yield) as a beige-brown solid. ^-NMR (500 MHz, 6-DMSO) S14.31 (s, 1H), 8.65 (d, 1H), 8.20 (d, 1H). MS: m/z 323, 325 [MH⁺].
77%	With N-iodo-succinimide In 1,2-dichloro-ethane for 6 h; Heating / reflux	5-bromo-1H-pyrazolo[3,4-b]pyridine (3.00 g, 15.2 mmol) and N-iodosuccinimide (3.60 g, 16.0 mmol) were dissolved in anhydrous dichloroethane (100 mL). The resulting mixture was stirred under reflux conditions for 6 h, cooled to room temperature and diluted with THF (300 mL). The resulting solution was washed with a saturated aqueous solution of sodium thiosulfate (100 mL) and brine, then dried over magnesium sulfate, filtered and concentrated. The residue was titurated with a 1:1 mixture of dichloromethane and ether and then ether before being dried in vacuum to afford 5-bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine (3.795 g, 77percent yield) as a beige-brown solid. ¹H-NMR (500 MHz, d₆-DMSO) δ 14.31 (s, 1H), 8.65 (d, 1H), 8.20 (d, 1H). MS: m/z 323, 325 [MH⁺].
75%	With N-iodo-succinimide In 1,1-dichloroethaneHeating; Reflux	N-Iodosuccinimide (8.1 g, 34.1 mmol) was added to a solution of 5- bromo-lH-pyrazolo[3,4-b]pyridine (4.5 g, 22.7 mmol) in dichloroethane (100 mL), and the reaction mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature and diluted with THF (300 mL). The organic layers were washed with saturated Na₂S₂O₃ (100 mL) and brine (100 mL). The organic layers were dried, filtered and concentrated to a solid. The crude product was triturated with DCM and ethyl acetate to give 5-bromo-3-iodo-lH-pyrazolo[3,4-b]pyridine (5.5 g, 75percent) as a solid.
70%	With N-iodo-succinimide In 1,2-dichloro-ethaneReflux	5-Bromo-1H-pyrazolo[3,4-b]pyridine (19.7 g, 100 mmol) was dissolved in 150 mL of 1,2-dichloroethane, and N-iodosuccinimide (24.8 g) was added. , 110 mmol), heated to reflux overnight.After the reaction was completed, the sodium thiosulfate solution was added and stirred for 20 min, and a yellow solid was charged and analyzed, and the mixture was filtered under reduced pressure. The filter cake was washed thoroughly with petroleum ether and dried in vacuo.A yellow solid was obtained 22.7 g (Yield: 70percent).
41.3%	Stage #1: With iodine In N,N-dimethyl-formamide at 20℃; for 0.0833333 h; Stage #2: With potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 3 h;	Four grams of compound d and 10.25 g of iodine were dissolved into 50 ml N,N-dimethylformamide, stirred for 5 minutes at room temperature. Slowly, 2.83 g of potassium hydroxide was added into the above solution, and further stirred at room temperature for 3 hours, the reaction was completed. The reactant liquid was poured into 1000 ml water, solid was precipitated, filtered, the filter cake was washed three times by water immersion, vacuum dried to obtain compound e (m=1.35 g, yield: 41.3percent). (0183) ¹H NMR (400 MHz, CDCl₃) δ 8.47 (d, J=2.1 Hz, 1H), 7.93 (d, J=2.1 Hz, 1H).

Reference： [1] Patent: WO2010/15803, 2010, A1, . Location in patent: Page/Page column 43
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 5, p. 2513 - 2529
[3] Patent: WO2016/26078, 2016, A1, . Location in patent: Paragraph 065
[4] Patent: WO2016/192063, 2016, A1, . Location in patent: Paragraph 0112; 0115; 0116
[5] Patent: WO2017/28314, 2017, A1, . Location in patent: Paragraph 0125
[6] Bioorganic Chemistry, 2016, vol. 65, p. 146 - 158
[7] Patent: CN103613591, 2016, B, . Location in patent: Paragraph 0342-0344
[8] Patent: WO2006/15124, 2006, A2, . Location in patent: Page/Page column 59
[9] Patent: US2008/261921, 2008, A1, . Location in patent: Page/Page column 73-74
[10] Patent: WO2009/111279, 2009, A1, . Location in patent: Page/Page column 83
[11] Patent: CN108117553, 2018, A, . Location in patent: Paragraph 0278; 0279; 0280-0282
[12] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 5, p. 543 - 547
[13] Patent: US2016/137640, 2016, A1, . Location in patent: Paragraph 0181; 0182
[14] Patent: WO2015/25025, 2015, A1, . Location in patent: Page/Page column 130
[15] Patent: WO2016/192064, 2016, A1, . Location in patent: Paragraph 0118-0119

2
[ 516-12-1 ]
[ 875781-17-2 ]
[ 875781-18-3 ]

Reference： [1] Journal of Medicinal Chemistry, 2013, vol. 56, # 3, p. 879 - 894

3
[ 2065-75-0 ]
[ 1225387-53-0 ]
[ 705263-10-1 ]
[ 875781-17-2 ]

Yield	Reaction Conditions	Operation in experiment
2.1%	at 20℃; Heating / reflux	A solution of 1 H-pyrazol-5-amine x79 (25 g, 1 eq, 0.3 mol) and bromomalonaldehyde x9 (45.4 g, 1 eq, 0.3 mol) ethanol (250 ml) is refluxed for 2 hours. After cooling, the reaction mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure and the crude is purified using chiral chromatography affording 5-bromo-1H-pyrazolo[3,4-b]pyridine x80 (yield: 2.1 percent; LC-MS (MH⁺): 198/200) and 6-bromopyrazolo[1 ,5-a]pyrimidine x81 (yield: 13.8 percent; LC-MS (MH⁺): 198/200).

Reference： [1] Patent: WO2006/128692, 2006, A2, . Location in patent: Page/Page column 86

4
[ 875781-15-0 ]
[ 875781-17-2 ]

Yield	Reaction Conditions	Operation in experiment
46%	With hydrazine In ethanolHeating / reflux	Preparation of 5-bromo-1H-pyrazolo[3,4-b]pyridine (D-1-3). <n="101"/>D-1-2 ^D"1-³A solution of compound D-1-2 (20 g, 0.1 mol) and anhydrous hydrazine (18 g, 0.56 mol) in ethanol was heated to reflux overnight. TLC (petroleum ether/EtOAc 2:1 ) indicated complete consumption of starting material. The reaction mixture was concentrated in vacuo to a volume of about 50 ml_ and poured into water (500 ml_), the resulting mixture was filtered. The cake was washed with water (50 ml_^χ3) and ether (20 ml_^χ3), then dried in vacuo to yield compound D-1-3 (9.0 g, 46percent) as a yellow solid.
40%	With hydrazine hydrate In ethanol at 100℃; for 8 h;	5-Bromo-2-fluoro-pyridine-3-carbaldehyde (4.1g, 20mmol) obtained from Preparation Example 129-1 was dissolved in ethanol (50ml). After adding hydrazine hydrate (5.0ml, 100mmol), the mixture was stirred for 8 hours at 100 and then distilled under reduced pressure. Water was added thereto and the residue was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (1.8g, 40percent).[1499] NMR:¹H-NMR(400HMz, CDCl₃); δ 11.29 (br s, 1H), 8.63 (s, 1H), 8.26 (s, 1H), 8.07 (s, 1H)
135 g	With hydrazine hydrate In ethanol at 75 - 80℃; for 12 h;	To a stirred solution of 5-bromo-2-fluoronicotinaldehyde (XV) (250 g, 1.23 mol, 1.0 eq) in EtOH (2.50 L) was added hydrazine hydrate (221 g, 4.41 mol, 3.6 eq) at 25°C. The reaction was then heated to 75~80°C and stirred for 12 h. The solvent was removed under reduced pressure at 45°C. The residual crude solid was triturated in water (750 mL) and EtOH (250 mL). The resultant suspension was filtered and washed with ethanol to give 5 -bromo- lH-pyrazolo[3,4- b]pyridine (XVI) (135 g, 0.68 mol, 55.4percent yield) as yellowish solid which was used directly for the next step without further purification. ESIMS found for CeLLtBrNs mlz 199.1 (M+H).

135 g

With hydrazine hydrate In ethanol at 25 - 80℃; for 12 h;

To a stirred solution of 5-bromo-2-fluoronicotinaldehyde (XV) (250 g, 1.23mol, 1.0 eq) in EtOH (2.50 L) was added hydrazine hydrate (221 g, 4.41 mol, 3.6 eq) at 25°C. The reaction was then heated to 7580°C and stirred for 12 h. The solvent was removed under reduced pressure at 45°C. The residual crude solid was triturated in water (750 mL) and EtOH (250 mL). The resultant suspension was filtered and washed with ethanol to give 5-bromo-1H- pyrazolo[3,4-bjpyridine (XVI) (135 g, 0.68 mol, 55.4percent yield) as yellowish solid which was used directly for the next step without further purification. ESIMS found for C6H4BrN3 mlz 199.1 (M+H).

Reference： [1] Journal of Organic Chemistry, 2017, vol. 82, # 14, p. 7420 - 7427
[2] Patent: WO2009/16460, 2009, A2, . Location in patent: Page/Page column 99-100
[3] Patent: WO2014/73904, 2014, A1, . Location in patent: Paragraph 1496-1499
[4] Patent: CN103980272, 2016, B, . Location in patent: Paragraph 0031; 0033
[5] Patent: WO2017/23987, 2017, A1, . Location in patent: Paragraph 0610; 0612
[6] Patent: WO2017/23981, 2017, A1, . Location in patent: Paragraph 0610; 0612
[7] Patent: WO2017/23973, 2017, A1, . Location in patent: Paragraph 0633
[8] Patent: WO2017/23996, 2017, A1, . Location in patent: Paragraph 0612

5
[ 875781-16-1 ]
[ 875781-17-2 ]

Reference： [1] Patent: US2008/261921, 2008, A1, . Location in patent: Page/Page column 73-74

6
[ 1083326-08-2 ]
[ 875781-17-2 ]

Reference： [1] Patent: US2008/293706, 2008, A1, . Location in patent: Page/Page column 85

7
[ 2065-75-0 ]
[ 1225387-53-0 ]
[ 705263-10-1 ]
[ 875781-17-2 ]

Yield	Reaction Conditions	Operation in experiment
2.1%	at 20℃; Heating / reflux	A solution of 1 H-pyrazol-5-amine x79 (25 g, 1 eq, 0.3 mol) and bromomalonaldehyde x9 (45.4 g, 1 eq, 0.3 mol) ethanol (250 ml) is refluxed for 2 hours. After cooling, the reaction mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure and the crude is purified using chiral chromatography affording 5-bromo-1H-pyrazolo[3,4-b]pyridine x80 (yield: 2.1 percent; LC-MS (MH⁺): 198/200) and 6-bromopyrazolo[1 ,5-a]pyrimidine x81 (yield: 13.8 percent; LC-MS (MH⁺): 198/200).

Reference： [1] Patent: WO2006/128692, 2006, A2, . Location in patent: Page/Page column 86

8
[ 2065-75-0 ]
[ 1225387-53-0 ]
[ 875781-17-2 ]

Yield	Reaction Conditions	Operation in experiment
25%	for 6 h; Heating; Reflux; Inert atmosphere of N₂	lH-Pyrazol-5-amine (5.3 g, 64 mmol) and 2-bromomalonaldehyde(9.9 g, 64 mmol) were suspended in acetic acid (100 mL). The reaction mixture was heated <n="82"/>to reflux under N₂ for 6 hours. The reaction mixture was cooled to room temperature and concentrated to give a solid. The crude solids were suspended in MeOH (200 mL) and absorbed onto silica gel (200 g). The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (4:1), hexanes/ethyl acetate (2:1) to give 5-bromo-lH- pyrazolo[3,4-b]pyridine as a solid (3.1 g, 25percent).

Reference： [1] Patent: WO2009/111279, 2009, A1, . Location in patent: Page/Page column 79-80

9
[ 1820-80-0 ]
[ 2065-75-0 ]
[ 875781-17-2 ]

Yield	Reaction Conditions	Operation in experiment
11%	for 2 h; Heating / reflux	Preparation 6; 5 -Bromo- 1 H-pyrazolo [3 ,4-b] pyridine; Dissolve 2-bromomalonaldehyde (Aldrich; 2.5 g, 16.5 mmol) and3-aminopyrazole (Aldrich; 1.38 g, 16.5 mmol) in glacial acetic acid (25 mL) and reflux under nitrogen for 2 h. Concentrate under reduced pressure and dissolve the residue in absolute methanol (150 mL), vacuum filter through a pad of diatomaceous earth and concentrate under reduced pressure. Purify via chromatography (silica gel, hexane to 50percent ethyl acetate/50percent hexane) to obtain 365 mg (11percent) of the title compound as a light EPO <DP n="25"/>yellow solid. TOF MS ES⁺ exact mass calculated for C₆H₅N₃Br (p+H): m/z =197.9667, Found: 197.9674.

Reference： [1] Patent: WO2006/52568, 2006, A2, . Location in patent: Page/Page column 23-24

10
[ 766-11-0 ]
[ 875781-17-2 ]

Reference： [1] Patent: WO2014/73904, 2014, A1,
[2] Patent: CN103980272, 2016, B,
[3] Patent: WO2017/23987, 2017, A1,
[4] Patent: WO2017/23981, 2017, A1,
[5] Patent: WO2017/23973, 2017, A1,
[6] Patent: WO2017/23996, 2017, A1,

11
[ 875781-17-2 ]
[ 74-88-4 ]
[ 887115-56-2 ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.5 h; Inert atmosphere Stage #2: at 25℃; Inert atmosphere	Step 1 5-bromo-1-methyl-1H-pyrazolo[3,4-b]pyridine (Compound 4-2) Sodium hydride (720 mg, 30 mmol) was added into a 100 ml reaction flask, and anhydrous THF (40 mL) was added to the reaction flask. After stirring at 0° C. for 5 min, the reaction substrate 5-bromo-1H-pyrazolo[3,4-b]pyridine (4.0 g, 20 mmol, commercially available) was dissolved in THF (20 ml), and the resulting solution was slowly added dropwise to the reaction flask through the constant pressure funnel, and stirred for 30 min. Afterwards, iodomethane (1.6 ml, 26 mmol) was added dropwise to the reaction system. After completion of the addition, the reaction solution was slowly warmed to room temperature and stirred overnight. The reaction progress was monitored by TLC. After completion of the reaction, 10 ml of ice water was added to the reaction system to quench the reaction, THF was removed by concentration under reduced pressure, and the residue was extracted with dichloromethane (60 ml) and water (20 ml*3). The organic layer was dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give 4.1 g brown solid, which was separated and purified by Combi-flash chromatography [PE:EA=10:90-40:60] to give the title compound 4-2 (3.1 g, 73percent). MS m/z (ESI): 211.9 [M+H]+.

Reference： [1] Patent: US2017/8889, 2017, A1, . Location in patent: Paragraph 0165; 0166

12
[ 875781-17-2 ]
[ 74-88-4 ]
[ 887115-56-2 ]

Reference： [1] Journal of Organic Chemistry, 2018, vol. 83, # 12, p. 6334 - 6353
[2] Journal of Organic Chemistry, 2018, vol. 83, # 12, p. 6334 - 6353

13
[ 875781-17-2 ]
[ 952182-02-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2692 - 2703
[2] Journal of Organic Chemistry, 2017, vol. 82, # 14, p. 7420 - 7427

14
[ 875781-17-2 ]
[ 1257628-77-5 ]

Reference： [1] Journal of Medicinal Chemistry, 2013, vol. 56, # 3, p. 879 - 894

[ 875781-17-2 ] Synthesis Path-Downstream 1~50

1
[ 1820-80-0 ]
[ 2065-75-0 ]
[ 875781-17-2 ]

Yield	Reaction Conditions	Operation in experiment
11%	With acetic acid; for 2h;Heating / reflux;	Preparation 6; 5 -Bromo- 1 H-pyrazolo [3 ,4-b] pyridine; Dissolve 2-bromomalonaldehyde (Aldrich; 2.5 g, 16.5 mmol) and3-aminopyrazole (Aldrich; 1.38 g, 16.5 mmol) in glacial acetic acid (25 mL) and reflux under nitrogen for 2 h. Concentrate under reduced pressure and dissolve the residue in absolute methanol (150 mL), vacuum filter through a pad of diatomaceous earth and concentrate under reduced pressure. Purify via chromatography (silica gel, hexane to 50% ethyl acetate/50% hexane) to obtain 365 mg (11%) of the title compound as a light EPO <DP n="25"/>yellow solid. TOF MS ES+ exact mass calculated for C6H5N3Br (p+H): m/z =197.9667, Found: 197.9674.

Reference： [1]Patent: WO2006/52568,2006,A2 .Location in patent: Page/Page column 23-24

2
[ 705262-42-6 ]
[ 875781-17-2 ]
5-[2-[6-methyl-(pyridin-2-yl)]-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-pyrazolo[3,4-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In water; dimethyl sulfoxide; at 110℃; for 0.166667h;Microwave irradiation;	Preparation 3A; General Suzuki Coupling Method A; Add 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[l ,2-b]pyrazole-3-boronic acid (Preparation 2) or 2-[6-methyl-(pyridin-2-yl)]-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole-3- boronic acid (Preparation 1) (1.0 eq), the heteroaryl halide (1.0-1.2 eq.), sodium bicarbonate (2.0 eq.) or potassium carbonate (1.0 eq), tetrakis(triphenylphosphine) palladium (0) (Strem, 0.02-0.05 eq.), 50% aqueous dimethylsulfoxide (0.5 M), to a microwave reactor vessel. Seal the reactor vessel and irradiate with 50 watts of microwave radiation for 10 min at 1100C. Cool the reaction to room temperature. Dilute the reaction with methanol and load the mixture onto a Varian Bond Elut SCX column. Rinse the column with absolute methanol, and then elute the column with 2 M ammonia in methanol. Purify by flash column chromatography (silica gel, eluting with the appropriate mixture of ethyl acetate /methanol) and concentrate in vacuo. If needed, further purify by recrystalization or reverse phase high-performance chromatography to provide the final compound.

Reference： [1]Patent: WO2006/52568,2006,A2 .Location in patent: Page/Page column 19; 28

3
[ 875781-17-2 ]
[ 99769-19-4 ]
[ 875781-27-4 ]

Yield	Reaction Conditions	Operation in experiment
65%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 110℃; for 15h;Microwave irradiation;	Step 1: Synthesis of methyl 3-(lH-pyrazolo[3,4-b]pyridin-5-yl)benzoate.[0239] A mixture of 5-bromo-lH-pyrazolo[3,4-b]pyridine (2.00 g, 10.10 rntnol), 3-(methoxycarbonyl)phenylboronic acid (2.20 g, 12.12 mmol), sodium bicarbonate (2.2 g,6.00 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.250 g, 0.202 mmol) indioxane/water (40 mL/10 mL) was stirred at 110 C for 15 hours. The mixture was thenpoured into ice water and extracted with ethyl acetate (3X). The organic layers werecombined, dried over sodium sulfate, filtered and concentrated to dryness. Silica gelchromatography of the crude product afforded methyl 3-(lH-pyrazolo[3,4-b]pyridin-5-yl)benzoate (8) (1.65 g, 65% yield) as yellow solids. MS: m/z 254.0 (M+H+).

Reference： [1]Patent: WO2006/15124,2006,A2 .Location in patent: Page/Page column 72

4
[ 875781-17-2 ]
[ 723281-55-8 ]
[ 875781-22-9 ]
[ 791-28-6 ]

Yield	Reaction Conditions	Operation in experiment
80%; 20%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 175℃; for 1h;Microwave irradiation;	Step 1: Synthesis of morpholin-4-yl-[3-(lH-pyrazolo[3,4-b]pyridin-5-yl)-phenyl]-methanone.[0227] A mixture of 5-bromo-l^pyrazolo[3,4-b]pyridine (1.50 g, 7.57 mmol), 3-(morpholin-4-carbonyl)phenylboronic acid (2.136 g, 9.09 mmol) andtetrakis(triphenylphosphine)palladium(0) (435 mL, 0.376 mmol) in dimethoxyethane (8mL) and saturated aqueous solution of sodium bicarbonate (8 mL) was irradiated in aPersonal Chemistry Optimizer at 175 C for 60 min. The crude reaction mixture wasdistributed between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The aqueous phase was then extracted with dichloromethane, and then ethylacetate and the combined organic phases were dried over sodium sulfate, filtered andconcentrated to afford a pale green foam containing 80 % of morpholin-4-yl-[3-(lJfZ-pyrazolo[3,4-b]pyridm-5-yl)-phenyl]-methanone (2.30 g, 80 % yield) and 20 % oftriphenylphosphine oxide. .H-NMR (500 MHz, J6-DMSO) S 13.75 (s, 1H), 8.87 (d, 1H),8.54 (d, 1H), 8.21 (d, 1H), 7.85 (m, 1H), 7.77 (m, 1H), 7.58 (t, 1H), 7.41 (m, 1H).

Reference： [1]Patent: WO2006/15124,2006,A2 .Location in patent: Page/Page column 62-63

5
C₁₂H₁₈BrN₃O₂*ClH [ No CAS ]
[ 875781-17-2 ]

Yield	Reaction Conditions	Operation in experiment
50%		Steps 2 and 3: Synthesis of 5-bromo-lH-pyrazoIo[3,4-b]pyridine.[0218] 5-bromo-2-fluoro-pyridine-3-carbaldehyde (13.66 g, 66.96 mmol), pinacol (8.75 g,74.0 mmol) and/?ara-toluenesulfonic acid monohydrate (1.50 g, 7.89 mmol) were placed ina flask equipped with a DEAN-STARK-condenser and dissolved in anhydrous benzene (400mL). The mixture was heated to reflux and solvent distilled off until the distillate remainsclear and the remaining volume was approximately 200 ml. The mixture was diluted withethyl acetate (300 mL) and washed with a saturated aqueous solution of sodium bicarbonateand brine, then dried over sodium sulfate, filtered and concentrated. The resulting residuewas dissolved in a mixture of ethanol (400 mL) and di-zso-propyl-ethyl-amine (25 mL).Anhydrous hydrazine (15 ml, 0.48 mol) was then added and the resulting mixture wasstirred under reflux conditions for 4 h. The mixture was then concentrated to dryness andthe resulting residue was distributed between water and toluene. The organic phase waswashed with brine twice, dried over sodium sulfate, filtered and concentrated. The residuewas dissolved in anhydrous ether (700 mL) and hydrogen chloride in anhydrous ether (2M,70 mL) was added slowly to the vigorously stirred solution. The precipitate was filtered off,washed with ether and hexane and then dried in vacuum. ^-NMR (500 MHz, de-DMSO) 810.31 (s,br, 1H), 8.86 (s, 1H), 8.37 (d, 1H), 7.88 (d, 1H), 6.08 (s, 1H), 3.56 (s,br), 1.27 (s,6H), 1.19 (s, 6H). MS: m/z 198, 200 [MH+].[0219] The above solid was dissolved in a mixture of water (500 mL), ethanol (200 mL)and concentrated aqueous hydrochloric acid (50 mL) at 50-65 C. The mixture was thenstirred at room temperature for 16 h before being neutralized to pH = 8 with sodiumbicarbonate. The resulting precipitate was filtered off and the aqueous phase extracted threetimes with ethyl acetate. The combined organic phases are washed with brine, dried oversodium sulfate, filtered and concentrated. The resulting residue and the precipitate obtainedare crystallized from ethanol to afford 5-bromo4No.-pyrazolo[3,4-b]pyridine (6.615 g, 50% yield) as a crystalline beige to pale olive-green solid. ^-NMR (500 MHz, J6-DMSO) S13.91 (s, 1H), 8.60 (d, 1H), 8.54 (d, 1H), 8.16 (s, br, 1H). MS: m/z 198, 200 [MH+].

Reference： [1]Patent: WO2006/15124,2006,A2 .Location in patent: Page/Page column 58-59

6
[ 875781-17-2 ]
[ 875781-18-3 ]

Yield	Reaction Conditions	Operation in experiment
97%		5-bromo-3 -iodo- 1 H-pyrazolo [3 ,4-bipyridine ( IV-A-I); To a stirred solution of the bromo-diazaindole III- A-I (1 g, 5.05 mmol) in DMF (14 mL) was added crushed KOH pellets (1.06 g, 19.03 mmol) in one portion. After 11 min, I2 (1.15 g, 4.54 mmol) was added and the mixture stirred vigorously for 3.5 h. The mixture was then partially concentrated in vacuo, diluted with EtOAc (40 mL): saturated NaHCO3 solution (20 mL) and partitioned. The aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to afford a 1 :1 mixture of III-A-1 and IV-A-I (1.377 g). This mixture was re-dissolved in 1,4-dioxane (14 mL) and treated with solid NaOH (0.7 g). The mixture was stirred for 5 min at RT and I2 (0.7 g) was added. The mixture was stirred at 40 0C for 23 h, diluted with EtOAc (50 mL) and washed with saturated aqueous Na2S2O3 solution (30 mL). The aqueous layer was extracted with EtOAc (2 x 30 mL) and the combined organic extracts were dried (MgSO4), filtered and concentrated to afford azaindazole IV-A-I (1.585 g, 97%). 1H NMR (400 MHz; CDCl3) delta 7.94 (d, J2.1, IH), 8.55 (d, J2.1, IH), 10.85 (brs, NH).
91%	With iodine; sodium hydroxide; In 1,4-dioxane; water; at 60℃;	To a solution of 5-bromo-lH-pyrazolo[3,4-b]pyridine (I) (5 g, 25.25 mmol, 1 eq) in 1,4- dioxane (100 mL) and 4 N aqueous NaOH (100 mL) was added iodine (64.1 g, 252.5 mmol, 10 eq). The mixture was stirred at 60 C overnight, and TLC showed the reaction was complete. The reaction mixture was extracted with EtOAc (100 ml x 2). The combined organic extracts were washed with saturated aqueous NaHS03 solution (100 mL x 3) and brine (50 mL), dried over Na2S04, filtered, and concentrated to give the title compound 5-bromo-3-iodo-lH- pyrazolo[3,4-b]pyridine as an off-white solid (7.5 g , yield:91%).
91%	With iodine; sodium hydroxide; In 1,4-dioxane; water; at 60℃;	[0116] To a solution of <strong>[875781-17-2]5-bromo-1H-pyrazolo[3,4-b]pyridine</strong> (I) (5 g, 25.25 mmol, 1 eq) in a mixture of 1 ,4-dioxane (100 mL) and 4 N aqueous NaOH (100 mL) was added iodine (64.1 g, 252.5 mmol, 10 eq). The resulting mixture was stirred at 60 C overnight, and TLC showed the reaction was complete. The resulting mixture was extracted with EtOAc (100 ml x 2). The combined organic layers were washed with saturated aqueous NaHSO3 (100 mL x 3) and brine (50 mL), dried over Na2504, and concentrated to give the title compound 5-bromo-3-iodo-JH- pyrazolo[3,4-b]pyridine (II) as an off-white solid (7.5 g , yield:91%), which was used in the next step without any further purification.

91%	With iodine; sodium hydroxide; In 1,4-dioxane; water; at 60℃;	To a solution of <strong>[875781-17-2]5-bromo-1H-pyrazolo[3,4-b]pyridine</strong> (I) (5 g, 25.25 mmol, 1 eq) in 1,4-dioxane (100 mL) and 4 N aqueous NaOH (100 mL) was added iodine (64.1 g, 252.5 mmol, 10 eq). The mixture was stirred at 60 C overnight, and TLC showed the reaction was complete. The reaction mixture was extracted with EtOAc (100 ml x 2). The combined organics were washed with saturated aqueous NaHSO3 (100 mL x 3) and brine (50 mL), dried over Na2SO4, and concentrated to give the title compound 5-bromo-3-iodo-JH-pyrazolo[3,4- b]pyridine (II) as an off-white solid (7.5 g , yield:91%), which was used in the next step without any further purification.
85.6%		To a solution of 5-Bromo-1H-pyrazolo[3,4-b]pyridine (2.0 g, 10.1 mmol) in DMF (20 mL) Potassium hydroxide (KOH, 1.2 g, 21.4 mmol) was added at 25 C. After stirring for 10 min, Iodine (2.8 g, 11.1 mmol) was added and stirred at 25 C for 4 h. The resulting mixture was diluted with water (30 mL), extracted with EtOAc (20 mL * 3). The organic phase was washed with sat. Na2S2O3 solution (30 mL * 2), brine (30 mL * 2), dried over Na2SO4, and concentrated to give compound 39 as a brown solid (2.8 g, 85.6% yield). 1H NMR (400 MHz, DMSO-d6) delta 14.30 (s, 1H, NH), 8.65 (s, 1H, Ar-H), 8.21 (s, 1H, Ar-H).
85.6%		The 5-bromo -1H-pyrazolo [3,4-b] pyridine (2.0g, 10 . 1mmol) adding 20mLN, in N-dimethyl formamide, stirring to dissolve, then adding flaky potassium hydroxide (1.2g, 21 . 4mmol), stir at room temperature the reaction 10 minutes, and then added with the solid iodine (2.8g, 11 . 1mmol), stir at room temperature the reaction 4 experimental, then water (30 ml) dilution, ethyl acetate (3×20 ml) extraction, then with saturated sodium thiosulfate solution (2×30 ml) and saturated salt water (2×30 ml) washing, the organic phase is dried with anhydrous sodium sulfate, concentrated. Then the solid plus dioxane (30 ml) is dissolved, add potassium hydroxide (1.2g, 21 . 4mmol), stir to react under room temperature for 10 minutes, then adding solid iodine (2.8g, 11 . 1mmol), stir at room temperature reaction sleepovers, water reaction is ended (30 ml) dilution, ethyl acetate (3×20 ml) extraction, then with saturated sodium thiosulfate solution (2×30 ml) and saturated salt water (2×30 ml) washing, the organic phase is dried with anhydrous sodium sulfate, concentrated to obtain pale brown solid (2.8g, 85.6%).
77%	With N-iodo-succinimide; In 1,2-dichloro-ethane; for 6h;Heating / reflux;	Step 4: Synthesis of 5-bromo-3-iodo-lH-pyrazolo[3,4-b]pyridine.[0220] 5-bromo-17J-pyrazolo[3,4-b]pyridine (3.00 g, 15.2 mmol) and A'-iodosuccinimide(3.60 g, 16.0 mmol) were dissolved in anhydrous dichloroethane (100 mL). The resultingmixture was stirred under reflux conditions for 6 h, cooled to room temperature and dilutedwith THF (300 mL). The resulting solution was washed with a saturated aqueous solutionof sodium thiosulfate (100 mL) and brine, then dried over magnesium sulfate, filtered andconcentrated. The residue was titurated with a 1:1 mixture of dichloromethane and etherand then ether before being dried in vacuum to afford 5-bromo-3-iodo-l//-pyrazolo[3,4-bjpyridine (3.795 g, 77% yield) as a beige-brown solid. ^-NMR (500 MHz, </6-DMSO) S14.31 (s, 1H), 8.65 (d, 1H), 8.20 (d, 1H). MS: m/z 323, 325 [MH+].
77%	With N-iodo-succinimide; In 1,2-dichloro-ethane; for 6h;Heating / reflux;	<strong>[875781-17-2]5-bromo-1H-pyrazolo[3,4-b]pyridine</strong> (3.00 g, 15.2 mmol) and N-iodosuccinimide (3.60 g, 16.0 mmol) were dissolved in anhydrous dichloroethane (100 mL). The resulting mixture was stirred under reflux conditions for 6 h, cooled to room temperature and diluted with THF (300 mL). The resulting solution was washed with a saturated aqueous solution of sodium thiosulfate (100 mL) and brine, then dried over magnesium sulfate, filtered and concentrated. The residue was titurated with a 1:1 mixture of dichloromethane and ether and then ether before being dried in vacuum to afford 5-bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine (3.795 g, 77% yield) as a beige-brown solid. 1H-NMR (500 MHz, d6-DMSO) delta 14.31 (s, 1H), 8.65 (d, 1H), 8.20 (d, 1H). MS: m/z 323, 325 [MH+].
75%	With N-iodo-succinimide; In 1,1-dichloroethane;Heating; Reflux;	N-Iodosuccinimide (8.1 g, 34.1 mmol) was added to a solution of 5- bromo-lH-pyrazolo[3,4-b]pyridine (4.5 g, 22.7 mmol) in dichloroethane (100 mL), and the reaction mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature and diluted with THF (300 mL). The organic layers were washed with saturated Na2S2O3 (100 mL) and brine (100 mL). The organic layers were dried, filtered and concentrated to a solid. The crude product was triturated with DCM and ethyl acetate to give 5-bromo-3-iodo-lH-pyrazolo[3,4-b]pyridine (5.5 g, 75%) as a solid.
70%	With N-iodo-succinimide; In 1,2-dichloro-ethane;Reflux;	5-Bromo-1H-pyrazolo[3,4-b]pyridine (19.7 g, 100 mmol) was dissolved in 150 mL of 1,2-dichloroethane, and N-iodosuccinimide (24.8 g) was added. , 110 mmol), heated to reflux overnight.After the reaction was completed, the sodium thiosulfate solution was added and stirred for 20 min, and a yellow solid was charged and analyzed, and the mixture was filtered under reduced pressure. The filter cake was washed thoroughly with petroleum ether and dried in vacuo.A yellow solid was obtained 22.7 g (Yield: 70%).
66%	With N-iodo-succinimide; In dimethyl sulfoxide; at 90℃; for 2h;	To a solution of <strong>[875781-17-2]5-bromo-1H-pyrazolo[3,4-b]pyridine</strong> (200 mg, 1.01 mmol) in DMSO (5 mL) was added NIS (341 mg, 1.52 mmol), and the resulting mixture was stirred at 90 C. for 2 h. H2O (10 mL) and sat. aq. Na2S2O3 (1 mL) were added, the mixture was extracted with EtOAc (3*10 mL), and the combined organic layers were washed with sat. aq. NaCl, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by SiO2 gel chromatography (0% to 30% EtOAc in hexanes) to give the title compound as a tan solid (215 mg, 66%). MS (ES+) C6H3BrIN3 requires: 323, found: 324 [M+H]+.
41.3%		Four grams of compound d and 10.25 g of iodine were dissolved into 50 ml N,N-dimethylformamide, stirred for 5 minutes at room temperature. Slowly, 2.83 g of potassium hydroxide was added into the above solution, and further stirred at room temperature for 3 hours, the reaction was completed. The reactant liquid was poured into 1000 ml water, solid was precipitated, filtered, the filter cake was washed three times by water immersion, vacuum dried to obtain compound e (m=1.35 g, yield: 41.3%). (0183) 1H NMR (400 MHz, CDCl3) delta 8.47 (d, J=2.1 Hz, 1H), 7.93 (d, J=2.1 Hz, 1H).
	With iodine; potassium hydroxide; In N,N-dimethyl-formamide; at 50℃; for 1.5h;	To a solution of <strong>[875781-17-2]5-bromo-1H-pyrazolo[3,4-b]pyridine</strong> (1000 mg, 5.05 mmol) inN,N-dimethylformamide (25.2 mL) was added potassium hydroxide (3.0 eq., 859 mg, 15.1 mmol)followed by iodine (1.8 eq., 2310 mg, 9.09 mmol). The reaction was heated to 50 C for 1.5 hours.The reaction was then cooled to room temperature and quenched with aqueous sodium thiosulfate until the dark colour disappeared. The solution was diluted with water and extracted 2 times with iPrOAc. The organic layers were combined, dried with sodium sulfate and concentrated to afford a yellow solid. The crude material was used directly in subsequent reactions.
	With iodine; sodium hydroxide; In 1,4-dioxane; water; at 60℃;	To a solution of 5-bromo-1H-pyrazolo [3, 4-b] pyridine (I) (5 g, 25.25 mmol, 1 eq) in a mixture of 1, 4-dioxane (100 mL) and 4 N aqueous NaOH (100 mL) was added iodine (64.1 g, 252.5 mmol, 10 eq) . The resulting mixture was stirred at 60 overnight, and TLC showed the reaction was complete. The resulting mixture was extracted with EtOAc (100 ml x 2) . The combined organic layers were washed with saturated aqueous NaHSO3(100 mL x 3) and brine (50 mL) , dried over Na2SO4, and concentrated to give the title compound 5-bromo-3-iodo-1H-pyrazolo [3, 4-b] pyridine (II) as an off-white solid (7.5 g , yield: 91) , which was used in the next step without any further purification.
10.92 g	With iodine; potassium hydroxide; In N,N-dimethyl-formamide; at 20 - 45℃; for 2h;	To a stirred mixture of <strong>[875781-17-2]5-bromo-1H-pyrazolo[3,4-b]pyridine</strong> ((I), 6.81 g, 34.4 mmol) and KOH (6.75 g, 120.4 mmol) in DMF (45 mL) was added iodine (9.60 g, 37.8 mmol) in one portion at RT. After a short induction period the exothermic reaction began. After 1 h, an additional 1 g portion of iodine was added and the mixture stirred at 45 C for 1 h. The mixture was poured into 300 mL of a dilute solution of Na2SO3 and the mixture was acidified with 2N HCl. The solids were collected by suction filtration, washed with water and dried in an oven at 110 C. Yield: 10.92 g, HPLC purity: 95 %, 1H NMR (200 MHz, DMSO) delta 14.29 (s, 1H), 8.62 (s, 1H), 8.17 (s, 1H); 13C NMR (50 MHz, DMSO) delta 150.53, 150.17, 131.86, 120.58, 112.43, 91.95; [M-H]- = 322.0 / 324.0.

Reference： [1]Patent: WO2010/15803,2010,A1 .Location in patent: Page/Page column 43
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 2513 - 2529
[3]Patent: WO2016/26078,2016,A1 .Location in patent: Paragraph 065
[4]Patent: WO2016/192063,2016,A1 .Location in patent: Paragraph 0112; 0115; 0116
[5]Patent: WO2017/28314,2017,A1 .Location in patent: Paragraph 0125
[6]Bioorganic Chemistry,2016,vol. 65,p. 146 - 158
[7]Patent: CN103613591,2016,B .Location in patent: Paragraph 0342-0344
[8]Patent: WO2006/15124,2006,A2 .Location in patent: Page/Page column 59
[9]Patent: US2008/261921,2008,A1 .Location in patent: Page/Page column 73-74
[10]Patent: WO2009/111279,2009,A1 .Location in patent: Page/Page column 83
[11]Patent: CN108117553,2018,A .Location in patent: Paragraph 0278; 0279; 0280-0282
[12]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 543 - 547
[13]Patent: US2019/298729,2019,A1 .Location in patent: Paragraph 0662-0663
[14]Patent: US2016/137640,2016,A1 .Location in patent: Paragraph 0181; 0182
[15]Patent: WO2015/25025,2015,A1 .Location in patent: Page/Page column 130
[16]Patent: WO2016/192064,2016,A1 .Location in patent: Paragraph 0118-0119
[17]Patent: WO2019/149738,2019,A1 .Location in patent: Page/Page column 51; 64

7
[ 854141-63-2 ]
[ 875781-17-2 ]
1-[(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)methyl]-4-propylpyrrolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
7.8%		A solution of 5-bromo-1 H-pyrazolo[3,4-b]pyridine x80 (1 g, 1 eq, 5.04 mmol) and 1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (1.58 g, 2 eq, 10.08 mmol) in trifluoroacetic acid (20 ml) is refluxed for 4 hours. The reaction mixture is poured on crushed ice, on saturated NaHCtheta3 aqueous solution, and the aqueous phase is extracted with dichloromethane. The cumulated organic layers are dried over MgSOphi filtered, evaporated under reduced pressure. The crude product is purified by preparative chromatography on silicagel affording 1-[(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)methyl]- 4-propylpyrrolidin-2-one 291 as a white solid. Yield: 7.8 %.LC-MS (MH+): 337/339.

Reference： [1]Patent: WO2006/128692,2006,A2 .Location in patent: Page/Page column 86

8
[ 2065-75-0 ]
[ 1225387-53-0 ]
[ 705263-10-1 ]
[ 875781-17-2 ]

Yield	Reaction Conditions	Operation in experiment
13.8%; 2.1%	In ethanol; at 20℃;Heating / reflux;	A solution of 1 H-pyrazol-5-amine x79 (25 g, 1 eq, 0.3 mol) and bromomalonaldehyde x9 (45.4 g, 1 eq, 0.3 mol) ethanol (250 ml) is refluxed for 2 hours. After cooling, the reaction mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure and the crude is purified using chiral chromatography affording 5-bromo-1H-pyrazolo[3,4-b]pyridine x80 (yield: 2.1 %; LC-MS (MH+): 198/200) and 6-bromopyrazolo[1 ,5-a]pyrimidine x81 (yield: 13.8 %; LC-MS (MH+): 198/200).

Reference： [1]Patent: WO2006/128692,2006,A2 .Location in patent: Page/Page column 86

9
[ 875781-16-1 ]
[ 875781-17-2 ]

Yield	Reaction Conditions	Operation in experiment
		The above solid was dissolved in a mixture of water (500 mL), ethanol (200 mL) and concentrated aqueous hydrochloric acid (50 mL) at 50-65 C. The mixture was then stirred at room temperature for 16 h before being neutralized to pH=8 with sodium bicarbonate. The resulting precipitate was filtered off and the aqueous phase extracted three times with ethyl acetate. The combined organic phases are washed with brine, dried over sodium sulfate, filtered and concentrated. The resulting residue and the precipitate obtained are crystallized from ethanol to afford 5-bromo-1H-pyrazolo[3,4-b]pyridine (6.615 g, 50% yield) as a crystalline beige to pale olive-green solid. 1H-NMR (500 MHz, d6-DMSO) delta 13.91 (s, 1H), 8.60 (d, 1H), 8.54 (d, 1H), 8.16 (s, br, 1H). MS: m/z 198, 200 [MH+].

Reference： [1]Patent: US2008/261921,2008,A1 .Location in patent: Page/Page column 73-74

10
[ 875781-17-2 ]
[ 1083325-84-1 ]
[ 1083320-98-2 ]

Yield	Reaction Conditions	Operation in experiment
26%	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 110℃; for 18h;	e) 2-(4-Morpholinyl)-7-(1H-pyrazolo[3,4-b]pyridin-5-yl)quinoxaline; A slurry of 2-(4-morpholinyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline (0.56 mmol), a heteroaryl bromide such as <strong>[875781-17-2]5-bromo-1H-pyrazolo[3,4-b]pyridine</strong> (0.47 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.05 mmol) and 2 M aqueous sodium carbonate (1.88 mmol) in 1,4-dioxane (5 ml) was heated at 110 C. for 18 hours. The reaction was cooled to ambient temperature then filtered through a short pad of silica (15 g) topped with anhydrous sodium sulfate (5 g), rinsing well with ethyl acetate. The filtrate was concentrated under reduced pressure to a brown residue then purified by column chromatography on silica (10% hexanes in ethyl acetate). The desired fractions were combined and concentrated to give the title compound (40 mg, 26%) as a light yellow solid. MS (ES)+ m/e 333.1 [M+H]+.

Reference： [1]Patent: US2008/293706,2008,A1 .Location in patent: Page/Page column 28

11
[ 1083326-08-2 ]
[ 875781-17-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; water; In ethanol; at 20 - 60℃;	c) 5-bromo-1H-pyrazolo[3,4-b]pyridine; Following the procedure described in WO2006015124 provided the title compound as a yellow solid (94%, 2 steps). MS (ES)+ m/e 197.7, 199.7 [M+H]+.

Reference： [1]Patent: US2008/293706,2008,A1 .Location in patent: Page/Page column 85

12
[ 875781-17-2 ]
[ 824-94-2 ]
[ 1111638-35-7 ]

Yield	Reaction Conditions	Operation in experiment
77.2%		Preparation of 1-(4-methoxybenzyl)-<strong>[875781-17-2]5-bromo-1H-pyrazolo[3,4-b]pyridine</strong> (D-1-4).D-1-3 _.,.4 To a solution of compound D-1-3 (3.47 g, 17.5 mmol) in dry DMF (50 mL) was added NaH (77 mg, 19.25 mmol) portionwise at 00C. After the addition, the resulting mixture was stirred at 00C for 30 minutes.PMBCI (3.29 g, 21 mmol) was then added dropwise at 0C. The resulting mixture was stirred at room temperature overnight. TLC (petroleum ether/EtOAc 1 :1 ) indicated complete consumption starting material. The reaction mixture was poured into H2O (100 mL) and extracted with EtOAc (100 mLchi3). The combined organic layers were washed with H2O (100 mLchi2) and saturated aqueous NaCI (100 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, petroleum ether/EtOAc from 50:1 to 4:1 ) to yield pure compound D-1-4 (4.3 g, yield: 77.2%) as a yellow solid.
68.3%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃;	5-bromo -1H-pyrazolo [3,4-b] pyridine (1.0g, 5 . 1mmol) dissolved in N, N-dimethylformamide (20 ml) cooled to 0 C, followed by the addition of sodium hydride (mass fraction of 60%, 408 mg, 10.2mmol), at 0 C stirred for 15 minutes,the added para methoxy benzylchloride(1.19g, 7 . 63mmol), to the stirring the mixture at room temperature for overnight, poured into ice water, filtered, the filter cake is washed with methanol washing, drying to obtain the title compound (1.1g, yield 68.3%).

Reference： [1]Patent: WO2009/16460,2009,A2 .Location in patent: Page/Page column 100
[2]Patent: CN105461714,2016,A .Location in patent: Paragraph 0309; 0310; 0311

13
[ 875781-15-0 ]
[ 875781-17-2 ]

Yield	Reaction Conditions	Operation in experiment
46%	With hydrazine; In ethanol;Heating / reflux;	Preparation of 5-bromo-1H-pyrazolo[3,4-b]pyridine (D-1-3). <n="101"/>D-1-2 D"1-3A solution of compound D-1-2 (20 g, 0.1 mol) and anhydrous hydrazine (18 g, 0.56 mol) in ethanol was heated to reflux overnight. TLC (petroleum ether/EtOAc 2:1 ) indicated complete consumption of starting material. The reaction mixture was concentrated in vacuo to a volume of about 50 ml_ and poured into water (500 ml_), the resulting mixture was filtered. The cake was washed with water (50 ml_chi3) and ether (20 ml_chi3), then dried in vacuo to yield compound D-1-3 (9.0 g, 46%) as a yellow solid.
40%	With hydrazine hydrate; In ethanol; at 100℃; for 8h;	5-Bromo-2-fluoro-pyridine-3-carbaldehyde (4.1g, 20mmol) obtained from Preparation Example 129-1 was dissolved in ethanol (50ml). After adding hydrazine hydrate (5.0ml, 100mmol), the mixture was stirred for 8 hours at 100 and then distilled under reduced pressure. Water was added thereto and the residue was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (1.8g, 40%).[1499] NMR:1H-NMR(400HMz, CDCl3); delta 11.29 (br s, 1H), 8.63 (s, 1H), 8.26 (s, 1H), 8.07 (s, 1H)
	With hydrazine hydrate; In tetrahydrofuran; ethanol; water; at 45 - 80℃; for 1h;Large scale;	50L in the reaction kettle, added to the above obtained a solution containing intermediates THF, 2.8 kg of hydrazine hydrate stirring, the temperature is increased to 45 C, TLC in control to the reaction is complete; the reaction the fluid turns on lathe steams concentrated to pasty; adding anhydrous ethanol, adding 0.5 times of hydrazine hydrate, the temperature is increased to 80 C reflux reaction; adding 9L anhydrous ethanol twice with water, adding activated carbon to the reaction end of the stirring 1h, the heat filters, filtrate concentrated to obtain yellow solid; the solid plus anhydrous ethyl ether pulping, centrifugal, dry containing the intermediate b 5-bromo -1H-pyrazolo [3,4-b] pyridine crude 2.35 kg, purity 94%, yield 75%.

135 g	With hydrazine hydrate; In ethanol; at 75 - 80℃; for 12h;	To a stirred solution of <strong>[875781-15-0]5-bromo-2-fluoronicotinaldehyde</strong> (XV) (250 g, 1.23 mol, 1.0 eq) in EtOH (2.50 L) was added hydrazine hydrate (221 g, 4.41 mol, 3.6 eq) at 25C. The reaction was then heated to 75~80C and stirred for 12 h. The solvent was removed under reduced pressure at 45C. The residual crude solid was triturated in water (750 mL) and EtOH (250 mL). The resultant suspension was filtered and washed with ethanol to give 5 -bromo- lH-pyrazolo[3,4- b]pyridine (XVI) (135 g, 0.68 mol, 55.4% yield) as yellowish solid which was used directly for the next step without further purification. ESIMS found for CeLLtBrNs mlz 199.1 (M+H).
135 g	With hydrazine hydrate; In ethanol; at 25 - 80℃; for 12h;	To a stirred solution of <strong>[875781-15-0]5-bromo-2-fluoronicotinaldehyde</strong> (XV) (250 g, 1.23mol, 1.0 eq) in EtOH (2.50 L) was added hydrazine hydrate (221 g, 4.41 mol, 3.6 eq) at 25C. The reaction was then heated to 7580C and stirred for 12 h. The solvent was removed under reduced pressure at 45C. The residual crude solid was triturated in water (750 mL) and EtOH (250 mL). The resultant suspension was filtered and washed with ethanol to give 5-bromo-1H- pyrazolo[3,4-bjpyridine (XVI) (135 g, 0.68 mol, 55.4% yield) as yellowish solid which was used directly for the next step without further purification. ESIMS found for C6H4BrN3 mlz 199.1 (M+H).
	With hydrazine hydrate; In ethanol; at 25 - 80℃; for 12h;	To a stirred solution of <strong>[875781-15-0]5-bromo-2-fluoronicotinaldehyde</strong> (XV) (250 g, 1.23 mol, 1.0 eq) in EtOH (2.50 L) was added hydrazine hydrate (221 g, 4.41 mol, 3.6 eq) at 25C. The reaction was then heated to 75~80C and stirred for 12 h. The solvent was removed under reduced pressure at 45C. The residual crude solid was triturated in water (750 mL) and EtOH (250 mL). The resultant suspension was filtered and washed with ethanol to give 5 -bromo- lH- pyrazolo[3,4-b]pyridine (XVI) (135 g, 0.68 mol, 55.4% yield) as yellowish solid which was used directly for the next step without further purification. ESIMS found for C6H4BrN3 m/z 199.1 (M+H).
	With hydrazine hydrate; In ethanol; at 75 - 80℃; for 12h;	To a stirred solution of <strong>[875781-15-0]5-bromo-2-fluoronicotinaldehyde</strong> (XV) (250 g, 1.23 mol, 1.0 eq) in EtOH (2.50 L) was added hydrazine hydrate (221 g, 4.41 mol, 3.6 eq) at 25C. The reaction was then heated to 75~80C and stirred for 12 h. The solvent was removed under reduced pressure at 45C. The residual crude solid was triturated in water (750 mL) and EtOH (250 mL). The resultant suspension was filtered and washed with ethanol to give 5 -bromo- lH- pyrazolo[3,4-b]pyridine (XVI) (135 g, 0.68 mol, 55.4% yield) as yellowish solid which was used directly for the next step without further purification. ESIMS found for CeLLBrNs mlz 199.1 (M+H).

Reference： [1]Journal of Organic Chemistry,2017,vol. 82,p. 7420 - 7427
[2]Patent: WO2009/16460,2009,A2 .Location in patent: Page/Page column 99-100
[3]Patent: WO2014/73904,2014,A1 .Location in patent: Paragraph 1496-1499
[4]Patent: CN103980272,2016,B .Location in patent: Paragraph 0031; 0033
[5]Patent: WO2017/23987,2017,A1 .Location in patent: Paragraph 0610; 0612
[6]Patent: WO2017/23981,2017,A1 .Location in patent: Paragraph 0610; 0612
[7]Patent: WO2017/23973,2017,A1 .Location in patent: Paragraph 0633
[8]Patent: WO2017/23996,2017,A1 .Location in patent: Paragraph 0612

14
[ 875781-17-2 ]
[ 76513-69-4 ]
[ 1186608-66-1 ]

Yield	Reaction Conditions	Operation in experiment
43%		NaH (0.082 g, 2.06 mmol, 60% suspension in mineral oil) was added portionwise to a cold (0C) solution of 5-bromo-lH-pyrazolo[3,4-b]pyridine (0.204 g, 1.03 mmol) in dry THF (10 mL). The reaction mixture was stirred at 0C for 10 minutes before 2- (trimethylsilyl)ethoxymethyl chloride (0.31 mL, 0.292 mmol) was added dropwise via a syringe. The reaction mixture was left at room temperature overnight. The reaction mixture was diluted with ethyl acetate (50 mL) and carefully quenched with water (10 mL). The aqueous layer was separated and extracted with ethyl acetate (3 X 50 mL). The combined organic layerss were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (50:1) to give 5-bromo-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[3,4-b]pyridine (0.146 g, 43%) as an oil.
		5-Bromo-1H-pyrazolo[3,4-b]pyridine (200 mg) was dissolved in N,N-dimethylformamide (5 ml). 55% Sodium hydride (53 mg) was added at 0 C., and the mixture was stirred at the same temperature for five minutes and then stirred at room temperature for 20 minutes. 2-(Chloromethoxy)ethyltrimethylsilane (0.213 ml) was added and the mixture was stirred at 0 C. for 2 hours. A saturated aqueous ammonium chloride solution was added under ice-cooling, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (0.224 g).1H-NMR (CDCl3) delta: 0.00 (9H, s), 0.96-1.00 (2H, m), 3.68-3.72 (2H, m), 5.90 (2H, s), 8.07 (1H, s), 8.27 (1H, d, J=2.2 Hz), 8.65 (1H, d, J=2.2 Hz).

Reference： [1]Patent: WO2017/133667,2017,A1 .Location in patent: Page/Page column 124; 125
[2]Patent: WO2009/111279,2009,A1 .Location in patent: Page/Page column 80
[3]Patent: US2011/82138,2011,A1 .Location in patent: Page/Page column 57-58

15
[ 2065-75-0 ]
[ 1225387-53-0 ]
[ 875781-17-2 ]

Yield	Reaction Conditions	Operation in experiment
25%	In acetic acid; for 6h;Heating; Reflux; Inert atmosphere of N2;	lH-Pyrazol-5-amine (5.3 g, 64 mmol) and 2-bromomalonaldehyde(9.9 g, 64 mmol) were suspended in acetic acid (100 mL). The reaction mixture was heated <n="82"/>to reflux under N2 for 6 hours. The reaction mixture was cooled to room temperature and concentrated to give a solid. The crude solids were suspended in MeOH (200 mL) and absorbed onto silica gel (200 g). The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (4:1), hexanes/ethyl acetate (2:1) to give 5-bromo-lH- pyrazolo[3,4-b]pyridine as a solid (3.1 g, 25%).

Reference： [1]Patent: WO2009/111279,2009,A1 .Location in patent: Page/Page column 79-80

16
[ 875781-17-2 ]
[ 98-09-9 ]
[ 1198438-24-2 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 120 5-Bromo-1 -(phenylsulfonyl)-1H-pyrazolo[3,4-fe]pyridine Sodium Hydride (0.667 g, 16.66 mmol) was added portion-wise over 15 mins to a stirred solution of 5-bromo-1 H-pyrazolo[3,4-b]pyridine (3 g, 15.15 mmol, available from ChemGenx LLC) in N,N-dimethylformamide (30 ml) that had been cooled in an ice bath to 0 0C and placed under nitrogen. The mixture was stirred for 20 mins, until hydrogen evolution ceased, and then benzenesulfonyl chloride (2.148 ml, 16.66 mmol) was added. The mixture was stirred for 18 hours, letting the ice melt over this time. The solution was poured into stirring water (10 ml) and rapidly stirred for 15 mins. The mixture was then poured onto water (70 ml) and filtered. The orange solid obtained was dried in the vacuum oven for 18h to afford the title compound (3.86 g). LCMS (Method D) R1 = 1.01 min, MH+= 340.

Reference： [1]Patent: WO2009/147188,2009,A1 .Location in patent: Page/Page column 145

17
[ 875781-17-2 ]
[ 1239879-66-3 ]
[ 1239879-39-0 ]

Yield	Reaction Conditions	Operation in experiment
10%	With sodium carbonate;palladium bis[bis(diphenylphosphino)ferrocene] dichloride; In ethanol; water; toluene; at 100℃; for 3h;Inert atmosphere; Microwave irradiation;	To a mixture of intermediate I-17 (100 mg, 0.27 mmol, 1.0 eq), 6-bromo-[1,2,4]triazolo-[4,3-a]pyridine (60 mg, 0.30 mmol, 1.1 eq) and Pd(dppf)Cl2 (20 mg, 0.03 mmol, 0.1 eq) was added an emulsion of Na2CO3 in water (0.6 mL, 1.2 mmol, 4.5 eq, 2.0 M), toluene (1.5 mL) and ethanol (1.5 mL). The reaction flask was purged 3 times with argon and reaction mixture was stirred at 100 C. for 3 hours under microwave irradiation. The crude reaction mixture was diluted with ethyl acetate, the solids were removed by filtration and the filtrate was concentrated by evaporation. The crude reaction product was purified by silicagel flash chromatography to give compound 223 (10 mg, 10%) as a white solid. 1H-NMR (400 MHz, CD3OD): delta 10.91 (br, 1H), 8.87 (d, J=2.4 Hz, 1H), 8.28 (d, J=1.6 Hz, 1H), 8.16 (s, 1H), 7.92 (d, J=1.2 Hz, 1H), 7.49-7.52 (m, 1H), 7.36-7.38 (m, 1H), 4.29-4.31 (m, 2H), 3.29-3.31 (m, 2H), 2.92-2.99 (m, 1H), 2.64-2.71 (m, 4H), 2.14-2.16 (m, 2H), 1.91-1.96 (m, 2H), 1.67-1.77 (m, 2H). MS (ESI): m/z 359.1 (M+H+).

Reference： [1]Patent: US2010/204214,2010,A1 .Location in patent: Page/Page column 93

18
[ 875781-17-2 ]
[ 98-59-9 ]
[ 1309785-56-5 ]

Yield	Reaction Conditions	Operation in experiment
		5-Bromo-1 /-/-pyrazolo[3,4-t)]pyridine (1.39 g) in DMF (6 ml) was cooled in an ice-bath under nitrogen and treated portionwise with sodium hydride (0.308 g) (60% dispersion in oil) over a period of about 15 min. The reaction was left to stir in the ice-bath for 40 min, then treated with tosyl chloride (1.469 g) in DMF (2 ml). The reaction was left to stir in the ice-bath under nitrogen and the ice left to melt overnight. The reaction was stirred for a total of 20 h. The reaction was treated cautiously with water (6 ml) and stirred for 5 min. The reaction was poured onto water (60 ml), filtered and the residue treated with DCM (20 ml). The mixture was stirred, and then pushed through a frit into a cartridge with a hydrophobic frit. The solution was allowed to drip through, and then this procedure was repeated with further DCM (2 x 15 ml). The combined filtrates were evaporated to dryness to give the title compound as a brown solid, 1.802g.LCMS (Method A); Rt = 2.75 min, MH+ = 354.
		5-Bromo-1 /-/-pyrazolo[3,4-t)]pyridine (1.39 g) in DMF (6 ml) was cooled in an ice-bath under nitrogen and treated portion-wise with sodium hydride (0.308 g) (60% dispersion in oil) over a period of about 15 min. The reaction was left to stir in the ice-bath for 40 min, then treated with tosyl chloride (1.469 g) in DMF (2 ml). The reaction was left to stir in the ice-bath under nitrogen and the ice left to melt overnight. The reaction was stirred for a total of 20 h. The reaction was treated cautiously with water (6 ml) and stirred for 5 min. The reaction was poured onto water (60 ml), filtered and the residue treated with DCM (20 ml). The mixture was stirred, and then pushed through a frit into a cartridge with a hydrophobic frit. This procedure was repeated with further DCM (2 x 15 ml). The combined filtrates were evaporated to dryness to give the title compound as a brown solid, 1.802 g.LCMS (method A); Rt = 2.75 min, MH+ = 354.
1.802 g		5-Bromo-1-[(4-methylphenyl)sulfonyl]-1H-pyrazolo[3,4-b]pyridine 5-Bromo-1H-pyrazolo[3,4-b]pyridine (1.39 g) in DMF (6 ml) was cooled in an ice-bath under nitrogen and treated portionwise with sodium hydride (0.308 g) (60% dispersion in oil) over a period of about 15 min. The reaction was left to stir in the ice-bath for 40 min, then treated with tosyl chloride (1.469 g) in DMF (2 ml). The reaction was left to stir in the ice-bath under nitrogen and the ice left to melt overnight. The reaction was stirred for a total of 20 h. The reaction was treated cautiously with water (6 ml) and stirred for 5 min. The reaction was poured onto water (60 ml), filtered and the residue treated with DCM (20 ml). The mixture was stirred, and then pushed through a frit into a cartridge with a hydrophobic frit. The solution was allowed to drip through, and then this procedure was repeated with further DCM (2*15 ml). The combined filtrates were evaporated to dryness to give the title compound as a brown solid, 1.802 g. LCMS (Method B); R=2.75 mi MH=354.

0.87 g

Step 1: (0677) Compound 66 (0.610 g, 3 mmol) was dissolved in THF (30 mL) at 0 C. Then sodium hydride (0.160 g, 4 mmol) was added to the solution in one portion. After 15 minutes, 4-methylbenzenesulfonyl chloride (0.646 g, 3 mmol) was added in one portion and the reaction was allowed to stir at ambient temperature overnight. The reaction was diluted with ethyl acetate and washed with brine (2×). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The crude material was purified by silica gel flash chromatography with a gradient of ethyl acetate in hexane (10-80%) to afford 0.87 g of compound 67.

Reference： [1]Patent: WO2011/67364,2011,A1 .Location in patent: Page/Page column 85
[2]Patent: WO2011/67365,2011,A1 .Location in patent: Page/Page column 80
[3]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 155
[4]Patent: US2016/326162,2016,A1 .Location in patent: Paragraph 0675; 0676; 0677

19
[ 875781-17-2 ]
[ 1312942-04-3 ]
[ 1312939-70-0 ]

Yield	Reaction Conditions	Operation in experiment
72%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; acetonitrile; at 145℃; for 0.75h;microwave irradiation;	In a microwave vial, propane- 1 -sulfonic acid {2,4-difIuoro-3-[5-(4,4,5,5-tetramethyl- [l ,3,2]dioxaborolan-2-yl)- 1 H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (30, 0.050 g, 0.099 mmol) is combined with 5-bromo-I H-pyrazolo[3,4-b]pyridine (31 , 0.030 g, 0.15 mmol), 1 mL of tetrahydrofuran, l mL of acetonitrile, tetrakis(triphenylphosphine)palladium(0) (0.050 g, 0.043 mmol), and potassium carbonate (0.400 mL, 1.00 M in water). The reaction is heated at 145 C for 45 minutes in a microwave, then extracted with ethyl acetate, and the organic layer is washed with water and brine. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with a gradient of methanohdichloromethane. Appropriate fractions are combined, concentrated under vacuum and the resulting solid is further washed with a mixture of ethyl acetate :hexane to provide the desired compound. MS (ESI) [M-H+]- = 495.05.

Reference： [1]Patent: WO2011/79133,2011,A2 .Location in patent: Page/Page column 177; 178

20
[ 875781-17-2 ]
[ 1066-54-2 ]
[ 1207351-08-3 ]

Yield	Reaction Conditions	Operation in experiment
73.7%	With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere;	5-Bromo-1H-pyrazolo [3,4-b] pyridine (36.64g, 0.186mol), Pd (pph3) Cl2 (3.25g, 4.65mmol), CuI (5.30g, 0.028mmol) and DIPEA ( 32.4 mL, 0.279 mol) was added to N, N dimethylformamide (150 mL). Under the protection of nitrogen, trimethylsilyl acetylene (21.89 g, 0.223 mol) was added, and the reaction was performed at room temperature for 1 h. The reaction solution was poured into 200 mL of water. Extracted with ethyl acetate (100 mL × 3), separated the organic phase, dried over anhydrous sodium sulfate, filtered, and concentrated. The product was isolated by column chromatography on silica gel to obtain 29.3 g of the product, with a yield of 73.7%.
73.7%	With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere;	5-Bromo-1H-pyrazolo [3,4-b] pyridine (36.64g, 0.186mol), tetrakis (triphenylphosphonium) palladium (10.73g, 9.29mmol), cuprous iodide (5.30g, 0.028 mmol) and N, N-diisopropylethylamine (32.4 mL, 0.279 mol) were added to N, N-dimethylformamide (150 mL),Under nitrogen protection, trimethylsilylacetylene (21.89g, 0.223mol) was injected into the reaction solution, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into 200mL of water and extracted with ethyl acetate (100mL × 3) The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. After column chromatography, the product was isolated on silica gel to obtain 29.3 g of the product, with a yield of 73.7%.
3.5 g	With copper(l) iodide; palladium bis[bis(diphenylphosphino)ferrocene] dichloride; triethylamine; In N,N-dimethyl-formamide; at 70℃; for 2h;Inert atmosphere;	The 3.0g5-bromo -1H-pyrazolo [3,4-b] pyridine is dissolved in DMF, then the 2.98g trimethyl silyl acetylene, 0.53gPd (dppf) 2 Cl 2, 0.29g cuprous iodide and 3.86g triethylamine is added to the solution, the air, plus N 2 protection, heating to 70 C react about 2h is finished. Extraction, anhydrous sodium sulfate for drying, filtering, turns on lathe does crude. Purification by silica gel column chromatography, using ethyl acetate: petroleum ether = 1:20-2:1 for gradient elution, to 3.5g title compound.

Reference： [1]Patent: CN110372705,2019,A .Location in patent: Paragraph 0299-0300; 0302-0303
[2]Patent: CN110467620,2019,A .Location in patent: Paragraph 0311; 0313-0315
[3]Journal of Medicinal Chemistry,2012,vol. 55,p. 10033 - 10046
[4]Journal of Medicinal Chemistry,2013,vol. 56,p. 879 - 894
[5]Patent: CN103370324,2016,B .Location in patent: Paragraph 0153-0155

21
[ 875781-17-2 ]
[ 24424-99-5 ]
tert-butyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With dmap; triethylamine; In acetonitrile; at 20℃; for 3.25h;Inert atmosphere;	[0151j A single necked round bottom flask equipped with a magnetic stir bar was charged with <strong>[875781-17-2]5-bromo-1H-pyrazolo[3,4-b]pyridine</strong> (1.0 g, 5 mmol), di-tert-butyl dicarbonate (1.4 g, 6.4 mmol) and acetonitrile (10 mL) under a mild stream of nitrogen at room temperature. Triethylamine (0.72 g, 1.0 mL, 7.1 mmol) was added in one portion to the above stirred homogeneous solution followed by portions-wise addition of 4-(dimethylamino)pyridine (0.74 g, 6.05 mmol) over a period of 15 mm. The homogenous reaction mixture was stirred at room temperature and the progress of reaction was monitored by TLC (50% EtOAc/hexanes). Stirring was discontinued after 3h, the reaction mixture concentrated and diluted with water (25 mL). The resultant off-brown solid was filtered and suction dried to provide the desired tert-butyl 5-bromo- 1H-pyrazolo[3,4-b]pyridine-1-carboxylate (1.4 g, 93%). The material obtained was used in the next step without further purification. ?H NMR (DMSO-d6): oe 8.77 (d, 1H, J = 2.0 Hz), 8.62 (d, 1H, J = 2.0 Hz), 8.39 (s, 1H), 1.60 (s, 9H). (dd, 1H, J = 1.8 and 4.7 Hz), 8.13 (s, 1H), 7.90 (dd, 1H, J = 1.7 and 4.7 Hz), 7.84 (s, 1H), 7.62 (d, 1H, J = 8.8 Hz), 7.51 (dd, 1H, J = 4.7 and 7.3 Hz),7.42 (dd, 1H, J = 1.4 and 8.5 Hz). LCMS: 97 %, MS (mle) 226 (MHttBu).
68%	With dmap; In tetrahydrofuran; for 14h;Reflux;	To a solution of 10a (770 mg, 3.88 mmol, 1.0 equiv) in THF(10 mL) was added (Boc)2O (930 mg, 4.3 mmol, 1.1 equiv) andDMAP (10 mg, 0.08 mmol, 0.02 equiv) at room temperature underargon. Then the reaction mixture was heated to reflux for 14h. Theresulting mixture was concentrated to crude product, which waspurified by flash chromatography (eluting with MeOH in DCM0-10%) to give 11a as a white solid (783 mg, 68%). 1H NMR(500 MHz, DMSO-d6) delta 8.80 (d, J 2.3 Hz, 1H), 8.63 (d, J 2.3 Hz,1H), 8.44 (s, 1H), 1.66 (s, 9H). 13C NMR (126 MHz, DMSO-d6) delta 151.15,149.47, 137.89, 133.63, 132.47, 119.71, 115.24, 85.06, 28.06. LC-MS(ESI, m/z): 298.0227 [MH].

Reference： [1]Patent: WO2015/157093,2015,A1 .Location in patent: Paragraph 0151
[2]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 875 - 880
[3]European Journal of Medicinal Chemistry,2020,vol. 188

22
[ 875781-17-2 ]
[ 1421783-64-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / acetonitrile / 20 h / 20 - 100 °C / Inert atmosphere 2: potassium carbonate; methanol / acetonitrile / 0.5 h / 20 °C / Inert atmosphere 3: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / acetonitrile / 20 h / 20 - 100 °C / Sealed tube; Inert atmosphere 4: ethanol

Reference： [1]Ren, Xiaomei; Pan, Xiaofen; Zhang, Zhang; Wang, Deping; Lu, Xiaoyun; Li, Yupeng; Wen, Donghai; Long, Huoyou; Luo, Jinfeng; Feng, Yubing; Zhuang, Xiaoxi; Zhang, Fengxiang; Liu, Jianqi; Leng, Fang; Lang, Xingfen; Bai, Yang; She, Miaoqin; Tu, Zhengchao; Pan, Jingxuan; Ding, Ke [Journal of Medicinal Chemistry, 2013, vol. 56, # 3, p. 879 - 894]

23
[ 875781-17-2 ]
[ 875781-19-4 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 879 - 894
[2]Patent: WO2015/25025,2015,A1
[3]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 543 - 547
[4]Patent: WO2016/26078,2016,A1
[5]Patent: WO2016/192063,2016,A1
[6]Patent: WO2016/192064,2016,A1
[7]Patent: CN108117553,2018,A
[8]Patent: WO2009/111279,2009,A1

24
[ 516-12-1 ]
[ 875781-17-2 ]
[ 875781-18-3 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 879 - 894

25
[ 875781-17-2 ]
[ 335033-27-7 ]
[ 1428798-95-1 ]

Yield	Reaction Conditions	Operation in experiment
10 mg	With palladium diacetate; N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine; In N,N-dimethyl-formamide; for 16h;Reflux;	A mixture of 1 (50mg), A (65mg), Pd(OAc)2 (19.7mg), P(o-tol)3 (53.6mg), DIPEA(142mg) in EtCN (0.8mL) and DMF (0.2mL) was refluxed forl6 h, the reaction cooled to room temperature. The solution was concentrated to dryness. The residue was purified by prep HPLC to obtain the desired VT-02- 00032(10mg) as off -white solid. MS(ESI): m/z 346(M+H)+
	With palladium diacetate; N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine; In N,N-dimethyl-formamide; for 16h;Reflux;	A mixture of 1 (50 mg), A (65 mg), Pd(OAc)2 (19.7 mg), P(o-tol)3 (53.6 mg), DIPEA (142 mg) in EtCN (0.8 mL) and DMF (0.2 mL) was refluxed for 16 h, the reaction cooled to room temperature. The solution was concentrated to dryness. The residue was purified by prep HPLC to obtain the desired VT-02-00032 (10 mg) as off-white solid. MS (ESI): m/z 346 (M+H)+

Reference： [1]Patent: WO2013/42035,2013,A1 .Location in patent: Page/Page column 18
[2]Patent: US2014/249170,2014,A1 .Location in patent: Paragraph 0074; 0075

26
[ 875781-17-2 ]
[ 540-51-2 ]
C₈H₈BrN₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 5h;	General procedure: As shown in step 2-i of Scheme 2, to a solution of a compound of formula M (1 equiv.) and K2CO3 (3 equiv.) in DMF (0.3 M) was added an alkyl bromide (2 equiv.) at room temperature. The reaction mixture was then stirred at 80 C. for 5 hours. The reaction was cooled down to room temperature and filtered over a pad of diatomaceous earth. The resulting cake was washed with EtOAc. To the filtrate was added H2O and the two phases were separated. The aqueous phase was extracted with EtOAc and the organic phase was washed with brine. The combined organic phases were dried over Na2SO4 and evaporated. The residue was purified by medium pressure silica gel chromatography (0?100% EtOAc in hexanes) to provide intermediate N.

Reference： [1]Patent: US2013/281431,2013,A1 .Location in patent: Paragraph 0200

27
[ 875781-17-2 ]
[ 1552300-42-1 ]
[ 1552300-56-7 ]

Yield	Reaction Conditions	Operation in experiment
28%		A mixture of <strong>[875781-17-2]5-bromo-1H-pyrazolo[3,4-b]pyridine</strong> (99 mg, 0.5 mmol), bis(pinacolato)diboron (152mg, 0.6 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (36.5 mg, 0.05 mmol) and potassium acetate (98 mg, 1 mmol) in 1,4-dioxane (5 mL) was degassed and stirred at 100 C under Argon atmosphere for 3 hrs. To the reaction mixute was added compound 8b (100 mg, 0.31 mmol), potassium carbonate (276 mg, 2 mmol) and water (1 mL). The resulting mixture was degassed and stirred at 100 C under Argon atmosphere for 3 hrs. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol/ammonium water 600:10:1, v/v) to give the title compound 9i (50 mg, 28% yield for two steps) as a yellow solid.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 790 - 793

28
[ 67-56-1 ]
[ 875781-17-2 ]
[ 201230-82-2 ]
[ 1196156-42-9 ]

Yield	Reaction Conditions	Operation in experiment
46%	With 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; triethylamine; In N,N-dimethyl-formamide; at 100℃; for 12h;	5-bromo-1H-pyrazole [3,4-b] pyrimidine (5.0 g, 25 mmol), Pd (OAc) 2 (0.28 g, 1.25 mmol), dppf (1.4 g, 2.5 mmol), methanol (5.0 mL, 125 mmol) and Et3N (7.0 mL, 50 mmol) were added to a 100 mL round bottom flask, dissolved in DMF (15.0 mL), and replaced with CO three times. The reaction was carried out at 100 C for 12 hours. After the reaction was completed, it was cooled to room temperature, filtered, spin-dried, and separated by silica gel column chromatography. The obtained yellow solid was the target product (2.0 g, yield: 46%).

Reference： [1]Patent: CN103539784,2016,B .Location in patent: Paragraph 0437-0443
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 2692 - 2703

29
[ 875781-17-2 ]
[ 1613639-39-6 ]
[ 1613638-94-0 ]

Yield	Reaction Conditions	Operation in experiment
8 mg	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 95℃; for 10h;Inert atmosphere;	To a solution of (i?)-5-(2-hydroxy-l-phenylethyl)-amino)-pyridin-3-yl)-boronic acid (149 mg, 0.75 mmol) in DME/H20 (5: 1, 6 mL) was added Pd(PPh3)4 (173 mg, 0.15 mmol), K2C03 (207 mg, 1.5 mmol) and 5-bromo-lH-pyrazolo[3,4-b]pyridine (193.5 mg, 0.75 mmol). The resulting mixture was degassed and then stirred for 10 hours at 95 C under an Ar atmosphere. After cooling, the mixture was diluted with water (30 mL) and then extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water and brine, and then dried. The solvent was concentrated and the residue was purified by Prep-HPLC to give (R)-2-phenyl-2-[5- (lH-pyrazolo[3,4-b]pyridin-5-yl)-pyridin-3-ylamino]-ethanol (8 mg).

Reference： [1]Patent: WO2014/90692,2014,A1 .Location in patent: Page/Page column 57

30
2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid [ No CAS ]
[ 875781-17-2 ]
2-(4-(1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)acetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In water; acetonitrile; at 100℃; for 3h;Inert atmosphere;	Step 1: To a stirred mixture of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)acetic acid (500 mg, 1.91 mmol) and 2-chloro-6,7-dimethoxyquinoxaline (429 mg, 1.91 mmol) in CH3CN (15 mL)were added 2M aqNa2CO3 (3.3 mL, 6.68 mmol) and Pd(dppf)C12 dichioromethane complex (78 mg, 0.095 mmol). The reaction mixture was flushed with argon for 10 mm before the reaction vessel was capped and heated at 100 oC for 3h. After cooling to rt, the reaction mixture was treated with 3N aq HC1 to pH5. The brown solid precipitate was collected by filtration and dried to give crude 2-(4-(6,7-dimethoxyquinoxalin-2- yl)phenyl)acetic acid (650 mg). LC-MS (ESI) mlz 325 (M+H)+.[000197] Step 1: 2-(4-(1H-Pyrazolo[3,4-b]pyridin-5-yl)phenyl)acetic acid (150 mg, 28%) was obtained as a brown solid using a procedure analogous to that described in Step 1 of Example 8, substituting 5 -bromo- 1 H-pyrazolo [3 ,4-b]pyridine for the 2-chloro-6,7- dimethoxyquinoxaline used in Example 8. LC-MS (ESI) m/z 254 (M+H).

Reference： [1]Patent: WO2015/31613,2015,A1 .Location in patent: Paragraph 000150; 00197

31
[ 875781-17-2 ]
N-(3-ethynyl-2,4-difluborophenyl)pyridine-3-ylsulfonamide [ No CAS ]
N-(3-((1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-2,4-difluorophenyl)pyridine-3-sulfonamide [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 543 - 547

32
[ 875781-17-2 ]
2,4-difluoro-3-ethynylaniline [ No CAS ]
3-((1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-2,4-difluoroaniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.15 g	With copper(l) iodide; bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); triethylamine; In dimethyl sulfoxide; at 120℃; for 1h;Microwave irradiation;	e) 3-((1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-2,4-difluoroaniline A mixture of 3-ethynyl-2,4-difluoroaniline (1.00 g), <strong>[875781-17-2]5-bromo-1H-pyrazolo[3,4-b]pyridine</strong> (1.29 g), triethylamine (2.74 mL), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.088 g), copper(I) iodide (0.044 g) and DMSO (15 mL) was stirred under microwave irradiation at 120 C. for 1 hr. The same reaction using the same amounts was performed 2 times in total. The reaction mixtures were combined, and saturated aqueous sodium hydrogen carbonate solution (50 mL) and ethyl acetate (50 mL) were added. Insoluble material was filtered, and insoluble material was washed with ethyl acetate/THF (3/1). The organic layer was collected from the filtrate and the aqueous layer was extracted 3 times with ethyl acetate/THF (5/1, 30 mL). The combined organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated to give a residue. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and subjected to ethyl acetate/IPE/hexane, and the precipitate was collected by filtration to give the title compound (2.15 g). 1H NMR (300 MHz, DMSO-d6) delta 5.22 (2H, s), 6.77-7.00 (2H, m), 8.21 (1H, s), 8.51 (1H, d, J=2.1 Hz), 8.67 (1H, d, J=2.1 Hz), 13.97 (1H, brs).

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 543 - 547
[2]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1498 - 1503
[3]Patent: US2019/169166,2019,A1 .Location in patent: Paragraph 0875; 0876

33
[ 875781-17-2 ]
[ 1220220-21-2 ]
N-[4-(1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-2-yl]acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.2%	With potassium phosphate; bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); In water; 1,2-dichloro-ethane; at 150℃; for 1h;Microwave irradiation;	[00326] A mixture of 5-bromo-1H-pyrazolo[3,4-b]pyridine (0.100 g, 0.505 mmol) , N-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (0.199 g, 0.758 mmol), amphosdichloropalladium(II) (0.0718 g, 0.101 mmol) and potassium phosphate (0.323 g, 1.52 mmol) was allowed to stir in water (0.27 mL) and DME (4.6 mL) and heated in the microwave at 150C for 60 mm. The reaction mixture was partitioned between water and EtOAc and the organic layer was washed with brine. The aqueous layer was further extracted with a DCM/MeOH mixture. The combined all organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. Added MeOH and filtered to remove solids and concentrated the supernatant by rotary evaporation. Purified by prep HPLC to yield N-[4-(1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-2-yl]acetamide (1.5 mg, 1.2%). LCMS(FA): m/z 254.4 (M+H).
1.2%	With potassium phosphate; bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); In 1,2-dimethoxyethane; water; at 150℃; for 1h;Microwave irradiation;	Example 33 N-[4-(1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-2-yl]acetamide I-189 A mixture of 5-bromo-1H-pyrazolo[3,4-b]pyridine (0.100 g, 0.505 mmol), <strong>[1220220-21-2]N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide</strong> (0.199 g, 0.758 mmol), amphosdichloropalladium(II) (0.0718 g, 0.101 mmol) and potassium phosphate (0.323 g, 1.52 mmol) was allowed to stir in water (0.27 mL) and DME (4.6 mL) and heated in the microwave at 150 C. for 60 min. The reaction mixture was partitioned between water and EtOAc and the organic layer was washed with brine. The aqueous layer was further extracted with a DCM/MeOH mixture. The combined all organic layers were dried over magnesium sulfate, filtered and concentrated by rotary evaporation. Added MeOH and filtered to remove solids and concentrated the supernatant by rotary evaporation. Purified by prep HPLC to yield N-[4-(1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-2-yl]acetamide (1.5 mg, 1.2%). LCMS(FA): m/z=254.4 (M+H).

Reference： [1]Patent: WO2015/108861,2015,A1 .Location in patent: Paragraph 00326
[2]Patent: US2015/225422,2015,A1 .Location in patent: Paragraph 0448-0449

34
[ 875781-17-2 ]
N-(3-ethynyl-4-methylphenyl)-N'-(4-((4-methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl)urea [ No CAS ]
N-[3-((1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methylphenyl]-N'-[4-((4-methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; tricyclohexylphosphine; In N,N-dimethyl-formamide; at 80℃; for 48h;Sealed tube; Inert atmosphere;	Step 4: Preparation of N-[3-((1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methylphenyl]-N'-[4-((4-methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]urea The product (108 mg, 0.25 mmol) obtained from Step 3, <strong>[875781-17-2]5-bromo-1H-pyrazolo[3,4-b]pyridine</strong> (62 mg, 0.31 mmol), Pd(PPh3)2Cl2 (1.4 mg, 0.02 mmol), tricyclohexylphosphine (10 mg, 0.04 mmol), Cs2CO3 (49 mg, 0.15 mmol) and DBU (6d) and DMF (5 ml) were added into a 50 ml sealed tube, and stirred at 80C for 48 hours under the protection of argon gas. The system was cooled to room temperature, filtered, and extracted with ethyl acetate (30 ml x 3) and H2O (30 ml). The organic phases were combined, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography, to give the title compound as a white viscous matter. 1H NMR (500 MHz, d6-DMSO) delta: 12.29 (s, 1H, N-H), 9.85 (s, 1H, Ar-H), 9.64 (s, 1H, Ar-H), 8.52 (s, 1H, Ar-H), 7.98-7.96 (t, 2H, Ar-H), 7.79-7.78 (d, 1H, Ar-H), 7.60 (s, 2H, N-H), 7.41-7.39 (m, 1H, Ar-H), 7.26-7.25 (d, 1H, Ar-H), 6.67-6.66 (d, 1H, Ar-H), 3.34 (s, 2H, NCH2), 2.45 (s, 3H, CH3), 2.38-2.33 (m, 8H, NCH2CH2N), 2.16 (s, 3H, CH3). ESI-MS m/z: [M+H]+=548.2, calculated: 548.2.

Reference： [1]Patent: EP2927232,2015,A1 .Location in patent: Paragraph 0061; 0065

35
[ 875781-17-2 ]
[ 832114-00-8 ]
3,5-dimethyl-4-(1H-pyrazolo[3,4-b]pyridin-5-yl)isoxazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium carbonate; In water; acetonitrile; at 110℃; for 0.25h;Microwave irradiation;	Step 1-Preparation of 3,5-dimethyl-4-(1H-pyrazolo[3,4-b]pyridin-5-yl)isoxazole (42): To <strong>[875781-17-2]5-bromo-1H-pyrazolo[3,4-b]pyridine</strong> (41, 1.5 g, 7.58 mmol) in acetonitrile (18 ml) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (3.38 g, 15.15 mmol), 1 M potassium carbonate in water (9 ml), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.58 g, 0.76 mmol). The reaction was allowed to stir at 110 C. in a microwave for 15 minutes. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 0% to 100% ethyl acetate in hexane to give product 42 (900 mg, 55%).

Reference： [1]Patent: US2016/75712,2016,A1 .Location in patent: Paragraph 0283; 0284

36
[ 557-21-1 ]
[ 875781-17-2 ]
1H-pyrazolo[3,4-b]pyridine-5-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With tetrakis(triphenylphosphine) palladium(0); In 1-methyl-pyrrolidin-2-one; at 92℃; for 5h;	A suspension of zinc cyanide (6.11 g, 52.0 mmol), tetrakis(triphenylphosphine)palladium(0) (3.01 g, 2.6 mmol) and 5- bromo-lH-Pyrazolo[3,4-b]pyridine (10.3 g, 52.0 mmol) in NMP (50 mL) was stirred at 92 C (bath) for 5 hours. After cooling to ambient temperature, ethyl acetate (100 mL) was added. Solid was removed by filtration. The filtrate was concentrated under reduced pressure. Water (200 mL) was added to resulting solution and stirred at ambient temperature for 10 minutes. The solids were collected by filtration then suspended in acetic acid (25 mL) and water (50 mL). The mixture was stirred at ambient temperature for 30 minutes. The solids were collected by filtration, washed with water and dried to give lH-pyrazolo[3,4-b]pyridine-5-carbonitrile (6.77 g, 90%) as a solid. LCMS ESI (+) m/z 145 (M+H).
535 g	With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 85℃; for 10h;Inert atmosphere; Large scale;	20L reaction flask, under the protection of nitrogen by adding 1.25 kg intermediate two crude product with DMF, stirred until complete dissolution; adding 5 times the intermediate two coarse dosing cyanidization zinc solid powder, stirring 0.5h, finally adding 0.1 times of the two coarse dosing of intermediate 4-triphenylphosphine palladium, the temperature is increased to 85 C reaction 10h, sampling HPLC central control, until the reaction is ended; and cooling down to room temperature, filtered, filtrate plus ice water stirring, add 30LEA extraction two, concentrated to obtain solid crude; solid crude the volume ratio of 1:1 mixed solution of methanol and chloroform of pulp washing, filtering, drying, to obtain secondary crude 1.47 kg, purity 95%, yield 82%. Taking 563g secondary crude product, adding 16L the mass concentration is 1% of the hydrogen chloride ethanol solvent, heating to reflux, after stirring the solution, adding 160g activated carbon, reflux 1h, heat filter, with 2L70 C hot ethanol washing, collecting filtrate is combined, concentrated to be half-dried, by adding 1.5L ether stirring pulping, filtering, drying 5h to graduated arm heavy, obtain 535g containing 5-cyano -1H-pyrazolo [3,4-b] pyridine finished, purity 98.4%, yield 95%.

Reference： [1]Patent: WO2019/232319,2019,A1 .Location in patent: Paragraph 0380; 0553
[2]Journal of Organic Chemistry,2017,vol. 82,p. 7420 - 7427
[3]Patent: CN103980272,2016,B .Location in patent: Paragraph 0038; 0039; 0044; 0045

37
[ 875781-17-2 ]
[ 100-97-0 ]
5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With acetic acid; In water; for 12h;Reflux;	The 5-bromo-1H-pyrazolo [3,4-b]pyridine (3) (15 g, 75.7 mmol), hexamethylenetetramine (HMTA) (14.8 g, 106 mmol), 50 mL acetic acid, and 100 mL H2O were taken and heated to reflux for 12 h. After the reaction solution was cooled to room temperature, the precipitate obtained was filtered, washed with water, and dried to get white solid. The crude compound was recrystallized from hexane to get the pure compound 4, 15.7 g with 92% in yield.

Reference： [1]Medicinal Chemistry Research,2016,vol. 25,p. 2392 - 2398

38
[ 875781-17-2 ]
[ 74-88-4 ]
[ 887115-56-2 ]

Yield	Reaction Conditions	Operation in experiment
73%		Step 1 5-bromo-1-methyl-1H-pyrazolo[3,4-b]pyridine (Compound 4-2) Sodium hydride (720 mg, 30 mmol) was added into a 100 ml reaction flask, and anhydrous THF (40 mL) was added to the reaction flask. After stirring at 0 C. for 5 min, the reaction substrate 5-bromo-1H-pyrazolo[3,4-b]pyridine (4.0 g, 20 mmol, commercially available) was dissolved in THF (20 ml), and the resulting solution was slowly added dropwise to the reaction flask through the constant pressure funnel, and stirred for 30 min. Afterwards, iodomethane (1.6 ml, 26 mmol) was added dropwise to the reaction system. After completion of the addition, the reaction solution was slowly warmed to room temperature and stirred overnight. The reaction progress was monitored by TLC. After completion of the reaction, 10 ml of ice water was added to the reaction system to quench the reaction, THF was removed by concentration under reduced pressure, and the residue was extracted with dichloromethane (60 ml) and water (20 ml*3). The organic layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 4.1 g brown solid, which was separated and purified by Combi-flash chromatography [PE:EA=10:90-40:60] to give the title compound 4-2 (3.1 g, 73%). MS m/z (ESI): 211.9 [M+H]+.

Reference： [1]Patent: US2017/8889,2017,A1 .Location in patent: Paragraph 0165; 0166

39
[ 875781-17-2 ]
[ 1312312-78-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C / Inert atmosphere 1.2: 25 °C / Inert atmosphere 2.1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 8 h / 90 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - US2017/8889, 2017, A1

40
[ 110-87-2 ]
[ 875781-17-2 ]
5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With pyridinium p-toluenesulfonate; In dichloromethane; acetonitrile; at 20℃; for 24h;	A mixture of 5-bromo- liT-pyrazolo[3,4-Z>]pyridine (5 g, 25.25 mmole), DHP (4.8 g, 76 mmole), and PPTS (0.5 g, 2.5 mmole) in DCM/MeCN (1 : 1, 80 mL) was stirred at RT for 24h. H20 was added, extracted with DCM (3x). The combined extracts were dried over Na2S04, concentrated and purified by ISCO (20% EtO Ac/Hexanes) to give the title compound (7.9 g, 100%). LC-MS (+ESI) M+H: 282.1.
60.7%	With toluene-4-sulfonic acid; at 25 - 30℃; for 3h;	To a stirred solution of 5-bromo-lH-pyrazolo[3,4-b]pyridine (XVI) (130 g, 656 mmol, 1.0 eq) in DCM (1300 mL) were added DHP ( 1 11 g, 1.31 mol, 2.0 eq) and p-TsOH (1 1.3 g, 65.6 mmol, 0.1 eq) at 25~30C. The reaction suspension was stirred at 25~30C for 3 h. The reaction suspension changed to a brown solution. The reaction solution was poured into saturated sodium bicarbonate (2.5 L) and separated. The aqueous layer was then extracted with DCM (500 mL x 2). The combined organic layer was washed with brine (500 mL), dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was purified by column chromatography (100% PE?PE:EtOAc = 10: 1) to give 5-bromo-l-(tetrahydro- 2H-pyran-2-yl)-lH-pyrazolo[3,4-b]pyridine (XVII) (1 12.5 g, 398.5 mmol, 60.7% yield) was obtained as a red oil. ESIMS found for CnHi2BrN30 mlz 283.0 (M+H).
60.7%	With toluene-4-sulfonic acid; In dichloromethane; at 25 - 30℃; for 3h;	To a stirred solution of 5-bromo-1H-pyrazolo[3,4-bjpyridine (XVI) (130 g,656 mmol, 1.0 eq) in DCM (1300 mL) were added DHP (111 g, 1.31 mol, 2.0 eq) and p-TsOH (11.3 g, 65.6 mmol, 0.1 eq) at 2530C. The reaction suspension was stirred at 2530C for 3 h. The reaction suspension changed to a brown solution. The reaction solution was poured into saturated sodium bicarbonate (2.5 L) and separated. The aqueous layer was then extracted with DCM (500 mL x 2). The combined organic layer was washed with brine (500 mL), dried over anhydrous sodium sulfate and concentrated to give the cmde product. The cmde product was purified by column chromatography (100% PE-*PE:EtOAc = 10:1) to give 5-bromo-1- (tetrahydro-2H-pyran-2-yl)- 1H-pyrazolo [3,4-bipyridine (XVII) (112.5 g, 398.5 mmol, 60.7% yield) was obtained as a red oil. ESIMS found for C11H12BrN3O mlz 283.0 (M+H).

112.5 g	With toluene-4-sulfonic acid; In dichloromethane; at 25 - 30℃; for 3h;	To a stirred solution of <strong>[875781-17-2]5-bromo-1H-pyrazolo[3,4-b]pyridine</strong> (XVI) (130 g, 656 mmol, 1.0 eq) in DCM (1300 mL) were added DHP (111 g, 1.31 mol, 2.0 eq) and p-TsOH (11.3 g, 65.6 mmol, 0.1 eq) at 25~30C. The reaction suspension was stirred at 25~30C for 3 h. The reaction suspension changed to a brown solution. The reaction solution was poured into saturated sodium bicarbonate (2.5 L) and separated. The aqueous layer was then extracted with DCM (500 mL x 2). The combined organic layer was washed with brine (500 mL), dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was purified by column chromatography (100% PE?PE:EtOAc = 10: 1) to give 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (XVII) (112.5 g, 398.5 mmol, 60.7% yield) was obtained as a red oil. ESIMS found for C11H12BrN3O m/z 283.0 (M+H
112.5 g	With toluene-4-sulfonic acid; In dichloromethane; at 25 - 30℃; for 3h;	To a stirred solution of 5-bromo-lH-pyrazolo[3,4-b]pyridine (XVI) (130 g, 656 mmol, 1.0 eq) in DCM (1300 mL) were added DHP ( 1 11 g, 1.31 mol, 2.0 eq) and p-TsOH (1 1.3 g, 65.6 mmol, 0.1 eq) at 25~30C. The reaction suspension was stirred at 25~30C for 3 h. The reaction suspension changed to a brown solution. The reaction solution was poured into saturated sodium bicarbonate (2.5 L) and separated. The aqueous layer was then extracted with DCM (500 mL x 2). The combined organic layer was washed with brine (500 mL), dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was purified by column chromatography (100% PE?PE:EtOAc = 10: 1) to give 5 -bromo-l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazolo[3,4-b]pyridine (XVII) (1 12.5 g, 398.5 mmol, 60.7% yield) was obtained as a red oil. ESIMS found for CnHi2BrN30 mlz 283.0 (M+H).

Reference： [1]Patent: WO2019/195634,2019,A1 .Location in patent: Page/Page column 202
[2]Patent: WO2019/198692,2019,A1 .Location in patent: Paragraph 0915-0916
[3]Patent: WO2017/23987,2017,A1 .Location in patent: Paragraph 0610; 0613
[4]Patent: WO2017/23981,2017,A1 .Location in patent: Paragraph 0610; 0613
[5]Patent: WO2017/23973,2017,A1 .Location in patent: Paragraph 0634
[6]Patent: WO2017/23996,2017,A1 .Location in patent: Paragraph 0613

41
[ 875781-17-2 ]
[ 1196156-42-9 ]

Reference： [1]Journal of Organic Chemistry,2017,vol. 82,p. 7420 - 7427

42
[ 875781-17-2 ]
[ 74-88-4 ]
[ 887115-56-2 ]
5-bromo-2-methyl-2H-pyrazolo[3,4-b]pyridine [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2018,vol. 83,p. 6334 - 6353
[2]Journal of Organic Chemistry,2018,vol. 83,p. 6334 - 6353

43
[ 875781-17-2 ]
5-bromo-1H-pyrazolo[3,4-b]pyridine 7-oxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dihydrogen peroxide; trifluoroacetic acid; at 60℃; for 12h;	To a stirred solution of 5-bromo-lH-pyrazolo[3,4-b]pyridine (5.00 g, 25.2 mmol) in TFA (50 mL) was added hydrogen peroxide (11 mL, 126 mmol) at 0 C. The reaction mixture turns to hazy solution and the the resulting reaction mixture was stirred at 60 C for 12 h. The volatiles were removed under vacuum to afford the crude title compound as yellow gummy solid which was processed to the next step as such. LC/MS: m/z = 214.3 [M+H] +. NMR (400 MHz, DMSO-de) delta ppm 8.65 (d, J=1.5 Hz, 1H), 8.27 (s, 1H), 8.13 (s, 1H)

Reference： [1]Patent: WO2018/203235,2018,A1 .Location in patent: Page/Page column 69-70

44
[ 875781-17-2 ]
ethyl 1-methyl-7-((trimethylsilyl)ethynyl)-1H-indole-2-carboxylate [ No CAS ]
ethyl 7-((1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-1-methyl-1H-indole-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With copper(l) iodide; tetrabutyl ammonium fluoride; triethylamine; In N,N-dimethyl-formamide;Heating;	Ethyl 1-methyl-7-((trimethylsilyl)ethynyl)-1H-indole-2-carboxylate (3.0 g, 10 mmol),<strong>[875781-17-2]5-bromo-1H-pyrazolo[3,4-b]pyridine</strong> (2.9 g, 15 mmol),Cuprous iodide (0.19 g, 1 mmol), tetrabutylammonium fluoride (2.6 g, 10 mmol), dissolved in a mixed solvent of triethylamine and dimethylformamide.Heat and stir until the reaction is completed.Ethyl acetate is extracted with water and the organic phase is concentrated.Column chromatography gave a yellow solid product of 1.4 g, yield 42%.

Reference： [1]Patent: CN109988151,2019,A .Location in patent: Paragraph 0227; 0230-0232

45
[ 875781-17-2 ]
[ 916325-85-4 ]

Reference： [1]Patent: WO2019/149738,2019,A1

46
[ 875781-17-2 ]
[ 86864-60-0 ]
5-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazolo[3,4-b]pyridine [ No CAS ]

Reference： [1]Patent: WO2019/198692,2019,A1 .Location in patent: Paragraph 0150; 1023-1024

47
[ 875781-17-2 ]
[ 1083326-55-9 ]
N-{2-chloro-5-[1H-pyrazolo(3,4-b)pyridin-5-yl]pyridin-3-yl}benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 25 - 80℃; for 0.0166667h;	(3) 5-bromopyridopyrazole (0.14 g, 0.72 mmol) and tetrakis(triphenylphosphine)palladium (0.017 g, 0.014 mmol), potassium carbonate (0.20 g, 1.44 mmol) Dissolved in 1,4-dioxane (1.2mL) to prepare reaction solution 4. The flow rate (0.1mL / min) set by the intelligent numerical control sampler is simultaneously entered into a three-way mixer (ambient temperature: 25 C) through a polytetrafluoroethylene tube with an inner diameter of 1,000 mum and the second effluent. Then, under its own pressure, it enters a polytetrafluoroethylene tube with an internal diameter of 1000 mum at a set temperature control (80 C).The Suzuki coupling reaction between the second effluent product and 5-bromo-7-azaindole was completed within the set residence time t3 (1min), and the target product N-{2-chloro-5-[1H-pyrazolo(3,4-b)pyridin-5-yl]pyridin-3-yl}benzenesulfonamide. (4) The above effluent, the solvent was distilled off under reduced pressure, and then separated through a silica gel column by column chromatography (DCM / MeOH, 3: 1), and then the solvent was distilled off under reduced pressure to obtain the target product N-{2-chloro-5-[1H-pyrazolo(3,4-b)pyridin-5-yl]pyridin-3-yl}benzenesulfonamide, yield 84%, purity 98%.

Reference： [1]Patent: CN110498798,2019,A .Location in patent: Paragraph 0148-0149; 0152-0153

48
[ 875781-17-2 ]
[ 1255099-13-8 ]
[ 2699128-62-4 ]

Yield	Reaction Conditions	Operation in experiment
75%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 80℃; for 5h; Inert atmosphere;

Reference： [1]Houska, Richard; Seitz, Oliver; Stutz, Marvin Björn [Chemical Science, 2021, vol. 12, # 40, p. 13450 - 13457]

49
[ 875781-17-2 ]
[ 1256818-99-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: methanesulfonic acid / dichloromethane; tetrahydrofuran / 3 h / 20 °C 2: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / N,N-dimethyl-formamide / 2 h / 100 °C 3: sodium hydroxide; dihydrogen peroxide / tetrahydrofuran; water / 2 h / 20 °C 4: N,N-dimethyl-formamide / 16.08 h / 0 - 20 °C 5: toluene-4-sulfonic acid / water; methanol / 2 h / 20 °C

Reference： [1]Current Patent Assignee: BANQUE DE VIZILLE; CRÉDIT INDUSTRIEL ET COMMERCIAL - CIC; SERVIER MONDE - WO2021/224320, 2021, A1

50
[ 875781-17-2 ]
[ 1221288-25-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; triethylamine / 16 h / 100 °C / 1551.49 Torr / Inert atmosphere 2: N-iodo-succinimide / acetonitrile / 16 h / 75 °C

Reference： [1]Current Patent Assignee: IKENA ONCOLOGY INC - WO2022/187520, 2022, A1

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Bromides

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