[ CAS No. 1261269-66-2 ] {[proInfo.proName]}

Name: 1261269-66-2|2,4,6-Trichloronicotinaldehyde|97%
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SKU: A132374
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Quality Control of [ 1261269-66-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1261269-66-2 ]

Product Details of [ 1261269-66-2 ]

CAS No. :	1261269-66-2	MDL No. :	MFCD17012148
Formula :	C₆H₂Cl₃NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	RESMQRUOHBZJCA-UHFFFAOYSA-N
M.W :	210.45	Pubchem ID :	20249151
Synonyms :

Calculated chemistry of [ 1261269-66-2 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	44.65
TPSA :	29.96 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) :	-5.55 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.44
Log Po/w (XLOGP3) :	2.86
Log Po/w (WLOGP) :	2.85
Log Po/w (MLOGP) :	1.58
Log Po/w (SILICOS-IT) :	3.45
Consensus Log Po/w :	2.44

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.28
Solubility :	0.109 mg/ml ; 0.00052 mol/l
Class :	Soluble
Log S (Ali) :	-3.15
Solubility :	0.15 mg/ml ; 0.000711 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.83
Solubility :	0.0313 mg/ml ; 0.000149 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.57

Safety of [ 1261269-66-2 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338-P310	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1261269-66-2 ]

* 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 [ 1261269-66-2 ]
Downstream synthetic route of [ 1261269-66-2 ]

[ 1261269-66-2 ] Synthesis Path-Upstream 1~3

1
[ 1261269-66-2 ]
[ 120422-90-4 ]

Reference： [1] Patent: WO2011/141756, 2011, A1,
[2] Patent: WO2017/42100, 2017, A1,

2
[ 16063-69-7 ]
[ 109-94-4 ]
[ 1261269-66-2 ]

Yield	Reaction Conditions	Operation in experiment
88%	Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h; Stage #2: at -78 - -74℃;	2,4,6-Trichloropyridine (5 g, 27.4 mmol) in anhydrous THF (100 ml) was cooled to -78° C. A solution of n-butyllithium (22.27 ml, 28.8 mmol) (1.6M in hexane) was added slowly at -78° C. The solution was stirred at -78° C. for 30 mins, then treated with a solution of ethyl formate (10.15 g, 137 mmol) maintaining an internal temperature below -74° C. The resulting solution was stirred at -78° C. until all starting material was consumed (monitored by TLC, 9:1 heptane/EtOAC), then it was quenched at -78° C. with a solution of saturated ammonium chloride and 50 ml 0.5N aq. HCl under vigorous stirring. It was then allowed to warm to r.t. The quenched mixture was extracted with EtOAc, the organic phase was washed with brine, dried over MgSO₄, and concentrated. The crude residue (light yellow solid) was purified by flash chromatography on silica gel with 0-20percent EtOAc/heptane to provide 5.1 g (88percent yield) of the desired 2,4,6-trichloronicotinaldehyde as a white solid. ¹H NMR (400 MHz, chloroform-d3) δ ppm=10.42 (s, 1H), 7.45 (s, 1H).
87%	Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.5 h; Inert atmosphere Stage #2: at -78℃; for 3 h; Inert atmosphere	n-BuLi (2M, 15 mL, 1.00 equiv) was added to a solution of 2,4,6-trichloropyridine (6 g, 32.89 mmol, 1.00 equiv) in THF (100 mL) at -78° C. under nitrogen. After being stirred for 0.5 h at -78° C. ethyl formate (3.192 g, 43.09 mmol, 1.30 equiv) was added and the resulting solution was stirred for 3 h at -78° C. After completion the reaction was quenched with ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column eluting with ethyl acetate/petroleum ether (1:20) to give the title compound (6 g, 87percent) as a white solid.
75%	Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h; Inert atmosphere Stage #2: at -78℃; Inert atmosphere	n-BuLi (35 mL, 2.5 M in hexanes) was added dropwise to a stuffed solution of 2,4,6-trichloropyridine (15 g, 82.22 mmol, 1.00 equiv) in anhydrous THF (200 mL) at -78 °C under nitrogen. After 30 minutes ethyl formate (10 mL, 215.31 mmol) was added at -78 °C . The resulting solution was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:10) to give the title compound (13 g, 75percent) as a white solid. LC-MS(ES, mlz): 210 [M+H]⁺

54%

Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.5 h; Inert atmosphere
Stage #2: at -78℃; for 0.5 h;

n-BuLi (2M, 16.8 mL) was added dropwise to a stined solution of 2,4,6-trichloropyridine (8 g,43.85 mmol, 1.00 equiv) in THF (80 mL) at -78 °C under nitrogen. After being stined at -78 °C for30 mm ethyl formate (4.88 g, 65.88 mmol, 1.50 equiv) was added to the reaction mixture and theresulting solution was stirred for another 30 mm at -78 °C. After completion the solution wasquenched with NH4C1 solution and extracted with ethyl acetate. The organic layers werecombined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:10) to give the title compound (5 g, 54percent) as a white solid. ‘HNMR (300 MHz, CDC13) ö 10.42 (s, 1H), 7.45 (s, 1H).

Reference： [1] Patent: US2018/111932, 2018, A1, . Location in patent: Paragraph 0388; 0389
[2] Patent: US2015/57260, 2015, A1, . Location in patent: Paragraph 0765; 0766; 1088; 1089
[3] Patent: WO2015/25026, 2015, A1, . Location in patent: Page/Page column 178; 179
[4] Patent: WO2015/25025, 2015, A1, . Location in patent: Page/Page column 399

3
[ 2591-86-8 ]
[ 16063-69-7 ]
[ 1261269-66-2 ]

Yield	Reaction Conditions	Operation in experiment
45%	Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78 - 73℃; for 1 h; Stage #2: at -78℃; for 1 h;	Intermediate 1 A solution of 2,4,6-trichloropyridine (9.85 g, 53.8 mmol) in THF (100 ml) was added dropwise to a solution of n-butyllithium, 1.6M in hexane (33.6 ml, 53.8 mmol) in THF (40 ml) whilst maintaining the temperature below -73°C. After the addition was complete, the mixture was stirred at -78°C for 1 hour. A solution of 1-formylpiperidine (6.0 ml, 53.8 mmol) in THF (10 ml) was added dropwise and the mixture was stirred at -78°C for 1 hour. The reaction mixture was quenched with sat. NH₄CI(aq) at -78°C and allowed to warm to rt. The mixture was extracted with ether and was washed successively with 1 HCI(aq), water, sat. NH₄HC0₃(aq), water and brine. The organic phase was dried and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 10:1 petrol-ethyl acetate to provide a yellow solid (5.18 g, 45percent). ¹H NMR (400 MHz, DMSO-ay δ ppm 8.09 (s, 1 H), 10.27 (s, 1 H).
2.94 g	Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h; Inert atmosphere Stage #2: at -78℃; for 1 h;	To a solution of 2,4,6-trichloro-pyridine (5.00 g) in tetrahydrofuran (anhydrous, 50,00 mL) at -78 00 under a nitrogen atmosphere was added n-butyl lithium (2.5M in hexane) (10,96 ml) dropwise. The mixture was stirred at -78 00 for 1 h and then piperidine-1- carbaldehyde (3.04 mL) was added drop wise. The reaction was stirred at -78 00 for 1 h. The reaction mixture was quenched with sat NH4CI aq (50 ml). The mixture was extracted with TBME (3 x 40 mL) and the organic phase washed successively with 1 M HCI (75 mL) and sat. ammonium carbonate (75 mL). The organic phase were dried (Na2504) and concentrated and the residue purified by Biotage Isolera FCC (5i02: 50 g) eluting with 10-50percent TBME in cyclohexane to give 2.94 g of product as a yellow solid.Analysis: HPLC-MS: R1 = 1.27 mm (method P)1H NMR (DMSO, 250 MHz) 68.07 (1H, s), 10.28 (1H, s)

Reference： [1] Patent: WO2011/141756, 2011, A1, . Location in patent: Page/Page column 48-49
[2] Patent: WO2017/42100, 2017, A1, . Location in patent: Page/Page column 49

[ 1261269-66-2 ] Synthesis Path-Downstream 1~36

1
[ 1261269-66-2 ]
[ 676-58-4 ]
[ 1347759-12-9 ]

Yield	Reaction Conditions	Operation in experiment
100%		Intermediate 2A solution of methylmagnesium chloride, 3M in THF (9.0 ml, 26.9 mmol) in THF (10 ml) was added dropwise to a stirred solution ofIntermediate 1 (5.18 g, 24.4 mmol) in THF (110 ml) at -78C. After the addition the reaction mixture was stirred at -78C for 30 minutes and then allowed to warm to rt. The mixture was quenched with sat. NH4CI(aq) and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated to give a yellow oil (5.57 g, 100%).1H NMR (400 MHz, DMSO-of6) delta ppm 1.46 (d, J=6.9 Hz, 3 H), 5.36 (m, 1 H), 5.57 (d, J=4.1 Hz, 1 H), 7.84 (s, 1 H).

Reference： [1]Patent: WO2011/141756,2011,A1 .Location in patent: Page/Page column 49

2
[ 2591-86-8 ]
[ 16063-69-7 ]
[ 1261269-66-2 ]

Yield	Reaction Conditions	Operation in experiment
45%		Intermediate 1 A solution of 2,4,6-trichloropyridine (9.85 g, 53.8 mmol) in THF (100 ml) was added dropwise to a solution of n-butyllithium, 1.6M in hexane (33.6 ml, 53.8 mmol) in THF (40 ml) whilst maintaining the temperature below -73C. After the addition was complete, the mixture was stirred at -78C for 1 hour. A solution of 1-formylpiperidine (6.0 ml, 53.8 mmol) in THF (10 ml) was added dropwise and the mixture was stirred at -78C for 1 hour. The reaction mixture was quenched with sat. NH4CI(aq) at -78C and allowed to warm to rt. The mixture was extracted with ether and was washed successively with 1 HCI(aq), water, sat. NH4HC03(aq), water and brine. The organic phase was dried and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 10:1 petrol-ethyl acetate to provide a yellow solid (5.18 g, 45%). 1H NMR (400 MHz, DMSO-ay delta ppm 8.09 (s, 1 H), 10.27 (s, 1 H).
2.94 g		To a solution of 2,4,6-trichloro-pyridine (5.00 g) in tetrahydrofuran (anhydrous, 50,00 mL) at -78 00 under a nitrogen atmosphere was added n-butyl lithium (2.5M in hexane) (10,96 ml) dropwise. The mixture was stirred at -78 00 for 1 h and then piperidine-1- carbaldehyde (3.04 mL) was added drop wise. The reaction was stirred at -78 00 for 1 h. The reaction mixture was quenched with sat NH4CI aq (50 ml). The mixture was extracted with TBME (3 x 40 mL) and the organic phase washed successively with 1 M HCI (75 mL) and sat. ammonium carbonate (75 mL). The organic phase were dried (Na2504) and concentrated and the residue purified by Biotage Isolera FCC (5i02: 50 g) eluting with 10-50% TBME in cyclohexane to give 2.94 g of product as a yellow solid.Analysis: HPLC-MS: R1 = 1.27 mm (method P)1H NMR (DMSO, 250 MHz) 68.07 (1H, s), 10.28 (1H, s)

Reference： [1]Patent: WO2011/141756,2011,A1 .Location in patent: Page/Page column 48-49
[2]Patent: WO2017/42100,2017,A1 .Location in patent: Page/Page column 49

3
[ 1261269-66-2 ]
[ 1347759-00-5 ]

Reference： [1]Patent: WO2011/141756,2011,A1

4
[ 1261269-66-2 ]
[ 1347759-13-0 ]

Reference： [1]Patent: WO2011/141756,2011,A1
[2]Patent: WO2017/42100,2017,A1

5
[ 1261269-66-2 ]
[ 120422-90-4 ]

Reference： [1]Patent: WO2011/141756,2011,A1
[2]Patent: WO2017/42100,2017,A1

6
[ 1261269-66-2 ]
[ 1347758-87-5 ]

Reference： [1]Patent: WO2011/141756,2011,A1

7
[ 1261269-66-2 ]
[ 1347758-88-6 ]

Reference： [1]Patent: WO2011/141756,2011,A1

8
[ 1261269-66-2 ]
[ 1347758-89-7 ]

Reference： [1]Patent: WO2011/141756,2011,A1

9
[ 1261269-66-2 ]
[ 1347758-90-0 ]

Reference： [1]Patent: WO2011/141756,2011,A1

10
[ 624-80-6 ]
[ 1261269-66-2 ]
4,6-dichloro-1-ethyl-1H-pyrazolo[4,3-c]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26%	With triethylamine; In ethanol; at -78 - 0℃; for 3h;Inert atmosphere;	Ethylhydrazine (2.16 g, 14.39 mmol, 1.00 equiv) was added to a solution of <strong>[1261269-66-2]2,4,6-trichloropyridine-3-carbaldehyde</strong> (3 g, 14.26 mmol, 1.00 equiv) and triethylamine (4.3 g, 42.49 mmol, 3.00 equiv) in ethanol (100 mL) at -78 C. under nitrogen. The resulting solution was stirred for 3 hours at 0 C. After completion the reaction was concentrated under vacuum and the residue was purified by a silica gel column eluting with ethyl acetate/petroleum ether (1:20) to give the title compound (800 mg, 26%) as a white solid. LC-MS (ES, m/z): 216 [M+H]+.
26%	With triethylamine; In ethanol; at -78 - 0℃; for 3h;Inert atmosphere;	Ethylhydrazine (2.16 g, 14.39 mmol, 1.00 equiv) was added to a solution of<strong>[1261269-66-2]2,4,6-trichloropyridine-3-carbaldehyde</strong> (3 g, 14.26 mmol, 1.00 equiv) and triethylamine (4.3 g,42.49 mmol, 3.00 equiv) in ethanol (100 mL) at -78C under nitrogen. The resulting solution was stilTed for 3 hours at 0 C. After completion the reaction was concentrated under vacuum and the residue was purified by a silica gel column eluting with ethyl acetate/petroleum ether (1:20) to give the title compound (800 mg, 26%) as a white solid. LC-MS (ES, m/z): 216 [M+H].

Reference： [1]Patent: US2015/57260,2015,A1 .Location in patent: Paragraph 1079; 1080
[2]Patent: WO2015/25026,2015,A1 .Location in patent: Page/Page column 238; 239

11
[ 1261269-66-2 ]
[ 60-34-4 ]
4,6-dichloro-1-methyl-1H-indazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With triethylamine; In ethanol; at -78℃; for 0.5h;	A solution of <strong>[1261269-66-2]2,4,6-trichloropyridine-3-carbaldehyde</strong> (3 g, 14.26 mmol, 1.00 equiv) in triethylamine (5.8 mL)/ethanol (100 mL) was cooled to -78C and methylhydrazine (1.55 mL,26.58 mmol, 1.90 equiv) was added slowly. After 30 minutes the resulting solution was concentrated, diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:10) to give the title compound (1.5 g, 52%) as a yellow solid. LC-MS (ES, m/z): 202 [M+H].

Reference： [1]Patent: WO2015/25026,2015,A1 .Location in patent: Page/Page column 179

12
[ 16063-69-7 ]
[ 109-94-4 ]
[ 1261269-66-2 ]

Yield	Reaction Conditions	Operation in experiment
88%		2,4,6-Trichloropyridine (5 g, 27.4 mmol) in anhydrous THF (100 ml) was cooled to -78 C. A solution of n-butyllithium (22.27 ml, 28.8 mmol) (1.6M in hexane) was added slowly at -78 C. The solution was stirred at -78 C. for 30 mins, then treated with a solution of ethyl formate (10.15 g, 137 mmol) maintaining an internal temperature below -74 C. The resulting solution was stirred at -78 C. until all starting material was consumed (monitored by TLC, 9:1 heptane/EtOAC), then it was quenched at -78 C. with a solution of saturated ammonium chloride and 50 ml 0.5N aq. HCl under vigorous stirring. It was then allowed to warm to r.t. The quenched mixture was extracted with EtOAc, the organic phase was washed with brine, dried over MgSO4, and concentrated. The crude residue (light yellow solid) was purified by flash chromatography on silica gel with 0-20% EtOAc/heptane to provide 5.1 g (88% yield) of the desired 2,4,6-trichloronicotinaldehyde as a white solid. 1H NMR (400 MHz, chloroform-d3) delta ppm=10.42 (s, 1H), 7.45 (s, 1H).
87%		n-BuLi (2M, 15 mL, 1.00 equiv) was added to a solution of 2,4,6-trichloropyridine (6 g, 32.89 mmol, 1.00 equiv) in THF (100 mL) at -78 C. under nitrogen. After being stirred for 0.5 h at -78 C. ethyl formate (3.192 g, 43.09 mmol, 1.30 equiv) was added and the resulting solution was stirred for 3 h at -78 C. After completion the reaction was quenched with ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column eluting with ethyl acetate/petroleum ether (1:20) to give the title compound (6 g, 87%) as a white solid.
75%		n-BuLi (35 mL, 2.5 M in hexanes) was added dropwise to a stuffed solution of 2,4,6-trichloropyridine (15 g, 82.22 mmol, 1.00 equiv) in anhydrous THF (200 mL) at -78 C under nitrogen. After 30 minutes ethyl formate (10 mL, 215.31 mmol) was added at -78 C . The resulting solution was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:10) to give the title compound (13 g, 75%) as a white solid. LC-MS(ES, mlz): 210 [M+H]+

54%

n-BuLi (2M, 16.8 mL) was added dropwise to a stined solution of 2,4,6-trichloropyridine (8 g,43.85 mmol, 1.00 equiv) in THF (80 mL) at -78 C under nitrogen. After being stined at -78 C for30 mm ethyl formate (4.88 g, 65.88 mmol, 1.50 equiv) was added to the reaction mixture and theresulting solution was stirred for another 30 mm at -78 C. After completion the solution wasquenched with NH4C1 solution and extracted with ethyl acetate. The organic layers werecombined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:10) to give the title compound (5 g, 54%) as a white solid. ?HNMR (300 MHz, CDC13) oe 10.42 (s, 1H), 7.45 (s, 1H).

Reference： [1]Patent: US2018/111932,2018,A1 .Location in patent: Paragraph 0388; 0389
[2]Patent: US2015/57260,2015,A1 .Location in patent: Paragraph 0765; 0766; 1088; 1089
[3]Patent: WO2015/25026,2015,A1 .Location in patent: Page/Page column 178; 179
[4]Patent: WO2015/25025,2015,A1 .Location in patent: Page/Page column 399

13
[ 1261269-66-2 ]
[ 60-34-4 ]
4,6-dichloro-1-methyl-1H-pyrazolo[4,3-c]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With triethylamine; In ethanol; at -78℃; for 0.5h;	A solution of <strong>[1261269-66-2]2,4,6-trichloropyridine-3-carbaldehyde</strong> (3 g, 14.26 mmol, 1.00 equiv) in triethylamine (5.8 mL)/ethanol (100 mL) was cooled to -78 C. and methylhydrazine (1.55 mL, 26.58 mmol, 1.90 equiv) was added slowly. After 30 minutes the resulting solution was concentrated, diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:10) to give the title compound (1.5 g, 52%) as a yellow solid. LC-MS (ES, m/z): 202 [M+H]+.

Reference： [1]Patent: US2015/57260,2015,A1 .Location in patent: Paragraph 0767; 0768

14
[ 1261269-66-2 ]
4,6-dichloro-3aH-pyrazolo[4,3-c]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With hydrazine hydrate; N-ethyl-N,N-diisopropylamine; In ethanol; at -20 - 30℃; for 32h;Inert atmosphere;	Under nitrogen hydrazine hydrate (3.8 g, 75.91 mmol, 4.00 equiv) was added to a solution of <strong>[1261269-66-2]2,4,6-trichloropyridine-3-carbaldehyde</strong> (4 g, 19.01 mmol, 1.00 equiv) and N-ethyl-N-isopropylpropan-2-amine (7.5 g, 58.03 mmol, 3.10 equiv) in ethanol (100 mL) at -20 C. The resulting solution was stirred for 16 h at -20 C. and 16 hours at 30 C. The resulting solution was concentrated under vacuum and the residue was purified by a silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:2). This resulted in the title compound (1.6 g, 45%) as a white solid. LC-MS (ES, m/z): 188 [M+H]+.
45%	With hydrazine hydrate; N-ethyl-N,N-diisopropylamine; In ethanol; at -20 - 30℃; for 32h;Inert atmosphere;	Under nitrogen hydrazine hydrate (3.8 g, 75.91 mmol, 4.00 equiv) was added to a solution of<strong>[1261269-66-2]2,4,6-trichloropyridine-3-carbaldehyde</strong> (4 g, 19.01 mmol, 1.00 equiv) andN-ethyl-N-isopropylpropan-2-amine (7.5 g, 58.03 mmol, 3.10 equiv) in ethanol (100 mL) at -20C. The resulting solution was stirred for 16 h at -20 C and 16 hours at 30 C. The resultingsolution was concentrated under vacuum and the residue was purified by a silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:2). This resulted in the title compound (1.6 g, 45%) as a white solid. LC-MS (ES, m/z): 188 [M+H].
22%	With hydrazine hydrate; In 1,2-dimethoxyethane; at 45℃; for 12h;	A suspension of <strong>[1261269-66-2]2,4,6-trichloropyridine-3-carbaldehyde</strong> (5 g, 23.76 mmol, 1.00 equiv) and hydrazine hydrate (3.6 g, 57.53 mmol, 3.00 equiv, 80%) in ethylene glycol dimethyl ether (25 mL) was stirred for 12 h at 45C. After completion the solution was quenched with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:10) to give the title compound (1 g, 22%) as a lightyellow solid. LC-MS (ES, m/z): 188 [M+H].

Reference： [1]Patent: US2015/57260,2015,A1 .Location in patent: Paragraph 1090; 1091
[2]Patent: WO2015/25026,2015,A1 .Location in patent: Page/Page column 240; 241
[3]Patent: WO2015/25025,2015,A1 .Location in patent: Page/Page column 401; 400

15
[ 1261269-66-2 ]
4,6-dichloro-1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridine [ No CAS ]

Reference： [1]Patent: US2015/57260,2015,A1
[2]Patent: WO2015/25026,2015,A1

16
[ 1261269-66-2 ]
(3R)-3-[2-(3-[6-chloro-1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl]phenyl)ethynyl]-3-hydroxy-1-methylpyrrolidin-2-one [ No CAS ]

Reference： [1]Patent: US2015/57260,2015,A1

17
[ 1261269-66-2 ]
4-[3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl]-1-methyl-1H-pyrazolo[4,3-c]pyridine-6-carboxamide [ No CAS ]

Reference： [1]Patent: US2015/57260,2015,A1

18
[ 1261269-66-2 ]
4,6-dichloro-3-iodo-1H-pyrazolo[4,3-c]pyridine [ No CAS ]

Reference： [1]Patent: WO2015/25025,2015,A1

19
[ 1261269-66-2 ]
6-chloro-3-iodo-N-methyl-1H-pyrazolo[4,3-c]pyridin-4-amine [ No CAS ]

Reference： [1]Patent: WO2015/25025,2015,A1

20
[ 1261269-66-2 ]
methyl 6-chloro-4-(methylamino)-1H-pyrazolo[4,3-c]pyridine-3-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/25025,2015,A1

21
[ 1261269-66-2 ]
[ 75-16-1 ]
[ 1347759-12-9 ]

Yield	Reaction Conditions	Operation in experiment
58.7%	In tetrahydrofuran; diethyl ether; at -78℃; for 0.5h;Inert atmosphere;	To methylmagnesium bromide (3M in diethyl ether, 3.83 mL) was added dropwise to a stirred solution of <strong>[1261269-66-2]2,4,6-trichloro-pyridine-3-carbaldehyde</strong> (2.20 g) in tetrahydrofuran (anhydrous, 44 mL) at -78 00 under a nitrogen atmosphere. The reaction was stirred at -78 00 for 30 mins and then allowed to warm to room temperature. The reaction was quenched with NH4CI (25 mL) and neutralised to pH 7-8 with 1 M HCI. The aqueous phase was extracted with EtOAc (3 x 50 mL) the combined organic phase dried (Na2504) and concentrated. The crude material was purified by Biotage Isolera (5i02 50 g) eluting in 0-100% EtOAc in Cyclohexane to give 1.39 g (58.7 %) as colourless oil.Analysis: HPLC-MS: R1 = 1.19 mm (method P), M+H = 226/228 1H NMR (ODd3, 500 MHz) 61.64 (3H, d, J=6.9 Hz), 2.67 (1H, d, J=9.2 Hz), 5.51 (1H, d, J=6.9 Hz), 7.33 (1H, s)

Reference： [1]Patent: WO2017/42100,2017,A1 .Location in patent: Page/Page column 49; 50

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[ 1261269-66-2 ]
(R)-4-[(R)-1-(6-chloro-2,3-dimethyl-2H-pyrazolo[4,3-c]pyridin-4-yloxy)ethyl]-1-[⁽⁵⁾-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one [ No CAS ]

Reference： [1]Patent: WO2017/42100,2017,A1

23
[ 1261269-66-2 ]
(R)-5-[(R)-1-(6-chloro-2,3-dimethyl-2H-pyrazolo[4,3-c]pyridin-4-yloxy)ethyl]-3-(4-methoxybenzyl)oxazolidin-2-one [ No CAS ]
C₂₁H₂₃ClN₄O₄ [ No CAS ]

Reference： [1]Patent: WO2017/42100,2017,A1

24
[ 1261269-66-2 ]
(R)-4-[(R)-1-(6-chloro-2,3-dimethyl-2H-pyrazolo[4,3-c]pyridin-4-yloxy)ethyl]pyrrolidin-2-one [ No CAS ]

Reference： [1]Patent: WO2017/42100,2017,A1

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[ 1261269-66-2 ]
(R)-4-{(R)-1-[6-(3-tert-butyl-1H-pyrazol-4-yl)-2,3-dimethyl-2H-pyrazolo[4,3-c]pyridin-4-yloxy]ethyl}pyrrolidin-2-one [ No CAS ]

Reference： [1]Patent: WO2017/42100,2017,A1

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[ 1261269-66-2 ]
C₂₈H₃₄N₆O₄ [ No CAS ]

Reference： [1]Patent: WO2017/42100,2017,A1

27
[ 1261269-66-2 ]
(R)-5-{(R)-1-[6-(1-tert-butyl-1H-pyrazol-4-yl)-2,3-dimethyl-2H-pyrazolo[4,3-c]pyridin-4-yloxy]ethyl}oxazolidin-2-one [ No CAS ]

Reference： [1]Patent: WO2017/42100,2017,A1

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[ 1261269-66-2 ]
4,6-dichloro-2,3-dimethyl-2H-pyrazolo[4,3-c]pyridine [ No CAS ]

Reference： [1]Patent: WO2017/42100,2017,A1

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[ 1261269-66-2 ]
C₃₈H₁₇Cl₈N₄ [ No CAS ]