[ CAS No. 163213-19-2 ] {[proInfo.proName]}

Name: 163213-19-2|tert-Butyl 6-hydrazinylnicotinate|97%
Brand: Ambeed
SKU: A214793
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Product Details of [ 163213-19-2 ]

CAS No. :	163213-19-2	MDL No. :	MFCD16659034
Formula :	C₁₀H₁₅N₃O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LGHKHMSCVFCTRZ-UHFFFAOYSA-N
M.W :	209.25	Pubchem ID :	45089857
Synonyms :

Safety of [ 163213-19-2 ]

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 [ 163213-19-2 ]

* 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 [ 163213-19-2 ]
Downstream synthetic route of [ 163213-19-2 ]

[ 163213-19-2 ] Synthesis Path-Upstream 1~2

1
[ 115309-57-4 ]
[ 163213-19-2 ]

Yield	Reaction Conditions	Operation in experiment
78%	With hydrazine hydrate In ethanol at 100℃; for 2 h;	18.0 g (84.2 mmol) of tert-butyl 6-chloropyridine-3-carboxylate are initially charged in 85 ml of ethanol. 42.2 g (842.0 mmol) of hydrazine hydrate are added, and the mixture is stirred at 100° C. for 2 h. The mixture is then concentrated, and the residue is taken up in a mixture of ethyl acetate and water. The phases are separated, and the organic phase is washed once with water and once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated again. The residue is triturated with petroleum ether, and the solid formed is filtered off and dried under high vacuum. Yield: 16.4 g (78percent of theory) LC-MS (Method 1): R_t=2.30 min; MS (ESIpos): m/z=210 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆): δ=8.49 (d, 1H), 8.30 (s, 1H), 7.82 (dd, 1H), 6.70 (d, 1H), 4.35 (s, 2H), 1.50 (s, 9H).

Reference： [1] Journal of Heterocyclic Chemistry, 2012, vol. 49, # 2, p. 442 - 445
[2] Patent: US2010/93803, 2010, A1, . Location in patent: Page/Page column 21-22

2
[ 5326-23-8 ]
[ 163213-19-2 ]

Reference： [1] Journal of Heterocyclic Chemistry, 2012, vol. 49, # 2, p. 442 - 445

[ 163213-19-2 ] Synthesis Path-Downstream 1~48

1
[ 115309-57-4 ]
[ 163213-19-2 ]

Yield	Reaction Conditions	Operation in experiment
78%	With hydrazine hydrate; In ethanol; at 100℃; for 2h;	18.0 g (84.2 mmol) of <strong>[115309-57-4]tert-butyl 6-chloropyridine-3-carboxylate</strong> are initially charged in 85 ml of ethanol. 42.2 g (842.0 mmol) of hydrazine hydrate are added, and the mixture is stirred at 100 C. for 2 h. The mixture is then concentrated, and the residue is taken up in a mixture of ethyl acetate and water. The phases are separated, and the organic phase is washed once with water and once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated again. The residue is triturated with petroleum ether, and the solid formed is filtered off and dried under high vacuum. Yield: 16.4 g (78% of theory) LC-MS (Method 1): Rt=2.30 min; MS (ESIpos): m/z=210 [M+H]+; 1H-NMR (400 MHz, DMSO-d6): delta=8.49 (d, 1H), 8.30 (s, 1H), 7.82 (dd, 1H), 6.70 (d, 1H), 4.35 (s, 2H), 1.50 (s, 9H).

Reference： [1]Journal of Heterocyclic Chemistry,2012,vol. 49,p. 442 - 445
[2]Patent: US2010/93803,2010,A1 .Location in patent: Page/Page column 21-22

2
[ 913839-75-5 ]
[ 163213-19-2 ]
tert-Butyl 6-(5-oxo-4-pyridin-3-yl-2,5-dihydro-1H-pyrazol-1-yl)pyridine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	In ethanol for 16h; Reflux;	15 tert-Butyl 6-(5-oxo-4-pyridin-3-yl-2,5-dihydro-1H-pyrazol-1-yl)pyridine-3-carboxylate 2.2 g (10.0 mmol) of the compound from Example 2A are initially charged in 50 ml of ethanol. 2.1 g (10.0 mmol) of the compound from Example 15A and 380 mg (2.0 mmol) of p-toluenesulfonic acid are added, and the mixture is stirred under reflux for 16 h. The mixture is then cooled to 0° C., and the solid formed is filtered off and washed once with a little ethanol (batch 1). The mother liquor is concentrated and the residue is triturated with a little ethanol. The solid obtained is filtered off and washed once with ethanol (batch 2). The two solids batches are combined and dried under high vacuum. The solid is then stirred in tert-butyl methyl ether for 30 min, filtered off again and dried under high vacuum. Yield: 2.7 g (79% of theory) LC-MS (Method 5): Rt=0.93 min; MS (ESIpos): m/z=339 [M+H]+; 1H-NMR (400 MHz, DMSO-d6): δ=9.11 (d, 1H), 8.91 (d, 1H), 8.57 (s, 1H), 8.51-8.49 (m, 1H), 8.40 (dd, 1H), 8.37-8.35 (m, 1H), 8.28 (d, 1H), 7.37 (dd, 1H), 1.58 (s, 9H).

Reference： [1]Current Patent Assignee: BAYER AG - US2010/93803, 2010, A1 Location in patent: Page/Page column 27

3
[ 163213-19-2 ]
Ethyl (2Z)-2-(5-bromopyridin-3-yl)-3-(dimethylamino)prop-2-enoate [ No CAS ]
tert-butyl 6-[4-(5-bromopyridin-3-yl)-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-carboxylate hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	Stage #1: tert-butyl 6-hydrazinylpyridine-3-carboxylate; Ethyl (2Z)-2-(5-bromopyridin-3-yl)-3-(dimethylamino)prop-2-enoate In ethanol for 24h; Reflux; Stage #2: With hydrogenchloride In 1,4-dioxane; ethanol at 20℃; for 0.5h;	9 tert-Butyl 6-[4-(5-bromopyridin-3-yl)-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-carboxylate hydrochloride 500 mg (1.7 mmol) of the compound from Example 9A and 350 mg (1.7 mmol) of the compound from Example 15A are dissolved in 2 ml of ethanol, and 58 mg (0.3 mmol) of p-toluenesulfonic acid are added. The mixture is heated under reflux for 24 h and then cooled to RT, and 0.5 ml of a 4 N solution of hydrogen chloride in dioxane is added. The mixture is stirred at RT for 30 min. The precipitate is filtered off, washed with ethanol and diethyl ether and dried under high vacuum. Yield: 425 mg (56% of theory) LC-MS (Method 5): Rt=1.47 min; MS (ESIpos): m/z=417 [M+H]+; 1H-NMR (400 MHz, DMSO-d6): δ=9.15 (s, 1H), 8.91 (s, 1H), 8.74 (d, 1H), 8.64 (d, 1H), 8.52-8.49 (m, 2H), 8.43 (d, 1H), 1.58 (s, 9H).

Reference： [1]Current Patent Assignee: BAYER AG - US2010/93803, 2010, A1 Location in patent: Page/Page column 26

Yield	Reaction Conditions	Operation in experiment
93%

5
[ 202003-10-9 ]
[ 163213-19-2 ]
6-[4-(4-cyano-1H-1,2,3-triazol-1-yl)-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-carboxylic acid tert-butyl ester hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8%	Stage #1: (4-Cyano-1H-1,2,3-triazol-1-yl)acetic acid ethyl ester; tert-butyl 6-hydrazinylpyridine-3-carboxylate In ethanol for 16h; Reflux; Stage #2: With hydrogenchloride In 1,4-dioxane at 20℃; for 0.5h;	99 6-[4-(4-Cyano-1H-1,2,3-triazol-1-yl)-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]pyridine 3-tert-butyl ester hydrochloride 150 mg (0.6 mmol) of the compound from Example 41A are initially introduced into 2.5 ml ethanol. 178 mg (0.6 mmol) of the compound from Example 22A and 24 mg (0.1 mmol) p-toluenesulfonic acid monohydrate are added and the mixture is stirred under reflux for 16 h. The reaction solution is purified directly by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions are combined, the mixture is concentrated and the residue is dried under a high vacuum. 5 ml of a 4 N solution of hydrogen chloride in dioxane are added to the residue obtained and the mixture is stirred at RT for 30 min. The solid is filtered off, washed with tert-butyl methyl ether and dried under a high vacuum.Yield: 21 mg (8% of th.)LC-MS (Method 7): Rt=1.96 min; MS (ESIpos): m/z=354 [M+H]+;1H-NMR (400 MHz, DMSO-d6): δ=9.39 (s, 1H), 8.94 (s, 1H), 8.63 (s, 1H), 8.46 (s, 2H), 1.58 (s, 9H).

Reference： [1]Current Patent Assignee: BAYER AG - US2010/305085, 2010, A1 Location in patent: Page/Page column 51

6
[ 163213-19-2 ]
[ 1192674-65-9 ]
6-[5-oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-carboxylic acid tert-butyl ester hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%	Stage #1: tert-butyl 6-hydrazinylpyridine-3-carboxylate; ethyl (2E/Z)-3-(dimethylamino)-2-(1H-1,2,3-triazol-1-yl)acrylate In ethanol for 16h; Reflux; Stage #2: With hydrogenchloride In 1,4-dioxane at 20℃; for 1h;	62 6-[5-oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-carboxylic acid tert-butyl ester hydrochloride 3.2 g (15.0 mmol) of the compound from Example 3A are initially introduced into 100 ml ethanol. 3.1 g (15.0 mmol) of the compound from Example 22A and 571 mg (3.0 mmol) p-toluenesulfonic acid monohydrate are added and the mixture is stirred under reflux for 16 h. The mixture is then concentrated and the residue is purified by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions are combined, the majority of the solvent is removed and the solid formed is filtered off. This is dried under a high vacuum and a 4 N solution of hydrogen chloride in dioxane is then added. The mixture is stirred at RT for 1 h and the solid is filtered off and dried under a high vacuum.Yield: 1.6 g (28% of th.)LC-MS (Method 1): Rt=3.32 min; MS (ESIpos): m/z=329 [M+H]+;1H-NMR (400 MHz, DMSO-d6): δ=8.94 (s, 1H), 8.53 (s, 1H), 8.50-8.40 (m, 3H), 7.91 (s, 1H), 1.58 (s, 9H).

Reference： [1]Current Patent Assignee: BAYER AG - US2010/305085, 2010, A1 Location in patent: Page/Page column 41

7
[ 163213-19-2 ]
[ 1154030-62-2 ]
6-[4-(1H-Imidazol-1-yl)-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-carboxylic acid tert-butyl ester hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23%	Stage #1: tert-butyl 6-hydrazinylpyridine-3-carboxylate; ethyl 3-(dimethylamino)-2-(1H-imidazol-1-yl)acrylate In ethanol at 20℃; for 16h; Stage #2: With hydrogenchloride In 1,4-dioxane at 20℃; for 1h;	63 6-[4-(1H-Imidazol-1-yl)-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-carboxylic acid tert-butyl ester hydrochloride 3.1 g (15.0 mmol) of the compound from Example 42A are initially introduced into 100 ml ethanol. 3.1 g (15.0 mmol) of the compound from Example 22A and 571 mg (3.0 mmol) p-toluenesulfonic acid monohydrate are added and the mixture is first stirred at RT for 16 h. It is subsequently stirred under reflux for a further 24 h and the solvent is then removed. The residue is purified by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product fractions are combined and the majority of the acetonitrile contained therein is removed. The solution which remains is lyophilized. A 4 N solution of hydrogen chloride in dioxane is added to the lyophilisate and the mixture is stirred at RT for 1 h. The solid is filtered off and dried under a high vacuum.Yield: 1.3 g (23% of th.)LC-MS (Method 7): Rt=0.99 min; MS (ESIpos): m/z=328 [M+H]+;1H-NMR (400 MHz, DMSO-d6): δ=9.55 (s, 1H), 8.94 (s, 1H), 8.70 (s, 1H), 8.53-8.42 (m, 2H), 8.10 (s, 1H), 7.88 (s, 1H), 1.58 (s, 9H).

Reference： [1]Current Patent Assignee: BAYER AG - US2010/305085, 2010, A1 Location in patent: Page/Page column 41-42

8
[ 163213-19-2 ]
[ 1154030-65-5 ]
6-{5-oxo-4-[4-(trifluoromethyl)-1H-imidazol-1-yl]-2,5-dihydro-1H-pyrazol-1-yl}pyridine-3-carboxylic acid tert-butyl ester hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12%	Stage #1: tert-butyl 6-hydrazinylpyridine-3-carboxylate; ethyl 3-(dimethylamino)-2-[4-(trifluoromethyl)-1H-imidazol-1-yl]acrylate In ethanol at 20℃; for 16h; Stage #2: With hydrogenchloride In 1,4-dioxane at 20℃; for 1h;	64 4.2 g (15.0 mmol) of the compound from Example 44A are initially introduced into 100 ml ethanol. 3.1 g (15.0 mmol) of the compound from Example 22A and 571 mg (3.0 mmol) p-toluenesulfonic acid monohydrate are added and the mixture is stirred at RT for 16 h. The solvent is then removed and the residue is purified by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product fractions are combined and the majority of the acetonitrile contained therein and some of the water are removed. The solid formed is filtered off and is dried in air. 20 ml of a 4 N solution of hydrogen chloride in dioxane are then added and the mixture is stirred at RT for 1 h. The solid is filtered off and purified again via preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product fractions are combined, 1 N hydrochloric acid is added and the mixture is lyophilizedYield: 750 mg (12% of th.)LC-MS (Method 7): Rt=2.10 min; MS (ESIpos): m/z=396 [M+H]+;1H-NMR (400 MHz, DMSO-d6): δ=8.93 (s, 1H), 8.59-8.38 (m, 3H), 8.19 (s, 1H), 8.14 (s, 1H), 1.59 (s, 9H).

Reference： [1]Current Patent Assignee: BAYER AG - US2010/305085, 2010, A1 Location in patent: Page/Page column 42

9
[ 163213-19-2 ]
[ 1154030-66-6 ]
6-[4-(4-Cyano-1H-imidazol-1-yl)-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-carboxylic acid tert-butyl ester hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: tert-butyl 6-hydrazinylpyridine-3-carboxylate; 3-(dimethylamino)-2-[4-cyano-1H-imidazol-1-yl]acrylic acid ethyl ester In tetrahydrofuran at 150℃; for 3h; Microwave irradiation; Stage #2: With hydrogenchloride In 1,4-dioxane at 20℃; for 1h;	78 6-[4-(4-Cyano-1H-imidazol-1-yl)-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-carboxylic acid tert-butyl ester hydrochloride 500 mg (purity 72%, 1.5 mmol) of the compound from Example 45A are initially introduced into 11 ml THF. 322 mg (1.5 mmol) of the compound from Example 22A and 58 mg (0.3 mmol) p-toluenesulfonic acid monohydrate are added and the mixture is reacted in a single mode microwave (CEM Explorer) at 150° C. for 3 h. Thereafter, the mixture is purified directly by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product fractions are combined and concentrated, a 1 N solution of hydrogen chloride in dioxane is added and the mixture is stirred at RT for 1 h. The precipitate is filtered off, washed twice with 0.5 ml dioxane each time and dried under a high vacuum.Yield: 144 mg (24% of th.)LC-MS (Method 8): Rt=2.10 min; MS (ESIpos): m/z=353 [M+H]+;1H-NMR (400 MHz, DMSO-d6): δ=8.94 (s, 1H), 8.54-8.42 (m, 4H), 8.20 (s, 1H), 1.58 (s, 9H).

Reference： [1]Current Patent Assignee: BAYER AG - US2010/305085, 2010, A1 Location in patent: Page/Page column 46

10
[ 5326-23-8 ]
[ 163213-19-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: dmap / tetrahydrofuran / 4.5 h / Reflux 2: hydrazine hydrate / <i>tert</i>-butyl alcohol / Reflux
	Multi-step reaction with 2 steps 1: dmap / tetrahydrofuran / 4 h / Reflux 2: hydrazine hydrate / ethanol; water / 2 h / 100 °C
	Multi-step reaction with 2 steps 1: dmap / tetrahydrofuran / 4 h / Reflux 2: hydrazine hydrate / ethanol; water / 2 h / 100 °C

Multi-step reaction with 2 steps 1: dmap / tetrahydrofuran / 4 h / Reflux 2: hydrazine hydrate / ethanol; water / 2 h / 100 °C

Reference： [1]Wright, Stephen W. [Journal of Heterocyclic Chemistry, 2012, vol. 49, # 2, p. 442 - 445]
[2]Current Patent Assignee: AKEBIA THERAPEUTICS, INC. - WO2021/188944, 2021, A1
[3]Current Patent Assignee: AKEBIA THERAPEUTICS, INC. - WO2021/188938, 2021, A1
[4]Current Patent Assignee: AKEBIA THERAPEUTICS, INC. - WO2021/188936, 2021, A1

11
[ 163213-19-2 ]
6-Aminonicotinic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With Raney nickel 2400 In isopropyl alcohol Reflux;

Reference： [1]Location in patent: experimental part Wright, Stephen W. [Journal of Heterocyclic Chemistry, 2012, vol. 49, # 2, p. 442 - 445]

12
[ 163213-19-2 ]
N²-[6-chloro-5-(trifluoromethyl)-1,3-benzoxazol-2-yl]-L-alaninamide [ No CAS ]
[ 4637-24-5 ]
tert-butyl 6-{5-[(1S)-1-[6-chloro-5-(trifluoromethyl)-1,3-benzoxazol-2-yl]amino}ethyl]-1H-1,2,4- triazol-1-yl}pyridine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	Stage #1: N²-[6-chloro-5-(trifluoromethyl)-1,3-benzoxazol-2-yl]-L-alaninamide; <i>N</i>,<i>N</i>-dimethyl-formamide dimethyl acetal In dichloromethane for 0.5h; Reflux; Stage #2: tert-butyl 6-hydrazinylpyridine-3-carboxylate In dichloromethane at 60℃; for 1h;	I-120 Example I-120 tert-Butyl 6-{5-[(1S)-1-[6-chloro-5-(trifluoromethyl)-1,3-benzoxazol-2-yl]amino}ethyl]-1H-1,2,4- triazol-1-yl}pyridine-3-carboxylate N2-[6-Chloro-5-(trifluoromethyl)-1,3-benzoxazol-2-yl]-L-alaninamide (intermediate 3A, 500 mg, 1.63 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (540 µl, 4.1 mmol) were dissolved in dichloromethane (10.0 mL)and heated to reflux for 30 min. The sovent was distilled, the residue was taken up into a mixture of 1,4-dioxane (10.0 mL) and acetic acid (2.0 ml, 34 mmol) and tert-butyl 6- hydrazinylpyridine-3-carboxylate (CAS RN 163213-19-2, 680 mg, 3.25 mmol) was added. This mixture was heated to 60 °C for 1 h, then cooled, poured into saturated aqueous sodium carbonate solution and basified with 1M sodium hydroxide and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, evaporated and eventually purified by preparative HPLC (RP C-18 phase with a gradient of water, acetonitrile with 0,1% ammonia) to give 760 mg (100 % purity, 92 % yield) of the title compound

Reference： [1]Current Patent Assignee: BAYER AG - WO2020/212235, 2020, A1 Location in patent: Page/Page column 141-142

13
[ 163213-19-2 ]
6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: toluene-4-sulfonic acid / ethanol / 12 h / 80 °C 2: trifluoroacetic acid / dichloromethane / 2 h / 40 °C

Reference： [1]Current Patent Assignee: AKEBIA THERAPEUTICS, INC. - WO2021/188944, 2021, A1

14
[ 163213-19-2 ]
6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinoyl chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: toluene-4-sulfonic acid / ethanol / 12 h / 80 °C 2: trifluoroacetic acid / dichloromethane / 2 h / 40 °C 3: thionyl chloride / dichloromethane / 3 h / 40 °C

Reference： [1]Current Patent Assignee: AKEBIA THERAPEUTICS, INC. - WO2021/188944, 2021, A1

15
[ 163213-19-2 ]
6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)-N-(methylsulfonyl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: toluene-4-sulfonic acid / ethanol / 12 h / 80 °C 2: trifluoroacetic acid / dichloromethane / 2 h / 40 °C 3: thionyl chloride / dichloromethane / 3 h / 40 °C 4: triethylamine / dichloromethane / 0 - 20 °C

Reference： [1]Current Patent Assignee: AKEBIA THERAPEUTICS, INC. - WO2021/188944, 2021, A1

16
[ 163213-19-2 ]
tert-butyl 6-(4-(4-cyanophenyl)-5-methoxy-1H-pyrazol-1-yl)nicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: toluene-4-sulfonic acid / ethanol / 12 h / 80 °C 2: diazomethyl-trimethyl-silane / dichloromethane; hexane / 25 °C

Reference： [1]Current Patent Assignee: AKEBIA THERAPEUTICS, INC. - WO2021/188944, 2021, A1

17
[ 163213-19-2 ]
6-(4-(4-cyanophenyl)-5-methoxy-1H-pyrazol-1-yl)nicotinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: toluene-4-sulfonic acid / ethanol / 12 h / 80 °C 2: diazomethyl-trimethyl-silane / dichloromethane; hexane / 25 °C 3: trifluoroacetic acid / dichloromethane / 2 h / 40 °C

Reference： [1]Current Patent Assignee: AKEBIA THERAPEUTICS, INC. - WO2021/188944, 2021, A1

18
[ 163213-19-2 ]
4-(1-(5-isocyanatopyridin-2-yl)-5-methoxy-1H-pyrazol-4-yl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: toluene-4-sulfonic acid / ethanol / 12 h / 80 °C 2: diazomethyl-trimethyl-silane / dichloromethane; hexane / 25 °C 3: trifluoroacetic acid / dichloromethane / 2 h / 40 °C 4: triethylamine; diphenyl phosphoryl azide / toluene / 3 h / 110 °C

Reference： [1]Current Patent Assignee: AKEBIA THERAPEUTICS, INC. - WO2021/188944, 2021, A1

19
[ 163213-19-2 ]
N-(6-(4-(4-cyanophenyl)-5-methoxy-1H-pyrazol-1-yl)pyridin-3-yl)morpholine-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: toluene-4-sulfonic acid / ethanol / 12 h / 80 °C 2: diazomethyl-trimethyl-silane / dichloromethane; hexane / 25 °C 3: trifluoroacetic acid / dichloromethane / 2 h / 40 °C 4: triethylamine; diphenyl phosphoryl azide / toluene / 3 h / 110 °C 5: dichloromethane / 20 °C

Reference： [1]Current Patent Assignee: AKEBIA THERAPEUTICS, INC. - WO2021/188944, 2021, A1

20
[ 163213-19-2 ]
6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)-N-methoxy-N-methylnicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: toluene-4-sulfonic acid / ethanol / 12 h / 80 °C 2: trifluoroacetic acid / dichloromethane / 2 h / 40 °C 3: thionyl chloride / dichloromethane / 3 h / 40 °C 4: N-ethyl-N,N-diisopropylamine / dichloromethane / 3 h / 0 °C

Reference： [1]Current Patent Assignee: AKEBIA THERAPEUTICS, INC. - WO2021/188944, 2021, A1

21
[ 163213-19-2 ]
4-(1-(5-acetylpyridin-2-yl)-5-hydroxy-1H-pyrazol-4-yl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: toluene-4-sulfonic acid / ethanol / 12 h / 80 °C 2: trifluoroacetic acid / dichloromethane / 2 h / 40 °C 3: thionyl chloride / dichloromethane / 3 h / 40 °C 4: N-ethyl-N,N-diisopropylamine / dichloromethane / 3 h / 0 °C 5: tetrahydrofuran; diethyl ether / 1 h / -20 - 0 °C

Reference： [1]Current Patent Assignee: AKEBIA THERAPEUTICS, INC. - WO2021/188944, 2021, A1

22
[ 163213-19-2 ]
4-(5-hydroxy-1-(5-propionylpyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: toluene-4-sulfonic acid / ethanol / 12 h / 80 °C 2: trifluoroacetic acid / dichloromethane / 2 h / 40 °C 3: thionyl chloride / dichloromethane / 3 h / 40 °C 4: N-ethyl-N,N-diisopropylamine / dichloromethane / 3 h / 0 °C 5: tetrahydrofuran; diethyl ether / 1 h / -20 - 0 °C

Reference： [1]Current Patent Assignee: AKEBIA THERAPEUTICS, INC. - WO2021/188944, 2021, A1

23
[ 163213-19-2 ]
4-(5-hydroxy-1-(5-isobutyrylpyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: toluene-4-sulfonic acid / ethanol / 12 h / 80 °C 2: trifluoroacetic acid / dichloromethane / 2 h / 40 °C 3: thionyl chloride / dichloromethane / 3 h / 40 °C 4: N-ethyl-N,N-diisopropylamine / dichloromethane / 3 h / 0 °C 5: tetrahydrofuran / 1 h / -20 - 0 °C

Reference： [1]Current Patent Assignee: AKEBIA THERAPEUTICS, INC. - WO2021/188944, 2021, A1

24
[ 163213-19-2 ]
ethyl (E)-2-(4-cyanophenyl)-3-(dimethylamino)acrylate [ No CAS ]
tert-butyl 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76.92%	With toluene-4-sulfonic acid In ethanol at 80℃; for 12h;	1 tert-butyl 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinate To a solution of ethyl (E)-2-(4-cyanophenyl)-3-(dimethylamino)acrylate (2.5 g, 10.86 mmol) and tert-butyl 6-hydrazineylnicotinate (2.27 g, 10.86 mmol) in ethanol (25.0 mL) was added p-toluenesulfonic acid monohydrate (410 mg, 2.17 mmol). The mixture was stirred at 80 oC for 12hr and concentrated to dryness. The residue was purified by flash chromatography (methanol/dichloromethane = 1/8) to afford tert- butyl 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinate (3.0 g, 8.35 mmol, 76.92% yield) as yellow solid. LCMS: m/z = 363.1 (M+H)+, retention time 1.98 min (Method A).

Reference： [1]Current Patent Assignee: AKEBIA THERAPEUTICS, INC. - WO2021/188944, 2021, A1 Location in patent: Paragraph 0338; 0342-0343

25
[ 163213-19-2 ]
methyl 2-(4-cyanophenyl)-3-oxobutanoate [ No CAS ]
tert-butyl 6-(4-(4-cyanophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)nicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58.7%	With acetic acid at 120℃; for 1h;	10 e/V-butyl 6-(4-(4-cyanophenyl)-5-hydro\y-3-methyl- l//-pyrazol- 1 -yl)nicotinate A solution of methyl 2-(4-cyanophenyl)-3-oxobutanoate (600 mg, 2.76 mmol) and /e/V-butyl 6-hydrazineylnicotinate (577 mg, 2.76 mmol) in acetic acid (5.0 mL) was stirred at 120 °C for 1.0 h and concentrated to give dryness. The residue was purified by flash chromatography (methanol/dichloromethane = 1/10) to afford tert- butyl 6-(4- (4-cyanophenyl)-5-hydroy-3-methyl- 1 //-pyrazol- 1 -yl)nicotinate (610 mg, 1.62 mmol, 58.7% yield) as yellow solid. LC-MS: m/z= 377.1 (M+H)+, retention time 2.24 min (Method A).

Reference： [1]Current Patent Assignee: AKEBIA THERAPEUTICS, INC. - WO2021/188938, 2021, A1 Location in patent: Paragraph 0407; 0411-0412

26
[ 163213-19-2 ]
6-(4-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-1-yl)nicotinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: acetic acid / 1 h / 120 °C 2: trifluoroacetic acid / dichloromethane / 2 h / 40 °C