[ CAS No. 3112-31-0 ] {[proInfo.proName]}

Name: 3112-31-0|1H-Pyrazole-3,5-dicarboxylic acid|97%
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Quality Control of [ 3112-31-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 3112-31-0 ]

Product Details of [ 3112-31-0 ]

CAS No. :	3112-31-0	MDL No. :	MFCD00005235
Formula :	C₅H₄N₂O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YDMVPJZBYSWOOP-UHFFFAOYSA-N
M.W :	156.10	Pubchem ID :	76559
Synonyms :

Calculated chemistry of [ 3112-31-0 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.0
Num. rotatable bonds :	2
Num. H-bond acceptors :	5.0
Num. H-bond donors :	3.0
Molar Refractivity :	32.51
TPSA :	103.28 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.3 cm/s

Lipophilicity

Log Po/w (iLOGP) :	-0.38
Log Po/w (XLOGP3) :	-0.07
Log Po/w (WLOGP) :	-0.19
Log Po/w (MLOGP) :	-1.05
Log Po/w (SILICOS-IT) :	-0.21
Consensus Log Po/w :	-0.38

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-0.97
Solubility :	16.8 mg/ml ; 0.108 mol/l
Class :	Very soluble
Log S (Ali) :	-1.65
Solubility :	3.52 mg/ml ; 0.0225 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	0.03
Solubility :	168.0 mg/ml ; 1.07 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.61

Safety of [ 3112-31-0 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P271-P280-P261-P264-P302+P352-P304+P340-P305+P351+P338-P312-P362+P364-P403+P233-P501	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 3112-31-0 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 3112-31-0 ]
Downstream synthetic route of [ 3112-31-0 ]

[ 3112-31-0 ] Synthesis Path-Upstream 1~12

1
[ 67-51-6 ]
[ 3112-31-0 ]
[ 402-61-9 ]

Yield	Reaction Conditions	Operation in experiment
33%	With potassium permanganate In water at 70 - 90℃;	3,5-Dimethyl-1H-pyrazole, 78.5 g (0.818 mol), was dissolved in 700 mL of water heated to 70°C, and 517 g (3.271 mol) of potassium permanganate was added to the hot solution, maintaining the temperature no higher than 90°C. The mixture was cooled to room temperature, the precipitate of MnO2 was filtered off and washed with water, and the filtrate was acidified with aqueous HCl to pH 2 and left overnight. The precipitate was filtered off and washed with water. Yield 41.75 g (33percent), white crystals, mp 257–258°C. 1H NMR spectrum: δ 7.07 ppm, s (1H, 4-H). 5-Methyl-1H-pyrazole-3-carboxylic acid (2). The aqueous filtrate obtained after separation of diacid 1, was neutralized to pH 5–6, and the precipitate of 2 was filtered off and washed with water. Yield 18.1 g (18percent), white crystals, mp 210–211°C. 1H NMR spectrum, δ, ppm: 2.25 s (3H, CH3), 6.42 s (1H, 4-H).

Reference： [1] Russian Journal of Organic Chemistry, 2016, vol. 52, # 9, p. 1322 - 1325[2] Zh. Org. Khim., 2016, vol. 52, # 9, p. 1334 - 1337,4

2
[ 3112-31-0 ]
[ 15878-00-9 ]

Reference： [1] Chemische Berichte, 1895, vol. 28, p. 688[2] Journal fuer Praktische Chemie (Leipzig), 1896, vol. <2> 53, p. 127

3
[ 3112-31-0 ]
[ 2075-45-8 ]

Reference： [1] Chemische Berichte, 1895, vol. 28, p. 688[2] Journal fuer Praktische Chemie (Leipzig), 1896, vol. <2> 53, p. 127

4
[ 3112-31-0 ]
[ 2075-46-9 ]

Reference： [1] Justus Liebigs Annalen der Chemie, 1894, vol. 279, p. 228 Anm.50
[2] Justus Liebigs Annalen der Chemie, 1894, vol. 279, p. 228 Anm.50

5
[ 67-56-1 ]
[ 3112-31-0 ]
[ 4077-76-3 ]

Yield	Reaction Conditions	Operation in experiment
63%	at 20℃; Reflux	A mixture of 31.7 g (0.203 mol) of diacid 1 and 125 mL of methanol was saturated with gaseous HCl. The mixture was refluxed for 3 h and left overnight at room temperature. The precipitate was filtered off and washed with methanol. Yield 23.5 g (63percent), white crystals, mp 142–143°C. IR spectrum, ν, cm–1: 3105 br (NH), 1710 s (C=O), 1240 s (C–O–C). 1H NMR spectrum, δ, ppm: 3.82 s (6H, CH3), 6.36 s (1H, 4-H), 14.43 s (1H, NH).

Reference： [1] Journal of Medicinal Chemistry, 1997, vol. 40, # 12, p. 1779 - 1788
[2] Journal of Organic Chemistry, 1999, vol. 64, # 21, p. 7751 - 7755
[3] Asian Journal of Chemistry, 2015, vol. 27, # 7, p. 2545 - 2547
[4] Russian Journal of Organic Chemistry, 2016, vol. 52, # 9, p. 1322 - 1325[5] Zh. Org. Khim., 2016, vol. 52, # 9, p. 1334 - 1337,4
[6] Chemische Berichte, 1894, vol. 27, p. 1097[7] Journal fuer Praktische Chemie (Leipzig), 1895, vol. <2> 52, p. 47
[8] Journal fuer Praktische Chemie (Leipzig), 1895, vol. <2>52, p. 47
[9] Journal of Structural Chemistry, 2003, vol. 44, # 2, p. 314 - 317
[10] Patent: EP1433788, 2004, A1, . Location in patent: Page 46
[11] Patent: EP2327704, 2011, A1, . Location in patent: Page/Page column 44
[12] Patent: EP2426135, 2012, A1, . Location in patent: Page/Page column 100
[13] Patent: US9096593, 2015, B2, . Location in patent: Page/Page column 171; 173

6
[ 3112-31-0 ]
[ 4077-76-3 ]

Reference： [1] Patent: US5821241, 1998, A,

7
[ 3112-31-0 ]
[ 77-78-1 ]
[ 33146-99-5 ]

Reference： [1] Journal of Medicinal Chemistry, 1985, vol. 28, # 11, p. 1568 - 1574

8
[ 3112-31-0 ]
[ 33146-99-5 ]

Reference： [1] Journal of Organic Chemistry, 1989, vol. 54, # 2, p. 428 - 431

9
[ 186581-53-3 ]
[ 3112-31-0 ]
[ 33146-99-5 ]

Reference： [1] Helvetica Chimica Acta, 1958, vol. 41, p. 1898,1902

10
[ 3112-31-0 ]
[ 64-17-5 ]
[ 37687-24-4 ]

Reference： [1] Chemical Communications, 2015, vol. 51, # 10, p. 1862 - 1865
[2] Journal of Organic Chemistry, 1999, vol. 64, # 17, p. 6135 - 6146

11
[ 3112-31-0 ]
[ 37687-24-4 ]

Reference： [1] Organic and Biomolecular Chemistry, 2009, vol. 7, # 16, p. 3212 - 3214

12
[ 3112-31-0 ]
[ 541-41-3 ]
[ 37687-24-4 ]

Reference： [1] Nucleosides and Nucleotides, 1995, vol. 14, # 3-5, p. 1053 - 1056

[ 3112-31-0 ] Synthesis Path-Downstream 1~88

1
[ 186581-53-3 ]
[ 3112-31-0 ]
[ 33146-99-5 ]

Reference： [1]Helvetica Chimica Acta,1958,vol. 41,p. 1898,1902

2
[ 67-51-6 ]
[ 3112-31-0 ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium permanganate In water monomer at 95℃; for 4h;
84%	With potassium permanganate In water monomer at 90℃; for 12h;
64%	With potassium permanganate; water monomer at 70 - 90℃; for 4h; Reflux;

49%	With potassium permanganate In water monomer at 70 - 95℃; for 2h;
47%	With potassium permanganate In water monomer Heating;
	With potassium permanganate
	With potassium permanganate In water monomer Heating;
	With potassium permanganate In water monomer at 100℃; for 4h;

Reference： [1]Fu, Pengfei; Li, Zeqing; Wang, Yuqiang; Yu, Pei [Asian Journal of Chemistry, 2015, vol. 27, # 7, p. 2545 - 2547]
[2]Dai, Changhao; Chen, Jieyi; Tang, Jie; Cheng, Guangbin; Yang, Hongwei [New Journal of Chemistry, 2021, vol. 45, # 38, p. 17960 - 17965]
[3]Uygun, Meltem Tan; Amudi, Karina; Turaçlı, İrem Doğan; Menges, Nurettin [Molecular Diversity, 2022, vol. 26, # 1, p. 113 - 124]
[4]Laine, Tanja M.; Kärkäs, Markus D.; Liao, Rong-Zhen; A˚kermark, Torbjörn; Lee, Bao-Lin; Karlsson, Erik A.; Siegbahn, Per E. M.; A˚kermark, Björn [Chemical Communications, 2015, vol. 51, # 10, p. 1862 - 1865]
[5]Lee, Ho H.; Cain, Bruce F.; Denny, William A.; Buckleton, John S.; Clark, George R. [Journal of Organic Chemistry, 1989, vol. 54, # 2, p. 428 - 431]
[6]v. Rothenburg [Chemische Berichte, 1894, vol. 27, p. 1097][Journal fuer Praktische Chemie (Leipzig), 1895, vol. <2> 52, p. 47] Knorr [Justus Liebigs Annalen der Chemie, 1894, vol. 279, p. 228 Anm.50] v.Rothenburg [Journal fur praktische Chemie (Leipzig 1954), 1895, vol. <2>52, p. 47] Marchetti [Gazzetta Chimica Italiana, 1893, vol. 23 I, p. 567] Marchesini [Gazzetta Chimica Italiana, 1892, vol. 22 I, p. 353][Chemisches Zentralblatt, 1892, vol. 63, # II, p. 44]
[7]Aran, Vicente J.; Kumar, Manoj; Molina, Jose; Lamarque, Laurent; Navarro, Pilar; Garcia-Espana, Enrique; Ramirez, Jose A.; Luis, Santiago V.; Escuder, Beatriz [Journal of Organic Chemistry, 1999, vol. 64, # 17, p. 6135 - 6146]
[8]Belousov, Yury A.; Drozdov, Andrey A.; Gontcharenko, Victoria E.; Kiskin, Mikhail A.; Lunev, Alexey M.; Sidoruk, Anastasia V.; Taydakov, Ilya V. [Inorganica Chimica Acta, 2022, vol. 537]

3
[ 67-56-1 ]
[ 3112-31-0 ]
[ 4077-76-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	With thionyl chloride; at 0 - 80℃; for 4h;Inert atmosphere;	In methanol (50 mL), 3,5-pyrazoldicarboxylic acid hydrate (5 g, 28.71 mmol) was dissolved, then thionyl chloride (6.28 mL, 86.15 mmol) was added thereto at 0C under a nitrogen atmosphere, and then the mixture was heated to 80C. The reaction solution was stirred for 4 hours and then concentrated to obtain Compound 119 (7.1 g, 99%). 1H-NMR (400 MHz, CDCl3) delta 7.34 (s, 1H), 3.96 (s, 6H) .
63%	With hydrogenchloride; at 20℃;Reflux;	A mixture of 31.7 g (0.203 mol) of diacid 1 and 125 mL of methanol was saturated with gaseous HCl. The mixture was refluxed for 3 h and left overnight at room temperature. The precipitate was filtered off and washed with methanol. Yield 23.5 g (63%), white crystals, mp 142-143C. IR spectrum, nu, cm-1: 3105 br (NH), 1710 s (C=O), 1240 s (C-O-C). 1H NMR spectrum, delta, ppm: 3.82 s (6H, CH3), 6.36 s (1H, 4-H), 14.43 s (1H, NH).
	With hydrogenchloride; at 20 - 25℃; for 48h;	Example 20: 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-pyrazole-3-carboxylic acid methyl ester(i) 1H-Pyrazole-3,5-dicarboxylic acid dimethyl ester To 12 g of 1H-Pyrazole-3,5-dicarboxylic acid 100 ml HCl in methanol (8M) were added at RT and stirred for 48h. Then the solvents were removed under reduced pressure and the residue codestilled with toluene (2X50 ml). Yield: 14g.

	With thionyl chloride; at 0℃; for 4h;Inert atmosphere; Reflux;	Step 1 To a solution of Compound 1 (60 g, 345 mmol) in methanol (600 mL), under nitrogen atmosphere, thionyl chloride (75 mL, 1034 mmol) was added at 0C, followed by heating at reflux for 4 hours. The reaction solution was concentrated in vacuo to yield crude product 2 (64.3 g). LC/MS (Method A): 0.93 min, [M+H]+ = 185.
	With thionyl chloride; at 0℃; for 4h;Reflux; Inert atmosphere;	Step 1; To a solution of Compound 14 (60 g, 345 mmol) in methanol (600 mL), under flow of nitrogen, thionyl chloride (75 mL, 1034 mmol) was added at 0C. The solution was then heated at reflux for 4 hours. The reaction mixture was concentrated in vacuo to yield crude product 15 (64.3 g). LC/MS (Method A): 0.93 min, [M+H]+ = 185.
	With hydrogenchloride; In water;	In a round bottom flask, 1H-pyrazole-3,5-dicarboxylic acid, hydrate (101, 21.1 g, 121 mmol) was combined with 350 mL of methanol and 10 mL of hydrochloric acid was added. The reaction was stirred at reflux overnight and the following day at room temperature. The reaction was concentrated under vacuum and the solid washed with ethyl acetate and hexanes to provide the desired compound. MS (ESI) [M+H+]+=185.

Reference： [1]Patent: EP3604311,2020,A1 .Location in patent: Paragraph 0267; 0268
[2]Journal of Medicinal Chemistry,1997,vol. 40,p. 1779 - 1788
[3]Journal of Organic Chemistry,1999,vol. 64,p. 7751 - 7755
[4]Asian Journal of Chemistry,2015,vol. 27,p. 2545 - 2547
[5]Journal of Medicinal Chemistry,2018,vol. 61,p. 10875 - 10894
[6]Russian Journal of Organic Chemistry,2016,vol. 52,p. 1322 - 1325
Zh. Org. Khim.,2016,vol. 52,p. 1334 - 1337,4
[7]Chemische Berichte,1894,vol. 27,p. 1097
Journal fuer Praktische Chemie (Leipzig),1895,vol. <2> 52,p. 47
[8]Journal of Structural Chemistry,2003,vol. 44,p. 314 - 317
[9]Patent: EP1433788,2004,A1 .Location in patent: Page 46
[10]Patent: EP2327704,2011,A1 .Location in patent: Page/Page column 44
[11]Patent: EP2426135,2012,A1 .Location in patent: Page/Page column 100
[12]Patent: US9096593,2015,B2 .Location in patent: Page/Page column 171; 173

4
[ 3112-31-0 ]
[ 15878-00-9 ]

Reference： [1]Chemische Berichte,1895,vol. 28,p. 688
Journal fuer Praktische Chemie (Leipzig),1896,vol. <2> 53,p. 127

5
[ 3112-31-0 ]
[ 77-78-1 ]
[ 33146-99-5 ]

Reference： [1]Journal of Medicinal Chemistry,1985,vol. 28,p. 1568 - 1574

6
[ 3112-31-0 ]
[ 74621-40-2 ]

Yield	Reaction Conditions	Operation in experiment
98%	With thionyl chloride at 140℃; for 2h;
98%	With thionyl chloride at 140℃; for 2h;
93%	With thionyl chloride at 140℃; for 2h;

92%	With thionyl chloride at 140℃; for 2h;
92%	With thionyl chloride at 140℃; for 2h;
85%	With thionyl chloride for 6h; Heating;
	With thionyl chloride In methanol for 24h; Heating;
	With thionyl chloride
	With thionyl chloride
	With thionyl chloride
	With thionyl chloride at 110 - 115℃; for 4h;
	With thionyl chloride at 110 - 115℃; for 4h;
	With thionyl chloride at 110 - 120℃; for 4h;
	With thionyl chloride at 110 - 120℃; for 4h; Reflux;	2.2. Preparation of ligand LH₃ (1-H pyrazole-3,5-dicarboxybis(phenylthiosemicarbazide)) The commercially obtained (Sigma Aldrich) 1H-pyrazole-3,5-dicarboxylicacid (0.01 M) was refluxed with thionylchloride (10 mL) in anhydrous condition for 4 h at about 110-120 °C. The content was then evaporated to dryness to remove the excess thionylchloride, thus obtained pasty mass was allowed to cool. Phenylthiosemicarbazide [17] in dry ethanol (0.02 M) was added dropwise and reflux was carried out for additional 3 h. Resultant solution was then cooled in ice bath to get a colorless amorphous solid, which is separated by filtration and dried over anhydrous CaCl2 and recrystalised from ethanol. The reaction pathway is represented in Fig. 1.
	With thionyl chloride at 115℃; for 4h; Inert atmosphere;
	With thionyl chloride In N,N-dimethyl-formamide for 5h; Reflux;
	With thionyl chloride at 90℃; for 15h;
	With thionyl chloride for 2h; Reflux; Inert atmosphere;	Synthesis and characterization data of Compound 25-H₃ A solution of the pyrazole 3,5-dicarboxylicacid (1.60 mmol, 0.25 g) in thionyl chloride (4 mL) was heated underreflux for 2 h. Excess solvent was then distilled off and the crude 23dried under vacuum. A solution of the crude pyrazole diacylchloride 23,triethylamine (4.8 mmol, 0.67 mL) and DMAP (0.32 mmol, 0.039 g) inanhydrous dichloromethane (13 mL) was cooled in an ice bath and theamine 24 (3.28 mmol, 0.782 g) was added slowly as a solution indichloromethane (3 mL). The reaction mixture was allowed to gradually warm up to room temperatureand stirred overnight. The mixture was then washed with 10% hydrochloric acid and water, and theorganic layer separated. The aqueous layer was further extracted two more times with dichloromethane.Combined organics were dried with anhydrous sodium sulfate, filtered, concentrated and purified by flashcolumn chromatography to furnish the title compound a white solid in 85% yield.

Reference： [1]Reviriego, Felipe; Navarro, Pilar; Garcia-Espana, Enrique; Albelda, M. Teresa; Frias, Juan C.; Domenech, Antonio; Yunta, Maria J. R.; Costa, Ruben; Orti, Enrique [Organic Letters, 2008, vol. 10, # 22, p. 5099 - 5102]
[2]Location in patent: experimental part Reviriego, Felipe; Navarro, Pilar; Aran, Vicente J.; Jimeno, Maria Luisa; Garcia-Espana, Enrique; Latorre, Julio; Yunta, Maria J. R. [Journal of Organic Chemistry, 2011, vol. 76, # 20, p. 8223 - 8231]
[3]Sanz, Ana M.; Navarro, Pilar; Gomez-Contreras, Fernando; Pardo, Mercedes; Pepe, Gerard; Samat, Andre [Canadian Journal of Chemistry, 1998, vol. 76, # 8, p. 1174 - 1179]
[4]Acerete, Carmen; Bueno, Jose M.; Campayo, Lucrecia; Navarro, Pilar; Isabel Rodriguez-Franco; Samat, Andre [Tetrahedron, 1994, vol. 50, # 16, p. 4765 - 4774]
[5]Campayo, Lucrecia; Bueno, Jose M.; Navarro, Pilar; Ochoa, Carmen; Jimenez-Barbero, Jesus; Pepe, Gerard; Samat, Andre [Journal of Organic Chemistry, 1997, vol. 62, # 9, p. 2684 - 2693]
[6]Maspero, Angelo; Brenna, Stefano; Galli, Simona; Penoni, Andrea [Journal of Organometallic Chemistry, 2003, vol. 672, # 1-2, p. 123 - 129]
[7]Lee, Ho H.; Cain, Bruce F.; Denny, William A.; Buckleton, John S.; Clark, George R. [Journal of Organic Chemistry, 1989, vol. 54, # 2, p. 428 - 431]
[8]Elguero, J.; Navarro, P.; Franco, M. I. Rodriguez [Chemistry Letters, 1984, p. 425 - 428]
[9]Konrad, Matthias; Meyer, Franc; Heinze, Katja; Zsolnai, Laszlo [Journal of the Chemical Society, Dalton Transactions, 1998, # 2, p. 199 - 205] Meyer, Franc; Ruschewitz, Uwe; Schober, Peter; Antelmann, Bjoern; Zsolnai, Laszlo [Journal of the Chemical Society, Dalton Transactions, 1998, # 7, p. 1181 - 1186]
[10]Buchler, Silke; Meyer, Franc; Jacobi, Albrecht; Kircher, Peter; Zsolnai, Laszlo [Zeitschrift fur Naturforschung, B: Chemical Sciences, 1999, vol. 54, # 10, p. 1295 - 1306]
[11]Location in patent: experimental part Budagumpi, Srinivasa; Kulkarni, Naveen V.; Kurdekar, Gurunath S.; Sathisha; Revankar, Vidyanand K. [European Journal of Medicinal Chemistry, 2010, vol. 45, # 2, p. 455 - 462]
[12]Location in patent: experimental part Budagumpi, Srinivasa; Kurdekar, Gurunath S.; Hegde, Ganesh S.; Bevinahalli, Nagaraj H.; Revankar, Vidyanand K. [Journal of Coordination Chemistry, 2010, vol. 63, # 8, p. 1430 - 1439]
[13]Location in patent: experimental part Kulkarni, Naveen V.; Revankar, Vidyanand K. [Journal of Coordination Chemistry, 2011, vol. 64, # 4, p. 725 - 741]
[14]Location in patent: experimental part Kulkarni, Naveen V.; Kamath, Anupama; Budagumpi, Srinivasa; Revankar, Vidyanand K. [Journal of Molecular Structure, 2011, vol. 1006, # 1-3, p. 580 - 588]
[15]Location in patent: experimental part Budagumpi, Srinivasa; Johnson, Renjith P.; Suh, Hongsuk; Ha, Chang-Sik; Kim, Il [Catalysis Letters, 2011, vol. 141, # 8, p. 1219 - 1227]
[16]Location in patent: experimental part Zhao, Cuirong; Xue, Xiaoxia; Li, Gang; Sun, Cuicui; Sun, Changjun; Qu, Xianjun; Li, Wenbao [Chemical Biology and Drug Design, 2012, vol. 80, # 3, p. 479 - 488]
[17]Kindermann, Nicole; Schober, Anne; Demeshko, Serhiy; Lehnert, Nicolai; Meyer, Franc [Inorganic Chemistry, 2016, vol. 55, # 21, p. 11538 - 11550]
[18]Das, Deepankar; Mal, Rudrajit; Mittal, Nisha; Zhu, Zhengbo; Emge, Thomas J.; Seidel, Daniel [Beilstein Journal of Organic Chemistry, 2018, vol. 14, p. 2002 - 2011]

7
[ 402-61-9 ]
alkaline permanganate [ No CAS ]
[ 3112-31-0 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1894,vol. 279,p. 228 Anm.50
[2]Patent: DE74619,
Fortschr. Teerfarbenfabr. Verw. Industriezweige,vol. 3,p. 939

8
(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)methanamine [ No CAS ]
[ 3112-31-0 ]
3,5--(tert-butyldimethylsilyloxymethyl)pyridine-2-yl-methyl]carbamoyl}pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: 3,5-pyrazoledicarboxylic acid With thionyl chloride In N,N-dimethyl-formamide Stage #2: (6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)methanamine In tetrahydrofuran at 20℃;

Reference： [1]Eisenwiener, Alexander; Neuburger, Markus; Kaden, Thomas A. [Dalton Transactions, 2007, # 2, p. 218 - 233]

9
N,N-bis(O-tert-butyldimethylsilyloxyethyl)ethylenediamine [ No CAS ]
[ 3112-31-0 ]
3,5-bis{N,N-bis[2-(O-tert-butyldimethylsilyloxyethylamino)ethyl]carbamoyl}pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	Stage #1: 3,5-pyrazoledicarboxylic acid With thionyl chloride In N,N-dimethyl-formamide Stage #2: N,N-bis(O-tert-butyldimethylsilyloxyethyl)ethylenediamine In tetrahydrofuran at 20℃;

Reference： [1]Eisenwiener, Alexander; Neuburger, Markus; Kaden, Thomas A. [Dalton Transactions, 2007, # 2, p. 218 - 233]

10
[ 3112-31-0 ]
[ 4104-45-4 ]
3,5-bis[(3-methylthio)propylcarbamoyl]pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: 3,5-pyrazoledicarboxylic acid With thionyl chloride In N,N-dimethyl-formamide Stage #2: 3-methylthio-1-propanamine In tetrahydrofuran at 20℃;

Reference： [1]Eisenwiener, Alexander; Neuburger, Markus; Kaden, Thomas A. [Dalton Transactions, 2007, # 2, p. 218 - 233]

11
[ 3112-31-0 ]
[ 115306-75-7 ]
3,5-bis[3-(tert-butyldimethylsilyloxy)propylcarbamoyl]pyrazole [ No CAS ]

Reference： [1]Dalton Transactions,2007,p. 218 - 233

12
[ 3112-31-0 ]
[ 33146-99-5 ]

Reference： [1]Journal of Organic Chemistry,1989,vol. 54,p. 428 - 431
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 10875 - 10894

13
[ 37622-89-2 ]
[ 3112-31-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: aqueous NaOH 2: KMnO₄; aqueous NaOH

Reference： [1]Nesmejanow; Kotschetkow [Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1951, p. 686,690][Chem.Abstr., 1952, p. 7565]

14
[ 3112-31-0 ]
[ 4077-76-3 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In methanol;	A solution of pyrazole-3,5-dicarboxylic acid (75 g, 431 mmol) in 11 of anhydrous methanol was treated with anhydrous HCl gas. The HCl addition was continued for 30 min after which, the solution was allowed to cool to room temperature and allowed to stand for 16 h. The solution was then heated at reflux for 3 h then cooled and the solvent removed at reduced pressure. The resulting white solid was treated with 600 ml of saturated NaHCO3 and extracted into CH2 Cl2 (3*500 ml). The pooled extracts were dried (Na2 SO4), filtered and evaporated at reduced pressure. The resulting white solid was recrystallized from methanol with the addition of anhydrous ether to give dimethyl pyrazole-3,5-dicarboxylate (3-1a). 1 H NMR (CDCl3) delta 7.38 (s, 1H); 3.98 (s, 3H); 3.93 (s, 3H).

Reference： [1]Patent: US5821241,1998,A

15
[ 12148-71-9 ]
[ 3112-31-0 ]
tetra-n-butylammonium hydroxide [ No CAS ]
[ 118611-33-9 ]

Reference： [1]Inorganic Chemistry,1991,vol. 30,p. 4771 - 4777

16
[ 12148-71-9 ]
[ 3112-31-0 ]
tetramethyl ammonium hydroxide [ No CAS ]
[ 118859-85-1 ]

Reference： [1]Inorganic Chemistry,1991,vol. 30,p. 4771 - 4777

17
[ 12148-71-9 ]
[ 3112-31-0 ]
tetrapropylammonium hydroxide [ No CAS ]
[ 136823-80-8 ]

Reference： [1]Inorganic Chemistry,1991,vol. 30,p. 4771 - 4777

18
[ 3112-31-0 ]
[ 3002-01-5 ]
[((benzyl)2Sn)6(pyrazole-3,5-dicarboxylate)4(μ-OH)2((benzyl)2SnCl)2]*4H2O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With KOH In ethanol; water acid was added to soln. of KOH in EtOH/H2O (2/1); mixt. was stirred for 5 min; Sn compd. was added; stirred at room temp. for 3 h; refluxed for 3 h; cooled; filtered; residue washed (H2O); recrystd. (THF/EtOH/MeOH, 4/2/1); elem. anal.;

Reference： [1]Chandrasekhar, Vadapalli; Thirumoorthi, Ramalingam; Azhakar, Ramachandran [Organometallics, 2007, vol. 26, # 1, p. 26 - 29]

19
[ 3112-31-0 ]
[ 1072147-19-3 ]
[ 1072147-21-7 ]

Yield	Reaction Conditions	Operation in experiment
87.5%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; for 13h;	55 Example 55; The title compound of Example 54 (2.445 g, 4.61 mmol) was dissolved in DMF (46 mL) at 0 0C. HOBT (623 mg, 4.61 mmol) and 3,5-pyrazole dicarboxylic acid monohydrate (402 mg, 2.31 mmol) were added, followed by the addition of DIPEA (1.00 mL, 5.76 mmol) and EDC (884 mg, 4.61 mmol). The reaction mixture was stirred for 1 hour at 0 0C, and then slowly warmed up to room temperature and stirred for 12 hours at room temperature. DMF was removed under vacuum and the residue was diluted with 30 mL EtOAc. The resulting solution was washed by HCl solution (IM), saturated NaHCO3 solution and brine. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 50% to 90% EtOAc/Hexane, then 2% to 10% MeOH/DCM gradually to give the title compound (1.756 g with 96% purity and 788 mg with 90% purity, 87.5%). The product and relative purity was confirmed byLCMS. 1H NMR (CDCl3): consistent with proposed structure.

Reference： [1]Current Patent Assignee: JOYANT PHARMACEUTICALS - WO2008/128121, 2008, A1 Location in patent: Page/Page column 114; 155

20
[ 3112-31-0 ]
[ 1257446-74-4 ]
[ 1375592-80-5 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 18h;	4.15 Example 4-15: Synthesis of 5-[(R)-1-(3''Chloro-biphenyl-4-ylmethyl)-2~ethoxycarbonyl- ethylcarbamoyO-1 H-pyrazole-3-carboxyUc acid; To a mixture of Intermediate 17-1 (130 mg, 0.367 mmol), 1H-pyrazole-3,5-dicarboxylic acid (74.5 mg, 0.477 mmol), EDCI (91 mg, 0.477 mmol) and HOBt (64.5 mg, 0.477 mmof) in DMF (3 ml) is added triethylamine (149 mg, 0.203 mmol) and the mixture is stirred at room temperature for 18 hours. Any insoluble material is removed by filtration and the filtrate is chromatographed by HPLC using a gradient of 10% MeCN/water to 100% MeCN (+0.1% TFA). Lyophitization of the proper fractions gives the title compound; HPLC Retention time 1.31 minutes (condition C); MS 456.2 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (t, J=7,07 Hz1 3H), 2.54-2.67 (m, 2H)1 2.84-2.97 (m, 2H), 4.02 (q. J=7.07 Hz, 2H), 4.54 (m, 1H)1 7.11 (s, broad, 1H), 7.32 (d, J=8.08 Hzt 2H), 7.39 (m, 1H), 7.46 (t, 1 H)1 7.62 (d, J=8.08 Hz, 3H)1 7.69 (s. 1H), 8.41 (s, broad, 1H).

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NIBR (in: Novartis); NOVARTIS AG - WO2010/136493, 2010, A1 Location in patent: Page/Page column 117

21
[ 3112-31-0 ]
[ 1297536-45-8 ]
[ 1297536-46-9 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃;	1.c 3,5-Pyrazoledicarboxylic acid monohydrate (8.02 g, 46.1 mmol) was dissolved in the mixture of dry DMF (35 ml), dry DCM (35 ml) and DIPEA (7.9 ml). l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 3.37 g, 17.6 mmol), HOBt (2.28 g, 16.9 mmol), and DIPEA (3 ml, 2.23 g, 17.3 mmol) were added at RT. The solution was mixed for 10 min. Then, 2-[5-(3,4-dichlorophenyl)- furan-2-yl]ethylamine hydrochloride (3.46 g, 1 1.8 mmol) dissolved in the mixture of dry DCM (35 ml) and DIPEA (2.0 ml, 1.48 g, 11.5 mmol) was dropped to the solution at RT. After stirring overnight water was added. The product was extracted into ethyl acetate. The organic phase was washed with water, dried and evaporated. The crude product was purified by flash chromatography using DCM as an eluent. The product was triturated in hot methanol. NMR (400 MHz, DMSO- ): 2.95 (2H, t), 3.56 (2H, m), 6.33 (IH, d), 7.01 (IH, d), about 7.03 (IH, broad s), 7.61 (IH, distorted dd), 7.63 (IH, distorted d), 7.83 (IH, d), about 8.45 (IH, broad s), about 14.05 (IH, broad s).

Reference： [1]Current Patent Assignee: ORION OYJ - WO2011/51540, 2011, A1 Location in patent: Page/Page column 31

22
[ 122-96-3 ]
[ 3112-31-0 ]
2C₅H₄N₂O₄*C₈H₁₈N₂O₂ [ No CAS ]

Reference： [1]CrystEngComm,2011,vol. 13,p. 753 - 758

23
[ 3112-31-0 ]
[ 1375592-80-5 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; triethylamine In N,N-dimethyl-formamide; acetonitrile	4.8 Synthesis of 5-[(R)-1-(3'-Chloro-biphenyl-4-ylmethyl)-2-ethoxycarbonyl-ethylcarbamoyl]-1H-pyrazole-3-carboxylic acid Example 4-8 Synthesis of 5-[(R)-1-(3'-Chloro-biphenyl-4-ylmethyl)-2-ethoxycarbonyl-ethylcarbamoyl]-1H-pyrazole-3-carboxylic acid To a mixture of Intermediate 8-1 (130 mg, 0.367 mmol), 1H-pyrazole-3,5-dicarboxylic acid (74.5 mg, 0.477 mmol), EDCl (91 mg, 0.477 mmol) and HOBt (64.5 mg, 0.477 mmol) in DMF (3 mL) is added triethylamine (149 mg, 0.203 mmol) and the mixture is stirred at room temperature for 18 hours. Any insoluble material is removed by filtration and the filtrate is chromatographed by HPLC using a gradient of 10% MeCN/water to 100% MeCN (+0.1% TFA). Lyophilization of the proper fractions gives the title compound; HPLC Retention time 1.31 minutes (condition C); MS 456.2 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (t, J=7.07 Hz, 3H), 2.54-2.67 (m, 2H), 2.84-2.97 (m, 2H), 4.02 (q, J=7.07 Hz, 2H), 4.54 (m, 1H), 7.11 (s, broad, 1H), 7.32 (d, J=8.08 Hz, 2H), 7.39 (m, 1H), 7.46 (t, 1H), 7.62 (d, J=8.08 Hz, 3H), 7.69 (s, 1H), 8.41 (s, broad, 1H).

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US2012/122844, 2012, A1

24
[ 3112-31-0 ]
[ 1382978-19-9 ]
[ 1382978-20-2 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3,5-pyrazoledicarboxylic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide for 0.5h; Stage #2: (R)-3-(N-Biphenyl-4-ylmethyl-hydrazino)-2-hydroxypropionic Acid Methyl Ester In N,N-dimethyl-formamide at 20℃;	1 1H-pyrazole-3,5-dicarboxylic acid (58.4 mg, 374 μmol, 1.2 eq.) was dissolved in DMF (2 mL). DIPEA (163 μL, 3.0 eq.) was added followed by HATU (142 mg, 374 mol, 1.2 eq.) and the resulting solution was stirred for 30 minutes. (R)-3-(N-Biphenyl-4-ylmethyl-hydrazino)-2-hydroxy-propionic acid methyl ester (93.7 mg, 312 μmol, 1.0 eq.) in DMF (2 mL) was then added and the mixture was stirred at room temperature overnight. The mixture was concentrated and the crude intermediate was used in the next step without further purification.

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2012/157386, 2012, A1 Location in patent: Page/Page column 38-39

25
[ 3112-31-0 ]
[ 1383027-21-1 ]
[ 76-05-1 ]
[ 1383005-80-8 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3,5-pyrazoledicarboxylic acid; (2R,4R)-4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid butyl ester hydrochloride With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide for 1h; Stage #2: trifluoroacetic acid	2.E (2R,4R)-4-Amino-5-biphenyl-4-yl-2-hydroxypentanoic acid butyl ester (HCl salt; 108 mg, 286 μmmol, 1.0 eq.), 3,5-pyrazoledicarboxylic acid (66.9 mg, 429 μmol, 1.5 eq.), and HATU (160 mg, 430 μmol, 1.5 eq.) were combined in DMF (5 mL), and the resulting mixture was stirred for 2 minutes. DIPEA (150 μL) was added and the mixture was stirred for 1 hour. The mixture was dried under vacuum, and the product was purified using reverse phase chromatography to yield the title compound as a TFA salt (60 mg; purity 98%). MS m/z [M+H]+ calc'd for C26H29N3O6, 480.21. found 480.4).

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2012/157383, 2012, A1 Location in patent: Page/Page column 48

26
[ 3112-31-0 ]
[ 1394019-96-5 ]
ammonium chloride [ No CAS ]
[ 1394019-63-6 ]

Yield	Reaction Conditions	Operation in experiment
93%	With DIPEA; acetic acid; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran	10.A A. A. 5-[(R)-2-Biphenyl-4-yl-1-(1-carboxy-cyclopropylmethyl)-ethylcarbamoyl]-2H-pyrazole-3-carboxylic acid (R7=H) 3,5-Pyrazoledicarboxylic acid (35.2 mg, 226 μmol, 1.0 eq.), DIPEA (126 μL) and HATU (85.9 mg, 226 μmol, 1.0 eq.) and DCM (5 mL) were combined and stirred for 5 minutes at room temperature. 1-((R)-2-Amino-3-biphenyl-4-yl-propyl)-cyclopropanecarboxylic acid (86.7 mg, 294 μmol, 2.3 eq,) and DIPEA (0.5 mL) in DCM (5 mL) was added, and the resulting mixture was stirred for 1 hour. The reaction was quenched with saturated aqueous NH4Cl and the product was extracted with DCM, dried and evaporated. The resulting product was combined with AcOH (1.5 mL) and purified with preparative HPLC to yield the title compound (21.4 mg; 93% purity). MS m/z [M+H]+ calc'd for C24H23N3O5, 434.16; found 433.5.

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2012/213807, 2012, A1

27
[ 3112-31-0 ]
[ 1394050-64-6 ]
[ 1394050-01-1 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3,5-pyrazoledicarboxylic acid With 4-methyl-morpholine; benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In N,N-dimethyl-formamide at 20℃; for 5h; Inert atmosphere; Stage #2: (2S,4R)-4-amino-5-(3'-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methyl-pentanoic acid With 4-methyl-morpholine In N,N-dimethyl-formamide for 0.25h; Inert atmosphere;	7 Example 7 5-[(1R,3S)-3-Carboxy-1-(3'-fluorobiphenyl-4-ylmethyl)-4-hydroxy-3-methyl-butylcarbamoyl]-1H-pyrazole-3-carboxylic Acid 3,5-Pyrazoledicarboxylic acid (37.7 mg, 241 μmol, 1.0 eq.), EDCI (42.7 μL, 241 μmol, 1.0 eq.), 4-methylmorpholine (53.1 μL, 2.0 eq.) and 1 HOBt (32.6 mg, 241 μmol, 1.0 eq.) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. A predissolved solution of (2S,4R)-4-amino-5-(3'-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methyl-pentanoic acid (80 mg, 240 μmol, 1.0 eq.) and 4-methylmorpholine (53.1 μL) in DMF (0.3 mL) was added and the resulting mixture was stirred for 15 minutes. The reaction was quenched by adding AcOH and the product was purified by preparative HPLC and lyophilized to yield the title compound (25 mg). MS m/z [M+H]+ calc'd for C24H24FN3O6, 470.17. found 470.4.

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2012/213806, 2012, A1 Location in patent: Page/Page column 71-72

28
[ 3112-31-0 ]
[ 269396-76-1 ]
[ 76-05-1 ]
5-[(R)-2-carboxy-1-(2-trifluoromethylbenzyl)-ethylcarbamoyl]-2H-pyrazole-3-carboxylic acid trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3,5-pyrazoledicarboxylic acid; (R)-3-amino-4-(2-trifluoromethyl-phenyl)-butyric acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: With water; sodium hydroxide In methanol at 60℃; for 1h; Stage #3: trifluoroacetic acid	12 (R)-3-Amino-4-(2-trifluoromethyl-phenyl)-butyric acid (63 mg, 260 μmol, 1.0 eq.), 3,5-pyrazoledicarboxylic acid (40 mg, 0.2 mmol, 1.0 eq.), and HATU (97 mg, 260 μmol, 1.0 eq.) were dissolved in DMF (5 mL) and stirred. DIPEA (200 μL, 4.0 eq.) was added and the resulting mixture was stirred at room temperature for 1 hour. The product was then vacuumed to dryness. This crude product was dissolved in MeOH (3 mL), and 10N NaOH (250 μL) was added. The resulting mixture was stirred at 60° C. for 1 hour. Glacial AcOH (250 μL) was added and the mixture was then vacuumed to dryness. The product was then purified by preparative HPLC to yield the title compound as a TFA salt (26.4 mg, 97% purity). MS m/z [M+H]+ calc'd for C16H14F3N3O5, 386.09; found 386.0.

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2012/308587, 2012, A1 Location in patent: Page/Page column 52

29
[ 3112-31-0 ]
[ 331846-92-5 ]
[ 76-05-1 ]
5-((R)-1-carboxymethyl-2-o-tolyl-ethylcarbamoyl)-2H-pyrazole-3-carboxylic acid trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3,5-pyrazoledicarboxylic acid; (R)-3-amino-4-(2-methylphenyl)butanoic acid hydrochloride With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: With water; sodium hydroxide In methanol at 60℃; for 1h; Stage #3: trifluoroacetic acid	13 (R)-3-Amino-4-(2-methylphenyl)butanoic acid (HCl salt, 59 mg, 260 μmol, 1.0 eq.), 3,5-pyrazoledicarboxylic acid (40 mg, 0.2 mmol, 1.0 eq.), and HATU (97 mg, 260 μmol, 1.0 eq.) were dissolved in DMF (5 mL) and stirred. DIPEA (200 μL, 4.0 eq.) was added and the resulting mixture was stirred at room temperature for 1 hour. The product was then vacuumed to dryness. This crude product was dissolved in MeOH (3 mL), and 10N NaOH (250 μL) was added. The resulting mixture was stirred at 60° C. for 1 hour. Glacial AcOH (250 μL) was added and the mixture was then vacuumed to dryness. The product was then purified by preparative HPLC to yield the title compound as a TFA salt (42.1 mg, 82% purity). MS m/z [M+H]+ calc'd for C16H17N3O5, 332.12; found 332.2.

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2012/308587, 2012, A1 Location in patent: Page/Page column 52

30
[ 3112-31-0 ]
[ 64-17-5 ]
[ 752963-23-8 ]
5-[(R)-1-(2-chloro-benzyl)-2-ethoxycarbonyl-ethylcarbamoyl]-2H-pyrazole-3-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3,5-pyrazoledicarboxylic acid; (R)-3-amino-4-(2-chloro-phenyl)-butyric acid ethyl ester With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: ethanol With sulfuric acid at 80℃; for 3h;	10 3,5-Pyrazoledicarboxylic acid (840 mg, 5.4 mmol, 1.0 eq.), (R)-3-amino-4-(2-chloro-phenyl)-butyric acid ethyl ester (1.3 g, 5.4 mmol, 1.0 eq.), and HATU (2.0 g, 5.4 mmol, 1.0 eq.) were combined in DMF (5 mL) and mixed with sonication. DIPEA (1.9 mL, 10.8 mmol, 2.0 eq.) was added and the mixture was stirred for 1 hour at room temperature, then vacuumed to dryness. The crude product was dissolved in EtOH (25 mL), and concentrated H2SO4 (100 μL) was added. The mixture was stirred at 80° C. for 3 hours, then vacuumed to near dryness. EtOAc (200 mL) was added and the product was washed with NaHCO3 (100 mL) and then saturated aqueous NaCl (100 mL). The organic layer was retained and dried over anhydrous MgSO4 for 10 minutes prior to filtration and evacuation to dryness to yield 5-[(R)-1-(2-chloro-benzyl)-2-ethoxycarbonyl-ethylcarbamoyl]-2H-pyrazole-3-carboxylic acid ethyl ester, which was used without further purification (1.1 g).

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2012/308587, 2012, A1 Location in patent: Page/Page column 50-51

31
[ 3112-31-0 ]
[ 64-17-5 ]
[ 1415312-28-5 ]
[ 1415512-66-1 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3,5-pyrazoledicarboxylic acid; (2R,3R)-3-Amino-4-(2-chloro-phenyl)-2-hydroxy-butyric acid Methyl Ester With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: ethanol With hydrogenchloride In water for 5h; Reflux;	5 (2R,3R)-3-Amino-4-(2-chloro-phenyl)-2-hydroxy-butyric acid methyl ester (735 mg, 3.0 mmol, 1.0 eq.), HATU (1.2 g, 3.2 mmol, 1.0 eq.), and 3,5-pyrazoledicarboxylic acid (0.5 g, 3.2 mmol, 1.0 eq.) were combined in DMF (5 mL) and stirred. DIPEA (2 mL, 4.0 eq.) was added and the mixture was stirred for 1 hour at room temperature. EtOAc (200 mL) was added and the mixture was washed with 1N HCl (100 mL), NaHCO3 ((100 mL), and saturated aqueous NaCl (100 mL). The organic layer was retained and dried over anhydrous MgSO4 for 10 minutes prior to filtration. The product was then vacuumed to dryness. The product was dissolved in absolute EtOH (100 mL) and concentrated HCl (1 mL) was added, and the mixture refluxed for 5 hours. EtOAc (200 mL) was added and the mixture was washed with 1N HCl (100 mL) followed by NaHCO3 (100 mL) and then saturated aqueous NaCl (100 mL). The organic layer was retained and dried over anhydrous MgSO4 for 10 minutes prior to filtration and evacuation to dryness to yield the title compound (750 mg).

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2012/308587, 2012, A1 Location in patent: Page/Page column 32

32
[ 3112-31-0 ]
[ 64-17-5 ]
[ 1415312-30-9 ]
[ 1415512-66-1 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3,5-pyrazoledicarboxylic acid; (2R,3R)-3-Amino-4-(2-chloro-phenyl)-2-hydroxy-butyric acid ethyl ester With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide for 1h; Stage #2: ethanol With hydrogenchloride at 100℃;	5 (2R,3R)-3-Amino-4-(2-chloro-phenyl)-2-hydroxy-butyric acid ethyl ester (1.0 g, 3.9 mmol, 1.0 eq.), HATU (1.5 g, 3.9 mmol, 1.0 eq.), and 3,5-pyrazoledicarboxylic acid (0.6 g, 3.9 mmol, 1.0 eq.) were combined in DMF (5 mL) and stirred for 2 minutes. DIPEA (3.0 eq.) was added and the mixture was stirred for 1 hour then vacuumed to dryness. EtOAc (200 mL) was added and the mixture was washed with 1N HCl (100 mL), NaHCO3 (100 mL), and saturated aqueous NaCl (100 mL). The organic layer was retained and dried over anhydrous MgSO4 for 10 minutes prior to filtration and evacuation to dryness. The product was then treated with 1.25M HCl in EtOH (20 mL), heated to 100° C. overnight, then vacuumed to dryness. The product was then purified by flash chromatography (0-75% EtOAc/hexanes) to yield the title compound (1.1 g).

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2012/308587, 2012, A1 Location in patent: Page/Page column 32

33
[ 3112-31-0 ]
lanthanide(III)chloride heptahydrate [ No CAS ]
[ 7732-18-5 ]
[La₂(3,5-pyrazoledicarboxylic acid-2H)₃(H₂O)₄]·2H₂O}_n [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With sodium hydroxide at 180℃; for 48h; Autoclave; High pressure;	Synthesis of compound 1 A mixture of LaCl3·7H2O (0.187g, 0.5mmol), H3pdc (0.175g, 1.0mmol), NaOH (0.041g, 1.0mmol) and H2O (5mL) was placed in a 23mL Teflon-lined Parr acid digestion bomb and heated for two days at 180°C under autogenous pressure. Upon cooling to room temperature, solution was separated from the solid phase, and after filtration precipitate washed with water and acetone, respectively. The product was dried at ambient temperature. The colorless crystals of 1 were obtained with high yield and the synthesized single crystals suited for X-ray diffraction analysis. Yield ca. 86% (based on La). Initial pH was 2.50; final pH was 1.88. Crystalline 1 is insoluble in water and common solvents and stable in air. Anal. Calc. for C15H15La2N6O18: C, 21.29; H, 1.78; N, 9.93. Found: C, 21.18; H, 2.18; N, 9.67%. IR data (KBr pellet, cm-1): 3410(m), 3160(m), 1593(vs), 1458(m), 1352(vs), 1311(vs), 1017(s), 837(w), 783(s), 629(w).

Reference： [1]Ay, Burak; Yildiz, Emel; Protasiewicz, John D.; Rheingold, Arnold L. [Inorganica Chimica Acta, 2013, vol. 399, p. 208 - 213]

34
[ 3112-31-0 ]
europium(III) chloride hexahydrate [ No CAS ]
[ 150-90-3 ]
[Eu₂(3,5-dicarboxypyrazolate)₂(succinate)(H₂O)₈]·(H₂O)_1.5 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	With sodium hydroxide; In water; for 72h;	Sodium succinate (0.273 mmol, 44 mg) was added to europium chloride (0.136 mmol, 50 mg) in water (20 mL) generating a colorless solution. Then a solution containing NaOH (0.136 mmol) and H2dcpz (0.136 mmol, 24 mg) was added to the initial reaction mixture. The resulting solution was allowed to stand at room temperature open to the air. After three days, translucent crystals suitable for single crystal X-ray diffraction were obtained. Yield: 49%. Anal. Calc. for C14H27Eu2N4O21.5: C, 18.70; H, 3.03; N, 6.23. Found: C, 18.84; H, 2.81; N, 6.04%.

Reference： [1]Polyhedron,2013,vol. 54,p. 1 - 7

35
[ 3112-31-0 ]
manganese(II) chloride dihydrate [ No CAS ]
[ 7732-18-5 ]
Mn₄(H₂O)₆(Hpdc)(pdc)₂·H₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With L-Tartaric acid; sodium hydroxide at 150℃; for 72h; Autoclave; High pressure;	2.3 Synthesis of Mn₄(H₂O)₆(Hpdc)(pdc)₂·H₂O, 2 0.19mmol (0.0326g) of H3dpc, 0.20mmol (0.0302g) of L-tta, 1.00mmol (0.1567g) of MnCl2 2H2O, and 20mL of distilled water were mixed. The reaction mixture was stirred and the pH value was adjusted to 5-6 by dropping NaOH solution (0.5M). The homogeneous mixture was sealed in a PTFE-lined stainless steel autoclave with an internal volume of 40mL and heated at 150°C for 3days under autogenous pressure. The single phase product of 2 was harvested by filtration, washed with distilled water (3*50mL), then air dried under ambient condition. Yield 0.060g, ∼40% based on H3dpc.

Reference： [1]Shi, Fa-Nian; Yang, Ting-Hai [Inorganica Chimica Acta, 2014, vol. 412, p. 79 - 87]

36
[ 3112-31-0 ]
manganese(II) chloride dihydrate [ No CAS ]
[ 7732-18-5 ]
Mn(H2O)2(Hpdc) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With 4,4'-bipyridine at 150℃; for 72h; Autoclave; High pressure;	2.2 Synthesis of Mn₂(H₂O)₈(Hpdc)₂·3H₂O, 1 and Mn(H₂O)₂(Hpdc), 3 In a typical synthesis, 0.17mmol (0.0300g) of H3dpc, 0.36mmol (0.0586g) of MnCl2 2H2O, 0.26mmol (0.0403g) of 4,4′-bpy and 10mL of distilled water were mixed. The reaction mixture was stirred until a homogeneous gel was formed (pH 4), sealed in a PTFE-lined stainless steel autoclave with an internal volume of 40mL and heated at 150°C for 3days under autogenous pressure. After cooling to room temperature, the resulting block single crystal particles that was confirmed to be compound 3 by XRD were filtered off, washed with distilled water (3*50mL), and dried in an ambient condition. Yield 0.031g, 73% based on H3dpc. The mother liquor was allowed to stand still for evaporation. After one week, small amount single crystals were found grown up on the wall of beaker. These crystal particles were collected and air dried at room temperature, single crystal X-ray diffraction data revealed that these particles were phase 1. Yield 0.010g, 9.4% based on H3dpc.

Reference： [1]Shi, Fa-Nian; Yang, Ting-Hai [Inorganica Chimica Acta, 2014, vol. 412, p. 79 - 87]

37
[ 7439-96-5 ]
[ 3112-31-0 ]
[ 7732-18-5 ]
[ 1569068-86-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium permanganate; yttrium(III) chloride hexahydrate at 180℃; for 72h; Autoclave; High pressure;	2.4 Synthesis of Mn(H₂O)(Hpdc), 4 4 was synthesized by mixing 0.0118g of Mn, 0.0164g of KMnO4, 0.0343g of YCl3·6H2O, 0.0544g of H3dpc, and 6.8g of distilled water. The homogeneous mixture was sealed into an autoclave (40mL) and put in a preheated oven at 180°C for 3days. The single crystal particles of 4 obtained mixed with other phases that cannot be well separated from each other. Efforts for synthesis pure 4 were unsuccessful due to the tendency to yielding 3.

Reference： [1]Shi, Fa-Nian; Yang, Ting-Hai [Inorganica Chimica Acta, 2014, vol. 412, p. 79 - 87]

38
[ 3112-31-0 ]
[ 7732-18-5 ]
[ 10108-64-2 ]
Cd(μ₃-3,5-pyrazoledicarboxylate)(μ-H₂O)(H₂O) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	at 120℃; for 24h; High pressure;	Synthesis of [Cd(μ₃-pzdc)(μ-H₂O)(H₂O)]_n (2) General procedure: A mixture of CdCl2 (0.1mmol, 18.3mg) and 4-aminopyrazole (4-Hampz, 0.2mmol, 16.2mg) in H2O (10mL) was heated in a 23mL Teflon-lined reactor at 120°C for 24h. After being cooled to room temperature, pale yellow crystals of 1 were collected by filtration, washed with water, and dried in air (54% yield based on Cd.)

Reference： [1]Seco, Jose Manuel; Calahorro, Antonio; Cepeda, Javier; Rodríguez-Diéguez, Antonio [Journal of Molecular Structure, 2015, vol. 1089, p. 135 - 145]

39
[ 3112-31-0 ]
aqueous cadmium chloride [ No CAS ]
[ 7732-18-5 ]
[Cd₃(pyrazole-3,5-dicarboxylic acid-3H)(pyrazole-3,5-dicarboxylic acid-2H)(pyrazole-3,5-dicarboxylic acid-H)(H₂O)]*H₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With oxalic acid dihydrate In water; acetonitrile at 150℃; for 120h; Autoclave;

Reference： [1]Liu, Guang-Ning; Zhang, Ming-Jian; Liu, Wan-Qing; Sun, Hui; Li, Xin-Yu; Li, Ke; Ren, Cai-Ze; Zhang, Zhen-Wei; Li, Cuncheng [Dalton Transactions, 2015, vol. 44, # 43, p. 18882 - 18892]

40
[ 3112-31-0 ]
[ 1394019-95-4 ]
[ 71-36-3 ]
[ 1394019-64-7 ]

Yield	Reaction Conditions	Operation in experiment
29 mg	Stage #1: 1-((R)-3-biphenyl-4-yl-2-t-butoxycarbonylaminopropyl)cyclopropanecarboxylic acid t-butyl ester; butan-1-ol With hydrogenchloride In 1,4-dioxane at 65℃; Stage #2: 3,5-pyrazoledicarboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In 1,4-dioxane; N,N-dimethyl-formamide; butan-1-ol for 0.5h;	10.B B. 5-[(R)-1-Biphenyl-4-ylmethyl-2-(1-butoxycarbonyl-cyclopropyl)-ethylcarbamoyl]-1H-pyrazole-3-carboxylic acid (R⁷ = -(CH₂)₃CH₃) B. 5-[(R)-1-Biphenyl-4-ylmethyl-2-(1-butoxycarbonyl-cyclopropyl)-ethylcarbamoyl]-1H-pyrazole-3-carboxylic acid (R7 = -(CH2)3CH3) 1-((R)-3-Biphenyl-4-yl-2-t-butoxycarbonylaminopropyl)cyclopropanecarboxylic acid t-butyl ester (1.0 g, 2.2 mmol, 1.0 eq.), 1-butanol (5 mL) and 4 M of HCl in 1,4-dioxane (2 mL) were combined and stirred at 65°C overnight. To this was added a mixture of 3,5-pyrazoledicarboxylic acid (34.6 mg, 221 μmol, 1.0 eq.), EDCI (39.2 μL, 221 μmol, 1.0 eq.) and HOBt (29.9 mg, 221 μmol, 1.0 eq.) that had been combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. The resulting mixture was stirred for 30 minutes. The reaction was then quenched with ACOH and the product was purified by preparative HPLC and lyophilized to yield the title compound (29 mg, 95% purity). MS m/z [M+H]+ calc'd for C28H31N3O5, 490.23; found 490.6.

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - EP2675792, 2016, B1 Location in patent: Paragraph 0249

41
[ 3112-31-0 ]
[ 1394019-96-5 ]
[ 1394019-63-6 ]

Yield	Reaction Conditions	Operation in experiment
21.4 mg	Stage #1: 3,5-pyrazoledicarboxylic acid With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 20℃; for 0.0833333h; Stage #2: 1-((R)-2-amino-3-biphenyl-4-yl-propyl)cyclopropanecarboxylic acid With N-ethyl-N,N-diisopropylamine In dichloromethane for 1h;	10.A A. 5-[(R)-2-Biphenyl-4-yl-1-(1-carboxy-cyclopropylmethyl)-ethylcarbamoyl]-2H-pyrazole-3-carboxylic acid (R⁷ = H) A. 5-[(R)-2-Biphenyl-4-yl-1-(1-carboxy-cyclopropylmethyl)-ethylcarbamoyl]-2H-pyrazole-3-carboxylic acid (R7 = H) 3,5-Pyrazoledicarboxylic acid (35.2 mg, 226 μmol, 1.0 eq.), DIPEA (126 μL) and HATU (85.9 mg, 226 μmol, 1.0 eq.) and DCM (5 mL) were combined and stirred for 5 minutes at room temperature. 1-((R)-2-Amino-3-biphenyl-4-yl-propyl)-cyclopropanecarboxylic acid (86.7 mg, 294 μmol, 2.3 eq,) and DIPEA (0.5 mL) in DCM (5 mL) was added, and the resulting mixture was stirred for 1 hour. The reaction was quenched with saturated aqueous NH4Cl and the product was extracted with DCM, dried and evaporated. The resulting product was combined with AcOH (1.5 mL) and purified with preparative HPLC to yield the title compound (21.4 mg; 93% purity). MS m/z [M+H]+ calc'd for C24H23N3O5, 434.16; found 433.5.

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - EP2675792, 2016, B1 Location in patent: Paragraph 0249

42
[ 3112-31-0 ]
hydrazinium hydrogen-3,5-pyrazoledicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With hydrazine hydrate In water Heating;	Preparation of (N₂H₅)HPzdca*H₂O To prepare the salt, the 3,5-pyrazoledicarboxylic acid monohydrate (0.8705 g, 0.005 mol) was treated with a 10 % hydrazine hydrate in a 1:1 molar ratio (2.5 mL, 0.005 mol) in 50 mL of distilled water. The resulting solution was heated over a water bath for about 20 min to obtain a clear solution. This solution (pH = 3.5) was cooled to room temperature and was placed in a vacuum desiccator over calcium chloride for crystallization. Needle-shaped colorless crystals of the title salt are separated after a week, and the crystals were washed with ice-cold absolute alcohol and air-dried. The salt was soluble in cold water, insoluble in alcohol, and was stable in air (yield: 85 %). Elemental analysis: C (%): 28.50 (Cald. 29.12); H(%): 5.10 (5.23); N (%): 27.93 (27.16); and hydrazine (%):15.10 (Cald. 15.52).

Reference： [1]Premkumar, Thathan; Srinivasan, Krishnan; Selvakumar, Rajendran; Rath, Nigam P.; Govindarajan, Subbiah [Journal of Thermal Analysis and Calorimetry, 2016, vol. 125, # 1, p. 1 - 9]

43
[ 110-85-0 ]
nickel(II) nitrate hexahydrate [ No CAS ]
[ 3112-31-0 ]
piperazinediium diaquabis(pyrazole-3,5-dicarboxylato)nickelate(II) hexahydrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: piperazine; 3,5-pyrazoledicarboxylic acid In water at 20℃; for 1h; Stage #2: nickel(II) nitrate hexahydrate In water for 3h; Reflux;	Synthesis of the complexes 1 and 2 General procedure: Pyrazole-3,5-dicarboxylic acid (0.348 g, 2 mmol) and0.168 g piperazine (2 mmol) were dissolved in 20 cm3distilled water. The mixture was stirred for 1 h at room temperature. Then metal salts, 0.291 g nickel(II) nitratehexahydrate (1 mmol) for 1 and 0.169 g manganese(II)sulfate tetrahydrate (1 mmol) for 2 were added into the above-mentioned solution. The reaction mixture was refluxed for 3 h. It was then gradually cooled to room temperature and kept until crystals suitable for X-ray diffraction were obtained.

Reference： [1]Sharif, Mahboubeh A.; Najafi, Gholam Reza [Monatshefte fur Chemie, 2016, vol. 147, # 9, p. 1557 - 1563]

44
[ 110-85-0 ]
[ 3112-31-0 ]
manganese(II) sulfate tetrahydrate [ No CAS ]
piperazinediium diaquabis(pyrazole-3,5-dicarboxylato)manganate(II) hexahydrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	Stage #1: piperazine; 3,5-pyrazoledicarboxylic acid In water at 20℃; for 1h; Stage #2: manganese(II) sulfate tetrahydrate In water for 3h; Reflux;	Synthesis of the complexes 1 and 2 General procedure: Pyrazole-3,5-dicarboxylic acid (0.348 g, 2 mmol) and0.168 g piperazine (2 mmol) were dissolved in 20 cm3distilled water. The mixture was stirred for 1 h at room temperature. Then metal salts, 0.291 g nickel(II) nitratehexahydrate (1 mmol) for 1 and 0.169 g manganese(II)sulfate tetrahydrate (1 mmol) for 2 were added into the above-mentioned solution. The reaction mixture was refluxed for 3 h. It was then gradually cooled to room temperature and kept until crystals suitable for X-ray diffraction were obtained.

Reference： [1]Sharif, Mahboubeh A.; Najafi, Gholam Reza [Monatshefte fur Chemie, 2016, vol. 147, # 9, p. 1557 - 1563]

45
[ 3112-31-0 ]
holmium(III) chloride hexahydrate [ No CAS ]
[ 7732-18-5 ]
[ 150-90-3 ]
[Ho₂(3,5-dicarboxypyrazolate)₂(succinate)(H₂O)₈]*(H₂O)_1.5 [ No CAS ]