[ CAS No. 35344-95-7 ] {[proInfo.proName]}

Name: 35344-95-7|1H-Pyrazole-4-carbaldehyde|97%
Brand: Ambeed
SKU: A435381
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Quality Control of [ 35344-95-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 35344-95-7 ]

Product Details of [ 35344-95-7 ]

CAS No. :	35344-95-7	MDL No. :	MFCD02179514
Formula :	C₄H₄N₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LRGBDJBDJXZTTD-UHFFFAOYSA-N
M.W :	96.09	Pubchem ID :	5130673
Synonyms :

Calculated chemistry of [ 35344-95-7 ]

Physicochemical Properties

Num. heavy atoms :	7
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	23.98
TPSA :	45.75 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) :	-7.56 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.23
Log Po/w (XLOGP3) :	-0.95
Log Po/w (WLOGP) :	0.22
Log Po/w (MLOGP) :	-1.04
Log Po/w (SILICOS-IT) :	1.2
Consensus Log Po/w :	-0.07

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-0.3
Solubility :	48.2 mg/ml ; 0.501 mol/l
Class :	Very soluble
Log S (Ali) :	0.47
Solubility :	286.0 mg/ml ; 2.98 mol/l
Class :	Highly soluble
Log S (SILICOS-IT) :	-1.1
Solubility :	7.69 mg/ml ; 0.08 mol/l
Class :	Soluble

Medicinal Chemistry

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

Safety of [ 35344-95-7 ]

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 [ 35344-95-7 ]

* 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 [ 35344-95-7 ]
Downstream synthetic route of [ 35344-95-7 ]

[ 35344-95-7 ] Synthesis Path-Upstream 1~11

1
[ 35344-95-7 ]
[ 74-88-4 ]
[ 25016-11-9 ]

Yield	Reaction Conditions	Operation in experiment
87%	With caesium carbonate In N,N-dimethyl-formamide at 60℃;	To a solution of lH-pyrazole-4-carbaldehyde (1.00 g, 10.4 mmol) in DMF (40 mL) was added iodomethane (1.48 g, 10.4 mmol) and CS2CO3 (10 g, 31.2 mmol). After stirring at 60°C overnight, the reaction mixture was added water (20 mL) and extracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried over Na₂S04 and concentrated to give intermediate 48 (1.00 g, 87percent yield).

Reference： [1] Patent: WO2018/50684, 2018, A1, . Location in patent: Page/Page column 67

2
[ 25222-43-9 ]
[ 35344-95-7 ]

Reference： [1] Patent: WO2017/40449, 2017, A1, . Location in patent: Paragraph 00175

3
[ 37622-90-5 ]
[ 35344-95-7 ]

Reference： [1] European Journal of Organic Chemistry, 2012, # 2, p. 260 - 263

4
[ 68-12-2 ]
[ 591-86-6 ]
[ 35344-95-7 ]

Reference： [1] European Journal of Medicinal Chemistry, 2018, vol. 152, p. 235 - 252

5
[ 18655-47-5 ]
[ 35344-95-7 ]

Reference： [1] Journal of Materials Chemistry, 2006, vol. 16, # 26, p. 2736 - 2745
[2] Bulletin de la Societe Chimique de France, 1990, # 5, p. 660 - 666
[3] Bulletin de la Societe Chimique de France, 1990, # 5, p. 660 - 666
[4] European Journal of Organic Chemistry, 2004, # 11, p. 2367 - 2374

6
[ 153687-35-5 ]
[ 35344-95-7 ]

Reference： [1] Patent: WO2005/813, 2005, A1, . Location in patent: Page 36

7
[ 2075-45-8 ]
[ 68-12-2 ]
[ 35344-95-7 ]

Reference： [1] Journal of Materials Chemistry, 2006, vol. 16, # 26, p. 2736 - 2745

8
[ 824-94-2 ]
[ 35344-95-7 ]
[ 153687-35-5 ]

Yield	Reaction Conditions	Operation in experiment
93.3%	With potassium carbonate In acetonitrile for 1 h; Reflux	To a mixture of 1H-pyrazole-4-carbaldehyde (100 mg, 1.04 mmol) and 1- (chloromethyl)-4-methoxybenzene (162 mg, 1.04 mmol) in CH₃CN (6 mL) was added potassium carbonate (287 mg, 2.08 mmol), the resulting mixture was stirred at reflux for 1 h. The mixture was poured into water (20 mL) and extracted with EtOAc (3×20 mL). The organic layer was dried over Na₂SO₄and concentrated to give 1-(4-methoxybenzyl)- 1H-pyrazole-4-carbaldehyde (220 mg, 93.3 percent) as a colorless oil

Reference： [1] Patent: KR2017/45749, 2017, A, . Location in patent: Paragraph 1087; 1090-1092

9
[ 24424-99-5 ]
[ 35344-95-7 ]
[ 821767-61-7 ]

Yield	Reaction Conditions	Operation in experiment
76%	at 20℃; for 0.5 h;	4-FORMYL-PYRAZOLE-1-CARBOXYLIC acid tert-butyl ester (56). To a solution of 55 (0.31 g, 3.26 mmol) in acetonitrile (30 ml) was added BOC anhydride (0.71 g, 3.26 mmol) followed by DMAP (0.02 g). After 30 minutes of stirring at room temperature, the solvent was evaporated, water and EtOAc were added. Organic layer was separated, washed with 0.5 N HCl (10 ml) and brine (15 ml), dried (NA2S04) and concentrated to give 0.41 g (76percent yield) of the desired product which was used in the next step to prepare di-Boc-protected 2 without purification.
71%	With dmap In acetonitrile at 20℃;	1003831 Step A: Boc2O (2183 mg, 10.0 mmol) was added to a stirred solution of iHpyrazole-4-carbaldehyde (961 mg, 10.0 mmol) in acetonitrile (30 mL) at room temperature, followed by 4-dimethylaminopyridine (“DMAP”) (61.1 mg, 0.500 mmol). After stirring overnight, the reaction was concentrated to dryness and partitioned between ethyl acetate (30 mL) and water (30 mL). The organics were isolated and washed with 0.5N HCL (30 mL) and with brine (30 mL). The organics were isolated, dried (Mg504), filtered and concentratedan oil, which was loaded onto a Biotage 40M column with 4/1 hexanes/ethyl acetate and eluted with the same solvent. Product containing fractions were pooled and concentratedan oil, which eventually solidified to a solid, tert-butyl 4-formyl-1H-pyrazole-1-carboxylate(1.4 g, 71percent).

Reference： [1] Patent: WO2005/813, 2005, A1, . Location in patent: Page 36
[2] Patent: WO2013/130976, 2013, A1, . Location in patent: Paragraph 00383

10
[ 35344-95-7 ]
[ 6482-24-2 ]
[ 304693-70-7 ]

Yield	Reaction Conditions	Operation in experiment
65%	With caesium carbonate In N,N-dimethyl-formamide at 60℃;	To a solution of lH-pyrazole-4-carbaldehyde (500 mg, 5.20 mmol) in DMF (20 mL) was added l-bromo-2-methoxyethane (713 mg, 5.2 mmol) and CS2CO3 (3.40 g, 10.4 mmol). After stirring at 60 °C overnight, water (20 mL) was added to the mixture and the mixture was extracted with EtOAc (50 ml x 3). The organic phase was washed with brine, dried over Na₂S0₄ and concentrated to yield intermediate 50 (520 mg, 65percent> yield).
55%	With caesium carbonate In acetonitrile for 2 h; Reflux	1H-pyrazole-4-carbaldehyde (0.5 g; 5.2 mmol) and cesium carbonate (3.39 g; 10.4mmol) were diluted in ACN (10 mL). Then, 2-bromoethyl methyl ether (0.636 mL; 6.77 mmol) was added and the reaction mixture was refluxed for 2 hours. The reaction mixture was partitionned between a saturated solution of NaHCO3 and EtOAc. The organic layer was separated, dried over MgSO4, filtered and concentrated.The residue was purified by silica gel chromatography (irregular Si02, 120 g, DCM/MeOH: 100/0 to 95/5). The fractions containing the product were mixed andconcentrated to afford 439 mg (55percent) of intermediate 35.

Reference： [1] Patent: WO2018/50684, 2018, A1, . Location in patent: Page/Page column 68
[2] Patent: WO2018/50686, 2018, A1, . Location in patent: Page/Page column 72; 73

11
[ 4333-56-6 ]
[ 35344-95-7 ]
[ 1082066-00-9 ]

Reference： [1] Patent: WO2008/141020, 2008, A1, . Location in patent: Page/Page column 61

[ 35344-95-7 ] Synthesis Path-Downstream 1~88

1
[ 18655-47-5 ]
[ 35344-95-7 ]

Reference： [1]Journal of Materials Chemistry,2006,vol. 16,p. 2736 - 2745
[2]Bulletin de la Societe Chimique de France,1990,p. 660 - 666
[3]Bulletin de la Societe Chimique de France,1990,p. 660 - 666
[4]European Journal of Organic Chemistry,2004,p. 2367 - 2374

2
[ 431-67-4 ]
[ 35344-95-7 ]
[ 102807-90-9 ]

Reference： [1]Journal of Medicinal Chemistry,1990,vol. 33,p. 317 - 327

3
[ 136609-85-3 ]
[ 35344-95-7 ]
5-methyl-6<2-(4-pyrazolyl)-5-benzimidazoyl>-2,3,4,5-tetrahydro-pyridazin-3-one [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,1993,vol. 28,p. 129 - 140

4
[ 2075-45-8 ]
[ 68-12-2 ]
[ 35344-95-7 ]

Reference： [1]Journal of Materials Chemistry,2006,vol. 16,p. 2736 - 2745

5
[ 14538-51-3 ]
[ 35344-95-7 ]
4-(1,3-dihydroxy-4,4,5,5-tetramethylimidazolidin-2-yl)pyrazole [ No CAS ]

Reference： [1]Journal of Materials Chemistry,2006,vol. 16,p. 2736 - 2745

6
[ 952674-99-6 ]
[ 35344-95-7 ]
[ 952675-00-2 ]

Yield	Reaction Conditions	Operation in experiment
36%	With dmap; In 1,1-dichloroethane; at 0 - 20℃; for 3h;	Step I. 1-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)-<strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong>; 2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (0.8 g, 1.9 mmol) was added to a solution of <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (0.6 g, 6.2 mmol) and DMAP (1.5 g, 12 mmol) in DCE (70 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. The solvent was concentrated and the product was purified by flash chromatography on silica gel using DCM/EtOAc (1:1) as eluent to provide the title compound as white solid. Yield: 0.34 g (36percent); MS (ESI) (M+H)+=465.0.
36%	With dmap; In 1,1-dichloroethane; at 0 - 20℃; for 3h;	Step I. 1-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)-<strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong>2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (0.8 g, 1.9 mmol) was added to a solution of <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (0.6 g, 6.2 mmol) and DMAP (1.5 g, 12 mmol) in DCE (70 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. The solvent was concentrated and the product was purified by flash chromatography on silica gel using DCM/EtOAc (1:1) as eluent to provide the title compound as white solid. Yield: 0.34 g (36percent); MS (ESI) (M+H)+=465.0.

Reference： [1]Patent: US2007/244092,2007,A1 .Location in patent: Page/Page column 57
[2]Patent: US2011/86853,2011,A1 .Location in patent: Page/Page column 55-56

7
[ 952675-18-2 ]
[ 35344-95-7 ]
1-({2-tert-butyl-1-[(trans-4-fluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)-1H-pyrazole-4-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%	With N-ethyl-N,N-diisopropylamine;dmap; In dichloromethane; at 20℃; for 3h;	Step B: 1-({2-tert-Butyl-1-[(trans-4-fluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)-<strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong>; 2-tert-Butyl-1-[(4-fluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (400 mg, 1.03 mmol), <strong>[35344-95-7]pyrazole-4-carboxaldehyde</strong> (300 mg, 3.09 mmol) (see Example 126, step H for preparation) and DMAP (catalytic) were stirred in 10 mL of DCM containing DIPEA (0.90 mL, 5.15 mmol) at rt for 3 h. The solution washed with saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography on silica gel using hexanes/EtOAc (1:1) as eluent. Yield: 131 mg (28percent). 1H NMR (400 MHz, CHLOROFORM-D) delta 1.16-1.26 (m, 2H), 1.35-1.48 (m, 2H), 1.54-1.56 (m, 9H), 1.72 (dd, J=8.69, 3.03 Hz, 2H), 1.95-2.04 (m, 1H), 2.11-2.19 (m, 2H), 4.17-4.21 (m, 2H), 4.37-4.46 (m, 1H), 4.50-4.59 (m, 1H), 7.44 (d, J=8.59 Hz, 1H), 7.96 (dd, J=8.69, 1.86 Hz, 1H), 8.08 (s, 1H), 8.44 (d, J=1.37 Hz, 1H), 8.64 (s, 1H), 9.91 (s, 1H).
28%	With N-ethyl-N,N-diisopropylamine;dmap; In dichloromethane; at 20℃; for 3h;	Step B: 1-({2-tert-Butyl-1-[(trans-4-fluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)-<strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong>2-tert-Butyl-1-[(4-fluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (400 mg, 1.03 mmol), <strong>[35344-95-7]pyrazole-4-carboxaldehyde</strong> (300 mg, 3.09 mmol) (see Example 126, step H for preparation) and DMAP (catalytic) were stirred in 10 mL of DCM containing DIPEA (0.90 mL, 5.15 mmol) at rt for 3 h. The solution was washed with saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography on silica gel using hexanes/EtOAc (1:1) as eluent. Yield: 131 mg (28percent). 1H NMR (400 MHz, CHLOROFORM-D) delta 1.16-1.26 (m, 2H), 1.35-1.48 (m, 2H), 1.54-1.56 (m, 9H), 1.72 (dd, J=8.69, 3.03 Hz, 2H), 1.95-2.04 (m, 1H), 2.11-2.19 (m, 2H), 4.17-4.21 (m, 2H), 4.37-4.46 (m, 1H), 4.50-4.59 (m, 1H), 7.44 (d, J=8.59 Hz, 1H), 7.96 (dd, J=8.69, 1.86 Hz, 1H), 8.08 (s, 1H), 8.44 (d, J=1.37 Hz, 1H), 8.64 (s, 1H), 9.91 (s, 1H).

Reference： [1]Patent: US2007/244092,2007,A1 .Location in patent: Page/Page column 95
[2]Patent: US2011/86853,2011,A1 .Location in patent: Page/Page column 91-92

8
[ 594-70-7 ]
[ 35344-95-7 ]
[ 204707-17-5 ]

Yield	Reaction Conditions	Operation in experiment
226.3 mg(51%)	With acetic acid; In ethanol;	Example 12 Production of alpha-(4-pyrazolyl)-N-t-butylnitrone To a suspension of 1,1-dimethylnitroethane (546.0 mg, 5.29 mmol) and zinc (515.5 mg, 7.89 mmol) in ethanol (3.0 ml) was added acetic acid (950.0 mg, 15.8 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for 45 minutes. After cooling the mixture to 5° C. again, <strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (255.4 mg, 2.66 mmol) was added dropwise to the mixture while stirring and stirred at room temperature overnight. Zinc acetate in the mixture was filtered off and the filtrate was concentrated and purified by silica gel chromatography (chloroform/methanol=10/1). Yield: 226.3 mg(51percent) 1H-NMR(CDCl3) 1.60(s, 9H), 6.56(d, 1H, J=2.0 Hz), 7.64(d, 1H, J=2.0 Hz), 7.71(s, 1H), 8.43(brs, 1H)

Reference： [1]Patent: US6194461,2001,B1

9
[ 945466-97-7 ]
[ 35344-95-7 ]
(6R,7S,7aS)-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluorophenyl)-2-[(1H-pyrazol-4-ylmethyl)amino]hexahydro-3H-pyrrolizin-3-one [ No CAS ]
(6R,7S,7aS)-2-[bis(1H-pyrazol-4-ylmethyl)amino]-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluorophenyl)-hexahydro-3H-pyrrolizin-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22%; 48%		To a solution of 20mg (0.04 mmol) (6R3 75, 7a5)-2-amino-6-{(lR)-l-[3,5- bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluorophenyl)hexahydro-3H-pyrrolizin-3-one in 1 mL anhydrous dichloromethane and 7 muL (0.04 mmol) DIEA under nitrogen atmosphere was added crushed 4A molecular sieves followed by 40 mg (0.04 mmol) aromatic heterocyclic aldehyde . After 5 minutes of stirring, the solution was then treated with 40 mg (0.2 mmol) Na(OAc)3BH and the resulting suspension stirred vigorously at room temperature, overnight. The mixture was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (2 x 5 mL). The organics were combined and treated as stated in Example 3, step E. The residue was purified by preparative TLC plate eluding with methanol/dichloromethane (1/9) to afford two products. The less polar product was found to be the mono substituted compound 5.3 mg (22percent),MS: 571 (MH)+,and the slightly more polar product 11.2 mg (48percent) was di-substituted,MS: 651 (MH)+. Conversion to the HCl salts of each were accomplished according to the procedure for Example GJM-5, step C.

Reference： [1]Patent: WO2007/87224,2007,A2 .Location in patent: Page/Page column 37

10
[ 7051-34-5 ]
[ 35344-95-7 ]
[ 1082065-99-3 ]

Yield	Reaction Conditions	Operation in experiment
56%		Preparation 53: 1 -Cyclopropylmethyl- 1 H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> <n="62"/>--61-Add lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (0.200 g, 2.08 mmol) to a suspension of sodium hydride (0.092 g, 2.29 mmol) in DMF (3 mL) at 0 0C. Stir for 20 min. at 0 0C. Add a solution of l-(bromomethyl)cyclopropane (0.295 g, 2.18 mmol) in DMF (4 mL) dropwise to the reaction mixture. Stir reaction to ambient temperature for 18 hr. Quench with aqueous saturated sodium bicarbonate solution and add ethyl acetate. Separate organic layer. Extract aqueous layer twice with ethyl acetate, dry combined organics (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0: 100 to 60:40 ethyl acetate:hexanes) to give the title preparation (175 mg, 56percent). GC-MS: m/z = 150 [M+].

Reference： [1]Patent: WO2008/141020,2008,A1 .Location in patent: Page/Page column 60-61

11
[ 35344-95-7 ]
[ 540-51-2 ]
[ 1082065-98-2 ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium carbonate; In acetonitrile; at 150℃; for 0.333333h;Microwave irradiation;	Preparation 12: 1 -(2-Hydroxy-ethyl)- lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong>Combine lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (0.110 g, 1.14 mmol), 2-bromoethanol(0.172 g, 1.37 mmol), and potassium carbonate (0.236 g, 1.71 mmol) in acetonitrile (2 mL). Heat in microwave at 150 0C for 20 min. Cool to room temperature and filter, wash with acetonitrile. Concentrate filtrate to give l-(2-hydroxy-ethyl)-lH-pyrazole-4- carbaldehyde (0.155 g, 97percent). GC-MS (m/z): 140 (M+).
97%	With potassium carbonate; In acetonitrile; at 150℃; for 0.333333h;Microwave irradiation;	Preparation 52: l-(2-Hydroxy-ethyl)-lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> Combine lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (0.110 g, 1.14 mmol), 2-bromoethanol(0.172 g, 1.37 mmol), and potassium carbonate (0.236 g, 1.71 mmol) in acetonitrile (2 mL). Heat in microwave at 150 0C for 20 min.. Cool to room temperature and filter, washing with acetonitrile. Concentrate filtrate to give the title preparation (0.155 g, 97percent). GC-MS: m/z = 140 [M+].
89%	With potassium carbonate; In acetonitrile; at 150℃; for 0.666667h;Sealed tube; Microwave irradiation;	1-(2-Hydroxyethyl)-<strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> In a 30-mL sealed tube, <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (500 mg, 5.20 mmol, 1.00 equiv), potassium carbonate (1.08 mg, 7.80 mmol, 1.50 equiv) and 2-bromoethan-1-ol (775.3 mg, 6.20 mmol, 1.19 equiv) were mixed in CH3CN (10 mL) at room temperature. The reaction mixture was then irradiated with microwave for 40 min at 150° C. After the reaction was done, the reaction mixture was cooled to room temperature, filtered through a celite pad and the filtrate was concentrated under reduced pressure. The residue was purified in a silica gel column eluting with dichloromethane/methanol (1percent to 5percent gradient) to afford 1-(2-hydroxyethyl)-<strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (650 mg, 89percent) as yellow solid. MS: m/z=140.8 [M+H]+

69%

With potassium carbonate; In acetonitrile; at 150℃; for 0.5h;Microwave irradiation;

1H-Pyrazole-4-carboxaldehyde (0.50 g, 5.21 mmol), 2-bromoethanol (1.30 g, 10.41 mmol) and potassium carbonate (0.79 g, 5.73 mmol) combined with acetonitrile (5 mL) in a microwave vial. The microwave vial was heated at 150 °C in a microwave for 30 minutes. The reaction mixture was filtered and the solvent evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with 0- 100percent ethyl acetate in iso-hexane to afford the title compound (0.50 g, 69percent). 1HNMR (400 MHz, CDCl3): delta 9.86 (s, 1 H); 8.02 (s, 1 H); 7.99 (s, 1 H); 4.33-4.25 (m, 2 H); 4.05 (t, J = 4.8 Hz, 2 H).

Reference： [1]Patent: WO2009/48765,2009,A1 .Location in patent: Page/Page column 16
[2]Patent: WO2008/141020,2008,A1 .Location in patent: Page/Page column 60
[3]Patent: US2016/96834,2016,A1 .Location in patent: Paragraph 0446
[4]Patent: WO2014/86924,2014,A1 .Location in patent: Paragraph 77

12
[ 433-06-7 ]
[ 35344-95-7 ]
[ 790254-33-0 ]

Yield	Reaction Conditions	Operation in experiment
42%		Preparation 55: 1 -(2,2,2-Trifluoro-ethyl)- 1 H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> Add 1 H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (0.40Og, 4.16 mmol) as a solution in DMF (2 mL) dropwise to a suspension of sodium hydride (0.333 g, 8.32 mmol) in DMF (5 mL) at 0 0C. Stir for 15 min. at 0 0C. Add 2,2,2-trifluoroethyl-p-toluenesulfonate (1.27 g, 5.00 mmol) and DMF (3 mL) to the reaction mixture. Heat to 60 0C for 18 hr. Quench with aqueous saturated sodium bicarbonate solution and add ethyl acetate. Separate organic layer. Extract aqueous layer twice with ethyl acetate, wash combined organics with brine, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0: 100 to 100:0 ethyl acetate:hexanes) to give the title preparation (309 mg, 42%). GC-MS: m/z = 178 [M+].

Reference： [1]Patent: WO2008/141020,2008,A1 .Location in patent: Page/Page column 61

13
[ 4333-56-6 ]
[ 35344-95-7 ]
[ 1082066-00-9 ]

Yield	Reaction Conditions	Operation in experiment
8.82%	With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 16h;Sealed tube;	To the stirred solution of lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> 19-4 (200 mg, 2.08 mmol) in DMF (2 ml) in a sealed tube were added potassium carbonate (719.19 mg, 5.20 mmol, 314.06 uL) and bromocyclopropane 19-5 (251.80 mg, 2.08 mmol, 166.76 uL). The reaction mixture was heated at H0C for 16 hours and then cooled to room temperature, diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography to afford l-cyclopropylpyrazole-4-carbafdehyde 19-6 (25 mg, 183.62 umol, 8.82% yield) as gum. NMR (400 MHz, DMSO-d6) d 9.75 (s, 1H), 8.53 (s, 1H), 7.95 (s, 1 1 1 ), 3.86-3.82 (m, 1 1 1 ), 1. 10-1.08 (m, 2) 1 ).. 1.03-0.98 (m, 21 1).
	With potassium carbonate; In N,N-dimethyl-formamide; at 130℃; for 18h;	Preparation 54: 1 -Cyclopropyl- 1 H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong>Dissolve lH-<strong>[35344-95-7]pyrazole-4-carboxaldehyde</strong> in N,N-dimethylformamide (1.9 mL). Add potassium carbonate (0.539 g, 3.90 mmol) and cyclopropylbromide (0.346 g, 2.86 mmol). Heat in a pressure tube to 130 0C for 18 hr. Cool to ambient temperature and add DCM and water. Separate layers and extract water layer 3 times with DCM. Wash combined DCM layers with brine, dry (magnesium sulfate), filter, and concentrated to give the free base of the title preparation. GC-MS: m/z = 136 [M+].

Reference： [1]Patent: WO2019/191112,2019,A1 .Location in patent: Page/Page column 318; 319
[2]Patent: WO2008/141020,2008,A1 .Location in patent: Page/Page column 61

14
[ 35344-95-7 ]
[ 137049-02-6 ]
[ 1082066-05-4 ]

Yield	Reaction Conditions	Operation in experiment
80%	With triethylamine; In dichloromethane; at 20℃; for 18h;	Preparation 61 : l-(l,2-Dimethyl-lH-imidazole-4-sulfonyl)-l H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong>Dissolve lH-<strong>[35344-95-7]pyrazole-4-carboxaldehyde</strong> (0.150 g, 1.56 mmol) in DCM (5 mL). Add triethylamine (240 muL, 1.72 mmol) and l,2-dimethyl-lH-imidazole-4-sulfonyl chloride (0.334g, 1.72 mmol). Stir at ambient temperature for 18 hr. Concentrate, and purify via silica gel chromatography, eluting with 50:50 to 100:0 ethyl acetate: hexanes to give the title preparation (317mg, 80percent). GC-MS: m/z = 254 [M+].

Reference： [1]Patent: WO2008/141020,2008,A1 .Location in patent: Page/Page column 62

15
[ 19788-37-5 ]
[ 35344-95-7 ]
[ 1082065-96-0 ]

Yield	Reaction Conditions	Operation in experiment
91%		Preparation 50: l-(3,5-Dimethylisoxazol-4-ylmethyl)-lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> Add N,N-dimethylformamide (3 mL) to sodium hydride (0.092 g, 2.29 mmol) and stir at 0 0C. Add l-H-<strong>[35344-95-7]pyrazole-4-carboxaldehyde</strong> (0.200 g, 2.08 mmol) and stir at 0 0C for 20 min.. Dissolve 4-chloromethyl-3,5-dimethylisoxazole (0.318 g, 2.18 mmol) in N,N-dimethylformamide (4 mL) and add to reaction mixture. Stir reaction at room temperature for 18 hr. Quench with aqueous saturated sodium bicarbonate solution. Add ethyl acetate and separate organic layer. Extract aqueous layer twice with ethyl acetate. Dry combined organic layers (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 25:75 to 75:25 ethyl acetate:hexanes), to give the title preparation (387 mg, 91percent). GC-MS: m/z = 205 [M+].

Reference： [1]Patent: WO2008/141020,2008,A1 .Location in patent: Page/Page column 60

16
[ 25676-75-9 ]
[ 35344-95-7 ]
[ 1082066-49-6 ]

Yield	Reaction Conditions	Operation in experiment
20%	With dimethylaminoacetic acid; potassium carbonate;copper(l) iodide; In dimethyl sulfoxide; at 110℃; for 66h;	Preparation 62: 1 -(I -Methyl- lH-imidazol-4-y I)- 1 H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong>In an oven-dried flask, combine 4-bromo-l -methyl- lH-imidazole (0.200 g, 1.24mmol), copper (I) iodide (0.022g, 0.113 mmol), N,N-dimethylglycine (0.023 g, 0.226 mmol), and potassium carbonate (0.312 g, 2.26 mmol). Purge with nitrogen 3 times.Add l-H-<strong>[35344-95-7]pyrazole-4-carboxaldehyde</strong> (0.109 g, 1.13 mmol), and DMSO (1.7 mL). Heat to 110 0C for 48 hr. Cool to ambient temperature and partition between ethyl acetate and water. Separate organic layer and extract aqueous layer twice with ethyl acetate. Dry <n="64"/>--63-combined organic layers (magnesium sulfate), filter and concentrate. Add copper (I) iodide (0.022 g, 0.113 mmol), N,N-dimethylglycine (0.023 g, 0.226 mmol), potassium carbonate (0.312 g, 2.26 mmol), and DMSO (1.7 mL). Purge with nitrogen 3 times. Heat to 110 0C for 18 hr. Cool to ambient temperature and partition between ethyl acetate and water. Separate organic layer and extract aqueous layer twice with ethyl acetate. Dry combined organic layers (magnesium sulfate), filter, concentrate, and purify (silica gel chromatography, eluting with 50:50 to 100:0 ethyl acetate: hexanes) to give the title preparation (39 mg, 20percent). GC-MS: m/z = 176 [M+].

Reference： [1]Patent: WO2008/141020,2008,A1 .Location in patent: Page/Page column 62-63

17
[ 19686-73-8 ]
[ 35344-95-7 ]
[ 1082066-01-0 ]

Yield	Reaction Conditions	Operation in experiment
73%	With potassium carbonate; In acetonitrile; at 150℃; for 0.333333h;Microwave irradiation;	Preparation 56: Racemic l-(2-Hydroxy-propyl)-l H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong>Combine 1 H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (0.150g, 1.56 mmol), racemic l-bromo-2- propanol (0.26Og, 1.87 mmol), and potassium carbonate (0.323g, 2.34 mmol) in <n="63"/>--62-acetonitrile (2 mL). Heat in microwave at 150 0C for 20 min.. Filter, wash with acetonitrile and concentrate filtrate. Purify via silica gel chromatography, eluting with 0: 100 to 100:0 ethyl acetate:hexanes) to give the title preparation (177 mg, 73percent). GC- MS: m/z = 154 [M+].

Reference： [1]Patent: WO2008/141020,2008,A1 .Location in patent: Page/Page column 61-62

18
copper(II) choride dihydrate [ No CAS ]
[ 21050-13-5 ]
[ 35344-95-7 ]
[ 1310-73-2 ]
(Ph3PNPPh3)3[Cu3(μ3-O)(μ-4-CHO-pyrazolate)3Cl3]Cl [ No CAS ]

Reference： [1]Inorganic Chemistry,2008,vol. 47,p. 7644 - 7650

19
[ 1056249-32-1 ]
[ 35344-95-7 ]
C₁₈H₁₃N₅O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4344 - 4347

20
[ 7703-74-4 ]
[ 35344-95-7 ]
2,6-bis(4-formylpyrazolylmethyl)pyridine [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2008,p. 1431 - 1440

21
[ 1018720-28-9 ]
[ 35344-95-7 ]
C₁₇H₁₉N₅O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 4042 - 4045

22
[ 911491-26-4 ]
[ 35344-95-7 ]
[ 911491-63-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 4245 - 4249

23
[ 1194-02-1 ]
[ 35344-95-7 ]
[ 1152958-56-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 60℃; for 6h;Inert atmosphere;	To a mixture of 4-fluorobenzonitrile (2.49 g, 20.6 mmol) and 4-formylpyrazole (1.98 g, 20.6 mmo) in 50 mL of DMF at 0 0C was added 95percent sodium hydride (0.54 g, 22.7 mmol) under nitrogen. The mixture was heated to 60 0C for 6 hours and cooled to room temperature, Water was added carefully and the mixture was then extracted with ethyl acetate. The combined extracts were washed with water and brine, and then dried over sodium sulfate, filtered, and concentrated in vacuo to provide crude 4~(4-formyMH-pyrazol-l-yl)benzonitrile.

Reference： [1]Patent: WO2010/19391,2010,A1 .Location in patent: Page/Page column 42-43

24
[ 503555-59-7 ]
[ 35344-95-7 ]
[ 1273318-79-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 1242 - 1255

25
[ 37622-90-5 ]
[ 35344-95-7 ]

Reference： [1]European Journal of Organic Chemistry,2012,p. 260 - 263

26
[ 1365627-50-4 ]
[ 35344-95-7 ]
[ 1365627-04-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2052 - 2062

27
[ 589-10-6 ]
[ 35344-95-7 ]
[ 1396722-54-5 ]

Yield	Reaction Conditions	Operation in experiment
71%		Alternate synthesis: l-(2-phenoxyethyl)-lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong>Sodium hydride (60percent>, 6.3 g, 1.0 eq) was added to a solution of lH-pyrazole-4- carbaldehyde (15 g, 156 mmol) in DMF (150 ml) at 0°C. The mixture was allowed to warm and was stirred at room temperature. (2-Bromoethoxy)benzene (30.2 g, 1 eq) was then added and the resulting mixture was stirred overnight at room temperature. It was quenched by addition of aqueous ammonium chloride, diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. The residue was purified by column chromatography using a hexane/EtOAc gradient (10: 1 to 0: 100). Pure fractions were combined and evaporated under reduced pressure to yield l-(2-phenoxyethyl)-lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (24 g, 71percent).
71%		Sodium hydride (60percent, 6.3 g, 1.0 eq) was added to a solution of <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (15 g, 156 mmol) in DMF (150 ml) at 0° C. The mixture was allowed to warm and was stirred at room temperature. (2-Bromoethoxy)benzene (30.2 g, 1 eq) was then added and the resulting mixture was stirred overnight at room temperature. It was quenched by addition of aqueous ammonium chloride, diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography using a hexane/ EtOAc gradient (10:1 to 0:100). Pure fractions were combined and evaporated under reduced pressure to yield 1-(2-phenoxyethyl)-<strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (24 g, 71percent).

Reference： [1]Patent: WO2012/118782,2012,A1 .Location in patent: Page/Page column 79; 80
[2]Patent: US2013/317003,2013,A1 .Location in patent: Paragraph 0440

28
[ 35344-95-7 ]
[ 1099-45-2 ]
[ 1396722-63-6 ]

Yield	Reaction Conditions	Operation in experiment
73%	In tetrahydrofuran; at 70℃; for 14h;	Intermediate 390A: Ethyl (E)- -(lH-pyrazol-4-yl)acrylate To a stirred solution of lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (2 g, 20.8 mmol) in THF (30 mL) was added (carbothoxymethylene)triphenylphosphorane (8 g, 22.9 mmol). The reaction mixture was then heated at 70 °C for 14 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (3percent methanol /chloroform) to isolate ethyl 3-(lH-pyrazol-4-yl)acrylate (2.5 g, 73percent yield). NMR (400 MHz, DMSO-de) delta 13.14 (br s, IH), 8.18 (s, IH), 7.93 (s, IH), 7.57 (d, J=15.6 Hz, IH), 6.32 (d, J=16.1 Hz, IH), 4.15 (q, J=7.0 Hz, 2H), 1.24 (t, J=7.3 Hz, 3H); LCMS m/z 165 (M-H).
60%	In tetrahydrofuran; at 70℃; for 8h;Inert atmosphere;	(E)-ethyl 3- ( lH-pyrazol-4-yl)acrylate[(Ethoxycarbonyl)methylene]triphenylphosphorane (0.836g, 2.4 mmol) was added to a solution of iH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (0.192 g, 2 mmol) in THF (6 mL) at room temperature. This solution was heated at 70°C under anitrogen atmosphere for 8h. HPLC/MS analysis indicated completion of the reaction and both E and Z isomers of product were observed. The reaction mixture was cooled down to room temperature and evaporated in vacuo to get the crude product. This crude was purified by silica gel column chromatography using 0-80percent EtOAc in hexanes as eluent to provide, after evaporation of pooled fractions, pure (E)-ethyl 3-( H-pyrazol-4-yl)acrylate (0.198g, 60percent) as a white solid. ES+ (M+H)+ 167
60%	In tetrahydrofuran; at 20 - 70℃; for 8h;Inert atmosphere;	[(Ethoxycarbonyl)methylene]triphenylphosphorane (0.836 g, 2.4 mmol) was added to a solution of <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (0.192 g, 2 mmol) in THF (6 mL) at room temperature. This solution was heated at 70° C. under a nitrogen atmosphere for 8 h. [0446] HPLC/MS analysis indicated completion of the reaction and both E and Z isomers of product were observed. The reaction mixture was cooled down to room temperature and evaporated in vacuo to get the crude product. This crude was purified by silica gel column chromatography using 0-80percent EtOAc in hexanes as eluent to provide, after evaporation of pooled fractions, pure (E)-ethyl 3-(1H-pyrazol-4-yl)acrylate (0.198 g, 60percent) as a white solid. ES+(M+H)+167

Reference： [1]Patent: WO2016/210034,2016,A1 .Location in patent: Page/Page column 223
[2]Patent: WO2012/118782,2012,A1 .Location in patent: Page/Page column 82-83
[3]Patent: US2013/317003,2013,A1 .Location in patent: Paragraph 0445; 0446

29
[ 5927-18-4 ]
[ 35344-95-7 ]
[ 1295583-21-9 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In 1,4-dioxane; dimethyl sulfoxide; at 20 - 100℃;	(E)-methyl 3-(l -methyl- lH-pyrazol-4-yl)acrylateCs2C03 (1.304g, 4 mmol) was added to a solution of lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (0.192 g, 2 mmol) in dioxane (8 mL) at room temperature. Trimethylphosphonoacetate (0.364g, 0.40 mmol) was added to this suspension, followed by DMSO (2 mL). The reaction mixture was heated to 100°C overnight. It was then diluted with EtOAc (40 mL), and washed with water (40 mL) and brine (20 mL). The organic layer was concentrated under vacuum. The crude was purified by silica gel column chromatography using a 0-100percent gradient of EtOAc in hexanes to provide (E)-methyl 3 -(1 -methyl- lH-pyrazol-4- yl)acrylate (0.278 g). ES+ (M+H)+ 167
0.278 g	With caesium carbonate; In 1,4-dioxane; dimethyl sulfoxide; at 20 - 100℃;	Cs2CO3 (1.304 g, 4 mmol) was added to a solution of <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (0.192 g, 2 mmol) in dioxane (8 mL) at room temperature. Trimethylphosphonoacetate (0.364 g, 0.40 mmol) was added to this suspension, followed by DMSO (2 mL). The reaction mixture was heated to 100° C. overnight. It was then diluted with EtOAc (40 mL), and washed with water (40 mL) and brine (20 mL). The organic layer was concentrated under vacuum. The crude was purified by silica gel column chromatography using a 0-100percent gradient of EtOAc in hexanes to provide (E)-methyl 3-(1-methyl-1H-pyrazol-4-yl)acrylate (0.278 g). ES+(M+H)+167

Reference： [1]Patent: WO2012/118782,2012,A1 .Location in patent: Page/Page column 74-75
[2]Patent: US2013/317003,2013,A1 .Location in patent: Paragraph 0429

30
[ 1396722-16-9 ]
[ 35344-95-7 ]
[ 1396722-21-6 ]

Yield	Reaction Conditions	Operation in experiment
		E) -tert-butyl (2-(3-(lH-pyrazol-4-yl)acrylamido)phenyl)carbamateA 60percent) suspension of NaH in paraffin oil (192mg, 5mmol) was added portionwise to a solution of tert-butyl (2-(2-(diethoxyphosphoryl)acetamido)phenyl)carbamate (1.93g, 5mmol) in anhydrous THF (25mL) at 0°C. The reaction mixture was stirred for 30min before being warmed up to room temperature. iH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (400 mg, 4.16mmol) dissolved in anhydrous THF (5 mL) was then added and the reaction mixture was stirred for 72h under a nitrogen atmosphere. After completion of the reaction as indicated by HPLC, the mixture was diluted with EtO Ac (80 mL) and quenched with a saturated NH4C1 solution (10 mL). The organic layer was separated and washed with water (40mL) and brine (20mL). It was dried over anhydrous Na2S04 and the solid was filtered. The filtrate was evaporated under vacuum. The isolated crude was purified by silica gel column chromatography using a gradient of 0-100percent EtOAc in hexanes to provide 986mg of (E)-tert-butyl (2-(3-(lH-pyrazol-4-yl)acrylamido)phenyl)carbamate as a white solid. 1HNMR (300MHz, CD3OD): delta 7.93 (broad s, 2H), 7.64 (d, 1H, J= 15.6 Hz), 7.56 (d, 1H, J= 7.2 Hz), 7.45 d, 1H, J= 7.8 Hz), 7.11-7.24 (m, 2H), 6.59 (d, 1H, J = 15.6 Hz), 1.50 (s, 9H), MS: ES+(M+Na)+: 351
986 mg		A 60percent suspension of NaH in paraffin oil (192 mg, 5 mmol) was added portionwise to a solution of tert-butyl (2-(2-(diethoxyphosphoryl)acetamido)phenyl)carbamate (1.93 g, 5 mmol) in anhydrous THF (25 mL) at 0° C. The reaction mixture was stirred for 30 min before being warmed up to room temperature. <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (400 mg, 4.16 mmol) dissolved in anhydrous THF (5 mL) was then added and the reaction mixture was stirred for 72 h under a nitrogen atmosphere. After completion of the reaction as indicated by HPLC, the mixture was diluted with EtOAc (80 mL) and quenched with a saturated NH4Cl solution (10 mL). The organic layer was separated and washed with water (40 mL) and brine (20 mL). It was dried over anhydrous Na2SO4 and the solid was filtered. The filtrate was evaporated under vacuum. The isolated crude was purified by silica gel column chromatography using a gradient of 0-100percent EtOAc in hexanes to provide 986 mg of (E)-tert-butyl (2-(3-(1H-pyrazol-4-yl)acrylamido)phenyl)carbamate as a white solid. 1HNMR (300 MHz, CD3OD): delta 7.93 (broad s, 2H), 7.64 (d, 1H, J=15.6 Hz), 7.56 (d, 1H, J=7.2 Hz), 7.45 d, 1H, J=7.8 Hz), 7.11-7.24 (m, 2H), 6.59 (d, 1H, J=15.6 Hz), 1.50 (s, 9H), MS: ES+(M+Na)+: 351

Reference： [1]Patent: WO2012/118782,2012,A1 .Location in patent: Page/Page column 67-68
[2]Patent: US2013/317003,2013,A1 .Location in patent: Paragraph 0420

31
[ 88-14-2 ]
[ 119072-55-8 ]
[ 769-92-6 ]
[ 35344-95-7 ]
[ 1417700-08-3 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 534 - 546

32
[ 78-81-9 ]
[ 35344-95-7 ]
[ 1431160-06-3 ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; In methanol; at 25℃; for 4h;	General procedure: To a solution of the aldehyde (1 equiv.) and amine (1 equiv.) in methanol was added a catylytic amount of glacial acetic acid (a few drops) and the contents were stirred at 25 °C as outlined in reaction Scheme 1. After 4 h, the methanol was removed under reduced pressure and the crude aldimine J_a was used in the next step without further purification.

Reference： [1]Patent: WO2013/27196,2013,A1 .Location in patent: Page/Page column 65
[2]Journal of Medicinal Chemistry,2016,vol. 59,p. 7950 - 7962

33
[ 35344-95-7 ]
[ 107-91-5 ]
[ 1428874-95-6 ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 5298 - 5301

34
[ 179380-98-4 ]
[ 35344-95-7 ]
[ 1432731-26-4 ]

Yield	Reaction Conditions	Operation in experiment
52.7%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 180℃; for 0.5h;Microwave irradiation;	7-(Bromomethyl)-4-(4-fluorophenyl)quinoline-2-carbonitrile (2-1, 100.0 mg, 0.293 mmol, 1.0 equiv.), DIEA (0.051 ml, 0.293 mmol, 1.0 equiv.), and l-H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (33.8 mg, 0.352 mmol, 1.2 equiv.) were added to acetonitrile (1.0 mL) in a microwave reaction vessel and the resulting mixture was irradiated with microwave at 180 °C for 30 minutes. The reaction mixture was cooled and concentrated and the residue was purified by reverse phase HPLC (H20/ CH3CN gradient w/ 0.1percent TFA modifier) to afford 4-(4-fluorophenyl)-7-[(4-formyl-l H-pyrazol-l-yl)methyl]quinoline-2-carbonitrile (3-8, 55.0 mg, 52.7percent) as a colorless solid. LRMS m/z (M+H)+ 357.1 found, 357.1 required.

Reference： [1]Patent: WO2013/66736,2013,A1 .Location in patent: Page/Page column 82

35
[ 76-83-5 ]
[ 35344-95-7 ]
[ 218594-00-4 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 20℃; for 1h;	[007101 Compound 80 was prepared in 4 steps from 1 H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> according to the following procedures: <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (2.1 mmol, 1.0 equiv) was dissolved in 20 mL methylene chloride followed by the addition of triethylamine (3.0 equiv) and trityl chloride (1.0 equiv). The reaction was stirred at RT for lh after it was quenched with water (lmL) and extrated with methylene chloride. The organic layers were concentrated and purified using flash silica gel chromatography (gradient 0-30percent methanol/methylene chloride with 0.5percent triethylamine). 1-Trity -]H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> was then converted to it?s corresponding alkyne using Method J after which it was coupled to compound B using the analogous coupling conditions in Example 1. The resulting compound was then deprotected under standard triflouroacetic acid in methylene chloride deprotection conditions after which it was concentrated and purified using flash silica gel chromatography (ISCO, gradient 0-5percent methanol/methylene chroride with 0.05percent triethylamine and then repurified using reverse-phase HPLC (Interchim Cl 8-Sunfire column, gradient of acetonitrile/water with 0.01percent formic acid) to provide compound 80. ESI-MS m/z: 515.0 [M+H]b.
	With triethylamine; In dichloromethane; at 20℃; for 1h;	[001366] Compound 80 was prepared in 4 steps from lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> according to the following procedures: lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (2.1 mmol, 1.0 equiv) was dissolved in 20 mL methylene chloride followed by the addition of triethylamine (3.0 equiv) and trityl chloride (1.0 equiv). The reaction was stirred at RT for lh after it was quenched with water (ImL) and extrated with methylene chloride. The organic layers were concentrated and purified using flash silica gel chromatography (gradient 0-30percent methanol/methylene chloride with 0.5percent triethylamine). 1-Trity -/H-pyrazole-4- carbaldehyde was then converted to it's corresponding alkyne using Method J after which it was coupled to compound B using the analogous coupling conditions in Example 1. The resulting compound was then deprotected under standard triflouroacetic acid in methylene chloride deprotection conditions after which it was concentrated and purified using flash silica gel chromatography (ISCO, gradient 0-5percent methanol/methylene chroride with 0.05percent triethylamine and then repurified using reverse-phase HPLC (Interchim C18-Sunfire column, gradient of acetonitrile/water with 0.01percent formic acid) to provide compound 80. ESI-MS m/z: 515.0 [M+H]+.

Reference： [1]Patent: WO2015/51244,2015,A1 .Location in patent: Paragraph 00710
[2]Patent: WO2015/143012,2015,A1 .Location in patent: Paragraph 001366

36
[ 5292-43-3 ]
[ 35344-95-7 ]
tert-butyl 2-(4-formylpyrazol-1-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%		Intermediate 62. Tert-butyl 2-(4-formylpyrazol-1-yl)acetate A mixture of <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (0.5 g, 5.2 mmol), potassium tert-butoxide (0.7 g, 6.25 mmol) in N,N-dimethylformamide (6 mL) was stirred at room temperature for 5 minutes. Tert-butylbromoacetate (1.11 g, 5.72 mmol) was added and the resulting mixture was stirred for 2 hours at room temperature. The reaction was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was collected, washed with water then brine, passed through a hydrophobic fit and the solvent was removed in vacuo. The crude material was purified by silica gel column chromatography, eluting with 15-100percent ethyl acetate in iso-hexane, to afford the title compound (0.678 g, 62percent) as colorless oil. 1H NMR (400 MHz, CDCl3): delta 9.89 (s, 1H), 8.02-8.00 (m, 2H), 4.86 (s, 2H), 1.48 (s, 9 H).
62%		A mixture of <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (0.5 g, 5.2 mmol), potassium tert-butoxide (0.7 g,6.25 mmol) in N,N-dimethylformamide (6 mL) was stirred at room temperature for 5 minutes. Tert-butyibromoacetate (1.11 g, 5.72 mmol) was added and the resulting mixture was stirred for 2 hours at room temperature. The reaction was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was collected,washed with water then brine, passed through a hydrophobic frit and the solvent was removed in vacuo. The crude material was purified by silica gel column chromatography, eluting with 15-100percent ethyl acetate in iso-hexane, to afford the title compound (0.678 g, 62percent) as colorless oil.?H NMR (400 MHz, CDC13): oe 9.89 (s, 1 H), 8.02-8.00 (m, 2 H), 4.86 (s, 2 H), 1.48 (s, 9 H).

Reference： [1]Patent: US2015/158858,2015,A1 .Location in patent: Paragraph 0455; 0456; 0457
[2]Patent: WO2015/82616,2015,A1 .Location in patent: Page/Page column 68

37
[ 75-30-9 ]
[ 35344-95-7 ]
1-isopropyl-1H-pyrazole-4-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69.54%	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;	To a stirred solution of lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (S2-1) (200 mg, 2.08 mmol) in DMF (2 rnL) was added 2-iodopropane (707.66 mg, 4.16 mmol, 416.27 uL) and Cesium carbonate (1.36 g, 4.16 mmol) at ambient temperature. The resulting mixture was heated at 80C for 16 hours. It was then cooled to room temperature, diluted with ice cold w'ater and extracted with ethyl acetate. The combined extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The reaction mixture was purified by flash chromatography (eluting with 30% ethyl acetate-hexane) to afford l-isopropylpyrazoJe-4-carbaldehyde (S2-2) (200 mg, 1.45 mmol, 69.54% yield) as brown liquid. LCMS: ES+ 139.1.
42%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 2h;	1-isopropyl-<strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> To a solution of lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (2.0 g, 21 mmol) and 2-iodopropane (5.32 g, 31.5 mmol) in DMF (10 mL) was added sodium hydride (60% dispersion in mineral oil, 0.83 g, 20.7 mmol) in one portion. The resulting mixture was stirred at room temperature for 2 hours, before being quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-50% EtO Ac/heptane to obtain 1- isopropyl<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (1.2 g, 42% yield). 1H NMR (400 MHz, CDC13) delta 9.86 (s, 1H), 7.97 (s, 2H), 4.54 (p, / = 6.7 Hz, 1H), 1.55 (d, / = 6.7 Hz, 6H).

Reference： [1]Patent: WO2019/191112,2019,A1 .Location in patent: Page/Page column 209; 300
[2]Patent: WO2015/135094,2015,A1 .Location in patent: Page/Page column 80-81

38
[ 574-98-1 ]
[ 35344-95-7 ]
1-[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)ethyl]-1H-pyrazole-4-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14%	With caesium carbonate; In acetonitrile; at 150℃; for 0.666667h;Microwave irradiation;	1-[2-(1,3-Dioxo-2,3-dihydro-1H-isoindol-2-yl)ethyl]-<strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> In a 30-mL vial, <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (2.0 g, 20.81 mmol, 1.00 equiv), 2-(2-bromoethyl)-2,3-dihydro-1H-isoindole-1,3-dione (6.3 g, 24.98 mmol, 1.20 equiv) and Cs2CO3 (13.5 g, 41.63 mmol, 2.00 equiv) were mixed in CH3CN (10 mL) at room temperature. The resulting mixture was irradiated with microwave for 40 min at 150° C. After the reaction was done, the reaction mixture was cooled to room temperature, diluted with 10 mL water and extracted with ethyl acetate (3*10 ml). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified in a silica gel column eluting with ethyl acetate in petroleum ether (1percent to 50percent gradient) to afford 1-[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)ethyl]-<strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (800 mg, 14percent) as white solid. MS: m/z=270.0 [M+H]+.

Reference： [1]Patent: US2016/96834,2016,A1 .Location in patent: Paragraph 0453

39
[ 76513-69-4 ]
[ 35344-95-7 ]
[ 869558-91-8 ]

Yield	Reaction Conditions	Operation in experiment
57%	With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 1h;	To a stirring solution of ?H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> SM1 (500 mg, 5.2mmol) in DMF (lOmL) was added NaH (248mg, 6.2mmol), followed by SEMC1 (1.03g,6.2mmol) at 0 °C and stirred at room temperature for ?H. The reaction mixture was diluted with water and extracted with EA. Combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude product, which was purified by silica gel column chromatography to afford compound 1 (800mg,57percent). TLC:20percent EtOAc/Hexane (Rf: 0.5). LC-MS: m/z = 227[(M+1)].

Reference： [1]Patent: WO2016/44777,2016,A1 .Location in patent: Page/Page column 65

40
[ 1221280-93-8 ]
[ 35344-95-7 ]
tert-butyl N-[trans-3-(4-formyl-1H-pyrazol-1-yl)cyclobutyl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;	1H- <strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (1.73 g, 18.00 mmol, 1.20 eq.) and Cs2CO3 (9.78 g, 30.02 mmol, 2.00 eq.) were added to a solution of tert-butyl N-[3-(methanesulfonyloxy)cyclobutyl]carbamate (4 g, 15.08 mmol, 1.00 eq.) in DMF (100 mL). The resulting solution was stirred for 16 hours at 80 C and then diluted with 300 mL of water. The resulting solution was extracted with ethyl acetate (3x300 mL) and the organic layers combined. The resulting mixture was washed with brine (3x500 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Flash with the following conditions: Column, C18 silica gel; mobile phase, X:H20 Y:ACN=70/30 increasing to X:H20 Y:ACN=20/80 within 30 mm;Detector, UV 254 nm. The isomers were separated by Prep-SFC with the following conditions (Prep SFC8O-2): Column, Chiralpak TB, 2*25cm, 5um; mobile phase, CO2 (80%), IPA (20%); Detector, UV 220nm. This resulted in 1.2 g (30%) of tert-butyl N-trans-3-(4-formyl-1H- pyrazol-1-yl)cyclobutyl]carbamate as a white solid.

Reference： [1]Patent: WO2015/196071,A1 .Location in patent: Paragraph 0343
Patent: ,2015, .Location in patent: Paragraph 0343

41
[ 1221280-93-8 ]
[ 35344-95-7 ]
tert-butyl N-[cis-3-(4-formyl-1H-pyrazol-1-yl)cyclobutyl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h;	into a 100-mL round-bottom flask, was placed a solution of tert-butyl N-[3-(methanesulfonyloxy)cyclobutyl]carbamate (2.65 g, 9.99 mmol, 1.00 eq.), <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (1.152 g, 11.99 mmol, 1.20 eq.) and Cs2CO3 (6.52 g, 20.01 mmol, 2.00 eq.) inDMF (20 mL). The resulting solution was stirred for 4 h at room temperature. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 100 mL of brine. The mixture was dried over anhydrous sodium sulfate andconcentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (CombiFlash-1): Column, C18 silica gel; mobile phase, MeCN/H20=60:40 increasing to MeCN/H20=70:30 within 3 mm; Detector, UV 254 nm. The crude product was purified by Prep-SFC with the following conditions (prep SFC 350-2):Column: Phenomenex Lux 5u Cellulose-4 250*50mm; mobile Phase A: C02:70, Mobile PhaseB: MeQH-HPLC:30; Flow rate: 150 mL/min; 254 nm; RT1:4.53; RT2:5.36. This resulted in 712 mg (54%) of tert-butyl N-[cis-3 -(4-formyl- 1 H-pyrazol- 1 -yl)cyclobutyl]carbamate as a white solid.

Reference： [1]Patent: WO2015/196071,A1 .Location in patent: Paragraph 0369
Patent: ,2015, .Location in patent: Paragraph 0369

42
[ 107-13-1 ]
[ 35344-95-7 ]
2-[hydroxy-(1H-pyrazol-4-yl)-methyl]-acrylonitrile [ No CAS ]

Reference： [1]RSC Advances,2016,vol. 6,p. 62778 - 62784

43
[ 1221280-93-8 ]
[ 35344-95-7 ]
tert-butyl N-trans-[3-(4-formyl-1H-pyrazol-1-yl)cyclobutyl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;	Step 3: tert-butyl Af-fra is-3-(4-formyI-lH-pyrazo -yl)cyclobutyl]carbamate: l H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (1.73 g, 18.00 mmol, 1.20 eq.) and Cs2C03 (9.78 g, 30.02 mmol, 2.00 eq.) were added to a solution of tert-butyl N-[3- (methanesulfonyloxy)cyclobutyl]carbamate (4 g, 15.08 mmol, 1.00 eq.) in DMF (100 mL). The resulting solution was stirred for 16 hours at 80 C and then diluted with 300 mL of water. The resulting solution was extracted with ethyl acetate (3x300 mL) and the organic layers combined. The resulting mixture was washed with brine (3x500 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Flash with the following conditions: Column, CI 8 silica gel; mobile phase, X:H20 Y:ACN=70/30 increasing to X:H20 Y:ACN=20/80 within 30 min; Detector, UV 254 nm. The isomers were separated by Prep-SFC with the following conditions (Prep SFC80-2): Column, Chiralpak IB, 2*25cm, 5um; mobile phase, CO2(80%), IPA(20%); Detector, UV 220nm. This resulted in 1.2 g (30%) of tert-butyl N-/ra5-3-(4-formyl-lH-pyrazol-l -yl)cyclobutyl]carbamate as a white solid.
30%	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;	lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (1.73 g, 18.00 mmol, 1.20 eq.) and Cs2C03 (9.78 g, 30.02 mmol, 2.00 eq.) were added to a solution of tert-butyl N-[3- (methanesulfonyloxy)cyclobutyl]carbamate (4 g, 15.08 mmol, 1.00 eq.) in DMF (100 mL). The resulting solution was stirred for 16 hours at 80 C and then diluted with 300 mL of water. The resulting solution was extracted with ethyl acetate (3x300 mL) and the organic layers combined. The resulting mixture was washed with brine (3x500 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Flash with the following conditions: Column, CI 8 silica gel; mobile phase, X:H20 Y:ACN=70/30 increasing to X:H20 Y:ACN=20/80 within 30 min; Detector, UV 254 nm. The isomers were separated by Prep-SFC with the following conditions (Prep SFC80-2): Column, Chiralpak IB, 2*25cm, 5um; mobile phase, C02 (80%), IPA (20%); Detector, UV 220nm. This resulted in 1.2 g (30%) of tert-butyl N-fra ,-3-(4-formyl-lH-pyrazol-l-yl)cyclobutyl]carbamate as a white solid.
30%	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;	lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (1.73 g, 18.00 mmol, 1.20 eq.) and Cs2C03 (9.78 g, 30.02 mmol, 2.00 eq.) were added to a solution of tert-butyl N-[3-(methanesulfonyloxy)cyclobutyl] carbamate (4 g, 15.08 mmol, 1.00 eq.) in DMF (100 mL). The resulting solution was stirred for 16 hours at 80 C and then diluted with 300 mL of water. The resulting solution was extracted with ethyl acetate (3x300 mL) and the organic layers combined. The resulting mixture was washed with brine (3x500 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Flash with the following conditions: Column, C18 silica gel; mobile phase, X:H20 Y:ACN=70/30 increasing to X:H20 Y:ACN=20/80 within 30 min; Detector, UV 254 nm. The isomers were separated by Prep-SFC with the following conditions (Prep SFC80-2): Column, Chiralpak IB, 2*25cm, 5um; mobile phase, CO2 (80%), IPA (20%); Detector, UV 220nm. This resulted in 1.2 g (30%) of tert-butyl N-trans-3-(4- formyl-lH-pyrazol-l-yl)cyclobutyl] carbamate as a white solid.

Reference： [1]Patent: WO2016/105468,2016,A1 .Location in patent: Paragraph 0182
[2]Patent: WO2016/115090,2016,A1 .Location in patent: Paragraph 0336
[3]Patent: WO2017/40606,2017,A1 .Location in patent: Paragraph 0295

44
[ 5305-59-9 ]
[ 35344-95-7 ]
1-(6-aminopyrimidin-4-yl)-1H-imidazole-4-formaldehyde [ No CAS ]

Reference： [1]Patent: CN105418592,2016,A .Location in patent: Paragraph 0164; 0165; 0166; 0167; 0168

45
[ 62-53-3 ]
[ 35344-95-7 ]
C₁₀H₉N₃ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 7950 - 7962

46
[ 35344-95-7 ]
[ 2516-47-4 ]
C₈H₁₁N₃ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 7950 - 7962

47
[ 617-79-8 ]
[ 35344-95-7 ]
C₁₀H₁₇N₃ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 7950 - 7962

48
[ 1003-03-8 ]
[ 35344-95-7 ]
C₉H₁₃N₃ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 7950 - 7962

49
((1r,3r)-3-(3-phenylisoxazole-5-carboxamido)cyclobutyl)methyl 4-methylbenzenesulfonate [ No CAS ]
[ 35344-95-7 ]
3-phenyl-N-[(1r,3r)-3-[(4-formyl-1H-pyrazol-1-yl)methyl]cyclobutyl]-1,2-oxazole-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
400 mg	With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 3h;	To a 50-mL round-bottom flask was placed a solution of [(l r,3r)- 3-(3-pheny 1- 1 ,2-oxazole-5-amido)cyclobuty ljmethyl 4-methylbenzene- 1 -sulfonate (980 mg, 2.30 mmol, 1.00 equiv) in DMF (20 mL), then lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (331 mg, 3.44 mmol, 1.50 equiv) and Cs2C03 (l . l g, 3.37 mmol, 1.50 equiv) were added. The resulting solution was stirred for 3 h at 70°C, diluted with 50 mL of H20, filtered, and then extracted with EtOAc. The organic extracts were combined, dried over anhydrous Na2S04, and concentrated under reduced pressure. The residue was applied onto a silica gel column and eluted with EtOAc/petroleum ether (1 :3) affording 400 mg (50percent) of 3-phenyl-N-[(l r,3r)-3-[(4- formyl-lH-pyrazol-l -yl)methyl]cyclobutyl]-l ,2-oxazole-5-carboxamide as a white solid. LCMS (ES, m/z): [M+H]+ = 351.1.

Reference： [1]Patent: WO2016/105485,2016,A2 .Location in patent: Paragraph 0319

50
[(1s,3s)-3-(3-phenyl-1,2-oxazole-5-amido)cyclobutyl]methyl 4-methylbenzene-1-sulfonate [ No CAS ]
[ 35344-95-7 ]
3-phenyl-N-[(1s,3s)-3-[(4-formyl-1H-pyrazol-1-yl)methyl]cyclobutyl]-1,2-oxazole-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3h;	To a 50-mL round-bottom flask was placed a solution of [( 1 s,3s)-3-(3-pheny 1- 1 ,2-oxazole-5-amido)cyclobuty l]methy 1 4-methylbenzene- 1 -sulfonate ( 1 g, 2.34 mmol, 1.00 equiv) in DMF (15 mL) then Cs2C03 (1.5 g, 4.60 mmol, 2.00 equiv) and lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (338 mg, 3.52 mmol, 1.50 equiv) were added. The resulting solution was stirred for 3 h at 100°C then the solids were removed by filtration. The crude product was purified by Flash-Prep-HPLC (CombiFlash-1 : Column, C18 silica gel; mobile phase, X: H20 (0.5percent NFUHCC ), Y: ACN, X/Y=90/10 increasing to X/Y=5/95 within 40 min; Detector, UV 254 nm) affording 460 mg (56percent) of 3-phenyl-N-[(l s,3s)-3-[(4-formyl-lH- pyrazol-l-yl)methyl]cyclobutyl]-l,2-oxazole-5-carboxamide as a yellow solid. LCMS (ES, m/z): [M+H]+ = 351.1.

Reference： [1]Patent: WO2016/105485,2016,A2 .Location in patent: Paragraph 0324

51
[ 33252-28-7 ]
[ 35344-95-7 ]
6-(4-formyl-1H-pyrazol-1-yl)nicotinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1 g	With potassium acetate; In dimethyl sulfoxide; at 100℃; for 2h;	To a solution of <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (500 mg, 5 mmol) and 6- chloronicotinonitrile (700 mg, 5 mmol ) in 20 mL DMSO was added KOAc (2.1 g, l5mmol). The resulting mixture was stirred at 100°C for 2 hours. The resulting mixture was concentrated and the crude product was purified by flash column chromatography to give the 6-(4-formyl- 1H- pyrazol-1-yl)nicotinonitrile (1.0 g). The structure was confirmed by LC-MS

Reference： [1]Patent: WO2016/127074,2016,A1 .Location in patent: Page/Page column 38

52
[ 1221280-93-8 ]
[ 35344-95-7 ]
tert-butyl N-[cis-3-(4-formyl-1H-pyrazol-1-yl)cyclobutyl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h;	into a 100-mL round-bottom flask, was placed a solution of tert-butyl N-[3- (methanesulfonyloxy)cyclobutyl]carbamate (2.65 g, 9.99 mmol, 1.00 eq.), lH-pyrazole-4- carbaldehyde (1.152 g, 11.99 mmol, 1.20 eq.) and Cs2C03 (6.52 g, 20.01 mmol, 2.00 eq.) in DMF (20 mL). The resulting solution was stirred for 4 h at room temperature. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (CombiFlash-1): Column, CI 8 silica gel; mobile phase, MeCN/H2O=60:40 increasing to MeCN/H2O=70:30 within 3 min; Detector, UV 254 nm. The crude product was purified by Prep-SFC with the following conditions (prep SFC 350-2): Column: Phenomenex Lux 5u Cellulose-4 250*50mm; mobile Phase A: CO2:70, Mobile Phase B: MeOH-HPLC:30; Flow rate: 150 mL/min; 254 nm; RTL4.53; RT2:5.36. This resulted in 712 mg (54%) of tert-butyl N-[cw-3-(4-formyl-lH-pyrazol-l-yl)cyclobutyl]carbamate as a white solid.
54%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h;	into a 100-mL round-bottom flask, was placed a solution of tert-butyl N-[3- (methanesulfonyloxy)cyclobutyl]carbamate (2.65 g, 9.99 mmol, 1.00 eq.), lH-pyrazole-4- carbaldehyde (1.152 g, 11.99 mmol, 1.20 eq.) and Cs2C03 (6.52 g, 20.01 mmol, 2.00 eq.) in DMF (20 mL). The resulting solution was stirred for 4 h at room temperature. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (CombiFlash-1): Column, CI 8 silica gel; mobile phase, MeCN/H2O=60:40 increasing to MeCN/H2O=70:30 within 3 min; Detector, UV 254 nm. The crude product was purified by Prep-SFC with the following conditions (prep SFC 350-2): Column: Phenomenex Lux 5u Cellulose-4 250*50mm; mobile Phase A: CO2:70, Mobile Phase B: MeOH-HPLC:30; Flow rate: 150 mL/min; 254 nm; RTL4.53; RT2:5.36. This resulted in 712 mg (54%) of tert-butyl N-[cw-3-(4-formyl-lH-pyrazol-l-yl)cyclobutyl]carbamate as a white solid.

Reference： [1]Patent: WO2016/115090,2016,A1 .Location in patent: Paragraph 0362
[2]Patent: WO2017/40606,2017,A1 .Location in patent: Paragraph 0321

53
1,1'-dihydroxylaminobis(cyclopentyl) sulfate monohydrate [ No CAS ]
[ 35344-95-7 ]
2-(1H-pyrazol-4-yl)-1,3-dihydroxy-4,5-bis(spirocyclopentyl)-4,5-dihydro-1H-imidazole [ No CAS ]

Reference： [1]Journal of Materials Chemistry C,2016,vol. 4,p. 11157 - 11163

54
8-(1-methyl-1H-indol-6-yl)quinoxalin-6-amine [ No CAS ]
[ 35344-95-7 ]
8-(1-methyl-1H-indol-6-yl)-N-(1H-pyrazol-4-ylmethyl)quinoxalin-6-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%		A mixture of 8-(1 -methyl-1 H-indol-6-yl)-quinoxalin-6-ylamine (Intermediate 22) (100.00 mg; 0.34 mmol; 1 .00 eqr.), 1 H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (41.89 mg; 0.44 mmol; 1.30 eg.) and CH3COOH (0.10 ml1.75 mmol; 5.22 eq.) in 1 ,2-dichloroethane (5.00 ml_) under argon at 5°C is stirred for 10 min and next 1 h at rt. After this time, RM is cooled to 5°C and NaBH(OAc)3 (96.80 mg; 0.44 mmol; 1.30 eq.) is added and then RM is stirred at rt overnight. RM is diluted with water and extracted with EtOAc. Combined organic layers are washed with brine, dried over Na2S04, filtered and evaporated. Brown residue is purified by FCC (DCM/MeOH; gradient) and repurified by preparative HPLC. 8-(1 -methyl-1 H-indol-6-yl)-N-(1 H-pyrazol-4- ylmethyl)quinoxalin-6-amine (55.00 mg; yield 46 percent; 99 percent by HPLC) as a yellow solid.

Reference： [1]Patent: WO2016/180536,2016,A1 .Location in patent: Page/Page column 165

55
[(1s,3s)-3-(3-phenyl-1,2-oxazole-5-amido)cyclobutyl]methyl 4-methylbenzene-1-sulfonate [ No CAS ]
[ 35344-95-7 ]
3-phenyl-N-[(1s,3s)-3-[(4-formyl-1H-pyrazol-1-yl)methyl]cyclobutyl]-1,2-oxazole-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3h;	To a 50-mL round-bottom flask was placed a solution of [(ls,3 s)-3 -(3-phenyl- 1 ,2-oxazole-5 -amido)cyclobutyljmethyl 4-methylbenzene- 1 -sulfonate (1g, 2.34 mmol, 1.00 equiv) in DMF (15 mL) then Cs2CO3 (1.5 g, 4.60 mmol, 2.00 equiv) and<strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (338 mg, 3.52 mmol, 1.50 equiv) were added. The resulting solution was stirred for 3 h at 100°C then the solids were removed by filtration. The crude product was purified by Flash-Prep-HPLC (CombiFlash-1: Column, C18 silica gel; mobile phase, X: H20 (0.5percent NH4HCO3), Y: ACN, X/Y=90/10 increasing to X/Y=5/95 within 40 mm;Detector, UV 254 nm) affording 460 mg (56percent) of 3-phenyl-N-[(ls,3s)-3-[(4-formyl-1H- pyrazol-1-yl)methyljcyclobutylj-1,2-oxazole-5-carboxamide as a yellow solid. LCMS (ES, m/z): [M+Hj?= 351.1.

Reference： [1]Patent: WO2017/19589,2017,A1 .Location in patent: Paragraph 0298

56
(1R,4R)-N1-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine [ No CAS ]
[ 35344-95-7 ]
(1R,4R)-N1-((1H-pyrazol-4-yl)methyl)-N4-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.6%	With sodium cyanoborohydride; acetic acid; at 15℃; for 16h;	Preparation of (IR R N^f H-pyrazol-^vDmethvD-N S-chloroA-fS- (c\cloprop\lmeth\l)-l-meth\l-lH-p\razol-4-\l)p\rimidin-2-\l)c\clohexane-lA- diamine (A-75) To a solution of A-51 (200.00 mg, 554.20 mupiiotaomicron, 1.00 eq) and lH-pyrazole-4- carbaldehyde (53.25 mg, 554.20 mupiiotaomicron, 1.00 eq) were added AcOH (34.86 mu,, 609.62 umol, 1.10 eq) and NaBCN (69.65 mg, 1.11 mmol, 2.00 eq). The mixture was sitrred at 15°C for 16 hours. The mixture was quenched with aqueous NaHCCb (1 mL) and concentrated. The residue was purified by prep-HPLC (column: Phenomenex Gemini 15025mm10um; mobile phase: [water (0.05percent ammonia hydroxide v/v)-ACN]; Bpercent: 39percent-39percent,12min) to give A-75 (4.00 mg, 9.04 mupiiotaomicron, 1.6percent yield, 99.7percent purity) as a yellow solid. LCMS: RT = 2.95 min, m/z 441.2 [M+H]+ NMR (CDC13, 400 MHz) S 8.21-8.12 (m, 2 H), 7.61 (s, 2 H), 4.90 (d, /=8.4Hz, IH), 3.91 (s, 3H), 3.85-3.80 (m, 3H), 3.06-3.05 (m, 2H), 2.70 (m, IH), 2.19-2.07 (m, 4H), 1.42-1.23 (m, 4H), 1.09 (m, IH), 0.50-0.45 (m, 2H), 0.18-0.14 (m, 2H).

Reference： [1]Patent: WO2017/21969,2017,A1 .Location in patent: Page/Page column 75

57
(1R,4R)-N1-((1H-pyrazol-4-yl)methyl)-N4-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine [ No CAS ]
[ 35344-95-7 ]
(1R,4R)-N1,N1-bis((1H-pyrazol-4-yl)methyl)-N4-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11.6%		Preparation of dR Rj-N N^bisfdH-pyrazol-^vDmethvD-N S-chloro-^S- (cyclopropylmethyl)-l-methyl-lH-pyrazol-4-yl)py mMin-2-yl)cyclohexan -l,4- di mine (A-96) To a solution of A-75 (50.00 mg, 113.4 mupiiotaomicron, 1.00 eq) and compound 1H- <strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (32.69 mg, 340.17 mupiiotaomicron, 3.00 eq) were added TEA (31.44 mu^, 226.78 mupiiotaomicron, 2.00 eq) and Ti(Oi-Pr)4 (67.1 mu^, 226.78 mupiiotaomicron, 2.00 eq). The mixture was stirred at 80 °C for 12 hours. NaBH3CN (21.38 mg, 340.17 muetaiotaomicron, 3.00 eq) was added and the resulting mixture was stirred at 15 °C for 4 hours. The reaction was quenched with a.q NaHC03 (1 mL) and filtered. The filtrate was purified by prep-HPLC (TFA and then basic condition) to give A-96 (7.00 mg, 13.10 umol, 11.6percent yield, 97.5percent purity) as a white solid. LCMS: RT = 2.382 m/z 521.3[M+H]+ NMR (MeOD, 400 MHz) delta 8.23 (m, 2H), 8.03 (s, 1H), 7.78 (s, 4H), 4.47-4.29 (m, 4H), 3.91-3.87 (m, 4H), 3.12 (d, /=6.4Hz, 2H), 2.27-2.22 (m, 4H), 1.94-1.85 (m, 2H), 1.46-1.36 (m, 2H), 1.01-1.00 (m, 1H), 0.45-0.44 (m, 2H), 0.14-0.13 (m, 2H).

Reference： [1]Patent: WO2017/21969,2017,A1 .Location in patent: Page/Page column 82

58
(1R,4R)-N1-(4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)cyclohexane-1,4-diamine hydrochloride [ No CAS ]
[ 35344-95-7 ]
(1R,4R)-N1-((1H-pyrazol-4-yl)methyl)-N4-(4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)cyclohexane-1,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium cyanoborohydride; acetic acid; In methanol; at 15℃; for 16h;	Prevaration of (IR Rj-N^fdH-pyrazol-^vDmethvD-N ^S- (cyclopropylmethyl)-l-methyl-lH-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)cyclohexane- 1,4-diamine (A-85) To a solution of A-86 (300.00 mg, 783.90 muetaiotaomicron, 1.00 eq) and lH-pyrazole-4- carbaldehyde (82.86 mg, 862.29 mupiiotaomicron, 1.10 eq) in MeOH (3 mL) were added AcOH (49.31 mu,, 862.29 mupiiotaomicron, 1.10 eq) and NaBH3CN (98.52 mg, 1.57 mmol, 2.00 eq). The mixture was sitrred at 15 °C for 16 hours. The mixture was quenched with a.q NaHC03 (1 mL) and concentrated. The residue product was purified by prep-HPLC (basic condition) to give A-85 (50.00 mg, 111.53 mupiiotaomicron, 14.2percent yield, 94.7percent purity) as a yellow solid. LCMS: RT = 2.472 min, mlz 425.3 [M+H]+ NMR (CDCb, 400 MHz) delta 8.10-8.09 (m, 1 H), 8.02-8.01 (m, 1 H), 7.60 (s, 1H), 4.80 (d, /=8.4Hz, 1H), 3.91 (s, 3H), 3.84 (m, 3H), 3.22-3.21 (m, 2H), 2.68 (s, 1H), 2.21-2.06 (m, 4H), 1.41-1.35 (m, 2H), 1.30-1.24 (m, 3H), 1.10-1.09 (m, 1H), 0.49-0.45 (m, 2H), 0.24-0.22 (m, 2H).

Reference： [1]Patent: WO2017/21969,2017,A1 .Location in patent: Page/Page column 84

59
(1R,4R)-N1-(4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine [ No CAS ]
[ 35344-95-7 ]
(1R,4R)-N1-((1H-pyrazol-4-yl)methyl)-N4-(4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8%	With sodium cyanoborohydride; acetic acid; at 15℃; for 16h;	Preparation of (lR, 4R)-N1-((lH-p\razol-4-\l)meth\l)-N4-(4-(5- (cvclopropylmethyl)-l-methyl-lH-pyrazol-4-yl)pyrimidin-2-yl)cvclohexane-l,4- diamine (A80) To a solution of A-14 (200.00 mg, 612.67 mupiiotaomicron, 1.00 eq) and lH-pyrazole-4- carbaldehyde (58.87 mg, 612.67 muetaiotaomicron, 1.00 eq) were added AcOH (36.79 mg, 612.67 02429524H5-01 muetaiotaomicron, 35.04 uL, 1.00 eq) and NaBH3CN (77.00 mg, 1.23 mmol, 2.00 eq). The mixture was sitrred at 15 °C for 16 hours. The mixture was quenched with aqueous NaHCCb (1 mL) and concentrated. The residue was purified by prep-HPLC (basic condition) to give A-80 (20.00 mg, 48.90 muiotaetaomicron, 8percent yield, 99.4percent purity) as a yellow solid. LCMS: RT = 2.418 min, m/z 407.2 [M+H]+ NMR (CDCb, 400 MHz) delta 8.17 (d, /=5.2Hz, IH), 7.83 (s, IH), 7.58 (s, IH), 6.71 (d, /=6.2Hz, IH), 4.88 (d, /=7.6Hz, IH), 3.89 (s, 4H), 3.81 (s, 2H), 3.21 (d, /=6.0Hz, 2H), 2.61 (s, IH), 2.21-2.03 (m, 4H), 1.36-1.25 (m, 4H), 1.09 (s, IH), 0.48-0.46 (m, 2H), 0.25-0.24 (m, 2H).

Reference： [1]Patent: WO2017/21969,2017,A1 .Location in patent: Page/Page column 76-77

60
[ 108052-76-2 ]
[ 35344-95-7 ]
tert-butyl 4-((4-formyl-1H-pyrazol-1-yl)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34.5%		Intermediate 7 (0.829 g, 8.63 mmol) was dissolved in DMF (0.43 mL), and the solution was cooled to 0 °C. NaH, 60percent dispersion in mineral oil (380 mg, 9.49 mmol) was added portionwise under argon. The reaction mixture was stirred for 15 minutes at 0°C, then a solution of tert-butyl 4-(bromomethyl)benzoate (2.57 g, 9.49 mmol) in 10 mLof DMF was added. The reaction mixture was allowed to warm to rt and stirred overnight. The reaction mixture was cooled to 0 °C and carefully quenched with water, then diluted with EtOAc, washed with 10percent LiC1 and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to provide 46A (0.85 g, 34.5percent). MS(ESI) m/z 287.1 (M+H)t

Reference： [1]Patent: WO2017/40449,2017,A1 .Location in patent: Paragraph 00258

61
[ 622-95-7 ]
[ 35344-95-7 ]
1-(4-chlorobenzyl)-1H-pyrazole-4-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
162 mg	With caesium carbonate; In acetonitrile; at 20℃; for 2h;	To a solution of <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (70 mg, 728 mumol) in MeCN (5 mL) was added 1-(bromomethyl)-4-chlorobenzene (149 mg, 728 mumol) and cesium carbonate (472 mg, 1.45 mmol). The mixture was stirred at r.t. for 2h. The mixture was concentrated, diluted with EA and water. The organic phase was washed with brine (10 mL x 2), dried over Na2SO4and concentrated to give 1-(4-chlorobenzyl)-1H- <strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (162 mg, 101 percent) as a white solid, which was used in the next step without further purification

Reference： [1]Patent: KR2017/45749,2017,A .Location in patent: Paragraph 1033; 1036-1038

62
[(1r,3r)-3-(3-phenyl-1,2-oxazole-5-amido)cyclobutyl]methyl 4-methylbenzene-1-sulfonate [ No CAS ]
[ 35344-95-7 ]
3-phenyl-N-[(1r,3r)-3-[(4-formyl-1H-pyrazol-1-yl)methyl]cyclobutyl]-1,2-oxazole-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 3h;	To a 50-mL round-bottom flask was placed a solution of [(lr,3r)-3 -(3 -phenyl- 1 ,2-oxazole-5-amido)cyclobutylj methyl 4-methylbenzene- 1 -sulfonate (980 mg,2.30 mmol, 1.00 equiv) in DMF (20 mL), then <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (331 mg, 3.44 mmol, 1.50 equiv) and Cs2CO3 (1.1 g, 3.37 mmol, 1.50 equiv) were added. The resulting solution was stirred for 3 h at 70°C, diluted with 50 mL of H20, filtered, and then extracted with EtOAc. The organic extracts were combined, dried over anhydrous Na2504, andconcentrated under reduced pressure. The residue was applied onto a silica gel column and eluted with EtOAc/petroleum ether (1:3) affording 400 mg (50percent) of 3-phenyl-N-[(lr,3r)-3-[(4- formyl- 1H-pyrazol- 1 -yl)methylj cyclobutyll -1 ,2-oxazole-5-carboxamide as a white solid. LCMS (ES,m/z): [M+Hj= 351.1.

Reference： [1]Patent: WO2017/112853,2017,A1 .Location in patent: Paragraph 0293

63
2-((3,5-dicyano-4-ethyl-6-(piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide trifluoroacetic acid [ No CAS ]
[ 35344-95-7 ]
2-((6-(4-((1H-pyrazol-4-yl)methyl)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%		2-((3,5-dicyano-4-ethyl-6-(piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide trifluoroacetic acid (synthesis described in example 176 step 2, 215 mg, 0.413 mmol) was dissolved in dichloromethane (15 mL) and DIEA (0.144 mL, 0.826 mmol). Acetic acid (0.047 mL, 0.826 mmol) was added followed by <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (79 mg, 0.826 mmol) The reaction was stirred for 30 minutes and sodium triacetoxyborohydride (350 mg, 1.652 mmol) was added. The reaction was stirred at 25 °C for 18Hous. The DCM solution was washed with water, a solution of saturated sodium bicarbonate, and then water. The DCM solution was dried then evaporated and the resulting solid was triturated with ethyl acetate to give after filtration pure product. The solid was dried in vacuum oven overnight to afford 2-((6-(4-((1H-pyrazol-4-yl)methyl)piperazin-1-yl)-3,5- dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide (75 mg, 0.149 mmol, 36percent yield) LCMS m/z = 487.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.20 (t, J=7.60 Hz, 3 H) 2.44 (br. s., 4 H) 2.75 (d, J=7.60 Hz, 2 H) 3.44 (s, 2 H) 3.86 (d, J=4.82 Hz, 4 H) 5.52 (s, 1 H) 7.28 - 7.44 (m, 4 H) 7.46 - 7.61 (m, 5 H) 7.91 (s, 1 H).

Reference： [1]Patent: WO2017/216726,2017,A1 .Location in patent: Page/Page column 761

64
[ 86864-60-0 ]
[ 35344-95-7 ]
C₁₂H₂₂N₂O₂Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With potassium carbonate; In acetonitrile; at 80℃; for 2h;	2-bromoethoxy- xit y Id i met y I si I ane (CAS [86864-60-0]) (2.4 mL; 1 1 .4 mmol ) was added to a solution of 1 H-pyrazo le-4-carbaldehyde (CAS [35344-95-7] ) (910 mg; 9.5 mmol ) and K2CO3 ( 1 .6 g; 1 1 .4 mmol) in ACN (18 mL ). The reaction was heated at 80C for 2h. The reaction mixture was partitioned between a saturated solution of NaHCO; and EtOAc. The organic layer was separated, dried over MgS04, filtered and evaporated till dryness. The residue was purified by chromatography ov er silica gel ( Stationary phase: irregular SiOH 40 iim 120g, mobile phase gradient from: 100% DCM, 0% MeOH to 95% DCM, 5% MeOH). The fractions containing product were collected and ev aporated to dryness yielding 1 .6 g (65%) of intermediate 12 .
65%	With potassium carbonate; In acetonitrile; for 2h;Reflux;	A solution of 2-bromoethoxy-tert-butyldimethylsilane(CAS [86864-60-0]), (2.44mL;11.37mmol), <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (CAS [35344-95-7]), (0.91g; 9.5mmol) and K2CO3 (1.57g; 11.37mmol) in ACN (18mL) was refluxed for 2 h. The mixture was cooled, poured into ice water and a saturated NaHCO3 solution, the aqueous layer was extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered and evaporated to dryness giving a crude compound which was purified by chromatography over silica gel (Stationary phase: irregular SiOH 15-40mum 120g, Mobile phase: Gradient from 100% DCM, 0% MeOH to 95% DCM, 5% MeOH). The fractions containing product were collected and evaporated to dryness yielding 1.56g (yield 65%) of intermediate 18.

Reference： [1]Patent: WO2018/50684,2018,A1 .Location in patent: Page/Page column 64-65
[2]Patent: WO2018/109088,2018,A1 .Location in patent: Page/Page column 72-73

65
[ 35344-95-7 ]
[ 74-88-4 ]
[ 25016-11-9 ]

Yield	Reaction Conditions	Operation in experiment
87%	With caesium carbonate; In N,N-dimethyl-formamide; at 60℃;	To a solution of lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (1.00 g, 10.4 mmol) in DMF (40 mL) was added iodomethane (1.48 g, 10.4 mmol) and CS2CO3 (10 g, 31.2 mmol). After stirring at 60°C overnight, the reaction mixture was added water (20 mL) and extracted with EtOAc (50 mL x 3). The organic phase was washed with brine, dried over Na2S04 and concentrated to give intermediate 48 (1.00 g, 87percent yield).

Reference： [1]Patent: WO2018/50684,2018,A1 .Location in patent: Page/Page column 67

66
2-bromo-4,6-dimethylpyrimidine-5-carbonitrile [ No CAS ]
[ 35344-95-7 ]
2-(4-formyl-1H-pyrazol-1-yl)-4,6-dimethylpyrimidine-5-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31.7%	With potassium carbonate; In acetonitrile; at 20℃; for 1.5h;	To a stirred solution of <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (0.40 g, 4.16 mmol) and Intermediate 83B (0.88 g, 4.16 mmol) in acetonitrile (20 mL) was added K2C03 ((1.72 g, 1249mmol) The resulting mixture was stirred at ambient temperature for 1.5 h. The reaction mixturewas diluted with ethyl acetate (20 rnL) and filtered through Celite®. The filtrate was evaporatedunder reduced pressure. The residue was purified by column chromatography (Redisep-24 g, 40percent EtOAc n?hexane) to obtain Intermediate 17C (0.30 g, 3 1.70 percent) as white solid. ?FT NMR(400 MHz, DMO-d6) 6 ppm 2.74 (s, 6 H), 8.36 (s, 1 H), ). 44 (s, I H), 10.01 (s, 1 H. LCMS(method?D), retention time 1.282 mi [M-t-H] 228.1.

Reference： [1]Patent: WO2018/93569,2018,A1 .Location in patent: Page/Page column 167

67
[ 24424-99-5 ]
(R)-5-(2-amino-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one [ No CAS ]
[ 35344-95-7 ]
tert-butyl (R)-((1H-pyrazol-4-yl)methyl)(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24.29%		To a stirred solution of iFi-pyrazole-4carbaldehyde (1.00 g, 10.41 mmoi) in MeOH (20 mL) was added acetic acid (0.60 mL, 10.41 mrnol), Intermediate 74 (2.59 g, 12.49 mmol) andthe reaction mixture was stirred at ambient temperature for 20 miii. Then NaCNI3H4 (1 .96 g,3 1.2 mmol) was added and stirring was continued at ambient temperature for 14 h. The reaction mixture was distilled under reduced pressure and basified with saturated sodium bicarbonate solution (50 mL). To the resulting aqueous mixture was added BOC2O (2.34 ml, 10.09 mniol) and stirred at ambient temperature for 2. h. The reaction mixture was diluted with water (20 mL) and extracted with 5percent mnethanoi:DCM (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Redisep-24 g, 4percent MeOHJCHCI3), to obtainintermediate 721 (095 g, 24.29percent). ?HNMR (300 MHz, DMSO-d6) 8 ppm 1.23 1.46 (in, 9 H)1.57 (s, I H) 2.26 (hr. s., 3 H) 308 - 3.26 (in, I H) 4.21 4.32 (m, 2 H) 5.07 - 5.19 (in, I H) 5.37(s, 2 H) 5.59 -5.71 (m, I H) 7.31 - 7.42 (m, I H) 7.69 (s, 3 H) 12.58- 12.73 (m, I H). LCMS(Method?H;): retention time 1.29 mm. [M-Hj 388.0.

Reference： [1]Patent: WO2018/93569,2018,A1 .Location in patent: Page/Page column 157; 158

68
6-bromo-4-methylnicotinonitrile [ No CAS ]
[ 35344-95-7 ]
6-(4-formyl-1H-pyrazol-1-yl)-4-methylnicotinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52.1%	With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; potassium carbonate; In 1,4-dioxane; at 110℃; for 1h;Inert atmosphere; Microwave irradiation;	To a stirred solution of <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (1.00 g. 10.4 mmoi) and6-bromo-4-rnethyinicotinonitrile (2.05 g, 10.4 mrnol) in dioxane (15 mL) were added K2C03 (4.31 g, 31.2 mrnol) The resulting reaction mixture was degassed with nitrogen for 5 minutes and was added copper(1) iodide (0595 g, 3. 12 mmoi), followed by trans_N,NLdimethylcyciohexanei .2-diamine (2.59 mL, 16.4 mmoi). The resulting reaction mixture was degassed with nitrogen for an additional 5 minutes and heated at110 °C for 1 h under microwave irradiation. The reaction mixture was cooled to ambient temperature, filtered through celite and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (Redisep-24 g, 20-40percent EtOAc/ n-hexane) to obtain Intermediate 9 (115 g, 52.1percent) as a pale yellow solid. ?H NMR (300 MHz, DMSO?d6) oe ppm 2.62 (s, 3 H), 8.10 (s, I Fl), 8.38 (s, I H), 8.95 (s, IH), 9.37 (s, I H), 998 (s, I H). LCMS (method-i)), retention time 1.68 mi [M+Hi213.2.
52.10%	With copper(l) iodide; potassium carbonate; trans-N,N'-dimethylcyclohexane-1,2-diamine; In 1,4-dioxane; at 110℃; for 1h;Inert atmosphere; Microwave irradiation;	To a stirred solution of 1Hpyrazole4carbaldehyde (1.00 g, 10.40 mmol) and 6bromo4methylnicotinonitrile (2.05 g, 10.40 mmol) in dioxane (15 mL) were added K2CO3 (4.31 g, 31.20 mmol). The resulting reaction mixture was degassed with nitrogen for 5 minutes then copper (I) iodide (0.59 g, 3.12 mmol) was added, followed by transN,N'dimethylcyclohexane1,2diamine (2.59 mL, 16.4 mmol). The resulting mixture was degassed again for 10 minutes and heated at 110 °C for 1 h under microwave irradiation. The reaction mixture was cooled to ambient temperature, filtered through Celite® and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (Redisep24 g, 2040percent EtOAc/ nhexane) to obtain Intermediate 6 (1.15 g, 52.10percent) as pale yellow solid. 1H NMR (300 MHz, DMSOd6) G^ppm 2.62 (s, 3 H), 8.10 (s, 1 H), 8.38 (s, 1 H), 8.95 (s, 1 H), 9.37 (s, 1 H), 9.98 (s, 1 H). LCMS (methodD), retention time 1.68 min, [M+H] 213.2.

Reference： [1]Patent: WO2018/93569,2018,A1 .Location in patent: Page/Page column 49; 50
[2]Patent: WO2018/222795,2018,A1 .Location in patent: Page/Page column 63; 64

69
[ 98626-95-0 ]
[ 35344-95-7 ]
1-(6-(methylsulfonyl)pyridin-3-yl)-1H-pyrazole-4-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 5h;Inert atmosphere;	To a stirred solution of 5-bromo-2-(methylsulfonyl)pyridine (0.05 g, 0.21 mmol) and 1H- <strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (0.02 g, 0.21 mmol) in 1,4-dioxane (3 mL) was added cesium carbonate (0.17 g, 0.53 mmol) and 9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane (0.01g, 0.021 mmol). The reaction mixture was degassed with nitrogen for 10 minutes and Pd2dba3 (0.02 g, 0.021 mmol) was added and the resulting mixture was degassed again for 10 minutes then was heated at 90 °C for 5 h. The reaction mixture was cooled to ambient temperature and diluted with ice cold 1.5 N HCl (2 mL). The solid precipite was collected by suction filtration and washed with ethanol (1 mL) to obtain Intermediate 38 (0.03 g, 56.00percent).1H NMR (400 MHz, DMSO- d6) delta ppm 2.53 (s, 3 H), 7.96 (d, J = 0.56 Hz, 1 H), 8.32 (d, J = 2.45 Hz, 1 H), 8.33 (s, 1 H), 8.71 (d, J = 2.45 Hz, 1 H), 9.29 (s, 1 H), 9.97 (s, 1 H). LCMS (Method-L) retention time 1.12 min, [M+H] 252.0.

Reference： [1]Patent: WO2018/93569,2018,A1 .Location in patent: Page/Page column 120; 121

70
[ 66909-33-9 ]
[ 35344-95-7 ]
6-(4-formyl-1H-pyrazol-1-yl)-5-methylnicotinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16.6%	With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; potassium carbonate; In 1,4-dioxane; at 110℃; for 1h;Inert atmosphere; Microwave irradiation;	General procedure: To a stirred solution of <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (1.00 g. 10.4 mmoi) and6-bromo-4-rnethyinicotinonitrile (2.05 g, 10.4 mrnol) in dioxane (15 mL) were added K2C03 (4.31 g, 31.2 mrnol) The resulting reaction mixture was degassed with nitrogen for 5 minutes and was added copper(1) iodide (0595 g, 3. 12 mmoi), followed by trans_N,NLdimethylcyciohexanei .2-diamine (2.59 mL, 16.4 mmoi). The resulting reaction mixture was degassed with nitrogen for an additional 5 minutes and heated at110 °C for 1 h under microwave irradiation. The reaction mixture was cooled to ambient temperature, filtered through celite and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (Redisep-24 g, 20-40percent EtOAc/ n-hexane) to obtain Intermediate 9 (115 g, 52.1percent) as a pale yellow solid. ?H NMR (300 MHz, DMSO?d6) oe ppm 2.62 (s, 3 H), 8.10 (s, I Fl), 8.38 (s, I H), 8.95 (s, IH), 9.37 (s, I H), 998 (s, I H). LCMS (method-i)), retention time 1.68 mi [M+Hi213.2.

Reference： [1]Patent: WO2018/93569,2018,A1 .Location in patent: Page/Page column 49; 50; 163

71
[ 1820-80-0 ]
[ 35344-95-7 ]
bis(3-aminopyrazol-4-yl)-pyrazol-4-yl-methane [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2017,vol. 82,p. 10549 - 10562

72
[ 137-45-1 ]
[ 35344-95-7 ]
bis(3-hydroxypyrazol-4-yl)-pyrazol-4-yl-methane [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2017,vol. 82,p. 10549 - 10562

73
[ 1006619-83-5 ]
[ 35344-95-7 ]
6-chloro-8-methyl-2-(1H-pyrazol-4-yl)-2,3-dihydroquinazolin-4(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	In methanol; at 20℃;	General procedure: Cyanuric chloride (28mg, 0.15mmol) was added to a mixture of 3a, 3b, 3k or 3s (1mmol) and 4b-4h (1.2mmol) in MeOH or DMSO (3mL). The mixture was stirred at room temperature for 0.5?2h. After completion, the mixture was extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (30/1) to afford D1-D12.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 152,p. 235 - 252

74
[ 68-12-2 ]
[ 591-86-6 ]
[ 35344-95-7 ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: The syntheses of compounds 4a-4h were mainly referred to literature method [41]. A mixture of semicarbazide hydrochloride (2g, 17.9mmol) and anhydrous CH3COONa (2g, 24.4mmol) in EtOH (20mL) was refluxed for 45min and filtered while hot. 10a-10h (16.6mmol) was added to the filtrate, and the mixture was refluxed for 1h. The mixture was stirred at room temperature for an additional 10h, and the precipitate that formed was filtered and dried to afford 11a-11h. POCl3 (3.6mL, 39mmol) was added dropwise to dry DMF (8.4mL, 108mmol) in ice bath, and the mixture was stirred at 0C for 1h, followed by the addition of 11a-11h (17mmol) in small portions. The mixture was heated at 80C for 1.5h and quickly poured onto ice (100mL), then treated with 30% aqueous NaOH to adjust pH=8-9, stirred for 30min and neutralized with conc. HCl. After stirred at room temperature for additional 18h, the resulting precipitate was filtered, washed with water, recrystallized from water and dried to afford 4a-4h.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 152,p. 235 - 252

75
2-N-(3-iodo-4-methoxyphenyl)-4-N,6-dimethylpyrimidine-2,4-diamine [ No CAS ]
[ 35344-95-7 ]
1-(2-methoxy-5-[[4-methyl-6-(methylamino)pyrimidin-2-yl]amino]phenyl)-1H-pyrazole-4-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With potassium phosphate; copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; In toluene; at 140℃; for 24h;	Into a 50-mL round-bottom flask, was placed 2-N-(3-iodo-4-methoxyphenyl)-4-N,6- dimethylpyrimidine-2,4-diamine (1 g, 2.70 mmol, 1.00 equiv), Tol (10 mL), Cul (154 mg, 0.81 mmol, 0.30 equiv), K3P04 (1.72 g, 8.10 mmol, 3.00 equiv), lH-pyrazole-4-carbaidehyde (262 mg, 2.73 mmol, 1.00 equiv), (l R,2R)-l-N,2-N-dimethylcyclohexane-l ,2-diamine (230 mg, 1.62 mmol, 0.60 equiv). The resulting solution was stirred for 24 h at 140°C. The residue was applied onto a silica gel column with water/ A CN (1 : 50-1 : 10). The collected fractions were combined and concentrated under vacuum. This resulted in 550 mg (60percent) of the title compound as an off-white solid.

Reference： [1]Patent: WO2018/118842,2018,A1 .Location in patent: Paragraph 0547; 0551-0553

76
[ 123-75-1 ]
[ 35344-95-7 ]
4-(pyrrolidin-1-ylmethyl)-1H-pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With titanium(IV) isopropylate; sodium tetrahydroborate; In ethanol; at 25℃; for 2h;	Into a 250-mL round-bottom flask was placed l H-pyrazole-3-carbaldehyde (1 g, 10,41 mmol, 1.00 equiv), Ti(OiPr)4 (10 g), ethanol (20 mL), pyrrolidine (740 mg, 10.40 mmol, 1.00 equiv), and NaBH3 (792 mg). The resulting solution was stirred for 2 h at 25 °C, The residue was applied onto a silica gel column with thOiCtbCN (83/17). This resulted in 570 mg (36percent) of the title compound as a white solid. LC-MS: (ES, m/z): RT = 0.395 min, LCMS31, m/z =152.2 [M+l].

Reference： [1]Patent: WO2018/118842,2018,A1 .Location in patent: Paragraph 0448-0451

77
[ 35344-95-7 ]
[ 1099-45-2 ]
C₈H₁₀N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	In toluene; at 90℃; for 2h;	To a solution of li/-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (300 mg, 3.12 mmol) was added ethyl 2-(triphenylphosphoranylidene)acetate (1360 mg, 3.90 mmol) in toluene (10 mL). The mixture was heated at 90 °C for 2 h. The solvent was removed in vacuo. The crude material was purified by flash chromatography to afford Example 7A (450 mg, 2.71 mmol, 87percent yield) as a white solid. LCMS (ES): m/z 167.1 [M+H]+.

Reference： [1]Patent: WO2018/89353,2018,A1 .Location in patent: Page/Page column 68

78
[ 110-87-2 ]
[ 35344-95-7 ]
[ 1197943-43-3 ]

Yield	Reaction Conditions	Operation in experiment
92%	With trifluoroacetic acid; In tetrahydrofuran; at 90℃; for 4h;	To a stirred solution of pyrazole carboxaldehyde (2-1, 300 mg, 3.1 mmol) in tetrahydrofuran was sequentially added 3,4-dihydro-2H-pyran (2-2, 867 mg, 10.3 mmol) and catalytic amount of trifluoroacetic acid. The resulting solution was refluxed for 4 h and then cooled to rt. The reaction was quenched by addition of trace amount of sodium hydride. Solvent was removed under vacuum and the residue was purified by silica gel chromatography to give 2-3 (520 mg, 92percent). MS (ESI+): m/z: 181.1 (M+H)+.
86%	With toluene-4-sulfonic acid; In dichloromethane; at 20 - 60℃; for 10.5h;	General procedure: para-Toluenesulfonic acid 206 mg (1.08 mmol) and DHP 1.85 ml (21.8 mmol) were added to a THF (30 ml)suspension of 1H-pyrazole-3-carbaldehyde 1.05 g (10.9 mmol), and the mixture was stirred at room temperature for 1hour. Next, methylene chloride 30 ml was added, and the mixture was stirred at room temperature for 4.5 hours and at60C for 5 hours. After the completion of the reaction, water was added to the reaction mixture, and followed by extractionwith ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography(eluting solvent: hexane: ethyl acetate) to give the title compound (including impurities).

Reference： [1]Patent: WO2019/46795,2019,A1 .Location in patent: Paragraph 00160; 00161
[2]Patent: EP3333163,2018,A1 .Location in patent: Paragraph 1638; 1639; 1641; 1642

79
[ 13755-95-8 ]
[ 35344-95-7 ]
2-(1H-pyrazol-4-yl)-1H-naphtho[2,3-d]imidazole-4,9-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium metabisulfite; In 1,2-dimethoxyethane; at 120℃;	General procedure: A solution of 2,3-diamino-1,4-naphthoquinone (1.0 mmol),appropriate aromatic aldehyde (1.0 mmol) with sodium pyrosulfitein DMF was stirred at 120 C overnight. On completion of the reactionmonitored by TLC, the solvent was evaporated and the residuewas purified by silica gel chromatography by DCM/MeOHsystem to afford the final product. If necessary, the crude productcould be recrystallized in methanol or DMSO to afford pure sample.4.1.5.1. 2-(2-Chlorophenyl)-1H-naphtho[2,3-d]imidazole-4,9-dione(T1). Pale yellow solid; yield 80percent;

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 157,p. 423 - 436

80
[ 1225276-07-2 ]
[ 35344-95-7 ]
tert-butyl 2-(4-formyl-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;Inert atmosphere;	In this case, C3 was reacted with <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> and cesium carbonate to afford tert-butyl 2-(4-formyl-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate. This material was treated with (diethylamino)sulfur trifluoride to provide the requisite tert-butyl 2-[4-(difluoromethyl)-1H-pyrazol-1-yl]-7-azaspiro[3.5]nonane-7-carboxylate.

Reference： [1]Patent: US2018/208607,2018,A1 .Location in patent: Paragraph 0226; 0409

81
tert-butyl 3-[(methylsulfonyl)oxy]-1-oxa-9-azaspiro[5.5]undecane-9-carboxylate [ No CAS ]
[ 35344-95-7 ]
tert-butyl 3-(4-formyl-1H-pyrazol-1-yl)-1-oxa-9-azaspiro[5.5]undecane-9-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;Inert atmosphere;	tert-Butyl 3-[(methylsulfonyl)oxy]-1-oxa-9-azaspiro[5.5]undecane-9-carboxylate was reacted with <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> and cesium carbonate to afford tert-butyl 3-(4-formyl-1H-pyrazol-1-yl)-1-oxa-9-azaspiro[5.5]undecane-9-carboxylate. This material was treated with (diethylamino)sulfur trifluoride to provide the requisite tert-butyl 3-[4-(difluoromethyl)-1H-pyrazol-1-yl]-1-oxa-9-azaspiro[5.5]undecane-9-carboxylate

Reference： [1]Patent: US2018/208607,2018,A1 .Location in patent: Paragraph 0226; 0409

82
[ 35344-95-7 ]
1H-pyrazole-4-carbaldehyde oxime [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydroxylamine hydrochloride; at 20℃;	A solution of <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (2.05 g, 21.4 mmoL) and hydroxylamine hydrochloride (1.63 g, 23.5 mmol) in MeOH (50 mL) was stirred at room temperature for 19 hrs. The reaction mixture was concentrated to give <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> oxime (3.3 g, crude) as a yellow solid.

Reference： [1]Patent: WO2018/132372,2018,A1 .Location in patent: Paragraph 01189

83
[ 1440422-13-8 ]
[ 35344-95-7 ]
2-((1r,4r)-4-(6-(phenylsulfonyl)-2-(1H-pyrazol-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9%	With sodium dithionite; In methanol; water; dimethyl sulfoxide; at 100℃; for 3h;Sealed tube;	To a 20 mL microwave vial were added 2-((lr,4r)-4-((5 -nitro- 1 -(phenyl sulfonyl)- 1H-pyrrolo[2, 3 -b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (Intermediate 1, 1070 mg, 2.44 mmol) and <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (444 mg, 4.62 mmol) as solids. DMSO (12 mL), MeOH (12 mL), and distilled water (6 mL) were added to the reaction mixture resulting in a yellow mixture. Next, sodium hydrosulfite (1060 mg, 6.09 mmol) wasadded as a solid and the vial sealed. The vial was placed into a preheated 100 °C heating block for 3 h. The reaction was cooled to room temperature and added dropwise to 60 mL water with stirring and continued stirring for 30 minutes. The white precipitate that formed was collected by filtration, washed with water (50 mL), and dried first in the open air and then under high vacuum overnight. A portion of the material (208 mg) was purified by flash columnchromatography (24 g 5i02, 0-15percent 2 N NH3-MeOHIEA) to provide the title compound (112 mg,9percent yield) as a white solid. MS (ESI): mass calcd. for C25H23N7025, 485.16; m/z found, 486.2 [M+H]t

Reference： [1]Patent: WO2018/112382,2018,A1 .Location in patent: Page/Page column 246

84
[ 98-59-9 ]
[ 35344-95-7 ]
[ 916257-05-1 ]

Yield	Reaction Conditions	Operation in experiment
84%	With pyridine; In dichloromethane; at 20℃; for 19h;	1H-Pyrazole-4-carbaldehyde (6.00 g, 62.44 mmol) was stirred as a suspension in DCM (200 mL). Pyridine (7.58 mL, 93.66 mmol) was added at room temperature and the reaction was stirred for 10 min. 4-Methylbenzenesulfonyl chloride (11.90 g, 62.44 mmol) was added and the reaction was stirred at room temperature for 3 h (Monitored by TLC (KMnO4 visualisation, 100percent EtOAc) which shows new higher running spot and complete conversion after 3 h). The reaction allowed to stand at RT for 16 h. The reaction was diluted with DCM (100 mL) and washed with a saturated aqueous solution of NaHCO3 (100 mL), water (2 x 100 mL), passed through a phase separation cartridge and concentrated under reduced pressure. The resulting residue was purified by flash silica chromatography eluting with 100percent DCM. Product containing fractions were concentrated under reduced pressure to afford 1-(p-tolylsulfonyl)<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (13.05 g, 84 percent) as a white solid. IR: 1691 (CO), 1373 (SO) , 1180 (SO), cm-1; 1H NMR (400 MHz, CDCl3) 2.45 (s, 3H), 7.38 (d, J = 8.5, 2H), 7.95 (d, J = 8.5, 2H), 8.10 (s, 1H), 8.61 (s, 1H), 9.92 (s, 1H); 13C NMR (400 MHz, CDCl3) 21.80, 125.29, 128.70, 130.35, 134.62, 143.49, 147.03, 183.26.; HRMS [M+H]+ measured 232.0465, C11H10N2O3S requires 232.0461.

Reference： [1]Tetrahedron Letters,2018,vol. 59,p. 4479 - 4482

85
[ 501-53-1 ]
[ 35344-95-7 ]
benzyl 4-formylpyrazole-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With triethylamine; In dichloromethane; at 0 - 4℃; for 1h;Inert atmosphere;	A suspension of <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (1.00 g, 10.41 mmol) in DCM (30 mL) was stirred under nitrogen. Triethylamine (1.45 mL, 10.41 mmol) was added resulting in a solution. The reaction was cooled to 0 oC with a cooling bath and benzyl carbonochloridate (1.49 mL, 10.41 mmol) was added as dropwise over 5 min maintaining the internal temperature below 10 oC. The reaction was allowed to stir at 4 oC with a cooling bath for 1 h. An aqueous 1M solution of hydrochloric acid (30 mL) was added cautiously. The layers were separated and the aqueous portion was extracted with DCM (2 x 30 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL). The combined organic extracts were passed through a phase separation cartridge and concentrated under reduced pressure. The resulting yellow residue was purified by flash silica chromatography eluting with a gradient of 0-50percent EtOAc in heptane. Product containing fractions were concentrated under reduced pressure to afford benzyl 4-formylpyrazole-1-carboxylate (1.78 g, 74percent) as a white solid. IR: 1736 (CO), 1674 (CO) cm-1; 1H NMR (400 MHz, CDCl3) 5.51 (s, 2H), 7.35 ? 7.47 (m, 3H), 7.47 ? 7.55 (m, 2H), 8.15 (s, 1H), 8.57 ? 8.71 (m, 1H), 9.96 (s, 1H); 13C NMR (400 MHz, CDCl3) 71.00, 126.11, 128.90, 129.02, 129.35, 133.62, 135.14, 142.86, 148.56, 183.49; HRMS [M+Na]+ measured 253.0578, C12H10O3N2 requires 253.0589.

Reference： [1]Tetrahedron Letters,2018,vol. 59,p. 4479 - 4482

86
C₉H₆N₆O₅ [ No CAS ]
[ 35344-95-7 ]
[ 112253-17-5 ]

Reference： [1]Mendeleev Communications,2018,vol. 28,p. 638 - 640

87
[ 35344-95-7 ]
[ 112253-17-5 ]
C₉H₆N₆O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	In acetonitrile; at 20℃; for 0.5h;	A nucleophile (1 mmol)was added to a solution of compound 1 or 2 (1 mmol) in MeCN or EtOH(10 ml) and the mixture was stirred at room temperature for 30 min (foradducts with 1) or 2?24 h (for adducts with 2). The precipitated productwas filtered off, washed with the same solvent (5 ml) and dried in air to give beige or brown solid adduct.

Reference： [1]Mendeleev Communications,2018,vol. 28,p. 638 - 640

88
5-(4,4-difluoropiperidin-3-yl)-4-methylisobenzofuran-1(3H)-one [ No CAS ]
[ 35344-95-7 ]
5-(1-((1H-pyrazol-4-yl)methyl)-4,4-difluoropiperidin-3-yl)-4-methylisobenzofuran-1(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61.60%		To a solution of Intermediate 4C (0.10 g, 0.37 mmol) in MeOH (2 mL) was added 1Hpyrazole4carbaldehyde (0.030 g, 0.37 mmol) and the reaction mixture was stirred at ambient temperature for 15 min. To this mixture was added NaCNBH3 (0.071 g, 1.12 mmol) and stirring was continued for 12 h. The reaction mixture was diluted with water (15 mL) and extracted with DCM (3 x 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was washed with diethyl ether (20 mL) to obtain Intermediate 4 (0.08 g, 61.60percent).1H NMR (400 MHz, DMSOd6) G ppm 2.08 2.18 (m, 2 H) 2.23 (s, 3 H) 2.76 (d, J = 11.04 Hz, 1 H) 2.86 (d, J = 11.55 Hz, 1 H) 3.45 (s, 2 H) 3.65 3.80 (m, 2 H) 4.78 (d, J = 8.03 Hz, 1 H) 5.33 5.43 (m, 2 H) 7.41 (br. s., 1 H) 7.52 7.71 (m, 3 H) 12.64 (br. s., 1 H). LCMS (MethodH): retention time 1.121 min, [M+H] 348.2.

Reference： [1]Patent: WO2018/222795,2018,A1 .Location in patent: Page/Page column 62; 63

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P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 35344-95-7 ] {[proInfo.proName]}

Quality Control of [ 35344-95-7 ]

Related Doc. of [ 35344-95-7 ]

Product Details of [ 35344-95-7 ]

Calculated chemistry of [ 35344-95-7 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 35344-95-7 ]

Application In Synthesis of [ 35344-95-7 ]

[ 35344-95-7 ] Synthesis Path-Upstream 1~11

[ 35344-95-7 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 35344-95-7 ]

Aldehydes

Related Parent Nucleus of [ 35344-95-7 ]

Pyrazoles

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 35344-95-7 ]

Related Parent Nucleus of
[ 35344-95-7 ]