[ CAS No. 27996-86-7 ] {[proInfo.proName]}

Name: 27996-86-7|4-(1H-1,2,4-Triazol-1-yl)benzaldehyde|97%
Brand: Ambeed
SKU: A224989
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Quality Control of [ 27996-86-7 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 27996-86-7 ]

SDS Specification

Alternatived Products of [ 27996-86-7 ]

Product Details of [ 27996-86-7 ]

CAS No. :	27996-86-7	MDL No. :	MFCD02681969
Formula :	C₉H₇N₃O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	TVEJNWMWDIXPAX-UHFFFAOYSA-N
M.W :	173.17	Pubchem ID :	2776488
Synonyms :

Calculated chemistry of [ 27996-86-7 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	11
Fraction Csp3 :	0.0
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	46.75
TPSA :	47.78 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.56 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.4
Log Po/w (XLOGP3) :	1.12
Log Po/w (WLOGP) :	1.08
Log Po/w (MLOGP) :	0.73
Log Po/w (SILICOS-IT) :	1.15
Consensus Log Po/w :	1.09

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.11
Solubility :	1.33 mg/ml ; 0.0077 mol/l
Class :	Soluble
Log S (Ali) :	-1.72
Solubility :	3.32 mg/ml ; 0.0192 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.5
Solubility :	0.549 mg/ml ; 0.00317 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.33

Safety of [ 27996-86-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 27996-86-7 ]

* 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 [ 27996-86-7 ]
Downstream synthetic route of [ 27996-86-7 ]

[ 27996-86-7 ] Synthesis Path-Upstream 1~7

1
[ 288-88-0 ]
[ 459-57-4 ]
[ 27996-86-7 ]

Yield	Reaction Conditions	Operation in experiment
72%	With potassium carbonate In N,N-dimethyl-formamide at 110℃;	General procedure: A mixture of 4-fluoro acetophenone/4-fluorobenzaldehyde (10 mmol) and imidazole/triazole (10 mmol) were dissolved in dry DMF (20 mL). K₂CO₃ (12 mmol) was added in small portion within a period of 15 min to the above stirred solution. Mixture was stirred for 10-12 h at 110 °C. Heating discontinued, K₂CO₃ was filtered off, filtrate extracted with ethyl acetate (3 .x. 15 mL). Organic layer was washed with water (3 .x. 15 mL), dried over anhydrous sodium sulphate and concentrated to given an oil which was purified on silica gel column (60-120 mesh) taking methanol: chloroform (1:99) as an eluent.
65%	With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 6 h;	Example 91Preparation of 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI5); To a stiffing solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K₂CO₃(13.3 g, 96.7 mmol) and 1,2,4-triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120° C. for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with H₂O and extracted with EtOAc (3.x.100 mL). The combined EtOAc layer was washed with H₂O and brine, dried over Na₂SO₄, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65percent): mp 145-149° C.: ¹H NMR (400 MHz, CDCl₃) δ 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]⁺).
65%	With potassium carbonate In N,N-dimethyl-formamide	Example 91 Preparation of 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI5) To a stirring solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K₂CO₃ (13.3 g, 96.7 mmol) and 1,2,4-triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120° C. for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with water and extracted with EtOAc (3*100 mL). The combined EtOAc layer was washed with water and brine, dried over Na₂SO₄, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65percent): mp 145-149° C.: ¹H NMR (400 MHz, CDCl₃) δ 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]⁺).

65%	With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 6 h;	Example 91: Preparation of 4-(lH-l,2,4-triazol-l-yl)benzaldehyde (DI5) To a stirring solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K₂CO₃ (13.3 g, 96.7 mmol) and 1,2,4- triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120 °C for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with H₂0 and extracted with EtOAc (3 xlOO mL). The combined EtOAc layer was washed with H₂0 and brine, dried over Na₂S0₄, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65percent): mp 145-149 °C: ^]H NMR (400 MHz, CDC1₃) δ 10.08 (s, IH), 8.70 (s, IH), 8.16 (s, IH), 8.06 (d, J = 8.0 Hz, 2H), 7.92 (d, J = 8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]⁺).
65%	With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 6 h;	To a stiffing solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K₂CO₃(13.3 g, 96.7 mmol) and 1,2,4-triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120° C. for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with H₂O and extracted with EtOAc (3×100 mL). The combined EtOAc layer was washed with H₂O and brine, dried over Na₂SO₄, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65percent): mp 145-149° C.: ¹H NMR (400 MHz, CDCl₃) δ 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]⁺).
65%	With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 6 h;	To a stiffing solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K₂CO₃ (13.3 g, 96.7 mmol) and 1,2,4-triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120° C. for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with H₂O and extracted with EtOAc (3*100 mL). The combined EtOAc layer was washed with H₂O and brine, dried over Na₂SO₄, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65percent): mp 145-149° C.: ¹H NMR (400 MHz, CDCl₃) δ 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]⁺).
65%	With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 6 h;	Example 91 Preparation of 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI5) To a stirring solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K₂CO₃(13.3 g, 96.7 mmol) and 1,2,4-triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120° C. for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with water and extracted with EtOAc (3×100 mL). The combined EtOAc layer was washed with water and brine, dried over Na₂SO₄, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65percent): mp 145-149° C.: ¹H NMR (400 MHz, CDCl₃) δ 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]⁺).

Reference： [1] European Journal of Medicinal Chemistry, 2009, vol. 44, # 7, p. 2930 - 2935
[2] European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 4302 - 4310
[3] Patent: US2012/329649, 2012, A1, . Location in patent: Page/Page column 72
[4] Patent: US2014/171314, 2014, A1, . Location in patent: Page/Page column
[5] Patent: WO2014/100163, 2014, A1, . Location in patent: Page/Page column 131
[6] Patent: US2014/171308, 2014, A1, . Location in patent: Paragraph 0656-0657
[7] Patent: US2014/171312, 2014, A1, . Location in patent: Paragraph 0821; 0822
[8] Patent: US9211280, 2015, B2, . Location in patent: Page/Page column 132-133
[9] Tetrahedron, 2001, vol. 57, # 22, p. 4781 - 4785
[10] Journal of Medicinal Chemistry, 1998, vol. 41, # 13, p. 2390 - 2410
[11] Asian Journal of Chemistry, 2014, vol. 26, # 1, p. 257 - 260
[12] Crystal Growth and Design, 2012, vol. 12, # 9, p. 4663 - 4668
[13] Journal of Organic Chemistry, 2013, vol. 78, # 7, p. 3222 - 3234
[14] Patent: US2014/107094, 2014, A1, . Location in patent: Paragraph 0593; 0594
[15] Patent: US2015/105366, 2015, A1, . Location in patent: Paragraph 0567; 0568
[16] Patent: WO2015/57205, 2015, A1, . Location in patent: Page/Page column 158
[17] Medicinal Chemistry Research, 2017, vol. 26, # 7, p. 1506 - 1515
[18] Molecules, 2017, vol. 22, # 8,
[19] Patent: CN107056716, 2017, A, . Location in patent: Paragraph 0032; 0033
[20] Patent: CN104119286, 2017, B, . Location in patent: Paragraph 0033

2
[ 288-88-0 ]
[ 459-57-4 ]
[ 27996-86-7 ]

Reference： [1] Patent: US6451973, 2002, B1,
[2] Patent: US5977075, 1999, A,
[3] Patent: US7138432, 2006, B1, . Location in patent: Page/Page column 44
[4] Patent: US5703106, 1997, A,

3
[ 459-57-4 ]
[ 288-88-0 ]
[ 27996-86-7 ]

Reference： [1] Journal of Medicinal Chemistry, 1987, vol. 30, # 6, p. 1023 - 1029
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 7, p. 1695 - 1697

4
[ 143426-50-0 ]
[ 27996-86-7 ]

Reference： [1] European Journal of Medicinal Chemistry, 1992, vol. 27, # 3, p. 219 - 228

5
[ 288-32-4 ]
[ 459-57-4 ]
[ 27996-86-7 ]

Reference： [1] Supramolecular Chemistry, 2017, vol. 29, # 3, p. 193 - 204

6
[ 451-46-7 ]
[ 27996-86-7 ]

Reference： [1] European Journal of Medicinal Chemistry, 1992, vol. 27, # 3, p. 219 - 228

7
[ 143426-48-6 ]
[ 27996-86-7 ]

Reference： [1] European Journal of Medicinal Chemistry, 1992, vol. 27, # 3, p. 219 - 228

[ 27996-86-7 ] Synthesis Path-Downstream 1~88

1
[ 459-57-4 ]
[ 288-88-0 ]
[ 27996-86-7 ]

Reference： [1]Journal of Medicinal Chemistry,1987,vol. 30,p. 1023 - 1029
[2]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 1695 - 1697

2
[ 123-76-2 ]
[ 27996-86-7 ]
[ 117606-94-7 ]

Reference： [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 342 - 350

3
[ 143426-50-0 ]
[ 27996-86-7 ]

Reference： [1]European Journal of Medicinal Chemistry,1992,vol. 27,p. 219 - 228

4
[ 79-24-3 ]
[ 27996-86-7 ]
[ 90514-74-2 ]

Reference： [1]Journal of Medicinal Chemistry,1987,vol. 30,p. 1023 - 1029

5
[ 867-13-0 ]
[ 27996-86-7 ]
[ 143426-70-4 ]

Reference： [1]European Journal of Medicinal Chemistry,1992,vol. 27,p. 219 - 228

6
[ 10308-82-4 ]
[ 27996-86-7 ]
[ 126937-33-5 ]

Reference： [1]European Journal of Medicinal Chemistry,1989,vol. 24,p. 349 - 355

7
[ 288-88-0 ]
[ 459-57-4 ]
[ 27996-86-7 ]

Yield	Reaction Conditions	Operation in experiment
75.2%	With aliquat 336; potassium carbonate; In dimethyl sulfoxide; at 80 - 90℃; for 24h;	6.91 g (100 mmol) of triazole was added to a 250 mL three-necked flask equipped with a magnet.14.86g (107.5mmol)Potassium carbonate and 80 mL of DMSO,Add 5 drops of Aliquat336 dropwise with stirring.After heating to 90 C, maintain 5 min;Further, 12.9 mL of p-fluorobenzaldehyde (120 mmol) was slowly added dropwise to the flask.The reaction was stopped after stirring at 80 C for 24 h.Hot filtered,Pour the filtrate into 500 mL of ice water.Stir,There is a lot of solid precipitation,Let stand layering,Filtering,Obtained white flocculent solid 13.03g,The yield is 75.2%,
72%	With potassium carbonate; In N,N-dimethyl-formamide; at 110℃;	General procedure: A mixture of 4-fluoro acetophenone/4-fluorobenzaldehyde (10 mmol) and imidazole/triazole (10 mmol) were dissolved in dry DMF (20 mL). K2CO3 (12 mmol) was added in small portion within a period of 15 min to the above stirred solution. Mixture was stirred for 10-12 h at 110 C. Heating discontinued, K2CO3 was filtered off, filtrate extracted with ethyl acetate (3 × 15 mL). Organic layer was washed with water (3 × 15 mL), dried over anhydrous sodium sulphate and concentrated to given an oil which was purified on silica gel column (60-120 mesh) taking methanol: chloroform (1:99) as an eluent.
65%	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 6h;	Example 91Preparation of 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI5); To a stiffing solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K2CO3 (13.3 g, 96.7 mmol) and 1,2,4-triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120 C. for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with H2O and extracted with EtOAc (3×100 mL). The combined EtOAc layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65%): mp 145-149 C.: 1H NMR (400 MHz, CDCl3) delta 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]+).

65%	With potassium carbonate; In N,N-dimethyl-formamide;	Example 91 Preparation of 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI5) To a stirring solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K2CO3 (13.3 g, 96.7 mmol) and 1,2,4-triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120 C. for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with water and extracted with EtOAc (3*100 mL). The combined EtOAc layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65%): mp 145-149 C.: 1H NMR (400 MHz, CDCl3) delta 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]+).
65%	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 6h;	Example 91: Preparation of 4-(lH-l,2,4-triazol-l-yl)benzaldehyde (DI5) To a stirring solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K2CO3 (13.3 g, 96.7 mmol) and 1,2,4- triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120 C for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with H20 and extracted with EtOAc (3 xlOO mL). The combined EtOAc layer was washed with H20 and brine, dried over Na2S04, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65%): mp 145-149 C: ]H NMR (400 MHz, CDC13) delta 10.08 (s, IH), 8.70 (s, IH), 8.16 (s, IH), 8.06 (d, J = 8.0 Hz, 2H), 7.92 (d, J = 8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]+).
65%	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 6h;	To a stiffing solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K2CO3 (13.3 g, 96.7 mmol) and 1,2,4-triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120 C. for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with H2O and extracted with EtOAc (3×100 mL). The combined EtOAc layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65%): mp 145-149 C.: 1H NMR (400 MHz, CDCl3) delta 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]+).
65%	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 6h;	To a stiffing solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K2CO3 (13.3 g, 96.7 mmol) and 1,2,4-triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120 C. for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with H2O and extracted with EtOAc (3*100 mL). The combined EtOAc layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65%): mp 145-149 C.: 1H NMR (400 MHz, CDCl3) delta 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]+).
65%	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 6h;	Example 91 Preparation of 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI5) To a stirring solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K2CO3 (13.3 g, 96.7 mmol) and 1,2,4-triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120 C. for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with water and extracted with EtOAc (3×100 mL). The combined EtOAc layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65%): mp 145-149 C.: 1H NMR (400 MHz, CDCl3) delta 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]+).
	With potassium carbonate; In N,N-dimethyl-formamide; at 23 - 105℃; for 3.5h;	4-Fluorobenzaldehyde (12.0 mL, 112 mmol) was added dropwise by syringe to a stirring, heterogeneous mixture of 1,2,4-triazole (11.6 g, 168 mmol) and potassium carbonate (24.7 g, 179 mmol) in dimethyl formamide (220 mL) at 23 C. The mixture was heated to 105 C. After 3.5 hours, the mixture was allowed to cool to 23 C. The cooled solution was transferred to a 2 L Erlenmeyer flask and diluted with water (500 mL) and ethyl acetate (1200 mL). The biphasic mixture was stirred until the layers cleanly separated. The layers were separated. The organic layer was washed with half-saturated aqueous sodium chloride solution (3*100 mL). The washed solution was dried with sodium sulfate, and the dried solution was filtered. The filtrate was concentrated to provide an off-white solid. The solid was suspended in a mixture of heptanes and isopropyl acetate (5:1, 600 mL). The mixture was filtered and the filter cake was washed with heptanes-isopropyl acetate (5:1). The solids were collected and dried under vacuum to afford the titled compound as a white solid.
	With potassium carbonate; In N,N-dimethyl-formamide; at 23 - 105℃; for 3.5h;	4-Fluorobenzaldehyde (12.0 mL, 112 mmol) was added dropwise by syringe to a stirring, heterogeneous mixture of 1,2,4-triazole (11.6 g, 168 mmol) and potassium carbonate (24.7 g, 179 mmol) in dimethyl formamide (220 mL) at 23 C. The mixture was heated to 105 C. After 3.5 hours, the mixture was allowed to cool to 23 C. The cooled solution was transferred to a 2 L Erlenmeyer flask and diluted with water (500 mL) and ethyl acetate (1200 mL). The biphasic mixture was stirred until the layers cleanly separated. The layers were separated. The organic layer was washed with half-saturated aqueous sodium chloride solution (3*100 mL). The washed solution was dried with sodium sulfate, and the dried solution was filtered. The filtrate was concentrated to provide an off-white solid. The solid was suspended in a mixture of heptanes and isopropyl acetate (5:1, 600 mL). The mixture was filtered and the filter cake was washed with heptanes-isopropyl acetate (5:1). The solids were collected and dried under vacuum to afford the title compound as a white solid.
	With potassium carbonate; In N,N-dimethyl-formamide; at 23 - 105℃; for 3.5h;	Intermediate 82: step a 4-(1H-1,2,4-triazol-1-yl)benzaldehyde 4- Fluorobenzaldehyde (12.0 mL, 1 12 mmol) was added dropwise by syringe to a stirring, heterogeneous mixture of 1,2,4-triazole (11.6 g, 168 mmol) and potassium carbonate (24.7 g, 179 mmol) in dimethyl formamide (220 mL) at 23 C. The mixture was heated to 105 C. After 3.5 hours, the mixture was allowed to cool to 23 C. The cooled solution was transferred to a 2 L Erlenmeyer flask and diluted with water (500 mL) and ethyl acetate ( 200 mL). The biphasic mixture was stirred until the layers cleanly separated. The layers were separated. The organic layer was washed with half-saturated aqueous sodium chloride solution (3 100 mL). The washed solution was dried with sodium sulfate, and the dried solution was filtered. The filtrate was concentrated to provide an off-white solid. The solid was suspended in a mixture of heptanes and isopropyl acetate (5: 1, 600 mL). The mixture was filtered and the filter cake was washed with heptanes-isopropyl acetate (5: 1). The solids were collected and dried under vacuum to afford the title compound as a white solid.
	With potassium carbonate; In N,N-dimethyl-formamide; at 300℃; for 36h;	General procedure: A mixture of 4-fluorobenzaldehyde (8.85 mL, 0.1 mol), the corresponding phenol, thiophenol or amine (0.1 mol), and a catalytic quantity of potassium carbonate (K2CO3) was refluxed in DMF (20 mL) for 36 h. After completion of the reaction, the mixture was poured into ice-water (50 mL), and the precipitated product was filtered, washed with deionised water, dried, and recrystallized from EtOH.
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 10h;	Weigh 0.691 g (10 mmol) of 1,2,4-triazole,Para-fluorobenzaldehyde 1.240 g (10 mmol) and anhydrous potassium carbonate 2.760 g (20 mmol) were weighed out,Was dissolved in 25 mL of N, N-dimethylformamide,Add to a thermometer,In a 50 mL four-necked flask equipped with a stirrer,80 under the reaction after 10h stop heating,Filtered to remove potassium carbonate,Ethyl acetate extraction,After the solvent was removed by rotary evaporation,An off-white solid,Recrystallized three times with ethanol,Get pure,Drying at 50 C in vacuo for 6h gave 4- (1-1,2,4-triazolyl) benzaldehyde.
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 10h;	Weigh 0.691 g (10 mmol) of 1,2,4-triazole,Para-fluorobenzaldehyde 1.240 g (10 mmol) and anhydrous potassium carbonate 2.760 g (20 mmol) were weighed out,Was dissolved in 25 mL of N, N-dimethylformamide,Add to a thermometer,In a 50 mL four-necked flask equipped with a stirrer,80 under the reaction after 10h stop heating,Filtered to remove potassium carbonate,Ethyl acetate extraction,After the solvent was removed by rotary evaporation,An off-white solid,Recrystallized three times with ethanol,Get pure,Drying at 50 C in vacuo for 6h gave 4- (1-1,2,4-triazolyl) benzaldehyde.
	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16h;	0.69 g (10 mmol) of 1,2,4-triazole, 2.07 g (15 mmol) of potassium carbonate, 1.49 g(12mmol) of p-fluorobenzaldehyde, and dissolved in 50 mL of N,N-dimethylformamide. It was placedina 100 mL three-neckedflaskequipped with a thermometer and a stirring device.The reaction was carried out under constant temperature stirring at 100 C for 16 h, cooled to room temperature, extracted, suction filtered, separated by column chromatography, washed with warm water, recrystallized from anhydrous ethanol, and dried under vacuum at 50 C for 8 h to obtain 1,2,4-triazole benzaldehyde.
	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16h;	0.69 g (10 mmol) of 1,2,4-triazole and 2.07 g (15 mmol) of potassium carbonate were weighed.1.24 g (10 mmol) of p-fluorobenzaldehyde,It was dissolved in 20 mL of N,N-dimethylformamide, and added to a 100 mL three-necked flask equipped with a thermometer and a stirring apparatus.The reaction was carried out under constant temperature stirring at 100C for 16 h, cooled to room temperature, extracted, suction filtered, separated by column chromatography, washed with warm water, recrystallized from anhydrous ethanol, and dried under vacuum at 50C for 8h that is, 1,2,4-triazole benzaldehyde.
	With potassium carbonate; In N,N-dimethyl-formamide; at 110℃;	To a stirred solution of 4-fluro benzaldehyde (1.0 g, 0.8 mmol) in dry DMF (5 mL), 1 H-1 ,2,4-triazole (660 mg, 0.9 mmol) and K2CO3 (2.2 g, 1.6 mmol) were added at RT and the resulting mixture was stirred overnight at 1 10 C. After completion of reaction, ice water (2 mL) was added and the mixture was extracted with EtOAc (2 x 20 ml_). The combined organic layer was washed with brine (2 ml_), dried over Na2S04 and concentrated under vacuum. The resulting product was used in next step without further purification. Yield: 46% (610 mg, white solid). LCMS: (Method A) 174.1 (M+H), Rt.1.27 min, 67.51 % (Max).

Reference： [1]RSC Advances,2020,vol. 10,p. 3048 - 3059
[2]Patent: CN109206405,2019,A .Location in patent: Paragraph 0023; 0040; 0041; 0042
[3]European Journal of Medicinal Chemistry,2009,vol. 44,p. 2930 - 2935
[4]European Journal of Medicinal Chemistry,2011,vol. 46,p. 4302 - 4310
[5]Patent: US2012/329649,2012,A1 .Location in patent: Page/Page column 72
[6]Patent: US2014/171314,2014,A1 .Location in patent: Page/Page column
[7]Patent: WO2014/100163,2014,A1 .Location in patent: Page/Page column 131
[8]Patent: US2014/171308,2014,A1 .Location in patent: Paragraph 0656-0657
[9]Patent: US2014/171312,2014,A1 .Location in patent: Paragraph 0821; 0822
[10]Patent: US9211280,2015,B2 .Location in patent: Page/Page column 132-133
[11]Tetrahedron,2001,vol. 57,p. 4781 - 4785
[12]Journal of Medicinal Chemistry,1998,vol. 41,p. 2390 - 2410
[13]Asian Journal of Chemistry,2014,vol. 26,p. 257 - 260
[14]Crystal Growth and Design,2012,vol. 12,p. 4663 - 4668
[15]Journal of Organic Chemistry,2013,vol. 78,p. 3222 - 3234
[16]Patent: US2014/107094,2014,A1 .Location in patent: Paragraph 0593; 0594
[17]Patent: US2015/105366,2015,A1 .Location in patent: Paragraph 0567; 0568
[18]Patent: WO2015/57205,2015,A1 .Location in patent: Page/Page column 158
[19]Medicinal Chemistry Research,2017,vol. 26,p. 1506 - 1515
[20]Molecules,2017,vol. 22
[21]Patent: CN107056716,2017,A .Location in patent: Paragraph 0032; 0033
[22]Patent: CN104119286,2017,B .Location in patent: Paragraph 0033
[23]Patent: CN109867683,2019,A .Location in patent: Paragraph 0032-0053
[24]Journal of Coordination Chemistry,2019,vol. 72,p. 1865 - 1875
[25]Patent: CN109761992,2019,A .Location in patent: Page/Page column 5-7
[26]Pharmaceutical Chemistry Journal,2019,vol. 53,p. 322 - 328
[27]Patent: WO2020/39027,2020,A1 .Location in patent: Page/Page column 150

8
[ 5452-35-7 ]
[ 27996-86-7 ]
Cycloheptyl-[1-(4-[1,2,4]triazol-1-yl-phenyl)-meth-(E)-ylidene]-amine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 2390 - 2410

10
[ 60126-31-0 ]
[ 27996-86-7 ]
3-Allyl-2-[(E)-2-(4-[1,2,4]triazol-1-yl-phenyl)-vinyl]-benzothiazol-3-ium; bromide [ No CAS ]

Reference： [1]Pharmazie,2000,vol. 55,p. 803 - 810

11
[ 27996-86-7 ]
2-methyl-3-prop-2-ynyl-benzothiazol-3-ium bromide [ No CAS ]
3-Prop-2-ynyl-2-[(E)-2-(4-[1,2,4]triazol-1-yl-phenyl)-vinyl]-benzothiazol-3-ium; bromide [ No CAS ]

Reference： [1]Pharmazie,2000,vol. 55,p. 803 - 810

12
[ 141-82-2 ]
[ 27996-86-7 ]
[ 575469-44-2 ]

Yield	Reaction Conditions	Operation in experiment
	With piperidine; In pyridine; for 2h;Reflux;	To a mixture of <strong>[27996-86-7]4-(1H-1,2,4-triazol-1-yl)benzaldehyde</strong> (1 mmol) and malonic acid (3 mmol) in 10 mL dry pyridine, 2-3 drops of piperidine were added and the mixture was refluxed for 2 h. After cooling, the reaction mixture was poured into crushed ice, and the pH was adjusted to 1.0 by adding conc. HCl, and stirred for 30 min. The product obtained was filtered, washed with water, dried and crystallized from ethanol.

Reference： [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 2603 - 2616
[2]Letters in drug design and discovery,2015,vol. 12,p. 650 - 660

13
[ 5242-26-2 ]
[ 27996-86-7 ]
4-methyl-<i>N</i>-[4-oxo-5-(4-[1,2,4]triazol-1-yl-benzylidene)-4,5-dihydro-thiazol-2-yl]-benzenesulfonamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 841 - 845

14
[ 27996-86-7 ]
(E)-1-((S)-2-Piperidin-1-ylmethyl-pyrrolidin-1-yl)-3-(4-[1,2,4]triazol-1-yl-phenyl)-propenone [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 2603 - 2616

15
[ 27996-86-7 ]
[ 179056-47-4 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 2390 - 2410

16
[ 27996-86-7 ]
1-Cycloheptyl-1-(4-[1,2,4]triazol-1-yl-benzyl)-3-(2,4,6-trimethyl-phenyl)-urea [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 2390 - 2410

17
[ 27996-86-7 ]
[ 117607-01-9 ]

Reference： [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 342 - 350

18
[ 27996-86-7 ]
[ 90514-77-5 ]

Reference： [1]Journal of Medicinal Chemistry,1987,vol. 30,p. 1023 - 1029

19
[ 27996-86-7 ]
(Z)-4-Dimethylamino-3-(4-[1,2,4]triazol-1-yl-phenyl)-but-3-en-2-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1987,vol. 30,p. 1023 - 1029

20
[ 27996-86-7 ]
[ 90514-82-2 ]

Reference： [1]Journal of Medicinal Chemistry,1987,vol. 30,p. 1023 - 1029

21
[ 451-46-7 ]
[ 27996-86-7 ]

Reference： [1]European Journal of Medicinal Chemistry,1992,vol. 27,p. 219 - 228

22
[ 143426-48-6 ]
[ 27996-86-7 ]

Reference： [1]European Journal of Medicinal Chemistry,1992,vol. 27,p. 219 - 228

23
[ 27996-86-7 ]
[ 143426-73-7 ]

Reference： [1]European Journal of Medicinal Chemistry,1992,vol. 27,p. 219 - 228

24
[ 27996-86-7 ]
[ 139311-96-9 ]

Reference： [1]European Journal of Medicinal Chemistry,1992,vol. 27,p. 219 - 228

25
[ 27996-86-7 ]
[ 575469-44-2 ]

Yield	Reaction Conditions	Operation in experiment
		Step 1 (E)-3-(4-(1,2,4-Triazol-1-yl)phenyl)acrylic Acid 1.9 g of (E)-3-(4-(1,2,4-triazol-1-yl)phenyl)acrylic acid were prepared as described for (E)-3-(4-(methanesulfonyloxy)phenyl)acrylic acid, using <strong>[27996-86-7]4-(1,2,4-triazol-1-yl)benzaldehyde</strong> instead of methanesulfonic acid 4-formylphenyl ester. 1H-NMR (DMSO-d6) delta 6.60 (d, 1 H); 7.65 (d, 1 H); 7.90 (AB, 4 H); 8.30 (s, 1 H); 9.40 (s, 1 H); 12.50 (br, 1 H).

Reference： [1]Patent: US2003/195190,2003,A1

26
[ 288-88-0 ]
[ 459-57-4 ]
4-(1,3,4-triazol-1-yl)-benzaldehyde [ No CAS ]
[ 27996-86-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In pyridine; methanol; dichloromethane; ethyl acetate; toluene;	14a p-(1,2,4-Triazol-1-yl)benzaldehyde and p-(1,2,4-Triazol-4-yl)benzaldehyde 21 ml (200 mmol) of 4-fluorobenzaldehyde (Fluka, Buchs, Switzerland), 30.48 g (220 mmol) of potassium carbonate and 13.8 g (200 mmol) of 1,2,4-triazole (Fluka, Buchs, Switzerland) are suspended in 100 ml of pyridine, after which 1.2 g of copper(I) oxide are added. The reaction mixture is boiled at reflux for 16 h. After that, the solvent is removed and the residue is taken up twice in toluene, followed by evaporation, and dissolved in methylene chloride. The insoluble material is removed by filtration and the solution is concentrated. This yields a mixture of the two 1,2,4-triazol-1-yl- and 1,2,4-triazol-4-yl-substituted benzaldehyde, which can be separated, after digesting with hexane, by means of chromatography on silica gel (mobile solvent: hexane/ethyl acetate 1:1, ethyl acetate and methylene chloride/5% methanol). p-(1,2,4-Triazol-1-yl)benzaldehyde: HPLC20-100: tret=8.50. 1H NMR (DMSO-D6; 200 MHz): 10.04/s (1H); 9.47/s (1H); 8.31/s (1H); 8.12 and 8.09/in each case d, J=10 (22H). p-(1,2,4-Triazol-4-yl)benzaldehyde: HPLC20-100: tret=5.96. 1H NMR (DMSO-D6; 200 MHz): 10.05/s (1H); 9.27/s (1H); 8.31/s (1H); 8.09 and 7.98/in each case d, J=9 (22H).
	With potassium carbonate; In pyridine; methanol; hexane; ethyl acetate;	A mixture of 1,2,4-triazole (4.06 g, 58.7 mmol), potassium carbonate (9.05 g, 65.5 mmol), 4-fluorobenzaldehyde (6.3 ml, 58.7 mmol), and copper(I) oxide (0.26 g, 1.82 mmol) in pyridine (30 ml) is heated under nitrogen atmosphere at reflux overnight. After pyridine is distilled, the residue is diluted with chloroform, filtered, and washed with chloroform. The combined filtrate is washed with water, dried over magnesium sulfate, and concentrated in vacuo. The crude material is purified by column chromatography on silica with hexane/ethyl acetate (1:2) to give 4-(1,2,4-triazol-1-yl)-benzaldehyde and with ethyl acetate/methanol (19:1) to give 4-(1,3,4-triazol-1-yl)-benzaldehyde.
	With pyridine; copper(I) oxide; potassium carbonate; at 20 - 125℃; for 18h;	Stage 79.3: 4-(1,2,4] Triazol-1-yl-benzaldehydeTo a solution of 6.44 ml (60 mmol) of p-fluorobenzaldehyde in 40 ml of pyridine, 4.14 g (60 mmol) of 1,2,4-triazole, 0.286 g (2 mmol) of copper(I)oxide and 9.12 g (66 mmol) of potasium carbonate are succesively added at r.t. After stirring for 18 h at 125 C., the reaction mixture is concentrated under reduced pressure. The residue is diluted with CHCl3 and filtered through celite. The filtrate is concetrated and purified by flash column chromatography on silica gel (eluent: n-Hexane:AcOEt=4:1?AcOEt only?AcOEt: MeOH=20:1) to give 4-[1,2,4] triazol-1-yl-benzaldehyde as major product and 4-[1,3,4] triazol-1-yl-benzaldehyde as minor product. 1H-NMR (400 MHz, CDCl3): 7.61 (d, 2H, J=8.56 Hz), 8.09 (d, 2H, J=8.56 Hz), 8.59 (s, 1H), 10.10 (s, 1H) (minor product); 7.91 (d, 2H, J=7.07 Hz), 8.05 (d, 2H, J=7.07 Hz), 8.16 (s, 1H), 8.69 (s, 1H), 10.07 (s, 1H) (major product).

With potassium carbonate; In pyridine; methanol; hexane; ethyl acetate;

A mixture of 1,2,4-triazole (4.06 g, 58.7 mmol), potassium carbonate (9.05 g, 65.5 mmol), 4-fluorobenzaldehyde (6.3 ml, 58.7 mmol), and copper(I) oxide (0.26 g, 1.82 mmol) in pyridine (30 ml) is heated under nitrogen atmosphere at reflux overnight. After pyridine is distilled, the residue is diluted with chloroform, filtered, and washed with chloroform. The combined filtrate is washed with water, dried over magnesium sulfate, and concentrated in vacuo. The crude material is purified by column chromatography on silica with hexane/ethyl acetate (1:2) to give 4-(1,2,4-triazol-1-yl)-benzaldehyde and with ethyl acetate/methanol (19:1) to give 4-(1,3,4-triazol-1-yl)-benzaldehyde.

Reference： [1]Patent: US6451973,2002,B1
[2]Patent: US5977075,1999,A
[3]Patent: US7138432,2006,B1 .Location in patent: Page/Page column 44
[4]Patent: US5703106,1997,A

27
[ 623-33-6 ]
[ 27996-86-7 ]
C₁₃H₁₄N₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With magnesium sulfate; triethylamine; In dichloromethane; at 20℃; for 18h;	Stage 79.4: (4-[1,2,4] Triazol-1-yl-benzylamino)-acetic acid ethyl esterTo a solution of 3.5 g (20 mmol) of 4-[1,2,4] triazol-1-yl-benzaldehyde and 4.19 g (30 mmol) of glycine ethyl ester hydrochloride in 100 ml of CH2Cl2, 4.18 ml (30 mmol) of triethyl amine and excess of MgSO4 (14 g) are successively added at r.t. After being stirred for 18 h at r.t., the reaction mixture is filtered through celite and concentrated under reduced pressure. The residue is diluted with AcOEt and filtered again. The filtrate is concentrated under reduced pressure to give the crude imine. To a solution of the crude imine in 12 ml of MeOH, 0.756 mg (20 mmol) of NaBH4 is added at -10 C. After being stirred for 1 h, the reaction is quenched with sat. NH4Cl and the reaction mixture is extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: n-Hexane: AcOEt=1:10) to give the title compound. 1H-NMR (400 MHz, CDCl3): 1.29 (t, 3H, J=7.04 Hz), 1.90 (brs, 1H), 3.43 (s, 2H), 3.88 (s, 2H), 4.21 (q, 2H, J=7.04 Hz), 7.49 (d, 2H, J=8.56 Hz), 7.64 (d, 2H, J=8.56 Hz), 8.10 (s, 1H), 8.55 (s, 1H).

Reference： [1]Patent: US7138432,2006,B1 .Location in patent: Page/Page column 45

Yield	Reaction Conditions	Operation in experiment
		Example 67 Compound 84 This compound was prepared by procedures analogous to those described in Schemes 2 and 3. The 4-(1,2,4-triazol-1-yl)phenylserine analog of 6 was synthesised by the same methods used to make 6. The required 4-(1,2,4-triazol-1-yl)benzaldehyde was prepared as described in the literature (Tanaka, A., et al., J. Med. Chem. 1998, 41, 2390-2410). 1H NMR (300 MHz, CD3OD): delta 4.33-4.76 (m, 3H), 5.04 (d, 1H, J=3.3), 6.26 (s, 1H), 7.59 (d, 2H, J=8.6), 7.78 (d, 2H, J=8.6), 8.14 (s, 1H), 9.05 (s, 1H). LRMS (ESI-) m/z: 345.0 (calc. for M-H+ C13H12Cl2FN4O2 345.0).

29
[ 2369-29-1 ]
[ 27996-86-7 ]
[ 1163728-92-4 ]

Reference： [1]European Journal of Medicinal Chemistry,2009,vol. 44,p. 2930 - 2935

30
[ 3471-05-4 ]
[ 27996-86-7 ]
3-[4-(1H-1,2,4-triazol-1-yl)-benzylidene]anabaseine trishydrochloride [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2010,vol. 45,p. 2433 - 2446

31
1-cyclobutyl[1,4]diazepane [ No CAS ]
[ 88333-03-3 ]
[ 27996-86-7 ]
[ 1177251-37-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 5165 - 5169

32
[ 10558-25-5 ]
[ 27996-86-7 ]
[ 1265614-72-9 ]

Reference： [1]Synthesis,2010,p. 3802 - 3810

33
[ 95-54-5 ]
[ 27996-86-7 ]
[ 1190394-60-5 ]

Reference： [1]Journal of the Chinese Chemical Society,2010,vol. 57,p. 1227 - 1231

34
[ 1044067-88-0 ]
[ 27996-86-7 ]
[ 1334929-23-5 ]

Yield	Reaction Conditions	Operation in experiment
69%	With sodium hydroxide; In ethanol; at 20℃;	General procedure: A mixture of azolyl ketone (1a/1b) (1 mmol) and aryloxy benzaldehyde (2a-f) (1 mmol) were dissolved in 10% NaOH-EtOH (5 mL), it was stirred at room temperature for 9-10 h. After completion, 5 mL water was added to the reaction mixture. The separated solid compound was filtered and washed with water. It was purified by crystallization with methanol/chloroform or basic alumina column chromatography to give the desired compounds (3-13).The compounds (16-31) were prepared by the reaction of their corresponding aldehyde and ketone partners.