[ CAS No. 21962-45-8 ] {[proInfo.proName]}

Name: 21962-45-8|4-Formyl-3-methoxybenzonitrile|98%
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Quality Control of [ 21962-45-8 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 21962-45-8 ]

CAS No. :	21962-45-8	MDL No. :	MFCD07779491
Formula :	C₉H₇NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZXENVSJZOHXCKL-UHFFFAOYSA-N
M.W :	161.16	Pubchem ID :	16659251
Synonyms :

Calculated chemistry of [ 21962-45-8 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.11
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	43.04
TPSA :	50.09 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) :	-6.1 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.63
Log Po/w (XLOGP3) :	1.66
Log Po/w (WLOGP) :	1.38
Log Po/w (MLOGP) :	0.47
Log Po/w (SILICOS-IT) :	1.96
Consensus Log Po/w :	1.42

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.12
Solubility :	1.21 mg/ml ; 0.00753 mol/l
Class :	Soluble
Log S (Ali) :	-2.33
Solubility :	0.761 mg/ml ; 0.00472 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.55
Solubility :	0.455 mg/ml ; 0.00282 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.46

Safety of [ 21962-45-8 ]

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

Application In Synthesis of [ 21962-45-8 ]

* 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 [ 21962-45-8 ]
Downstream synthetic route of [ 21962-45-8 ]

[ 21962-45-8 ] Synthesis Path-Upstream 1~15

1
[ 21962-45-8 ]
[ 84102-89-6 ]

Yield	Reaction Conditions	Operation in experiment
61%	Stage #1: With boron tribromide In dichloromethane at -78 - 20℃; Inert atmosphere Stage #2: With sodium hydrogencarbonate In dichloromethane	Example 24A 4-Formyl-3-hydroxybenzonitrile 100 ml of a boron tribromide solution in dichloromethane (1 M, 100 mmol) are added dropwise to a solution of 8 g (49.64 mmol) of 4-formyl-3-methoxybenzonitrile in 80 ml of anhydrous dichloromethane at -78° C. under an argon atmosphere. The reaction mixture is stirred at RT until the precursor has completely reacted (about 5 days). The reaction solution is then neutralized at 0° C. with saturated sodium bicarbonate solution. The phases are separated and the organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 3:1). 4.5 g (61percent of theory) of the title compound are obtained as a yellow solid. LC-MS (method 1): R_t=1.38 min; [M-H]^-=146 ¹H-NMR (300 MHz, CDCl₃): δ=7.38 (d, 1H), 7.38 (s, 1H), 7.77 (d, 1H), 10.33 (s, 1H), 11.38 (s, 1H).
61%	With boron tribromide In dichloromethane at -78 - 20℃; for 120 h; Inert atmosphere	Dichloromethane (1 M, 100 mmol) of a solution of boron tribromide solution in 100 mL of anhydrous dichloromethane and 80 mL at -78 under argon atmosphere 4-formyl-3-methoxy-benzonitrile 8 g (49.64 mmol) It was added dropwise. Until the precursor to respond fully Paper (about 5 days) and the reaction mixture was stirred at room temperature. Thereafter, the reaction solution at 0 with saturated sodium bicarbonate solution And neutralized. Separating the phases and washing the organic phase with saturated sodium chloride solution, dried over magnesium sulfate And concentrated. Column chromatography on silica gel of the residue (mobile phase: cyclohexane / ethyl acetate 3: 1) determined by the It was first. The title compound 4.5 g (61percent of theory) as a yellow solid.

Reference： [1] Patent: US2010/305052, 2010, A1, . Location in patent: Page/Page column 20-21
[2] Patent: KR101614164, 2016, B1, . Location in patent: Paragraph 0328-0331
[3] Patent: US2010/136142, 2010, A1,

2
[ 959934-76-0 ]
[ 21962-45-8 ]

Yield	Reaction Conditions	Operation in experiment
71%	With sodium periodate In tetrahydrofuran; water at 20 - 30℃; for 2 h;	79 g (370 mmol) of sodium metaperiodate are added in portions to a vigorously stirred solution of 48 g (185 mmol) of tert-butyl (2E)-3-(4-cyano-2-methoxyphenyl)acrylate, 207 mg (0.81 mmol) of osmium tetroxide and 1.4 g (6.14 mmol) of benzyltriethylammonium chloride in 750 ml of water/THF (2:1), keeping the reaction temperature below 30° C. The solution is stirred at RT for a further 1 h. Water (2000 ml) is added and the mixture is then filtered. The remaining solid is dissolved in ethyl acetate, and the solution is washed with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. The residue is stirred with petroleum ether. 21.18 g (71percent of theory) of the title compound are obtained as a white solid. LC-MS (method 4): R_t=1.87 min; MS (EIpos): m/z=162 [M+H]⁺ ¹H-NMR (300 MHz, DMSO-d₆): δ=3.98 (s, 3H), 7.53 (d, 1H), 7.80 (s, 1H), 7.81 (d, 1H), 10.37 (s, 1H).
71%	With sodium periodate In tetrahydrofuran; water at 20 - 25℃; for 2 h;	79 g (370 mmol) of sodium metaperiodate are added in portions to a vigorously stirred solution of 48 g (185 mmol) of tert-butyl (2E)-3-(4-cyano-2-methoxyphenyl)acrylate, 207 mg (0.81 mmol) of osmium tetroxide and 1.4 g (6.14 mmol) of benzyltriethylammonium chloride in 750 ml of water/THF (2:1), keeping the reaction temperature below 30° C. The solution is stirred further at RT for 1 h. Water (2000 ml) is added, and the mixture is then filtered. The remaining solid is dissolved in ethyl acetate, and the solution is washed with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. The residue is stirred with petroleum ether. 21.18 g (71percent of theory) of the title compound are obtained as a white solid.LC-MS (Method 1): R_t=1.87 min; MS (Elpos): m/z=162 [M+H]⁺ ¹H-NMR (300 MHz, DMSO-d₆): δ=3.98 (s, 3H), 7.53 (d, 1H), 7.80 (s, 1H), 7.81 (d, 1H), 10.37 (s, 1H).
71%	With sodium periodate; osmium(VIII) oxide; N-benzyl-N,N,N-triethylammonium chloride In tetrahydrofuran; water at 20 - 30℃;	a): trifluoromethanesulfonic anhydride, pyridine, 0° C.-->RT, 30 min; b): tert-butyl acrylate, bis(triphenylphosphine)dichloropalladium(II), DMF, 120° C., 24 h; c): cat. osmium tetroxide, cat. benzyltriethylammonium chloride, sodium periodate, THF/water, 20-25° C., 2 h; Example 15A 4-Formyl-3-methoxybenzonitrile 79 g (370 mmol) of sodium metaperiodate are added in portions to a vigorously stirred solution of 48 g (185 mmol) of tert-butyl (2E)-3-(4-cyano-2-methoxyphenyl)acrylate, 207 mg (0.81 mmol) of osmium tetroxide and 1.4 g (6.14 mmol) of benzyltriethylammonium chloride in 750 ml of water/THF (2:1), keeping the reaction temperature below 30° C. The solution is stirred at RT for a further 1 h. Water (2000 ml) is added and the mixture is then filtered. The remaining solid is dissolved in ethyl acetate, and the solution is washed with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. The residue is stirred with petroleum ether. 21.18 g (71percent of theory) of the title compound are obtained as a white solid. LC-MS (method 4): R_t=1.87 min; MS (EIpos): m/z=162 [M+H]⁺ ¹H-NMR (300 MHz, DMSO-d₆): δ=3.98 (s, 3H), 7.53 (d, 1H), 7.80 (s, 1H), 7.81 (d, 1H), 10.37 (s, 1H).

71%

With sodium periodate; osmium(VIII) oxide; N-benzyl-N,N,N-triethylammonium chloride In tetrahydrofuran; water at 20 - 30℃; for 1 h;

While maintaining the reaction temperature below 30 , sodium meta-periodate flops date 79 g (370 mmol) of water / THF (2: 1) of 750 mL tert-butyl(2E)-3-(4-cyano-2-methoxyphenyl)acrylate 48 g (185 mmol), osmium tetroxide 207 mg (0.81 mmol) was added little by little, and the strongly stirred solution of benzyl triethyl ammonium chloride, 1.4 g (6.14 mmol). At room temperature, the solution Stirred for 1 hour. After addition of water (2000 ml), the mixture was filtered. The remaining solid in ethyl acetate Was dissolved, the solution was washed with a saturated aqueous sodium chloride solution. When drying the organic phase over magnesium sulfate and concentrated It turned on. The residue was stirred with petroleum ether. (71percent of theory) the title compound was obtained as a white solid 21.18 g All.

Reference： [1] Patent: US2010/35902, 2010, A1, . Location in patent: Page/Page column 10; 19
[2] Patent: US2010/240620, 2010, A1, . Location in patent: Page/Page column 7; 13
[3] Patent: US2010/305052, 2010, A1, . Location in patent: Page/Page column 8; 18
[4] Patent: KR101614164, 2016, B1, . Location in patent: Paragraph 0323-0326
[5] Patent: US2010/136142, 2010, A1,

3
[ 43192-33-2 ]
[ 21962-45-8 ]

Yield	Reaction Conditions	Operation in experiment
87%	With palladium diacetate; sodium carbonate In N,N-dimethyl-formamide at 120℃; for 3 h;	719 g (3.34 mol) of 4-bromo-2-methoxybenzaldehyde (XVI) as a solution in 4.5 l of DMF were charged with 313 g (0.74 mol) of potassium hexacyanoferrate (K₄[Fe(CN)₆]) and 354 g (3.34 mol) of sodium carbonate and a further 1.2 l of DMF and 3.8 g (0.017 mol) of palladium acetate were added. The mixture was stirred at 120° C. for 3 hours. The mixture was left to cool to 20° C. and 5.7 l of water were added to the mixture. The mixture was extracted with 17 l of ethyl acetate and the aqueous phase was washed once more with 17 l of ethyl acetate. The organic phases were combined and substantially concentrated, taken up in 5 l of isopropanol and concentrated to about 2 l. The mixture was heated to boiling and 2 l of water were added dropwise. The mixture was allowed to cool to 50° C. and another 2 l of water were added. The mixture was cooled to 3° C. and stirred at this temperature for one hour. The product was filtered off and washed with water (2*1.2 1). The product was dried at 40° C. under vacuum. Yield: 469 g (87percent of theory) of a beige solid. HPLC-Method A: RT ca. 8.3 min. MS (Elpos): m/z=162 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ=3.98 (s, 3H), 7.53 (d, 1H), 7.80 (s, 1H), 7.81 (d, 1H), 10.37 (s, 1H).
87%	With palladium diacetate; sodium carbonate In N,N-dimethyl-formamide at 120℃; for 3 h;	719 g (3.34 mol) of 4-bromo-2-methoxybenzaldehyde (XVI) as a solution in 4.5 l of DMF were charged with 313 g (0.74 mol) of potassium hexacyanoferrate (K₄[Fe(CN)₆]) and 354 g (3.34 mol) of sodium carbonate and a further 1.2 l of DMF and 3.8 g (0.017 mol) of palladium acetate were added. The mixture was stirred at 120° C. for 3 hours. The mixture was left to cool to 20° C. and 5.7 l of water were added to the mixture. The mixture was extracted with 17 l of ethyl acetate and the aqueous phase was washed once more with 17 l of ethyl acetate. The organic phases were combined and substantially concentrated, taken up in 5 l of isopropanol and concentrated to about 2 l. The mixture was heated to boiling and 2 l of water were added dropwise. The mixture was allowed to cool to 50° C. and another 2 l of water were added. The mixture was cooled to 3° C. and stirred at this temperature for one hour. The product was filtered off and washed with water (2*1.2 l). The product was dried at 40° C. under vacuum. Yield: 469 g (87percent of theory) of a beige solid. HPLC method A: RT about 8.3 mm.MS (Elpos): mlz=162 [M+H]+1H NMR (300 MHz, DMSO-d6): ö=3.98 (s, 3H), 7.53 (d, 1H), 7.80 (s, 1H), 7.81 (d, 1H), 10.37 (s, 1H).
469 g	With palladium diacetate; sodium carbonate In N,N-dimethyl-formamide at 120℃; for 3 h; Large scale	719 g (3.34 mol) of 4-bromo-2-methoxybenzaldehyde (XVI) as a solution in 4.5 l of DMF are charged with 313 g (0.74 mol) of potassium hexacyanoferrate (-K₄[Fe(CN)₆]) and 354 g (3.34 mol) of sodium carbonate and a further 1.2 l of DMF and 3.8 g (0.017 mol) of palladium acetate are added. The mixture is stirred at 120° C. for 3 hours. The mixture is allowed to cool to 20° C. and 5.7 l of water is added to the mixture. The mixture is extracted with 17 l of ethyl acetate and the aqueous phase washed once more with 17 l of ethyl acetate. The organic phases are combined and substantially concentrated, taken up in 5 l of isopropanol and concentrated to ca. 2 l. The mixture is heated to boiling and 2 l of water added dropwise. The mixture is allowed to cool to 50° C. and 2 l of water added anew. The mixture is cooled to 3° C. and stirred at this temperature for one hour. The product is filtered off and washed with water (2 times 1.2 l). The product is dried at 40° C. under vacuum. Yield: 469 g (87percent of theory) of a beige solid. -Pos=36,Num=13 218 H-0:h-00322 219 H-0:h-00323 220 220 220 220 220 220 220 220 220 220 --3:p-00324 220 --3:p-00325 P=1,E=2,S=2,R=1,K=1,He=1,ED=1,Pr=1,V=7PVVESVVExVVRVdVVKVSVxVSVSVVdVdxVVe125-1-0-20-6-14-15-16-10-11-11-9-6-6lpE-EEEEE-WWERIDX=5(53), Sub=1 ,OBJ=36, lRES=13, COD=00-90-02-02-4-INAM346INAM341INAM28INAM347INAM32INAM61INAM18INAM62INAM63--11-22-11-1-1-44-- INAM346 4.5 l -3105200HPLC method A: RT ca. 8.3 min.4-Formyl-3-methoxybenzonitrile (VI)3.d200-HPLC method A: RT ca. 8.3 min. MS (EIpos): m/z=162 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ=3.98 (s, 3H), 7.53 (d, 1H), 7.80 (s, 1H), 7.81 (d, 1H), 10.37 (s, 1H).

Reference： [1] Patent: US2018/244668, 2018, A1, . Location in patent: Paragraph 0178; 0179; 0180; 0181; 0182
[2] Patent: US2018/244670, 2018, A1, . Location in patent: Paragraph 0183-0188
[3] Patent: US2017/217957, 2017, A1, . Location in patent: Paragraph 0147-0151

4
[ 914106-35-7 ]
[ 21962-45-8 ]

Yield	Reaction Conditions	Operation in experiment
99%	With silver nitrate In ethanol; water for 0.5 h; Heating / reflux	4-Cyano-2-methoxybenzaldehyde (44f). A solution of silver nitrate (25.0 g, 147 mmol) in water (75 mL) was added dropwise to a solution of α, β-dibromotoluene 65 (18.22 g, 59.74 mmol) in refluxing EtOH (300 mL). The mixture was maintained at reflux for 30 min, filtered and evaporated to dryness. The residue was diluted with water and extracted into EtOAc to give a white solid (9.55 g, 99percent): mp 109-111 °C; ¹H NMR 810.37 (d, J = 0.8 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 1.0 Hz, 1H), 7.54 (dm, J = 7.8 Hz, 1H), 3.99 (s, 3H); HPLC (Method B) t_R 3.56 min (100 area percent at 254 nm). Anal. (C₉H₇N₅O₂) C, H, N. The synthesis of benzaldehyde chlorooxime synthons 52 is depicted in Scheme 4, below. Of the eight aldehydes 44e-f and 74a-f, only 44e and 74d were commercially available. The preparation of aldehyde 44f began with the known three-step transformation of 4-methyl-3-nitrobenzonitrile 63 to methoxy compound 64. See Reiner, J. E., et al., Bioorg. Med. Chem. Lett., 12, 1203-1208 (2002). α-Bromination of 64 using one equivalent of N-bromosuccinimide gave little selectivity between the mono- and dibromo adducts, but the analogous reaction using 2.5 equivalents gave dibromide 65 almost exclusively. Silver nitrate oxidation of dibromide 65 gave aldehyde 44f. See Hill. R. A., et al., J. Chem. Soc., Perkin Trans., 1, 2209-2215 (1987). The reaction of the o-nitrotoluene 63 with N,N-dimethylformamide dimethyl acetal in DMF gave the enamine 66, which underwent oxidative cleavage using sodium periodate in THF, see Riesgo, E. C., et al., J. Org. Chem., 61, 3017-3022 (1996), to give aldehyde 74a via a more facile preparation than previously reported. See Dann, O., et al., Liebigs Ann. Chem., 3, 409-425 (1984). Aldehyde 74b also has been prepared previously. See Schultz, E. M., et al., J. Med. Chem., 19(6), 783-787 (1976). A more expedient preparation of 74b began with chlorotoluene 67 undergoing α-bromination to 68, see Gilbert, A. M., et al., J. Med. Chem., 43, 1203-1214 (2000), by a modification of the original procedure. See Liu, P., et al., Synthesis, 14, 2078-2080 (2001). The reaction of 68 with 2-nitropropane and sodium ethoxide in ethanol gave 74b. See Mallory, F. M., et al., Tetrahedron, 57, 3715-3724 (2001). Commercially available aldehyde 69 and aldehyde 71, see Hino, K., et al., Chem. Pharm. Bull., 36(6), 3462-3467 (1988), which had been prepared via a Sandmeyer reaction from commercially available 70, were converted to methyl esters 72 and 73, respectively. The esters were converted to aldehydes 74c and 74e, respectively, using Red-Al.(R).(sodium bis(2-methoxyethoxy)aluminium hydride) (Aldrich Chemical Co., Inc., Milwaukee, Wisconsin, United States of America), pyrrolidine, and potassium tert-butoxide in methyl tert-butyl ether. See Abe, T., et al., Tetrahedron, 57, 2701-2710 (2001). Cyanoaldehyde 74f was prepared by debromocyanation of 44d. See Laali, K. K., et al., J. Org. Chem., 58, 1385-1392 (1993). Aldehydes 44e-44f and 74a-74f were converted to oxime derivatives 75a-h (of which 75a,e were known previously), see Quan, M. L., et al., J. Med. Chem., 42(15), 2752-2759 (1999), using hydroxylamine hydrochloride in either water/ethanol or pyridine/ethanol. The oximes were treated with N-chlorosuccinimide in DMF to give chlorooximes 52a-h, following the procedure reported for 52e. See Liu. K.-C., et al., J. Org. Chem., 45, 3916-3918 (1980). The chlorooximes 52 were reacted with acetylenes 51 without further purification.; Reagents and conditions: (a) H₂, 10percent Pd/C, EtOH; (b) NaNO₂, aq. H₂SO₄; (c) CH₃l, NaH, DMF; (d) NBS, benzoyl peroxide, CCl₄; (e) AgNO₃, aq. EtOH; (f) DMFDMA, DMF; (g) NalO₄; aq. THF; (h) diethyl phosphite, (i-Pr)₂NEt, THF; (j) 2-nitropropane, NaOEt, EtOH; (k) NaNO₂, aq. HCl, then CuCN, KCN; (I) MeOH, H₂SO₄; (m) DCC, DMAP, MeOH, CH₂Cl₂; (n) Red-Al.(R)., t-BuOK, pyrrolidine, MTBE; (o) NH₂OH HCl, H₂O/EtOH or Py/EtOH (p) NCS, DMF.

Reference： [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 10, p. 2468 - 2485
[2] Patent: EP1719767, 2006, A1, . Location in patent: Page/Page column 24-26; 28; 33

5
[ 102361-94-4 ]
[ 21962-45-8 ]

Yield	Reaction Conditions	Operation in experiment
55%	With lithium tri-t-butoxyaluminum hydride In tetrahydrofuran; diethylene glycol dimethyl ether at -78℃; for 3.5 h;	Thionyl chloride (50 ml) was added to 2-methoxy-4-cyano benzoic acid (Tetrahedron Letters, 1986, 27(49), 5997-6000) (8 g, 45.2 mmol) in dichloromethane (70 ml) and the solution was refluxed for 5 h. After cooling to room temperature, the solvent was removed under reduced pressure. The crude benzoyl chloride was dissolved in diglime (120 ml), cooled at -78° C. and 1M lithium tritertbutoxyaluminium hydride in THF (46 ml, 46 mmol) was added dropwise in 3 h. Stirring was continued for 30 min at -78° C. then the reaction was allowed to reach 0° C. and quenched with water (15 ml) and 2N NaOH (15 ml). The reaction mixture was stirred for 1 h, filtered and the organic phase was removed under reduced pressure. The crude residue was purified by column chromatography eluting with n-hexane/ethyl acetate 80:20 to give 4 g of the title compound (yield 55percent) as a yellow powder, mp=112-114° C. [0187] 1H-NMR (CDCl3) δ=10.5 (s, 1H); 7.93 (d, 1H); 7.30 (d, 1H); 7.16 (s, 1H); 4.01 (s, 3H).

Reference： [1] Patent: US2005/38095, 2005, A1, . Location in patent: Page/Page column 9

6
[ 890038-13-8 ]
[ 21962-45-8 ]

Yield	Reaction Conditions	Operation in experiment
53 g	With manganese(IV) oxide In dichloromethane at 39℃; for 8 h;	A four-neck reaction flask was charged with 128.7 g of 4-hydroxymethyl-3-methoxybenzonitrile (IV) (0.788 mol), 205.6 g of manganese dioxide (2.364 mol) and 1600 g of dichloromethane, and heated to 39°C. The reaction was refluxed for about 8 hours. The reaction was completed. The reaction was cooled to room temperature and filtered. The filter cake was washed well with dichloromethane. The filtrate was concentrated to give a crude product. The crude product was mixed with 80 g of dichloromethane, 80 g of ethanol, and 240 g of petroleum ether. Recrystallization gave 53 g of 2-methoxy-4-cyanobenzaldehyde (V) in 42percent yield.

Reference： [1] Patent: WO2006/60461, 2006, A1, . Location in patent: Page/Page column 197-198
[2] Patent: CN107721869, 2018, A, . Location in patent: Paragraph 0047; 0048; 0061; 0073; 0085

7
[ 3556-60-3 ]
[ 21962-45-8 ]

Reference： [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 10, p. 2468 - 2485
[2] Patent: CN107721869, 2018, A,

8
[ 139102-34-4 ]
[ 21962-45-8 ]

Reference： [1] Patent: US2017/217957, 2017, A1,
[2] Patent: US2018/244668, 2018, A1,
[3] Patent: US2018/244670, 2018, A1,

9
[ 1666-28-0 ]
[ 21962-45-8 ]

Reference： [1] Patent: US2017/217957, 2017, A1,
[2] Patent: US2018/244668, 2018, A1,
[3] Patent: US2018/244670, 2018, A1,

10
[ 626-02-8 ]
[ 21962-45-8 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 9, p. 3223 - 3228

11
[ 38170-02-4 ]
[ 21962-45-8 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 9, p. 3223 - 3228

12
[ 4421-08-3 ]
[ 21962-45-8 ]

Reference： [1] Patent: KR101614164, 2016, B1,

13
[ 7151-68-0 ]
[ 21962-45-8 ]

Reference： [1] Patent: CN107721869, 2018, A,

14
[ 87808-44-4 ]
[ 21962-45-8 ]

Reference： [1] Patent: CN107721869, 2018, A,

15
[ 139102-37-7 ]
[ 21962-45-8 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 9, p. 3223 - 3228

[ 21962-45-8 ] Synthesis Path-Downstream 1~16

1
[ 21962-45-8 ]
[ 6136-68-1 ]
3-(4-cyano-2-methoxyphenyl)-1-(3-cyanophenyl)-2-propen-1-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485

2
[ 3556-60-3 ]
[ 21962-45-8 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485
[2]Patent: CN107721869,2018,A

3
[ 21962-45-8 ]
[ 10495-09-7 ]
ethyl 2-(4-cyano-2-methoxybenzylidene)-4,4-diethoxy-3-oxobutanoate [ No CAS ]
ethyl 2-(4-cyano-2-methoxybenzylidene)-4,4-diethoxy-3-oxobutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid;piperidine; In dichloromethane;Reflux;	618.2 mg (2.83 mmol) of <strong>[10495-09-7]ethyl 4,4-diethoxy-3-oxobutanoate</strong> [Johnson et al., J. Am. Chem. Soc. 41, 812 (1919)], 500.0 mg (2.58 mmol) of 4-formyl-3-methoxybenzonitrile, 232.0 mg (3.86 mmol) of acetic acid and 43.9 mg (0.51 mmol) of piperidine are dissolved in 20 ml of dichloromethane and heated under reflux with an inverse water trap ovemight. Cooling is followed by washing twice with water, and the organic phase is dried with magnesium sulfate. The solvent is removed in a rotary evaporator, and the residue is purified by column chromatography (silica gel, mobile phase:cyclohexane/ethyl acetate 4:1). 824 mg (77.0% of theory) of the title compound are obtained as a mixture of the E/Z isomers. LC-MS (method 4): Rt=2.63 min and 2.69 min; [M-EtOH+H]+ (EIpos): m/z=316.

Reference： [1]Patent: US2010/35902,2010,A1 .Location in patent: Page/Page column 21-22

4
[ 21962-45-8 ]
[ 84102-89-6 ]

Yield	Reaction Conditions	Operation in experiment
61%		Example 24A 4-Formyl-3-hydroxybenzonitrile 100 ml of a boron tribromide solution in dichloromethane (1 M, 100 mmol) are added dropwise to a solution of 8 g (49.64 mmol) of 4-formyl-3-methoxybenzonitrile in 80 ml of anhydrous dichloromethane at -78 C. under an argon atmosphere. The reaction mixture is stirred at RT until the precursor has completely reacted (about 5 days). The reaction solution is then neutralized at 0 C. with saturated sodium bicarbonate solution. The phases are separated and the organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 3:1). 4.5 g (61% of theory) of the title compound are obtained as a yellow solid. LC-MS (method 1): Rt=1.38 min; [M-H]-=146 1H-NMR (300 MHz, CDCl3): delta=7.38 (d, 1H), 7.38 (s, 1H), 7.77 (d, 1H), 10.33 (s, 1H), 11.38 (s, 1H).
61%	With boron tribromide; In dichloromethane; at -78 - 20℃; for 120.0h;Inert atmosphere;	Dichloromethane (1 M, 100 mmol) of a solution of boron tribromide solution in 100 mL of anhydrous dichloromethane and 80 mL at -78 under argon atmosphere 4-formyl-3-methoxy-benzonitrile 8 g (49.64 mmol) It was added dropwise. Until the precursor to respond fully Paper (about 5 days) and the reaction mixture was stirred at room temperature. Thereafter, the reaction solution at 0 with saturated sodium bicarbonate solution And neutralized. Separating the phases and washing the organic phase with saturated sodium chloride solution, dried over magnesium sulfate And concentrated. Column chromatography on silica gel of the residue (mobile phase: cyclohexane / ethyl acetate 3: 1) determined by the It was first. The title compound 4.5 g (61% of theory) as a yellow solid.
	With boron tribromide; In dichloromethane; ethyl acetate;	Example 11A 4-Formyl-3-hydroxybenzonitrile 100 ml of a boron tribromide solution in dichloromethane (1 M, 100 mmol) are added dropwise to a solution of 8 g (49.64 mmol) of 4-formyl-3-methoxybenzonitrile in 80 ml of anhydrous dichloromethane at -78 C. under an argon atmosphere. The reaction mixture is stirred at RT until the precursor has completely reacted (about 5 days). The reaction solution is then neutralized at 0 C. with saturated sodium bicarbonate solution. The phases are separated and the organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 3:1). 4.5 g (61% of theory) of the title compound are obtained as a yellow solid. LC-MS (method 1): Rt=1.38 min; [M-H]-=146 1H-NMR (300 MHz, CDCl3): delta=7.38 (d, 1H), 7.38 (s, 1H), 7.77 (d, 1H), 10.33 (s, 1H), 11.38 (s, 1H).

Reference： [1]Patent: US2010/305052,2010,A1 .Location in patent: Page/Page column 20-21
[2]Patent: KR101614164,2016,B1 .Location in patent: Paragraph 0328-0331
[3]Patent: US2010/136142,2010,A1

5
[ 21962-45-8 ]
[ 10230-68-9 ]
[ 38767-72-5 ]
[ 959984-55-5 ]

Yield	Reaction Conditions	Operation in experiment
2%	With acetic acid; In isopropyl alcohol; for 12h;Reflux;	Example 47A 3-Methoxy-4-(2-methyl-3-nitro-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridin-4-yl)benzonitrile 688 mg (4.26 mmol) of 4-formyl-3-methoxybenzonitrile are dissolved with 440 mg (4.26 mmol) of 1-nitroacetone, 470 mg (4.26 mmol) of <strong>[38767-72-5]4-aminopyridin-2(1H)-one</strong> [Searls, T., McLaughlin, L. W., Tetrahedron 55, 11985-11996 (1999)] and 367 mul (6.40 mmol) of acetic acid in 10 ml of isopropanol and heated under reflux under argon for 12 h. After cooling, DMSO (5 ml) is added and the reaction solution is purified directly by preparative HPLC. 41 mg (2% of theory) of the title compound are obtained as a brown solid. LC-MS (method 1): Rt=1.30 min; [M+H]+=339.

Reference： [1]Patent: US2010/305052,2010,A1 .Location in patent: Page/Page column 27

6
[ 21962-45-8 ]
[ 38767-72-5 ]
[ 70807-22-6 ]
[ 959984-40-8 ]

Yield	Reaction Conditions	Operation in experiment
94%	With acetic acid; In isopropyl alcohol; for 12h;Reflux; Inert atmosphere;	Example 30A 4-(4-Cyano-2-methoxyphenyl)-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carbonitrile 1.05 g (6.51 mmol) of 4-formyl-3-methoxybenzonitrile are dissolved with 684 mg (6.51 mmol) of sodium 1-cyanoprop-1-en-2-olate, 789 mg (7.16 mmol) of <strong>[38767-72-5]4-aminopyridin-2(1H)-one</strong> [Searls, T., McLaughlin, L. W., Tetrahedron 55, 11985-11996 (1999)] and 600 mul (9.77 mmol) of acetic acid in 30 ml of isopropanol and heated under reflux under argon for 12 h. Cooling is followed by filtration, and the remaining solid is washed with diethyl ether (40 ml). 1.96 g (94% of theory) of the title compound are obtained as a white solid. LC-MS (method 4): Rt=1.17 min; [M+H]+=319 1H-NMR (300 MHz, DMSO-d6): delta=2.01 (s, 3H), 3.83 (s, 3H), 5.02 (s, 1H), 5.94 (d, 1H), 7.03 (d, 1H), 7.19 (d, 1H), 7.32 (d, 1H), 7.45 (s, 1H), 9.88 (s, 1H), 11.06 (s, 1H).

Reference： [1]Patent: US2010/305052,2010,A1 .Location in patent: Page/Page column 22

7
[ 21962-45-8 ]
[ 1286736-41-1 ]
[ 38767-72-5 ]
[ 959984-54-4 ]

Yield	Reaction Conditions	Operation in experiment
34%	With acetic acid; In isopropyl alcohol; for 12h;Reflux; Inert atmosphere;	Example 46A 4-(4-Cyano-2-methoxyphenyl)-5-oxo-2-(trifluoromethyl)-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carbonitrile 500 mg (3.1 mmol) of 4-formyl-3-methoxybenzonitrile are dissolved with 493 mg (3.1 mmol) of sodium 1-cyano-3,3,3-trifluoroprop-1-en-2-olate, 341 mg (3.1 mmol) of <strong>[38767-72-5]4-aminopyridin-2(1H)-one</strong> [Searls, T., McLaughlin, L. W., Tetrahedron 55, 11985-11996 (1999)] and 266 mul (4.65 mmol) of acetic acid in 40 ml of isopropanol and heated under reflux under argon for 12 h. After cooling, the solution is concentrated, and the residue is again stirred in 45 ml of acetic acid under reflux overnight. The solution is cooled and then concentrated, and the residue is purified by preparative HPLC. 392 mg (34% of theory) of the title compound are obtained as a white solid. LC-MS (method 1): Rt=1.63 min; [M+H]+=373 1H-NMR (300 MHz, DMSO-d6): delta=3.83 (s, 3H), 5.12 (s, 1H), 6.12 (d, 1H), 7.21 (d, 1H), 7.25 (d, 1H), 7.38 (dd, 1H), 7.51 (d, 1H), 10.29 (s, 1H), 11.22 (s, 1H).

Reference： [1]Patent: US2010/305052,2010,A1 .Location in patent: Page/Page column 27

8
[ 38170-02-4 ]
[ 21962-45-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3223 - 3228

9
[ 139102-37-7 ]
copper(l) cyanide [ No CAS ]
[ 21962-45-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3223 - 3228

10
[ 21962-45-8 ]
[ 1736-70-5 ]
[ 105-45-3 ]
4-(4-cyano-2-methoxy-phenyl)-6-methyl-2-thioxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9.79 g	With trimethylsilyl-polyphosphoric acid; In 1,2-dimethoxyethane; at 70℃; for 18h;	A stirred solution in DME (65 mL) of 4-formyl-3-methoxy-benzonitrile (3.22 g, 19.98 mmol), 3-trifluoromethylphenyl thiourea (4.40 g, 19.98 mol) and trimethylsilyl-polyphosphoric acid (6.50 g, 2 wt equiv.) was treated with methyl acetoacetate (2.53 g, 2.35 mL, 21.78 mmol). The resulting mixture was warmed to 70 C. for 18 h and the reaction was concentrated in vacuo to give a yellow/orange foam, which was partitioned between EtOAc and water. The aqueous extract was further extracted with EtOAc (×2) and the combined organic extract was washed with water and brine, then dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as an orange foam (9.79 g). (0402) LCMS (Method 1): Rt 3.69 min, m/z 461.9 [M+H]+

Reference： [1]Patent: US2015/353561,2015,A1 .Location in patent: Paragraph 0400; 0401; 0402

11
[ 21962-45-8 ]
[ 344-95-6 ]
N'-(4-cyano-2-methoxybenzylidene)-2-(trifluoromethyl)benzohydrazide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With potassium hydroxide; In ethanol; at 20℃; for 2.5h;	General procedure: To a mixture of 2-(trifluoromethyl) (1 mmol) and aromatic aldehyde (1 mmol) in ethanol (5 mL), was added (4 mmol) of 50 % of potassium hydroxide. Stirred the reaction mass for 2-3 h reaction was monitored by TLC. After completion of the reaction the ethanol was distilled off from the reaction mass, the solid mass poured in to cold water (25 mL) filtered off the product then washed with cold water and the compounds were confirmed by their spectral data.

Reference： [1]Asian Journal of Chemistry,2016,vol. 28,p. 1351 - 1360

12
[ 571178-40-0 ]
[ 21962-45-8 ]
[ 38767-72-5 ]
allyl 4-(4-cyano-2-methoxyphenyl)-2-hydroxy-5-oxo-2-(trifluoromethyl)-1,2,3,4,5,6-hexahydro-1,6-naphthyridine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol;Reflux;	The title compound is 4-formyl-3-methoxy-benzonitrile in the stoichiometric amount (Example 10A), 4-aminopyridine -2 (1H) - one (lit. [Searls, T., McLaughlin, LW, Tetrahedron 55, 11985-11996 (1999)) and allyl 4,4,4-trifluoro-3-oxo-butanoate (lit. [Moseley, JD, Tetrahedron Lett. 46, 3179-3181 (2005)) prepared starting from was then, first over night at reflux temperature di-hydrochloride was performed without adding the additive from ethanol synthesis of pyridine. then, the resulting first intermediate allyl 4- (4-cyano-2-methoxyphenyl) -2-hydroxy-5-oxo-2- (trifluoromethyl) -1,2,3,4,5,6- hexahydro- 1,6-naphthyridine-3-carboxylate Process Based on the literature (literature [Moseley, J.D., Tetrahedron Lett. 46, 3179-3181 (2005)] reference) and dehydrated by using acetic acid. Then, Example 29A uihap performance similar manner as triethyl orthoformate and the reaction of allyl 4 - (4-cyano-2 - methoxyphenyl) -5-ethoxy-2- (trifluoromethyl) -1 , to give a 4-dihydro-1,6-naphthyridine-3-carboxylate. Finally, cutting the allyl ester of the acid using a Wilkinson (Wilkinson) catalyst [tris (triphenylphosphine) rhodium (I) chloride], To give the title compound (see the literature [Moseley, J.D., Tetrahedron Lett. 46, 3179-3181 (2005)])

Reference： [1]Patent: KR101614164,2016,B1 .Location in patent: Paragraph 0465-0468

13
[ 21962-45-8 ]
[ 65193-87-5 ]
[ 38767-72-5 ]
[ 1050477-35-4 ]

Yield	Reaction Conditions	Operation in experiment
27%	In isopropyl alcohol; for 72h;Reflux; Inert atmosphere;	Example 10A From the compound of 14.63 g (90.81 mmol), 4 - aminopyridine -2 (1H) - one 10.00 g (90.81 mmol) (literature [Searls, T., McLaughlin, LW, Tetrahedron 55, 11985-11996 (1999)]) and 2-cyanoethyl 3-oxo-butanoate 15.65 g (90.81 mmol) (literature [Yamamoto, T., et al., Bioorg. Med. Chem. Lett. 16, 798-802 (2006)]) isopropanol dissolved in 300 mL and stirred for 3 days at reflux temperature under argon. Then, the mixture was concentrated, purified by column chromatography (silica gel; mobile phase: 1: first ethyl acetate, then dichloromethane / methanol to 10) of the And purified it. The resulting product fractions was concentrated, then dissolved in a small amount of ethyl acetate. The precipitated product was filtered, dried under vacuum overnight at 40 . To give the title compound 10.11 g (27% of theory).

Reference： [1]Patent: KR101614164,2016,B1 .Location in patent: Paragraph 0375-0378

14
[ 139102-34-4 ]
[ 21962-45-8 ]

Reference： [1]Patent: US2017/217957,2017,A1
[2]Patent: US2018/244668,2018,A1
[3]Patent: US2018/244670,2018,A1

15
[ 43192-33-2 ]
potassium ferrocyanide [ No CAS ]
[ 21962-45-8 ]

Yield	Reaction Conditions	Operation in experiment
87%	With palladium diacetate; sodium carbonate; In N,N-dimethyl-formamide; at 120℃; for 3h;	719 g (3.34 mol) of <strong>[43192-33-2]4-bromo-2-methoxybenzaldehyde</strong> (XVI) as a solution in 4.5 l of DMF were charged with 313 g (0.74 mol) of potassium hexacyanoferrate (K4[Fe(CN)6]) and 354 g (3.34 mol) of sodium carbonate and a further 1.2 l of DMF and 3.8 g (0.017 mol) of palladium acetate were added. The mixture was stirred at 120 C. for 3 hours. The mixture was left to cool to 20 C. and 5.7 l of water were added to the mixture. The mixture was extracted with 17 l of ethyl acetate and the aqueous phase was washed once more with 17 l of ethyl acetate. The organic phases were combined and substantially concentrated, taken up in 5 l of isopropanol and concentrated to about 2 l. The mixture was heated to boiling and 2 l of water were added dropwise. The mixture was allowed to cool to 50 C. and another 2 l of water were added. The mixture was cooled to 3 C. and stirred at this temperature for one hour. The product was filtered off and washed with water (2*1.2 1). The product was dried at 40 C. under vacuum. Yield: 469 g (87% of theory) of a beige solid. HPLC-Method A: RT ca. 8.3 min. MS (Elpos): m/z=162 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): delta=3.98 (s, 3H), 7.53 (d, 1H), 7.80 (s, 1H), 7.81 (d, 1H), 10.37 (s, 1H).
87%	With palladium diacetate; sodium carbonate; In N,N-dimethyl-formamide; at 120℃; for 3h;	719 g (3.34 mol) of <strong>[43192-33-2]4-bromo-2-methoxybenzaldehyde</strong> (XVI) as a solution in 4.5 l of DMF were charged with 313 g (0.74 mol) of potassium hexacyanoferrate (K4[Fe(CN)6]) and 354 g (3.34 mol) of sodium carbonate and a further 1.2 l of DMF and 3.8 g (0.017 mol) of palladium acetate were added. The mixture was stirred at 120 C. for 3 hours. The mixture was left to cool to 20 C. and 5.7 l of water were added to the mixture. The mixture was extracted with 17 l of ethyl acetate and the aqueous phase was washed once more with 17 l of ethyl acetate. The organic phases were combined and substantially concentrated, taken up in 5 l of isopropanol and concentrated to about 2 l. The mixture was heated to boiling and 2 l of water were added dropwise. The mixture was allowed to cool to 50 C. and another 2 l of water were added. The mixture was cooled to 3 C. and stirred at this temperature for one hour. The product was filtered off and washed with water (2*1.2 l). The product was dried at 40 C. under vacuum. Yield: 469 g (87% of theory) of a beige solid. HPLC method A: RT about 8.3 mm.MS (Elpos): mlz=162 [M+H]+1H NMR (300 MHz, DMSO-d6): oe=3.98 (s, 3H), 7.53 (d, 1H), 7.80 (s, 1H), 7.81 (d, 1H), 10.37 (s, 1H).
469 g	With palladium diacetate; sodium carbonate; In N,N-dimethyl-formamide; at 120℃; for 3h;Large scale;	719 g (3.34 mol) of <strong>[43192-33-2]4-bromo-2-methoxybenzaldehyde</strong> (XVI) as a solution in 4.5 l of DMF are charged with 313 g (0.74 mol) of potassium hexacyanoferrate (-K4[Fe(CN)6]) and 354 g (3.34 mol) of sodium carbonate and a further 1.2 l of DMF and 3.8 g (0.017 mol) of palladium acetate are added. The mixture is stirred at 120 C. for 3 hours. The mixture is allowed to cool to 20 C. and 5.7 l of water is added to the mixture. The mixture is extracted with 17 l of ethyl acetate and the aqueous phase washed once more with 17 l of ethyl acetate. The organic phases are combined and substantially concentrated, taken up in 5 l of isopropanol and concentrated to ca. 2 l. The mixture is heated to boiling and 2 l of water added dropwise. The mixture is allowed to cool to 50 C. and 2 l of water added anew. The mixture is cooled to 3 C. and stirred at this temperature for one hour. The product is filtered off and washed with water (2 times 1.2 l). The product is dried at 40 C. under vacuum. Yield: 469 g (87% of theory) of a beige solid. -Pos=36,Num=13 218 H-0:h-00322 219 H-0:h-00323 220 220 220 220 220 220 220 220 220 220 --3:p-00324 220 --3:p-00325 P=1,E=2,S=2,R=1,K=1,He=1,ED=1,Pr=1,V=7PVVESVVExVVRVdVVKVSVxVSVSVVdVdxVVe125-1-0-20-6-14-15-16-10-11-11-9-6-6lpE-EEEEE-WWERIDX=5(53), Sub=1 ,OBJ=36, lRES=13, COD=00-90-02-02-4-INAM346INAM341INAM28INAM347INAM32INAM61INAM18INAM62INAM63--11-22-11-1-1-44-- INAM346 4.5 l -3105200HPLC method A: RT ca. 8.3 min.4-Formyl-3-methoxybenzonitrile (VI)3.d200-HPLC method A: RT ca. 8.3 min. MS (EIpos): m/z=162 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): delta=3.98 (s, 3H), 7.53 (d, 1H), 7.80 (s, 1H), 7.81 (d, 1H), 10.37 (s, 1H).

Reference： [1]Patent: US2018/244668,2018,A1 .Location in patent: Paragraph 0178; 0179; 0180; 0181; 0182
[2]Patent: US2018/244670,2018,A1 .Location in patent: Paragraph 0183-0188
[3]Patent: US2017/217957,2017,A1 .Location in patent: Paragraph 0147-0151

16
[ 21962-45-8 ]
[ 1050477-31-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1: piperidine; acetic acid / isopropyl alcohol / 4.5 h / 0 - 30 °C / Large scale 2: isopropyl alcohol / 24 h / 100 °C / 1050.11 Torr / Sealed tube; Large scale 3: sulfuric acid / 1-methyl-pyrrolidin-2-one / 1.5 h / 115 °C / Large scale 4: sodium hydroxide; water / tetrahydrofuran / 1.75 h / 0 °C / Large scale 5: dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C / Large scale 6: tetrahydrofuran / 22 h / Reflux; Large scale 7: water / tetrahydrofuran / 4 h / 5 °C / Reflux; Large scale 8: Chiralpak AS-V, 20 μm. / methanol; acetonitrile / 22502.3 Torr / Resolution of racemate; Large scale 9: nitric acid / acetonitrile / 9.5 h / 9 - 20 °C / Inert atmosphere 10: N,N,N,N-tetraethylammonium tetrafluoroborate / methanol / 5 h / Electrochemical reaction
	Multi-step reaction with 10 steps 1: piperidine; acetic acid / isopropyl alcohol / 4.5 h / 0 - 30 °C / Large scale 2: isopropyl alcohol / 24 h / 100 °C / 1050.11 Torr / Sealed tube; Large scale 3: sulfuric acid / 1-methyl-pyrrolidin-2-one / 1.5 h / 115 °C / Large scale 4: sodium hydroxide; water / tetrahydrofuran / 1.75 h / 0 °C / Large scale 5: dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C / Large scale 6: tetrahydrofuran / 22 h / Reflux; Large scale 7: water / tetrahydrofuran / 4 h / 5 °C / Reflux; Large scale 8: Chiralpak AS-V, 20 μm. / methanol; acetonitrile / 22502.3 Torr / Resolution of racemate; Large scale 9: nitric acid / acetonitrile / 9.5 h / 9 - 20 °C / Inert atmosphere 10: N,N,N,N-tetraethylammonium tetrafluoroborate / methanol / 6 h / Electrochemical reaction
	Multi-step reaction with 10 steps 1: piperidine; acetic acid / isopropyl alcohol / 4.5 h / 0 - 30 °C / Large scale 2: isopropyl alcohol / 24 h / 100 °C / 1050.11 Torr / Sealed tube; Large scale 3: sulfuric acid / 1-methyl-pyrrolidin-2-one / 1.5 h / 115 °C / Large scale 4: sodium hydroxide; water / tetrahydrofuran / 1.75 h / 0 °C / Large scale 5: dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C / Large scale 6: tetrahydrofuran / 22 h / Reflux; Large scale 7: water / tetrahydrofuran / 4 h / 5 °C / Reflux; Large scale 8: Chiralpak AS-V, 20 μm. / methanol; acetonitrile / 22502.3 Torr / Resolution of racemate; Large scale 9: 2,3-dicyano-5,6-dichloro-p-benzoquinone / dichloromethane / 1 h / 20 °C 10: N,N,N,N-tetraethylammonium tetrafluoroborate / methanol / 5 h / Electrochemical reaction

	Multi-step reaction with 8 steps 1: piperidine; acetic acid / isopropyl alcohol / 4.5 h / 0 - 30 °C / Large scale 2: isopropyl alcohol / 24 h / 100 °C / 1050.11 Torr / Sealed tube; Large scale 3: sulfuric acid / 1-methyl-pyrrolidin-2-one / 1.5 h / 115 °C / Large scale 4: sodium hydroxide; water / tetrahydrofuran / 1.75 h / 0 °C / Large scale 5: dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C / Large scale 6: tetrahydrofuran / 22 h / Reflux; Large scale 7: water / tetrahydrofuran / 4 h / 5 °C / Reflux; Large scale 8: Chiralpak AS-V, 20 μm. / methanol; acetonitrile / 22502.3 Torr / Resolution of racemate; Large scale
	Multi-step reaction with 4 steps 1: piperidine; acetic acid / dichloromethane / 4 h / Reflux 2: iso-butanol / 20 h / 0 - 120 °C / Large scale 3: sulfuric acid / N,N-dimethyl acetamide / 1.5 h / 50 - 115 °C / Large scale 4: Chiralpak AS-V / methanol; acetonitrile / Resolution of racemate; Large scale
	Multi-step reaction with 5 steps 1.1: acetic acid / 0.5 h / 20 °C 1.2: 8 h / 80 °C 2.1: sulfuric acid / 130 °C 3.1: sodium tetrahydroborate / tetrahydrofuran / 0 - 50 °C / Inert atmosphere 4.1: N-ethyl-N,N-diisopropylamine; C₂₀H₂₀N₃O₃⁽¹⁺⁾*BF₄^(1-) / dichloromethane / 40 °C / Inert atmosphere 5.1: ammonium hydroxide / 16 h / 0 - 5 °C
	Multi-step reaction with 6 steps 1.1: piperidine; acetic acid / isopropyl alcohol / 1 h / 30 - 40 °C 2.1: toluene-4-sulfonic acid / toluene / 16 h / Reflux 3.1: sulfuric acid / N,N-dimethyl-formamide / 4 h / 20 °C 4.1: potassium trimethylsilonate / tetrahydrofuran / 8 h / 30 °C 5.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 8 h / 60 °C / Reflux 5.2: 12 h / Reflux 6.1: S2O8^2-/ZrO2/γ-Al2O3 / 5,5-dimethyl-1,3-cyclohexadiene / 8 h / Reflux 6.2: 4 h / 30 °C / Reflux
	Multi-step reaction with 7 steps 1.1: piperidine; acetic acid / dichloromethane / 18 h / Dean-Stark; Reflux 2.1: iso-butanol / 20 h / Reflux 3.1: sulfuric acid / N,N-dimethyl acetamide / 2 h / 115 °C 4.1: 10% Pd/C; hydrogen / tetrahydrofuran / 3 h / 20 °C / Inert atmosphere 5.1: ethanol / 3 h / 40 °C 6.1: water / 30 min / 20 °C 7.1: 1,1'-carbonyldiimidazole; dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C 7.2: 22 h / Reflux
	Multi-step reaction with 7 steps 1.1: piperidine; acetic acid / dichloromethane / 18 h / Dean-Stark; Reflux 2.1: iso-butanol / 20 h / Reflux 3.1: sulfuric acid / N,N-dimethyl acetamide / 2 h / 115 °C 4.1: 10% Pd/C; hydrogen / tetrahydrofuran / 3 h / 20 °C / Inert atmosphere 5.1: ethanol / 3 h / 40 °C 6.1: water / 30 min / 20 °C 7.1: 1,1'-carbonyldiimidazole; dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C 7.2: 22 h / Reflux
	Multi-step reaction with 7 steps 1.1: piperidine; acetic acid / dichloromethane / 18 h / Dean-Stark; Reflux 2.1: iso-butanol / 20 h / Reflux 3.1: sulfuric acid / N,N-dimethyl acetamide / 2 h / 115 °C 4.1: 10% Pd/C; hydrogen / tetrahydrofuran / 3 h / 20 °C / Inert atmosphere 5.1: ethanol / 3 h / 40 °C 6.1: water / 30 min / 20 °C 7.1: 1,1'-carbonyldiimidazole; dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C 7.2: 22 h / Reflux
	Multi-step reaction with 7 steps 1.1: piperidine; acetic acid / dichloromethane / 18 h / Dean-Stark; Reflux 2.1: iso-butanol / 20 h / Reflux 3.1: sulfuric acid / N,N-dimethyl acetamide / 2 h / 115 °C 4.1: 10% Pd/C; hydrogen / tetrahydrofuran / 3 h / 20 °C / Inert atmosphere 5.1: ethanol / 3 h / 40 °C 6.1: water / 30 min / 20 °C 7.1: 1,1'-carbonyldiimidazole; dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C 7.2: 22 h / Reflux
	Multi-step reaction with 7 steps 1.1: piperidine; acetic acid / dichloromethane / 18 h / Dean-Stark; Reflux 2.1: iso-butanol / 20 h / Reflux 3.1: sulfuric acid / N,N-dimethyl acetamide / 2 h / 115 °C 4.1: 10% Pd/C; hydrogen / tetrahydrofuran / 3 h / 20 °C / Inert atmosphere 5.1: ethanol / 3 h / 40 °C 6.1: water / 30 min / 20 °C 7.1: 1,1'-carbonyldiimidazole; dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C 7.2: 22 h / Reflux
	Multi-step reaction with 7 steps 1.1: piperidine; acetic acid / dichloromethane / 18 h / Dean-Stark; Reflux 2.1: iso-butanol / 20 h / Reflux 3.1: sulfuric acid / N,N-dimethyl acetamide / 2 h / 115 °C 4.1: 10% Pd/C; hydrogen / tetrahydrofuran / 3 h / 20 °C / Inert atmosphere 5.1: ethanol / 3 h / 40 °C 6.1: water / 30 min / 20 °C 7.1: 1,1'-carbonyldiimidazole; dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C 7.2: 22 h / Reflux
	Multi-step reaction with 7 steps 1.1: piperidine; acetic acid / dichloromethane / 18 h / Dean-Stark; Reflux 2.1: iso-butanol / 20 h / Reflux 3.1: sulfuric acid / N,N-dimethyl acetamide / 2 h / 115 °C 4.1: 10% Pd/C; hydrogen / tetrahydrofuran / 3 h / 20 °C / Inert atmosphere 5.1: ethanol / 3 h / 40 °C 6.1: water / 30 min / 20 °C 7.1: 1,1'-carbonyldiimidazole; dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C 7.2: 22 h / Reflux
	Multi-step reaction with 7 steps 1.1: piperidine; acetic acid / dichloromethane / 18 h / Dean-Stark; Reflux 2.1: iso-butanol / 20 h / Reflux 3.1: sulfuric acid / N,N-dimethyl acetamide / 2 h / 115 °C 4.1: 10% Pd/C; hydrogen / tetrahydrofuran / 3 h / 20 °C / Inert atmosphere 5.1: 1,4-dioxane; water / 3 h / 20 °C 6.1: water / 30 min / 20 °C 7.1: 1,1'-carbonyldiimidazole; dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C 7.2: 22 h / Reflux
	Multi-step reaction with 6 steps 1.1: acetic acid; piperidine / dichloromethane / 18 h / Reflux 1.2: 20 h / Reflux 2.1: sulfuric acid / N,N-dimethyl acetamide / 2 h / 115 °C 3.1: dichloromethane / 3 h / 35 °C 4.1: sodium phosphate / water / 3 h 5.1: 10% Pd/C; hydrogen / tetrahydrofuran / 3 h / 20 °C / Inert atmosphere 6.1: 1,1'-carbonyldiimidazole; dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C 6.2: 22 h / Reflux
	Multi-step reaction with 6 steps 1.1: acetic acid; piperidine / dichloromethane / 18 h / Reflux 1.2: 20 h / Reflux 2.1: sulfuric acid / N,N-dimethyl acetamide / 2 h / 115 °C 3.1: tetrahydrofuran / 3 h / 60 °C 4.1: sodium phosphate / water / 3 h 5.1: 10% Pd/C; hydrogen / tetrahydrofuran / 3 h / 20 °C / Inert atmosphere 6.1: 1,1'-carbonyldiimidazole; dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C 6.2: 22 h / Reflux
	Multi-step reaction with 6 steps 1.1: acetic acid; piperidine / dichloromethane / 18 h / Reflux 1.2: 20 h / Reflux 2.1: sulfuric acid / N,N-dimethyl acetamide / 2 h / 115 °C 3.1: tetrahydrofuran / 3 h / 60 °C 4.1: sodium phosphate / water / 3 h 5.1: 10% Pd/C; hydrogen / tetrahydrofuran / 3 h / 20 °C / Inert atmosphere 6.1: 1,1'-carbonyldiimidazole; dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C 6.2: 22 h / Reflux
	Multi-step reaction with 6 steps 1.1: acetic acid; piperidine / dichloromethane / 18 h / Reflux 1.2: 20 h / Reflux 2.1: sulfuric acid / N,N-dimethyl acetamide / 2 h / 115 °C 3.1: tetrahydrofuran / 3 h / 60 °C 4.1: sodium phosphate / water / 3 h 5.1: 10% Pd/C; hydrogen / tetrahydrofuran / 3 h / 20 °C / Inert atmosphere 6.1: 1,1'-carbonyldiimidazole; dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C 6.2: 22 h / Reflux
	Multi-step reaction with 6 steps 1.1: acetic acid; piperidine / dichloromethane / 18 h / Reflux 1.2: 20 h / Reflux 2.1: sulfuric acid / N,N-dimethyl acetamide / 2 h / 115 °C 3.1: 3 h / 70 °C 4.1: sodium phosphate / water / 3 h 5.1: 10% Pd/C; hydrogen / tetrahydrofuran / 3 h / 20 °C / Inert atmosphere 6.1: 1,1'-carbonyldiimidazole; dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C 6.2: 22 h / Reflux
	Multi-step reaction with 6 steps 1.1: acetic acid; piperidine / dichloromethane / 18 h / Reflux 1.2: 20 h / Reflux 2.1: sulfuric acid / N,N-dimethyl acetamide / 2 h / 115 °C 3.1: ethyl acetate / 3 h / 60 °C 4.1: sodium phosphate / water / 3 h 5.1: 10% Pd/C; hydrogen / tetrahydrofuran / 3 h / 20 °C / Inert atmosphere 6.1: 1,1'-carbonyldiimidazole; dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C 6.2: 22 h / Reflux
	Multi-step reaction with 6 steps 1.1: acetic acid; piperidine / dichloromethane / 18 h / Reflux 1.2: 20 h / Reflux 2.1: sulfuric acid / N,N-dimethyl acetamide / 2 h / 115 °C 3.1: acetone / 3 h / 60 °C 4.1: sodium phosphate / water / 3 h 5.1: 10% Pd/C; hydrogen / tetrahydrofuran / 3 h / 20 °C / Inert atmosphere 6.1: 1,1'-carbonyldiimidazole; dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C 6.2: 22 h / Reflux
	Multi-step reaction with 6 steps 1.1: acetic acid; piperidine / dichloromethane / 18 h / Reflux 1.2: 20 h / Reflux 2.1: sulfuric acid / N,N-dimethyl acetamide / 2 h / 115 °C 3.1: 1,2-dimethoxyethane / 3 h / 70 °C 4.1: sodium phosphate / water / 3 h 5.1: 10% Pd/C; hydrogen / tetrahydrofuran / 3 h / 20 °C / Inert atmosphere 6.1: 1,1'-carbonyldiimidazole; dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C 6.2: 22 h / Reflux
	Multi-step reaction with 7 steps 1.1: piperidine; acetic acid / dichloromethane / 18 h / Reflux 2.1: iso-butanol / 20 h / Reflux 3.1: sulfuric acid / N,N-dimethyl acetamide / 2 h / 115 °C 4.1: 10% Pd/C; hydrogen / tetrahydrofuran / 3 h / 20 °C 5.1: ethanol / 3 h / 40 °C 6.1: water / 3 h / 20 °C / pH 7 - 7.5 7.1: 1,1'-carbonyldiimidazole; dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C 7.2: 22 h / Reflux
	Multi-step reaction with 7 steps 1.1: piperidine; acetic acid / dichloromethane / 18 h / Reflux 2.1: iso-butanol / 20 h / Reflux 3.1: sulfuric acid / N,N-dimethyl acetamide / 2 h / 115 °C 4.1: 10% Pd/C; hydrogen / tetrahydrofuran / 3 h / 20 °C 5.1: ethanol / 3 h / 40 °C 6.1: water / 3 h / 20 °C / pH 7 - 7.5 7.1: 1,1'-carbonyldiimidazole; dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C 7.2: 22 h / Reflux
	Multi-step reaction with 7 steps 1.1: piperidine; acetic acid / dichloromethane / 18 h / Reflux 2.1: iso-butanol / 20 h / Reflux 3.1: sulfuric acid / N,N-dimethyl acetamide / 2 h / 115 °C 4.1: 10% Pd/C; hydrogen / tetrahydrofuran / 3 h / 20 °C 5.1: ethanol / 3 h / 40 °C 6.1: water / 3 h / 20 °C / pH 7 - 7.5 7.1: 1,1'-carbonyldiimidazole; dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C 7.2: 22 h / Reflux
	Multi-step reaction with 7 steps 1.1: piperidine; acetic acid / dichloromethane / 18 h / Reflux 2.1: iso-butanol / 20 h / Reflux 3.1: sulfuric acid / N,N-dimethyl acetamide / 2 h / 115 °C 4.1: 10% Pd/C; hydrogen / tetrahydrofuran / 3 h / 20 °C 5.1: ethanol / 3 h / 40 °C 6.1: water / 3 h / 20 °C / pH 7 - 7.5 7.1: 1,1'-carbonyldiimidazole; dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C 7.2: 22 h / Reflux
	Multi-step reaction with 7 steps 1.1: piperidine; acetic acid / dichloromethane / 18 h / Reflux 2.1: iso-butanol / 20 h / Reflux 3.1: sulfuric acid / N,N-dimethyl acetamide / 2 h / 115 °C 4.1: 10% Pd/C; hydrogen / tetrahydrofuran / 3 h / 20 °C 5.1: ethanol / 3 h / 40 °C 6.1: water / 3 h / 20 °C / pH 7 - 7.5 7.1: 1,1'-carbonyldiimidazole; dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C 7.2: 22 h / Reflux
	Multi-step reaction with 7 steps 1.1: piperidine; acetic acid / dichloromethane / 18 h / Reflux 2.1: iso-butanol / 20 h / Reflux 3.1: sulfuric acid / N,N-dimethyl acetamide / 2 h / 115 °C 4.1: 10% Pd/C; hydrogen / tetrahydrofuran / 3 h / 20 °C 5.1: ethanol / 3 h / 40 °C 6.1: water / 3 h / 20 °C / pH 7 - 7.5 7.1: 1,1'-carbonyldiimidazole; dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C 7.2: 22 h / Reflux
	Multi-step reaction with 7 steps 1.1: piperidine; acetic acid / dichloromethane / 18 h / Reflux 2.1: iso-butanol / 20 h / Reflux 3.1: sulfuric acid / N,N-dimethyl acetamide / 2 h / 115 °C 4.1: 10% Pd/C; hydrogen / tetrahydrofuran / 3 h / 20 °C 5.1: ethanol / 3 h / 40 °C 6.1: water / 3 h / 20 °C / pH 7 - 7.5 7.1: 1,1'-carbonyldiimidazole; dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C 7.2: 22 h / Reflux
	Multi-step reaction with 7 steps 1.1: piperidine; acetic acid / dichloromethane / 18 h / Reflux 2.1: iso-butanol / 20 h / Reflux 3.1: sulfuric acid / N,N-dimethyl acetamide / 2 h / 115 °C 4.1: 10% Pd/C; hydrogen / tetrahydrofuran / 3 h / 20 °C 5.1: 1,4-dioxane; water / 3 h / 20 °C 6.1: water / 3 h / 20 °C / pH 7 - 7.5 7.1: 1,1'-carbonyldiimidazole; dmap / tetrahydrofuran / 3.5 h / 20 - 50 °C 7.2: 22 h / Reflux

Reference： [1]Current Patent Assignee: BAYER AG - US2018/244668, 2018, A1
[2]Current Patent Assignee: BAYER AG - US2018/244668, 2018, A1
[3]Current Patent Assignee: BAYER AG - US2018/244668, 2018, A1
[4]Current Patent Assignee: BAYER AG - US2018/244668, 2018, A1
[5]Current Patent Assignee: BAYER AG - US2018/244670, 2018, A1
[6]Current Patent Assignee: SHANGHAI DINGYA PHARMACEUTICAL CHEMICALS; SHANGHAI TRIPOD MEDICINAL CHEMISTRY SCIENCE AND TECH - CN114149427, 2022, A
[7]Current Patent Assignee: ZHEJIANG KEJIANG BIOMEDICAL - CN114605410, 2022, A
[8]Current Patent Assignee: ARITE PHARMACEUTICAL - CN115340540, 2022, A
[9]Current Patent Assignee: ARITE PHARMACEUTICAL - CN115340540, 2022, A
[10]Current Patent Assignee: ARITE PHARMACEUTICAL - CN115340540, 2022, A
[11]Current Patent Assignee: ARITE PHARMACEUTICAL - CN115340540, 2022, A
[12]Current Patent Assignee: ARITE PHARMACEUTICAL - CN115340540, 2022, A
[13]Current Patent Assignee: ARITE PHARMACEUTICAL - CN115340540, 2022, A
[14]Current Patent Assignee: ARITE PHARMACEUTICAL - CN115340540, 2022, A
[15]Current Patent Assignee: ARITE PHARMACEUTICAL - CN115340540, 2022, A
[16]Current Patent Assignee: ARITE PHARMACEUTICAL; AURISCO PHARMACEUTICAL - CN115340539, 2022, A
[17]Current Patent Assignee: ARITE PHARMACEUTICAL; AURISCO PHARMACEUTICAL - CN115340539, 2022, A
[18]Current Patent Assignee: ARITE PHARMACEUTICAL; AURISCO PHARMACEUTICAL - CN115340539, 2022, A
[19]Current Patent Assignee: ARITE PHARMACEUTICAL; AURISCO PHARMACEUTICAL - CN115340539, 2022, A
[20]Current Patent Assignee: ARITE PHARMACEUTICAL; AURISCO PHARMACEUTICAL - CN115340539, 2022, A
[21]Current Patent Assignee: ARITE PHARMACEUTICAL; AURISCO PHARMACEUTICAL - CN115340539, 2022, A
[22]Current Patent Assignee: ARITE PHARMACEUTICAL; AURISCO PHARMACEUTICAL - CN115340539, 2022, A
[23]Current Patent Assignee: ARITE PHARMACEUTICAL; AURISCO PHARMACEUTICAL - CN115340539, 2022, A
[24]Current Patent Assignee: ARITE PHARMACEUTICAL - CN115340540, 2022, A
[25]Current Patent Assignee: ARITE PHARMACEUTICAL - CN115340540, 2022, A
[26]Current Patent Assignee: ARITE PHARMACEUTICAL - CN115340540, 2022, A
[27]Current Patent Assignee: ARITE PHARMACEUTICAL - CN115340540, 2022, A
[28]Current Patent Assignee: ARITE PHARMACEUTICAL - CN115340540, 2022, A
[29]Current Patent Assignee: ARITE PHARMACEUTICAL - CN115340540, 2022, A
[30]Current Patent Assignee: ARITE PHARMACEUTICAL - CN115340540, 2022, A
[31]Current Patent Assignee: ARITE PHARMACEUTICAL - CN115340540, 2022, A

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Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
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. 21962-45-8 ] {[proInfo.proName]}

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[ 21962-45-8 ] Synthesis Path-Upstream 1~15

[ 21962-45-8 ] Synthesis Path-Downstream 1~16

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Nitriles

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[ 21962-45-8 ]

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