[ CAS No. 7149-10-2 ] {[proInfo.proName]}

Name: 7149-10-2|4-(Aminomethyl)-2-methoxyphenol hydrochloride|98%
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Quality Control of [ 7149-10-2 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 7149-10-2 ]

SDS Specification

Alternatived Products of [ 7149-10-2 ]

Product Details of [ 7149-10-2 ]

CAS No. :	7149-10-2	MDL No. :	MFCD00012864
Formula :	C₈H₁₂ClNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PUDMGOSXPCMUJZ-UHFFFAOYSA-N
M.W :	189.64	Pubchem ID :	165576
Synonyms :	Vanillylamine hydrochloride	Chemical Name :	4-(Aminomethyl)-2-methoxyphenol hydrochloride

Calculated chemistry of [ 7149-10-2 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.25
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	49.6
TPSA :	55.48 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-7.08 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	0.53
Log Po/w (WLOGP) :	1.51
Log Po/w (MLOGP) :	0.92
Log Po/w (SILICOS-IT) :	0.95
Consensus Log Po/w :	0.78

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.59
Solubility :	4.9 mg/ml ; 0.0258 mol/l
Class :	Very soluble
Log S (Ali) :	-1.27
Solubility :	10.3 mg/ml ; 0.0542 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.98
Solubility :	1.99 mg/ml ; 0.0105 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.15

Safety of [ 7149-10-2 ]

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 [ 7149-10-2 ]

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

Upstream synthesis route of [ 7149-10-2 ]
Downstream synthetic route of [ 7149-10-2 ]

[ 7149-10-2 ] Synthesis Path-Upstream 1~6

1
[ 764-85-2 ]
[ 7149-10-2 ]
[ 2444-46-4 ]

Yield	Reaction Conditions	Operation in experiment
91.5%	With sodium hydrogencarbonate In dichloromethane; water at 20 - 42℃; for 2.5 h;	1) Preparation of crude product mixture: 105 g of vanillinamine hydrochloride was added to a mixture consisting of 200 g of sodium hydrogencarbonate, 500 mL of dichloromethane and 600 mL of water, and the mixture was stirred well and the mixture was further heated at room temperature (Methylene chloride: volume: 146.4 mL) was added dropwise over 1 hour. After completion of the dropwise addition, the temperature was raised to 42 ° C and maintained at that temperature for 1.5 hours. To obtain a crude product mixture (1420 mL);(2) Crystallization purification: The crude product mixture was cooled to room temperature, first using 200 mL of 25percentHydrochloric acid solution was shaken and allowed to stand for separation. The organic phase was separated (about 750 mL), and 150 mL of a 20percentOf the sodium hydroxide solution was shaken and the organic phase was washed and allowed to stand for separation. The organic phase was separated again750 mL), washed with 200 mL of water, and partitioned. After washing with water, the organic phase (about 750 mL)150 mL of methylene chloride was distilled off to give a concentrated organic phase (ca. 600 mL), which was added to the concentrated organic phase1080mL petroleum ether after cooling crystallization, cooling rate of 0.25 / min, crystallization termination temperature of aboutAt -10 & lt; 0 & gt; C, maintaining the crystallization termination temperature for at least 30 min, filtering at the crystallization termination temperature,Dried to obtain solid synthetic capsaicin 148.6g, the yield was 91.5percent, by high performance liquid chromatography(HPLC) to determine the purity of 99.5percent.

Reference： [1] Patent: , 2016, , . Location in patent: Paragraph 0040; 0041; 0042
[2] Journal of Agricultural and Food Chemistry, 2010, vol. 58, # 6, p. 3342 - 3349

2
[ 112-05-0 ]
[ 7149-10-2 ]
[ 2444-46-4 ]

Yield	Reaction Conditions	Operation in experiment
81.1%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 0 - 20℃;	Into a reactor equipped with a heating, stirring, and a thermometer, 112 g of vanillin amine hydrochloride obtained above was added to 670 ml of a DMF solvent, and the mixture was stirred at room temperature until the solid was completely dissolved and 95.2 g Nonanoic acid was added thereto.The was cooled to 0°C with an ice bath, 134.4g of triethylamine was added, the temperature was stabilized at 0-5°C, and 235.2g of a condensing agent HBTU was added under stirring. The reaction was naturally warmed to room temperature and stirred overnight. After the reaction was completely detected by TLC, Add 1100 ml of ethyl acetate and 330 ml of water to the reaction mixture. Stir well and place in liquid in a separatory funnel. Discard the aqueous layer and obtain ethyl acetate layers of 5 wtpercent sodium bicarbonate solution, 2 wtpercent hydrochloric acid, respectively. The saturated brine was washed three times each, 1200 ml/time, and then 100 g of anhydrous sodium sulfate was added to the ethyl acetate layer for drying for 3 hours. The sodium sulfate was removed by filtration, and the filtrate was placed in a reactor and heated to 45° C. with stirring and reduced. About 820 ml of ethyl acetate was distilled off and cooled to room temperature. 540 ml of petroleum ether was added to crystallize for 3 hours and filtered. The solid was dried at 40-45° C. for 10 hours to obtain 156.4 g of Nonivamide as the target product. The total yield was 81.1percent. The obtained capsaicin was analyzed by HPLC and its purity was 98.8percent.

Reference： [1] Patent: CN103288665, 2017, B, . Location in patent: Paragraph 0029; 0031; 0032; 0034

3
[ 2874-33-1 ]
[ 7149-10-2 ]

Yield	Reaction Conditions	Operation in experiment
90.5%	Stage #1: With hydrogen In ethanol at 40℃; for 8 h; Stage #2: With hydrogenchloride In ethanol; water	The invention vanilla element amine hydrochloride of the preparation method, the preparation method of the detailed steps are as follows:A, in order to 3 - methoxy -4 - hydroxybenzene carbaldehyde oxime as raw materials, using ethanol as solvent; first will be 3 - methoxy -4 - hydroxybenzene carbaldehyde oxime 133.6g (0.80 µM) added is provided with a stirrer, thermometer of the 2L three flasks, then adding 1400 ml ethanol and 13.0g aluminum zinc-nickel composite catalyst, under the condition of normal inletting hydrogen to carry out protection, heating to 40 °C, at which temperature reaction under the condition of 8h;B, after the reaction is filtered (the resulting filter residue is unreacted compound catalyst, to carry out the recycling), the resulting filtrate is added in the mass concentration is 30percent hydrochloric acid 70 ml, adjusting the pH value of the filtrate 1, separating white crystal, filtering the separated white crystal, vacuum drying to obtain vanilla element amine hydrochloride finished 136.8g, the yield of 90.5percent.
76%	With hydrogenchloride; hydrogen In water; isopropyl alcohol at 20℃; Autoclave	General procedure: A solutionof oxime 1a—k (23 mmol) in isopropyl alcohol (100 mL) was loaded into the autoclave with the fl uoroplastic bush, concentratedHCl (10.5 mL) was added, and a block of the regeneratedcatalyst was fi xed. Hydrogenation was conducted for 3—5 h at20 C and a hydrogen pressure of 10 atm, which was maintainedat this level during the reaction. The reaction course was monitoredby TLC. After the initial oxime disappeared completely,the reaction solution was poured out of the autoclave, the catalystblock was washed with methanol (3×30 mL), and the combinedsolutions were fi ltered from mechanical impurities. The solventwas evaporated, and analytically pure aromatic benzylamines3a—k were obtained.When hydrogenation was conducted in methanol (100 mL),solvent removal was followed by drying residue using azeotropicdistillation with isopropyl alcohol (250 mL). For the hydrogenationof compound 1k, the reaction mixture was additionallypurifi ed by refl ux with active carbon for 1 h. The blockcatalyst was regenerated directly in the reactor at 400 C ina hydrogen fl ow and further used in the next hydrogenationprocedure.
3.31 g	With hydrogenchloride; palladium 10% on activated carbon; hydrogen In ethanol	Second step, 3-methoxy-4-dihydroxybenzaldehyde oxime (2.99 g) and concentrated HCl (8 ml) in EtOH (70 ml) was subjected to hydrogenation at atmospheric pressure in the presence of 10percent Pd/C (700 mg). The reaction solution was filtered and the filtrate was concentrated. Then EtOAc was added to the residue and the suspension was filtered to yield 3-methoxy-4-hydroxybenzylamine hydrochloride (3.31 g) as a white solid.

3.31 g

With hydrogenchloride; palladium 10% on activated carbon; hydrogen In ethanol; water

weigh precisely 2.99 g of 3-methoxy-4-hydroxybenzaldehyde oxime and add 10percent Pd / C (700 mg) and concentrated hydrochloric acid (8 mL), dissolved in ethanol (70 mL) Hydrogenation of the reaction solution, filtration of the reaction solution, except for Pd / C, evaporate the filtrate, add ethyl acetate, mix well, dissolve, filter white crystals3.31 g of 3-methoxy-4-hydroxyphenylmethylamine hydrochloride are obtained.

Reference： [1] Polymer, 2011, vol. 52, # 9, p. 1908 - 1916
[2] Journal of Organic Chemistry, 1988, vol. 53, # 5, p. 1064 - 1071
[3] Patent: CN106366004, 2017, A, . Location in patent: Paragraph 0017-0028
[4] Patent: JP2005/527478, 2005, A, . Location in patent: Page/Page column 4
[5] Russian Chemical Bulletin, 2018, vol. 67, # 8, p. 1394 - 1400[6] Izv. Akad. Nauk, Ser. Khim., 2018, # 8, p. 1394 - 1400,7
[7] Patent: JP2005/527478, 2005, A, . Location in patent: Page/Page column 4
[8] Patent: EP2511283, 2012, A1, . Location in patent: Page/Page column 49
[9] Patent: US2013/45942, 2013, A1, . Location in patent: Paragraph 0162
[10] Patent: JP2015/172077, 2015, A, . Location in patent: Paragraph 0115

4
[ 121-33-5 ]
[ 7149-10-2 ]

Yield	Reaction Conditions	Operation in experiment
112 g	Stage #1: With ammonia In methanol at 20℃; for 3 h; Stage #2: at 45℃; Stage #3: With hydrogenchloride In water at 0℃; for 3 h;	100 g of vanillin was added to 800 g of a methanol solution containing 20 wtpercent of ammonia in a reactor equipped with a heating, stirring, and a thermometer, and after stirring for 3 hours at room temperature, 270 g of sodium borohydride was added, and the temperature was raised to 45 after the reaction was detected by TLC. °C, 600 ml of methanol was distilled off under reduced pressure. After the reaction solution was cooled to room temperature, it was poured into 300 ml of distilled water at a temperature of 10° C., 800 ml of ethyl acetate was added, and the mixture was stirred uniformly and placed in a separatory funnel to obtain an organic phase. The ethyl acetate layer was successively washed with 5 wtpercent sodium bicarbonate solution and saturated brine three times with an amount of 800 ml/time, and then 100 g of anhydrous sodium sulfate was added to the ethyl acetate layer of the organic phase and dried for 3 hours to remove sodium sulfate by filtration. The filtrate was placed in a reactor, and the temperature was lowered to 0° C. with an ice-water bath while stirring. 120 g of dry hydrogen chloride gas was introduced and the temperature was maintained for 3 hours while stirring. The resulting solid was washed with 200 ml of ethyl acetate and then dried at 40-. Drying at 45°C for 10 hours yielded 112 g of the intermediate vanillin amine hydrochloride.

Reference： [1] Patent: EP2511283, 2012, A1,
[2] Patent: US2013/45942, 2013, A1,
[3] Patent: CN103288665, 2017, B, . Location in patent: Paragraph 0029; 0030; 0032; 0033
[4] Journal of Medicinal Chemistry, 2018, vol. 61, # 18, p. 8255 - 8281

5
[ 134283-49-1 ]
[ 7149-10-2 ]

Reference： [1] Journal of Medicinal Chemistry, 2018, vol. 61, # 18, p. 8255 - 8281

6
[ 93249-67-3 ]
[ 7149-10-2 ]

Reference： [1] Journal of Organic Chemistry, 1988, vol. 53, # 5, p. 1064 - 1071

[ 7149-10-2 ] Synthesis Path-Downstream 1~88

1
[ 2874-33-1 ]
[ 7149-10-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogenchloride; palladium 10% on activated carbon; hydrogen In ethanol at 20℃; for 3h;
98%	With hydrogenchloride; hydrogen In ethanol for 4h;
90.5%	Stage #1: vanillin oxime With hydrogen In ethanol at 40℃; for 8h; Stage #2: With hydrogenchloride In ethanol; water	1 Embodiment 1 The invention vanilla element amine hydrochloride of the preparation method, the preparation method of the detailed steps are as follows:A, in order to 3 - methoxy -4 - hydroxybenzene carbaldehyde oxime as raw materials, using ethanol as solvent; first will be 3 - methoxy -4 - hydroxybenzene carbaldehyde oxime 133.6g (0.80 µM) added is provided with a stirrer, thermometer of the 2L three flasks, then adding 1400 ml ethanol and 13.0g aluminum zinc-nickel composite catalyst, under the condition of normal inletting hydrogen to carry out protection, heating to 40 °C, at which temperature reaction under the condition of 8h;B, after the reaction is filtered (the resulting filter residue is unreacted compound catalyst, to carry out the recycling), the resulting filtrate is added in the mass concentration is 30% hydrochloric acid 70 ml, adjusting the pH value of the filtrate 1, separating white crystal, filtering the separated white crystal, vacuum drying to obtain vanilla element amine hydrochloride finished 136.8g, the yield of 90.5%.

82%	Stage #1: vanillin oxime With hydrogenchloride; hydrogen In water; acetic acid at 10℃; for 4h; Stage #2: With water In acetic acid at 60℃; for 1h; Stage #3: With hydrogenchloride more than 3 stages;
76%	With hydrogenchloride; hydrogen In water; isopropyl alcohol at 20℃; Autoclave;	Hydrogenation of oximes 1a-k General procedure: A solutionof oxime 1a-k (23 mmol) in isopropyl alcohol (100 mL) was loaded into the autoclave with the fl uoroplastic bush, concentratedHCl (10.5 mL) was added, and a block of the regeneratedcatalyst was fi xed. Hydrogenation was conducted for 3-5 h at20 C and a hydrogen pressure of 10 atm, which was maintainedat this level during the reaction. The reaction course was monitoredby TLC. After the initial oxime disappeared completely,the reaction solution was poured out of the autoclave, the catalystblock was washed with methanol (3×30 mL), and the combinedsolutions were fi ltered from mechanical impurities. The solventwas evaporated, and analytically pure aromatic benzylamines3a-k were obtained.When hydrogenation was conducted in methanol (100 mL),solvent removal was followed by drying residue using azeotropicdistillation with isopropyl alcohol (250 mL). For the hydrogenationof compound 1k, the reaction mixture was additionallypurifi ed by refl ux with active carbon for 1 h. The blockcatalyst was regenerated directly in the reactor at 400 C ina hydrogen fl ow and further used in the next hydrogenationprocedure.
53%	With hydrogenchloride; hydrogen In water; acetic acid at 0℃; for 2.5h;
	With hydrogenchloride; hydrogen In ethanol; water	23 First step, hydroxyamine hydrochloride (2.52 g) and NaOAc (3.26 g) were added to a solution of 3-methoxy-4-hydroxybenzaldehyde (3.04 g) in EtOH (80 ml). The reaction mixture was stirred at room temperature for 6h. EtOH was removed under reduced pressure. H2O (40 ml) was added to the residue, and extracted with EtOAc (3 × 40 ml). The EtOAc of the combined organic layer was removed by rotary evaporation under reduced pressure to yield 3-methoxy-4-dihydroxybenzaldehyde oxime (2.99 g) as a pale yellowish solid. Second step, 3-methoxy-4-dihydroxybenzaldehyde oxime (2.99 g) and concentrated HCl (8 ml) in EtOH (70 ml) was subjected to hydrogenation at atmospheric pressure in the presence of 10% Pd/C (700 mg). The reaction solution was filtered and the filtrate was concentrated. Then EtOAc was added to the residue and the suspension was filtered to yield 3-methoxy-4-hydroxybenzylamine hydrochloride (3.31 g) as a white solid. Third step, a mixture of 3-methoxy-4-dihydroxybenzylamine (3.31 g, the hydrochloride), 6-chloropurine riboside (1 g) and N, N-diisopropylethyl amine (14 ml) in PrOH (70 ml) was heated to 70°C and reacted for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (15 : 1) to yield N6-(3-methoxy-4-hydroxybenzyl)-adenosine(1.02 g) as a colorless solid: positive ESIMS m/z 404[M + H]+; negative ESIMS m/z 402 [M - H]- and 438[M + Cl]-; 1H NMR (300 MHz, DMSO): the adenosine moiety δ 8.35 (1H, s, H-2), 8.29 (1H, brs, -NH), 8.20 (1H, brs, H-8), 5.87 (1H, d, J= 6.3 Hz, H-1), 5.37-5.44 (2H, m, -OH x 2), 5.18 (1H, J = 4.5 Hz, -OH), 4.60 (1H, m, H-2'), 4.11 (1H, m, H-3'), 3.95 (1H, m, H-4'), 3.66 (1H, m, H-5'a), 3.54 (1H, m, 5'b); the 3-methoxy-4-hydroxybenzyl moiety δ 8.77 (1H, s, -OH), 6.96 (1H, d, J= 1.5 Hz, H-2"), 6.72 (1H, dd, J= 8.1, 1.5 Hz, H-6"), 6.66 (1H, d, J = 8.1 Hz, H-5"), 4.60 (2H, m, H-7"), 3.71 (3H, s, -OCH3); 13C NMR (125 MHz, DMSO-d6): the adenosine moiety δ 154.4 (C-6), 152.3 (C-2), 147.3 (C-4), 139.8 (C-8), 119.8 (C-5), 87.9 (C-1), 85.9 (C-4'), 73.4 (C-2'), 70.6 (C-3'), 61.6 (C-5'); the 3-methoxy-4-hydroxybenzyl moiety δ 147.3 (C-4"), 145.3 (C-3"), 130.7 (C-1), 115.3 (C-2"), 119.8 (C-6"), 112.0 (C-5"), 55.5 (-OCH3), 42.7 (C-7")o
3.31 g	With hydrogenchloride; palladium 10% on activated carbon; hydrogen In ethanol	23 Second step, 3-methoxy-4-dihydroxybenzaldehyde oxime (2.99 g) and concentrated HCl (8 ml) in EtOH (70 ml) was subjected to hydrogenation at atmospheric pressure in the presence of 10% Pd/C (700 mg). The reaction solution was filtered and the filtrate was concentrated. Then EtOAc was added to the residue and the suspension was filtered to yield 3-methoxy-4-hydroxybenzylamine hydrochloride (3.31 g) as a white solid.
3.31 g	With hydrogenchloride; palladium 10% on activated carbon; hydrogen In ethanol; water	23.2 Second step weigh precisely 2.99 g of 3-methoxy-4-hydroxybenzaldehyde oxime and add 10% Pd / C (700 mg) and concentrated hydrochloric acid (8 mL), dissolved in ethanol (70 mL) Hydrogenation of the reaction solution, filtration of the reaction solution, except for Pd / C, evaporate the filtrate, add ethyl acetate, mix well, dissolve, filter white crystals3.31 g of 3-methoxy-4-hydroxyphenylmethylamine hydrochloride are obtained.

Reference： [1]Location in patent: experimental part Liu, Hefang; Lepoittevin, Bénédicte; Roddier, Céline; Guerineau, Vincent; Bech, Loïc; Herry, Jean-Marie; Bellon-Fontaine, Marie-Noelle; Roger, Philippe [Polymer, 2011, vol. 52, # 9, p. 1908 - 1916]
[2]Gannett, Peter M.; Nagel, Donald L.; Reilly, Pam J.; Lawson, Terence; Sharpe, Jody; Toth, Bela [Journal of Organic Chemistry, 1988, vol. 53, # 5, p. 1064 - 1071]
[3]Current Patent Assignee: HENAN CHEMICAL IND RES INST - CN106366004, 2017, A Location in patent: Paragraph 0017-0028
[4]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - JP2005/527478, 2005, A Location in patent: Page/Page column 4
[5]Ignatov; Varakutin; Solov’eva; Karmanova; Kozlov; Semenova; Semenov [Russian Chemical Bulletin, 2018, vol. 67, # 8, p. 1394 - 1400][Izv. Akad. Nauk, Ser. Khim., 2018, # 8, p. 1394 - 1400,7]
[6]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - JP2005/527478, 2005, A Location in patent: Page/Page column 4
[7]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - EP2511283, 2012, A1 Location in patent: Page/Page column 49
[8]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - US2013/45942, 2013, A1 Location in patent: Paragraph 0162
[9]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - JP2015/172077, 2015, A Location in patent: Paragraph 0115

2
[ 93249-67-3 ]
[ 7149-10-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; hydrogen In ethanol for 4h;

Reference： [1]Gannett, Peter M.; Nagel, Donald L.; Reilly, Pam J.; Lawson, Terence; Sharpe, Jody; Toth, Bela [Journal of Organic Chemistry, 1988, vol. 53, # 5, p. 1064 - 1071]

3
[ 124-10-7 ]
[ 7149-10-2 ]
[ 69693-12-5 ]

Yield	Reaction Conditions	Operation in experiment
57%	With novozyme 435 In water at 70℃; for 72h; borate buffer;	2 The substitution reaction of acyl group using a lipase, which is disclosed by JP-A-No. H11-206396, is used to synthesize N-vanillylmyristamide (C14). In the method, 37.8 mg (0.2 mmol) of vanillyl amine hydrochloride is dissolved in 10 ml of 10 mM borate buffer (pH 9.0), and then 1000 mg of Novozyme 435 (Immobilized preparation of enzyme derived from Mucor miehei:Novo Nordisk A/S), 5.80 g of methyl myristate (24 mmol) are added thereto. The mixture is reacted at 70 degrees Celsius for a given time with stirring. After the reaction, the obtained N-vanillylmyristamide is determined quantitatively. Where an amount of vanillyl amine consumed is used as a standard, the reaction yield will be about 30%, where the reaction time is 24 hours, and about 57%, where the reaction time is 72 hours.
17.2%	With borate buffer; N-ethyl-N,N-diisopropylamine In water at 37℃; for 48h; pH = 9.0, chicken liver acetone powder (Sigma Chem_. Co_.);

Reference： [1]Current Patent Assignee: KUREHA CORP. - US2004/110844, 2004, A1 Location in patent: Page/Page column 4
[2]Kobata, Kenji; Yoshikawa, Koichi; Kohashi, Masahiro; Watanabe, Tatsuo [Tetrahedron Letters, 1996, vol. 37, # 16, p. 2789 - 2790]

4
[ 24424-99-5 ]
[ 7149-10-2 ]
[ 130972-89-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydrogencarbonate In tetrahydrofuran; water at 0℃; for 5h;	Vanillylamine hydrochloride (1.90 g, 10.0 mmol), NaHCO3(2.52 g, 30.0 mmol), and (Boc)2O (2.18 g, 10.0 mmol) were addedinto 40 mL mixture of H2O/THF (v/v 1:1) at 0 C. After 5 h, EA(50 mL) was added and the mixture was extracted. Compound 8(2.50 g, 100%) was obtained as a white solid after the organic phasewas dried and evaporated. 1H NMR (400 MHz, CDCl3) d 6.85 (d,J 8.0 Hz, 1H), 6.81(d, J 2.0 Hz, 1H), 6.76 (dd, J 8.0, 2.0 Hz, 1H),5.66 (s, 1H), 4.82 (s, 1H), 4.22 (d, J 5.9 Hz, 2H), 3.87 (s, 3H), 1.46 (s,9H); 13C NMR (100 MHz, CDCl3) d 155.9, 146.6, 144.9, 130.9, 120.5,114.3, 110.3, 79.5, 55.9, 44.6, 28.4 (3C).
99%	With triethylamine In 1,4-dioxane; water at 20℃; for 24h;
97%	With triethylamine In dichloromethane at 0 - 20℃; for 5h;	13.A A. A 500 mL round bottom flask was charge with 4-hydroxy-3- methoxybenzylamine hydrochloride (Compound 13a, 5.0 g, 26.4 mmol), Et3N (12.0 mL, 86.1 mmol), and DCM (130 mL). The mixture was cooled using an ice/water bath. Di-te/f-butyl dicarbonate (5.8 g, 26.6 mmol) was added in three portions. The mixture was stirred at room temperature for 5 h, diluted with DCM (300 mL), and washed with 1N HCI (100 mL). The organic layer was dried using MgSO4, filtered through Celite, and concentrated in vacuo to give 6.5 g (97%) of Compound 13b as a white solid. 1H NMR (300 MHz, CDCI3) δ 6.75-6.87 (m, 3 H), 4.78 (bs, 1 H), 4.22 (d, J = 5.8 Hz, 2 H), 3.88 (s, 3 H), and 1.46 (s, 9 H).

89%	With triethylamine In 1,4-dioxane; water Ambient temperature;
86%	Stage #1: vanillylamine hydrochloride With potassium hydroxide In water; acetonitrile for 0.25h; Stage #2: di-<i>tert</i>-butyl dicarbonate In water; acetonitrile at 0 - 20℃; for 48h;	Step 1 4-hydroxy-3-methoxybenzylamine hydrochloride (3b, 2.382 g, 12.6 mmol)was dissolved in a mixture of 15 ml of water and 30 ml of acetonitrile and 9.4 ml (18.8 mmol)of 2N KOH solution was added to the solution. After stirring for 15 min, Boc2O (3.02 g, 13.8mmol) in 15 ml of acetonitrile was added at 0 oC. Then the mixture was stirred at ambienttemperature for 2 days. After evaporation the residue was dissolved in water, extracted withDCM and the combined organic phase was dried and evaporated. After columnchromatography 2.748 g (86%) of (4-hydroxy-3-methoxybenzyl)carbamic acid tert-butyl ester(3c) was isolated. Molecular Formula: C13H19NO4; (M+H)+ = 254; Rt = 2.89 min (B), purity96.5 %.

Reference： [1]Pei, Fang-Ning; Tang, Jie; Wang, Zhi-Cheng; Wei, Bingyan; Yang, Cai-Guang; Yang, Fan; Yang, Song; Yang, Teng; Yu, Li-Fang [European Journal of Medicinal Chemistry, 2020, vol. 198]
[2]Lee, Jeewoo; Lee, Jiyoun; Kang, Myung-Sim; Kim, Kang-Pil; Chung, Suk-Jae; Blumberg, Peter M.; Yi, Jung-Bum; Park, Young Ho [Bioorganic and Medicinal Chemistry, 2002, vol. 10, # 4, p. 1171 - 1179]
[3]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2007/81995, 2007, A2 Location in patent: Page/Page column 196
[4]Wrigglesworth, Roger; Walpole, Christopher S. J.; Bevan, Stuart; Campbell, Elizabeth A.; Dray, Andy; Hughes, Glyn A.; James, Iain; Masdin, Kay J.; Winter, Janet [Journal of Medicinal Chemistry, 1996, vol. 39, # 25, p. 4942 - 4951]
[5]Bata, Imre; Tömösközi, Zsuzsanna; Buzder-Lantos, Péter; Vasas, Attila; Szeleczky, Gábor; Bátori, Sándor; Barta-Bodor, Veronika; Balázs, László; Ferenczy, György G. [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 22, p. 5418 - 5428]

5
[ 68215-54-3 ]
[ 7149-10-2 ]
[ 184003-09-6 ]

Yield	Reaction Conditions	Operation in experiment
87%	With sodium hydroxide In N,N-dimethyl-formamide

Reference： [1]Wrigglesworth, Roger; Walpole, Christopher S. J.; Bevan, Stuart; Campbell, Elizabeth A.; Dray, Andy; Hughes, Glyn A.; James, Iain; Masdin, Kay J.; Winter, Janet [Journal of Medicinal Chemistry, 1996, vol. 39, # 25, p. 4942 - 4951]

6
[ 4698-08-2 ]
[ 7149-10-2 ]
(E)-N-(4-hydroxy-3-methoxybenzyl)-3,7-dimethylocta-2,6-dienamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With diethyl cyanophosphonate; triethylamine In tetrahydrofuran

Reference： [1]Appendino, Giovanni; Minassi, Alberto; Morello, Aniello Schiano; De Petrocellis, Luciano; Di Marzo, Vincenzo [Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3739 - 3745]

7
[ 22352-56-3 ]
[ 7149-10-2 ]
(E)-(7R,11R)-3,7,11,15-Tetramethyl-hexadec-2-enoic acid 4-hydroxy-3-methoxy-benzylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With diethyl cyanophosphonate; triethylamine In tetrahydrofuran

Reference： [1]Appendino, Giovanni; Minassi, Alberto; Morello, Aniello Schiano; De Petrocellis, Luciano; Di Marzo, Vincenzo [Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3739 - 3745]

8
[ 112-80-1 ]
[ 7149-10-2 ]
[ 58493-49-5 ]

Yield	Reaction Conditions	Operation in experiment
81%	With diethyl cyanophosphonate; triethylamine In tetrahydrofuran

Reference： [1]Appendino, Giovanni; Minassi, Alberto; Morello, Aniello Schiano; De Petrocellis, Luciano; Di Marzo, Vincenzo [Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3739 - 3745]

9
R-12-hydroxyoctadecanoic acid [ No CAS ]
[ 7149-10-2 ]
(R)-12-Hydroxy-octadecanoic acid 4-hydroxy-3-methoxy-benzylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With diethyl cyanophosphonate; triethylamine In tetrahydrofuran

Reference： [1]Appendino, Giovanni; Minassi, Alberto; Morello, Aniello Schiano; De Petrocellis, Luciano; Di Marzo, Vincenzo [Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3739 - 3745]

10
trans-ximenynic acid [ No CAS ]
[ 7149-10-2 ]
(E)-Octadec-11-en-9-ynoic acid 4-hydroxy-3-methoxy-benzylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With diethyl cyanophosphonate; triethylamine In tetrahydrofuran

Reference： [1]Appendino, Giovanni; Minassi, Alberto; Morello, Aniello Schiano; De Petrocellis, Luciano; Di Marzo, Vincenzo [Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3739 - 3745]

11
[ 925-44-0 ]
[ 7149-10-2 ]
12-oxo-octadecanoic acid 4-hydroxy-3-methoxy-benzylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With diethyl cyanophosphonate; triethylamine In tetrahydrofuran

Reference： [1]Appendino, Giovanni; Minassi, Alberto; Morello, Aniello Schiano; De Petrocellis, Luciano; Di Marzo, Vincenzo [Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3739 - 3745]

12
[ 3515-84-2 ]
[ 7149-10-2 ]
(Z)-Henicos-12-enoic acid 4-hydroxy-3-methoxy-benzylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With diethyl cyanophosphonate; triethylamine In tetrahydrofuran

Reference： [1]Appendino, Giovanni; Minassi, Alberto; Morello, Aniello Schiano; De Petrocellis, Luciano; Di Marzo, Vincenzo [Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3739 - 3745]

13
[ 506-32-1 ]
[ 7149-10-2 ]
[ 128007-31-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	With diethyl cyanophosphonate; triethylamine In tetrahydrofuran for 1.5h;
79%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In dichloromethane; ethyl acetate at 0℃; for 0.25h;

Reference： [1]Appendino, Giovanni; Minassi, Alberto; Morello, Aniello Schiano; De Petrocellis, Luciano; Di Marzo, Vincenzo [Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3739 - 3745]
[2]Sancho, Rocio; De La Vega, Laureano; Appendino, Giovanni; Di Marzo, Vincenzo; Macho, Antonio; Munoz, Eduardo [British Journal of Pharmacology, 2003, vol. 140, # 6, p. 1035 - 1044]

14
[ 302-79-4 ]
[ 7149-10-2 ]
Retvanil [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With diethyl cyanophosphonate; triethylamine In tetrahydrofuran

Reference： [1]Appendino, Giovanni; Minassi, Alberto; Morello, Aniello Schiano; De Petrocellis, Luciano; Di Marzo, Vincenzo [Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3739 - 3745]

15
[ 471-53-4 ]
[ 7149-10-2 ]
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-Hydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydro-picene-2-carboxylic acid 4-hydroxy-3-methoxy-benzylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With diethyl cyanophosphonate; triethylamine In tetrahydrofuran

Reference： [1]Appendino, Giovanni; Minassi, Alberto; Morello, Aniello Schiano; De Petrocellis, Luciano; Di Marzo, Vincenzo [Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3739 - 3745]

16
[ 26771-06-2 ]
[ 7149-10-2 ]
(1S,3R)-2,2-Dimethyl-3-(2-methyl-propenyl)-cyclopropanecarboxylic acid 4-hydroxy-3-methoxy-benzylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With diethyl cyanophosphonate; triethylamine In tetrahydrofuran

Reference： [1]Appendino, Giovanni; Minassi, Alberto; Morello, Aniello Schiano; De Petrocellis, Luciano; Di Marzo, Vincenzo [Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3739 - 3745]

17
[ 4586-68-9 ]
[ 7149-10-2 ]
ilicic acid vanillamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With diethyl cyanophosphonate; triethylamine In tetrahydrofuran

Reference： [1]Appendino, Giovanni; Minassi, Alberto; Morello, Aniello Schiano; De Petrocellis, Luciano; Di Marzo, Vincenzo [Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3739 - 3745]

18
[ 7149-10-2 ]
[ 57-11-4 ]
[ 58493-50-8 ]

Yield	Reaction Conditions	Operation in experiment
76%	With diethyl cyanophosphonate; triethylamine In tetrahydrofuran

Reference： [1]Appendino, Giovanni; Minassi, Alberto; Morello, Aniello Schiano; De Petrocellis, Luciano; Di Marzo, Vincenzo [Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3739 - 3745]

19
[ 14936-79-9 ]
[ 7149-10-2 ]
acetylrinvanil [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With propylphosphonic anhydride; triethylamine In dichloromethane at 0 - 20℃;
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In dichloromethane

Reference： [1]Appendino, Giovanni; Minassi, Alberto; Morello, Aniello Schiano; De Petrocellis, Luciano; Di Marzo, Vincenzo [Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3739 - 3745]
[2]Appendino, Giovanni; De Petrocellis, Luciano; Trevisani, Marcello; Minassi, Alberto; Daddario, Nives; Moriello, Aniello Schiano; Gazzieri, David; Ligresti, Alessia; Campi, Barbara; Fontana, Gabriele; Pinna, Christian; Geppetti, Pierangeio; Di Marzo, Vincenzo [Journal of Pharmacology and Experimental Therapeutics, 2005, vol. 312, # 2, p. 561 - 570]

20
2-benzoyl-1-benzyl-6-(2,3-dioxo-3-pyrrolidin-1-ylpropyl)-5-oxo-octahydrocyclopenta[c]pyrrole-1-carboxylic acid methyl ester [ No CAS ]
[ 7149-10-2 ]
5-benzoyl-4-benzyl-1-(4-hydroxy-3-methoxybenzyl)-2-(pyrrolidinyl-1-carbonyl)-3b,4,5,6,6a,7-hexahydro-1H-1,5-diazacyclopenta[a]pentalene-4-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With acetic acid In ethanol at 50℃; for 2h;

Reference： [1]Brummond, Kay M.; Curran, Dennis P.; Mitasev, Branko; Fischer, Stefan [Journal of Organic Chemistry, 2005, vol. 70, # 5, p. 1745 - 1753]

21
[ 10266-06-5 ]
[ 201230-82-2 ]
[ 7149-10-2 ]
[ 19408-84-5 ]

Yield	Reaction Conditions	Operation in experiment
82%	Stage #1: 1-iodo-7-methyloctane; carbon monoxide; vanillylamine hydrochloride With potassium carbonate; 1,1,1,3,3,3-hexamethyl-disilazane In benzene for 16h; Photolysis; Stage #2: With tetrabutyl ammonium fluoride In tetrahydrofuran; chloroform at 20℃; for 3h;

Reference： [1]Fukuyama, Takahide; Nishitani, Satoshi; Inouye, Takaya; Morimoto, Keisuke; Ryu, Ilhyong [Organic Letters, 2006, vol. 8, # 7, p. 1383 - 1386]

22
[ 110-44-1 ]
[ 7149-10-2 ]
(2E,4E)-Hexa-2,4-dienoic acid 4-hydroxy-3-methoxy-benzylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With propylphosphonic anhydride; triethylamine In dichloromethane at 0 - 20℃;

Reference： [1]Appendino, Giovanni; Minassi, Alberto; Morello, Aniello Schiano; De Petrocellis, Luciano; Di Marzo, Vincenzo [Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3739 - 3745]

23
[ 123-99-9 ]
[ 7149-10-2 ]
azelaic acid vanillamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With propylphosphonic anhydride; triethylamine In dichloromethane at 0 - 20℃;

Reference： [1]Appendino, Giovanni; Minassi, Alberto; Morello, Aniello Schiano; De Petrocellis, Luciano; Di Marzo, Vincenzo [Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3739 - 3745]

24
[ 141-22-0 ]
[ 7149-10-2 ]
[ 457643-60-6 ]

Reference： [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 3739 - 3745

25
[ 112-38-9 ]
[ 7149-10-2 ]
[ 5555-46-4 ]

Yield	Reaction Conditions	Operation in experiment
91%	With propylphosphonic anhydride; triethylamine In dichloromethane at 0 - 20℃;

Reference： [1]Appendino, Giovanni; Minassi, Alberto; Morello, Aniello Schiano; De Petrocellis, Luciano; Di Marzo, Vincenzo [Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3739 - 3745]

26
[ 506-24-1 ]
[ 7149-10-2 ]
N-vanillyl-9-octadecynamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With propylphosphonic anhydride; triethylamine In dichloromethane at 0 - 20℃;

Reference： [1]Appendino, Giovanni; Minassi, Alberto; Morello, Aniello Schiano; De Petrocellis, Luciano; Di Marzo, Vincenzo [Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3739 - 3745]

27
[ 23635-14-5 ]
[ 7149-10-2 ]
(S)-perillic acid vanillamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 3739 - 3745

28
[ 81-25-4 ]
[ 7149-10-2 ]
cholic acid vanillidamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With propylphosphonic anhydride; triethylamine In dichloromethane at 0 - 20℃;

Reference： [1]Appendino, Giovanni; Minassi, Alberto; Morello, Aniello Schiano; De Petrocellis, Luciano; Di Marzo, Vincenzo [Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3739 - 3745]

29
[ 112-77-6 ]
[ 7149-10-2 ]
[ 58493-49-5 ]

Yield	Reaction Conditions	Operation in experiment
95.8%	Stage #1: vanillylamine hydrochloride With sodium hydrogencarbonate In water at 20℃; for 0.5h; Stage #2: (Z)-9-octadecenoyl chloride In chloroform; water at 20℃; for 0.5h;
	With pyridine

Reference： [1]Wang, Bo; Yang, Fan; Shan, Yi-Fan; Qiu, Wen-Wei; Tang, Jie [Tetrahedron, 2009, vol. 65, # 27, p. 5409 - 5412]
[2]Morita, Akihito; Iwasaki, Yusaku; Kobata, Kenji; Iida, Tohko; Higashi, Tomohiro; Oda, Kyoko; Suzuki, Asami; Narukawa, Masataka; Sasakuma, Shiho; Yokogoshi, Hidehiko; Yazawa, Susumu; Tominaga, Makoto; Watanabe, Tatsuo [Life Sciences, 2006, vol. 79, # 24, p. 2303 - 2310]

30
[ 7149-10-2 ]
[ 112-13-0 ]
[ 31078-36-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: vanillylamine hydrochloride With sodium hydrogencarbonate In chloroform; water at 20℃; for 0.75h; Stage #2: n-decanoyl chloride In chloroform; water for 0.5h;	5.2.1. General procedure for synthesis of compounds 1-3 General procedure: To a solution of vanillylamine hydrochloride (1.90 g, 10.0 mmol)in water (30 mL), NaHCO3 (2.52 g, 30.0 mmol) was added. Themixture was stirred for 30 min at room temperature and thenchloroform (30 mL) was added. After stirring for 15 min, a solutionof acyl chloride (10.0 mmol) in chloroform (20 mL) was addeddropwise. The mixture was stirred for 30 min and monitored forcompletion by TLC. The organic layer was separated, and the waterlayer was extracted with chloroform (3 20 mL). The organicphases were combined and dried by anhydrous sodium sulfate. Thesolvent was removed under reduced pressure and the residue wasrecrystallized (when needed) to yield the product. 5.2.1.1. N-(4-hydroxy-3-methoxybenzyl)decanamide (1). Whitesolid; yield: 2.92 g, 95%; 1H NMR (400 MHz, DMSO-d6) d 8.82 (s, 1H),8.18 (t, J 5.9 Hz, 1H), 6.86 (s, 1H), 6.75 (d, J 8.0 Hz, 1H), 6.68 (d,J 7.9 Hz, 1H), 4.20 (d, J 5.8 Hz, 2H), 3.79 (s, 3H), 2.16 (t, J 7.4 Hz,2H), 1.63e1.51 (m, 2H), 1.37e1.26 (m, 12H), 0.91 (t, J 6.5 Hz, 3H);13C NMR (100 MHz, DMSO-d6) d 171.8, 147.3, 145.2, 130.4, 119.5,115.0, 111.6, 55.4, 41.7, 35.2, 31.1, 28.8, 28.7, 28.5, 28.5, 25.2, 21.9,13.8.
94.7%	Stage #1: vanillylamine hydrochloride With sodium hydrogencarbonate In water at 20℃; for 0.5h; Stage #2: n-decanoyl chloride In chloroform; water at 20℃; for 0.5h;
62.92%	Stage #1: vanillylamine hydrochloride With sodium hydroxide In water; N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere; Cooling with ice; Stage #2: n-decanoyl chloride In tetrahydrofuran; water; N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere; Cooling with ice;

With pyridine

Reference： [1]Pei, Fang-Ning; Tang, Jie; Wang, Zhi-Cheng; Wei, Bingyan; Yang, Cai-Guang; Yang, Fan; Yang, Song; Yang, Teng; Yu, Li-Fang [European Journal of Medicinal Chemistry, 2020, vol. 198]
[2]Wang, Bo; Yang, Fan; Shan, Yi-Fan; Qiu, Wen-Wei; Tang, Jie [Tetrahedron, 2009, vol. 65, # 27, p. 5409 - 5412]
[3]Location in patent: experimental part Barbero, Gerardo F.; Molinillo, Jose M. G.; Varela, Rosa M.; Palma, Miguel; MacIas, Francisco A.; Barroso, Carmelo G. [Journal of Agricultural and Food Chemistry, 2010, vol. 58, # 6, p. 3342 - 3349]
[4]Morita, Akihito; Iwasaki, Yusaku; Kobata, Kenji; Iida, Tohko; Higashi, Tomohiro; Oda, Kyoko; Suzuki, Asami; Narukawa, Masataka; Sasakuma, Shiho; Yokogoshi, Hidehiko; Yazawa, Susumu; Tominaga, Makoto; Watanabe, Tatsuo [Life Sciences, 2006, vol. 79, # 24, p. 2303 - 2310]

31
[ 7149-10-2 ]
[ 112-64-1 ]
[ 69693-12-5 ]

Yield	Reaction Conditions	Operation in experiment
94.6%	Stage #1: vanillylamine hydrochloride With sodium hydrogencarbonate In water at 20℃; for 0.5h; Stage #2: tetradecanoyl chloride In chloroform; water at 20℃; for 0.5h;
62.48%	Stage #1: vanillylamine hydrochloride With sodium hydroxide In water; N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere; Cooling with ice; Stage #2: tetradecanoyl chloride In tetrahydrofuran; water; N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere; Cooling with ice;
	With pyridine

Reference： [1]Wang, Bo; Yang, Fan; Shan, Yi-Fan; Qiu, Wen-Wei; Tang, Jie [Tetrahedron, 2009, vol. 65, # 27, p. 5409 - 5412]
[2]Location in patent: experimental part Barbero, Gerardo F.; Molinillo, Jose M. G.; Varela, Rosa M.; Palma, Miguel; MacIas, Francisco A.; Barroso, Carmelo G. [Journal of Agricultural and Food Chemistry, 2010, vol. 58, # 6, p. 3342 - 3349]
[3]Morita, Akihito; Iwasaki, Yusaku; Kobata, Kenji; Iida, Tohko; Higashi, Tomohiro; Oda, Kyoko; Suzuki, Asami; Narukawa, Masataka; Sasakuma, Shiho; Yokogoshi, Hidehiko; Yazawa, Susumu; Tominaga, Makoto; Watanabe, Tatsuo [Life Sciences, 2006, vol. 79, # 24, p. 2303 - 2310]

32
[ 7149-10-2 ]
[ 112-76-5 ]
[ 58493-50-8 ]

Yield	Reaction Conditions	Operation in experiment
96%	Stage #1: vanillylamine hydrochloride With sodium hydrogencarbonate In water at 20℃; for 0.5h; Stage #2: Stearoyl chloride In chloroform; water at 20℃; for 0.5h;
	With pyridine

33
[ 7149-10-2 ]
(2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-(4-hydroxy-3-methoxybenzyl)prop-2-enamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23%	Stage #1: (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid With <i>N</i>-methyl-acetamide; oxalyl dichloride In tetrahydrofuran at 20℃; for 1h; Stage #2: vanillylamine hydrochloride With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; for 14h;	110 Example 110 (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-(4-hydroxy-3-methoxybenzyl)prop-2-enamide To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of 4-hydroxy-3-methoxybenzylamine hydrochloride (183 mg, 0.968 mmol), diisopropylethylamine (0.737 ml, 4.24 mmol) and THF (2 ml), and the mixture was stirred under ice-cooling for 2 hours and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the objective product as a solid material. Yield (amount) 94.0 mg, yield (rate) 23.0% 1H-NMR (CDCl3) δ: 1.95-2.32 (4H, m), 2.58 (3H, s), 2.73 (3H, s), 2.88-3.18 (2H, m), 3.86 (3H, s), 4.39 (2H, d, J = 5.4 Hz), 5.69 (1H, s), 6.04 (1H, t, J = 5.4 Hz), 6.49 (1H, d, J = 7.8 Hz), 6.65-7.33 (10H, m). IR (KBr) cm-1; 3274, 2215, 1661, 1622, 1590, 1516, 1451, 1429, 1325, 1273, 1206, 1155, 1125, 1036, 910, 733. [M+H]+ = 507

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1535922, 2005, A1 Location in patent: Page/Page column 60

34
[ 7149-10-2 ]
[ 1196-92-5 ]

Yield	Reaction Conditions	Operation in experiment
92.2%	With sodium hydroxide In water for 0.166667h;	1.3 3) Preparation of vanillin amine 1000ml three-necked flask, fitted with a stirrer, a thermometer, and thereto was added 350mL of water, 34.0g of vanilla hydrochloride, was slowly added dropwise with vigorous stirring 9mL sodium hydroxide solution (2mol / L), a heavy white precipitate appeared, stirring was continued for 10min, the suspension was suction filtered, the solid washed with 100mL, set 50 ~ 60 in a vacuum oven and dried under vacuum to give 25g of white solid amine vanillin, yield 92.2%,
	With sodium hydroxide In water at 40 - 42℃; for 0.333333h;	1 Example 1; Synthesis of N-vanillyl-4,7,10,13,16,19-Docosahexaenamide (Referred to as Dohevanil Herein Below) Dohevanil was synthesised by reacting vanillyl amine with 4,7,10,13,16,19-docosahexaenoic acid (C22:6, DHA) according to the procedure described below. 1.23 g Of vanillyl amine hydrochloride (ALDRICH) was dissolved in 5 ml of tepid water at 42 degrees Celsius, 10% sodium hydroxide (2.62 ml) in an equimolar amount was added and then the mixture was stirred at 40 degrees Celsius for 20 minutes.The deposited precipitate was filtered and washed three times with cold distilled water.The filtered precipitate was dried under reduced pressure at 110 degrees Celsius for three hours and further dried under vacuum at an ambient temperature for 30 minutes to obtain 0.801 g of the vanillyl amine. 0.230 g Of the vanillyl amine and 0.591 g of 4, 7, 10, 13, 16, 19-docosahexaenic acid (DOOSAN SERDARY RESEARCH LABORATORIES) were dissolved in 13.8 ml of chloroform.Then, 0.310 g of dicyclohexylcarbodiimide (DCC) (Tokyo Kasei Kogyo Co., Ltd), 0.037 g of dimethylaminopyridine (DMAP) (Tokyo Kasei Kogyo Co., Ltd), and a very small amount of butylhydoxytoluene were added.The mixture was stirred at an ambient temperature for 42 hours.After the reaction terminated, the reaction mixture was filtered to remove the precipitate and then the filtrate was condensed to about 0.5 ml by rotary evaporator.The condensed filtrate was fractionated by silicagel column chromatography (40 g of silicagel, developing solvent: hexane/ethyl acetate=6/4 (vol/vol)).The fraction of Dohevanil was collected, concentrated and dried to give a solid by rotary evaporator and then further dried under vacuum to give 0.311 g of colorless or citrine amorphous-like solid of Dohevanil. The obtained Dohevanil was analyzed by NMR. The result is as follows: 1H-NMR (200 MHz, CDCl3): δ=0.97 (3H, t, J=7.6 Hz, -C-CH3), 2.1 (2H, m, Me-CH2-C=C-), 2.25 (2H, m, -CH2-CH2-CH =CH-), 2.4 (2H, m, -CO-C2-CH=CH-), 2.83 (10H, m, -C=C -CH2-C=C-5), 3.88 (3H, S, -OCH3), 4.35 (2H, d, J=2.8 Hz, -NH-CH2-), 5.37 (12H, m, -CH=CH-6), 5.6 (1H, d, J=1 Hz, -OH), 6.82 (3H, m, aromatic proton).
	With triethylamine In tert-Amyl alcohol at 30℃; for 0.5h; Molecular sieve;

With sodium hydroxide In water

Reference： [1]Current Patent Assignee: ANHUI YIXINMING PHARMACEUTICAL TECH - CN105439889, 2016, A Location in patent: Paragraph 0033
[2]Current Patent Assignee: KUREHA CORP. - US2004/110844, 2004, A1 Location in patent: Page/Page column 4
[3]Location in patent: experimental part Castillo, Edmundo; Regla, Ignacio; Demare, Patricia; Luviano-Jardón, Axel; López-Munguía, Agustín [Synlett, 2008, # 18, p. 2869 - 2873]
[4]Location in patent: experimental part Liu, Hefang; Lepoittevin, Bénédicte; Roddier, Céline; Guerineau, Vincent; Bech, Loïc; Herry, Jean-Marie; Bellon-Fontaine, Marie-Noelle; Roger, Philippe [Polymer, 2011, vol. 52, # 9, p. 1908 - 1916]

35
[ 7149-10-2 ]
[ 108235-80-9 ]
CPS-116 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In diethyl ether at 0 - 20℃;	1 Synthesis of the carboxamides is usually achieved by reaction of the free amine with the appropriate acid chloride in the presence of a suitable acceptor for hydrogen chloride, which could be an excess of the free amine or another base, e.g. triethylamine. The reaction is carried out in a suitable organic solvent, but, depending on the reactivity of the acid chloride, may also be carried out in a mixed aqueous/organic solvent system, in which case a convenient base is sodium bicarbonate. The synthesis commences with the reaction of a carbonyl chloride with the appropriate arylalkylamine derivative. The acid chloride, or carbonyl chloride, may be obtained by many methods known to the art. As an example, 2-isopropyl-5-methylcyclohexane carbonyl chloride is prepared from L-menthol, via the following route: firstly, reaction with zinc chloride in hydrochloric acid to prepare 2-isopropyl-5-methylcyclohexyl chloride; next preparation of the Grignard reagent and carbonation to yield 2-isopropyl-5-methylcyclohexane carboxylic acid; and finally reaction with thionyl chloride to yield the carbonyl chloride. Many substituted arylalkylamines may be obtained from commercial sources such Sigma-Aldrich Corp., St. Louis, Mos. For example, 2-ethoxybenzylamine, 4-methoxybenzylamine, 4-methoxyphenylethylamine, and 3-methoxyphenylpropylamine are listed in the 2003-2004 Aldrich Catalog. The acid chloride is reacted with the appropriate arylalkylamine to form the N-arylSalkyl-cCarboxamide. Synthesis of 4-Hydroxy-3-methoxy-N-benzyl-(1R,2S,5R)-2-Isopropyl-5-methyl-cyclohexanecarboxamide (synonym:(1R,2S,5R)-2-Isopropyl-5-methyl-cyclohexanecarboxylic acid 4-hydroxy-3-methoxy-benzylamide). 1 mmol (0.19 g) of 4-hydoxy-3-methoxy-benzylamine HCl (Sigma Aldrich, Co.) was dissolved in 4.5 ml of ether in a 25 ml flask, and two equivalents (0.3 ml) of triethylamine was added and stirred, followed by 0.20 g (0.14 ml) of p-menthoyl chloride. The reaction vessel was first kept in ice for about 1 hr then stirred overnight at room temperature. The resulting product was extracted with 20 ml of ethylacetate and the organic layer washed 3× with 15 ml water. The aqueous layer was further extracted with ethylacetate, and the solvent dried with sodium sulfate, and the solids filtered out. The combined ethylacetate was evaporated and 0.326 g product was obtained. The purity of the product was ascertained by thin-layer chromatography (5:1, hexane:ethylacetate) and the structure confirmed by nuclear magnetic resonance. This compound was assigned the code of CPS-116.

Reference： [1]Current Patent Assignee: WEI (inventors); PAGET HUGH CHARLES EDWARD - US2005/187211, 2005, A1 Location in patent: Page/Page column 6

36
[ 108-24-7 ]
[ 7149-10-2 ]
[ 35103-38-9 ]

Yield	Reaction Conditions	Operation in experiment
75%	With pyridine at 20℃; for 6h;	1.1 1.1. Synthesis of 4-acetyloxy-3-methoxy--Y-acetyl-benzylamine; Acetic anhydride (1 ml, 10.5 mmol) was added to a solution of 4-hydroxy-3-methoxy-benzylamine hydrochloride (0.5 g, 2.63 mmol) in pyridine (5 ml) and the mixture was stirred at room temperature for 6 hours.The solvent was removed under reduced pressure and the residue was suspended in water (100 ml). The aqueous layer was extracted with ethyl EPO acetate (3 x 20 ml) and the combined organic phases were anhydrified (Na2SO4) and evaporated under reduced pressure to afford the title compound as white solid (0.45 g, yield 75%).1H-NMR(CDCl3) 5 2.01 (s, 3H, CH3), 2.31 (s, 3H, CH3), 3.81 (s, 3H, OCH3), 4.38 (d, 2H, J=6, CH2), 5.90 (bs, IH, NH), 6.90 (m, 3H3 aromatic).MS: m/z 238.1 (M+ C12H15NO4).
75%	With pyridine at 20℃; for 6h;	1.1.1 1.1. Synthesis of 4-acetoxy-3-methoxy-N-acetyl-benzylamine Acetic anhydride (1 ml, 10.5 mmol) was added to a solution of 4-hydroxy-3-methoxy-benzylamine hydrochloride (0.5 g, 2.63 mmol) in pyridine (5 ml) and the mixture was stirred at room temperature for 6 hours. The solvent was evaporated off under reduced pressure and the residue was suspended in water (100 ml). The aqueous layer was extracted with ethyl acetate (3 x 20 ml) and the combined organic phases were anhydrified (Na2SO4) and evaporated under reduced pressure to afford the title compound as white solid (0.45 g, yield 75%). 1H-NMR(CDCl3) δ 2.01 (s, 3H, CH3), 2.31 (s, 3H, CH3), 3.81 (s, 3H, OCH3), 4.38 (d, 2H, J=6, CH2), 5.90 (bs, 1H, NH), 6.90 (m, 3H, aromatic). MS: m/z 238.1 (M+ C12H15NO4).
75%	With pyridine at 20℃; for 6h;	1.1 Acetic anhydride (1 ml, 10.5 mmol) was added to a solution of 4-hydroxy-3-methoxy-benzylamine hydrochloride (0.5 g, 2.63 mmol) in pyridine (5 ml) and the mixture was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure and the residue was suspended in water (100 ml). The aqueous layer was extracted with ethyl acetate (3 x 20 ml) and the combined organic phases were anhydrified (Na2S04) and evaporated under reduced pressure to afford the title compound as white solid (0.45 g, yield 75%). ¹H-NMR (CDCl3) 8 2.01 (s, 3H, CH3), 2.31 (s, 3H, CH3), 3.81 (s, 3H, OCH3), 4.38 (d, 2H, J=6, CH2), 5.90 (bs, 1H, NH), 6.90 (m, 3H, aromatic). MS: m/z 238.1 (M+ C12H15NO4).

Reference： [1]Current Patent Assignee: PHARMESTE SRL - WO2006/45498, 2006, A1 Location in patent: Page/Page column 6-7
[2]Current Patent Assignee: SERENTRIX - EP1939173, 2008, A1 Location in patent: Page/Page column 5
[3]Current Patent Assignee: PHARMESTE S R 1; PHARMESTE SRL - WO2005/123666, 2005, A1 Location in patent: Page/Page column 4

37
[ 1208-65-7 ]
[ 7149-10-2 ]
para-tert.-butyl-trans-N-(4-hydroxy-3-methoxybenzyl)-cinnamic acid amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In dichloromethane; N,N-dimethyl-formamide at 5 - 20℃; for 16h;
	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; N,N-dimethyl-formamide	4.b b) b) Synthesis of para-tert.-butyl-trans-N-(4-hydroxy-3-methoxybenzyl)-cinnamic acid amide 400 mg (1.96 mmol) of para-tert.-butyl-trans-cinnamic acid were dissolved at 5° C. in DMF (10 ml) together with 290 mg (1.94 mmol) of 4-hydroxy-3-methoxybenzyl-amine hydrochloride and 0.48 ml (6.50 mmol) of triethylamine. After the addition of a solution of 870 mg (1.97 mmol) of BOP in DCM (9 ml), stirring was continued for 16 h at RT. The reaction solution was then poured into water and extracted twice with a mixture of DIPE/EA (1:1). The combined organic phases were washed with 2M eq. hydrochloric acid and three times with 1 M eq. of sodium hydrogen carbonate solution and dried over magnesium sulfate. Follwing removal of the solvents and recrystallisation from DIPE, 384 mg (1.13 mmol, 58% of theoretical) of para-tert.-butyl-trans-N-(4-hydroxy-3-methoxybenzyl)-cinnamic acid amide were obtained.

Reference： [1]Current Patent Assignee: Gruenenthal Pharma GmbH & Co. Kommanditgesellschaft - WO2006/18406, 2006, A1 Location in patent: Page/Page column description
[2]Current Patent Assignee: Gruenenthal Pharma GmbH & Co. Kommanditgesellschaft - US2007/208083, 2007, A1

38
9Z-octadecenyl chloride (oleoylchloride) [ No CAS ]
[ 7149-10-2 ]
[ 95548-23-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide In chloroform; N,N-dimethyl-formamide	I EXAMPLE I EXAMPLE I N-vanillyl-9Z-octadecenamide (N-vanillyloleamide) was synthesised by the following method: STR4 Specifically, 3.15 g of 4-hydroxy-3-methoxybenzylamine-HCl was suspended in 25 ml of N,N-dimethylformamide (DMF), and stirred. Added were 6.6 ml of a 5N solution of NaOH, and the mixture was stirred for an additional 10 to 15 minutes. The DMF mixture was chilled in an ice bath, and 5 g of 9Z-octadecenyl chloride (oleoylchloride), dissolved in chloroform, was added dropwise. The mixture was then stirred for 3 hours, allowing it to come to room temperature. The mixture was then poured into 300 ml water, layers separated, and the aqueous layer extracted with ethyl ether. The extracts were washed with HCl, sodium bicarbonate, water, and brine, and then dried and filtered. 7.63 g of crude N-vanillyl-9Z-octadecenamide was obtained. Purification by chromatography (silica gel with 40% ethyl acetate/hexane) and recrystallization from methanol and water gave 5.9 g of analytically pure product.

Reference： [1]Current Patent Assignee: PROCTER & GAMBLE CO - US4493848, 1985, A

39
[ 7149-10-2 ]
[ 57-13-6 ]
[ 51749-22-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	In toluene for 6h; Heating / reflux;	1 N-vanillyl urea was prepared by mixing 2g of vanillin amine hydrochloride and 2g of urea in 25ml of toluene and refluxing for 6 hours. A precipitate was formed in the solvent. The precipitate was isolated by filtration, grinded and subsequenty washed with ethyl acetate and, successively, with a small amount of water and then dried under vacuum at 50 0C. The product was analyzed with NMR and shown to be N-vanillyl urea with a purity >90%. The yield of the reaction was calculated to be 80%.

Reference： [1]Current Patent Assignee: GIVAUDAN SA - WO2007/13811, 2007, A2 Location in patent: Page/Page column 13

40
[ 7149-10-2 ]
[ 93605-62-0 ]
N-(3-methoxy-4-hydroxybenzyl)-N'-octylurea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With triethylamine In N,N-dimethyl-formamide at 50 - 60℃;	6.B Synthesis of N-octyl-N'-vanillyl urea (method B): A suspension of 4.5 g of vanillyl amine HCl in 30 ml DMF was heated to 50 0C. A solution of 6.5 g of N-octyl-lH-imidazole-l-carboxamide (6.5) in 15 ml of DMF was added at 50 0C. After 10 minutes a clear solution was obtained. 4 g of triethyl amine was added and stirring was continued at 60 0C overnight. The solvent was removed using a rotary evaporator. 40 ml of a 5 % solution of aqueous hydrochloric acid was added to the residue and the mixture was stirred for 10 minutes. The insoluble crystals were filtered and recrystallized from alcohol/water. The formed crystals were filtered, washed with water and dried in a vacuum oven at 50 0C for 2 hours. The dried cream crystals (3,9 g) were sampled for NMR and TLC analysis. Yield was 96 %. Purity was about 95 %.

Reference： [1]Current Patent Assignee: GIVAUDAN SA - WO2007/13811, 2007, A2 Location in patent: Page/Page column 14

41
[ 3158-26-7 ]
[ 7149-10-2 ]
N-(3-methoxy-4-hydroxybenzyl)-N'-octylurea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine In N,N-dimethyl-formamide at 20 - 35℃; for 7h;	5.A Synthesis of N-octyl-N'-vanillyl urea (method A): To a suspension containing 4.5 g vanillyl amine HCl and 3 g triethyl amine in 20 ml of DMF a solution of N-octyl isocyanate in 10 ml of DMF was added dropwise at a temperature of between 20 and 35 0C without external cooling. The mixture was stirred for 7hrs. The white precipitate (triethylamine HCl) was filtered and 40 ml of a 5 % aqueous solution of hydrochloric acid was added to the filtrate. The mixture was stirred for 10 minutes and the insoluble crystals were filtered, washed with water and recrystallized from methano I/water. The white crystals (4.1 g) were dried in a vacuum oven at 70 0C for 1 hour and sampled for NMR and TLC analysis. Yield was 100 %. Purity was about 95 %.

Reference： [1]Current Patent Assignee: GIVAUDAN SA - WO2007/13811, 2007, A2 Location in patent: Page/Page column 14

42
[ 39716-58-0 ]
[ 7149-10-2 ]
[ 1032831-36-9 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: vanillylamine hydrochloride With sodium hydroxide In water; N,N-dimethyl-formamide for 0.25h; Stage #2: pent-4-enoyl chloride In dichloromethane; water; N,N-dimethyl-formamide at 0 - 20℃; for 3h;	3 Example 3 - 4-AUylacetic acid vanillamide3.15 g of vanillamine HCl have been suspended in 25 ml of DMF and added with 6.6 ml of a 5N solution of NaOH, and the mixture stirred for 15 minutes. The DMF mixture has been chilled in an ice bath, and 2.4 g of undecylenoyl chloride dissolved in 5 ml of CH2Cl2 added dropwise. The mixture has been stirred for 3 hours, allowing it warm to room temperature. After, it has been poured into 300 ml water, the layers separated, and the aqueous layer extracted with CH2Cl2. The organic phase has been washed with diluted HCl, sodium bicarbonate, water, and brine, dried and filtered. The crude product in purified on silica gel ethyl acetate/hexane (40:60) and recrystallized from methanol and water affording the product of formula (III):1H-NMR δ: 7.59 (s, 2H, NH e OH), 6.70 (d, 1η, ArH), 6.62 (d, 1η, ArH), 6.60 (s, 1η, ArH), 5.82 (m, 1η, =CH), 5.02 (dd, 1η, (Z)H2C=), 4.93 (dd, 1η, (E)H2C=), 4.48 (s, 2η, NHCH2), 3.57 (s, 3η, OCH3), 2.16 (t, 2η, CH2CO), 2.04 (m, 2η, CH2CH=CH2); m.p. 48-50°C.

Reference： [1]Current Patent Assignee: GHISALBERTI, Carlo - WO2008/72072, 2008, A1 Location in patent: Page/Page column 8-9

43
[ 112-16-3 ]
[ 7149-10-2 ]
[ 69693-11-4 ]

Yield	Reaction Conditions	Operation in experiment
95.1%	Stage #1: vanillylamine hydrochloride With sodium hydrogencarbonate In water at 20℃; for 0.5h; Stage #2: n-dodecanoyl chloride In chloroform; water at 20℃; for 0.5h;
61.25%	Stage #1: vanillylamine hydrochloride With sodium hydroxide In water; N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere; Cooling with ice; Stage #2: n-dodecanoyl chloride In tetrahydrofuran; water; N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere; Cooling with ice;

44
[ 205651-88-3 ]
[ 7149-10-2 ]
[ 19408-84-5 ]

Yield	Reaction Conditions	Operation in experiment
94.5%	Stage #1: vanillylamine hydrochloride With sodium hydrogencarbonate In water at 20℃; for 0.5h; Stage #2: 8-methyl-nonanoyl chloride In chloroform; water at 20℃; for 0.5h;

Reference： [1]Wang, Bo; Yang, Fan; Shan, Yi-Fan; Qiu, Wen-Wei; Tang, Jie [Tetrahedron, 2009, vol. 65, # 27, p. 5409 - 5412]

45
[ 609-65-4 ]
[ 7149-10-2 ]
[ 1175539-67-9 ]

Yield	Reaction Conditions	Operation in experiment
95.7%	Stage #1: vanillylamine hydrochloride With sodium hydrogencarbonate In water at 20℃; for 0.5h; Stage #2: o-chlorobenzoyl chloride In chloroform; water at 20℃; for 0.5h;

Reference： [1]Wang, Bo; Yang, Fan; Shan, Yi-Fan; Qiu, Wen-Wei; Tang, Jie [Tetrahedron, 2009, vol. 65, # 27, p. 5409 - 5412]

46
[ 7149-10-2 ]
[ 98-88-4 ]
[ 105026-89-9 ]

Yield	Reaction Conditions	Operation in experiment
93.7%	Stage #1: vanillylamine hydrochloride With sodium hydrogencarbonate In water at 20℃; for 0.5h; Stage #2: benzoyl chloride In chloroform; water at 20℃; for 0.5h;
87%	Stage #1: vanillylamine hydrochloride With sodium hydrogencarbonate In chloroform; water at 20℃; for 0.75h; Stage #2: benzoyl chloride In chloroform; water at 40℃; for 0.5h;	2.1 Synthesis of N-(4-hydroxy-3-methoxybenzyl)benzamide (3) The synthesis of compound 3 was carried out by interfacial reaction between vanillylamine hydrochloride and acyl chloride in biphase H2O/CHCl3 system according to the synthetic procedure provided in [20]. The chemical structure and purity of the compound were confirmed by comparison with the previously reported data [20]. (0008) 0.150g (0.79×10-3 mol) 4-hydroxy-3-methoxybenzylamine hydrochloride were dissolved in 1.6ml water and 0.218g (2.6×10-3 mol) NaHCO3 were added to the solution. After stirring the mixture for 30min at 20°C, 2.26ml of chloroform were added. The mixture was stirred for another 15min and then 0.1ml CHCl3 solution of benzoylchloride (0.79×10-3 mol in 0.62ml CHCl3) was added dropwise. The mixture was stirred for 30min, heated to 40°C, and the organic layer was separated. The water layer was extracted by chloroform (3×0.6ml). The combined organic layers were washed with 2% HCl solution and dried with anhydrous NaSO4. The solvent was removed under vacuum and the crude product was recrystallized in absolute ethanol. (0009) Yield: 87%; mp 140-142°C; Rf=0.676 (C6H6:CH3OH=3:1); IR (ATR-FTIR): ν(cm-1) 3213 (νN-H), 3071 (ν(C-H)Ar), 2960, 2917, 2834 (ν(C-H)Alk), 1685 (νC=O), 1523 (δ(N-H)), 1282, 1272 (ν(C-O)), 1257 (ν(C-N)); 1H NMR (600MHz, CDCl3, δ): 7.76 (d, 2H, Ar), 7.50 (t, 1H, Ar), 7.40-7.44 (m, 2H, Ar), 6.90-6.82 (m, 3H, Ar), 6.30 (br s, 1H, OH), 5.60 (s, 1H, NH), 4.55 (d, 2H, CH2), 3.88 (s, 3H, OCH3); Analysis: Calc. for C15H15NO3: C, 70.02; H, 5.88; N, 5.44; O, 18.66; Found: C, 70.00; H, 5.85; N, 5.42.

Reference： [1]Wang, Bo; Yang, Fan; Shan, Yi-Fan; Qiu, Wen-Wei; Tang, Jie [Tetrahedron, 2009, vol. 65, # 27, p. 5409 - 5412]
[2]Anichina, K.; Nikolova, S.; Stamboliyska, B.; Stoyanov, S.; Velcheva, E.; Yancheva, D. [Chemical Physics, 2020, vol. 535]

47
[ 7149-10-2 ]
[ 142-61-0 ]
[ 58570-67-5 ]

Yield	Reaction Conditions	Operation in experiment
93.6%	Stage #1: vanillylamine hydrochloride With sodium hydrogencarbonate In water at 20℃; for 0.5h; Stage #2: Hexanoyl chloride In chloroform; water at 20℃; for 0.5h;
61.24%	Stage #1: vanillylamine hydrochloride With sodium hydroxide In water; N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere; Cooling with ice; Stage #2: Hexanoyl chloride In tetrahydrofuran; water; N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere; Cooling with ice;

48
[ 7149-10-2 ]
[ 141-75-3 ]
[ 89575-11-1 ]

Yield	Reaction Conditions	Operation in experiment
92.9%	Stage #1: vanillylamine hydrochloride With sodium hydrogencarbonate In water at 20℃; for 0.5h; Stage #2: butyryl chloride In chloroform; water at 20℃; for 0.5h;
60.79%	Stage #1: vanillylamine hydrochloride With sodium hydroxide In water; N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere; Cooling with ice; Stage #2: butyryl chloride In tetrahydrofuran; water; N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere; Cooling with ice;

49
[ 7149-10-2 ]
[ 111-64-8 ]
[ 58493-47-3 ]

Yield	Reaction Conditions	Operation in experiment
94.1%	Stage #1: vanillylamine hydrochloride With sodium hydrogencarbonate In water at 20℃; for 0.5h; Stage #2: n-octanoic acid chloride In chloroform; water at 20℃; for 0.5h;
57.6%	Stage #1: vanillylamine hydrochloride With sodium hydroxide In water; N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere; Cooling with ice; Stage #2: n-octanoic acid chloride In tetrahydrofuran; water; N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere; Cooling with ice;

50
[ 7149-10-2 ]
[ 112-67-4 ]
[ 69693-13-6 ]

Yield	Reaction Conditions	Operation in experiment
95.1%	Stage #1: vanillylamine hydrochloride With sodium hydrogencarbonate In water at 20℃; for 0.5h; Stage #2: n-hexadecanoyl chloride In chloroform; water at 20℃; for 0.5h;
60.36%	Stage #1: vanillylamine hydrochloride With sodium hydroxide In water; N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere; Cooling with ice; Stage #2: n-hexadecanoyl chloride In tetrahydrofuran; water; N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere; Cooling with ice;

51
[ 508210-91-1 ]
N,N-disuccinimidyl carbamate [ No CAS ]
[ 7149-10-2 ]
[ 508212-64-4 ]

Yield	Reaction Conditions	Operation in experiment
68.2%	Stage #1: methyl 5-amino-2-benzhydryloxybenzoate; N,N-disuccinimidyl carbamate With N-ethyl-N,N-diisopropylamine In acetonitrile at 0℃; for 1h; Stage #2: vanillylamine hydrochloride With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 12h;	38 Example 38; methyl 2-(benzhydryloxy)-5-([(4-hydroxy-3-methoxybenzyl)amino]carbonyl}amino)benzoate To a solution (5 ML) of methyl 5-amino-2-benzhydryloxybenzoate (200 mg, 0.600 mmole) and diisopropylethyl amine (0.123 ML, 0.720 mmole) in acetonitrile was added N,N-disuccinimidyl carbamate (184 mg, 0.720 mmole) at 0°C, and the mixture was stirred for 1 hour at 0°C. To this solution were added diisopropylethyl amine (0.247 ML, 1.44 mmole) and 4-hydroxy-3-methoxybenzyl amine hydrochloride (136 mg, 0.720 mmole), and the mixture was stirred for 12 hours at room temperature.. The solvent was distilled off under reduced pressure, and the residue was poured into water and was extracted with ethyl acetate.. The extracted solution was washed with water, was dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.. The residue was purified by silicagel column chromatography (hexane:ethyl acetate = 1:2), which was recrystallized from hexane and ethyl acetate, to obtain 187 mg (68.2%) of the titled compound as a solid. 1H-NMR (CDCl3) δ; 3.82 (3H, s), 3.86 (3H, s), 4.28 (2H, d, J = 5.4 Hz), 4.96 (1H, t, J = 5.4 Hz), 5.59 (1H, s), 6.22 (1H, s), 6.32 (1H, s), 6.70 to 7.51 (15H, m), 7.61 (1H, d, J = 3.0 Hz)

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1437344, 2004, A1 Location in patent: Page 28

52
[ 1150586-51-8 ]
[ 7149-10-2 ]
[ 1150586-74-5 ]

Yield	Reaction Conditions	Operation in experiment
87%	With N-cyclohexyl-N'-β-(4-methylmorpholinium)ethylcarbodiimide p-toluenesulfonate; benzotriazol-1-ol In dichloromethane at 0 - 20℃; Inert atmosphere;

Reference： [1]Brizzi, Antonella; Brizzi, Vittorio; Cascio, Maria Grazia; Corelli, Federico; Guida, Francesca; Ligresti, Alessia; Maione, Sabatino; Martinelli, Adriano; Pasquini, Serena; Tuccinardi, Tiziano; Di Marzo, Vincenzo [Journal of Medicinal Chemistry, 2009, vol. 52, # 8, p. 2506 - 2514]

53
[ 1216851-83-0 ]
[ 7149-10-2 ]
[ 1216851-79-4 ]

Yield	Reaction Conditions	Operation in experiment
84%	With triethylamine In 2-methyltetrahydrofuran	17 Example 17Synthesis of N-(4-hydroxy-3-methoxybenzyl)-4-methyl-1,2-dithiolane-4-carboxamide (Compound 16); 24.3 mmol of N-hydroxysuccinimide are added to 24.3 mmol of dithiolane acid dissolved in 60 ml of dichloromethane cooled to 0° C. (on an ice bath). The reaction medium is stirred for 30 minutes at 0° C. A solution of 24.3 mmol of DCC in 50 ml of dichloromethane is added and the mixture is then stirred at 20° C. for 4 hours. The reaction medium is filtered and washed, and the filtrate is then evaporated to dryness on a rotavapor at 40° C. under vacuum to give 1-[(4-methyl-1,2-dithiolan-4-yl)carbonyl]oxy}pyrrolidine-2,5-dione (m=7 g, quantitative yield). 10 mg of MeTHF, 3.16 mmol) of 4-(aminomethyl)-2-methoxyphenol hydrochloride and 3.16 mmol of triethylamine are added to 1.58 mmol of 1-[(4-methyl-1,2-dithiolan-4-yl)carbonyl]oxy}pyrrolidine-2,5-dione. After stirring overnight, the mixture is filtered, rinsed with MeTHF and then evaporated. Flash chromatography, eluting with 98/2 dichloromethane/methanol, gives compound 16 in the form of a yellow oil (84% yield).1H NMR (DMSO-d6): δ ppm 1.39 (s, 3H); 3.03 (d, 2H); 3.56 (d, 2H), 3.63 (s, 3H, OCH3), 4.21 (d, 2H), 6.64 (dd, 1H, Ar), 6.69 (d, 1H, Ar), 6.80 (d, 1H, Ar), 8.31 (t, 1H, NH), 8.79 (s, 1H, OH)ESI+: [(M, H)+]=300 m/z

Reference： [1]Current Patent Assignee: L'OREAL SA - US2010/197759, 2010, A1 Location in patent: Page/Page column 23

54
[ 764-85-2 ]
[ 7149-10-2 ]
[ 2444-46-4 ]

Yield	Reaction Conditions	Operation in experiment
91.5%	With sodium hydrogencarbonate; In dichloromethane; water; at 20 - 42℃; for 2.5h;	1) Preparation of crude product mixture: 105 g of vanillinamine hydrochloride was added to a mixture consisting of 200 g of sodium hydrogencarbonate, 500 mL of dichloromethane and 600 mL of water, and the mixture was stirred well and the mixture was further heated at room temperature (Methylene chloride: volume: 146.4 mL) was added dropwise over 1 hour. After completion of the dropwise addition, the temperature was raised to 42 C and maintained at that temperature for 1.5 hours. To obtain a crude product mixture (1420 mL);(2) Crystallization purification: The crude product mixture was cooled to room temperature, first using 200 mL of 25%Hydrochloric acid solution was shaken and allowed to stand for separation. The organic phase was separated (about 750 mL), and 150 mL of a 20%Of the sodium hydroxide solution was shaken and the organic phase was washed and allowed to stand for separation. The organic phase was separated again750 mL), washed with 200 mL of water, and partitioned. After washing with water, the organic phase (about 750 mL)150 mL of methylene chloride was distilled off to give a concentrated organic phase (ca. 600 mL), which was added to the concentrated organic phase1080mL petroleum ether after cooling crystallization, cooling rate of 0.25 / min, crystallization termination temperature of aboutAt -10 & lt; 0 & gt; C, maintaining the crystallization termination temperature for at least 30 min, filtering at the crystallization termination temperature,Dried to obtain solid synthetic capsaicin 148.6g, the yield was 91.5%, by high performance liquid chromatography(HPLC) to determine the purity of 99.5%.

Reference： [1]Patent: ,2016, .Location in patent: Paragraph 0040; 0041; 0042
[2]Journal of Agricultural and Food Chemistry,2010,vol. 58,p. 3342 - 3349

55
[ 7149-10-2 ]
[ 112-67-4 ]
N-palmitoyl-vanillamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With 4-methyl-morpholine; hydrogenchloride In <i>N</i>-methyl-acetamide; tert-butyl methyl ether; chloroform; water	1 Preparation of N-palmitoyl-vanillamide (Palvanil) Example 1 Preparation of N-palmitoyl-vanillamide (Palvanil) 4.475 g of 4-hydroxy-3-methoxybenzylamine hydrochloride and 0.556 g of 4-methylmorpholine are dissolved in 10 ml of dimethylformamide at 0° C. A solution of 0.605 g of palmitoyl chloride in 5 ml of chloroform is added dropwise slowly over 30 min with continuous stirring. The resulting mixture is stirred overnight at 0° C. and 25 ml of water are then added and this mixture is extracted 3 times with 10 ml of ethyl acetate. The organic phases are washed twice with 5 ml of 1N hydrochloric acid and twice with 4 ml of water; the organic phases are then combined, decolorized with animal charcoal, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue is crystallized from 7 ml of tert-butyl methyl ether; the product, separated out by filtration, is washed twice with 3 ml of cold tert-butyl methyl ether and is finally dried under high vacuum. The reaction yield is about 91%. The physicochemical properties of the product N-(4-hydroxy-3-methoxybenzyl)palmitoylamide are as follows: Physical state: white crystalline powder Empirical formula: C24H41NO3

Reference： [1]Current Patent Assignee: EPITECH GROUP SRL - US2012/115808, 2012, A1

56
[ 121-33-5 ]
[ 7149-10-2 ]

Yield	Reaction Conditions	Operation in experiment
53.4%	Stage #1: vanillin With pyridoxal 5'-phosphate; ω-transaminase from Bacillus megaterium; isopropylamine for 24h; Enzymatic reaction; Stage #2: With hydrogenchloride In diethyl ether
	Multi-step reaction with 2 steps 1: hydroxylamine hydrochloride; sodium acetate / ethanol / 6 h / 20 °C 2: hydrogenchloride; hydrogen / palladium 10% on activated carbon / ethanol; water / 760.05 Torr
	Multi-step reaction with 2 steps 1: hydroxylamine hydrochloride; sodium acetate / ethanol / 6 h / 20 °C 2: hydrogenchloride; hydrogen; palladium 10% on activated carbon / ethanol / 760.05 Torr

112 g	Stage #1: vanillin With ammonia In methanol at 20℃; for 3h; Stage #2: With methanol; sodium tetrahydroborate at 45℃; Stage #3: With hydrogenchloride In water at 0℃; for 3h;	2 Example 2 100 g of vanillin was added to 800 g of a methanol solution containing 20 wt% of ammonia in a reactor equipped with a heating, stirring, and a thermometer, and after stirring for 3 hours at room temperature, 270 g of sodium borohydride was added, and the temperature was raised to 45 after the reaction was detected by TLC. °C, 600 ml of methanol was distilled off under reduced pressure. After the reaction solution was cooled to room temperature, it was poured into 300 ml of distilled water at a temperature of 10° C., 800 ml of ethyl acetate was added, and the mixture was stirred uniformly and placed in a separatory funnel to obtain an organic phase. The ethyl acetate layer was successively washed with 5 wt% sodium bicarbonate solution and saturated brine three times with an amount of 800 ml/time, and then 100 g of anhydrous sodium sulfate was added to the ethyl acetate layer of the organic phase and dried for 3 hours to remove sodium sulfate by filtration. The filtrate was placed in a reactor, and the temperature was lowered to 0° C. with an ice-water bath while stirring. 120 g of dry hydrogen chloride gas was introduced and the temperature was maintained for 3 hours while stirring. The resulting solid was washed with 200 ml of ethyl acetate and then dried at 40-. Drying at 45°C for 10 hours yielded 112 g of the intermediate vanillin amine hydrochloride.
	Multi-step reaction with 2 steps 1: hydroxylamine hydrochloride; sodium acetate trihydrate / water / 2 h / 80 °C 2: palladium 10% on activated carbon; hydrogenchloride; hydrogen / ethanol / 24 h / 20 °C / 760.05 Torr

Reference： [1]Yu, Jinhai; Zong, Weilu; Ding, Yingying; Liu, Junzhong; Chen, Lina; Zhang, Hongjuan; Jiao, Qingcai [Advanced Synthesis and Catalysis, 2022, vol. 364, # 2, p. 380 - 390]
[2]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - EP2511283, 2012, A1
[3]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - US2013/45942, 2013, A1
[4]Current Patent Assignee: SHANGHAI HUAYI (GROUP) COMPANY - CN103288665, 2017, B Location in patent: Paragraph 0029; 0030; 0032; 0033
[5]Schiano Moriello, Aniello; López Chinarro, Silvia; Novo Fernández, Olalla; Eras, Jordi; Amodeo, Pietro; Canela-Garayoa, Ramon; Vitale, Rosa Maria; Di Marzo, Vincenzo; De Petrocellis, Luciano [Journal of Medicinal Chemistry, 2018, vol. 61, # 18, p. 8255 - 8281]

57
[ 7149-10-2 ]
[ 2004-06-0 ]
[ 722505-89-7 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In propan-1-ol at 70℃; for 8h;	23 First step, hydroxyamine hydrochloride (2.52 g) and NaOAc (3.26 g) were added to a solution of 3-methoxy-4-hydroxybenzaldehyde (3.04 g) in EtOH (80 ml). The reaction mixture was stirred at room temperature for 6h. EtOH was removed under reduced pressure. H2O (40 ml) was added to the residue, and extracted with EtOAc (3 × 40 ml). The EtOAc of the combined organic layer was removed by rotary evaporation under reduced pressure to yield 3-methoxy-4-dihydroxybenzaldehyde oxime (2.99 g) as a pale yellowish solid. Second step, 3-methoxy-4-dihydroxybenzaldehyde oxime (2.99 g) and concentrated HCl (8 ml) in EtOH (70 ml) was subjected to hydrogenation at atmospheric pressure in the presence of 10% Pd/C (700 mg). The reaction solution was filtered and the filtrate was concentrated. Then EtOAc was added to the residue and the suspension was filtered to yield 3-methoxy-4-hydroxybenzylamine hydrochloride (3.31 g) as a white solid. Third step, a mixture of 3-methoxy-4-dihydroxybenzylamine (3.31 g, the hydrochloride), 6-chloropurine riboside (1 g) and N, N-diisopropylethyl amine (14 ml) in PrOH (70 ml) was heated to 70°C and reacted for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (15 : 1) to yield N6-(3-methoxy-4-hydroxybenzyl)-adenosine(1.02 g) as a colorless solid: positive ESIMS m/z 404[M + H]+; negative ESIMS m/z 402 [M - H]- and 438[M + Cl]-; 1H NMR (300 MHz, DMSO): the adenosine moiety δ 8.35 (1H, s, H-2), 8.29 (1H, brs, -NH), 8.20 (1H, brs, H-8), 5.87 (1H, d, J= 6.3 Hz, H-1), 5.37-5.44 (2H, m, -OH x 2), 5.18 (1H, J = 4.5 Hz, -OH), 4.60 (1H, m, H-2'), 4.11 (1H, m, H-3'), 3.95 (1H, m, H-4'), 3.66 (1H, m, H-5'a), 3.54 (1H, m, 5'b); the 3-methoxy-4-hydroxybenzyl moiety δ 8.77 (1H, s, -OH), 6.96 (1H, d, J= 1.5 Hz, H-2"), 6.72 (1H, dd, J= 8.1, 1.5 Hz, H-6"), 6.66 (1H, d, J = 8.1 Hz, H-5"), 4.60 (2H, m, H-7"), 3.71 (3H, s, -OCH3); 13C NMR (125 MHz, DMSO-d6): the adenosine moiety δ 154.4 (C-6), 152.3 (C-2), 147.3 (C-4), 139.8 (C-8), 119.8 (C-5), 87.9 (C-1), 85.9 (C-4'), 73.4 (C-2'), 70.6 (C-3'), 61.6 (C-5'); the 3-methoxy-4-hydroxybenzyl moiety δ 147.3 (C-4"), 145.3 (C-3"), 130.7 (C-1), 115.3 (C-2"), 119.8 (C-6"), 112.0 (C-5"), 55.5 (-OCH3), 42.7 (C-7")o
1.02 g	With 3-methyl-N-(3-methylbutyl)-1-butanamine In propan-1-ol at 70℃; for 8h;	23 Preparation of N6-(3-methoxy-4-hydroxybenzyl)-adenosine Third step, a mixture of 3-methoxy-4-dihydroxybenzylamine (3.31 g, the hydrochloride), 6-chloropurine riboside (1 g) and N,N-diisopropylethyl amine (14 ml) in PrOH (70 ml) was heated to 70° C. and reacted for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (15:1) to yield N6-(3-methoxy-4-hydroxybenzyl)-adenosine (1.02 g) as a colorless solid: positive ESIMS m/z 404[M+H]+; negative ESIMS m/z 402 [M-H]- and 438[M+Cl]-; 1H NMR (300 MHz, DMSO): the adenosine moiety δ 8.35 (1H, s, H-2), 8.29 (1H, brs, -NH), 8.20 (1H, brs, H-8), 5.87 (1H, d, J=6.3 Hz, H-1'), 5.37-5.44 (2H, m, -OH*2), 5.18 (1H, J=4.5 Hz, -OH), 4.60 (1H, m, H-2'), 4.11 (1H, m, H-3'), 3.95 (1H, m, H-4'), 3.66 (1H, m, H-5'a), 3.54 (1H, m, 5'b); the 3-methoxy-4-hydroxybenzyl moiety δ 8.77 (1H, s, -OH), 6.96 (1H, d, J=1.5 Hz, H-2"), 6.72 (1H, dd, J=8.1, 1.5 Hz, H-6"), 6.66 (1H, d, J=8.1 Hz, H-5"), 4.60 (2H, m, H-7"), 3.71 (3H, s, -OCH3); 13C NMR (125 MHz, DMSO-d6): the adenosine moiety δ 154.4 (C-6), 152.3 (C-2), 147.3 (C-4), 139.8 (C-8), 119.8 (C-5), 87.9 (C-1'), 85.9 (C-4'), 73.4 (C-2'), 70.6 (C-3'), 61.6 (C-5'); the 3-methoxy-4-hydroxybenzyl moiety δ 147.3 (C-4"), 145.3 (C-3"), 130.7 (C-1"), 115.3 (C-2"), 119.8 (C-6"), 112.0 (C-5"), 55.5 (-OCH3), 42.7 (C-7").
1.02 g	With N-ethyl-N,N-diisopropylamine In propan-1-ol at 70℃; for 8h;	23.3 Third step 3.31 g of 3-methoxy-4-hydroxyphenylmethylamine hydrochloride was taken,6-Chloropurine nucleoside (1 g), dissolved in propanol (70 mL)And N,N-diisopropylethylamine base (14 mL) were added, heating at 70 °C, reacting for 8 hours, recovering the solvent with the reaction solution, washing out with chloroform-methanol (15: 1) separated by silica gel column chromatography,1.02 g of colorless crystalline N6-(3-methoxy-4-hydroxybenzyl)adenosine is obtained

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - EP2511283, 2012, A1 Location in patent: Page/Page column 49-50
[2]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - US2013/45942, 2013, A1 Location in patent: Paragraph 0160; 0163
[3]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - JP2015/172077, 2015, A Location in patent: Paragraph 0115

58
3',5'-diacetyl-2'-deoxy-6-bromo-adenosine [ No CAS ]
[ 7149-10-2 ]
N<SUP>6</SUP>-(3-methoxy-4-hydroxybenzyl)-2'-deoxy-3',5'-diacetyl adenosine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In ethanol for 5h; Reflux;	148 First step, a mixture of 2-deoxy-adenosine(3.6 g), acetic anhydride (5.47 g), trimethyl (4.07 g) and DMAP (0.16 g) in anhydrous acetonitrile (40 ml) was refluxed for 8 h. Acetonitrile was removed under reduced pressure. H2O (40 ml) was added to the residue, and the resulting solution was extracted with EtOAc (3 × 40 ml). The EtOAc of the combined organic layer was dried with sodium acetate and The EtOAc layer was filtered and the filtrate was concentrated. The residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (100 : 1) to yield 3',5'-diacetyl-2'-deoxy-adenosine (4.0 g). Second step, a mixture of 3', 5'- diacetyl-2'-deoxy-adenosine(1.2 g), tert-butyl nitrite (7.42 g), and tribromomethane (20 ml) was refluxed for 2 h. The excess tert-butyl nitrite was removed under reduced pressure. The residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (80 : 1) to yield 3',5'-diacetyl-2'-deoxy-6-bromo-adenosine (595 mg). Third step, a mixture of 3', 5'- diacetyl-2'-deoxy-6-bromo-adenosine (398 mg), 3-methoxy-4-hydroxybenzylamine (379.3 mg, the hydrochloride) and triethylamine (253 mg) in anhydrous EtOH (20 ml) was refluxed for 5 h. After evaporation, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (50 : 1) to yield N6-(3-methoxy-4-hydroxy-benzyl)-2-deoxy-3, 5'-diacetyl adenosine (340 mg): 1H NMR (300 MHz, acetone-d6):the 2-deoxy- adenosine moiety δ 8.29 (1H, s, H-8), 8.16 (1H, s, H-2), 7.33 (1H, t, J= 6.0 Hz, NH), 6.44 (1H, dd, J= 7.8, 6.3 Hz, H-1), 5.48 (1H, m, H-3'), 4.36 (1H, dd, J= 6.3, 12.9 Hz, H-5'a), 4.30 (1H, dd, J= 6.0, 12.9 Hz, H-5'b), 4.29 (1H, m, H-4'), 3.21 (1H, ddd, J= 7.5, 7.8, 15.0 Hz, H-2'a), 2.59 (1H, ddd, J = 2.4, 6.0, 15.0, H-2'b); the 3-methoxy-4-hydroxybenzyl moiety δ 7.63 (1H, brs, OH), 7.05 (1H, d, J= 1.5 Hz, H-2"), 6.87 (1H, dd, J= 7.8, 1.5 Hz, H-6"), 6.74 (1H, d, J= 7.8 Hz, H-5"), 4.76 (2H, brs, H-7"), 3.75 (3H, s, OMe); the acetyl δ2.09 (3H, s, CH3CO), 2.01 (3H, s, CH3CO); 13C NMR (300 MHz, acetone-d6):the 2-deoxy- adenosine moiety δ 155.9 (C-6), 153.6 (C-2), 149.1 (C-4), 139.9 (C-8), 121.2 (C-5), 85.2 (C-1), 83.1 (C-4'), 75.6 (C-3'), 64.5 (C-5'), 37.0 (C-2'); the 3-methoxy-4-hydroxy moiety δ 148.2 (C-3"), 146.5 (C-4"), 132.0 (C-1), 121.2 (C-2"), 115.6 (C-6"), 112.3 (C-5"), 56.1 (OMe), 44.2 (C-7"); the acetyl δ170.8, 170.7, 20.9, 20.6ο

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - EP2511283, 2012, A1 Location in patent: Page/Page column 116

59
[ 7149-10-2 ]
[ 385806-26-8 ]
N<SUP>6</SUP>-(3-methoxy-4-hydroxybenzyl)-2'-deoxy-3',5'-diacetyl adenosine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
340 mg	With triethylamine In ethanol for 5h; Reflux;	148 Preparation of N6-(3-methoxy-4-hydroxy-benzyl)-2'-deoxy-3',5'-diacetyl adenosine Third step, a mixture of 3',5'-diacetyl-2'-deoxy-6-bromo-adenosine (398 mg), 3-methoxy-4-hydroxybenzylamine (379.3 mg, the hydrochloride) and triethylamine (253 mg) in anhydrous EtOH (20 ml) was refluxed for 5 h. After evaporation, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (50:1) to yield N6-(3-methoxy-4-hydroxy-benzyl)-2'-deoxy-3',5'-diacetyl adenosine (340 mg): 1H NMR (300 MHz, acetone-d6): the 2'-deoxy-adenosine moiety δ 8.29 (1H, s, H-8), 8.16 (1H, s, H-2), 7.33 (1H, t, J=6.0 Hz, NH), 6.44 (1H, dd, J=7.8, 6.3 Hz, H-1'), 5.48 (1H, m, H-3'), 4.36 (1H, dd, J=6.3, 12.9 Hz, H-5'a), 4.30 (1H, dd, J=6.0, 12.9 Hz, H-5'b), 4.29 (1H, m, H-4'), 3.21 (1H, ddd, J=7.5, 7.8, 15.0 Hz, H-2'a), 2.59 (1H, ddd, J=2.4, 6.0, 15.0, H-2'b); the 3-methoxy-4-hydroxybenzyl moiety δ 7.63 (1H, brs, OH), 7.05 (1H, d, J=1.5 Hz, H-2"), 6.87 (1H, dd, J=7.8, 1.5 Hz, H-6"), 6.74 (1H, d, J=7.8 Hz, H-5"), 4.76 (2H, brs, H-7"), 3.75 (3H, s, OMe); the acetyl 62.09 (3H, s, CH3CO), 2.01 (3H, s, CH3CO); 13C NMR (300 MHz, acetone-d6): the 2'-deoxy-adenosine moiety δ 155.9 (C-6), 153.6 (C-2), 149.1 (C-4), 139.9 (C-8), 121.2 (C-5), 85.2 (C-1'), 83.1 (C-4'), 75.6 (C-3'), 64.5 (C-5'), 37.0 (C-2'); the 3-methoxy-4-hydroxy moiety δ 148.2 (C-3"), 146.5 (C-4"), 132.0 (C-1"), 121.2 (C-2"), 115.6 (C-6"), 112.3 (C-5"), 56.1 (OMe), 44.2 (C-7"); the acetyl 6170.8, 170.7, 20.9, 20.60
340 mg	With triethylamine In ethanol for 5h; Reflux;	148.3 Third step 3',5'-diacetyl-2'-deoxy-6-bromoadenosine (398.0 mg), Vanillamine amine monohydrochloride (379.3 mg) and triethylamine (253.0 mg)Was precisely weighed, dissolved in absolute ethanol (20 mL), heated to reflux,React for 5 hours, recover the solvent with the reaction solution, and obtain crude product.It was separated by silica gel column chromatography, Wash off with chloroform-methanol (50: 1) N6-(3-methoxy-4-hydroxybenzyl)-2'-deoxy-3',5'- acetyladenosine (340 mg)

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - US2013/45942, 2013, A1 Location in patent: Paragraph 0492; 0495
[2]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - JP2015/172077, 2015, A Location in patent: Paragraph 0240

60
[ 7149-10-2 ]
[ 501-53-1 ]
[ 289903-29-3 ]

Yield	Reaction Conditions	Operation in experiment
78%	With sodium hydrogencarbonate In dichloromethane; water at 20℃; for 1h; Cooling with ice;	1 4-Hydroxy-3-methoxybenzylamine hydrochloride (27-1) (316 mg, 1.67 mmol) was dissolved in a mixed solvent of dichloromethane (CH2Cl2, 4 ml) and water (H2O, 4 ml) at room temperature, and the mixture was cooled in an ice bath. Sodium hydrogen carbonate (741 mg, 8.35 mmol) and carbobenzoxy chloride (Cbz-Cl, 0.715 ml, 5.01 mmol) were added. After stirring for 10 minutes, the ice bath was removed and the mixture was warmed to room temperature, and stirred for 1 hour. After 2 times of extraction with dichloromethane (5 ml), the combined organic layer was washed with 15% brine (30 ml). The combined organic layer was dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient; ethyl acetate:n-hexane=4:21→7:28) to give compound 27-2 (375 mg, 1.31 mmol, yield 78%) as a colorless solid.1H-NMR (400 MHz, CDCl3) δ: 3.86 (s, 3H), 4.30 (d, 2H, J=5.8 Hz), 5.00 (s, 0.7H), 5.14 (s, 2H), 5.57 (s, 0.9H), 6.76-6.78 (m, 2H), 6.86 (d, 1H, J=8.0 Hz), 7.31-7.38 (m, 5H). ESIMS (m/z): 288.0 ([M+H]+), 310.0 ([M+Na]+), 326.0 ([M+K]+)

Reference： [1]Current Patent Assignee: PEPPER REVOLUTION LLC - US2013/288992, 2013, A1 Location in patent: Paragraph 0323; 0324

61
C₁₆H₂₇NO₄ [ No CAS ]
[ 7149-10-2 ]
(S,E)-3,7-dimethylocta-2,6-dien-1-yl (1-((4-hydroxy-3-methoxybenzyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; Inert atmosphere;	B.1 B) Condensation reactions 1. Amide formation The -acylated amino acid (1 eq), -Hydroxybenzoiiiazole (HOBt) (1.05 eq) and. HMBA hydrochloride (1.05 eq) were placed in a round bottom flask equipped with a stilling bar and fitted with a rabber septum. Dry CH2C12 (4inL/mrfiol) and NEt3 (1.05 eq) were added under positive N2 pressure via a syringe through the rabber septum. The flask was immersed in an ice bath, and the reaction mixture was stored. After sufficient chilling, - Ethyl-3-(3-dimetliylaininopiOpyl)carbodiiinide (EDC) (1.05 eq) was added in one portion, and the reaction mixture was allowed to stir to room temperature overnight. TLC (96:4, CHiCfe/MeOH, v/v) revealed completion of reaction. The reaction mixture was diluted with CEC2C12 and washed with IN HCI, 0 and saturated NaCl. The organic phase was dried over MgS04 (anhydrous), filtered and concentrated on the rotary evaporator. The residue was dried under high vacuum, and the crude product was purified by column chromatography on silica gel eluting with 9:1, CH2Cl2/acetone, v/v. NDH 4486: Mp = 135-136°C; Rf = 0.54 (9: 1 , CH2Cl2/acetone); Yield (ESI) calculated for C24H37N2O5 [M+H] 433.2697, found 433.2676.

Reference： [1]Current Patent Assignee: LEHIGH UNIVERSITY - WO2014/144073, 2014, A2 Location in patent: Page/Page column 30

62
C₁₅H₃₁NO₄Si [ No CAS ]
[ 7149-10-2 ]
C₂₃H₃₉NO₆Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; Cooling with ice;	A Step 2, the N-substituted valine derivative (229.6 nig, 0.723 mmol), HOBt (103 m , 1.05 x 0.723 mmol), 4-hydroxy-3-methoxybenzylamine hydrochloride, also known as vamllylamine hydrochloride, (144 mg, 1.05 x 0.723 mmol) and E (77 mg, 106 μΤ,, 1.05 x 0.723 mmol) were dissolved in CH2CI2 (7 mL). The solution was stirred and chilled in an ice bath. To the cold mixture was added EDC (153 mg, 1.1 x 0.723 mmol). The mixture was allowed to stir to room temperature overnight. The mixture was diluted with CH2CI2 and extracted with water, IN HCL saturated NaHCf = 0.40, to give a 70% yield. Although Scheme III, Step 2 shows the incorporation of vaniDylainine, any iiucleophilic anti-inflannnatory could be used (e.g. , a phenolic-protected vanillyl alcohol).

Reference： [1]Current Patent Assignee: LEHIGH UNIVERSITY - WO2014/144073, 2014, A2 Location in patent: Page/Page column 40-41

63
C₁₀H₁₇ClO [ No CAS ]
[ 7149-10-2 ]
[ 7553-53-9 ]

Yield	Reaction Conditions	Operation in experiment
3.1g	Stage #1: vanillylamine hydrochloride With sodium hydroxide In water; N,N-dimethyl-formamide at 20 - 35℃; Inert atmosphere; Stage #2: C₁₀H₁₇ClO In diethyl ether; water; N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere;	4 Step-4: Synthesis of Compound 7: Step-4: Synthesis of Compound 7: 4-Hydroxy-3-methoxy benzylamine HCl salt 6 (3.35 g) and dimethylformamide (10 ml) were added to a 100 ml 3-necked RB flask equipped with an additional funnel, a thermometer and a magnetic stirrer under nitrogen. 5N NaOH (7 ml) was added portion-wise at room temperature. The mixture was stirred at 35° C. for 30 minutes. The mixture was then cooled to about 0° C. to about 5° C. Acid chloride 5 in anhydrous ether (30 ml) was added dropwise at about 0° C. to about 5° C. or 10° C. for about 20 minutes. An additional 5 ml of anhydrous dimethylformamide was added. The mixture was gradually warmed to room temperature and stirred under nitrogen overnight. Water (150 ml) was added. The mixture was extracted with ethyl acetate (1100 ml and 150 ml). The ethyl acetate extract was washed with IN HCl (260 ml) followed by saturated NaHCO3 (2100 ml) and brine. The extract was then dried over anhydrous Na2SO4 and filtered. Solvents were removed under vacuum at about 35° C. to about 40° C. to give a thick light orange/pink residue (wt.=3.4 g). The crude product was purified by column chromatography using from about 150 to about 160 g of silica gel eluted with a 1:1 mixture of ethyl acetate/hexane. Collections from the column purification were combined, concentrated under vacuum at about 40° C. and dried under vacuum to produce 3.1 g of the desired product as a white solid compound 7.

Reference： [1]Current Patent Assignee: CELLIXBIO PRIVATE LTD - US2015/119423, 2015, A1 Location in patent: Paragraph 0115-0117

64
[ 7149-10-2 ]
[ 426463-05-0 ]
4-(((5-iodo-3-nitropyridin-2-yl)amino)methyl)-2-methoxyphenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 100℃; for 1.0h;	Example 3-57-1 Preparation of 4-(((5-iodo-3-nitropyridin-2-yl)amino)methyl)-2-methoxyphenol To a stirred suspension of 4-hydroxy-3-methoxybenzylamine hydrochloride (1.32 g, 6.82 mmol) and <strong>[426463-05-0]2-chloro-5-iodo-3-nitropyridine</strong> (2.00 g, 6.82 mmol) in acetonitrile (20 mL) was added N,N-disopropylethylamine (5.96 ml, 34.10 mmol) The suspension was stirred and heated to 100 C. After 1 h, the mixture was allowed to cool to room temperature, and 2N aqueous potassium hydroxide solution (0.68 mL) was added. The mixture was concentrated to provide 4-(((5-iodo-3-nitropyridin-2-yl)amino)methyl)-2-methoxyphenol as an impure solid.

Reference： [1]Patent: US2015/158847,2015,A1 .Location in patent: Paragraph 0526

65
[ 108-30-5 ]
[ 7149-10-2 ]
4-[(4-hydroxy-3-methoxybenzyl)amino]-4-oxobutanoicacid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: vanillylamine hydrochloride With triethylamine In tetrahydrofuran at 20℃; for 0.5h; Stage #2: succinic acid anhydride In tetrahydrofuran at 20℃;	1 Example 1Preparation of capsaicin - like common hapten Vanillinamine hydrochloride (0.28 g) was dissolved in 6 ml of tetrahydrofuran,0.15 g of triethylamine was added dropwise with stirring,Stir at room temperature for 30 min.0.15 g (0.0015 mol) of succinic anhydride was accurately weighed into the above reaction solution,Stir overnight at room temperature.To the reaction solution was added 3 mL of ethyl acetate, and the mixture was stirred at room temperature for 2 minutes.The resulting precipitate after filtration was a mixture of 4 - [(4-hydroxy-3-methoxy)(4 - [(4-hydroxy-3-methoxybenzyl) amino] -4-oxobutanoic acid)Molecular formula C12H15NO5.

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF AGRICULTURAL SCIENCES - CN105541655, 2016, A Location in patent: Paragraph 0028; 0029; 0030

66
[ 186534-01-0 ]
[ 7149-10-2 ]
N-(4-hydroxy-3-methoxybenzyl)-3,5,6-trimethylpyrazine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82.6%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 12h;
82.6%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 12h;	9 Example 9 N-(4-hydroxy-3-methoxybenzyl)-3,5,6-trimethylpyrazine-2-carboxamide(3c).378 mg (2.0 mmol) of vanillinamine hydrochloride was added to the round bottom bottle.332mg (2.0mmol) TMP acid,458 mg (2.4 mmol) of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride,324 mg (2.4 mmol) of 1-hydroxybenzotriazole,308 mg (2.4 mmol) of N,N-diisopropylethylamine;Add 20mL of N,N-dimethylformamide,The reaction was stirred at room temperature for 12 h.TLC [V (petroleum ether): V (acetone) = 2:1] The reaction was found to be substantially complete, the reaction was stopped and filtered. The filtrate is added in 5 times the amountThe mixture was diluted with EtOAc (3 mL).The residue was separated into a white solid (yield: 499.24mg).M.P.: 151.3-152.1 ° C,The yield was 82.6%.

Reference： [1]Zhang, Chenze; Yan, Wenqiang; Zhao, Rui; Xu, Bing; Fang, Xiong; Yan, Mengmeng; Zhang, Yuzhong; Wang, Penglong; Lei, Haimin [MedChemComm, 2017, vol. 8, # 3, p. 652 - 656]
[2]Current Patent Assignee: Lei Pengcheng; Zhang Chenze; Wang Penglong - CN108456178, 2018, A Location in patent: Paragraph 0086-0088

67
[ 112-05-0 ]
[ 7149-10-2 ]
[ 2444-46-4 ]

Yield	Reaction Conditions	Operation in experiment
81.1%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃;	Into a reactor equipped with a heating, stirring, and a thermometer, 112 g of vanillin amine hydrochloride obtained above was added to 670 ml of a DMF solvent, and the mixture was stirred at room temperature until the solid was completely dissolved and 95.2 g Nonanoic acid was added thereto.The was cooled to 0C with an ice bath, 134.4g of triethylamine was added, the temperature was stabilized at 0-5C, and 235.2g of a condensing agent HBTU was added under stirring. The reaction was naturally warmed to room temperature and stirred overnight. After the reaction was completely detected by TLC, Add 1100 ml of ethyl acetate and 330 ml of water to the reaction mixture. Stir well and place in liquid in a separatory funnel. Discard the aqueous layer and obtain ethyl acetate layers of 5 wt% sodium bicarbonate solution, 2 wt% hydrochloric acid, respectively. The saturated brine was washed three times each, 1200 ml/time, and then 100 g of anhydrous sodium sulfate was added to the ethyl acetate layer for drying for 3 hours. The sodium sulfate was removed by filtration, and the filtrate was placed in a reactor and heated to 45 C. with stirring and reduced. About 820 ml of ethyl acetate was distilled off and cooled to room temperature. 540 ml of petroleum ether was added to crystallize for 3 hours and filtered. The solid was dried at 40-45 C. for 10 hours to obtain 156.4 g of Nonivamide as the target product. The total yield was 81.1%. The obtained capsaicin was analyzed by HPLC and its purity was 98.8%.

Reference： [1]Patent: CN103288665,2017,B .Location in patent: Paragraph 0029; 0031; 0032; 0034

68
[ 134283-49-1 ]
[ 7149-10-2 ]

Yield	Reaction Conditions	Operation in experiment
74%	With hydrogenchloride; palladium 10% on activated carbon; hydrogen In ethanol at 20℃; for 24h;

Reference： [1]Schiano Moriello, Aniello; López Chinarro, Silvia; Novo Fernández, Olalla; Eras, Jordi; Amodeo, Pietro; Canela-Garayoa, Ramon; Vitale, Rosa Maria; Di Marzo, Vincenzo; De Petrocellis, Luciano [Journal of Medicinal Chemistry, 2018, vol. 61, # 18, p. 8255 - 8281]

69
[ 10389-65-8 ]
[ 7149-10-2 ]
di-[(2R)-N-Boc-amino-1-((4'-hydroxy-3'-methoxybenzyl)amino)-1-oxoprop-3-yl]disulfane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: di-t-butoxycarbonyl-L-cystine; vanillylamine hydrochloride With benzotriazol-1-ol; triethylamine In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; for 20h;

70
[ 59320-77-3 ]
[ 7149-10-2 ]
[ 404-86-4 ]

Yield	Reaction Conditions	Operation in experiment
75%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In N,N-dimethyl-formamide at 20℃; for 2h; Schlenk technique;	5.4 4.5.4 Capsaicin (1) A 100 mL round-bottom flask equipped with Schlenk adapter and stirring bar was charged with 750 mg (4.41 mmol, 1.0 eq.) 13 and 20 mL dry DMF were added. After cooling the reaction mixture to 0 °C, 1.83 mL (13.22 mmol, 3.0 eq.) Et3N, 1.7 g (5.29 mmol, 1.2 eq.) TBTU and 1.0 g (5.29 mmol, 1.2 eq.) vanillylamine hydrochloride were added successively. The yellowish suspension was stirred at RT for 2 h. The reaction mixture was quenched by the addition of 100 mL brine. A colorless precipitate formed which dissolved in water by the addition of water. The reaction solution was extracted with EtOAc (3 * 70 mL) and the combined organic layers were washed with 1 M HCl (1 * 50 mL), saturated NaHCO3-solution (1 * 50 mL), and brine (1 * 50 mL). The combined organic layers were dried over Na2SO4 and the solvent was evaporated under reduced pressure. The product was purified via flash chromatography (75 g silica gel, cyclohexane/EtOAc = 2/1, fraction size: 50 mL) yielding a sticky oil which crystallized under high vacuum and freezing in liquid nitrogen. (1.01 g, 75 %) m.p. = 58-61 °C. 1H NMR (300.36 MHz; CDCl3) δ = 6.80 (m, 3H), 5.70 (s, 2H), 5.30 (m, 2H), 4.34 (d, 3JHH = 5.5 Hz, 2H), 3.86 (s, 3H), 2.23 (m, 2H), 1.99 (m, 2H), 1.66 (m, 2H), 1.37 (m, 2H), 0.93 (d, 3JHH = 6.2 Hz, 6H) 13C NMR (75.53 MHz; CDCl3) δ = 173.0, 146.9, 145.3, 130.5, 138.2, 126.6, 120.9, 114.5, 110.8, 56.1, 43.7, 36.8, 32.4, 31.1, 29.4, 25.4, 22.8.

Reference： [1]Migglautsch, Anna K.; Willim, Melissa; Schweda, Bettina; Glieder, Anton; Breinbauer, Rolf; Winkler, Margit [Tetrahedron, 2018, vol. 74, # 43, p. 6199 - 6204]

71
[ 60142-89-4 ]
[ 7149-10-2 ]
tert-butyl (7-((4-hydroxy-3-methoxybenzyl)amino)-7-oxoheptyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: To a mixture of amine (300mg, 1.71mmol, 1M eq., HCl) and the required carboxylic acid (440.03mg, 1.79mmol, 1.05M eq.) in 39 DMF (10mL) was added 40 DIEA (662.36mg, 5.12mmol, 893muL, 3M eq.). The mixture was stirred at 30C for 5min, and added 41 HATU (682.0mg, 1.79mmol, 1.05M eq.) in one portion at 30C. The mixture was stirred at 30C for 16h. The reaction was followed by LC-MS. The aqueous phase was extracted with ethyl acetate (2×50mL), dried with anhydrous MgSO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO; 40g Sepa Flash Silica Flash Column, Eluent of 0-65% 42 ethyl acetate/petroleum ether gradient at 35mL/min) (petroleum ether : ethyl acetate=1:3, Rf=0.5). Compound 43 3 (600mg, 1.42mmol, 83% yield, 90% purity) was obtained as a white oil. 1H NMR (400MHz, DMSO-d6) delta=8.82 (s, 1H), 8.17 (br. t, J=5.4Hz, 1H), 6.86-6.73 (m, 2H), 6.72-6.58 (m, 2H), 4.14 (br. d, J=5.7Hz, 2H), 3.73 (s, 3H), 2.90 (s, 2H), 2.10 (br. t, J=7.6Hz, 2H), 1.50 (br. s, 2H), 1.55-1.45 (m, 1H), 1.37 (s, 9H), 1.23 (br. s, 4H), 1.22-1.13 (m, 2H).

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 2531 - 2536

72
[ 27219-07-4 ]
[ 7149-10-2 ]
tert-butyl (5-((4-hydroxy-3-methoxybenzyl)amino)-5-oxopentyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 5-(N-tert-butyloxycarbonyl)aminopentanoic acid; vanillylamine hydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 30℃; for 0.0833333h; Stage #2: With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 30℃; for 16h;	4 4.3.2 tert-butyl (7-((4-hydroxy-3-methoxybenzyl)amino)-7-oxoheptyl)carbamate (3) General procedure: To a mixture of amine (300mg, 1.71mmol, 1M eq., HCl) and the required carboxylic acid (440.03mg, 1.79mmol, 1.05M eq.) in 39 DMF (10mL) was added 40 DIEA (662.36mg, 5.12mmol, 893µL, 3M eq.). The mixture was stirred at 30°C for 5min, and added 41 HATU (682.0mg, 1.79mmol, 1.05M eq.) in one portion at 30°C. The mixture was stirred at 30°C for 16h. The reaction was followed by LC-MS. The aqueous phase was extracted with ethyl acetate (2×50mL), dried with anhydrous MgSO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO; 40g Sepa Flash Silica Flash Column, Eluent of 0-65% 42 ethyl acetate/petroleum ether gradient at 35mL/min) (petroleum ether : ethyl acetate=1:3, Rf=0.5). Compound 43 3 (600mg, 1.42mmol, 83% yield, 90% purity) was obtained as a white oil.

Reference： [1]Baker, Charlotte; Rodrigues, Tiago; de Almeida, Bernardo P.; Barbosa-Morais, Nuno L.; Bernardes, Gonçalo J.L. [Bioorganic and Medicinal Chemistry, 2019, vol. 27, # 12, p. 2531 - 2536]

73
[ 4530-20-5 ]
[ 7149-10-2 ]
tert-butyl (2-((4-hydroxy-3-methoxybenzyl)amino)-2-oxoethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; for 72h;
	Stage #1: BOC-glycine; vanillylamine hydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 30℃; for 0.0833333h; Stage #2: With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 30℃; for 16h;	5 4.3.2 tert-butyl (7-((4-hydroxy-3-methoxybenzyl)amino)-7-oxoheptyl)carbamate (3) General procedure: To a mixture of amine (300mg, 1.71mmol, 1M eq., HCl) and the required carboxylic acid (440.03mg, 1.79mmol, 1.05M eq.) in 39 DMF (10mL) was added 40 DIEA (662.36mg, 5.12mmol, 893µL, 3M eq.). The mixture was stirred at 30°C for 5min, and added 41 HATU (682.0mg, 1.79mmol, 1.05M eq.) in one portion at 30°C. The mixture was stirred at 30°C for 16h. The reaction was followed by LC-MS. The aqueous phase was extracted with ethyl acetate (2×50mL), dried with anhydrous MgSO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO; 40g Sepa Flash Silica Flash Column, Eluent of 0-65% 42 ethyl acetate/petroleum ether gradient at 35mL/min) (petroleum ether : ethyl acetate=1:3, Rf=0.5). Compound 43 3 (600mg, 1.42mmol, 83% yield, 90% purity) was obtained as a white oil.

Reference： [1]Lee, Seonae; Kim, Ka Young; Jung, Sung Ho; Lee, Ji Ha; Yamada, Mihoko; Sethy, Ramarani; Kawai, Tsuyoshi; Jung, Jong Hwa [Angewandte Chemie - International Edition, 2019, vol. 58, # 52, p. 18878 - 18882][Angew. Chem., 2019, vol. 131, # 52, p. 19054 - 19058,5]
[2]Baker, Charlotte; Rodrigues, Tiago; de Almeida, Bernardo P.; Barbosa-Morais, Nuno L.; Bernardes, Gonçalo J.L. [Bioorganic and Medicinal Chemistry, 2019, vol. 27, # 12, p. 2531 - 2536]

74
[ 4478-93-7 ]
[ 7149-10-2 ]
C₁₄H₂₂N₂O₃S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	Stage #1: vanillylamine hydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.166667h; Inert atmosphere; Stage #2: D,L-sulforaphane In N,N-dimethyl-formamide at 20℃; for 10h;	2 The synthesis of compound 20a is as follows Take a dry 25 mL round bottom flask.The vanillinamine hydrochloride (100 mg, 0.53 mmol) was dissolved in 1 mL of re-distilled DMF, then DIPEA (68.20 mg, 0.53 mmol) was added with stirring.The reaction system was protected with argon gas and stirred at room temperature for 10 min to dissolve the material.Then, Compound 18 (93.48 mg, 0.53 mmol) dissolved in 1 mL of DMF was added to the reaction, and the reaction was stirred at normal temperature for 10 h. The reaction of the reaction raw materials was monitored by TLC.The reaction solution was quenched with water and extracted with dichloromethane (5 mL×3).The organic phase was collected and dried over anhydrous sodium sulfate, filtered, concentrated and purified on silica gel.The pale yellow viscous oily liquid product (190 mg, yield 98%) was obtained.

Reference： [1]Current Patent Assignee: TIANJIN INT JOINT ACADEMY BIOMEDICINE - CN110272337, 2019, A Location in patent: Paragraph 0167-0173

75
[ 7149-10-2 ]
[ 134-96-3 ]
C₂₆H₃₁NO₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	Stage #1: vanillylamine hydrochloride; syringic aldehyde In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #3: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; Inert atmosphere;	Na(OAc)3BH reaction General procedure: To a 250 mL round bottom flask were added vanillylamine hydrochloride (0.20 g, 1.05 mmol) and THF (100 mL). Then, the first equivalent of syringaldehyde (0.22 g, 1.21 mmol) was added to the reaction mixture. The reaction vessel was flushed with argon and the mixture was allowed to stir for 0.5 h. Subsequently, DBU (0.18 mL, 1.21 mmol) was added. After stirring for 0.5 h, Na(OAc)3BH (0.26 g, 1.23 mmol) was added next. After stirring for 5 h, the second equivalent of syringaldehyde (0.22 g, 1.21 mmol) was added to the reaction mixture and allowed to stir for 0.5 h. Then, Na(OAc)3BH (0.27 g, 1.27 mmol) was added and stirred overnight. After the target formation was confirmed by ESI-MS and TLC, the crude reaction mixture was filtered and the filtrate was dried on the rotovap. The resulting residue was dissolved in 5 mL of chloroform, loaded onto a silica column, and purified with a gradient hexane-acetone (5:1 → 3:1) solvent system.

Reference： [1]Anamoah, Charles; Brinkman, Hannah F.; Chapman, Kelli N.; Knoll, Allison N.; Lee, Choon Young; Malone, James I.; Semenya, Julius; Sharma, Ajit [Tetrahedron Letters, 2020]

76
[ 2420-16-8 ]
[ 7149-10-2 ]
C₂₂H₂₁Cl₂NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	Stage #1: 4-hydroxy-3-chlorobenzaldehyde; vanillylamine hydrochloride In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #3: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; Inert atmosphere;	Na(OAc)3BH reaction General procedure: To a 250 mL round bottom flask were added vanillylamine hydrochloride (0.20 g, 1.05 mmol) and THF (100 mL). Then, the first equivalent of syringaldehyde (0.22 g, 1.21 mmol) was added to the reaction mixture. The reaction vessel was flushed with argon and the mixture was allowed to stir for 0.5 h. Subsequently, DBU (0.18 mL, 1.21 mmol) was added. After stirring for 0.5 h, Na(OAc)3BH (0.26 g, 1.23 mmol) was added next. After stirring for 5 h, the second equivalent of syringaldehyde (0.22 g, 1.21 mmol) was added to the reaction mixture and allowed to stir for 0.5 h. Then, Na(OAc)3BH (0.27 g, 1.27 mmol) was added and stirred overnight. After the target formation was confirmed by ESI-MS and TLC, the crude reaction mixture was filtered and the filtrate was dried on the rotovap. The resulting residue was dissolved in 5 mL of chloroform, loaded onto a silica column, and purified with a gradient hexane-acetone (5:1 → 3:1) solvent system.

Reference： [1]Anamoah, Charles; Brinkman, Hannah F.; Chapman, Kelli N.; Knoll, Allison N.; Lee, Choon Young; Malone, James I.; Semenya, Julius; Sharma, Ajit [Tetrahedron Letters, 2020]

77
[ 2973-78-6 ]
[ 7149-10-2 ]
C₂₂H₂₁Br₂NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	Stage #1: 3-bromo-4-hydroxybenzylaldehyde; vanillylamine hydrochloride In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #3: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; Inert atmosphere;	Na(OAc)3BH reaction General procedure: To a 250 mL round bottom flask were added vanillylamine hydrochloride (0.20 g, 1.05 mmol) and THF (100 mL). Then, the first equivalent of syringaldehyde (0.22 g, 1.21 mmol) was added to the reaction mixture. The reaction vessel was flushed with argon and the mixture was allowed to stir for 0.5 h. Subsequently, DBU (0.18 mL, 1.21 mmol) was added. After stirring for 0.5 h, Na(OAc)3BH (0.26 g, 1.23 mmol) was added next. After stirring for 5 h, the second equivalent of syringaldehyde (0.22 g, 1.21 mmol) was added to the reaction mixture and allowed to stir for 0.5 h. Then, Na(OAc)3BH (0.27 g, 1.27 mmol) was added and stirred overnight. After the target formation was confirmed by ESI-MS and TLC, the crude reaction mixture was filtered and the filtrate was dried on the rotovap. The resulting residue was dissolved in 5 mL of chloroform, loaded onto a silica column, and purified with a gradient hexane-acetone (5:1 → 3:1) solvent system.

Reference： [1]Anamoah, Charles; Brinkman, Hannah F.; Chapman, Kelli N.; Knoll, Allison N.; Lee, Choon Young; Malone, James I.; Semenya, Julius; Sharma, Ajit [Tetrahedron Letters, 2020]

78
[ 3011-34-5 ]
[ 7149-10-2 ]
C₂₃H₂₄N₂O₇ [ No CAS ]
C₂₂H₂₁N₃O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5%	Stage #1: 4-hydroxy-3-nitrobenzaldehyde; vanillylamine hydrochloride In methanol at 20℃; for 0.5h; Stage #2: With 1,8-diazabicyclo[5.4.0]undec-7-ene In methanol at 20℃; for 0.5h; Stage #3: With 2-picoline borane complex In tetrahydrofuran at 20℃; for 5h; Inert atmosphere;	2-Picoline borane reaction To a 250 mL round bottom flask, vanillylamine hydrochloride (1.03 g, 5.43 mmol) was dissolved in methanol (200 mL). 4-Hydroxy-3-nitrobenzaldehyde (0.98 g, 5.86 mmol) was then added while stirring. After 0.5 h, DBU (0.84 mL, 5.63 mmol) was added and stirred for 0.5 h. Then, 2-picoline borane (0.62 g, 5.96 mmol) was added to the reaction mixture. After stirring for 5 h at room temperature, the second equivalent of 4-hydroxy-3-nitrobenzaldehyde (1.01 g, 6.04 mmol) was added and allowed to stir for 0.5 h. Then, 2-picoline borane (0.65 g, 6.25 mmol) was added. The reaction was run overnight. After removal of methanol, the reaction mixture was purified on a silica gel column using a hexane-acetone gradient solvent system (5:1 → 3:1).

Reference： [1]Anamoah, Charles; Brinkman, Hannah F.; Chapman, Kelli N.; Knoll, Allison N.; Lee, Choon Young; Malone, James I.; Semenya, Julius; Sharma, Ajit [Tetrahedron Letters, 2020]

79
[ 7149-10-2 ]
[ 123-08-0 ]
C₂₃H₂₅NO₅ [ No CAS ]
C₂₂H₂₃NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	Stage #1: vanillylamine hydrochloride; 4-hydroxy-benzaldehyde In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #3: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; Inert atmosphere;	Na(OAc)3BH reaction General procedure: To a 250 mL round bottom flask were added vanillylamine hydrochloride (0.20 g, 1.05 mmol) and THF (100 mL). Then, the first equivalent of syringaldehyde (0.22 g, 1.21 mmol) was added to the reaction mixture. The reaction vessel was flushed with argon and the mixture was allowed to stir for 0.5 h. Subsequently, DBU (0.18 mL, 1.21 mmol) was added. After stirring for 0.5 h, Na(OAc)3BH (0.26 g, 1.23 mmol) was added next. After stirring for 5 h, the second equivalent of syringaldehyde (0.22 g, 1.21 mmol) was added to the reaction mixture and allowed to stir for 0.5 h. Then, Na(OAc)3BH (0.27 g, 1.27 mmol) was added and stirred overnight. After the target formation was confirmed by ESI-MS and TLC, the crude reaction mixture was filtered and the filtrate was dried on the rotovap. The resulting residue was dissolved in 5 mL of chloroform, loaded onto a silica column, and purified with a gradient hexane-acetone (5:1 → 3:1) solvent system.

Reference： [1]Anamoah, Charles; Brinkman, Hannah F.; Chapman, Kelli N.; Knoll, Allison N.; Lee, Choon Young; Malone, James I.; Semenya, Julius; Sharma, Ajit [Tetrahedron Letters, 2020]

80
[ 7149-10-2 ]
[ 121-33-5 ]
[ 1372608-33-7 ]

Yield	Reaction Conditions	Operation in experiment
27%	Stage #1: vanillylamine hydrochloride; vanillin In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #3: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; Inert atmosphere;	Na(OAc)3BH reaction General procedure: To a 250 mL round bottom flask were added vanillylamine hydrochloride (0.20 g, 1.05 mmol) and THF (100 mL). Then, the first equivalent of syringaldehyde (0.22 g, 1.21 mmol) was added to the reaction mixture. The reaction vessel was flushed with argon and the mixture was allowed to stir for 0.5 h. Subsequently, DBU (0.18 mL, 1.21 mmol) was added. After stirring for 0.5 h, Na(OAc)3BH (0.26 g, 1.23 mmol) was added next. After stirring for 5 h, the second equivalent of syringaldehyde (0.22 g, 1.21 mmol) was added to the reaction mixture and allowed to stir for 0.5 h. Then, Na(OAc)3BH (0.27 g, 1.27 mmol) was added and stirred overnight. After the target formation was confirmed by ESI-MS and TLC, the crude reaction mixture was filtered and the filtrate was dried on the rotovap. The resulting residue was dissolved in 5 mL of chloroform, loaded onto a silica column, and purified with a gradient hexane-acetone (5:1 → 3:1) solvent system.

Reference： [1]Anamoah, Charles; Brinkman, Hannah F.; Chapman, Kelli N.; Knoll, Allison N.; Lee, Choon Young; Malone, James I.; Semenya, Julius; Sharma, Ajit [Tetrahedron Letters, 2020]

81
[ 39978-57-9 ]
[ 7149-10-2 ]
N-(4-hydroxy-3-methoxybenzyl)-5-nitrothiophene-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	Stage #1: vanillylamine hydrochloride With sodium hydrogencarbonate In chloroform; water at 20℃; for 0.75h; Stage #2: 5-nitrothiophene-2-carbonyl chloride In chloroform; water for 0.5h;	5.2.1. General procedure for synthesis of compounds 1-3 General procedure: To a solution of vanillylamine hydrochloride (1.90 g, 10.0 mmol)in water (30 mL), NaHCO3 (2.52 g, 30.0 mmol) was added. Themixture was stirred for 30 min at room temperature and thenchloroform (30 mL) was added. After stirring for 15 min, a solutionof acyl chloride (10.0 mmol) in chloroform (20 mL) was addeddropwise. The mixture was stirred for 30 min and monitored forcompletion by TLC. The organic layer was separated, and the waterlayer was extracted with chloroform (3 20 mL). The organicphases were combined and dried by anhydrous sodium sulfate. Thesolvent was removed under reduced pressure and the residue wasrecrystallized (when needed) to yield the product.

Reference： [1]Pei, Fang-Ning; Tang, Jie; Wang, Zhi-Cheng; Wei, Bingyan; Yang, Cai-Guang; Yang, Fan; Yang, Song; Yang, Teng; Yu, Li-Fang [European Journal of Medicinal Chemistry, 2020, vol. 198]

82
[ 25084-14-4 ]
[ 7149-10-2 ]
N-(4-hydroxy-3-methoxybenzyl)-5-nitrofuran-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	Stage #1: vanillylamine hydrochloride With sodium hydrogencarbonate In chloroform; water at 20℃; for 0.75h; Stage #2: 5-nitrofuran-2-carboxylic chloride In chloroform; water for 0.5h;	5.2.1. General procedure for synthesis of compounds 1-3 General procedure: To a solution of vanillylamine hydrochloride (1.90 g, 10.0 mmol)in water (30 mL), NaHCO3 (2.52 g, 30.0 mmol) was added. Themixture was stirred for 30 min at room temperature and thenchloroform (30 mL) was added. After stirring for 15 min, a solutionof acyl chloride (10.0 mmol) in chloroform (20 mL) was addeddropwise. The mixture was stirred for 30 min and monitored forcompletion by TLC. The organic layer was separated, and the waterlayer was extracted with chloroform (3 20 mL). The organicphases were combined and dried by anhydrous sodium sulfate. Thesolvent was removed under reduced pressure and the residue wasrecrystallized (when needed) to yield the product.

Reference： [1]Pei, Fang-Ning; Tang, Jie; Wang, Zhi-Cheng; Wei, Bingyan; Yang, Cai-Guang; Yang, Fan; Yang, Song; Yang, Teng; Yu, Li-Fang [European Journal of Medicinal Chemistry, 2020, vol. 198]

83
4-(4-((4-butyl-2,6-dichlorophenyl)diazenyl)-3,5-dichlorophenyl)butanoic acid [ No CAS ]
[ 7149-10-2 ]
red-AzCA-4 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	Stage #1: 4-(4-((4-butyl-2,6-dichlorophenyl)diazenyl)-3,5-dichlorophenyl)butanoic acid With triethylamine; O‐(1H‐benzotriazol‐1‐yl)‐N,N,N′,N′‐tetramethyluronium tetrafluoroborate In ethyl acetate at 20℃; for 1.16667h; Schlenk technique; Stage #2: vanillylamine hydrochloride In ethyl acetate at 20℃; for 2h;

Reference： [1]Frank, James A.; Antonini, Marc-Joseph; Chiang, Po-Han; Canales, Andres; Konrad, David B.; Garwood, Indie C.; Rajic, Gabriela; Koehler, Florian; Fink, Yoel; Anikeeva, Polina [ACS Chemical Neuroscience, 2020, vol. 11, # 22, p. 3802 - 3813]

84
[ 866363-70-4 ]
[ 7149-10-2 ]
N-vanillyl-6-aminohexamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With triethylamine In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere;

Reference： [1]Kimani, Flora W.; Manna, Saikat; Moser, Brittany; Shen, Jingjing; Nihesh, Naorem; Esser-Kahn, Aaron P. [ACS Medicinal Chemistry Letters, 2021, vol. 12, # 9, p. 1441 - 1448]

85
[ 6089-09-4 ]
[ 7149-10-2 ]
C₁₃H₁₅NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 24h; Inert atmosphere;	3; 104; 107-119 The method of preparation of capsaicin derivatives shown in Formula II-1 above, comprising the following steps: In the reaction vessel were added 5-(aminomethyl)-2-methoxyphenol hydrochloride, alkali, 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-hydroxybenzotriazole, alkyne acid and organic solvent, reacted at 20 °C for 24 hours to obtain the reaction liquid, to be cooled to room temperature, vacuum concentration, residue over 200 mesh silicone column chromatography to give the capsaicin derivative shown in formula II-1, wherein: Silica gel column chromatography uses a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:1 as the eluent; The molar ratio of 5-(aminomethyl)-2-methoxyphenol hydrochloride, base, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-hydroxybenzotriazole, alkyne acid, organic solvent is 1:4:1.5:1.5:1:1:40. Further, the base is N,N- diisopropylethylamine. Further, the organic solvent is acetonitrile.

Reference： [1]Current Patent Assignee: INST CHINESE MATERIA MEDICA CHINA ACADEMY OF CMS - CN114524747, 2022, A Location in patent: Paragraph 0038-0043; 0084-0087; 0096

86
[ 2777-65-3 ]
[ 7149-10-2 ]
N-(4-hydroxy-3-methoxybenzyl)undec-10-ynamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In acetonitrile at 30℃; for 16h; Inert atmosphere;	6 The method of preparation of capsaicin derivatives shown in formula II-4 above, comprising the following steps: In the reaction vessel were added 5-(aminomethyl)-2-methoxyphenol hydrochloride, alkali, 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-hydroxybenzotriazole, alkyne and organic solvents, reacted at 30 °C for 16 hours to obtain the reaction liquid, after the reaction liquid was cooled to room temperature, vacuum concentrated, the residue was obtained after 300 mesh silica gel column chromatography, that is, the capsaicin derivative shown in formula II-4, the yield was 78% of it: Silica gel column chromatography uses a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:1 as the eluent; 5-(Aminomethyl)-2-methoxyphenol hydrochloride or 5-(aminomethyl)-2-methoxybenzene hydrochloride, alkali, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-hydroxybenzotriazole, alkyne acid, organic solvent Molar ratio of 1: 4: 1.5: 1.5: 1: 1: 30. Further, the base is N,N- diisopropylethylamine. Further, the organic solvent is one of acetonitrile.

Reference： [1]Current Patent Assignee: INST CHINESE MATERIA MEDICA CHINA ACADEMY OF CMS - CN114524747, 2022, A Location in patent: Paragraph 0056-0061

87
[ 30964-00-2 ]
[ 7149-10-2 ]
C₁₅H₁₉NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In acetonitrile at 30℃; for 18h; Inert atmosphere;	5; 106 The preparation method of capsaicin derivatives shown in formula II-3 above, comprising the following steps: In the reaction vessel were added 5-(aminomethyl)-2-methoxyphenol hydrochloride, alkali, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-hydroxybenzotriazole, alkyne acid and organic solvent, reacted at 30 °C for 18 hours to obtain the reaction liquid, to be cooled to room temperature, vacuum concentrated, the residue over 250 mesh silicone column chromatography is given white solid is given the capsaicin derivative shown in formula II-3, the yield is 73%, wherein: Silica gel column chromatography uses a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1 as the eluent; 5-(Aminomethyl)-2-methoxyphenol hydrochloride, alkali, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-hydroxybenzotriazole, alkyne acid, organic solvent molar ratio of 1:4:1.5:1.5:1:1:30. Further, the base is N,N- diisopropylethylamine. Further, the organic solvent is acetonitrile.

Reference： [1]Current Patent Assignee: INST CHINESE MATERIA MEDICA CHINA ACADEMY OF CMS - CN114524747, 2022, A Location in patent: Paragraph 0050-0055; 0092-0095

88
[ 53293-00-8 ]
[ 7149-10-2 ]
C₁₄H₁₇NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 50℃; for 12h;	105 The preparation method of capsaicin derivative shown in formula (II), comprises the following steps: 5-(aminomethyl)-2-methoxybenzene hydrochloride, alkali, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-hydroxyl Benzotriazole, alkynoic acid and organic solvent were reacted at 50°C for 12 hours to obtain a reaction solution. After the reaction solution was cooled to room temperature, it was concentrated in vacuo, and the residue was subjected to 300-mesh silica gel column chromatography to obtain the formula (II). Derivatives of capsaicin, wherein:Silica gel column chromatography adopts the mixture of petroleum ether and ethyl acetate according to the volume ratio of 10: 1 as eluent;5-(Aminomethyl)-2-methoxybenzene hydrochloride, base, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-hydroxybenzotriazole, alkyne The molar ratio of acid and organic solvent is 2:4:3:3:2:50.Further, the base is N,N-diisopropylethylamine.Further, the organic solvent is 1,4-dioxane.Further, the structural formula of the alkynoic acid is, wherein:R3is ethylene.

Reference： [1]Current Patent Assignee: INST CHINESE MATERIA MEDICA CHINA ACADEMY OF CMS - CN114524747, 2022, A Location in patent: Paragraph 0088-0091

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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. 7149-10-2 ] {[proInfo.proName]}

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[ 7149-10-2 ] Synthesis Path-Upstream 1~6

[ 7149-10-2 ] Synthesis Path-Downstream 1~88

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Aryls

Ethers

Amines

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[ 7149-10-2 ]