[ CAS No. 619-57-8 ] {[proInfo.proName]}

Name: 619-57-8|4-Hydroxybenzamide|97%
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SKU: A115793
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Quality Control of [ 619-57-8 ]

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SDS Specification

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Product Details of [ 619-57-8 ]

CAS No. :	619-57-8	MDL No. :	MFCD00007997
Formula :	C₇H₇NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QXSAKPUBHTZHKW-UHFFFAOYSA-N
M.W :	137.14	Pubchem ID :	65052
Synonyms :

Calculated chemistry of [ 619-57-8 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	2.0
Molar Refractivity :	36.56
TPSA :	63.32 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.9 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.76
Log Po/w (XLOGP3) :	0.33
Log Po/w (WLOGP) :	0.49
Log Po/w (MLOGP) :	0.58
Log Po/w (SILICOS-IT) :	0.5
Consensus Log Po/w :	0.53

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.28
Solubility :	7.26 mg/ml ; 0.0529 mol/l
Class :	Very soluble
Log S (Ali) :	-1.22
Solubility :	8.2 mg/ml ; 0.0598 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.38
Solubility :	5.69 mg/ml ; 0.0415 mol/l
Class :	Soluble

Medicinal Chemistry

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

Safety of [ 619-57-8 ]

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

Application In Synthesis of [ 619-57-8 ]

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

Upstream synthesis route of [ 619-57-8 ]
Downstream synthetic route of [ 619-57-8 ]

[ 619-57-8 ] Synthesis Path-Upstream 1~6

1
[ 619-57-8 ]
[ 25984-63-8 ]

Yield	Reaction Conditions	Operation in experiment
87%	With Lawessons reagent In tetrahydrofuran at 20℃; for 6 h;	4-Hydroxybenzamide (3.6 g, 26.5 mmol) was dissolved in dryTHF (100 mL), and then Lawesson's reagent (11.77 g, 29.1 mmol)was added. The reaction mixture was stirred at room temperaturefor 6 h. The solvent was then evaporated under reduced pressureand the residue was partitioned between aq. NaHCO3 (0.2 M,50 mL) and ethyl acetate (50 mL x 2). The organic solvent wasseparated and dried over anhydrous MgSO4. The crude product wasfurther purified by silica gel flash chromatography, using EtOAc:Petroleum ether (85:15) to yield the corresponding thioamide as ayellow solid (3.5 g, 87percent); m.p 172-176°C.

Reference： [1] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 604 - 613

2
[ 55-21-0 ]
[ 618-49-5 ]
[ 619-57-8 ]
[ 18543-22-1 ]
[ 65-45-2 ]

Yield	Reaction Conditions	Operation in experiment
35%	With (difluoroboryl)dimethylglyoximatocobalt(II) bis(acetonitrile); water; 3-cyano-1-methylquinolinium cation In acetonitrile at 20℃; for 5 h; Inert atmosphere; Irradiation; Green chemistry	Using 1-methyl-3-cyanoquinoline salt as photosensitizer, cobalt oxime complex 2 as cobalt catalyst and 5mL of acetonitrile, 2.69mg (1 × 10-2mmol) photosensitizer and 2.80mg ) Cobalt catalyst, the atmosphere was replaced with Ar atmosphere, Then 0.2 mmol of benzamide (R1 is CONH2, R2, R3, R4 are independently H) and 2 mmol H2O. Room temperature, high pressure mercury lamp irradiation 5h. After completion of the reaction, H2 production was detected by GC (TCD), benzene conversion by GC (FID) was detected, and then column separation was performed. Nuclear magnetic hydrogenSpectroscopy and mass spectrometry identified products as 2-hydroxybenzamide, 3-hydroxybenzamide,4-hydroxybenzamide and Ν- (3-carbamoylphenyl) benzamide. The conversion of benzamide was 63percent, the yields of 2-hydroxybenzamide, 3-hydroxybenzamide and 4-hydroxybenzamide were 35percent, 8percent, 11percentThe yield of N- (2-carbamoylphenyl) benzamide was 9percent and the yield of H2 was 58percent.

Reference： [1] Patent: CN107324975, 2017, A, . Location in patent: Paragraph 0118-0119
[2] Journal of the American Chemical Society, 2016, vol. 138, # 32, p. 10080 - 10083

3
[ 109-65-9 ]
[ 619-57-8 ]
[ 4344-55-2 ]

Reference： [1] Molecular Crystals and Liquid Crystals, 2015, vol. 606, # 1, p. 1 - 11

4
[ 619-57-8 ]
[ 616-82-0 ]
[ 74230-08-3 ]
[ 99-96-7 ]

Yield	Reaction Conditions	Operation in experiment
13%	at 80℃; for 21 h; Inert atmosphere	4-Hydroxybenzamide (0.2743 g, 2 mmol) was dissolved in acetic acid (4 mL), and to the stirringsolution was added amyl nitrite (1.20 mL, 6 mmol). The reaction was placed under N₂ atmosphere andheated to 80 °C. At specified time points (15 min., 30 min., 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr)a 100 μL aliquot of the solution was syringed out of the reaction and quenched by mixing with 1 mLsolution of 5percent Et₃N in MeOH. Each aliquot was then condensed and dried in vacuum before beinganalysed via ¹H-NMR

Reference： [1] Tetrahedron Letters, 2015, vol. 56, # 37, p. 5153 - 5156

5
[ 619-57-8 ]
[ 87-66-1 ]
[ 31127-54-5 ]

Yield	Reaction Conditions	Operation in experiment
70.6%	With aluminum (III) chloride In i-Amyl alcohol at 90 - 130℃; for 5.5 h; Inert atmosphere	Will be acylatedReagents p-hydroxybenzoic acid amine0.09 mol, pyrogallol 0.1 mol,0.013 mol of aluminum trichloride and 300 ml of isoamyl alcohol were mixed in a reactor, an inert gas was introduced,When the system temperature was raised to 90-100 , stop the access, continue heating at 110-130 reaction 5.5h, TLC trace to the end of the reaction, the reaction temperature was completed to 50-60 , incubated for 1h,Water 200ml was added and the layers were separated. The organic layer was crystallized at 0-5 ° C, filtered and dried to give the product. The molar yield of the product was 70.60percent, HPLC≥98.5percent.

Reference： [1] Patent: CN106365961, 2017, A, . Location in patent: Paragraph 0048; 0049

6
[ 619-57-8 ]
[ 109384-19-2 ]
[ 609781-33-1 ]

Yield	Reaction Conditions	Operation in experiment
21%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃;	(a) Synthesis of tert-butyl 4-[4-(aminocarbonyl)-phenoxy]piperidine-1-carboxylate To a solution of p-hydroxybenzamide (343 mg, 2.50 mmol) in tetrahydrofuran (10 ml) were added tert-butyl 4-hydroxy-1-piperidinecarboxylate (503 mg, 2.50 mmol) and triphenylphosphine (656 mg, 2.50 mmol), followed by adding thereto ethyl azodicarboxylate (1.15 ml, 2.50 mmol) under ice-cooling, and the resulting mixture was stirred overnight at room temperature. Then, the reaction mixture was concentrated and the crude product thus obtained was purified by a silica gel column chromatography (chloroform/methanol = 99/1) to obtain tert-butyl 4-[4-(aminocarbonyl)phenoxy]-piperidine-1-carboxylate (169 mg, 21percent). ¹H-NMR (DMSO-d₆) δ; 1.39(s, 9H), 1.45-1.6 0(1H, m), 1.89-1.92 (1H, m), 3.13-3.20(2H, m), 3.62 - 3.69 (2H, m), 4.61-4.66 (1H, m), 6. 99 (2H, d, J=8.8Hz), 7.15(1H, m), 7.80 (1H, m), 7.81 (2H, d, J=8.8Hz).

Reference： [1] Patent: EP1500643, 2005, A1, . Location in patent: Page 24

[ 619-57-8 ] Synthesis Path-Downstream 1~88

1
[ 99-76-3 ]
[ 619-57-8 ]

Yield	Reaction Conditions	Operation in experiment
67%	With ammonium hydroxide at 100℃; for 5h; Autoclave;	1-4 Example 3 This embodiment provides a method for preparing p-hydroxybenzamide, including the following steps:In a 500 mL autoclave, 10 g of methyl parahydroxybenzoate (65.7 mmol) and 50 mL of concentrated ammonia water (25% to 28% by mass) were added. After stirring, the temperature was raised. After heating to 100 ° C for 5 hours, Distilled under reduced pressure to about one third of the original mass, cooled and crystallized, and filtered to obtain 6.04 g of p-hydroxybenzamide with a yield of 67%.
	With ammonium hydroxide at 130 - 140℃;

Reference： [1]Current Patent Assignee: HUBEI UNIVERSITY - CN110818590, 2020, A Location in patent: Paragraph 0050-0059; 0062-0064
[2]Williams [Biochemical Journal, 1938, vol. 32, p. 878,881] Bray; Ryman; Thorpe [Biochemical Journal, 1947, vol. 41, p. 212,214, 216]

2
[ 99-96-7 ]
[ 619-57-8 ]

Yield	Reaction Conditions	Operation in experiment
98.7%	With 1,4-diaza-bicyclo[2.2.2]octane; methyl carbamate at 130 - 180℃; for 4.5h;	1.1; 2.1; 3.1 1) In a 500ml reactor, add 139.6g of p-hydroxybenzoic acid, 90.7g of methyl carbamate, and 4.2g of triethylenediamine. Slowly increase the temperature to 130°C for 30 minutes, and then slowly increase the temperature to 180°C. React for 4 hours at the temperature. After the temperature reaches 180°C, the content of p-hydroxybenzoic acid will be detected. When the content of p-hydroxybenzoic acid is less than 0.1%, the reaction is considered complete. At this temperature, the reaction is completed in 4 hours. The product is P-Hydroxybenzamide; the liquid phase shows that the content is ≥99%. After the reaction is completed, the methyl carbamate and triethylenediamine are recovered by vacuum distillation to obtain 137.5 g of p-hydroxybenzamide white powder with a melting point of 161°C. The purity is 99.5% and the yield is 98.7% after liquid phase detection;
69%	With zirconium(IV) oxychloride; urea at 80℃; for 0.0111111h; Sealed tube; Microwave irradiation;	3 A method for efficiently synthesizing an amide derivative by carboxylic acid and urea according to the present invention,It includes the following steps General procedure: (1) mixing a mixture of 1 mmol of carboxylic acid and 2 mmol of urea with 10 mol% of a transition metal salt zirconium oxychloride,In the specific time of 20-80s,Place the mixture in a sealed tube of a single-mode microwave device and radiate to 80C at a 100W range; (2) monitoring the endpoint of the reaction by TLC thin layer chromatography with a ratio of cyclohexane to ethyl acetate of 4: 1,Cool the reaction to room temperature,Extraction with ethyl acetate,Then use 2mol / L hydrochloric acid,The extract was washed with 5% sodium bicarbonate solution and water in sequence,The organic layer was dried over anhydrous magnesium sulfate,Solvent distillation under reduced pressure,Get an amide derivative; (3) Residue of the used catalyst under the same conditions,And a second reaction with a fresh mixture of 1 mmol of carboxylic acid and 2 mmol of urea,Monitor the rate of the reaction; (4) Repeat the above steps 1-3 to recycle the catalyst.
65%	With pyridine; urea for 0.00555556h; microwave irradiation;

51%	Stage #1: 4-hydroxy-benzoic acid With niobium pentachloride In 1,4-dioxane Stage #2: With ammonia In 1,4-dioxane at 45 - 50℃; for 1h;
47%	With 1H-imidazole; urea for 0.0694444h; microwave irradiation;
	With phosphoramide
	Multi-step reaction with 2 steps 1: hydrogen chloride 2: aqueous ammonia / 130 °C / im geschlossenen Rohr
	Stage #1: 4-hydroxy-benzoic acid With 1-methyl-pyrrolidin-2-one; benzotriazol-1-ol; diisopropyl-carbodiimide Stage #2: With trifluoroacetic acid In water
	Multi-step reaction with 2 steps 1: thionyl chloride / 0.5 h / 83 °C / Inert atmosphere 2: water; dichloromethane / 20 °C / Cooling with ice
	Multi-step reaction with 2 steps 1: thionyl chloride / 0.5 h / 85 °C / Reflux 2: ammonium hydroxide / dichloromethane / 0.5 h / Cooling with ice
	Stage #1: 4-hydroxy-benzoic acid With benzotriazol-1-ol; diisopropyl-carbodiimide In N,N-dimethyl-formamide at 20℃; for 2h; Stage #2: With trifluoroacetic acid In dichloromethane at 20℃; for 0.5h;
	With ammonia at 250℃; for 0.5h;	A Amide Intermediate Preparation Example A General procedure: Into a 1L open reactor was added 500g of carboxylic acid raw material (chemically pure) and stirring was turned on (600 r/min) from the reactorThe bottom is continuously fed with ammonia gas (chemical purity, water content of 5.1% by weight, flow rate of 100 g/min) to the carboxylic acid feed. After the reaction was allowed to proceed for TC hours at the reaction temperature TA, ammonia gas flow was stopped. The contents of the reactor were sampled and subjected to nuclear magnetic proton and elemental analysis to characterize the amide intermediate. Specific reaction conditions and characterization results are shown in Table A-1, Table A-2, Table A-3, Table A-4, Table A-5 and Table A-6. These characterization results show that the amide intermediates obtained have an extremely high purity (above 99%).In this embodiment, the ammonia gas can be directly replaced with waste ammonia gas (from Yangzi Petrochemical Plant, containing approximately50wt% of ammonia gas, the rest were toluene, oxygen, nitrogen, steam, carbon monoxide, and carbon dioxide, and the flow rate of this waste ammonia was 130g/min).

Reference： [1]Current Patent Assignee: ZHENGZHOU KEKUANG BIOLOGICAL TECH - CN112552207, 2021, A Location in patent: Paragraph 0039-0041; 0045-0047; 0051-0053
[2]Current Patent Assignee: NANTONG ZHENGYAN NEW MATERIALS TECH - CN110372541, 2019, A Location in patent: Paragraph 0022-0030
[3]Pasha, M. Afzal; Jayashankara [Journal of the Indian Chemical Society, 2005, vol. 82, # 7, p. 675 - 676]
[4]Nery, Marcelo S.; Ribeiro, Renata P.; Lopes, Claudio C.; Lopes, Rosangela S. C. [Synthesis, 2003, # 2, p. 272 - 276]
[5]Khalafi-Nezhad, Ali; Mokhtari, Babak; Rad, Mohammad Navid Soltani [Tetrahedron Letters, 2003, vol. 44, # 39, p. 7325 - 7328]
[6]Skrowaczewska; Mastalerz [Roczniki Chemii, 1957, vol. 31, p. 531,535][Chem.Abstr., 1958, p. 2798]
[7]Hartmann [Journal fur praktische Chemie (Leipzig 1954), 1877, vol. <2> 16, p. 36]
[8]Location in patent: experimental part Agerbirk, Niels; Warwick, Suzanne I.; Hansen, Paul R.; Olsen, Carl E. [Phytochemistry, 2008, vol. 69, # 17, p. 2937 - 2949]
[9]Li, Min; Luo, Bingling; Liu, Qi; Hu, Yumin; Ganesan; Huang, Peng; Wen, Shijun [Organic Letters, 2014, vol. 16, # 1, p. 10 - 13]
[10]Wu, Youzhi; Sun, Peng; Zhang, Kaifan; Yang, Tie; Yao, Hequan; Lin, Aijun [Journal of Organic Chemistry, 2016, vol. 81, # 5, p. 2166 - 2173]
[11]Burglova, Kristyna; Okorochenkov, Sergei; Hlavac, Jan [Organic Letters, 2016, vol. 18, # 14, p. 3342 - 3345]
[12]Current Patent Assignee: CHINA PETROCHEMICAL CORPORATION - CN104557357, 2018, B Location in patent: Paragraph 0135; 0136; 0137; 0141

3
[ 619-57-8 ]
[ 24171-03-7 ]
[ 51073-96-2 ]

Reference： [1]Indian Journal of Chemistry,1973,vol. 11,p. 868 - 870

4
4-hydroxybenzaldehyde oxime [ No CAS ]
[ 619-57-8 ]

Yield	Reaction Conditions	Operation in experiment
99%	With chloro(η4-1,5-cyclooctadiene)(1,3-dimesitylimidazole-2-ylidene)rhodium(I); 4-cyanophenol; toluene-4-sulfonic acid In toluene at 80℃; for 6h;
62%	With copper diacetate; acetonitrile In ethanol at 78℃; for 3h;	Preparation of amides from aldoximes; general procedures General procedure: To a 25 mL round-bottom flask equipped with a magnetic stirrer were added aldoximes (5 mmol), copper(II) acetate (45 mg, 0.25 mmol),acetonitrile (10 mg, 0.25 mmol) and EtOH (15 mL). The mixture was stirred for 4-8 h at 78 °C or for 12 h at room temperature. After removal of the solvent, the residue was purified by column chromatography to afford the desired product.
	With nickel diacetate In water

Reference： [1]Kim, Min; Lee, Jinwoo; Lee, Hee-Yoon; Chang, Sukbok [Advanced Synthesis and Catalysis, 2009, vol. 351, # 11-12, p. 1807 - 1812]
[2]Ma, Xiaoyun; Lu, Ming [Journal of Chemical Research, 2016, vol. 40, # 10, p. 594 - 596]
[3]Field,L. et al. [Journal of the American Chemical Society, 1961, vol. 83, p. 1983 - 1987]

5
[ 619-57-8 ]
[ 767-00-0 ]

Yield	Reaction Conditions	Operation in experiment
96%	With resin catalyst supported with palladium salt In water; acetonitrile at 50℃; for 7h;	5-15; 1 Example 15 General procedure: This embodiment provides a method for preparing p-hydroxybenzonitrile, including the following steps:In a 100 mL flask, 1.28 g of p-hydroxybenzamide (9.3 mmol) was dissolved in a mixed solution consisting of 24 mL of water, 24 mL of acetonitrile, and 24 mL of methanol. After stirring at 50 ° C, 8 mL of a palladium salt-loaded Resin catalyst, after reacting for 7h in 60 water bath,The resin is obtained by filtration, and the resin catalyst supporting the palladium salt is recovered for reuse;The filtrate was distilled to remove the solvent under reduced pressure to obtain a evaporated dry solid. After adding 4 mL of water to the evaporated dry solid to dissolve and disperse it, it was extracted with 24 mL of isopropyl ether three times. After extraction, the isopropyl ether layer was collected and backwashed with water, and then washed with water After the isopropyl ether layer was evaporated to dryness, 1.07 g of p-hydroxybenzonitrile was obtained,The yield was 96%.
94%	With trichloromethyl chloroformate In various solvent(s) 0-5 deg C then heated to 60 deg C, 5 min;
94%	Stage #1: p-hydroxybenzamide With C₃₉H₄₅N₂ In acetonitrile at 20℃; Schlenk technique; Glovebox; Inert atmosphere; Stage #2: With phenylsilane In acetonitrile at 20℃; for 12h; Schlenk technique; Inert atmosphere; Sealed tube;

91%	With lead acetate In dichloromethane for 12h; Reflux;
80%	With (dimethoxy)methylsilane; copper diacetate; 1,2-bis-(dicyclohexylphosphino)ethane In tetrahydrofuran at 20℃; for 12h; Sealed tube;
80%	at 325℃; for 1h;	A Amide Intermediate Preparation Example A General procedure: Into a 1L open reactor was added 500g of carboxylic acid raw material (chemically pure) and stirring was turned on (600 r/min) from the reactorThe bottom is continuously fed with ammonia gas (chemical purity, water content of 5.1% by weight, flow rate of 100 g/min) to the carboxylic acid feed. After the reaction was allowed to proceed for TC hours at the reaction temperature TA, ammonia gas flow was stopped. The contents of the reactor were sampled and subjected to nuclear magnetic proton and elemental analysis to characterize the amide intermediate. Specific reaction conditions and characterization results are shown in Table A-1, Table A-2, Table A-3, Table A-4, Table A-5 and Table A-6. These characterization results show that the amide intermediates obtained have an extremely high purity (above 99%).In this embodiment, the ammonia gas can be directly replaced with waste ammonia gas (from Yangzi Petrochemical Plant, containing approximately50wt% of ammonia gas, the rest were toluene, oxygen, nitrogen, steam, carbon monoxide, and carbon dioxide, and the flow rate of this waste ammonia was 130g/min).
75%	With zinc(II) chloride In water; acetonitrile for 0.00555556h; microwave irradiation;
75%	With Triethoxysilane; [(2,5-F₂C₆H₂-CH=N-C₁₀H₆)Co(III)(H)(PMe₃)₂] In tetrahydrofuran at 60℃; for 24h; Schlenk technique;	2.2 General procedure for the dehydration of amides to nitriles General procedure: To a 25 mL Schlenk tube containing a solution of 2 in 2 mL of THF was added amide (1.0 mmol) and (EtO)3SiH (0.50 g, 3.0 mmol). The reaction mixture was stirred at 60 °C until there was no amide left (monitored by TLC and GC-MS). The product was purified according to literature procedures by Beller
71%	With C₂₀H₂₅Cl₂CoN₃; sodium triethylborohydride In tetrahydrofuran; toluene at 60℃; for 18h; Inert atmosphere;	13 Example 13: Dehydration of p-hydroxybenzamide to p-hydroxybenzonitrile: Under an inert atmosphere, the substrate p-hydroxybenzamide (137mg, 1mmol), polymethylhydrosiloxane (1.1g, 5mmol), Co-2 catalyst (4.4mg, 0.01mmol), three Sodium ethyl borohydride (73.2mg, 0.06mmol) and toluene (1mL)The solvent was mixed with tetrahydrofuran (1 mL), and the resulting mixture was stirred uniformly.The reaction was carried out in an oil bath at 60°C for 18 hours. The reaction system was cooled to room temperature, diluted with ethyl acetate, quenched, and concentrated. The crude product was obtained by flash silica gel column chromatography to obtain the final product as 84 mg of white crystals.Yield: 71%.
		6 EXAMPLE 6 Thereafter, the reactional medium is treated as in Example 2. Thus, there is isolated 31 g of p-hydroxy-benzonitrile containing 4 g of p-hydroxybenzamide which is purified by distillation under vacuum. B.p.=148+-2° C.
6 %Spectr.	With triethylamine; ethanaminium,N-(difluoro-λ⁴-sulfanylidene)-N-ethyl-,tetrafluoroborate In ethyl acetate at 20℃; for 1h; Inert atmosphere;	Dehydration of Oximes and Amides to Nitriles; General Procedure General procedure: To a solution of the aldoxime or the amide (1.0 mmol) and Et3N (1.5mmol) in EtOAc (1 mL, 1 M) at r.t. was added XtalFluor-E8 (1.1 mmol)portionwise over ca. 2 min. The resulting solution was stirred at r.t.for 1 h. The reaction mixture was quenched with sat. aq Na2CO3 and extracted with CH2Cl2 (2 × 10 mL). The combined organic layers were washed with H2O and brine, dried (MgSO4), and concentrated under vacuum to afford the crude nitrile, which was purified by flash chromatography, if required.
	With sieve-supported lead catalyst at 200℃; for 0.3h;	23 General procedure: The height of the fixed-bed reactor is L=1500mm, the inner diameter D=100mm; 5000g of catalyst is set inside.The top of the fixed bed reactor is equipped with a pre-heater, and the set temperature of the pre-heater is 150°C,The reaction temperature (bed temperature) in the fixed bed reactor is 200After being heated at the top of the fixed bed reactor, benzamide enters the fixed bed reactor in a liquid form from the top of the fixed bed, and the pressure in the fixed bed reactor is 0.3 MPa.The bed temperature is 200°C, and the feed rate is controlled (about 4.7 g/min) to maintain the benzamide residence time at 0.3 h.(3) The reacted materials are drawn from the bottom of the fixed bed and analyzed by GC, the conversion rate of the raw materials is 97.1%, and the selectivity is 100%.The reacted materials are subjected to vacuum distillation, and the distillate is water and crude benzonitrile in sequence.The bottom liquid is unreacted benzamide, which can be recycled as a raw material into the fixed bed reactor. The purity of the crude benzonitrile was 97.0%. The crude benzonitrile product is further conventionally purified through rectification to obtain the benzonitrile product. The purity of the benzonitrile product is greater than 99.5%,The yield was 95.0%.

Reference： [1]Current Patent Assignee: HUBEI UNIVERSITY - CN110818590, 2020, A Location in patent: Paragraph 0065-0104
[2]Mai, Khuong; Patil, Ghanshyam [Tetrahedron Letters, 1986, vol. 27, # 20, p. 2203 - 2206]
[3]Ahmed, Jasimuddin; Hota, Pradip Kumar; Maji, Subir; Mandal, Swadhin K.; Rajendran, N. M. [Chemical Communications, 2020, vol. 56, # 4, p. 575 - 578]
[4]Ruan, Shixiang; Ruan, Jiancheng; Chen, Xinzhi; Zhou, Shaodong [Molecular catalysis, 2021, vol. 499]
[5]Liu, Richard Y.; Bae, Minwoo; Buchwald, Stephen L. [Journal of the American Chemical Society, 2018, vol. 140, # 5, p. 1627 - 1631]
[6]Current Patent Assignee: CHINA PETROCHEMICAL CORPORATION - CN104557357, 2018, B Location in patent: Paragraph 0150; 0151; 0152; 0155
[7]Manjula, Krishnappa; Pasha, Mohamed Afzal [Synthetic Communications, 2007, vol. 37, # 9, p. 1545 - 1550]
[8]Ren, Shishuai; Wang, Yangyang; Yang, Fei; Sun, Hongjian; Li, Xiaoyan [Catalysis Communications, 2019, vol. 120, p. 72 - 75]
[9]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN112961079, 2021, A Location in patent: Paragraph 0081-0083
[10]Current Patent Assignee: SANOFI - US4385006, 1983, A
[11]Keita, Massaba; Vandamme, Mathilde; Paquin, Jean-François [Synthesis, 2015, vol. 47, # 23, p. 3758 - 3766]
[12]Current Patent Assignee: ZHEJIANG UNIVERSITY - CN112028726, 2020, A Location in patent: Paragraph 0033-0054; 0061-0065

6
[ 619-57-8 ]
[ 106-51-4 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium hydrogen sulfate; [bis(acetoxy)iodo]benzene In water; acetonitrile at 20℃; for 0.75h;	GENERAL PROCEDURE. General procedure for synthesis of benzoquinone derivatives. General procedure: (Diacetoxyiodo) benzene (5 mmol, 1.61g) and NaHSO4.H2O (1mmol, 0.138g) were stirred for 10-15 min, at room temperature in aqueous solution of acetonitrile (5 ml water and 5 mlacetonitrile). In this reaction mixture benzamide (1mmol) was added and stirring was continuing till reaction goes to completion (TLC). After completion of reaction, the reaction mixture was quenched with water and further extracted with chloroform (3×10 ml). The combined chloroform layers were washed with water (3×20ml) dried over Na2SO4, and concentrated on rota-evaporator to get the crude residue. The residue was further purified by column chromatography on silica gel using ethyl acetate: hexane (1:9) as an eluent to afford pure benzoquinone.
23%	With potassium nitrososulfonate; PO₄HNa₂-PO₄H₂Na In chloroform further p-hydroxybenzamides;

Reference： [1]Sasane, Kulbhushan A.; Telvekar, Vikas N. [Synthetic Communications, 2014, vol. 44, # 4, p. 468 - 473]
[2]Saa, Jose M.; Llobera, Antonia; Deya, Pedro M. [Chemistry Letters, 1987, p. 771 - 774]

7
[ 767-00-0 ]
[ 619-57-8 ]

Yield	Reaction Conditions	Operation in experiment
99%	With Wilkinson's catalyst; Acetaldehyde oxime In toluene at 110℃;
99%	With Wilkinson's catalyst; Acetaldehyde oxime In toluene at 110℃; for 4h;
98%	With water at 120℃; for 40h; Inert atmosphere;

96%	With Acetaldehyde oxime; nickel(II) chloride hexahydrate; water for 8h; Reflux; chemoselective reaction;
95%	With Acetaldehyde oxime; copper(II) oxide In water for 12h; Reflux;	Experimental Procedures for Hydration of Various Nitriles General procedure: To a 25 mL round-bottom flask equipped with magnetic stirrer were added nitrile (2.5 mmol), acetaldoxime (3.75 mmol), copper oxide (0.25 mmol) and H2O (10 mL). The mixture was heated to reflux for 2-14 h. After cooling to room temperature, the solution was directly evaporated to dryness and the residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give the corresponding amides. The commercially available amides were characterised by melting points, 2-amino-5-bromobenzamide (Table 2, entry 6) and 3,4-dichloropicolinamide (Table 2, entry 13) were characterised by NMR spectra and LC-MS.
92%	With dichloro( 1,5-cyclooctadiene)platinum(ll); 4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]phosphepine-4-oxide; water; silver nitrate In tert-Amyl alcohol at 80℃; for 1h; chemoselective reaction;
92%	With water; [RuCl₂(dmso)₃(NH₃)]PF₆Cl at 60℃; for 24h;
91%	With rhodium(III) chloride hydrate; water; (1,3,5-triaza-7-phosphaadamantane) at 100℃; for 24h; Green chemistry;	1.1f Example 1 The catalytic activity of 5 mol % [RuCl2(PTA)4] toward nitrile hydration was evaluated in aqueous solution at 100 ° C. with 1 mmol nitrile in a culture tube under air (Scheme 2). Under the conditions described here, RuCl3 (5 mol %) provided a 54% conversion of benzonitrile to benzamide in 24 hours. Benzonitrile hydration by 2 mol % RuCl3 was previously reported to yield 28% benzamide after 3 h at 130° C. No hydration was observed in the absence of a catalyst, or with PTA, [RuCl2(η6-toluene)]2, or [RuCl2(PPh3)3] as catalysts. Benzonitrile hydration by [RuCl2(PTA)4] did not occur at 50° C. and provided only 23% conversion after 24 h at 75° C. The hydration of benzonitrile catalyzed by [RuCl2(PTA)4] showed a >99% conversion to benzamide at 100° C. after 7 hours, in contrast to the inactive [RuCl2(PPh3)3], potentially demonstrating a cooperative effect of the nitrogen-containing PTA versus PPh3. For comparison, nitrile hydration catalyzed by 5 mol % [RuCl2(η6-arene)(PTA)] (η6-arene=benzene, p-cymene, 1,3,5-trimethylbenzene, and hexamethylbenzene), showed >98% conversions in 4-9 h for aqueous benzonitrile hydration under N2 at 100° C. An in situ generated catalyst formed by the addition of RuCl3 hydrate with 6 equivalence of PTA provided results similar to the preformed complex RuCl2PTA4 (Table 1).The conversion of various nitriles (1a-1n) to the corresponding amides (2a-2n) was explored with results summarized in Table 1. All nitriles were efficiently converted to amides with 67-99% conversion in 7 hours and >99% conversions by 24 hours, with the exception of 2-cyanopyridine (1j, 81% after 24 h). After completion, the reaction was cooled to 0° C. and, in most cases, the product amides crystallized out as white needles and were easily isolated in 67-81% yield by decantation. Identity of the isolated amides (2a-2n) was confirmed by GC-MS and NMR spectroscopy. Substituted benzonitriles bearing electron-withdrawing groups (Table 1 above, entries 1g-1i) exhibited slightly more efficient conversions to amides than those with electron-donating groups (entries 1b-1f). Presumably, the presence of the electron-withdrawing group makes the nitrile carbon more susceptible to nucleophilic attack by an activated water molecule. As previously reported for ortho-substituted benzonitriles, o-tolunitrile exhibited lower conversion relative to m- and p-tolunitriles (Table 1, entries 1b-1d), which is attributed to steric hindrance of the o-tolunitriles. Hydration of 4-cyanobenzaldehyde led to 4-formylbenzamide in a 99% conversion in 7 h with an intact formyl moiety (entry 1i). The coordinating ability of the pyridyl functionality reduced catalytic activity as hydration of 2-cyanopyridine to picolinamide resulted in only 81% conversion after 24 h (entry 1j).[RuCl2(PTA)4] was also effective as a hydration catalyst for the less reactive aliphatic nitriles (Table 1, entries 1k-1m). 4-Methylbenzyl cyanide was transformed with 99% conversion in 7 hours (entry 1k) into the amide. Hydration of the sterically bulky pivalonitrile (1m) to pivalamide proceeded with a 99% conversion in 24 h although a modest conversion of 67% was observed after 7 h (entry 1m). The resistance of tertiary nitriles toward hydrolysis has been noted. The industrially important acrylonitrile was almost quantitatively converted into acrylamide in 7 hours without observation of polymerization or hydrolysis byproducts (Table 1, entry 1n). For all the nitrile hydrations studied, the corresponding amides were the only product observed (no carboxylic acids were detected by GC-MS). Thus, the catalytic conditions described here are compatible with ether (entry 1e), hydroxyl (entry 10, nitro (entry 1g), bromo (entry 1h), formyl (entry 1i), pyridyl (entry 1j), benzyl (entry 1k), alkyl (entries 1l-1m), and olefinic (entry 1n) functional groups, which establishes a wide synthetic scope.
90%	With [RuCl₂(PTA)4]; water at 100℃; for 24h;
89%	With sodium tetrahydroborate In ethanol; water at 80℃; for 8h;
87%	With trans-[RuCl₂(1,3,5-triaza-7-phosphatricyclo[3.3.1.1^3,7]decane)₄] In aq. phosphate buffer at 100℃; for 1.75h; Sealed tube; Green chemistry;
85%	With [2,2]bipyridinyl; water; palladium diacetate at 70℃; for 24h; Schlenk technique; Sealed tube;	General Procedure XII - Synthesis of Primary Amide Products in Water General procedure: To an oven dried Schlenk carousel tube containing the appropriate nitrile (1 mmol) was added palladium acetate (11 mg, 5 mol%), 2,2'-bipyridine (7.8 mg, 5 mol%) and water (2 mL, 0.5 M). The tube was then sealed and the reaction mixture heated at 70 °C for 24 hours. After being allowed to cool to room temperature, the reaction mixture was diluted with methanol (5 mL) and the solvent removed in vacuo on a rotary evaporator whilst azeotroping with toluene. Where the reaction had gone to quantitative conversion or the starting nitrile was volatile, the crude reaction mixture was passed through a short plug of silica to remove the catalyst (eluting with DCM/MeOH, 95:5). Otherwise, the primary amide products were purified by column chromatography (eluting with DCM/MeOH, 95:5, unless otherwise stated).
83%	With N-ethyl-N-hydroxy-ethanamine; water at 100℃; for 5h;
81%	With C₄₃H₄₂Cl₂NRu; water at 20℃; for 4h;
78%	With [Ru(OTf){η⁶:κ¹(P)-PPh₂-binaphthyl}{PPh₂(OH)}][OTf] In water at 100℃; for 5h; Inert atmosphere; Sealed tube;
73%	With [RuCl₂(η³:η³-C₁₀H₁₆){PMe₂(OH)}]; water at 60℃; for 7h; Inert atmosphere; Schlenk technique; Sealed tube;
73%	With [RuCl₂(η³:η³-2,7-dimethylocta-2,6-diene-1,8-diyl)(PMe₂OH)] In water at 60℃; for 7h; Inert atmosphere; Sealed tube;
71%	With water at 110℃; for 6h;	2.2 General Procedure for Hydration of Nitriles to Amides General procedure: Two milli liter water at room temperature was added to astirred mixture of nitrile (1mmol) and catalyst (40mg) thenheated with an oil bath maintained at 110°C, and stirred. After completion of the reaction (monitored by TLC), thecatalyst was removed from the reaction mixture by externalmagnet. Then the mixture was extracted with ethyl acetate,subsequently purified by column chromatography on silicagel to provide the corresponding amide products.
65%	With [(η⁶-toluene)RuCl(κ²-(P,N)-(1,3,5-triaza-7-phosphaadamantan-6-yl)CPh₂NHPh)]Cl; water at 100℃; for 7h;
61%	With sodium perborate; water In methanol at 50℃;
60%	With oxygen; copper; ammonium bromide In chlorobenzene at 75℃; Sealed tube;	14 Synthesis Example 14 Synthesis of 4-hydroxybenzamide In the reaction vessel was added 10mol% Cu, the reaction tube was evacuated, filled with oxygen,In an oxygen atmosphere, 0.2 mmol of 4-hydroxybenzonitrile, 0.4 mmol of ammonium bromide and 2 ml of chlorobenzene were added, the reaction vessel was sealed, and reacted at 75 ° C,After the reaction is completed, it is washed with water, extracted with ethyl acetate, dried and concentrated under reduced pressure to remove the solvent. The crude product is separated by column chromatography to give the desired product in a yield of 60%.
53%	With manganese(IV) oxide; silica gel for 0.2h; microwave irradiation;
50%	With acetamide; zinc(II) chloride In tetrahydrofuran; water for 0.00833333h; microwave irradiation;
50%	With ammonium hydroxide; cesiumhydroxide monohydrate at 100℃; for 24h; Schlenk technique; Sealed tube;
33%	With manganese(IV) oxide; silica gel In chlorobenzene for 5h; Heating;
	With nitrile hydratase from Rhodopseudomonas palustris CGA₀₀₉ In dimethyl sulfoxide at 30℃; for 17h; aq. phosphate buffer; chemoselective reaction;
96 %Chromat.	With water at 80℃; for 10h; chemoselective reaction;
	With [Ru(η⁶-p-cymene)Cl₂(tris(dimethylamino)phosphine)]; water In tetrahydrofuran at 70℃; Inert atmosphere;
	With C₄₀H₄₅ClN₃O₂PRu In methanol; water at 20℃; for 4h; Inert atmosphere; Schlenk technique; Green chemistry;	4.7. General procedure for the hydration of nitriles to amides General procedure: Organic nitrile (1 mmol) and distilled water (1 mL) were sequentially added to 3 mL methanol solution of the [Ru-NHC] catalyst (0.5 mol%) and the reaction mixture was stirred at room temperature. The progress of the reaction in each case was monitored by TLC analysis. After completion of reaction the catalyst was extracted from the reaction mixture by the addition of CH2Cl2/petroleum ether followed by filtration. The filtrate was subjected to GC analysis and the product was identified with authentic samples.

Reference： [1]Lee, Jinwoo; Kim, Min; Chang, Sukbok; Lee, Hee-Yoon [Organic Letters, 2009, vol. 11, # 24, p. 5598 - 5601]
[2]Kang, Dahye; Lee, Jinwoo; Lee, Hee-Yoon [Organic Syntheses, 2012, vol. 89, p. 66 - 72]
[3]Matsuoka, Aki; Isogawa, Takahiro; Morioka, Yuna; Knappett, Benjamin R.; Wheatley, Andrew E. H.; Saito, Susumu; Naka, Hiroshi [RSC Advances, 2015, vol. 5, # 16, p. 12152 - 12160]
[4]Location in patent: experimental part Ma, Xiaoyun; He, Ying; Wang, Pengcheng; Lu, Ming [Applied Organometallic Chemistry, 2012, vol. 26, # 7, p. 377 - 382]
[5]Ma, Xiao-Yun; He, Ying; Hu, Yu-Lin; Lu, Ming [Tetrahedron Letters, 2012, vol. 53, # 4, p. 449 - 452]
[6]Gulyás, Henrik; Rivilla, Ivan; Curreli, Simona; Freixa, Zoraida; Van Leeuwen, Piet W. N. M. [Catalysis science and technology, 2015, vol. 5, # 7, p. 3822 - 3828]
[7]Trivedi, Manoj; Dubey, Santosh Kumar; Kaur, Gurmeet; Rath, Nigam P. [New Journal of Chemistry, 2021, vol. 45, # 37, p. 17339 - 17346]
[8]Current Patent Assignee: NEVADA SYSTEM OF HIGHER EDUCATION - US2013/96344, 2013, A1 Location in patent: Paragraph 0030; 0031; 0032; 0033; 0034
[9]Lee, Wei-Chih; Frost, Brian J. [Green Chemistry, 2012, vol. 14, # 1, p. 62 - 66]
[10]Verma, Praveen Kumar; Kumar, Neeraj; Sharma, Upendra; Bala, Manju; Kumar, Vishal; Singh, Bikram [Synthetic Communications, 2013, vol. 43, # 21, p. 2867 - 2875]
[11]Ounkham, Whalmany L.; Weeden, Jason A.; Frost, Brian J. [Chemistry - A European Journal, 2019, vol. 25, # 42, p. 10013 - 10020]
[12]Sanz Sharley, Daniel D.; Williams, Jonathan M.J. [Tetrahedron Letters, 2017, vol. 58, # 43, p. 4090 - 4093]
[13]Location in patent: experimental part Ma, Xiao-Yun; Lu, Ming [Journal of Chemical Research, 2011, vol. 35, # 8, p. 480 - 483]
[14]Nirmala, Muthukumaran; Adinarayana, Mannem; Ramesh, Karupnaswamy; Maruthupandi, Mannarsamy; Vaddamanu, Moulali; Raju, Gembali; Prabusankar, Ganesan [New Journal of Chemistry, 2018, vol. 42, # 18, p. 15221 - 15230]
[15]Toms-Mendivil, Eder; Menndez-Rodrguez, Luca; Francos, Javier; Crochet, Pascale; Cadierno, Victorio [RSC Advances, 2014, vol. 4, # 108, p. 63466 - 63474]
[16]Tomás-Mendivil, Eder; Suárez, Francisco J.; Díez, Josefina; Cadierno, Victorio [Chemical Communications, 2014, vol. 50, # 68, p. 9661 - 9664]
[17]Tomás-Mendivil, Eder; Francos, Javier; González-Fernández, Rebeca; González-Liste, Pedro J.; Borge, Javier; Cadierno, Victorio [Dalton Transactions, 2016, vol. 45, # 34, p. 13590 - 13603]
[18]Kazemi Miraki, Maryam; Arefi, Marzban; Salamatmanesh, Arefeh; Yazdani, Elahe; Heydari, Akbar [Catalysis Letters, 2018, vol. 148, # 11, p. 3378 - 3388]
[19]Lee, Wei-Chih; Sears, Jeremiah M.; Enow, Raphel A.; Eads, Kelly; Krogstad, Donald A.; Frost, Brian J. [Inorganic Chemistry, 2013, vol. 52, # 4, p. 1737 - 1746]
[20]McKillop, Alexander; Kemp, Duncan [Tetrahedron, 1989, vol. 45, # 11, p. 3299 - 3306]
[21]Current Patent Assignee: HUBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY - CN106478442, 2017, A Location in patent: Paragraph 0064; 0065; 0066
[22]Khadilkar, Bhushan M.; Madyar, Virendra R. [Synthetic Communications, 2002, vol. 32, # 11, p. 1731 - 1734]
[23]Manjula, Krishnappa; Pasha, Mohamed Afzal [Synthetic Communications, 2007, vol. 37, # 9, p. 1545 - 1550]
[24]Li, Yang; Chen, Haonan; Liu, Jianping; Wan, Xujun; Xu, Qing [Green Chemistry, 2016, vol. 18, # 18, p. 4865 - 4870]
[25]Khadilkar, Bhushan M.; Madyar, Virendra R. [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2003, vol. 42, # 11, p. 2814 - 2819]
[26]Location in patent: experimental part Black, Gary W.; Gregson, Thomas; McPake, Christopher B.; Perry, Justin J.; Zhang, Meng [Tetrahedron Letters, 2010, vol. 51, # 13, p. 1639 - 1641]
[27]Location in patent: scheme or table Liu, Yong-Mei; He, Lin; Wang, Miao-Miao; Cao, Yong; He, He-Yong; Fan, Kang-Nian [ChemSusChem, 2012, vol. 5, # 8, p. 1392 - 1396]
[28]Knapp, Spring Melody M.; Sherbow, Tobias J.; Yelle, Robert B.; Zakharov, Lev N.; Juliette, J. Jerrick; Tyler, David R. [Organometallics, 2013, vol. 32, # 3, p. 824 - 834]
[29]Nirmala, Muthukumaran; Saranya, Gandhi; Viswanathamurthi, Periasamy [Inorganica Chimica Acta, 2016, vol. 442, p. 134 - 144]

8
[ 619-57-8 ]
[ 109-70-6 ]
[ 111627-48-6 ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium carbonate In acetone for 24h; Heating;
95%	With potassium carbonate In ethyl acetate for 24h; Reflux;
82%	With potassium carbonate In acetonitrile for 4h; Industry scale; Reflux;	1 10.5 kg of 4-hydroxybenzamide, 10.58 kg of potassium carbonate and 83 kg of acetonitrile are introduced into a reactor. The mixture is stirred and then there are added 24.14 kg of a solution of 1-bromo-3-chloropropane. The reaction mixture is heated at reflux for 4 hours. Water (105 L) is added in the hot state, the mixture is then cooled to 5° C. and filtered. The filter cake is washed with water and then with acetonitrile. The title product is obtained in the form of a powder in a yield of 82%.Melting point: 144° C.

75.5 g (97%)	With potassium carbonate In water; acetone	39 4-(3-Chloropropoxy)benzamide PREPARATION 39 4-(3-Chloropropoxy)benzamide A mixture of 50 g (0.365 mole) of 4-hydroxybenzamide, 114.8 g (0.729 mole) of 1-bromo-3-chloropropane and 151.3 g (1.1 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 20 hr. The mixture was concentrated under reduced pressure and the residue was stirred with 1.2 liter of water to remove inorganic solids. The mixture was filtered and the filter cake was washed with water and petroleum ether and dried to yield 75.5 g (97%) of white solid. The solid was recrystallized from ethyl acetate, m.p. 142°-145° C. Analysis: Calculated for C10 H12 ClNO2: C, 56.22; H, 5.66; N, 6.56. Found: C, 55.92; H, 5.61; N, 5.56.
	With caesium carbonate In acetonitrile for 5h; Reflux;	1.A.1 EXAMPLE 1; Synthesis Route A: 4-{3-[(1R,5S)-3-Azabicyclo[3.1.0]hex-3-yl]propoxy}-benzamide hydrochloride; Step 1: 4-(3-Chloropropoxy)benzamide; A mixture composed of 0.004 mole of 4-hydroxybenzamide, 0.004 mole of 1-bromo-3-chloropropane and 0.006 mole of caesium carbonate in 10 ml of acetonitrile is heated at reflux for 5 hours.
	With potassium carbonate In butanone at 80℃;
	With caesium carbonate In acetonitrile for 5h; Reflux;	1.A.1 A mixture composed of 0.004 mol of 4-hydroxybenzamide, 0.004 mol of 1-bromo-3-chloropropane and 0.006 mol of caesium carbonate in 10 ml of acetonitrile is heated at reflux for 5 hours
	With caesium carbonate In acetonitrile for 5h; Reflux;	1.A.1 Step 1: 4-(3-Chloropropoxy)benzamide; A mixture composed of 0.004 mol of 4-hydroxybenzamide, 0.004 mol of 1-bromo-3-chloropropane and 0.006 mol of caesium carbonate in 10 ml of acetonitrile is heated at reflux for 5 hours.
	With potassium carbonate In butanone for 48h; Heating / reflux;	1.1 A mixture of 4-hydroxybenzamide (5 g, 36.5 mmol, 1 eq), potassium carbonate (10.08 g, 72.9 mmol, 2 eq), 3-chloro-l-bromopropane (4.7 ml, 47.4 mmol, 1.3 eq) in butanone is stirred at reflux for 48 h. The solvent is then removed under vacuum and the residue is triturated in hexane and filtered. The solid is taken up in ethyl acetate and washed with a saturated solution of sodium hydrogencarbonate. The organic layer is dried over magnesium sulfate and concentrated to give 4-(3-chloropropoxy)benzamide ax54 (6.8 g) as a white solid.Yield: 87 %.LC-MS (MH+): 214/216.

Reference： [1]Walsh, David A.; Franzyshen, Stephen K.; Yanni, John M. [Journal of Medicinal Chemistry, 1989, vol. 32, # 1, p. 105 - 118]
[2]Location in patent: scheme or table Denonne, Frederic; Celanire, Sylvain; Christophe, Bernard; Defays, Sabine; Delaunoy, Christel; Delporte, Marie-Laure; Detrait, Eric; Durieu, Veronique; Gillard, Michel; Lamberty, Yves; Lorent, Genevieve; Nicolas, Jean-Marie; van Bellinghen, Alain; van Houtvin, Nathalie; Provins, Laurent [ChemMedChem, 2011, vol. 6, # 9, p. 1559 - 1565]
[3]Current Patent Assignee: SERVIER MONDE - US2012/316214, 2012, A1 Location in patent: Page/Page column 4
[4]Current Patent Assignee: PFIZER INC - US4950674, 1990, A
[5]Current Patent Assignee: SERVIER MONDE - US2009/312389, 2009, A1 Location in patent: Page/Page column 3
[6]Location in patent: scheme or table Denonne, Frederic; Atienzar, Franck; Celanire, Sylvain; Christophe, Bernard; Delannois, Frederique; Delaunoy, Christel; Delporte, Marie-Laure; Durieu, Vronique; Gillard, Michel; Lallemand, Bndicte; Lamberty, Yves; Lorent, Genevive; Vanbellinghen, Alain; Van Houtvin, Nathalie; Verbois, Valrie; Provins, Laurent [ChemMedChem, 2010, vol. 5, # 2, p. 206 - 212]
[7]Current Patent Assignee: SERVIER MONDE - US2011/136886, 2011, A1 Location in patent: Page/Page column 3
[8]Current Patent Assignee: SERVIER MONDE - US2012/283245, 2012, A1 Location in patent: Page/Page column 4
[9]Current Patent Assignee: UCB - WO2006/103045, 2006, A1 Location in patent: Page/Page column 84

9
[ 619-57-8 ]
[ 106-89-8 ]
[ 28763-58-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In butanone Heating;
	With potassium carbonate In DMF (N,N-dimethyl-formamide) at 70℃; for 18h;	26 Example 26: Synthesis of [3-AMINO-6- {4- [3- (4-CARBAMOYL-PHENOXY)-2-HYDROXY-] [PROPYLAMINO]-PIPERIDIN-1-YL}-4-PROPYL-THIENO] [2, 3-b] pyridine-2-carboxylic acid amide To a sealed tube was added 4-hydroxybenzamide (200 mg, 1.458 mmol), epichlorohydrin (135 mg, 1.458 mmol) and potassium carbonate (403 mg, 2.916 mmol) in 7 mL of dry DMF. The reaction mixture was stirred at [70 °C] for 18 h. The reaction mixture was filtered and concentrated. The residue was purified by flash chromatography, eluting with 0-5% 2M [NH3] in [MEOH/CH2CL2.] The product fractions were collected and concentrated to afford 80 mg of 4-oxiranylmethoxy-benzamide as a white solid.

Reference： [1]Vanotti, E.; Bani, M.; Favara, D.; Gobetti, M.; Lombroso, M.; et al. [European Journal of Medicinal Chemistry, 1994, vol. 29, # 4, p. 287 - 294]
[2]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG; PTP GROUP LTD - WO2003/103661, 2003, A1 Location in patent: Page 111-112

10
[ 123-08-0 ]
[ 619-57-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	With aluminum oxide; hydroxylamine hydrochloride; methanesulfonyl chloride at 100℃; for 1.5h;
95%	With hydroxylamine hydrochloride In acetonitrile for 0.0636111h; Microwave irradiation;
91%	With hydroxylamine hydrochloride; methanesulfonyl chloride In neat (no solvent) at 70℃; for 3.5h;

90%	With hydroxylamine hydrochloride; C₂₇H₂₇ClIrNO; sodium hydrogencarbonate In dimethyl sulfoxide at 50℃; for 6h;
89%	With hydroxylamine hydrochloride; C₂₁H₂₇ClIrNO; sodium hydrogencarbonate In water at 50℃; for 6h;
87%	With iron(III) chloride; hydroxylamine hydrochloride; caesium carbonate In water at 100℃; for 25h; chemoselective reaction;
87%	With C₃₁H₂₈ClNRuS; hydroxylamine hydrochloride; sodium hydrogencarbonate In toluene for 18h; Inert atmosphere; Reflux;	4.5. General procedure for the conversion of aldehyde to amide General procedure: Under a nitrogen atmosphere, the reaction vessel was chargedwith aldehyde (1 mmol), NaHCO3 (1 mmol), NH2OH.HCl (1 mmol)and ruthenium catalyst (0.01 mmol) and the mixture was refluxedin toluene for 18 h. The reaction mixture was cooled to roomtemperature. On completion of the reaction, 2mL of methanol wasadded to the mixture, followed by filtration through celite toremove the NaHCO3 and ruthenium catalyst. The crude product was then purified by column chromatography (CH2Cl2/MeOH, 1:1 ratio) over silica gel using as solid phase, providing the amide in good yield. The identity of the resulting amides was assessed by comparison of their 1H NMR spectroscopic data with those reported in the literature [52].
85%	With triacetonitrile 4′-(4-chlorophenyl)-2,2′:6′,2″-terpyridine ruthenium(II) nitrate; hydroxylamine hydrochloride; sodium acetate In water at 100℃; for 11h; Inert atmosphere;
80%	With alumina sulfuric acid; hydroxylamine hydrochloride at 150℃; for 4h;
80%	With nitromethane; trifluoromethylsulfonic anhydride; acetic acid In formic acid at 80 - 120℃;	54 Example 54 p-Hydroxybenzamide Take a reaction tube, add 60-100mg (1.2mmol) of nitromethane, 30-40mg (0.3mmol) of p-hydroxybenzaldehyde, 0.5mL of acetic acid,Trifluoromethanesulfonic anhydride 150-200mg (0.6mmol), formic acid 30-60mg (0.75mmol), stirred at 80-120°C for 1-72 hours. After the reaction was completed, 10 mL of sodium hydroxide solution was added to quench the reaction, extracted with ethyl acetate 3 times, the organic phase was washed with 5 mL of brine, and the organic phases were combined and separated by column chromatography to obtain 32.9 mg of p-hydroxybenzamide with a yield of 80%.
80%	With formic acid; nitromethane; trifluoromethylsulfonic anhydride In acetic acid at 100℃; for 12h;
79%	With [Ru(L₁)Cl(CO)(PPh₃)₂]; hydroxylamine hydrochloride; sodium hydrogencarbonate In toluene for 12h; Inert atmosphere; Reflux;	2.4 Representative procedure for the rearrangement of aldehydes to amides General procedure: Conversion of aldehydes to amides was carried out using the procedure described in the literature [34]. Under nitrogen atmosphere, the corresponding aldehyde (1mmol), NH2OH·HCl (1mmol), NaHCO3 (1mmol), toluene (3mL) and ruthenium(II) catalyst 1 (0.01mmol) were introduced into a RB flask, and the reaction mixture was stirred at 120°C in an oil bath for 12h. After the completion of reaction, 2-3mL of MeOH was added to the reaction mixture. The catalyst and NaHCO3 which settled down the flask was removed by filtration through Celite. The filtrate has been dried and the crude product was purified by the use of column chromatography (MeOH/CH2Cl2). Finally, the isolated amide was characterized by the aid of 1H NMR.
78%	With copper(ll) sulfate pentahydrate; hydroxylamine hydrochloride; sodium acetate at 110℃; for 6h; Neat (no solvent);	Typical procedure for synthesis of primary amide 1a from aldehyde 1: General procedure: To an intimate mixture of neat piperonal 1 (150 mg, 1 mmol), NH2OH.HCl (69 mg, 1 mmol) and NaOAc (90 mg, 1.1 mmol) taken in a dried round bottomed flask was added CuSO4.5H2O (13 mg, 5 mol %) and the mixture was heated at 110 °C on an oil bath with thorough stirring for 2 h (TLC monitoring). After cooling the reaction mixture, water (2 mL) was added to it to quench the reaction followed by extraction with EtOAc (3 × 6 mL). The combined extract was washed with brine (2 × 3 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product so obtained was filtered through a short pad of silica gel (60-120 mesh, Spectrochem, India) using EtOAc-n-hexane (1:1) as eluent to afford 3,4-methylenedioxybenzamide 1a as a white crystalline solid (161 mg, 98%), mp 166-168 °C (lit 169 °C).10
75%	With hydroxylamine hydrochloride; zinc(II) oxide at 140℃; for 1h;
75%	With C₂₉H₂₉ClN₂ORu; hydroxylamine hydrochloride; sodium hydrogencarbonate In acetonitrile at 78℃; for 5h; Inert atmosphere;	4.3. Typical procedure for the one-pot conversion of aldehydes toamides General procedure: To an oven-dried round-bottom flask equipped with magneticstirring bar was added complex (1) (1 mol%), the aldehyde(1 mmol), NH2OHHCl (1 mmol) and NaHCO3 (1 mmol) and themixture was placed under an atmosphere of N2. Dry and degassedMeCN (2 mL) was added and the reaction mixture was refluxed forthe time specified under an N2 atmosphere. The reaction wascooled to room temperature and the solvent evaporated. The residuewas dissolved in CH2Cl2, filtered and the solvent removed. Thecrude product was then purified using silica gel chromatography(CHCl3/MeOH) giving the amides in high isolated yields. Characterizationdetails for each amide are given in the supporting informationS16-S20.
70%	With hydroxylamine hydrochloride at 140℃; for 2h;
70%	With hydroxylamine hydrochloride; C₃₀H₃₀ClNO₂Ru; sodium hydrogencarbonate In acetonitrile for 7h; Reflux; Inert atmosphere;	4.3. Typical procedure for the one-pot conversion of aldehydes toamides General procedure: The reaction mixture containing complex catalyst 2 (1 mol%),the aldehyde (1 mmol), NH2OHHCl (1 mmol) and NaHCO3(1 mmol) in 5 mL of acetonitrile was refluxed for the time specifiedunder an N2 atmosphere. Then, the resulting was cooled to roomtemperature and the solvent was evaporated. The residue obtainedwas dissolved in CH2Cl2 and the solvent was removed. The crudeproduct was then purified using silica gel chromatography usingCHCl3/MeOH as an eluent.
67%	With hydroxylamine hydrochloride; caesium carbonate In tetrahydrofuran; water at 0 - 250℃; for 0.0833333h;
36%	With tert.-butylhydroperoxide; titanium superoxide; saccharin In 1,4-dioxane; hexane at 90℃; for 1h; Green chemistry;
75 % Spectr.	Stage #1: 4-hydroxy-benzaldehyde With aluminum oxide; methanesulfonic acid at 100℃; Stage #2: With hydroxylamine hydrochloride at 140℃; for 3.5h;
	With C₃₃H₂₇ClN₃OPRu; hydroxylamine hydrochloride; sodium hydrogencarbonate In toluene at 20 - 110℃; for 8.25h; Inert atmosphere; Schlenk technique;	2.7 Representative procedure for ruthenium-catalyzedaldehydes to amides conversion General procedure: The reaction vessel was charged with aldehyde (1mmol), NH2OH·HCl (1 mmol), NaHCO3 (1 mmol),[Ru-NHC] catalyst (0.5 mol %) and the mixture wasplaced under an atmosphere of N2. About 2 mL of dryand degassed toluene was added and the mixture wasstirred for 15 min at room temperature followed byreflux for 8 h. On completion of the reaction, 2-3 mLmethanol was added to the mixture followed by filtrationthrough Celite to remove the catalyst and NaHCO3.The crude product was then purified by column chromatography(MeOH/CH2Cl2, 1:1) using silica (200-400 mesh) as solid phase provided the amide in goodyield. The resultant amide solution was subjected to GCanalysis and the product was identified in comparisonwith authentic samples
94 %Chromat.	With hydroxylamine hydrochloride; C₂₇H₂₆Cl₂NORh; sodium hydrogencarbonate In water at 39.84℃; for 2h;

Reference： [1]Sharghi, Hashem; Sarvari, Mona Hosseini [Tetrahedron, 2002, vol. 58, # 52, p. 10323 - 10328]
[2]Location in patent: experimental part Datta, Bandita; Pasha [Bulletin of the Korean Chemical Society, 2012, vol. 33, # 7, p. 2129 - 2130]
[3]Khalafi-Nezhad, Ali; Mohammadi, Somayeh [RSC Advances, 2014, vol. 4, # 27, p. 13782 - 13787]
[4]Fan, Xiao-Nan; Deng, Wei; Liu, Zhen-Jiang; Yao, Zi-Jian [Inorganic Chemistry, 2020, vol. 59, # 22, p. 16582 - 16590]
[5]Wang, Yang; Guo, Wen; Guan, Ai-Lin; Liu, Shuang; Yao, Zi-Jian [Inorganic Chemistry, 2021, vol. 60, # 15, p. 11514 - 11520]
[6]Gowda, Ravikumar R.; Chakraborty, Debashis [European Journal of Organic Chemistry, 2011, # 12, p. 2226 - 2229]
[7]Premkumar, Muniyappan; Vijayan, Paranthaman; Venkatachalam, Galmari [Journal of Organometallic Chemistry, 2019, vol. 902]
[8]Joarder, Dripta De; Gayen, Subrata; Sarkar, Rajarshi; Bhattacharya, Rajarshi; Roy, Sima; Maiti, Dilip K. [Journal of Organic Chemistry, 2019, vol. 84, # 13, p. 8468 - 8480]
[9]Hosseini-Sarvari, Mona; Sharghi, Hashem [Journal of Chemical Research, 2006, # 3, p. 205 - 208]
[10]Current Patent Assignee: PEKING UNIVERSITY - CN112574054, 2021, A Location in patent: Paragraph 0282-0284
[11]Jiao, Ning; Liu, Jianzhong; Qiu, Xu; Song, Song; Wei, Jialiang; Wen, Xiaojin; Zhang, Cheng; Zhang, Ziyao [Science, 2020, vol. 367, # 6475, p. 281 - 285]
[12]Vinoth, Govindasamy; Indira, Sekar; Bharathi, Madheswaran; Sounthararajan, Muniyan; Sakthi, Dharmalingam; Bharathi, Kuppannan Shanmuga [Journal of Organometallic Chemistry, 2019, vol. 894, p. 67 - 77]
[13]Location in patent: experimental part Ganguly, Nemai C.; Roy, Sushmita; Mondal, Pallab [Tetrahedron Letters, 2012, vol. 53, # 11, p. 1413 - 1416]
[14]Sharghi, Hashem; Hosseini, Mona [Synthesis, 2002, # 8, p. 1057 - 1060]
[15]Nandhini, Raja; Venkatachalam, Galmari [Journal of Organometallic Chemistry, 2019, vol. 895, p. 15 - 22]
[16]Sharghi, Hashem; Hosseini Sarvari, Mona [Journal of Chemical Research - Part S, 2003, # 3, p. 176 - 178]
[17]Nagalakshmi, Veerasamy; Nandhini, Raja; Brindha, Veerappan; Krishnamoorthy, Bellie Sundaram; Balasubramani, Kasthuri [Journal of Organometallic Chemistry, 2020, vol. 912]
[18]Ambreen, Nida; Wirth, Thomas [European Journal of Organic Chemistry, 2014, vol. 2014, # 34, p. 7590 - 7593]
[19]Kamble, Rohit B.; Mane, Kishor D.; Rupanawar, Bapurao D.; Korekar, Pranjal; Sudalai; Suryavanshi, Gurunath [RSC Advances, 2019, vol. 10, # 2, p. 724 - 728]
[20]Sharghi; Sarvari [Journal of Chemical Research - Part S, 2001, # 10, p. 446 - 449]
[21]Nirmala, Muthukumaran; Viswanathamurthi, Periasamy [Journal of Chemical Sciences, 2016, vol. 128, # 11, p. 1725 - 1735]
[22]Jia, Wei-Guo; Li, Xiao-Dong; Zhi, Xue-Ting; Zhong, Rui [Applied Organometallic Chemistry, 2022, vol. 36, # 4]

11
[ 619-57-8 ]
C₂₀H₁₆N₈O₅ [ No CAS ]
C₂₁H₁₈N₈O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	Stage #1: p-hydroxybenzamide With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: C₂₀H₁₆N₈O₅ In N,N-dimethyl-formamide at 20℃;

Reference： [1]Wanner, Martin J.; Koch, Melle; Koomen, Gerrit-Jan [Journal of Medicinal Chemistry, 2004, vol. 47, # 27, p. 6875 - 6883]

12
[ 619-57-8 ]
[ 98-59-9 ]
[ 106473-33-0 ]

Yield	Reaction Conditions	Operation in experiment
72%	With sodium hydroxide In water at 20℃; for 20h;

Reference： [1]Klapars, Artis; Campos, Kevin R.; Chen, Cheng-Yi; Volante, Ralph P. [Organic Letters, 2005, vol. 7, # 6, p. 1185 - 1188]

13
[ 619-57-8 ]
[ 18162-48-6 ]
4-((tert-butyldimethylsilyl)oxy)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With 1H-imidazole In N,N-dimethyl-formamide at 20℃; Cooling with ice;
63%	With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 48h;

Reference： [1]Li, Min; Luo, Bingling; Liu, Qi; Hu, Yumin; Ganesan; Huang, Peng; Wen, Shijun [Organic Letters, 2014, vol. 16, # 1, p. 10 - 13]
[2]Qian, Hua; Widenhoefer, Ross A. [Organic Letters, 2005, vol. 7, # 13, p. 2635 - 2638]

14
[ 635731-89-4 ]
[ 619-57-8 ]
amino-4-(4-carbamoylphenoxymethyl)-6-methylthieno[2,3-b]pyridine-2-carboxylic acid amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 24h;
19%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 24h;	13 Example 13: Synthesis [OF AMINO-4- (4-CARBAMOYL-PHENOXYMETHYL)-6-METHYL-] thieno [2, [3-B] PYRIDINE-2-CARBOXYLIC] acid amide DIAD (23 mg, 0.116 mmol) was added to a solution of 3-amino-4-hydroxymethyl-6- methyl-thieno [2, [3-B] PYRIDINE-2-CARBOXYLIC] acid amide (see Example 12) (25 mg, 0.105 mmol), 4-hydroxy-benzamide (15 mg, 0.116 mmol), [ANDPH3P (30] mg, 0.116 mmol) in THF (2.5 mL) at [0 °C.] The mixture was warmed to room temperature and stirred for 24 h. The reaction mixture was concentrated and triturated with 2: 1 EtOAc: MeOH giving the title compound (7 mg, 19%) as an orange solid, m. p. > [250 °C.]

Reference： [1]Morwick, Tina; Berry, Angela; Brickwood, Janice; Cardozo, Mario; Catron, Katrina; DeTuri, Molly; Emeigh, Jonathan; Homon, Carol; Hrapchak, Matt; Jacober, Stephen; Jakes, Scott; Kaplita, Paul; Kelly, Terence A.; Ksiazek, John; Liuzzi, Michel; Magolda, Ronald; Mao, Can; Marshall, Daniel; McNeil, Daniel; Prokopowicz II, Anthony; Sarko, Christopher; Scouten, Erika; Sledziona, Cynthia; Sun, Sanxing; Watrous, Jane; Wu, Jiang Ping; Cywin, Charles L. [Journal of Medicinal Chemistry, 2006, vol. 49, # 10, p. 2898 - 2908]
[2]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG; PTP GROUP LTD - WO2003/103661, 2003, A1 Location in patent: Page 83

15
[ 619-57-8 ]
[ 1000700-36-6 ]

Yield	Reaction Conditions	Operation in experiment
17%	Stage #1: [2-(2,6-dichloroanilino)phenyl]acetic acid With benzotriazol-1-ol; dicyclohexyl-carbodiimide In chloroform; N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: p-hydroxybenzamide In N,N-dimethyl-formamide at 0 - 20℃; for 4h;	2 Synthesis of 4-carbamoylphenyl 2-[2-(2,6-dichlorophenylamino)-phenyl]acetate (5) Synthesis of 4-carbamoylphenyl 2-[2-(2,6-dichlorophenylamino)-phenyl]acetate (5) To the solution of 1 (diclofenac, 890 mg, 3.0 mmol) in 50 mL of N,N-dimethylformamide, hydroxybenzotriazole (445 mg, 3.3 mmol) and DCC (680 mg, 3.3 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture 4-hydroxybenzamide (4, 616 mg, 4.5 mmol) was added and stirred for 1 h at 0° C. and 3 hs at room temperature. After filtration, the filtrate was evaporated under reduced pressure and the oily residue thus obtained was dissolved in chloroform; the organic layer was washed with brine, dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude product 5 was loaded on a silica gel open column and eluted with CH2Cl2/MeOH (9/1), from which 4-carbamoylphenyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate (5) was obtained (212 mg, 17% yield).

Reference： [1]Current Patent Assignee: ANTIBE THERAPEUTICS, INC. - US2008/4245, 2008, A1 Location in patent: Page/Page column 10-11

16
[ 619-57-8 ]
[ 1000700-37-7 ]

Yield	Reaction Conditions	Operation in experiment
35%	Stage #1: lumiracoxib With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: p-hydroxybenzamide In N,N-dimethyl-formamide at 0 - 20℃; for 4h;	4 Synthesis of 4-carbamoylphenyl-2-(2-(2-chloro-6-fluorophenylamino)-5-methylphenyl)acetate (5) Synthesis of 4-carbamoylphenyl-2-(2-(2-chloro-6-fluorophenylamino)-5-methylphenyl)acetate (5) To the solution of 1 (lumiracoxib, 223 mg, 0.75 mmol) in 15 mL of dimethylformamide, hydroxybenzotriazole (111 mg, 0.825 mmol) and DCC (170 mg, 0.825 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture 4-hydroxybenzamide (4, 154 mg, 1.125 mmol) was added and stirred for 1 h at 0° C. and 3 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in chloroform; the organic layer was washed with brine, dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude product 5 was loaded on a silica gel open column and eluted with CH2Cl2/MeOH (9/1), from which 4-carbamoylphenyl-2-(2-(2-chloro-6-fluorophenylamino)-5-methylphenyl)acetate (5) was obtained (111 mg, 35% yield).

Reference： [1]Current Patent Assignee: ANTIBE THERAPEUTICS, INC. - US2008/4245, 2008, A1 Location in patent: Page/Page column 12

17
[ 619-57-8 ]
[ 1000700-38-8 ]

Yield	Reaction Conditions	Operation in experiment
47%	Stage #1: aspirin With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: p-hydroxybenzamide In N,N-dimethyl-formamide at 0 - 20℃; for 4h;	6 Synthesis of 4-carbamoylphenyl 2-acetoxybenzoate (5) Synthesis of 4-carbamoylphenyl 2-acetoxybenzoate (5) To the solution of 1 (acetylsalicylic acid, 500 mg, 2.77 mmol) in 15 mL of dimethylformamide, hydroxybenzotriazole (412 mg, 3.05 mmol) and DCC (628 mg, 3.05 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture 4-hydroxybenzamide (4, 418 mg, 3.05 mmol) was added and stirred for 1 h at 0° C. and 3 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in chloroform; the organic layer was washed with brine, dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude product 5 was loaded on a silica gel open column and eluted with CH2Cl2/MeOH (9/1), from which 4-carbamoylphenyl 2-acetoxybenzoate (5) was obtained (410 mg, 47% yield).

Reference： [1]Current Patent Assignee: ANTIBE THERAPEUTICS, INC. - US2008/4245, 2008, A1 Location in patent: Page/Page column 13

18
[ 619-57-8 ]
[ 1000700-39-9 ]

Yield	Reaction Conditions	Operation in experiment
12%	Stage #1: [1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: p-hydroxybenzamide In N,N-dimethyl-formamide at 0 - 20℃; for 3h;	8 Synthesis of 4-carbamoylphenyl-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-indol-3-yl]-acetate (5) Synthesis of 4-carbamoylphenyl-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-indol-3-yl]-acetate (5) To the solution of 1 (indomethacin, 3 g, 8.38 mmol) in 60 mL of dimethylformamide, hydroxybenzotriazole (1.25 g, 9.22 mmol) and DCC (1.9 g, 9.22 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture 4-hydroxybenzamide (4, 1.72 g, 12.6 mmol) was added and stirred for 1 h at 0° C. and 2 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in ethyl acetate; the organic layer was washed with brine, with NaHCO3 5%, with citric acid 10% and than dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude product 5 was loaded on a silica gel open column and eluted with CH2Cl2/MeOH (9.5/0.5), from which 4-carbamoylphenyl-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-indol-3-yl]-acetate (5) was obtained (479 mg, 12% yield).

Reference： [1]Current Patent Assignee: ANTIBE THERAPEUTICS, INC. - US2008/4245, 2008, A1 Location in patent: Page/Page column 14

19
[ 619-57-8 ]
[ 1000700-41-3 ]

Yield	Reaction Conditions	Operation in experiment
40%	Stage #1: ibuprofen With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: p-hydroxybenzamide In N,N-dimethyl-formamide at 0 - 20℃; for 3h;	11 Synthesis of 4-thiocarbamoylphenyl 2-(4-isobutylphenyl)propanoate (Compound XXIX) ;Synthesis of 4-thiocarbamoylphenyl 2-(4-isobutylphenyl)propanoate (Compound XXIX) To the solution of 1 (ibuprofen, 3.87 g, 18.8 mmol) in 80 mL of dimethylformamide, hydroxybenzotriazole (2.8 g, 20.7 mmol) and DCC (4.27 g, 20.7 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture 4-hydroxybenzamide (2, 3.9 g, 28 mmol) was added and stirred for 1 h at 0° C. and 2 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in ethyl acetate; the organic layer was washed with brine, with NaHCO3 5%, with citric acid 10% and than dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude product 3 was loaded on a silica gel open column and eluted with CH2Cl2/MeOH (9.5/0.5), from which 4-carbamoylphenyl 2-(4-isobutylphenyl)propanoate (3) was obtained (2.48 g, 40% yield).

Reference： [1]Current Patent Assignee: ANTIBE THERAPEUTICS, INC. - US2008/4245, 2008, A1 Location in patent: Page/Page column 16

20
[ 619-57-8 ]
[ 1000700-42-4 ]

Yield	Reaction Conditions	Operation in experiment
42%	Stage #1: ketoprofen With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: p-hydroxybenzamide In N,N-dimethyl-formamide at 0 - 20℃; for 3h;	12 Synthesis of 4-carbamoylphenyl 2-(4-oxophenyl)-phenyl propanoate (3) Synthesis of 4-carbamoylphenyl 2-(4-oxophenyl)-phenyl propanoate (3) To the solution of 1 (ketoprofen, 3 g, 11.8 mmol) in 80 mL of dimethylformamide, hydroxybenzotriazole (1.76 g, 13 mmol) and DCC (2.68 g, 13 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture 4-hydroxybenzamide (2, 2.43 g, 17.7 mmol) was added and stirred for 1 h at 0° C. and 2 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in ethyl acetate; the organic layer was washed with brine, with NaHCO3 5%, with citric acid 10% and than dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude product 3 was loaded on a silica gel open column and eluted with CH2Cl2/MeOH (9.5/0.5), from which 4-carbamoylphenyl 2-(4-oxophenyl)-phenyl propanoate (3) was obtained (1.84 g, 42% yield).

Reference： [1]Current Patent Assignee: ANTIBE THERAPEUTICS, INC. - US2008/4245, 2008, A1 Location in patent: Page/Page column 16-17

21
[ 619-57-8 ]
[ 1000700-43-5 ]

Yield	Reaction Conditions	Operation in experiment
37%	Stage #1: fluorobiprofen With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: p-hydroxybenzamide In N,N-dimethyl-formamide at 0 - 20℃; for 3h;	13 Synthesis of 4-carbamoylphenyl 2-(3-fluoro, 4-phenyl)phenyl propanoate (3) Synthesis of 4-carbamoylphenyl 2-(3-fluoro, 4-phenyl)phenyl propanoate (3) To the solution of 1 (flurbiprofen, 2 g, 8.2 mmol) in 80 mL of dimethylformamide, hydroxybenzotriazole (1.22 g, 9.02 mmol) and DCC (1.86 g, 9.02 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture 4-hydroxybenzamide (2, 1.7 g, 12.2 mmol) was added and stirred for 1 h at 0° C. and 2 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in ethyl acetate; the organic layer was washed with brine, with NaHCO3 5%, with citric acid 10% and than dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude product 3 was loaded on a silica gel open column and eluted with CH2Cl2/MeOH (9.5/0.5), from which 4-carbamoylphenyl 2-(3-fluoro, 4-phenyl)phenyl propanoate (3) was obtained (1.09 g, 37% yield).

Reference： [1]Current Patent Assignee: ANTIBE THERAPEUTICS, INC. - US2008/4245, 2008, A1 Location in patent: Page/Page column 17

22
[ 619-57-8 ]
[ 1000700-40-2 ]

Yield	Reaction Conditions	Operation in experiment
32%	Stage #1: naproxen With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: p-hydroxybenzamide In N,N-dimethyl-formamide at 0 - 20℃; for 3h;	10 Synthesis of 4-carbamoylphenyl 2-(2-methoxynaphthalen-6-yl)propanoate (5) Synthesis of 4-carbamoylphenyl 2-(2-methoxynaphthalen-6-yl)propanoate (5)To the solution of 1 (naproxen, 4 g, 17.4 mmol) in 80 mL of dimethylformamide, hydroxybenzotriazole (2.59 g, 19.14 mmol) and DCC (2.59 g, 19.14 mmol) were added with stirring at 0 C. for 1 h. To the reaction mixture 4-hydroxybenzamide (4, 3.58 g, 26.1 mmol) was added and stirred for 1 h at 0 C. and 2 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in ethyl acetate; the organic layer was washed with brine, with NaHCO3 5%, with citric acid 10% and than dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude product 5 was loaded on a silica gel open column and eluted with CH2Cl2/MeOH (9.5/0.5), from which 4-carbamoylphenyl 2-(2-methoxynaphthalen-6-yl)-propanoate (5) was obtained (1.91 g, 32% yield).

Reference： [1]Current Patent Assignee: ANTIBE THERAPEUTICS, INC. - US2008/4245, 2008, A1 Location in patent: Page/Page column 15

23
1-[6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-(2,2,2-trifluoro-acetylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester [ No CAS ]
[ 619-57-8 ]
[ 733748-31-7 ]

Yield	Reaction Conditions	Operation in experiment
65%	With potassium carbonate In DMF (N,N-dimethyl-formamide) at 80℃; for 0.0333333h; Irradiation;	12 Compound A34; 1- [6- (4-CARBAMOYL-PHENOXY)-5-NITRO-PYRIMIDIN-4-YL]-PIPERIDINE-4-CARBOXYLIC acid ethyl ester; General Method la: A mixture of compound 7 (63 mg, 0.2 MMOL), 4-hydroxybenzene carboxamide (35 mg, 0.26 mmol) and potassium carbonate (36 mg, 0.26 mmol) in DMF (1 ml) was heated in microwave for 2 minutes at 80 °C. Following the general procedure, compound A34 was obtained as a yellow solid (65 %). IHNMR (CDC13, 400 MHz) 8 1.19 (t, 3H), 1.70-1. 80 (M, 2H), 1.98-2. 03 (M, 2H), 2.65-2. 80 (m, 1H), 3.22 (t, 2H), 3.82-3. 96 (m, 2H), 4.07 (q, 2H), 7.25 (d, 2H), 7.40 (s, 1H), 7.92 (d, 2H), 8.00 (s, 1H), 8.20 (s, 1H). Exact mass calculated for CIGH2LNSO6 415.15, found 416. 2 (MIT).

Reference： [1]Current Patent Assignee: PFIZER INC - WO2004/65380, 2004, A1 Location in patent: Page 137

24
[ 619-57-8 ]
[ 109384-19-2 ]
[ 609781-33-1 ]

Yield	Reaction Conditions	Operation in experiment
21%	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃;	(a) Synthesis of tert-butyl 4-[4-(aminocarbonyl)-phenoxy]piperidine-1-carboxylate To a solution of p-hydroxybenzamide (343 mg, 2.50 mmol) in tetrahydrofuran (10 ml) were added tert-butyl 4-hydroxy-1-piperidinecarboxylate (503 mg, 2.50 mmol) and triphenylphosphine (656 mg, 2.50 mmol), followed by adding thereto ethyl azodicarboxylate (1.15 ml, 2.50 mmol) under ice-cooling, and the resulting mixture was stirred overnight at room temperature. Then, the reaction mixture was concentrated and the crude product thus obtained was purified by a silica gel column chromatography (chloroform/methanol = 99/1) to obtain tert-butyl 4-[4-(aminocarbonyl)phenoxy]-piperidine-1-carboxylate (169 mg, 21%). 1H-NMR (DMSO-d6) delta; 1.39(s, 9H), 1.45-1.6 0(1H, m), 1.89-1.92 (1H, m), 3.13-3.20(2H, m), 3.62 - 3.69 (2H, m), 4.61-4.66 (1H, m), 6. 99 (2H, d, J=8.8Hz), 7.15(1H, m), 7.80 (1H, m), 7.81 (2H, d, J=8.8Hz).

Reference： [1]Patent: EP1500643,2005,A1 .Location in patent: Page 24

25
[ 39856-50-3 ]
[ 619-57-8 ]
[ 860298-64-2 ]

Yield	Reaction Conditions	Operation in experiment
38%	With caesium carbonate In DMF (N,N-dimethyl-formamide) at 50℃;	9.a a) 4-[(6-n itro-3-pyrid invl) oxy] benzamide 4-hydroxybenzamide (150 mg, 1.1 mmol) and caesium carbonate (394 mg, 1.21 mmol) was dissolved in dimethylformamide (7ml). 5-bromo-2-nitropyridine (244 mg, 1.21 mmol) was then added. The mixture was left at 50 degrees until the starting material was consumed according to TLC (1 % methanol in ether). Purification by flash chromatography yielded 4-[(6-nitro-3-pyridinyl) oxy] benzamide (110 mg, 38 %) 1H NMR (CDCl3) : 8. 37 (d, 1H), 8. 29 (d, 1H), 7.94 (m, 2H), 7.51 (dd, 1H), 7.18 (m, 2H).

Reference： [1]Current Patent Assignee: MEDIVIR AB - WO2005/66131, 2005, A1 Location in patent: Page/Page column 36

26
trans-tert-butyl [(1S,2S)-1-[(3S)-3-fluoropyrrolidin-1-yl]carbonyl}-2-(4-hydroxycyclohexyl)propyl]carbamate [ No CAS ]
cis-tert-butyl [(1S,2S)-1-[(3S)-3-fluoropyrrolidin-1-yl]carbonyl}-2-(4-hydroxycyclohexyl)propyl]carbamate [ No CAS ]
[ 619-57-8 ]
trans-tert-butyl ((1S,2S)-2-(4-[4-(aminocarbonyl)phenoxy]cyclohexyl)-1-([(3S)-3-fluoropyrrolidin-1-yl]carbonyl)propyl)carbamate [ No CAS ]
cis-tert-butyl ((1S,2S)-2-(4-[4-(aminocarbonyl)phenoxy]cyclohexyl)-1-([(3S)-3-fluoropyrrolidin-1-yl]carbonyl)propyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 14h;	16.A EXAMPLE 16 4-f (4-1 ( 1S,2S)-2-Amino-3-f (3S)-3-fluoropyrrolidin-1-yll-1-methyl-3- oxopropyl }cyc1ohexyl)oxylbenzamide, trifluoroacetic acid salt Step A: tert-Butyl (( lS,25)-2-( 4-[4-(aminocarbonyllphenoxylcyclohexyl ) - I -( I(3SP3- fluoropyrrolidin-1-yl] carbonyl}propyl)carbamate; To a solution of Intermediate 10 (0.068 g, 0.18 mmol) in THF (1 mL) at 0 °C was added triphenylphosphine (0.072 g, 0.27 mmol) followed by 4-hydroxybenzamide (0.037 g, 0.27 mmol) and diisopropyl azodicarboxylate (0.054 mL, 0.27 mmol). The resulting solution was allowed to warm to ambient temperature. After 14 h the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with 70% ethyl acetate in hexane to afford a mixture of cis and trans isomers. These diastereomers were separated by chiral HPLC (Chiralcel OJ column eluting with 20% ethanol in hexane) to afford the faster eluting diastereomer as a pure isomer. LC/MS 392.3 (M+1-Boc).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2005/116029, 2005, A1 Location in patent: Page/Page column 74-75

27
[ 4377-41-7 ]
[ 619-57-8 ]
[ 251297-41-3 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 18h;	45 Preparation 45 4-(Quinolin-2-ylmethoxy)-benzamide To a solution of 2-Chloromethyl-quinoline (1.57 g) and 4-Hydroxy-benzamide (995 mg) in dimethyl formamide (20 mL) was added cesium carbonate (7.3 g) and the reaction mixture heated at 80° C. for 18 h. The reaction mixture was poured into water and extracted with chloroform, dried magnesium sulfate, filtered and concentrated to provided the title compound (909 mg). MS: (M+H -m/z=279.3).

Reference： [1]Current Patent Assignee: PFIZER INC - US2006/154931, 2006, A1 Location in patent: Page/Page column 35

28
Paramax Wang resin [ No CAS ]
[ 619-57-8 ]
C₂₁H₁₈NO₃Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: Paramax Wang resin; p-hydroxybenzamide With triphenylphosphine In tetrahydrofuran at 0℃; for 0.333333h; Stage #2: With diethylazodicarboxylate In tetrahydrofuran at 20℃; for 24h;	26.26b 26b) 4-Hydroxybenzamide anchored onto resin; A mixture of 7.86 g (6.288 mmol) of Wang resin (Novabiochem; capacity: 0.8 mM/g; size: 100-200 mesh), 200 ml of tetrahydrofuran, 2.9 g (21.1 mmol) of 4-hydroxybenzamide (Aldrich), 6.3 g (24.0 mmol) of triphenylphosphine is stirred at 0 °C for 20 min, then 3.8 ml (24.1 mmol) of diethyl azodicarboxylate is added. The reaction mixture is stirred at 20 °C for 24 h, then the product is filtered off, washed twice with 300 ml of dimethylformamide,.twice with 200 ml of tetrahydrofuran, twice with 300 ml of methanol and twice with 200 ml of tetrahydrofuran. The product is dried at room temperature to yield 8.8 g of the title compound.

Reference： [1]Current Patent Assignee: angolul : Chemical Works of Gedeon Richter Plc. Gedeon Richter Plc. - WO2006/10966, 2006, A1 Location in patent: Page/Page column 24

29
[ 910054-82-9 ]
[ 619-57-8 ]
[ 910055-28-6 ]

Yield	Reaction Conditions	Operation in experiment
45%	With caesium carbonate In N,N-dimethyl-formamide at 60℃;	B A suspension of alkyl bromide 36 or 37 (1.0 equiv.), CS2CO3 or K2CO3 (2.5 equiv.) and the phenol/imidazole (1.5-3.0 equiv.) in anhydrous DMF (~1.5 mL/60 mg of bromide) in a screw cap vial was shaken at 600C overnight. The reaction was quenched with 10% aqueous citric acid or saturated NH4CI and extracted with ethyl acetate or dichloromethane. The organic layer was washed twice with water then with brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography.

Reference： [1]Current Patent Assignee: HARVEY ANDREW; THE WALTER AND ELIZA HALL INSTITUTE OF MEDICAL RESEARCH; UNIVERSITY OF CALIFORNIA; BAELL JONATHAN - WO2006/96911, 2006, A1 Location in patent: Page/Page column 47; 51; 54; 66

30
[ 288-42-6 ]
[ 70-23-5 ]
[ 619-57-8 ]
ethyl 2-(4-Hydroxyphenyl)oxazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	In ethyl acetate	O.38.A A. A. Ethyl 2-(4-Hydroxyphenyl)oxazole-4-carboxylate A mixture of 25.0 g (182.3 mmol) of 4-hydroxybenzamide and 23.0 mL (182.3 mmol) of ethyl bromopyruvate was stirred and heated at 115 °C for 30 minutes. The mixture cooled to room temperature and sat under N2atmosphere overnight. Ethyl acetate (100 mL) was added and the mixture stirred for 1 hour. The solid oxazole (36.99 g, 158.6 mmol) was collected by suction filtration in 87% yield: 1H NMR (CDCl3) δ 10.21 (broad s, 1H), 8.82 (s, 1H), 7.83 (d, J= 8.7 Hz, 2H), 6.90 (d, J= 8.7 Hz, 2H), 4.29 (q, 2H), 1.29 (t, 3H); IR (cm-1) 3400, 3169, 1731, 1612, 1731, 1507, 1444; FDMS 233. Anal. (C12H11NO4) C, H, N.
87%	In ethyl acetate	O.38.A (E)-6-[4-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]phenyl]-6-(3-pyridyl)hex-5-enoic Acid A. Ethyl 2-(4-Hydroxyphenyl)oxazole-4-carboxylate A mixture of 25.0 g (182.3 mmol) of 4-hydroxybenzamide and 23.0 mL (182.3 mmol) of ethyl bromopyruvate was stirred and heated at 115 °C for 30 minutes. The mixture cooled to room temperature and sat under N2atmosphere overnight. Ethyl acetate (100 mL) was added and the mixture stirred for 1 hour. The solid oxazole (36.99 g, 158.6 mmol) was collected by suction filtration in 87% yield: 1H NMR (CDCl3) δ 10.21 (broad s, 1H), 8.82 (s, 1H), 7.83 (d, J= 8.7 Hz, 2H), 6.90 (d, J= 8.7 Hz, 2H), 4.29 (q, 2H), 1.29 (t, 3H); IR (cm-1) 3400, 3169, 1731, 1612, 1731, 1507, 1444; FDMS 233. Anal. (C12H11NO4) C, H, N.
87%	In ethyl acetate	O.38.A A. A. Ethyl 2-(4-Hydroxyphenyl)oxazole-4-carboxylate A mixture of 25.0 g (182.3 mmol) of 4-hydroxybenzamide and 23.0 mL (182.3 mmol) of ethyl bromopyruvate was stirred and heated at 115° C. for 30 minutes. The mixture cooled to room temperature and sat under N2 atmosphere overnight. Ethyl acetate (100 mL) was added and the mixture stirred for 1 hour. The solid oxazole (36.99 g, 158.6 mmol) was collected by suction filtration in 87% yield: 1 H NMR (CDCl3) δ 10.21 (broad s, 1H), 8.82 (s, 1H), 7.83 (d, J=8.7 Hz, 2H), 6.90 (d, J=8.7 Hz, 2H), 4.29 (q, 2H), 1.29 (t, 3H); IR (cm-1) 3400, 3169, 1731, 1612, 1731, 1507, 1444; FDMS 233. Anal. (C12 H11 NO4) C, H, N.

Reference： [1]Current Patent Assignee: ELI LILLY & CO - EP811621, 1997, A2
[2]Current Patent Assignee: ELI LILLY & CO - EP816361, 1998, A2
[3]Current Patent Assignee: ELI LILLY & CO - US5849922, 1998, A

31
[ 638-07-3 ]
[ 619-57-8 ]
[ 876617-40-2 ]

Yield	Reaction Conditions	Operation in experiment
80%	at 110℃; for 4h;	A mixture of 4-hydroxybenzamide (25.2 g, 0.18 mol) and ethyl chloroacetoacetate (90 mL) is heated to 110 °C. After 1 h, more ethyl chloroacetoacetate (30 mL) is added, and continue to heat for 3 h more. The mixture is cooled to approximately 60 °C, and MeOH is added. The mixture is filtered and dried to yield the title compound (36.6 g, 80%) as an off-white solid. MS (m/e): 248.3 (M+l)

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2006/19833, 2006, A1 Location in patent: Page/Page column 68

32
[ 32807-28-6 ]
[ 619-57-8 ]
[ 911134-91-3 ]

Yield	Reaction Conditions	Operation in experiment
41%	In propiononitrile at 98℃; for 72h; Heating / reflux;	9.1 A solution of 4-hydroxybenzamide (10 g, 7.3 mmol, 1 eq) and methyl 4-chloro-3- oxobutanoate (15 g, 11 mmol, 5 eq) in propionitrile (300 ml) is stirred at reflux (98 °C) during 3 days. After concentration under reduced pressure, the residue is purified over silicagel (eluent: dichloromethane/methanol/ammonia 90:9:1) to yield 7 g of methyl [2-(4- hydroxyphenyl)-l,3-oxazol-4-yl]acetate i50.Yield: 41 %.LC-MS (MH+): 234.

Reference： [1]Current Patent Assignee: UCB - WO2006/103045, 2006, A1 Location in patent: Page/Page column 101

33
[ 619-57-8 ]
[ 75390-09-9 ]
Trans-4-[(4-hydroxy-1-phenylmethyl-pyrrolidin-3-yl)oxy]benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
19%	In ethyl acetate;	EXAMPLE 36 Trans-4-[(4-hydroxy-1-phenylmethyl-pyrrolidin-3-yl)oxy]benzamide A mixture of 28 g. of <strong>[75390-09-9]1-benzyl-3,4-epoxypyrrolidine</strong> and 20.6 g. of 4-hydroxybenzamide was heated at 130 C. for 8 hrs. The cooled mixture was columned on silica gel using 5% methanol in ethyl acetate to elute the product, which was then crystallized from chloroform-benzene-methanol. The yield was 19% of product melting at 133.0-6.0 C. Analysis: Calculated for C18 H20 N2 O3: C,69.21; H,6.45; N,8.97. Found: C,69.11; H,6.46; N,8.82.
19%	In ethyl acetate;	EXAMPLE 36 Trans-4-[(4-hydroxy-1-phenylmethyl-pyrrolidin-3-yl)oxy]benzamide A mixture of 28 g. of <strong>[75390-09-9]1-benzyl-3,4-epoxypyrrolidine</strong> and 20.6 g. of 4-hydroxybenzamide was heated at 130 C. for 8 hrs. The cooled mixture was columned on silica gel using 5% methanol in ethyl acetate to elute the product, which was then crystallized from chloroform-benzene-methanol. The yield was 19% of product melting at 133.0-6.0 C. Analysis: Calculated for C18 H20 N2 O3: C, 69.21; H, 6.45; N, 8.97. Found: C, 69.11; H, 6.46; N, 8.82.

Reference： [1]Patent: US4585785,1986,A
[2]Patent: US4452809,1984,A

34
[ 619-57-8 ]
4-hydroxy-3-iodobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With Iodine monochloride; acetic acid In methanol	19.a a. a. 4-Hydroxy-3-iodobenzamide A sample of 47 g (0.29 mole) of ICl was added to a solution of 40 g (0.29 mole) of 4-hydroxybenzamide in 400 ml of MeOH and 800 ml of acetic acid in the absence of light. The mixture was stirred for 70 hr under N2 at 25° C. A precipitate was collected by filtration. The filtrate was diluted with water and a second crop of crystals collected by filtration. A third crop was obtained by evaporation of solvent from the second filtrate. The combined solids were recrystallized from 95% ethanol. The solid which precipitated and was collected (28 g). It was largely diiodinated material. The filtrate was evaporated in vacuo and the residue recrystallized from MeOH. The precipitated solid was collected by filtration (2.0 g). It was again diiodinated material. The filtrate was concentrated to dryness in vacuo to give 23 g (30% yield) of brownish crystalline 4-hydroxy-3-iodobenzamide, mp 90°-95° C.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US4652584, 1987, A

35
[ 619-57-8 ]
[ 3647-69-6 ]
[ 909253-73-2 ]

Yield	Reaction Conditions	Operation in experiment
23%	Stage #1: p-hydroxybenzamide With potassium carbonate In acetonitrile for 0.5h; Stage #2: 4-(2-chloroethyl)morpholine hydrochride In N,N-dimethyl-formamide; acetonitrile at 40℃; for 16h;	46 4-(2-Morpholin-4-ylethoxy)benzamide 4-(2-Morpholin-4-ylethoxy)benzamide Potassium carbonate (15.1 g, 109 mmol, 3 eq.), acetonitrile (73 mL) and then 4-hydroxybenzamide (5 g, 36.5 mmol, 1 eq.) are placed in a 250 mL round-bottomed flask. The suspension is stirred for 30 minutes, followed by addition of 4-(2-chloroethyl)morpholine hydrochloride (8.82 g, 47 mmol, 1.3 eq.). 10 mL of dimethylformamide are added to this suspension, and the mixture is then stirred at a temperature in the region of 40° C. for 16 hours. The solvent is then evaporated off and the residue is diluted with water and extracted with dichloromethane. The aqueous phase is acidified with 5 N hydrochloric acid and reextracted with dichloromethane. The organic phases are combined, dried over magnesium sulfate and then concentrated to dryness under vacuum. 4-(2-Morpholin-4-ylethoxy)benzamide 2.17 g (23%) is thus obtained in the form of a white solid, which is used directly in the following step.

Reference： [1]Current Patent Assignee: SANOFI - US2008/146542, 2008, A1 Location in patent: Page/Page column 42-43

36
[ 1087351-83-4 ]
[ 619-57-8 ]
[ 1087351-84-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 0.666667h; In a microwave (150W);	90 A mixture of C-(4-chloroquinolin-8-yl)methylamine (Preparation 89) (129mg, 0.67mmol), K2CO3 (186mg, 1.34mmol) and 4-hydroxybenzamide (HOmg, 0.81mmol) in DMF (4mL) were heated in a microwave at 1000C for 40min (150W). Solvent removed in vacuo. The mixture was partitioned between EtOAc (5OmL) and water (2OmL), and the aqueous phase was further extracted with EtOAc (2x20mL). The combined organic phase was washed with brine (2OmL) and dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (0.25% to 0.75% NH4OH (aq), 2% to 8% MeOH in DCM) to give the title compound: RT = 2.15min; m/z (ES+) = 294.1 [M + H]+.

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2008/142454, 2008, A1 Location in patent: Page/Page column 40-41

37
[ 351324-72-6 ]
[ 619-57-8 ]
[ 1087351-30-1 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: p-hydroxybenzamide With sodium hydride In N,N-dimethyl-formamide for 1h; Stage #2: 1-chloroisoquinoline-4-carbaldehyde In N,N-dimethyl-formamide at 120℃; for 16h;	16 To a solution of 4-hydroxybenzamide (0.96g, 7.0mmol) in DMF (15mL) at rt was added sodium hydride (0.28g, 7.0mmol). After Ih, l-chloro-isoquinoline-4-carbaldehyde (WO01/53274, 1.34g, 7.0mmol) was added and the reaction heated at 12O0C for 16h. The solvent was removed in vacuo and the residue washed with water (10OmL), ether (5OmL) and MeCN (5OmL) to give the title compound: RT = 3.13min; m/z (ES+) = 292.9 [M + H]+.

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2008/142454, 2008, A1 Location in patent: Page/Page column 23

38
[ 619-57-8 ]
[ 1189140-50-8 ]
[ 1189135-03-2 ]

Yield	Reaction Conditions	Operation in experiment
	With di-tert-butyl-diazodicarboxylate; PS-triphenylphosphine In tetrahydrofuran at 20℃; for 22h;	31 Example 314-{ [1- (3-chloro-4-cyanophenyl) -3, 5-dimethyl-lH-pyrazol~4- yl]methoxy}benzamide[0425] [0426]A resin reagent PS-triphenylphosphine (about 190 mg) was added to a polypropylene tube equipped with a filter and a cap for preconditioning. Then, a solution (0.300 mol/L, 0.400 mL) of 4-hydroxybenzamide in THF and a solution (0.200 mol/L, 0.400 mL) of 2-chloro-4-[4- (hydroxymethyl)-3,5-dimethyl-lH- pyrazol-l-yl]benzonitrile obtained in Reference Example 21 in THF were added, and the mixture was stirred. A solution (0.500 mol/L, 0.400 mL) of di-tert-butyl azodicarboxylate in THF was added, and the mixture was stirred at room temperature for 22 hr. The reaction mixture was filtered and washed to remove the resin reagent and the filtrate was concentrated. The residue was purified by reversed-phase preparative HPLC (Gilson, Inc. UniPoint system, YMC ODS column 30x75 millimeter, 0.1% TFA containing acetonitrile-water [5:95 - 100:0]), and the obtained fraction was concentrated and crystallized from diisopropyl ether to give the title compound (14.8 mg) . MS (ESI+, m/e) 381 (M+l)1H-NMR (DMSO-d6) δ:2.24 (3H, s) , 2.45 (3H, s) , 5.01 (2H, s) , 7.07 (2H, d) , 7.19 (IH, brs), 7.77 (IH, dd) , 7.84 (IH, brs) , 7.86 (2H, d) , 7.97 (IH, d) , 8.11 (IH, d)

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2009/119880, 2009, A1 Location in patent: Page/Page column 202-203

39
[ 791852-35-2 ]
[ 619-57-8 ]
[ 1196485-31-0 ]

Yield	Reaction Conditions	Operation in experiment
18%	With potassium carbonate In N,N-dimethyl-formamide at 160℃; for 0.166667h; Microwave irradiation;	62 Example 624-[4-(4-Carbamoyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester; A mixture of 4-hydroxy-benzamide (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 13 mg, 0.089 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 30 mg, 0.089 mmol), and potassium carbonate (27 mg, 0.196 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to give 4-[4-(4-carbamoyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (7 mg, 18%) as a white solid. Mass spectrum MH+=439.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2009/286812, 2009, A1 Location in patent: Page/Page column 48-49

40
[ 619-57-8 ]
[ 1186367-46-3 ]
[ 1186375-45-0 ]

Yield	Reaction Conditions	Operation in experiment
66%	With potassium carbonate In DMF (N,N-dimethylformamide) at 180℃; for 0.333333h; Microwave irradiation;	82 Example 82: N-[4-(6-Oxo-5,6-dihvdro-benzo[c1[1 ,81naphthyridin-9-yloxy)-phenyl1-acetamide (82); 9-Fluoro-5H-benzo[c][1 ,8]naphthyridin-6-one (40 mg, 0.19 mmol), 4-hydroxybenzamide (77 mg, 0.56 mmol), and potassium carbonate (129 mg, 0.93 mmol) were suspended in DMF (1.5 ml_), and stirred for 20 minutes at 180 0C in the microwave. The reaction mixture was quenched with H2O. The resulting precipitate was filtered, and washed with H2O. The precipitate was triturated with MeOH, filtered, washed with MeOH, and dried under vacuum to provide 81 (41 mg, 66 % yield) as a tan solid. LC-MS (M+H = 332, obsd. = 332). 1H NMR (400 MHz, d6-DMSO) : δ 12.00 (s, 1 H), 10.04 (s, 1 H), 8.77 (dd, 1 H), 8.51 (dd, 1 H), 8.37 (d, 1 H), 8.21 (d, 1 H), 7.98 (m, 2H), 7.33 (s, 1 H), 7.30 (m, 2H), 7.21 (m, 2H).

Reference： [1]Current Patent Assignee: MERCK KGAA - WO2009/108670, 2009, A1 Location in patent: Page/Page column 88

41
[ 870959-62-9 ]
[ 619-57-8 ]
4-[(4-([6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]amino)-3,6-dioxocyclohexa-1,4-dien-1-yl)oxy]benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: p-hydroxybenzamide With sodium hydroxide In dichloromethane; water for 0.25h; Stage #2: 2-chloro-5-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]amino}benzo-1,4-quinone In dichloromethane; water for 2 - 48h;	193 Examples 193-211; A phenol (0.152 mmol) and the phase transfer catalyst tricaprylylmethylammonium chloride (0.01 mmol) were treated with an equivalent amount of 1 N NaOH, to which methylene chloride (2 ml) and water (1 ml) were added. This solution was stirred for 15 minutes. The biphasic mixture was then treated with the 2-chloro-5-[6-methoxy- 7-(2-methoxyethoxy)quinazolin-4-yl]amino)benzo-1,4-quinone (0.101 mmol) in a methylene chloride solution to give a total volume of 8 ml in the reaction. The reactions were agitated with a vortex shaker for a time ranging from 2 to 48 hours. Completion of the reaction was determined by LC-MS. The organic layers were then separated and the aqueous solution was extracted further with methylene choride (2x 2 ml). The organic layers were combined and dried over magnesium sulfate and concentrated. The reactions, which showed only desired quinone as the major component, were purified by either recrystallization from acetonitrile or silica gel chromatography. Some reactions showed a substantial amount of the desired product in reduced form. These reactions were treated with an excess of DDQ in methylene chloride (2 ml) and were agitated with a vortex shaker overnight. The reactions were washed with a saturated potassium carbonate solution (3x 2 ml) and the organic layers dried over magnesium sulfate and concentrated. Again, the reactions which showed only desired quinone as the major component were purified by either recrystallization from acetonitrile or silica gel chromatography. By using this method, the compounds of this invention listed in Table 13 were prepared starting with the indicated phenol.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2005/115145, 2005, A2 Location in patent: Page/Page column 108

42
[ 619-57-8 ]
[ 1227089-75-9 ]
[ 1227089-88-4 ]

Yield	Reaction Conditions	Operation in experiment
20%	With potassium carbonate In N,N-dimethyl-formamide at 155℃; for 1h; Microwave irradiation;	19 Example 19 4-(6-( 1 H-indazol-4-yl)- 1 -methyl- 1 H-pyrazolo [3 ,4-b]pyridin-4- yloxy)benzamide 109[00229] 4-Chloro-6-( 1 H-indazol-4-yl)- 1 -methyl- 1 H-pyrazolo [3 ,4-b]pyridine 7(0.04Og, 0.141mmoles) was dissolved in 2mL DMF. 4-Hydroxybenzamide 8d (0.038 g, 0.281 mmol) was added followed by the addition of potassium carbonate (0.2 g, 1.41 mmol) and the resultant reaction mixture was heated in a microwave at 155 0C for 1 hour. The reaction mixture was diluted with ethyl acetate and filtered and the organic portions were washed with saturated sodium bicarbonate solution followed by brine, dried over anhydrous sodium sulfate, solvent removed and purified to obtain 109 as a white solid (10 mg, 20%). 1H NMR (400 MHz, DMSO) δ 13.25 (s, IH), 8.72 (s, IH), 8.04 (d, J= 8.7, 3H), 7.83-7.59 (m, 3H), 7.59-7.29 (m, 4H), 7.23 (s, IH), 4.16 (d, J= 9.1, 3H). MS (ESI) m/z 385.1 (M+l)+

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2010/59788, 2010, A1 Location in patent: Page/Page column 60

43
[ 619-57-8 ]
[ 1202889-76-6 ]
[ 1233696-65-5 ]

Yield	Reaction Conditions	Operation in experiment
22.3%	With potassium carbonate In 1-methyl-pyrrolidin-2-one at 110℃; for 12h; Inert atmosphere;	1.F Methyl 6-cyano-7-fluorochroman-4-carboxylate (300 mg, 1.28 mmol), 4-hydroxybenzamide (227 mg, 1.66 mmol) and potassium carbonate (423 mg, 3.06 mmol) were diluted with dry NMP (4 mL). The reaction was bubbled with argon for 10 minutes and then heated at 1100C for 12 hours. The reaction was cooled and loaded directly onto a bioatge 4OM cartridge (silica gel), eluting with 5% ethyl acetate/hexanes to 100% ethyl acetate to yield methyl 7-(4-carbamoylphenoxy)-6-cyanochroman-4-carboxylate (100 mg, 22.3% yield).

Reference： [1]Current Patent Assignee: PFIZER INC - WO2010/75200, 2010, A1 Location in patent: Page/Page column 61

44
[ 619-57-8 ]
[ 1233696-70-2 ]
[ 1233696-72-4 ]

Yield	Reaction Conditions	Operation in experiment
83.2%	With potassium carbonate In 1-methyl-pyrrolidin-2-one at 120℃; for 12h; Inert atmosphere;	2.C tert-butyl 6-cyano-7-fluorochroman-4-carboxylate (290 mg, 1.05 mmol), 4- hydroxybenzamide (172 mg, 1.25 mmol) and potassium carbonate (347 mg, 2.51 mmol) were diluted with dry NMP (4 mL). The reaction was bubbled with argon for 10 minutes and then heated at 1200C for 12 hours under a slight argon bubble. The reaction was cooled and loaded directly onto a biotage 40 M cartridge, eluting with 20% ethyl acetate/hexanes to 100% ethyl acetate to yield 1 g of the crude product which was found to contain NMP. The residue was taken up in ethyl acetate and washed twice with water and then brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to provide the desired product (343 mg, 83.2% yield) as a white foam.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2010/75200, 2010, A1 Location in patent: Page/Page column 62-63

45
[ 31930-36-6 ]
[ 619-57-8 ]
[ 1234562-82-3 ]

Yield	Reaction Conditions	Operation in experiment
91%	With copper(l) iodide; 2-(2'-pyridyl)benzimidazole; caesium carbonate In N,N-dimethyl-formamide at 40℃; for 2h; Inert atmosphere;

Reference： [1]Location in patent: experimental part Kabir, M. Shahjahan; Namjoshi, Ojas A.; Verma, Ranjit; Polanowski, Rebecca; Krueger, Sarah M.; Sherman, David; Rott, Marc A.; Schwan, William R.; Monte, Aaron; Cook, James M. [Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 12, p. 4178 - 4186]

46
[ 619-57-8 ]
[ 24424-99-5 ]
[ 1262651-96-6 ]

Yield	Reaction Conditions	Operation in experiment
97%	With 6,7-dimethoxyisoquinoline In dichloromethane at 20℃; for 10h; Inert atmosphere; chemoselective reaction;

Reference： [1]Location in patent: experimental part Saito, Yukako; Yoshimura, Yuichi; Takahata, Hiroki [Tetrahedron Letters, 2010, vol. 51, # 52, p. 6915 - 6917]

47
[ 619-57-8 ]
[ 459-57-4 ]
[ 676494-67-0 ]

Yield	Reaction Conditions	Operation in experiment
57%	With potassium carbonate In dimethyl sulfoxide at 140℃;	9.9a 9a) 4-(4-formyl-phenoxy)-benzamide3.1 g (23 mmol) of 4-hydroxybenzamide and 2.8 g (23 mmol) of 4-fluorobenzaldehyde were dissolved in DMSO, combined with 4.4 g (32 mmol) of K2CO3 and stirred overnight at 140° C., filtered through basic Alox, washed with DMF, concentrated by rotary evaporation and purified by chromatography (silica gel column, dichloromethane with a gradient of 10-20% methanol). As there was still some DMF present, the mixture was triturated with water, suction filtered and driedYield: 57% of theoryC14H11NO3 (241.25)Mass spectrum (EI):M+.=241

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2011/263626, 2011, A1 Location in patent: Page/Page column 46

48
[ 619-57-8 ]
[ 99-96-7 ]

Yield	Reaction Conditions	Operation in experiment
83%	With niobium(V) oxide; water In neat (no solvent) for 20h; Reflux; Inert atmosphere;
	With water; sodium nitrite at 0℃; for 0.25h;

Reference： [1]Siddiki; Rashed, Md. Nurnobi; Touchy, Abeda Sultana; Jamil, Md. A. R.; Jing, Yuan; Toyao, Takashi; Maeno, Zen; Shimizu, Ken-Ichi [Catalysis science and technology, 2021, vol. 11, # 5, p. 1949 - 1960]
[2]Location in patent: experimental part Aksenov, Alexander V.; Aksenov, Nicolai A.; Nadein, Oleg N.; Aksenova, Inna V. [Synthetic Communications, 2012, vol. 42, # 4, p. 541 - 547]

49
[ 108-86-1 ]
[ 619-57-8 ]
[ 14121-97-2 ]

Yield	Reaction Conditions	Operation in experiment
86%	With di-tert-butyl{2′-isopropoxy-[1,1′-binaphthalen]-2-yl}phosphane; caesium carbonate; bis(dibenzylideneacetone)-palladium⁽⁰⁾ In <i>tert</i>-butyl alcohol at 100℃; for 20h; Inert atmosphere;
82%	With copper(I) iodide; potassium carbonate In ethylene glycol; isopropyl alcohol at 70℃; for 5h;

Reference： [1]Location in patent: experimental part Ma, Fangfang; Xie, Xiaomin; Zhang, Lei; Peng, Zhiyong; Ding, Lina; Fu, Lei; Zhang, Zhaoguo [Journal of Organic Chemistry, 2012, vol. 77, # 12, p. 5279 - 5285]
[2]Kumar, Atul; Bishnoi, Ajay Kumar [RSC Advances, 2014, vol. 40, # 78, p. 41631 - 41635]

50
[ 619-56-7 ]
[ 619-57-8 ]

Yield	Reaction Conditions	Operation in experiment
93%	With dicyclohexyl-(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine; boric acid; palladium diacetate; caesium carbonate In 1-methyl-pyrrolidin-2-one at 100℃; for 14h; Schlenk technique; Inert atmosphere;
58%	With trans-di(μ-acetato)bis[o-(di-o-tolyl-phosphino)benzyl]dipalladium(II); C₂₉H₄₅Pt; potassium carbonate In water; N,N-dimethyl-formamide at 115℃; for 0.5h; Inert atmosphere; Microwave irradiation;

Reference： [1]Song, Zhi-Qiang; Wang, Dong-Hui [Organic Letters, 2020, vol. 22, # 21, p. 8470 - 8474]
[2]Yu, Chao-Wu; Chen, Grace S.; Huang, Chen-Wei; Chern, Ji-Wang [Organic Letters, 2012, vol. 14, # 14, p. 3688 - 3691]

51
[ 623-05-2 ]
[ 619-57-8 ]

Yield	Reaction Conditions	Operation in experiment
80%	With iron(III) chloride; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; hydroxylamine hydrochloride; iodine; potassium carbonate In 1,2-dichloro-ethane at 90℃; for 16h;

Reference： [1]Location in patent: experimental part Das, Rima; Chakraborty, Debashis [Catalysis Communications, 2012, vol. 26, p. 48 - 53]

52
[ 619-57-8 ]
[ 3993-78-0 ]
[ 1401518-53-3 ]

Yield	Reaction Conditions	Operation in experiment
38%	With potassium hydroxide In water at 165℃; for 0.166667h; Microwave;	4-(2-aminopyrimidin-4-yloxy)benzamide (10c). A mixture of 2-amino-4- chloropyrimidine (0.092g, 0.715mmol), 4-hydroxybenzamide (0.108g, 0.787 mmol) in water (2.5 ml) was stirred in a Biotage microwave reactor for 10 min at 165 °C in presence of aq. KOH (2M, 0.392 ml). After cooling to room temperature, the precipitate was filtered, washed with cold water, and dried under vacuum. Pure 10c (0.062 g, 0.269 mmol, 38%) as an a white solid. 1H NMR (400 MHz, OMSO-d6) δ 8.11 (d, J = 5.5 Hz, 1H), 7.97 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.36 (s, 1H), 7.21 (d, J= 8.5 Hz, 2H), 6.64 (s, 2H), 6.15 (d, J = 5.5 Hz, 1H). HRMS (ESI+ve) calculated for CnHnN402 (M+H)+ 231.0876, found 231.0877.

Reference： [1]Current Patent Assignee: H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE - WO2012/135697, 2012, A2 Location in patent: Page/Page column 119

53
[ 35573-93-4 ]
[ 619-57-8 ]
[ 1409760-30-0 ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 18h;	2.A 500 mg of 4-hydroxybenzamide, 1.51 g of potassium carbonate, 10 mL of DMF and 730 mg of 3-chloro-1,1-diethoxypropane are added to a flask. The reaction mixture is stirred at 100° C. for 18 hours and then 5 mL of water are added. The aqueous phase is extracted with ethyl acetate, and then the organic phases are collected, washed with water and concentrated under reduced pressure. The product is obtained in the form of a powder in a yield of 89% and with a chemical purity of 95%.Melting point: 108° C

Reference： [1]Current Patent Assignee: SERVIER MONDE - US2012/316214, 2012, A1 Location in patent: Page/Page column 4

54
[ 619-57-8 ]
[ 27006-76-4 ]
[ 1152557-17-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 110℃; for 16h; Inert atmosphere;	General experimental procedures General procedure: All reactions were carried out in vials under nitrogen atmosphere. Step 1: A solution of compound 8 (100 μmol, 1.0 equiv) and compound 9 (150 μmol, 1.5 equiv) in DMF (0.1 M) was treated with K2CO3 (300 μmol, 3.0 equiv) and stirred at 110 °C for 16 h (LCMS check). The reaction was filtered and the filtrate concentrated to afford 10. The crude aldehyde 10 (100 μmol, 1.0 equiv) was dissolved in acetone:water (2:1, 0.1 M) and treated with KMnO4 (600 μmol, 6 equiv) and stirred at 30 °C for 16 h (LCMS check). The reaction was filtered and the filtrate concentrated to afford 11. The crude acid 11 (100 μmol, 1.0 equiv) was treated with HATU (120 μmol, 1.20 equiv) followed by the crude amine (100 μmol, 1.0 equiv) and NEt3 (300 μmol, 3.0 equiv). The reaction was stirred at 30 °C for 16 h (LCMS check). The reactions were concentrated and purified directly by reversed phase preparative HPLC using a C18 column and eluting with acetonitrile-water (0.225% formic acid or pH = 10 NH4OH) gradient. All compounds were deemed greater than 95% purity by LCMS and HPLC.

Reference： [1]Londregan, Allyn T.; Piotrowski, David W.; Futatsugi, Kentaro; Warmus, Joseph S.; Boehm, Markus; Carpino, Philip A.; Chin, Janice E.; Janssen, Ann M.; Roush, Nicole S.; Buxton, Joanne; Hinchey, Terri [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 5, p. 1407 - 1411]

55
[ 619-57-8 ]
[ 85622-93-1 ]
2C₆H₆N₆O₂*C₇H₇NO₂ [ No CAS ]

Reference： [1]Crystal Growth and Design,2013,vol. 13,p. 2208 - 2219

56
[ 619-57-8 ]
[ 141699-55-0 ]
tert-butyl 3-(4-carbamoylphenoxy)azetidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	Stage #1: p-hydroxybenzamide With 1,3-bis(2,6-diisopropylphenyl)-2,2-difluoro-2,3-dihydro-1h-imidazole; 1-(Trimethylsilyl)imidazole In 1,4-dioxane at 23℃; for 0.5h; Inert atmosphere; Schlenk technique; Glovebox; Stage #2: tert-butyl 3-hydroxyazetidine-1-carboxylate In 1,4-dioxane at 80℃; for 26h; Inert atmosphere; Schlenk technique; Glovebox;

Reference： [1]Shen, Xiao; Neumann, Constanze N.; Kleinlein, Claudia; Goldberg, Nathaniel W.; Ritter, Tobias [Angewandte Chemie - International Edition, 2015, vol. 54, # 19, p. 5662 - 5665][Angew. Chem., 2015, vol. 126, # 19, p. 5754 - 5757,4][Angewandte Chemie, 2015, vol. 126, # 19, p. 5754 - 5757,4]

57
[ 619-57-8 ]
N-[4-(methoxymethoxy)benzyl]-N-[2-(oxiran-2-yl)ethyl]propan-1-amine [ No CAS ]
C₂₃H₃₂N₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 106℃; for 26h;	c) Phenol derivatives (method C): General procedure: To a solution of the appropriate phenol K, L, M, N or O (0.4 mmol) in DMF (0.5 mL) was added a solution of the epoxide 6, 7, 8, 9 or 10 (0.2 mmol) in DMF (1.5 mL) and potassium carbonate (0.6 mmol). The mixture was stirred at 106 °C for 26 h and then cooled to room temperature. A saturated solution of sodium bicarbonate (2 mL) was carefully added and the mixture extracted with CH2Cl2. After the solvent was evaporated under vacuum, the protecting group of the oily product obtained was hydrolyzed following the method described below.