[ CAS No. 2835-99-6 ] {[proInfo.proName]}

Name: 2835-99-6|4-Amino-3-methylphenol|97%
Brand: Ambeed
SKU: A131170
Price: 8.0 USD
Availability: InStock
Rating: 99 (27 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

DV 2D 3D

3d Animation Molecule Structure of 2835-99-6

Structure of 2835-99-6 * Storage: {[proInfo.prStorage]}

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 110K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 2835-99-6 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 2835-99-6 ]

SDS Specification

Alternatived Products of [ 2835-99-6 ]

Product Details of [ 2835-99-6 ]

CAS No. :	2835-99-6	MDL No. :	MFCD00007871
Formula :	C₇H₉NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QGNGOGOOPUYKMC-UHFFFAOYSA-N
M.W :	123.15	Pubchem ID :	17819
Synonyms :

Calculated chemistry of [ 2835-99-6 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	2.0
Molar Refractivity :	37.84
TPSA :	46.25 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.41 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.19
Log Po/w (XLOGP3) :	0.9
Log Po/w (WLOGP) :	1.29
Log Po/w (MLOGP) :	1.15
Log Po/w (SILICOS-IT) :	1.11
Consensus Log Po/w :	1.13

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.66
Solubility :	2.67 mg/ml ; 0.0217 mol/l
Class :	Very soluble
Log S (Ali) :	-1.46
Solubility :	4.31 mg/ml ; 0.035 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.8
Solubility :	1.93 mg/ml ; 0.0157 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.0

Safety of [ 2835-99-6 ]

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

Application In Synthesis of [ 2835-99-6 ]

* 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 [ 2835-99-6 ]
Downstream synthetic route of [ 2835-99-6 ]

[ 2835-99-6 ] Synthesis Path-Upstream 1~5

1
[ 543-87-3 ]
[ 2835-99-6 ]
[ 144-55-8 ]
[ 15579-15-4 ]

Reference： [1] Patent: EP1256574, 2002, A1,

2
[ 2835-99-6 ]
[ 15579-15-4 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 1, p. 350 - 364

3
[ 611-22-3 ]
[ 2835-99-6 ]
[ 95-53-4 ]
[ 87-63-8 ]
[ 95-69-2 ]

Reference： [1] Canadian Journal of Chemistry, 1996, vol. 74, # 7, p. 1321 - 1328

4
[ 2835-99-6 ]
[ 452-70-0 ]

Reference： [1] Tetrahedron, 1996, vol. 52, # 1, p. 23 - 36
[2] Journal of Fluorine Chemistry, 1991, vol. 51, # 2, p. 299 - 304

5
[ 2835-99-6 ]
[ 133921-27-4 ]

Yield	Reaction Conditions	Operation in experiment
47%	Stage #1: With hydrogenchloride; sodium nitrite In tetrahydrofuran; water at 0℃; Stage #2: With potassium iodide In tetrahydrofuran; water at 0℃; for 0.25 h;	Example 25: Synthesis of(E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-phenylbut-l-en-l-yl)-3- methylphenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide Step-1: Synthesis of 4-iodo-3-methylphenol 3 M HCI/ J To a solution of 4-amino-3-methylphenol (10 g, 81 mmol) in THF (45 mL) was added 3M HC1 (35 mL) at 0 °C over a period of 10 min followed by NaN0₂ (6.1 g, 89 mmol). To the above reaction mixture, potassium iodide (53.89 g, 166 mmol) in water (140 mL) was added dropwise and stirred at 0 °C for 15 min. After completion of reaction, reaction mixture was extracted with EtOAc. Organic layer was washed water followed by brine, concentared under reduced pressure to obtain the crude compound. Crude material was purified by column chromatography over 230-400 mesh silica gel using 10percent EtOAc in n-hexane to give the title compound (9 g, 47percent).
15%	Stage #1: With sulfuric acid; sodium nitrite In water at 0℃; for 0.333333 h; Stage #2: With copper(l) iodide; sulfuric acid; potassium iodide In water at 0℃; for 3 h; Heating / reflux	15 g (122 mol) of 4-hydroxy-2-methylaniline are dissolved in 180 ml of 20percent sulphuric acid and then the reaction medium is cooled to 0° C. A solution of sodium nitrite (11.3 g, 163 mmol) in 60 ml of water is then added dropwise and then the medium is stirred for 20 minutes. This solution is then slowly added to a solution at 0° C. of CuI (32.5 g, 170 mmol) and KI (31.9 g, 193 mmol) in 180 ml of 20percent sulphuric acid. The reaction medium is heated under reflux for 3 hours, poured into 1 l of water and extracted with ethyl ether. The organic phases are washed with a saturated sodium thiosulphate solution, of water, dried over magnesium sulphate and concentrated under reduced pressure. After purification on a silica column (ethyl acetate 30-heptane 70), a brown oil is obtained (m 4.2 g; Y=15percent).

Reference： [1] Patent: WO2016/196342, 2016, A1, . Location in patent: Page/Page column 129
[2] Patent: US6689922, 2004, B1, . Location in patent: Page column 85
[3] Journal of the Chemical Society, 1951, p. 1184,1186
[4] Patent: US6562823, 2003, B1,

[ 2835-99-6 ] Synthesis Path-Downstream 1~78

1
[ 2581-34-2 ]
[ 2835-99-6 ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1982,vol. 80,p. 105 - 118
[2]Justus Liebigs Annalen der Chemie,1890,vol. 259,p. 217
[3]Journal of the American Chemical Society,1930,vol. 52,p. 3978,3982
[4]Bulletin of the Chemical Society of Japan,1975,vol. 48,p. 2127 - 2133
[5]Journal of Organic Chemistry,1989,vol. 54,p. 3740 - 3744
[6]Inorganic Chemistry,2014,vol. 53,p. 5692 - 5697
[7]Journal of Nanoscience and Nanotechnology,2018,vol. 18,p. 3954 - 3959
[8]Dalton Transactions,2018,vol. 47,p. 17401 - 17411

2
[ 2835-99-6 ]
[ 41438-18-0 ]
4-hydroxy-2-methyl-benzaldehyde-(4-hydroxy-2-methyl-phenylimine) [ No CAS ]

Reference： [1]Nippon Kagaku Zasshi,1956,vol. 77,p. 1072,1074
Chem.Abstr.,1959,p. 5175

3
[ 2835-99-6 ]
[ 133921-27-4 ]

Yield	Reaction Conditions	Operation in experiment
47%		Example 25: Synthesis of(E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-phenylbut-l-en-l-yl)-3- methylphenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide Step-1: Synthesis of 4-iodo-3-methylphenol 3 M HCI/ J To a solution of 4-amino-3-methylphenol (10 g, 81 mmol) in THF (45 mL) was added 3M HC1 (35 mL) at 0 C over a period of 10 min followed by NaN02 (6.1 g, 89 mmol). To the above reaction mixture, potassium iodide (53.89 g, 166 mmol) in water (140 mL) was added dropwise and stirred at 0 C for 15 min. After completion of reaction, reaction mixture was extracted with EtOAc. Organic layer was washed water followed by brine, concentared under reduced pressure to obtain the crude compound. Crude material was purified by column chromatography over 230-400 mesh silica gel using 10% EtOAc in n-hexane to give the title compound (9 g, 47%).
15%		15 g (122 mol) of 4-hydroxy-2-methylaniline are dissolved in 180 ml of 20% sulphuric acid and then the reaction medium is cooled to 0 C. A solution of sodium nitrite (11.3 g, 163 mmol) in 60 ml of water is then added dropwise and then the medium is stirred for 20 minutes. This solution is then slowly added to a solution at 0 C. of CuI (32.5 g, 170 mmol) and KI (31.9 g, 193 mmol) in 180 ml of 20% sulphuric acid. The reaction medium is heated under reflux for 3 hours, poured into 1 l of water and extracted with ethyl ether. The organic phases are washed with a saturated sodium thiosulphate solution, of water, dried over magnesium sulphate and concentrated under reduced pressure. After purification on a silica column (ethyl acetate 30-heptane 70), a brown oil is obtained (m 4.2 g; Y=15%).
	With hydrogenchloride; potassium iodide; sodium nitrite; In tetrahydrofuran; water;	Step A Preparation of 4-Iodo-3-methylphenol To a solution of 4-amino-meta-cresol (20.59 g, 167 mmol) in 90 mL of tetrahydrofuran and 280 mL of 3M HCl solution at 0 C. was added a solution of NaNO2 (12.73 g, 184 mmol) in 40 mL of water dropwise over 5 minutes. After 25 minutes, a solution of potassium iodide (112.5 g, 678 mmol) in 85 mL of water was added, and stirring was continued for 15 minutes. The solution was poured into EtOAc and the organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting product was purified by silica gel chromatography (0-50% EtOAc/hexane) to provide the desired product as a dark crystalline solid.

Reference： [1]Patent: WO2016/196342,2016,A1 .Location in patent: Page/Page column 129
[2]Patent: US6689922,2004,B1 .Location in patent: Page column 85
[3]Journal of the Chemical Society,1951,p. 1184,1186
[4]Patent: US6562823,2003,B1

4
[ 2835-99-6 ]
[ 108-24-7 ]
[ 39495-15-3 ]

Yield	Reaction Conditions	Operation in experiment
58%	In ethanol;	5.0 g (40.6 mmol)4-hydroxy-2-methylaniline was taken up in 120 ml ethanol to give a cloudy, pale orange suspension. To the stirred mixture was added dropwise 4.0 <Desc/Clms Page number 71>ml(4. 3 g, 42.3 mmol) acetic anhydride, causing the suspension to dissolve. The solution was left stirring overnight. All volatiles were subsequently removed under reduced pressure at80 C, followed by rapid washing with 100 ml water, followed by drying under vacuum. 3.85 g (58% yield) light brown solid recovered.

Reference： [1]Patent: WO2005/90371,2005,A1 .Location in patent: Page/Page column 70-71
[2]Journal of Medicinal Chemistry,1986,vol. 29,p. 1737 - 1743
[3]Justus Liebigs Annalen der Chemie,1890,vol. 259,p. 217
[4]Journal of the American Chemical Society,1929,vol. 51,p. 905
[5]Journal of the American Chemical Society,1930,vol. 52,p. 3978,3982
[6]Molecular Crystals and Liquid Crystals Science and Technology, Section A: Molecular Crystals and Liquid Crystals,2001,vol. 364,p. 801 - 808

5
[ 2835-99-6 ]
[ 108-24-7 ]
[ 145823-43-4 ]

Yield	Reaction Conditions	Operation in experiment
67%	With sodium acetate; acetic acid; at 125℃; for 1h;	Intermediate 204-amino-3-methyl-5-nitro-phenol Step 1: 4-acetylamino-3-methyl-phenyl acetate; 4.66 g (37.5 mmol) <strong>[2835-99-6]4-amino-3-methylphenol</strong>, 5.00 mL glacial acetic acid, 0.500 g (6.09 mmol) sodium acetate and 7.87 mL (83.3 mmol) acetic anhydride were combined and stirred for 1 h at 125 C. After cooling to RT, ice water was added to the reaction mixture. The precipitate formed was suction filtered, washed with water and dried under HV.Yield: 5.20 g (67% of theory)ESI-MS: m/z=208 (M+H)+ Rt(HPLC): 0.92 min (method B)

Reference： [1]Patent: US2012/88755,2012,A1 .Location in patent: Page/Page column 61-62
[2]Journal of the American Chemical Society,1929,vol. 51,p. 905

6
[ 2835-99-6 ]
[ 452-70-0 ]

Reference： [1]Tetrahedron,1996,vol. 52,p. 23 - 36
[2]Journal of Fluorine Chemistry,1991,vol. 51,p. 299 - 304

7
[ 7647-01-0 ]
[ 101816-75-5 ]
[ 875-59-2 ]
[ 2835-99-6 ]

Reference： [1]Chemische Berichte,1925,vol. 58,p. 41

8
[ 343775-72-4 ]
[ 2835-99-6 ]
[ 343775-73-5 ]

Reference： [1]Journal of the American Chemical Society,2001,vol. 123,p. 4475 - 4479

9
[ 50-00-0 ]
[ 2835-99-6 ]
4-[(4-hydroxy-2-methyl-phenyl)-methyl-amino]-methyl}-benzoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%		Preparation 25; 4- [(4-Hydroxy-2-methyl-phenyl)-methyl-amino]-methyU -benzoic acid methyl ester; To an ambient temperature solution of 4-amino-3 -methyl-phenol (1.0 g, 8.12 mmol) in MeOH (77 mL) is added 4-formyl-benzoic acid methyl ester (1.47 g, 8.93 mmol) and decaborane (329 mg, 2.68 mmol). The reaction is stirred at room temperature. After 2h, formaldehyde (1.23 mL, 16.93 mmol, 37 % in water) and decaborane (329 mg, 2.68 mmol) are added to the reaction. The reaction mixture is stirred overnight. The <n="32"/>reaction mixture is concentrated under reduced pressure and the residue is purified via chromatography to yield the title compound (2.07 g, 90 %). LC-ES/MS m/e 286.2 (M+ 1).The following compound is prepared essentially according to the preparation 54- [(4-hydroxy-2-methyl-phenyl)-methyl-amino]-methyl} -benzoic acid methyl ester using the appropriate starting material

Reference： [1]Patent: WO2007/140174,2007,A2 .Location in patent: Page/Page column 30-31

10
[ 2835-99-6 ]
[ 501-53-1 ]
[ 568594-96-7 ]

Yield	Reaction Conditions	Operation in experiment
93%	With sodium hydrogencarbonate; In tetrahydrofuran; water; for 1h;	Step A; To a suspension of 4-amino-3 -methyl-phenol (10.8 g, 88 mmol) in THF (80 mL) and sat. sodium bicarbonate (50 mL) is added benzyl chloroformate (18.0 g, 105 mmol) dropwise. The reaction mixture is stirred for 1.0 h. The two phases are separated and the organic phase is concentrated to a residue. The residue is partitioned between EtOAc (100 mL) and 5% HCl (50 mL). The organic phase is washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography to give (4-Hydroxy-2-methyl)-carbamic acid benzyl ester as brown solid (21.Og, 93 %). LC-ES/MS: 258.3 (M+l), 256.0 (M-I).

Reference： [1]Patent: WO2007/140174,2007,A2 .Location in patent: Page/Page column 38

11
[ 74733-23-6 ]
[ 2835-99-6 ]
4-((4-hydroxy-2-methylphenylamino)methyl)-2-methylbenzoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%		Preparation 58; 4-((4-Hydroxy-2-methylphenylamino)methyl)-2-methyl benzoic acid, methyl ester; 4-Amino-m-cresol (242 g, 1.96 mol) is added to a slurry of 4-formyl-2-methyl- benzoic acid, methyl ester (350 g, 1.96 mol) and acetic acid (3100 mL) at room temperature. Sodium triacetoxyborohydride (728 g, 3.44 mol) is added portionwise, <n="48"/>keeping the temperature below 30 0C using an ice water bath. After overnight stirring, the reaction mixture is concentrated under reduced pressure. The residue is adjusted to pH 5 using aqueous saturated sodium bicarbonate. The resulting solid is filtered off, washed with water, and dried under vacuum overnight to give the title compound (460 g, 82%) as a brown powder. ES/MS m/e 179 (M+ 1)

Reference： [1]Patent: WO2007/140174,2007,A2 .Location in patent: Page/Page column 46-47

12
[ 2835-99-6 ]
[ 220000-87-3 ]
[ 284462-74-4 ]

Yield	Reaction Conditions	Operation in experiment
73.4%		Compound 4a (2.00 g, 16.26 mmol) was dissolved in dry DMF (20.0 mL), cesium carbonate (9.26 g, 28.5 mmol) In 50 and nitrogen under the protection of 1hr, the system gradually changed from yellow to green color. A solution of compound 3 (2.50 g, 14.7 mmol) in DMF (10.0 mL) was then added dropwise, heated to 105 C, stirred under nitrogen for 8 hr, TLC is monitored until the raw material is fully reacted. After the solution is cooled, Filter out the cesium carbonate solid, The filter cake was washed with ethyl acetate (100 mL) to give a tan filtrate. A saturated sodium chloride solution (100 mL) was added to the filtrate and the aqueous layer was separated, Extracted with ethyl acetate (60.0 mL x 3) The organic phases were combined, washed with saturated aqueous sodium chloride (4 x 100 mL) The resulting organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, The solvent was recovered under reduced pressure to give a brown oil. (2.83 g, 73.4%).
58.7%		Compound 4b (1.88g, 15.25mmol) was dissolved in anhydrous DMF (30mL), and sodium hydroxide (1.22 g, 30.5 mmol), at 50 deg. C, under nitrogen, stirred for 2H (dark brown system). Thereto were then added dropwise compound 3 (2.56g, 15.25mmol) in DMF (10mL) solution, heated to 80 deg. C, the reaction was stirred for 7h, TLC monitored the reaction to completion. Ethyl acetate was added (100 mL), saturated sodium chloride solution (100 mL), the aqueous layer is separated, and extracted with ethyl acetate (60mL × 2), the combined organic phases, and washed with saturated sodium chloride solution (4 × 100mL) the organic phase was dried over anhydrous sodium sulfate, filtered, and solvent was recovered under reduced pressure to give a brown oil which was dried under reduced pressure to remove the residual solvent. Column chromatography (eluent P: E = 1: 1), and dried to give grayish brown solid (2.30g), yield 58.7%,
	With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 20 - 75℃; for 12h;	Step 1. Synthesis of 4-(4-amino-3-methylphenoxy)-N-methylpicolinamide To the solution of 4-amino-m-cresol (125 mg, 1.01 mmol, 1.0 eq) in 1 mL of NMP was added 4-chloro-N-methylpicolinamide (189 mg, 1.11 mmol, 1.1 eq) and cesium carbonate (658 mg, 2.02 mmol, 2.0 eq) at room temperature. The reaction mixture was stirred at 75 C. for 12 hours, thereafter the mixture was diluted with water (ca. 50 mL) and aqueous layer extracted with ethyl acetate (ca. 50 mL*3). Combined organic layers were dried over sodium sulfate, filtered and condensed under reduced pressure to give sufficiently pure crude product which was carried to next step without further purification. LC/MS (m/z) [258.1] (MH+).

Reference： [1]Patent: CN106543077,2017,A .Location in patent: Paragraph 0045; 0049
[2]Patent: CN105753841,2016,A .Location in patent: Paragraph 0064; 0065; 0066
[3]Patent: US2008/45528,2008,A1 .Location in patent: Page/Page column 94

13
[ 2835-99-6 ]
[ 18162-48-6 ]
[ 347196-56-9 ]

Yield	Reaction Conditions	Operation in experiment
91%	With 1H-imidazole; In tetrahydrofuran; at 0 - 25℃;	To a solution of <strong>[2835-99-6]4-amino-3-methylphenol</strong> (4.25 g, 33.5 mmol) and imidazole (2.53 g, 36.8 mmol) in THF (100 ml) is added tert-butyl(chloro)dimethylsilane (5.78 g, 37.1 mmol) at 0 C. The reaction mixture is warmed to RT and stirred for 3 hr. The mixture is concentrated under vacuum, diluted with Et2O, and the combined organic layers are washed with satd. NaHCO3, brine, and dried (MgSO4), filtered, and concentrated under vacuum. The residue is purified by silica gel chromatography (50% EtOAc/n-heptane) to give a brown oil 7.2 g (91% yield). 1H NMR (400 MHz, CDCl3) delta 6.93, 6.61, 6.56, 2.18, 0.98, 0.18. Phenyl 4-[tert-butyl(dimethyl)silyl]oxy}-2-methylphenylcarbamate (from 4-[tert-butyl(dimethyl)silyl]oxy}-2-methylaniline and phenyl chloroformate) is prepared by following Step 1 of Example 407, making non-critical modifications. The residue is purified by silica gel chromatography (CH2C12) followed by recrystallization from hexane to give a white solid 3.3 g (61% yield). HRMS (ESI) calcd for C20H27NO3Si+H 358.1838, found 358.1848. 4-(Pentafluoroethyl)-1,3-thiazol-2-amine is prepared from thiourea and 1-bromo-3,3,4,4,4-pentafluoro-2-butanone by the general procedure described in Biotechnology and Bioengineering (Combinatorial Chemistry), 2000, 71(1), 9. The free base is obtained by the procedure described in the preparation of N-(4-ethyl-1,3-thiazol-2-yl)-N'-(4-methoxy-2-methylphenyl)urea. Pure 4-(pentafluoroethyl)-1,3-thiazol-2-amine may also be obtained by dissolving the crude reaction product in MeOH (150 mL) and adding Dowex O50WX2-400 acidic ion exchange resin (10 g) and stirring the mixture overnight at RT. The mixture is filtered and the resin is washed sequentially with MeOH (150 mL) and 20% aqueous NH4OH in MeOH (200 mL). The 20% aqueous NH4OH in MeOH wash is concentrated and the resulting light brown crystals are washed with cold hexane and dried to yield 4-(pentafluoroethyl)-1,3-thiazol-2-amine (1.8 g). N-(4-[tert-butyl(dimethyl)silyl]oxy}-2-methylphenyl)-N'-[4-(pentafluoroethyl)-1,3-thiazol-2-yl]urea (from 4-(pentafluoroethyl)-1,3-thiazol-2-amine and phenyl 4-[tert-butyl(dimethyl)silyl]oxy}-2-methylphenylcarbamate) is prepared by following Method D, making non-critical modifications to give a brown solid (0.3 g), which is dissolved in THF (3.0 ml) and 1.0M solution of tetra-butyl ammonium fluoride (2.0 ml, 2.0 mmol) is added. The reaction mixture is stirred at RT for 15 min. The mixture is diluted with H2O, extracted with CH2Cl2, and the combined organic layers are dried (MgSO4), filtered, and concentrated under vacuum. The residue is purified by silica gel chromatography (30% EtOAc/n-heptane) followed by trituration with CH2Cl2 to give Example 406 as a white solid 0.110 g (43% yield). HRMS (ESI) calcd for C13H10N3O2SF5+H 368.0492, found 368.0490.
86%	With 1H-imidazole; In dichloromethane; N,N-dimethyl-formamide; toluene; at 0 - 20℃; for 3h;	<strong>[2835-99-6]4-amino-3-methylphenol</strong> (1.02 g, 8.28 mmol) was dissolved in 2 ml of DMF and 10 ml DCM was added. Imidazole (620 mg, 9.11 mmol) was added and the solution was cooled to 0C. A solution of TBDMSCl (2.75 ml, 50 wt. % in toluene, 9.11 mmol) was added dropwise and the mixture was allowed to warm up to rt. After stirring for 3h at rt, the reaction was quenched by addition of 15 ml saturated aqueous NaHCO3. The phases were separated and the aqueous phase was extracted with DCM (2 x 20ml). The combined organic phases were filtered through a phase separator and the solvent was evaporated. The residue was purified by flash column chromatography with pentane-methyl tert-butylether (3:1) as eluent to yield 22 (1.69 g, 86%) as a light yellow oil: 1H NMR (500 MHz, CDCl3) 0.00 (s, 6H), 0.82 (s, 9H), 1.97 (s, 3H), 3.17 (bs, 2H), 6.38-6.39 (m, 2H), 6.42-6.42 (m, 1H); 13C NMR (125 MHz, CDCl3) 0.00, 22.02, 22.66, 30.23, 120.38, 122.55, 126.47, 128.30, 142.92, 152.55; MS (ESI): m/z 238 [M+H]+.

Reference： [1]Patent: US2003/236287,2003,A1 .Location in patent: Page 42
[2]Organic Letters,2012,vol. 14,p. 6306 - 6309
[3]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4839 - 4843

14
[ 2835-99-6 ]
[ 329-01-1 ]
N-(4-hydroxy-2-methylphenyl)-N'-[3-(trifluoromethyl)phenyl]urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34%		N-(4-Hydroxy-2-methylphenyl)-N'-[3-(trifluoromethyl)phenyl]urea (from <strong>[2835-99-6]4-amino-3-methylphenol</strong> and 1-isocyanato-3-(trifluoromethyl)benzene) is prepared following the Method A, making non-critical modifications. The resulting residue is diluted with MeOH (10 ml) and DOWEX 50WX2-400 ion-exchange resin (1.5 g) is added; the mixture is allowed to spin submerged in a water bath (35-40 C.) for 20 min, is filtered, and the resin washed with MeOH. The product is liberated from the resin by treatment with a solution of 20% NH4OH/MeOH. The basic alcohol washes are concentrated in vacuo to give an off white solid, which is triturated with EtOAc/CH2Cl2 to give an off white solid 0.085 g (34% yield). HRMS (ESI) calcd for C15H13N2O2F3+H 311.1007, found 311.1002.

Reference： [1]Patent: US2003/236287,2003,A1 .Location in patent: Page 36

15
[ 625119-98-4 ]
[ 2835-99-6 ]
N-(4-hydroxy-2-methylphenyl)-N'-[4-(trifluoromethyl)-1,3-thiazol-2-yl]urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%	With triethylamine; In tetrahydrofuran; at 50℃;	To a solution of 4-(trifluoromethyl)-1,3-thiazol-2-amine (1 g, 5.95 mmol) in CH2Cl2 (150 mL) at 0 C. is added drop-wise phenyl chloroformate (2.2 mL, 17.9 mmol), followed by DMAP (36 mg, 0.3 mmol) and pyridine (0.47 mL, 5.95 mmol). After 20 min., additional pyridine (0.1 mL) is added. Upon completion of the reaction, the mixture is washed with 0.1N HCl followed by 5% NaHCO3, brine and concentrated. The resulting solid is recrystallized from hexane to afford phenyl-4-(trifluoromethyl)-1,3-thiazol-2-yl-carbamate as a white crystalline solid (1.1 g, 65% yield). HRMS (ESI) calcd for C11H7F3N2O2S +H 289.0258, found 289.0265. To a solution of phenyl-4-(trifluoromethyl)-1,3-thiazol-2-yl-carbamate (0.23 g, 0.8 mmol) and 4-amino-m-cresol (0.1 g, 0.8 mmol) in THF (5 mL) is added TEA (0.11 mL, 0.8 mmol). The reaction is heated 50 C. overnight and the solvent is removed. The residue is purified by flash chromatography (SiO2 gel, 30% EtOAc/hexanes) to afford Example 400 as a white solid (90 mg, 35% yield). HRMS (ESI) calcd for C12H10F3N3O2S+H 318.0524, found 318.0517. [0764] The following compounds are made from a phenyl carbamate and an aniline according to Method D, making non-critical variations.

Reference： [1]Patent: US2003/236287,2003,A1 .Location in patent: Page 41

16
[ 24424-99-5 ]
[ 2835-99-6 ]
[ 201741-17-5 ]

Yield	Reaction Conditions	Operation in experiment
99%	In tetrahydrofuran; at 20℃; for 24h;	A solution of 4-AMINO-3-METHYLPHENOL (3.0 g, 24 MMOL) in tetrahydrofuran (30 mL) was stirred with DI-TERT-BUTYLDICARBONATE (5.32 g, 24 MMOL) for 24 hours at ambient temperature. The solvent was evaporated and the resulting residue was partitioned in diethyl ether and aqueous sodium HYDROGENSULFATE. The organic layer was washed with water (2x 50 mL), brine (50 mL), dried over anhydrous magnesium sulfate, filtered and condensed to a residue. Yield = 5.4 g. (99%) of tert-butyl 4-hydroxy-2- METHYLPHENYLCARBAMATE.

Reference： [1]Patent: WO2004/48349,2004,A1 .Location in patent: Page 47

17
[ 2835-99-6 ]
[ 220000-87-3 ]
[ 284462-42-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; potassium tert-butylate; In diethyl ether; ISOPROPYLAMIDE;	Synthesis of 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline HCl Salt A solution of <strong>[2835-99-6]4-amino-3-methylphenol</strong> (5.45 g, 44.25 mmol) in dry dimethylacetamide (75 mL) was treated with potassium tert-butoxide (10.86 g, 96.77 mmol) and the black mixture was stirred at room temp. until the flask had reached room temp. The contents were then treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step 3b; 7.52 g, 44.2 mmol) and heated at 110 C. for 8 h. The mixture was cooled to room temp. and diluted with water (75 mL). The organic layer was extracted with EtOAc (5*100 mL). The combined organic layers were washed with a saturated NaCl solution (200 mL), dried (MgSO4) and concentrated under reduced pressure. The residual black oil was treated with Et2O (50 mL) and sonicated. The solution was then treated with HCl (1 M in Et2O; 100 mL) and stirred at room temp. for 5 min. The resulting dark pink solid (7.04 g, 24.1 mmol) was removed by filtration from solution and stored under anaerobic conditions at 0 C. prior to use: 1H NMR (DMSO-d6) delta2.41 (s, 3H), 2.78 (d, J=4.4 Hz, 3H), 4.93 (br s, 2H), 7.19 (dd, J=8.5, 2.6 Hz, 1H), 7.23 (dd, J=5.5, 2.6 Hz, 1H), 7.26 (d, J=2.6 Hz, 1H), 7.55 (d, J=2.6 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 8.55 (d, J=5.9 Hz, 1H), 8.99 (q, J=4.8 Hz, 1H).
	With hydrogenchloride; potassium tert-butylate; In diethyl ether; ISOPROPYLAMIDE;	Synthesis of 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline HCl Salt A solution of <strong>[2835-99-6]4-amino-3-methylphenol</strong> (5.45 g, 44.25 mmol) in dry dimethylacetamide (75 mL) was treated with potassium tert-butoxide (10.86 g, 96.77 mmol) and the black mixture was stirred at room temp. until the flask had reached room temp. The contents were then treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step 3b; 7.52 g, 44.2 mmol) and heated at 110 C. for 8 h. The mixture was cooled to room temp. and diluted with water (75 mL). The organic layer was extracted with EtOAc (5*100 mL). The combined organic layers were washed with a saturated NaCl solution (200 mL), dried (MgSO4) and concentrated under reduced pressure. The residual black oil was treated with Et2O (50 mL) and sonicated. The solution was then treated with HCl (1 M in Et2O; 100 mL) and stirred at room temp. for 5 min. The resulting dark pink solid (7.04 g, 24.1 mmol) was removed by filtration from solution and stored under anaerobic conditions at 0 C. prior to use: 1H NMR (DMSO-d6) delta 2.41 (s, 3H), 2.78 (d, J=4.4 Hz, 3H), 4.93 (br s, 2H), 7.19 (dd, J=8.5, 2.6 Hz, 1H), 7.23 (dd, J=5.5, 2.6 Hz, 1H), 7.26 (d, J=2.6 Hz, 1H), 7.55 (d, J=2.6 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 8.55 (d, J=5.9 Hz, 1H), 8.99 (q, J=4.8 Hz, 1H).
		A solution of <strong>[2835-99-6]4-amino-3-methylphenol</strong> (5.45 g, 44.25 mmol) in dry dimethylacetamide (75 mL) was treated with potassium tert-butoxide (10.86 g, 96.77=mol) and the black mixture was stirred at room temp. until the flask had reached room temp. The contents were then treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step 3b; 7.52 g, 44.2 mmol) and heated at 110 C. for 8 h. The mixture was cooled to room temp. and diluted with water (75 mL). The organic layer was extracted with EtOAc (5×100 mL). The combined organic layers were washed with a saturated NaCl solution (200 mL), dried (MgSO4) and concentrated under reduced pressure. The residual black oil was treated with Et2O (50 mL) and sonicated. The solution was then treated with HCl (1 M in Et2O; 100 mL) and stirred at room temp. for 5 min. The resulting dark pink solid (7.04 g, 24.1 mmol) was removed by filtration from solution and stored under anaerobic conditions at 0 C. prior to use: 1H NMR (DMSO-d6) delta 2.41 (s, 3H), 2.78 (d, J=4.4 Hz, 3H), 4.93 (br s, 2H), 7.19 (dd, J=8.5, 2.6 Hz, 1H), 7.23 (dd, J=5.5, 2.6 Hz, 1H), 7.26 (d, J=2.6 Hz, 1H), 7.55 (d, J=2.6 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 8.55 (d, J=5.9 Hz, 1H), 8.99 (q, J=4.8 Hz, 1H).

Reference： [1]Patent: US2003/144278,2003,A1
[2]Patent: US2001/11135,2001,A1
[3]Patent: US2003/207872,2003,A1 .Location in patent: Page/Page column 10

18
[ 220854-19-3 ]
[ 2835-99-6 ]
1-(2-methyl-4-hydroxyphenyl)-4-oxo-6-trifluoromethoxy-2,3,4,5-tetrahydropyrrolo[3,2-c]quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	In ethylene glycol;	(Step 1) Preparation of 1-(2-methyl-4-hydroxyphenyl)-4-oxo-6-trifluoromethoxy-2,3,4,5-tetrahydropyrrolo[3,2-c]quinoline 4-Oxo-6-trifluoromethoxy-2,3,4,5-tetrahydrofuro[3,2-c]quinoline(5.0 g, 19 mmol) was dissolved in ethylene glycol(30 ml) and 4-amino-m-cresol (5.6 g, 46 mmol) was added under nitrogen. The reaction mixture was refluxed at 250 for 15 hours. After diluting the reaction mixture in brine(20 ml), the aqueous layer was extracted with dichloromethane (15 ml) for 3 times. The organic layer was washed with water(15 ml) for 3 times, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 6.6 g of desired compound as solid in 91% of yield. 1 H NMR(CDCl3, 200 MHz) delta 2.27(s, 3H), 3.20-3.28(m, 2H), 3.71-3.80(m, 1H), 4.10-4.15(m, 1H), 6.52-6.85(m, 4H), 7.12(d, J=8.5 Hz, 1H), 7.28-7.34(m, 1H); m/e 376(M+, 100), 375(85.4), 335(23.5).
91%	In ethylene glycol;	(Step 1) Preparation of 1-(2-methyl-4-hydroxyphenyl)-4-oxo-6-trifluoromethoxy-2,3,4,5-tetrahydropyrrolo[3,2-c]quinoline 4-Oxo-6-trifluoromethoxy-2,3,4,5-tetrahydrofuro[3,2-c]quinoline(5.0 g, 19 mmol) was dissolved in ethylene glycol(30 ml) and 4-amino-m-cresol (5.6 g, 46 mmol) was added under nitrogen. The reaction mixture was refluxed at 250 C for 15 hours. After diluting the reaction mixture in brine(20 ml), the aqueous layer was extracted with dichloromethane(15 ml) for 3 times. The organic layer was washed with water(15 ml) for 3 times, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 6.6 g of desired compound as solid in 91 % of yield. 1H NMR(CDCl3, 200 MHz) delta 2.27(s, 3H), 3.20-3.28(m, 2H), 3.71-3.80(m, 1H), 4.10-4.15(m, 1H), 6.52-6.85(m, 4H), 7.12(d, J=8.5Hz, 1H), 7.28-7.34(m, 1H); m/e 376(M+, 100), 375(85.4), 335(23.5).

Reference： [1]Patent: US6011044,2000,A
[2]Patent: EP966466,2002,B1

19
4-Oxo-6-β,β,β-trifluoroethoxy-2,3,4,5-tetrahydropyrrolo[3,2-c] quinoline [ No CAS ]
[ 2835-99-6 ]
[ 220854-59-1 ]

Yield	Reaction Conditions	Operation in experiment
83%	In diethylene glycol;	(Step 1) Preparation of 1-(2-methyl-4-hydroxyphenyl)-4-oxo-6-beta,beta,beta-trifluoroethoxy-2,3,4,5-tetrahydropyrrolo[3,2-c]quinoline 4-Oxo-6-beta,beta,beta-trifluoroethoxy-2,3,4,5-tetrahydropyrrolo[3,2-c]quinoline(4.6 g, 16 mmol) was dissolved in diethylene glycol(30 ml) and 4-amino-m-cresol(2.2 g, 18 mmol) was added under nitrogen. The reaction mixture was refluxed at 250 C. for 20 hours. The reaction mixture was diluted in brine(20 ml), and the aqueous layer was extracted with dichloromethane(15 ml) for 3 times. The organic layer was washed with water(15 ml) for 3 times, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 5.2 g of desired compound as solid in 83% of yield. m.p 235-237 C.; 1 H NMR(CDCl3, 200 MHz) delta 2.19(s, 3H), 3.06-3.29(m, 2H), 3.80(q, J=9.1 Hz, 1H), 3.93-4.12(m, 1H), 4.44(q, J=8.3 Hz, 2H), 6.46(d, J=8.5 Hz, 1H), 6.67-6.85(m, 5H), 6.96(d, J=8.5 Hz, 1H), 8.71(brs, 1H), 8.85(brs, 1H); m/e 391(M+ +1, 19.1), 390(M+, 94.0), 389(100), 388(65.5), 321(17.8), 305(9.7).
83%	In diethylene glycol;	(Step 1) Preparation of 1-(2-methyl-4-hydroxyphenyl)-4-oxo-6-beta,beta,beta-trifluoroethoxy-2,3,4,5-tetrahydropyrrolo[3,2-c]quinoline 4-Oxo-6-beta,beta,beta-trifluoroethoxy-2,3,4,5-tetrahydropyrrolo[3,2-c] quinoline(4.6 g, 16 mmol) was dissolved in diethylene glycol(30 ml) and 4-amino-m-cresol(2.2 g, 18 mmol) was added under nitrogen. The reaction mixture was refluxed at 250 C for 20 hours. The reaction mixture was diluted in brine(20 ml), and the aqueous layer was extracted with dichloromethane(15 ml) for 3 times. The organic layer was washed with water(15 ml) for 3 times, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 5.2 g of desired compound as solid in 83 % of yield. m.p 235-237 C; 1H NMR(CDCl3, 200 MHz) delta 2.19(s, 3H), 3.06-3.29(m, 2H), 3.80(q, J=9.1Hz, 1H), 3.93-4.12(m, 1H), 4.44(q, J=8.3Hz, 2H), 6.46(d, J=8.5Hz, 1H), 6.67-6.85(m, 5H), 6.96(d, J=8.5Hz, 1H), 8.71(brs, 1H), 8.85(brs, 1H); m/e 391(M++1, 19.1), 390(M+, 94.0), 389(100), 388(65.5), 321(17.8), 305(9.7).

Reference： [1]Patent: US6011044,2000,A
[2]Patent: EP966466,2002,B1

20
[ 2835-99-6 ]
[ 115607-93-7 ]
3-isobutyryl-4-(4-hydroxy-2-methylphenylamino)-8-methoxyquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With tributyl-amine; In 1,4-dioxane; ethanol;	EXAMPLE 12 Preparation of 3-isobutyryl-4-(4-hydroxy-2-methylphenylamino)-8-methoxyquinoline A solution of 3-isobutyryl-4-chloro-8-methoxyquinoline (1.32 g, 5 mmol) and <strong>[2835-99-6]4-amino-3-methylphenol</strong> (0.62 g, 5 mmol) in dioxan (50 ml) was heated at reflux for 1 hour, then cooled and the solid filtered off. This was taken up in a hot mixture of ethanol and tributylamine, cooled, and the solid filtered off. Recrystallisation from ethanol gave 3-isobutyryl-4-(4-hydroxy-2-methylphenylamino)-8-methoxyquinoline (0.97 g, 55%), m.p. 243-5. Found; C 71.49, H 6.06, N 7.95. Requires; C 71.43, H 6.36, N 7.93.

Reference： [1]Patent: US5143920,1992,A

21
[ 2835-99-6 ]
[ 27568-05-4 ]
ethyl 8-methoxy-4-(4-hydroxy-2-methylphenylamino)-quinoline-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; chloroform;	EXAMPLE 9 Ethyl 8-methoxy-4-(4-hydroxy-2-methylphenylamino)-quinoline-3-carboxylate Ethyl 8-methoxy-4-chloroquinoline-3-carboxylate (2.6 g, 0.0098 mol) and 4-hydroxy-2-methylaniline (2.4 g, 0.0196 mol) in ethanol (150 ml) were heated under refulx for 30 minutes. The solvent was evaporated under reduced pressure. The residue was dissolved in chloroform and extracted with 2N hydrochloric acid (3*100 ml). On basification of the chloroform extracts, a solid precipitated out, this was collected by filtration and dried. Recrystallisation from dimethylformamide gave the title compound. Yield=2.52 g, m.p. 277-279 C. Found; C 68.12, H 5.84, N 8.09. Requires; C 68.17, H 5.72, N 7.95.

Reference： [1]Patent: US5143920,1992,A

22
[ 2835-99-6 ]
[ 98-88-4 ]
4-hydroxy-2-methylphenylbenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With triethylamine; In N,N-dimethyl-formamide;	PRODUCTION EXAMPLE 3 Production of 4-hydroxy-2-methylphenylbenzamide 4-Amino-3-methylphenol (370 mg, 3.00 mmols) was put into a 30-ml conical flask, purged with argon, and dissolved in 1.3 ml of dry DMF. Next, 0.42 ml (1 eq.) of dry triethylamine was added. Then, a dry DMF solution (3.0 ml) of benzoyl chloride (0.35 ml) was added, and stirred at room temperature for 12 hours. The resulting reaction mixture was poured into 50 ml of cold water, suction filtered, extracted with methylene chloride, and washed with water. The methylene chloride layer was dried with sodium sulfate, and methylene chloride was removed by evaporation under reduced pressure. Next, the residue was purified by column clromnatography (silica gel eluted with methylene chloride) to obtain 400 mg of the intended product, 4-hydroxy-2-methylphenylbenzamide (yield: 60%). 1H-NMR (200 MHz, DMSO-d6), delta: 2.13 (3H, s), 6. 60 (1H, dd, J=2.7 and 8.5), 6.66 (1H, d, J=2.7), 7.05 (1H, d, J=8.5), 7.45 to 7.60 (3H, m), 7.95 (2H, d, J=7.1), 9.25 (1H, s), 9.65 (1H, s).

Reference： [1]Patent: US6180844,2001,B2

23
[ 2835-99-6 ]
[ 14002-51-8 ]
4-hydroxy-2-methylphenyl-4-pheenylbenzamide [ No CAS ]
4-hydroxy-2-methylphenyl-4-phenylbenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With triethylamine; In N,N-dimethyl-formamide;	PRODUCTION EXAMPLE 2 Production of 4-hydroxy-2-methylphenyl-4-pheenylbenzamide 4-Amino-3-methylphenol (270 mg, 2.20 mmols) was put into a 30-ml conical flask, purged with argon, and dissolved in 1.0 ml of dry DMF. Next, 0.3 ml (1 eq.) of dry triethylamine was added. Next, a dry DMF solution (3.0 ml) of 4-phenylbenzoyl chloride (478 mg) was added, and stirred at room temperature for 12 hours. The resulting reaction mixture was poured into 100 ml of cold water, suction filtered, extracted with methylene chloride, and washed with water. The methylene chloride layer was dried with sodium sulfate, and methylene chloride was removed by evaporation under reduced pressure. Next, the residue was purified by column chromatography (silica gel eluted with methylene chloride) to obtain 648 mg of the intended product, 4-hydroxy-2-methylphenyl-4-phenylbenzamide (yield: 96%). 1H-NMR (200 MHz, DMSO-d6), delta: 2.14 (3H, s), 6.61 (1H, dd, J=2.7 and 8.4), 6.68 (1H, d, J=2.5), 7.08 (1H, d, J=8.4), 7.38 to 7.55 (3H, m), 7.73 to 7.83 (4H, m), 8.60 (2H, d, J=8.2), 9.28 (1H, s), 9.72 (1H, s).

Reference： [1]Patent: US6180844,2001,B2

24
[ 2835-99-6 ]
[ 64248-64-2 ]
[ 756839-58-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 16h;Product distribution / selectivity;	In a 3 L5 4-necked flask that had been evacuated and back-filled with argon, 2,5- difluorobenzonitrile (295.3 ml, 812.0 mmol) and 4-amino-3-methylphenol (100.0 g, 812.0 mmol) were dissolved in dry DMSO (2.75 M) with rapid stirring at room temperature. The solution was evacuated/backfilled with argon (3x). Potassium carbonate (185.2 g, 1340 mmol) (-325 mesh) was added. The reaction mixture was evacuated/backfilled with argon (3x) and warmed to 80 0C (internal probe) for 16 hours. TLC indicated complete conversion. The reaction mixture was cooled to room temperature and poured slowly into 2 L of ice water with rapid stirring. The residue in the round bottom flask was taken up in water repeatedly and poured into the ice water until a total volume of 3 L was achieved and all solids were in the ice water. The suspension was stirred rapidly for 2 hours as it came to room temperature. The brown solids were collected by filtration, washed with water (3 L), air dried, dried with latex dam, and dried under high vacuum at 40 0C for 44 hours to provide 194 g (99 %) of the desired product as a tan solid. MS (APCI +) m/z 243 (M+l) was detected. 1H NMR (400 MHz5 CDCl3) delta 7.38 (m, IH), 7.18 (m5 IH), 6.65-6.85 (m, 5H), 3.60 (br, 2H), 2.17 (s, 3H).
99%	With potassium carbonate; In dimethyl sulfoxide; at 81℃; for 14h;	100115] Steps E 1-E6: Preparation of 2-(5-(2-(aminomethyl)-4-fluorophenoxy)- 1 H-; [001 6] Step El: Preparation of 2-(4-amino-3-methylphenoxy)-5-fluorobenzonitrile:In a 5 L ilask that had been evacuated and back-filled with Argon, 2,5-diiluorobeiizonitrile (1092 mL, 3057 mmol) and 4-amino-3-methylphenol (376.5 g, 3057 ramol) were dissolved in dry DMSO (2.75 M) with rapid stirring at ambient temperature. The solution was evacuated/backfilled with Argon. Potassium carbonate (697.2 g, 5044 mmol) was added. The reaction wras evacuated/backfilled with Argon and warmed to 81C for 14 hours. After cooling to ambient temperature, the reaction was poured slowly into 3 separate beakers, each containing 2.5 L of rapidly stirring ice water to prevent clumping. The residue in the round bottom flask was taken up in water repeatedly and poured into the beakers until a total volume of 3.5 L was realized in each of the three beakers. The suspension was stirred rapidly for 2 hours as it came to ambient temperature. The brown solids were collected by filtration , washed with water (15 L), air dried, dried with latex dam, and dried under high vacuum at 45 0C for 72 hours to provide 734 g (99%) of desired product as a tan solid. MS M+l (243),
75%	With potassium carbonate; In dimethylsulfoxide-d6; at 90℃;	General procedure: A solution of the corresponding 4a-4b (1 equiv.) and 4-amino-3-methylphenol (10 mmol) was stirred 2 h at 90 C in the presence of K2CO3 (4.14g 30 mmol) in DMSO (50 mL). Then the solution was extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), filtered and evaporated to dryness. The product was separated by column chromatography using PE/EA (3:1)as eluent.

Reference： [1]Patent: WO2007/89646,2007,A1 .Location in patent: Page/Page column 13-14; 50
[2]Patent: WO2009/15000,2009,A1 .Location in patent: Page/Page column 24
[3]Molecules,2016,vol. 21

25
[ 2835-99-6 ]
[ 214487-30-6 ]
4-(4-hydroxy-2-methyl-phenylamino)-6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinoline-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine hydrochloride In 2-ethoxy-ethanol for 1.5h; Heating / reflux;	312 A mixture of 0.3 g of 4-chloro-6-methoxy-7-(3-morpholin-4-yl- propoxy)-quinoline-3-carbonitrile derivative, 0.12 g of 4-amino-m-cresol, 0.1 g of pyridine hydrochloride and 4 ml of 2-ethoxy ethanol was stirred under nitrogen at reflux temperature for 1.5 hr. The mixture was cooled and added to the mixture of ethyl acetate and saturated solution of sodium bicarbonate, stirred for 15 minutes. Following separation of layers, the organic layer was dried over anhydrous sodium sulfate, filtered and filtrate was evaporated to yield dark oil. The oil was purified by silica gel flash chromatography utilizing a gradient of methylene chloride/methanol (95:5 to 90:10 ) to give 0.23 g of the title compound as a tan solid,mpl20-126C; mass spectrum (electrospray,m/e):M+H 449.

Reference： [1]Current Patent Assignee: PFIZER INC - EP973746, 2003, B1 Location in patent: Page/Page column 91-92

26
[ 263270-52-6 ]
[ 2835-99-6 ]
[ 1114592-03-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 0 - 20℃; for 12h;	A cooled (0 0C) solution of 4-amino-m-cresol (Fluka, 4.17g, 33.9 mmol) and triethylamine (23.6 mL, 0.170 mol) in dry dichloromethane (100 mL) was treated with 6-chloropyhmidine-4-carbonyl chloride, obtained as described above for Intermediate 7, step 1 (6.0 g, 34 mmol) and the resulting mixture <n="104"/>was stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic layers were dried on magnesium sulfate and evaporated in vacuo. The crude product was purified by column chromatography (silica) using as eluent petroleum ether/EtOAc to afford the title compound as yellow solid.MS (ESI"): 247.7. HPLC (Condition A): Rt 2.19 min (HPLC purity 96.0%). 1H NMR (DMSO-c/e, 400MHz): delta 10.26 (1 H, s), 9.33 (1 H,s), 9.25 (1 H,s), 8.17 (1 H, s), 7.26 (1 H, d, J= 9.0 Hz), 6.67 (1 H, s), 6.60 (1 H, d, J= 9.0 Hz), 2.15 (3H, s). MS (ESI"): 262.0. HPLC (Condition A): Rt 2.81 min (HPLC purity 96.5%). TLC: Chlorofrom/methanol (9/1 ): Rf - 0.4

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 1516 - 1519
[2]Patent: WO2009/19167,2009,A1 .Location in patent: Page/Page column 102-103

27
[ 5735-99-9 ]
[ 2835-99-6 ]
[ 1021151-19-8 ]

Yield	Reaction Conditions	Operation in experiment
78%	With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; 1-hydroxy-1,2,3-triazole; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 12h;	0.89g (3.44mmol) of 3,3-ethylene glycosyldodecanoyl acid obtained in Reference Example 1 and 0.85g (6.87mmol) of <strong>[2835-99-6]4-amino-3-methylphenol</strong> were dissolved in 20mL of dichloromethane. 0.84g (6.87mmol) of dimethylaminopyridine, 0.98g (7.6mmol) of diisopropylethylamine, 1.05g (6.86mmol) of 1-hydroxy-1,2,3 triazole and 1.32g (6.87mmol) of 1-ethyl-3-dimethylaminopropyl carbodiimide were added to the solution, and the mixture was stirred at room temperature for 12 hours. The reaction liquid was concentrated under reduced pressure, and the residue was subjected to extraction with ethyl acetate. The obtained organic layer was washed with diluted hydrochloric acid and saturated saline, dried with magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (developing solvent: hexane/ethyl acetate=3/7) to obtain N-(4-hydroxy-2-methylphenyl)-3,3-ethyleneglycosyl dodecanoyl amide denoted by the following formula. [Show Image] Quantity Yield: 0.97g (2.68mmol) Percent Yield: 78% 1H-NMR (CDCl3, 500MHz); 0.88ppm (t, 3H), 1.23ppm (m, 12H), 1.37ppm (m, 2H), 1.72ppm (m, 2H), 2.37ppm (s, 3H), 3.99ppm (m, 4H), 6.70ppm (m, 2H), 7.43ppm (d, 1H), 9.04ppm (br, 1H).

Reference： [1]Patent: EP2077109,2009,A1 .Location in patent: Page/Page column 16-17

28
[ 2835-99-6 ]
[ 6980-08-1 ]
[ 884339-71-3 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 3881 - 3891

29
[ 13329-40-3 ]
[ 2835-99-6 ]
[ 1198117-99-5 ]
[ 1198118-00-1 ]