[ CAS No. 90536-66-6 ] {[proInfo.proName]}

Name: 90536-66-6|2-(4-(Methylsulfonyl)phenyl)acetic acid|97%
Brand: Ambeed
SKU: A314848
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Quality Control of [ 90536-66-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 90536-66-6 ]

Product Details of [ 90536-66-6 ]

CAS No. :	90536-66-6	MDL No. :	MFCD00216495
Formula :	C₉H₁₀O₄S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HGGWOSYNRVOQJH-UHFFFAOYSA-N
M.W :	214.24	Pubchem ID :	572345
Synonyms :

Calculated chemistry of [ 90536-66-6 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.22
Num. rotatable bonds :	3
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	51.08
TPSA :	79.82 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) :	-6.67 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.96
Log Po/w (XLOGP3) :	1.32
Log Po/w (WLOGP) :	1.8
Log Po/w (MLOGP) :	1.16
Log Po/w (SILICOS-IT) :	0.88
Consensus Log Po/w :	1.22

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-2.12
Solubility :	1.63 mg/ml ; 0.0076 mol/l
Class :	Soluble
Log S (Ali) :	-2.6
Solubility :	0.542 mg/ml ; 0.00253 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.5
Solubility :	0.685 mg/ml ; 0.0032 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.64

Safety of [ 90536-66-6 ]

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

Application In Synthesis of [ 90536-66-6 ]

* 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 [ 90536-66-6 ]
Downstream synthetic route of [ 90536-66-6 ]

[ 90536-66-6 ] Synthesis Path-Upstream 1~11

1
[ 10297-73-1 ]
[ 90536-66-6 ]

Yield	Reaction Conditions	Operation in experiment
52%	Stage #1: for 10 h; Heating / reflux Stage #2: With sodium hydroxide In water at 84℃; for 12 h;	The synthesis was carried out as described in Scheme 2. Step a. A mixture of 4-(methylsulfonyl)acetophenone (5.5 g, 27.8 mmol), morpholine (2.5 mL), and sulfur (0.89 g, 27.8 mmol) was refluxed for 10 h, and poured into ice. The precipitated solid was filtered, and washed with cold ethyl acetate. The solid was added to 10percent sodium hydroxide (55 mL), heated to 84° C. for 12 h, and the alkaline solution was acidified with 12 N HCl. The resulting solid was filtered, dried, and recrystallized from hexane-ethyl acetate (1:1) to give 4-methylsulfonylphenylacetic acid (white solid, 4.2 g, 52percent overall yield). Step b. 2-Bromoacetophenone (1.02 g, 5.12 mmol), dissolved in acetonitrile, was added to Et3N (1.74 mL), followed by 4-methylsulfonylphenylacetic acid (1 g, 4.67 mmol). After 1.5 h at room temperature, 1,8-diazabicyclo[5,4,0]undec-7-ene (1.67 mL) was added. The reaction mixture was stirred for another 1 h, and then treated with 1 N HCl (35 mL). The product was extracted with ethyl acetate, dried over sodium sulfate, and recrystallized from ethyl acetate-hexane (1:1) to give 46b (880 mg, 60percent overall yield). 1H NMR (CDCl3) δ 3.08 (s, 3H), 5.24 (s, 2H), 7.18-7.30 (m, 5H), 7.66 (dd, J=1.9, 6.7 Hz, 2H), 7.96 (dd, J=1.9, 6.7 Hz, 2H); HRMS calc'd for M+ 314.0605, found 314.0632. Anal. (C17H14O4S)C, H.

Reference： [1] Patent: US2003/236294, 2003, A1, . Location in patent: Page 19
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 5, p. 1549 - 1553

2
[ 300355-18-4 ]
[ 90536-66-6 ]

Yield	Reaction Conditions	Operation in experiment
51%	With sodium hydroxide In methanol; water at 20℃; for 12 h;	General procedure: Scheme I(c) lntermediate-9 Reagents and conditions: i) Methanol, cone, sulfuric acid, reflux, 3 h; ii) methyl iodide, potassium carbonate, NN-dimethylformamide, RT, 3 h; iii) m-chloroperbenzoic acid, dichloromethane, RT, 12 h; iv) sodium hydroxide, methanol, water, RT, 12 h. Step iv: 2-(4-(methylsulfonyl)phenyl)acetic acid The process of this step was adopted from step-v of Scheme 1(a) to obtain the title compound [0.56 g, 51 percent]. NMR (300 MHz, DMSO-d₆): δ 12.58 (s, 1H), 7.88-7.85 (m, 2H), 7.54-7.52 (m, 2H), 3.73 (s, 2H), 3.20 (s, 3H). Step v: 2-(4-(ethylsulfonyl)phenyl)acetic acidTo a 50 mL round bottom flask, were added ethyl 2-(4-(ethylsulfonyl)phenyl)acetate (2.5 g, 0.0098 mol) and ethanol (18 mL). To the same flask, was added a solution of sodium hydroxide in water (1.42 g, 0.0355 mol in 18 mL of water) and then stirred at RT for 12 h. The volatiles were evaporated under reduced pressure to obtain residue. The residue was acidified to pH 5.0 with dil. hydrochloric acid and was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to get the title compound [2.4 g, 91 percent]. NMR (400 MHz, DMSO-de): δ 12.5 (brs, 1H), 7.84 (d, 2H), 7.56 (d, 2H), 3.74 (s, 2H), 3.13 (q, 2H), 1.20 (t, 3H).

Reference： [1] Patent: WO2015/101928, 2015, A1, . Location in patent: Page/Page column 33; 35; 37

3
[ 100-68-5 ]
[ 90536-66-6 ]

Reference： [1] Patent: US6127545, 2000, A,
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 5, p. 1549 - 1553
[3] Patent: CN107556223, 2018, A,
[4] Patent: CN107556223, 2018, A,

4
[ 109347-44-6 ]
[ 90536-66-6 ]

Yield	Reaction Conditions	Operation in experiment
84%	With sodium tungstate; dihydrogen peroxide; sodium carbonate In water	In a 500 mL dry three-necked bottle, 50.0 g of 4-methanesulfonyl phenylacetaldehyde was added, 200 mL of water was added, and sodium carbonate was added.30g, add 0.5g of sodium tungstate under stirring,70 mL of 30percent hydrogen peroxide solution was slowly added dropwise, and the reaction solution gradually became clear as the reaction proceeded.TLC test, after the end of the reaction, filtration, the filtrate was slowly added 10percent hydrochloric acid, adjust the pH to 2-3, filtered,This gave crude 4-methanesulfonylphenylacetic acid.The above 4-methylsulfonylphenyl acetic acid was dissolved in 1percent sodium hydroxide, and saturated sodium thiosulfate solution was added in 10 mL.After extracting 50 mL of ethyl acetate twice, 200 mL of ethyl acetate was added to the aqueous layer, and 10percent hydrochloric acid was added to adjust the pH to 2-3.The ethyl acetate layer was separated. The aqueous layer was extracted once with 200 mL of ethyl acetate.Combine the ethyl acetate layers, heat to reflux, add 200 mL of n-heptane, slowly cool to 0-5 °C,The mixture was stirred at this temperature for 1 hour, filtered and vacuum dried to give 54.2 g of 4-methanesulfonylphenylacetic acid. Yield: 84.0percent.

Reference： [1] Patent: CN107556223, 2018, A, . Location in patent: Paragraph 0038-0045

5
[ 201230-82-2 ]
[ 53606-06-7 ]
[ 90536-66-6 ]

Reference： [1] Tetrahedron Letters, 2000, vol. 41, # 40, p. 7601 - 7604

6
[ 16188-55-9 ]
[ 90536-66-6 ]

Reference： [1] Patent: EP975596, 2004, B1, . Location in patent: Page 10-11

7
[ 1778-09-2 ]
[ 90536-66-6 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 5, p. 1549 - 1553

8
[ 3446-89-7 ]
[ 90536-66-6 ]

Reference： [1] Patent: CN107556223, 2018, A,
[2] Patent: CN107556223, 2018, A,

9
[ 5470-70-2 ]
[ 90536-66-6 ]
[ 221615-75-4 ]

Yield	Reaction Conditions	Operation in experiment
1.8 kg	With tert-butylmagnesium chloride In tetrahydrofuran at 70 - 80℃; Large scale	4-methanesulfonylphenylacetic acid (3.0 kg) was added tetrahydrofuran (6 L),A solution of 1 M t-butylmagnesium chloride in tetrahydrofuran (40 L) was added dropwise,Heating 70 ~ 80 ,A solution of methyl 6-methylnicotinate (1.7 kg) in tetrahydrofuran (5 L) was slowly added dropwise,About 2 to 3 hours dripping.After refluxing for 1 hour.Cooling to 20 ~ 25 ,add water,The pH of the sodium hydroxide aqueous solution (the mass concentration refers to the mass of sodium hydroxide as a percentage of the total mass of the aqueous sodium hydroxide solution) is adjusted to pH = 7 to 8,Precipitate a lot of solid.Centrifugal,The filter cake was rinsed with water and dried in vacuo at 50 ° C for 16 hours,About 3.6 kg of a yellow solid was obtained.Recrystallization from dichloromethane (20 L) gave 1.8 kg of etoposide intermediate II.

Reference： [1] Journal of Organic Chemistry, 2000, vol. 65, # 25, p. 8415 - 8420
[2] Patent: EP2551265, 2013, A1, . Location in patent: Paragraph 0062-0066
[3] Patent: CN106632003, 2017, A, . Location in patent: Paragraph 0046; 0047; 0048

10
[ 5470-70-2 ]
[ 90536-66-6 ]
[ 1421227-97-5 ]
[ 221615-75-4 ]

Reference： [1] Patent: EP2551265, 2013, A1, . Location in patent: Paragraph 0090-0099

11
[ 90536-66-6 ]
[ 1421227-97-5 ]
[ 221615-75-4 ]

Reference： [1] Patent: EP2551265, 2013, A1,

[ 90536-66-6 ] Synthesis Path-Downstream 1~74

1
[ 64-17-5 ]
[ 90536-66-6 ]
[ 58058-86-9 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; at -10 - 20℃; for 16h;	SOC12 (8.2mL, 112. 0mmol) was added to a stirred suspension of (4- methanesulfonylphenyl) acetic acid (20. 00G, 93. 3MMOL) in ETOH (80ML) AT-10 C. The mixture was allowed to warm up to 20 C over 16h, then the solvents were removed under reduced pressure. The remainder was dissolved in EtOAc, then the resulting solution was washed with H20 until the pH of the aqueous phase was neutral. The EtOAc solution was washed further with saturated aqueous NA2C03, before being dried (MGS04). Filtration and solvent evaporation furnished the title compound: M/Z (ES+) = 284.1 [M+ MECN + H] +.
	With sulfuric acid; at 80℃;	The ethyl-4-(methylsulfonyl)phenylacetate was prepared by refluxing 4-(methylsulfonyl)-phenylaceticacid (1) in excess absolute ethanol at 80 C in the presence of few drops of concentrated sulfuric acid and excess ethanol was removed and quenched to water. Aqueous layer was basified to neutral pH using 5% sodium bicarbonate solution. The product was extracted from aqueous layer using ethyl acetate. The solvent was removed. The compound was obtained as low melting (32-34 C) white solid.IR (KBr, gammamax, cm-1): 3014 (Ar-H), 1691(CO), 1407 (SO), 1138 (SO); Anal. Calcd. (%) for C11H14O4S: C, 54.53, H, 5.82; found C, 54.50, H, 5.80.
	With thionyl chloride; at -10 - 20℃; for 16h;	Preparation 2: Ethyl (4-methanesulfonylphenyl)acetate; SOC12 (8.2mL, 112.0mmol) was added to a stirred suspension of (4- methanesulfonylphenyl) acetic acid (20.00g, 93.3mmol) in EtOH (80mL) at -10C. The mixture was allowed to warm up to 20C over 16h, then the solvents were removed under reduced pressure. The remainder was dissolved in EtOAc and the resulting solution was washed with H20 until the pH of the aqueous phase was neutral. The EtOAc solution was washed further with saturated aqueous Na2C03, before being dried (MgS04). Filtration and solvent evaporation gave the title compound: m/z (ES+) = 284.1 [M+ MeCN + H]+.

Reference： [1]Journal of Organic Chemistry,2000,vol. 65,p. 8415 - 8420
[2]Journal of the Chemical Society,1948,p. 1506
[3]Patent: WO2004/72031,2004,A2 .Location in patent: Page 29-30
[4]European Journal of Medicinal Chemistry,2012,vol. 54,p. 59 - 64
[5]Patent: WO2005/103021,2005,A1 .Location in patent: Page/Page column 17

2
[ 5470-70-2 ]
[ 90536-66-6 ]
[ 221615-75-4 ]

Yield	Reaction Conditions	Operation in experiment
	With tert-butylmagnesium chloride; In tetrahydrofuran; at 65 - 70℃; for 1.5h;	In a 4-neck anhydrous flask there are introduced at 20-25C 5.0 g of (4-methylsulfonyl)phenyl acetic acid of formula (IV) (1.0 mol. equiv.), 100 mL of Anhydrous THF and the mixture is heated to 65-70C (up to reflux). Maintaining at T=65-70 C there are simultaneously dosed in the mixture in about 1 hour: a) 62.0 g of t-BuMgCl 1.0 M solution in THF (about 70.0 mL) (3.0 mol. equiv.) andb) a solution of 2.3 g of methyl ester of 6-methylpyridine-3-carboxylic acid of formula (III - R=Me) (0.65 mol. equiv.) in 7.5 mL of Anhydrous THF. After completing addition, maintain at 65-70 C for 30 minutes. The reaction is controlled through HPLC: HPLC purity 72.05% (A%) and Impurity '408' = 0.26% (A%).
1.8 kg	With tert-butylmagnesium chloride; In tetrahydrofuran; at 70 - 80℃;Large scale;	4-methanesulfonylphenylacetic acid (3.0 kg) was added tetrahydrofuran (6 L),A solution of 1 M t-butylmagnesium chloride in tetrahydrofuran (40 L) was added dropwise,Heating 70 ~ 80 ,A solution of methyl 6-methylnicotinate (1.7 kg) in tetrahydrofuran (5 L) was slowly added dropwise,About 2 to 3 hours dripping.After refluxing for 1 hour.Cooling to 20 ~ 25 ,add water,The pH of the sodium hydroxide aqueous solution (the mass concentration refers to the mass of sodium hydroxide as a percentage of the total mass of the aqueous sodium hydroxide solution) is adjusted to pH = 7 to 8,Precipitate a lot of solid.Centrifugal,The filter cake was rinsed with water and dried in vacuo at 50 C for 16 hours,About 3.6 kg of a yellow solid was obtained.Recrystallization from dichloromethane (20 L) gave 1.8 kg of etoposide intermediate II.

Reference： [1]Journal of Organic Chemistry,2000,vol. 65,p. 8415 - 8420
[2]Patent: EP2551265,2013,A1 .Location in patent: Paragraph 0062-0066
[3]Patent: CN106632003,2017,A .Location in patent: Paragraph 0046; 0047; 0048

3
[ 201230-82-2 ]
[ 53606-06-7 ]
[ 90536-66-6 ]

Reference： [1]Tetrahedron Letters,2000,vol. 41,p. 7601 - 7604

4
[ 90536-66-6 ]
[ 74426-50-9 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride;Heating / reflux;	A mixture of 1.5 mmol of 4-methylsulfonyl ( or aminosulfonyl )phenacetic acid and 5 ml of thionyl chloride was heated under reflux and in nitrogen atmosphere to give a clear solution. Removal of the excess of thionyl chloride under reduced pressure a light yellow solid was obtained and without purification put into the next reaction.
	With thionyl chloride; for 1h;Heating / reflux;	Example 79; (a) 2-[4-(methylsulfonyl)phenyl]acetic acid (650 mg, 3.0 mmol) was heated at reflux in 5 mL of thionyl chloride for 1 hr. The reaction mixture was cooled and concentrated by rotary evaporator. The crude residue was dissolved in 10 mL of THF and then added to a freshly distilled solution of diazomethane in diethyl ether (?10 mmol, prepared from diazald) at 0 C. The reaction mixture was stirred for 30 min at 0 C then 2 mL of conc HCl was added. After stirring 30 min at 0 C, the reaction was allowed to warm to rt and stirred 1 hr. Quenched excess diazomethane with acetic acid. Diluted with EtOAc and washed with water and sat NaHCO3. The EtOAc extracts were dried over MgSO4 then solution was filtered and concentrated by rotary evaporator to give 79a which was taken to the next step without further purification.
	With thionyl chloride;	Step 1 First, a mixture of 110 g (0.51 mole) of 4-methylsulfonylphenylacetic acid and 110 ml (1.51 moles) of thionyl chloride was heated at 90 C. for 2 hours. After completion of the reaction, an excess of thionyl chloride was distilled off under reduced pressure, giving about 120 g of 4-methylsulfonylphenylacetyl chloride as a light brown solid.

	With thionyl chloride;Heating / reflux;	Example 98 4-Methylsulfonylphenylacetonphenone A mixture of 5.0 g (0.023 mol) of 4-methylsulfonylphenacetic acid and 10 ml of thionyl chloride were heated under reflux to give a clear solution. Removal of the excess of thionyl chloride under reduced pressure to give a light yellow solid and without purification put into the next reaction. To the solution of the solid obtained above in 30 ml of dry benzene was added in portions 4.7 g (0.035 mol) of anhydrous aluminum chloride at 20-25 C. When addition was complete, the mixture was heated to reflux for 2 h, then cooled and poured into a mixture of ice and 10 ml of 1N hydrochloride acid. The benzene was removed in vacuo and the crude product was separated by filtration and washed with sodium carbonate and water. The filter cake is sucked reasonably dry and recrystallized from 95% ethanol to give 3.9 g of the title compound as light yellow crystal, yield 60.9%, m.p. 190-192 C.
	With thionyl chloride; In tetrahydrofuran; for 1.5h;Reflux;	4-(Methylsulfonyl)phenylacetic acid (300 mg, 1.4 mmol) and thionyl chloride (102 muL, 1.4 mmol) were refluxed in anhydrous THF (1 mL) for 1.5 hours, and the resulting reaction solution was added to a solution containing 9d (100 mg, 0.335 mmol) and DIPEA (155 muL, 0.89 mmol) in THF (1 mL). After stirring for 1 day, the reaction mixture was taken up in EtOAc, washed with 1M aqueous HCl, washed with 5% aqueous Na2CO3, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel (hexane/EtOAc 2:1) to yield a white solid (170 mg, ~99%). A 57 mg sample was further purified by HPLC (1.0 mg). 1H NMR (300 MHz, CDCl3) delta 11.3 (br s, 1H,, NH), 7.96 (d, J = 8.1 Hz, 2H, Ar-H), 7.56 (d, J = 8.1 Hz, 2H, Ar-H), 4.55 (s, 2H, 7-CH2), 4.33 (q, J = 7.1 Hz, 2H, CH2CH3), 4.20 (q, J = 7.1 Hz, 2H, CH2CH3), 3.91 (s, 2H, CH2Ar), 3.70 (m, 2H, 5-CH2), 3.06 (s, 3H, OCH3), 2.88 (m, 2H, 4-CH2), 1.39 (t, J = 7.1 Hz, 3H, CH2CH3), 1.29 (t, J = 6.9 Hz, 3H, CH2CH3). HRMS calcd C22H26N2O7S [M + H]+ 495.1254; Found 495.1237.
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h;	To a solution of 4-methylsulfonylphenylacetic acid (3.72 g, 17.4 mmol) in CH2Cl2 (100 mL) was added 10 drops DMF and oxalyl chloride (4.4 mL, 50 mmol). The reaction mixture was stirred at room temperature for 2 h before concentration in vacuo. The residue was dissolved in 100 mL of THF to provide a 0.17 M solution of (4-methane-sulfonylphenyl)-acetyl chloride.
	With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 3h;	To a suspension of <strong>[90536-66-6]4-(methylsulfonyl)phenylacetic acid</strong> (388 mg, 1.8 mmol) in dry DCM (5 mL) was added oxalyl chloride (320 iL, 3.6 mmol) followed byDMF (2 drops). The reaction mixture was stirred at RT for 3 h then the solvent was removed in vacuo. The resultant residue was taken up in DCM (2 mL) and added dropwise to a stirring solution of 5-bromo-4-methyl-3-(3-trifluoromethyl-phenyl)- pyridin-2-ylamine (Int. 1, 500 mg, 1.51 mmol) and triethylamine (420 iL,36.02 mmol) in DCM (2 mL) at 0-5C. The reaction mixture was stirred at 0-5C for 3 h then gradually warmed to RT over 5 h. The reaction mixture was partitioned between saturated sodium hydrogen carbonate solution and DCM. The organic phase was concentrated in vacuo and purified by flash chromatographyeluting with a gradient of 0-100% EtOAc in cyclohexane to give the title compound as an orange glass (308 mg).LC-MS (Method 2): Rt = 3.43 mi mlz = 526.9, 528.9 [M+H]

Reference： [1]Bioorganic and Medicinal Chemistry,2003,vol. 11,p. 5539 - 5544
[2]Patent: US2004/29951,2004,A1 .Location in patent: Page/Page column 6
[3]Patent: US2006/154973,2006,A1 .Location in patent: Page/Page column 46
[4]Patent: US5082974,1992,A
[5]Patent: US2004/58977,2004,A1 .Location in patent: Page/Page column 9; 24
[6]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 7089 - 7093
[7]Patent: US2012/149718,2012,A1 .Location in patent: Page/Page column 30
[8]Journal of Materials Chemistry C,2013,vol. 1,p. 5309 - 5314
[9]Patent: WO2014/9425,2014,A1 .Location in patent: Page/Page column 83; 84
[10]RSC Advances,2014,vol. 4,p. 38726 - 38742

5
[ 5445-25-0 ]
[ 90536-66-6 ]
ethoxycarbonyl-α-(4-chlorophenyl)methyl 4-methylsulfonylphenylacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With triethylamine In tetrahydrofuran Heating;

Reference： [1]Weber, Valerie; Rubat, Catherine; Duroux, Eliane; Lartigue, Claire; Madesclaire, Michel; Coudert, Pascal [Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 14, p. 4552 - 4564]

6
[ 3132-99-8 ]
[ 90536-66-6 ]
[ 346629-82-1 ]

Yield	Reaction Conditions	Operation in experiment
73%	With potassium acetate; acetic anhydride; at 120℃; for 24h;	General procedure: Potassium acetate (982 mg, 10 mmol) or triethylamine (1.5 mL, 10.75 mmol; for the synthesis of 13, 14, 15, 18, 20, 22, 23, and 25) was added to a stirred mixture of the appropriate arylacetic acid (7.5 mmol), aromatic aldehyde (7.5 mmol) and acetic anhydride (3 mL, 32 mmol). The reaction mixture was stirred at 100-140 C for 3.5-70 h. Then it was cooled to rt, water was added (40 mL) and the mixture was treated with a solution of 10 M NaOH until pH 12 was reached, followed by conc. HCl (to pH 1). The resulting mixture was extracted with CH2Cl2 (3 × 80 mL). Organic phases were extracted with 2 M NaOH (3 × 80 mL) and water (80 mL). The combined aqueous solutions were washed with CH2Cl2 (100 mL) to remove the impurities and traces of starting materials, then acidified with conc. HCl (until pH was 1), and finally extracted with CH2Cl2 (4 × 50 mL). The methylene chloride phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, evaporated to dryness and the residue was crystallized from a suitable solvent.

Reference： [1]European Journal of Medicinal Chemistry,2013,vol. 62,p. 89 - 97
[2]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5241 - 5246

7
[ 90536-66-6 ]
[ 118493-85-9 ]
[ 346629-84-3 ]

Reference： [1]Organic Process Research and Development,2006,vol. 10,p. 36 - 45
[2]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5241 - 5246

8
[ 90536-66-6 ]
[ 103-73-1 ]
[ 346413-00-1 ]

Yield	Reaction Conditions	Operation in experiment
69%	With thionyl chloride;aluminium chloride; In N-methyl-acetamide; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran;	EXAMPLE 4 1-(4-Ethoxyphenyl)-2-[4-(methylsulfonyl)phenyl]ethanone To a stirred suspension of 4-methylsulfonylphenylacetic acid 1 (10 g) in DCM (80 mL) was added dimethylformamide (0.18 mL). The mixture was heated to 30 C., treated with thionyl chloride (3.6 mL) and stirred for 11/2 hours. The resulting solution was cooled to 15 C., treated with granular aluminium chloride (11.8 g) and stirred for further 15 minutes. Ethoxybenzene (7.1 mL) was added and the resultant mixture was warmed to 20 C. and stirred for 2 hours. The reaction mixture was cooled to 10 C. and treated dropwise with IMS (17 mL). The mixture was then diluted with DCM (120 mL) and water (60 mL) was then added over 20 minutes. The mixture was warmed to 30 C. and the layers separated. The organic layer was washed with 5M hydrochloric acid (240 mL), saturated sodium bicarbonate solution (40 mL) and then concentrated by distillation at atmospheric pressure to 40 mL. The mixture was cooled to 22 C. and aged for 18 hours. The product was isolated by filtration, washed with DCM:iso-octane (1:1, 220 mL) and dried in vacuo at 40 C. to give the title compound as a white crystalline solid (10.3 g, 69%). MH+ 319 1H-NMR (CDCl3) delta: 7.98(m, J=9.1 Hz, 2H, 2* p-di-substituted aromatic CH); 7.91(m, J=8.5 Hz, 2H, 2* p-di-substituted aromatic CH); 7.47(m, J=8.5 Hz, 2H, 2* p-di-substituted aromatic CH); 6.95(m, J=9.1 Hz, 2H, 2* p-di-substituted aromatic CH); 4.34(s, 2H, CH2); 4.12(q, J=7.2 Hz, 2H, ethoxy-CH2); 3.05(s, 3H, CH3); 1.45(t, J=7.2 Hz, 3H, ethoxy-CH3).

Reference： [1]Organic Letters,2011,vol. 13,p. 2232 - 2235
[2]Patent: US2003/78267,2003,A1
[3]Tetrahedron Letters,2007,vol. 48,p. 911 - 913

9
[ 90536-66-6 ]
[ 202409-33-4 ]

Reference： [1]Journal of Organic Chemistry,2000,vol. 65,p. 8415 - 8420
[2]Journal of Organic Chemistry,2000,vol. 65,p. 8415 - 8420
[3]Journal of Organic Chemistry,2000,vol. 65,p. 8415 - 8420

10
[ 90536-66-6 ]
[ 25025-07-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: sulfuric acid 2: aqueous ammonia 3: phosphorus oxychloride; chloroform

Reference： [1]Forrest; Walker [Journal of the Chemical Society, 1948, p. 1506]

11
[ 67-56-1 ]
[ 90536-66-6 ]
[ 300355-18-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sulfuric acid; for 16h;Heating / reflux;	Methyl 4-(methanesulfonyl)phenyl acetate: A solution of 4-(methanesulfonyl)phenyl acetic acid (21.8 g, 101 mmol), methanol (250 mL), and concentrated sulfuric acid (1 mL) was heated under reflux for 16 h. The reaction mixture was allowed to cool to 25 C. and evaporated to dryness in vacuo. The residue was taken up in 10% aqueous sodium bicarbonate (200 mL) and ethyl acetate (200 mL). The isolated water phase was extracted with further ethyl acetate (2×200 mL), and the combined organic phases were washed with water (100 mL), dried with anhydrous sodium sulphate, and evaporated to dryness in vacuo to give methyl 4-(methanesulfonyl)phenyl acetate. Yield: 24.0 g (100%). 1H-NMR (CDCl3, delta ppm): 7.91 (d, 2H); 7.50 (d, 2H); 3.74 (s, 2H); 3.73 (s, 3H); 3.05 (s, 3H).
100%	With sulfuric acid; for 16h;Heating / reflux;	Methyl 4-(methanesulfonyl)phenyl acetate:; A solution of 4- (methanesulfonyl)phenyl acetic acid (21.8 g, 101 mmol), methanol (250 ml_), and concentrated sulfuric acid (1 ml_) was heated under reflux for 16 h. The reaction mixture was allowed to cool to 25 C and evaporated to dryness/n vacuo. The residue was taken up in 10% aqueous sodium bicarbonate (200 ml_) and ethyl acetate (200 ml_). The isolated water phase was extracted with further ethyl acetate (2 x 200 ml_), and the combined organic phases were washed with water (100 ml_), dried with anhydrous sodium sulphate, and evaporated to dryness in vacuo to give methyl 4-(methanesulfonyl)phenyl acetate. Yield: 24.0 g (100 %). 1H-NMR (CDCI3, delta ppm): 7.91 (d, 2H); 7.50 (d, 2H); 3.74 (s, 2H); 3.73 (s, 3H); 3.05 (s, 3H).
99%	sulfuric acid; for 24h;Heating / reflux;	(4-Methanesulfonyl-phenyl)-acetic acid methyl ester (Ol-I):A solution of (4-Methanesulfonyl-phenyl)-acetic acid (25 g, 116.69 mmol) in methanol (300 ml) is treated with catalytic amount of sulfuric acid (2 ml). The reaction mixture was refluxed for 24 h. The solvent was then removed under reduced pressure, residue was dissolve in ethyl acetate (200 ml), the organic layer washed with water (2x100 ml), brine (100 ml), dried over sodium sulfate, and solvent was removed under reduced pressure to give (4-Methanesulfonyl-phenyl)-acetic acid methyl ester 26.37 g, 99 %). 1H NMR (400 MHz, CDCl3): delta 3.06 (s, 3H), 3.73 (s, 3H), 7.50 (d, J = 8.4Hz, 2H), 7.91 (d, J = 8.4 Hz, 2H).

98%	With sulfuric acid; for 19h;Heating / reflux;	[0174] A solution of 4-(methanesulfonyl)phenyl acetic acid (43.63 g, 0.204 mol) in methanol (509 mL) was treated slowly with concentrated sulfuric acid (2 mL). The resulting reaction mixture was heated under reflux for 19 h. The reaction mixture was allowed to cool to 25 C. and then concentrated in vacuo to remove methanol. The residue was diluted with ethyl acetate (800 mL). The organic phase was washed with a saturated aqueous sodium bicarbonate solution (1×200 mL) and a saturated aqueous sodium chloride solution (1×200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 1/1 hexanes/ethyl acetate) afforded 4-(methanesulfonyl)phenyl acetic acid methyl ester (45.42 g, 98%) as a yellow oil which solidified to a cream colored solid upon sitting over time at 25 C.: mp 78-80 C.; EI-HRMS m/e calcd for C10H12O4S (M+) 228.0456, found 228.0451. [0175] A solution of diisopropylamine (0.67 mL, 4.82 mmol) in tetrahydrofuran (30 mL) cooled to -78 C. under an argon atmosphere was treated with a 2.5M solution of n-butyllithium in hexanes (1.93 mL, 4.82 mmol). The reaction mixture was stirred at -78 C. for 15 min. At this time, the reaction was treated with a solution of (4-methanesulfonyl-phenyl)-acetic acid methyl ester (1.00 g, 4.38 mmol) in tetrahydrofuran (6 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). The bright yellow solution was allowed to stir at -78 C. for 1 h, after which time, a solution of 2-bromomethyl-tetrahydro-pyran (0.67 mL, 5.26 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL) was added via a cannula. The reaction mixture was then allowed to warm to 25 C., where it was stirred for 16 h. The reaction mixture was then quenched by the addition of a saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (3×15 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 70/30 hexanes/ethyl acetate) afforded 2-(4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid methyl ester (157 mg, 11%) as a colorless oil: EI-HRMS m/e calcd for C16H22O5S (M+) 326.1188, found 326.1189. [0176] A solution of 2-(4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid methyl ester (75 mg, 0.23 mmol), methylurea (34 mg, 0.46 mmol), and a solution of magnesium methoxide in methanol (7.4 wt. %, 0.49 mL, 0.35 mmol) and methanol (0.5 mL) was heated at 100 C. for 8 h. Over time, the reaction mixture turned cloudy in appearance. At this time, the reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate (10 mL) and then filtered through a pad of silica gel. The filtrate was concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 30/70 hexanes/ethyl acetate) afforded 1-[2-(4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionyl]-3-methyl-urea (5 mg, 6%) as a colorless oil: FAB-HRMS m/e calcd for C17H24N2O5S (M+H)+ 369.1484, found 369.1495.
98%	With sulfuric acid; at 20℃;Product distribution / selectivity;	Step 1: A solution of 4-methylsulfonylphenylacetic acid (20 g, 93 mmol) in methanol (200 mL) and 3 drops of concentrated H2SO4 was stirred at room temperature overnight. An additional 6 drops of concentrated H2SO4 were added and stirring was continued at room temperature overnight. The reaction mixture was concentrated in vacuo to afford (4-methanesulfonylphenyl)acetic acid methyl ester (20.7 g, 98%).

Reference： [1]Patent: US2008/139562,2008,A1 .Location in patent: Page/Page column 14
[2]Patent: WO2006/58923,2006,A1 .Location in patent: Page/Page column 47
[3]Patent: WO2008/104994,2008,A2 .Location in patent: Page/Page column 78
[4]Patent: US2003/225283,2003,A1 .Location in patent: Page 19
[5]Patent: US2012/149718,2012,A1 .Location in patent: Page/Page column 32

12
[ 10297-73-1 ]
[ 90536-66-6 ]

Yield	Reaction Conditions	Operation in experiment
52%		The synthesis was carried out as described in Scheme 2. Step a. A mixture of 4-(methylsulfonyl)acetophenone (5.5 g, 27.8 mmol), morpholine (2.5 mL), and sulfur (0.89 g, 27.8 mmol) was refluxed for 10 h, and poured into ice. The precipitated solid was filtered, and washed with cold ethyl acetate. The solid was added to 10% sodium hydroxide (55 mL), heated to 84 C. for 12 h, and the alkaline solution was acidified with 12 N HCl. The resulting solid was filtered, dried, and recrystallized from hexane-ethyl acetate (1:1) to give 4-methylsulfonylphenylacetic acid (white solid, 4.2 g, 52% overall yield). Step b. 2-Bromoacetophenone (1.02 g, 5.12 mmol), dissolved in acetonitrile, was added to Et3N (1.74 mL), followed by 4-methylsulfonylphenylacetic acid (1 g, 4.67 mmol). After 1.5 h at room temperature, 1,8-diazabicyclo[5,4,0]undec-7-ene (1.67 mL) was added. The reaction mixture was stirred for another 1 h, and then treated with 1 N HCl (35 mL). The product was extracted with ethyl acetate, dried over sodium sulfate, and recrystallized from ethyl acetate-hexane (1:1) to give 46b (880 mg, 60% overall yield). 1H NMR (CDCl3) delta 3.08 (s, 3H), 5.24 (s, 2H), 7.18-7.30 (m, 5H), 7.66 (dd, J=1.9, 6.7 Hz, 2H), 7.96 (dd, J=1.9, 6.7 Hz, 2H); HRMS calc'd for M+ 314.0605, found 314.0632. Anal. (C17H14O4S)C, H.

Reference： [1]Patent: US2003/236294,2003,A1 .Location in patent: Page 19
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1549 - 1553

13
[ 90536-66-6 ]
N-ethyl-2-(4-methanesulfonyl-phenyl)-N-piperidin-4-yl-acetamide dihydrochloride [ No CAS ]
[ 374725-41-4 ]

Yield	Reaction Conditions	Operation in experiment
76%	With N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide;dmap; In dichloromethane; at 20℃; for 20h;	To a solution of 1-phenylmethyl-4-ethylaminopiperidine dihydrochloride (32. 0g, 11 Ommol) in DCM (500mL) was added N, N-diisopropylethylamine (60mL) with stirring to ensure complete dissolution. 4-Methanesulfonylphenylacetic acid (25. 0g, 117mmol), 4- Dimethylaminopyridine (2. 0g) and dicyclohexylcarbodiimide (25. 0g, 121mmol) were added and the resulting mixture was stirred at room temperature for 20h. The precipitate was removed by filtration and the resulting solution was washed successively with 2N aqueous HCl, water and IN aqueous NaOH, dried (MgS04) and evaporated. The residue was purified by silica gel chromatography (eluent: 10% MeOH/ethyl acetate) to afford the sub-titled compound (35g, 76%); NMR: 1.00 and 1.14 (t, 3H), 1.45 and 1.70 (m, 2H), 1.95 (br m, 2H), 2.80 (br m, 2H), 3. 18 (s, 3H), 3.20 and 3.33 (q, 2H), 3.45 (s, 2H), 3.80 and 3.87 (s, 2H), 3.70 and 4.10 (m, 1H), 7.2-7. 3 (m, 5H), 7.48 (m, 2H), 7.82 (m, 2H); MS: 415 (MH+).
76%	With dmap; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 20h;	Step 2: Preparation of N-(l-benzylpiperidin-4-yl)-./V-ethyl-2-[4-(methylsulfonyl)phenyl]acetamide.; To a solution of l-phenylmethyl-4-ethylaminopiperidine dihydrochloride (32.Og,1 lOmmol) in DCM (500mL) was added N,N-diisopropylethylamine (60mL) with stirring toensure complete dissolution. 4-Methanesulfonylphenylacetic acid (25.Og, 117mmol), 4-dimethylaminopyridine (2.0g) and dicyclohexylcarbodiimide (25.Og, 121mmol) were addedand the resulting mixture was stirred at room temperature for 20h. The precipitate wasremoved by filtration and the resulting solution was washed successively with 2N aqueousHC1, water and IN aqueous NaOH, dried (MgSC^) and evaporated. The residue was purifiedby silica gel chromatography (eluent: 10% MeOH/ethyl acetate) to afford the sub-titledcompound (35 g, 76%); NMR: 1.00 and 1.14 (t, 3H), 1.45 and 1.70 (m, 2H), 1.95 (br m, 2H),2.80 (br m, 2H), 3.18 (s, 3H), 3.20 and 3.33 (q, 2H), 3.45 (s, 2H), 3.80 and 3.87 (s, 2H), 3.70and 4.10 (m, 1H), 7.2 - 7.3 (m, 5H), 7.48 (m, 2H), 7.82 (m, 2H); MS: 415 (MH+).
76%	With dmap; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 20h;	To a solution of (1-benzyl-piperidin-4-yl)-ethyl-amine dihydrochloride (32. 0g, [I L OMMOL)] in DCM (500mL) was added [N, N-DIISOPROPYLETHYLAMINE] (60mL) with stirring to ensure complete dissolution. 4-Methanesulfonylphenylacetic acid (25. [0G,] 117mmol), 4- [DIMETHYLAMINOPYRIDINE] [(4-DMAP)] (2. 0g) and [DICYCLOHEXYLCARBODIIMIDE] [(DCCI)] (25. 0g, 121 mmol) were added and the resulting mixture was stirred at room temperature for 20 h. The precipitate was removed by filtration and the resulting solution was washed successively with 2N aqueous HC1, water and 1N aqueous [NAOH,] dried (MgS04) and evaporated. The residue was purified by silica gel chromatography (eluent 10% [MEOH/ETHYL] acetate) to afford the sub- titled compound (35 g, 76%). 'H NMR: 1.00 and 1.14 (t, 3H), 1.45 and 1.70 (m, 2H), 1.95 (br m, 2H), 2.80 (br m, 2H), 3.18 (s, 3H), 3.20 and 3.33 (q, 2H), 3.45 (s, 2H), 3.80 and 3.87 (s, 2H), 3.70 and 4.10 (m, 1H), 7.2-7. 3 (m, [5H),] 7.48 (m, 2H), 7.82 (m, 2H). MS: 415 (MH+).

Reference： [1]Patent: WO2005/58881,2005,A1 .Location in patent: Page/Page column 27
[2]Patent: WO2006/1751,2006,A1 .Location in patent: Page/Page column 36-37
[3]Patent: WO2004/18425,2004,A1 .Location in patent: Page 26-27

14
[ 16188-55-9 ]
[ 90536-66-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tungstate; dihydrogen peroxide; Aliquat 336; In water; ethyl acetate; for 0.5h;	[15.1] [] 4-(Methylthio)phenylacetic acid 4 (FW=182.3)(0.402mol)Na2WO4? H2O (FW=329.9)2.64g (0.008mol)Aliquat 336 (FW=404)8.08g (0.020mol)Hydrogen peroxide (FW=34.0, 30wt% in water)136g (1.200mol,123mL) A flask equipped for mechanical stirring was charged with 3 (from reaction above, in EtOAc), Aliquat 336, and Na2WO4? 2H2O (dissolved in ca. 15mL H2O). Hydrogen peroxide was added slowly via an addition funnel over ca. 30 min. Completion of reaction was checked by HPLC. The reaction was washed with 2 x 400mL H2O and dried over MgSO4. Quantification of product in the organic layer gave 61.29g 5 (71% yield from thioanisole). On concentration of the solution, a white solid precipitated. The slurry was filtered, and washed with hexanes. Recovery was 49.02g 5 (57% from thioanisole).

Reference： [1]Patent: EP975596,2004,B1 .Location in patent: Page 10-11

15
[ 614-18-6 ]
[ 90536-66-6 ]
[ 40061-50-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	With tert-butylmagnesium chloride; In tetrahydrofuran; at 20 - 50℃;	4-Methylsulfonylbenzyl-3-pyridylketone from ethyl nicotinate and 4-methylsulfonylphenylacetic acid [] 4-Methylsulfonylphenyl Acetic Acid (MW = 217)10g (46.7 mmol)t-Butyl magnesium chloride (1N/THF)128.11ml (128.11mmol)Ethyl nicotinate (MW = 151.2; d = 1.107)5.54ml (39.4mmol)THF400ml Phenyl acetic acid was dissolved in THF under nitrogen. 1.9 equivalents (88.73ml) of t-butyl magnesium chloride were added over 5 minutes to the solution. The Reaction was exothermic. The temperature rose from 20C to 50C. After addition of the first equivalent of t-butyl magnesium chloride, the solution turned red. The reaction temperature was maintained at 50C. After one hour, 0.5 equivalents of ethyl nicotinate were added. The solution turned yellow and a white precipitate formed. After one hour, 0.5 equivalents of t-butyl magnesium chloride were added at 50C. The solution turned red. This sequence of addition was repeated using 0.25eq., 0.125eq., 0.0625eq. of ethyl nicotinate and t-butyl magnesium chloride. The reaction mixture was aged for 1 hour between each addition. After the last addition, the reaction was quenched by adding the reaction mixture into vigorously stirred 2N hydrochloric acid (100ml). The solids at the bottom of the reaction mixture dissolved with effervescence when stirred in hydrochloric acid. The pH of the aqueous phase of the reaction mixture was adjusted to 10 with sodium carbonate. LC assay showed 91% yield of ketone
	In tetrahydrofuran;	Ivanov-Claisen Condensation for the Preparation of 1-(3-pyridyl)-2-((4-methylsulfonyl)phenyl)ethane-1-one (4-Methylsulfonyl)phenylacetic acid was dissolved in THF under nitrogen and 1.9 equivalents (88.73 ml) of t-butyl magnesium chloride were added over 5 minutes to the solution. The reaction was exothermic and the temperature rose from 20 C. to 50 C. After addition of the first equivalent of t-butyl magnesium chloride, the solution turned red. The reaction temperature was maintained at 50 C. After one hour, 0.5 equivalents of ethyl nicotinate were added. The solution turned yellow and a white precipitate formed.

Reference： [1]Patent: EP975596,2004,B1 .Location in patent: Page 11-12
[2]Patent: US5861419,1999,A

16
[ 477721-55-4 ]
[ 90536-66-6 ]
methyl 4-({4-hydroxy-1-[2-(4-methanesulfonylphenyl)-acetyl]piperidin-4-ylmethyl}methylamino)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 1h;	1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.68 g) was added to a dichloromethane solution (15 mL) of the compound (0.90 g) obtained in Step 3 of Example 25 and 4-methylsulfonylphenylacetic acid (0.76 g) and the mixture was stirred at room temperature for one hour. The reaction mixture was poured into cold water (80 mL) and then separated, and the aqueous layer was extracted with dichloromethane. The organic layer was combined and washed with water and brine successively, and then dried over anhydrous sodium sulfate. After the solvent was removed under reduce pressure, the residue was purified by silica gel column chromatography (eluent; dichloromethane : methanol = 8: 1) to obtain the titled compound (1.36 g) as crystals.

Reference： [1]Patent: EP1391452,2004,A1 .Location in patent: Page 32

17
[ 90536-66-6 ]
[ 300355-18-4 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sulfuric acid; In methanol;	EXAMPLE 13 (2R)-3-Cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide A solution of 4-(methanesulfonyl)phenyl acetic acid (43.63 g, 0.204 mol) in methanol (509 mL) was treated slowly with concentrated sulfuric acid (2 mL). The resulting reaction mixture was heated under reflux for 19 h. The reaction mixture was allowed to cool to 25 C. and then concentrated in vacuo to remove methanol. The residue was diluted with ethyl acetate (800 mL). The organic phase was washed with a saturated aqueous sodium bicarbonate solution (1200 mL), washed with a saturated aqueous sodium chloride solution (1200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 1/1 hexanes/ethyl acetate) afforded 4-(methanesulfonyl)phenyl acetic acid methyl ester (45.42 g, 98%) as a yellow oil which solidified to a cream colored solid upon sitting over time at 25 C.: mp 78-80 C.; EI-HRMS m/e calcd for C10H12O4S (M+) 228.0456, found 228.0451.

Reference： [1]Patent: US2001/39344,2001,A1
[2]Angewandte Chemie - International Edition,2012,vol. 51,p. 548 - 551

18
[ 27935-87-1 ]
[ 90536-66-6 ]
[ 300354-95-4 ]

Yield	Reaction Conditions	Operation in experiment
52%	With hydrogenchloride; n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 82 3-Cyclopentyl-2-(4-sulfamoyl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (3.3 mL, 23.5 mmol) in dry tetrahydrofuran (50 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (2.35 mL, 23.5 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-methylsulfonylphenylacetic acid (2.40 g, 11.2 mmol) in a small amount of dry tetrahydrofaran. After approximately one-half of the 4-methylsulfonylphenylacetic acid in dry tetrahydrofuran was added, a precipitate formed. Upon further addition of the remaining 4-methylsulfonylphenylacetic acid in dry tetrahydrofuran, the reaction mixture became thick in nature. After complete addition of the 4-methylsulfonylphenylacetic acid in dry tetrahydrofuran, the reaction mixture was very thick and became difficult to stir. An additional amount of dry tetrahydrofuran (20 mL) was added to the thick reaction mixture, and the reaction mixture was stirred at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (2.35 g, 11.2 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 15 h. The reaction mixture was quenched with water (100 mL), and the resulting yellow reaction mixture was concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was acidified to pH=2 using concentrated hydrochloric acid. The aqueous layer was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/3 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid (1.80 g, 52%) as a white solid: mp 152-154 C.; EI-HRMS m/e calcd for C15H20O4S (M+) 296.1082, found 296.1080.

Reference： [1]Patent: US2001/39344,2001,A1
[2]Journal of Medicinal Chemistry,2010,vol. 53,p. 3618 - 3625

19
1-ethyl-3-(3-dimethylaminopropyl)carboiimide hydrochloride [ No CAS ]
[ 90536-66-6 ]
[ 304646-59-1 ]
[ 329317-51-3 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; triethylamine In acetonitrile	25 Example 25 Example 25 N-(2-Ethylamino-5-trifluoromethanesulfonyl-phenyl)-2-(4-methanesulfonyl-phenyl)-acetamide (25). To a solution of 4-methylsulfonylphenylacetic acid (100 mg, 0.467 mmol) in acetonitrile was added 1-hydroxybenzotriazole (76 mg, 0.56 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carboiimide hydrochloride (108 mg, 0.56 mmol), triethylamine (0.143 mL, 1.03 mmol) and N1-ethyl-4-[(trifluoromethyl)sulfonyl]benzene-1,2-diamine (125 mg, 0.467 mmol). The mixture was stirred at room temperature for overnight. The reaction was extracted with ethyl acetate, washed with water and brine, dried, concentrated and recrystallized from ethyl acetate to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ9.54 (br s, 1H, NH), 7.88 (d, J=8.3 Hz, 2H), 7.75 (d, J=2.1 Hz, 1H), 7.64 (dd, 1H), 7.61 (d, J=8.3 Hz, 2H), 6.90 (d, J=9.0 Hz, 1H), 6.70 (t, J=5.2 Hz, 1H, NH), 3.86 (s, 2H, CH2), 3.31 (s, 3H, CH3), 3.29 (m, 2H, NCH2CH3), 1.20 (t, J=7.1 Hz, 3H, NCH2CH3). MS 465 [M++1].

Reference： [1]Current Patent Assignee: PFIZER INC - US6596772, 2003, B1

20
[ 100-68-5 ]
[ 90536-66-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride;AlCl3; In sodium hydroxide; water;	PREPARATION OF STARTING MATERIALS PREP 1 SYNTHESIS OF 4-METHYLSULFONYLPHENYLACETIC ACID The ethyloxalyl chloride and ODCB were charged to a flask equipped with an overhead mechanical stirrer and cooled to 0 C. The AlCl3 was added slowly. The addition of the AlCl3 was exothermic. The thioanisole 2 was added dropwise via an addition funnel over 1.5 h. The reaction mixture rapidly turns a dark violet color. This addition was also exothermic. After 1 h, the reaction was complete by HPLC. The reaction was quenched by the slow addition of 300 mL of 1N HCl at 0 C. After warming to room temperature, water and ODCB (50 mL each) were added. The layers were mixed and cut. The organic (bottom) phase was washed with 1250 mL water and then dried over MgSO4. This quench was also exothermic. The reaction mixture turned from dark violet to pale green during the quench. The dried ODCB solution was charged to a Morton flask equipped with mechanical stirring. A solution of 1N NaOH (800 mL) was added. The biphasic mixture was stirred vigorously and heated to 50 C. Hydrolysis to 3 was complete in 2-3 h by HPLC. The product-containing aqueous phase was taken directly into the Wolf-Kishner reaction. The hydrazine and NaOH were charged to a Morton flask equipped with mechanical stirring. After heating the hydrazine solution to 75 C., the solution of 3 in NaOH was added over 35-40 min. At the end of the addition the reaction mixture was brought to reflux for 5 days. HPLC showed the reaction to be ca. 95% complete at this point. The starting material was largely consumed in under 24 h, but a third peak which took several days to convert to 4. The reaction was acidified with concentrated HCl to pH=1.5 and extracted with EtOAc (1750 mL and 1250 mL). The combined product-containing organic phases were washed 2250 mL 1N HCl.

Reference： [1]Patent: US6127545,2000,A
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1549 - 1553
[3]Patent: CN107556223,2018,A
[4]Patent: CN107556223,2018,A

21
[ 625113-20-4 ]
[ 90536-66-6 ]
[ 108-18-9 ]
2-(4-methanesulfonyl-phenyl)-3-[2-(tetrahydropyran-2-yloxy)-cyclopentyl]-propionic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%		[0241] A solution of diisopropylamine (846 muL, 6.04 mmol) in dry tetrahydrofuran (4.4 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.4 mL) was cooled to -78 C. and then treated with a 2.5M solution of n-butyllithium in hexanes (2.4 mL, 6.04 mmol). The reaction mixture was stirred at -78 C. for 30 min and then was treated with a solution of (4-methanesulfonyl-phenyl)-acetic acid methyl ester (prepared as in Example 8, 1.06 g, 4.64 mmol) in dry tetrahydrofuran (4.4 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.4 mL). The resulting reaction mixture was allowed to stir at -78 C. for 45 min and then the reaction mixture was treated with a solution of 2-(2-iodomethyl-cyclopentyloxy)-tetrahydropyran (prepared as in Example 24, 1.87 g, 6.04 mmol) in a small amount of dry tetrahydrofuran. The reaction mixture was stirred at -78 C. and then allowed to warm to 25 C., where it was stirred for 68 h. The reaction mixture was quenched with water (100 mL) and then concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 7/3 hexanes/ethyl acetate) afforded the 2-(4-methanesulfonyl-phenyl)-3-[2-(tetrahydropyran-2-yloxy)-cyclopentyl]-propionic acid methyl ester (859.2 mg, 45%) as a light yellow oil: FAB-HRMS m/e calcd for C21H30O6S (M+H)+ 411.1841, found 411.1831. [0242] 2-Aminothiazole (314.3 mg, 3.14 mmol) and 2-(4-methanesulfonyl-phenyl)-3-[2-(tetrahydropyran-2-yloxy)-cyclopentyl]-propionic acid methyl ester (859.2 g, 2.09 mmol) were treated with a solution of magnesium methoxide in methanol (7.4 wt. %, 12 mL, 8.37 mmol). The resulting reaction mixture was heated under reflux for 24 h. The reaction mixture was allowed to cool to 25 C. and then filtered through a pad of celite. The pad of celite was washed well with ethyl acetate until the washings indicated the absence of product by thin layer chromatography. The filtrate was then washed with a 10% aqueous hydrochloric acid solution (3×100 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 1/1 hexanes/ethyl acetate) afforded 2-(4-methanesulfonyl-phenyl)-3-[2-(tetrahydropyran-2-yloxy)-cyclopentyl]-N-thiazol-2-yl-propionamide (377.4 mg, 38%) as a yellow oil: EI-HRMS m/e calcd for C23H30N2O5S2 (M+) 478.1596, found 478.1604. [0243] A solution of 2-(4-methanesulfonyl-phenyl)-3-[2-(tetrahydropyran-2-yloxy)-cyclopentyl]-N-thiazol-2-yl-propionamide (350.8 mg, 0.73 mmol) in ethanol (7.3 mL) was treated with pyridinium p-toluenesulfonate (18.4 mg, 0.073 mmol). The resulting reaction mixture was heated at 60 C. for 4 h. The reaction mixture was allowed to cool to 25 C. and then concentrated in vacuo. The resulting yellow residue was diluted with ethyl acetate (100 mL) and then washed with a saturated aqueous sodium chloride solution (1×100 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 1/3 hexanes/ethyl acetate) afforded the 3-(2-hydroxy-cyclopentyl)-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (77.0 mg, 27%) as a white solid: mp 205-206 C.; EI-HRMS m/e calcd for C18H22N2O4S2 (M+) 394.1021, found 394.1018.

Reference： [1]Patent: US2003/225283,2003,A1 .Location in patent: Page 29-30

22
[ 243968-43-6 ]
[ 90536-66-6 ]
[ 330192-77-3 ]

Yield	Reaction Conditions	Operation in experiment
69%		EXAMPLE 34; 7-((2-(4-Methanesulfonyl-phenyl)-acetylamino)-methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid; To a solution of (4-methanesulfonyl-phenyl)-acetic acid (90.4 mg, 0.42 mmol) in a mixture of dichloromethane (3 ml) and N,N-dimethylformamide (1 ml) cooled at 0 C was added diisopropyl-ethylamine (306 mul, 1.76 mmol), diisopropylazodicarboxylate (72 mul, 0.45 mmol) and 1-hydroxy-benzotriazole (56.6 mg, 0.42 mmol). After being stirred for 20 minutes, 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acidtert-butyl ester (100 mg, 0.35 mmol) dissolved in dichloromethane (1 ml) was added via syringe. The reaction mixture was stirred for 18 hours while slowly warming to room temperature. The volatiles were evaporated invacuo and the residue diluted with ethyl acetate (50 ml). The organic phase was washed with saturated sodium bicarbonate (3 x 50 ml), 1 % hydrochloric acid (3 x 50 ml), brine (3 x 50 ml), dried (MgSO4), filtered, and the solvent evaporated invacuo. The resultant oil was subjected to preparative thin layer chromatography using a mixture of methanol/dichloromethane (1:9) as eluent. Fraction with Rf=0.5 was isolated which afforded after evaporating the solvent invacuo 115 mg (69 %) of 2-amino-7-((2-(4-methanesulfonyl-phenyl)acetylamino)-methyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.1H-NMR (300 MHz, CDCl3) delta 7.87 (d, 2H, J = 8.7 Hz), 7.39 (d, 2H, J = 7.5 Hz), 5.91 (bs, 2H), 4.65 (m, 1H), 4.09 (dt, 1H, J = 7.8 Hz and J = 3.3 Hz), 3.85-3.65 (m, 2H), 3.61 (s, 2H), 3.45-3.38 (m, 2H), 3.05 (s, 3H), 2.75 (m, 2H), 1.56 (s, 9H). MS: APCI (+): m/z: 481 [M+H].
69%		7-((2-(4-Methanesulfonyl-phenyl)-acetylamino)-methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid; To a solution of (4-methanesulfonyl-phenyl)-acetic acid (90.4 mg, 0.42 mmol) in a mixture of dichloromethane (3 ml) and N,N-dimethylformamide (1 ml) cooled at 0 C. was added diisopropyl-ethylamine (306 mul, 1.76 mmol), diisopropylazodicarboxylate (72 mul, 0.45 mmol) and 1-hydroxy-benzotriazole (56.6 mg, 0.42 mmol). After being stirred for 20 minutes, 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (100 mg, 0.35 mmol) dissolved in dichloromethane (1 ml) was added via syringe. The reaction mixture was stirred for 18 hours while slowly warming to room temperature. The volatiles were evaporated in vacuo and the residue diluted with ethyl acetate (50 ml). The organic phase was washed with saturated sodium bicarbonate (3×50 ml), 1% hydrochloric acid (3×50 ml), brine (3×50 ml), dried (MgSO4), filtered, and the solvent evaporated in vacuo. The resultant oil was subjected to preparative thin layer chromatography using a mixture of methanol/dichloromethane (1:9) as eluent. Fraction with Rf=0.5 was isolated which afforded after evaporating the solvent in vacuo 115 mg (69%) of 2-amino-7-((2-(4-methanesulfonyl-phenyl)acetylamino)-methyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.1H-NMR (300 MHz, CDCl3) delta 7.87 (d, 2H, J=8.7 Hz), 7.39 (d, 2H, J=7.5 Hz), 5.91 (bs, 2H), 4.65 (m, 1H), 4.09 (dt, 1H, J=7.8 Hz and J=3.3 Hz), 3.85-3.65 (m, 2H), 3.61 (s, 2H), 3.45-3.38 (m, 2H), 3.05 (s, 3H), 2.75 (m, 2H), 1.56 (s, 9H).MS: APCI (+): m/z: 481 [M+H].

Reference： [1]Patent: EP1214325,2005,B1 .Location in patent: Page/Page column 53-54
[2]Patent: US7019026,2006,B1 .Location in patent: Page/Page column 78

23
[ 90536-66-6 ]
[ 343788-69-2 ]
[ 872850-51-6 ]

Yield	Reaction Conditions	Operation in experiment
		Step 3: Preparation of tert-butyl 4-(ethyl[4-(methylsulfonyl)phenyl]acetyl}amino)-4-methylpiperidine-1 -carboxylate; :OTo a solution of 4-methylsulfonyl phenylacetic acid (1.49g) in dichloromethane(10ml) was added oxalyl chloride (0.66ml) then a catalytic amount of dimethylformamide.The resulting mixture was stirred at room temperature for 2 hours. After this time the mixturewas evaporated to dryness and then redissolved in dichloromethane. This was added tosolution of tert-butyl 4-(ethylamino)-4-methylpiperidine-l -carboxylate (0.84mg) indichloromethane (10ml). The resulting mixture was stirred at 60C for 2 hours and then atroom temperature for 18 hours. The reaction mixture was partitioned betweendichloromethane water. The organic extracts were dried (MgSC>4) and evaporated to dryness.The crude mixture was purified on silica using a gradient elution 1:1 Ethyl acetate: Hexane toEthyl acetate to yield tert-butyl 4-(ethyl[4-(methylsulfonyl)phenyl]acetyl}amino)-4-methylpiperidine-1 -carboxylate 0.45g.NMR (CDC13): 1.4 (t, 3H), 1.55 (s, 9H), 1.6 (s, 3H), 2.1 (m, 4H), 3.15 (s, 3H), 3.2 (m,2H), 3.45 (m, 2H), 3.75 (m, 2H), 3.85 (s, 2H), 7.5 (d, 2H), 8.0 (d, 2H).

Reference： [1]Patent: WO2006/1752,2006,A1 .Location in patent: Page/Page column 88-89

24
[ 90536-66-6 ]
[ 741687-07-0 ]
tert-butyl 4-ethyl-4-([4-(methylsulfonyl)benzyl]amino}carbonyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 2: Preparation offers-butyl 4-ethyl-4-([4-(methylsulfonyl)benzyl]amino}carbonyl)piperidine-1 -carboxylate; .To a solution of [4-(methylsulfonyl)phenyl]acetic acid (395mg) in dichloromethane(20ml) was added disopropyldiethylamine (0.38ml) followed by HATU (VOOmg) and mixturewas stirred for 10 minutes before the addition of tert-butyl 4-amino-4-ethylpiperidine-l-carboxylate (420mg). The resulting mixture was stirred at room temperature for 18 hours. Thereaction mixture was partitioned between dichloromethane and water. The organic extractswere dried (MgSCU) and evaporated to dryness. The residue was purified chromatography onsilica eluting with gradient of ethyl acetate and isohexane to give the sub-title compound asan oil (750mg). NMR (CDC13): 0.9 (t, 3H), 1.5 (s, 9H), 1.5 (m, 2H), 1.9 (m, 2H), 2.1 (m, 2H),3.0 (m, 2H), 3.1 (s, 3H), 3.7 (s, 2H), 3.8 (m, 2H), 5.2 (s, 1H), 7.6 9d, 2H), 8.0 (d, 2H).

Reference： [1]Patent: WO2006/1752,2006,A1 .Location in patent: Page/Page column 81

25
[ 243968-43-6 ]
[ 90536-66-6 ]
[ 330191-50-9 ]

Yield	Reaction Conditions	Operation in experiment
69%		Example 34 7-((2-(4-Methanesulfonyl-phenyl)-acetylamino)-methyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid; To a solution of (4-methanesulfonyl-phenyl)-acetic acid (90.4 mg, 0.42 mmol) in a mixture of dichloromethane (3 ml) and N,N-dimethylformamide (1 ml) cooled at 0 C. was added diisopropyl-ethylamine (306 mul, 1.76 mmol), diisopropylazodicarboxylate (72 mul, 0.45 mmol) and 1-hydroxy-benzotriazole (56.6 mg, 0.42 mmol). After being stirred for 20 minutes, 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (100 mg, 0.35 mmol) dissolved in dichloromethane (1 ml) was added via syringe. The reaction mixture was stirred for 18 h. while slowly warming to room temperature. The volatiles were evaporated in vacuo and the residue diluted with ethyl acetate (50 ml). The organic phase was washed with saturated sodium bicarbonate (3×50 ml), 1% hydrochloric acid (3×50 ml), brine (3×50 ml), dried (MgSO4), filtered, and the solvent evaporated in vacuo. The resultant oil was subjected to preparative thin layer chromatography using a mixture of methanol/dichloromethane (1:9) as eluant. Fraction with Rf=0.5 was isolated which afforded after evaporating the solvent in vacuo 115 mg (69%) of 2-amino-7-((2-(4-methanesulfonyl-phenyl)acetylamino)-methyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.1H NMR (300 MHz, CDCl3) delta 7.87 (d, J=8.7, 2H), 7.39 (d, J=7.5, 2H), 5.91 (bs, 2H), 4.65 (m, 1H), 4.09 (dt, J=7.8, 3.3, 1H), 3.85-3.65 (m, 2H), 3.61 (s, 2H), 3.45-3.38 (m, 2H), 3.05 (s, 3H), 2.75 (m, 2H), 1.56 (s, 9H).MS: APCI (+): 481 (M+H).

Reference： [1]Patent: US7115624,2006,B1 .Location in patent: Page/Page column 91-92

26
[ 17279-56-0 ]
[ 90536-66-6 ]
[ 941883-55-2 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	Preparation of the final product[4-(MethyIsulfonyl)phenyl]acetic acid (188 mg), (2-amino-4-phenyl-l ,3-thiazol-5- yl)(phenyl)methanone (intermediate la, 123 mg), EDC (202 mg) and HOBt (161 mg) were added into a 10 mL vial. Dichloromethane (DCM) (5 mL) was added. The reaction mixture was stirred at RT overnight. DCM was removed. The obtained crude was redissolved in DMF and submitted to MDAP for purification. Solvent was evaporated in vacuo to give the required product 2-[4- (methylsulfonyl)phenyl]-N-[4-phenyl-5-(phenylcarbonyl)-l,3-thiazol-2-yl]acetamide (155.5 mg) as a white powder. -NMR (400 MHz, CDC13) 6 ppm 3.07 (s, 3H), 3.60 (s, 2H), 7.17-7.25 (m, 5H), 7.36-7.42 (m, 5H), 7.63 (d, J= 8.2 Hz, 2H), 7.94 (d, J= 8.3 Hz, 2H), 10.19 (br s, 1H); MS(ES+) m/z Ml (Ml-f ).

Reference： [1]Patent: WO2012/28100,2012,A1 .Location in patent: Page/Page column 12

27
[ 1361414-20-1 ]
[ 90536-66-6 ]
[ 1361413-37-7 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	A mixture of [2-amino-4-(3-chlorophenyl)-l,3-thiazol-5-yl](4-chlorophenyl)methanone (intermediate 42b, 55 mg), [4-(methylsulfonyl)phenyl]acetic acid (35.4 mg), EDC (39.2 mg) and HOBt (27.7 mg) in dichloromethane (DCM) (3 mL) was stirred at room temperature overnight. Solvent was removed under reduced pressure and the residue was purified by MDAP to afford N-{4- (3-chlorophenyl)-5-[(4-chlorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4-(methylsulfonyl)phenyl]acetamide (20 mg) as a white solid. ¾-NMR (400 MHz, DMSO- ) delta ppm 3.22 (s, 3H), 4.02 (s, 2H), 7.24 (t, J = 7.8 Hz, 1H), 7.32-7.36 (m, 4H), 7.40 (t, J = 1.8 Hz, 1H), 7.53- 7.57 (m, 2H), 7.63 (d, J = 8.3 Hz, 2H), 7.91-7.93 (m, 2H), 13.13 (s, 1H); MS(ES+) m/z 545 (MH+).

Reference： [1]Patent: WO2012/27965,2012,A1 .Location in patent: Page/Page column 52-53

28
[ 1361413-64-0 ]
[ 90536-66-6 ]
[ 1361413-36-6 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	A mixture of [2-amino-4-(3-chlorophenyl)-l,3-thiazol-5-yl](2-chlorophenyl)methanone(intermediate 9a, 60 mg), [4-(methylsulfonyl)phenyl]acetic acid (38.6 mg), EDC (42.8 mg) and HOBt (30.2 mg) in dichloromethane (DCM) (3 mL) was stirred at room temperature overnight. Solvent was removed under reduced pressure and the residue was purified by MDAP to afford N-{4-(3- chlorophenyl)-5-[(2-chlorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4- (methylsulfonyl)phenyl]acetamide (42 mg) as a white solid. ¾-NM (400 MHz, DMSO- 6) delta ppm 3.22 (s, 3H), 4.01 (s, 2H), 7.19-7.42 (m, 7H), 7.41 (dd, J= 1.4 Hz, J= 7.5 Hz, 1H), 7.62 (d, J= 8.3 Hz, 2H), 7.90-7.92 (m, 2H), 13.16 (s, 1H); MS(ES+) m/z 545 (MH+).

Reference： [1]Patent: WO2012/27965,2012,A1 .Location in patent: Page/Page column 52

29
[ 1361413-71-9 ]
[ 90536-66-6 ]
[ 1361413-35-5 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 48h;Inert atmosphere;	A mixture of [2-amino-4-(3-chlorophenyl)-l,3-thiazol-5-yl](3-chlorophenyl)methanone (intermediate 13a, 60 mg), [4-(methylsulfonyl)phenyl]acetic acid (38.6 mg), EDC (42.8 mg) and HOBt (30.2 mg) in dichloromethane (DCM) (3.5 mL) was stirred at room temperature under nitrogen for 2 days. Solvent was removed under reduced pressure and the residue was purified by MDAP to afford N-{4-(3-chlorophenyl)-5-[(3-chlorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4-(methylsulfonyl)phenyl]acetamide (14 mg) as a white solid. ¾-NMR (400 MHz, DMSO- 6) delta ppm 3.22 (s, 3H), 4.02 (s, 2H), 7.21-7.33 (m, 4H), 7.40 (t, J= 1.7 Hz, 1H), 7.45-7.49 (m, 3H), 7.63 (d, J = 8.3 Hz, 2H), 7.92 (d, J= 8.3 Hz, 2H), 13.15 (s, 1H); MS(ES+) m/z 545 (MH+).

Reference： [1]Patent: WO2012/27965,2012,A1 .Location in patent: Page/Page column 51

30
[ 24424-99-5 ]
[ 90536-66-6 ]
[ 1380646-42-3 ]

Yield	Reaction Conditions	Operation in experiment
45%	With dmap; In tert-butyl alcohol; at 20℃;	Step 1: To a solution of 4-methylsulfonylphenylacetic acid (5.0 g, 23.3 mmol) in tert-butanol (100 mL) was added DMAP (0.85 g, 7 mmol) and di-tert-butyl-dicarbonate. The reaction mixture was stirred at room temperature over night, concentrated in vacuo and purified by chromatography to afford (4-methanesulfonylphenyl)acetic acid tert-butyl ester (2.8 g, 45%): 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 1.45 (s, 9H) 3.05 (s, 3H) 3.63 (s, 2H) 7.48 (m, J=8.29 Hz, 2H) 7.90 (m, J=8.29 Hz, 2H).

Reference： [1]Patent: US2012/149718,2012,A1 .Location in patent: Page/Page column 32

31
[ 4570-41-6 ]
[ 90536-66-6 ]
[ 1380646-35-4 ]

Yield	Reaction Conditions	Operation in experiment
53%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 6h;Product distribution / selectivity;	Step 1:To a solution of 4-methylsulfonylphenylacetic acid (214 mg, 1 mmol) and <strong>[4570-41-6]2-amino-benzoxazole</strong> (147 mg, 1.1 mmol) in CH2Cl2 (10 mL) was added DMAP (37 mg, 0.3 mmol) and EDC.HCl (230 mg, 1.2 mmol).The reaction mixture was stirred at room temperature for 6 h.The reaction mixture was concentrated in vacuo.Purification by chromatography (silica, 10-75percent ethyl acetate/hexanes gradient) afforded N-benzooxazol-2-yl-2-(4-methanesulfonyl-phenyl)acetamide (175 mg, 53percent): LC/MS-ESI observed [M+H]+ 331.

Reference： [1]Patent: US2012/149718,2012,A1 .Location in patent: Page/Page column 29

32
[ 90536-66-6 ]
[ 428508-13-8 ]

Yield	Reaction Conditions	Operation in experiment
49%	With hydrazine hydrate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane;	According to the procedure described in Scheme 5 above,2- (4- (methylsulfonyl) phenyl) acetohydrazide (8a) was obtained (yield: 49%).

Reference： [1]Patent: KR2018/38293,2018,A .Location in patent: Paragraph 0359-0362
[2]European Journal of Medicinal Chemistry,2012,vol. 54,p. 59 - 64

33
2-Amino-5-(4-methyl-phenyl)-thiophene-3-carboxylic Acid Amide [ No CAS ]
[ 90536-66-6 ]
[ 1393911-81-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In chloroform; at 120℃;Microwave irradiation;	General procedure: To a mixture of 2-amino-5-(4-methylphenyl) thiophene-3-carboxamide 1a (0.25 g, 0.107 mol) and 4-benzyloxy benzoic acid 4a (0.319 g, 0.140 mol) in anhydrous chloroform (4 ml) was added triethylamine (0.32 g, 0.323 mol) and phosphonic acid cyclic anhydride (1.02 g, 0.323 mol). The reaction mixture was irradiated at 120 C in a microwave initiator for a given period of time (Table 1, entry 1). Once the substrate was completely consumed as monitored by TLC, the brown reaction mixture was cooled and poured into ice-cold water (10 ml). The product was extracted with ethyl acetate (2 × 25 ml) and the combined organic phase was washed with water, brine solution and dried over anhydrous sodium sulfite. The solvent was removed under vacuum and the brown residue was passed through a small plug of silica gel using petroleum ether/ethyl acetate (9/1) to afford 429 mg (94%) of 2a as a yellow solid.

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 4639 - 4643

34
[ 1391981-99-9 ]
[ 90536-66-6 ]
[ 1391982-04-9 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;Inert atmosphere; Reflux;	Step 1: To a solution of 4-(3-chlorophenyl)thiophen-2-amine hydrochloride (0.50 g, see step 3 for synthesis of Example 2), 2-(4-(methylsulfonyI)phenyl)acetic acid (0.46 g), EDC (0.62 g) and HOBt (0.43 g) in dichloromethane (DCM) (20 mL) was added dropwise DIPEA (0.75 mL) at room temperature. The reaction mixture was heated at reflux under nitrogen overnight. The reaction mixture was partitioned between DCM (60 mL) and water (30 mL). The organic phase was washed with water (20 mL x 2), brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (silica gel, EtOAc : PE = 1:3 to 1 : 1) to give N-(4-(3- chloropbenyl)thiophen-2-yl)-2-(4-(methylsulfonyl)phenyl)acetarnide (0.40 g) as a pale brown solid. MS(ES+) m/z 406 (MH+).

Reference： [1]Patent: WO2012/100732,2012,A1 .Location in patent: Page/Page column 17-18

35
[ 5470-70-2 ]
[ 90536-66-6 ]
[ 1421227-97-5 ]
[ 221615-75-4 ]

Yield	Reaction Conditions	Operation in experiment
		In an anhydrified 4-neck flask there were introduced at 20-25C 5.0 g of (4-methylsulfonyl)phenyl acetic acid of formula (IV) and 100 mL of anhydrous THF and stirring is carried out at 20-25C. 1.0 g of sodium hydride dispersion in mineral oil (60% w/w, MW: 24.00; 1.1 molar equivalents) is added in portions in about 5 minutes, ensuring that the temperature does not exceed 45-50C. After completing the addition the mixture is heated to 65-70C for 1 hr. Maintaining at T=65-70C there are rapidly added 21 g (1.0 equiv.) of t-BuMgCl 1.0 M solution in THF (PM116.87) (23 mL). The mixture is left under stirring for 1 hr at 65-70C then is rapidly added, still at 65-70C, a solution of 1.78 g (0.5 equiv.) of methyl ester of the 6-methylpyridine-3-carboxylic acid of formula (III - R=Me) in 5 ml of Anhydrous THF. After completing the addition the mixture is maintained at 65-70C for 1 hr. Maintaining at T=65-70C there are rapidly added 10.5 g (0.5 equiv.) of t-BuMgCl 1.0 M solution in THF (PM 116.87) (11.5 mL). The mixture is left under stirring for 1 hr at 65-70C then there is rapidly added, still at 65-70C, a solution of 260 mg (0.075 equiv.) of methyl ester of 6-methylpyridine-3-carboxylic acid of formula (III - R=Me) in 1 mL of anhydrous THF. After completing addition the mixture is maintained at 65-70 C for 1 hr. Maintaining at T=65-70 C there are rapidly added 10.5 g (0.5 equiv.) of t-BuMgCl 1.0 M solution in THF (PM 116.87) (11.5 mL). The mixture is left under stirring for 1 hr at 65-70 C then there is rapidly added, still at 65-70 C, a solution of 260 mg (0.075 equiv.) of methyl ester of the 6-methylpyridine-3-carboxylic acid of formula (III - R=Me) in 1 mL of Anhydrous THF. After completing addition the mixture is maintained at 65-70 C for 1 hr. Cooling is carried out to 20-25C. The yield is calculated in solution through titration: 80%. The product is isolated according to the preceding example. It is obtained a molar yield equivalent to 73% and with 94.4% HPLC purity (A%) and amount of impurity '408' = 2.02% (A%) (see figure 4).

Reference： [1]Patent: EP2551265,2013,A1 .Location in patent: Paragraph 0090-0099

36
[ 90536-66-6 ]
[ 1421227-95-3 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium hydroxide; In methanol; at 35 - 40℃; for 1.5h;pH 14.0;	In a 4-neck flask there are introduced at 20-25C 25 g of (4-methylsulfonyl)phenyl acetic acid of formula (IV) and 125 mL of Methanol. The mixture is heated up to 35-40C and stirred for about 5-10 minutes up to obtaining complete solubilisation. A solution of 5.6 g of NaOH in form of pearls (1.2 molar equivalents) in 25 mL of Methanol is prepared separately. The sodium hydroxide solution in methanol is added in 1 h at 35-40C into the acid sulfone solution. After the addition, the pH is about 14 (litmus paper). It is left under stirring for 30 minutes then it is cooled to T= 0-5C and it is left under stirring up to complete precipitation. The suspension is filtered and the solid is washed using cold methanol. The product is dried at 60C under vacuum for 8 hrs to obtain 22 g of product as a white solid for a molar yield equivalent to 80%. 1H-NMR (Figure 1) : 3.26 (s, 3H, CH3); 3.58 (s, 2H, CH2); 7.45 (d,J=8 Hz,2H, Ar); 7.80 (d,J=8 Hz,2H, Ar); Melting point = 275.4C (determined through DSC); HPLC purity = 99.82 (A%). K.F. =0.13%.

Reference： [1]Patent: EP2551265,2013,A1 .Location in patent: Paragraph 0040-0046

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[ 90536-66-6 ]
[ 1421227-97-5 ]
[ 221615-75-4 ]

Reference： [1]Patent: EP2551265,2013,A1

38
[ 90536-66-6 ]
[ 1421227-96-4 ]

Yield	Reaction Conditions	Operation in experiment
88%	With lithium hydroxide monohydrate; In methanol; at 35 - 40℃; for 1h;	In a 4-neck flask there are introduced at 20-25C 150 g of (4-methylsulfonyl)phenyl acetic acid of formula (IV) (1.0 mol. equiv.) and 750 mL of Methanol. Stirring is carried out at 35-40C up to obtaining complete solubilisation. 32 g of LiOH monohydrate (1.08 molar equivalents) are added maintaining at T=35/40C. The precipitation of the lithium salt occurred. Stirring is carried out at 35-40C for one hour then it is cooled to room temperature and stirring is carried out for 2 hours. The suspension is filtered and the solid is washed using Methanol. The solid is dried under vacuum at T=90C for 8 hours to afford 136 g of product as a white solid for a molar yield equivalent to 88%. 1H-NMR: 3.26 (s, 3H, CH3); 3.65 (s, 2H, CH2); 7.45 (d,J=8 Hz,2H, Ar); 7.89 (d,J=8 Hz,2H, Ar); Melting point = 334C (determined through DSC); HPLC purity = 99,51 (A%). K.F. = 0.11%.

Reference： [1]Patent: EP2551265,2013,A1 .Location in patent: Paragraph 0047-0051

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[ 90536-66-6 ]
[ 456-48-4 ]
[ 1430809-26-9 ]