[ CAS No. 168618-42-6 ] {[proInfo.proName]}

Name: 168618-42-6|(2-(Methylthio)phenyl)boronic acid|97%
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SKU: A151876
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Quality Control of [ 168618-42-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 168618-42-6 ]

Product Details of [ 168618-42-6 ]

CAS No. :	168618-42-6	MDL No. :	MFCD01318165
Formula :	C₇H₉BO₂S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QXBWTYBCNFKURT-UHFFFAOYSA-N
M.W :	168.02	Pubchem ID :	2773543
Synonyms :

Calculated chemistry of [ 168618-42-6 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	2.0
Molar Refractivity :	47.99
TPSA :	65.76 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) :	-6.37 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	1.34
Log Po/w (WLOGP) :	0.09
Log Po/w (MLOGP) :	0.88
Log Po/w (SILICOS-IT) :	-0.2
Consensus Log Po/w :	0.42

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.0
Solubility :	1.69 mg/ml ; 0.0101 mol/l
Class :	Very soluble
Log S (Ali) :	-2.32
Solubility :	0.799 mg/ml ; 0.00476 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.78
Solubility :	2.79 mg/ml ; 0.0166 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.04

Safety of [ 168618-42-6 ]

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

Application In Synthesis of [ 168618-42-6 ]

* 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 [ 168618-42-6 ]
Downstream synthetic route of [ 168618-42-6 ]

[ 168618-42-6 ] Synthesis Path-Upstream 1~5

1
[ 5419-55-6 ]
[ 19614-16-5 ]
[ 168618-42-6 ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -75℃; Stage #2: at 20℃; Cooling Stage #3: With hydrogenchloride; water In tetrahydrofuran; hexane at 20℃; Cooling with ice	Part A: Preparation of 2-methylthiophenylboronic acid. 2-Bromothioanisole (29.0 g, 143 mmol) was dissolved in dry THF (400 mL) and cooled to -75°C. N-BuLi (62.0 mL, 2.5 M in hexane, 155 mmol) was added over 50 min. After stirring 25 min, triisopropyl borate (46 mL, 199 mmol) was added over 35 min. The cold bath was removed and the reaction was stirred at room temperature for 16 h. The resulting solution was cooled in an ice bath, and 6 M HCl (100 mL) was added. This -mixture was stirred at room temp 5 h and concentrated to about half of the original volume. The concentrated solution was partitioned between Et₂O and water. The organic layer was extracted with 2 M NaOH, which was subsequently reacidified with 6 M HCl and extracted several times back into Et₂O. These Et₂O washes were dried over Na₂SO₄, filtered, and evaporated to yield a beige solid (20.4 g, 85percent). ¹H-NMR(CDCl₃) δ: 8.01 (dd, 1H, J=7.3, J'=1.4), 7.53 (dd, 1H, J=7.7, J'=1.1), 7.43 (td, 1H, J=7.3, J'=1.8), 7.34 (td, 1H, J=7.3, J'=1.5). 6.22 (s, 2H), 2.50 (s, 3H).

Reference： [1] Patent: EP946508, 2009, B1, . Location in patent: Page/Page column 60
[2] Patent: EP1491187, 2004, A1, . Location in patent: Page 26

2
[ 109-72-8 ]
[ 5419-55-6 ]
[ 168618-42-6 ]

Yield	Reaction Conditions	Operation in experiment
85%	With hydrogenchloride In tetrahydrofuran; hexane	Part A Preparation of 2-methylthiophenylboronic Acid 2-Bromothioanisole (29.0 g, 143 mmol) was dissolved in dry THF (400 mL) and cooled to -75° C. N-BuLi (62.0 mL, 2.5 M in hexane, 155 mmol) was added over 50 min. After stirring 25 min, triisopropyl borate (46 mL, 199 mmol) was added over 35 min. The cold bath was removed and the reaction was stirred at room temperature for 16 h. The resulting solution was cooled in an ice bath, and 6 M HCl (100 mL) was added. This mixture was stirred at room temp 5 h and concentrated to about half of the original volume. The concentrated solution was partitioned between Et₂ O and water. The organic layer was extracted with 2 M NaOH, which was subsequently reacidified with 6 M HCl and extracted several times back into Et₂ O. These Et₂ O washes were dried over Na₂ SO₄, filtered, and evaporated to yield a beige solid (20.4 g, 85percent). ¹ H-NMR (CDCl₃) δ: 8.01 (dd, 1H, J=7.3, J-=1.4), 7.53 (dd, 1H, J=7.7, J'=1.1), 7.43 (td, 1H, J=7.3, J'=1.8), 7.34 (td, 1H, J=7.3, J'=1.5), 6.22 (s, 2H), 2.50 (s, 3H).
74%	With hydrogenchloride In tetrahydrofuran; hexane	Part A. Preparation of 2-methylthiophenylboronic acid 2-Bromothioanisole (8.56 g, 42 mmol) was dissolved in 90 mL of dry THF and cooled to -78°C. n-Butyllithium (18.6 mL, 2.5M in hexane, 47 mmol) was added dropwise over 20 minutes, and the resulting solution stirred 90 min. Triisopropylborate (13.7 mL, 59 mmol) was added dropwise over 10 minutes, and the resulting solution stirred at -78°C for 45 minutes before removing the cooling bath.. The reaction was stirred overnight at room temperature. HCl (40 mL of a 6M aqueous solution) was added and stirred vigorously 8h. The reaction was diluted with 100 mL water and extracted three times with Et₂O. The organic extracts were combined and extracted twice with 80 mL of 2M NaOH. The basic layers were combined and acidified with 50 mL 6M HCl and 25ml 2M HCl. The resulting cloudy solution was extracted three times with 50 mL of Et₂O, dried over MgSO₄, filtered, and evaporated to yield a white solid (5.22g, 74percent).¹H NMR (CDCl₃) δ: 8.01 (dd, 1H), 7.53 (dd, 1H), 7.43 (td, 1H), 7.34 (td, 1H), 6.22 (s, 2H), 2.50 (s, 3H).
74%	With hydrogenchloride In tetrahydrofuran; hexane	Part A. Preparation of 2-methylthiophenylboronic acid 2-Bromothioanisole (8.56 g, 42 mmol) was dissolved in 90 mL of dry THF and cooled to -78° C. n-Butyllithium (18.6 mL, 2.5M in hexane, 47 mmol) was added dropwise over 20 minutes, and the resulting solution stirred 90 min. Triisopropylborate (13.7 mL, 59 mmol) was added dropwise over 10 minutes, and the resulting solution stirred at -78° C. for 45 minutes before removing the cooling bath. The reaction was stirred overnight at room temperature. HCl (40 mL of a 6M aqueous solution) was added and stirred vigorously 8 h. The reaction was diluted with 100 mL water and extracted three times with Et₂O. The organic extracts were combined and extracted twice with 80 mL of 2M NaOH. The basic layers were combined and acidified with 50 mL 6M HCl and 25 ml 2M HCl. The resulting cloudy solution was extracted three times with 50 mL of Et₂O, dried over MgSO₄, filtered, and evaporated to yield a white solid (5.22 g, 74percent). ¹H NMR (CDCl₃) δ: 8.01 (dd, 1H), 7.53 (dd, 1H), 7.43 (td, 1H), 7.34 (td, 1H), 6.22 (s, 2H), 2.50 (s, 3H).

Reference： [1] Patent: US6020357, 2000, A,
[2] Patent: EP946528, 2003, B1,
[3] Patent: US6187797, 2001, B1,

3
[ 5419-55-6 ]
[ 168618-42-6 ]

Yield	Reaction Conditions	Operation in experiment
85%	With hydrogenchloride; n-butyllithium In tetrahydrofuran; hexane	2-Methylthiophenylboronic acid 2-Bromothioanisole (29.0 g, 143 mmol) was dissolved in dry THF (400 mL) and cooled to -75° C. n-BuLi (62.0 mL, 2.5 M in hexane, 155 mmol) was added over 50 minutes. After stirring 25 minutes, triisopropyl borate (46 mL, 199 mmol) was added over 35 minutes. The cold bath was removed and the reaction was stirred at room temp for 16 hours. The resulting solution was cooled in an ice bathours, and 6 M HCl (100 mL) was added. This mixture was stirred at room temp 5 hours and concentrated to about half of the original volume. The concentrated solution was partitioned between Et₂ O and water. The organic layer was extracted with 2 M NaOH, which was subsequently reacidified with 6 M HCl and extracted several times back into Et₂ O. These Et₂ O washes were dried over Na₂ SO₄, filtered, and evaporated to yield a beige solid (20.4 g, 85percent). ¹ H NMR (CDCl₃): δ8.01 (dd, 1H, J=7.3, J'=1.4), 7.53 (dd, 1H, J=7.7, J'=1.1), 7.43 (td, 1H, J=7.3, J'=1.8), 7.34 (td, 1H, J=7.3, J'=1.5), 6.22 (s, 2H), 2.50 (s, 3H).

Reference： [1] Patent: US5998424, 1999, A,
[2] Patent: EP1331221, 2003, A1,

4
[ 19614-16-5 ]
[ 168618-42-6 ]

Reference： [1] Chemical Communications, 2010, vol. 46, # 34, p. 6380 - 6381

5
[ 5419-55-6 ]
[ 168618-42-6 ]

Reference： [1] ChemCatChem, 2018, vol. 10, # 19, p. 4253 - 4257

[ 168618-42-6 ] Synthesis Path-Downstream 1~88

1
[ 911370-10-0 ]
[ 168618-42-6 ]
4-(2-methylsulfanylphenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,6-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium carbonate In 1,4-dioxane; water at 150℃; for 0.333333h; Microwave irradiation;	36 Example 36; OH OH ethylamino)-8-(2,6-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-30 7 -one (50mg, 0.13mmol) in dioxane / H2O (3 : 1, 4.8mL) was mixed with 2-methylthiophenyl boronic acid (33.8mg, 0.20mmol) and K2CO3 (54.3mg, 0.39mmol). The resultant mixture was bubbled with argon for 5 minutes, and added by Pd(PPh3)4 (3.0mg5 0.0026mmol). The reaction tube was sealed and heated with "Smith Creator" (microwave, 15O0C) for 15minutes. The mixture was concentrated under vaco. Flash chromatography (EtOAc / Hexane, 3 : 1) then provided the title compound (89%): MS (ES) m/z All (M+H)+; 1H-NMR(CDCl3) δ EPO 2.45 (s, 3H), 2.55 (s, br, 2H), 3.72 (m, br, 5H), 6.25 (m, br, IH), 6.41 (m, IH), 7.11 (m, 2H), 7.30 (m, 2H), 7.45 (m, 2H), 7.51 (m, 2H).
89%	With potassium carbonate In 1,4-dioxane; water at 150℃; for 0.333333h; Microwave;	36 A solution of 4-Chloro-2-(2-hydroxy-l-hydroxymethyl-ethylamino)-8- (2, 6-difluoro-phenyl)-8H-pyrido[2, 3-dJpyrimidin- 7 -one (5 Omg, 0.13mmol) in dioxane / H2O (3 : 1, 4.8mL) was mixed with 2-25 methylthiophenyl boronic acid (33.8mg, 0.20mmol) and K2CO3 (54.3mg, 0.39mmol). The resultant mixture was bubbled with argon for 5 minutes, and added by Pd(PPh3)4 (3. Omg, 0.0026mmol). The reaction tube was sealed and heated with "Smith Creator" (microwave, 15O0C) for 15minutes. The mixture was concentrated under vaco. Flash chromatography (EtOAc / Hexane, 3 : 1) then provided the title compound (89%): MS (ES) m/z 471 (M+H)+; 1H-NMR(CDCl3) δ 2.45 (s, 3H), 2.55 (s, br, 2H), 3.72 (m, br, 5H), 6.25 (m, br, IH), 6.41 (m, IH), 7.11 (m, 2H), 7.30 (m, 2H), 7.45 (m, 2H), 7.51 (m, 2H).
88%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In 1,4-dioxane; water at 150℃; for 0.25h; Irradiation; microwave;

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/104917, 2006, A2 Location in patent: Page/Page column 72-73
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2007/147104, 2007, A2 Location in patent: Page/Page column 70
[3]Yan, Hongxing; Boehm, Jeffrey C.; Jin, Qi; Kasparec, Jiri; Li, Huijie; Zhu, Chongjie; Widdowson, Katherine L.; Callahan, James F.; Wan, Zehong [Tetrahedron Letters, 2007, vol. 48, # 7, p. 1205 - 1207]

2
[ 911370-08-6 ]
[ 168618-42-6 ]
4-(2-methylsulfanyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium carbonate In 1,4-dioxane; water at 150℃; for 0.333333h; Microwave irradiation;	10 Example 10; 4-(2-Methylsulfanyl-phenylV2-f 2-hydroxy- 1 -hydroxymethyl- ethylamino)-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3- tf\|pyrimidin-7-one A solution of 4-Chloro-2 '-(2 '-hydroxy- 1- hydroxymethyl-ethylamino)-8-(4'trifluoromethyl-phenyl)-8H- pyrido[2,3-d]pyrimidin-7-one (50mg, 0.12mmol) in dioxane / H2O (3 : 1, 4.8mL) was mixed with 2-methylthiophenyl boronic acid (30.4mg, 0.18mmol) and K2CO3 (50.1mg, 0.36mmol). The resultant mixture was bubbled with argon for 5 minutes, and added by Pd(PPh3)4 (2.8mg, 0.0024mmol). The reaction tube was sealed and heated with "Smith Creator" (microwave, 15O0C) for 15minutes. The mixture was concentrated under vaco. Flash chromatography (EtOAc / Hexane, 3 : 1) then provided the title compound (88%): MS (ES) m/z 503 (M+H)+; 1H-NMR(CDCl3) δ 2.48 (s, 3H), 2.65 (s, br, 2H), 3.70 (m, br, 5H), 6.20 (m, br, IH), 6.45 (m, IH), 7.43 (m, 6H), 7.68 (m, IH), 7.83 (m, 2H). EPO
88%	With potassium carbonate In 1,4-dioxane; water at 150℃; for 0.333333h; Microwave;	10 A solution of 4-Chloro-2-(2-hydroxy- 1 -hydroxymethyl-ethylamino)- 8- (4-trifluoromethyl-phenyl)-8H-pyrido[2, 3-dJpyrimidin- 7 -one (5 Omg,0.12mmol ') in dioxane / H -2.O (V3 : 1J, 4.8mL/) was mixed with 2- methylthiophenyl boronic acid (30.4mg, 0.18mmol) and K2CO3 (50.1mg, 0.36mmol). The resultant mixture was bubbled with argon for 5 minutes, and added by Pd(PPh3)4 (2.8mg, 0.0024mmol). The reaction tube was sealed and heated with "Smith Creator" (microwave, 15O0C) for 15minutes. The mixture was concentrated under vaco. Flash chromatography (EtOAc / Hexane, 3 : 1) then provided the title compound (88%): MS (ES) m/z 503 (M+H)+; 1H-NMR(CDCl3) δ 2.48 (s, 3H), 2.65 (s, br, 2H), 3.70 (m, br, 5H), 6.20 (m, br, IH), 6.45 (m, IH), 7.43 (m, 6H), 7.68 (m, IH), 7.83 (m, 2H).
85%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In 1,4-dioxane; water at 150℃; for 0.25h; Irradiation; microwave;

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/104917, 2006, A2 Location in patent: Page/Page column 64
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2007/147104, 2007, A2 Location in patent: Page/Page column 62
[3]Yan, Hongxing; Boehm, Jeffrey C.; Jin, Qi; Kasparec, Jiri; Li, Huijie; Zhu, Chongjie; Widdowson, Katherine L.; Callahan, James F.; Wan, Zehong [Tetrahedron Letters, 2007, vol. 48, # 7, p. 1205 - 1207]

3
[ 76228-06-3 ]
[ 168618-42-6 ]
[ 1001004-06-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 6481 - 6488

4
[ 22190-35-8 ]
[ 168618-42-6 ]
C₁₆H₁₇NS [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 6481 - 6488

5
[ 168618-42-6 ]
[ 321436-06-0 ]
2,3-dihydro-7-[2-(methylthio)phenyl]-1,4-benzoxazin-3-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 6481 - 6488

6
[1-(4-bromo-phenylcarbamoyl)-cyclopentyl]-carbamic acid tert-butyl ester [ No CAS ]
[ 168618-42-6 ]
[1-(2'-methylsulfanyl-biphenyl-4-ylcarbamoyl)-cyclopentyl]-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With sodium carbonate In water; toluene for 22h; Heating / reflux;	1.2 Step 2: [[1- (2'-METHYLSULFANYL-BIPHENYL-4-YLCARBAMOYL)-CYCLOPENTYL]-CARBAMIC] acid tert-butyl ester [(LB).] A mixture of la (0.25 g, 0.652 mmol), 2- (methylthio) benzeneboronic acid (0.131 g, 0.782 mmol), tetrabutylammonium bromide (0.011 g, 0.033 mmol), sodium carbonate (0.138 [G,] 1.304 mmol), and water (1 mL) in toluene (6 mL) was degassed with a stream of argon. Tetrakis (triphenylphosphine) Pd [(0)] (0.038 g, 0.0326 mmol) was then added, and the mixture heated at reflux under an argon atmosphere for 22 [H.] The resulting solution was allowed to cool to RT and concentrated to a solid which was partitioned between EtOAc and water. The organic layer was separated and washed with brine and dried over [MGS04.] Concentration of the organic layer, and purification of the resulting residue by MPLC resulted in the product [1B] (0.160 g, 57%) as a light yellow solid.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2004/24679, 2004, A1 Location in patent: Page 60-61

7
[1-(4-bromo-phenylcarbamoyl)-cyclopropyl]-carbamic acid tert-butyl ester [ No CAS ]
[ 168618-42-6 ]
[1-(2'-methylsulfanyl-biphenyl-4-ylcarbamoyl)-cyclopropyl]-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With sodium carbonate In water; toluene for 1.5h; Heating / reflux;	2.2 Step 2: [[1- (2'-METHYLSULFANYL-BIPHENYL-4-YLCARBAMOYL)-CYCLOPROPYL]-] carbamic acid tert-butyl ester (2b). A mixture of 2a (0.680 g, 1.91 [MMOL),] 2- [(METHYLTHIO)] benzene boronic acid (0.385 g, 2.29 [MMOL),] tetrabutylammonium bromide (0.031 g, 0.096 mmol), sodium carbonate (0.405 g, 3.82 mmol), and water (2 mL) in toluene (20 mL) was degassed with a stream of argon. Tetrakis (triphenylphosphine) Pd [(0)] (0.220 g, 0.191 mmol) was added, and the mixture heated at reflux under an argon atmosphere for 1. [5] h. The resulting solution was allowed to cool to RT and concentrated to a solid which was partitioned between EtOAc and water. The organic layer was separated and washed with brine and dried over [MGS04. CONCENTRATION] of the organic layer, and purification of the resulting residue by MPLC resulted in the product 2b (0.630 g, 83%) as a yellow solid.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2004/24679, 2004, A1 Location in patent: Page 62

8
[1-(4-bromo-phenylcarbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester [ No CAS ]
[ 168618-42-6 ]
[1-(2'-methylsulfanyl-biphenyl-4-ylcarbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With sodium carbonate In water; toluene for 2h; Heating / reflux;	10.2 Step 2: [[1- (2'-METHYLSULFANYL-BIPHENYL-4-YLCARBAMOYL)-CYCLOHEXYL]-CARBAMIC] acid tert-butyl ester [(LOB).] A mixture of 10a (0.80 g, 2.01 [MMOL),] 2- (methylthio) benzeneboronic acid (0.405 g, 2.41 [MMOL), TETRABUTYLAMMONIUM] bromide (0.032 g, 0.10 mmol), sodium carbonate (0. [426 G,] 4.02 mmol), and water (3 mL) in toluene (22 mL) was degassed with a stream of argon. Tetrakis (triphenylphosphine) Pd [(0)] (0.232 g, 0.201 mmol) was added, and the mixture heated at reflux under an argon atmosphere for 2 h. The resulting solution was allowed to cool to RT and concentrated to a solid that was partitioned between EtOAc and water. The organic layer was separated and washed with brine and dried over [MGS04. CONCENTRATION] of the organic layer, and purification of the resulting residue by MPLC resulted in 10b (0.610 g, 66%) as a light yellow solid.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2004/24679, 2004, A1 Location in patent: Page 72

9
[ 409359-31-5 ]
[ 168618-42-6 ]
[ 409359-32-6 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrabutylammomium bromide; sodium carbonate In water; toluene at 85℃; for 15h;	30 Reference Example 30; 5-Cyano-2-methoxy-N-[2-(3-methoxymethoxy-2'-methylthiobiphenyl-4-yl)ethyl]benzenesulfonamide Reference Example 30 5-Cyano-2-methoxy-N -[2-(3-methoxymethoxy-2'-methylthiobiphenyl-4-yl)ethyl]benzenesulfonamide A mixture of 24.75 g of 4-[ 2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-3-methoxymethoxyphenyl trifluoromethanesulfonate, 8.32 g of 2-(methylthio)phenylboronic acid, 2.73 g of tetrakis (triphenylphosphine) palladium (0), 728 mg of tetra-n-butylammonium bromide, 10.00 g of sodium carbonte, 48 mL of water and 285 mL of toluene was heated under an argon atmosphere at 85°C for 15 hours. The precipitate was collected by filtration, washed successively with ethyl acetate and water to give 19.74 g of 5-cyano-2-methoxy-N-[2-(3-methoxy-methoxy-2'-methylthiobiphenyl-4-yl)ethyl]benzenesulfonamide as an yellow powder. 1H-NMR (CDCl3) δ ppm: 2.40 (3H, s), 2.88 (2H, t, J=6.3Hz), 3.19-3.27 (2H, m), 3.43 (3H, s), 3.82 (3H, s), 5.04 (1H, t, J=5.7H z), 5.17 (2H, s), 6.95-7.05 (2H, m), 7.08 (1H, d, J=7.6Hz), 7.10-7.25 (3H, m), 7.25-7.30 (1H, m), 7.30-7.40 (1H, m), 7.79 (1H, dd, J=8.8, 2.2Hz), 8.22 (1H, d, J=2.2Hz)
	With tetrabutylammomium bromide; sodium In water; toluene	R.30 5-Cyano-2-methoxy-N-[2-(3-methoxymethoxy-2'-methylthiobiphenyl-4-yl)ethyl]benzenesulfonamide Reference Example 30 5-Cyano-2-methoxy-N-[2-(3-methoxymethoxy-2'-methylthiobiphenyl-4-yl)ethyl]benzenesulfonamide A mixture of 24.75 g of 4-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-3-methoxymethoxyphenyl trifluoromethanesulfonate, 8.32 g of 2-(methylthio)phenylboronic acid, 2.73 g of tetrakis(triphenylphosphine)palladium(0), 728 mg of tetra-n-butylammonium bromide, 10.00 g of sodium carbonte, 48 mL of water and 285 mL of toluene was heated under an argon atmosphere at 85ØC for 15 hours. The precipitate was collected by filtration, washed successively with ethyl acetate and water to give 19.74 g of 5-cyano-2-methoxy-N-[2-(3-methoxymethoxy-2'-methylthiobiphenyl-4-yl)ethyl]benzenesulfonamide as an yellow powder. 1H-NMR (CDCl3) δ ppm: 2.40 (3H, s), 2.88 (2H, t, J=6.3Hz), 3.19-3.27 (2H, m), 3.43 (3H, s), 3.82 (3H, s), 5.04 (1H, t, J=5.7H z), 5.17 (2H, s), 6.95-7.05 (2H, m), 7.08 (1H, d, J=7.6Hz), 7.10-7.25 (3H, m), 7.25-7.30 (1H, m), 7.30-7.40 (1H, m), 7.79 (1H, dd, J=8.8, 2.2Hz), 8.22 (1H, d, J=2.2Hz)
	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; tetrabutylammomium bromide; sodium carbonate In water; toluene at 85℃;

With tetrabutylammomium bromide; sodium hydrogencarbonate In water; toluene at 85℃; for 15h;

1.11 (Step 11); 5-Cyano-2-methoxy-N-[2-(3-methoxymethoxy-2'-methylthiobiphenyl-4-yl)ethyl]benzenesulfonamide (Step 11) 5-Cyano-2-methoxy-N-[2-(3-methoxymethoxy-2'-methylthiobiphenyl-4-yl)ethyl]benzenesulfonamide A mixture of 24.75 g of 4-[2-(5-cyano-2-methoxybenzene sulfonylamino)ethyl]-3-methoxymethoxyphenyl trifluormethane sulfonate, 8.32 g of 2-(methylthio)phenylboronic acid, 2.73 g of tetrakis(triphenylphosphine)palladium(0), 728 mg of tetra-n-butylammonium bromide, 10.00 g of sodium carbonte, 48 mL of water and 285 mL of toluene was heated under an argon atmosphere at 85° C for 15 hours. The precipitate was collected by filtration, washed successively with ethyl acetate and water to give 19.74 g of 5-cyano-2-methoxy-N-[2-(3-methoxymethoxy-2'-methylthiobiphenyl-4-yl)ethyl]benzenesulfonamide as an yellow powder. 1H-NMR(CDCl3)δppm: 2.40 (3H, s), 2.88 (2H, t, J=6.3Hz), 3.19-3.27 (2H, m), 3.43 (3H, s), 3.82 (3H, s), 5.04 (1H, t, J=5.7H z), 5.17 (2H, s), 6.95-7.05 (2H, m), 7.08 (1H, d, J=7.6Hz), 7.10-7.25 (3H, m), 7.25-7.30 (1H, m), 7.30-7.40 (1H, m), 7.79 (1H, dd, J=8.8, 2.2Hz), 8.22 (1H, d, J=2.2Hz)

Reference： [1]Current Patent Assignee: KISSEI PHARMACEUTICAL COMPANY LIMITED - EP1491187, 2004, A1 Location in patent: Page 28
[2]Current Patent Assignee: KISSEI PHARMACEUTICAL COMPANY LIMITED - EP1331221, 2003, A1
[3]Location in patent: scheme or table Uchida, Masahiko; Okazaki, Kosuke; Mukaiyama, Harunobu; Isawa, Hidetoshi; Kobayashi, Hiroaki; Shiohara, Hiroaki; Muranaka, Hideyuki; Kai, Yuichiro; Kikuchi, Norihiko; Takeuchi, Hideki; Yokoyama, Kenji; Tsuji, Eiichi; Ozawa, Tomonaga; Hoyano, Yuji; Koizumi, Takashi; Misawa, Keiko; Hara, Kiyoto; Nakano, Shigeru; Murakami, Yasuoki; Okuno, Hiroaki [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 16, p. 4682 - 4687]
[4]Current Patent Assignee: KISSEI PHARMACEUTICAL COMPANY LIMITED - EP1486485, 2004, A1 Location in patent: Page 6

10
[ 5419-55-6 ]
[ 19614-16-5 ]
[ 168618-42-6 ]

Yield	Reaction Conditions	Operation in experiment
85%		Part A: Preparation of 2-methylthiophenylboronic acid. 2-Bromothioanisole (29.0 g, 143 mmol) was dissolved in dry THF (400 mL) and cooled to -75C. N-BuLi (62.0 mL, 2.5 M in hexane, 155 mmol) was added over 50 min. After stirring 25 min, triisopropyl borate (46 mL, 199 mmol) was added over 35 min. The cold bath was removed and the reaction was stirred at room temperature for 16 h. The resulting solution was cooled in an ice bath, and 6 M HCl (100 mL) was added. This -mixture was stirred at room temp 5 h and concentrated to about half of the original volume. The concentrated solution was partitioned between Et2O and water. The organic layer was extracted with 2 M NaOH, which was subsequently reacidified with 6 M HCl and extracted several times back into Et2O. These Et2O washes were dried over Na2SO4, filtered, and evaporated to yield a beige solid (20.4 g, 85%). 1H-NMR(CDCl3) delta: 8.01 (dd, 1H, J=7.3, J'=1.4), 7.53 (dd, 1H, J=7.7, J'=1.1), 7.43 (td, 1H, J=7.3, J'=1.8), 7.34 (td, 1H, J=7.3, J'=1.5). 6.22 (s, 2H), 2.50 (s, 3H).
	With iodine; magnesium; In tetrahydrofuran; at 0 - 20℃; for 5.33333h;Heating / reflux;	Reference Example 24 2-(Methylthio)phenylboronic acid Magnesium (9.52 g) was suspended in 119 mL of tetrahydrofuran, and to the suspension were added 3.00 g of <strong>[19614-16-5]2-bromothioanisole</strong> and about 20 mg of iodine. After the reaction was started by heating employing a dryer, 72 g of <strong>[19614-16-5]2-bromothioanisole</strong> was dropped to the mixture during 20 minutes. After being heated for 1 hour, the reaction mixture was diluted with 1000 mL of tetrahydrofuran, and cooled to 0C. To the mixture was added 102 mL of triisopropyl borate at the same temperature, and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added water, and the solvent was removed under reduced pressure. The residue was added 500 mL of 2 mol/L hydrochloric acid, and the mixture was extracted with 300 mL of diethyl ether. The organic layer was extracted with 500 mL of 2 mol/L aqueous sodium hydroxide solution, and the aqueous layer was acidified by addition of concentrated hydrochloric acid under ice-cooling. The residual diethyl ether was removed under reduced pressure, and the precipitate was collected by filtration to give 45.95 g of 2-(methylthio)-phenylboronic acid. 1H-NMR (DMSO-d6) delta ppm: 2.50 (3H, s), 6.21-6.29 (2H, br s), 7.34 (1H, td, J=7.3, 1.3Hz), 7.42 (1H, td, J=7.3, 1.3Hz), 7.52 (1H, dd, J=7.3, 1.3Hz), 8.01 (1H, dd, J=7.3,1.3Hz)

Reference： [1]Patent: EP946508,2009,B1 .Location in patent: Page/Page column 60
[2]Patent: EP1491187,2004,A1 .Location in patent: Page 26

11
[ 851192-85-3 ]
[ 168618-42-6 ]
C₂₁H₁₈N₂O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With cesium fluoride In 1,2-dimethoxyethane at 100℃; for 16h;	DII.III; E-37 Dissolve 3- (4-bromo-phenyl)-4-cyano-1-methyl-lH-pyrrole-2- carboxylic acid ethyl ester (0. 331 mmol, prepared in example E-3a or E-3b) and aryl boronic acid (0.397 mmol, structure 7) in DME (3.0 mL). Add anhydrous cesium fluoride (1. 16 mmol) to the mixture. Degas the mixture under reduced pressure for 20 minutes until no bubbles are produced. Recharge the reaction atmosphere with nitrogen. Add PdCl2 (dppf) (0.066 mmol). Seal the flask and heat the reaction mixture at 100 °C for 16h. Add H20 (20 mL) and methylene chloride (20 mL) into the reaction mixture. Extract the aqueous layer with methylene chloride (3 x 30 mL). Combine the organic layers, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography to provide the compound of Formula IIg.

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2005/40110, 2005, A1 Location in patent: Page/Page column 116

12
[ 904297-87-6 ]
[ 168618-42-6 ]
benzoic acid N'-[2-(5-fluoro-2'-methylsylfanyl-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With sodium carbonate In 1,2-dimethoxyethane; water at 90℃; for 12h;	13 Preparation of benzoic acid N'-[2-(5-fluoro-2'-methylsylfanyl-biphenyl-2-yloxy)-acetyl]-N'-isopropyl-hydrazide A solution of benzoic acid N'-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N'-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2-methylthiophenylboronic acid (31 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a white solid (36 mg, 0.0795 mmol, 65%). MS m/e 453.19 (M+H+)

Reference： [1]Current Patent Assignee: SYNTA PHARMACEUTICALS CORP. - US2006/178532, 2006, A1 Location in patent: Page/Page column 21

13
Pd⁽⁰⁾ [ No CAS ]
[ 497-19-8 ]
[ 168618-42-6 ]
[ 321436-06-0 ]
2,3-dihydro-7-[2-(methylthio)phenyl]-1,4-benzoxazin-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	In 1,2-dimethoxyethane; water;	Example 16 4-[[1-(3-Amino-1,2-benzisoxazol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl]-2,3-dihydro-7-[2-(methylsulfonyl)phenyl]-2H-1,4-benzoxazine A solution of 7-bromo-1,4-benzoxazin-3-one (0.5 g, 2.2 mmol) and thioanisole-2-boronic acid (0.74 g, 2.2 mmol) in a mixture of ethylene glycol dimethyl ether (20 mL) and aqueous sodium carbonate (10 mL) was deoxygenated by a rapid stream of nitrogen applied to the system for 20 min, then treated with Pd(0) at once. The reaction was refluxed for 18 h, cooled down, filtered through Celite and washed with THF (20 mL). The filtrate evaporated to dryness, taken up in water and extracted with EtOAc (3*). Ethyl acetate extracts were dried over sodium sulfate and concentrated. The crude residue was purified by flash chromatography (hexane/EtOAc, 1:3) to afford 2,3-dihydro-7-[2-(methylthio)phenyl]-1,4-benzoxazin-3-one (0.43 g, 72%).

Reference： [1]Patent: US6429205,2002,B1

14
[ 209958-42-9 ]
aq. sodium carbonate [ No CAS ]
[ 168618-42-6 ]
[ 256512-31-9 ]

Yield	Reaction Conditions	Operation in experiment
88%	With tetrabutylammomium bromide;bis(triphenylphosphine)palladium(II)-chloride; In benzene;	Part B: Preparation of 4-(t-butoxycarbonylamino)-3-fluoro-2'-methylthio-[1,1']-biphenyl. A flask containing a mixture of 4-bromo-N-t-butoxycarbonyl-2-fluoroaniline (6.44 g, 22 mmol), 2-(methylthio)phenylboronic acid (6.00 g, 36 mmol), aq. sodium carbonate (2.0 M, 36 mL, 72 mmol), tetrabutylammonium bromide (360 mg, 1.1 mmol), and bis(triphenylphosphine)palladium(II) chloride in benzene (180 mL) was evacuated twice under brief high vacuum, filled with argon, and heated at reflux for 5 h. After cooling to room temperature, the layers were separated, and the aqueous layer was extracted with EtOAc. The organic extracts were combined, dried over Na2 SO4, filtered, and evaporated. The crude product was chromatographed on silica gel (0-30% EtOAc/hexanes) to yield the desired product (6.50 g, 88%). 1 H-NMR(CHCl3)δ: 8.14 (bt, 1H, J=8.1), 7.30 (m, 2H), 7.17 (m, 4H), 6.75 (bs, 1H), 2.37 (s, 3H), 1.54 (s, 9H)ppm.

Reference： [1]Patent: US6020357,2000,A

15
[ 209959-33-1 ]
aq. sodium carbonate [ No CAS ]
[ 1643-19-2 ]
[ 168618-42-6 ]
2-[Bis(tert-butoxycarbonyl)amino]-5-(2'-methylthiophenyl)-pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	bis(triphenylphosphine)palladium(II) dichloride; In benzene;	2-[Bis(tert-butoxycarbonyl)amino]-5-(2'-methylthiophenyl) pyrimidine <strong>[209959-33-1]2-[Bis(tert-butoxycarbonyl)amino]-5-bromopyrimidine</strong> (2.00 g, 5.3 mmol) was dissolved in benzene (130 mL). 2-methylthiophenylboronic acid (2.24 g, 13.3 mmol), aq. sodium carbonate (13 mL, 2.0 M, 26 mmol), tetrabutyl ammonium bromide (86 mg, 0.26 mmol), and bis(triphenylphosphine)palladium(II)chloride (190 mg, 0.27 mmol) were added, and the resulting mixture was first purged with vacuum and argon, then refluxed 17 hours. The cooled mixture was diluted with EtOAc and water. The layers were separated, and the organic was dried over Na2 SO4, filtered, and evaporated. The crude product was chromatographed on silica gel (50% EtOAc/hexanes), evaporated, and chromatographed a second time on silica gel (30-50% EtOAc/hexanes) to yield the desired product (2.13 g, 96%). 1 H NMR (CDCl3): delta8.81 (s, 2H), 7.41 (m, 2H), 7.25 (m, 2H), 2.39 (s, 3H), 1.49 (s, 18H).
96%	bis(triphenylphosphine)palladium(II) dichloride; In benzene;	Part C Preparation of 2-[bis(tert-butoxycarbonyl)amino]-5-(2'-methylthiophenyl)pyrimidine <strong>[209959-33-1]2-[Bis(tert-butoxycarbonyl)amino]-5-bromopyrimidine</strong> (2.00 g, 5.3 mmol) was dissolved in benzene (130 mL). 2-methylthiophenylboronic acid (2.24 g, 13.3 mmol), aq. sodium carbonate (13 mL, 2.0 M, 26 mmol), tetrabutyl ammonium bromide (86 mg, 0.26 mmol), and bis(triphenylphosphine)palladium(II)chloride (190 mg, 0.27 mmol) were added, and the resulting mixture was purged with vacuum and argon and then refluxed 17 h. The cooled mixture was diluted with EtOAc and water. The layers were separated, and the organics were dried over Na2 SO4, filtered, and evaporated. The crude product was chromatographed on silica gel (50% EtOAc/hexanes), evaporated, and chromatographed a second time on silica gel (30-50% EtOAc/hexanes) to yield the desired product (2.13 g, 96%). 1 H-NMR (CDCl3)delta: 8.81 (s, 2H), 7.41 (m, 2H), 7.25 (m, 2H), 2.39 (s, 3H), 1.49 (s, 18H).

Reference： [1]Patent: US5998424,1999,A
[2]Patent: US6020357,2000,A

16
aq. sodium carbonate [ No CAS ]
[ 209959-28-4 ]
[ 1643-19-2 ]
[ 168618-42-6 ]
[ 209959-29-5 ]

Yield	Reaction Conditions	Operation in experiment
87.1%	In benzene	112.B Part B Part B Preparation of 2-[bis(tertbutoxycarbonyl)amino]-5-(2'-methylthiophenyl)pyridine 2-[Bis(tertbutoxycarbonyl)amino]-5-bromopyridine (1.87 g, 5.0 mmol) was dissolved in benzene (120 mL). 2-Methylthiophenylboronic acid (1.95 g, 11.5 mmol), aq. sodium carbonate (12 mL, 2.0 M, 24 mmol), tetrabutyl ammonium bromide (80 mg, 0.25 mmol), and bis(triphenylphosphine)palladium(II)chloride (175 mg, 0.25 mmol) were added, and the resulting mixture was purged with vacuum and argon and then refluxed 16 h. The cooled mixture was diluted with EtOAc and water. The layers were separated, and the organic phase was washed with brine, dried over Na2 SO4, filtered, and evaporated. The crude product was chromatographed on silica gel (10-20% EtOAc/hexanes) to yield a thick oil (1.82 g, 87.1%). 1 H-NMR (CDCl3)δ: 8.51 (d, 1H, J=2.2), 7.83 (dd, 1H, J=8.1, J'=2.2), 7.30 (m, 5H), 2.35 (s, 3H), 1.47 (s, 18H).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US6020357, 2000, A

17
[ 29786-93-4 ]
2-bromothioanisole [ No CAS ]
[ 5419-55-6 ]
[ 168618-42-6 ]

Yield	Reaction Conditions	Operation in experiment
85%	With hydrogenchloride In tetrahydrofuran; hexane	A Part A Part A Preparation of 2-methylthiophenylboronic Acid 2-Bromothioanisole (29.0 g, 143 mmol) was dissolved in dry THF (400 mL) and cooled to -75° C. N-BuLi (62.0 mL, 2.5 M in hexane, 155 mmol) was added over 50 min. After stirring 25 min, triisopropyl borate (46 mL, 199 mmol) was added over 35 min. The cold bath was removed and the reaction was stirred at room temperature for 16 h. The resulting solution was cooled in an ice bath, and 6 M HCl (100 mL) was added. This mixture was stirred at room temp 5 h and concentrated to about half of the original volume. The concentrated solution was partitioned between Et2 O and water. The organic layer was extracted with 2 M NaOH, which was subsequently reacidified with 6 M HCl and extracted several times back into Et2 O. These Et2 O washes were dried over Na2 SO4, filtered, and evaporated to yield a beige solid (20.4 g, 85%). 1 H-NMR (CDCl3) δ: 8.01 (dd, 1H, J=7.3, J-=1.4), 7.53 (dd, 1H, J=7.7, J'=1.1), 7.43 (td, 1H, J=7.3, J'=1.8), 7.34 (td, 1H, J=7.3, J'=1.5), 6.22 (s, 2H), 2.50 (s, 3H).
74%	With hydrogenchloride In tetrahydrofuran; hexane	3.A Part A. Part A. Preparation of 2-methylthiophenylboronic acid 2-Bromothioanisole (8.56 g, 42 mmol) was dissolved in 90 mL of dry THF and cooled to -78°C. n-Butyllithium (18.6 mL, 2.5M in hexane, 47 mmol) was added dropwise over 20 minutes, and the resulting solution stirred 90 min. Triisopropylborate (13.7 mL, 59 mmol) was added dropwise over 10 minutes, and the resulting solution stirred at -78°C for 45 minutes before removing the cooling bath.. The reaction was stirred overnight at room temperature. HCl (40 mL of a 6M aqueous solution) was added and stirred vigorously 8h. The reaction was diluted with 100 mL water and extracted three times with Et2O. The organic extracts were combined and extracted twice with 80 mL of 2M NaOH. The basic layers were combined and acidified with 50 mL 6M HCl and 25ml 2M HCl. The resulting cloudy solution was extracted three times with 50 mL of Et2O, dried over MgSO4, filtered, and evaporated to yield a white solid (5.22g, 74%).1H NMR (CDCl3) δ: 8.01 (dd, 1H), 7.53 (dd, 1H), 7.43 (td, 1H), 7.34 (td, 1H), 6.22 (s, 2H), 2.50 (s, 3H).
74%	With hydrogenchloride In tetrahydrofuran; hexane	3.A Part A. Part A. Preparation of 2-methylthiophenylboronic acid 2-Bromothioanisole (8.56 g, 42 mmol) was dissolved in 90 mL of dry THF and cooled to -78° C. n-Butyllithium (18.6 mL, 2.5M in hexane, 47 mmol) was added dropwise over 20 minutes, and the resulting solution stirred 90 min. Triisopropylborate (13.7 mL, 59 mmol) was added dropwise over 10 minutes, and the resulting solution stirred at -78° C. for 45 minutes before removing the cooling bath. The reaction was stirred overnight at room temperature. HCl (40 mL of a 6M aqueous solution) was added and stirred vigorously 8 h. The reaction was diluted with 100 mL water and extracted three times with Et2O. The organic extracts were combined and extracted twice with 80 mL of 2M NaOH. The basic layers were combined and acidified with 50 mL 6M HCl and 25 ml 2M HCl. The resulting cloudy solution was extracted three times with 50 mL of Et2O, dried over MgSO4, filtered, and evaporated to yield a white solid (5.22 g, 74%). 1H NMR (CDCl3) δ: 8.01 (dd, 1H), 7.53 (dd, 1H), 7.43 (td, 1H), 7.34 (td, 1H), 6.22 (s, 2H), 2.50 (s, 3H).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US6020357, 2000, A
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP946528, 2003, B1
[3]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US6187797, 2001, B1

18
2-bromothioanisole [ No CAS ]
[ 5419-55-6 ]
[ 168618-42-6 ]

Yield	Reaction Conditions	Operation in experiment
85%	With hydrogenchloride; n-butyllithium In tetrahydrofuran; hexane	58 2-Methylthiophenylboronic acid 2-Methylthiophenylboronic acid 2-Bromothioanisole (29.0 g, 143 mmol) was dissolved in dry THF (400 mL) and cooled to -75° C. n-BuLi (62.0 mL, 2.5 M in hexane, 155 mmol) was added over 50 minutes. After stirring 25 minutes, triisopropyl borate (46 mL, 199 mmol) was added over 35 minutes. The cold bath was removed and the reaction was stirred at room temp for 16 hours. The resulting solution was cooled in an ice bathours, and 6 M HCl (100 mL) was added. This mixture was stirred at room temp 5 hours and concentrated to about half of the original volume. The concentrated solution was partitioned between Et2 O and water. The organic layer was extracted with 2 M NaOH, which was subsequently reacidified with 6 M HCl and extracted several times back into Et2 O. These Et2 O washes were dried over Na2 SO4, filtered, and evaporated to yield a beige solid (20.4 g, 85%). 1 H NMR (CDCl3): δ8.01 (dd, 1H, J=7.3, J'=1.4), 7.53 (dd, 1H, J=7.7, J'=1.1), 7.43 (td, 1H, J=7.3, J'=1.8), 7.34 (td, 1H, J=7.3, J'=1.5), 6.22 (s, 2H), 2.50 (s, 3H).
	With hydrogenchloride; iodine; magnesium In tetrahydrofuran; water	R.24 2-(Methylthio)phenylboronic acid Reference Example 24 2-(Methylthio)phenylboronic acid Magnesium (9.52 g) was suspended in 119 mL of tetrahydrofuran, and to the suspension were added 3.00 g of 2-bromothioanisole and about 20 mg of iodine. After the reaction was started by heating employing a dryer, 72 g of 2-bromothioanisole was dropped to the mixture during 20 minutes. After being heated for 1 hour, the reaction mixture was diluted with 1000 mL of tetrahydrofuran, and cooled to 0ØC. To the mixture was added 102 mL of triisopropyl borate at the same temperature, and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added water, and the solvent was removed under reduced pressure. The residue was added 500 mL of 2 mol/L hydrochloric acid, and the mixture was extracted with 300 mL of diethyl ether. The organic layer was extracted with 500 mL of 2 mol/L aqueous sodium hydroxide solution, and the aqueous layer was acidified by addition of concentrated hydrochloric acid under ice-cooling. The residual diethyl ether was removed under reduced pressure, and the precipitate was collected by filtration to give 45.95 g of 2-(methylthio)-phenylboronic acid. 1H-NMR (DMSO-d6) δ ppm: 2.50 (3H, s), 6.21-6.29 (2H, br s), 7.34 (1H, td, J=7.3, 1.3Hz), 7.42 (1H, td, J=7.3, 1.3Hz), 7.52 (1H, dd, J=7.3, 1.3Hz), 8.01 (1H, dd, J=7.3,1.3Hz)

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US5998424, 1999, A
[2]Current Patent Assignee: KISSEI PHARMACEUTICAL COMPANY LIMITED - EP1331221, 2003, A1

19
[ 891842-46-9 ]
[ 168618-42-6 ]
[ 891842-55-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate In 1,2-dimethoxyethane; water at 150℃; for 0.0833333h; microwave irradiation;	93.1 A suspension of 66.3 (48 mg, 0.06 mmol), 2-(methylthio)phenylboronic acid (12.5 mg, 0.2 mmol), Na2CO3 (28 mg, 0.24 mmol) in 3:1 DME/H2O (2 mL) was degassed and then added in Pd(PPh3)4 (10 mg). The reaction mixture was heated to 150° C. for 5 min in microwave. The reaction mixture was then partionated between EtOAc and sat. NaCl, the organic layer was collected and dried(Na2SO4), filtered and concentrated. The crude product of Intermediate 93.1 used as is for the next step. LCMS (4 min gradient) RT=4.87 min, 816.3 (M+H).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2006/211720, 2006, A1 Location in patent: Page/Page column 57

20
[ 911370-09-7 ]
[ 168618-42-6 ]
4-(3-methylsulfanyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,4-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate In 1,4-dioxane; water at 150℃; for 0.333333h; Microwave irradiation;	21 Example 21; 4-(3 -Methylsulfanyl-phenyiy 2-(2-hydroxy- 1 -hydroxymethyl-- mixed with 3-methylthiophenyl boronic acid (33.8mg, 0.20mmol) and K2CO3(54.3mg, 0.39mmol). The resultant mixture was bubbled with argon for 5 minutes follwoed by the addition of Pd(PPh3)4 (3.0mg, 0.0026mmol). The reaction tube was sealed and heated with "Smith Creator" (microwave, 15O0C) for 15minutes. The mixture was concentrated under vaco. Flash chromatography (EtOAc / Hexane, 3 : 1) then provided the title compound (90%): MS (ES) m/z All (M+H)+; 1H-NMR(CDCl3) δ 2.40 (s, br, 2H), 2.40 (s, 3H), 3.90 (m, br, 5H), 6.00 (m, br, IH), 6.45 (m, IH), 7.15 (m, 2H), 7.40 (m, 5H), 7.85 (m, IH).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/104917, 2006, A2 Location in patent: Page/Page column 68

21
[ 25016-01-7 ]
[ 168618-42-6 ]
[ 923281-46-3 ]

Yield	Reaction Conditions	Operation in experiment
96%	With potassium carbonate In tetrahydrofuran; water for 18h; Heating / reflux;	3 Reference Example 3; 4-methoxy-2' - (methylthio) biphenyl-3-carbaldehyde; EPO A mixture of 5-bromo-2-methoxybenzaldehyde (10 g) , [2- (methylthio) phenyl ]boronic acid (7.8 g) , Pd(PPh3 )4i (1.6 g) and potassium carbonate (12.8 g) in THF/water (2/1) (150 mL) was heated under reflux for 18 hr under a nitrogen atmosphere. After cooling, the reaction mixture was concentrated, and the residue was partitioned between ethyl' acetate and water. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 30-»70% ethyl acetate/hexane) to give the title compound (11.5 g, 96%) as a colorless oil.1H-NMR (300MHz, CDCl3): δ 2.36 (3H, s) , 3.96 (3H, s) , 7.04 (IH, d, J=8.5Hz), 7.19 (IH, d, J=3.6Hz), 7.25-7.36 (3H, m) , 7.64 (IH, dd, J=8.5, 2.4Hz), 7.89 (IH, d, J=2.4Hz), 10.5 (IH, s)

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2007/15588, 2007, A1 Location in patent: Page/Page column 82-83

22
[ 881676-32-0 ]
[ 168618-42-6 ]
[ 928324-87-2 ]

Yield	Reaction Conditions	Operation in experiment
69%	With sodium carbonate In 1,2-dimethoxyethane; water at 105℃; for 16h;	148 Reference Example 148 5-[2-(methylthio)phenyl]-1H-pyrrole-3-carbaldehyde; 5-Bromo-1H-pyrrole-3-carbaldehyde (174 mg), [2-(methylthio)phenyl]boronic acid (202 mg) and sodium carbonate (254 mg) were suspended in a mixed solvent of 1,2-dimethoxyethane (5 mL) and water (2 mL), and the mixture was sufficiently degassed under a nitrogen atmosphere. Tetrakis(triphenylphosphine)palladium (58 mg) was added, and the mixture was further degassed and stirred at 105° C. for 16 hr. The reaction mixture was allowed to cool to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give the title compound as pale-yellow crystals (yield 150 mg, 69%). 1H-NMR (CDCl3)δ: 2.38 (3H, s), 6.94-6.95 (1H, m), 7.21-7.31 (2H, m), 7.39-7.42 (1H, m), 7.48-7.53 (2H, m), 9.85 (1H, s), 9.95 (1H, br).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2007/60623, 2007, A1 Location in patent: Page/Page column 44

23
[ 1065482-66-7 ]
[ 168618-42-6 ]
[ 1065483-18-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate In water; acetonitrile at 85℃;	28 N-((S)-l-(7-Fluoro-2-(2-(methylsulfonyl)phenyl)quinolin-3-yl)ethyl)-9H- purin-6-amine; A mixture of (R)-N-((S)-l-(2-chloro-7-fluoroquinolin-3-yl)ethyl)-2- methylpropane-2-sulfinamide (164 mg, 0.4 mmol), 2-(methylthio)phenylboronic acid (92 mg, 1.1 eq), Na2CO3 (214 mg, 5.0 eq), Pd(PPh3)4 (31 mg, 5%), MeCN (3 mL) and water (1 mL) was heated to 85 0C under N2 over night. After cool to rt, the reaction was partitioned between EtOAc (10 mL) and water (5 mL). The organic layer was separated, washed, dried and concentrated. The residue was purified by column chromatography on silica gel to give a white solid. A solution of this solid (140 mg, 0.34 mmol) in MeOH (2 mL) was treated with 4 N HCl in dioxane (1 mL) for 2 h at rt before removal of solvents. The residue was dissolved in THF (3 mL) and treated with Et3N (2 eq, 93 μL) followed with BoC2O (1.1 eq, 81 mg) at 70 0C. After over night, the reaction mixture was worked up and purified on column chromatography on silica gel (EtOAc/hexane, 1/9) to give a white foam (100 mg, 72%) as tert-butyl (S)-l-(7-fluoro-2-(2-(methylsulfonyl)- phenyl)-quinolin-3-yl)ethylcarbamate. This material (100 mg, 0.24 mmol) in CHCl3 (3 mL) was treated with mCPBA (174 mg, 72%, 3.0 eq) at rt for 2 h. LCMS showed the desired MW + 16. Work up. The residue was purified by column chromatography on silica gel (EtOAc/hexane, 1/1) to give two fractions, 1st (50 mg) and 2nd (20 mg) with the same M + 1 = 461 on LCMS. The compounds were dissolved in MeOH (2 mL) and water (1 mL) and treated with TiCl3 in water (30%, 10 drops) at rt for 2 h. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated and washed with water, brine, dried and concentrated to give a white solid (83 mg), which was treated with TFA (1 mL) in DCM (1 mL) at rt for 2 h. The residue after removal of solvents was treated with 6-chloro-9H-purine (32 mg, 1.1 eq) and hunig's base (104 μl, 1.2 eq) in BuOH (2 mL) at 130 0C over night. After cool to rt, the reaction mixture was purified by reverse HPLC (MeCN/water/0.1 TFA, 10% to 60 %) to give a white solid. 1H-NMR (400 Hz, CD3OD) δ 9.35 (s,lH), 8.53-8.47 (m, 2H), 8.25 (s, IH), 7.98-7.76 (m, 6H), 5.85 (s, br, 0.4 H), 5.58-5.56 (m, 0.6H), 3.19 (s, 3H), 1.88-1.81 (m, 3H). Mass Spectrum (ESI) m/e = 463 (M + 1).

Reference： [1]Current Patent Assignee: AMGEN INC - WO2008/118468, 2008, A1 Location in patent: Page/Page column 82-83

24
[ 1021732-69-3 ]
[ 168618-42-6 ]
[ 1021733-45-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate In water; N,N-dimethyl-formamide at 20 - 80℃;	28.A Step A: 1,1 '-bis(diphenylphophino)ferrocene-palladium(II)dichloride dichloromethane complex (61 mg, 0.075 mmol) was added to a degassed, ambient temperature solution of 2-[2-(4- bromophenyl)- 1 -hydroxy- 1 -methylethyl]-4-(2,2-dimethylbutyl)-N, JV-dimethyl- lH-imidazole- 1 - sulfonamide (Intermediate 11) (354 mg, 0.75 mmol), sodium carbonate (239 mg, 2.25 mmol) and [2-(methylthio)phenyl]boronic acid (252 mg, 1.5 mmol) in N,N-dimethylformamide/water (2:1) (22.5 mL). After stirring at 80°C overnight, the reaction mixture was cooled, poured into water and extracted with diethyl ether. The combined organic extracts were dried (magnesium sulfate) EPO and concentrated in vacuo. Chromatography over silica eluting with 0-40% ethyl acetate/hexane afforded 4-(2,2-dimethylbutyl)-2- { 1 -hydroxy- 1 -methyl-2-[2'-(methylthio)biphenyl-4-yl]ethyl} - N,N-dimethyl- lH-imidazole- 1 -sulfonamide.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2008/51404, 2008, A2 Location in patent: Page/Page column 83; 84

25
[ 657408-07-6 ]
[ 39856-58-1 ]
potassium phosphate [ No CAS ]
[ 168618-42-6 ]
[ 1158807-07-8 ]

Yield	Reaction Conditions	Operation in experiment
	tris-(dibenzylideneacetone)dipalladium(0); In water; toluene;	Step 1. The 500 mL round-bottom flask, equipped with magnetic stirrer and reflux condenser was charged with 2-(methylthio)phenylboronic acid (9.48 g, 56 mmol), 3-amino-2-bromopyridine (7.15 g, 57 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (S-Phos, 0.92 g, 4 mol %), Pd2(dba)3 (1.02 g, 2 mol %), potassium phosphate hydrate (39 g, 3 equivalents), 100 mL of toluene. The flask was filled with nitrogen and heated to reflux under nitrogen atmosphere for 24 hours. Then the reaction was cooled down to room temperature, diluted with 500 ml of water and extracted with ethyl acetate (5*40 mL). Organic fractions were combined, dried over sodium sulfate, filtered and evaporated. The residue was subjected to column chromatography on silica gel with eluent hexane/ethyl acetate gradient mixture, providing 2-(2-(methylthio)phenyl)pyridin-3-amine as yellow crystals (9.5 g). NMR confirmed the structure.

Reference： [1]Patent: US2009/134784,2009,A1

26
[ 2302-25-2 ]
[ 168618-42-6 ]
[ 1048983-17-0 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 4968 - 4977

27
[ 209958-42-9 ]
[ 168618-42-6 ]
[ 256512-31-9 ]

Yield	Reaction Conditions	Operation in experiment
88%	With tetrabutylammomium bromide; sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; benzene; for 5h;Reflux;	Part B: Preparation of 4-(t-butoxycarbonylamino)-3-fluoro-2'-methylthio-[1,1']-biphenyl. A flask containing a mixture of 4-bromo-N-t-butoxycarbonyl-2-fluoroaniline (6.44 g, 22 mmol), 2-(methylthio)phenylboronic acid (6.00 g, 36 mmol), aq. sodium carbonate (2.0 M, 36 mL, 72 mmol), tetrabutylammonium bromide (360 mg, 1.1 mmol), and bis(triphenylphosphine)palladium(II) chloride in benzene (180 mL) was evacuated twice under brief high vacuum, filled with argon, and heated at reflux for 5 h. After cooling to room temperature, the layers were separated, and the aqueous layer was extracted with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered, and evaporated. The crude product was chromatographed on silica gel (0-30% EtOAc / hexanes) to yield the desired product (6.50 g, 88%). 1H-NMR(CHCl3)δ: 8.14 (bt, 1H, J = 8.1), 7.30 (m, 2H), 7.17 (m, 4H), 6.75 (bs, 1H), 2.37 (s, 3H), 1.54 (s, 9H)ppm.

Reference： [1]Patent: EP946508,2009,B1 .Location in patent: Page/Page column 34

28
[ 209959-33-1 ]
[ 168618-42-6 ]
2-[Bis(tert-butoxycarbonyl)amino]-5-(2'-methylthiophenyl)-pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With tetrabutylammomium bromide; sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; benzene; for 17h;Reflux;	Part C: Preparation of 2-[bis(tert-butoxycarbonyl)amino]-5-(2'-methylthiophenyl)pyrimidine. <strong>[209959-33-1]2-[Bis(tert-butoxycarbonyl)amino]-5-bromopyrimidine</strong> (2.00 g, 5.3 mmol) was dissolved in benzene (130 mL). 2-methylthiophenylboronic acid (2.24 g, 13.3 mmol), aq. sodium carbonate (13 mL, 2.0 M, 26 mmol), tetrabutyl ammonium bromide (86 mg, 0.26 mmol), and bis(triphenylphosphine)palladium(II)chloride (190 mg, 0.27 mmol) were added, and the resulting mixture was purged with vacuum and argon and then refluxed 17 h. The cooled mixture was diluted with EtOAc and water. The layers were separated, and the organics were dried over Na2SO4, filtered, and evaporated. The crude product was chromatographed on silica gel (50% EtOAc/hexanes), evaporated, and chromatographed a second time on silica gel (30-50% EtOAc/hexanes) to yield the desired product (2.13 g, 96%). 1H-NMR(CDCl3)delta: 8.81 (s, 2H), 7.41 (m, 2H), 7.25 (m, 2H), 2.39 (s, 3H), 1.49 (s, 18H).

Reference： [1]Patent: EP946508,2009,B1 .Location in patent: Page/Page column 60

29
[ 209959-28-4 ]
[ 168618-42-6 ]
[ 209959-29-5 ]

Yield	Reaction Conditions	Operation in experiment
87.1%	With tetrabutylammomium bromide; sodium carbonate In water; benzene for 16h; Reflux;	112.B 1-(3-amidinophenyl)-3-methyl-5-([5-(2'-methylsulfonylphenyl)pyrid-2-yl]aminocarbonyl)pyrazole trifluoroacetate Part B: Preparation of 2-[bis(tertbutoxycarbonyl)amino]-5-(2'-methylthiophenyl)pyridine. 2-[Bis(tertbutoxycarbonyl)amino]-5-bromopyridine (1.87 g, 5.0 mmol) was dissolved in benzene (120 mL). 2-Methylthiophenylboronic acid (1.95 g, 11.5 mmol), aq. sodium carbonate (12 mL, 2.0 M, 24 mmol), tetrabutyl ammonium bromide (80 mg, 0.25 mmol), and bis(triphenylphosphine)palladium(II)chloride (175 mg, 0.25 mmol) were added, and the resulting mixture was purged with vacuum and argon and then refluxed 16 h. The cooled mixture was diluted with EtOAc and water. The layers were separated, and the organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated. The crude product was chromatographed on silica gel (10-20% EtOAc/hexanes) to yield a thick oil (1.82 g, 87.1%). 1H-NMR(CDCl3)δ: 8.51 (d, 1H, J=2.2), 7.83 (dd, 1H, J=8.1, J'=2.2), 7.30 (m, 5H), 2.35 (s, 3H), 1.47 (s, 18H).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP946508, 2009, B1 Location in patent: Page/Page column 59

30
[ 209960-46-3 ]
[ 168618-42-6 ]
[ 209960-47-4 ]

Yield	Reaction Conditions	Operation in experiment
95%	With tetrabutylammomium bromide; sodium carbonate In benzene at 80℃; for 24h;	239.D 1-[6-amidinopyrid-2-yl]-3-methyl-5-[3-fluoro-(2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole, trifluoroacetic acid salt Part D. Preparation of 1-[(6-(N-tert-butyloxycarbonyl)aminoiminomethyl)pyrid-2-yl]-3-methyl-5-[3-fluoro-(2'-thiomethoxy-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole. To a solution of 1-[(6-(N-tert-butyloxycarbonyl)aminoiminomethyl)pyrid-2-yl]-3-methyl-5-[(1-bromo-3-fluorophenyl-4-yl)aminocarbonyl]pyrazole (0.15 g, 0.29 mmol) in 15 mL of benzene was added 2-thiomethoxyphenyl boronic acid (0.07 g, 0.42 mmol), tetrabutylammonium bromide (0.01 g, 0.03 mmol), sodium carbonate (0.09 g, 0.85 mmol) and 0.80 mL of water. This mixture was degassed with a stream of nitrogen and then tetrakis triphenylphosphine palladium (0.06 g, 0.05 mmol) was added. The mixture was stirred at 80° C for 24 h. The reaction was allowed to cool and then was diluted with ethyl acetate, washed with saturated aq sodium bicarbonate and brine, dried (MgSO4), filtered through celite and concentrated in vacuo to afford 0.157 g (95%) of the title compound. This material was sufficiently pure to be used without purification. 1H-NMR(CDCl3) δ: 8.40 (t, 1H), 8.02 (broad s, 2H), 7.60-7.20 (m, 10H), 6.56 (s, 1H), 2.34 (s, 3H), 2.33 (s, 3H), 1.46 (s, 9H)ppm. ESI mass spectrum analysis m/z(relative intensity) 560.9 (M+H, 100).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP946508, 2009, B1 Location in patent: Page/Page column 100

31
[ 1055880-27-7 ]
[ 168618-42-6 ]
[ 1055880-41-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium carbonate In ethanol; water; toluene at 95℃; for 12h; Inert atmosphere;	20.1 Example 20; 9-[2-(methylthio)phenyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride; (1) tert-butyl 9-[2-(methylthio)phenyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate; A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 2-methylthiophenylboronic acid (153 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95°C for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (170 mg, 80.0%) as an oil. 1H-NMR (CDCl3) δ; 1.45 (9H, s), 2.36 (3H, s), 3.74 (2H, br s), 3.86 (1H, br s), 4.03 (1H, br s), 4.47-4.53 (2H, m), 7.04-7.36 (7H, m).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2123644, 2009, A1 Location in patent: Page/Page column 54

32
[ 861966-90-7 ]
[ 168618-42-6 ]
3-(4'-carboxymethyl-biphenyl-4-yl)-4-cyano-5-ethyl-thiophene-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	Stage #1: (2-methylsulfanylphenyl)boronic acid With potassium carbonate In water for 0.25h; Stage #2: 3-(4-bromo-phenyl)-4-cyano-5-ethyl-thiophene-2-carboxylic acid ethyl ester With pyrographite In water; ethyl acetate at 70.5℃;	E-91 Example E-91 4-Cyano-5-ethyl-3- (2'-metliylsulfanvl-biphenvl-4-yl)-thiophene-2-carboxylic acid ethyl ester Combine potassium carbonate (54.4 g, 0.3937 moles, 2.1 eq) and water (1.32 L) in a 3 L 3-neck flask equipped with an overhead stirrer. Add 2-thiomethylphenyl boronic acid (34.65 g, 0.206 moles, 1.1 eq) to the resulting carbonate solution and stir about 15 minutes. Add Darco G-60 (7 g), and stir an additional 15 min at room temperature. Filter the suspension and add the filtrate to a 5 L 3-neck flask equipped with an overhead stirrer, heating mantle, thermocouple, condenser, and nitrogen inlet. Add palladium black 0.7 g (0. 0658mol) and ethyl acetate (250 ml) and sweep the headspace with nitrogen for about 10 minutes. Add 4-cyano-5-ethyl-3- (4-bromo-phenyl)-thiophene-2-carboxylic acid ethyl ester (68.3 g, 0.1875 moles, 1.0 eq. ) and ethyl acetate (250 ml) and stir the mixture to dissolve the 4-cyano-5-ethyl-3- (4-bromo-phenyl)-thiophene-2-carboxylic acid ethyl ester. Set the flask for a nitrogen by-pass through a bubbler and heat to reflux at 70. 5C until substantial depletion of 4-cyano-5-ethyl-3- (4-bromo-phenyl)-thiophene-2-carboxylic acid ethyl ester. HPLC. (mobile phase = 27% 0.1% TFA in water, 73% ACN, 1.5 ml/min isocratic ; Column = Zorbax SB-Phenyl 5um 4.6mm x 25cm at 35C ; UV detection at 210 nm). Cool the mixture to 60C and filter to remove palladium black. Separate the phases and extract the aqueous phase with 100 ml ethyl acetate. Combine the organic phases and strip to a solid. Dissolve the solid in hot (75 C) ethanol (600 ml) and transfer the resulting solution to a 1 L flask equipped with an overhead stirrer, condenser, and thermocouple. Cool the solution to 65C, seed with 4-cyano-5-ethyl-3- (2'- methylsulfanyl-biphenyl-4-yl) -thiophene-2-carboxylic acid ethyl ester, and further cool to 18C. Filter the resulting precipitate and rinse with cool (10 C) ethanol. Vacuum dry the solids at 50 C, which affords the title compound (68.0 g, 89.0% yield). HPLC = 98. 1%. (mobile phase = 27% 0. 1% TFA in water, 73% ACN, 1.5 ml/min isocratic; Column = Zorbax SB-Phenyl Sum 4.6mm x 25cm at 35C; UV detection at 210 nm).

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2005/70916, 2005, A1 Location in patent: Page/Page column 153-154

33
[ 211308-81-5 ]
[ 168618-42-6 ]
[ 1235878-54-2 ]

Yield	Reaction Conditions	Operation in experiment
81%	With tetrakis(triphenylphosphine)palladium (0); In water; toluene;	Step 1: Synthesis of 5-chloro-3-(2-methylthiophenyl)pyridin-2-amine First, 4.99 g of <strong>[211308-81-5]5-chloro-3-iodopyridin-2-amine</strong>, 5.00 g of 2-methylthiophenylboronic acid, 8.32 g of potassium carbonate, 200 mL of toluene, and 100 mL of water were put into a 1-L three-neck flask equipped with a reflux pipe, and the air in the flask was replaced with nitrogen. The mixture was degassed by being stirred under reduced pressure, and then 1.10 g of tetrakis(triphenylphosphine)palladium(0) (abbreviation: Pd(PPh3)4) was added and the mixture was refluxed for 2 hours. Then, 0.55 g of Pd(PPh3)4 was added, and the mixture was refluxed for 8.5 hours. Furthermore, 0.55 g of Pd(PPh3)4 was added, and the mixture was refluxed for 8 hours. Then, 4.96 g of 2-methylthiophenylboronic acid, 4.11 g of potassium carbonate, and 0.55 g of Pd(PPh3)4 were added, and the mixture was refluxed for 8 hours to cause a reaction. Water was added to the reacted solution, and the organic layer was extracted with ethyl acetate. The obtained solution was washed with saturated saline, and magnesium sulfate was added for drying. The solution obtained by the drying was filtered. The solvent of the filtrate was distilled off, and then the resulting residue was purified by silica gel column chromatography using hexane and ethyl acetate as a developing solvent in a ratio of 2:1, so that the target pyridine derivative 5-chloro-3-(2-methylthiophenyl)pyridin-2-amine was obtained (yellow white powder, yield of 81%). Synthesis Scheme (E2-1) of Step 1 is shown below.
81%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; toluene; for 26h;Inert atmosphere;	First, <strong>[211308-81-5]5-chloro-3-iodo-2-amine</strong> and 4.99g, 2-thiophenyl boronic acid and 5.00g, and 8.32g of potassium carbonate, and 200mL of toluene, 100mL of the water reflux tube was attached to 1L a three-necked flask was replaced with nitrogen the flask. After degassed by stirring under reduced pressure, tetrakis (triphenylphosphine) palladium (0) (abbreviation: Pd (PPh3) 4) was added to 1.10g was refluxed for 2 hours. Here, it was added to Pd (PPh3) 4 0.55g was refluxed for 8 hours. And, Pd (PPh3) 4 and a further 0.55g of methyl 2-thiophenyl boronic acid with 4.96g, 4.11g of potassium carbonate and then refluxed for 8 hours, Pd (PPh3) 4 0.55gAnd the mixture was reacted under reflux for 8 hours. Water was added to the reaction solution, the organic layer was extracted with ethyl acetate. The obtained extract was washed with saturated brine and dried over magnesium sulfate. The solution was filtered after drying. After removal of the solution by evaporating the solvent, the resulting residue hexane: ethyl acetate = 2: 1 was purified by silica gel column chromatography as a developing solvent, a 5-chloro-3-pyridine derivatives The desired (2 to give the methyl thiophenyl) pyridine-2-amine (pale yellow powder, yield 81%).
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene;Reflux; Inert atmosphere;	Step 2. Mixture of 2-(methylthio)phenylboronic acid (5.0 g, 29.8 mmol), <strong>[211308-81-5]5-chloro-3-iodopyridin-2-amine</strong> (7.56 g, 29.8 mmol), sodium carbonate (9.0 g, in 50 mL of water), Pd(PPh3)4 (621 mg) and 100 mL of toluene was refluxed overnight under N2. reaction mixture was cooled down to room temperature, organic layer was separated and concentrated in vacuum. The residue was subjected to column chromatography on silica gel with hexane/ethyl acetate gradient mixture as eluent, providing 3.5 g of 5-chloro-3-(2-(methylthio)phenyl)pyridin-2-amine.

Reference： [1]Patent: US2016/93818,2016,A1
[2]Patent: KR2016/38850,2016,A .Location in patent: Paragraph 0323-0325
[3]Chemical Communications,2013,vol. 49,p. 1446 - 1448
[4]Patent: US2010/187984,2010,A1 .Location in patent: Page/Page column 120

34
[ 523-27-3 ]
[ 168618-42-6 ]
[ 885516-15-4 ]

Yield	Reaction Conditions	Operation in experiment
57.5%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In toluene for 24h; Inert atmosphere; Reflux;
26%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In ethanol; water; toluene at 110℃; for 48h; Inert atmosphere; Schlenk technique;	Synthesis of Ligand syn 1 A Schlenk tube was charged with 2-(methylthio)benzeneboronic acid (150 mg, 0.89mmol), 9,10-dibromoanthracene (120 mg, 0.36 mmol), tetrakis(triphenylphosphine)palladium (21 mg, 5 mol %) and potassium carbonate (248 mg, 1.8 mmol). The mixture was degassed and flushed with argon for three times. The nthe degassed solvent toluene/ethanol/water (6 mL, 4:1:1) was added. The resulting mixture was stirred at 110 °C for 48 h. After cooling to room temperature, the suspension was filtered through a pad of celite and washed with dichloromethane. The filtrate was dried over magnesium sulfate, then concentrated and purified by column chromatography on silica gel (eluent: petrol ether/ethyl acetate, 75: 1) to afford syn-atropisomer 1 as a light yellow solid (180 mg, 26% yield).

Reference： [1]Du, Chunyan; Ye, Shanghui; Liu, Yunqi; Guo, Yunlong; Wu, Ti; Liu, Hongtao; Zheng, Jian; Cheng, Cheng; Zhu, Minliang; Yu, Gui [Chemical Communications, 2010, vol. 46, # 45, p. 8573 - 8575]
[2]Cao, Zhen; Lacoudre, Aline; Rossy, Cybille; Bibal, Brigitte [Beilstein Journal of Organic Chemistry, 2019, vol. 15, p. 2465 - 2472]

35
[ 918422-41-0 ]
[ 168618-42-6 ]
[ 1259080-84-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In 1,2-dimethoxyethane at 85℃; for 142.5h;	10 A mixture of 2-(l-(3-bromo-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-yl)ethyl)iso- indoline-l,3-dione (0.9836 g, 2.470 mmol), 2-(methylthio)phenylboronic acid (0.623 g, 3.71 mmol), tetrakis(triphenylphosphine)palladium(0) (0.143 g, 0.124 mmol), and potassium carbonate (1.024 g, 7.41 mmol) in DME (12.35 mL) was stirred at 85 0C. After 25.5 h, to the mixture were added 2-(methylthio)phenyl- boronic acid (0.623 g, 3.71 mmol), tetrakis(triphenylphosphine)palladium(0) (0.143 g, 0.124 mmol), and potassium carbonate (1.024 g, 7.41 mmol) and the mixture was stirred at 85 0C. After 4 days 21 h, the mixture was cooled to rt. The insoluble solid was filtered off and the solid was washed with DCM (50 mL). The filtrate was cond under reduced pressure. The residue was dissolved in DCM (50 mL), washed with brine (50 mL x 2), dried over Na2SO4, filtered, and cond under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g Redi-Sep column using 0 to 50% gradient of EtOAc in hexane over 14 min and then 50% isocratic of EtOAc for 20 min as eluent to give 2-(l-(3-(2- (methylthio)phenyl)-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-yl)ethyl)isoindoline-l,3- dione as a yellow syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.96 (1 H, ddd, J=7.2, 1.6, 0.8 Hz), 7.98 - 8.05 (1 H, m), 7.77 - 7.84 (2 H, m), 7.68 - 7.75 (3 H, m), 7.43 (1 H, td, J=6.9, 1.5 Hz), 7.31 (1 H, dd, J=8.1, 0.9 Hz), 7.18 - 7.24 (1 H, m), 6.79 - 6.85 (1 H, m), 6.70 - 6.76 (1 H, m), 5.36 - 5.44 (1 H, m), 2.41 (3 H, s), 1.64 (3 H, d, J=7.2 Hz); Mass Spectrum (ESI) m/e = 442.1 (M+l).

Reference： [1]Current Patent Assignee: AMGEN INC - WO2010/151735, 2010, A2 Location in patent: Page/Page column 66

36
[ 88223-35-2 ]
[ 168618-42-6 ]
[ 1187461-86-4 ]

Reference： [1]Chemistry - A European Journal,2009,vol. 15,p. 8275 - 8282

37
[ 168618-42-6 ]
[ 226070-05-9 ]
[ 1187461-87-5 ]

Reference： [1]Chemistry - A European Journal,2009,vol. 15,p. 8275 - 8282

38
[ 619-44-3 ]
[ 168618-42-6 ]
[ 1147096-55-6 ]

Yield	Reaction Conditions	Operation in experiment
81%	With sodium carbonate In methanol at 25 - 30℃; for 0.5h; Reflux;	4.1 Example 4; Preparation of S-(2-[4-(N-{2-[N-(5-chloro-2-pyridyl)carbamoyl]-4-chlorophenyl}carbamoyl)phenyl]-phenyl)-S-methyl sulfoximideStep 1: Preparation of 2'-Methylsulfanyl-biphenyl-4-carboxylic acid methyl esterTo a stirring solution of 4-iodobenzoic acid methyl ester (5 g, 0.0019 mol), sodium carbonate (4.04 g, 0.038 mol) and Palladium acetate (4.2 mg, 0.00019 mol) in methanol (30 mL), was added 2-methylmercapto phenyl boronic acid (3.53 g, 0.02 mol) in one lot at 25-30° C. After reflux of 30 min., reaction mixture was poured in ice cold water (100 mL) and product was extracted in ethyl acetate (250 mL). Column purification (100-200 mesh silica gel, 5% hexane in ethyl acetate) gave 4 g of titled product in 81% yield.

Reference： [1]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - US2011/65717, 2011, A1 Location in patent: Page/Page column 11-12

39
[ 80-07-9 ]
[ 168618-42-6 ]
4,4'-bis(2-methylthiophenyl)diphenyl sulfone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 90℃; for 20h;	Comparative Example 2Synthesis of 4,4'-bis(2-methylthiophenyl)diphenyl sulfoneThe compound (4,4'-bis(2-methylthiophenyl)diphenyl sulfone) described below was synthesized and experiments on the optical characteristics and the practicality described later were performed. A synthesis method of the compound in the present comparative example will be explained below. (1) The following reagents and solvents were put into a reaction container. 4,4'-dichlorodiphenyl sulfone: 0.4 g 2-methylthiophenylboric acid: 0.6 g sodium hydrogen carbonate: 0.8 g 1,4-dioxane: 20 ml water: 10 ml tetrakistriphenylphosphine palladium: 0.07 g Subsequently, the reaction solution was heated to 90 C. and agitation was performed at this temperature for 20 hours. At this time, the degree of proceeding of the reaction was ascertained with TLC appropriately. Then, the reaction solution was diluted with water, and an organic phase was recovered through solvent extraction. The resulting organic phase was washed with water and saturated saline solution in that order. The resulting organic phase was dried with anhydrous magnesium sulfate and, thereafter, a crude product was obtained through concentration under reduced pressure. The resulting crude product was subjected to recrystallization with a hexane/ethyl acetate mixed solvent, so that 0.5 g (yield 72%) of 4,4'-bis(2-methylthiophenyl)diphenyl sulfone was obtained as a light yellow crystal.The structure of the resulting compound was ascertained with 1H-NMR.1H-NMR (CDCl3; TMS): delta 2.37 (s, 6H), 7.14-7.40 (m, 8H), 7.56-7.62 (m, 4H), 8.00-8.06 (m, 4H)

Reference： [1]Patent: US2011/288330,2011,A1 .Location in patent: Page/Page column 22-23

40
[ 101-55-3 ]
[ 168618-42-6 ]
[ 291533-88-5 ]

Yield	Reaction Conditions	Operation in experiment
89%	With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 90℃; for 20h;	Comparative Example 3Synthesis of 4-(4-methylthiophenyl)diphenyl etherThe compound (4-(4-methylthiophenyl)diphenyl ether) described below was synthesized and experiments on the optical characteristics and the practicality described later were performed. A synthesis method of the compound in the present comparative example will be explained below. (1) The following reagents and solvents were put into a reaction container. 4-bromodiphenyl ether: 0.8 g 4-methylthiophenylboric acid: 0.6 g sodium hydrogen carbonate: 0.8 g dioxane: 20 ml water: 10 ml tetrakistriphenylphosphine palladium: 0.1 g Subsequently, the reaction solution was heated to 90 C. and agitation was performed at this temperature for 20 hours. At this time, the degree of proceeding of the reaction was ascertained with TLC appropriately. Then, the reaction solution was diluted with water, and an organic phase was recovered through solvent extraction. The resulting organic phase was washed with water and saturated saline solution in that order. The resulting organic phase was dried with anhydrous magnesium sulfate and, thereafter, a crude product was obtained through concentration under reduced pressure. The resulting crude product was subjected to recrystallization with a hexane/ethyl acetate mixed solvent, so that 0.8 g (yield 89%) of 4-(4-methylthiophenyl)diphenyl ether was obtained.The structure of the resulting compound was ascertained with 1H-NMR.1H-NMR (CDCl3; TMS): delta 2.51 (s, 3H), 7.03-7.15 (m, 4H), 7.28-7.39 (m, 5H), 7.46-7.55 (m, 4H)

Reference： [1]Patent: US2011/288330,2011,A1 .Location in patent: Page/Page column 23

41
[ 25121-87-3 ]
[ 168618-42-6 ]
[ 1381839-79-7 ]

Reference： [1]Organic Letters,2012,vol. 14,p. 3300 - 3303

42
[ 1196501-25-3 ]
[ 168618-42-6 ]
[ 1415022-75-1 ]

Yield	Reaction Conditions	Operation in experiment
52.4%	With palladium diacetate; potassium carbonate; triphenylphosphine In ethanol; toluene at 60℃; for 12h; Inert atmosphere;	3. Synthesis of N-([1,1':3',1''-terphenyl]-5'-yl)-2,2-dichloroacetamide derivatives. General procedure: The general procedure for the preparation of N-(3-phenyl)-2,2-dichloroacetamide heterocyclic derivatives was as follows. A mixture of 0.2mmol 2,2-dichloro-N-(3,5-diiodo-phenyl)acetamide, 0.6 mmol substituted phenylboronic acid, 0.8 mmol K2CO3, 0.16mmol triphenyl phosphine, and 0.04 mmol palladium acetate were stirred in 3 mL toluene and 3 mL ethanol at 60℃ under a argon atmosphere. The progress of the reaction was monitored by TLC (petroleum ether/ethyl acetate). After the reaction finished, the reaction mixture was filtered. The filtrate was concentrated to dryness and subjected to flash column chromatography (silica gel), eluting with petroleum ether/ethyl acetate, to give N-([1,1':3',1''-terphenyl]-5'-yl)-2,2-dichloroacetamide derivatives.

Reference： [1]Li, Tianwen; Yang, Yongchong; Cheng, Changmei; Tiwari, Amit K.; Sodani, Kamlesh; Zhao, Yufen; Abraham, Ioana; Chen, Zhe-Sheng [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 23, p. 7268 - 7271]

43
[ 1353892-45-1 ]
[ 168618-42-6 ]
[ 1464832-35-6 ]

Yield	Reaction Conditions	Operation in experiment
84%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium carbonate In N,N-dimethyl-formamide at 100℃; for 3h; Inert atmosphere;	1 2-((1S)-1-(8-fluoro-2-(2-(methylthio)phenyl)quinolin-3-yl)ethyl)isoindoline-1,3-dione (S)-2-(1-(2-Chloro-8-fluoroquinolin-3-yl)ethyl)isoindoline-1,3-dione (14.0 g, 39.5 mmol), 2-(methylthio)phenylboronic acid (9.95 g, 59.2 mmol), and potassium carbonate (16.4 g, 118 mmol) were combined in 300 mL of anhydrous DMF under an atmosphere of N2. The solution was sparged with N2 for 5 min before adding PdCl2(dppf)CH2Cl2 (3.22 g, 3.95 mmol). The solution was heated at 100° C. for 3 h, and then cooled to 50° C. The solution was concentrated under vacuum to give a brownish residue, which was diluted with EtOAc (600 mL). The organic layers were then washed with H2O (3×80 mL), followed by brine (1×100 mL). The combined aq. layers were extracted with DCM (3×200 mL). The combined organic layers were dried over MgSO4 and then concentrated under vacuum. The residue obtained was purified by silica gel flash chromatography eluting with a gradient of 20% hexane to 40% EtOAc/hexane. The fractions containing the pure product were combined and concentrated under vacuum to give 2-((1S)-1-(8-fluoro-2-(2-(methylthio)phenyl)quinolin-3-yl)ethyl)isoindoline-1,3-dione (14.6 g, 33.0 mmol, 84% yield) as a light yellow foam. The proton NMR reflects a 53/47 ratio of atropisomers at 25° C. 1H NMR (500 MHz, CDCl3) δ ppm 8.71 (br s, 0.53H), 8.65 (br s, 0.47H), 7.79 (m, 1H), 7.66 (s, 4H), 7.55 (m, 1H), 7.45-7.27 (series of m, 3.6H), 6.87 (m, 1.4H), 5.70 (q J=6.4 Hz, 0.47H), 5.63 (q, J=6.8 Hz, 0.53H), 2.47 (br s, 1.4H), 1.91 (m, 3H), 1.52 (br s, 1.6H). Mass Spectrum (ESI) m/e=443.2 (M+1)

Reference： [1]Current Patent Assignee: AMGEN INC - US2013/267524, 2013, A1 Location in patent: Paragraph 0069-0070

44
[ 1464832-59-4 ]
[ 168618-42-6 ]
[ 1464832-61-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium carbonate In N,N-dimethyl-formamide at 100℃; for 4h; Inert atmosphere;	5 2-((1S)-1-(5-chloro-3-(2-(methylthio)phenyl)quinoxalin-2-yl)ethyl)isoindoline-1,3-dione A 5 L three-necked round-bottomed flask equipped with a mechanical stirrer, a condenser, a nitrogen gas inlet and a temperature probe was charged with DMF (2.16 L), (S)-2-(1-(3,5-dichloroquinoxalin-2-yl)ethyl)isoindoline-1,3-dione (273 g, 733 mmol) and 2-(methylthio)phenylboronic acid (136 g, 807 mmol). To the mixture, was added potassium carbonate (203 g, 147 mmol) and [1,1-bis(di-phenylphosphino)ferrocene]palladium(ii) chloride, complex with DCM (29.9 g, 36.7 mmol). The mixture was vacuum purged with N2 (2×), and heated to 100° C. The reaction was monitored by LC-MS, and deemed complete after 4 h. The reaction was cooled to rt (21° C.), and then divided into two batches. Each batch was partitioned between EtOAc (1.08 L) and water (1.35 L) in a 4 L separatory funnel. After phase separation, the organic layer was washed with brine (2×500 mL) and concentrated to afford the crude product. The combined batches of crude material were loaded on silica gel and purified by flash chromatography (ISCO/RediSep) (hexane:EtOAc=10:0 to 6:4) to provide the product as a light brown solid 320 g with 98% LC purity and 95% yield. [0128] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.15-8.31 (m, 1H), 8.07 (m, 1H), 7.93 (m, 1H), 7.77 (m, 2H), 7.64 (br.s., 2H), 7.16-7.55 (m, 3H), 6.58-7.02 (m, 1H), 5.72-5.98 (m, 1H), 3.29 (s, 3H), 1.79 (d, J=6.9 Hz, 3H) Mass Spectrum (ESI) m/z=460.0 (M+1).

Reference： [1]Current Patent Assignee: AMGEN INC - US2013/267524, 2013, A1 Location in patent: Paragraph 0126-0128

45
[ 1240186-20-2 ]
[ 168618-42-6 ]
(S)-tert-butyl (1-(7-fluoro-2-(2-(methylthio)phenyl)quinolin-3-yl)ethyl)-carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.8%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In water; acetonitrile at 85℃; Inert atmosphere;	2 (S)-tert-butyl (1-(7-fluoro-2-(2-(methylthio)phenyl)quinolin-3-yl)ethyl)-carbamate A mixture of (S)-tert-butyl (1-(2-chloro-7-fluoroquinolin-3-yl)ethyl)carbamate (382 mg, 1.2 mmol), 2-(methylthio)phenylboronic acid (257 mg, 1.3 eq), Na2CO3 (623 mg, 5.0 eq), Pd(PPh3)4 (93 mg, 5%), MeCN (9 mL) and water (3 mL) was heated to 85° C. under N2 overnight. After cooling to rt, the reaction was partitioned between EtOAc (10 mL) and water (5 mL). The organic layer was separated, washed, dried and concentrated. The residue was purified by column chromatography on silica gel to give a white solid (S)-tert-butyl (1-(7-fluoro-2-(2-(methylthio)phenyl)quinolin-3-yl)ethyl)carbamate (460 mg, 94.8%). Mass Spectrum (ESI) m/e=413 (M+1).

Reference： [1]Current Patent Assignee: AMGEN INC - US2013/267524, 2013, A1 Location in patent: Paragraph 0090-0091

46
[ 800402-12-4 ]
[ 168618-42-6 ]
2-chloro-5-[2-(methylthio)phenyl]pyridin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 12h;	Place 2-chloro-5-iodo-4-pyridylamine (30g, 1eq) in a dry two-necked bottle,2-methylthiophenylboronic acid (19.81g, 1eq), Pd (PPh3) 4 (6.81g, 0.05eq),Potassium carbonate (40.73g, 2.5eq), then add 500mL of a 3: 1 mixture of dioxane and water, stir the reaction at 100 C for 12 hours, cool to room temperature, and spin dry after the reaction is completeUse dichloromethane and water solution, dry with magnesium sulfate and spin dry, then purify through silica gel column.A solid intermediate (8-c) was obtained with a yield of 90%.
51%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; for 24h;Inert atmosphere; Reflux;	A mixture of 2-chloro-5-iodopyridin-4-amine (7.0 g, 27.2 mmol), 2-(methylthio)phenylboronic acid (4.6 g, 27.2 mmol), potassium carbonate (11.3 g, 81.7 mmol), 90 ml of tetrahydrofuran (THF) and 30 mL of distilled water were stirred and bubbled with N2 gas for30 min. Tetrakis(triphenylphosphine)palladium(0) (0.94 g, 8.17 mmol) was added to the above reaction mixture and the resulting solution was refluxed for 24 h under N2. The solution was cooled down to room temperature, and extracted with ethyl acetate and distilled water. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to give the crude product, which was purified by column chromatography on silica gel with n-hexane/ethyl acetate gradient mixture as an eluent, providing 3.5 g of 1. Yield 51%. MS (FAB) m/z 251 [(M + H)]. 1H NMR (500 MHz, CDCl3): delta 2.40 (s, 3H), 4.18 (s, 2H), 6.66 (s, 1H), 7.16 (d, 1H, J=3.7 Hz), 7.24 (t, 1H, J=5.0 Hz), 7.30 (d, 1H, J=4.0 Hz), 7.41 (t, 1H, J=5.2 Hz), 7.88 (s, 1H).

Reference： [1]Patent: CN110981895,2020,A .Location in patent: Paragraph 0314; 0321-0323
[2]Dyes and Pigments,2013,vol. 99,p. 390 - 394

47
ethyl 2-acetylamino-6-bromo-7-[2-(N,N-diethylamino)ethyloxy] benzo[b]thiophene-3-carboxylate [ No CAS ]
[ 168618-42-6 ]
ethyl 2-acetylamino-7-[2-(N,N-diethylamino)ethyloxy]-6-(2-(methylthio)phenyl)benzo[b]thiophene-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With tripotassium phosphate "n" hydrate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) In water; acetonitrile at 80℃; for 12h; Inert atmosphere;	12.17 (17) Synthesis of Ethyl 2-acetylamino-7-[2-(N,N-diethylamino)ethyloxy]-6-(2-me thylthiophenyl)benzo[b]thiophene-3-carboxylate (TMD-517) (17) Synthesis of Ethyl 2-acetylamino-7-[2-(N,N-diethylamino)ethyloxy]-6-(2-me thylthiophenyl)benzo[b]thiophene-3-carboxylate (TMD-517) Under an argon atmosphere, a solution of ethyl 2-acetylamino-6-bromo-7-[2-(N,N-diethylamino)ethyloxy] benzo[b]thiophene-3-carboxylate (compound No.09) (23mg, 50 μmol), 2-methylthiophenylboronic acid (17 mg, 0.10 mmol), potassium phosphate n hydrate (23 mg, ca. 1 mmol), and bis[di-t-butyl(4-dimethylaminophenyl)phosphine]dichlor opalladium (1.6 mg, 2.5 μmol) in acetonitrile (2.0 mL) and water (0.20 mL) was stirred at 80°C for 12 hours. After filtration, the solution was concentrated under vacuum, and the residue was purified by preparative thin-layer chromatography (eluent: methylene chloride/methanol=10/1). Thus, ethyl 2-acetylamino-7-[2-(N,N-diethylamino)ethyloxy]-6-(2-me thylthiophenyl)benzo[b]thiophene-3-carboxylate (TMD-517) (18 mg, 73%) was obtained as a brown solid: TLC Rf=0.36 (methylene chloride/methanol=10/1); 1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.2 Hz, 6H), 1.50 (t, J=7.2 Hz, 3H), 2.17 (s, 3H), 2.35-2.42 (m, 5H), 2.61 (t, J=6.8 Hz, 2H), 3.74-2.83 (br, 2H), 4.49 (q, J=7.2 Hz, 2H), 7.20 (ddd, J=1.2, 7.2, 7, 2 Hz, 1H), 7.27-7.39 (m, 4H), 8.03 (d, J=8.0 Hz, 1H), 11.76 (br s, 1H).

Reference： [1]Current Patent Assignee: TOKYO MEDICAL AND DENTAL UNIVERSITY - EP2813226, 2014, A1 Location in patent: Paragraph 0191; 0192

48
[ 381233-96-1 ]
[ 168618-42-6 ]
5-bromo-3-(2'-methylsulfanylphenyl)pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 50℃;Inert atmosphere;	(2-Methylsulfanylphenyl)boronic acid (5.96 mmol, 1.0 g), 5-bromo-3-iodopyridin-2-amine (5.95 mmol, 1.0 g) and K2CO3 (32 mmol, 4.44 g) are dissolved in toluene (40 ml), ethanol (20 ml) and water (10 ml) under argon. The solution is degassed. Pd(PPh3)4 (0.15 mmol, 172 mg) is added and stirring is continued at 50 C over night. After cooling to room temperature the mixture is poured into water (100 ml) and ethyl acetat (50 ml). The layers are separated and the aqueous layer is extracted with ethyl acetate (2 x 100 ml). The combined organic layers are washed with brine and were dried over MgS04. The solvent is removed in vacuo and the curde product is purified via column chromatography with silica and heptane/ethyl acetate 7:3. 5-Bromo-3-(2'-methylsulfanylphenyl)pyridin-2-amine is isolated as yellow solid (1.49 g, 5.05 mmol, 85%). H NMR (CDCb, 300 MHz), delta [ppm] = 5.18 (s, 1 H, - SCHs), 7.17 (dd, 1 H, H-6', 3J = 7.3 Hz, 4J = 1.5 Hz), 7.26 (td, 1 H, H-5', 3J = 7.3 Hz, 4J = 1.5 Hz), 7.32 (d, 1 H, H-3', 3J = 8.1 Hz), 7.44 (td, 1 H, H-4', 3 J = 8.1 Hz, 4J = 1.8 Hz), 7.55 (d, 1 H, H-4, 4J = 2.2 Hz), 8.08 (d, 1 H, H-6, 4J = 2.2 Hz).
74%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene;Inert atmosphere; Reflux;	a) 4.95 g (16.60 mmol) of 5-bromo-3-iodo-pyridin-2-amine, 2.86 g (17.04 mmol) of (2- methylsulfanylphenyl)boronic acid, 6.86 g (50 mmol) of potassium carbonate, 45 ml of toluene, 25 ml of ethanol and 6 ml of water are mixed and evacuated and flushed with argon four times. Then 574 mg (0.03 mmol) of tetrakis triphenyl phosphine palladium are added. The mixture is evacuated and flushed with argon four times and heated to reflux over night while stirring, then cooled to room temperature. The phases are separated and the aqueous phase extracted twice with toluene (50 ml each). The combined organic phases are washed three times with water (30 ml each), dried with magnesium sulfate, filtered and the solvent is evaporated on the rotavap. The crude product (5.1 g) is purified by flash chromatography using heptane/ethyl acetate as eluent yielding 3.6 g (74%) of 5-bromo-3-(2-methylsulfanylphenyl)pyridin-2-amine.

Reference： [1]Patent: WO2015/114102,2015,A1 .Location in patent: Page/Page column 83-84
[2]Patent: WO2015/63046,2015,A1 .Location in patent: Page/Page column 151; 152

49
[ 89827-45-2 ]
[ 168618-42-6 ]
C₁₉H₁₄OS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In ethanol; water; toluene at 120℃; for 3h;	2 Preparation of compound 2-1 After introducing compound 4-bromodibenzofuran (50g, 202.35mmol), 2-methyithiophenylboronic acid (34g, 202.35mmol), tetrakis(triphenylphosphine)palladium (1 1.7g, 10.1 l7mmol), sodium carbonate (64g, 607.O6mmol), toluene (l000mL), ethanol (300mL), and distilled water (300mL) into a reaction vessel, the mixture was stirred at 120°C for 3 hours. After the reaction, the mixture was washed with distilled water, and extracted with ethyl acetate. The extracted organic layer was dried with magnesium sulfate, and the solvent was removed therefrom by a rotary evaporator. The products were purified by column chromatography to obtain compound 2-1 (58g, 99%).

Reference： [1]Current Patent Assignee: DOW INC - WO2015/99507, 2015, A1 Location in patent: Paragraph 238; 239

50
[ 97511-05-2 ]
[ 168618-42-6 ]
4-[2-(methylthio)phenyl]dibenzothiophene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In ethanol; water; toluene at 120℃; for 3h;	1 Preparation of compound 1-1 After introducing compound 4-bromodibenzothiophene (50g, 1 89.98mmol),2-methyithiophenylboronic acid (31 .9g, 189. 89mmol), tetrakis(triphenylphosphine)palladium (1 ig, 9.499mmo1), sodium carbonate (60g, 569.94mmol), toluene (900mL), ethanol (280mL) and distilled water (280mL) into a reaction vessel, the mixture was stirred at 120°C for 3 hours. After the reaction, the mixture was washed with distilled water, and extracted with ethyl acetate. The obtained organic layer was dried with magnesium sulfate, and the solvent was removed therefrom by a rotary evaporator. The products were purified by column chromatography to obtain compound 1-1 (58g, 99%).

Reference： [1]Current Patent Assignee: DOW INC - WO2015/99507, 2015, A1 Location in patent: Paragraph 215; 216

51
[ 915946-48-4 ]
[ 168618-42-6 ]
4-chloro-3-(2-(methylthio)phenyl)-5-phenyl-2,6-dimethylpyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; palladium diacetate In toluene at 90℃; Inert atmosphere;	Arylation of 67: General procedure: A vigorously stirred mixture of 67 (1 equiv), arylboronic acid (1.3 equiv), Pd(OAc)2 (5 mol %), S-Phos (10 mol %) and K3PO4 (3.0 equiv) in toluene (8 ml) was heated at 90 °C (oil bath) under argon atmosphere for 1-3 hours. The reaction was monitored by GC-MS. The mixture was than cooled and quenched with cold water (20 ml). The toluene layer was separated and water layer was additionally extracted with ethyl acetate (2 × 5 ml). The combined organic solutions were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The products were separated and purified by column chromatography.