[ CAS No. 473923-97-6 ] {[proInfo.proName]}

Name: 473923-97-6|3-Chloro-5-hydroxybenzonitrile|98%
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Quality Control of [ 473923-97-6 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 473923-97-6 ]

SDS Specification

Alternatived Products of [ 473923-97-6 ]

Product Details of [ 473923-97-6 ]

CAS No. :	473923-97-6	MDL No. :	MFCD11226540
Formula :	C₇H₄ClNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GHYUOOZZOMUNSY-UHFFFAOYSA-N
M.W :	153.57	Pubchem ID :	21949878
Synonyms :

Calculated chemistry of [ 473923-97-6 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	38.19
TPSA :	44.02 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.31 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.4
Log Po/w (XLOGP3) :	2.71
Log Po/w (WLOGP) :	1.92
Log Po/w (MLOGP) :	1.39
Log Po/w (SILICOS-IT) :	1.96
Consensus Log Po/w :	1.88

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.94
Solubility :	0.175 mg/ml ; 0.00114 mol/l
Class :	Soluble
Log S (Ali) :	-3.29
Solubility :	0.0792 mg/ml ; 0.000515 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.51
Solubility :	0.477 mg/ml ; 0.0031 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.43

Safety of [ 473923-97-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 473923-97-6 ]

* 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 [ 473923-97-6 ]
Downstream synthetic route of [ 473923-97-6 ]

[ 473923-97-6 ] Synthesis Path-Upstream 1~4

1
[ 473923-97-6 ]
[ 1829-33-0 ]

Yield	Reaction Conditions	Operation in experiment
84%	With pyridine; sodium hypophosphite monohydrate; acetic acid In water at 50℃; for 1 h; Inert atmosphere	500 mg (3.27 mmol) of 3-chloro-5-hydroxybenzonitrile are dissolved in a mixture of 4 ml of pyridine/acetic acid/water (2/1/1). 630 mg (6.54 mmol) of sodium hypophosphite monohydrate are added, followed by several drops of Raney nickel in water, and the mixture is stirred at 50°C for 1 hour under argon. After cooling to ambient temperature, the mixture is filtered carefully on Celite and the Celite is washed several times with ethyl acetate. The combined filtrates are evaporated under reduced pressure to give the crude product which is directly purified by flash chromatography on a 60 g silica gel column with an ethyl acetate/hexane mixture as eluent. 426 mg of a white solid are obtained. Yield: 84percent.

Reference： [1] Patent: EP3170822, 2017, A1, . Location in patent: Paragraph 0464-0466

2
[ 473923-96-5 ]
[ 473923-97-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: With lithium iodide In 2,4,6-trimethyl-pyridine at 170℃; for 4 h; Stage #2: With hydrogenchloride In 2,4,6-trimethyl-pyridine; water at 20℃;	A 250 mL flask was charged with 24b (7.0 g, 41.766 mmol) and 2,4,6-collidine (100 mL). The mixture was heated to 170° C. and Lil (16.76 g, 125.298 mmol) was added and the reaction mixture was heated for 4 h. When 24b was consumed the reaction was cooled to RT and quenched with 10percent aqueous HCl. The resulting mixture was extracted with EtOAc and washed with water and brine. The EtOAc extract was dried over (Na₂SO₄) and filtered. The solvent was removed in vacuo to afford a yellow oil which was purified by silica gel chromatography eluting with EtOAc/hexane (10:90) to afford 6.0 g (94percent) of 24c.
94%	at 170℃; for 4 h;	A 250 mL flask was charged with R-3b (7.0 g, 41.766 mmol) and 2,4,6-collidine (100 mL). The mixture was heated to 170° C., LiI (16.76 g, 125.298 mmol) was added and the reaction mixture was heated for 4 h. When R-3b was consumed the reaction was cooled to RT and quenched with 10percent aqueous HCl. The resulting mixture was extracted with EtOAc and washed with water and brine. The EtOAc extract was dried over (Na₂SO₄) and filtered. The solvent was removed in vacuo to afford a yellow oil which was purified by silica gel chromatography eluting with EtOAc/hexane (10:90) to afford 6.0 g (94percent) of R-3c.
94%	at 170℃; for 4 h;	step 2-A 250 mL flask was charged with 5-chloro-3-methoxy-benzonitrile (7.0 g, 41.766 mmol) and 2,4,6-collidine (100 μL). The mixture was heated to 170° C. and LiI (16.76 g, 125.298 mmol) was added and the reaction mixture was heated for 4 h. When R-3b was consumed the reaction was cooled to RT and quenched with 10percent aqueous HCl. The resulting mixture was extracted with EtOAc and washed with water and brine. The EtOAc extract was dried over (Na₂SO₄) and filtered. The solvent was removed in vacuo to afford a yellow oil which was purified by silica gel chromatography eluding with EtOAc/hexane (10:90) to afford 6.0 g (94percent) of 3-chloro-5-hydroxy-benzonitrile.

94%	Stage #1: at 170℃; for 4 h; Stage #2: With hydrogenchloride In water at 20℃;	A 250 mL flask was charged with 5-chloro-3-methoxy-benzonitrile (7.0 g, 41.766 mmol) and 2,4,6-collidine (100 mL). The mixture was heated to 170° C. and LiI (16.76 g, 125.298 mmol) was added and the reaction mixture was heated for 4 h. When R-3b was consumed the reaction was cooled to RT and quenched with 10percent aqueous HCl. The resulting mixture was extracted with EtOAc and washed with water and brine. The EtOAc extract was dried over (Na₂SO₄) and filtered. The solvent was removed in vacuo to afford a yellow oil which was purified by silica gel chromatography eluting with EtOAc/hexane (10:90) to afford 6.0 g (94percent) of 3-chloro-5-hydroxy-benzonitrile.
94%	Stage #1: at 170℃; for 4 h;	step 2-A 250 mL flask was charged with R-3b (7.0 g, 41.766 mmol) and 2,4,6-collidine (100 mL). The mixture was heated to 170° C. and LiI (16.76 g, 125.298 mmol) was added and the reaction mixture was heated for 4 h. When R-3b was consumed the reaction was cooled to RT and quenched with 10percent aqueous HCl. The resulting mixture was extracted with EtOAc and washed with water and brine. The EtOAc extract was dried over (Na₂SO₄) and filtered. The solvent was removed in vacuo to afford a yellow oil which was purified by silica gel chromatography eluting with EtOAc/hexane (10:90) to afford 6.0 g (94percent) of R-3c.
94%	Stage #1: at 170℃; for 4 h; Stage #2: at 20℃;	250 mL flask was charged with 5-chloro-3-methoxy-benzonitrile (7.O g, Al .166 mmol) and 2,4,6-collidine (100 mL). The mixture was heated to 170° C and LiI (16.76 g, 125.298 mmol) was added and the reaction mixture was heated for 4 h. When the methyl ether was consumed the reaction was cooled to RT and quenched with 10percent aqueous HCl. The resulting mixture was extracted with EtOAc and washed with water and brine. The EtOAc extract was dried over (Na₂SO₄) and filtered. The solvent was removed in vacuo to afford a yellow oil which was purified by silica gel chromatography eluting with EtOAc/hexane (10:90) to afford 6.0 g (94percent) of 3-chloro-5-hydroxy- benzonitrile.
91%	at 175℃; for 3 h;	A 250 mL round bottom flask was charged with 43 (4.2 g; 25.05 mmol) and 2,4,6-collidine (60 mL) was added. The mixture was stirred under an argon atmosphere until the solution was homogeneous. Anhydrous lithium iodide (10.06 g; 75.18 mmol) was added and the mixture was heated to 175° C. for 3 h. The reaction mixture was cooled to RT and partitioned between 10percent HCl and EtOAc. The EtOAc phase was washed sequentially with 10percent HCl and brine, dried (Na₂SO₄), filtered and evaporated in vacuo to afford a oil which was crystallized from hexanes to afford 3-chloro-5-hydroxybenzonitrile (44, 3.5 g, 91percent theory).
91%	Stage #1: With lithium iodide In 2,4,6-trimethyl-pyridine at 175℃; for 3 h; Stage #2: With hydrogenchloride In 2,4,6-trimethyl-pyridine; water; ethyl acetate at 20℃;	Step 2 A 250 ML round bottom flask was charged 3-chloro-5-methoxybenzonitrile (4.2 g; 25.05 mmol) and 2,4,6-collidine (60 ML) was added.The mixture was stirred under an argon atmosphere until the solution was homogeneous.anhydrous lithium iodide (10.06 g; 75.18 mmol) was added and the mixture was heated to 175° C. for 3 h.The reaction mixture was cooled to RT and partitioned between 10percent HCl and EtOAc. The EtOAc phase was washed sequentially with 10percent HCl and brine, dried (Na2SO4), filtered and evaporated in vacuo to afford a oil which was crystallized from hexanes to afford 3-chloro-5-hydroxybenzonitrile (130c, 3.5 g, 91percent theory).
76%	Stage #1: at 185℃; for 8 h; Inert atmosphere Stage #2: With hydrogenchloride In waterCooling with ice	3-Chloro-5-methoxybenzonitrile (46.48 g, 277.4 mmol) and anhydrous lithium iodide (60.77 g, 454.4 mmol) were suspended in anhydrous 2,4,6-collidine (200 ml.) and heated at 185 °C for 8 h under dry nitrogen. Upon cooling to rt, the reaction mixture solidified. The solid was broken up and poured onto a slurry of 10percent HCI and ice with additional concentrated HCI added to acidify the mixture. This mixture was extracted with EtOAc (3 x 200 ml_), the organic phases combined, dried over magnesium sulfate, filtered and concentrated to dryness. The resultant solid was triturated in a mixture of hexanes and EtOAc and filtered to afford an off-white solid. A second crop of product was obtained from the filtrate. The two portions were combined and dried under vacuum to afford the title compound (32.40 g, 76percent). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.69 (s, 1 H), 7.37 (t, 1 H), 7.09 - 7.13 (m, 2 H). LCMS m/z = 152.1 (M+H).
76%	Stage #1: at 185℃; for 8 h; Inert atmosphere Stage #2: With hydrogenchloride In waterCooling with ice	3-Chloro-5-methoxybenzonitrile (46.48 g, 277.4 mmol) and anhydrous lithium iodide (60.77 g, 454.4 mmol) were suspended in anhydrous 2,4,6-collidine (200 ml.) and heated at 185 ⁰C for 8 h under dry nitrogen. Upon cooling to rt, the reaction mixture solidified. The solid was broken up and poured onto a slurry of 10percent HCI and ice with additional concentrated HCI added to acidify the mixture. This mixture was extracted with EtOAc (3 x 200 ml_), the organic phases combined, dried over magnesium sulfate, filtered and concentrated to dryness. The resultant solid was triturated in a mixture of hexanes and EtOAc and filtered to afford an off-white solid. A second crop of product was obtained from the filtrate. The two portions were combined and dried under vacuum to afford the title compound (32.40 g, 76percent). ¹H NMR (400 MHz, DMSO-c/₆) δ ppm 10.69 (s, 1 H), 7.37 (t, 1 H), 7.09 - 7.13 (m, 2 H). LCMS m/z = 152.1 (M+H).
76%	at 185℃; for 8 h; Inert atmosphere	3-Chloro-5-(methyloxy)benzonitrile (46.48 g, 277 mmol) and anhydrous LiI (60.77 g, 454.4 mmol) were suspended in anhydrous 2,4,6-collidine (200 mL) under nitrogen and heated to 185 ⁰C for 8 h. The reaction mixture was cooled to RT and solidified upon standing. The solid was broken-up and added to a mixture of 10percent HCI and ice. The solution was extracted with EtOAc (3 X 200 mL), dried over MgSO₄ and evaporated. The solid was triturated in hexanes and EtOAc to afford an off-white solid and a second crop of product was obtained from the filtrate. The combined material was dried under vacuum to afford the title compound (32.40 g, 76percent) as a solid. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 10.69 (s, 1 H), 7.37 (t, 1 H), 7.09 - 7.13 (m, 2 H). MS: m/z 152.1 (M-1 ).

Reference： [1] Patent: US2007/88015, 2007, A1, . Location in patent: Page/Page column 22
[2] Patent: US2008/45511, 2008, A1, . Location in patent: Page/Page column 17-18
[3] Patent: US2008/293664, 2008, A1, . Location in patent: Page/Page column 15
[4] Patent: US2008/249151, 2008, A1, . Location in patent: Page/Page column 20
[5] Patent: US2009/170856, 2009, A1, . Location in patent: Page/Page column 20
[6] Patent: WO2008/145562, 2008, A1, . Location in patent: Page/Page column 30
[7] Patent: US2005/234236, 2005, A1, . Location in patent: Page/Page column 16
[8] Patent: US2004/198736, 2004, A1, . Location in patent: Page/Page column 85
[9] Patent: WO2008/157273, 2008, A1, . Location in patent: Page/Page column 40
[10] Patent: WO2008/157330, 2008, A1, . Location in patent: Page/Page column 38
[11] Patent: WO2008/154271, 2008, A1, . Location in patent: Page/Page column 57
[12] Patent: WO2004/31178, 2004, A1, . Location in patent: Page 27
[13] Patent: WO2004/29051, 2004, A1, . Location in patent: Page 34
[14] Patent: US2006/25462, 2006, A1, . Location in patent: Page/Page column 12

3
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[ 473923-97-6 ]

Reference： [1] Patent: WO2008/145562, 2008, A1,
[2] Patent: WO2008/157330, 2008, A1,
[3] Patent: WO2008/157273, 2008, A1,
[4] Patent: WO2008/154271, 2008, A1,

4
[ 1213790-87-4 ]
[ 473923-97-6 ]

Reference： [1] Organic Process Research and Development, 2010, vol. 14, # 2, p. 477 - 480

[ 473923-97-6 ] Synthesis Path-Downstream 1~16

1
[ 473923-96-5 ]
[ 473923-97-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: 3-chloro-5-methoxybenzonitrile With lithium iodide In 2,4,6-trimethyl-pyridine at 170℃; for 4h; Stage #2: With hydrogenchloride In 2,4,6-trimethyl-pyridine; water at 20℃;	3.2; 3.3 A 250 mL flask was charged with 24b (7.0 g, 41.766 mmol) and 2,4,6-collidine (100 mL). The mixture was heated to 170° C. and Lil (16.76 g, 125.298 mmol) was added and the reaction mixture was heated for 4 h. When 24b was consumed the reaction was cooled to RT and quenched with 10% aqueous HCl. The resulting mixture was extracted with EtOAc and washed with water and brine. The EtOAc extract was dried(Na2SO4) and filtered. The solvent was removed in vacuo to afford a yellow oil which was purified by silica gel chromatography eluting with EtOAc/hexane (10:90) to afford 6.0 g (94%) of 24c.
94%	With 2,4,6-trimethyl-pyridine; lithium iodide at 170℃; for 4h;	A.2 A 250 mL flask was charged with R-3b (7.0 g, 41.766 mmol) and 2,4,6-collidine (100 mL). The mixture was heated to 170° C., LiI (16.76 g, 125.298 mmol) was added and the reaction mixture was heated for 4 h. When R-3b was consumed the reaction was cooled to RT and quenched with 10% aqueous HCl. The resulting mixture was extracted with EtOAc and washed with water and brine. The EtOAc extract was dried(Na2SO4) and filtered. The solvent was removed in vacuo to afford a yellow oil which was purified by silica gel chromatography eluting with EtOAc/hexane (10:90) to afford 6.0 g (94%) of R-3c.
94%	With 2,4,6-trimethyl-pyridine; lithium iodide at 170℃; for 4h;	1.2 step 2-A 250 mL flask was charged with 5-chloro-3-methoxy-benzonitrile (7.0 g, 41.766 mmol) and 2,4,6-collidine (100 μL). The mixture was heated to 170° C. and LiI (16.76 g, 125.298 mmol) was added and the reaction mixture was heated for 4 h. When R-3b was consumed the reaction was cooled to RT and quenched with 10% aqueous HCl. The resulting mixture was extracted with EtOAc and washed with water and brine. The EtOAc extract was dried(Na2SO4) and filtered. The solvent was removed in vacuo to afford a yellow oil which was purified by silica gel chromatography eluding with EtOAc/hexane (10:90) to afford 6.0 g (94%) of 3-chloro-5-hydroxy-benzonitrile.

94%	Stage #1: 3-chloro-5-methoxybenzonitrile With 2,4,6-trimethyl-pyridine; lithium iodide at 170℃; for 4h; Stage #2: With hydrogenchloride In water at 20℃;	2.2 A 250 mL flask was charged with 5-chloro-3-methoxy-benzonitrile (7.0 g, 41.766 mmol) and 2,4,6-collidine (100 mL). The mixture was heated to 170° C. and LiI (16.76 g, 125.298 mmol) was added and the reaction mixture was heated for 4 h. When R-3b was consumed the reaction was cooled to RT and quenched with 10% aqueous HCl. The resulting mixture was extracted with EtOAc and washed with water and brine. The EtOAc extract was dried(Na2SO4) and filtered. The solvent was removed in vacuo to afford a yellow oil which was purified by silica gel chromatography eluting with EtOAc/hexane (10:90) to afford 6.0 g (94%) of 3-chloro-5-hydroxy-benzonitrile.
94%	Stage #1: 3-chloro-5-methoxybenzonitrile With 2,4,6-trimethyl-pyridine; lithium iodide at 170℃; for 4h; Stage #2: With hydrogenchloride; water	A.2 step 2-A 250 mL flask was charged with R-3b (7.0 g, 41.766 mmol) and 2,4,6-collidine (100 mL). The mixture was heated to 170° C. and LiI (16.76 g, 125.298 mmol) was added and the reaction mixture was heated for 4 h. When R-3b was consumed the reaction was cooled to RT and quenched with 10% aqueous HCl. The resulting mixture was extracted with EtOAc and washed with water and brine. The EtOAc extract was dried(Na2SO4) and filtered. The solvent was removed in vacuo to afford a yellow oil which was purified by silica gel chromatography eluting with EtOAc/hexane (10:90) to afford 6.0 g (94%) of R-3c.
94%	Stage #1: 3-chloro-5-methoxybenzonitrile With 2,4,6-trimethyl-pyridine; lithium iodide at 170℃; for 4h; Stage #2: With hydrogenchloride; water at 20℃;	1.2 250 mL flask was charged with 5-chloro-3-methoxy-benzonitrile (7.O g, Al .166 mmol) and 2,4,6-collidine (100 mL). The mixture was heated to 170° C and LiI (16.76 g, 125.298 mmol) was added and the reaction mixture was heated for 4 h. When the methyl ether was consumed the reaction was cooled to RT and quenched with 10% aqueous HCl. The resulting mixture was extracted with EtOAc and washed with water and brine. The EtOAc extract was dried(Na2SO4) and filtered. The solvent was removed in vacuo to afford a yellow oil which was purified by silica gel chromatography eluting with EtOAc/hexane (10:90) to afford 6.0 g (94%) of 3-chloro-5-hydroxy- benzonitrile.
91%	With 2,4,6-trimethyl-pyridine; lithium iodide at 175℃; for 3h;	5.1 A 250 mL round bottom flask was charged with 43 (4.2 g; 25.05 mmol) and 2,4,6-collidine (60 mL) was added. The mixture was stirred under an argon atmosphere until the solution was homogeneous. Anhydrous lithium iodide (10.06 g; 75.18 mmol) was added and the mixture was heated to 175° C. for 3 h. The reaction mixture was cooled to RT and partitioned between 10% HCl and EtOAc. The EtOAc phase was washed sequentially with 10% HCl and brine, dried (Na2SO4), filtered and evaporated in vacuo to afford a oil which was crystallized from hexanes to afford 3-chloro-5-hydroxybenzonitrile (44, 3.5 g, 91% theory).
91%	Stage #1: 3-chloro-5-methoxybenzonitrile With lithium iodide In 2,4,6-trimethyl-pyridine at 175℃; for 3h; Stage #2: With hydrogenchloride In 2,4,6-trimethyl-pyridine; water; ethyl acetate at 20℃;	35.2 Step 2 Step 2 A 250 ML round bottom flask was charged 3-chloro-5-methoxybenzonitrile (4.2 g; 25.05 mmol) and 2,4,6-collidine (60 ML) was added.The mixture was stirred under an argon atmosphere until the solution was homogeneous.anhydrous lithium iodide (10.06 g; 75.18 mmol) was added and the mixture was heated to 175° C. for 3 h.The reaction mixture was cooled to RT and partitioned between 10% HCl and EtOAc. The EtOAc phase was washed sequentially with 10% HCl and brine, dried (Na2SO4), filtered and evaporated in vacuo to afford a oil which was crystallized from hexanes to afford 3-chloro-5-hydroxybenzonitrile (130c, 3.5 g, 91% theory).
76%	Stage #1: 3-chloro-5-methoxybenzonitrile With 2,4,6-trimethyl-pyridine; lithium iodide at 185℃; for 8h; Inert atmosphere; Stage #2: With hydrogenchloride In water Cooling with ice;	3.B 3-Chloro-5-methoxybenzonitrile (46.48 g, 277.4 mmol) and anhydrous lithium iodide (60.77 g, 454.4 mmol) were suspended in anhydrous 2,4,6-collidine (200 ml.) and heated at 185 °C for 8 h under dry nitrogen. Upon cooling to rt, the reaction mixture solidified. The solid was broken up and poured onto a slurry of 10% HCI and ice with additional concentrated HCI added to acidify the mixture. This mixture was extracted with EtOAc (3 x 200 ml_), the organic phases combined, dried over magnesium sulfate, filtered and concentrated to dryness. The resultant solid was triturated in a mixture of hexanes and EtOAc and filtered to afford an off-white solid. A second crop of product was obtained from the filtrate. The two portions were combined and dried under vacuum to afford the title compound (32.40 g, 76%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.69 (s, 1 H), 7.37 (t, 1 H), 7.09 - 7.13 (m, 2 H). LCMS m/z = 152.1 (M+H).
76%	Stage #1: 3-chloro-5-methoxybenzonitrile With 2,4,6-trimethyl-pyridine; lithium iodide at 185℃; for 8h; Inert atmosphere; Stage #2: With hydrogenchloride In water Cooling with ice;	3.B 3-Chloro-5-methoxybenzonitrile (46.48 g, 277.4 mmol) and anhydrous lithium iodide (60.77 g, 454.4 mmol) were suspended in anhydrous 2,4,6-collidine (200 ml.) and heated at 185 0C for 8 h under dry nitrogen. Upon cooling to rt, the reaction mixture solidified. The solid was broken up and poured onto a slurry of 10% HCI and ice with additional concentrated HCI added to acidify the mixture. This mixture was extracted with EtOAc (3 x 200 ml_), the organic phases combined, dried over magnesium sulfate, filtered and concentrated to dryness. The resultant solid was triturated in a mixture of hexanes and EtOAc and filtered to afford an off-white solid. A second crop of product was obtained from the filtrate. The two portions were combined and dried under vacuum to afford the title compound (32.40 g, 76%). 1H NMR (400 MHz, DMSO-c/6) δ ppm 10.69 (s, 1 H), 7.37 (t, 1 H), 7.09 - 7.13 (m, 2 H). LCMS m/z = 152.1 (M+H).
76%	With 2,4,6-trimethyl-pyridine; lithium iodide at 185℃; for 8h; Inert atmosphere;	12.B 3-Chloro-5-(methyloxy)benzonitrile (46.48 g, 277 mmol) and anhydrous LiI (60.77 g, 454.4 mmol) were suspended in anhydrous 2,4,6-collidine (200 mL) under nitrogen and heated to 185 0C for 8 h. The reaction mixture was cooled to RT and solidified upon standing. The solid was broken-up and added to a mixture of 10% HCI and ice. The solution was extracted with EtOAc (3 X 200 mL), dried over MgSO4 and evaporated. The solid was triturated in hexanes and EtOAc to afford an off-white solid and a second crop of product was obtained from the filtrate. The combined material was dried under vacuum to afford the title compound (32.40 g, 76%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 10.69 (s, 1 H), 7.37 (t, 1 H), 7.09 - 7.13 (m, 2 H). MS: m/z 152.1 (M-1 ).
	With boron trichloride; tetra-(n-butyl)ammonium iodide In dichloromethane at -78 - 20℃; for 14h;	5 Preparation 5 Preparation 5 [3-CHLORO-5-HYDROXYBENZONITRILE] Boron trichloride (1. 0M solution in dichloromethane, 26.0 ml, 26.0 [MMOL)] was added dropwise to a stirred solution of the nitrile of Preparation 3 (1.80 g, 10.0 [MMOL)] and tetrabutylammonium iodide (4.36 g, 11.0 [MMOL)] in [DICHLOROMETHANE] (50 ml) [AT-78°C.] The reaction mixture was warmed to room temperature and stirred for 14 hours. The reaction mixture was cooled to [0°C] and ice and dichloromethane (100 [ML)] were added. The organic phase was washed with water [(3X40] [ML)] and brine (40 [ML),] dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using ethyl acetate in cyclohexane as eluant (20: 80) to give the title compound as a white solid (900 mg).[H-NMR (400MHZ, DMSO-D6)] : 87. 12 (m, 2H), 7.38 (s, [1H),] 10.65 (s, 1H). Microanalysis : Found: C, 54.76 ; H, 2.81 ; N, 8.94. [C7H4CINO] requires; C, 54.75 ; H, 2.63 ; N, 9. [12%.]
	With boron trichloride; tetra-(n-butyl)ammonium iodide In dichloromethane at -78 - 20℃; for 14h;	8 Boron trichloride (1. 0M solution in [DICHLOROMETHANE,] 26.0 [ML,] 26.0 [MMOL)] was added dropwise to a stirred solution of the nitrile of Preparation 7 (1.80 g, 10.0 [MMOL)] and tetrabutylammonium iodide (4.36 g, 11.0 [MMOL)] in [DICHLOROMETHANE] (50 [ML) AT-78°C.] The reaction mixture was warmed to room temperature and stirred for 14 hours. The reaction mixture was cooled to [0°C] and ice and [DICHLOROMETHANE] (100 ml) were added. The organic phase was washed with water [(3X40] [ML)] and brine (40 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using ethyl acetate in cyclohexane as eluant (20: 80) to give the title compound as a white solid (900 mg). [1H-NMR] [(400MHZ,] DMSO d6) : [8 7.] 12 (m, 2H), 7.38 (s, [1H),] 10.65 (s, [1H).] Microanalysis : Found: C, 54.76 ; H, 2.81 ; N, 8.94. [C7H4CINO] requires; C, 54.75 ; H, 2.63 ; N, 9.12%.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2007/88015, 2007, A1 Location in patent: Page/Page column 22
[2]Current Patent Assignee: ROCHE HOLDING AG - US2008/45511, 2008, A1 Location in patent: Page/Page column 17-18
[3]Current Patent Assignee: ROCHE HOLDING AG - US2008/293664, 2008, A1 Location in patent: Page/Page column 15
[4]Current Patent Assignee: ROCHE HOLDING AG - US2008/249151, 2008, A1 Location in patent: Page/Page column 20
[5]Current Patent Assignee: ROCHE HOLDING AG - US2009/170856, 2009, A1 Location in patent: Page/Page column 20
[6]Current Patent Assignee: ROCHE HOLDING AG - WO2008/145562, 2008, A1 Location in patent: Page/Page column 30
[7]Current Patent Assignee: ROCHE HOLDING AG - US2005/234236, 2005, A1 Location in patent: Page/Page column 16
[8]Current Patent Assignee: ROCHE HOLDING AG - US2004/198736, 2004, A1 Location in patent: Page/Page column 85
[9]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2008/157273, 2008, A1 Location in patent: Page/Page column 40
[10]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2008/157330, 2008, A1 Location in patent: Page/Page column 38
[11]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2008/154271, 2008, A1 Location in patent: Page/Page column 57
[12]Current Patent Assignee: PFIZER INC - WO2004/31178, 2004, A1 Location in patent: Page 27
[13]Current Patent Assignee: PFIZER INC - WO2004/29051, 2004, A1 Location in patent: Page 34
[14]Current Patent Assignee: ROCHE HOLDING AG - US2006/25462, 2006, A1 Location in patent: Page/Page column 12

2
[ 473923-97-6 ]
[ 644985-24-0 ]
[ 867366-95-8 ]

Yield	Reaction Conditions	Operation in experiment
83%	With propyl cyanide; potassium carbonate; for 4.5h;Heating / reflux;	To a solution of 3-chloro-5-hydroxy-benzonitrile (3.84 g), K2CO3 powder (4.2 g) and n-butyl nitrile was added 54d (5.57 g). The reaction mixture was heated to reflux for 4.5 h when the reaction appeared complete by gc/ms. The reaction mixture was cooled and poured into water and then EtOAc was added. The resulting mixture was allowed to stand until the layers separated. Some crystals were present at the interface and along the walls of the upper layer which were filtered and washed with water and hexanes. The filtrate was evaporated in vacuo, the residue taken up in IPA and re-evaporated. The solid was triturated with hexane and filtered. The mother liquor was evaporated and the residue purified by SiO2 chromatography eluting with hexane/EtOAc (80:20). The product was triturated with IPA, filtered and washed with hexanes and the product fractions combined to afford 1.45 g (83%) of 56a
83%	With potassium carbonate; In 1-nitrobutane; for 4.5h;Heating / reflux;	To a solution of R-3c (3.84 g), K2CO3 powder (4.2 g) and n-butyl nitrile was added R-43d (5.57 g). The reaction mixture was heated to reflux for 4.5 h when the reaction appeared complete by gc/ms. The reaction mixture was cooled and poured into water and then EtOAc was added. The resulting mixture was allowed to stand until the layers separated. Some crystals were present at the interface and along the walls of the upper layer which were filtered and washed with water and hexanes. The filtrate was evaporated in vacuo, the residue taken up in IPA and re-evaporated. The solid was triturated with hexane and filtered. The mother liquor was evaporated and the residue purified by SiO2 chromatography eluting with hexane/EtOAc (80:20). The product was triturated with IPA, filtered and washed with hexanes and the product fractions combined to afford 1.45 g (83%) of R-44a.
83%	With propyl cyanide; potassium carbonate; for 4.5h;	step 4-To a solution of 3-chloro-5-hydroxy-benzonitrile (3.84 g), K2CO3 powder (4.2 g) and n-butyl nitrile was added R-43d (5.57 g). The reaction mixture was heated to reflux for 4.5 h when the reaction appeared complete by gc/ms. The reaction mixture was cooled and poured into water and then EtOAc was added. The resulting mixture was allowed to stand until the layers separated. Some crystals were present at the interface and along the walls of the upper layer which were filtered and washed with water and hexanes. The filtrate was evaporated in vacuo, the residue taken up in IPA and re-evaporated. The solid was triturated with hexane and filtered. The mother liquor was evaporated and the residue purified by SiO2 chromatography eluting with hexane/EtOAc (80:20). The product was triturated with IPA, filtered and washed with hexanes and the product fractions combined to afford 1.45 g (83%) of R-44a.

83%	With 1-nitrobutane; potassium carbonate; for 4.5h;Heating / reflux;	step 4-To a solution of 3-chloro-5-hydroxy-benzonitrile (3.84 g), K2CO3 powder (4.2 g) and n-butyl nitrile was added 23d (5.57 g). The reaction mixture was heated to reflux for 4.5 h when the reaction appeared complete by gc/ms. The reaction mixture was cooled and poured into water and then EtOAc was added. The resulting mixture was allowed to stand until the layers separated. Some crystals were present at the interface and along the walls of the upper layer which were filtered and washed with water and hexanes. The filtrate was evaporated in vacuo, the residue taken up in IPA and re-evaporated. The solid was triturated with hexane and filtered. The mother liquor was evaporated and the residue purified by SiO2 chromatography eluting with hexane/EtOAc (80:20). The product was triturated with IPA, filtered and washed with hexanes and the product fractions combined to afford 1.45 g (83%) of 24a.
83%	With potassium carbonate; In 1-nitrobutane; for 4.5h;Heating / reflux;	step 4-; To a solution of 3-chloro-5-hydroxy-benzonitrile (3.84 g), K2CO3 powder (4.2 g) and n-butyl nitrile was added 1d (5.57 g). The reaction mixture was heated to reflux for 4.5 h when the reaction appeared complete by gc/ms. The reaction mixture was cooled and poured into water EtOAc was added. The resulting mixture was allowed to stand until the layers separated. Some crystals were present at the interface and along the walls of the upper layer which were filtered and washed with water and hexanes. The filtrate was evaporated in vacuo, the residue taken up in IPA and re-evaporated. The solid was triturated with hexane and filtered. The mother liquor was evaporated and the residue purified by SiO2 chromatography eluting with hexane/EtOAc (80:20). The product was triturated with IPA, filtered and washed with hexanes and the product fractions combined to afford 1.45 g (83%) of 2a.

Reference： [1]Patent: US2005/239881,2005,A1 .Location in patent: Page/Page column 50
[2]Patent: US2008/45511,2008,A1 .Location in patent: Page/Page column 23-24
[3]Patent: US2009/170856,2009,A1 .Location in patent: Page/Page column 26
[4]Patent: US2006/25462,2006,A1 .Location in patent: Page/Page column 11; 21
[5]Patent: US2006/223874,2006,A1 .Location in patent: Page/Page column 5; 9

3
[ 473923-97-6 ]
[ 156682-52-9 ]
[ 1007571-62-1 ]

Yield	Reaction Conditions	Operation in experiment
82%		Preparation of tert-butyl 3-[4-Bromo-3-(3-chloro-5-cyano-phenoxy)-2-fluoro-phenyl]-propionate (Step Numbers Refer to Scheme B)step 1-To a solution 3-chloro-5-hydroxy-benzonitrile (153 mg, 1 mmol) and DMA (1 muL) was added NaH (42 mg, 1.05 equiv., 60% mineral oil dispersion) and the resulting mixture was stirred at 50 C. for 30 min. To the solution was added B-1 (2.7 g, 10 mmol) and the resulting mixture was heated at 125 C. for 2 h. The solution was cooled and diluted with EtOAc and the resulting solution washed with an equal volume of 10% H2SO4. The organic extract was dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with 10% EtOAc/hexane to afford 331 mg (82%) of B-2a (Ar=3-chloro-5-cyano-phenyl).
82%		To a solution 3-chloro-5-hydroxy-benzonitrile (153 mg, 1 mmol) and DMA (1 mL) was added NaH (42 mg, 1.05 equiv., 60% mineral oil dispersion) and the resulting mixture was stirred at 50 C. for 30 min. To the solution was added A-1 (2.7 g, 10 mmol) and the resulting mixture was heated at 125 C. for 2 h. The solution was cooled and diluted with EtOAc and the resulting solution washed with an equal volume of 10% H2SO4. The organic extract was dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with 10% EtOAc/hexane to afford 331 mg (82%) of A-2a.
82%		To a solution 3-chloro-5-hydroxy-benzonitrile (153 mg, 1 mmol) and DMA (1 mL) was added NaH (42 mg, 1.05 equiv., 60% mineral oil dispersion) and the resulting mixture was stirred at 50 C for 30 min. To the solution was added A-I (2.7 g, 10 mmol) and the resulting mixture was heated at 125 C for 2 h. The solution was cooled and diluted with EtOAc and the resulting solution washed with an equal volume of 10% H2SO4. The organic extract was dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with 10% EtOAc/hexane to afford 331 mg (82%) of A-2a.

Reference： [1]Patent: US2008/293664,2008,A1 .Location in patent: Page/Page column 18
[2]Patent: US2009/12034,2009,A1 .Location in patent: Page/Page column 13
[3]Patent: WO2008/145562,2008,A1 .Location in patent: Page/Page column 20; 30

4
[ 473923-97-6 ]
[ 79562-49-5 ]
[ 1068604-80-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In tetrahydrofuran; at 50 - 70℃; for 27.5h;	To a solution of 59 (0.75 g, 4.9 mmol), 58 (0.86 g, 4.9 mmol), K2CO3 (1.01 g, 7.35 mmol) and THF (12 mL) was heated to 50 C. and stirred under a N2 atmosphere. After 2 h one addition equivalent of K2CO3 was and heating continued overnight. After 22 h excess K2CO3 was added and the temperature raised to 70 C. After 3.5 h the solution was cooled and sat'd aqueous NH4Cl and EtOAc were added. The EtOAc layer was separated, washed with brine, dried, filtered and evaporated to afford 1.2 g of 60a.

Reference： [1]Patent: US2008/249151,2008,A1 .Location in patent: Page/Page column 28-29

5
[ 3512-17-2 ]
[ 473923-97-6 ]
[ 1155847-15-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at -50 - 26℃;	Step 1: 3-chloro-5-[(2,6-difluoropyridin-4-yl)oxy]benzonitrile (8-1) Compound 1-4 (577 mg; 3.76 mmol) and potassium carbonate (779 mg; 5.64 mmol) were added to a solution of 2,4,6 trifluoropyridine (500 mg; 3.76 mmol) in DMF with stirring at -5O0C. The reaction mixture was slowly warmed to room temperature and then diluted water and EtOAc, after which the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water (3x), brine (2x), dried over MgStheta4, and concentrated to an oil. The crude residue was purified via column chromatography (0-25% EtOAc in hexanes.) to give the title compound. MS M+l = 266.9. lH NMR (CDCI3): 6.32 (m, 2H), 7.30 (m, IH),7.36 (m, IH), 7.56 (m, IH).

Reference： [1]Patent: WO2009/67166,2009,A2 .Location in patent: Page/Page column 93

6
[ 473923-97-6 ]
[ 2879-42-7 ]
[ 1155846-91-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at -40 - 26℃; for 2.5h;	A solution of 3-chloro-5-cyanophenol (1-4; 218 mg; 1.41 mmol) and 3-chloro- 2,5,6-trifluoropyridine (1-5; 250 mg; 1.49 mmol) in anhydrous DMF (2 mL) was cooled to -4O0C under a nitrogen atmosphere. The reaction mixture was then treated with 260 mg (1.94 mmol) of anhydrous potassium carbonate added in one portion, and the reaction mixture was vigorously stirred and allowed to warm to room temperature slowly over 90 minutes. The reaction mixture was then stirred for another hour at room temperature. The reaction mixture was diluted with a large excess of water, and a thick precipitate formed. After trituration, the suspension was filtered and the solid dried to give the title compound as an off white amorphous solid. lH NMR (CDCI3): 7.91 (m,2H), 7.99(t,lH), 8.60(q,lH). MS M+l = 302.

Reference： [1]Patent: WO2009/67166,2009,A2 .Location in patent: Page/Page column 77

7
[ 3512-13-8 ]
[ 473923-97-6 ]
[ 1210835-59-8 ]

Yield	Reaction Conditions	Operation in experiment
61%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 1h;	To <strong>[3512-13-8]2,3,4,6-tetrafluoropyridine</strong> (5.9 g, 39 mmol) in DMF (20 mL) at r.t, 3-chloro-5-cyanophenol (6.0 g, 20 mmol) was added, followed by potassium carbonate (7.0 g, 51 mmol). Stirred for 1 h. Partitioned between ethyl acetate and water, organic layer washed with brine, water, dried over sodium sulfate, concentrated. Purified by flash column, eluted with 0% to 10% ethyl acetate in Hexane, obtained white solid 6.7 g, yield 61%.

Reference： [1]Patent: US2010/56535,2010,A1 .Location in patent: Page/Page column 27

8
[ 473923-97-6 ]
[ 34667-88-4 ]
C₁₄H₆ClN₃O₃ [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2011,vol. 133,p. 15686 - 15696

9
[ 473923-97-6 ]
[ 243128-37-2 ]
[ 895572-19-7 ]

Yield	Reaction Conditions	Operation in experiment
23%	With potassium carbonate; In dimethyl sulfoxide; at 130℃; for 5h;	General procedure: A mixture of the commercially available phenol (3.0 mmol), <strong>[243128-37-2]4-fluoro-3-methoxybenzonitrile</strong> (57) (0.47 g, 6.0 mmol) in DMSO (4.0 mL) and anhydrous K2C03 (0.62 g, 4.5 mmol) was heated at 130 C for 5 h. The reaction mixture was poured into ice water and extracted with EtOAc (3 x 50 mL). The organic layer was sequentially washed with brine (2 x 75 mL), dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by column chromatography to give 66 a-f. 4-(3-chloro-5-cyanophenoxy)-3-methoxybenzonitrile (66 a): yield (0.2 g, 23 %) .H NMR(500 MHz, CDC13) delta 7.39 - 7.32 (m, 2H), 7.30 (t, J= 4.69 Hz, 1H), 7.17 - 7.10 (m, 2H), 7.05 (dd, J= 1.31, 2.33 Hz, 1H), 3.78 (s, 3H). 13C NMR (126 MHz, DMSO) delta 163.73, 151.12, 145.96, 130.20, 124.24, 123.89, 122.06, 117.04, 115.54, 114.40, 100.50, 66.76, 47.15. LRMS (ES) calcd for C15H9C1N202 289.4, found 289.2 [M]+.

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 8582 - 8591
[2]Patent: WO2013/56003,2013,A2 .Location in patent: Page/Page column 59-60

10
[ 473923-97-6 ]
[ 74-88-4 ]
[ 473923-96-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In acetone at 70℃;	11 Synthesis of Intermediate (1) Molecular Weight: 153.6 Molecular Weight: 167.6[00311] In a 3-neck 100 mL round-bottomed flask, 3 -Chloro-5 -hydroxy benzonitrile(5.0 g, 1.0 eq) was dissolved in Acetone(50 mL). CH3I(9.27 g, 2.0 eq) and K2C03(6.68 g, 1.5 eq) was added to this reaction mixture. Reaction mixture was heated at 70 C for 3-4 h. Theprogress of reaction was followed by TLC using ethyl acetate: hexane (1 : 1) as mobile phase. The resulting slurry was poured in 100 mL water and compound was extracted in the Ethyl acetate (25 mL x 3). Organic layer was washed with brine solution (25 mL x 3) followed by drying using anhydrous sodium sulphate. Organic layer was concentrated under reduced pressure to afford 5 gof crude compound. Yield (92.08 %). Mass/LCMS: Confirmed.
	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 4h; Inert atmosphere;	14.1 Step 1: 3-Chloro-5-methoxybenzonitrile 3-Chloro-5-hydroxybenzonitrile (1.302 mmol, 0.200 g), potassium carbonate (2.600 mmol, 0.360 g), N,N-dimethyl formamide (4 ml) and iodomethane (26.0 mmol, 3.700 g) were added into a flask under nitrogen atmosphere. The resulting mixture was stirred for 4 h at 70 °C. The solvent was evaporated, the residue was dissolved in dichloromethane and washed with water. The water phase was washed twice with dichloromethane. The organic phases were separated and evaporated. 0.185 g of the title compound was obtained. 1H NMR (400 MHz, CDCl3) δ ppm 3.84 (s, 3 H) 6.96 - 7.29 (m, 3 H).
	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 4h; Inert atmosphere;	1 Intermediate 14: (3-ChIoro-5-methoxyphenyl)methanamineStep 1: 3-Chloro-5-methoxybenzonitrile 3-Chloro-5-hydroxybenzonitrile (1.302 mmol, 0.200 g), potassium carbonate (2.600 mmol, 0.360 g), Ν,Ν-dimethyl formamide (4 ml) and iodomethane (26.0 mmol, 3.700 g) were added into a flask under nitrogen atmosphere. The resulting mixture was stirred for 4 h at 70 °C. The solvent was evaporated, the residue was dissolved in dichloromethane and washed with water. The water phase was washed twice with dichloromethane. The organic phases were separated and evaporated. 0.185 g of the title compound was obtained.1H NMR (400 MHz, CDC13) δ ppm 3.84 (s, 3 H) 6.96 - 7.29 (m, 3 H).

Reference： [1]Current Patent Assignee: KARYOPHARM THERAPEUTICS INC - WO2011/109799, 2011, A1 Location in patent: Page/Page column 115-116
[2]Current Patent Assignee: ORION OYJ - EP2520566, 2012, A1 Location in patent: Page/Page column 17
[3]Current Patent Assignee: ORION OYJ - WO2012/152983, 2012, A1 Location in patent: Page/Page column 32-33

11
[ 473923-97-6 ]
[ 1114809-02-7 ]
[ 1360621-07-3 ]

Reference： [1]Organic Process Research and Development,2012,vol. 16,p. 605 - 611

12
[ 6575-00-4 ]
[ 473923-97-6 ]

Reference： [1]Patent: WO2008/145562,2008,A1
[2]Patent: WO2008/157330,2008,A1
[3]Patent: WO2008/157273,2008,A1
[4]Patent: WO2008/154271,2008,A1

13
[ 473923-97-6 ]
[ 1338225-97-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide; water / 12 h / 50 °C / Inert atmosphere 2.1: potassium 2-methylbutan-2-olate / toluene 2.2: 0.23 h / -10 - 10 °C 3.1: ammonia / methanol; toluene / 18 h / 60 °C 4.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one; tert-Amyl alcohol / 22 h / 20 °C / Large scale
	Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide; water / 12 h / 50 °C 2.1: potassium 2-methylbutan-2-olate; triethylamine / toluene / -20 °C / Flow reactor; Large scale 2.2: 6 - 8 °C / Flow reactor; Large scale 3.1: ammonia / methanol / 6 h / 60 °C / 310.3 - 2637.52 Torr / Autoclave; Large scale 4.1: N-ethyl-N,N-diisopropylamine; 1-methyl-pyrrolidin-2-one / tert-Amyl alcohol / 22 h / 20 °C / Large scale
	Multi-step reaction with 5 steps 1.1: potassium carbonate / acetone / 4 h / 50 - 55 °C 2.1: sodium hexamethyldisilazane / toluene / 0.5 h / -15 - -10 °C 2.2: -10 - 0 °C 3.1: triethylamine; trifluoroacetic anhydride / toluene / 1.25 h / 30 °C 4.1: ammonia / methanol / 12 h / 80 °C 5.1: N-ethyl-N,N-diisopropylamine; 1-methyl-pyrrolidin-2-one / tert-Amyl alcohol / 22 h / 20 °C / Large scale

Multi-step reaction with 5 steps 1: N-ethyl-N,N-diisopropylamine / water; N,N-dimethyl-formamide / 12 h / 50 °C / Inert atmosphere 2: potassium 2-methylbutan-2-olate / toluene / 20 h / -10 °C 3: triethylamine; trifluoroacetic anhydride / toluene; methanol / 10 - 20 °C 4: ammonia / toluene; methanol / 18 h / 60 °C 5: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one; tert-Amyl alcohol / 22 h / 20 °C / Large scale

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2014/89140, 2014, A1
[2]Gauthier, Donald R.; Sherry, Benjamin D.; Cao, Yang; Journet, Michel; Humphrey, Guy; Itoh, Tetsuji; Mangion, Ian; Tschaen, David M. [Organic Letters, 2015, vol. 17, # 6, p. 1353 - 1356]
[3]Gauthier, Donald R.; Sherry, Benjamin D.; Cao, Yang; Journet, Michel; Humphrey, Guy; Itoh, Tetsuji; Mangion, Ian; Tschaen, David M. [Organic Letters, 2015, vol. 17, # 6, p. 1353 - 1356]
[4]Current Patent Assignee: MERCK & CO INC - WO2015/84763, 2015, A2

14
[ 473923-97-6 ]
[ 16420-13-6 ]
O-(3-chloro-5-cyanophenyl) N,N-dimethylcarbamothioate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With dmap; triethylamine In ethyl acetate at 55 - 60℃; for 24h;	1 Step 1:0-(3-chloro-5-cyanophenyl) dimethylcarbamothioate 38.9 mL (279 mmol) triethylamine, 1.14 g (9.3 mmol) N,N-dimethylpyridin-4-amine (DMAP) and 13.8 g (112 mmol) dimethylcarbamothioyl chloride were successively added to a vigorously stirred suspension of 14.3 g (93 mmol) 3-chloro-5-hydroxybenzonitrile in 450 mL anhydrous EtOAc. The reaction mixture was brought to 55-60°C and was stirred at this temperature for 24 h. After cooling down to room temperature the reaction mixture was washed with 450 mL water and 450 mL brine. The organic layer was separated, dried over Na2S04 and filtered. The filtrate was concentrated in vacuo to a volume of about 50 mL. The concentrate was diluted with 150 mL n-hexane, the precipitate formed was filtered off, washed with 150 mL of a 1 : 1 mixture diethyl ether and n-hexane and vacuum dried at 60 °C (1 tor, 3 h) to give 9.3 g (86%) of 0-(3-chloro-5-cyanophenyl) dimethylcarbamothioate as colorless crystals. NMR (400 MHz, CDC13) d: 3.35 (s, 3H), 3.46 (s, 3H), 7.30 (s, 1H), 7.35 (s, 1H), 7.53 (s, 1H) (measured on a Varian Gemini 2000 machine).
86%	With dmap; triethylamine In ethyl acetate at 55 - 60℃; for 24h;	1 0-(3-chloro-5-cyanophenyl) dimethylcarbamothioate 38.9 mL (279 mmol) triethylamine, 1.14 g (9.3 mmol) N,N-dimethylpyridin-4-amine (DMAP) and 13.8 g (112 mmol) dimethylcarbamothioyl chloride were successively added to a vigorously stirred suspension of 14.3 g (93 mmol) 3-chloro-5-hydroxybenzonitrile in 450 mL anhydrous EtOAc. The reaction mixture was brought to 55-60°C and was stirred at this temperature for 24 h. After cooling down to room temperature the reaction mixture was washed with 450 mL water and 450 mL brine. The organic layer was separated, dried over Na3SC>4 and filtered. The filtrate was concentrated in vacuo to a volume of about 50 mL. The concentrate was diluted with 150 mL n-hexane, the precipitate formed was filtered off, washed with 150 mL of a 1:1 mixture diethyl ether and n-hexane and vacuum dried at 60 °C (1 tor, 3 h) to give 9.3 g (86%) of 0-(3-chloro-5-cyanophenyl) dimethylcarbamothioate as colorless crystals. NMR (400 MHz, CDC13) d: 3.35 (s, 3H), 3.46 (s, 3H), 7.30 (s, 1H), 7.35 (s, 1H), 7.53 (s, 1H) (measured on a Varian Gemini 2000 machine).
86%	With dmap; triethylamine In ethyl acetate at 55 - 60℃; for 24h;	Step 1: 0-(3-chloro-5-cyanophenyl) dimethylcarbamothioate 38.9 mL (279 mmol) triethylamine, 1. 14 g (9.3 mmol) N,N-dimethylpyridin-4-amine (DMAP) and 13.8 g (112 mmol) dimethylcarbamothioyl chloride were successively added to a vigorously stirred suspension of 14.3 g (93 mmol) 3-chloro-5-hydroxybenzonitrile in 450 mL anhydrous EtOAc. The reaction mixture was brought to 55-60°C and was stirred at this temperature for 24 h. After cooling down to room temperature the reaction mixture was washed with 450 mL water and 450 mL brine. The organic layer was separated, dried over Na^SCf and filtered. The filtrate was concentrated in vacuo to a volume of about 50 mL. The concentrate was diluted with 150 mL n-hexane, the precipitate formed was filtered off, washed with 150 mL of a 1: 1 mixture diethyl ether and n-hexane and vacuum dried at 60 °C (1 tor, 3 h) to give 9.3 g (86%) of 0-(3-chloro-5-cyanophenyl) dimethylcarbamothioate as colorless crystals. NMR (400 MHz, CDCI3) d: 3.35 (s, 3H), 3.46 (s, 3H), 7.30 (s, 1H), 7.35 (s, 1H), 7.53 (s, 1H) (measured on a Varian Gemini 2000 machine).

63.8%

With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 20h;

i45 -3-chloro-S-cyanophenyl dimethylcarbamothioate To a mixture of 3-chloro-5-hydroxy-benzonitrile (2.5 g, 16.28 mmol) in DMF (25 mL) ) cooled to 0°C was added sodiumhydride (0.43 g, 17.91 mmol) followed by dimethylthiocarbamoyl chloride (2.21 g, 17.91 mmol). The reaction mixture was stirred at room temperature for a 20 h followed by addition of water (50 ml), followed by extraction with DCM (100 ml *2). The combined organics were washed with brine, dried over Na2S04 and evaporated to dryness to obtain crude product. Purification on silica gel (PE/EtOAc=10/l) to gav the target compound 2.5 g (63.80%) as a white solid. -

Reference： [1]Current Patent Assignee: BAYER AG - WO2021/13719, 2021, A1 Location in patent: Page/Page column 91-92
[2]Current Patent Assignee: BAYER AG - WO2021/13720, 2021, A1 Location in patent: Page/Page column 101-102
[3]Current Patent Assignee: BAYER AG - WO2021/105091, 2021, A1 Location in patent: Page/Page column 138; 139
[4]Current Patent Assignee: GALECTO BIOTECH AB - WO2016/120403, 2016, A1 Location in patent: Page/Page column 149

15
[ 473923-97-6 ]
[ 1829-33-0 ]

Yield	Reaction Conditions	Operation in experiment
84%	With pyridine; sodium hypophosphite monohydrate; acetic acid; In water; at 50℃; for 1.0h;Inert atmosphere;	500 mg (3.27 mmol) of 3-chloro-5-hydroxybenzonitrile are dissolved in a mixture of 4 ml of pyridine/acetic acid/water (2/1/1). 630 mg (6.54 mmol) of sodium hypophosphite monohydrate are added, followed by several drops of Raney nickel in water, and the mixture is stirred at 50C for 1 hour under argon. After cooling to ambient temperature, the mixture is filtered carefully on Celite and the Celite is washed several times with ethyl acetate. The combined filtrates are evaporated under reduced pressure to give the crude product which is directly purified by flash chromatography on a 60 g silica gel column with an ethyl acetate/hexane mixture as eluent. 426 mg of a white solid are obtained. Yield: 84%.

Reference： [1]Patent: EP3170822,2017,A1 .Location in patent: Paragraph 0464-0466

16
[ 473923-97-6 ]
[ 628692-22-8 ]
3-chloro-5-((2-chloro-4-(trifluoromethyl)pyridin-3-yl)oxy)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90.5%	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 80℃; for 8h;	reaction mixture of <strong>[628692-22-8]2-chloro-3-fluoro-4-(trifluoromethyl)pyridine</strong>(11, 5 g, 25 mmol) and 3-chloro-5-hydroxybenzonitrile (4.62 g,30 mmol) in 50 mL of N-methyl pyrrolidinone(NMP) in the presence ofpotassium carbonate (4.16 g, 30 mmol) was stirred at 80 C for 8 h. Thesolution was cooled to room temperature, and 100 mL of ice water wasadded to it slowly. Then the solid was filtered, washed with 20 mL ofDMF/water (1 : 1), and dried to give 3-chloro-5-((2-chloro-4-(trifluoromethyl)pyridin-3-yl)oxy)benzonitrile (12). Yield: 90.5%, mp:163-165 C. 1H NMR (400 MHz, DMSO-d6, ppm) delta: 8.69 (d, J=5.0 Hz,1H), 8.00 (d, J=5.0 Hz, 1H), 7.84 (t, J=1.4 Hz, 1H), 7.70 (t,J=2.1 Hz, 1H), 7.69 (dd, J=2.3, 1.2 Hz, 1H). 13C NMR (100 MHz,DMSO-d6, ppm) delta: 157.67, 148.80, 145.76, 142.83, 133.5, 135.94,127.78, 122.22, 122.18, 121.67, 118.51, 117.19, 114.61.C13H5Cl2F3N2O (333.09).

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 447 - 456

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