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[ CAS No. 179898-34-1 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}

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3d Animation Molecule Structure of 179898-34-1

Chemical Structure| 179898-34-1

Chemical Structure| 179898-34-1

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Quality Control of [ 179898-34-1 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 179898-34-1 ]

SDS Specification

Alternatived Products of [ 179898-34-1 ]

Product Details of [ 179898-34-1 ]

CAS No. :	179898-34-1	MDL No. :	MFCD04038227
Formula :	C₇H₃BrFN	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IADLVSLZPQYXIF-UHFFFAOYSA-N
M.W :	200.01	Pubchem ID :	2783330
Synonyms :

Calculated chemistry of [ 179898-34-1 ]

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 :	0.0
Molar Refractivity :	38.82
TPSA :	23.79 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) :	-5.79 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.95
Log Po/w (XLOGP3) :	2.43
Log Po/w (WLOGP) :	2.88
Log Po/w (MLOGP) :	2.63
Log Po/w (SILICOS-IT) :	2.9
Consensus Log Po/w :	2.56

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.05
Solubility :	0.176 mg/ml ; 0.000881 mol/l
Class :	Soluble
Log S (Ali) :	-2.57
Solubility :	0.535 mg/ml ; 0.00268 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.62
Solubility :	0.0481 mg/ml ; 0.00024 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.84

Safety of [ 179898-34-1 ]

Signal Word:	Danger	Class:	6.1
Precautionary Statements:	P501-P261-P270-P271-P264-P280-P337+P313-P305+P351+P338-P361+P364-P332+P313-P301+P310+P330-P302+P352+P312-P304+P340+P311-P403+P233-P405	UN#:	3439
Hazard Statements:	H301+H311+H331-H315-H319	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 179898-34-1 ]

* 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 [ 179898-34-1 ]
Downstream synthetic route of [ 179898-34-1 ]

[ 179898-34-1 ] Synthesis Path-Upstream 1~13

1
[ 1435-51-4 ]
[ 179898-34-1 ]

Yield	Reaction Conditions	Operation in experiment
35%	With pyridine In N,N-dimethyl-formamide for 3 h; Reflux	Example 14 3-Bromo-5-fluorobenzonitrile A 250-mL round-bottom flask equipped with a magnetic stir bar was charged with 1,3-dibromo-5-fluorobenzene (7.70 g, 30.3 mmol), DMF (45 mL), pyridine (4.9 mL), and copper (I) cyanide (2.72 g, 30.3 mmol) under nitrogen. A reflux condenser was attached to the flask. The green, cloudy mixture was stirred at reflux for 3 h. Once lower Rf impurities were observed, the reaction was allowed to cool to room temperature. The reaction was quenched with 30 mL of ether, and a precipitate formed in the dark solution. The precipitate was gravity-filtered though Celite. The filtrate was rinsed three times with ether (100 mL/50 g bromide). The isolated solution was added to a separatory funnel. The organic layer was washed with a 2:1 mixture of water and concentrated ammonium hydroxide (30 mL), followed by saturated ammonium chloride solution (230 mL) and saturated sodium bicarbonate (30 mL). The aqueous layers were extracted with ether (340 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The product was purified by flash column chomatography to yield 3-bromo-5-fluorobenzonitrile (2.10 g, 35percent). ¹H NMR (400 MHz, CDCl₃) δ 7.62 (s, 1H), 7.54-7.50 (m, 1H), 7.35-7.32 (m, 1H).
35%	With pyridine In N,N-dimethyl-formamide for 3 h; Reflux; Inert atmosphere	Example 14 3-Bromo-5-fluorobenzonitrile A 250-mL round-bottom flask equipped with a magnetic stir bar was charged with 1,3-dibromo-5-fluorobenzene (7.70 g, 30.3 mmol), DMF (45 mL), pyridine (4.9 mL), and copper (I) cyanide (2.72 g, 30.3 mmol) under nitrogen. A reflux condenser was attached to the flask. The green, cloudy mixture was stirred at reflux for 3 h. Once lower Rf impurities were observed, the reaction was allowed to cool to room temperature. The reaction was quenched with 30 mL of ether, and a precipitate formed in the dark solution. The precipitate was gravity-filtered though Celite. The filtrate was rinsed three times with ether (100 mL/50 g bromide). The isolated solution was added to a separatory funnel. The organic layer was washed with a 2:1 mixture of water and concentrated ammonium hydroxide (30 mL), followed by saturated ammonium chloride solution (230 mL) and saturated sodium bicarbonate (30 mL). The aqueous layers were extracted with ether (340 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The product was purified by flash column chomatography to yield 3-bromo-5-fluorobenzonitrile (2.10 g, 35percent). ¹H NMR (400 MHz, CDCl₃) δ 7.62 (s, 1H), 7.54-7.50 (m, 1H), 7.35-7.32 (m, 1H).
35%	With pyridine In N,N-dimethyl-formamide for 3 h; Inert atmosphere; Reflux	Example 14 3-Bromo-5-fhiorobenzonitrileA 250-mL round-bottom flask equipped with a magnetic stir bar was charged with 1,3- dibromo-5-fluorobenzene (7.70 g, 30.3 mmol), DMF (45 mL), pyridine (4.9 mL), and copper (I) cyanide (2.72 g, 30.3 mmol) under nitrogen. A reflux condenser was attached to the flask. The green, cloudy mixture was stirred at reflux for 3 h. Once lower Rf impurities were observed, the reaction was allowed to cool to room temperature. The reaction was quenched with 30 mL of ether, and a precipitate formed in the dark solution. The precipitate was gravity- filtered though Celite. The filtrate was rinsed thee times with ether (100 mL/50 g bromide). The isolated solution was added to a separatory funnel. The organic layer was washed with a 2:1 mixture of water and concentrated ammonium hydroxide (30 mL), followed by saturated ammonium chloride solution (2 x 30 mL) and saturated sodium bicarbonate (30 mL). The aqueous layers were extracted with ether (3 x 40 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The product was purified by flash column chomatography to yield 3-bromo-5-fluorobenzonitrile (2.1O g, 35percent). ¹H NMR (400 MHz, CDCl₃) δ 7.62 (s, 1 H), 7.54-7.50 (m, 1 H), 7.35-7.32 (m, 1 H).

23%

With pyridine In N,N-dimethyl-formamide at 150℃; for 4.5 h; Inert atmosphere

A mixture of 1,3-dibromo-5-fluorobenzene (7.4 g, 29.3 mmol), copper(I) cyanide (2.6 g, 29.3 mmol), pyridine (3 mL) and N,N-dimethylformamide (30 mL) under an argon atmosphere was heated to 150 °C for 4.5 h. Mixture was allowed to room temperature, diethyl ether (100 mL) was added and the formed precipitate was removed via filtration, the precipitate was washed with diethyl ether (100 mL), the filtrate was washed consecutively with: 1) 10 percent ammonium hydroxide (100 mL), 2) saturated ammonium chloride (100 mL), and 3) saturated sodium bicarbonate (100 mL), dried over magnesium sulfate and evaporated. Purification of the residue by flash chromatography, using a stepwise gradient of heptane to heptane:ethyl acetate 9:1 afforded the title compound (1.3 g, 23percent). ¹H NMR (400 MHz, CDCl₃) d ppm 7.30 - 7.37 (m, 1 H), 7.48 (dt, J=7.83, 1.89 Hz, 1 H), 7.58 (s, 1 H); ¹³C NMR (101 MHz, CDCl₃) d 115.5, 115.6, 116.4, 116.5, 118.5, 118.7, 123.9, 124.0, 124.4, 124.7, 131.4, 131.4, 161.1, 163.6.

Reference： [1] Patent: US2009/203657, 2009, A1, . Location in patent: Page/Page column 46
[2] Patent: US2009/203677, 2009, A1, . Location in patent: Page/Page column 49
[3] Patent: WO2009/100169, 2009, A1, . Location in patent: Page/Page column 124
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 22, p. 6974 - 6979,6

2
[ 1435-51-4 ]
[ 179898-34-1 ]

Yield	Reaction Conditions	Operation in experiment
65%	With pyridine; ammonium hydroxide; ammonium chloride; sodium hydrogencarbonate In water; N,N-dimethyl-formamide	3-Bromo-5-fluorobenzonitrile To a 1 liter r.b. flask equivuipped with a magnetic stir bar, commercially available 1,3-dibromo-5-fluorobenzene (44.0 g, 173.3 mmol), DMF (268 mL), pyridine (28.0 mL), and copper (I) cyanide (15.5 g, 173.3 mmol) were added under nitrogen. A reflux condenser was attached to the flask. The green cloudy mixture was stirred at reflux for 3 h. The reaction progress was difficult to monitor by TLC, so once lower Rf impurities were observed the reaction was allowed to cool to rt. The reaction mixture was quenched with 200 mL ether which formed a precipitate in the dark solution. The precipitate was gravity filtered through Celite. The filtrate was rinsed three times with ether (100 mL). The isolated solution was added to a separatory funnel. The organic layer was washed with 2 to 1 mixture of water and ammonium hydroxide (200 mL) followed by saturated ammonium chloride solution (2200 mL) and saturated sodium bicarbonate (200 mL). The aqueous layers were extracted with ether (3100 mL). The organic layers were combined and dried (Na₂ SO₄). The product, 3-bromo-5-fluorobenzonitrile, was purified by flash column chromatography (300 mL silica, hexane) followed by re, crystallization from hexane to afford 22.3 g (65percent) of the product as white crystals. Data for 3-bromo-5-fluorobenzonitrile: ¹ H NMR (400 MHz, acetone-d₆) 7.81 (s, 1H), 7.73 (dd, J=8.4, 1.9, 1H), 7.65 (dd, J=8.5, 2.0, 1H).
65%	With pyridine; ammonium hydroxide; ammonium chloride; sodium hydrogencarbonate In water; N,N-dimethyl-formamide	3-Bromo-5-fluorobenzonitrile To a 1 liter r.b. flask equivuipped with a magnetic stir bar, commercially available 1,3-dibromo-5-fluorobenzene (44.0 g, 173.3 mmol), DMF (268 mL), pyridine (28.0 mL), and copper (I) cyanide (15.5 g, 173.3 mmol) were added under nitrogen. A reflux condenser was attached to the flask. The green cloudy mixture was stirred at reflux for 3 h. The reaction progress was difficult to monitor by TLC, so once lower Rf impurities were observed the reaction was allowed to cool to rt. The reaction mixture was quenched with 200 mL ether which formed a precipitate in the dark solution. The precipitate was gravity filtered through Celite. The filtrate was rinsed three times with ether (100 mL). The isolated solution was added to a separatory funnel. The organic layer was washed with 2 to 1 mixture of water and ammonium hydroxide (200 mL) followed by saturated ammonium chloride solution (2200 mL) and saturated sodium bicarbonate (200 mL). The aqueous layers were extracted with ether (3100 mL). The organic layers were combined and dried (Na₂ SO₄). The product, 3-bromo-5-fluorobenzonitrile, was purified by flash column chromatography (300 mL silica, hexane) followed by recrystallization from hexane to afford 22.3 g (65percent) of the product as white crystals. Data for 3-bromo-5-fluorobenzonitrile: ¹ H NMR (400 MHz, acetone-d₆) 7.81 (s, 1 H), 7.73 (dd, J=8.4, 1.9, 1 H), 7.65 (dd, J=8.5, 2.0, 1 H).
65 %	With pyridine; ammonium hydroxide; ammonium chloride; sodium hydrogencarbonate In water; N,N-dimethyl-formamide	EXAMPLE 171 6-(3-Cyano-5-fluorophenyl)-1,2-dihydro-2,2,4-trimethylquinoline (Compound 271, structure 4 of Scheme II, where R¹ =-cyano-5-fluorophenyl) 3-Bromo-5-fluorobenzonitrile. To a 1 liter r.b. flask equivuipped with a magnetic stir bar, commercially available 1,3-dibromo-5-fluorobenzene (44.0 g, 173.3 mmol), DMF (268 mL), pyridine (28.0 mL), and copper (I) cyanide (15.5 g, 173.3 mmol) were added under nitrogen. A reflux condenser was attached to the flask. The green cloudy mixture was stirred at reflux for 3 h. The reaction progress was difficult to monitor by TLC, so once lower Rf impurities were observed the reaction was allowed to cool to rt. The reaction mixture was quenched with 200 mL ether which formed a precipitate in the dark solution. The precipitate was gravity filtered through Celite. The filtrate was rinsed three times with ether (100 mL). The isolated solution was added to a separatory funnel. The organic layer was washed with 2 to 1 mixture of water and ammonium hydroxide (200 mL) followed by saturated ammonium chloride solution (2200 mL) and saturated sodium bicarbonate (200 mL). The aqueous layers were extracted with ether (3100 mL). The organic layers were combined and dried (Na₂ SO₄). The product, 3-bromo-5-fluorobenzonitrile, was purified by flash column chromatography (300 mL silica, hexane) followed by recrystallization from hexane to afford 22.3 g (65 percent) of the product as white crystals. Data for 3-bromo-5-fluorobenzonitrile: 1It NMR (400 MHz, acetone-d₆) 7.81 (s, 1 H), 7.73 (dd, J=8.4, 1.9, 1 H), 7.65 (dd, J=8.5, 2.0, 1 H).

65%

With pyridine; ammonium hydroxide; ammonium chloride; sodium hydrogencarbonate In water; N,N-dimethyl-formamide

3-Bromo-5-fluorobenzonitrile.
To a 1 liter r.b. flask equivuipped with a magnetic stir bar, commercially available 1,3-dibromo-5-fluorobenzene (44.0 g, 173.3 mmol), DMF (268 mL), pyridine (28.0 mL), and copper (I) cyanide (15.5 g, 173.3 mmol) were added under nitrogen.
A reflux condenser was attached to the flask.
The green cloudy mixture was stirred at reflux for 3 h.
The reaction progress was difficult to monitor by TLC, so once lower Rf impurities were observed the reaction was allowed to cool to rt.
The reaction mixture was quenched with 200 mL ether which formed a precipitate in the dark solution.
The precipitate was gravity filtered through Celite.
The filtrate was rinsed three times with ether (100 mL).
The isolated solution was added to a separatory funnel.
The organic layer was washed with 2 to 1 mixture of water and ammonium hydroxide (200 mL) followed by saturated ammonium chloride solution (2*200 mL) and saturated sodium bicarbonate (200 mL).
The aqueous layers were extracted with ether (3*100 mL).
The organic layers were combined and dried (Na₂ SO₄).
The product, 3-bromo-5-fluorobenzonitrile, was purified by flash column chromatography (300 mL silica, hexane) followed by recrystallization from hexane to afford 22.3 g (65percent) of the product as white crystals.
Data for 3-bromo-5-fluorobenzonitrile: ¹ H NMR (400 MHz, acetone-d₆) 7.81 (s, 1 H), 7.73 (dd, J=8.4, 1.9, 1 H), 7.65 (dd, J=8.5, 2.0, 1 H).

Reference： [1] Patent: US5688808, 1997, A,
[2] Patent: US5693646, 1997, A,
[3] Patent: US5696133, 1997, A,
[4] Patent: US5696130, 1997, A,

3
[ 1435-51-4 ]
[ 179898-34-1 ]

Yield	Reaction Conditions	Operation in experiment
35%	With pyridine In N,N-dimethyl-formamide for 3 h; Inert atmosphere; Reflux	Example 17 3-Bromo-5-fluorobenzonitrile A 250-mL round-bottom flask equipped with a magnetic stir bar was charged with 1,3-dibromo-5-fluorobenzene (7.70 g, 30.3 mmol), DMF (45 mL), pyridine (4.9 mL), and copper (I) cyanide (2.72 g, 30.3 mmol) under nitrogen. A reflux condenser was attached to the flask. The green, cloudy mixture was stirred at reflux for 3 h. Once lower Rf impurities were observed, the reaction was allowed to cool to room temperature. The reaction was quenched with 30 mL of ether, and a precipitate formed in the dark solution. The precipitate was gravity-filtered though Celite. The filtrate was rinsed three times with ether (100 mL/50 g bromide). The isolated solution was added to a separatory funnel. The organic layer was washed with a 2:1 mixture of water and concentrated ammonium hydroxide (30 mL), followed by saturated ammonium chloride solution (230 mL) and saturated sodium bicarbonate (30 mL). The aqueous layers were extracted with ether (340 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The product was purified by flash column chromatography to yield 3-bromo-5-fluorobenzonitrile (2.10 g, 35percent). ¹H NMR (400 MHz, CDCl₃): δ 7.62 (s, 1H), 7.54-7.50 (m, 1H), 7.35-7.32 (m, 1H).

Reference： [1] Patent: US2009/197871, 2009, A1, . Location in patent: Page/Page column 48-49

4
[ 1435-51-4 ]
[ 544-92-3 ]
[ 179898-34-1 ]

Reference： [1] Journal of Medicinal Chemistry, 1998, vol. 41, # 18, p. 3461 - 3466
[2] Patent: WO2006/115895, 2006, A2, . Location in patent: Page/Page column 9

5
[ 142-71-2 ]
[ 179898-34-1 ]

Reference： [1] Patent: US6391907, 2002, B1,
[2] Patent: US6462032, 2002, B1,

6
[ 304876-25-3 ]
[ 179898-34-1 ]

Reference： [1] Patent: US6355648, 2002, B1, . Location in patent: Page column 34

7
[ 933585-20-7 ]
[ 179898-34-1 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 11, p. 3243 - 3247

8
[ 176548-70-2 ]
[ 179898-34-1 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 11, p. 3243 - 3247

9
[ 887266-90-2 ]
[ 179898-34-1 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 11, p. 3243 - 3247

10
[ 179898-34-1 ]
[ 176548-70-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	for 2 h; Reflux	A mixture of 3-bromo-5-fluorobenzonitrile (2.8 g, 13.8 mmol) and aqueous sodium hydroxide (5 M, 28 mL) was heated to reflux for 2 h. After cooling to room temperature, pH was adjusted to 1 by the addition of concentrated hydrochloric acid. The formed precipitate was collected by filtration, the solid was washed with cold water and dried to afford the title compound (2.8 g, 94percent). ¹H NMR (400 MHz, CD₃OD) d ppm 6.31 (dt, J=8.08, 2.02 Hz, 1 H), 6.37 - 6.43 (m, 1 H), 6.68 (s, 1 H).

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 22, p. 6974 - 6979,6

11
[ 179898-34-1 ]
[ 334792-52-8 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 22, p. 6974 - 6979,6

12
[ 124-41-4 ]
[ 179898-34-1 ]
[ 867366-91-4 ]

Reference： [1] Patent: WO2007/39736, 2007, A1, . Location in patent: Page/Page column 65
[2] Patent: US2008/293775, 2008, A1, . Location in patent: Page/Page column 41

13
[ 68-12-2 ]
[ 179898-34-1 ]
[ 1003708-42-6 ]

Yield	Reaction Conditions	Operation in experiment
99%	Stage #1: With isopropylmagnesium bromide In tetrahydrofuran at 0 - 20℃; for 1.33333 h; Stage #2: at 0 - 20℃; for 18 h;	3 -fluoro-5 -formylbenzonitrile : A solution of 3 -bromo-5 -fluorobenzonitrile(5.00 g, 25.0 mmol) in dry THF (25 mL) was cooled to 0 °C and 2M iPrMgCl (15.0 mL, 30.0 mmol) in THF was added dropwise over 5 minutes. The mixture was stirred at 0 °C for 15 minutes then at ambient temperature for 1 hour. The mixture was cooled to 0 °C and dry DMF (5.81 mL, 75.0 mmol) was added. The mixture was stirred for 17 hours during which time the temperature reached ambient temperature after 2 hours. The mixture was added to ice water (150 mL) and Et₂0 (100 mL). The biphasic mixture was stirred and treated with 6M HC1 to aqueous pH=3. The organic layer was removed and the aqueous layer extracted with Et₂0 (2X). The combined Et₂0 fractions were washed with saturated NaCl and dried over MgS0₄/activated carbon. The dried solution was filtered through a S1O₂ plug eluting with Et₂0. The filtrate was concentrated to give the title compound as a yellow solid that was dried in vacuum (3.68 g, 99percent). 1H NMR (CDC1₃) δ 10.0 (s, 1H), 8.00 (s, 1H), 7.81-7.86 (m, 1H), 7.62-7.67 (m, 1H).
99%	Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at 0 - 20℃; for 1.25 h; Stage #2: at 0 - 20℃; for 17 h;	Step A: 3-fluoro-5-formylbenzonitrile: A solution of 3-bromo-5- fluorobenzonitrile (5.00 g, 25.0 mmol) in dry THF (25 mL) was cooled to 0 °C and 2M iPrMgCl (15.0 mE, 30.0 mmol) in THF was added dropwise over 5 minutes. The mixture was stirred at 0 °C for 15 minutes then at ambient temperature for 1 hour. The mixture was cooled to 0 °C and dry DMF (5.81 mL, 75.0 mmol) was added. The mixture was stirred for 17 hours during which time the temperature reached ambient temperature after 2 hours. The mixture was added to ice water (150 mL) and Et20 (100 mL). The biphasic mixture was stirred and treated with 6M HC1 to aqueous pH=3. The organic layer was removed and the aqueous layer extracted with Et20 (2X). The combined Et20 fractions were washed with saturated NaC1 and dried over MgSO4/activated carbon. The dried solution was filtered through a Si02 plug eluting with Et20. The filtrate was concentrated to give the title compound as a yellow solid that was dried in vacuum (3.68 g, 99percent). ‘H NMR (CDC13) ö 10.0 (s, 1H), 8.00 (s, 111), 7.81-7.86 (m, 111), 7.62-7.67 (m, 111).
99%	Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at 0 - 20℃; for 1.33333 h; Stage #2: at 0 - 20℃; for 17 h;	1003751 Step A: 3-fluoro-5-formylbenzonitrile: A solution of 3-bromo-5- fluorobenzonitrile (5.00 g, 25.0 mmol) in dry THF (25 mL) was cooled to 0 °C and 2M iPrMgCl (15.0 mE, 30.0 mmol) in TUF was added dropwise over 5 minutes. The mixture was stirred at 0 °C for 15 minutes then at ambient temperature for 1 hour. The mixture was cooled to 0 °C and dry DMF (5.81 mL, 75.0 mmol) was added. The mixture was stirred for 17 hours during which time the temperature reached ambient temperature after 2 hours. The mixture was added to ice water (150 mE) and Et20 (100 mE). The biphasic mixture was stirred and treated with 6M HC1 to aqueous pH=3. The organic layer was removed and the aqueous layer extracted with Et20 (2X). The combined Et20 fractions were washed with saturated NaC1 and dried over MgSO4/activated carbon. The dried solution was filtered through a Si02 plug eluting with Et20. The filtrate was concentrated to give the title compound as a yellow solid that was dried in vacuum (3.68 g, 99percent). ‘H NMR (CDCI3) 8 10.0 (s, 1H), 8.00 (s, 1H), 7.81- 7.86 (m, 111), 7.62-7.67 (m, 1H).

99%

Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at 0 - 20℃; for 1.33333 h;
Stage #2: at 0 - 20℃; for 19 h;

Preparation 0-100 Trans-3-(4-amino- 1 -(2-methoxyethyl)pyrrolidin-3-yl)-5-fluorobenzonitrile 1005731 Step A: 3-fluoro-5-fonnylbenzonitrile: A solution of 3-bromo-5- fluorobenzonitrile (5.00 g, 25.0 mmol) in dry THF (25 mL) was cooled to 0 °C and 2M iPrMgCl (15.0 mL, 30.0 mmol) in THF was added dropwise over 5 minutes. The mixture was stirred at 0 °C for 15 minutes then at ambient temperature for 1 hour. The mixture was cooled to 0 °C and dry DMF (5.81 mL, 75.0 mmol) was added. The mixture was stirred for 17 hours during which time the temperature reached ambient temperature after 2 hours. The mixture was added to ice water (150 mL) and Et20 (100 mE). The biphasic mixture was stirred and treated with 6M HC1 to aqueous pH=3. The organic layer was removed and the aqueous layer extracted with Et20 (2X). The combined Et20 fractions were washed with saturated NaCl and dried over MgSO4lactivated carbon. The dried solution was filtered through a Si02 plug eluting with Et20. The filtrate was concentrated to give the title compound as a yellow solid that was dried in vacuum (3.68 g, 99percent). ‘H NMR (CDC13) ö 10.0 (s, 1H), 8.00 (s, 1H), 7.81- 7.86 (m, 1H), 7.62-7.67 (m, 1H).

Reference： [1] Patent: WO2012/158413, 2012, A2, . Location in patent: Page/Page column 90
[2] Patent: WO2014/78323, 2014, A1, . Location in patent: Paragraph 00542
[3] Patent: WO2014/78372, 2014, A1, . Location in patent: Paragraph 00375
[4] Patent: WO2014/78378, 2014, A1, . Location in patent: Paragraph 00573

[ 179898-34-1 ] Synthesis Path-Downstream 1~52

1
[ 179898-34-1 ]
[ 304876-35-5 ]
[ 304875-56-7 ]

Yield	Reaction Conditions	Operation in experiment
44%		5'-(3-Cyano-5-fluorophenyl)-spiro[cyclopentane-1,3'-[3H]indol]-2'(1'H)-one: A solution of 3-cyano-5-fluoro-bromobenzene (0.5 g, 2.6 mmol), and tetrakis (triphenylphosphine)palladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2 for 20 minutes. To this mixture was then (spiro[cyclopentane-1,3'-[3H]indol]-2'(1'H)-one-5-yl) boronic acid (0.9 g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the subtitled compound (0.35 g, 44%) as white needles. mp: 235-237 C.; 1H NMR (DMSO-d6) delta 10.5 (s, 1H), 8.1 (s, 1H), 8.0 (dt, 1H, J=1.7, 2.0, 7.0 Hz), 7.8-7.7 (m, 2H), 7.6 (dd, 1H, J=1.8, 6.4 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0-1.9 (m, 8H); MS (EI) M+ m/z 306.

Reference： [1]Patent: US6355648,2002,B1 .Location in patent: Page column 47
[2]Bioorganic and medicinal chemistry letters,2002,vol. 12,p. 3487 - 3490

2
[ 179898-34-1 ]
[ 304876-18-4 ]
[ 304875-03-4 ]

Yield	Reaction Conditions	Operation in experiment
48%		To a solution of 3,5-dibromofluorobenzene in diethyl ether (100 cm3) at -78 C. was added n-butyl lithium (2.5 M, 8 cm3, 20 mmol) dropwise. After 30 min. the mixture was treated with DMF (20 cm3) in diethyl ether (10 cm3) and stirring was continued at -78 C. After 30 min. the mixture was quenched with dilute HCl aq., separated and the aqueous layer was extracted with EtOAc. The combined organic layers were combined, washed with water, brine, dried (MgSO4) and evaporated to give 3-fluoro-5-bromobenzaldehyde (4.0 g, 19.7 mmol, 100%) as an oil: 1H NMR (CDCl3) delta inter alia 7.50-7.53 (m, 2H), 7.82 (s, 1H) and 9.93 (m, 1H); MS (EI) m/z 202, 204 [M+]. To a solution of the last cited compound (4.0 g, 19.7 mmol) in ethanol:water (8:2, 50 cm3), was added sodium acetate (1.72 g, 21 mmol) and hydroxylamine hydrochloride (1.45 g, 21 mmol), and the mixture was heated under reflux. After 30 min., the mixture was cooled, evaporated and the residue partitioned between water and EtOAc. The aqueous layer was re-extracted with EtOAc and the combined organic layers were washed with water, saturated sodium hydrogen carbonate solution, brine, dried (MgSO4) and evaporated to give 3-fluoro-5-bromobenzaldehyde oxime (3.76 g, 17.24 mmol, 87%) which was used without further purification: 1H NMR (CDCl3) delta 7.24-7.27 (m, 2H), 7.50 (s, 1H), 7.68 (s, 1H) and 8.04 (s, 1H); MS (EI) m/z 217 [M+]. The above oxime (3.76 g, 17.24 mmol) and copper (II) acetate (370 mg) were dissolved in acetonitrile (100 cm3) under nitrogen and heated under reflux. After 5 h, the mixture was evaporated, the residue taken into EtOAc, washed with sulfuric acid (1N), water, brine, dried (MgSO4) and evaporated to give <strong>[179898-34-1]3-fluoro-5-bromobenzonitrile</strong> (3.08 g, 15.39 mmol, 89%) which was used without further purification. The above bromide (3.0 g, 15 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.86 g, 0.75 mmol) were dissolved in dimethoxyethane (130 cm3) under nitrogen. After 15 min. (2'-oxo-2,3-dihydrospiro[cyclohexane-1,3'-[3H]indol]-5'-yl) boronic acid (2.82 g, 11.5 mmol) and sodium carbonate (3.1 g, 29.3 mmol) dissolved in water (40 cm3) were added, and the mixture heated under reflux. After 8 h the mixture was cooled, poured into water and extracted with EtOAc (×3). The combined organic layers were then washed with water, dried (MgSO4) and evaporated. The residue was then purified by column chromatography (EtOAc:hexane, gradient elution), and the product recrystallized from methanol to give 3-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-5-fluorobenzonitrile (1.78 g, 5.55 mmol, 48%): mp 199-205 C.; 1H NMR (CDCl3) delta 1.64-2.03 (m, 10H), 7.03 (d, 1H, J=8 Hz), 7.31 (dt, 1H, J=7.7 and 1.6 Hz), 7.41 (dd, 1H, J=8, 1.7 Hz), 7.49 (dt, 1H, J=9.6, 2 Hz), 7.58 (d, 1H, J=2 Hz), 7.64 (s, 1H) and 8.37 (s, 1H): MS (EI) m/z 320 [M+].

Reference： [1]Patent: US6355648,2002,B1 .Location in patent: Page column 33-34
[2]Bioorganic and medicinal chemistry letters,2002,vol. 12,p. 3487 - 3490

3
[ 179898-34-1 ]
[ 1066-54-2 ]
[ 914948-32-6 ]

Yield	Reaction Conditions	Operation in experiment
88%	With triethylamine;bis(acetato)bis(triphenylphosphine)palladium(0); In toluene; at 95℃; for 0.5h;	A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (2.5g, 12.5mmol), (trimethylsilyl)acetylene(2.86ml,20mmol), bis(acetate)bis(triphenylphoshpino)Palladium(II) (936mg, 1.25mmol) and triethylamine (35ml) in toluene (35ml) was degassed by bubbling nitrogen through the solution and then stirred at 950C for 30 minutes. Filtration and concentration to yield a crude product. It was diluted with EtOAc (150ml). The organic phase was washed with saturated NaHCO3 solution (50ml), brine (50ml) and the organic layer was dried over sodium sulfate. Filtration EPO <DP n="198"/>and concentration to yield a product A293.1 (2Ag, 88%). HPLC: 95%, retention time: 4.05 minute (condition A). LC/MS (M+H)+ = 218.2.
	With copper(l) iodide; triethylamine;tetrakis(triphenylphosphine) palladium(0); at 40℃; for 3h;	INTERMEDIATE 2; 3-ethynyl-5-fluorobenzonitrile; 3-bromo-5-cyanofluorobenezene (7 g, 35 mmol), TMS acetylene (5.1 g, 53 mmol), Palladium tetrakis(triphenylphosphine) (0.4 g, 0.35 mmol), copper (I) iodide (0.07 g, 0.35 mmol), and triethylamine (100 mL) were combined and heated to 40 C for 3 hours. The solution was filtered, solvent evaporated and the crude material purified on silica (20% EtOAc/hexanes) to yield a white solid. The solid material was dissolved in THF (50 mL) and 1 equivalent of TBAF was added and the solution was stirred for 1 hour at room temperature. Methylene chloride was added and the organic layer was washed 3 times with water and evaporated to yield a colorless oil.

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3256 - 3266
[2]ACS Medicinal Chemistry Letters,2012,vol. 3,p. 544 - 549
[3]Patent: WO2006/122137,2006,A1 .Location in patent: Page/Page column 196-197
[4]Patent: WO2006/115895,2006,A2 .Location in patent: Page/Page column 10

4
[ 72287-26-4 ]
6-bromo-8-methoxy-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one [ No CAS ]
[ 73183-34-3 ]
[ 179898-34-1 ]
[ 305800-55-9 ]

Yield	Reaction Conditions	Operation in experiment
33%	With potassium acetate; sodium carbonate; In water; ethyl acetate; N,N-dimethyl-formamide;	A mixture of 6-bromo-8-methoxy-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (1.6 g, 5.6 mmol), bis(pinacolato)diboron (1.6 g, 6.3 mmol), potassium acetate (1.5 g, 15.3 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) chloride (1:1 complex with methylene chloride, 0.5 g, 0.6 mmol) in DMF (30 mL) was subject to a positive flow of nitrogen to remove oxygen and then heated at 85° C. under a blanket of nitrogen for 18 hours. The reaction mixture was allowed to cool to ambient temperature, treated with 3-bromo-5-fluoro-benzonitrile (1.2 g, 6 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) chloride (1:1 complex with methylene chloride, 0.5 g, 0.6 mmol), and sodium carbonate (2 g, 19 mmol) in water (10 mL). The resulted solution was heated at 85° C. for 3 hours under a blanket of nitrogen, cooled to rt, and treated with brine (50 mL). Ethyl acetate (100 mL) was added, organic layer was separated, dried (MgSO4), and evaporated. The residue was purified by a flash silica gel column chromatography (THF:hexane/2:3) to yield 3-(4,4-dimethyl-8-methoxy-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile as a white solid (0.6 g, 33percent): mp 252-253° C.; 1H-NMR (DMSO-d6) delta9.76 (s, 1H), 8.21 (s, 1H), 8.07 (d, 1H, J=10.6 Hz), 7.82 (m,1H), 7.39 (s 1H), 7.36 (s, 1H), 3.93 (s, 3H), 1.66 (s, 6H). MS (ESI) m/z 325 [M-H]-.
33%	With potassium acetate; sodium carbonate; In water; ethyl acetate; N,N-dimethyl-formamide;	A mixture of 6-bromo-8-methoxy-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (1.6 g, 5.6 mmol), bis(pinacolato)diboron (1.6 g, 6.3 mmol), potassium acetate (1.5 g, 15.3 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) chloride (1:1 complex with methylene chloride, 0.5 g, 0.6 mmol) in DMF (30 mL) was subject to a positive flow of nitrogen to remove oxygen and then heated at 85° C. under a blanket of nitrogen for 18 hours. The reaction mixture was allowed to cool to ambient temperature, treated with 3-bromo-5-fluoro-benzonitrile (1.2 g, 6 mmol), [1,1'-bis(diphenylphosphino)-ferrocene]palladium (II) chloride (1:1 complex with methylene chloride, 0.5 g, 0.6 mmol), and sodium carbonate (2 g, 19 mmol) in water (10 mL). The resulted solution was heated at 85° C. for 3 hours under a blanket of nitrogen, cooled to rt, and treated with brine (50 mL). Ethyl acetate (100 mL) was added, organic layer was separated, dried (MgSO4), and evaporated. The residue was purified by a flash silica gel column chromatography (THF:hexane/2:3) to yield 3-(4,4-dimethyl-8-methoxy-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile as a white solid (0.6 g, 33percent): mp 252-253° C.; 1H-NMR (DMSO-d6) delta9.76 (s, 1H), 8.21 (s, 1H), 8.07 (d, 1H, J=10.6 Hz), 7.82 (m, 1H), 7.39 (s 1H), 7.36 (s, 1H), 3.93 (s, 3H), 1.66 (s, 6H). MS (ESI) m/z 325 [M-H]-.

Reference： [1]Patent: US2002/49204,2002,A1
[2]Patent: US6444668,2002,B1

5
(spiro[cyclopentane-1,3'-[3H]indol]-2'(1'H)-one-5-yl) boronic acid [ No CAS ]
[ 179898-34-1 ]
[ 304875-56-7 ]

Yield	Reaction Conditions	Operation in experiment
44%	With sodium carbonate;tetrakis(triphenylphosphine)palladium (0); In 1,2-dimethoxyethane; water;	EXAMPLE 80 5'-(3-Cyano-5-fluorophenyl)-spiro[cyclopentane-1,3'-[3H]indol]-2'(1'H)-one A solution of 3-cyano-5-fluoro-bromobenzene (0.5 g, 2.6 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2 for 20 minutes. To this mixture was then added (spiro[cyclopentane-1,3'-[3H]indol]-2'(1'H)-one-5-yl) boronic acid (0.9 g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (*3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the title compound (0.35 g, 44%) as white needles. mp: 235-237 C.; 1H NMR (DMSO-d6) delta10.5 (s, 1H), 8.1 (s, 1H), 8.0 (dt, 1H, J=1.7, 2.0, 7.0 Hz), 7.8-7.7 (m, 2H), 7.6 (dd, 1H, J=1.8, 6.4 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0-1.9 (m, 8H); MS (EI) M+a m/z 306.
44%	With sodium carbonate;tetrakis(triphenylphosphine)palladium (0); In 1,2-dimethoxyethane; water;	EXAMPLE 80 5'-(3Cyano-5-fluorophenyl)-spiro [cyclopentane-1,3'-[3H]indol]-2'(1'H)-one A solution of 3-cyano-5-fluoro-bromobenzene (0.5 g, 2.6 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2 for 20 minutes. To this mixture was then added (spiro[cyclopentane-1,3'-[3H]indol]-2'(1'H)-one-5-yl)boronic acid (0.9 g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (*3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the title compound (0.35 g, 44%) as white needles. mp: 235-237 C.; 1H NMR (DMSO-d6) delta 10.5 (s, 1H), 8.1 (s, 1H), 8.0 (dt, 1H, J=1.7, 2.0, 7.0 Hz), 7.8-7.7 (m, 2H), 7.6 (dd, 1H, J=1.8, 6.4 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0-1.9 (m, 8H); MS (EI) M-am/z 306.

Reference： [1]Patent: US6391907,2002,B1
[2]Patent: US6462032,2002,B1

6
[ 124-41-4 ]
[ 179898-34-1 ]
[ 867366-91-4 ]

Yield	Reaction Conditions	Operation in experiment
	With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; at 20℃; for 2.0h;	(i) 3-bromo~5-methoxybenzonitrileSodium methoxide (2.02 g) was added to a stirred solution of 3-fluoro-5-bromobenzonitile (5.0 g) in DMPU (20 ml) and stirred at RT for 2 h. The reaction was diluted with water and the resulting solid formed was filtered and washed with water, then dried in vacuo to give the subtitle compound (5.10 g). lH NMR DMSO-d6: delta 7.39-7.38 (IH, s), 7.30-7.26 (IH, m), 7.11 (IH, s), 3.83 (3H, s).
	In 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; at 20℃; for 2.0h;	(i) 3-bromo-5-methoxybenzonitrile Sodium methoxide (2.02 g) was added to a stirred solution of 3-fluoro-5-bromobenzonitile (5.0 g) in DMPU (20 ml) and stirred at RT for 2 h. The reaction was diluted with water and the resulting solid formed was filtered and washed with water, then dried in vacuo to give the subtitle compound (5.10 g). 1H NMR DMSO-d6: 7.39-7.38 (1H, s), 7.30-7.26 (1H, m), 7.11 (1H, s), 3.83 (3H, s).

Reference： [1]Patent: WO2007/39736,2007,A1 .Location in patent: Page/Page column 65
[2]Patent: US2008/293775,2008,A1 .Location in patent: Page/Page column 41

7
[ 686768-23-0 ]
[ 179898-34-1 ]
[thiazole-4-14C] 3-fluoro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) iodide; tetrabutyl ammonium fluoride;bis-triphenylphosphine-palladium(II) chloride; In N,N-dimethyl-formamide; at 80℃; for 3h;	EXAMPLE 22; [Thiazole-4-14C]3-fluoro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]benzonitrile (IIIa); A solution of 15 mg of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong>, 5.4 mg of dichlorobis(triphenylphosphine)palladium(II), 3 mg of copper (I) iodide, 54 muL of triethylamine, 4 mCi (15 mg) of [thiazole-4-14C]2-methyl-4-[(trimethylsilyl)ethynyl]-1,3-thiazole and 1 mL of dimethylformamide was heated to 50 C. under a nitrogen atmosphere. This was followed by the addition of 77 muL of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran and the temperature was raised to 80 C. After 3 hr, the reaction mixture was cooled to room temperature, diluted with 5 ml of 1:1 ethyl acetate:hexane and washed with 1:1 brine:H2O (1×10 mL). The aqueous portion was then extracted with 1:1 ethyl acetate:hexane (2×5 mL). The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was then dissolved in 3 mL of acetonitrile and filtered through a 0.2 muM filter. After preparative HPLC chromatography (Zorbax XDB C18 250×21.2 mm column, 20% acetonitrile:H2O (0.1% TFA) to 100% acetonitrile, 60 min linear gradient, 20 mL/min, 2×1.5 mL injections) 1.2 mCi (5.6 mg) of product was obtained which had a radiochemical purity of >99.5% by HPLC (Zorbax SB C18 column, 4.6×150 mm, 40% acetonitrile:H2O (0.1% TFA) for 20 min, to 100% acetonitrile in 10 min, hold at 100% for 15 min, 1 mL/min, tR=19.3 min) and coeluted with an authentic sample of [Thiazole-4-14C]3-fluoro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]benzonitrile. LC/MS m/z=245.

Reference： [1]Patent: US2007/60618,2007,A1 .Location in patent: Page/Page column 24

8
[ 194222-05-4 ]
[ 179898-34-1 ]
[ 945565-37-7 ]

Yield	Reaction Conditions	Operation in experiment
58%	With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 0.5h;	3-Bromo-5-fluorobenzonitrile (8.62g, 43mmol) was dissolved in DMF (2OmL). Sodium hydride (2.46g, 62mmol) was added portionwise to the stirred solution under an atmosphere of nitrogen. Exo tert-Butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (7.Og, 31 mmol) was then added and then reaction was stirred at ambient temperature for15 30 minutes. The reaction was quenched with water then the solution was extracted with DCM. The organic layers were combined and dried over MgSO4. The organic layer was concentrated to leave a brown gum, which was dissolved in DCM (5OmL) and washed with water (3x40mL). The organic layer was combined and dried over MgSO4. The organic layer was concentrated in vacuo to leave a brown gum. The crude material was then20 purified by chromatography on silica gel. Elution with 10:90 ethyl acetate:heptane afforded exo terf-butyl 3-(3-bromo-5-cyanophenoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (7.23g, 17.8mmol, 58%) as a pale yellow solid.

Reference： [1]Patent: WO2007/63071,2007,A1 .Location in patent: Page/Page column 54
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 271 - 275

9
exo-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]
[ 179898-34-1 ]
exo tert-butyl 3-(3-bromo-5-cyanophenoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 0.5h;	EXAMPLE IX.1 exo 3-(8-Azabicyclo[3.2.1]oct-3-yloxy)-5-(3-fluoropyridin-2-yl)benzonitrile 3-Bromo-5-fluorobenzonitrile (8.62 g, 43 mmol) was dissolved in DMF (20 mL). Sodium hydride (2.46 g, 62 mmol) was added portionwise to the stirred solution under an atmosphere of nitrogen. Exo tert-Butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (7.0 g, 31 mmol) was then added and then reaction was stirred at ambient temperature for 30 minutes. The reaction was quenched with water then the solution was extracted with DCM. The organic layers were combined and dried over MgSO4. The organic layer was concentrated to leave a brown gum, which was dissolved in DCM (50 mL) and washed with water (3*40 mL). The organic layer was combined and dried over MgSO4. The organic layer was concentrated in vacuo to leave a brown gum. The crude material was then purified by chromatography on silica gel. Elution with 10:90 ethyl acetate:heptane afforded exo tert-butyl 3-(3-bromo-5-cyanophenoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (7.23 g, 17.8 mmol, 58%) as a pale yellow solid.

Reference： [1]Patent: US2007/185156,2007,A1 .Location in patent: Page/Page column 29

10
[ 136656-76-3 ]
[ 179898-34-1 ]
[ 937842-56-3 ]

Yield	Reaction Conditions	Operation in experiment
~ 100%		3-Bromo-5-[(1S)-2-tert-butoxy-1-methylethoxy]benzonitrile All glassware was oven dried and cooled under nitrogen-inertion was maintained throughout experiment. To a stirred suspension of sodium bis(trimethylsilyl)amide (74.25 mmol; 14.33 g) in DMF (150 mL) at 23 C. was added (S)-tert-butoxy-2-propanol (74.25 mmoles, 9.82 g) over 15 minutes. A slight exotherm was observed (cold water cooling bath applied). A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (49.50 mmol, 10.0 g) in DMF (40 mL) was added over 15 minutes with cold water bath still present. An exotherm (3 C.) was observed and the mixture turned from yellow to brown. DMF (10 mL) was added and the mixture stirred at ambient temperature for 1 hour. The reaction was quenched by addition of aqueous HCl (2M, 100 mL), maintaining temperature below 25 C. The mixture was diluted with water (200 mL) and extracted with 2:1 EtOAc/MTBE (3200 mL). The organic layers were combined, washed with water (3200 mL) and dried over MgSO4, and the solvent removed in vacuo affording the title compound as an orange oil (17.4 g). Further drying in vacuo at 23 C. gave the title product (15.5 g, ~100%). 1H NMR: (400 MHz, CDCl3) delta 7.38-7.35 (m, 1H), 7.34-7.31 (m, 1H), 7.18-7.14 (m, 1H), 4.51-4.41 (m, 1H), 3.53 (dd, 1H), 3.42 (dd, 1H), 1.31 (d, 3H), 1.17 (s, 9H).

Reference： [1]Patent: US2008/300412,2008,A1 .Location in patent: Page/Page column 7; 10-11
[2]Organic Process Research and Development,2018,vol. 22,p. 996 - 1006

11
[ 135631-90-2 ]
[ 179898-34-1 ]
[ 304858-24-0 ]

Reference： [1]Patent: US6358948,2002,B1 .Location in patent: Example 41

12
[ 67-63-0 ]
[ 179898-34-1 ]
[ 1119779-02-0 ]

Yield	Reaction Conditions	Operation in experiment
79.0%		To a solution of IM NaHMDS (74.26 ml, 74.26 mmol) in DMF was added 2-propanal (5.69 ml, 74.26 mmol) at r.t. After stiring for 5 min <strong>[179898-34-1]3-bromo-5-fluoro-benzonitrile</strong> was added. The reaction mixture was stirred at r.t. for 2 hrs, concentrated down. The residue was then partitioned between EtOAc and water. The organic layer was collected and the water layer was back-extracted with EtOAc once. The combined organic layers were dried over MgSO4, filtrated, concentrated, purified by Biotage (5% EtOAc) to afford the final product 3- bromo-5-isopropoxy-benzonitrile (9.46g, 79.0%). 1H NMR (300 MHz, OMSO-d6): delta 7.62 (m, 1 H), 7.47 (m, IH), 7.44 (m, IH), 4.73 (m, 2H), 1.24 (d, J= 6.3 Hz, 6H). LC-MS m/z = 241.4 [ClOHlOBrNO + H]+.

Reference： [1]Patent: WO2009/23718,2009,A2 .Location in patent: Page/Page column 143-144

13
[ 24424-99-5 ]
[ 179898-34-1 ]
[ 1177558-40-5 ]

Yield	Reaction Conditions	Operation in experiment
69%	With sodium tetrahydroborate;nickel dichloride; In ethanol; at 0 - 20℃;	Example 15 1,1-Dimethylethyl [(3-bromo-5-fluorophenyl)methyl]carbamate NaBH4 (1.99 g, 52.5 mmol) was cautiously added to a solution of NiCl2 (1.36 g, 10.5 mmol), Boc2O (4.58 g, 21.0 mmol) and <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (2.10 g, 10.5 mmol) in absolute ethanol (30 mL) at 0 C. (vigorous reaction with the formation of a black precipitate). Once the reaction had subsided the mixture was left to stir at room temperature for 30 min. Ethanol was removed under reduced pressure and the precipitate was dissolved in EtOAc, filtered and repeatedly washed with EtOAc. The combined organic phases were washed with saturated NaHCO3, and dried (Na2SO4). After removing the solvent, the product, was purified by flash column chomatography to yield 1,1-dimethylethyl [(3-bromo-5-fluorophenyl)methyl]carbamate (2.20 g, 69%). 1H NMR (400 MHz, CDCl3) delta 1.46 (S, 9H), 4.28-4.32 (m, 2H), 4.87 (br, 1H), 6.93-7.29 (m, 3H); 13C NMR (100 MHz, CDCl3) delta 20.3, 43.6, 44.1, 79.7, 80.0, 113.0, 114.0, 117.7, 122.5, 126.0, 123.0, 141.7, 155.9, 161.5, 164.0.
69%	With sodium tetrahydroborate; ethanol;nickel dichloride; at 0 - 20℃;	Example 15 1,1-Dimethylethyl[(3-bromo-5-fluorophenyl)methyl]carbamate NaBH4 (1.99 g, 52.5 mmol) was cautiously added to a solution of NiCl2 (1.36 g, 10.5 mmol), Boc2O (4.58 g, 21.0 mmol) and <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (2.10 g, 10.5 mmol) in absolute ethanol (30 mL) at 0 C. (vigorous reaction with the formation of a black precipitate). Once the reaction had subsided the mixture was left to stir at room temperature for 30 min. Ethanol was removed under reduced pressure and the precipitate was dissolved in EtOAc, filtered and repeatedly washed with EtOAc. The combined organic phases were washed with saturated NaHCO3, and dried (Na2SO4). After removing the solvent, the product, was purified by flash column chomatography to yield 1,1-dimethylethyl[(3-bromo-5-fluorophenyl)methyl]carbamate (2.20 g, 69%). 1H NMR (400 MHz, CDCl3) delta 1.46 (S, 9H), 4.28-4.32 (m, 2H), 4.87 (br, 1H), 6.93-7.29 (m, 3H); 13C NMR (100 MHz, CDCl3) delta 20.3, 43.6, 44.1, 79.7, 80.0, 113.0, 114.0, 117.7, 122.5, 126.0, 123.0, 141.7, 155.9, 161.5, 164.0.
69%	With sodium tetrahydroborate; nickel dichloride; In ethanol; at 0 - 20℃;	Example 18 1,1-Dimethylethyl [(3-bromo-5-fluorophenyl)methyl]carbamate NaBH4 (1.99 g, 52.5 mmol) was cautiously added to a solution of NiCl2 (1.36 g, 10.5 mmol), Boc2O (4.58 g, 21.0 mmol) and <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (2.10 g, 10.5 mmol) in absolute ethanol (30 mL) at 0 C. (vigorous reaction with the formation of a black precipitate). Once the reaction had subsided the mixture was left to stir at room temperature for 30 min. Ethanol was removed under reduced pressure and the precipitate was dissolved in EtOAc, filtered and repeatedly washed with EtOAc. The combined organic phase was washed with saturated NaHCO3, and dried over Na2SO4. After removing the solvent, the product was purified by flash column chromatography to yield 1,1-dimethylethyl [(3-bromo-5-fluorophenyl)methyl]carbamate (2.20 g, 69%). 1H NMR (400 MHz, CDCl3): delta 1.46 (S, 9H), 4.28-4.32 (m, 2H), 4.87 (br, 1H), 6.93-7.29 (m, 3H); 13C NMR (100 MHz, CDCl3): delta 20.3, 43.6, 44.1, 79.7, 80.0, 113.0, 114.0, 117.7, 122.5, 126.0, 123.0, 141.7, 155.9, 161.5, 164.0.

69%

With sodium tetrahydroborate; ethanol; nickel dichloride; at 0 - 20℃; for 0.5h;

Example 15 1,1-Dimethylethyl [(3-bromo-5-fhiorophenyl)methyl]carbamateNaBH4 (1.99 g, 52.5 mmol) was cautiously added to a solution of NiCl2 (1.36 g,10.5 mmol), BOC2O (4.58 g, 21.0 mmol) and <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (2.10 g, 10.5 mmol) in absolute ethanol (30 mL) at 0 0C (vigorous reaction with the formation of a black precipitate). Once the reaction had subsided the mixture was left to stir at room temperature for 30 min. Ethanol was removed under reduced pressure and the precipitate was dissolved in EtOAc, filtered and repeatedly washed with EtOAc. The combined organic phases were washed with saturated NaHCO3, and dried (Na2SO4). After removing the solvent, the product, was purified by flash column chomatography to yield 1 , 1 -dimethylethyl [(3-bromo-5-fluorophenyl) methyljcarbamate (2.20 g, 69%). 1H NMR (400 MHz, CDCl3) delta 1.46 (S, 9 H), 4.28-4.32 (m, 2 H), 4.87 (br, 1 H), 6.93-7.29 (m, 3 H); 13C NMR (100 MHz, CDCl3) delta 20.3, 43.6, 44.1, 79.7, 80.0, 113.0, 114.0, 117.7, 122.5, 126.0, 123.0, 141.7, 155.9, 161.5, 164.0.

Reference： [1]Patent: US2009/203657,2009,A1 .Location in patent: Page/Page column 46-47
[2]Patent: US2009/203677,2009,A1 .Location in patent: Page/Page column 49; 50
[3]Patent: US2009/197871,2009,A1 .Location in patent: Page/Page column 49
[4]Patent: WO2009/100169,2009,A1 .Location in patent: Page/Page column 124

14
[ 73183-34-3 ]
[ 179898-34-1 ]
[ 935685-88-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 100℃; for 18h;Inert atmosphere;	3-Bromo-5-fluoro benzonitrile (30 g, 150 mmol), bis(pinacolato)diborane (41.9 g,0.lSmol) and potassium acetate (44.2 g, 0.45mo1) were combined in 1,4-dioxane(300 mL) and degassed with N2 for 10 mins. [1,1-Bis(dipheny[phosphino)ferrocene] pa[[adium(II) dichloride (5.5 g, 7.5 mmo[) wasadded and the mixture degassed with N2 for a further 10 mm before heating at 100C under an atmosphere of nitrogen for 18 h. The mixture was filtered throughCelite and the solids washed with ethyl acetate. The filtrate was washed withbrine, the organic phase separated, dried over MgSO4, filtered and concentratedunder reduced pressure. The crude material was purified by filtration through a silica plug, eluting with EtOAc, and the resultant filtrate concentrated under reduced pressure to afford 43.7 g (quantitative yield assumed, 84 % purity) of the title compound as brown oil1H NMR (500MHz, DMSO-d6): 6 [ppm] 1.31 (5, 12H), 7.65-7.72 (m, 1H), 7.79-7.83 (m, 1H), 8.00 (ddd, J = 8.8, 2.7, 1.4 Hz, 1H).LCMS (Analytical Method A) Rt = 0.91 mm.
97%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃; for 2h;	Intermediate T5: 3-fluoro-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile A mixture of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (0.300 g, 1.5 mmol), bis(pinacolato) diboron (0.762 g, 3 mmol), KOAc (0.589 g, 6.0 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.110 g, 0.15 mmol) in dioxane (15 mL) was stirred at 90 C. for 2 h. The solvent was removed and the residue was purified by flash chromatography on Biotage silica 50 g cartridge (cyclohexane to cyclohexane:EtOAc=70:30) to afford title compound (0.360 g, 1.46 mmol, 97% yield). 1H NMR (400 MHz, DMSO-d6) delta ppm 7.98-8.03 (m, 1H), 7.81-7.85 (m, 1H), 7.68-7.73 (M, 1H), 1.33 (s, 12H).
92%	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; dichloromethane; dimethyl sulfoxide; at 90℃;Inert atmosphere;	Example 5A 3-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenecarbonitrile Under argon, 3.60 g (18.0 mmol) of <strong>[179898-34-1]3-bromo-5-fluorobenzenecarbonitrile</strong>, 5.03 g (19.8 mmol) of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane and 5.30 g (54.0 mmol) of potassium acetate are provided in 72 ml of degassed 1,4-dioxane/DMSO (10/1), and 441 mg (0.54 mmol) of 1,1'-bis(diphenylphosphine)ferrocenedichloropalladium(II)/dichloromethane complex are added. The mixture is stirred at 90 C. overnight. Water is subsequently added, the phases are separated, the aqueous phase is extracted with ethyl acetate and the combined organic phases are concentrated. The crude product is purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 10:1). 4.48 g (92% of theory) of the title compound are obtained. 1H-NMR (400 MHz, DMSO-d6): delta=8.01 (ddd, 1H), 7.82 (s, 1H), 7.70 (ddd, 1H), 1.32 (s, 12H). GC-MS (Method 11): Rt=4.94 min; MS (EIpos): m/z=247 [M]+.

92%	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; dimethyl sulfoxide; at 90℃;Inert atmosphere;	Under argon, 3.60 g (18.0 mmol) of <strong>[179898-34-1]3-bromo-5-fluorobenzenecarbonitrile</strong>, 5.03 g (19.8 mmol) of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane and 5.30 g (54.0 mmol) of potassium acetate are provided in 72 ml of degassed 1,4-dioxane/DMSO (10/1), and 441 mg (0.54 mmol) of 1,1'-bis(diphenylphosphine)ferrocenedichloropalladium(II)/dichloromethane complex are added. The mixture is stirred at 90 C. overnight. Water is subsequently added, the phases are separated, the aqueous phase is extracted with ethyl acetate and the combined organic phases are concentrated. The crude product is purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 10:1). 4.48 g (92% of theory) of the title compound are obtained.1H-NMR (400 MHz, DMSO-d6): delta=8.01 (ddd, 1H), 7.82 (s, 1H), 7.70 (ddd, 1H), 1.32 (s, 12H).GC-MS (Method 11): Rt=4.94 min; MS (EIpos): m/z=247 [M]+.
92%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; dimethyl sulfoxide; at 90℃;Inert atmosphere;	Example 21A 3-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenecarbonitrile Under argon, 3.60 g (18.0 mmol) of <strong>[179898-34-1]3-bromo-5-fluorobenzenecarbonitrile</strong>, 5.03 g (19.8 mmol) of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane and 5.30 g (54.0 mmol) of potassium acetate are provided in 72 ml of degassed 1,4-dioxane/DMSO (10/1), and 441 mg (0.54 mmol) of 1,1'-bis(diphenylphosphine)ferrocenedichloropalladium(II)/dichloromethane complex are added. The mixture is stirred at 90 C. overnight. Water is subsequently added, the phases are separated, the aqueous phase is extracted with ethyl acetate and the combined organic phases are concentrated. The crude product is purified by flash chromatography (mobile phase:cyclohexane/ethyl acetate 10:1). 4.48 g (92% of theory) of the title compound are obtained. 1H-NMR (400 MHz, DMSO-d6): delta=8.01 (ddd, 1H), 7.82 (s, 1H), 7.70 (ddd, 1H), 1.32 (s, 12H). GC-MS (Method 11): Rt=4.94 min; MS (EIpos): m/z=247 [M]+.
	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 80℃; for 4h;	Example 1; 3-fluoro-5-{5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridin-2-yl}benzonitrile; Step 1: 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile; 3-Bromo-5-fluorobenzonitrile (30.0 mmol, 9.23 g), bis(pinacolato)diboron (30.0 mmol, 7.62 g), PdCl2(dppf)2 (1:1 complex with dichloromethane, 1.2 mmol, 980 mg), and potassium acetate (105 mmol, 10.3 g) were combined in deoxygenated dioxane (150 mL) and heated at 80 C. for 4 hrs, at which time the reaction was determined to be complete by GC/MS analysis. The reaction was cooled to room temperature, and poured in to a separatory funnel containing EtOAc (300 mL) and water (200 mL). The aqueous layer was back extracted with EtOAc (75 mL), and the combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was carried on to the next step with out further purification or characterization.
	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 100 - 110℃; for 6h;	Intermediate 20. 3-fluoro-5-(4 A5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzonitrile; [0186] To a mixture of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (100 g, 0.5 mol, Oakwood Products, Inc., West Columbia, SC, USA), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (280 g, 1.4 mol), potassium acetate (135 g, 1.1 mol) in DMF (1200 mL) was added Pd(dppf)Cl2 (21 g, 28 mmol). The mixture was heated at 100-110 C for 6 h. DMF was evaporated and the residue was suspended in water and extracted with EtOAc (3X). The combined EtOAc layers were dried over Na2SO4 and evaporated. The residue was purified by column chromatography (PE : EA = 10 : 1 v/v) to give 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzonitrile (20) (190 g in 60% purity).[0187] 1HNMR (CDCl3, 400MHz): delta 7.84 (s, 1H), 7.68 (d, 1H), 7.38 (m, 1H), 1.32 (s, 12H).

Reference： [1]Patent: WO2016/91776,2016,A1 .Location in patent: Page/Page column 206; 207
[2]Patent: US2015/361100,2015,A1 .Location in patent: Paragraph 0785; 0786
[3]Patent: US2012/22123,2012,A1 .Location in patent: Page/Page column 12
[4]Patent: US2012/22059,2012,A1 .Location in patent: Page/Page column 11
[5]Patent: US2013/45999,2013,A1 .Location in patent: Paragraph 0224; 0225; 0226; 0227
[6]Patent: US2009/203903,2009,A1 .Location in patent: Page/Page column 9
[7]Patent: WO2010/102154,2010,A2 .Location in patent: Page/Page column 52

15
[ 1177558-51-8 ]
[ 179898-34-1 ]
[ 1177558-54-1 ]

Yield	Reaction Conditions	Operation in experiment
60%		Example 54 3'-([(1,1-Dimethylethyl)(dimethyl)silyl]oxy}methyl)-5-fluoro-3-biphenylcarbonitrile <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (5.00 g, 25.0 mmol), Pd(OAc)2 (0.15 g), PPh3 (0.60 g) and K2CO3 (5.18 g, 37.5 mmol) were dissolved in dioxane (60 mL). The mixture was heated at 70 C. for 30 min, then [3-([(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)phenyl]boronic acid (7.99 g, 30.0 mmol) was added. The mixture reaction was stirred at reflux overnight. The solvent was removed under reduced pressure, then diluted with CH2Cl2 (100 mL). The organic layer was washed with water (50 mL) and brine (50 mL). And the organic layer was dried over Na2SO4. The product 3'-([(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-5-fluoro-3-biphenylcarbonitrile (5.10 g, 60%) was purified by flash column chomatography. 1H NMR (400 MHz, CDCl3) delta 7.67 (t, J=5.2 Hz, 1H), 7.54-7.32 (m, 5H), 4.81 (s, 2H), 0.94 (s, 9H), 0.13 (s, 6H).
60%		Example 54 3 '-({ [(1 ,1-Dimethylethyl)(dimethyl)silyl] oxy} methyl)-5-fluoro- 3- biphenylcarbonitrile<strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (5.00 g, 25.0 mmol), Pd(OAc)2 (0.15 g), PPh3 (0.60 g) and K2CO3 (5.18 g, 37.5 mmol) were dissolved in dioxane (60 mL). The mixture was heated at 700C for 30 min, then [3 -([(l,l-dimethylethyl)(dimethyl)silyl] oxy} methyl) phenyljboronic acid (7.99 g, 30.0 mmol) was added. The mixture reaction was stirred at reflux overnight. The solvent was removed under reduced pressure, then diluted with CH2Cl2 (100 mL). The organic layer was washed with water (50 mL) and brine (50 mL). And the organic layer was dried over Na2SOzI. The product 3'-([(l,l-dimethylethyl) (dimethyl)silyl]oxy} methyl)-5-fluoro-3-biphenylcarbonitrile (5.10 g, 60%) was purified by flash column chomatography. 1H NMR (400 MHz, CDCl3) delta 7.67 (t, J=5.2 Hz, 1 H), 7.54-7.32 (m, 5 H), 4.81 (s, 2 H), 0.94 (s, 9 H), 0.13 (s, 6 H).
		Example 54 3'-([(1,1-Dimethylethyl)(dimethyl)silyl]oxy}methyl)-5-fluoro-3-biphenylcarbonitrile <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (5.00 g, 25.0 mmol), Pd(OAc)2 (0.15 g), PPh3 (0.60 g) and K2CO3 (5.18 g, 37.5 mmol) were dissolved in dioxane (60 mL). The mixture was heated at 70 C. for 30 min, then [3-([(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)phenyl]boronic acid (7.99 g, 30.0 mmol) was added. The mixture reaction was stirred at reflux overnight. The solvent was removed under reduced pressure, then diluted with CH2Cl2 (100 mL). The organic layer was washed with water (50 mL) and brine (50 mL). And the organic layer was dried over Na2SO4. The product 3'-([(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-5-fluoro-3-biphenylcarbonitrile (5.10 g, 60%) was purified by flash column chomatography. 1H NMR (400 MHz, CDCl3) delta 7.67 (t, J=5.2 Hz, 1H), 7.54-7.32 (m, 5H), 4.81 (s, 2H), 0.94 (s, 9H), 0.13 (s, 6H).

With potassium carbonate;palladium diacetate; triphenylphosphine; In 1,4-dioxane; at 70℃;Heating; Reflux;

Example 57 3'-([(1,1-Dimethylethyl)(dimethyl)silyl]oxy}methyl)-5-fluoro-3-biphenylcarbonitrile 3-Bromo-5-fluorobenzonitrile (5.00 g, 25.0 mmol), Pd(OAc)2 (0.15 g), PPh3 (0.60 g) and K2CO3 (5.18 g, 37.5 mmol) were dissolved in dioxane (60 mL). The mixture was heated at 70 C. for 30 min, then [3-([(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)phenyl]boronic acid (7.99 g, 30.0 mmol) was added. The mixture reaction was stirred at reflux overnight. The solvent was removed under reduced pressure, then diluted with CH2Cl2 (100 mL). The organic layer was washed with water (50 mL) and brine (50 mL). And the organic layer was dried over Na2SO4. The product 3'-([(1,1-dimethylethyl) (dimethyl)silyl]oxy}methyl)-5-fluoro-3-biphenylcarbonitrile (5.10 g, 60%) was purified by flash column chromatography. 1H NMR (400 MHz, CDCl3): delta 7.67 (t, J=5.2 Hz, 1H), 7.54-7.32 (m, 5H), 4.81 (s, 2H), 0.94 (s, 9H), 0.13 (s, 6H).

Reference： [1]Patent: US2009/203677,2009,A1 .Location in patent: Page/Page column 59
[2]Patent: WO2009/100169,2009,A1 .Location in patent: Page/Page column 141
[3]Patent: US2009/203657,2009,A1 .Location in patent: Page/Page column 56
[4]Patent: US2009/197871,2009,A1 .Location in patent: Page/Page column 58-59

16
[ 1435-51-4 ]
copper(l) cyanide [ No CAS ]
[ 179898-34-1 ]

Yield	Reaction Conditions	Operation in experiment
35%	With pyridine; In N,N-dimethyl-formamide; for 3h;Reflux;	Example 14 3-Bromo-5-fluorobenzonitrile A 250-mL round-bottom flask equipped with a magnetic stir bar was charged with <strong>[1435-51-4]1,3-dibromo-5-fluorobenzene</strong> (7.70 g, 30.3 mmol), DMF (45 mL), pyridine (4.9 mL), and copper (I) cyanide (2.72 g, 30.3 mmol) under nitrogen. A reflux condenser was attached to the flask. The green, cloudy mixture was stirred at reflux for 3 h. Once lower Rf impurities were observed, the reaction was allowed to cool to room temperature. The reaction was quenched with 30 mL of ether, and a precipitate formed in the dark solution. The precipitate was gravity-filtered though Celite. The filtrate was rinsed three times with ether (100 mL/50 g bromide). The isolated solution was added to a separatory funnel. The organic layer was washed with a 2:1 mixture of water and concentrated ammonium hydroxide (30 mL), followed by saturated ammonium chloride solution (230 mL) and saturated sodium bicarbonate (30 mL). The aqueous layers were extracted with ether (340 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The product was purified by flash column chomatography to yield 3-bromo-5-fluorobenzonitrile (2.10 g, 35%). 1H NMR (400 MHz, CDCl3) delta 7.62 (s, 1H), 7.54-7.50 (m, 1H), 7.35-7.32 (m, 1H).
35%	With pyridine; In N,N-dimethyl-formamide; for 3h;Reflux; Inert atmosphere;	Example 14 3-Bromo-5-fluorobenzonitrile A 250-mL round-bottom flask equipped with a magnetic stir bar was charged with <strong>[1435-51-4]1,3-dibromo-5-fluorobenzene</strong> (7.70 g, 30.3 mmol), DMF (45 mL), pyridine (4.9 mL), and copper (I) cyanide (2.72 g, 30.3 mmol) under nitrogen. A reflux condenser was attached to the flask. The green, cloudy mixture was stirred at reflux for 3 h. Once lower Rf impurities were observed, the reaction was allowed to cool to room temperature. The reaction was quenched with 30 mL of ether, and a precipitate formed in the dark solution. The precipitate was gravity-filtered though Celite. The filtrate was rinsed three times with ether (100 mL/50 g bromide). The isolated solution was added to a separatory funnel. The organic layer was washed with a 2:1 mixture of water and concentrated ammonium hydroxide (30 mL), followed by saturated ammonium chloride solution (230 mL) and saturated sodium bicarbonate (30 mL). The aqueous layers were extracted with ether (340 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The product was purified by flash column chomatography to yield 3-bromo-5-fluorobenzonitrile (2.10 g, 35%). 1H NMR (400 MHz, CDCl3) delta 7.62 (s, 1H), 7.54-7.50 (m, 1H), 7.35-7.32 (m, 1H).
35%	With pyridine; In N,N-dimethyl-formamide; for 3h;Inert atmosphere; Reflux;	Example 14 3-Bromo-5-fhiorobenzonitrileA 250-mL round-bottom flask equipped with a magnetic stir bar was charged with 1,3- dibromo-5-fluorobenzene (7.70 g, 30.3 mmol), DMF (45 mL), pyridine (4.9 mL), and copper (I) cyanide (2.72 g, 30.3 mmol) under nitrogen. A reflux condenser was attached to the flask. The green, cloudy mixture was stirred at reflux for 3 h. Once lower Rf impurities were observed, the reaction was allowed to cool to room temperature. The reaction was quenched with 30 mL of ether, and a precipitate formed in the dark solution. The precipitate was gravity- filtered though Celite. The filtrate was rinsed thee times with ether (100 mL/50 g bromide). The isolated solution was added to a separatory funnel. The organic layer was washed with a 2:1 mixture of water and concentrated ammonium hydroxide (30 mL), followed by saturated ammonium chloride solution (2 x 30 mL) and saturated sodium bicarbonate (30 mL). The aqueous layers were extracted with ether (3 x 40 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The product was purified by flash column chomatography to yield 3-bromo-5-fluorobenzonitrile (2.1O g, 35%). 1H NMR (400 MHz, CDCl3) delta 7.62 (s, 1 H), 7.54-7.50 (m, 1 H), 7.35-7.32 (m, 1 H).

23%

With pyridine; In N,N-dimethyl-formamide; at 150℃; for 4.5h;Inert atmosphere;

A mixture of <strong>[1435-51-4]1,3-dibromo-5-fluorobenzene</strong> (7.4 g, 29.3 mmol), copper(I) cyanide (2.6 g, 29.3 mmol), pyridine (3 mL) and N,N-dimethylformamide (30 mL) under an argon atmosphere was heated to 150 C for 4.5 h. Mixture was allowed to room temperature, diethyl ether (100 mL) was added and the formed precipitate was removed via filtration, the precipitate was washed with diethyl ether (100 mL), the filtrate was washed consecutively with: 1) 10 % ammonium hydroxide (100 mL), 2) saturated ammonium chloride (100 mL), and 3) saturated sodium bicarbonate (100 mL), dried over magnesium sulfate and evaporated. Purification of the residue by flash chromatography, using a stepwise gradient of heptane to heptane:ethyl acetate 9:1 afforded the title compound (1.3 g, 23%). 1H NMR (400 MHz, CDCl3) d ppm 7.30 - 7.37 (m, 1 H), 7.48 (dt, J=7.83, 1.89 Hz, 1 H), 7.58 (s, 1 H); 13C NMR (101 MHz, CDCl3) d 115.5, 115.6, 116.4, 116.5, 118.5, 118.7, 123.9, 124.0, 124.4, 124.7, 131.4, 131.4, 161.1, 163.6.

Reference： [1]Patent: US2009/203657,2009,A1 .Location in patent: Page/Page column 46
[2]Patent: US2009/203677,2009,A1 .Location in patent: Page/Page column 49
[3]Patent: WO2009/100169,2009,A1 .Location in patent: Page/Page column 124
[4]Bioorganic and medicinal chemistry letters,2012,vol. 22,p. 6974 - 6979,6

17
[ 110-91-8 ]
[ 179898-34-1 ]
[ 1129540-92-6 ]

Yield	Reaction Conditions	Operation in experiment
	at 120℃;

Reference： [1]Location in patent: experimental part Kamenecka, Ted; Jiang, Rong; Song, Xinyi; Duckett, Derek; Chen, Weimin; Ling, Yuan Yuan; Habel, Jeff; Laughlin, John D.; Chambers, Jeremy; Figuera-Losada, Mariana; Cameron, Michael D.; Lin, Li; Ruiz, Claudia H.; LoGrasso, Philip V. [Journal of Medicinal Chemistry, 2010, vol. 53, # 1, p. 419 - 431]

18
[ 107-98-2 ]
[ 179898-34-1 ]
[ 883907-45-7 ]

Yield	Reaction Conditions	Operation in experiment
95%		NaHMDS (148 mmol; 27.2 g) was charged to a 1000ml round-bottomed flask (4 necks, thermometer, pressure-equalising dropping funnel, stopper, nitrogen inlet, magnetically stirred, oven dried, nitrogen purged), followed by DMF (300ml). The mixture was stirred for 5 minutes then l-methoxy-2-propanol (1.50 equiv; 148 mmol; 14.3 ml; 13.4 g) was added dropwise over a 10-minute period. The reaction temperature increased to 25C. The mixture was cooled using a cold-water bath to 230C, then 3-bromo-5- fluorobenzonitrile (1.00 equiv; 99.0 mmol; 20.0 g) in DMF (90ml) was added over a 5 minutes period (cold water bath still present). The mixture warmed to 270C during addition, turning from yellow to brown. A line wash of DMF (10ml) was added. The mixture was stirred at ambient temperature for 30 minutes, then quenched by addition of HCl solution (2M, aqueous, 200ml), the dark brown reaction mixture turning pale yellow. The mixture was poured into water (400ml) and extracted with EtOAc (3x400ml). The combined organic extracts were washed with water (3x400ml) and dried over MgSO4, filtered and the solvent removed in vacuo affording 3-bromo-5-(2-methoxy-l- methylethoxy)benzonitrile as an orange oil (25.38g, 95%). 1H NMR (400 MHz, CDCl3) delta: 7.32 (s, IH), 7.26 (s, IH), 7.11 (s, IH), 4.58-4.55 (m, IH), 3.59-3.48 (m, 2H), 3.41 (s, 3H), 1.33-1.31 (d, 3H).

Reference： [1]Patent: WO2006/40527,2006,A1 .Location in patent: Page/Page column 36

19
[ 1246892-63-6 ]
[ 179898-34-1 ]
[ 1246892-16-9 ]

Yield	Reaction Conditions	Operation in experiment
31%	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 100℃;	To a solution of 2-(pyridin-2-yl)-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine (20 mg, 0.1 mmol) in toluene was added <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (30 mg, 0.15 mmol), Cs2CO3 (65 mg, 0.2 mmol), Pd(OAc)2 (1 mg, cat.), and Xantphos (2 mg, cat.). The mixture was heated to 1000C and stirred overnight. The mixture was cooled, dissolved in MeOH, and filtered. The filtrate was concentrated and the residue was purified by preparative TLC to afford 3-fluoro-5-(2-(pyridin-2-yl)-6,7-dihydrooxazolo- [5,4-c]pyridin-5(4H)-yl)benzonitrile (10 mg, 31%) as a yellow solid. 1H NMR (400 MHz, CDCl3): delta 8.68 (d, IH); 8.05 (d, IH), 7.77 (t, IH), 7.32 (t, IH), 6.90 (s, IH), 6.75 (m, 2H), 4.40 (s, 2H), 3.68 (t, 2H), 2.80 (t, 2H); LC/MS: m/e = 321 (M+H)+.

Reference： [1]Patent: WO2010/114971,2010,A1 .Location in patent: Page/Page column 99
[2]Journal of Medicinal Chemistry,2010,vol. 53,p. 7107 - 7118

20
[ 1247883-97-1 ]
[ 179898-34-1 ]
[ 1247879-87-3 ]

Yield	Reaction Conditions	Operation in experiment
26%	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 100℃;	To a solution of 7-methyl-2-(pyridin-2-yl)-4,5,6,7-tetrahydrooxazolo[5,4- c]pyridine (1-81.11) (20 mg, 0.1 mmol) in toluene (2 mL) was added 3-bromo-5- fluorobenzonitrile (28 mg, 0.15 mmol), Cs2CO3 (65 mg, 0.2 mmol), Pd(OAc)2 (1 mg, cat.), and Xantphos (2 mg, cat.). The mixture was heated to 1000C and stirred overnight. The reaction was cooled, dissolved in MeOH and filtered. The filtrate was concentrated and the residue was purified by preparative TLC to afford 3-fluoro-5-(7-methyl-2- (pyridin-2-yl)-6,7-dihydrooxazolo[5,4-c]pyridin-5(4H)-yl)benzonitrile (8 mg, 26%) as a yellow solid. 1H NMR (400 MHz, CDCl3): delta 8.67 (d, IH), 8.05 (d, IH), 7.76 (t, IH), 7.30 (t, IH), 6.88 (s, IH), 6.70-6.79 (m, 2H), 4.36 (q, 2H), 3.72 (dd, IH), 3.20 (q, IH), 3.00-3.10 (m, IH), 1.31 (d, 3H); LC/MS: m/e = 335 (M+H)+.

Reference： [1]Patent: WO2010/114971,2010,A1 .Location in patent: Page/Page column 137-138

21
[ 1247884-63-4 ]
[ 179898-34-1 ]
[ 1247880-00-7 ]

Yield	Reaction Conditions	Operation in experiment
7%	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 100℃;	A mixture of 5,6,7, 8-tetrahydro-2-(pyridin-2-yl)-4H-oxazolo[5,4-c]azepine (1-90.10) (20 mg, 0.09 mmol), <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (18 mg, 0.09 mmol), Pd(OAc)2 (1.0 mg, 0.005 mmol), Xantphos (3 mg, 0.005 mmol), and Cs2CO3 (91 mg, 0.28 mmol) in toluene (5 mL) was stirred at 1000C overnight. The solvent was removed in vacuo and DCM (5 mL) was added. The mixture was filtered and the filtrate was purified by preparative TLC (PE : EtOAc = 1:1) to afford the product 3-fluoro-5-(7,8- dihydro-2-(pyridin-2-yl)-4H-oxazolo[5,4-c] azepin-5(6H)-yl)benzonitrile (2.1 mg, 7%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): delta 8.73 (d, IH), 8.07 (d, IH) , 7.83- 7.79 (m, IH), 7.38-7.31 (m, IH), 6.82 (s, IH), 6.72-6.63 (m, 2H), 4.64 (s, IH), 3.80 (t, 2H), 2.87 (t, 2H), 2.03-1.97 (m, 2H); LC/MS: m/e = 335 (M+H)+.

Reference： [1]Patent: WO2010/114971,2010,A1 .Location in patent: Page/Page column 161

22
[ 1246892-67-0 ]
[ 179898-34-1 ]
[ 1246892-69-2 ]

Yield	Reaction Conditions	Operation in experiment
25%	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 100℃;	To a solution of 2-(pyridin-2-yl)-5,6,7,8-tetrahydro-4H-oxazolo[4,5- c]azepine (1-98.8) (50 mg, 0.23 mmol) in toluene (3 mL) was added 3-bromo-5- fluorobenzonitrile (69 mg, 0.35 mmol), Cs2CO3 (151 mg, 0.46 mmol), Pd(OAc)2 (2 mg, cat.), and Xantphos (4 mg, cat.). The mixture was heated overnight at 1000C. The reaction was quenched into MeOH and filtered. The filtrate was concentrated and the residue purified by preparative TLC to afford 3-fluoro-5-(2-(pyridin-2-yl)-7,8-dihydro- 4H-oxazolo[4,5-c]azepin-5(6H)-yl) benzonitrile (20 mg, 25%) as a yellow solid. 1H NMR (400 MHz, CDCl3): delta 8.65 (d, IH), 8.00 (d, IH), 7.75 (t, IH), 7.27-7.31 (m, IH), 6.77 (s, IH), 6.62-6.69 (m, IH), 6.59 (d, IH), 4.47 (s, 2H), 3.65 (t, 2H), 2.95 (t, 2H), 1.90-2.00 (m, 2H); LC/MS: m/e = 335 (M+H)+.

Reference： [1]Patent: WO2010/114971,2010,A1 .Location in patent: Page/Page column 169
[2]Journal of Medicinal Chemistry,2010,vol. 53,p. 7107 - 7118

23
[ 1017170-40-9 ]
[ 179898-34-1 ]
[ 1246891-72-4 ]

Yield	Reaction Conditions	Operation in experiment
3%	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 80℃;Inert atmosphere;	2-(Pyridin-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (1-105.2) (107 mg, 0.49 mmol), tris(dibenzylideneacetone)dipalladium(0) (31 mg, 0.034 mmol), BINAP (77 mg, 0.12 mmol), and <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (97 mg, 0.49 mmol) were combined in toluene (4 mL). The reaction was flushed with nitrogen. Sodium tert-butoxide (56 mg, 0.59 mmol) was added, the reaction flushed once again with nitrogen and heated at 800C under nitrogen overnight. The solvent was concentrated removed under vacuum. The residue was purified by silica gel chromatography (EtOAc (10%MeOEta)/Etaexanes), followed by recrystallization in MeOH to give the product as a yellow solid (5.3 mg, 3%). 1U NMR (400 MHz, CDCl3) delta 8.60 (d, IH), 8.12 (d, IH), 7.76-7.81 (m, IH), 7.30- 7.33 (m, IH), 6.99 (s, IH), 6.84-6.88 (m, IH), 6.78 (d, IH), 4.57 (s, 2H), 3.77 (t, 2H), 3.08 (t, 2H); LC/MS: m/e = 337 (M+H)+.

Reference： [1]Patent: WO2010/114971,2010,A1 .Location in patent: Page/Page column 175
[2]Journal of Medicinal Chemistry,2010,vol. 53,p. 7107 - 7118

24
[ 1246892-84-1 ]
[ 179898-34-1 ]
[ 1246892-86-3 ]

Yield	Reaction Conditions	Operation in experiment
13%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In xylene; at 150℃; for 0.5h;Microwave irradiation;	3-(4-Methoxybenzyl)-2-(pyridine-2-yl)-4,5,6,7-tetrahydro-3H-imidazo[4,5- c]pyridine (108 mg, 0.34 mmol), tris(dibenzylideneacetone)dipalladium(0) (6.2 mg, 0.007 mmol), 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene (12 mg, 0.02 mmol), Cs2CO3 (220 mg, 0.67 mmol), and <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> were combined in xylene (4 mL). The mixture was heated under microwave at 1500C for 30 minutes. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by reverse phase purification (Gilson GX-281 (NH4HCO3/Acetonitrile)) to give a yellow/brown (20 mg, 13%). 1H NMR (400 MHz, CDCl3): delta 8.50 (d, IH), 8.15 (m, IH), 7.75 (t, IH), 7.19 (m, IH), 7.1 (m, IH), 6.87 (s, IH), 6.85 (s, IH), 6.75-6.8 (d, 2H), 6.7 (d, IH), 6.58 (m, IH), 5.9 (s, IH), 4.12 (s, IH), 3.78 (s, IH), 3.74 (s, IH), 3.65 (t, 2H), 2.83 (t, 2H); LC/MS: m/e = 440 (M+H)+.

Reference： [1]Patent: WO2010/114971,2010,A1 .Location in patent: Page/Page column 184-185
[2]Journal of Medicinal Chemistry,2010,vol. 53,p. 7107 - 7118

25
[ 1246891-77-9 ]
[ 179898-34-1 ]
[ 1247880-28-9 ]

Yield	Reaction Conditions	Operation in experiment
0.6%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In xylene; at 150℃; for 0.5h;Microwave irradiation;	2-(Pyridin-2-yl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[l,5-alpha]pyrazine (1-112.5) (112 mg, 0.56 mmol), tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.011 mmol), Xantphos (19 mg, 0.033 mmol), Cs2CO3 (362 mg, 1.11 mmol), and 3-bromo-5- fluorobenzonitrile (245 mg, 1.22 mmol) were combined in xylene (4 mL). The mixture was stirred under microwaves at 1500C for 30 minutes. The solvent was evaporated and the crude material was purified by silica gel chromatography (9/1 DCM/MeOEta). The fractions containing the desired product were collected and combined and then purified by reverse phase purification (Gilson GX-281 (NH4HCO3 / Acetonitrile)) to give the desired product as a colorless oil (1.1 mg, 0.6%). 1H NMR (400 MHz, CDCl3): delta 8.72 (s, IH), 8.09 (d, IH), 7.8 (t, IH), 7.33 (t, IH), 7.1 (s, IH), 6.9 (t, 2H), 4.65 (s, 2H), 4.45 (s, 2H), 3.9 (s, 2H); LC/MS: m/e = 321 (M+H)+.

Reference： [1]Patent: WO2010/114971,2010,A1 .Location in patent: Page/Page column 185
[2]Journal of Medicinal Chemistry,2010,vol. 53,p. 7107 - 7118

26
[ 1247885-34-2 ]
[ 179898-34-1 ]
[ 1247881-26-0 ]

Yield	Reaction Conditions	Operation in experiment
28%	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); XPhos; In toluene; at 110℃; for 1h;Microwave irradiation;	A mixture of 8-methyl-2-(pyridin-2-yl)-5,6,7,8-tetrahydro-4H-oxazolo[4,5- c]azepine (18 mg, 0.08 mmol), Pd2(dba)3 (18 mg, 0.02 mmol), Xphos (19 mg, 0.04 mmol), <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (20 mg, 0.1 mmol), and Na-O^Bu (30 mg, 0.3 mmol) in toluene (1 mL) was heated to 1100C by microwave and stirred for 1 h. The mixture was evaporated to dryness. The residue was diluted with water and extracted with dichloromethane. The combined organic layers were dried with sodium sulfate, filtered, evaporated and purified by prep-TLC to obtain the title compound as a yellow solid (8 mg, 28%). 1H NMR (400 MHz, MeOH-J4): delta 8.63 (s, IH), 8.04-8.13 (m, 2H), 7.56 (s, IH), 6.97 (s, IH), 6.85-6.89 (s, IH), 6.71-6.72 (d, IH), 4.51-4.63 (m, 2H), 3.99-4.05 (m, IH), 3.75-3.81 (m, IH), 3.27-3.30 (m, IH), 2.03-2.12 (m, IH), 1.76-1.84 (m, IH), 1.39-1.42 (m, IH); LC/MS: m/e = 349 (M+H)+.

Reference： [1]Patent: WO2010/114971,2010,A1 .Location in patent: Page/Page column 229-230

27
[ 1187929-95-8 ]
[ 179898-34-1 ]
[ 1247879-33-9 ]

Yield	Reaction Conditions	Operation in experiment
5%	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 120℃;Inert atmosphere;	2-Phenyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine hydrochloride (purchased from Anichem) (150mg, 0.63 mmol), tris(dibenzylideneacetone)dipalladium(0) (40 mg, 0.04 mmol), BINAP (97 mg, 0.16 mmol) and <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (126 mg, 0.63 mmol) were combined in toluene (3 mL). The mixture was first flushed with nitrogen before and after the addition of sodium tert-butoxide (73 mg, 0.76 mmol). The solution was heated at 1200C under nitrogen overnight. The solvent was concentrated and removed under vacuum. The residue was then purified by silica gel column (EtOAc (10% MeOEta)/hexanes), followed by recrystallization in methanol to give a white solid (10 mg, 5%). 1H NMR (400 MHz, CDCl3): delta 8.01 (m, 2H), 7.46 (m, 3H), 6.97 (s, IH), 6.81-6.85 (m, IH), 6.78 (m, IH), 4.32 (m, 2H), 3.77 (t, 2H), 2.95-2.98 (m, 2H); LC/MS: m/e = 320 (M+H)+.

Reference： [1]Patent: WO2010/114971,2010,A1 .Location in patent: Page/Page column 106-107

28
[ 127972-02-5 ]
[ 179898-34-1 ]
[ 1260097-24-2 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 140℃; for 0.666667h;microwave; Inert atmosphere; Sealed;	Intermediate 210: 3-(3-cyano-5-fluoro-phenyl)-4-methoxybenzaldehyde210[0179] To a solution of 5-formyl-2-methoxyphenylboronic acid (540 mg, 3 mmol, 1 eq, Frontier Scientific Inc., Logan, UT, USA) in dioxane : H2O (4: 1 ; 15 mL) was added <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (478 mg, 2.4 mmol, 0.8 eq.), Na2CO3 (736 mg, 6 mmol, 2 eq.) and Pd(PPh3)4 (173 mg, 0.15 mmol, 0.05 eq.). The microwave tube was degassed by N2 for one minute and sealed. The mixture was heated for 40 min at 140 0C by microwave. After cooling to room temperature, the reaction mixture was poured into ethyl acetate (40 mL) and washed by water (15 mL). The organic layer was dried (Na2SO4) and evaporated to dryness. Purification via flash chromatography to yield 535 mg (70 % yield) of intermediate 210.

Reference： [1]Patent: WO2011/2814,2011,A2 .Location in patent: Page/Page column 59-60

29
[ 97674-02-7 ]
[ 179898-34-1 ]
3-acetyl-5-fluorobenzenecarbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%		824 mg (0.900 mmol) of tris(dibenzylideneacetone)dipalladium and 1.23 g (1.98 mmol) of rac-1,1'-binaphthalene-2,2'-diylbis(diphenylphosphane) are added to 9.00 g (45.0 mmol) of <strong>[179898-34-1]3-bromo-5-fluorobenzenecarbonitrile</strong> in toluene (300 ml) under an argon atmosphere. After the addition of 19.5 g (54.0 mmol) of (1-ethoxyvinyl)tributylstannane, the mixture is stirred under reflux overnight. The reaction mixture is subsequently concentrated and the residue is taken up in 300 ml of THF. After the addition of 100 ml of an aqueous 2N hydrogen chloride solution the mixture is stirred at room temperature for 2 h. The reaction mixture is subsequently neutralized with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 9:1). 7.11 g (97% of theory) of the title compound are obtained.1H-NMR (400 MHz, DMSO-d6): delta=8.28 (t, 1H), 8.18-8.14 (m, 1H), 8.08-8.04 (m, 1H), 2.65 (s, 3H).GC-MS (Method 11): Rt=3.97 min; MS (EIpos): m/z=163 [M]+.
97%		Example 23A 3-Acetyl-5-fluorobenzenecarbonitrile Under an argon atmosphere, 824 mg (0.900 mmol) of tris(dibenzylideneacetone)dipalladium and 1.23 g (1.98 mmol) of rac-1,1'-binaphthalene-2,2'-diylbis(diphenylphosphane) are added to 9.00 g (45.0 mmol) of <strong>[179898-34-1]3-bromo-5-fluorobenzenecarbonitrile</strong> in toluene (300 mol). After the addition of 19.5 g (54.0 mmol) of (1-ethoxyvinyl)tributylstannane, the mixture is stirred under reflux overnight. The reaction mixture is subsequently concentrated and the residue is taken up in 300 ml of THF. After the addition of 100 ml of an aqueous 2N hydrogen chloride solution, the mixture is stirred at room temperature for 2 h. The reaction mixture is subsequently neutralized using a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 9:1). 7.11 g (97% of theory) of the title compound are obtained. 1H-NMR (400 MHz, DMSO-d6): delta=8.28 (t, 1H), 8.18-8.14 (m, 1H), 8.08-8.04 (m, 1H), 2.65 (s, 3H). GC-MS (Method 11): Rt=3.97 min; MS (EIpos): m/z=163 [M]+.

Reference： [1]Patent: US2011/124618,2011,A1 .Location in patent: Page/Page column 38-39
[2]Patent: US2013/45999,2013,A1 .Location in patent: Paragraph 0232; 0233; 0234; 0235

30
[ 176548-70-2 ]
[ 179898-34-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3243 - 3247

31
[ 872428-46-1 ]
[ 179898-34-1 ]
[ 1312923-99-1 ]

Yield	Reaction Conditions	Operation in experiment
68%		General procedure: To a solution of 7 (500 mg, 2.64 mmol) in 10 mL of DMF was successively added Et3N (1.47 mL, 10.56 mmol), 9a (600 mg, 2.64 mmol), CuI (50 mg, 0.26 mmol), and trans-dichlorobis(triphenylphosphine)palladium (184 mg, 0.26 mmol). The resulting solution was warmed to 60 oC, and TBAF 1M in THF (2.9 ml, 2.90mmol) was added dropwise. After 2h at this temperature the mixture was hydrolyzed with 50 mL of H2O and, extracted with AcOEt (4 X 30 mL). The organic layer was washed with saturated NaCl (3 X 30 mL), dry over anhydrous Na2SO4, and concentrated on a rotary evaporator. Purification of the residue by column chromatography (hexane/AcOEt 8/2) yielded 487 mg (70 %) of 3a as an off white solid.1H NMR (CDCl3), d = 2.32 (s, 3H, CH3); 7.40 (d, 1H, J=8.0 Hz, CHAr); 7.49 (dt, 1H, J=8.0, 1.0 Hz, CHAr); 8.02 (s, 1H, CHAr); 8.35 (s, 1H, CHAr); 8.40 (d, 1H, J=1.0 Hz, CHAr); 8.50 (s, 1H, CHAr). 13C NMR (CDCl3), d = 18.6 (1C, CH3); 83.5 (1C, C?C); 93.5 (1C, C?C); 114.4 (1C, Cq); 115.9 (1C, Cq); 126.2 (1C, Cq); 126.4 (1C, CHAr); 127.2 (1C, CHAr); 130.1 (1C, CHAr); 134.5 (1C, Cq); 137.0 (1C, CHAr); 138.6 (1C, Cq); 140.0 (1C, CHAr); 148.2 (1C, Cq); 151.0 (1C, CHAr). Anal (C15H9N3O2, HCl) C, H, N.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3243 - 3247

32
[ 887266-90-2 ]
[ 179898-34-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3243 - 3247

33
[ 179898-34-1 ]
[ 329203-85-2 ]
[ 864063-09-2 ]

Yield	Reaction Conditions	Operation in experiment
68%		General procedure: To a solution of 5 (500 mg, 2.55 mmol) in 10 mL of DMF was successively added Et3N (1.42 mL, 10.2mmol), 9a (579 mg, 2.55 mmol), CuI (48 mg, 0.25 mmol), and trans-dichlorobis(triphenylphosphine)palladium (177 mg, 0.25 mmol). The resulting solution was warmed to 60 oC, and TBAF 1M in THF (2.8 ml, 2.80mmol) was added dropwise. After 2h at this temperature the mixture was hydrolyzed with 50 mL of H2O and, extracted with AcOEt (4 X 30 mL). The organic layer was washed with saturated NaCl (3 X 30 mL), dry over anhydrous Na2SO4, and concentrated on a rotary evaporator. Purification of the residue by column chromatography (hexane/AcOEt 8/2) yielded 439 mg (64 %) of 1a as an off white solid. 1H NMR (CDCl3), d = 2.67 (s, 3H, CH3); 7.46 (s, 1H, CHAr); 8.00 (t, 1H, J= 1.6 Hz, CHAr); 8.35 (t, 1H, J=1.6 Hz, CHAr); 8.47 (t, 1H, J=1.6 Hz, CHAr). 13C NMR (CDCl3), d = 19.6 (1C, CH3); 84.6 (1C, C?C); 89.1 (1C, C?C); 114.8 (1C, Cq); 116.3 (1C, Cq); 125.5 (1C, CHAr); 126.5 (1C, CHAr); 126.6 (1C, CHAr); 130.4 (1C, CHAr); 135.4 (1C, Cq); 140.1 (1C, CHAr); 148.6 (1C, Cq); 166.9 (1C, Cq). Anal (C13H7N3O2S, HCl) C, H, N.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3243 - 3247
[2]Chemical Communications,2016,vol. 52,p. 8361 - 8364

34
[ 179898-34-1 ]
[ 656800-40-7 ]
[ 1224431-15-5 ]

Yield	Reaction Conditions	Operation in experiment
61%		General procedure: To a solution of 6 (500 mg, 2.64 mmol) in 10 mL of DMF was successively added Et3N (1.47 mL, 10.56 mmol), 9a (600 mg, 2.64 mmol), CuI (50 mg, 0.26 mmol), and trans-dichlorobis(triphenylphosphine)palladium (184 mg, 0.26 mmol). The resulting solution was warmed to 60 oC, and TBAF 1M in THF (2.9 ml, 2.90mmol) was added dropwise. After 2h at this temperature the mixture was hydrolyzed with 50 mL of H2O and, extracted with AcOEt (4 X 30 mL). The organic layer was washed with saturated NaCl (3 X 30 mL), dry over anhydrous Na2SO4, and concentrated on a rotary evaporator. Purification of the residue by column chromatography (hexane/AcOEt 8/2) yielded 473 mg (68 %) of 2a as an off white solid.1H NMR (CDCl3), d = 2.50 (s, 3H, CH3); 7.13 (d, 1H, J=7.6 Hz, CHAr); 7.32 (d, 1H, J=7.6 Hz, CHAr); 7.56 (t, 1H, J=7.6 Hz, CHAr); 8.04 (t, 1H, J=1.6 Hz, CHAr); 8.35 (t, 1H, J=1.6 Hz, CHAr); 8.52 (t, 1H, J=1.6 Hz, CHAr). 13C NMR (CDCl3), d = 24.5 (1C, CH3); 83.4 (1C, C?C); 93.6 (1C, C?C); 114.4 (1C, Cq); 115.9 (1C, Cq); 124.4 (1C, CHAr); 124.9 (1C, CHAr); 126.1 (1C, Cq); 126.4 (1C, CHAr); 130.3 (1C, CHAr); 136.7 (1C, CHAr); 140.1 (1C, CHAr); 140.7 (1C, Cq); 148.1 (1C, Cq); 159.5 (1C, Cq). Anal (C15H9N3O2, HCl) C, H, N.

Reference： [1]ACS Medicinal Chemistry Letters,2012,vol. 3,p. 544 - 549
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3243 - 3247

35
[ 1311265-24-3 ]
[ 179898-34-1 ]
[ 1311261-25-2 ]

Yield	Reaction Conditions	Operation in experiment
41%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 90℃; for 17h;Inert atmosphere; Sealed tube;	Example 76 3-(2'-amino-r,2,2-trimethyl-5'-oxo-r,5'-dihydrospiro[chroman-4,4'-imidazole]-6-yl)-5- fluorobenzonitrile2'-Amino-1^2,2 rimethyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)spiro[chroman-4,4'-imidazol]- 5'(l'H)-one (0.050 g, 0.13 mmol), <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (0.052 g, 0.26 mmol), and Pd(PPh3)4 (0.015 g, 0.013 mmol) were combined in dioxane (0.65 mL) and 2M Na2C03 (0.26 mL, 0.52 mmol) (both degassed with nitrogen sparge for 45 minutes prior to use), nitrogen purged headspace, and the reaction vial was capped. The reaction mixture was heated in a 90C reaction block and stirred for 17 hours. The reaction mixture was then diluted with DCM, Na2S04 was added, and the mixture was stirred 10 minutes. The mixture was filtered through a cotton-plugged pipet topped with Na2S04, rinsed with DCM, and the filtrate was concentrated. The crude was purified by preparative TLC (1 mm plate, 9: 1 DCM:7NNH3/MeOH) to give 3-(2'-amino- 1 ',2,2-trimethyl-5'-oxo- 1 ',5'-dihydrospiro[chroman-4,4'-imidazole]-6-yl)- 5-fluorobenzonitrile (0.020 g, 41% yield) as a powder. NMR (400 MHz, CDC13) delta 7.52 (s, 1H), 7.43- 7.32 (m, 2H), 3.32-7.22 (m, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.91 (s, 1H), 3.23 (s, 3H), 2.53 (d, J = 14.0 Hz, 1H), 1.98 (d, J = 14.0 Hz, 1H), 1.53 (s, 3H), 1.44 (s, 3H). m/z (APCI+) (M+l) = 379.

Reference： [1]Patent: WO2011/72064,2011,A1 .Location in patent: Page/Page column 91

36
[ 179898-34-1 ]
[ 1374518-04-3 ]

Yield	Reaction Conditions	Operation in experiment
52%		General procedure: Into an oven-dried flask equipped with a magnetic stir bar was added aryl fluoride (1.00 g, 1.0 eq.), Na2S (1.1 eq.) and DMF (5 mL) under argon. The reaction mixture was stirred at room temperature for 1 h. Then 1 M NaOH (50 mL) was added and was washed with CH2Cl2 (2 x 25 mL). The aqueous layer was acidified to pH ~ 1-2 with 6 N HCl and extracted with CH2Cl2 (2 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to provide a crude residue. To the residue was added 10% HCl (40 mL) and cooled with an ice-water bath. Then zinc dust (4 g) was added and the mixture was stirred for 1 h. Then EtOAc (100 mL) was added and the mixture was stirred for an additional 30 minutes. The organic layer was separated and washed with water (40 mL) and brine (40 mL), dried over MgSO4, filtered and concentrated to provide the desired product with satisfactory purity.

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 2548 - 2551

37
[ 179898-34-1 ]
[ 141-91-3 ]
[ 1394909-57-9 ]

Yield	Reaction Conditions	Operation in experiment
51%	With 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 120℃; for 2h;Inert atmosphere; Sealed tube;	3-[(2R,6S)-2,6-dimethyl-4-morpholinyl]-5-fluoro-benzonitrile (Intermediate 13)(Intermediate 13)A mixture of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (55.56 g, 277.80 mmol), cis-2,6- dimethylmorpholine (34.40 mL, 277.80 mmol), sodium tert-butoxide (40.05 g, 416.70 mmol) and dry toluene (300 mL) was introduced in a pressure tube and was degassed with nitrogen for 5 min. Xantphos [161265-03-8] (9.64 g, 16.67 mmol) and Pd2(dba)3 (5.09 g, 5.55 mmol) were added and the mixture was further degassed for 5 min. The tube was sealed and the reaction mixture was stirred at 120 C for 2 h. The reaction mixture was diluted with CH2CI2 and washed with water. The aqueous layer was extracted with CH2CI2. The combined organic layers were washed with water, dried on MgS04, filtered and evaporated. The residue was purified by column chromatography on silica gel (eluent gradient from 100% DCM to 99/1 DCM/MeOH). The desired fractions were evaporated. The residue was triturated in Et20 and was filtered, yielding 33 g of Intermediate 13 (51 %) as a white solid after drying in a vacuum oven overnight.

Reference： [1]Patent: WO2012/113850,2012,A2 .Location in patent: Page/Page column 38-39

38
[ 1394909-69-3 ]
[ 179898-34-1 ]
[ 1394909-71-7 ]

Yield	Reaction Conditions	Operation in experiment
44%		3-fluoro-5-[(2S)-2-(trifluoromethyl)-4-morpholinyl]-benzonitrile (Intermediate(Intermediate 24)A mixture of Intermediate 22 (4.94 g; 25 mmol) and sodium tert-butoxide (6 g, 62.5 mmol) in monoglyme (50 mL) was degassed for 15 min with nitrogen. The Nolan catalyst ([478980-01-7], 718 mg, 1.25 mmol) was added, followed by 3-bromo-5- fluorobenzonitrile (5 g, 25 mmol). The reaction mixture was stirred at 50 C for 48 h. The reaction mixture was poured into ice/water. The mixture was neutralized with IN HC1 and was extracted twice with EtOAc. The combined organic layer was washed with brine, dried on MgS04, filtered and evaporated. The residue was purified by column chromatography on silica gel (eluent 50/50 DCM/heptane). The desired fractions were evaporated and the residue was crystallized in iPr20/heptane 1/10, yielding 3 g of Intermediate 24 (44 %) after drying in a vacuum oven at 50C overnight.

Reference： [1]Patent: WO2012/113850,2012,A2 .Location in patent: Page/Page column 42-43

39
[ 179898-34-1 ]
[ 176548-70-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	With water; sodium hydroxide; for 2h;Reflux;	A mixture of 3-bromo-5-fluorobenzonitrile (2.8 g, 13.8 mmol) and aqueous sodium hydroxide (5 M, 28 mL) was heated to reflux for 2 h. After cooling to room temperature, pH was adjusted to 1 by the addition of concentrated hydrochloric acid. The formed precipitate was collected by filtration, the solid was washed with cold water and dried to afford the title compound (2.8 g, 94%). 1H NMR (400 MHz, CD3OD) d ppm 6.31 (dt, J=8.08, 2.02 Hz, 1 H), 6.37 - 6.43 (m, 1 H), 6.68 (s, 1 H).

Reference： [1]Bioorganic and medicinal chemistry letters,2012,vol. 22,p. 6974 - 6979,6

40
[ 179898-34-1 ]
[ 334792-52-8 ]

Reference： [1]Bioorganic and medicinal chemistry letters,2012,vol. 22,p. 6974 - 6979,6

41
[ 179898-34-1 ]
[ 887266-90-2 ]

Reference： [1]Bioorganic and medicinal chemistry letters,2012,vol. 22,p. 6974 - 6979,6

42
[ 68-12-2 ]
[ 179898-34-1 ]
[ 1003708-42-6 ]

Yield	Reaction Conditions	Operation in experiment
99%		3 -fluoro-5 -formylbenzonitrile : A solution of 3 -bromo-5 -fluorobenzonitrile(5.00 g, 25.0 mmol) in dry THF (25 mL) was cooled to 0 C and 2M iPrMgCl (15.0 mL, 30.0 mmol) in THF was added dropwise over 5 minutes. The mixture was stirred at 0 C for 15 minutes then at ambient temperature for 1 hour. The mixture was cooled to 0 C and dry DMF (5.81 mL, 75.0 mmol) was added. The mixture was stirred for 17 hours during which time the temperature reached ambient temperature after 2 hours. The mixture was added to ice water (150 mL) and Et20 (100 mL). The biphasic mixture was stirred and treated with 6M HC1 to aqueous pH=3. The organic layer was removed and the aqueous layer extracted with Et20 (2X). The combined Et20 fractions were washed with saturated NaCl and dried over MgS04/activated carbon. The dried solution was filtered through a S1O2 plug eluting with Et20. The filtrate was concentrated to give the title compound as a yellow solid that was dried in vacuum (3.68 g, 99%). 1H NMR (CDC13) delta 10.0 (s, 1H), 8.00 (s, 1H), 7.81-7.86 (m, 1H), 7.62-7.67 (m, 1H).
99%		Step A: 3-fluoro-5-formylbenzonitrile: A solution of 3-bromo-5- fluorobenzonitrile (5.00 g, 25.0 mmol) in dry THF (25 mL) was cooled to 0 C and 2M iPrMgCl (15.0 mE, 30.0 mmol) in THF was added dropwise over 5 minutes. The mixture was stirred at 0 C for 15 minutes then at ambient temperature for 1 hour. The mixture was cooled to 0 C and dry DMF (5.81 mL, 75.0 mmol) was added. The mixture was stirred for 17 hours during which time the temperature reached ambient temperature after 2 hours. The mixture was added to ice water (150 mL) and Et20 (100 mL). The biphasic mixture was stirred and treated with 6M HC1 to aqueous pH=3. The organic layer was removed and the aqueous layer extracted with Et20 (2X). The combined Et20 fractions were washed with saturated NaC1 and dried over MgSO4/activated carbon. The dried solution was filtered through a Si02 plug eluting with Et20. The filtrate was concentrated to give the title compound as a yellow solid that was dried in vacuum (3.68 g, 99%). ?H NMR (CDC13) oe 10.0 (s, 1H), 8.00 (s, 111), 7.81-7.86 (m, 111), 7.62-7.67 (m, 111).
99%		1003751 Step A: 3-fluoro-5-formylbenzonitrile: A solution of 3-bromo-5- fluorobenzonitrile (5.00 g, 25.0 mmol) in dry THF (25 mL) was cooled to 0 C and 2M iPrMgCl (15.0 mE, 30.0 mmol) in TUF was added dropwise over 5 minutes. The mixture was stirred at 0 C for 15 minutes then at ambient temperature for 1 hour. The mixture was cooled to 0 C and dry DMF (5.81 mL, 75.0 mmol) was added. The mixture was stirred for 17 hours during which time the temperature reached ambient temperature after 2 hours. The mixture was added to ice water (150 mE) and Et20 (100 mE). The biphasic mixture was stirred and treated with 6M HC1 to aqueous pH=3. The organic layer was removed and the aqueous layer extracted with Et20 (2X). The combined Et20 fractions were washed with saturated NaC1 and dried over MgSO4/activated carbon. The dried solution was filtered through a Si02 plug eluting with Et20. The filtrate was concentrated to give the title compound as a yellow solid that was dried in vacuum (3.68 g, 99%). ?H NMR (CDCI3) 8 10.0 (s, 1H), 8.00 (s, 1H), 7.81- 7.86 (m, 111), 7.62-7.67 (m, 1H).

99%

Preparation 0-100 Trans-3-(4-amino- 1 -(2-methoxyethyl)pyrrolidin-3-yl)-5-fluorobenzonitrile 1005731 Step A: 3-fluoro-5-fonnylbenzonitrile: A solution of 3-bromo-5- fluorobenzonitrile (5.00 g, 25.0 mmol) in dry THF (25 mL) was cooled to 0 C and 2M iPrMgCl (15.0 mL, 30.0 mmol) in THF was added dropwise over 5 minutes. The mixture was stirred at 0 C for 15 minutes then at ambient temperature for 1 hour. The mixture was cooled to 0 C and dry DMF (5.81 mL, 75.0 mmol) was added. The mixture was stirred for 17 hours during which time the temperature reached ambient temperature after 2 hours. The mixture was added to ice water (150 mL) and Et20 (100 mE). The biphasic mixture was stirred and treated with 6M HC1 to aqueous pH=3. The organic layer was removed and the aqueous layer extracted with Et20 (2X). The combined Et20 fractions were washed with saturated NaCl and dried over MgSO4lactivated carbon. The dried solution was filtered through a Si02 plug eluting with Et20. The filtrate was concentrated to give the title compound as a yellow solid that was dried in vacuum (3.68 g, 99%). ?H NMR (CDC13) oe 10.0 (s, 1H), 8.00 (s, 1H), 7.81- 7.86 (m, 1H), 7.62-7.67 (m, 1H).

Reference： [1]Patent: WO2012/158413,2012,A2 .Location in patent: Page/Page column 90
[2]Patent: WO2014/78323,2014,A1 .Location in patent: Paragraph 00542
[3]Patent: WO2014/78372,2014,A1 .Location in patent: Paragraph 00375
[4]Patent: WO2014/78378,2014,A1 .Location in patent: Paragraph 00573

43
[ 179898-34-1 ]
[ 214360-65-3 ]
[ 1261859-03-3 ]

Yield	Reaction Conditions	Operation in experiment
84%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 14h;Inert atmosphere; Sealed tube;	Example 11 2-[(4-Fluoro-benzenesulfonyl)-methyl-amino]-N-(5-fluoro-4'-trifluoromethyl-biphenyl-3- ylmethyl)-acetamide A solution of 4,4,5,5-tetramethyl-2-(4-trifluoromethyl-phenyl)-[l,3,2]dioxaborolane(1.00 g, 3.68 mmol), <strong>[179898-34-1]3-bromo-5-fluoro-benzonitrile</strong> (0.74 g, 3.68 mmol) and potassium carbonate (0.51 g, 3.68 mmol) in DMF (5 mL) at 25C was purged with nitrogen gas and evacuated three times. The solution was then treated with teira 3s(triphenylphosphine)palladium(0) (212 mg, 184 muiotaetaomicron) and then sealed and heated to 120C for 14 h. The reaction mixture was cooled to 25 C, unsealed and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (80/20 hexanes/ethyl acetate) afforded 5-fluoro-4'- trifluoromethyl-biphenyl-3-carbonitrile (820 mg, 84%) as a white solid.

Reference： [1]Patent: WO2014/49047,2014,A1 .Location in patent: Page/Page column 55; 56

44
[ 35309-35-4 ]
[ 179898-34-1 ]
[ 1609265-56-6 ]
[ 1609265-55-5 ]

Reference： [1]Patent: WO2014/70976,2014,A1

45
[ 35309-35-4 ]
[ 179898-34-1 ]
[ 1609264-24-5 ]

Yield	Reaction Conditions	Operation in experiment
	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere;	Step 1:2a1 (Synchem-inc, 1.72 g, 12 mmol), 2a2 (Matrix, 2 g, 10 mmol), cesium carbonate (4.9 g, 15mmol), tris(dibenzylideneacetone)dipalladium(O) (229 mg, 0.25 mmol) and 4,5-bisdiphenylphosphanyl-9,9-dimethyi-9H-xanthene (289 mg, 0.5 mmol) are placed in 1 ,4-dioxane(20 ml). The mixture is degassed with argon for 20 min and heated at 1 OOQC for 16 h. Thereaction mixture is cooled toRT, EtOAc is added and the organic layer is washed with waterand brine. The organic layer is dried over Na2S04, filtered and concentrated in vacuo. Theproduct is purified by flash chromatography (1 0%-80% EtOAc:hexanes) to afford 2a3 (tR = 1.3min, (M+Ht 263.1 ).

Reference： [1]Patent: WO2014/70976,2014,A1 .Location in patent: Page/Page column 18

46
6-(trifluoromethyl)-3-pyridinylboronic acid [ No CAS ]
[ 179898-34-1 ]
3-fluoro-5-[6-(trifluoromethyl)pyridin-3-yl]benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere;	A mixture of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (10 g, 50.00 mmol, 1.00 equiv), [6- (trifluoromethyl)pyridin-3-yl]boronic acid (9.6 g, 50.28 mmol, 1.00 equiv), potassium carbonate (27.6 g, 199.70 mmol, 4.00 equiv), and Pd(dppf)C12 (3.67 g, 5.02 mmol, 0.10 equiv) in dioxane (400 mL)/water(80 mL) was stirred overnight at 100C under nitrogen. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column eluting with ethyl acetate/petroleum ether (10:100) to afford the title compound (11.4 g, 86%) as a light yellow solid.

Reference： [1]Patent: WO2015/52264,2015,A1 .Location in patent: Paragraph 01690; 01691

47
[ 179898-34-1 ]
(3-bromo-5-fluoro-phenyl)methanamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53.5%		Step 1 (0884) A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (XCV) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH3-Me2S (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20 C. Then it was stirred at 80 C. for 2 h, HCl (6 N, 100 mL) was added to the mixture slowly at 20 C. The mixture was stirred at 80 C. for 1 h, then it was washed with EtOAc (300 ml). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (XCVI) (24.0 g, 117.62 mmol, 53.5% yield). 1H NMR (CDCl3, 300 MHz) 3.86 (s, 2H), 7.01 (d, J=8 Hz, 1H), 7.12 (d, J=8 Hz, 1H), 7.28 (s, 1H); ESIMS found C7H7BrFN m/z 203.9 (Br79M+H).
53.5%		Step 1 A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (CIV) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH3-Me2S (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20 C. Then it was stirred at 80 C. for 2 h, HCl (6 N, 100 mL) was added to the mixture slowly at 20 C. The mixture was stirred at 80 C. for 1 h, then it was washed with EtOAc (300 ml). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL*3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (CV) (24.0 g, 117.62 mmol, 53.5% yield). 1H NMR (CDCl3, 300 MHz) 3.86 (s, 2H), 7.01 (d, J=8 Hz, 1H), 7.12 (d, J=8 Hz, 1H), 7.28 (s, 1H); ESIMS found C7H7BrFN m/z 203.9 (Br79M+H).
53.5%		A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (XCIX) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH3-Me2S (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20C. Then it was stirred at 80C for 2 h, HCl (6 N, 100 mL) was added to the mixture slowly at 20C. The mixture was stirred at 80C for 1 h, then it was washed with EtOAc (300 ml). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (C) (24.0 g, 1 17.62 mmol, 53.5% yield). 1H NMR (CDCl3, 300 MHz) 3.86 (s, 2H), 7.01 (d, J=8Hz, 1H), 7.12 (d, J=8Hz, 1H), 7.28 (s, 1H); ESIMS found C7H7BrFN mlz 203.9 (Br79M+H).

53.5%		A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (CXIV) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH3-Me25 (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20C. Then it was stirred at 80C for 2 h, HC1 (6 N, 100 mL) was added to the mixture slowly at 20C. The mixture was stirred at 80C for 1 h, then it was washed with EtOAc (300 ml). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc(300 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentratedin vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (CXV) (24.0 g, 117.62 mmol,53.5% yield). ?H NMR (CDC13, 300 MHz) ppm 3.86 (s, 2H), 7.01 (d, J=8Hz, 1H), 7.12 (d,J=8Hz, 1H), 7.28 (s, 1H); ESIMS found C7H7BrFN mlz 203.9 (Br79M+H).
53.5%	With dimethylsulfide borane complex; In tetrahydrofuran; at 80℃; for 2h;	A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (LXVI) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH3-Me25 (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20C. Then it was stirred at 80C for 2 h, HC1 (6 N, 100 mL) was added to the mixture slowly at 20C. The mixture was stirred at 80C for 1 h, then it was washed with EtOAc (300 mL). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL x 3). The combined organic layers were dried over anhydrous Na2504 and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (LXVII) (24.0 g, 117.62 mmol, 53.5% yield). ?HNMR(CDC13, 300 MHz) ppm 3.86 (s, 2H), 7.01 (d, J=8Hz, 1H), 7.12 (d, J=8Hz, 1H), 7.28 (s, 1H); ESIMS found C7H7BrFN mlz 203.9 (Br79M+H).
53.5%		A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (LXVI) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH3-Me2S (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20C. Then it was stirred at 80C for 2 h, HC1 (6 N, 100 mL) was added to the mixture slowly at 20C. The mixture was stirred at 80C for 1 h, then it was washed with EtOAc (300 mL). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL x 3). The combined organic layers were dried over anhydrous Na2504 and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (LXVII) (24.0 g, 117.62 mmol, 53.5% yield). ?H NMR (CDC13, 300 MHz) ppm 3.86 (s, 2H), 7.01 (d, J=8Hz, 1H), 7.12 (d, J=8Hz, 1H), 7.28 (s, 1H); ESIMS found C7H7BrFN mlz 203.9 (Br79M+H).
53.5%		j0687j A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (LXXXIII) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH3-Me2S (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20C. Then it was stirred at 80C for 2 h, HC1 (6 N, 100 mL) was added to the mixture slowly at 20C. The mixture was stirred at 80C for 1 h, then it was washed with EtOAc (300 mL). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL x 3). The combined organic layers were dried over anhydrous Na2504 and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (LXXXIV) (24.0 g, 117.62 mmol, 53.5% yield). ?HNMR(CDC13, 300 MHz) ppm 3.86 (s, 2H), 7.01 (d,J=8Hz, 1H), 7.12 (d,J=8Hz, 1H), 7.28 (s, 1H); ESIMS found C7H7BrFN mlz 203.9 (Br79M+H).
53.5%	With dimethylsulfide borane complex; In tetrahydrofuran; at 80℃; for 2h;	A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (LXVI) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH3-Me2S (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20C. Then it was stirred at 80C for 2 h, HC1 (6 N, 100 mL) was added to the mixture slowly at 20C. The mixture was stirred at 80C for 1 h, then it was washed with EtOAc (300 mL). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (LXVII) (24.0 g, 117.62 mmol, 53.5% yield). 'H NMR (CDC13, 300 MHz) ppm 3.86 (s, 2H), 7.01 (d, J=8Hz, 1H), 7.12 (d, J=8Hz, 1H), 7.28 (s, 1H); ESIMS found C7H7BrFN mlz 203.9 (Br79M+H).
53.5%		j0705j A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (CV) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH3-Me2S (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20C. Then it was stirred at 80C for 2 h, HC1 (6 N, 100 mL) was added to the mixture slowly at 20C. The mixture was stirred at 80C for 1 h, then it was washed with EtOAc (300 mL). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL x 3). The combined organic layers were dried over anhydrous Na2504 and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (CVI) (24.0 g, 117.62 mmol, 53.5% yield). ?H NMR (CDC13, 300 MHz) ppm 3.86 (s, 2H), 7.01 (d, J=8Hz, 1H), 7.12 (d, J=8Hz, 1H), 7.28 (s, 1H); ESIMS found C7H7BrFN mlz 203.9 (Br79M+H).
53.5%	With dimethylsulfide borane complex; In tetrahydrofuran; at 80℃; for 2h;	[0687] A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (LXXXIII) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH3-Me2S (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20C. Then it was stirred at 80C for 2 h, HCl (6 N, 100 mL) was added to the mixture slowly at 20C. The mixture was stirred at 80C for 1 h, then it was washed with EtOAc (300 mL). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (LXXXIV) (24.0 g, 117.62 mmol, 53.5% yield). NMR (CDC13, 300 MHz) ppm 3.86 (s, 2H), 7.01 (d, J=8Hz, IH), 7.12 (d, J=8Hz, IH), 7.28 (s, IH); ESIMS found C7H7BrFN mlz 203.9 (Br79M+H).
53.5%		A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (LXVI) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH3-Me2S (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20C. Then it was stirred at 80C for 2 h, HC1 (6 N, 100 mL) was added to the mixture slowly at 20C. The mixture was stirred at 80C for 1 h, then it was washed with EtOAc (300 mL). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL x 3). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (LXVII) (24.0 g, 117.62 mmol, 53.5% yield). NMR (CDC13, 300 MHz) ppm 3.86 (s, 2H), 7.01 (d, J=8Hz, IH), 7.12 (d, J=8Hz, IH), 7.28 (s, IH); ESIMS found C7H7BrFN mlz 203.9 (Br79M+H).
53.5%	With dimethylsulfide borane complex; In tetrahydrofuran; at 20 - 80℃; for 2h;	A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (LXVI) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH3-Me2S (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20C. Then it was stirred at 80C for 2 h, HCl (6 N, 100 mL) was added to the mixture slowly at 20C. The mixture was stirred at 80C for 1 h, then it was washed with EtOAc (300 mL). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (LXVII) (24.0 g, 117.62 mmol, 53.5% yield). NMR (CDC13, 300 MHz) ppm 3.86 (s, 2H), 7.01 (d, J=8Hz, 1H), 7.12 (d, J=8Hz, 1H), 7.28 (s, 1H); ESIMS found C7H7BrFN mlz 203.9 (Br79M+H).
53.5%		A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (LXVI) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH3-Me2S (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20C. Then it was stirred at 80C for 2 h, HC1 (6 N, 100 mL) was added to the mixture slowly at 20C. The mixture was stirred at 80C for 1 h, then it was washed with EtOAc (300 mL). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL x 3). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (LXVII) (24.0 g, 117.62 mmol, 53.5% yield). NMR (CDC13, 300 MHz) ppm 3.86 (s, 2H), 7.01 (d, J=8Hz, IH), 7.12 (d, J=8Hz, IH), 7.28 (s, IH); ESIMS found C7H7BrFN mlz 203.9 (Br79M+H).
53.5%	With dimethylsulfide borane complex; In tetrahydrofuran; at 80℃; for 2h;	A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (LXXXIII) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH3-Me2S (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20C. Then it was stirred at 80C for 2 h, HCl (6 N, 100 mL) was added to the mixture slowly at 20C. The mixture was stirred at 80C for 1 h, then it was washed with EtOAc (300 mL). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (LXXXIV) (24.0 g, 117.62 mmol, 53.5% yield). NMR (CDC13, 300 MHz) ppm 3.86 (s, 2H), 7.01 (d, J=8Hz, IH), 7.12 (d, J=8Hz, IH), 7.28 (s, IH); ESIMS found C7H7BrFN mlz 203.9 (Br79M+H).
53.5%		A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (LXVI) (44.0 g, 220.0 mmol, 1.0eq) was dissolved in THF (30 mL). BH3-Me25 (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20C. Then it was stirred at 80C for 2 h, HC1 (6 N, 100 mL) was added to the mixture slowly at 20C. The mixture was stirred at 80C for 1 h, then it was washed with EtOAc (300 mL). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL x 3). The combined organic layers were dried over anhydrous Na2504 and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (LXVII) (24.0 g, 117.62 mmol, 53.5% yield). ?H NMR (CDC13, 300 MHz) ppm 3.86 (s, 2H), 7.01 (d, J=8Hz, 1H), 7.12 (d, J=8Hz, 1H), 7.28 (s, 1H); ESIMS found C7H7BrFN mlz 203.9 (Br79M+H).
53.5%		A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (LXXXIII) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH3-Me2S (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20C. Then it was stirred at 80C for 2 h, HCl (6 N, 100 mL) was added to the mixture slowly at 20C. The mixture was stirred at 80C for 1 h, then it was washed with EtOAc (300 mL). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (LXXXIV) (24.0 g, 1 17.62 mmol, 53.5% yield). NMR (CDC13, 300 MHz) ppm 3.86 (s, 2H), 7.01 (d, J=8Hz, IH), 7.12 (d, J=8Hz, IH), 7.28 (s, IH); ESIMS found C7H7BrFN mlz 203.9 (Br79M+H).
53.5%	With dimethylsulfide borane complex; In tetrahydrofuran; at 20 - 80℃; for 2h;	A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (CXII) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH3-Me2S (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20C. Then it was stirred at 80C for 2 h, HC1 (6 N, 100 mL) was added to the mixture slowly at 20C. The mixture was stirred at 80C for 1 h, then it was washed with EtOAc (300 mL). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (CXIII) (24.0 g, 117.62 mmol, 53.5% yield). NMR (CDC13, 300 MHz) ppm 3.86 (s, 2H), 7.01 (d, J=8Hz, 1H), 7.12 (d, J=8Hz, 1H), 7.28 (s, 1H); ESIMS found C7H7BrFN mlz 203.9 (Br79M+H).
53.5%		Scheme 14 Step 1 [0667] A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (LXVI) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH3-Me2S (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20C. Then it was stirred at 80C for 2 h, HC1 (6 N, 100 mL) was added to the mixture slowly at 20C. The mixture was stirred at 80C for 1 h, then it was washed with EtOAc (300 mL). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL x 3). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (LXVII) (24.0 g, 117.62 mmol, 53.5% yield). NMR (CDC13, 300 MHz) ppm 3.86 (s, 2H), 7.01 (d, J=8Hz, IH), 7.12 (d, J=8Hz, IH), 7.28 (s, IH); ESIMS found C7H7BrFN mlz 203.9 (Br79M+H).
53.5%		A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (LXVI) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH3-Me2S (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20C. Then it was stirred at 80C for 2 h, HCl (6 N, 100 mL) was added to the mixture slowly at 20C. The mixture was stirred at 80C for 1 h, then it was washed with EtOAc (300 mL). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (LXVII) (24.0 g, 117.62 mmol, 53.5% yield). 1H NMR (CDCI3, 300 MHz) ppm 3.86 (s, 2H), 7.01 (d, J=8Hz, 1H), 7.12 (d, J=8Hz, 1H), 7.28 (s, 1H); ESIMS found C7H7BrFN m/z 203.9 (Br79M+H).
53.5%		Step 1 [0668] A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (LXVI) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH3-Me2S (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20C. Then it was stirred at 80C for 2 h, HCl (6 N, 100 mL) was added to the mixture slowly at 20C. The mixture was stirred at 80C for 1 h, then it was washed with EtOAc (300 mL). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL x 3). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (LXVII) (24.0 g, 117.62 mmol, 53.5% yield). NMR (CDC13, 300 MHz) ppm 3.86 (s, 2H), 7.01 (d, J=8Hz, IH), 7.12 (d, J=8Hz, IH), 7.28 (s, IH); ESIMS found C7H7BrFN mlz 203.9 (Br79M+H).
53.5%	With dimethylsulfide borane complex; at 80℃; for 2h;	[0705] A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (CII) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH3-Me2S (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20C. Then it was stirred at 80C for 2 h, HCl (6 N, 100 mL) was added to the mixture slowly at 20C. The mixture was stirred at 80C for 1 h, then it was washed with EtOAc (300 mL). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (CIII) (24.0 g, 117.62 mmol, 53.5% yield). NMR (CDC13, 300 MHz) delta ppm 3.86 (s, 2H), 7.01 (d, J=8Hz, IH), 7.12 (d, J=8Hz, IH), 7.28 (s, IH); ESIMS found C7H7BrFN mlz 203.9 (Br79M+H).
53.5%		A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (LXVI) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH3-Me2S (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20C. Then it was stirred at 80C for 2 h, HC1 (6 N, 100 mL) was added to the mixture slowly at 20C. The mixture was stirred at 80C for 1 h, then it was washed with EtOAc (300 mL). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL x 3). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (LXVII) (24.0 g, 117.62 mmol, 53.5% yield). NMR (CDC13, 300 MHz) ppm 3.86 (s, 2H), 7.01 (d, J=8Hz, IH), 7.12 (d, J=8Hz, IH), 7.28 (s, IH); ESIMS found C7H7BrFN mlz 203.9 (Br79M+H).
53.5%		A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (LXVI) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH3-Me25 (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20C. Then it was stirred at 80C for 2 h, HC1 (6 N, 100 mL) was added to the mixture slowly at 20C. The mixture was stirred at 80C for 1 h, then it was washed with EtOAc (300 mL). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (LXVII) (24.0 g, 117.62 mmol, 53.5% yield). ?HNMR(CDC13, 300 MHz) ppm 3.86 (s, 2H), 7.01 (d, J=8Hz, 1H), 7.12 (d, J=8Hz, 1H), 7.28 (s, 1H); ESIMS found C7H7BrFN mlz 203.9 (Br79M+H).
53.5%		10911] A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (CXV) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mE). 13H3-Me2S (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20 C. Then it was stirred at 80 C. for 2 h, HC1 (6 N, 100 mE) was added to the mixture slowly at 20 C. The mixture was stirred at 80 C. for 1 h, then it was washed with EtOAc (300 ml). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mEx3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to produce (3-bromo-5- fluoro-phenyl)methanamine (CXVI) (24.0 g, 117.62 mmol, 53.5% yield). ?H NMR (CDC13, 300 MHz) 3.86 (s, 2H), 7.01 (d, J=8 Hz, 1H), 7.12 (d, J=8 Hz, 1H), 7.28 (s, 1H); ESIMS found C7H7BrFN mlz 203.9 (Br79M+H).
53.5%	With dimethylsulfide borane complex; In tetrahydrofuran; at 20 - 80℃; for 2h;	Step 1 A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (XCVIII) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH3-Me2S (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20 C. Then it was stirred at 80 C. for 2 h, HCl (6 N, 100 mL) was added to the mixture slowly at 20 C. The mixture was stirred at 80 C. for 1 h, then it was washed with EtOAc (300 ml). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL*3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (XCIX) (24.0 g, 117.62 mmol, 53.5% yield). 1H NMR (CDCl3, 300 MHz) 3.86 (s, 2H), 7.01 (d, J=8 Hz, 1H), 7.12 (d, J=8 Hz, 1H), 7.28 (s, 1H); ESIMS found C7H7BrFN m/z 203.9 (Br79M+H).
53.5%		Preparation of intermediate N-(3-(2,3-diaminopyridin-4-yl)-5-fluorobenzyl)methanesulfonamide (CVIII) is depicted below in Scheme 21. Step 1 (0891) A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (CIII) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH3-Me2S (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20 C. Then it was stirred at 80 C. for 2 h, HCl (6 N, 100 mL) was added to the mixture slowly at 20 C. The mixture was stirred at 80 C. for 1 h, then it was washed with EtOAc (300 ml). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (CIV) (24.0 g, 117.62 mmol, 53.5% yield). 1H NMR (CDCl3, 300 MHz) 3.86 (s, 2H), 7.01 (d, J=8 Hz, 1H), 7.12 (d, J=8 Hz, 1H), 7.28 (s, 1H); ESIMS found C7H7BrFN m/z 203.9 (Br79M+H).
53.5%	With dimethylsulfide borane complex; In tetrahydrofuran; at 80℃; for 2h;	A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (CVII) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH3-Me2S (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20 C. Then it was stirred at 80 C. for 2 h, HCl (6 N, 100 mL) was added to the mixture slowly at 20 C. The mixture was stirred at 80 C. for 1 h, then it was washed with EtOAc (300 ml). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (CVIII) (24.0 g, 117.62 mmol, 53.5% yield). 1H NMR (CDCl3, 300 MHz) 3.86 (s, 2H), 7.01 (d, J=8 Hz, 1H), 7.12 (d, J=8 Hz, 1H), 7.28 (s, 1H); ESIMS found C7H7BrFN m/z 203.9 (Br79M+H).
53.5%	With dimethylsulfide borane complex; In tetrahydrofuran; at 80℃; for 3h;	Step 1 (0915) A solution of <strong>[179898-34-1]3-bromo-5-fluorobenzonitrile</strong> (CXVIII) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH3-Me2S (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20 C. Then it was stirred at 80 C. for 2 h, HCl (6 N, 100 mL) was added to the mixture slowly at 20 C. The mixture was stirred at 80 C. for 1 h, then it was washed with EtOAc (300 ml). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (CXIX) (24.0 g, 117.62 mmol, 53.5% yield). 1H NMR (CDCl3, 300 MHz) 3.86 (s, 2H), 7.01 (d, J=8 Hz, 1H), 7.12 (d, J=8 Hz, 1H), 7.28 (s, 1H); ESIMS found C7H7BrFN m/z 203.9 (Br79M+H).

Reference： [1]Patent: US2016/68548,2016,A1 .Location in patent: Paragraph 0884
[2]Patent: US2016/68550,2016,A1 .Location in patent: Paragraph 1157
[3]Patent: WO2016/40193,2016,A1 .Location in patent: Paragraph 0797
[4]Patent: WO2017/23989,2017,A1 .Location in patent: Paragraph 0714; 0715
[5]Patent: WO2017/23975,2017,A1 .Location in patent: Paragraph 0667; 0668
[6]Patent: WO2017/23993,2017,A1 .Location in patent: Paragraph 0672; 0673
[7]Patent: WO2017/24021,2017,A1 .Location in patent: Paragraph 0686; 0687
[8]Patent: WO2017/23987,2017,A1 .Location in patent: Paragraph 0667; 0668
[9]Patent: WO2017/23972,2017,A1 .Location in patent: Paragraph 0704; 0705
[10]Patent: WO2017/24013,2017,A1 .Location in patent: Paragraph 0686; 0687
[11]Patent: WO2017/24004,2017,A1 .Location in patent: Paragraph 0668
[12]Patent: WO2017/24025,2017,A1 .Location in patent: Paragraph 0668
[13]Patent: WO2017/24003,2017,A1 .Location in patent: Paragraph 0667; 0668
[14]Patent: WO2017/24010,2017,A1 .Location in patent: Paragraph 070; 071
[15]Patent: WO2017/23981,2017,A1 .Location in patent: Paragraph 0667; 0668
[16]Patent: WO2017/23986,2017,A1 .Location in patent: Paragraph 0690; 0691
[17]Patent: WO2017/24015,2017,A1 .Location in patent: Paragraph 0111
[18]Patent: WO2017/23984,2017,A1 .Location in patent: Paragraph 0667
[19]Patent: WO2017/23973,2017,A1 .Location in patent: Paragraph 0689
[20]Patent: WO2017/23980,2017,A1 .Location in patent: Paragraph 0668
[21]Patent: WO2017/23988,2017,A1 .Location in patent: Paragraph 0705
[22]Patent: WO2017/23996,2017,A1 .Location in patent: Paragraph 0668
[23]Patent: WO2017/24026,2017,A1 .Location in patent: Paragraph 0671; 0672
[24]Patent: US2016/75701,2016,A1 .Location in patent: Paragraph 0910; 0911
[25]Patent: US2016/68547,2016,A1 .Location in patent: Paragraph 0885; 0886
[26]Patent: US2016/68551,2016,A1 .Location in patent: Paragraph 0890-0891
[27]Patent: US2016/68529,2016,A1 .Location in patent: Page/Page column 0896
[28]Patent: US2016/90380,2016,A1 .Location in patent: Paragraph 0915

48
[ 864377-33-3 ]
[ 179898-34-1 ]
3'-(9H-carbazol-9-yl)-5-fluoro-[1,1'-biphenyl]-3-carbonitrile [ No CAS ]

Reference： [1]Journal of Materials Chemistry C,2018,vol. 6,p. 10308 - 10314

49
[ 1151802-22-0 ]
[ 179898-34-1 ]
3-(1-cyclopropyl-1H-pyrazol-4-yl)-5-fluorobenzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
686 mg	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,2-dimethoxyethane; at 80℃; for 2h;Inert atmosphere;	A mixture of 3-bromo-5-fluorobenzonitrile (618 mg), <strong>[1151802-22-0]1-<strong>[1151802-22-0]cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong></strong> (1.0 g), PdCl2(dppf) (113 mg), 2 M aqueous potassium carbonate solution (3.86 mL) and DME (10 mL) was stirred under a nitrogen atmosphere at 80C for 2 hr. To the reaction mixture was added water at room temperature, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (686 mg). MS: [M+H]+ 228.0

Reference： [1]Patent: EP3514149,2019,A1 .Location in patent: Paragraph 0318

50
[ 18628-07-4 ]
[ 179898-34-1 ]
[ 2446091-39-8 ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: 9-(9H-carbazol-3-yl)-9H-carbazole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: 3-bromo-5-fluorobenzonitrile In N,N-dimethyl-formamide; mineral oil at 150℃; for 18h;	1.1 (1) Synthesis of Intermediate (A) 15.0 g (45.1 mmol) of 9H-3,9′-bicarbazole was dissolved in 100 mL of dimethylformamide (DMF) and cooled to a temperature of 0° C. 1.90 g (47.4 mmol) of NaH (60% dispersion in mineral oil) was slowly added thereto and stirred at a temperature of 0° C. for 30 minutes. A solution in which 9.93 g (49.6 mmol) of 3-bromo-5-fluorobenzonitrile was diluted in 50 mL of DMF was slowly added to the reaction mixture for 10 minutes. The reaction temperature was raised to a temperature of 150° C. and the reaction mixture was additionally stirred for 18 hours. After the reaction was completed, the reaction product was cooled to room temperature, saturated aqueous ammonium chloride (NH4Cl) solution was added thereto, and an organic layer was extracted and separated therefrom by using dichloromethane (DCM). The organic layer was dried by using anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. Then, the product obtained therefrom was separated by silica gel column chromatography to obtain 18.3 g (yield of 79%) of Intermediate (A). (0402) LC-Mass (calc'd.: 511.07 g/mol, found: M+1=512 g/mol).

Reference： [1]Current Patent Assignee: SAMSUNG SDI CO.,LTD.; SAMSUNG ELECTRONICS CO.,LTD. - US2020/203625, 2020, A1 Location in patent: Paragraph 03099; 0400-0402

51
[ 57102-93-9 ]
[ 179898-34-1 ]
9-(3-bromo-5-cyanophenyl)-9H-carbazole-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With copper(l) iodide; 1,10-Phenanthroline; potassium carbonate In N,N-dimethyl-formamide for 24h; Reflux;	4.1.a a) 10.0 g (52.0 mmol) of 9H-carbazole-3-carbonitrile, 15.6 g (78.0 mmol) of 3-bromo-5-fluorobenzonitrile, 1.98 g (10.4 mmol) of copper iodide (Cul), 28.8 g (208 mmol) of potassium carbonate (K2CO3), and 3.75 g (20.8 mmol) of 1,10-phenanthroline were dissolved in 175 mL of DMF and stirred for 24 hours under reflux. After the reaction was completed, the reaction product was cooled to room temperature and then filtered under reduced pressure through silica gel, and a filtrate was concentrated under reduced pressure. A crude product obtained therefrom was separated by silica gel column chromatography to obtain 14.3 g (yield of 74%) of 9-(3-bromo-5-cyanophenyl)-9H-carbazole-3-carbonitrile. (0428) LC-Mass (calc'd.: 371.01 g/mol, found: M+1=372 g/mol).
73%	Stage #1: (9H)-carbazole-3-carbonitrile With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: 3-bromo-5-fluorobenzonitrile In N,N-dimethyl-formamide; mineral oil at 130℃; for 18.16h;	8.1 (1) Synthesis of Intermediate (21) 4.65 g (24.2 mmol) of 9H-carbazole-3-carbonitrile was mixed with 55 mE of dimethyl formamide, followed by slowly adding 0.97 g (24.2 mmol) of sodium hydride (60% dispersion in mineral oil) thereto and stirring at a temperature of 0° C. for 30 minutes. A solution, in which 5.32 g (26.6 mmol) of 3-bromo-5-fluorobenzonitrile was diluted in 40 mE of dimethyl formamide, was slowly added to the resulting product for 10 minutes. Subsequently, the reaction temperature was raised to 130° C., followed by stirring for 18 hours. Once the reaction was complete, the resulting mixture was cooled to room temperature, followed by addition of ammonium chloride aqueous solution to extract an organic layer using dichloromethane. From the resulting product, water was removed using magnesium sulfate. Subsequently, the obtained filtrate was concentrated under reduced pressure, and the resulting product was separated and purified by silica gel colunm chromatography to obtain a desired compound, 6.55 g of Intermediate (21) (at a yield of 73%).LC-MS (calculated value: 371.01 g/mol, measured value: M+1=372 g/mol)

Reference： [1]Current Patent Assignee: SAMSUNG SDI CO.,LTD.; SAMSUNG ELECTRONICS CO.,LTD. - US2020/203625, 2020, A1 Location in patent: Paragraph 0426; 0427; 0428
[2]Current Patent Assignee: SAMSUNG ELECTRONICS CO.,LTD.; SAMSUNG SDI CO.,LTD. - US2020/274074, 2020, A1 Location in patent: Paragraph 0357-0359

52
[ 81879-64-3 ]
[ 179898-34-1 ]
3-[3-benzyl-9-hydroxy-3-azabicyclo[3.3.1]nonan-9-yl]-5-fluorobenzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70.9%		To a stirred solution3-bromo-5-fluorobenzonitrile (5.0 g, 25.0 mmol, 1.0 equiv) in THF (150 mL) was added iPrMgCI.LiCI (29.0 mL, 37.7 mmol, 1.5 equiv) dropwise at 0 C under nitrogen atmosphere. The resulting solution was stirred at 0 C for 1 hour. To the above mixture was added <strong>[81879-64-3]3-benzyl-3-azabicyclo[3.3.1]nonan-9-one</strong> (6.88 g, 30.0 mmol, 1.2 equiv) dropwise at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. The reaction was quenched with sat. NH4CI (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 x 500mL). The combined organic layers were washed with water (2 x 500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to afford 3-[3-benzyl-9-hydroxy-3- azabicyclo[3.3.1]nonan-9-yl]-5-fluorobenzonitrile (7.5 g, 70.9%) as a yellow oil. LCMS: m/z (ES+), [M+H]+ = 351.

Reference： [1]Patent: WO2021/26380,2021,A1 .Location in patent: Page/Page column 32; 37

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H200	Unstable explosive
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