[ CAS No. 461-87-0 ] {[proInfo.proName]}

Name: 461-87-0|2-Fluoro-4-methylpyridine|98%
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Quality Control of [ 461-87-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 461-87-0 ]

CAS No. :	461-87-0	MDL No. :	MFCD00041224
Formula :	C₆H₆FN	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZBFAXMKJADVOGH-UHFFFAOYSA-N
M.W :	111.12	Pubchem ID :	2737403
Synonyms :

Calculated chemistry of [ 461-87-0 ]

Physicochemical Properties

Num. heavy atoms :	8
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	29.16
TPSA :	12.89 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) :	-6.03 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.64
Log Po/w (XLOGP3) :	1.34
Log Po/w (WLOGP) :	1.95
Log Po/w (MLOGP) :	1.24
Log Po/w (SILICOS-IT) :	2.28
Consensus Log Po/w :	1.69

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.93
Solubility :	1.31 mg/ml ; 0.0118 mol/l
Class :	Very soluble
Log S (Ali) :	-1.21
Solubility :	6.81 mg/ml ; 0.0613 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.63
Solubility :	0.261 mg/ml ; 0.00235 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.41

Safety of [ 461-87-0 ]

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

Application In Synthesis of [ 461-87-0 ]

* 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 [ 461-87-0 ]
Downstream synthetic route of [ 461-87-0 ]

[ 461-87-0 ] Synthesis Path-Upstream 1~15

1
[ 461-87-0 ]
[ 695-34-1 ]

Reference： [1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 41, p. 7564 - 7567

2
[ 695-34-1 ]
[ 461-87-0 ]

Reference： [1] Patent: US5583148, 1996, A,

3
[ 108-89-4 ]
[ 461-87-0 ]

Reference： [1] Tetrahedron Letters, 1987, vol. 28, # 3, p. 255 - 258
[2] Journal of Organic Chemistry, 1989, vol. 54, # 7, p. 1726 - 1731

4
[ 695-34-1 ]
[ 461-87-0 ]

Reference： [1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
[2] Journal of the American Chemical Society, 1949, vol. 71, p. 4152
[3] Journal of Medicinal Chemistry, 1990, vol. 33, # 6, p. 1667 - 1675
[4] Journal of Labelled Compounds and Radiopharmaceuticals, 2011, vol. 54, # 6, p. 312 - 317

5
[ 4926-28-7 ]
[ 461-87-0 ]

Reference： [1] Tetrahedron Letters, 2009, vol. 50, # 37, p. 5257 - 5259

6
[ 108-89-4 ]
[ 461-87-0 ]
[ 5327-32-2 ]

Reference： [1] Synthetic Communications, 1994, vol. 24, # 16, p. 2387 - 2392

7
[ 108-89-4 ]
[ 75-05-8 ]
[ 461-87-0 ]
[ 5327-32-2 ]

Reference： [1] Synthetic Communications, 1994, vol. 24, # 16, p. 2387 - 2392

8
[ 116241-53-3 ]
[ 461-87-0 ]

Reference： [1] Journal of Organic Chemistry, 1989, vol. 54, # 7, p. 1726 - 1731

9
[ 461-87-0 ]
[ 4931-00-4 ]

Yield	Reaction Conditions	Operation in experiment
51%	With hydrazine hydrate In 2-ethoxy-ethanol at 150℃; for 16 h;	3.3 g (30.0 mmol) of 2-fluoro-4-methylpyridine are initially charged in 40 ml of ethylene glycol monoethyl ether, 14.6 ml (15.0 g, 300 mmol) of hydrazine hydrate are added to the solution and the mixture is stirred at boiling point (bath temperature 150° C.) for 16 h. The reaction solution is then concentrated on a rotary evaporator, and the residue is added to 100 ml of water and extracted with ethyl acetate (three times 100 ml each). The combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue obtained is dried under reduced pressure. Yield: 1.90 g (51percent of theory) LC-MS (Method 1): R_t=0.80 min; MS (ESIpos): m/z=124 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆): δ=7.83 (d, 1H), 7.22 (s, 1H), 6.51 (s, 1H), 6.38 (d, 1H), 4.04 (s, 2H), 2.17 (s, 3H).
51%	With hydrazine hydrate In 2-ethoxy-ethanol for 16 h; Reflux	33 g (30.0 mmol) 2-fluoro-4-methylpyridine are initially introduced into 40 ml 2-ethoxyethanol, 14.6 ml (15.0 g, 300 mmol) hydrazine hydrate are added to the solution and the mixture is stirred at the boiling point (150° C. bath temperature) for 16 h. Thereafter, the reaction solution is concentrated on a rotary evaporator, the residue is added to 100 ml water and the mixture is extracted with ethyl acetate (three times with 100 ml each time). The combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue obtained is dried in vacuo.Yield: 1.90 g (51percent of th.)¹H-NMR (400 MHz, DMSO-d₆): δ=7.83 (d, 1H), 7.22 (s, 1H), 6.51 (s, 1H), 6.38 (d, 1H), 4.04 (s, 2H), 2.17 (s, 3H).LC-MS (Method 1): R_t=0.80 min; MS (ESIpos): m/z=124 [M+H]⁺.

Reference： [1] Patent: WO2006/114213, 2006, A1, . Location in patent: Page/Page column 27-28
[2] Patent: US2010/93803, 2010, A1, . Location in patent: Page/Page column 20
[3] Patent: US2010/305085, 2010, A1, . Location in patent: Page/Page column 15
[4] ChemMedChem, 2018, vol. 13, # 10, p. 988 - 1003

10
[ 461-87-0 ]
[ 402-65-3 ]

Yield	Reaction Conditions	Operation in experiment
42%	With pyridine; hydrogenchloride; potassium hydroxide; potassium permanganate In water; ethyl acetate	a Preparation of 2-fluoroisonicotinic acid: 5.00 g (45 mmol) of 2-fluoro-4-methylpyridine and 1.00 g (17 mmol) of KOH were treated with 50 ml of pyridine and heated under reflux. 20.00 g (127 mmol) of potassium permanganate were added in portions in the course of 30 minutes at this temperature and the mixture was heated under reflux for a further 1.5 h. It was then cooled in an ice bath, treated with 100 ml of water, and brought to a pH of 1 using concentrated hydrochloric acid. After the addition of 100 ml of ethyl acetate, the insoluble residue was filtered off and the aqueous phase was extracted a further two times with 100 ml of ethyl acetate each time. The combined ethyl acetate phases were dried over magnesium sulfate and concentrated under reduced pressure. 2.70 g of 2-fluoroisonicotinic acid were obtained. Yield: 42percent.

Reference： [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 8, p. 2745 - 2766
[2] Patent: US6358978, 2002, B1,
[3] Journal of Medicinal Chemistry, 1990, vol. 33, # 6, p. 1667 - 1675
[4] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
[5] Journal of the American Chemical Society, 1949, vol. 71, p. 4152
[6] Patent: US5583148, 1996, A,
[7] Journal of Labelled Compounds and Radiopharmaceuticals, 2011, vol. 54, # 6, p. 312 - 317
[8] Patent: EP1726590, 2006, A1, . Location in patent: Page/Page column 57

11
[ 461-87-0 ]
[ 455-69-6 ]

Reference： [1] Journal of the American Chemical Society, 1949, vol. 71, p. 4152

12
[ 461-87-0 ]
[ 131747-69-8 ]

Reference： [1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
[2] Patent: US6358978, 2002, B1,

13
[ 461-87-0 ]
[ 118289-17-1 ]

Reference： [1] Tetrahedron Letters, 2001, vol. 42, # 39, p. 6815 - 6818

14
[ 461-87-0 ]
[ 131747-60-9 ]

Reference： [1] Synthesis, 2007, # 16, p. 2529 - 2533

15
[ 461-87-0 ]
[ 131747-60-9 ]

Reference： [1] Journal of Organic Chemistry, 2000, vol. 65, # 23, p. 7718 - 7722
[2] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
[3] Journal of Medicinal Chemistry, 2011, vol. 54, # 8, p. 2745 - 2766
[4] Patent: EP1726590, 2006, A1,

[ 461-87-0 ] Synthesis Path-Downstream 1~88

1
[ 695-34-1 ]
[ 461-87-0 ]

Yield	Reaction Conditions	Operation in experiment
51%	With tetrafluoroboric acid; sodium nitrite 0 deg C to rt;
	With tetrafluoroboric acid; sodium nitrite Diazotization;
	With tetrafluoroboric acid; sodium nitrite Multistep reaction;

With pyridine hydrogenfluoride

Reference： [1]Ashimori; Ono; Uchida; Ohtaki; Fukaya; Watanabe; Yokoyama [Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458]
[2]Roe et al. [Journal of the American Chemical Society, 1949, vol. 71, p. 4152]
[3]Anderson, Wayne K.; Dean, Dennis C.; Endo, Toshiyasu [Journal of Medicinal Chemistry, 1990, vol. 33, # 6, p. 1667 - 1675]
[4]Location in patent: scheme or table Al Jammaz; Al-Otaibi; Okarvi; Amartey [Journal of labelled compounds and radiopharmaceuticals, 2011, vol. 54, # 6, p. 312 - 317]

2
[ 461-87-0 ]
[ 402-65-3 ]

Yield	Reaction Conditions	Operation in experiment
42%	With pyridine; hydrogenchloride; potassium hydroxide; potassium permanganate; In water; ethyl acetate;	a Preparation of 2-fluoroisonicotinic acid: 5.00 g (45 mmol) of 2-fluoro-4-methylpyridine and 1.00 g (17 mmol) of KOH were treated with 50 ml of pyridine and heated under reflux. 20.00 g (127 mmol) of potassium permanganate were added in portions in the course of 30 minutes at this temperature and the mixture was heated under reflux for a further 1.5 h. It was then cooled in an ice bath, treated with 100 ml of water, and brought to a pH of 1 using concentrated hydrochloric acid. After the addition of 100 ml of ethyl acetate, the insoluble residue was filtered off and the aqueous phase was extracted a further two times with 100 ml of ethyl acetate each time. The combined ethyl acetate phases were dried over magnesium sulfate and concentrated under reduced pressure. 2.70 g of 2-fluoroisonicotinic acid were obtained. Yield: 42%.
	With potassium permanganate; In water;	A stirred mixture of 30 grams of the above 2-fluoro-4-methylpyridine and potassium permanganate (100 g) in water (1.2 L) was heated at reflux. Additional potassium permanganate (50 g) was added after 1.5 hours and the stirred mixture was maintained at reflux for 15 hours. The reaction mixture was then steam distilled to remove unreacted starting material, the hot residual aqueous solution was filtered, and the filtrate was concentrated in vacuo to 450 mL. The solution was cooled on an ice-bath and acidified with concentrated HCl to pH 2.0. The resulting precipitate was collected and crystallized from water and gave 13.56 g of 2-fluoropyridine-4-carboxylic acid having a melting point of 220-224 C.
		20 g of 2-fluoro-4-methylpyridine was suspended in 500 mL of water, and 100 g of potassium permanganate was added thereto and stirred at 115C for 20 hours. The reaction solution was filtered through Celite while hot, and then the filtrate was concentrated under reduced pressure until the amount of the solvent became 1/3. The solution was neutralized with aqueous sodium hydroxide solution, and then aqueous hydrochloric acid solution was added thereto until its pH became 2. The formed white solid was taken out through filtration, and the filtrate was extracted twice with ethyl acetate, washed with saturated saline water and dried with sodium sulfate. The solvent was evaporated off under reduced pressure, and the resulting white solid was combined with the solid taken out through filtration to obtain 9.51 g of the entitled compound.

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 2745 - 2766
[2]Patent: US6358978,2002,B1
[3]Journal of Medicinal Chemistry,1990,vol. 33,p. 1667 - 1675
[4]Chemical and Pharmaceutical Bulletin,1990,vol. 38,p. 2446 - 2458
[5]Journal of the American Chemical Society,1949,vol. 71,p. 4152
[6]Patent: US5583148,1996,A
[7]Journal of labelled compounds and radiopharmaceuticals,2011,vol. 54,p. 312 - 317
[8]Patent: EP1726590,2006,A1 .Location in patent: Page/Page column 57

3
[ 108-89-4 ]
[ 461-87-0 ]

Yield	Reaction Conditions	Operation in experiment
31%	With fluorine In 1,1,2-Trichloro-1,2,2-trifluoroethane at -25℃;
	Multi-step reaction with 2 steps 1: 70 percent / NaBF₄, 20percent F₂/N₂ / acetonitrile / -40 °C 2: 80 percent Chromat_. / Et₃N / 0.08 h / Ambient temperature

Reference： [1]Puy, Michael Van Der [Tetrahedron Letters, 1987, vol. 28, # 3, p. 255 - 258]
[2]Umemoto, Teruo; Tomizawa, Ginjiro [Journal of Organic Chemistry, 1989, vol. 54, # 7, p. 1726 - 1731]

4
[ 461-87-0 ]
[ 155705-46-7 ]
4-(dichloromethyl)-2-fluoropyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 69% 2: 17%	With N-chloro-succinimide; acetic acid; dibenzoyl peroxide In acetonitrile for 1.5h; Heating;
1: 69% 2: 17%	With hydrogenchloride; N-chloro-succinimide; dibenzoyl peroxide In acetic acid; acetonitrile for 1.5h; Heating;
	With N-chloro-succinimide; Perbenzoic acid In tetrachloromethane for 4h; Heating; Yield given. Yields of byproduct given. Title compound not separated from byproducts;

Reference： [1]Pesti; Huhn; Yin; Xing; Fortunak; Earl [Journal of Organic Chemistry, 2000, vol. 65, # 23, p. 7718 - 7722]
[2]Pesti; Huhn; Yin; Xing; Fortunak; Earl [Journal of Organic Chemistry, 2000, vol. 65, # 23, p. 7718 - 7722]
[3]Earl, Richard A.; Zaczek, Robert; Teleha, Christopher A.; Fisher, Barbara N.; Maciag, Carla M.; Marynowski, Maria E.; Logue, Andrew R.; Tam, S. William; Tinker, William J.; Huang, Shiew-Mei; Chorvat, Robert J. [Journal of Medicinal Chemistry, 1998, vol. 41, # 23, p. 4615 - 4622]

5
[ 461-87-0 ]
[ 116332-62-8 ]
[ 188345-23-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	With n-butyllithium In tetrahydrofuran at -78℃;
	With lithium diisopropyl amide 1.) THF, hexane, -78 deg C, 15 min, 2.) THF, hexane, -78 deg C, 5 min; Yield given; Multistep reaction;
	With lithium diisopropyl amide In tetrahydrofuran at -78℃;

	With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane; water; ethyl acetate	27 2-(2-Fluoropyridin-4-yl)-1-(3-trifluoromethylphenyl)ethanone 2-(2-Fluoropyridin-4-yl)-1-(3-trifluoromethylphenyl)ethanone To a solution of diisopropylamine (17.69 mL, 0.135 mole) in THF (200 mL) at -78° C., under argon, was added n-butyllithium (54.0 mL, 2.5M in hexane, 0.135 mole), followed after 5 min. by a solution of 2-fluoro-4-methylpyridine (Lancaster Synthesis Inc.) (10 g, 0.090 mole) in THF (20 mL). After stirring for 15 min. at -78° C., a solution of N-methoxy-N-methyl-3-trifluoromethylbenzamide (23.08 g, 0.099 mole) in THF (10 mL) was added. After stirring for 5 min, the reaction was allowed to warm to 0° C. and quenched by pouring into water (400 mL) and ethyl acetate (400 mL). The layers were separated, and the aqueous layer washed with ethyl acetate (200 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to an oil which was chromatographed on silica gel with 20% ethyl acetate in hexane to give 21.6 g of the title compound. NMR (300 MHz, CDCl3) d: 8.25 (1H, s); 8.20 (1H, d, J=5.1 Hz); 8.18 (1H, d, J=9.3 Hz); 7.88 (1H, d, J=7.8 Hz); 7.67 (1H, t, J=7.5 Hz); 7.09 (1H, d, J=5.1 Hz); 6.86 (1H, s); 4.37 (2H, s).
	Stage #1: 2-fluoro-4-methylpyridine With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.25h; Stage #2: N-methoxy-N-methyl-3-trifluoromethylbenzamide In tetrahydrofuran; hexane at -78℃; for 0.0833333h;	27.A 2-(2-Fluoropyridin-4-yl)-1-(3-trifluoromethylphenyl)ethanone Step 27-A 2-(2-Fluoropyridin-4-yl)-1-(3-trifluoromethylphenyl)ethanone To a solution of diisopropylamine (17.69 mL, 0.135 mole) in THF (200 mL) at -78°C, under argon, was added n-butyllithium (54.0 mL, 2.5M in hexane, 0.135 mole), followed after 5 min. by a solution of 2-fluoro-4-methylpyridine (Lancaster Synthesis Inc.) (10 g, 0.090 mole) in THF (20 mL). After stirring for 15 min. at -78°C, a solution of N-methoxy-N-methyl-3-trifluoromethylbenzamide (23.08 g, 0.099 mole) in THF (10 mL) was added. After stirring for 5 min, the reaction was allowed to warm to 0°C and quenched by pouring into water (400 mL) and ethyl acetate (400 mL). The layers were separated, and the aqueous layer washed with ethyl acetate (200 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to an oil which was chromatographed on silica gel with 20% ethyl acetate in hexane to give 21.6 g of the title compound. NMR (300 MHz, CDCl3) d: 8.25 (1H, s); 8.20 (1H, d, J =5.1Hz); 8.18 (1H, d, J =9.3Hz); 7.88 (1H, d, J =7.8Hz); 7.67 (1H, t, J= 7.8Hz); 7.09 (1H, d, J =5.1Hz); 6.86 (1H, s); 4.37 (2H, s).

Reference： [1]Claiborne, Christopher F.; Liverton, Nigel J.; Nguyen, Kevin T. [Tetrahedron Letters, 1998, vol. 39, # 49, p. 8939 - 8942]
[2]Liverton, Nigel J.; Butcher, John W.; Claiborne, Christopher F.; Claremon, David A.; Libby, Brian E.; Nguyen, Kevin T.; Pitzenberger, Steven M.; Selnick, Harold G.; Smith, Garry R.; Tebben, Andrew; Vacca, Joseph P.; Varga, Sandor L.; Agarwal, Lily; Dancheck, Kim; Forsyth, Amy J.; Fletcher, Daniel S.; Frantz, Betsy; Hanlon, William A.; Harper, Coral F.; Hofsess, Scott J.; Kostura, Matthew; Lin, Jiunn; Luell, Sylvie; O'Neill, Edward A.; Orevillo, Chad J.; Pang, Margaret; Parsons, Janey; Rolando, Anna; Sahly, Yousif; Visco, Denise M.; O'Keefe, Stephen J. [Journal of Medicinal Chemistry, 1999, vol. 42, # 12, p. 2180 - 2190]
[3]Tamayo, Nuria; Liao, Lillian; Goldberg, Martin; Powers, David; Tudor, Yan-Yan; Yu, Violeta; Wong, Lu Min; Henkle, Bradley; Middleton, Scot; Syed, Rashid; Harvey, Timothy; Jang, Graham; Hungate, Randall; Dominguez, Celia [Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 9, p. 2409 - 2413]
[4]Current Patent Assignee: MERCK & CO INC - US5717100, 1998, A
[5]Current Patent Assignee: MERCK & CO INC - EP854870, 2009, B1 Location in patent: Page/Page column 46-47

6
[ 461-87-0 ]
[ 78-82-0 ]
[ 260981-46-2 ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium hexamethylsilazane; In toluene; for 1.0h;Reflux;	Preparation of 2-methyl-2-(4-methylpyridin-2-yl)propanenitrile; 2-Fluoro-4-methylpyridine (1.0 g, 9 mmol), KH(Si(CH3)3)2, (27 mL, 13.5 mmol, 0.5 M solution in toluene) and 2-methylpropanenitrile (3.2 mL) were refluxed in toluene for 1 h. The reaction was quenched with saturated NH4Cl, the organics separated, dried (MgSO4), concentrated in-vacuo and the residue purified by column chromatography (20% EtOAc/pet ether) to give 2-methyl-2-(4-methylpyridin-2-yl)propanenitrile (1.22 g, 92%). MS m/z 161.4 (calc'd for C10H12N2).
70%	With potassium hexamethylsilazane; In toluene; for 1.0h;Heating / reflux;	Method 122; 2-Methyl-2-f4-memylpyridin-2-yl)propanenitrile; A solution of 2-fluoro-4-methylpyridine (1.00 g, 9.00 mmol) and 2- methylpropanenitrile in toluene (30 ml) was treated with potassium hexamethyldisilazide (13.5 mmol) and the reaction was refluxed for 1 h before being cooled to 25 C. The reaction was then quenched with saturated aqueous NH4Cl (50 ml) and the mixture was extracted with EtOAc. The combined organic phase was dried with MgSO4 (s) and concentrated under reduced pressure. The product was purified by column chromatography utilizing an ISCO system (hexanes/EtOAc 5:1) giving 0.990 g of the title compound as a colourless oil (70 %); m/z 162.
60%	With potassium hexamethylsilazane; In toluene; at 115℃; for 1.0h;	Method 28; 2-Methyl-2-("4-methylpyridin-2-yl)propanenitrile; Postassium bis(trimethylsilyl)amide (13.5 mmol) was added to a solution of 2-fluoro- 4-rnethylpyridine (1.00 g, 9.00 mmol) and 2-methylpropanenitrile (2.48 g, 36 mmol) in anhydrous toluene (30 ml) and stirred for 1 h at 115 0C. The reaction mixture was quenched with NH4Cl(sat) and extracted with EtOAc. The organic layer was washed with NaCl(sat) and dried with Na2SO4(S). The organics were removed under reduced pressure and the crude residue was purified by column chromatography (hexanes/EtOAc) to give the title compound as a colourless oil (60%). m/z 161.

60%		A 100 ml round bottom flask fitted with a reflux condenser was charged with 2-fiuoro- 4-methylpyridine (1.00 g, 9.00 mmol), 2-methylpropanenitrile (2.48 g, 36 mmol), and toluene (30 ml). Potassium Etaexamethyldisilazide (13.5 mmol) was added and the reaction was refluxed for 1 h. before being cooled to 25 0C. The reaction was then quenched with NEta4Cl(sat) (50 ml) and the mixture was extracted with EtOAc (2 x 50 ml). The combined organic phase was dried with MgSO4 and concentrated in vacuo to yield the crude reaction product which was purified on 40 g SiO2 hexanes-EtOAc (5:1) as eluent giving 0.870 g of the title compound as a colourless oil (60 %); m/z 161.
60%	With potassium hexamethylsilazane; In toluene; for 1.0h;Heating / reflux;	Method 59; 2-Methyl-2-(4-methylpyridin-2-yl)propanenitrile; A solution of 2-fluoro-4-methylpyridine (1.00 g, 9.00 mmol), 2-methylpropanenitrile (2.48 g, 36 mmol) in toluene (30 ml) was treated with potassium hexamethyldisilazide (13.5 mmol) and the reaction was refluxed for 1 h. The reaction was quenched with NH4Cl(sat) and extracted with EtOAc. The organics were dried with MgSO4(s) and concentrated under reduced pressure. The residue was purified by column chromatography utilizing an ISCO system (hexane-EtOAc) to give 0.870 g (60 %) of a colourless oil; m/z 161.
60%	With potassium hexamethylsilazane; In toluene; for 1.0h;Heating / reflux;	Method 19; 2-Methyl-2-(4-methylpyridin-2-yl)propanenitrile; 2-Fluoro-4-methylpyridine (1.00 g, 9.00 mmol) and 2-methylpropanenitrile (2.48 g, 36 mmol) were dissolved in anhydrous toluene (30 ml). Postassium Hexamethyldisilazide (13.5 mmol) was added and the reaction was refluxed for 1 h. The reaction was then quenched with saturated aqueous NH4CI (50 ml) and the mixture was extracted with EtOAc (2 x 50 ml). The combined organic phase was dried with MgS04 and concentrated in vacuo to yield the crude reaction product which was purified on 40 g Si02 hexanes-EtOAc 5: 1 as eluent giving 0.870 g (60 %)
	With potassium hexamethylsilazane; In toluene; for 1.5h;Reflux;	Step 1: To a mixture of 2-fluoro-4-methylpyridine (1.0 equiv.) and isobutyronitrile (4.0 equiv.) was cannulated KHMDS (1.2 equiv.) in toluene. The mixture was heated to reflux for 1.5 hours at which time the reaction was cooled to RT, quenched with NH4Cl (aq), extracted with EtOAc, dried over Na2SO4, filtered, and concentrated. The crude material was used in next step. LCMS (m/z) (M+H)=161.1, Rt=0.48 min.

Reference： [1]Patent: US2009/270394,2009,A1 .Location in patent: Page/Page column 11-12
[2]Journal of the American Chemical Society,2000,vol. 122,p. 712 - 713
[3]Patent: WO2006/40568,2006,A1 .Location in patent: Page/Page column 80
[4]Patent: WO2006/79791,2006,A1 .Location in patent: Page/Page column 41
[5]Patent: WO2006/24834,2006,A1 .Location in patent: Page/Page column 84
[6]Patent: WO2007/71963,2007,A2 .Location in patent: Page/Page column 57
[7]Patent: WO2005/123696,2005,A1 .Location in patent: Page/Page column 70
[8]Patent: US2014/275003,2014,A1 .Location in patent: Paragraph 0161; 0162

7
[ 461-87-0 ]
[ 451-46-7 ]
[ 302839-09-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃; for 3h; Inert atmosphere;	1-(4-Fluorophenyl)-2-(2-fluoropyridin-4-yl)-ethan-1-one (3) NaHMDS (66.7 mL 2 M solution in THF,133 mmol) was slowly added to a stirred solution of 2-fluoro-4-methylpyridine (10.6 mL, 103 mmol) andethyl 4-fluorobenzoate (18.1 mL, 123 mmol) in 40 mL anhyd. THF at 0 °C under a nitrogen atmosphere.After stirring at 0 °C for 2 h the reaction was allowed to reach rt and stirring continued for 1 h.The mixture was diluted with ethyl acetate and washed twice with 10% aq. HCl. The organic layer wasdried over anhyd. Na2SO4 and solvent was removed under reduced pressure. Recrystallization fromethyl acetate afforded 3 as colorless solid. Yield 23.9 g (quant.); C13H9F2NO (Mr 233.22); m.p. 102 °C;1H-NMR (DMSO-d6): δ= 4.59 (s, 2H, CH2), 7.10 (s, 1H, C3H, Pyr), 7.25-7.27 (m, 1H, C5H, Pyr), 7.37-7.43(m, 2H, C3/5H, F-Phe), 8.11-8.19 (m, 3H, C2/6H, F-Phe, C6H, Pyr) ppm; 13C-NMR (DMSO-d6): δ= 43.6(d, 4JCF = 2.8 Hz, CH2), 110.8 (d, 2JCF = 37.6 Hz, C3H, Pyr), 115.8 (d, 2JCF = 22.0 Hz, C3/5H, F-Phe),123.8 (d, 4JCF = 3.8 Hz, C5H, Pyr), 131.3 (d, 3JCF = 9.6 Hz, C2/6H, F-Phe), 132.9 (d, 4JCF = 2.7 Hz, C1,F-Phe), 147.0 (d, 5JCF = 15.5 Hz, C6H, Pyr), 150.7 (d, 3JCF = 8.5 Hz, C1, Pyr), 163.1 (d, 1JCF = 234.3 Hz,C2F, Pyr), 165.2 (d, 1JCF = 252.0 Hz, C4F, F-Phe), 194.6 (CO) ppm; MS (ESI, 70 eV) m/z 234 [MH]+.
94%	With sodium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃; for 3h;
94%	With sodium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃; for 3h; Inert atmosphere;	9 Example 9. 1-(4-Fluorphenyl)-2-(fluorpyridin-4-yl)ethanone (9) 2-Fluoro-4-methylpyridine (4.44 g, 0.04 mol) and ethyl 4-fluorobenzoate (6.73 g, 0.04 mol) were dissolved in dry THF under argon atmosphere. The solution was cooled to 0° C. and NaHMDS (40 mL, 0.08 mol) was added dropwise. The mixture was allowed to stir at this temperature for 2 h and additional 1 h at room temperature. The reaction was treated with EtOAc and washed with 10% HCl (2*). The organic layer was dried over Na2SO4 and the solvent removed in vacuo to afford a colorless solid. yield: 8.81 g (94%)

86%	Stage #1: 2-fluoro-4-methylpyridine With sodium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.75h; Stage #2: 4-fluorobenzoic acid ethyl ester In tetrahydrofuran at 0 - 20℃; for 1.5h;
82%	Stage #1: 2-fluoro-4-methylpyridine With sodium hexamethyldisilazane In tetrahydrofuran at 2℃; for 0.75h; Stage #2: 4-fluorobenzoic acid ethyl ester In tetrahydrofuran for 1.5h;
69%	Stage #1: 2-fluoro-4-methylpyridine With sodium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.75h; Stage #2: 4-fluorobenzoic acid ethyl ester In tetrahydrofuran at 0 - 20℃; for 0.75h;
	In tetrahydrofuran; ethyl acetate	8.x Example 9 1-(4-Fluorphenyl)-2-(fluorpyridin-4-yl)ethanone Example 9 2-Fluoro-4-methylpyridine (4.44 g, 0.04 mol) and ethyl 4-fluorobenzoate (6.73 g, 0.04 mol) were dissolved in dry THF under argon atmosphere. The solution was cooled to 0° C. and NaHMDS (40 mL, 0.08 mol) was added dropwise. The mixture was allowed to stir at this temperature for 2 h and additional 1 h at room temperature. The reaction was treated with EtOAc and washed with 10% HCl (2*). The organic layer was driedNa2SO4 and the solvent removed in vacuo to afford a colorless solid. yield: 8.81 g (94%) 1H-NMR (DMSO) δ4.58 (s, 2H, CH2), 7.09 (s, 1H, C3-H 2-F-Pyr), 7.25 (d, 1H, J=4.92 Hz, 1H, C5-H 2-F-Pyr.), 7.38 (t, 2H, J=8.4 Hz, 4-F-Ph), 8.12-8.18 (m, 3H, 4-F-Ph, C6-H 2-F-Pyr) IR (ATR) v (cm-1) 3070, 2917, 2845, 1684 (CO), 1615, 1553, 1510, 1411, 1271, 1234 (CF), 998, 829, 813, 792

Reference： [1]Halekotte, Jakob; Witt, Lydia; Ianes, Chiara; Krüger, Marc; Bührmann, Mike; Rauh, Daniel; Pichlo, Christian; Brunstein, Elena; Luxenburger, Andreas; Baumann, Ulrich; Knippschild, Uwe; Bischof, Joachim; Peifer, Christian; Koch, Pierre; Laufer, Stefan [Molecules, 2017, vol. 22, # 4]
[2]El-Gokha, Ahmed; Laufer, Stefan A.; Koch, Pierre [Organic and Biomolecular Chemistry, 2015, vol. 13, # 43, p. 10699 - 10704]
[3]Current Patent Assignee: SYNOVO GMBH - US2017/313661, 2017, A1 Location in patent: Paragraph 0243; 0244; 0245
[4]Laufer, Stefan A.; Liedtke, Andy J. [Tetrahedron Letters, 2006, vol. 47, # 40, p. 7199 - 7203]
[5]Thompson, James E.; Cubbon, Rose M.; Cummings, Richard T.; Wicker, Linda S.; Frankshun, Robert; Cunningham, Barry R.; Cameron, Patricia M.; Meinke, Peter T.; Liverton, Nigel; Weng, Youmin; DeMartino, Julie A. [Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 8, p. 1219 - 1223]
[6]Günther, Marcel; Lategahn, Jonas; Juchum, Michael; Döring, Eva; Keul, Marina; Engel, Julian; Tumbrink, Hannah L.; Rauh, Daniel; Laufer, Stefan [Journal of Medicinal Chemistry, 2017, vol. 60, # 13, p. 5613 - 5637]
[7]Current Patent Assignee: SYNOVO GMBH - US2009/270462, 2009, A1

8
[ 461-87-0 ]
[ 100-59-4 ]
[ 3475-21-6 ]

Reference： [1]Journal of Organic Chemistry,2002,vol. 67,p. 8991 - 8994

9
[ 461-87-0 ]
[ 116332-54-8 ]
[ 302839-09-4 ]

Reference： [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 3230 - 3244

10
[ 461-87-0 ]
[ 21384-43-0 ]
[ 303162-49-4 ]

Yield	Reaction Conditions	Operation in experiment
53%	Stage #1: 2-fluoro-4-methylpyridine With lithium diisopropyl amide In tetrahydrofuran; hexane at -10℃; for 1h; Stage #2: 1-(3-methylbenzoyl)-2-methylaziridine In tetrahydrofuran; hexane at -78℃; for 2h;
52%	With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane; water	R.A.36 2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone Reference Example A 36 2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone A solution of diisopropylamine (44 mL, 0.31 mol) in anhydrous tetrahydrofuran (300 mL) was cooled to -78ØC under an argon atmosphere, and 1.6 M n-butyllithium/hexane solution (190 mL, 0.31 mol) was added dropwise with stirring. After completion of the dropwise addition, the mixture was stirred for 10 min, and a solution of 2-fluoro-4-methylpyridine (34.5 g, 0.31 mol) in anhydrous tetrahydrofuran (30 mL) was added. The reaction mixture was stirred at -10ØC for 30 min. The reaction solution was cooled to -78ØC and a solution of N-(3-methylbenzoyl)propyleneimine (52 g, 0.30 mol) in anhydrous tetrahydrofuran (30 mL) was added dropwise. After completion of dropwise addition, the mixture was stirred at room temperature for 2 h. To the reaction mixture was added water (100 mL), and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and the solvent was evaporated. The residue was recrystallized from isopropyl ether to give the title compound (35 g, yield 52%). melting point: 66-67ØC.
52%	With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane; water	R.A.36 2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone Reference Example A 36 2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone A solution of diisopropylamine (44 mL, 0.31 mol) in anhydrous tetrahydrofuran (300 mL) was cooled to -78°C under an argon atmosphere, and 1.6 M n-butyllithium/hexane solution (190 mL, 0.31 mol) was added dropwise with stirring. After completion of the dropwise addition, the mixture was stirred for 10 min, and a solution of 2-fluoro-4-methylpyridine (34.5 g, 0.31 mol) in anhydrous tetrahydrofuran (30 mL) was added. The reaction mixture was stirred at -10°C for 30 min. The reaction solution was cooled to -78°C and a solution of N-(3-methylbenzoyl)propyleneimine (52 g, 0.30 mol) in anhydrous tetrahydrofuran (30 mL) was added dropwise. After completion of dropwise addition, the mixture was stirred at room temperature for 2 h. To the reaction mixture was added water (100 mL), and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and the solvent was evaporated. The residue was recrystallized from isopropyl ether to give the title compound (35 g, yield 52%). m.p.: 66-67°C.

52%	With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane; water	R.L.11 2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone Reference Example L 11 2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone Under an argon atmosphere, a solution of diisopropylamine (44 mL, 0.31 mol) in anhydrous tetrahydrofuran (300 mL) was cooled to -78°C and, with stirring, a solution of 1.6M n-butyl lithium in hexane (190 mL, 0.31 mol) was added dropwise. After the completion of the dropwise addition, the mixture was stirred for 10 min. and a solution of 2-fluoro-4-methylpyridine (34.5 g, 0.31 mol) in anhydrous tetrahydrofuran (30 mL) was added. The reaction mixture was stirred at -10°C for 30 min. The reaction solution was cooled to -78°C and a solution of N-(3-methylbenzoyl)propyleneimine (52 g, 0.30 mol) in anhydrous tetrahydrofuran (30 mL) was added dropwise. After the completion of the dropwise addition, the mixture was stirred at room temperature for 2 hrs. Water (100 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and the solvent was evaporated. The residue was recrystallized from isopropyl ether to give the title compound (35 g, yield 52%). m.p.: 66-67°C.
52%	Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.166667h; Stage #2: 2-fluoro-4-methylpyridine In tetrahydrofuran; hexane at -10℃; for 0.166667h; Stage #3: 1-(3-methylbenzoyl)-2-methylaziridine In tetrahydrofuran; hexane at -78 - 20℃; for 20h;	R.11 2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone Reference Example 11 2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone Under an argon atmosphere, a solution of diisopropylamine (44 mL, 0.31 mol) in anhydrous tetrahydrofuran (300 mL) was cooled to -78°C and, with stirring, a solution of 1.6M n-butyl lithium in hexane (190 mL, 0.31 mol) was added dropwise. After the completion of the dropwise addition, the mixture was stirred for 10 min. and a solution of 2-fluoro-4-methylpyridine (34.5 g, 0.31 mol) in anhydrous tetrahydrofuran (30 mL) was added. The reaction mixture was stirred at -10°C for 30 min. The reaction solution was cooled to -78°C and a solution of N-(3-methylbenzoyl)propyleneimine (52 g, 0.30 mol) in anhydrous tetrahydrofuran (30 mL) was added dropwise. After the completion of the dropwise addition, the mixture was stirred at room temperature for 2 hrs. Water (100 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and the solvent was evaporated. The residue was recrystallized from isopropyl ether to give the title compound (35 g, yield 52%). melting point: 66-67°C.
52%	With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane; water	R.36 2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone Reference Example 36 2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone A solution of diisopropylamine (44 mL, 0.31 mol) in anhydrous tetrahydrofuran (300 mL) was cooled to -78°C under an argon atmosphere, and 1.6 M n-butyllithium/hexane solution (190 mL, 0.31 mol) was added dropwise with stirring. After completion of the dropwise addition, the mixture was stirred for 10 min, and a solution of 2-fluoro-4-methylpyridine (34.5 g, 0.31 mol) in anhydrous tetrahydrofuran (30 mL) was added. The reaction mixture was stirred at -10°C for 30 min. The reaction solution was cooled to -78°C and a solution of N-(3-methylbenzoyl)propyleneimine (52 g, 0.30 mol) in anhydrous tetrahydrofuran (30 mL) was added dropwise. After completion of dropwise addition, the mixture was stirred at room temperature for 2 h. To the reaction mixture was added water (100 mL), and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and the solvent was evaporated. The residue was recrystallized from isopropyl ether to give the title compound (35 g, yield 52%). melting point: 66-67°C.

Reference： [1]Miwatashi, Seiji; Arikawa, Yasuyoshi; Kotani, Etsuo; Miyamoto, Maki; Naruo, Ken-Ichi; Kimura, Hiroyuki; Tanaka, Toshimasa; Asahi, Satoru; Ohkawa, Shigenori [Journal of Medicinal Chemistry, 2005, vol. 48, # 19, p. 5966 - 5979]
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1354603, 2003, A1
[3]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1402900, 2004, A1
[4]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1402900, 2004, A1
[5]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1364949, 2003, A1 Location in patent: Page/Page column 80
[6]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1205478, 2002, A1

11
[ 461-87-0 ]
[ 76783-59-0 ]
[ 188345-23-5 ]

Reference： [1]Tetrahedron Letters,2006,vol. 47,p. 7199 - 7203

12
[ 461-87-0 ]
[ 383426-37-7 ]

Yield	Reaction Conditions	Operation in experiment
	With tert.-butylnitrite; potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; for 2h;	1 Example 1; Preparation of Compound 18; Compound 18 was prepared as outlined in Scheme 4. Accordingly, potassium t-butoxide (6.1 g) was added slowly to a stirred solution of tert-butylnitrite (5.5 mL) and 2-fluoro-4-methylpyridine (compound 1001, 4.0 g) in 75 mL of THF at 0° C. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the crude product extracted with ethyl acetate (4×50 mL). The resulting solid was washed with hexanes to yield (2-fluoropyridin-4-yl)methan-N-hydroxyimine (compound 1002; 4.0 g; ESMS: M+H+=141).
	With tert.-butylnitrite; potassium <i>tert</i>-butylate In tetrahydrofuran

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - US2007/270386, 2007, A1 Location in patent: Page/Page column 35
[2]Frey, Lisa F; Marcantonio, Karen; Frantz, Doug E; Murry, Jerry A; Tillyer, Richard D; Grabowski, Edward J.J; Reider, Paul J [Tetrahedron Letters, 2001, vol. 42, # 39, p. 6815 - 6818]

13
[ 461-87-0 ]
[ 457081-00-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium bis(trimethylsilyl)amide / tetrahydrofuran / 0.75 h / 0 °C 1.2: 86 percent / tetrahydrofuran / 1.5 h / 0 - 20 °C 2.1: 84 percent / NaNO₂ / H₂O; acetic acid / 1 h / 20 °C
	Multi-step reaction with 2 steps 1.1: LDA / tetrahydrofuran; hexane / -85 °C 1.2: 99 percent / tetrahydrofuran; hexane / -85 - 0 °C 2.1: 86 percent / aq. NaNO₂; AcOH / 10 - 20 °C
	Multi-step reaction with 2 steps 1.1: NaHMDS / tetrahydrofuran / 0.75 h / 2 °C 1.2: 82 percent / tetrahydrofuran / 1.5 h 2.1: 98 percent / ethanolic HCl; t-butyl nitrite

	Multi-step reaction with 2 steps 1: sodium hexamethyldisilazane / tetrahydrofuran / 3 h / 0 - 20 °C 2: acetic acid; sodium nitrite / water / 0.5 h / 10 - 20 °C
	Multi-step reaction with 2 steps 1: sodium hexamethyldisilazane / tetrahydrofuran / 3 h / 0 - 20 °C / Inert atmosphere 2: sodium nitrite; acetic acid / water / 1 h / 10 - 20 °C
	Multi-step reaction with 2 steps 1.1: sodium hexamethyldisilazane / tetrahydrofuran / 0.75 h / 0 °C 1.2: 0.75 h / 0 - 20 °C 2.1: sodium nitrite; acetic acid / water / 10 - 20 °C
	Multi-step reaction with 2 steps 1: sodium hexamethyldisilazane / tetrahydrofuran / 3 h / 0 - 20 °C / Inert atmosphere 2: acetic acid; sodium nitrite / water / 3.5 h / 10 - 20 °C

Reference： [1]Laufer, Stefan A.; Liedtke, Andy J. [Tetrahedron Letters, 2006, vol. 47, # 40, p. 7199 - 7203]
[2]Laufer, Stefan A.; Wagner, Gerd K.; Kotschenreuther, Dunja A.; Albrecht [Journal of Medicinal Chemistry, 2003, vol. 46, # 15, p. 3230 - 3244]
[3]Thompson, James E.; Cubbon, Rose M.; Cummings, Richard T.; Wicker, Linda S.; Frankshun, Robert; Cunningham, Barry R.; Cameron, Patricia M.; Meinke, Peter T.; Liverton, Nigel; Weng, Youmin; DeMartino, Julie A. [Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 8, p. 1219 - 1223]
[4]El-Gokha, Ahmed; Laufer, Stefan A.; Koch, Pierre [Organic and Biomolecular Chemistry, 2015, vol. 13, # 43, p. 10699 - 10704]
[5]Halekotte, Jakob; Witt, Lydia; Ianes, Chiara; Krüger, Marc; Bührmann, Mike; Rauh, Daniel; Pichlo, Christian; Brunstein, Elena; Luxenburger, Andreas; Baumann, Ulrich; Knippschild, Uwe; Bischof, Joachim; Peifer, Christian; Koch, Pierre; Laufer, Stefan [Molecules, 2017, vol. 22, # 4]
[6]Günther, Marcel; Lategahn, Jonas; Juchum, Michael; Döring, Eva; Keul, Marina; Engel, Julian; Tumbrink, Hannah L.; Rauh, Daniel; Laufer, Stefan [Journal of Medicinal Chemistry, 2017, vol. 60, # 13, p. 5613 - 5637]
[7]Current Patent Assignee: SYNOVO GMBH - US2017/313661, 2017, A1

14
[ 461-87-0 ]
[ 549505-59-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sodium bis(trimethylsilyl)amide / tetrahydrofuran / 0.75 h / 0 °C 1.2: 86 percent / tetrahydrofuran / 1.5 h / 0 - 20 °C 2.1: 84 percent / NaNO₂ / H₂O; acetic acid / 1 h / 20 °C 3.1: 100 percent / hydrogen chloride; H₂ / Pd/C / propan-2-ol / 6.5 h / 20 °C / 760 Torr 4.1: 77 percent / dimethylformamide / 0.75 h / 160 °C
	Multi-step reaction with 5 steps 1.1: LDA / tetrahydrofuran; hexane / -85 °C 1.2: 99 percent / tetrahydrofuran; hexane / -85 - 0 °C 2.1: 86 percent / aq. NaNO₂; AcOH / 10 - 20 °C 3.1: H₂; HCl / Pd/C / propan-2-ol / 20 °C / atmospheric pressure 4.1: 91 percent / dimethylformamide / Heating 5.1: 30 percent / ethanol; tetrahydrofuran / 40 h / Heating

15
[ 461-87-0 ]
[ 581098-56-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sodium bis(trimethylsilyl)amide / tetrahydrofuran / 0.75 h / 0 °C 1.2: 86 percent / tetrahydrofuran / 1.5 h / 0 - 20 °C 2.1: 84 percent / NaNO₂ / H₂O; acetic acid / 1 h / 20 °C 3.1: 100 percent / hydrogen chloride; H₂ / Pd/C / propan-2-ol / 6.5 h / 20 °C / 760 Torr 4.1: 56 percent / dimethylformamide / 0.75 h / 160 °C
	Multi-step reaction with 5 steps 1.1: LDA / tetrahydrofuran; hexane / -85 °C 1.2: 99 percent / tetrahydrofuran; hexane / -85 - 0 °C 2.1: 86 percent / aq. NaNO₂; AcOH / 10 - 20 °C 3.1: H₂; HCl / Pd/C / propan-2-ol / 20 °C / atmospheric pressure 4.1: 91 percent / dimethylformamide / Heating 5.1: 12 percent / ethanol; tetrahydrofuran / 1.5 h / Heating

16
[ 461-87-0 ]
2-amino-1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethananone hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium bis(trimethylsilyl)amide / tetrahydrofuran / 0.75 h / 0 °C 1.2: 86 percent / tetrahydrofuran / 1.5 h / 0 - 20 °C 2.1: 84 percent / NaNO₂ / H₂O; acetic acid / 1 h / 20 °C 3.1: 100 percent / hydrogen chloride; H₂ / Pd/C / propan-2-ol / 6.5 h / 20 °C / 760 Torr
	Multi-step reaction with 3 steps 1.1: LDA / tetrahydrofuran; hexane / -85 °C 1.2: 99 percent / tetrahydrofuran; hexane / -85 - 0 °C 2.1: 86 percent / aq. NaNO₂; AcOH / 10 - 20 °C 3.1: H₂; HCl / Pd/C / propan-2-ol / 20 °C / atmospheric pressure
	Multi-step reaction with 3 steps 1: sodium hexamethyldisilazane / tetrahydrofuran / 3 h / 0 - 20 °C 2: acetic acid; sodium nitrite / water / 0.5 h / 10 - 20 °C 3: palladium 10% on activated carbon; hydrogen; hydrogenchloride / isopropyl alcohol

	Multi-step reaction with 3 steps 1: sodium hexamethyldisilazane / tetrahydrofuran / 3 h / 0 - 20 °C / Inert atmosphere 2: sodium nitrite; acetic acid / water / 1 h / 10 - 20 °C 3: palladium 10% on activated carbon; hydrogenchloride / isopropyl alcohol / 12 h / 20 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1.1: sodium hexamethyldisilazane / tetrahydrofuran / 0.75 h / 0 °C 1.2: 0.75 h / 0 - 20 °C 2.1: sodium nitrite; acetic acid / water / 10 - 20 °C 3.1: acetic acid; zinc / 0 °C 3.2: -10 °C

Reference： [1]Laufer, Stefan A.; Liedtke, Andy J. [Tetrahedron Letters, 2006, vol. 47, # 40, p. 7199 - 7203]
[2]Laufer, Stefan A.; Wagner, Gerd K.; Kotschenreuther, Dunja A.; Albrecht [Journal of Medicinal Chemistry, 2003, vol. 46, # 15, p. 3230 - 3244]
[3]El-Gokha, Ahmed; Laufer, Stefan A.; Koch, Pierre [Organic and Biomolecular Chemistry, 2015, vol. 13, # 43, p. 10699 - 10704]
[4]Halekotte, Jakob; Witt, Lydia; Ianes, Chiara; Krüger, Marc; Bührmann, Mike; Rauh, Daniel; Pichlo, Christian; Brunstein, Elena; Luxenburger, Andreas; Baumann, Ulrich; Knippschild, Uwe; Bischof, Joachim; Peifer, Christian; Koch, Pierre; Laufer, Stefan [Molecules, 2017, vol. 22, # 4]
[5]Günther, Marcel; Lategahn, Jonas; Juchum, Michael; Döring, Eva; Keul, Marina; Engel, Julian; Tumbrink, Hannah L.; Rauh, Daniel; Laufer, Stefan [Journal of Medicinal Chemistry, 2017, vol. 60, # 13, p. 5613 - 5637]

17
[ 461-87-0 ]
[ 549505-63-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: LDA / tetrahydrofuran; hexane / -85 °C 1.2: 99 percent / tetrahydrofuran; hexane / -85 - 0 °C 2.1: 86 percent / aq. NaNO₂; AcOH / 10 - 20 °C 3.1: H₂; HCl / Pd-C / 20 °C / atmospheric pressure 4.1: 45 percent / dimethylformamide / Heating

Reference： [1]Laufer, Stefan A.; Wagner, Gerd K.; Kotschenreuther, Dunja A.; Albrecht [Journal of Medicinal Chemistry, 2003, vol. 46, # 15, p. 3230 - 3244]

18
[ 461-87-0 ]
[ 549505-65-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: LDA / tetrahydrofuran; hexane / -85 °C 1.2: 99 percent / tetrahydrofuran; hexane / -85 - 0 °C 2.1: 86 percent / aq. NaNO₂; AcOH / 10 - 20 °C 3.1: H₂; HCl / Pd/C / propan-2-ol / 20 °C / atmospheric pressure 4.1: 91 percent / dimethylformamide / Heating 5.1: 30 percent / ethanol; tetrahydrofuran / 40 h / Heating 6.1: 41 percent / 7 h / 160 °C

Reference： [1]Laufer, Stefan A.; Wagner, Gerd K.; Kotschenreuther, Dunja A.; Albrecht [Journal of Medicinal Chemistry, 2003, vol. 46, # 15, p. 3230 - 3244]

19
[ 461-87-0 ]
[ 581098-38-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: LDA / tetrahydrofuran; hexane / -85 °C 1.2: 99 percent / tetrahydrofuran; hexane / -85 - 0 °C 2.1: 86 percent / aq. NaNO₂; AcOH / 10 - 20 °C 3.1: H₂; HCl / Pd/C / propan-2-ol / 20 °C / atmospheric pressure 4.1: 91 percent / dimethylformamide / Heating
	Multi-step reaction with 4 steps 1: sodium hexamethyldisilazane / tetrahydrofuran / 3 h / 0 - 20 °C 2: acetic acid; sodium nitrite / water / 0.5 h / 10 - 20 °C 3: palladium 10% on activated carbon; hydrogen; hydrogenchloride / isopropyl alcohol 4: methanol / 1.5 h / Reflux
	Multi-step reaction with 4 steps 1.1: sodium hexamethyldisilazane / tetrahydrofuran / 0.75 h / 0 °C 1.2: 0.75 h / 0 - 20 °C 2.1: sodium nitrite; acetic acid / water / 10 - 20 °C 3.1: acetic acid; zinc / 0 °C 3.2: -10 °C 4.1: N,N-dimethyl-formamide / Reflux

Multi-step reaction with 4 steps 1: sodium hexamethyldisilazane / tetrahydrofuran / 3 h / 0 - 20 °C / Inert atmosphere 2: acetic acid; sodium nitrite / water / 3.5 h / 10 - 20 °C 3: hydrogenchloride; palladium 10% on activated carbon; hydrogen / isopropyl alcohol / 6 h / 20 °C 4: methanol / 1.5 h / Reflux

Reference： [1]Laufer, Stefan A.; Wagner, Gerd K.; Kotschenreuther, Dunja A.; Albrecht [Journal of Medicinal Chemistry, 2003, vol. 46, # 15, p. 3230 - 3244]
[2]El-Gokha, Ahmed; Laufer, Stefan A.; Koch, Pierre [Organic and Biomolecular Chemistry, 2015, vol. 13, # 43, p. 10699 - 10704]
[3]Günther, Marcel; Lategahn, Jonas; Juchum, Michael; Döring, Eva; Keul, Marina; Engel, Julian; Tumbrink, Hannah L.; Rauh, Daniel; Laufer, Stefan [Journal of Medicinal Chemistry, 2017, vol. 60, # 13, p. 5613 - 5637]
[4]Current Patent Assignee: SYNOVO GMBH - US2017/313661, 2017, A1

20
[ 461-87-0 ]
[ 581098-40-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: LDA / tetrahydrofuran; hexane / -85 °C 1.2: 99 percent / tetrahydrofuran; hexane / -85 - 0 °C 2.1: 86 percent / aq. NaNO₂; AcOH / 10 - 20 °C 3.1: H₂; HCl / Pd-C / 20 °C / atmospheric pressure 4.1: 13 percent / aq. HCl / 0.5 h / Heating

Reference： [1]Laufer, Stefan A.; Wagner, Gerd K.; Kotschenreuther, Dunja A.; Albrecht [Journal of Medicinal Chemistry, 2003, vol. 46, # 15, p. 3230 - 3244]

21
[ 461-87-0 ]
[ 581098-39-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: LDA / tetrahydrofuran; hexane / -85 °C 1.2: 99 percent / tetrahydrofuran; hexane / -85 - 0 °C 2.1: 86 percent / aq. NaNO₂; AcOH / 10 - 20 °C 3.1: H₂; HCl / Pd-C / 20 °C / atmospheric pressure 4.1: 31 percent / aq. HCl / 0.5 h / Heating

Reference： [1]Laufer, Stefan A.; Wagner, Gerd K.; Kotschenreuther, Dunja A.; Albrecht [Journal of Medicinal Chemistry, 2003, vol. 46, # 15, p. 3230 - 3244]

22
[ 461-87-0 ]
4-[5-(4-fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]-2-methoxypyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: LDA / tetrahydrofuran; hexane / -85 °C 1.2: 99 percent / tetrahydrofuran; hexane / -85 - 0 °C 2.1: 86 percent / aq. NaNO₂; AcOH / 10 - 20 °C 3.1: H₂; HCl / Pd-C / 20 °C / atmospheric pressure 4.1: 31 percent / aq. HCl / 0.5 h / Heating 5.1: 26 percent / methanol / 3 h / Heating

Reference： [1]Laufer, Stefan A.; Wagner, Gerd K.; Kotschenreuther, Dunja A.; Albrecht [Journal of Medicinal Chemistry, 2003, vol. 46, # 15, p. 3230 - 3244]

23
[ 461-87-0 ]
[ 581098-42-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: LDA / tetrahydrofuran; hexane / -85 °C 1.2: 99 percent / tetrahydrofuran; hexane / -85 - 0 °C 2.1: 86 percent / aq. NaNO₂; AcOH / 10 - 20 °C 3.1: 48 percent / HCl / 2.5 h / Heating 4.1: H₂; HCl / Pd/C / propan-2-ol / 20 °C / atmospheric pressure 5.1: 70 percent / dimethylformamide / Heating

Reference： [1]Laufer, Stefan A.; Wagner, Gerd K.; Kotschenreuther, Dunja A.; Albrecht [Journal of Medicinal Chemistry, 2003, vol. 46, # 15, p. 3230 - 3244]

24
[ 461-87-0 ]
4-[5-(4-fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]-2-isopropoxypyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: LDA / tetrahydrofuran; hexane / -85 °C 1.2: 99 percent / tetrahydrofuran; hexane / -85 - 0 °C 2.1: 86 percent / aq. NaNO₂; AcOH / 10 - 20 °C 3.1: 48 percent / HCl / 2.5 h / Heating 4.1: H₂; HCl / Pd/C / propan-2-ol / 20 °C / atmospheric pressure 5.1: 70 percent / dimethylformamide / Heating 6.1: NaH / tetrahydrofuran / 0.08 h / 20 °C 6.2: 50 percent / tetrahydrofuran / 1 h / 20 °C

Reference： [1]Laufer, Stefan A.; Wagner, Gerd K.; Kotschenreuther, Dunja A.; Albrecht [Journal of Medicinal Chemistry, 2003, vol. 46, # 15, p. 3230 - 3244]

25
[ 461-87-0 ]
{4-[5-(4-fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]-pyridin-2-yl}-phenyl-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: LDA / tetrahydrofuran; hexane / -85 °C 1.2: 99 percent / tetrahydrofuran; hexane / -85 - 0 °C 2.1: 86 percent / aq. NaNO₂; AcOH / 10 - 20 °C 3.1: H₂; HCl / Pd/C / propan-2-ol / 20 °C / atmospheric pressure 4.1: 91 percent / dimethylformamide / Heating 5.1: 30 percent / ethanol; tetrahydrofuran / 40 h / Heating 6.1: 12 percent / 6 h / Heating

Reference： [1]Laufer, Stefan A.; Wagner, Gerd K.; Kotschenreuther, Dunja A.; Albrecht [Journal of Medicinal Chemistry, 2003, vol. 46, # 15, p. 3230 - 3244]

26
[ 461-87-0 ]
benzyl {4-[5-(4-fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]-pyridin-2-yl}-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: LDA / tetrahydrofuran; hexane / -85 °C 1.2: 99 percent / tetrahydrofuran; hexane / -85 - 0 °C 2.1: 86 percent / aq. NaNO₂; AcOH / 10 - 20 °C 3.1: H₂; HCl / Pd/C / propan-2-ol / 20 °C / atmospheric pressure 4.1: 91 percent / dimethylformamide / Heating 5.1: 30 percent / ethanol; tetrahydrofuran / 40 h / Heating 6.1: 41 percent / 5 h / 160 °C

Reference： [1]Laufer, Stefan A.; Wagner, Gerd K.; Kotschenreuther, Dunja A.; Albrecht [Journal of Medicinal Chemistry, 2003, vol. 46, # 15, p. 3230 - 3244]

27
[ 461-87-0 ]
4-(4-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-5-yl)-N-((R)-1-phenylethyl)pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: LDA / tetrahydrofuran; hexane / -85 °C 1.2: 99 percent / tetrahydrofuran; hexane / -85 - 0 °C 2.1: 86 percent / aq. NaNO₂; AcOH / 10 - 20 °C 3.1: H₂; HCl / Pd/C / propan-2-ol / 20 °C / atmospheric pressure 4.1: 91 percent / dimethylformamide / Heating 5.1: 30 percent / ethanol; tetrahydrofuran / 40 h / Heating 6.1: 36 percent / 7 h / 170 °C

Reference： [1]Laufer, Stefan A.; Wagner, Gerd K.; Kotschenreuther, Dunja A.; Albrecht [Journal of Medicinal Chemistry, 2003, vol. 46, # 15, p. 3230 - 3244]

28
[ 461-87-0 ]
4-(4-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-5-yl)-N-((S)-1-phenylethyl)pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: LDA / tetrahydrofuran; hexane / -85 °C 1.2: 99 percent / tetrahydrofuran; hexane / -85 - 0 °C 2.1: 86 percent / aq. NaNO₂; AcOH / 10 - 20 °C 3.1: H₂; HCl / Pd/C / propan-2-ol / 20 °C / atmospheric pressure 4.1: 91 percent / dimethylformamide / Heating 5.1: 30 percent / ethanol; tetrahydrofuran / 40 h / Heating 6.1: 36 percent / 13 h / 170 °C

Reference： [1]Laufer, Stefan A.; Wagner, Gerd K.; Kotschenreuther, Dunja A.; Albrecht [Journal of Medicinal Chemistry, 2003, vol. 46, # 15, p. 3230 - 3244]

29
[ 461-87-0 ]
benzyl-{4-[5-(4-fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]-pyridin-2-yl}-methylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: LDA / tetrahydrofuran; hexane / -85 °C 1.2: 99 percent / tetrahydrofuran; hexane / -85 - 0 °C 2.1: 86 percent / aq. NaNO₂; AcOH / 10 - 20 °C 3.1: H₂; HCl / Pd/C / propan-2-ol / 20 °C / atmospheric pressure 4.1: 91 percent / dimethylformamide / Heating 5.1: 30 percent / ethanol; tetrahydrofuran / 40 h / Heating 6.1: 46 percent / 7 h / 180 °C

Reference： [1]Laufer, Stefan A.; Wagner, Gerd K.; Kotschenreuther, Dunja A.; Albrecht [Journal of Medicinal Chemistry, 2003, vol. 46, # 15, p. 3230 - 3244]

30
[ 461-87-0 ]
{4-[5-(4-fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]-pyridin-2-yl}-phenethylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: LDA / tetrahydrofuran; hexane / -85 °C 1.2: 99 percent / tetrahydrofuran; hexane / -85 - 0 °C 2.1: 86 percent / aq. NaNO₂; AcOH / 10 - 20 °C 3.1: H₂; HCl / Pd/C / propan-2-ol / 20 °C / atmospheric pressure 4.1: 91 percent / dimethylformamide / Heating 5.1: 30 percent / ethanol; tetrahydrofuran / 40 h / Heating 6.1: 38 percent / 5.5 h / 160 °C

Reference： [1]Laufer, Stefan A.; Wagner, Gerd K.; Kotschenreuther, Dunja A.; Albrecht [Journal of Medicinal Chemistry, 2003, vol. 46, # 15, p. 3230 - 3244]

31
[ 461-87-0 ]
L-790,070 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: 1.) LDA / 1.) THF, hexane, -78 deg C, 15 min, 2.) THF, hexane, -78 deg C, 5 min 2: 96 percent / tert-butyl nitrite, HCl / ethanol / 2 h / Ambient temperature 3: ammonium acetate, AcOH / 2 h / 80 °C 4: TiCl₃, aq. HCl / methanol / 3 h / 20 °C 5: 66 percent / 100 h / 150 °C 6: 61 percent / Cs₂CO₃ / dimethylformamide / 3 h / -30 - 20 °C 7: 100 percent / H₂ / 10 percent Pd/C / propan-2-ol / 24 h / 760 Torr
	Multi-step reaction with 10 steps 1: 80 percent / n-BuLi / tetrahydrofuran / -78 °C 2: 95 percent / t-BuONO, HCl / ethanol / -5 deg C, 1 h; 23 deg C, 2 h 3: 91 percent / H₂ / Pd/C / ethanol / 760 Torr 4: 10 h / Heating 5: BH₃*THF / tetrahydrofuran / 2 h / 24 °C 6: 95 percent / triethylamine / CH₂Cl₂ / 0.33 h / 25 °C 7: oxalyl chloride, DMSO, Et₃N / CH₂Cl₂ / -78 - 23 °C 8: ammonium trifluoroacetate / 0.08 h / 150 °C 9: 76 percent / 2 h / 150 °C 10: 98 percent / H₂ / Pd/C / ethanol / 4 h

Reference： [1]Liverton, Nigel J.; Butcher, John W.; Claiborne, Christopher F.; Claremon, David A.; Libby, Brian E.; Nguyen, Kevin T.; Pitzenberger, Steven M.; Selnick, Harold G.; Smith, Garry R.; Tebben, Andrew; Vacca, Joseph P.; Varga, Sandor L.; Agarwal, Lily; Dancheck, Kim; Forsyth, Amy J.; Fletcher, Daniel S.; Frantz, Betsy; Hanlon, William A.; Harper, Coral F.; Hofsess, Scott J.; Kostura, Matthew; Lin, Jiunn; Luell, Sylvie; O'Neill, Edward A.; Orevillo, Chad J.; Pang, Margaret; Parsons, Janey; Rolando, Anna; Sahly, Yousif; Visco, Denise M.; O'Keefe, Stephen J. [Journal of Medicinal Chemistry, 1999, vol. 42, # 12, p. 2180 - 2190]
[2]Claiborne, Christopher F.; Liverton, Nigel J.; Nguyen, Kevin T. [Tetrahedron Letters, 1998, vol. 39, # 49, p. 8939 - 8942]

32
[ 461-87-0 ]
[ 131747-69-8 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1990,vol. 38,p. 2446 - 2458
[2]Patent: US6358978,2002,B1

33
[ 461-87-0 ]
[ 123412-95-3 ]

Reference： [1]Journal of Medicinal Chemistry,1990,vol. 33,p. 1667 - 1675
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 2745 - 2766

34
[ 461-87-0 ]
[ 455-69-6 ]

Reference： [1]Journal of the American Chemical Society,1949,vol. 71,p. 4152

35
[ 461-87-0 ]
[ 100-52-7 ]
[ 434899-28-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: 2-fluoro-4-methylpyridine With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 4h; Stage #2: benzaldehyde In tetrahydrofuran; hexane
94%	With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 4.25h;	24.One EXAMPLE 24 [00276] Synthesis of (3S)-3-(3-isopropoxyphenyl)-3-({2-[2-oxo-4-(2-phenylethyl)pyridin-1(2H)-yl]hexanoyl}amino)propanoic acid EXAMPLE 24 [00276] Synthesis of (3S)-3-(3-isopropoxyphenyl)-3-({2-[2-oxo-4-(2-phenylethyl)pyridin-1(2H)-yl]hexanoyl}amino)propanoic acid. [00277] Step One: To a solution of diisopropylamine (2.94 g, 29.1 mmol) in THF (20 mL) cooled to -78° C. under a dry nitrogen atmosphere, butyllithium (12.8 mL of a 2.5 M solution in hexanes, 32.0 mmol) was added by syringe and stirred at -78° C. for 15 minutes. The solution was added by cannula to a solution of 2-fluoro-4-methyl-pyridine (2.15 g, 9.40 mmol) in THF (20 mL) cooled to -78° C. under a dry nitrogen atmosphere. The resulting mixture was stirred at -78° C. for 4 hours, and then quenched with benzaldehyde (2.17 mL, 21.3 mmol). The resulting yellow solution was warmed to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with 7:3 hexanes:ethyl acetate to give 69 (1.92 g, 94%) as a yellow oil.

Reference： [1]Current Patent Assignee: PFIZER INC - EP1213288, 2002, A1 Location in patent: Page 39
[2]Current Patent Assignee: PFIZER INC - US6723711, 2004, B2 Location in patent: Page column 54

36
[ 461-87-0 ]
[ 64992-03-6 ]

Yield	Reaction Conditions	Operation in experiment
55.5%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 80℃; for 48h;	178 4-(bromomethyl)-2-fluoropyridine The mixture of 2-fluoro-4-methyl-pyridine (2 g, 18.00 mmol, 1 eq ), NBS (3.52 g, 19.80 mmol, 1.1 eq) and AIBN (295.5 mg, 1.80 mmol, 0.1 eq) in CCL (20 mL) was stirred at 80 °C for 48 hr. The reaction mixture was diluted with H20 (60 mL) and extracted with DCM (10 mL * 3). The combined organic phase was washed with brine (10 mL * 2), dried with anhydrous Na2S04, filtered and concentrated in vacuum. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=l/0 to 10: 1). Compound 4-(bromomethyl)-2-fluoro-pyridine (1.9 g, 10.00 mmol, 55.5% yield) was obtained as a yellow oil and obtained as a yellow oil and used into the next step without further purification.
44.9%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 18h; Reflux;	66 Preparation of 4-(bromomethyl)-2-fluoropyridine Preparation of 4-(bromomethyl)-2-fluoropyridine After 4-methyl-2-fluoropyridine (1.0 g, 9 mmol) was dissolved in carbon tetrachloride (20 mL), N-bromosuccinimide (1.76 g, 9.9 mmol) and benzoyl peroxide (12.6 mg) were added thereto, and the mixture was refluxed for 18 hours. The reaction material was cooled to room temperature, and stirred for 10 minutes after normal-hexane (150 mL) was added thereto. After the produced solids were removed by filtration, the filtrate was concentrated under reduced pressure, and then the residue was purified using silica gel column chromatography (ethyl acetate/normal-hexane=1/20) to give a target compound (525 mg, 44.9%). 1H-NMR (300 MHz, CDCl3) δ 4.39 (s, 2H), 6.96 (s, 1H), 7.20 (d, 1H), 8.10 (d, 1H); MS (EI, m/e)=190 (M+)
44.9%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 18h; Reflux;	66 Preparation of 4-(bromomethyl)-2-fluoropyridine After 4-methyl-2-fluoropyridine (1.0 g, 9 mmol) was dissolved in carbon tetrachloride (20 mL), N-bromosuccinimide (1.76 g, 9.9 mmol) and benzoyl peroxide (12.6 mg) were added thereto, and the mixture was refluxed for 18 hours. The reaction material was cooled to room temperature, and stirred for 10 minutes after normal-hexane (150 mL) was added thereto. After the produced solids were removed by filtration, the filtrate was concentrated under reduced pressure, and then the residue was purified using silica gel column chromatography (ethyl acetate/normal-hexane=1/20) to give a target compound (525 mg, 44.9%). 1H-NMR (300 MHz, CDCl3) δ 4.39 (s, 2H), 6.96 (s, 1H), 7.20 (d, 1H), 8.10 (d, 1H); MS (EI, m/e)=190 (M+).

35%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 20 - 80℃; for 21h; Inert atmosphere;
30%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 80℃;	General procedure A General procedure: A solution of the corresponding fluoro-methylpyridine (100 mg, 1 eq, 0.90 mmol) in CCl4 (2 mL) was treated with NBS (168 mg, 1.05 eq, 0.95 mmol) and AIBN (44 mg, 0.3 eq, 0.27 mmol) and stirred overnight at 80 °C. After filtration of the reaction mixture, the solvent was removed by rotary evaporation. The remaining residue was dissolved in EA (20 mL) and the organic phase was washed with water (3 x 20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered and evaporated to dryness. The crude product was purified by flash chromatography (silica, gradient ethyl acetate / petroleum ether (EA/PE1:8 → 1:7 → 1:6) to give the corresponding bromomethyl-fluoropyridine (3a-d) as colorless oil.
28%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 5h; Heating / reflux; UV-irradiation;	H Example H 4-Bromomethyl-2-fluoro-pyridine (35): The mixture of 2-Fluoro-4-methyl-pyridine (10 g, 90 mmol), N-bromosuccinimide (19.2 g, 108 mmol), and benzoyl peroxide (2.18 g, 9 mmol) in carbon tetrachloride (100 ml) was refluxed for 5 hr under a light of 500 W tungsten light. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated in vacuo to give a brown oil, which was purified by silica gel column chromatography (eluent, ether:hexane (1:9)) to afford 4.85 g (28%) of a pale brown oil; 1H NMR (200 MHz, CDCl3) δ: 4.40 (2H, s), 6.95 (1H, m), 7.19 (1H, m), 8.18 (1H, d, J=5.2 Hz); m/z (EI): 189(M+), 191(M+2+).
28%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane Reflux;
27%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 25 - 85℃; for 5h; Inert atmosphere;	2 Preparation 2: 4-Bromomethyl-2-fluoropyridine (1-2) To a solution of 2-fluoro-4-methylpyridine (75.0 g, 0.675 mole) in Cd4 (200 mL) under N2 atmosphere at 25 °C was added N-bromosuccinimide (160 g, 0.90 mole) and benzoyl peroxide (24.52 g, 0.101 mole). The reaction mass was gradually heated to 85 °C and stirred for 5 hours at this temperature. The reaction mass after cooling to RT was filtered under vacuum and washed with Cd4 (50 mL). The filtratewas concentrated under vacuum to obtain the crude residue, which was purified by flash chromatography using ethyl acetate: n-hexane (02: 98) to afford the title compound.Yield: 35.2 g (27 %); ‘H - NMR (CDC13, 400 MHz) ö ppm: 4.71 (s, 2H), 7.27 (s, 1H),7.42 - 7.43 (d, J = 4.9 Hz, 1H), 8.24 - 8.25 (d, J = 5.1 Hz, 1H); Mass (mlz): 190.0(M+H), 192.1 (M+H).
23.4%	With N-Bromosuccinimide; acetic acid; dibenzoyl peroxide In tetrachloromethane at 25 - 80℃; for 20h;	2.1 Step-i: To a stirred solution of 2-fluoro-4-methylpyridine (5g, 44.99 mmol) in dry carbon tetrachloride (114 ml) was added glacial Acetic acid (3.3m1) at 25° C. Then reaction mixture was heated to 50° C and N-bromo succinimide (8 g, 44.9 mmol) followed by Benzoyl peroxide (1.1 g, 4.49 mmol) was added. After complete addition reaction mixture was stirred at 80° C for 20h. The progress of the reaction was monitored byTLC (1:9, Ethyl acetate : pet. ether). After completion of reaction, reaction mixture was cooled to room temperature quenched with cold water and extracted with DCM (4 x 200 mL). The combined organic layer was washed with saturated NaC1 (100 mL) solution, dried over anhydrous Na2504, filtered and concentrated. The crude was purified by column chromatography (60-120 mesh silica gel) using 2% Ethyl acetate inpet ether as eluent to yield pure 4-(bromomethyl)-2-fluoropyridine (2.8 g, 23.4%) as a pale yellow oil.
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In chloroform; ethyl acetate; pentane	R.75 4-Bromomethyl-2-fluoropyridine REFERENCE EXAMPLE 75 4-Bromomethyl-2-fluoropyridine A solution of 2-fluoro-4-methylpyridine (0.5 g) in chloroform (50 ml) was treated with N-bromosuccinimide (1.35 g) and azobisisobutyronitrile (0.25 g). The mixture was heated at reflux for 30 hours, cooled to room temperature and washed with water (30 ml). The chloroform solution was evaporated and the resulting brown oil purified by flash chromatography on silica eluding initially with a mixture of ethyl acetate and pentane (1:9, v/v) then with a mixture of ethyl acetate and pentane (15:85, v/v). Fractions homogenous in the required product were combined and evaporated affording the title compound (0.18 g) as a yellow oil.
	Stage #1: 2-fluoro-4-methylpyridine With acetic acid In tetrachloromethane at 20 - 50℃; Stage #2: With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 50 - 80℃; for 16h;	215.a REFERENCE EXAMPLE 215a; 2-Fluoro-4-(bromomethyl)pyridine 0.073 ml of acetic acid is added to a solution of 0.111 g of 2-fluoro-4-methylpyridine in 2.5 ml of carbon tetrachloride, under an inert atmosphere of argon at a temperature in the region of 20° C. The mixture is brought, with stirring, to a temperature of 50° C. 0.356 g of N-bromosuccinimide and 0.048 g of benzoyl peroxide are successively added at this temperature. The mixture is brought to 80° C. over about 16 hours. After cooling, the reaction medium is placed on a cartridge 20 mm in diameter packed with 10 g of 20-40 μm silica not conditioned beforehand, and then eluted with dichloromethane at a flow rate of 5 muminute. The fractions between 28 and 38 ml are concentrated to dryness under reduced pressure. 0.063 g of 2-fluoro-4-(bromomethyl)pyridine is thus obtained.
	With N-Bromosuccinimide; 1,1'-azobis(1-cyanocyclohexanenitrile) In tetrachloromethane for 24h; Heating / reflux;	8.a; 294.a To a solution of 2-fluoro-4-methylpyridine (1.0 g, ex Lancaster) in carbon tetrachloride (10 ml) was added N-bromosuccinimide (1.6 g, ex Lancaster) and 1, 1'- azobis (cyclohexanecarbonitrile) (100 mg, ex Aldrich). The mixture was then refluxed for 24h. Carbon tetrachloride was removed under reduced pressure and the crude oily solid was used in the next stage without purification. LC/MS, t = 2.38 min, [MEt] 190 and 192.; To a solution of 2-fluoro-4-methylpyridine (1. 0 g, ex Lancaster) in carbon tetrachloride (10 ml) was added N-bromosuccinimide (1.6 g, ex Lancaster) and 1, 1'- azobis (cyclohexanecarbonitrile) (100 mg, ex Aldrich). The mixture was then refluxed for 24h. Carbon tetrachloride was removed under reduced pressure and the crude oily solid was used in the next stage without purification. LC/MS, t = 2. 3 8 min, [EF] 190 and 192.; Example 294: 2- (3-Chloro-phenylamino)-4-triflnoromethyl-pyrimidine-5-carboxylic acid (2- fluoro-pyridin-4-ylmethyl)-amide. (a). 4-Bromomethyl-2-fluoro-pyridine. To a solution of 2-fluoro-4-methylpyridine (1. 0 g, ex Lancaster) in carbon tetrachloride (10 ml) was added N-bromosuccinimide (1.6 g, ex Lancaster) and 1, 1'- azobis (cyclohexanecarbonitrile) (100 mg, ex Aldrich). The mixture was then refluxed for 24h. Carbon tetrachloride was removed under reduced pressure and the crude oily solid was used in the next stage without purification. LC/MS, t = 2. 3 8 min, [EF] 190 and 192
	With N-Bromosuccinimide; 1,1'-azobis(1-cyanocyclohexanenitrile) In tetrachloromethane for 24h; Heating / reflux;	36.a Intermediate 36: C- (2-Fluoro-pyridin-4-yl)-methylamine dihydrochloride; (a). 4-Bromomethyl-2-fluoro-pyridine.; To a solution of 2-fluoro-4-methylpyridine (1.0 g, ex Lancaster) in carbon tetrachloride (10 ml) was added N-bromosuccinimide (1.6 g, ex Lancaster) and 1, l'-azobis (cyclohexanecarbonitrile) (100 mg, ex Aldrich). The mixture was then refluxed for 24h. Carbon tetrachloride was removed under reduced pressure and the crude oily solid was used in the next stage without purification. LC/MS, t = 2. 38 min, [MH+] 190 consistent with C6Hs79BrFN.
	With N-Bromosuccinimide In tetrachloromethane at 90℃; for 21h;	25 To a solution of 2-fluoro-4-methylpyridine (0.510 g, 4.59 mmol) in 20 mL of carbontetrachloride was added iV-bromosuccinimide (0.899 g, 5.05 mmol) and benzoyl peroxide (0.148 g, 0.459 mmol). The mixture was heated to 90 0C for 1 h, and then additional benzoyl peroxide (0.074 g, 0.23 mmol) was added. After 20 h, the reaction was diluted with dichloromethane, washed 3x with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-10% ethyl acetate in hexanes to provide the 4-(bromomethyl)-2-fluoropyridine that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 191.9 (81Br) for [M+H]+.
	With N-Bromosuccinimide; dibenzoyl peroxide
1.1 g	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 85℃; for 5h; Inert atmosphere;	1 Preparation 1: 4-Bromomethyl-2-fluo (1-1) To a solution of 2-fluoro-4-methylpyridine (2.5 g, 0.022 mole) in CC (75 mL) under N2 atmosphere at 25 °C was added N-bromosuccinimide (4.4 g, 0.024 mole) and benzoyl peroxide (0.81 g, 0.003 mole). Reaction mixture was heated to 85 °C for 5 hours, cooled to RT, filtered under vacuum and washed with CCU (40 mL). The filtrate was concentrated under vacuum to obtain the crude compound, which was further purified by flash chromatography using ethyl acetate: n-hexane (02: 98) to afford the title compound. Yield: 1.1 g; lH - NMR (CDC13, 400 MHz) δ ppm: 4.71 (s, 2H), 7.27 (s, 1H), 7.42 - 7.43 (d, J = 4.9 Hz, 1H), 8.24 - 8.25 (d, J = 5.1 Hz, 1H); Mass (m/z): 190.0, 192.1 (M+H)+.
	With N-Bromosuccinimide; 1,1'-azobis(1-cyanocyclohexanenitrile) In tetrachloromethane for 24h; Heating / reflux;	29.a Example 29: 2-(3-Chloro-phyenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid [(2-FLUORO-PYRIDIN-4-YLMETHYL)-AMIDE.] (a). 4-Bromomethyl-2-fluoro-pyridine. To a solution of 2-fluoro-4-methylpyridine (1.0 g, ex Lancaster) in carbon tetrachloride (10 ml) was added N-bromosuccinimide (1.6 g, ex Lancaster) and 1, 1'- azobis (cyclohexanecarbonitrile) (100 mg, ex Aldrich). The mixture was then refluxed for 24h. Carbon tetrachloride was removed under reduced pressure and the crude oily solid was used in the next stage without purification. [LC/MS,] [T =] 2.38 min, [[MH+]] 190 and 192.

Reference： [1]Current Patent Assignee: VIVACE THERAPEUTICS - WO2020/97389, 2020, A1 Location in patent: Paragraph 00639
[2]Current Patent Assignee: ST PHARM CO.,LTD. - US2014/249162, 2014, A1 Location in patent: Paragraph 0471; 0472; 0473
[3]Current Patent Assignee: ST PHARM CO.,LTD. - EP2781519, 2014, A1 Location in patent: Paragraph 0452; 0453; 0454
[4]Betts, Helen M.; Milicevic Sephton, Selena; Tong, Carmen; Awais, Ramla O.; Hill, Philip J.; Perkins, Alan C.; Aigbirhio, Franklin I. [Journal of Medicinal Chemistry, 2016, vol. 59, # 20, p. 9422 - 9430]
[5]Dukić-Stefanović, Sladjana; Hang Lai, Thu; Toussaint, Magali; Clauß, Oliver; Jevtić, Ivana I.; Penjišević, Jelena Z.; Andrić, Deana; Ludwig, Friedrich-Alexander; Gündel, Daniel; Deuther-Conrad, Winnie; Kostić-Rajačić, Sladjana V.; Brust, Peter; Teodoro, Rodrigo [Bioorganic and Medicinal Chemistry Letters, 2021, vol. 48]
[6]Current Patent Assignee: KOREA RESEARCH INSTITUTE OF CHEMICAL TECHNOLOGY - US2008/70920, 2008, A1 Location in patent: Page/Page column 37-38
[7]Location in patent: scheme or table Mitchell, Michael L.; Son, Jong Chan; Lee, Ill Young; Lee, Chong-Kyo; Kim, Hae Soo; Guo, Hongyan; Wang, Jianhong; Hayes, Jaclyn; Wang, Michael; Paul, Amber; Lansdon, Eric B.; Chen, James M.; Eisenberg, Gene; Geleziunas, Romas; Xu, Lianhong; Kim, Choung U. [Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 5, p. 1585 - 1588]
[8]Current Patent Assignee: SUVEN LIFE SCIENCES LIMITED - WO2017/42643, 2017, A1 Location in patent: Page/Page column 23
[9]Current Patent Assignee: GENERAL ELECTRIC CO - WO2016/97345, 2016, A1 Location in patent: Page/Page column 12
[10]Current Patent Assignee: SANOFI - US6048893, 2000, A Current Patent Assignee: SANOFI - US6124343, 2000, A
[11]Current Patent Assignee: SANOFI - US2004/248884, 2004, A1 Location in patent: Page 121
[12]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2005/74939, 2005, A1 Location in patent: Page/Page column 38; 110
[13]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2005/80350, 2005, A1 Location in patent: Page/Page column 39
[14]Current Patent Assignee: MERCK & CO INC - WO2011/25851, 2011, A1 Location in patent: Page/Page column 70
[15]Location in patent: body text Lesuisse, Dominique; Mauger, Jacques; Nemecek, Conception; Maignan, Sébastien; Boiziau, Janine; Harlow, Greg; Hittinger, Augustin; Ruf, Swen; Strobel, Hartmut; Nair, Anil; Ritter, Kurt; Malleron, Jean-Luc; Dagallier, Anne; El-Ahmad, Youssef; Guilloteau, Jean-Pierre; Guizani, Houlfa; Bouchard, Hervé; Venot, Corinne [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 8, p. 2224 - 2228]
[16]Current Patent Assignee: SUVEN LIFE SCIENCES LIMITED - WO2018/42362, 2018, A1 Location in patent: Page/Page column 39
[17]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2004/18434, 2004, A1 Location in patent: Page 36-37

37
[ 461-87-0 ]
[ 128-08-5 ]
[ 64992-03-6 ]

Yield	Reaction Conditions	Operation in experiment
	With 1,1'-azobis(1-cyanocyclohexanenitrile) In tetrachloromethane for 24h; Heating / reflux;	8.a Description 8; C-(2-fluoro-pyridin-4-yl)-methylamine dihydrochloride. (a). 4-bromomethyl-2-fluoro-pyridine To a solution of 2-fluoro-4-methylpyridine (1.0 g, ex Lancaster) in carbon tetrachloride (10 ml) was added N-bromosuccinimide (1.6 g, ex Lancaster) and 1,1'-azobis(cyclohexanecarbonitrile) (100 mg, ex Aldrich). The mixture was then refluxed for 24h. Carbon tetrachloride was removed under reduced pressure and the crude oily solid was used in the next stage without purification. LC/MS, t = 2.38 min, [MH+] 190 and 192

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2004/29027, 2004, A1 Location in patent: Page 26

38
[ 461-87-0 ]
[ 554-84-7 ]
[ 28369-90-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide	49 Preparation 49 Preparation 49 A suspension of 2-fluoro-4-methylpyridine (1.11 g), 3-nitrophenol (1.67 g) and potassium carbonate (1.80 g) in N,N-dimethylformamide (10 ml) was stirred at 130° C. for 24 hours. After cooling, the mixture was poured into water and stirred for 30 minutes. The precipitate was collected by filtration and dried to give 3-(4-methylpyridin-2-yloxy)-nitrobenzene (935 mg). 1H-NMR (CDCl3): δ2.36(3H,s), 7.01(1H,s), 7.05(1H,d,J=5.1 Hz), 7.6-7.8(2H,m), 7.94(1H,t,J=2.2 Hz), 8.0-8.2(2H,m)

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - US6521643, 2003, B1

39
[ 461-87-0 ]
[ 99724-19-3 ]
[ 289469-56-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide	18 Preparation 18 Preparation 18 A suspension of 2-fluoro-4-methylpyridine (1.11 g), 3-(tert-butoxycarbonylamino)pyrrolidine (1.68 g) and potassium carbonate (1.49 g) in N,N-dimethylformamide (20 ml) was stirred at 100° C. for 16 hours. After cooling, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water five times and brine, dried over sodium sulfate and evaporated under reduced pressure to give 1-(4-methylpyridin-2-yl)-3-(tert-butoxycarbonylamino)pyrrolidine (1.36 g). 1H-NMR (CDCl3): δ1.45(9H,s), 1.9-2.1(1H,m), 2.2-2.4(1H,m), 2.25(3H,s), 3.3-3.8(4H,m), 4.2-4.4(1H,m), 4.6-4.8(1H,m), 6.18(1H,s), 6.41(1H,d,J=5.0 Hz), 8.01(1H,d,J=5.0 Hz)

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - US6521643, 2003, B1

40
[ 461-87-0 ]
[ 3034-38-6 ]
4-methyl-2-(4-nitro-1H-imidazol-1-yl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide;	Preparation 22 A suspension of 2-fluoro-4-methylpyridine (1.11 g), 4-nitroimidazole (1.24 g) and potassium carbonate (1.65 g) in N,N-dimethylformamide (10 ml) was stirred at 130 C. for 21 hours. After cooling, the mixture was poured into water and stirred for 30 minutes. The precipitate was collected by filtration and dried to give 1-(4-methylpyridin-2-yl)-4-nitroimidazole (698 mg). 1H-NMR (CDCl3): delta2.50(3H,s), 7.22(1H,d,J=5.0 Hz), 7.30(1H,s), 8.29(1H,s), 8.40(1H,d,J=1.5 Hz), 8.48(1H,d,J=1.5 Hz)
1.34 mmol	With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 100℃; for 72h;	Step d. A solution of 2-fluoro-4-methylpyridine (9.0 mmol), K2C03 (27.0 mmol) and KI (9.0 mmol) in DMF (10 ml) was stirred at rt for 5 min. 4-Nitroimidazole (9.0 mmol) was added to the reaction mixture and then heated at 100C for 72 h. The resulting reaction mixture was poured into water (50 ml) and extracted with EtOAc (3 x 100 ml). The combined organic phase was dried over Na2S04, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (90-100% EtOAc in hexane) yielding 4- methyl-2-(4-nitro-lH-imidazol-l-yl)pyridine (1.34 mmol). MS: ES+ 205.23; XH NMR (400 MHz, DMSO-de) delta ppm 9.07 (d, J=1.2 Hz, 1 H), 8.69 (d, J=1.2 Hz, 1 H), 8.44 (d, J=5.2 Hz, 1 H), 7.93 (s, 1 H), 7.38 (d, J=5.2 Hz, 1 H), 2.44 (s, 3 H).

Reference： [1]Patent: US6521643,2003,B1
[2]Patent: WO2016/46530,2016,A1 .Location in patent: Page/Page column 141-142

41
[ 461-87-0 ]
[ 116332-62-8 ]
L-790,070 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane; water; ethyl acetate	27 (S)-4-[5-(2-(1-PHENYLETHYLAMINO)-PYRIDIN-4-YL)-1-METHYL-4-(3-TRIFLUOROMETHYLPHENYL)-1H-IMIDAZOL-2-YL]PIPERIDINE STR89 Step 27-A 2-(2-Fluoropyridin-4-yl)-1-(3-trifluoromethylphenyl)ethanone EXAMPLE 27 (S)-4-[5-(2-(1-PHENYLETHYLAMINO)-PYRIDIN-4-YL)-1-METHYL-4-(3-TRIFLUOROMETHYLPHENYL)-1H-IMIDAZOL-2-YL]PIPERIDINE STR89 Step 27-A 2-(2-Fluoropyridin-4-yl)-1-(3-trifluoromethylphenyl)ethanone To a solution of diisopropylamine (17.69 mL, 0.135 mole) in THF (200 mL) at -78° C., under argon, was added n-butyllithium (54.0 mL, 2.5M in hexane, 0.135 mole), followed after 5 min. by a solution of 2-fluoro-4-methylpyridine (Lancaster Synthesis Inc.) (10 g, 0.090 mole) in THF (20 mL). After stirring for 15 min. at -78° C., a solution of N-methoxy-N-methyl-3-trifluoromethylbenzamide (23.08 g, 0.099 mole) in THF (10 mL) was added. After stirring for 5 min, the reaction was allowed to warm to 0° C. and quenched by pouring into water (400 mL) and ethyl acetate (400 mL). The layers were separated, and the aqueous layer washed with ethyl acetate (200 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to an oil which was chromatographed on silica gel with 20% ethyl acetate in hexane to give 21.6 g of the title compound. NMR (300 MHz, CDCl3) d: 8.25 (1H, s); 8.20 (1H, d, J=5.1 Hz); 8.18 (1H, d, J=9.3 Hz); 7.88 (1H, d, J=7.8 Hz); 7.67 (1H, t, J=7.8 Hz); 7.09 (1H, d, J=5.1 Hz); 6.86 (1H, s); 4.37 (2H, s).

Reference： [1]Current Patent Assignee: MERCK & CO INC - US6083949, 2000, A

42
[ 461-87-0 ]
[ 155705-46-7 ]

Yield	Reaction Conditions	Operation in experiment
	With N-chloro-succinimide; dibenzoyl peroxide In tetrachloromethane	2 Preparation of 2-Fluoro-4-chloromethylpyridine Preparation of 2-Fluoro-4-chloromethylpyridine To a 1000 ml Single Neck RBF, equipped with a magnetic stirrer, reflux condenser, heating mantle was added 2-fluoro-4-picoline (13.33 g, 120 mmol) and carbon tetrachloride (~250 ml), N-chlorosuccinimide (23.98 g, 180 mmol, 1.5 eq.) and benzoyl peroxide (1.5 g). The reaction was heated to reflux for 6 hours, additional benzoyl peroxide (1.5 g) was added and the heating maintained overnight. Monitor by TLC (1:1 toluene/methylene chloride). [At higher concentrations, more di-chloro product is formed.] The reaction was worked up by cooling to room temperature or below, filtered through Celite, and the precipatate was washed with more CCl4. The organic solution was washed with sat. sodium thiosulfate (Na2 S2 O3), saturated sodium bicarbonate, water, and brine. Following drying over magnesium sulfate, the filtrate was evaporated to an oil, determine product ratio by NMR. This material can be used in the next step without further purification. [For the two batches of the above reaction was obtained 32.94 g product mixture, which was 60% desired product, 16% di-chloro, and 24% SM.]
	With N-chloro-succinimide; acetic acid; dibenzoyl peroxide In acetonitrile at 20℃; for 2h; Heating / reflux;	1 4-Chloromethyl-2-fluoropyridine (Reference compound No. 1-1) Reference Example 1 4-Chloromethyl-2-fluoropyridine (Reference compound No. 1-1) N-Chlorosuccinimide (8.8 g, 66 mmol), acetic acid (0.15 mL) and benzoyl peroxide (220 mg, 0.91 mmol) were added to a solution of 2-fluoro-4-picoline (5.0 g, 45 mmol) in acetonitrile (25 mL) at room temperature, and the mixture was refluxed for 2 hours. The reaction mixture was cooled to room temperature, water (200 mL) was added thereto, and then the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with brine (200 mL) and dried over anhydrous magnesium sulfate. The organic layer was evaporated under reduced pressure, hexane / ethyl acetate (1: 1) was added to the resulting residue, and then the insoluble matter was filtered out. The filtrate was evaporated under reduced pressure to give 6.5 g of the title reference compound as a crude product. 1H-NMR (500MHz, DMSO-d6) δ 4.83(s, 2H), 7.26 (s, 1H),7.43 (d, J = 5.2 Hz, 1H), 8.27 (d, J = 5.2 Hz, 1H)

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US5594001, 1997, A
[2]Current Patent Assignee: SANTEN PHARMACEUTICAL CO LTD - EP1717229, 2006, A1 Location in patent: Page/Page column 28-29

43
[ 695-34-1 ]
ice-salt [ No CAS ]
[ 461-87-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium nitrite In tetrafluoroboric acid; water	I 2-Fluoropyridine-4-carbonyl chloride EXAMPLE I 2-Fluoropyridine-4-carbonyl chloride Sodium nitrite (160 g, 2.32 mol) was gradually added in small portions, so that the reaction temperature never exceeded 10° C., to a mechanically stirred, ice-salt cooled solution of 2-amino-4-methylpyridine (250 g, 2.31 mol) in 48% fluoroboric acid (808 mL) and water (161 mL) contained in a 2 L three-necked round bottom flask. The solution was stirred at ice-salt bath temperature for 30 min. following the addition and then at 45° C. for 30 min. The solution was cooled to 0° C., neutralized to pH 7 with sodium carbonate and thereafter steam distilled. The pale yellow oil that separated from the distillate was removed and the remaining water layer was extracted with ether. The combined oil and ether extract was dried with sodium sulfate and concentrated in vacuo. The residue was distilled and gave 141 grams of 2-fluoro-4-methylpyridine having a boiling point of 63°-64° C.

Reference： [1]Current Patent Assignee: STATE UNIVERSITY OF NEW YORK - US5583148, 1996, A

44
[ 461-87-0 ]
[ 4931-00-4 ]

Yield	Reaction Conditions	Operation in experiment
73%	With hydrazine at 150℃; for 0.166667h; Inert atmosphere;	22.A A. 2-hydrazinyl-4-methylpyridine, cpd 22a A 2-5 mL capacity Biotage microwave vial with stirbar was charged with 2-fluoro-4-methylpyridine (201.3 mg, 1.81 mmol) and hydrazine (0.57 mL, 18.2 mmol). The resulting clear colorless solution was evacuated/flushed with argon 4* and stirred at 150° C. for 10 min, and then concentrated at 150° C. under a stream of argon to give an off-white slightly translucent solution. This was cooled to room temperature, partitioned with toluene (2 mL) and water (0.1 mL), and the organic layer was dried (Na2SO4), filtered, and concentrated to provide the title compound as a beige solid (162 mg, 73%). 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J=6.06 Hz, 1H), 6.52 (m, 2H), 5.72 (br s, 1H), 3.80 (br s, 2H), 2.27 (s, 3H).
51%	With hydrazine In 2-ethoxy-ethanol at 150℃; for 16h;
51%	With hydrazine hydrate In 2-ethoxy-ethanol at 150℃; for 16h;	10A 2-Hydrazino-4-methylpyridine 3.3 g (30.0 mmol) of 2-fluoro-4-methylpyridine are initially charged in 40 ml of ethylene glycol monoethyl ether, 14.6 ml (15.0 g, 300 mmol) of hydrazine hydrate are added to the solution and the mixture is stirred at boiling point (bath temperature 150° C.) for 16 h. The reaction solution is then concentrated on a rotary evaporator, and the residue is added to 100 ml of water and extracted with ethyl acetate (three times 100 ml each). The combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue obtained is dried under reduced pressure. Yield: 1.90 g (51% of theory) LC-MS (Method 1): Rt=0.80 min; MS (ESIpos): m/z=124 [M+H]+; 1H-NMR (400 MHz, DMSO-d6): δ=7.83 (d, 1H), 7.22 (s, 1H), 6.51 (s, 1H), 6.38 (d, 1H), 4.04 (s, 2H), 2.17 (s, 3H).

51%	With hydrazine hydrate In 2-ethoxy-ethanol for 16h; Reflux;	1.A 2-Hydrazino-4-methylpyridine 33 g (30.0 mmol) 2-fluoro-4-methylpyridine are initially introduced into 40 ml 2-ethoxyethanol, 14.6 ml (15.0 g, 300 mmol) hydrazine hydrate are added to the solution and the mixture is stirred at the boiling point (150° C. bath temperature) for 16 h. Thereafter, the reaction solution is concentrated on a rotary evaporator, the residue is added to 100 ml water and the mixture is extracted with ethyl acetate (three times with 100 ml each time). The combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue obtained is dried in vacuo.Yield: 1.90 g (51% of th.)1H-NMR (400 MHz, DMSO-d6): δ=7.83 (d, 1H), 7.22 (s, 1H), 6.51 (s, 1H), 6.38 (d, 1H), 4.04 (s, 2H), 2.17 (s, 3H).LC-MS (Method 1): Rt=0.80 min; MS (ESIpos): m/z=124 [M+H]+.
51%	With hydrazine hydrate In 2-ethoxy-ethanol at 150℃; for 16h;

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2019/381019, 2019, A1 Location in patent: Paragraph 0630-0632
[2]Current Patent Assignee: BAYER AG - WO2006/114213, 2006, A1 Location in patent: Page/Page column 27-28
[3]Current Patent Assignee: BAYER AG - US2010/93803, 2010, A1 Location in patent: Page/Page column 20
[4]Current Patent Assignee: BAYER AG - US2010/305085, 2010, A1 Location in patent: Page/Page column 15
[5]Beck, Hartmut; Jeske, Mario; Thede, Kai; Stoll, Friederike; Flamme, Ingo; Akbaba, Metin; Ergüden, Jens-Kerim; Karig, Gunter; Keldenich, Jörg; Oehme, Felix; Militzer, Hans-Christian; Hartung, Ingo V.; Thuss, Uwe [ChemMedChem, 2018, vol. 13, # 10, p. 988 - 1003]

45
[ 461-87-0 ]
n-butyllithium hexane [ No CAS ]
[ 21384-43-0 ]
[ 303162-49-4 ]

Yield	Reaction Conditions	Operation in experiment
52%	With diisopropylamine In tetrahydrofuran; water	R.G.12 2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone Reference Example G 12 2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone Under an argon atmosphere, a solution of diisopropylamine (44mL, 0.31mol) in anhydrous tetrahydrofuran (300 mL) was cooled to -78°C, and to this was added dropwise a 1.6 M n-butyllithium hexane solution (190 mL, 0.31 mol) with stirring. After completion of the addition, the solution was stirred for 10 minutes, subsequently, a solution of 2-fluoro-4-methylpyridine (34.5 g, 0.31 mol) in anhydrous tetrahydrofuran (30 mL) was added. The reaction mixture was stirred for 30 minutes at -10°C. The reaction solution was cooled to -78°C, and a solution of N-(3-methylbenzoyl)propyleneimine (52 g, 0.30 mol) in anhydrous tetrahydrofuran (30 mL) was added dropwise. After completion of the addition, the mixture was stirred for 2 hours at room temperature. To the reaction mixture was added water (100 mL), and extracted with ethyl acetate. The extracted solution was washed with water, dried, then, the solvent was distilled off. The residue was re-crystallized from isopropyl ether to obtain the title compound (35 g, yield 52%). m.p.: 66 - 67°C.
52%	With diisopropylamine In tetrahydrofuran; water	R.12 2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone Reference Example 12 2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone Under an argon atmosphere, a solution of diisopropylamine (44 mL, 0.31 mol) in anhydrous tetrahydrofuran (300 mL) was cooled to -78° C., and to this was added dropwise a 1.6 M n-butyllithium hexane solution (190 mL, 0.31 mol) with stirring. After completion of the addition, the solution was stirred for 10 minutes, subsequently, a solution of 2-fluoro-4-methylpyridine (34.5 g, 0.31 mol) in anhydrous tetrahydrofuran (30 mL) was added. The reaction mixture was stirred for 30 minutes at -10° C. The reaction solution was cooled to -78° C., and a solution of N-(3-methylbenzoyl)propyleneimine (52 g, 0.30 mol) in anhydrous tetrahydrofuran (30 mL) was added dropwise. After completion of the addition, the mixture was stirred for 2 hours at room temperature. To the reaction mixture was added water (100 mL), and extracted with ethyl acetate. The extracted solution was washed with water, dried, then, the solvent was distilled off. The residue was recrystallized from isopropyl ether to obtain a title compound (35 g, yield 52%). m.p. 66-67° C.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1402900, 2004, A1
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2004/53973, 2004, A1

46
[ 461-87-0 ]
[ 620-24-6 ]
[ 1020333-42-9 ]

Yield	Reaction Conditions	Operation in experiment
81%	With caesium carbonate In dimethyl sulfoxide at 110℃; for 16h;	72.1 Example 72; Synthesis of 4-{3-[(4-methylpyridin-2-yl)oxy]benzylidene}-N-pyridin-3-ylpiperidine-1-carboxamide; Step 1; [3-(4-Methyl-pyridin-2-yloxy)-phenyl]-methanol3-Hydroxymethyl-phenol (3.69 g, 29.7 mmol), 2-fluoro-3-methyl-pyridine (3.00 g, 27 mmol,) and cesium carbonate (9.68 g, 29.7 mmol) were suspended in dimethylsulfoxide (25 mL) and heated to 110° C. After stirring for 16 h, reaction partitioned between water (250 mL) and ethyl acetate (250 mL). The organic layer was separated and the aqueous was extracted again with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel chromatography (10-75%, EtOAc:heptane) to afford the desired product (4.75 g, 81%) as a thick oil.

Reference： [1]Current Patent Assignee: PFIZER INC - US2008/261941, 2008, A1 Location in patent: Page/Page column 47

47
[ 461-87-0 ]
[ 24424-99-5 ]
[ 1104643-31-3 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: 2-fluoro-4-methylpyridine With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: di-<i>tert</i>-butyl dicarbonate In tetrahydrofuran; hexane at -78 - 20℃; for 2h;

Reference： [1]Location in patent: experimental part Augustine, John Kallikat; Arthoba Naik; Vairaperumal, Veeramani; Narasimhan, Sharmila [Tetrahedron, 2009, vol. 65, # 1, p. 134 - 138]

48
[ 461-87-0 ]
[ 24424-99-5 ]
[ 1104643-37-9 ]

Yield	Reaction Conditions	Operation in experiment
93%	Stage #1: 2-fluoro-4-methylpyridine With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: di-<i>tert</i>-butyl dicarbonate In tetrahydrofuran; hexane at -78 - 20℃; for 2h;

Reference： [1]Location in patent: experimental part Augustine, John Kallikat; Arthoba Naik; Vairaperumal, Veeramani; Narasimhan, Sharmila [Tetrahedron, 2009, vol. 65, # 1, p. 134 - 138]

49
[ 461-87-0 ]
[ 5815-08-7 ]
[ 1000188-57-7 ]

Yield	Reaction Conditions	Operation in experiment
76%	Stage #1: 2-fluoro-4-methylpyridine; tert-Butoxybis(dimethylamino)methane at 180℃; for 18h; Stage #2: With hydroxylamine-O-sulfonic acid In water at 20℃; for 0.5h;	184.a Example 184 3-(4-Fluorophenyl)-4-[4-(2-fluoropyridyl)]-5-(phenylacetylamino)isoxazole; a) 4-(2-Fluoropyridyl)acetonitrile A mixture of 1.0 g of 2-fluoro-4-methylpyridine and 2.2 g of t-butoxybisdimethylaminomethane was stirred at 180°C for 18 hours. The reaction solution was cooled, from which t-butoxybisdimethylaminomethane was distilled off under reduced pressure, to provide a dark brown, oily residue. To the residue, 10 mL of water and 2.5 g of hydroxylamine-O-sulfonic acid were added and stirred at room temperature for 30 minutes. The reaction solution was rendered basic by addition of saturated aqueous sodium hydrogencarbonate solution under cooling with ice, and extracted with methylene chloride. The methylene chloride extract was dried over anhydrous magnesium sulfate, and removed of the solvent by reduced pressure distillation to provide 0.93 g (yield, 76%) of the title compound as pale yellow crystals. 1H-NMR(CDCl3)δ:8.26(d,J=5.0Hz,1H),7.20-7.17(m,1H), 6.97-6.95(m,1H),3.81(s,2H) Mass,m/e:136(M+,base)

Reference： [1]Current Patent Assignee: ASKA PHARMACEUTICAL CO., LTD. - EP2036905, 2009, A1 Location in patent: Page/Page column 45

50
[ 461-87-0 ]
[ 873-75-6 ]
[ 936342-71-1 ]

Yield	Reaction Conditions	Operation in experiment
58.8%	Stage #1: 4-bromobenzenemethanol With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.833333h; Stage #2: 2-fluoro-4-methylpyridine In N,N-dimethyl-formamide at 0 - 20℃; for 2.5h;	43.1.1 Manufacturing Example 43-1-1 2-(4-Bromo-benzyloxy)-4-methyl-pyridine; To a mixture of 4-bromobenzyl alcohol (4.54 g, 24.3 mmol) and N,N-dimethylformamide (50.0 mL) were added sodium hydride (1.00 g, 25.0 mmol, 60% in oil) was added at 0° C. under nitrogen atmosphere, which was stirred for 50 minutes at room temperature. 2-Fluoro-4-methylpyridine (1.80 g, 16.2 mmol) was then added thereto at 0° C., and stirred for 2 hours and 30 minutes at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, and filtered. The filtrate was evaporated under a reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:15) to obtain the title compound (2.65 g, 58.8%).1H-NMR Spectrum (CDCl3) δ (ppm): 2.28 (3H, s), 5.31 (2H, s), 6.60-6.61 (1H, m), 6.69 -6.71(1H, m), 7.29-7.32 (2H, m), 7.46-7.48 (2H, m), 8.00-8.01 (1H, m).
58.8%	Stage #1: 4-bromobenzenemethanol With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.833333h; Stage #2: 2-fluoro-4-methylpyridine In N,N-dimethyl-formamide at 0 - 20℃; for 2.5h;	43.1.1 To a mixture of 4-bromobenzyl alcohol (4.54 g, 24.3 mmol) and N,N-dimethylformamide (50.0 mL) were added sodium hydride (1.00 g, 25.0 mmol, 60% in oil) was added at 0° C. under nitrogen atmosphere, which was stirred for 50 minutes at room temperature. 2-Fluoro-4-methylpyridine (1.80 g, 16.2 mmol) was then added thereto at 0° C., and stirred for 2 hours and 30 minutes at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, and filtered. The filtrate was evaporated under a reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:15) to obtain the title compound (2.65 g, 58.8%). 1H-NMR Spectrum (CDCl3) δ (ppm): 2.28 (3H, s), 5.31 (2H, s), 6.60-6.61 (1H, m), 6.69-6.71 (1H, m), 7.29-7.32 (2H, m), 7.46-7.48 (2H, m), 8.00-8.01 (1H, m).

Reference： [1]Current Patent Assignee: EISAI CO LTD - US2009/82403, 2009, A1 Location in patent: Page/Page column 90-91
[2]Current Patent Assignee: EISAI CO LTD - US2007/105904, 2007, A1 Location in patent: Page/Page column 89

51
[ 461-87-0 ]
[ 91419-52-2 ]
[ 1144505-15-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hexamethyldisilazane In tetrahydrofuran at -78 - 20℃;	2 A mixture of tert-butyl 4-cyanopiperidine-l-carboxylate (15.2 g, 72.3 mmol) and 2-fluoro-4-methylpyridine (9.64 g, 87.0 mmol) was dissolved in 361 mL of THF. The reaction was purged with a stream of nitrogen and cooled to -78 0C. To this reaction was added 1.0 M sodium bis(trimethylsilyl)amide in THF (101 mL, 101 mmol), which was stirred for 1 hour. The reaction was warmed to ambient temperature, stirred for 36 hours, and quenched with a saturated ammonium chloride solution. The mixture was extracted with dichloromethane (3 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered, concentrated, and subjected to silica gel chromatography eluting with 0-25% EtOAc in hexanes to yield tert-butyl 4-cyano-4-(4-methylpyridin-2-yl)piperidine- 1 -carboxylate. The above carboxylate (12.8 g, 42.5 mmol) was dissolved in a 1 :1 EtOAc:DCM(424 mL) and was cooled to 0 0C. Anhydrous HCl gas was then bubbled through the solution for 5 minutes. The reaction was warmed to ambient temperature and stirred for 1 hour. The reaction mixture was concentrated of volatiles and slowly neutralized with a saturated sodium bicarbonate solution. The resulting slurry was washed with 10% MeOH in DCM and filtered through a Buchner funnel in vacuo. The filtrate was concentrated to give 4-(4-methylpyridin-2- yl)piperidine-4-carbonitrile.A mixture of the ethyl l-formyl-4-oxo-4H-quinolizine-3 -carboxylate (2.60 g, 10.6 mmol), 4-(4-methylpyridin-2-yl)piperidine-4-carbonitrile (1.78 g, 8.83 mmol), and 36.8 mL of anhydrous THF was cooled to 10 0C and stirred vigorously. To the stirring mixture was added sodium triacetoxyborohydride (2.62 g, 12.4 mmol), portionwise over a period of 1 hour. The mixture was heated to 50 0C for 18 hours. The reaction was quenched with a 10% sodium bicarbonate solution and extracted with EtOAc (3 x 50 mL). The organic layers were combined, acidified with 1 NHCl, and extracted with DCM (8 x 150 mL). In a 500 mL Erlenmeyer flask, the aqueous layer was neutralized slowly with solid sodium carbonate under continuous stirring until pH ~ 7-8 and then extracted with DCM (3 x 200 mL). The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated to afford the ethyl l-[4-cyano-4-(4- methylpyridin-2-yl)piperidin-l-yl]methyl}-4-oxo-4H-quinolizine-3-carboxylate that gave a proton NMR spectrum consistent with theory and a mass spectrum (ES+) m/z of 431.0 calculated for M+H+: 1U NMR (400 MHz, CDCl3) δ 9.51 (d, J= 7.1 Hz, IH), 8.43 (d, J= 4.95 Hz, IH), 8.32 (s, IH), 8.14 (d, J= 8.9 Hz, IH), 7.70 (t, J= 7.8 Hz, IH), 7.43 (s, IH), 7.26 (m, IH), 7.06 (d, J= 4.9 Hz, IH), 4.44 (q, J= 7.1 Hz, 2H), 3.75 (s, 2H), 3.01 (d, J= 12.0 Hz, 2H), 2.56 (t, J= 11.3 Hz, 2H), 2.39 (s, 3H), 2.29 (t, J= 12.9 Hz, 2H), 2.05 (d, J= 12.4 Hz, 2H), 1.44 (t, J= 7.1 Hz, 3H). The above carboxylate (1.55 g, 3.60 mmol) was dissolved in a 2:1 THF:EtOH solution (36 mL), treated with 1 NNaOH (3.78 mL, 3.78 mmol), and warmed to 50 0C for 20 hours. The reaction temperature was increased to 60 0C for 2 hours. The reaction was treated with additional 1 NNaOH (0.18 mL, 0.18 mmol) and warmed to 70 0C for 4 hours. The reaction was reduced in volume under vacuum, diluted with deionized water (50 mL), and extracted with EtOAc (2 x 100 mL). The aqueous layer was concentrated to dryness to afford the title compound that gave a proton NMR spectrum consistent with theory and a high resolution mass spectrum (ES+) m/z of 403.1772 calculated for M+H+ [C23H22N4O3: 403.1765]: 1H NMR (500 MHz, CD3OD) δ 9.36 (d, J= 7.3 Hz, IH), 8.38 (d, J= 5.0 Hz, IH), 8.29 (s, IH), 8.18 (d, J= 9.0 Hz, IH), 7.68 (t, J = 7.5 Hz, IH), 7.45 (s, IH), 7.29 (t, J= 6.7 Hz, IH), 7.18 (d, J= 5.0 Hz, IH), 3.81 (s, 2H), 3.09 (d, J= 12.1 Hz, 2H), 2.51 (t, J= 10.9 Hz, 2H), 2.40 (s, 3H), 2.21 (t, J= 12.7 Hz, 2H), 2.11 (d, J= 12.1 Hz, 2H).
	Stage #1: 1-tert-butoxycarbonyl-4-cyanopiperidine With potassium hexamethylsilazane In tetrahydrofuran at 25℃; Stage #2: 2-fluoro-4-methylpyridine In tetrahydrofuran
	With sodium hexamethyldisilazane In tetrahydrofuran; diethyl ether at -78 - 20℃;	1.1 Step 1: Preparation of 4-(4-methylpyridin-2-yl)piperidine-4-carbonitriIe: tert-Butyl 4- cyanopiperidine-l-carboxylate (0.220 g, 1.05 mmol) and 2-fluoro-4-methylpyridine (0.107 g, 1.10 mmol, 1.05 equiv) were suspended in THF (5 mL), cooled to -78 °C, and treated with sodium bis(trimethylsilyl)amide (1 M solution in diethyl ether, 1.47 mL, 1.47 mmol, 1.40 equiv) dropwise. After 1 hour, the mixture was warmed to ambient temperature, treated with saturated aqueous ammonium chloride, and extracted with dichloromethane (3x). The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (100:0 to 4:1 hexanes : ethyl acetate), providing tert-butyl 4-cyano-4-pyridin-2-ylpiperidine-l-carboxylate. The resulting clear oil was suspended in ethyl acetate (5 mL), cooled to 0 °C and saturated with gaseous hydrogen chloride. The mixture was warmed to ambient temperature and after 18 hours, was concentrated in vacuo, providing the titled compound.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2009/51715, 2009, A1 Location in patent: Page/Page column 26-28
[2]Location in patent: scheme or table Zhao, Zhijian; Leister, William H.; O'Brien, Julie A.; Lemaire, Wei; Williams Jr., David L.; Jacobson, Marlene A.; Sur, Cyrille; Kinney, Gene G.; Pettibone, Doug J.; Tiller, Philip R.; Smith, Sheri; Hartman, George D.; Lindsley, Craig W.; Wolkenberg, Scott E. [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 5, p. 1488 - 1491]
[3]Current Patent Assignee: MERCK & CO INC - WO2011/137049, 2011, A1 Location in patent: Page/Page column 25

52
[ 461-87-0 ]
[ 547-63-7 ]
[ 927383-83-3 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-fluoro-4-methylpyridine With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at 0℃; for 0.5h; Stage #2: Methyl isobutyrate In tetrahydrofuran; hexane at 0℃;	1 To a solution of diisopropylamine (12.6 ml_, 89.9 mmol) in anhydrous THF (50 ml_) is added n-butyllithum (42.2 ml_ of an 1.6M in hexane) dropwise at 0 0C. After 30 min at 0 0C, 2-fluoro-4-methylpyridine (5 g, 45 mmol) is added. The resulting mixture is stirred at 0 0C for 30 min. After the addition of methyl isobutyrate (5.4 ml_, 47.3 mmol) at 0 0C, the reaction mixture is stirred overnight. The reaction mixture is quenched with acetic acid at 0 0C, diluted with water, and extracted with ethyl ether. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by flash chromatography (SiO2, EtOAc/heptane 7:93 to 60:40) to give 4.8 g of 1-(2-fluoro-pyridin-4-yl)-3-methyl- butan-2-one as a light yellowish solid. LCMS: 182 (M+H)+

Reference： [1]Current Patent Assignee: OTSUKA HOLDINGS CO LTD; NOVARTIS AG; Novartis (w/o Sandoz) - WO2009/71701, 2009, A1 Location in patent: Page/Page column 40

53
[ 75-21-8 ]
[ 461-87-0 ]
[ 1176209-59-8 ]

Yield	Reaction Conditions	Operation in experiment
53%	Stage #1: 2-fluoro-4-methylpyridine With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -80℃; for 1h; Stage #2: oxirane In tetrahydrofuran; hexane at -80 - 20℃; for 13h; Stage #3: With ammonium chloride In tetrahydrofuran; hexane; water	8 To a solution of diisopropylamine (13.8 mL, 97.8 mmol) in anhydrous tetrahydrofuran (140 mL) was added dropwise at -80 °C, under argon, a 2.5 M n-butyllithium solution in hexane (40.0 mL, 0.10 mol). The mixture was stirred at -80 °C for 1 h before addition dropwise of a solution of 2-fluoro-4-picoline (41) (7.00 g, 6.30 mmol) in anhydrous tetrahydrofuran (70 mL). The mixture was stirred at -80 °C for 1 h once again before addition dropwise of ethylene oxide (4.20 mL, 84.1 mmol) previously cooled to -50 °C. The mixture was stirred at -80 °C for 1 h and then at room temperature for 12 h. A saturated aqueous ammonium chloride solution (350 mL) was then added to the mixture. The mixture was decanted and the aqueous layer was extracted with ethyl acetate (4 * 250 mL). The organic layers were combined, dried on magnesium sulfate, filtered and evaporated under vacuum. The residue was chromatographed (SiO2, AcOEt/pentane, 6/4, v/v) to give alcohol 48 (5.16 g, 33.3 mmol) as a yellow oil. Yield 53%; Rf (SiO2, AcOEt/pentane 5/5, v/v): 0.52; IR (CCl4) ν 1412, 1613, 2939, 3639 cm-1; 1H NMR (200 MHz, CDCl3) δ 1.84 (m, 2H), 2.72 (t, 2H, J = 7.4 Hz), 3.14 (se, 1H), 3.62 (t, 2H, J = 6.2 Hz), 6.72 (s, 1H), 6.98 (m, 1H), 8.01 (d, 1H, J= 5.1 Hz); 13C NMR (100 MHz, CDCl3) δ 31.3 (d, 4JC-F = 2 Hz), 32.8, 61.1, 109.2 (d, 2JC-F = 36 Hz), 121.8 (d, 4JC-F = 3 Hz), 147.0 (d, 3JC-F = 15 Hz), 157.5 (d, 3JC-F = 8 Hz), 164.0 (d, 1JC-F = 237 Hz).
53%	Stage #1: 2-fluoro-4-methylpyridine With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -80℃; for 1h; Inert atmosphere; Stage #2: oxirane In tetrahydrofuran; hexane at -80 - 20℃; for 13h; Inert atmosphere;

Reference： [1]Current Patent Assignee: COMMISSARIAT A L'ENERGIE ATOMIQUE ET AUX ENERGIES ALTERNATIVES; LABORATOIRES CYCLOPHARMA; UNIVERSITY OF CLERMONT AUVERGNE; NATIONAL INSTITUTE OF HEALTH AND MEDICAL RESEARCH - EP2085390, 2009, A1 Location in patent: Page/Page column 31-32
[2]Location in patent: experimental part Maisonial, Aurélie; Kuhnast, Bertrand; Papon, Janine; Boisgard, Raphaël; Bayle, Martine; Vidal, Aurélien; Auzeloux, Philippe; Rbah, Latifa; Bonnet-Duquennoy, Mathilde; Miot-Noirault, Elisabeth; Galmier, Marie-Josèphe; Borel, Michèle; Askienazy, Serge; Dollé, Frédéric; Tavitian, Bertrand; Madelmont, Jean-Claude; Moins, Nicole; Chezal, Jean-Michel [Journal of Medicinal Chemistry, 2011, vol. 54, # 8, p. 2745 - 2766]

54
[ 461-87-0 ]
[ 50-00-0 ]
[ 1000562-43-5 ]

Yield	Reaction Conditions	Operation in experiment
57%	Stage #1: 2-fluoro-4-methylpyridine With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -80℃; for 2h; Stage #2: formaldehyd In tetrahydrofuran; hexane at -80 - 20℃; for 13h; Stage #3: With ammonium chloride In tetrahydrofuran; hexane; water	7 To a solution of diisopropylamine (18.5 mL, 0.13 mol) in anhydrous tetrahydrofuran (160 mL) was added dropwise at -80 °C, under argon, a 1.3 M n-butyllithium solution in hexane (100 mL, 0.13 mol). The mixture was stirred at -80 °C for 1 h before addition dropwise of a solution of 2-fluoro-4-picoline (41) (9.00 g, 6.30 mmol) in anhydrous tetrahydrofuran (60 mL). The mixture was stirred at -80 °C for 1 h once again before addition dropwise of a p-formaldehyde (16.6 g, 0.55 mol) suspension in anhydrous tetrahydrofuran (100 mL). The mixture was stirred at -80 °C for 1 h and then at room temperature for 12 h. A saturated aqueous ammonium chloride solution (450 mL) was added to the mixture. The solution was decanted and the aqueous layer was extracted with dichloromethane (4 x 200 mL). The organic layers were combined, dried on magnesium sulfate, filtered and evaporated under vacuum. The residue obtained was chromatographed (Al2O3, CH2Cl2/EtOH, 99/1, v/v) to give alcohol 42 (7.25 g, 51.4 mmol) as an orange-coloured oil. Yield 57%; Rf(Al2O3, CH2Cl2/EtOH, 99/1, v/v): 0.32; IR (CCl4) ν 1046, 1149, 1278, 1413, 1613, 2800-3000, 3100-3600, 3634 cm-1; 1H NMR (200 MHz, CDCl3) δ 2.87 (t, 2H, J = 6.3 Hz), 3.87 (t, 2H, J = 6.3 Hz), 6.82 (s, 1H), 7.07 (d, 1H, J = 5.2 Hz), 8.01 (d, 1H, J = 5.2 Hz); 13C NMR (50 MHz, CDCl3) δ 37.7 (d, 4JC-F = 3 Hz), 60.9, 109.5 (d, 2JC-F = 36 Hz), 122.0 (d, 4JC-F = 4 Hz), 146.2 (d, 3JC-F = 14 Hz), 155.0 (d, 3JC-F = 8 Hz), 163.2 (d, 1JC-F = 239 Hz).
57%	Stage #1: 2-fluoro-4-methylpyridine With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -80℃; for 1h; Inert atmosphere; Stage #2: formaldehyd In tetrahydrofuran; hexane at -80 - 20℃; for 13h; Inert atmosphere;

Reference： [1]Current Patent Assignee: COMMISSARIAT A L'ENERGIE ATOMIQUE ET AUX ENERGIES ALTERNATIVES; LABORATOIRES CYCLOPHARMA; UNIVERSITY OF CLERMONT AUVERGNE; NATIONAL INSTITUTE OF HEALTH AND MEDICAL RESEARCH - EP2085390, 2009, A1 Location in patent: Page/Page column 29-30
[2]Location in patent: experimental part Maisonial, Aurélie; Kuhnast, Bertrand; Papon, Janine; Boisgard, Raphaël; Bayle, Martine; Vidal, Aurélien; Auzeloux, Philippe; Rbah, Latifa; Bonnet-Duquennoy, Mathilde; Miot-Noirault, Elisabeth; Galmier, Marie-Josèphe; Borel, Michèle; Askienazy, Serge; Dollé, Frédéric; Tavitian, Bertrand; Madelmont, Jean-Claude; Moins, Nicole; Chezal, Jean-Michel [Journal of Medicinal Chemistry, 2011, vol. 54, # 8, p. 2745 - 2766]

55
[ 461-87-0 ]
[ 1206835-58-6 ]
[ 1206835-65-5 ]

Yield	Reaction Conditions	Operation in experiment
40.7%	Stage #1: 2-fluoro-4-methylpyridine With sodium hexamethyldisilazane In tetrahydrofuran at 0℃; for 1h; Stage #2: 3-dibenzylamino-2,6-difluoro-benzoic acid benzyl ester In tetrahydrofuran at 0℃;	26.A.e Method A; Step e; 1-(3-Dibenzylamino-2,6-difluoro-phenyl)-2-(2-fluoro-pyridin-4-yl)-ethanone; To a solution of 2-fluoro-4-methyl-pyridine (5.76 mL, 0.056 mol) in anhydrous tetrahydrofuran (200 mL) at 00C sodium hexamethyldisilazide (NaHMDS, 2 M in tetrahydrofuran, 36 mL, 0112 mol) was added and the reaction was stirred for 1 hour. A solution of 3-dibenzylamino-2,6-difluoro-benzoic acid benzyl ester (25 g, 0.056 mol) in tetrahydrofuran (80 mL) was then added dropwise to the reaction mixture, which was stirred at 00C for one hour and allowed to warm at room temperature. The reaction mixture was then poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by silica gel column chromatography eluting with ethyl acetate 15 % in hexane (40.7 %).HPLC (254 nm): Rt: 7.891H-NMR (401 MHz, DMSO-d6) δ = 8.19 (d, J = 5.1 Hz, 1 H), 7.09 (s, 1 H), 7.02 - 7.17 (m, 2 H), 6.93 - 7.02 (m, 1 H), 4.40 (s, 2 H), 4.25 - 4.29 (m, 4 H).HRMS (ESI) calcd for C13H9F3N2O [M+H]+ 447.1679, found 447.1666.

Reference： [1]Current Patent Assignee: NERVIANO MEDICAL SCIENCES S.R.L. - WO2010/10154, 2010, A1 Location in patent: Page/Page column 127

56
[ 461-87-0 ]
[ 78-84-2 ]
[ 1177418-40-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: 2-fluoro-4-methylpyridine With lithium diisopropyl amide In tetrahydrofuran at -78℃; Stage #2: isobutyraldehyde In tetrahydrofuran at -78℃; for 2h;

Reference： [1]Peifer, Christian; Abadleh, Mohammed; Bischof, Joachim; Hauser, Dominik; Schattel, Verena; Hirner, Heidrun; Knippschild, Uwe; Laufer, Stefan [Journal of Medicinal Chemistry, 2009, vol. 52, # 23, p. 7618 - 7630]

57
[ 461-87-0 ]
[ 145959-21-3 ]
[ 365427-96-9 ]

Yield	Reaction Conditions	Operation in experiment
77%		A solution of 2-fluoro-4-methylpyridine (3.O g, 27.0 itimol) in anhydrous tetrahydrofurane (14 itiL) was cooled to - 78 C and a 1.8M lithium diisopropylamide-hexane solution (17 mL, 34 mmol) was added thereto dropwise while stirring. After completion of dropwise addition, the mixture was stirred for 30min, then, a solution of 3-chloro-N-methoxy-N- methylbenzylamide (5.4 g, 27.3 mmol) in anhydrous tetrahydrofurane (3 mL) was added dropwise. After completion of dropwise addition, the temperature was raised to room temperature, water (50 m£) was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over MgSO4 and the solvent was evaporated. The residue was recrystallized from tert-butyl methyl ketone/hexane to give the title compound (5.2 g, 20.8 mmol, yield 77%) .1H-NMR (CDCl3) delta: 4.32 (s, 2H), 6.86 (s, IH), 7.09 (d, IH), 7.47 (t, IH), 7.60 (m, IH), 7.88 (m, IH), 7.98 (t, IH), 8.21 (d, IH)

Reference： [1]Patent: WO2006/137658,2006,A1 .Location in patent: Page/Page column 123

58
[ 461-87-0 ]
[ 51-17-2 ]
[ 111-83-1 ]
[ 1258750-00-3 ]

Yield	Reaction Conditions	Operation in experiment
83%	Stage #1: 2-fluoro-4-methylpyridine; benzoimidazole With potassium carbonate In N,N-dimethyl-formamide at 140℃; for 12h; Stage #2: 1-bromo-octane In N,N-dimethyl-formamide at 100℃; for 12h;

Reference： [1]Chang, Wei-Chun; Chen, Huei-Siou; Li, Ting-Yu; Hsu, Nai-Mu; Tingare, Yogesh S.; Li, Chung-Yen; Liu, Yi-Cheng; Su, Chaochin; Li, Wen-Ren [Angewandte Chemie - International Edition, 2010, vol. 49, # 44, p. 8161 - 8164]

59
[ 461-87-0 ]
[ 51-17-2 ]
[ 141776-91-2 ]
[ 1258750-03-6 ]

Yield	Reaction Conditions	Operation in experiment
81%	Stage #1: 2-fluoro-4-methylpyridine; benzoimidazole With potassium carbonate In N,N-dimethyl-formamide at 140℃; for 12h; Stage #2: 1-bromomethyl-3,5-difluoro-benzene In N,N-dimethyl-formamide at 100℃;

60
[ 461-87-0 ]
[ 1176209-55-4 ]
[ 552331-57-4 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 2745 - 2766

61
[ 288-32-4 ]
[ 461-87-0 ]
[ 1343307-61-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 80℃;
	With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 80℃;	1 Compound 2: In a round-bottom flask, compound 1 (200 mg, 1.80 mmol) and imidazole (147 mg, 2.16 mmol) were dissolved in DMF (9 mL) at 0° C. To the above reaction mixture, sodium hydride (60% dispersion in mineral oil, 95 mg, 2.38 mmol) was added and stirred at room temperature for 10 min. The temperature of the reaction mixture was then raised to 80° C. and maintained overnight. The resulting solution was cooled to room temperature and the solvent was evaporated under reduced pressure. After adding CH2Cl2 (50 mL), the organic phase was extracted with H2O (3×25 mL). The combined organic layer was dried (Na2SO4) and concentrated. The dried residue was dissolved in DMF (8 mL) and 3,5-difluorobenzyl bromide (410 mg, 1.98 mmol) was added to the solution, which was then stirred at 100° C. for 12 h. After the removal of solvent, the crude compound 2 (560 mg, 85% yield) was washed with ether (15 mL) and used in the subsequent reaction step without further purification. 1H NMR (300 MHz, CDCl3): δ 2.54 (s, 3H), 6.20 (s, 2H), 6.82 (tt, J=2.4, 8.7 Hz, 1H), 7.20-7.27 (m, 3H), 7.54 (s, 1H), 8.24-8.25 (m, 2H), 8.35 (d, J=4.8 Hz, 1H), 11.80 (s, 1H).
	With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 80℃;

Reference： [1]Chen, Huei-Siou; Chang, Wei-Chun; Su, Chaochin; Li, Ting-Yu; Hsu, Nai-Mu; Tingare, Yogesh S.; Li, Chung-Yen; Shie, Jun-Han; Li, Wen-Ren [Dalton Transactions, 2011, vol. 40, # 25, p. 6765 - 6770]
[2]Current Patent Assignee: NATIONAL TAIPEI UNIVERSITY OF TECHNOLOGY; NATIONAL CENTRAL UNIVERSITY - US2012/178936, 2012, A1 Location in patent: Page/Page column 4
[3]Akula, Suri Babu; Chen, Huei-Siou; Su, Chaochin; Chen, Bo-Ren; Chiou, Jiunn-Jie; Shieh, Chia-Hsuan; Lin, Ya-Fen; Li, Wen-Ren [Inorganic Chemistry, 2017, vol. 56, # 21, p. 12987 - 12995]

62
[ 6457-49-4 ]
[ 461-87-0 ]
[ 1250205-01-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine at 150℃; for 1h; Microwaves;	12.A Piperidin-4-ylmethanol (8.68 mmol, 1 g), 2-fluoro-4-methylpyridine (26.0 mmol, 2.89 g) and triethylamine (26.0 mmol, 3.63 ml_, 2.64 g) were combined and heated to 150 °C for 1 hour in the microwave. The solvent was removed at reduced pressure and the residue purified by silica chromatography eluting with DCM - 2% MeOH/ CM to afford (1 -(4-methylpyridin-2-yl)piperidin-4-yl)methanol. (0.75g) MS m/z 207.2 (M+H).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2011/86125, 2011, A1 Location in patent: Page/Page column 39

63
[ 288-13-1 ]
[ 461-87-0 ]
[ 1247667-40-8 ]

Yield	Reaction Conditions	Operation in experiment
99%	Stage #1: NH-pyrazole With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 20 - 40℃; for 0.333333h; Stage #2: 2-fluoro-4-methylpyridine In dimethyl sulfoxide at 110℃;	1 0.95 g (14.0 mmol, 2 eq) of Pyrazole was dissolved in 20 mL of DMSO at room temperature and 1.57 g (14.0 mmol, 2 eq) of KO'Bu was added. The mixture was heated to 40 °C for 20 min. and then 0.78 g (7.0 mmol, 1 eq) of 30 2-Fluoro-4-picoline (2-Fluoro-4-methyl-pyridine) was added and the mixture was heated to 110 °C overnight. After cooling to room temperature the mixture was diluted with water and extracted with Et20 (3x). The combined colourless organic layers were washed with water, dried over MgS04 and concentrated. The yellow oil was purified by column chromatography using CH2Cl2/EtOAc = 6/1 as solvent mixture. The pure product was obtained as colourless liquid in 99% yield (1.11 g, 6.9 mmol).

Reference： [1]Current Patent Assignee: ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE - WO2012/114316, 2012, A1 Location in patent: Page/Page column 43-44

64
[ 461-87-0 ]
[ 687-47-8 ]
[ 1438984-00-9 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (S)-Ethyl lactate With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 2-fluoro-4-methylpyridine In N,N-dimethyl-formamide at 20℃;	A 2-((4-memylpyridm-2-yl)oxy)propanoate A mixture of (S)-eihyl 2-hydroxypropanoate (1.18 g, 10 inmol), NaH (480 mg, 12 mmol) in DMF (15 mL) was stirred at RT for 30 min. Then 2-f.uoro-4- methylpyridine ( 1.1 g, 10 mmol) was added. The reaction mixture was stirred at RT overnight. The mixture was partitioned between EtOAc (30 mL) and water (20 mL), the organic layer was separated and washed with water (20 mL), brine, dried over Na2S04, then concentrated. The residue was purified by column chromatography to afford the titled compound. ]H NMR (CHLOROFORM-d): 7.95 (d, J - 5.4 Hz, 1H), 6.72 (d, J - 5.1 Hz, I H), 6.68 (s, IH), 5.33 (q, J = 7.0 Hz, IH), 4.18 - 4.29 (m, 2H), 2.32 (s, 3H), 1 .61 (d, J - 7.0 Hz, 3H), 1.27 (dt, J - 9.4, 7.1 Hz, 3H) LC--MS: m/z 2 Ι 0. Ι ( 1 · Ι Ι >

Reference： [1]Current Patent Assignee: EMBER THERAPEUTICS INC - WO2013/78233, 2013, A1 Location in patent: Page/Page column 61

65
[ 110-91-8 ]
[ 461-87-0 ]
[ 449180-76-1 ]

Yield	Reaction Conditions	Operation in experiment
84%	With bis(1,5-cyclooctadiene)nickel ⁽⁰⁾; sodium t-butanolate; 1,3-bis[2,6-bis(1-methylethyl)phenyl]-1,3-dihydro-2H-imidazol-2-ylidene monohydrochloride In toluene at 100℃; for 20h; Inert atmosphere; Schlenk technique;

Reference： [1]Zhu, Feng; Wang, Zhong-Xia [Advanced Synthesis and Catalysis, 2013, vol. 355, # 18, p. 3694 - 3702]

66
[ 461-87-0 ]
[ 4294-57-9 ]
[ 80635-92-3 ]

Reference： [1]Organic and Biomolecular Chemistry,2014,vol. 12,p. 6414 - 6424

67
[ 461-87-0 ]
[ 4606-07-9 ]
[ 1626419-32-6 ]

Reference： [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 754 - 759

68
[ 461-87-0 ]
[ 1431473-05-0 ]
(2R,5R)-tert-butyl 2-methyl-5-((4-methylpyridin-2-yl)oxy)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 1 : (2i?,5i?)-tert-butyl 2-methyl-5-((4-methylpyridin-2-yl)oxy)piperidine-l-carboxylate (6) A solution of (2R,5R)-tert-butyl 5-hydroxy-2-methylpiperidine-l-carboxylate (10.0 g, 46.4 mmol) in DMSO (186 ml) was treated in portions with NaH (dry powder, 1.28 g, 53.4 mmol). After stirring for ~15 mins, 2-fluoro-4-picoline (10.32 g, 93 mmol) was added and the reaction was heated at 45 C for 2.5 h. The reaction was cooled at 0 C and quenched with saturated, aqu. NH4C1. The reaction was diluted with saturated, aqu. NaHC03 and extracted 2x with EtOAc. The combined organics were washed with brine, dried over MgS04, filtered, concentrated, dried, and purified by silica gel gradient chromatography (0-35% EtOAc in hexanes), providing the titled compound as a colorless oil. 1H NMR (400 MHz, CDC13) delta 7.98 (d, J= 5.0 Hz, 1 H), 6.67 (d, J= 5.0 Hz, 1 H), 6.53 (s, 1 H), 5.10 (s, 1 H), 4.53 (br s, 1 H), 4.34 (d, J= 14.8 Hz, 1 H), 3.04 (dd, J= 14.8, 2.0 Hz, 1 H), 2.27 (s, 3 H), 2.12-2.21 (m, 1 H), 1.88-1.92 (m, 2 H), 1.32-1.46 (m, 1 H), 1.28 (s, 9 H), 1.18 (d, J= 6.8 Hz, 3 H) ppm. LRMS m/z (M+H) 307.5 found, 307.4 required.

Reference： [1]Patent: WO2015/88865,2015,A1 .Location in patent: Page/Page column 34

69
[ 461-87-0 ]
[ 105-58-8 ]
ethyl 2-(2-fluororopyridin-4-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34.3%	Stage #1: 2-fluoro-4-methylpyridine With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 2h; Inert atmosphere; Stage #2: Diethyl carbonate In tetrahydrofuran; hexane at -78 - 20℃; for 12h;	6.1 To a stirred solution of DIP A (2.4 g, 23.77 mmol, 2.2 eq) in dry THF (20 mL) was added n-BuLi [1.6M in hexane; (13.5 mL, 21.61 mmol, 2 eq) dropwise at -78°C under nitrogen. The mixture was stirred at same temperature for 30 minutes. A solution of 2- fluoro-4-methyl pyridine (1.2 g, 10.80 mmol, 1 eq) in dry THF (12 mL) was added to the previous solution at -78°C dropwise. The reaction mixture was stirred at -78°C for 2h. Diethyl carbonate (2.55 g, 21.61 mmol, 2 eq) was added dropwise at -78°C and RM was allowed stirred at ambient temperature for further 12 h. The completion of the reaction was monitored by TLC (2:8, ethyl acetate: pet ether). After completion of the reaction the RM was quenched with ice cold saturated NH4C1 solution and crude was extracted with EtOAc (3 X 70 ml). The combined organic layer was dried over anhydrous sodium sulfate. The crude product obtained on concentration was purified by column chromatography (60-120 mesh silica gel, 6 % ethyl acetate in pet ether) to afford ethyl 2-(2-fluororopyridin-4-yl)acetate as colorless oil (0.68 g, 34.3%).

Reference： [1]Current Patent Assignee: GENERAL ELECTRIC CO - WO2016/97339, 2016, A1 Location in patent: Page/Page column 20

70
[ 461-87-0 ]
[ 100-39-0 ]
2-fluoro-4-(2-phenylethyl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: 2-fluoro-4-methylpyridine With lithium diisopropyl amide In tetrahydrofuran at -84 - 20℃; for 0.666667h; Inert atmosphere; Stage #2: benzyl bromide In tetrahydrofuran at -84 - 20℃; Inert atmosphere;

Reference： [1]McDonald, Chriss E.; Ramsey, Jeremy D.; McAtee, Christopher C.; Mauck, Joseph R.; Hale, Erin M.; Cumens, Justin A. [Journal of Organic Chemistry, 2016, vol. 81, # 14, p. 5903 - 5914]

71
[ 461-87-0 ]
[ 93-89-0 ]
2-(2-fluoropyridin-4-yl)-1-phenylethan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	Stage #1: 2-fluoro-4-methylpyridine With sodium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.75h; Stage #2: benzoic acid ethyl ester In tetrahydrofuran at 0 - 20℃; for 0.75h;

Reference： [1]Günther, Marcel; Lategahn, Jonas; Juchum, Michael; Döring, Eva; Keul, Marina; Engel, Julian; Tumbrink, Hannah L.; Rauh, Daniel; Laufer, Stefan [Journal of Medicinal Chemistry, 2017, vol. 60, # 13, p. 5613 - 5637]

72
[ 461-87-0 ]
[ 67515-63-3 ]
1-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(2-fluoropyridin-4-yl)ethan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: 2-fluoro-4-methylpyridine With sodium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.75h; Stage #2: ethyl 4-fluoro-3-(trifluoromethyl)benzoate In tetrahydrofuran at 0 - 20℃; for 0.75h;

73
[ 461-87-0 ]
[ 50-00-0 ]
[ 84-11-7 ]
1-(4-methylpyridin-2-yl)-1H-phenanthro[9,10-d]imidazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: formaldehyd; 9,10-phenanthrenequinone With ammonium acetate; acetic acid for 24h; Reflux; Stage #2: 2-fluoro-4-methylpyridine With potassium carbonate In N,N-dimethyl-formamide at 140℃; for 12h;

Reference： [1]Akula, Suri Babu; Chen, Huei-Siou; Su, Chaochin; Chen, Bo-Ren; Chiou, Jiunn-Jie; Shieh, Chia-Hsuan; Lin, Ya-Fen; Li, Wen-Ren [Inorganic Chemistry, 2017, vol. 56, # 21, p. 12987 - 12995]

74
[ 461-87-0 ]
1-methyl-4-((phenylsulfinyl)methyl)benzene [ No CAS ]
4-methyl-1-(4-methylbenzyl)pyridin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	Stage #1: 2-fluoro-4-methylpyridine; 1-methyl-4-((phenylsulfinyl)methyl)benzene With trifluoromethylsulfonic anhydride In dichloromethane at -43 - 20℃; for 10h; Schlenk technique; Stage #2: With water; sodium hydrogencarbonate at 20℃; for 0.166667h;

Reference： [1]Hu, Gang; Xu, Jiaxi; Li, Pingfan [Organic and Biomolecular Chemistry, 2018, vol. 16, # 22, p. 4151 - 4158]

75
[ 461-87-0 ]
[ 71426-20-5 ]
1-(4-methoxybenzyl)-4-methylpyridin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	Stage #1: 2-fluoro-4-methylpyridine; 1-methoxy-4-((phenylsulfinyl)methyl)benzene With trifluoromethylsulfonic anhydride In dichloromethane at -43 - 20℃; for 10h; Schlenk technique; Stage #2: With water; sodium hydrogencarbonate at 20℃; for 0.166667h;

Reference： [1]Hu, Gang; Xu, Jiaxi; Li, Pingfan [Organic and Biomolecular Chemistry, 2018, vol. 16, # 22, p. 4151 - 4158]

76
[ 461-87-0 ]
[ 1193-82-4 ]
4-methyl-1-((phenylthio)methyl)pyridin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	Stage #1: 2-fluoro-4-methylpyridine; racemic methyl phenyl sulfoxide With trifluoromethylsulfonic anhydride In dichloromethane at -43 - 20℃; for 10h; Schlenk technique; Stage #2: With water; sodium hydrogencarbonate at 20℃; for 0.166667h;

Reference： [1]Hu, Gang; Xu, Jiaxi; Li, Pingfan [Organic and Biomolecular Chemistry, 2018, vol. 16, # 22, p. 4151 - 4158]

77
[ 461-87-0 ]
[ 695-34-1 ]

Yield	Reaction Conditions	Operation in experiment
46%	With acetamidine hydrochloride; sodium hydroxide In water; dimethyl sulfoxide at 130℃; for 24h; Schlenk technique; chemoselective reaction;

Reference： [1]Li, Yibiao; Huang, Shuo; Liao, Chunshu; Shao, Yan; Chen, Lu [Organic and Biomolecular Chemistry, 2018, vol. 16, # 41, p. 7564 - 7567]

78
[ 461-87-0 ]
[ 3939-14-8 ]

Reference： [1]Tetrahedron Letters,2001,vol. 42,p. 6815 - 6818

79
[ 461-87-0 ]
[ 16872-09-6 ]
C₈H₁₇B₁₀N [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	Stage #1: 1,2-dicarba-closo-dodecaborane⁽¹²⁾ With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 0.5h; Inert atmosphere; Schlenk technique; Stage #2: 2-fluoro-4-methylpyridine In tetrahydrofuran; hexane at 70℃; for 3h; Inert atmosphere; Schlenk technique;

Reference： [1]Lu, Ju-You; Zhao, Bo; Du, Yongmei; Yang, Jianxin; Lu, Jian [Organic and Biomolecular Chemistry, 2019, vol. 17, # 32, p. 7438 - 7441]

80
[ 461-87-0 ]
[ 99548-30-8 ]

Yield	Reaction Conditions	Operation in experiment
60%	With water; caesium carbonate In dimethyl sulfoxide at 110℃; for 12h;
60%	With water; caesium carbonate In dimethyl sulfoxide at 110℃; for 12h;	2 Example 2 This example provides a synthetic method of 4,4'-dimethyl-2H-[1,2'-bipyridin]-2-one. The synthetic route is: In a 25mL reaction tube, add 2-fluoro-4-methylpyridine (22mg, 0.2mmo1), cesium carbonate (65mg, 0.2mmo1), water (18mg, 1mmo1), in dimethyl sulfoxide (1mL) conditions Under the condition that the reaction temperature is 110°C, the reaction is stirred for 12 hours.After the reaction was completed, ethyl acetate was added to quench the reaction, and then saturated brine was added to wash, the organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate to combine the organic phases.Anhydrous sodium sulfate was added for drying, the solvent was removed by distillation under reduced pressure, and then separated by column chromatography to obtain a brown liquid (24 mg, 60%) after separation.

Reference： [1]Liao, Chunshu; Li, Jianrong; Chen, Xiaoqiong; Lu, Jingjun; Liu, Qiang; Chen, Lu; Huang, Yubing; Li, Yibiao [Organic and Biomolecular Chemistry, 2020, vol. 18, # 6, p. 1185 - 1193]
[2]Current Patent Assignee: WUYI UNIVERSITY - CN111285799, 2020, A Location in patent: Paragraph 0036-0040

81
[ 461-87-0 ]
C₂₄H₂₀BN₃O₃ [ No CAS ]
C₃₀H₂₅BN₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium carbonate In N,N-dimethyl-formamide at 150℃; for 24h; Inert atmosphere; Schlenk technique;

Reference： [1]Meng, Guoyun; Peng, Tai; Shi, Yonggang; Li, Haijun; Wang, Xiang; Yin, Xiaodong; Yang, Deng-Tao; Wang, Suning; Wang, Suning; Wang, Nan [Journal of Materials Chemistry C, 2020, vol. 8, # 23, p. 7749 - 7754]

82
[ 461-87-0 ]
[ 108-95-2 ]
[ 75390-50-0 ]

Yield	Reaction Conditions	Operation in experiment
79%	With caesium carbonate; copper(l) chloride In N,N-dimethyl-formamide at 140℃; for 20h; Sealed tube; Inert atmosphere;

Reference： [1]Januszewski, Rafał; Kownacki, Ireneusz; Kubicki, MacIej; Oh, Myong Joon; Orwat, Bartosz; Zaranek, MacIej [Inorganic Chemistry, 2020]

83
[ 461-87-0 ]
[ 124-42-5 ]
[ 5327-32-2 ]

Yield	Reaction Conditions	Operation in experiment
80%	With water; caesium carbonate In dimethyl sulfoxide at 90℃; for 18h; Schlenk technique; chemoselective reaction;

Reference： [1]Chen, Lu; Huang, Shuo; Ji, Xiaoliang; Li, Jiaming; Li, Jian; Li, Yibiao; Liu, Jiasheng; Peng, Shiyong; Zhang, Kun [Organic and Biomolecular Chemistry, 2020, vol. 18, # 45, p. 9292 - 9299]

84
[ 461-87-0 ]
[ 4857-06-1 ]
2-chloro-1-(4-methylpyridin-2-yl)-1H-benzo[d]imidazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5%	With copper(l) iodide; potassium carbonate In dimethyl sulfoxide at 130℃; for 24h; Schlenk technique;	4.3. General procedure for synthesis of ligand (L3) 2Fluoro4methylpyridine (1.0 mmol, 105 lL), 2chloro1Hbenzo[d]imidazole (1.1 mmol, 171.3 mg), K2CO3 (3.0 mmol,414.0 mg) and DMSO (2 mL) were successively put into a 25 mLSchlenk tube. The Schlenk tube was put into the magnetic stirrerand heated under 130 C for 24 h. After the reaction, brine(30 mL) was added to dilute the reaction mixtures and extractedthree times with dichloromethane (3 30 mL). Then the organicphase was dried and collected, the solvent was removed under vacuum,and the desired product L3 was purified by column chromatographyand characterized by NMR, HRMS and IRspectroscopy. Purification for 2chloro1(4methylpyridin2yl)1H-benzo[d]imidazole by flash chromatography (petroleumether/EtOAc = 15:1) gave a colorless oil (12.2 mg, 5%). 1H NMR(400 MHz, CDCl3) d 8.56 (d, J = 4.2 Hz, 1H), 7.75-7.73 (m, 1H),7.41-7.39 (m, 1H),7.34-7.26 (m, 4H), 2.50 (s, 3H). 13C NMR (100 MHz, CDCl3): d 150.7, 149.5, 148.5, 141.7, 139.2, 135.6,125.0, 124.1, 123.5, 121.9, 119.5, 111.2, 21.2. IR (KBr, neat):3061, 1604, 1456, 1355, 1302, 1260, 1158, 748 cm1. HRMS (ESI)m/z: [M + H]+ Calcd for C13H11ClN3 244.0642; Found 244.0639.

Reference： [1]Chen, Fei; Tao, Sheng; Liu, Ning; Dai, Bin [Polyhedron, 2021, vol. 196]

85
[ 461-87-0 ]
(S)-N-(1-hydroxy-2-methylpropan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide [ No CAS ]
(S)-N-(2-methyl-1-((4-methylpyridin-2-yl)oxy)propan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16%	Stage #1: (S)-N-(1-hydroxy-2-methylpropan-2-yl)-2-(1-methylpyrrolidin-2-yl)acetamide With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: 2-fluoro-4-methylpyridine In N,N-dimethyl-formamide at 20℃; for 16h;	102 EXAMPLE 102: (S)-N -(2-methyl-l-((4-methylpyridin-2-yl)oxy)propan-2-yl)-2-(l- methylpyrrolidin-2-yl)acetamide To a solution of (S)-N -(l-hydroxy-2-methylpropan-2-yl)-2-(l-methylpyrrolidin-2- yl)acetamide (25 mg, 0.117 mmol) in DMF (1.17 mL) was added NaH (60 wt%, 7.0 mg, 0.175 mmol). The reaction mixture was stirred at room temperature for 5 minutes. Next, 2- fluoro-4-methylpyridine (14.3 mg, 0.128 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours and then was quenched with aqueous 1 N HC1 (0.15 mL) and purified by preparative HPLC (Phenomenex Gemini C18, 5 μm, ID 30 mm x 150 mm) using a gradient of 10-70% water/ ACN in water (basic mode). The title compound was obtained as a colorless oil (5.8 mg, 16%). 1HNMR (400 MHz, CD3OD) δ ppm 1.43 (d, J = 3.0 Hz, 6 H), 1.50 - 1.65 (m, 1 H), 1.70 - 1.87 (m, 2 H), 1.91 - 2.01 (m, 1 H), 2.11 - 2.28 (m, 2 H), 2.31 (s, 3 H), 2.33 (s, 3 H), 2.38 - 2.45 (m, 1 H), 2.51 (qd, J = 8.0, 4.5 Hz, 1 H), 3.02 (ddd, J = 9.6, 7.3, 2.8 Hz, 1 H), 4.27 - 4.42 (m, 2 H), 6.66 (dt, J = 1.4, 0.7 Hz, 1 H), 6.77 - 6.87 (m, 1 H), 7.96 (d, J = 5.3 Hz, 1 H); ESI-MS m/z [M+H]+ 306.2.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2021/202781, 2021, A1 Location in patent: Paragraph 0626-0627

86
[ 461-87-0 ]
[ 78-82-0 ]
[ 872091-92-4 ]

Yield	Reaction Conditions	Operation in experiment
40%	With 1,1,1,3,3,3-hexamethyldisilazane potassium In toluene at 110℃; for 1h;	162.1 Step 1 : Synthesis of 2-methyl-2-(4-methylpyridin-2-yl)propanenitrile To a solution of 2-fluoro-4-methylpyridine (1.11 g, 10 mmol) in toluene (10 mL) was added isobutyronitrile (1.38 g, 20 mmol) and KHMDS (IM in toluene) (20 mL). The mixture was stirred at 110°C for Ih. LCMS showed the reaction completed. The reaction mixture was diluted to water (10 mL), extracted by EA (10 mL x 3). The combined organic phase was washed by brine (20 mL), dried over anhydrous Na2SO4, concentrated to obtain 2-methyl-2-(4- methylpyridin-2-yl)propanenitrile (630 mg, 40%yield). LCMS (M+H+) m/z: 161.0.

Reference： [1]Current Patent Assignee: ABM THERAPEUTICS - WO2022/32071, 2022, A1 Location in patent: Paragraph 0985-0986

87
[ 461-87-0 ]
[ 7788-14-9 ]
N-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With lithium tert-butylate In dimethyl sulfoxide at 150℃; for 12h;

Reference： [1]Cai, Qian; Li, Zihao; Qiu, Kongxi; Yang, Xiao; Zhou, Wei [Organic Letters, 2022, vol. 24, # 16, p. 2989 - 2992]

88
[ 461-87-0 ]
[ 55809-36-4 ]
3,3-dimethyl-1-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)butan-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With lithium tert-butylate In dimethyl sulfoxide at 100℃; for 12h;

Reference： [1]Cai, Qian; Li, Zihao; Qiu, Kongxi; Yang, Xiao; Zhou, Wei [Organic Letters, 2022, vol. 24, # 16, p. 2989 - 2992]

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P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 461-87-0 ] {[proInfo.proName]}

Quality Control of [ 461-87-0 ]

Related Doc. of [ 461-87-0 ]

Product Details of [ 461-87-0 ]

Calculated chemistry of [ 461-87-0 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 461-87-0 ]

Application In Synthesis of [ 461-87-0 ]

[ 461-87-0 ] Synthesis Path-Upstream 1~15

[ 461-87-0 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 461-87-0 ]

Fluorinated Building Blocks

Related Parent Nucleus of [ 461-87-0 ]

Pyridines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 461-87-0 ]

Related Parent Nucleus of
[ 461-87-0 ]