842136-58-7|2-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine| Ambeed

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Quality Control of [ 842136-58-7 ] Purity: 98% SDS Specification

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Product Details of [ 842136-58-7 ]

CAS No. :	842136-58-7
Formula :	C₁₁H₁₅BFNO₂
M.W :	223.05
SMILES Code :	CC1(C)C(C)(C)OB(C2=CC=CC(F)=N2)O1
MDL No. :	MFCD08063029
InChI Key :	WGPVNHXZZUGSMO-UHFFFAOYSA-N
Pubchem ID :	42614576

Safety of [ 842136-58-7 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Application In Synthesis of [ 842136-58-7 ]

* 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.

Downstream synthetic route of [ 842136-58-7 ]

[ 842136-58-7 ] Synthesis Path-Downstream 1~35

1
[ 144100-07-2 ]
[ 73183-34-3 ]
[ 842136-58-7 ]

Yield	Reaction Conditions	Operation in experiment
76%	With (dppf)2PdCl2.HCl; potassium acetate; In 1,4-dioxane; at 20 - 115℃; for 1h;Inert atmosphere;	2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Pd(dppf)2Cl2.HCl (102 mg, 0.14 mmol) was added to a degassed mixture of 2-bromo-6-fluoropyridine (410 mg, 2.33 mmol), bis(pinacolato)diboron (828 mg, 3.26 mmol) and KOAc (685 mg, 6.99 mmol) in dioxane (6 mL) at room temperature. The mixture was heated at 115 C. for 1 h. The solid material was then filtered off the solvent evaporated and the crude compound purified by chromatography (silica, MeOH in DCM 0:100 to 10:90). The desired fractions were collected to obtain the title compound (400 mg, 76%). 1H NMR (400 MHz, CDCl3) 7.78 (td, J=8.1, 7.2 Hz, 1H), 7.70 (ddd, J=6.9, 2.8, 0.9 Hz, 1H), 6.98 (ddd, J=8.1, 2.7, 0.9 Hz, 1H), 1.38 (s, 12H),
	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 80℃; for 3h;	2-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 2-bromo-6-fluoropyridine (200 mg, 1.136 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (317 mg, 1.250 mmol), potassium acetate (335 mg, 3.41 mmol), PdCl2(dppf) (83 mg, 0.114 mmol) were collected in a vial, deareated, and then suspended in DMSO (10 ml) under nitrogen atmosphere. The resulting mixture was stirred at 80 C. for 3 hours, diluted with DCM (500 ml) and washed with water (5*100 ml). The resulting organic phase was concentrated under vacuum to give 250 mg of a crude residue which was used in the next step without any further purification. UPLC-MS: 0.38 min, 142 [M-C6H10+H]+
	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 100℃; for 18h;	A mixture of 2-bromo-6-fluoropyridine (1.056 g, 6 mmol), 4, 4, 4', 4', 5, 5,5', 5'- octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (1.60 g, 6.30 mmol), PdCI2(dppf) CH2CI2 adduct (0.294 g, 0.360 mmol) and potassium acetate (1.767 g, 18.00 mmol) in dioxane (12 mL) was stirred at 100 C for 18 hrs. The reaction mixture was cooled to room temperature, diluted with EtOAc (40 mL), filtered and concentrated under reduced pressure. The crude material of 2-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine was directly used in the next step without further purification. LCMS (m/z): 142.0 [MS fragment]; Rt = 0.35 min. [Note: LCMS shows only boronic acid fragment.]

	With Nonafluorobutanesulfonyl fluoride;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 100℃; for 18h;	A mixture of 2-bromo-6-fluoropyridine (1 .056 g, 6 mmol), 4, 4, 4', 4', 5, 5,5', 5'- octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (1 .60 g, 6.30 mmol), PdCI2(dppf) CH2CI2 adduct(0.294 g, 0.360 mmol) and potassium acetate (1 .767 g, 18.00 mmol) in dioxane (12 mL) was stirred at 100 C for 18 hrs. The reaction mixture was cooled to room temperature, diluted with EtOAc (40 mL), filtered and concentrated under reduced pressure. The crude material of 2-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine was directly used in the next step without further purification. LCMS (m/z): 142.0 [MS fragment]; Rt = 0.35 min. [Note: LCMS shows only boronic acid fragment.]
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 110℃; for 10h;Inert atmosphere;	To a solution of 2-bromo-6-fluoropyridine (5.0 g, 28.4 mmol) in 1,4-dioxane (150 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (8.6 g, 34.1 mmol), and potassium acetate (5.6 g, 56.8 mmol) followed by [l,l '-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (1.2 g, 1.4 mmol) and the mixture was degassed with nitrogen. The mixture was heated at 1 10C for 10 hours, diluted with ethyl acetate and filtered through diatomaceous earth. The filtrate was concentrated and purified by column chromatography (silica gel, 20% ethyl acetate in hexane) to afford the title compound. LCMS: 224 (M+H)+.
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 80℃;Inert atmosphere;	To a solution of 2-bromo-6-fluoropyridine (5.32 g,30.23 mmol), potassium acetate (9.02 g, 90.70 mmol) andbis(pinacolato)diboron(8.11 g, 31.75 mmol) in 1,4-dioxane was added[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane (1:1) (7.89 g, 1.81 mmol), followed by stirring at 80Covernight under a nitrogen atmosphere. After cooling, the reaction mixture wasdiluted with ethyl acetate (40 mL), then filtered through pad of Celite. Thefiltrate was concentrated under reduced pressure to afford 25.65 g of 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine,which was used directly without further purification. To a solution of thiscrude compound (7.08 g), compound 7 (4.00g, 8.34 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II),complex with dichloromethane (1:1) (0.72 g, 0.88 mmol) in 1,2-dimethoxyethane(80 mL) was added sodium bicarbonate (2.0 M in water, 22.5 mL, 45.0 mmol),followed by stirring at 95C for 1 hour under a nitrogen atmosphere. Aftercooling, the mixture was diluted with chloroform, and washed with saturatedaqueous brine solution. The organic layer was dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (75:25 to 50:50 hexane/ethyl acetate) togive 4.34 g (quant) of compound 8a.

References: [1]Patent: US2014/275120,2014,A1 .Location in patent: Paragraph 0531; 0532.
[2]Patent: US2009/203705,2009,A1 .Location in patent: Page/Page column 43.
[3]Patent: WO2012/101063,2012,A1 .Location in patent: Page/Page column 143-144.
[4]Patent: WO2012/101064,2012,A1 .Location in patent: Page/Page column 185.
[5]Patent: WO2014/139328,2014,A1 .Location in patent: Page/Page column 403.
[6]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 2320 - 2326.

2
[ 842136-58-7 ]
[ 1177269-19-0 ]
[ 1177267-93-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 80℃;	Example 4-37 (Trans)-8-([6-(6-fluoro-2-pyridinyl)-3-pyridazinyl]amino}methyl)-3-(3-pyridazinyl)-1-oxa-3-azaspiro[4.5]decan-2-one Dihydrochloride (Trans)-8-[(6-chloro-3-pyridazinyl)amino]methyl}-3-(3-pyridazinyl)-1-oxa-3-azaspiro[4.5]decan-2-one (Intermediate 42 procedure 42a, 100 mg, 0.267 mmol), 2M K3PO4 aq solution (0.267 ml, 0.534 mmol), tetrakis(triphenylphosphine)palladium(0) (15.41 mg, 0.013 mmol), <strong>[842136-58-7]2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (Intermediate 70, 130 mg, 0.583 mmol) were collected in a vial, deareated, and then suspended in N,N-dimethylformamide (4 ml). The reaction mixture was then shaken at 80 C. for 5 hours. Further <strong>[842136-58-7]2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (120 mg, 0.267 mmol) was added and the reaction mixture was shaken at 80 C. overnight then diluted with DCM (300 ml) and washed with water (3*100 ml). The resulting organic phase was separated and concentrated under vacuum to give a crude. The crude was purified twice by reverse phase flash chromatography (Biotage SP1, C18 60 g SNAP cartridge) eluding with a gradient of ACN and water (made up with 0.1% HCOOH). Fractions containing the required compound were collected and passed through a SCX cartridge (1g, Varian) and eluted with 2M ammonia in MeOH to give (trans)-8-([6-(6-fluoro-2-pyridinyl)-3-pyridazinyl]amino}methyl)-3-(3-pyridazinyl)-1-oxa-3-azaspiro[4.5]decan-2-one (7.5 mg). 1H NMR (400 MHz, CDCl3): delta 8.97 (dd, 1H), 8.57 (dd, 1H), 8.44 (dd, 1H), 8.20 (d, 1H), 7.94 (q, 1H), 7.50 (dd, 1H), 6.94 (ddd, 1H), 6.79 (d, 1H), 5.10 (br s, 1H), 4.24 (s, 2H), 3.52-3.47 (m, 2H), 2.13-1.13 (m, 9H); UPLC-MS: 0.52 min, 436 [M+H]+.

References: [1]Patent: US2009/203705,2009,A1 .Location in patent: Page/Page column 93.

3
[ 842136-58-7 ]
[ 281225-12-5 ]
[ 1257425-53-8 ]

References: [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 8421 - 8439.

4
[ 842136-58-7 ]
[ 1263374-68-0 ]
[ 1263374-69-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 100℃; for 2h;	Step 2. Preparation of tert-butyl 4-(5'-chloro-6-fluoro-2,4'-bipyridin-2'-yl-amino)piperidine-1-carboxylate; A mixture of tert-butyl 4-(5-chloro-4-iodopyridin-2-yl-amino)piperidine-1-carboxylate (468 mg, 1.069 mmol), <strong>[842136-58-7]2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (429 mg, 1.925 mmol), PdCl2(dppf).CH2Cl2 adduct (87 mg, 0.107 mmol), DME (7.5 ml), and 2M sodium carbonate (2.406 ml, 4.81 mmol) reaction mixture was stirred at 100 C. for 2 hr. The reaction mixture mixture was cooled to room temperature, mixed with 20 ml of ethyl acetate, filtered and concentrated to yield a crude material. The crude material was purified by silica gel chromatography using a 40 g column, eluting from 0%-40% ethyl acetate with hexane. The desired fractions were combined and concentrated to constant mass, giving 360 mg of the title compound as free base. LCMS (m/z): 407.2 (MH+), retention time=0.85 min.
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 100℃; for 2h;	A mixture of tert-butyl 4-(5-chloro-4-iodopyridin-2-yl-amino)piperidine-1- carboxylate (468 mg, 1.069 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine (429 mg, 1.925 mmol), PdCI2(dppf).CH2CI2 adduct (87 mg, 0.107 mmol), DME (7.5 ml), and 2M sodium carbonate (2.406 ml, 4.81 mmol) reaction mixture was stirred at 100 C for 2 hr. The reaction mixture was cooled to room temperature, mixed with 20 ml of ethyl acetate, filtered and concentrated to yield a crude material. The crude material was purified by silica gel chromatography using a 40g column, eluting from 0%-40% ethyl acetate with hexane. The desired fractions were combined and concentrated to constant mass, giving 360 mg of the title compound as free base. LCMS (m/z): 407.2 (MH+), retention time = 0.85 min.
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 100℃; for 2h;	Step 2. Preparation of tert-butyl 4-(5'-chloro-6-fluoro-2,4'-bipyridin-2'-yl-amino)piperidine- 1-carboxylateA mixture of tert-butyl 4-(5-chloro-4-iodopyridin-2-yl-amino)piperidine-1- carboxylate (468 mg, 1.069 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine (429 mg, 1.925 mmol), PdCI2(dppf).CH2CI2 adduct (87 mg, 0.107 mmol), DME (7.5 ml), and 2M sodium carbonate (2.406 ml, 4.81 mmol) reaction mixture was stirred at 100 C for 2 hr. The reaction mixture was cooled to room temperature, mixed with 20 ml of ethyl acetate, filtered and concentrated to yield a crude material. The crude material was purified by silica gel chromatography using a 40g column, eluting from 0%-40% ethyl acetate with hexane. The desired fractions were combined and concentrated to constant mass, giving 360 mg of the title compound as free base. LCMS (m/z): 407.2 (MH+), retention time = 0.85 min.

With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 100℃; for 2h;

Step 2. Preparation of tert-butyl 4-(5'-chloro-6-fluoro-2,4'-bipyridin-2'-yl-amino)piperidine- 1 -carboxylate A mixture of tert-butyl 4-(5-chloro-4-iodopyridin-2-yl-amino)piperidine-1- carboxylate (468 mg, 1.069 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine (429 mg, 1.925 mmol), PdCI2(dppf).CH2CI2 adduct (87 mg, 0.107 mmol), DME (7.5 ml), and 2M sodium carbonate (2.406 ml, 4.81 mmol) reaction mixture was stirred at 100 C for 2 hr. The reaction mixture was cooled to room temperature, mixed with 20 ml of ethyl acetate, filtered and concentrated to yield a crude material. The crude material was purified by silica gel chromatography using a 40g column, eluting from 0%-40% ethyl acetate with hexane. The desired fractions were combined and concentrated to constant mass, giving 360 mg of the title compound as free base. LCMS (m/z): 407.2 (MH+), retention time = 0.85 min.

References: [1]Patent: US2011/28492,2011,A1 .Location in patent: Page/Page column 33.
[2]Patent: WO2012/101065,2012,A2 .Location in patent: Page/Page column 153.
[3]Patent: WO2012/101062,2012,A1 .Location in patent: Page/Page column 110.
[4]Patent: WO2012/101066,2012,A1 .Location in patent: Page/Page column 136.

5
[ 842136-58-7 ]
[ 5750-76-5 ]
[ 1263374-62-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 80℃;	Step 1. Preparation of 2,5-dichloro-4-(6-fluoropyridin-2-yl)pyrimidine; A mixture of 2,4,5-trichloropyrimidine (49.3 mg, 0.269 mmol), <strong>[842136-58-7]2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (50 mg, 0.224 mmol), PdCl2(dppf).CH2Cl2 adduct (18.31 mg, 0.022 mmol), DME (0.7 ml), and 2M sodium carbonate (0.247 ml, 0.493 mmol) reaction mixture was stirred at about 80 C. until the reaction mixture was complete, as indicated by LCMS. The reaction mixture mixture was cooled, diluted with 5 ml of ethyl acetate and 1 ml of methanol, filtered and concentrated to yield a crude solid. The crude material was purified by silica gel chromatography using a 12 g column, eluting from 0%-40% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, to yield 39.5 mg of titled compound as a free base. LCMS (m/z): 244.0 (MH+), retention time=0.89 min.
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; ethanol; at 80℃;	A mixture of 2,4,5-trichloropyrimidine (49.3 mg, 0.269 mmol), 2-fluoro-6-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (50 mg, 0.224 mmol), PdCl2(dppf).CH2Cl2 adduct (18.31 mg, 0.022 mmol), DME (0.7 ml), and 2M sodium carbonate (0.247 ml, 0.493 mmol) reaction mixture was stirred at about 80 C until the reaction mixture was complete, as indicated by LCMS. The reaction mixture was cooled, diluted with 5 ml of ethyl acetate and 1 ml of methanol, filtered and concentrated to yield a crude solid. The crude material was purified by silica gel chromatography using a 12g column, eluting from 0%-40% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, to yield 39.5 mg of titled compound as a free base. LCMS (m/z): 244.0 (MH+), retention time = 0.89 min
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 80℃;	Example 3 (Compound 3)frans-N1-(5-chloro-4-(6-(cyclohexylmethylamino)pyridin-2-yl)pyrimidin-2-yl)cyclohexane- 1 ,4-diamine Step 1. Preparation of 2,5-dichloro-4-(6-fluoropyridin-2-yl)pyrimidine A mixture of 2,4,5-trichloropyrimidine (49.3 mg, 0.269 mmol), 2-fluoro-6-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (50 mg, 0.224 mmol), PdCl2(dppf).CH2Cl2 adduct (18.31 mg, 0.022 mmol), DME (0.7 ml), and 2M sodium carbonate (0.247 ml, 0.493 mmol) reaction mixture was stirred at about 80 C until the reaction mixture was complete, as indicated by LCMS. The reaction mixture was cooled, diluted with 5 ml of ethyl acetate and 1 ml of methanol, filtered and concentrated to yield a crude solid. The crude material was purified by silica gel chromatography using a 12g column, eluting from 0%-40% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, to yield 39.5 mg of titled compound as a free base. LCMS (m/z): 244.0 (MH+), retention time = 0.89 min.

	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 80℃;	Example 3 (Compound 3)frans-N1-(5-chloro-4-(6-(cyclohexylmethylamino)pyridin-2-yl)pyrimidin-2-yl)cyclohexane- 1 ,4-diamine Step 1. Preparation of 2,5-dichloro-4-(6-fluoropyridin-2-yl)pyrimidine A mixture of 2,4,5-trichloropyrimidine (49.3 mg, 0.269 mmol), 2-fluoro-6-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (50 mg, 0.224 mmol), PdCl2(dppf).CH2Cl2 adduct (18.31 mg, 0.022 mmol), DME (0.7 ml), and 2M sodium carbonate (0.247 ml, 0.493 mmol) reaction mixture was stirred at about 80 C until the reaction mixture was complete, as indicated by LCMS. The reaction mixture was cooled, diluted with 5 ml of ethyl acetate and 1 ml of methanol, filtered and concentrated to yield a crude solid. The crude material was purified by silica gel chromatography using a 12g column, eluting from 0%-40% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, to yield 39.5 mg of titled compound as a free base. LCMS (m/z): 244.0 (MH+), retention time = 0.89 min.
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 80℃;	A mixture of 2,4,5-trichloropyrimidine (49.3 mg, 0.269 mmol), 2-fluoro-6-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (50 mg, 0.224 mmol), PdCI2(dppf).CH2Cl2 adduct (18.31 mg, 0.022 mmol), DME (0.7 ml), and 2M sodium carbonate (0.247 ml, 0.493 mmol) reaction mixture was stirred at about 80 C until the reaction mixture was complete, as indicated by LCMS. The reaction mixture was cooled, diluted with 5 ml of ethyl acetate and 1 ml of methanol, filtered and concentrated to yield a crude solid. The crude material was purified by silica gel chromatography using a 12g column, eluting from 0%-40% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, to yield 39.5 mg of titled compound as a free base. LCMS (m/z): 244.0 (MH+), retention time = 0.89 min.

References: [1]Patent: US2011/28492,2011,A1 .Location in patent: Page/Page column 32.
[2]Patent: WO2012/101065,2012,A2 .Location in patent: Page/Page column 149.
[3]Patent: WO2012/101062,2012,A1 .Location in patent: Page/Page column 106-107.
[4]Patent: WO2012/101066,2012,A1 .Location in patent: Page/Page column 133.
[5]Patent: WO2012/101064,2012,A1 .Location in patent: Page/Page column 78-79.

6
[ 842136-58-7 ]
trans-N₁-(5-chloro-4-iodopyridin-2-yl)cyclohexane-1,4-diamine trifluoroacetate [ No CAS ]
trans-N₁-(5'-chloro-6-fluoro-2,4'-bipyridin-2'-yl)cyclohexane-1,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; ethanol; at 90℃;	Step 2. Preparation of trans-N1-(5'-chloro-6-fluoro-2,4'-bipyridin-2'-yl)cyclohexane-1,4-diamine; A mixture of trans-N1-(5-chloro-4-iodopyridin-2-yl)cyclohexane-1,4-diamine (from step 1 above, 300 mg, 0.853 mmol), <strong>[842136-58-7]2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (285 mg, 1.280 mmol), PdCl2(dppf).CH2Cl2 adduct (84 mg, 0.102 mmol), DME (4 ml), Ethanol (1 ml), and 2M sodium carbonate (1.706 ml, 3.41 mmol) reaction mixture was stirred at about 90 C. until done by LCMS. The reaction mixture mixture was cooled, then diluted with 25 ml of ethyl acetate and 10 ml of methanol, filtered, and concentrated to yield a crude solid. The crude solid was dissolved in DMSO, filtered and purified by prep LC. After lyapholization, 200 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 321.0 (MH+), retention time=0.48 min.

References: [1]Patent: US2011/28492,2011,A1 .Location in patent: Page/Page column 30.

7
[ 842136-58-7 ]
trans-N₁-(4-bromopyridin-2-yl)cyclohexane-1,4-diamine [ No CAS ]
trans-N₁-(6-fluoro-2,4'-bipyridin-2'-yl)cyclohexane-1,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; ethanol; at 85℃;	Step 2. Preparation of trans-N1-(6-fluoro-2,4'-bipyridin-2'-yl)cyclohexane-1,4-diamine; A mixture of trans-N1-(4-bromopyridin-2-yl)cyclohexane-1,4-diamine (102 mg, 0.377 mmol), <strong>[842136-58-7]2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (80 mg, 0.359 mmol), PdCl2(dppf).CH2Cl2 adduct (29.3 mg, 0.036 mmol), DME (2 ml), Ethanol (0.2 ml), and 2M sodium carbonate (0.717 ml, 1.435 mmol) reaction mixture was stirred at about 85 C. until completion, as indicated by LCMS. The crude mixture was cooled to room temperature, diluted with 5 ml of ethyl acetate and 2 ml of methanol, filtered and concentrated to yield a crude solid. The solid was dissolved in DMSO, refiltered, purified by prep LC, and lyophilized to yield 64 mg of the title compound as its TFA salt. LCMS (m/z): 287.2 (MH+), retention time=0.43 min.

References: [1]Patent: US2011/28492,2011,A1 .Location in patent: Page/Page column 31.

8
[ 842136-58-7 ]
tert-butyl ((trans-4-(5-chloro-4-iodopyridin-2-yl-amino)cyclohexyl)methyl)carbamate [ No CAS ]
tert-butyl ((trans-4-(5'-chloro-6-fluoro-2,4'-bipyridin-2'-yl-amino)cyclohexyl)methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 100℃; for 2h;	Step 2. Preparation of tert-butyl(trans-4-(5'-chloro-6-fluoro-2,4'-bipyridin-2'-yl-amino)cyclohexyl)methylcarbamate; A mixture of tert-butyl(trans-4-(5-chloro-4-iodopyridin-2-yl-amino)cyclohexyl)methylcarbamate (510 mg, 1.095 mmol), <strong>[842136-58-7]2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (440 mg, 1.971 mmol), PdCl2(dppf).CH2Cl2 adduct (89 mg, 0.109 mmol), DME (7.5 ml), and 2M sodium carbonate (2.464 ml, 4.93 mmol) reaction mixture was stirred at about 100 C. for about 2 hours. The reaction mixture mixture was cooled to room temperature, mixed with 20 ml ethyl acetate, filtered and concentrated to yield a crude solid. The crude solid was purified by silica gel chromatography using 40 g column, eluting from 0%-45% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, yielding 396 mg of titled compound as a free base. LCMS (m/z): 435.2 (MH+), retention time=0.85 min.
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 100℃; for 2h;	A mixture of tert-butyl (frans-4-(5-chloro-4-iodopyridin-2-yl- amino)cyclohexyl)methylcarbamate (510 mg, 1.095 mmol), 2-fluoro-6-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (440 mg, 1.971 mmol), PdCl2(dppf).CH2Cl2 adduct (89 mg, 0.109 mmol), DME (7.5 ml), and 2M sodium carbonate (2.464 ml, 4.93 mmol) reaction mixture was stirred at about 100 C for about 2 hours. The reaction mixture was cooled to room temperature, mixed with 20 ml ethyl acetate, filtered and concentrated to yield a crude solid. The crude solid was purified by silica gel chromatography using 40g column, eluting from 0%-45% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, yielding 396 mg of titled compound as a free base. LCMS (m/z): 435.2(MH+), retention time = 0.85 min
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 100℃; for 2h;	Step 2. Preparation of tert-butyl (frans-4-(5'-chloro-6-fluoro-2,4'-bipyridin-2'-yl- amino)cyclohexyl)methylcarbamateA mixture of tert-butyl (frans-4-(5-chloro-4-iodopyridin-2-yl- amino)cyclohexyl)methylcarbamate (510 mg, 1.095 mmol), 2-fluoro-6-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (440 mg, 1.971 mmol), PdCl2(dppf).CH2Cl2 adduct (89 mg, 0.109 mmol), DME (7.5 ml), and 2M sodium carbonate (2.464 ml, 4.93 mmol) reaction mixture was stirred at about 100 C for about 2 hours. The reaction mixture was cooled to room temperature, mixed with 20 ml ethyl acetate, filtered and concentrated to yield a crude solid. The crude solid was purified by silica gel chromatography using 40g column, eluting from 0%-45% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, yielding 396 mg of titled compound as a free base. LCMS (m/z): 435.2(MH+), retention time = 0.85 min..

With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 100℃; for 2h;

Step 2. Preparation of tert-butyl (frans-4-(5'-chloro-6-fluoro-2,4'-bipyridin-2'-yl- amino)cyclohexyl)methylcarbamateA mixture of tert-butyl (frans-4-(5-chloro-4-iodopyridin-2-yl- amino)cyclohexyl)methylcarbamate (510 mg, 1.095 mmol), 2-fluoro-6-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (440 mg, 1.971 mmol), PdCl2(dppf).CH2Cl2 adduct (89 mg, 0.109 mmol), DME (7.5 ml), and 2M sodium carbonate (2.464 ml, 4.93 mmol) reaction mixture was stirred at about 100 C for about 2 hours. The reaction mixture was cooled to room temperature, mixed with 20 ml ethyl acetate, filtered and concentrated to yield a crude solid. The crude solid was purified by silica gel chromatography using 40g column, eluting from 0%-45% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, yielding 396 mg of titled compound as a free base. LCMS (m/z): 435.2(MH+), retention time = 0.85 min..

References: [1]Patent: US2011/28492,2011,A1 .Location in patent: Page/Page column 32-33.
[2]Patent: WO2012/101065,2012,A2 .Location in patent: Page/Page column 151.
[3]Patent: WO2012/101062,2012,A1 .Location in patent: Page/Page column 108-109.
[4]Patent: WO2012/101066,2012,A1 .Location in patent: Page/Page column 134-135.

9
[ 842136-58-7 ]
trans-4-(5-chloro-4-iodopyridin-2-yl-amino)cyclohexanol [ No CAS ]
trans-4-(5'-chloro-6-fluoro-2,4'-bipyridin-2'-yl-amino)cyclohexanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 95℃; for 2h;	Step 2. Preparation of trans-4-(5'-chloro-6-fluoro-2,4'-bipyridin-2'-yl-amino)cyclohexanol; A mixture of trans-4-(5-chloro-4-iodopyridin-2-yl-amino)cyclohexanol (575 mg, 1.631 mmol), <strong>[842136-58-7]2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (655 mg, 2.94 mmol), PdCl2(dppf).CH2Cl2 adduct (133 mg, 0.163 mmol), DME (15 ml), and t 2M sodium carbonate (4.48 ml, 8.97 mmol) reaction mixture was stirred at 95 C. for 2 hr, followed by LCMS. The reaction mixture was cooled to room temperature, mixed with 20 ml of ethyl acetate, 15 ml of methanol, filtered and concentrated to yield a crude product. The crude was purified by silica gel chromatography using a 40 g column, eluting from 35%-85% ethyl acetate with hexane. The desired fractions were combined and concentrated to constant mass, giving 440 mg of titled compound as free base. LCMS (m/z): 322.2 (MH+), retention time=0.53 min.
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 95℃; for 2h;	mixture of frans-4-(5-chloro-4-iodopyridin-2-yl-amino)cyclohexanol (575 mg, 1.631 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (655 mg, 2.94 mmol), PdCI2(dppf).CH2Cl2 adduct (133 mg, 0.163 mmol), DME (15 ml), and 1 2M sodium carbonate (4.48 ml, 8.97 mmol) reaction mixture was stirred at 95 C for 2 hr, followed by LCMS. The reaction mixture was cooled to room temperature, mixed with 20 ml of ethyl acetate, 15 ml of methanol, , filtered and concentrated to yield a crude product. The crude was purified by silica gel chromatography using a 40g column, eluting from 35%-85% ethyl acetate with hexane. The desired fractions were combined and concentrated to constant mass, giving 440 mg of titled compound as free base. LCMS (m/z): 322.2(MH+), retention time = 0.53 min
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 95℃; for 2h;	Step 2. Preparation of frans-4-(5'-chloro-6-fluoro-2,4'-bipyridin-2'-yl-amino)cyclohexanolA mixture of frans-4-(5-chloro-4-iodopyridin-2-yl-amino)cyclohexanol (575 mg, 1.631 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (655 mg, 2.94 mmol), PdCI2(dppf).CH2Cl2 adduct (133 mg, 0.163 mmol), DME (15 ml), and 1 2M sodium carbonate (4.48 ml, 8.97 mmol) reaction mixture was stirred at 95 C for 2 hr, followed by LCMS. The reaction mixture was cooled to room temperature, mixed with 20 ml of ethyl acetate, 15 ml of methanol, , filtered and concentrated to yield a crude product. The crude was purified by silica gel chromatography using a 40g column, eluting from 35%-85% ethyl acetate with hexane. The desired fractions were combined and concentrated to constant mass, giving 440 mg of titled compound as free base. LCMS (m/z): 322.2(MH+), retention time = 0.53 min.

With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 95℃; for 2h;

Step 2. Preparation of frans-4-(5'-chloro-6-fluoro-2,4'-bipyridin-2'-yl-amino)cyclohexanolA mixture of frans-4-(5-chloro-4-iodopyridin-2-yl-amino)cyclohexanol (575 mg, 1.631 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (655 mg, 2.94 mmol), PdCI2(dppf).CH2Cl2 adduct (133 mg, 0.163 mmol), DME (15 ml), and 1 2M sodium carbonate (4.48 ml, 8.97 mmol) reaction mixture was stirred at 95 C for 2 hr, followed by LCMS. The reaction mixture was cooled to room temperature, mixed with 20 ml of ethyl acetate, 15 ml of methanol, , filtered and concentrated to yield a crude product. The crude was purified by silica gel chromatography using a 40g column, eluting from 35%-85% ethyl acetate with hexane. The desired fractions were combined and concentrated to constant mass, giving 440 mg of titled compound as free base. LCMS (m/z): 322.2(MH+), retention time = 0.53 min.

References: [1]Patent: US2011/28492,2011,A1 .Location in patent: Page/Page column 35.
[2]Patent: WO2012/101065,2012,A2 .Location in patent: Page/Page column 156.
[3]Patent: WO2012/101062,2012,A1 .Location in patent: Page/Page column 113-114.
[4]Patent: WO2012/101066,2012,A1 .Location in patent: Page/Page column 140.

10
[ 842136-58-7 ]
[ 1187669-38-0 ]
[ 1313590-99-6 ]

Yield	Reaction Conditions	Operation in experiment
41%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In ethanol; water; N,N-dimethyl-formamide; toluene; at 90℃; for 16h;	General procedure: PdCl2(dppf) (0.03 mmol) was added to a stirred, degassed solution of bromo- or iodopyridine (0.29 mmol), boronic acid or ester (0.45 mmol) and K2CO3 (3.00 mmol) in a mixture of toluene/EtOH/H2O/DMF (5:3:1.5:4, 13.5 mL) and the mixture was heated at 90 C for 16 h. After cooling to 20 C, the mixture was partitioned between EtOAc (100 mL) and water (50 mL), the combined organic phase was washed with H2O (3 × 50 mL), washed with brine (50 mL), dried and the solvent was evaporated. The residue was purified by column chromatography, eluting with an appropriate blend of EtOAc/pet. ether or aqueous NH3/MeOH/DCM, to give the Suzuki product.

References: [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 3347 - 3356.

11
[ 842136-58-7 ]
[ 1321503-82-5 ]
[ 1321503-83-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;bis(tri-t-butylphosphine)palladium(0); In 1,4-dioxane; at 60℃; for 3h;Inert atmosphere;	4-ethoxy-3-(6-fluoropyridin-2-yl)-l-trityl-lH-pyrazolo[3,4-i/]pyrimidine4-ethoxy-3-iodo-l-trityl-pyrazolo[3,4-d]pyrimidine (590 mg, 1.11 mmol), 2-fluoro-6-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (296.7 mg, 1.33 mmol) and a2C03 (1.662 mL of 2 M, 3.324 mmol) were suspended in anhydrous Dioxane (25 mL) and degassed (vacuum/nitrogen cycles x 5). Pd[P(tBu)3]2 (56.62 mg, 0.11 mmol) was added and the reaction mixture was degassed again (vacuum / nitrogen cycles x 5) and stirred at 60 C for 3 hours. After this time, the reaction mixture was allowed to cool to ambient temperature. DCM, saturated aqueous a2C03 and brine were added and the aqueous layer was extracted with DCM (4 x 50 mL). The combined organics were dried ( a2S04), filtered and concentrated in vacuo. The crude mixture was purified by column chromatography (ISCO Companion, 120 g column, eluting with EtOAc/petroleum ether) to give the sub title compound (139.1 mg, 25% Yield). XH NMR (400 MHz, DMSO) delta 8.17 (1H, s), 7.77 (1H, m), 7.63 (1H, m), 7.24-7.11 (15H, m), 6.89-6.81 (1H, m), 4.50 (2H, q) and 1.44 (3H, t).

References: [1]Patent: WO2011/94290,2011,A1 .Location in patent: Page/Page column 48.

12
[ 842136-58-7 ]
trans-N₁-(5-chloro-4-(6-fluoropyridin-2-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine trifluoroacetate [ No CAS ]

References: [1]Patent: WO2012/101065,2012,A2 .
[2]Patent: WO2012/101062,2012,A1 .

13
[ 842136-58-7 ]
trans-N₁-(5-chloro-4-(6-(cyclohexylmethylamino)pyridin-2-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine trifluoroacetate [ No CAS ]

References: [1]Patent: WO2012/101065,2012,A2 .
[2]Patent: WO2012/101062,2012,A1 .

14
[ 842136-58-7 ]
trans-N₁-(5-chloro-4-iodopyridin-2-yl)cyclohexane-1,4-diamine trifluoroacetate [ No CAS ]
trans-N₁-(5'-chloro-6-fluoro-2,4'-bipyridin-2'-yl)cyclohexane-1,4-diamine trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; ethanol; at 90℃;	A mixture of frans-N1-(5-chloro-4-iodopyridin-2-yl)cyclohexane-1 ,4-diamine (from step 1 above, 300 mg, 0.853 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)pyridine (285 mg, 1.280 mmol), PdCI2(dppf).CH2CI2 adduct (84 mg, 0.102 mmol), DME (4 ml), Ethanol (1 ml), and 2M sodium carbonate (1.706 ml, 3.41 mmol) reaction mixture was stirred at about 90 C until done by LCMS. The reaction mixture was cooled, then diluted with 25 ml of ethyl acetate and 10 ml of methanol, filtered, and concentrated to yield a crude solid. The crude solid was dissolved in DMSO, filtered and purified by prep LC. After lyophilization, 200 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 321.0 (MH+), retention time = 0.48 min.
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; ethanol; at 90℃;	Step 2. Preparation of frans-N1-(5'-chloro-6-fluoro-2,4'-bipyridin-2'-yl)cyclohexane-1 ,4- diamineA mixture of frans-N1-(5-chloro-4-iodopyridin-2-yl)cyclohexane-1 ,4-diamine (from step 1 above, 300 mg, 0.853 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)pyridine (285 mg, 1.280 mmol), PdCI2(dppf).CH2CI2 adduct (84 mg, 0.102 mmol), DME (4 ml), Ethanol (1 ml), and 2M sodium carbonate (1.706 ml, 3.41 mmol) reaction mixture was stirred at about 90 C until done by LCMS. The reaction mixture was cooled, then diluted with 25 ml of ethyl acetate and 10 ml of methanol, filtered, and concentrated to yield a crude solid. The crude solid was dissolved in DMSO, filtered and purified by prep LC. After lyophilization, 200 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 321.0 (MH+), retention time = 0.48 min.

References: [1]Patent: WO2012/101065,2012,A2 .Location in patent: Page/Page column 145.
[2]Patent: WO2012/101062,2012,A1 .Location in patent: Page/Page column 103.

15
[ 842136-58-7 ]
trans-N₁-(4-bromopyridin-2-yl)cyclohexane-1,4-diamine trifluoroacetate [ No CAS ]
trans-N₁-(6-fluoro-2,4'-bipyridin-2'-yl)cyclohexane-1,4-diamine trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; ethanol; at 85℃;	A mixture of frans-N1-(4-bromopyridin-2-yl)cyclohexane-1 ,4-diamine (102 mg, 0.377 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (80 mg, 0.359 mmol), PdCI2(dppf).CH2CI2 adduct (29.3 mg, 0.036 mmol), DME (2 ml), Ethanol (0.2 ml), and 2M sodium carbonate (0.717 ml, 1.435 mmol) reaction mixture was stirred at about 85 C until completion, as indicated by LCMS. The crude mixture was cooled to room temperature, diluted with 5 ml of ethyl acetate and 2 ml of methanol, filtered and concentrated to yield a crude solid. The solid was dissolved in DMSO, refiltered, purified by prep LC, and lyophilized to yield 64 mg of the title compound as its TFA salt. LCMS (m/z): 287.2 (MH+), retention time = 0.43 min.
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; ethanol; at 85℃;	Step 2. Preparation of frans-N1-(6-fluoro-2,4'-bipyridin-2'-yl)cyclohexane-1 ,4-diamine A mixture of frans-N1-(4-bromopyridin-2-yl)cyclohexane-1 ,4-diamine (102 mg,0.377 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (80 mg, 0.359 mmol), PdCI2(dppf).CH2CI2 adduct (29.3 mg, 0.036 mmol), DME (2 ml), Ethanol (0.2 ml), and 2M sodium carbonate (0.717 ml, 1.435 mmol) reaction mixture was stirred at about 85 C until completion, as indicated by LCMS. The crude mixture was cooled to room temperature, diluted with 5 ml of ethyl acetate and 2 ml of methanol, filtered and concentrated to yield a crude solid. The solid was dissolved in DMSO, refiltered, purified by prep LC, and lyophilized to yield 64 mg of the title compound as its TFA salt. LCMS (m/z): 287.2 (MH+), retention time = 0.43 min.

References: [1]Patent: WO2012/101065,2012,A2 .Location in patent: Page/Page column 148.
[2]Patent: WO2012/101062,2012,A1 .Location in patent: Page/Page column 106.

16
[ 842136-58-7 ]
[ 1270077-79-6 ]

References: [1]Patent: WO2012/101064,2012,A1 .

17
[ 842136-58-7 ]
(R)-piperidine-3-carboxylic acid [5'-chloro-6-(cyclohexylmethylamino)-[2,4']bipyridinyl-2'-yl]amide trifluoroacetate [ No CAS ]

References: [1]Patent: WO2012/101063,2012,A1 .
[2]Patent: WO2012/101064,2012,A1 .

18
[ 842136-58-7 ]
[ 1269754-97-3 ]
[ 1270077-44-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 95℃; for 1.5h;	To a mixture of (R)-tert-butyl 3-(5-chloro-4-iodopyridin-2-ylcarbamoyl)piperidine-1- carboxylate (1.050 g, 2.255 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine (1.106 g, 4.96 mmol) and PdCI2(dppf) CH2CI2 adduct (0.184 g, 0.225 mmol) in DME (18 mL) was added 2M aqueous sodium carbonate solution (6.20 mL, 12.40 mmol). The reaction mixture was stirred at 95 C for 90 min. The mixture was cooled to room temperature and diluted with EtOAc (20 mL) and MeOH (15 mL), filtered and concentrated under reduced pressure. The crude material was purified by column chromatography [silica gel, 40 g, EtOAc/heptane = 10/90 to 40/60] providing (R)-tert- butyl 3-(5'-chloro-6-fluoro-2,4'-bipyridin-2'-ylcarbamoyl)piperidine-1-carboxylate (851 mg). LCMS (m/z): 435.1 [M+H]+; Rt = 0.99 min.
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 95℃; for 1.5h;	To a mixture of (R)-tert-butyl 3-(5-chloro-4-iodopyridin-2-ylcarbamoyl)piperidine-1 - carboxylate (1 .050 g, 2.255 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine (1 .106 g, 4.96 mmol) and PdCI2(dppf) CH2CI2 adduct (0.184 g, 0.225 mmol) in DME (18 mL) was added 2M aqueous sodium carbonate solution (6.20 ml_, 12.40 mmol). The reaction mixture was stirred at 95 C for 90 min. The mixture was cooled to room temperature and diluted with EtOAc (20 mL) and MeOH (15 mL), filtered and concentrated under reduced pressure. The crude material was purified by column chromatography [silica gel, 40 g, EtOAc/heptane = 10/90 to 40/60] providing (R)-tert-butyl 3-(5'-chloro-6-fluoro-2,4'- bipyridin-2'-ylcarbamoyl)piperidine-1-carboxylate (851 mg). LCMS (m/z): 435.1 [M+H]+; Rt = 0.99 min.

References: [1]Patent: WO2012/101063,2012,A1 .Location in patent: Page/Page column 144.
[2]Patent: WO2012/101064,2012,A1 .Location in patent: Page/Page column 186.

19
[ 842136-58-7 ]
trans-N₁-(5-chloro-4-iodopyridin-2-yl)cyclohexane-1,4-diamine trifluoroacetate [ No CAS ]
[ 76-05-1 ]
trans-N₁-(5'-chloro-6-fluoro-2,4'-bipyridin-2'-yl)cyclohexane-1,4-diamine trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 2. Preparation of frans-N1-(5'-chloro-6-fluoro-2,4'-bipyridin-2'-yl)cyclohexane-1 ,4- diamineA mixture of frans-N1-(5-chloro-4-iodopyridin-2-yl)cyclohexane-1 ,4-diamine (from step 1 above, 300 mg, 0.853 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)pyridine (285 mg, 1.280 mmol), PdCI2(dppf).CH2CI2 adduct (84 mg, 0.102 mmol), DME (4 ml), Ethanol (1 ml), and 2M sodium carbonate (1.706 ml, 3.41 mmol) reaction mixture was stirred at about 90 C until done by LCMS. The reaction mixture was cooled, then diluted with 25 ml of ethyl acetate and 10 ml of methanol, filtered, and concentrated to yield a crude solid. The crude solid was dissolved in DMSO, filtered and purified by prep LC. After lyophilization, 200 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 321.0 (MH+), retention time = 0.48 min.

References: [1]Patent: WO2012/101066,2012,A1 .Location in patent: Page/Page column 129.

20
[ 842136-58-7 ]
trans-N₁-(4-bromopyridin-2-yl)cyclohexane-1,4-diamine [ No CAS ]
[ 76-05-1 ]
trans-N₁-(6-fluoro-2,4'-bipyridin-2'-yl)cyclohexane-1,4-diamine trifluoroacetate [ No CAS ]

References: [1]Patent: WO2012/101066,2012,A1 .Location in patent: Page/Page column 132.

21
[ 842136-58-7 ]
N₂'-(trans-4-aminocyclohexyl)-5'-chloro-N₆-(3-fluorobenzyl)-2,4'-bipyridine-2',6-diamine [ No CAS ]