845305-83-1|4-[(Piperidin-4-yl)oxy]piperidine-1-carboxylic acid tert-butyl ester| Ambeed

Structure of 845305-83-1

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Quality Control of [ 845305-83-1 ] Purity: 98% SDS Specification

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Product Details of [ 845305-83-1 ]

CAS No. :	845305-83-1
Formula :	C₁₅H₂₈N₂O₃
M.W :	284.39
SMILES Code :	O=C(N1CCC(OC2CCNCC2)CC1)OC(C)(C)C
MDL No. :	MFCD09261176
InChI Key :	UTDIXFSPTJESFX-UHFFFAOYSA-N
Pubchem ID :	53407862

Safety of [ 845305-83-1 ]

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

Application In Synthesis of [ 845305-83-1 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 845305-83-1 ]

[ 845305-83-1 ] Synthesis Path-Downstream 1~35

1
[ 308386-35-8 ]
[ 845305-83-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	With platinum(IV) oxide; palladium on activated carbon; hydrogen; acetic acid; at 55℃; for 16h;	To a stirred solution of tert-butyl 4-(pyridin-4-yloxy)piperidine-1-carboxylate (6.00 g, 21.6 mmol,) in AcOH (150.00 mL) were added anhydrous PtO2(900.00 mg, 3.963 mmol) and Pd/C (600.00 mg, 0.564 mmol, 10 wt%) at room temperature under nitrogen atmosphere. The mixture was hydrogenated at 55 C for 16 h under hydrogen atmosphere using a hydrogen balloon at room temperature. The mixture was then filtered through a Celite pad and the filter cake was washed with CH2Cl2 (3 × 50 mL). The filtrates were evaporated under reduced pressure, and H2O was added to the residue. Then, NH3H2O (20 wt%) was added dropwise to adjust the pH to 10, and the mixture was extracted CH2Cl2(3 × 100 mL).The collected organic layers were dried, filtered, and concentrated to afford tert-butyl 4-(piperidin-4-yloxy)piperidine-1-carboxylate (6 g, 98%) as a colorless oil;1H NMR (400 MHz, Chloroform-d) d 3.96-3.67 (m, 3H), 3.62-3.56 (m, 1H), 3.51-3.45 (m, 1H), 3.15-2.97 (m, 4H), 2.65-2.58 (m, 2H), 1.95-1.70 (m, 6H), 1.54-1.38 (m, 11H); LC/MS (ESI, m/z): [(M + 1)]+ = 285.2.
60%		Pyridyl ether IA (1 g, 3.6 mmol) was dissolved in 20 mL of absolute ethanol. The solution was degassed under vacuum, and placed under nitrogen atmosphere. Platinum oxide (0.25 g, 0.25 weight equiv.) was added and the resulting mixture was degassed again, then <n="45"/>placed under nitrogen atmosphere. Concentrated sulfuric acid (0.19 mL, 3.6 mmol) was added, the reaction was degassed a third time, and then put under H2 atmosphere using a gas-filled balloon. The reaction was allowed to stir at room temperature for about 14 hours and was then poured into 50 mL of an ice cold 1.0 M NaOH aqueous solution. The resulting solution was rinsed with a small volume OfCH2Cl2, and filtered through a Celite pad. The organic solvent was removed in vacuo and the remaining aqueous solution was extracted with CH2Cl2 (50 mL x 3). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo to provide an oily residue, which was purified using flash column chromatography, eluting with CH2Cl2-MeOH (10:1, 5:1, and 1 :1, v/v) to provide 0.61g of bis- N-heterocylic alkyl ether IB (60%, MH+ = 285.21 ).
	With hydrogen; acetic acid;5% rhodium on alumina; under 2585.81 Torr;	EXAMPLE 11 Preparation of 4-(Piperidin-4-yloxy)piperidine-1-carboxylic acid tert-butyl ester (41). To 1.0 g (3.6 mmol) of 4-(pyridin-4-yloxy)piperidine-1-carboxylic acid tert-butyl ester (40) dissolved in 4.0 mL of HOAc was added 0.2 g of 5% Rh/Al2O3. The reaction mixture was put under 50 psi of H2 gas overnight, filtered through Celite and the solvent was removed by rotary evaporation to yield 41 as a colorless oil.

0.5 g	With palladium 10% on activated carbon; hydrogen; acetic acid; In ethanol; at 80℃; under 30003.0 Torr; for 16h;	To a 500 ml round bottom flask, purged and maintained under inert atmosphere, were added tert- butyl 4-(pyridin-4-yloxy)piperidine-1 -carboxylate (2 g, 7.2 mmol), EtOH (100 ml), AcOH (5 ml) and Pd/C (10%) (0.4 g). The RM was stirred at 80C for 16 h under an atmosphere of hydrogen (4 MPa). The mixture was filtered through Celite, the filtrate was concentrated and purified by chromatography on silica gel eluting with MeOH in DCM (1 :10) yielding the title compound as an oil (0.5 g).Method D: Rt = 1 .32 min; MS m/z [M+H]+285.3.
0.5 g	With palladium on activated charcoal; hydrogen; acetic acid; In ethanol; at 80℃; under 30003.0 Torr; for 16h;	In a 500 ml round bottom flask, purged and maintained under inert atmosphere were mixed tert- butyl 4-(pyridin-4-yloxy)piperidine-1 -carboxylate (2 g, 7.2 mmol), EtOH (100 ml), AcOH (5 ml) and palladium on carbon (0.4 g). The RM was stirred at 80C for 16 h under under H2 atmosphere (4 MPa). The mixture was filtered through Hyflo, and the filtrate was concentrated under reduced pressure. Purification of the crude mixture by chromatography on silica gel eluting with 10% MeOH in DCM afforded 0.5 g of the title compound as a colorless oil.LC-MS (method H): Rt = 1 .32 min, [M+H]+ = 285.3.
31 g	With palladium 10% on activated carbon; hydrogen; acetic acid; In ethanol; at 80℃; under 45004.5 Torr; for 24h;	To a 500 ml high pressure reactor were added tert-butyl 4-(pyridin-4- yloxy)piperidine-1-carboxylate (32 g, 115 mmol), Pd/C (10 %, 9.6 g), EtOH (300 ml) and HOAc (30 ml). The mixture was stirred under H2 atmosphere (60 bar) at 80 C for 24 h. The mixture was cooled to RT and filtered. The filtrate was diluted with DCM (1 L) and the organic phase was washed with an aq. solution of NaOH (2 M, 2 x 200 mL), water (200 mL), brine (2 x 100 ml) and dried over Na2SO4, yielding the title compound as a solid (31 g). Method B: Rt = 1.96 min; [M+H]+= 285.

References: [1]Patent: WO2020/113233,2020,A1 .Location in patent: Paragraph 005203; 005206-005207.
[2]Tetrahedron Letters,2007,vol. 48,p. 791 - 794.
[3]Patent: WO2009/45313,2009,A2 .Location in patent: Page/Page column 43-44.
[4]Patent: US2007/32475,2007,A1 .Location in patent: Page/Page column 37.
[5]Patent: WO2019/186343,2019,A1 .Location in patent: Page/Page column 81.
[6]Patent: WO2019/186358,2019,A1 .Location in patent: Page/Page column 83.
[7]Patent: WO2021/77010,2021,A1 .
[8]Patent: WO2021/55295,2021,A1 .Location in patent: Page/Page column 187; 188.

2
[ 626-64-2 ]
[ 845305-83-1 ]

References: [1]Tetrahedron Letters,2007,vol. 48,p. 791 - 794.
[2]Patent: WO2019/186343,2019,A1 .
[3]Patent: WO2019/186358,2019,A1 .
[4]Patent: WO2020/113233,2020,A1 .
[5]Patent: WO2021/77010,2021,A1 .
[6]Patent: WO2021/55295,2021,A1 .

3
[ 109384-19-2 ]
[ 845305-83-1 ]

4
[ 845305-83-1 ]
[ 49608-01-7 ]
[ 845305-95-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; at 60℃;	Step 1: Ethyl 6-{4-[(1-[(1, 1-DIMETHYLETHYL) oxy] CARBONYL}-4-PIPERIDINYL) OXY]-1- PIPERIDINYL}-3-PYRIDINECARBOXYLATE tert-Butyl 4- (4-piperidinyloxy)-1-piperidinecarboxylate (D4) (1. 7G), potassium carbonate (1.5g) and ethyl 6-chloro-3-pyridinecarboxylate (1.0 G) were heated at 60C under argon overnight. The reaction mixture was evaporated and redissolved in DCM (100 ML) and washed with saturated sodium hydrogen carbonate (3 x 50ml), dried (MgSO4) and evaporated to give a crude product which was chromatographed [silica gel, eluting with (10% NH3 in MeOH/DCM, 0-10%] to give the subtitle compound (1.43 g).

References: [1]Patent: WO2005/14571,2005,A1 .Location in patent: Page/Page column 24.

5
[ 845305-83-1 ]
[ 33252-28-7 ]
[ 845306-22-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dimethyl sulfoxide; at 60℃; for 4h;	Example 2 6- {4- [ (1-CYCLOBUTYL-4-PIPERIDINYL) OXY]-1-PIPERIDINYL}-3-PYRIDINECARBONITRILE hydrochloride (E2) Step 1: tert-Butyl 4- ( [L- (5-CYANO-2-PYRIDINYL)-4-PIPERIDINYL] OXY)-L- piperidinecarboxylate tert-Butyl 4- (4-piperidinyloxy)-1-piperidinecarboxylate (D4) (0.118g) was reacted with 2- chloro-5-cyano-pyridine (0.0573g) in DMSO (5ML) containing potassium carbonate (0.069g) for 4h at 60C. The reaction was then evaporated to a minimum volume and the residue redissolved in DCM (20MOL) and washed with saturated sodium hydrogen carbonate solution. Evaporation of the dried (MgSO4) organic layer provided the subtitle compound as an oil which crystallised on standing (0.191g).

References: [1]Patent: WO2005/14571,2005,A1 .Location in patent: Page/Page column 32-33.

6
[ 845305-83-1 ]
[ 1191-95-3 ]
[ 845305-84-2 ]

Yield	Reaction Conditions	Operation in experiment
		Description 5 tert-Butyl 4- [ (L-CYCLOBUTYL-4-PIPERLDINYL) OXY]-L-PIPERIDINECARBOXYLATE (D5) To tert-butyl 4- (4-PIPERIDINYLOXY) PIPERIDINECARBOXYLATE (D4) (7. 0g) and triethylamine (6. 9ML) in DCM (300ml) was added cyclobutyl ketone and after 5min sodium TRIACETOXYBOROHYDRIDE (10.46g) was added. After 16h the reaction was washed with a solution of saturated potassium carbonate (2x200ml) and brine (200ML). The organic layer was dried (MgSO4) and evaporated to give the title compound (D5) as a white solid (8. 11g).

References: [1]Patent: WO2005/14571,2005,A1 .Location in patent: Page/Page column 20.

7
[ 845305-83-1 ]
[ 1194-02-1 ]
[ 845306-84-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 5h;	Example 3 4- {4- [ (1-CYCLOBUTYL-4-PIPERIDINYL) OXY]-1-PIPERIDINYL} BENZONITRILE HYDROCHLORIDE (E3) Step 1: 4- 4- [ (1-TERT-BUTOXYCARBONYL-4-PIPERIDINYL) OXY]-1-PIPERIDINYL} BENZONITRILE tert-Butyl 4- (4-PIPERIDINYLOXY)-1-PIPERIDINECARBOXYLATE (D4) (0.340g) was reacted with 4- fluorobenzonitrile (0.218g) in DMSO (10ml) containing potassium carbonate (0.331g) for 5h at 120C. The reaction was then evaporated to a minimum volume and the residue redissolved in EtOAc (50ml) and washed with saturated sodium hydrogen carbonate (3No.30ML) and saturated brine (30MOI). Evaporation of the dried (MGS04) organic layer provided the subtitle compound as a pale yellow solid (0.422g).

References: [1]Patent: WO2005/14571,2005,A1 .Location in patent: Page/Page column 33.

8
[ 845305-83-1 ]
[ 66194-68-1 ]
[ 845306-11-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In DMF (N,N-dimethyl-formamide); acetonitrile; at 95℃;	Description 43 1- [ (1S)-1-METHYLPROPYL]-4- (4-PIPERIDINYLOXY) PIPERIDINE (D43) Step 1: tert-Butyl 4- ( {1- [ (1S)-1-METHYLPROPYL]-4-PIPERIDINYL} oxy) -1- piperidinecarboxylate tert-Butyl 4- (4-PIPERIDINYLOXY)-1-PIPERIDINECARBOXYLATE (D4) (3. 1G), (1R)-1-METHYLPROPYL methanesulfonate (Burns et al., J Am. Chem. Soc. , 1997,119, 2125) (2. 0G), and potassium carbonate (1.8g) were dissolved in ACETONITRILE (20ml)/DMF (15ml) and heated at 95C overnight. The reaction mixture was then filtered through a plug of potassium carbonate. The filtrate was evaporated, redissolved in ethyl acetate (100ML) and washed with saturated potassium carbonate solution (3 x 70MOI), dried (MGS04), and then purified by chromatography [silica gel, eluting with (10% NH3 in MeOH/DCM, 0-10%] to give the subtitle compound (1.73 g).

References: [1]Patent: WO2005/14571,2005,A1 .Location in patent: Page/Page column 28.

9
[ 845305-82-0 ]
[ 845305-83-1 ]

Yield	Reaction Conditions	Operation in experiment
		Description 4 tert-Butyl 4- (4-PIPERIDINYLOXY)-1-PIPERIDINECARBOXYLATE (D4) Method A To 1-BENZYL-4- [ (1-TERT-BUTOXYCARBONYL-4-PIPERIDINYL) oxy] pyridinium bromide (D3) (15g) in MeOH (500ML) was slowly added LITHIUM BOROHYDRIDE (100ML, 2M SOLUTION IN THF) under a stream of argon whilst the temperature was kept below 30C. After 2h formic acid was added (30ML) UNTIL pH-4. Ammonium formate (50g) in MeOH (100ML) was added as a slurry followed by palladium on carbon (2g, 10% Pd/C). After 2 days the reaction was filtered and evaporated, redissolved in EtOAc (400ML) and washed with saturated sodium hydrogen carbonate solution and brine. The organic layer was dried (MGS04), evaporated, and redissolved in MeOH (200ml). Acetic acid (20MOI) was added followed by Pd on carbon (2g, 10% Pd/C), and the reaction hydrogenated at rt for 16h followed by 80C for 2h. The reaction mixture was filtered, evaporated, REDISSOLVED in EtOAc (300ML) and washed with saturated sodium hydrogen carbonate solution, followed by brine, before being dried (MGS04) and evaporated to give the title compound (D4) as an oil (1. 75G).
		Method B 1-BENZYL-4- [ (1-TERT-BUTOXYCARBONYL-4-PIPERIDINYL) oxy] pyridinium bromide (D3) (60g) was stirred in methanol (500MOI) under argon and sodium borohydride (pellets, 20.2g) was added portionwise over 40min. The reaction was stirred for a further 45min and then acetone (65MOI) was added and the reaction stirred for 1 h 20min. The resulting solution was then treated using either Step 1 or Step 2 below. Step 2: An aliquot of the above solution (20MI ; approx 2. 1G enol ether) was treated with decolourising charcoal powder (2g) for 2h. The mixture was filtered and evaporated. The residue was REDISSOLVED in ethyl acetate (30ml) and washed with saturated sodium hydrogen carbonate solution (3 x 20ml) and brine (20ML). The organic layer was dried (MGSO4) and evaporated to give a white solid (1.5g). The solid was dissolved in methanol (25ml) and ammonium formate (2. 54G) was added followed by 10% Pd/C (paste, 0. 7g). The reaction was heated to 55C (bath temperature) (when internal temperature achieved 30C effervescence was observed), maintained at 55C for 1 h and then at 60C for 30MIN. The reaction was filtered and concentrated. The residue was re- dissolved in ethyl acetate (50ML) and washed with saturated potassium carbonate solution (3 x 30MUT), dried (MGSO4) and evaporated to give an oil which crystallised on standing to give the title compound (D4) as a white solid (0.83g). MS electrospray (+ve ion) 285 (MH+). 'H NMR 8 (CDCI3) : 3.79 (2H, m), 3.65-3. 38 (2H, m), 3.06 (4H, m), 2.60 (2H, m), 1.91-1. 67 (4H, m), 1.59-1. 31 (13H, m).
		Method B 1-BENZYL-4- [ (1-TERT-BUTOXYCARBONYL-4-PIPERIDINYL) oxy] pyridinium bromide (D3) (60g) was stirred in methanol (500MOI) under argon and sodium borohydride (pellets, 20.2g) was added portionwise over 40min. The reaction was stirred for a further 45min and then acetone (65MOI) was added and the reaction stirred for 1 h 20min. The resulting solution was then treated using either Step 1 or Step 2 below. Step 1: 10% Pd/C (paste, 20g) was added to the solution above and the mixture was hydrogenated at atmospheric pressure for 2h. The reaction was then filtered, evaporated, redissolved in ethyl acetate (500ML) and washed with saturated sodium hydrogen carbonate solution (3 x 300ML) and brine (300ML). The organic layer was dried (MgSO4) and evaporated to give a yellow oil (41G). The oil was dissolved in methanol (700ML) and ammonium formate (69. 4G) was added followed by 10% Pd/C (paste, 20g). The reaction was heated to 55C (bath temperature) (when internal temperature achieved 30C effervescence was observed), maintained at 55C for 1 h and then at 60C for 30min. The reaction was filtered and concentrated. The residue was re- dissolved in ethyl acetate (700MUT) and washed with saturated potassium carbonate solution (3 x 300MOI), dried (MGS04) and evaporated to give an oil which crystallised on standing to give the title compound (D4) as a white solid (26. 0G). MS ELECTROSPRAY (+ve ion) 285 (MH+).'H NMR 8 (CDCI3) : 3.79 (2H, m), 3.65-3. 38 (2H, m), 3.06 (4H, m), 2.60 (2H, m), 1.91-1. 67 (4H, m), 1.59-1. 31 (13H, m).

References: [1]Patent: WO2005/14571,2005,A1 .Location in patent: Page/Page column 18-19.
[2]Patent: WO2005/14571,2005,A1 .Location in patent: Page/Page column 19.
[3]Patent: WO2005/14571,2005,A1 .Location in patent: Page/Page column 19.
[4]Patent: WO2021/77010,2021,A1 .

10
[ 845305-83-1 ]
[ 194151-99-0 ]
[ 1138448-11-9 ]

Yield	Reaction Conditions	Operation in experiment
15%		5,6,7,8-Tetrahydroquinolin-5-ol (110 mg, 0.743 mmol) was dissolved in 6 mL of CH2Cl2 and the resulting solution was cooled to 0 0C. Triethylamine (0.26 mL, 1.87 mmol) <n="49"/>was then added followed by methanesulfonyl chloride (72 uL, 0.926 mmol) and the reaction was allowed to stir for about 2 hours at 0 0C, then stirred at room temperature for an additional 2 hours. The reaction mixture was then added dropwise to a stirred mixture of compound IB (200 mg, 0.703 mmol, available from Example 1 Step B) and triethylamine (0.3 mL, 2.15 mmol) in 5 mL OfCH2Cl2. The reaction was heated to reflux and allowed to stir at this temperature for about 15 hours. The reaction mixture was then cooled to RT, diluted with CH2Cl2 and the organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo to provide a crude yellow oil. The crude oil was purified using preparative TLC (CH2Cl2 - MeOH = 25 :1, v/v) to provide 46 mg of compound 7A (15%) as a near colorless oil.

References: [1]Patent: WO2009/45313,2009,A2 .Location in patent: Page/Page column 47-48.

11
[ 845305-83-1 ]
[ 62802-42-0 ]
[ 1138448-13-1 ]

Yield	Reaction Conditions	Operation in experiment
19.5%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; toluene; at 90℃; for 48h;	To a stirred solution of compound IB (270 mg, 0.95 mmol) in 2 mL Of CH2Cl2 and 3 mL of toluene was added 2-chloro-5-fluoro-pyrimidine (0.1 g, 0.755 mmol), followed by diisopropylethylamine (0.2 mL, 1.148 mmol). The reaction was heated to 90 C and allowed to stir at this temperature for about 48 hours. The reaction was then cooled to RT and concentrated in vacuo to provide an oily residue which was purified using preparative TLC (CH2Cl2-MeOH = 50:1, v/v) to provide 56 mg of compound 8A (19.5%, MH+ = 381.2) as a near colorless oil which solidified on standing.

References: [1]Patent: WO2009/45313,2009,A2 .Location in patent: Page/Page column 48.

12
[ 845305-83-1 ]
[ 97112-03-3 ]
[ 1138448-24-4 ]

Yield	Reaction Conditions	Operation in experiment
30%		To a stirred first solution of 5,6,7,8-tetrahydroisoquinolin-5-ol (165 mg, 1.106 mmol) in 5 mL OfCH2Cl2 was added triethylamine (0.25 mL, 1.794 mmol) and methanesulfonyl chloride (0.14 mL, 1.182 mmol). The reaction was allowed to stir at room temperature for 45 minutes. In a separate flask, sodium hydride (45 mg, 1.125 mmol, 60% in mineral oil) was added to a solution of compound IB (292 mg, 1.026 mmol) in 5 mL of DMF. This second solution was stirred for 30 minutes, then added to the first solution and the resulting reaction was allowed to stir for about 36 hours. Water was then added to the reaction mixture and the resulting aqueous mixture was extracted with CH2Cl2 (50 mL x 3). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo to provide an oily residue which was purified using preparative TLC (CH2Cl2 - 7N NH3 in MeOH = 30:1 v/v) to provide 128 mg of compound 36A (30%, MH+ = 416.2).

References: [1]Patent: WO2009/45313,2009,A2 .Location in patent: Page/Page column 57.

13
[ 845305-83-1 ]
[ 39901-94-5 ]
[ 1138447-98-9 ]

Yield	Reaction Conditions	Operation in experiment
68%	With triethylamine; In dichloromethane; at 20℃; for 60h;	To a stirred solution of compound IB (180 mg, 0.633 mmol) in 7 mL OfCH2Cl2 was added triethylamine (0.31 mL, 2.22 mmol), followed by picolinoyl chloride hydrochloride (141 mg, 0.792 mmol). The reaction was allowed to stir at RT for about 60 hours, then was diluted with CH2Cl2 (6OmL), washed sequentially with saturated aqueous NaHCO3 solution, then brine, dried over Na2SO4, and concentrated in vacuo. The oily residue obtained was purified using preparative TLC (CH2C12-7N NH3 in MeOH = 30 :1, v/v) to provide 167 mg of the amide1C (68%, MH+ = 390.2).

References: [1]Patent: WO2009/45313,2009,A2 .Location in patent: Page/Page column 44.

14
[ 845305-83-1 ]
[ 39718-32-6 ]
[ 1138448-35-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 20℃; for 18h;	Compound IB (200 mg, 0.704 mmol) was dissolved in 10 mL Of CH2Cl2. Triethylamine (213 mg, 2.112 mmol) was added followed by 2,5-difluorophenylisocyanate (328 mg, 2.112 mmol) and the resulting reaction was stirred at room temperature for 18 hours. The reaction mixture was then diluted with CH2Cl2, washed with a IN NaOH aqueous solution, and the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue obtained was purified using flash column chromatography (EtOAc/Hexanes, 1 :2) to provide compound 5A as a yellow oil.

References: [1]Patent: WO2009/45313,2009,A2 .Location in patent: Page/Page column 46.

15
[ 845305-83-1 ]
[ 494769-34-5 ]
[ 1138448-17-5 ]

Yield	Reaction Conditions	Operation in experiment
55%	With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 15h;	To a stirred solution of compound IB (284 mg, 1.0 mmol), in 6 mL Of CH2Cl2 at room temperature was added N-boc-2-aminothiazole-4-carboxaldehyde (296 mg, 1.297 mmol). The mixture was then treated with sodium triacetoxyborohydride (275 mg, 1.298 mmol) and a catalytic amount of acetic acid. The reaction was allowed to stir for about 15 hours, then H2O was added and the aqueous mixture was extracted with CH2Cl2. The organic extract was washed with brine, dried over Na2SO4, and concentrated in vacuo to provide a crude yellow solid. The crude solid was purified using preparative TLC (CH2Cl2 - 7N NH3 in MeOH =30:1, v/v) to provide 271 mg of compound 24A (55%, MH+ = 497.22) as a light yellow solid.

References: [1]Patent: WO2009/45313,2009,A2 .Location in patent: Page/Page column 51-52.

16
[ 845305-83-1 ]
[ 58551-83-0 ]
[ 1138448-37-9 ]

Yield	Reaction Conditions	Operation in experiment
		Compound IB (200 mg, 0.704 mmol) was dissolved in 10 mL Of CH2Cl2. 2,4,6- trifluorobenzaldehyde (225 mg, 1.408 mmol) and acetic acid (0.1 mL) were then added and the reaction was allowed to stir for 10 minutes. Na(OAc)3BH (313 mg, 1.408 mmol) was then added and the resulting mixture was allowed to stir at room temperature for 18 hours, then diluted with CH2Cl2, washed with a IN NaOH aqueous solution and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified using flash column chromatography on silica gel (MeOH-CH2Cl2, 1 : 10) to provide compound 6A as a yellow oil.

References: [1]Patent: WO2009/45313,2009,A2 .Location in patent: Page/Page column 47.

17
[ 845305-83-1 ]
[ 41404-58-4 ]
[ 1138448-39-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium t-butanolate;palladium diacetate; johnphos; In toluene; at 100℃; for 4h;	To a solution of 2-bromo-5-fluoropyridine (259 mg, 2.84 mmol) and compound IB(350 mg, 1.23 mmol) in toluene (15 mL) was added anhydrous NaO1Bu (165 mg, 1.72 mmol), Pd(OAc)2 (28 mg, 0.123 mmol) and 2-(di-t-butylphosphino)biphenyl (33 mg, 0.111 mmol). The reaction was heated to 1000C and allowed to stir at this temperature for 4 hours under N2 atmosphere. The reaction mixture was then cooled to room temperature, filtered through a pad of Celite and concentrated in vacuo. The residue obtained was purified using flash column chromatography (EtOAc/Hexanes, 1 :9, then 1 :4) to provide compound 9A as a yellow oil.

References: [1]Patent: WO2009/45313,2009,A2 .Location in patent: Page/Page column 49.

18
[ 1172626-94-6 ]
[ 845305-83-1 ]

References: [1]Synlett,2009,p. 1051 - 1054.

19
tert-butyl 4-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)oxy)piperidine-1-carboxylate [ No CAS ]
[ 845305-83-1 ]

Yield	Reaction Conditions	Operation in experiment
89.5%	With palladium 10% on activated carbon; hydrogen; In isopropyl alcohol; at 35℃;	To a solution of tert-butyl 4-[(1-benzyl-3,6-dihydro-2H-pyridin-4-yl)oxy]piperidine- 1-carboxylate (12.0 g, 32.2 mmol, 1.0 equiv) in isopropyl alcohol (300 mL) was added Pd/C (10%, 1.0 g) under nitrogen atmosphere in a 500 mL round bottom flask. The flask was then vacuumed and flushed with hydrogen. The reaction mixture was hydrogenated at 35 C in an oil bath overnight under hydrogen atmosphere using a hydrogen balloon, then filtered through a Celite pad and the filtrate was concentrated under reduced pressure. This resulted in 8.2 g (89.50%) of tert-butyl 4-(piperidin-4-yloxy)piperidine-1-carboxylate as a white solid.

References: [1]Patent: WO2021/77010,2021,A1 .Location in patent: Paragraph 00512; 00513.
[2]Synlett,2009,p. 1051 - 1054.

20
[ 845305-83-1 ]
[ 893420-19-4 ]
tert-butyl 4-((1-(3-chloro-4-(dimethylcarbamoyl)phenyl)piperidin-4-yl)oxy)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
790 mg	With palladium diacetate; sodium t-butanolate; DavePhos; In toluene; at 100℃;Inert atmosphere;	Step 1 : tert-butyl 4-((l-(3-chloro-4-(dimethylcarbamoyl)phenyl)piperidin-4-yl)oxy)piperidine-l- carboxylate A mixture of tert-butyl 4-(piperi din-4-yloxy)piperi dine- 1-carboxy late ( 611.2mg, 2.15 mmol), 4- bromo-2-chloro-N,N-dimethylbenzamide (564 mg, 2.15 mmol), 2-dicyclohexylphosphino-2'- (N,N-dimethylamino)biphenyl (127 mg, 0.32 mmol), palladium (II) acetate ( 24.1 mg, 0.11 mmol), and sodium tert-butoxide (310mg, 3.22 mmol) in Toluene (10.7 ml) was degassed by bubbling with N2 and heated at 100C overnight. The reaction mixture was cooled to room temperature, filtered and then concentrated to dryness. The residue was purified by ISCO column chromatography (ISCO 80g prepacked , eluting with 0-100% EtOAc/Hexane) to give the title compound (790 mg). LCMS m/z (M+H): Calc'd 466.2, found 466.4.

References: [1]Patent: WO2017/95758,2017,A1 .Location in patent: Page/Page column 167-168.

21
[ 845305-83-1 ]
2-chloro-N,N-dimethyl-4-(4-(piperidin-4-yloxy)piperidin-1-yl)benzamide [ No CAS ]

References: [1]Patent: WO2017/95758,2017,A1 .

22
[ 845305-83-1 ]
4-nitrophenyl 4-((1-(3-chloro-4-(dimethylcarbamoyl)phenyl)piperidin-4-yl)oxy)piperidine-1-carboxylate [ No CAS ]

References: [1]Patent: WO2017/95758,2017,A1 .

23
[ 845305-83-1 ]
2-chloro-4-(4-((1-(3-hydroxy-3-(trifluoromethyl)azetidine-1-carbonyl)piperidin-4-yl)oxy)piperidin-1-yl)-N_.N-dimethylbenzamide [ No CAS ]

References: [1]Patent: WO2017/95758,2017,A1 .

24
[ 845305-83-1 ]
3-(2,4-dioxotetrahydropyrimidin-1 (2H)-yl)-4-methoxybenzoic acid [ No CAS ]
tert-butyl 4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)oxy)piperidin-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.43 g	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2.5h;	3-(2,4-Dioxotetrahydropyrimidin-1 (2H)-yl)-4-methoxybenzoic acid (intermediate 5, 1 .20 g, 4.54 mmol) was dissolved in DMF (15 ml), tert-butyl 4-(piperidin-4-yloxy)piperidine-1 -carboxylate (intermediate 10, 1 .292 g, 4.54 mmol) and DIPEA (1 .586 ml, 9.08 mmol) were added, followed by HBTU (2.067 g, 5.45 mmol) and the RM was stirred at RT for 2.5 h. The RM was poured into ice-water and the mixture was extracted with DCM. The combined organic phases were dried over MgS04, evaporated and the residue was purified by chromatography on silica gel eluting with MeOH in DCM (from 0 to 20%) to afford an oil. The oil was dissolved in EtOAc, the solution was washed with a mixture of water and brine (1 :1), brine, dried over MgS04, and concentrated to afford the title compound as a solid (2.43 g).Method A: Rt = 0.93 min; [M+H]+= 531 .4.
686 mg	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;	To a 50 ml round bottom flask were added HATU (691 mg, 1.817 mmol), 3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid (intermediate 25, 400 mg, 1.514 mmol), DIPEA (0.800 ml, 4.58 mmol) and DMF (10 ml). The RM was stirred at RT for 30 min, <strong>[845305-83-1]tert-butyl 4-(piperidin-4-yloxy)piperidine-1-carboxylate</strong> (intermediate 1, 431 mg, 1.514 mmol) was added and the RM was stirred at RT overnight. The mixture was directly purified by reversed phase chromatography on a REDISEP Gold HP C18 column (50 g) eluting with ACN (from 0 % to 100 %) in an aq. solution of NH4HCO3 (0.1 %), yielding the title compound as asolid (686 mg). Method D: Rt = 0.92 min; [M+H]+= 531.

References: [1]Patent: WO2019/186343,2019,A1 .Location in patent: Page/Page column 146; 147.
[2]Patent: WO2021/55295,2021,A1 .Location in patent: Page/Page column 223.

25
[ 845305-83-1 ]
N-(3-(6-(4-(2-(4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)oxy)piperidin-1-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide [ No CAS ]