[ CAS No. 75844-69-8 ] {[proInfo.proName]}

Name: 75844-69-8|tert-Butyl piperidine-1-carboxylate|98%
Brand: Ambeed
SKU: A199786
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Quality Control of [ 75844-69-8 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 75844-69-8 ]

CAS No. :	75844-69-8	MDL No. :	MFCD02093935
Formula :	C₁₀H₁₉NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	RQCNHUCCQJMSRG-UHFFFAOYSA-N
M.W :	185.26	Pubchem ID :	7010304
Synonyms :

Calculated chemistry of [ 75844-69-8 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.9
Num. rotatable bonds :	3
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	56.59
TPSA :	29.54 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.04 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.82
Log Po/w (XLOGP3) :	1.96
Log Po/w (WLOGP) :	2.03
Log Po/w (MLOGP) :	1.71
Log Po/w (SILICOS-IT) :	1.44
Consensus Log Po/w :	1.99

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.03
Solubility :	1.75 mg/ml ; 0.00943 mol/l
Class :	Soluble
Log S (Ali) :	-2.21
Solubility :	1.15 mg/ml ; 0.00623 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.5
Solubility :	5.79 mg/ml ; 0.0313 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.93

Safety of [ 75844-69-8 ]

Signal Word:	Danger	Class:	6.1
Precautionary Statements:	P261-P273-P301+P310-P305+P351+P338	UN#:	2810
Hazard Statements:	H227-H301-H315-H319-H335-H410	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 75844-69-8 ]

* 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 [ 75844-69-8 ]

[ 75844-69-8 ] Synthesis Path-Downstream 1~40

1
[ 110-89-4 ]
[ 24424-99-5 ]
[ 75844-69-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	With guanidine hydrochloride; In ethanol; at 35 - 40℃; for 0.0166667h;	General procedure: Amine (1 mmol) was added to a magnetically stirred solution of guanidine hydrochloride (15 mol%) and di-tert-butyl dicarbonate (1.2 mmol) in EtOH (1 mL), at 35-40C and stirred for appropriate time (Table 1). After completion of the reaction (followed by TLC or GC), EtOH was evaporated under vacuum and the residue either was washed with water to remove the catalyst or was dissolved in CH2Cl2 (or EtOAc) and filtered off to separate out the catalyst. Evaporation of the organic solvent (if used in work up) gives almost a pure product. In the cases of using an excess (Boc)2O the product was washed with petroleum ether or hexane to recover the residual (Boc)2O. If necessary, the product was further purified either by crystallization (hexane and dichloromethane, or diethyl ether and petroleum ether) or silica gel column chromatography using EtOAc-hexane (1: 6) as eluent.
100%	at 20℃; for 0.0833333h;Ionic liquid;	To the ionic liquid [TPA][Pro] (1 mL) was added amine (1-14; Table-1) (1 mmol) and di-tert-butyl dicarbonate (1.2 mmol). The reaction was stirred at room temperature for an appropriate time (Table-1). After completion of the reaction as monitored by TLC, water was added to the reaction mixture and the product was extracted into ethyl acetate (3 × 20 mL). The combined organic layer was washed with brine solution and concentrated under reduced pressure to give crude product, which was purified over silica gel column to afford corresponding N-tert-butylcarbamate. The ionic liquid [TPA][Pro] in aqueous solution was recovered by removing water under reduced pressure and dried. The recovered ionic liquid was reused for five times without loss of its activity. Finally, all the compounds confirmed by their m.p.?s, IR, 1H NMR, 13C NMR, mass spectral data and elemental analysis wherever needed.
96%	With iron(III) trifluoromethanesulfonate; In neat (no solvent); at 20℃; for 0.0833333h;Green chemistry;	General procedure: Fe(OTf)3 (1 mol%) was added to a magnetically stirred mixture of anamine (1 mmol) and Boc2O (1 mmol) at room temperature. The mixturewas stirred until completion of the reaction (TLC), then diluted withEtOAc and washed with water. The organic layer was dried overanhydrous MgSO4, then the solvent was distillated off under vacuum toyield the highly pure N-Boc derivatives

80%	With magnesium bromide ethyl etherate; at 20℃; for 16h;	General procedure: Boc2O (1.0 mmol) was added to a mixture of phenol or amine (1.0 mmol) andMgBr2 · OEt2 (0.1 mmol) in a round-bottom flask, at which point an evolution of gas occurs, and the reaction mixture was stirred magnetically at room temperature (ifnecessary, reactions was heated to?60 C). After complete consumption of the phenolor amine (by thin-layer chromatography, TLC; 3-16 h), the reaction mixture wasdiluted with water and extracted with EtOAc (3 × 20mL), and the combined EtOAcextracts were dried with Na2SO4 and concentrated under vacuum rotary evaporation.The residue was isolated by column chromatography through a bed of silicagel and eluted with 5-30% ethyl acetate in hexane to afford the desired Bocprotectedproduct.
36.1 g (97%)	With sodium hydrogencarbonate; In tetrahydrofuran;	N-Boc-Piperidine A solution of di-tert-butyl dicarbonate (43.7 g, 0.2 mol) in 200 mL of THF was cooled to 0 C. and treated with piperidine (29.7 mL, 0.3 mol) dropwise. The mixture was stirred for 10 min, warmed to room temperature, and then stirred for 30 minutes. The mixture was diluted with of 10% sodium bicarbonate solution and extracted with ether. The extracts were washed with brine, and combined extracts were dried over K2CO3 and then concentrated to give a crude product as an oil. Purification by distillation under reduced pressure afforded 36.1 g (97%) of product as a clear oil which was homogeneous by TLC analysis. 1H NMR (250 MHz) delta3.37-3.33 (br. t, 4 H), 1.56-1.44 (m, 15 H); 13C NMR (62.7 MHz) 154.8 (s), 78.9 (s), 44.5 (br. s), 28.4 (s), 25.6 (s), 24.4 (s) ppm.

Reference： [1]Synthesis,2006,p. 2784 - 2788
[2]Tetrahedron Letters,2007,vol. 48,p. 8318 - 8322
[3]Tetrahedron Letters,2008,vol. 49,p. 2527 - 2532
[4]Tetrahedron Letters,2011,vol. 52,p. 1260 - 1264
[5]Monatshefte fur Chemie,2011,vol. 142,p. 1035 - 1043
[6]Asian Journal of Chemistry,2017,vol. 29,p. 1313 - 1316
[7]Chemistry - A European Journal,2019,vol. 25,p. 16120 - 16127
[8]Tetrahedron Letters,2006,vol. 47,p. 455 - 458
[9]Tetrahedron Letters,2010,vol. 51,p. 3855 - 3858
[10]RSC Advances,2016,vol. 6,p. 78576 - 78584
[11]Journal of the American Chemical Society,2010,vol. 132,p. 7260 - 7261
[12]Journal of Organic Chemistry,1997,vol. 62,p. 7726 - 7735
[13]Organic Letters,2013,vol. 15,p. 1918 - 1921
[14]Journal of Chemical Research,2013,vol. 37,p. 757 - 760
[15]Organic and Biomolecular Chemistry,2018,vol. 16,p. 1971 - 1975
[16]Organic Letters,2006,vol. 8,p. 3259 - 3262
[17]Tetrahedron Letters,2008,vol. 49,p. 3527 - 3529
[18]Synthesis,2008,p. 3126 - 3130
[19]Organic and Biomolecular Chemistry,2017,vol. 15,p. 5364 - 5372
[20]Tetrahedron,2001,vol. 57,p. 9033 - 9043
[21]Synlett,2007,p. 806 - 808
[22]Letters in Organic Chemistry,2011,vol. 8,p. 38 - 42
[23]Organic and Biomolecular Chemistry,2016,vol. 14,p. 7084 - 7091
[24]New Journal of Chemistry,2018,vol. 42,p. 10142 - 10147
[25]Journal of Organic Chemistry,1993,vol. 58,p. 1109 - 1117
[26]Synlett,2006,p. 1110 - 1112
[27]Tetrahedron Letters,2004,vol. 45,p. 6963 - 6965
[28]Monatshefte fur Chemie,2012,vol. 143,p. 631 - 635
[29]RSC Advances,2015,vol. 5,p. 19790 - 19798
[30]Journal of Organic Chemistry,2006,vol. 71,p. 8283 - 8286
[31]Journal of the Iranian Chemical Society,2012,vol. 9,p. 495 - 502
[32]Organic Letters,2010,vol. 12,p. 4176 - 4179
[33]Journal of the American Chemical Society,2017,vol. 139,p. 8267 - 8276
[34]Synthetic Communications,2015,vol. 45,p. 653 - 660
[35]Synthetic Communications,1989,vol. 19,p. 3139 - 3142
[36]Journal of the Chemical Society. Perkin transactions I,1998,p. 1463 - 1464
[37]Patent: US6369078,2002,B1
[38]Bulletin of the Korean Chemical Society,2010,vol. 31,p. 735 - 738
[39]Organic Letters,2018,vol. 20,p. 5661 - 5665
[40]Journal of Organic Chemistry,2020,vol. 85,p. 4740 - 4752

2
[ 75844-69-8 ]
[ 131667-57-7 ]

Reference： [1]Journal of Organic Chemistry,2010,vol. 75,p. 4069 - 4077
[2]ACS Catalysis,2019,vol. 9,p. 9513 - 9517
[3]Tetrahedron Letters,1990,vol. 31,p. 6385 - 6386
[4]Organic Letters,2013,vol. 15,p. 1918 - 1921

3
[ 75844-69-8 ]
[ 131667-57-7 ]
tert-butyl 2-azidopiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 48% 2: 35%	With trimethylsilylazide; o-iodosobenzoic acid In dichloromethane Heating;

Reference： [1]Magnus, Philip; Hulme, Christopher; Weber, Wolfgang [Journal of the American Chemical Society, 1994, vol. 116, # 10, p. 4501 - 4502]

4
[ 67-56-1 ]
[ 75844-69-8 ]
[ 195964-51-3 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 4618 - 4621
[2]Chemistry Letters,2009,vol. 38,p. 160 - 161
[3]Tetrahedron Letters,2006,vol. 47,p. 455 - 458
[4]Journal of the Chemical Society. Perkin transactions I,1997,p. 2163 - 2165
[5]Journal of Agricultural and Food Chemistry,2014,vol. 62,p. 1233 - 1239

5
[ 815-24-7 ]
[ 75844-69-8 ]
[ 325794-29-4 ]

Yield	Reaction Conditions	Operation in experiment
43%	Stage #1: t-butyl piperidinecarboxylate With N,N,N,N,-tetramethylethylenediamine; sec.-butyllithium In diethyl ether; cyclohexane at -78℃; for 4h; Stage #2: Di-t-butyl ketone In diethyl ether; cyclohexane at -78 - 25℃; Further stages.;

Reference： [1]Bertini Gross; Beak [Journal of the American Chemical Society, 2001, vol. 123, # 2, p. 315 - 321]

6
[ 75-77-4 ]
[ 75844-69-8 ]
[ 906371-08-2 ]
[ 408331-89-5 ]

Yield	Reaction Conditions	Operation in experiment
		At first, s-BuLi (1.2 M, 1.20 mL, 1.44 mmol) was added dropwise to a stirred solution of (R,R)-10 (372 mg, 1.2 mmol) and N-Boc-piperidine (0.22 mL, 1.05 mmol) in Et2O (3 mL) at -78 C, under N2 atmosphere. After 5 h stirring at this temperature, TMSCl (0.24 mL, 1.89 mmol) was added dropwise. The mixture was allowed warm to room temperature slowly over 16 h. Satd aq NH4Cl solution (5 mL) was added and stirred for 20 min. The resulting mixture was extracted with Et2O (5 * 5 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure to yield (S)-19 which was detected in trace amounts by GC analysis (21:79 e.r.). Enantioselectivity was determined by GC analysis on Beta DEXTM capillary column: tr = 38.8 (S-enantiomer) and 39.0 min (R-enantiomer) (85 C hold for 20 min, ramp 2 C/min to 180 C, hold for 5 min, ramp 10 C to 230 C, hold 5 min).

Reference： [1]Journal of the American Chemical Society,2002,vol. 124,p. 1889 - 1896
[2]Tetrahedron Asymmetry,2007,vol. 18,p. 2113 - 2119
[3]Chemical Communications,2007,p. 4534 - 4536
[4]Chemical Communications,2007,p. 4534 - 4536
[5]Chemical Communications,2006,p. 2607 - 2609
[6]Chemical Communications,2008,p. 4174 - 4176
[7]Chemical Communications,2008,p. 4174 - 4176
[8]Chemistry - A European Journal,2010,vol. 16,p. 4082 - 4090
[9]Chemistry - A European Journal,2010,vol. 16,p. 4082 - 4090
[10]Journal of the American Chemical Society,2010,vol. 132,p. 7260 - 7261
[11]Journal of the American Chemical Society,2012,vol. 134,p. 16845 - 16855
[12]Synlett,2015,vol. 26,p. 2381 - 2384
[13]Tetrahedron Asymmetry,2016,vol. 27,p. 1160 - 1167

7
[ 75844-69-8 ]
[ 122135-83-5 ]
1,1-dimethylethyl 2-(2-carboethoxy-1-cyclohexen-1-yl)-1-piperidinecarboxylate [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2003,vol. 68,p. 969 - 973

8
[ 75844-69-8 ]
[ 63359-20-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 79 percent / Electrochemical reaction 2: 75 percent / AlCl₃ / acetonitrile / 0.25 h / 0 - 20 °C

Reference： [1]Le Gall, Erwan; Gosmini, Corinne; Troupel, Michel [Tetrahedron Letters, 2006, vol. 47, # 4, p. 455 - 458]

9
[ 741287-80-9 ]
[ 75844-69-8 ]
4-[5-(4-fluorophenyl)-1-(6-methoxy-pyridin-3-yl)pyrazole-3-carbonyl]piperazine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 13h;	[Example 66]; 4-[5-(4-Fluorophenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]piperazine-1-carboxylic acid tert-butyl ester ; [] To a solution containing, in methylene chloride (5 mL), 5-(4-fluorophenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid (313 mg) obtained in Referential Example 136, piperidine-1-carboxylic acid tert-butyl ester (186 mg), 1-hydroxybenzotriazole (135 mg), and triethylamine (488 muL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (288 mg) was added, and the mixture was stirred at room temperature for 13 hours. The solvent was removed under reduced pressure. Water and ethyl acetate were added to the residue, thereby forming an aqueous layer and an organic layer. The organic layer was washed with water and saturated brine, followed by drying over sodium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure. The thus-obtained solid was recrystallized from ethyl acetate - hexane, to thereby give the title compound (241 mg). Separately, the solvent of the above-obtained layer was removed under reduced pressure. The residue was purified through silica gel thin-layer chromatography (hexane - ethyl acetate), to thereby give the title compound as crystals (170 mg). The former crystals and the latter crystals were combined (411 mg, 85%).1H-NMR(4.00MHz,CDCl3)delta: 1.48(9H,s), 3.48-3.57(4H,br), 3.74-3.82(2H,br), 3.95(3H,s), 4.07-4.13(2H,br), 6.74(1H,d,J=8.8Hz), 6.92(1H,s), 7.00-7.08(2H,m), 7.18-7.25(2H,m), 7.47(1H,dd,J=8.8,2.7Hz 8.09(1H,d,J=2.7Hz). MS (ESI)m/z: 482(M+H)+. Elementary analysis: as C25H28FN5O4·0.5H2O Calculated: C,61.21;H,5.96;N,14.28;F,3.87. Found: C, 61 . 41;H, 5.76;N, 14. 18; F, 3.95.

Reference： [1]Patent: EP1591443,2005,A1 .Location in patent: Page/Page column 138-139

10
[ 24424-99-5 ]
[ 75844-69-8 ]

Yield	Reaction Conditions	Operation in experiment
94%	With triethylamine; In tetrahydrofuran; ethyl acetate;	Part A: In dry equipment under N2, 4-hydroxypiperidine (20.2 g, 0.2 mol) was dissolved in tetrahydrofuran (200 mL) and triethylamine (29 mL, 0.21 mol). A solution of di-t-butyldicarbonate (43.65 g, 0.2 mol) was added at such a rate that the temperature remained below 30 C. After stirring at ambient temperature for four hr, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, 5% KHSO4, saturated NaHCO3, brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the BOC piperidine as a white solid (37.7 g, 94%).
	With potassium carbonate;	Step 5 44(752 mg, 2.10 mmol), di-t-butyl-dicarbonate (550 mg, 2.5 mmol), and K2CO3 (870 mg, 6.3 mmol) were partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc. the combined EtOAc layers were washed with brine and dried with Na2SO4. Filtration and concentration gave the crude N-Boc piperidine 45as a yellow oil. Purification via flash chromatography (4/1 hexanes/EtOAc, SiO2) gave 606 mg (63%) of 45as a colorless foam.
26.2 g (100%)	In tetrahydrofuran; ethyl acetate;	Part A. to a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in tetrahydrofuran (100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in tetrahydrofuran (5 mL) dropwise over 20 min. The solution was stirred overnight at ambient temperature and concentrated in vacuo to yield a light oil. The oil was filtered through silica gel using ethyl acetate/hexanes then concentrated in vacuo to afford 26.2 g (100%) of the desired BOC-piperidine as a clear, colorless oil.

Reference： [1]Patent: US6372758,2002,B1
[2]Patent: US2003/8877,2003,A1
[3]Patent: US2004/24024,2004,A1
[4]Journal of Agricultural and Food Chemistry,2014,vol. 62,p. 1233 - 1239
[5]Patent: US6372758,2002,B1
[6]Patent: US6372758,2002,B1

11
[ 29264-56-0 ]
[ 24424-99-5 ]
N-Boc-protection [ No CAS ]
[ 75844-69-8 ]

Yield	Reaction Conditions	Operation in experiment
87%	palladium-carbon; In ethyl acetate;	EXAMPLE 6 Hydrogenolysis and in situ N-Boc-protection To a stirred solution of the Acetoxypiperidine 8 (3.63 g, 11 mmol) in 70 ml EtOAc was added 0.98 g of 10% Pd/C and 2.54 g of Boc2O (11.6 mmol). The resulting solution was agitated under hydrogen atmosphere (40 psi) for 24 h. The crude mixture was filtered over the pad of Celite and evaporated to give 3.3 g of N-Boc-piperidine 9 as a yellow oil (87% yield). 1H NMR: 1.43(s, 9H), 1.55(m, 2H), 1.75(m, 2H), 1.92(m, 2H), 2.00(s, 3H), 2.86(m, 1H), 4.01(d, 1H), 5.15(q, 1H), 5.53(d, 1H), 7.31(m, 3H), 7.42(d, 2H)

Reference： [1]Patent: US2002/19532,2002,A1

12
[ 24424-99-5 ]
[ 75844-69-8 ]
[ 109384-19-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	With triethylamine; In tetrahydrofuran; ethyl acetate;	Part A: Preparation of 1,1-Dimethylethyl 4-hydroxy-1-piperidinecarboxylate. In dry equipment under N2, 4-hydroxypiperidine (20.2 g, 0.2 mol) was dissolved in tetrahydrofuran (200 mL) and triethylamine (29 mL, 0.21 mol). A solution of di-t-butyldicarbonate (43.65 g, 0.2 mol) was added at such a rate that the temperature remained below 30 C. After stirring at ambient temperature for four hr, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, 5% KHSO4, saturated NaHCO3, saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo to give the BOC piperidine as a white solid (37.7 g, 94%).
94%	With triethylamine; In tetrahydrofuran; ethyl acetate;	Part A: Preparation of 1,1-Dimethylethyl 4-hydroxy-1-piperidinecarboxylate. In dry equipment under N2, 4-hydroxypiperidine (20.2 g, 0.2 mol) was dissolved in tetrahydrofuran (200 mL) and triethylamine (29 mL, 0.21 mol). A solution of di-t-butyldicarbonate (43.65 g, 0.2 mol) was added at such a rate that the temperature remained below 30 C. After stirring at ambient temperature for four hr, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, 5% KHSO4, saturated NaHCO3, saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo to give the BOC piperidine as a white solid (37.7 g, 94%).
94%	With triethylamine; In tetrahydrofuran; ethyl acetate;	Part A: Preparation of 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate. In dry equipment under N2, 4-hydroxypiperidine (20.2 g, 0.2 mol) was dissolved in tetrahydrofuran (200 mL) and triethylamine (29 mL, 0.21 mol). A solution of di-t-butyldicarbonate (43.65 g, 0.2 mol) was added at such a rate that the temperature remained below 30 C. After stirring at ambient temperature for four hr, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, 5% KHSO4, saturated NaHCO3, saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo to give the BOC piperidine as a white solid (37.7 g, 94%).

94%	With triethylamine; In tetrahydrofuran; ethyl acetate;	Part A: Preparation of 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate. In dry equipment under N2, 4-hydroxypiperidine (20.2 g, 0.2 mol) was dissolved in tetrahydrofuran (200 mL) and triethylamine (29 mL, 0.21 mol). A solution of di-t-butyldicarbonate (43.65 g, 0.2 mol) was added at such a rate that the temperature remained below 30 C. After stirring at ambient temperature for four hr, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, 5% KHSO4, saturated NaHCO3, saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo to give the BOC piperidine as a white solid (37.7 g, 94%).
94%	With triethylamine; In tetrahydrofuran; ethyl acetate;	Part A: Preparation of 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate. In dry equipment under N2, 4-hydroxypiperidine (20.2 g, 0.2 mol) was dissolved in tetrahydrofuran (200 mL) and triethylamine (29 mL, 0.21 mol). A solution of di-t-butyldicarbonate (43.65 g, 0.2 mol) was added at such a rate that the temperature remained below 30 C. After stirring at ambient temperature for four hr, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, 5% KHSO4, saturated NaHCO3, saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo to give the BOC piperidine as a white solid (37.7 g, 94%).
94%	With triethylamine; In tetrahydrofuran; ethyl acetate;	Part A: Preparation of 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate. In dry equipment under N2, 4-hydroxypiperidine (20.2 g, 0.2 mol) was dissolved in tetrahydrofuran (200 mL) and triethylamine (29 mL, 0.21 mol). A solution of di-t-butyldicarbonate (43.65 g, 0.2 mol) was added at such a rate that the temperature remained below 30 C. After stirring at ambient temperature for four hr, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, 5% KHSO4, saturated NaHCO3, saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo to give the BOC piperidine as a white solid (37.7 g, 94%).
94%	With triethylamine; In tetrahydrofuran; ethyl acetate;	Part A: Preparation of 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate. In dry equipment under N2, 4-hydroxypiperidine (20.2 g, 0.2 mol) was dissolved in tetrahydrofuran (200 mL) and triethylamine (29 mL, 0.21 mol). A solution of di-t-butyldicarbonate (43.65 g, 0.2 mol) was added at such a rate that the temperature remained below 30 C. After stirring at ambient temperature for four hr, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, 5% KHSO4, saturated NaHCO3, saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo to give the BOC piperidine as a white solid (37.7 g, 94%).
94%	With triethylamine; In tetrahydrofuran; ethyl acetate;	Part A: Preparation of 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate. In dry equipment under N2, 4-hydroxypiperidine (20.2 g, 0.2 mol) was dissolved in tetrahydrofuran (200 mL) and triethylamine (29 mL, 0.21 mol). A solution of di-t-butyldicarbonate (43.65 g, 0.2 mol) was added at such a rate that the temperature remained below 30 C. After stirring at ambient temperature for four hr, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, 5% KHSO4, saturated NaHCO3, saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo to give the BOC piperidine as a white solid (37.7 g, 94%).
94%	With triethylamine; In tetrahydrofuran; ethyl acetate;	Part A: Preparation of 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate. In dry equipment under N2, 4-hydroxypiperidine (20.2 g, 0.2 mol) was dissolved in tetrahydrofuran (200 mL) and triethylamine (29 mL, 0.21 mol). A solution of di-t-butyldicarbonate (43.65 g, 0.2 mol) was added at such a rate that the temperature remained below 30 C. After stirring at ambient temperature for four hr, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, 5% KHSO4, saturated NaHCO3, saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo to give the BOC piperidine as a white solid (37.7 g, 94%).
94%	With triethylamine; In tetrahydrofuran; ethyl acetate;	Part A: Preparation of 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate. In dry equipment under N2, 4-hydroxypiperidine (20.2 g, 0.2 mol) was dissolved in tetrahydrofuran (200 mL) and triethylamine (29 mL, 0.21 mol). A solution of di-t-butyldicarbonate (43.65 g, 0.2 mol) was added at such a rate that the temperature remained below 30 C. After stirring at ambient temperature for four hr, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, 5% KHSO4, saturated NaHCO3, saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo to give the BOC piperidine as a white solid (37.7 g, 94%).
94%	With triethylamine; In tetrahydrofuran; ethyl acetate;	Part A: Preparation of 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate. In dry equipment under N2, 4-hydroxypiperidine (20.2 g, 0.2 mol) was dissolved in tetrahydrofuran (200 mL) and triethylamine (29 mL, 0.21 mol). A solution of di-t-butyldicarbonate (43.65 g, 0.2 mol) was added at such a rate that the temperature remained below 30 C. After stirring at ambient temperature for four hr, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, 5% KHSO4, saturated NaHCO3, saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo to give the BOC piperidine as a white solid (37.7 g, 94%).
94%	With triethylamine; In tetrahydrofuran; ethyl acetate;	Part A: Preparation of 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate. In dry equipment under N2, 4-hydroxypiperidine (20.2 g, 0.2 mol) was dissolved in tetrahydrofuran (200 mL) and triethylamine (29 mL, 0.21 mol). A solution of di-t-butyldicarbonate (43.65 g, 0.2 mol) was added at such a rate that the temperature remained below 30 C. After stirring at ambient temperature for four hr, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, 5% KHSO4, saturated NaHCO3, saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo to give the BOC piperidine as a white solid (37.7 g, 94%).
94%	With triethylamine; In tetrahydrofuran; ethyl acetate;	Part A: Preparation of 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate. In dry equipment under N2, 4-hydroxypiperidine (20.2 g, 0.2 mol) was dissolved in tetrahydrofuran (200 mL) and triethylamine (29 mL, 0.21 mol). A solution of di-t-butyldicarbonate (43.65 g, 0.2 mol) was added at such a rate that the temperature remained below 30 C. After stirring at ambient temperature for four hr, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, 5% KHSO4, saturated NaHCO3, saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo to give the BOC piperidine as a white solid (37.7 g, 94%).
94%	With triethylamine; In tetrahydrofuran; ethyl acetate;	Part A: Preparation of 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate. In dry equipment under N2, 4-hydroxypiperidine (20.2 g, 0.2 mol) was dissolved in tetrahydrofuran (200 mL) and triethylamine (29 mL, 0.21 mol). A solution of di-t-butyldicarbonate (43.65 g, 0.2 mol) was added at such a rate that the temperature remained below 30 C. After stirring at ambient temperature for four hr, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, 5% KHSO4, saturated NaHCO3, saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo to give the BOC piperidine as a white solid (37.7 g, 94%).
94%	With triethylamine; In tetrahydrofuran; ethyl acetate;	Part A: Preparation of 1,1-Dimethylethyl 4-hydroxy-1-piperidinecarboxylate. In dry equipment under N2, 4-hydroxypiperidine (20.2 g, 0.2 mol) was dissolved in tetrahydrofuran (200 mL) and triethylamine (29 mL, 0.21 mol). A solution of di-t-butyldicarbonate (43.65 g, 0.2 mol) was added at such a rate that the temperature remained below 30 C. After stirring at ambient temperature for four hr, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, 5% KHSO4, saturated NaHCO3, saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo to give the BOC piperidine as a white solid (37.7 g, 94%).
94%	With triethylamine; In tetrahydrofuran; ethyl acetate;	Part A: Preparation of 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate. In dry equipment under N2, 4-hydroxypiperidine (20.2 g, 0.2 mol) was dissolved in tetrahydrofuran (200 mL) and triethylamine (29 mL, 0.21 mol). A solution of di-t-butyldicarbonate (43.65 g, 0.2 mol) was added at such a rate that the temperature remained below 30 C. After stirring at ambient temperature for four hr, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, 5% KHSO4, saturated NaHCO3, brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the BOC piperidine as a white solid (37.7 g, 94%).

Reference： [1]Patent: US6372758,2002,B1
[2]Patent: US6372758,2002,B1
[3]Patent: US6372758,2002,B1
[4]Patent: US6372758,2002,B1
[5]Patent: US6372758,2002,B1
[6]Patent: US6372758,2002,B1
[7]Patent: US6372758,2002,B1
[8]Patent: US6372758,2002,B1
[9]Patent: US6372758,2002,B1
[10]Patent: US6372758,2002,B1
[11]Patent: US6372758,2002,B1
[12]Patent: US6372758,2002,B1
[13]Patent: US6372758,2002,B1
[14]Patent: US6372758,2002,B1
[15]Patent: US6372758,2002,B1
[16]Patent: US6372758,2002,B1

13
[ 24424-99-5 ]
[ 412016-31-0 ]
[ 75844-69-8 ]

Yield	Reaction Conditions	Operation in experiment
94%	With triethylamine; In tetrahydrofuran; ethyl acetate;	Part A: Preparation of 1,1-fimethylethyl 4-hydroxy-1-piperidinecarboxylate. In dry equipment under N2, 4-hydroxypiperidine (20.2 g, 0.2 mol) was dissolved in tetrahydrofuran (200 mL) and triethylamine (29 mL, 0.21 mol). A solution of di-t-butyldicarbonate (43.65 g, 0.2 mol) was added at such a rate that the temperature remained below 30 C. After stirring at ambient temperature for four hr, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, 5% KHSO4, saturated NaHCO3, saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo to give the BOC piperidine as a white solid (37.7 g, 94%).

Reference： [1]Patent: US6372758,2002,B1

14
[ 38256-93-8 ]
[ 75844-69-8 ]
[ 885675-72-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; at 20℃;	{ 1 -[2-(I H-Indazol-4- ylV4-morpholin-4-yl-thieno[3 ,2-d]pyrimidin-6-ylmethyl] - piperidin-4-yU -( 2-methoxy-ethyl)-methyl-amine (81).Prepared via [l-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6- ylmethyl)-piperidin-4-yl]-(2-methoxy-ethyl)-methyl-amine, prepared from (2- methoxy-ethyl)-methyl-piperidin-4-yl-amine.Amine preparation: a mixture of N-BOC-4-piperidine (500mg), N-(2- methoxyethyl)methylamine (335mg), acetic acid (0.15mL) and sodium triacetoxyborohydride (797mg) was stirred at room temperature in 1,2- dichloroethane (5mL). After stirring overnight, the reaction mixture was diluted with chloroform, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash column chromatography to yield 4-[(2-methoxy-ethyl)-methyl-amino]-piperidine-l- carboxylic acid tert-butyl ester. Treatment of this compound with HCl in DCM/MeOH yielded the desired compound, which was isolated as the hydrochloride salt. 1H NMR (400MHz, CDCl3): 1.62-1.72 (2H, m), 1.76-1.84 (2H, m), 2.10-2.18 (2H, m), 2.36 (3H, s), 2.40-2.48 (IH, m), 2.68 (2H, t, J=6.0Hz), 3.04-3.11 (2H, m), 3.38 (3H, s), 3.50 (2H, t, J=6.3Hz), 3.85 (2H, s), 3.92-3.97 (4H, m), 4.08-4.12 (4H, m), 7.39 (IH, s), 7.52 (IH, t, J=8.0Hz), 7.60 (IH, d, J=6.3Hz), 8.30 (IH, d, J=7.0Hz), 9.02 (IH, s), 10.10 (IH, br); MS (ESt) 522 (MH+). EPO <DP n="45"/>3-4-[2-(lH-Indazol-4-y?-4-morpholin-4-yl-thieno[3.2-d]pyrimidin-6-ylmethyl]- piperazine- 1 -sulfonyll -propyD-dimethyl-amine (82).Prepared via {3-[4-(2-Chloro-4-mophiholin-4-yl-thieno[3,2-d]pyrimidin-6- ylmethyl)-piperazine-l-sulfonyl]-propyl}-dimethyl-amine, prepared from dimethyl- [3-(piperazine-l-sulfonyl)-propyl]-amine. The amine preparation was as for compound 80 above.1H NMR (400MHz, CDCl3): 2.00-2.08 (2H, m), 2.26 (6H, s), 2.42 (2H, t, J=6.7), 2.68-2.72 (4H, m), 3.00-3.05 (2H, m), 3.37-3.41 (4H, m), 3.90 (2H, s), 3.92-3.96 (4H, m), 4.08-4.12 (4H, m),7.39 (IH, s), 7.52 (IH, t, J=8.0), 7.60 (IH, d, J=6.3), 8.30 (IH, d, J=7.0), 9.02 (IH, s), 10.10 (IH, br); MS (ESI+) 585 (MH+).
	With acetic acid;sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃;	A mixture of N-BOC-4-piperidine (500 mg), N-(2-methoxyethyl)methylamine(335 mg), acetic acid (0.15mL) and sodium triacetoxyborohydride (797 mg) was stirred at room temperature in 1,2-dichloroethane (5 mL). After stirring overnight, the reaction mixture was diluted with chloroform, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to yield <n="191"/>4-[(2-methoxy-ethyl)-methyl-amino]-piperidine-l-carboxylic acid tert-butyl ester. Treatment of this compound with HCl in dichloromethane/methanol yielded (2-methoxy-ethyl)-methyl- piperidin-4-yl-amine, which was isolated as the hydrochloride salt.

Reference： [1]Patent: WO2006/46031,2006,A1 .Location in patent: Page/Page column 42
[2]Patent: WO2008/70740,2008,A1 .Location in patent: Page/Page column 188-189

15
[ 75844-69-8 ]
[ 105258-93-3 ]
[ 934664-27-4 ]

Yield	Reaction Conditions	Operation in experiment
13%	With N,N,N,N,-tetramethylethylenediamine; (2-methylpropyl)lithium; In diethyl ether; cyclohexane; at -78 - 20℃;	To a solution of 1,1-dimethylethyl piperidine-1-carboxylate (0.50 g, 2.7 mmol) in anhydrous diethyl ether (9.0 mL) under anhydrous nitrogen gas was added N,N,lambda^lambdaP-tetramethylethane-l,2-diamine (0.41 mL, 2.7 mmol), and the solution was cooled to -780C. To this solution was added (2-methylpropyl)lithium (2.1 mL, 1.4 M in cyclohexane, 3.0 mmol) in small portions. To this anion solution was added phenylmethyl 3-oxoazetidine-l-carboxylate (1.0 g, 5.4 mmol), prepared using procedures as described in Reference 3, in anhydrous ether (2.0 mL), while maintaining the internal temperature at less than -6O0C. The solution was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water, and partitioned between water and diethyl ether. The layers were separated and the aqueous layer was extracted with diethyl ether twice. The combined organic layers were dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography (silica gel, 3:1 hexanes/ethyl acetate) gave 0.13 g (13%) of 1,1- dimethylethyl 2-(3 -hydroxy- 1 - { [(phenylmethyl)oxy] carbonyl } azetidin-3 - yl)piperidine-l-carboxylate. 1H NMR (400 MHz, CDCl3): 7.31 (m, 5H), 5.08 (s, 2H), 4.05 (d, 1H)S 4.00 (d, IH), 3.84 (d, 2H), 3.80 (broad s, IH), 3.55 (broad s, IH), 3.10 (broad s, IH), 1.92 (m, IH), 1.45-1.62 (m, 6H), 1.43 (s, 9H). MS (EI) for C21H30N2O5: 335 (M-tBu), 315 (M-OtBu).
13%	With N,N,N,N,-tetramethylethylenediamine; (2-methylpropyl)lithium; In diethyl ether; cyclohexane; at -78 - 20℃;	To a solution of 1 , 1 -dimethylethyl piperidine-1-carboxylate (0.50 g, 2.7 mmol) in anhydrous diethyl ether (9.0 mL) under anhydrous nitrogen gas was added N5JVyV5N1- tetramethylethane-l,2-diamine (0.41 mL, 2.7 mmol), and the solution was cooled to -780C. To this solution was added (2-methylpropyl)lithium (2.1 mL, 1.4 M in cyclohexane, 3.0 mmol) in small portions. To this anion solution was added phenylmethyl 3-oxoazetidine-l- carboxylate (1.0 g, 5.4 mmol), prepared using procedures as described in Reference 3, in anhydrous ether (2.0 mL), while maintaining the internal temperature at less than -600C. The solution was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water, and partitioned between water and diethyl ether. The layers were separated and the aqueous layer was extracted with diethyl ether twice. The combined organic layers were dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography (silica gel, 3:1 hexanes/ethyl acetate) gave 0.13 g (13%) of 1,1- dimethylethyl 2-(3 -hydroxy- 1 - { [(phenylmethyl)oxy] carbonyl } azetidin-3 -yl)piperidine- 1 - carboxylate. 1H NMR (400 MHz, CDCl3): 7.31 (m, 5H), 5.08 (s, 2H), 4.05 (d, IH), 4.00 (d, IH), 3.84 (d, 2H), 3.80 (broad s, IH), 3.55 (broad s, IH), 3.10 (broad s, IH), 1.92 (m, IH), 1.45-1.62 (m, 6H), 1.43 (s, 9H). MS (EI) for C2iH30N2O5: 335 (M-tBu), 315 (M-OtBu).

Reference： [1]Patent: WO2008/76415,2008,A1 .Location in patent: Page/Page column 332
[2]Patent: WO2008/124085,2008,A2 .Location in patent: Page/Page column 182

16
[ 7677-24-9 ]
[ 75844-69-8 ]
[ 153749-89-4 ]

Reference： [1]Organic and Biomolecular Chemistry,2009,vol. 7,p. 351 - 356
[2]Tetrahedron Letters,2008,vol. 49,p. 5098 - 5100

17
CN^(1-)*C₃H₉NPol⁽¹⁺⁾ [ No CAS ]
[ 75844-69-8 ]
[ 153749-89-4 ]

Reference： [1]Journal of the American Chemical Society,2008,vol. 130,p. 10496 - 10497

18
[ 10442-39-4 ]
[ 75844-69-8 ]
[ 153749-89-4 ]

Reference： [1]Journal of the American Chemical Society,2008,vol. 130,p. 10496 - 10497

19
[ 1169848-41-2 ]
[ 75844-69-8 ]
[ 1169848-42-3 ]

Yield	Reaction Conditions	Operation in experiment
68%		To a stirring suspension of compound 15-1 (54.6 mg, 0.09 mmol) and N-Boc-4- piperidine (21.5 mg, 0.11 mmol) in dichloroethane (0.6 ml_) is added TEA (17 mul_, 0.13 mmol). After stirring the mixture at room temperature for 1 hour, sodium triacetoxyborohydride (28.6 mg, 0.13 mmol) is added and the reaction is stirred for 24 hours at room temperature. The mixture is diluted with ethyl acetate, washed with aqueous sodium bicarbonate, water and brine, dried over sodium sulfate and concentrated to dryness. The residue is purified by flash column chromatography on silica gel (methanol/DCM 0% to 10%) to give the title compound 16-1 as a white solid (39 mg, 68%).1H NMR (400 MHz, DMSO-d6): delta [ppm] 4.49 (m, 1 H), 4.10 (q, 1 H), 3.90 (m, 4H), 3.18 (m, 1 H), 3.0 (t, 1 H), 2.77 (m, 1 H), 2.60 (m, 2H), 2.35 (m, 1H), 2.08 (m, 2H), 1.84 (m, 3H), 1.78 - 0.94 (m, 47H), 0.90 (s, 3H), 0.88 (s, 3H), 0.81 (m, 7H). LC/MS: m/z = 753.7 (M+H+).
68%	With sodium tris(acetoxy)borohydride; triethylamine; In 1,2-dichloro-ethane; at 20℃; for 25h;	To a stirring suspension of compound 15-1 (54.6 mg, 0.09 mmol) and N-Boc-4-piperidine (21.5 mg, 0.11 mmol) in dichloroethane (0.6 mL) is added TEA (17 muL, 0.13 mmol). After stirring the mixture at room temperature for 1 hour, sodium triacetoxyborohydride (28.6 mg, 0.13 mmol) is added and the reaction is stirred for 24 hours at room temperature. The mixture is diluted with ethyl acetate, washed with aqueous sodium bicarbonate, water and brine, dried over sodium sulfate and concentrated to dryness. The residue is purified by flash column chromatography on silica gel (methanol/DCM 0% to 10%) to give the title compound 16-1 as a white solid (39 mg, 68%). 1H NMR (400 MHz, DMSO-d6): delta [ppm] 4.49 (m, 1H), 4.10 (q, 1H), 3.90 (m, 4H), 3.18 (m, 1H), 3.0 (t, 1H), 2.77 (m, 1H), 2.60 (m, 2H), 2.35 (m, 1H), 2.08 (m, 2H), 1.84 (m, 3H), 1.78-0.94 (m, 47H), 0.90 (s, 3H), 0.88 (s, 3H), 0.81 (m, 7H). LC/MS: m/z=753.7 (M+H+).

Reference： [1]Patent: WO2009/82819,2009,A1 .Location in patent: Page/Page column 59
[2]Patent: US2011/77227,2011,A1 .Location in patent: Page/Page column 20; 21

20
[ 75844-69-8 ]
[ 117068-71-0 ]
[ 1092848-12-8 ]

Yield	Reaction Conditions	Operation in experiment
71%	With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 120℃; for 0.166667h;Microwave irradiation;	Step 2 0.50 g (1.9 mmol) of the compound obtained in Step 1 was placed in a microwave reactor dried with nitrogen gas, 0.53 g (2.9 mmol) of tert-butyl piperidine-1-carboxylate, 17 mg (1 mol%) of tris(dibenzylideneacetone)dipalladium, 18 mg (1.5 mol%) of BINAP [(+/-)-2,2'-bis(diphenylphosphino)-l,l'-binaphthyl], 0.25 g (2.6 eq) of sodium fert-butoxide and 4 mL of toluene was added thereto, and the reactor was sealed with a septum. The reactor was kept at 120 C for 10 mins and cooling to room temperature, followed filtering the reaction mixture through a cellite in concurrence with washing with ethyl acetate. The resulting mixture was distilled under a reduced pressure, and the resulting residue was subjected to silica gel column chromatography(n-hexane:ethylacetate=19:l) to obtain /er/-butyl 4-(6-(benzyloxy)pyridin-2-yl)piperazine-l-carboxylate (yield: 71%).

Reference： [1]Patent: WO2008/153325,2008,A1 .Location in patent: Page/Page column 47

21
[ 75844-69-8 ]
[ 79-22-1 ]
[ 200184-53-8 ]
[ 164456-75-1 ]

Reference： [1]Journal of the American Chemical Society,2010,vol. 132,p. 7260 - 7261
[2]Organic Letters,2013,vol. 15,p. 5424 - 5427

22
[ 75844-69-8 ]
[ 79-22-1 ]
[ 768-33-2 ]
[ 1228307-52-5 ]
[ 958457-72-2 ]
[ 200184-53-8 ]
[ 164456-75-1 ]

Reference： [1]Journal of the American Chemical Society,2010,vol. 132,p. 7260 - 7261

23
[ 937046-98-5 ]
[ 75844-69-8 ]
[ 937048-05-0 ]

Yield	Reaction Conditions	Operation in experiment
32%		Chlorotrimethylsilane (89 m._, 0.70 mol) was added drop wise to a stirred solution of 7- bromopyrrolo[2,1-f][1 ,2,4]triazin-4-amne in tetrahydrofuran (1.6L, anhydrous) and stirring was continued for 3 h. The solution was cooled to 0 0C and 2-propyl magnesium chloride solution (2M in THF, 740 mL, 1.48 mol) was slowly added. The reaction was warmed to 25 0C and stirring continued for 2 h, then cooled back down to -5 C and a solution of N- terf-butoxycarbonyl piperidine (91.0 g, 0.68 mol) in THF (1L) was added drop wise. The reaction was continued for 18 h at 25 0C, then the mixture was poured into vigorously- stirred ice water (8 L). The aqueous mixture was extracted with ethyl acetate (3x3L) and the combined organic portions were dried over magnesium sulfate. Filtration and concentration in vacuo gave a dark-orange oil which was dissolved in a minimal volume of dichloromethane and crystallization induced. After cooling (-10 0C) the mixture for several hours, the crystalline product was collected by suction filtration, washed with diethyl ether and dried to give a colorless solid (61 g, 52%). Purification of the filtrate by silica gel chromatography (5% methanol/ dichloromethane) yielded additional product (37 g, 32%). 1H-NMR (DMSOd6) delta 7.77 (s, 1H), 7.69 (br s, 2H), 6.80 (d, 1 H), 6.55 (d, 1 H), 5.74 (s, 1H), 3.77 (m, 2H), 3.15 (br m, 2H), 2.48 (m, 2H), 1.70 (d, 2H), 1.40 (s, 9H). ES- MS m/£=334.1 [M+H]+, RT (min) 2.15.

Reference： [1]Patent: WO2007/56170,2007,A2 .Location in patent: Page/Page column 139-140

24
[ 75844-69-8 ]
[ 79-22-1 ]
[ 164456-75-1 ]

Reference： [1]Journal of the American Chemical Society,2010,vol. 132,p. 12216 - 12217

25
[ 445-02-3 ]
[ 75844-69-8 ]
C₁₇H₂₃F₃N₂O₂ [ No CAS ]
[ 1261081-84-8 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 394 - 397

26
[ 19158-51-1 ]
[ 75844-69-8 ]
[ 153749-89-4 ]

Reference： [1]Chemistry - A European Journal,2018,vol. 24,p. 8051 - 8055
[2]Synthesis,2013,vol. 45,p. 874 - 887

27
[ 75844-69-8 ]
[ 146397-87-7 ]
C₁₇H₂₂F₃NO₂ [ No CAS ]
C₁₇H₂₂F₃NO₂ [ No CAS ]

Reference： [1]Chemical Science,2013,vol. 4,p. 2241 - 2247

28
[ 670-98-4 ]
[ 75844-69-8 ]
[ 1609960-09-9 ]

Reference： [1]Organic and Biomolecular Chemistry,2014,vol. 12,p. 3499 - 3512

29
[ 328-70-1 ]
[ 75844-69-8 ]
tert-butyl 2-(3,5-bis(trifluoromethyl)phenyl)piperidine-1-carboxylate [ No CAS ]
C₁₈H₂₁F₆NO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%; 32%		To an oven-dried, septum-capped round bottom flask equipped with a stir bar, was added freshly distilled TMEDA (2 mL, 12 mmol, 1.2 equiv) and Et2O (20 mL) under argon. The mixture was cooled to -80 C and 1.0 M solution of s-BuLi in cyclohexane (11 mL, 11 mmol, 1.1 equiv) was added. A precooled solution of N-Boc-piperidine (1.85 g, 10.0 mmol, 1.0 equiv) in Et2O (5 mL)was added to the flask containing the TMEDA/s-BuLi/Et2O mixture. After 4 h at this temperature, a freshly prepared solution of ZnCl2 (6 mL, 1.0 M solution in THF, 0.6 equiv), was added slowly over a ten minute period and the mixture was stirred for 30 minutes, removed from the cold bath and warmed to room temperature. After 30 minutes, Pd(OAc)2 (100 mg, 4 mol%), t-Bu3P·HBF4 (230 mg, 8 mol%) and 1,3-Bis(trifluoromethyl)-5-bromobenzene (1.9 mL, 11mmol, 1.1 equiv) were added sequentially. The mixture was diluted with THF (50 mL) andheated to 40C. After stirring for 24 h at room temperature, NH4OH (20 mL, 10% aqueous solution) was added dropwise and the mixture was stirred for 30 minutes. The resulting slurry was filtered through Celite and rinsed with 50 mL Et2O. The filtrate was washed with 1 M HCl(aq) (50 mL), then with water (2 x 50 mL), dried over Na2SO4 and evaporated under reduced pressure to obtain the crude product. Purification by silica gel chromatography eluting with hexane-EtOAc (98:2) afforded 2.30 g of the 2-arylated product as an oil in 58% yield. Note: A significant amount of the 3-arylated piperidine (32%) was identified as a byproduct formed presumably via a 1,2-aryl migration. This byproduct was not observed when the arylation was performed at room temperature for 3 days.

Reference： [1]Tetrahedron Letters,2015,vol. 56,p. 119 - 122

30
2-[4-(2-chloroethoxy)phenyl]-6-(4-chlorophenoxy)benzoxazole [ No CAS ]
[ 75844-69-8 ]
4-(2-{4-[6-(4-chlorophenoxy)benzoxazol-2-yl]phenoxy}ethyl)piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With sodium carbonate; potassium iodide; In butan-1-ol; at 105℃;	General procedure: A mixture of compounds 24a (for compounds 26-30; 1.0 equiv)or 25a-25e (for compounds 31-75; 1.0 equiv), secondary amine(1.5 equiv), KI (2.0 equiv), and Na2CO3 (6.0 equiv) in n-BuOH washeated to 105 C for 24 h. The mixtures was cooled to room temperatureand evaporated under reduced pressure. The residuewas dissolved in EtOAc and then washed with water, and brine.The organic layer was dried over sodium sulfate and concentratedin vacuum. The resulting residue was purified by silica gel chromatographyto afford the corresponding products (18-99%).

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 4919 - 4935

31
[ 75844-69-8 ]
[ 146397-87-7 ]
C₁₇H₂₂F₃NO₂ [ No CAS ]
C₁₇H₂₂F₃NO₂ [ No CAS ]

Reference： [1]Organic Syntheses,2016,vol. 92,p. 76 - 90

32
[ 75844-69-8 ]
[ 172876-96-9 ]
[ 153749-89-4 ]

Reference： [1]Organic and Biomolecular Chemistry,2018,vol. 16,p. 1971 - 1975

33
C₂₂H₂₀BrNO [ No CAS ]
[ 75844-69-8 ]
C₃₂H₃₈N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%		Compound 36-d (3.6 g, 9.1 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL) and the reaction solutionwas cooled to -78C. Then n-butyllithium(7.5 mL, 18.75 mmol, 2.5 M solution in n-hexane), was added dropwise to theabove solution, and stirring was continued for 3 hours after the addition. A solution of N-Boc-piperidone (3.62 g, 18.7mmol) in anhydrous tetrahydrofuran (20 mL) was added dropwise to the above reaction solution. The reaction mixturewas stirred at room temperature for 16 hours and then diluted with saturated aqueousammonium chloridesolution (50mL). The mixed solution was extracted with dichloromethane (50 mL 3 3). The combined organic phases were washedsuccessively with water (50 mL 3 3) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate wasconcentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4: 1) to deliver a white solid 37-c (2.5 g, yield: 53%). LC-MS (ESI): m/z = 515 [M+H] +

Reference： [1]Patent: EP3287463,2018,A1 .Location in patent: Paragraph 0285; 0286

34
[ 75844-69-8 ]
[ 3466-81-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sec.-butyllithium; N,N,N,N,-tetramethylethylenediamine / tetrahydrofuran / 3 h / -78 °C 1.2: -78 - 20 °C 1.3: 15 h 2.1: hydrogenchloride / dichloromethane / 5 h / 20 °C

Reference： [1]Zhong, Linlin; Tran, Tuan; Baguley, Tyler D; Lee, Sang Jun; Henke, Adam; To, Andrew; Li, Sijia; Yu, Shan; Grieco, Fabio A; Roland, Jason; Schultz, Peter G; Eizirik, Decio L; Rogers, Nikki; Chartterjee, Arnab K; Tremblay, Matthew S; Shen, Weijun [British Journal of Pharmacology, 2018, vol. 175, # 17, p. 3470 - 3485]

35
[ 301673-14-3 ]
[ 75844-69-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	With bismuth(III) oxide; N-ethyl-N,N-diisopropylamine; para-thiocresol; In dichloromethane; for 4h;Irradiation;	General procedure: Iodide compound 4 (18 mg),Bismuth oxide (0.1mg, 1mol%),P-methylthiophenol (10 mg, 5 equiv) was weighed into a 5 mL reaction flask.Then add dichloromethane (0.17ml)And N,N-diisopropylethylamine (15 muL, 5 equiv),The reaction was carried out under the illumination of 1W blue LED light.The reaction was terminated after the consumption of the iodo compound 4 (0.5 h).The reaction solvent and the volatile matter were removed by rotary distillation, and purified by column chromatography to give Compound 4a (15.6 mg).

Reference： [1]Patent: CN109265499,2019,A .Location in patent: Paragraph 0099; 0100; 0102; 0124; 0129

36
[ 75844-69-8 ]
[ 95388-79-7 ]
tert-butyl (4-chlorobutyl)(formyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 12% 2: 40%	With ammonium peroxydisulfate; N-chloro-succinimide; silver nitrate In water; acetone at 22 - 23℃; for 0.5h; Inert atmosphere;	3.f To a l -dram vial was added sequentially la (33.9 mg, 0.200 mmol), AgNCh (136 mg, (1166) 0.800 mmol), ammonium persulfate (183 mg, 0.800 mmol), /V-chlorosuccinimide (NCS: 107 mg, 0.800 mmol) and 1.0 mL of a 1 :9 acetone: H20 solution. The resulting mixture was allowed to stir at room temperature. After 30 min, the reaction mixture was partitioned with EtOAc (0.5 mL) and FLO (0.5 mL) and the phases were separated. The aqueous phase was extracted with EtOAc (1.5 mL x 3) and the combined organic layers were concentrated under reduced pressure. The crude residue was purified by preparative thin-layer chromatography (33% EtO Ac/hexanes) to provide A-(4- chlorobutyl)pivalamide (2a) (47.3 mg, 81%) as a colorless oil. NMR (600 MHz, CDCh): d 5.76 (br, 1H), 3.54 (t, J= 6.5 Hz, 2H), 3.26 (q, J= 6.5 Hz, 2H), 1.78 (quint, J= 6.5 Hz, 2H), 1.65 (quint, J= 6.5 Hz, 2H), 1.17 (s, 9H); 13C NMR (151 MHz, CDCh): d 178.8, 44.7, 38.84, 38.77, 29.9, 27.7, 27.1 ; HRMS (ESI): Calc’d for C9H19CINO [M+H]+: 192.1150, found: 192.1146.

Reference： [1]Current Patent Assignee: UNIVERSITY OF CALIFORNIA - WO2020/10228, 2020, A1 Location in patent: Paragraph 0464-0467

37
[ 75844-69-8 ]
tert-butyl (4,4-dibromobutyl)(formyl)carbamate [ No CAS ]
[ 164365-88-2 ]

Yield	Reaction Conditions	Operation in experiment
36%; 29%	With ammonium peroxydisulfate; N-Bromosuccinimide; silver nitrate; In water; acetone; at 22 - 23℃; for 0.5h;Inert atmosphere;	To a l-dram vial was added sequentially la (36.7 mg, (1218) 0.200 mmol), AgN03 (135 mg, 0.800 mmol), ammonium persulfate (182 mg, 0.800 mmol), N- bromosuccinimide (NBS: 142 mg, 0.800 mmol) and 1.0 mL of a 1 :9 acetone: H20 solution. The resulting mixture was allowed to stir at room temperature. After 30 min, the reaction mixture was partitioned with EtO Ac (0.5 mL) and fbO (0.5 mL) and the phases were separated. The aqueous phase was extracted with EtO Ac (1.5 mL x 3) and the combined organic layers were concentrated under reduced pressure. The crude residue was purified by preparative thin-layer chromatography (33% EtO Ac/hexanes) to provide A'-(4-broniobutyl)benzamide (4a) (25.4 mg, 54%) as a yellow waxy solid. NMR (400 MHz, CDCb): d 5.67 (s, 1H), 3.43 (t, J= 7.0 Hz, 2H), 3.27 (q, J= 7.0 Hz, 2H), 1.88 (quint, J= 7.0 Hz, 2H), 1.66 (quint, J= 7.0 Hz, 2H), 1.19 (s, 9H); 13C NMR (l 5l MHz, CDCh) d 178.7, 38.8, 38.7, 33.5, 30.2, 28.5, 27.8; HRMS (ESI): Calc?d for CsHisBrNNaO [M+Na]+: 258.0464, found: 258.0459.

Reference： [1]Patent: WO2020/10228,2020,A1 .Location in patent: Paragraph 0482-0485

38
[ 2700-22-3 ]
[ 75844-69-8 ]
C₂₀H₂₅N₃O₂ [ No CAS ]

Reference： [1]ACS Catalysis,2020,vol. 10,p. 2627 - 2632

39
[ 75844-69-8 ]
[ 73183-34-3 ]
[ 1048970-17-7 ]
[ 1312713-37-3 ]

Yield	Reaction Conditions	Operation in experiment
	With 2-methyl-1,10-phenanthroline; (1,5-cyclooctadiene)(methoxy)iridium(I) dimer In Cyclooctan at 100℃; Inert atmosphere; Overall yield = 41 percent; regioselective reaction;

Reference： [1]Oeschger, Raphael; Su, Bo; Yu, Isaac; Ehinger, Christian; Romero, Erik; He, Sam; Hartwig, John [Science, 2020, vol. 368, # 6492, p. 736 - 741]

40
[ 1003858-50-1 ]
[ 180695-79-8 ]
[ 1276045-26-1 ]
[ 75844-69-8 ]
[ 85838-94-4 ]

Reference： [1]ACS Catalysis,2022,vol. 12,p. 1905 - 1918

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[ CAS No. 75844-69-8 ] {[proInfo.proName]}

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