[ CAS No. 137076-22-3 ] {[proInfo.proName]}

Name: 137076-22-3|tert-Butyl 4-formylpiperidine-1-carboxylate|97%
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SKU: A103974
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Quality Control of [ 137076-22-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 137076-22-3 ]

CAS No. :	137076-22-3	MDL No. :	MFCD02179019
Formula :	C₁₁H₁₉NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JYUQEWCJWDGCRX-UHFFFAOYSA-N
M.W :	213.27	Pubchem ID :	1514430
Synonyms :

Calculated chemistry of [ 137076-22-3 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.82
Num. rotatable bonds :	4
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	61.6
TPSA :	46.61 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) :	-6.84 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.4
Log Po/w (XLOGP3) :	1.07
Log Po/w (WLOGP) :	1.45
Log Po/w (MLOGP) :	1.05
Log Po/w (SILICOS-IT) :	1.24
Consensus Log Po/w :	1.44

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.57
Solubility :	5.71 mg/ml ; 0.0268 mol/l
Class :	Very soluble
Log S (Ali) :	-1.64
Solubility :	4.88 mg/ml ; 0.0229 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.23
Solubility :	12.6 mg/ml ; 0.059 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.01

Safety of [ 137076-22-3 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P264-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P362+P364-P403+P233-P501	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 137076-22-3 ]

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

Upstream synthesis route of [ 137076-22-3 ]
Downstream synthetic route of [ 137076-22-3 ]

[ 137076-22-3 ] Synthesis Path-Upstream 1~13

1
[ 137076-22-3 ]
[ 71879-55-5 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 8, p. 2305 - 2308

2
[ 137076-22-3 ]
[ 62718-31-4 ]

Reference： [1] Synthesis (Germany), 2015, vol. 47, # 23, p. 3758 - 3766

3
[ 137076-22-3 ]
[ 91419-52-2 ]

Yield	Reaction Conditions	Operation in experiment
73%	With potassium hexafluorophosphate; tert.-butylnitrite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; oxygen; 1,1,1,3,3,3-hexamethyl-disilazane In acetonitrile at 30℃; for 8 h;	In a 100-ml flask, 30 mL of acetonitrile, 10 mmol of HMDS, 0.4 mmol of TEMPO, 0.4 mmol of KPF6 and 0.6 mmol of TBN were charged. The air was replaced with oxygen. The mixture was heated to 30 ° C in a preheated water bath and 4 mmol of N-Boc-4-piperidinecarboxaldehyde (as shown in formula (1-8)) was added slowly for 8 h. The reaction mixture was stirred with sodium thiosulfate solution and extracted with ether. The organic layer was separated, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography. The mixture was stirred at a volume ratio of ethyl acetate / petroleum ether of 1: 100 The eluent containing the title compound was collected and the solvent was evaporated to give N-Boc-4-piperidinecarbonitrile in an isolation yield of 70percent.; The reaction procedure was the same as in Example 20, except that the amount of acetonitrile used was 80 mL, and the isolated yield of N-Boc-4-piperidinecarbonitrile was 73percent.

Reference： [1] Synlett, 2009, # 20, p. 3378 - 3382
[2] Journal of Organic Chemistry, 2012, vol. 77, # 20, p. 9334 - 9337,4
[3] Journal of Organic Chemistry, 2012, vol. 77, # 20, p. 9334 - 9337
[4] Patent: CN105481624, 2016, A, . Location in patent: Paragraph 0041; 0042
[5] Advanced Synthesis and Catalysis, 2016, vol. 358, # 7, p. 1157 - 1163
[6] RSC Advances, 2017, vol. 7, # 3, p. 1484 - 1489
[7] Synlett, 2011, # 15, p. 2223 - 2227
[8] Synthesis (Germany), 2015, vol. 47, # 23, p. 3758 - 3766

4
[ 137076-22-3 ]
[ 89151-44-0 ]

Reference： [1] Patent: US6635657, 2003, B1,

5
[ 137076-22-3 ]
[ 162504-75-8 ]

Reference： [1] Journal of Medicinal Chemistry, 1998, vol. 41, # 14, p. 2492 - 2502

6
[ 90965-06-3 ]
[ 137076-22-3 ]
[ 287192-97-6 ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium carbonate In methanol at 20℃;	At 0 C, to a stirred mixture of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (358 mg, 1.68 mmols) and potassium carbonate (464 rng, 3.36 mmols) in methanol (16 ml) was added dropwise a solution of (1-diazo-2-oxo-propyl)- phosphonic acid dimethyl ester (323 mg, 1.68 mmols) in methanol (2 ml). The resulting mixture was stirred at room temperature overnight, filtered and concentrated. The residue was chromatographed on silica gel using a solution of ethyl acetate in hexanes (1:5) to provide the title compound (308 mg, 88percent) as colorless crystals. LCMS m/e (154, M - M3u + 2H). (J. Am. Chem. Soc. 2003, 125, 3714.)
88%	With potassium carbonate In methanol at 20℃;	At 0 C, to a stirred mixture of 4-formyl-piperidine-1-carboxylic acid fert-butyl ester (358 mg, 1.68 mmols) and potassium carbonate (464 mg, 3.36 mmols) in methanol (16 ml) was added dropwise a solution of (1-diazo-2-oxo-propyl)- phosphonic acid dimethyl ester (323 mg, 1.68 mmols) in methanol (2 ml). The resulting mixture was stirred at room temperature overnight, filtered and concentrated. The residue was chromatographed on silica gel using a solution of ethyl acetate in hexanes (1 :5) to provide the title compound (308 mg, 88percent) as colorless crystals. LCMS m/e (154, M - f-Bu + 2H). (J. Am. Chem. Soc. 2003, 725, 3714.)
81%	With potassium carbonate In methanol at 20℃; for 18 h;	A solution of compound 7 (0.1 g, 0.41 mmol) in methanolwas stirred at room temperature for 10 min. Then compound8 (95 mg, 0.49 mmol) and K2CO3 (113 mg, 0.82 mmol) were added and stirred at room temperature for 18 h. Thereaction mixture was filtered through a celite pad to removeK2CO3. The solvent was evaporated under vacuum. Thenwater was added and the product was extracted by ethylacetate (3 × 30 ml). The crude material was purified bycolumn chromatography to obtain product. Compound 9 Yield 81percent, white solid powder; MS: [M+H]+ 210.09; 1H-NMR (400MHz, CDCl3-D) δ 3.72 (m, 2H),3.20 (m, 2H), 2.06 (s, 1H), 2.12 (d, J = 2.4 Hz, 1H), 1.81(m, 2H), 1.60 (m, 2H), 1.47 (s, 9H). 13C-NMR (100MHz,CDCl3-D) δ 154.8, 86.4, 79.5, 69.5, 31.2, 28.4, 26.7.

55%

With potassium carbonate In methanol for 20 h;

Example 124; Preparation of tert-butyl 4-(2-(7-(4-(1-(carbamoyl)cyclopropanecarboxamido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)ethynyl)piperidine-1-carboxylate; Step A: Preparation of tert-butyl 4-ethynylpiperidine-1-carboxylate; To a stirred suspension of tert-butyl 4-formylpiperidine-1-carboxylate (0.427 g, 2.00 mmol), K₂CO₃(0.553 g, 4.00 mmol), and MeOH (25 mL) was added all at once the Bestman-Ohira reagent, dimethyl 2-oxo-1-diazo-propylphosphonate (0.461 g, 2.40 mmol, see Synthesis 2004, 1, 59-62). Stirring was continued for 20 hours under nitrogen. The reaction was diluted with Et₂O (50 mL), washed with a 2:1 mixture of water and aqueous saturated NaHCO₃(20 mL), dried (Na₂SO₄), filtered, and concentrated in vacuo. Yield: 253 mg (55percent). ¹H NMR (400 MHz, CDCl₃) δ 3.72 (m, 2H), 3.19 (m, 2H), 2.58 (m, 1H), 2.10 (d, J=2 Hz, 1H), 1.77 (m, 2H), 1.61 (m, 2H), 1.46 (s, 9H).

Reference： [1] Journal of the American Chemical Society, 2003, vol. 125, # 13, p. 3714 - 3715
[2] Patent: WO2007/97937, 2007, A1, . Location in patent: Page/Page column 191
[3] Patent: WO2008/156739, 2008, A1, . Location in patent: Page/Page column 222
[4] Tetrahedron Letters, 2006, vol. 47, # 11, p. 1729 - 1731
[5] Medicinal Chemistry Research, 2018, vol. 27, # 11-12, p. 2437 - 2445
[6] Patent: US2007/197537, 2007, A1, . Location in patent: Page/Page column 101
[7] Journal of Medicinal Chemistry, 2004, vol. 47, # 12, p. 3111 - 3130
[8] Patent: US2014/275153, 2014, A1, . Location in patent: Paragraph 0541
[9] Patent: US2015/218165, 2015, A1, . Location in patent: Paragraph 1175
[10] MedChemComm, 2016, vol. 7, # 9, p. 1797 - 1801
[11] Patent: WO2017/194734, 2017, A1, . Location in patent: Page/Page column 44

7
[ 96854-79-4 ]
[ 137076-22-3 ]
[ 287192-97-6 ]

Reference： [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 1, p. 68 - 83

8
[ 137076-22-3 ]
[ 301221-57-8 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 13, p. 3419 - 3424
[2] Patent: US2012/252815, 2012, A1,
[3] Patent: US2014/249146, 2014, A1,
[4] Journal of Medicinal Chemistry, 2017, vol. 60, # 24, p. 10056 - 10070
[5] Patent: WO2006/113837, 2006, A2,
[6] Patent: WO2013/50448, 2013, A1,

9
[ 137076-22-3 ]
[ 74-88-4 ]
[ 189442-92-0 ]

Yield	Reaction Conditions	Operation in experiment
43.8%	With potassium <i>tert</i>-butylate In dichloromethane at 0 - 20℃; for 2 h;	Tert-butyl 4-formylpiperidine-l-carboxylate (35.0 g, 164.1 mmol) was dissolved in dichloromethane (200 mL) and cooled to 0 ⁰C. Potassium tert-butoxide (23.9 g, 213 mmol) was added followed by addition of iodomethane (69.9 g, 492 mmol). The reaction was stirred at 0 ⁰C for 30 minutes, and then warmed to ambient temperature and stirred for 1.5 hr. The reaction mixture was poured into brine (400 mL) and the organic layer was separated, dried, and filtered, and concentrated and purified by silica gel to provide tert-butyl 4-formyl-4- methylpiperidine-1-carboxylate (16.36 g, 72.0 mmol, 43.8 percent yield
37.5%	With potassium <i>tert</i>-butylate In dichloromethane at 0 - 20℃; for 2 h;	To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (4.5 g, 21.10 mmol) in CH2C12 (50 mL) at 0°C was added t-BuOK (3.08 g, 27.4 mmol) followed by Mel (3.96 mL, 63.3 mmol) at 0 °C. The resulting mixture was stirred 30 mm, and then warmed to room temp and stirred for 1.5 h. The reaction mixture was then poured into brine and themixture was extracted with dichloromethane, dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (0-20percent EtOAc/hexane) to afford tert-butyl 4-formyl-4-methylpiperidine-1-carboxylate (1.8 g, 7.92 mmol, 37.5 percent yield) as colorless oil. ‘H NMR (500 MHz, CDC13) 9.48 (s, 1H), 3.7 1-3.66 (m, 2H), 3.19 - 3.05 (m, 2H), 1.93 (dt, J=13.7, 4.1 Hz, 2H), 1.47 (s, 9H), 1.46 - 1.37 (m,2H), 1.10 (s, 3H). LCMS (M+H) = 228.1.
37.5%	With potassium <i>tert</i>-butylate In dichloromethane at 0 - 20℃; for 2 h;	To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (4.5 g, 21.10 mmol) in CH₂Cl₂ (50 mL) at 0°C was added KOtBu (3.08 g, 27.4 mmol) followed by Mel (3.96 mL, 63.3 mmol) and the resulting mixture was stirred at 0°C for 30 min, and then warmed to room temp and stirr for 1.5 h. The reaction mixture was then poured into brine and the mixture was extracted with dichloromethane, dried (Na₂SO₄), filtered and concentrated. The residue was then purified by Biotage (0-20percent EtOAc/hexane) to afford tert-butyl 4-formyl-4-methylpiperidine-1-carboxylate (1.8 g, 7.92 mmol, 37.5 percent yield) as colorless oil. ¹H NMR (500MHz, CDCl₃) δ 9.48 (s, 1H), 3.71-3.66 (m, 2H), 3.19 - 3.05 (m, 2H), 1.93 (dt, J=13.7, 4.1 Hz, 2H), 1.47 (s, 9H), 1.46 - 1.37 (m, 2H), 1.10 (s, 3H). LCMS (M+H) = 228.1.

37.5%

With potassium tert-butylate In dichloromethane at 0 - 20℃; for 2 h;

Prepared according to the procedure reported in W02008/118718. To a solution oftert-butyl4-formylpiperidine-1-carboxylate (4.5 g, 21.10 mmol) in CH2 Cb (50 mL) at ooc wasadded KOtBu (3.08 g, 27.4 mmol) followed by Mel (3.96 mL, 63.3 mmol) and the resulting mixture was stirred at 0 oc for 30 min, and then warmed to room temp and stirr for 1.5 h. The reaction mixture was then poured into brine and the mixture wasextracted with dichloromethane, dried (Na2 S04), filtered and concentrated. The residue was then purified by Biotage (0-20percent EtOAc/hexane) to afford tert-butyl 4- formyl-4-methylpiperidine-1-carboxylate (1.8 g, 7.92 mmol, 37.5percent yield) as colorless oil. 1H NMR (500MHz, CDCh) 8 9.48 (s, 1H), 3.71-3.66 (m, 2H), 3.19-3.05 (m, 2H), 1.93 (dt, J=13.7, 4.1 Hz, 2H), 1.47 (s, 9H), 1.46- 1.37 (m, 2H), 1.10 (s,3H). LCMS (M+H) = 228.1.

Reference： [1] Patent: WO2008/118718, 2008, A2, . Location in patent: Page/Page column 84
[2] Patent: WO2014/28384, 2014, A1, . Location in patent: Page/Page column 112
[3] Patent: WO2014/164467, 2014, A1, . Location in patent: Page/Page column 65
[4] Patent: WO2014/164428, 2014, A1, . Location in patent: Page/Page column 61
[5] Patent: WO2013/127828, 2013, A1, . Location in patent: Page/Page column 62
[6] Patent: US2013/225601, 2013, A1, . Location in patent: Paragraph 0259

10
[ 19493-09-5 ]
[ 137076-22-3 ]
[ 180307-56-6 ]

Reference： [1] Patent: US2007/10513, 2007, A1, . Location in patent: Page/Page column 20

11
[ 137076-22-3 ]
[ 1181267-36-6 ]

Reference： [1] Patent: CN106146459, 2016, A,

12
[ 137076-22-3 ]
[ 1023595-19-8 ]

Reference： [1] Patent: WO2014/15495, 2014, A1,
[2] Patent: WO2015/17305, 2015, A1,
[3] Patent: WO2016/60941, 2016, A1,

13
[ 137076-22-3 ]
[ 1250994-14-9 ]

Reference： [1] Patent: WO2015/94803, 2015, A1,
[2] Patent: WO2016/190847, 2016, A1,
[3] Patent: CN104974163, 2017, B,
[4] Patent: CN104672250, 2017, B,

[ 137076-22-3 ] Synthesis Path-Downstream 1~88

1
[ 137076-22-3 ]
[ 190446-85-6 ]

Yield	Reaction Conditions	Operation in experiment
99.2%	With hydroxylamine hydrochloride; sodium carbonate In methanol; water at 0 - 15℃; Cooling with ice;	4.A A solution of tert-butyl 4-formylpiperidine-l-carboxylate (50.0 g, 234 mmol) in MeOH (200 mL) and water (200 mL) was cooled in an ice-bath and then hydroxylamine hydrochloride (19.5 g, 272 mmol) and sodium carbonate (12.4 g, 117 mmol) were added. The resulting mixture was stirred at 13-15 °C overnight. The solution was concentrated in vacuo to an aqueous suspension, which was extracted with EtOAc. The organic extract was washed with 100 mL brine, dried (MgSO4), filtered, concentrated to provide tert-butyl 4-((hydroxyimino)methyl)piperidine-l-carboxylate (53.1 g, 99.2% yield) as a white crystalline solid.
98%	With hydroxylamine hydrochloride; sodium carbonate In methanol; water at 0 - 20℃;	7.F Step F: Preparation of tert-butyl 4-((hvdroxyimino)methyl)piperidine-l- carboxylate: A mixture of tert-Butyl 4-formylpiperidine-l-carboxylate (30.0 g, 140 mmol), MeOH (150 mL, 3700 mmol) and water (150 mL, 8330 mmol) was cooled in an ice-water bath. Hydroxylamine hydrochloride (11.7 g, 160 mmol) and sodium carbonate (7.45 g, 70 mmol) were added and the resulting mixture was stirred in the ice bath, then allowed to warm to ambient temperature overnight. The reaction was concentrated to an aqueous suspension and was extracted with ethyl acetate. The organic extract was washed with brine, dried, and concentrated to afford the title compound as a white solid (31.3 g, 98%).
82%	With sodium hydroxide; hydroxylamine hydrochloride In methanol at 0 - 20℃;

	With pyridine; hydroxylamine hydrochloride at 20℃;
	With hydroxylamine hydrochloride In dimethyl sulfoxide at 70℃;
	With hydroxylamine hydrochloride; triethylamine In dichloromethane at 20℃; for 16h; Inert atmosphere;	Aldoximes; General Procedure General procedure: To a solution of the aldehyde in CH2Cl2 (0.2 M) was added hydroxylamine hydrochloride (2.0 equiv) and Et3N (4.2 equiv) and the mixture was stirred at r.t. for 16 h. The reaction was quenched with sat. aq NaHCO3 and extracted with CH2Cl2. The combined organic layers were washed with aq 1 M HCl, dried (MgSO4), and concentrated to give the crude aldoxime, which was purified by flash chromatography. The known aldoximes 1,18 4a,5i 4b,19 4c,20 4d,18 4e,21 4f,22 4g,18 4h,23 4i,244j,20 7,25 10a,25 10b,26 10c,18 10d,27 10e,27 10f,28 10j,5i and 1929 were synthesized following the general procedure described above.
	With hydroxylamine hydrochloride; sodium hydrogencarbonate
	With hydroxylamine hydrochloride; potassium carbonate In methanol; water at 20℃;
	With hydroxylamine hydrochloride; sodium carbonate In methanol; water at 20℃; Cooling with ice;	Tetrahydrofuran-3-carbaldehyde oxime (33b). General procedure: Sodium carbonate (5.29 g, 49.9 mmol) and hydroxyl amine hydrochloride (8.33 g, 120 mmol) were added to a solution of 50% by weight solution of tetrahydrofuran-3-carbaldehyde (20.0 g, 99.9 mmol) in water dissolved in methanol (100 mL) and water (90 mL) in an ice bath. The reaction was warmed to room temperature and stirred overnight. The MeOH was removed in vacuo and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to afford tetrahydrofuran-3-carbaldehyde oxime (5.25 g, 45.6% yield) as a 2:1 mixture of isomers.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2008/118718, 2008, A2 Location in patent: Page/Page column 48
[2]Current Patent Assignee: PFIZER INC - WO2008/91770, 2008, A1 Location in patent: Page/Page column 36
[3]Xue, Chu-Biao; Wityak, John; Sielecki, Thais M.; Pinto, Donald J.; Batt, Douglas G.; Cain, Gary A.; Sworin, Michael; Rockwell, Arlene L.; Roderick, John J.; Wang, Shuaige; Orwat, Michael J.; Frietze, William E.; Bostrom, Lori L.; Liu, Jie; Higley, C. Anne; Rankin, F. Wayne; Tobin, A. Ewa; Emmett, George; Lalka, George K.; Sze, Jean Y.; Di Meo, Susan V.; Mousa, Shaker A.; Thoolen, Martin J.; Racanelli, Adrienne L.; Hausner, Elizabeth A.; Reilly, Thomas M.; DeGrado, William F.; Wexler, Ruth R.; Olson, Richard E. [Journal of Medicinal Chemistry, 1997, vol. 40, # 13, p. 2064 - 2084]
[4]Shankaran; Donnelly, Karla L.; Shah, Shrenik K.; Guthikonda, Ravindra N.; MacCoss, Malcolm; Mills, Sander G.; Gould, Sandra L.; Malkowitz, Lorraine; Siciliano, Salvatore J.; Springer, Martin S.; Carella, Anthony; Carver, Gwen; Hazuda, Daria; Holmes, Karen; Kessler, Joseph; Lineberger, Janet; Miller, Michael D.; Emini, Emilio A.; Schleif, William A. [Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 13, p. 3419 - 3424]
[5]Location in patent: experimental part Augustine, John Kallikat; Bombrun, Agnes; Atta, Rajendra Nath [Synlett, 2011, # 15, p. 2223 - 2227]
[6]Keita, Massaba; Vandamme, Mathilde; Paquin, Jean-François [Synthesis, 2015, vol. 47, # 23, p. 3758 - 3766]
[7]Chalyk, Bohdan A.; Kandaurova, Inna Y.; Hrebeniuk, Kateryna V.; Manoilenko, Olga V.; Kulik, Irene B.; Iminov, Rustam T.; Kubyshkin, Vladimir; Tverdokhlebov, Anton V.; Ablialimov, Osman K.; Mykhailiuk, Pavel K. [RSC Advances, 2016, vol. 6, # 31, p. 25713 - 25723]
[8]Yang, Kai; Zhang, Feng; Fang, Tongchang; Zhang, Guan; Song, Qiuling [Angewandte Chemie - International Edition, 2019, vol. 58, # 38, p. 13421 - 13426][Angew. Chem., 2019, vol. 131, # 38, p. 13555 - 13560,6]
[9]Aicher, Thomas D.; Baer, Brian R.; Boyd, Steven A.; Chicarelli, Mark D.; Condroski, Kevin R.; DeWolf, Walter E.; Fischer, John; Frank, Michele; Hingorani, Gary P.; Hinklin, Ronald J.; Lee, Patrice A.; Neitzel, Nickolas A.; Pratt, Scott A.; Singh, Ajay; Sullivan, Francis X.; Turner, Timothy; Voegtli, Walter C.; Wallace, Eli M.; Williams, Lance [Bioorganic and medicinal chemistry, 2020, vol. 28, # 1]

2
[ 139290-70-3 ]
[ 137076-22-3 ]

Yield	Reaction Conditions	Operation in experiment
100%		To a stirred solution of the above Weinreb amide (20) (2.70 g, 10 mmol) in THF (100 mL) at -10 C. was added LiAlH4 (460 mg, 12 mmol). After the starting material was consumed completely (10-20 min), a solution of KHSO4 (2.8 g) in H2O (100 mL) was added slowly, then followed by 1 N HCl (50 mL). The mixture was stirred for 15 minutes and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with sat NaHCO3 (50 mL), brine (50 mL), dried (MgSO4), and concentrated to give an oil (21) (2.14 g, 100%). 1H NMR (500 MHz, CDCL3) delta9.66 (s, 1H), 3.98 (br d, J=11.5 Hz, 2H), 2.93 (m, 2H), 2.41 (m, 1H), 1.90 (m, 2H), 1.55 (m, 2H), 1.46 (s, 9H); MS (ESI+) m/z 158.67 (M+H+-isobutylene).
85%		Synthesis of 4-Formyl-piperidine-carboxylic acid t-butyl ester 4-(methoxy-methylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (1.0 eq, 16.4 mmol) was dissolved in 100 ml dry tetrahydrofurane under inert atmosphere. This solution was added dropwise over a period of 1 h to a suspension of lithiumalanate (3.0 eq, 49.6 mmol) in 70 ml dry tetrahydrofurane at -50 C. During the adding of the mixture, the temperature was held at -50 C. and then allowed to warm to 0 C. within 3 h. The mixture was cooled to -78 C. and quenched carefully with 100 ml 1 M citric acid. The mixture was warmed up to r.t. and diluted with 400 ml ethylacetate. The phases were separated and the aqueous phase was extracted 3 times with 70 ml ethylacetate, The combined organic layers were extracted 3 times with 100 ml 1 M citric acid, aqueous sodium carbonate and 2 times with 100 ml brine, dried over MgSO4 and filtrated. The solvent was removed and the residue was purified by distillation resulting in a yield of 85%
85%		Synthesis of 4-Forniyl-piperidine-l-carboxyIic acid t-butyl ester4-(methoxy-methyl-carbamoyl)-piperidine-l-carboxylic acid tert-butyl ester (1.0 eq, 16.4 mmol) was dissolved in 100 ml dry tetrahydrofurane under inert atmosphere. This solution was added dropwise over a period of 1 h to a suspension of lithiumalanate (3.0 eq, 49.6 mmol) in 70 ml dry tetrahydrofurane at -50C. During the adding of the mixture, the temperature was held at - 50C and then allowed to warm to 00C within 3 h. The mixture was cooled to -78 C and quenched carefully with 100 ml 1 M citric acid. The mixture was warmed up to r.t. and diluted with 400 ml ethylacetate. The phases were separated and the aqueous phase was extracted 3 times with 70 ml ethylacetate. The combined organic layers were extracted 3 times with 100 ml 1 M citric acid, aqueous sodium carbonate and 2 times with 100 ml brine, dried over MgSO4 and filtrated. The solvent was removed and the residue was purified by distillation resulting in a yield of 85%

85%		<strong>[139290-70-3]4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester</strong> (1.0 eq, 16.4 mmol) was dissolved in 100 ml dry tetrahydrofurane under inert atmosphere. This solution was added dropwise over a period of 1 h to a suspension of lithiumalanate (3.0 eq, 49.6 mmol) in 70 ml dry tetrahydrofurane at -50C. During the adding of the mixture, the temperature was held at - 50C and then allowed to warm to 0C within 3 h. The mixture was cooled to -78 C and quenched carefully with 100 ml 1 M citric acid. The mixture was warmed up to r.t. and diluted with 400 ml ethylacetate. The phases were separated and the aqueous phase was extracted 3 times with 70 ml ethylacetate. The combined organic layers were extracted 3 times with 100 ml 1 M citric acid, aqueous sodium carbonate and 2 times with 100 ml brine, dried over MgSO4 and filtrated. The solvent was removed and the residue was purified by distillation resulting in a yield of 85%
85%	With lithium aluminium tetrahydride; In tetrahydrofuran; at -50 - 0℃; for 4h;	4-(methoxy-methyl-carbamoyl)-piperidine-l-carboxylic acid tert-butyl ester (1.0 eq, 16.4 mmol) was dissolved in 100 ml dry tetrahydrofurane under inert atmosphere. This solution was added dropwise over a period of 1 h to a suspension of lithiumalanate (3.0 eq, 49.6 mmol) in 70 ml dry tetrahydrofurane at -5O0C. During the adding of the mixture, the temperature was held at - 500C and then allowed to warm to 00C within 3 h.The mixture was cooled to -78 0C and quenched carefully with 100 ml 1 M citric acid. The mixture was warmed up to r.t. and diluted with 400 ml ethylacetate. The phases were separated and the aqueous phase was extracted 3 times with 70 ml ethylacetate. The combined organic layers were extracted 3 times with 100 ml 1 M citric acid, aqueous sodium carbonate and 2 times with 100 ml brine, dried over MgSO4 and filtrated. The solvent was removed and the residue was purified by distillation resulting in a yield of 85%
85%		<strong>[139290-70-3]4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester</strong> (1.0 eq, 16.4 mmol) was dissolved in 100 ml dry tetrahydrofurane under inert atmosphere. This solution was added dropwise over a period of 1 h to a suspension of lithiumalanate (3.0 eq, 49.6 mmol) in 70 ml dry tetrahydrofurane at -50 C. During the adding of the mixture, the temperature was held at -50 C. and then allowed to warm to 0 C. within 3 h.The mixture was cooled to -78 C. and quenched carefully with 100 ml 1 M citric acid. The mixture was warmed up to r.t. and diluted with 400 ml ethylacetate. The phases were separated and the aqueous phase was extracted 3 times with 70 ml ethylacetate. The combined organic layers were extracted 3 times with 100 ml 1 M citric acid, aqueous sodium carbonate and 2 times with 100 ml brine, dried over MgSO4 and filtrated. The solvent was removed and the residue was purified by distillation resulting in a yield of 85%
85%		Synthesis of 4-Formyl-piperidine-1-carboxylic acid t-butyl ester 4-(methoxy-methyl-carbanloyl)-piperidine-1-carboxylic acid tert-butyl ester (1.0 eq, 16.4 mmol) was dissolved in 100 ml dry tetrahydrofurane under inert atmosphere. This solution was added dropwise over a period of 1 h to a suspension of lithiumalanate (3.0 eq, 49.6 mmol) in 70 ml dry tetrahydrofurane at -50C. During the adding of the mixture, the temperature was held at - 50C and then allowed to warm to 0C within 3 h. The mixture was cooled to -78 C and quenched carefully with 100 ml 1 M citric acid. The mixture was warmed up to r.t. and diluted with 400 ml ethylacetate. The phases were separated and the aqueous phase was extracted 3 times with 70 ml ethylacetate. The combined organic layers were extracted 3 times with 100 ml 1 M citric acid, aqueous sodium carbonate and 2 times with 100 ml brine, dried over MgSO4 and filtrated. The solvent was removed and the residue was purified by distillation resulting in a yield of 85%
84%		To a mixture of lithium aluminum hydride (1M THF solution, 4.4 ml) in ether (4 ml) was added dropwise at - 60 C 4-(methoxy-methyl-carbamoyl)-piperidine-1- carboxylic acid tert-butyl ester (1g, 3.67 mmols) in ether (6 ml)- The reaction mixture was allowed to warm to 0-5 C and then re-cooled to -60 C. Celite was added and reaction was quenched with a solution of KHSO4 (1g) in water (3 ml), filtered through Celite. The filtrate was washed with cold 1 N HCI, saturated NaHCO3, brine and dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel eluting with ethyl acetate in hexanes (1 :1 ) to provide title compound (656 mg, 84%). (Org. Prep. Proced. Int., 2000, 32, 96.)
84%		To a mixture of lithium aluminum hydride (1 M THF solution, 4.4 ml) in ether (4 ml) was added dropwise at - 60 C 4-(methoxy-methyl-carbamoyl)-piperidine-1- carboxylic acid tert-butyl ester (1g, 3.67 mmols) in ether (6 ml). The reaction mixture was allowed to warm to 0-5 C and then re-cooled to -60 C. Celite was added and reaction was quenched with a solution of KHSO4 (1g) in water (3 ml), filtered through Celite. The filtrate was washed with cold 1 N HCI, saturated NaHCO3, brine and dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel eluting with ethyl acetate in hexanes (1 :1 ) to provide title compound (656 mg. 84%). (Org. Prep. Proced.. Int., 2000, 32, 96.)
	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 3h;	To a solution of 1-(tert-butoxycarbonyl)-4-(N,O-dinmethylhydroxylamino carbonyl)piperidine (8.00 g) in tetrahydrofuran (150 ml) at 0 C. was added lithium aluminum hydride (1.23 g) portionwise over 5 minutes. The resulting suspension was stirred at 0 C. for 3 hours and then water (1 ml), 2M aqueous sodium hydroxide solution (1 ml) and water (4 ml) were added and the suspension filtered through celite. The filter cake was washed with dichloromethane and the combined organic extracts evaporated to give 1-(tert-butoxycarbonyl)-4-(formyl)piperidine (7.04 g) as an oil: NMR (CDCl3): 1.40 (s, 9H), 1.60 (m, 2H), 2.40 (m, 1H), 2.90 (m. 2H), 3.40 (d, 1H), 4.00 (m, 3H), 9.70 (s, 1H).
		The Weinreb amide (50MMOL) in tetrahydrofuran (THF) (LOOML) is cooled to 0C and 1M lithium aluminum hydride in THF (LAH/THF) (55ML, 55MMOL) is added dropwise. The reaction is stirred for 1 hour at 0C and ethyl acetate (EtOAc) (55ML) is carefully added to quench any unreacted LAH. The reaction is worked-up at 0C by the careful addition OF H20, 15% aqueous (aqueous NAOH), H20 (3x). The organic layer is stirred for 1 hour at room temperature and the solids that formed are filtered off. The filtrate is evaporated the residue is partitioned between methylene chloride and brine. The organic layer is dried (Magnesium Sulfate), filtered and evaporated. The material is chromatographed with silica gel using 15% ethyl ACETATE/METHYLENE chloride to give 5.22 g of the aldehyde.
		A suspension of lithium aluminum hydride (3.11 g, 0.082 mol) in [ET20] (250 mL) was cooled at-55 C under Argon. A solution of Compound 3b (18.5 g, 0.068 mol) in Et20 (75 [MLJ'WAS] added dropwise over a period of 15 min so that the temperature did not [EXCEED-50 C. THE] cooling bath was removed and the mixture was warmed up to [5 C,] cooled again to-35 C and celite (50 g) was added. The mixture was quenched slowly with bisulphate solution (15. [30] g in 43 mL [OF H20) WHILE] the temperature was kept at [- 30 C.] The resulting mixture was warmed to [0 C,] filtered over celite and the solid residue on the filter was washed with EtOAc (750 mL) and [H2O] (500 mL). The organic layer was separated, washed with [0.] 5N [HC1] (100 mL), saturated [NAHC03] (100 mL) and brine (100 mL). The aqueous layer was extracted with EtOAc (500 mL) and the combined organic layers were dried, filtered and evaporated. The resulting residue was purified by [KUGELROHR] distillation [(120-140 C] at 1.5-2 mm Hg) to yield Compound 13a as a colorless oil. A mixture of 3-bromoquinoline (10.40 g, 0.05 mol), trimethylsilylacetylene (8.48 mL, 0.06 mol), [CUPROUS] iodide (0.5 g) and trans-dichlorobis (triphenylphosphine) palladium [(1] g) and TEA (15 mL) was heated at [70 C] in a sealed tube for 1 h. H20 (150 mL) was added, followed by [ET2O] (300 mL). The organic layer was separated and the aqueous layer extracted with [ET20] (200 mL). The combined organic layers were dried [(NA2SO4)] and concentrated. The residue was purified by flash column chromatography (eluent: 100% DCM) to give [3- (TRIMETHYLSILYLETHYNYL)] quinoline as a brown oil. [3-(TRIMETHYLSILYLETHYNYL)] quinoline was dissolved in anhydrous MeOH (100 mL) and [K2CO3] (0.69 g, 5 mmol) was added. The mixture was stirred at rt for 1 h and DCM (250 mL) was added. The mixture was filtered over celite. The filtrate was evaporated and the residue was purified by flash column chromatography to give Compound 13b as an off-white solid. Butyllithium (2. 5M in hexane, 9.44 mL, 23.6 mmol) was added dropwise to a solution of Compound 13b [(3.] 62 g, 23.6 mmol) in THF (150 mL) under argon, such that the temperature did not [EXCEED-60 C,] then the mixture was cooled [TO-70 C.] The mixture was stirred at-70 C for 15 min and a solution of Compound 13a in THF (40 mL) was added dropwise while maintaining the temperature between-60 [AND-70 C.] After stirring at-70 C for 30 min, the mixture was warmed to [0 C] over a period of 20 min and [H2O] [(1] mL) was added'. The resulting mixture was dried over [K2C03,] 1 filtered and evaporated. The residue was purified by flash column chromatography (eluent gradient: DCM/MeOH : 100: 0 to 95 : 5) to yield Compound 13c as an oil. A mixture of Compound 13c (6.05 g) in pyridine (100 mL) was hydrogenated in the presence of [LINDLAR'S] catalyst [(1] g) at 1 psi of hydrogen for 7 h. The catalyst was removed by filtration over celite and the solvent was evaporated. The residue was purified by flash column chromatography (eluent gradient: [HEXANE/ETOAC] : 9: 1 to 1: 1) to yield Compound 13d as a solid. A solution of methyl 3-chloro-3-oxopropionate (1.24 mL, 11.53 mmol) in DCM (20 mL) was added dropwise over a period of 30 min to a solution of Compound 13d (4.25 g, 11.53 mmol) and TEA (1.81 mL, 13 mmol) in DCM (80 mL) at [0 C] under argon. The mixture was stirred overnight at rt. Aqueous NH4C1 solution (50 mL) and DCM (150 mL) were added. The organic layer was separated and washed with sat. [NAHC03] (100 mL) and brine (100 mL), dried [(NA2S04),] filtered and evaporated. The residue was purified by flash column chromatography (eluent gradient: [HEXANE/ETOAC] : 4: 1 to 1: 1) to yield Compound 13e as an oil. A solution of Compound 13e (4.45 g, 9.5 mmol) in THF (20 mL) was added dropwise to a flask containing sodium hydride (60% in mineral oil, 0.57 g, 14.25 mmol, triple washed with hexane (3 x 25 mL) ) at [60 C] under argon. The mixture was heated to 60 [C] for 15 min. Chlorotrimethylsilane (2.41 g, 19 mmol) was added via syringe and the mixture was heated for 4 h at [60 C. H20] (0.5 mL) was added and the mixture was stirred overnight at rt. The reaction mixture was evaporated, DCM (250 mL) was added and the mixture was'dried [(NA2S04).] After filtration and evaporation, the residue was heated at [130 C] for 2 h under vacuum. Purification by flash column chromatography (eluent: 1% MeOH in DCM) gave Compound 13f as a yellow oil. A solution of Compound [13F] (0.375 g, 0.88 mmol) in MeOH (50 mL) was hydrogenated in the presence of 10% palladium on carbon (120 mg) at 1 psi of hydrogen for 2 h. The catalyst was removed by filtration over celite and the solvent was evaporated to give a crude Compound 13g, which was used as such for the next reaction. TFA (10 mL) was added to a solution of Compound 13g (0.35 g, 0.82 mmol) [ ] in DCM (10 mL). The mixture was stirred at rt for 1 h and concentrated under vacuum to give crude Compound 13h, which was used as such for the next reaction. I...
	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 2h;Inert atmosphere;	Tert-butyl 4-formylpiperidine-1-carboxylate was synthesized following the published procedure (Caroon JM, POT Int. AppI. 9943657, Sep 02, 1999) starting from tert-butyl 4-(methoxy(methyl)carmaboyl)piperidine-1 -carboxylate. The crude product wasused in the Wittig reaction without further purification.

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[13]Organic Preparations and Procedures International,2000,vol. 32,p. 96 - 99
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[16]Patent: US6335341,2002,B1 .Location in patent: Example 1
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[18]Patent: WO2004/100946,2004,A1 .Location in patent: Page 53
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[22]Journal of Medicinal Chemistry,2020,vol. 63,p. 1361 - 1387

3
[ 867-13-0 ]
[ 137076-22-3 ]
[ 198895-61-3 ]

Yield	Reaction Conditions	Operation in experiment
81%	Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.25h; Inert atmosphere; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In tetrahydrofuran; mineral oil at 0℃; for 1h; Inert atmosphere;
68%	Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With sodium hydride In tetrahydrofuran at 0℃; for 0.166667h; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In tetrahydrofuran at 0℃; for 0.5h;	35.b b) Ethyl 2-(diethoxyphosphoryl)acetate (0.542 ml, 2.73 mmol) was added at 0 °C to a suspension of sodium hydride (60 %, 109 mg, 2.73 mmol) in THF (10 ml), and the whole was stirred at 0 °C for 10 minutes. A solution of tert-butyl 4-formylpiperidine- 1-carboxylate (530 mg, 2.49 mmol) in THF (10 ml) was added and the whole was stirred at 0 0C for 30 minutes. The reaction mixture was quenched with saturated H2O, and the aqueous phase was extracted with ethyl acetate (50 ml x 2). The combined organic phase was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane: 0/100 to 20/80) to give (E)-tert-butyl 4-(3-ethoxy-3-oxoprop-l-enyl)piperidine-l- carboxylate (475 mg, 68 %) as a colorless oil.
52.7%	Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In tetrahydrofuran; mineral oil at 20℃; for 1h;	9.1; 19.1 Step-1 To a suspension of sodium hydride (60% in mineral oil, 1.03 g, 25.8 mmol, 1.1 eq) inTHF (50 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (10.51 g, 46.9 mmol, 2.0 eq)dropwise at 0 °C and the mixture was allowed to stir at the same temperature for 30 mm. To thismixture was added a solution of tert-butyl 4-formylpiperidine-1-carboxylate (5.0 g, 23.5 mmol)in THF (5 mL) and the resulting mixture was allowed to stir at room temperature for 1 h.Progress was monitored by TLC. After completion, the mixture was diluted with saturated aqueous NH4C1 (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated to dryness under vacuum. The crude product was purified by CombiFlash to afford tert-butyl (E)-4-(3-ethoxy-3-oxoprop- 1-en-i -yl)piperidine- 1 -carboxylate (3.5 g, 52.7%).LCMS: 284 [M+i]

52.7%	Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In tetrahydrofuran; mineral oil at 20℃; for 1h;	9.1; 19.1 Step-1 To a suspension of sodium hydride (60% in mineral oil, 1.03 g, 25.8 mmol, 1.1 eq) in THF (50 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (10.51 g, 46.9 mmol, 2.0 eq) dropwise at 0° C. and the mixture was allowed to stir at the same temperature for 30 min. To this mixture was added a solution of tert-butyl 4-formylpiperidine-1-carboxylate (5.0 g, 23.5 mmol) in THF (5 mL) and the resulting mixture was allowed to stir at room temperature for 1 h. Progress was monitored by TLC. After completion, the mixture was diluted with saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated to dryness under vacuum. The crude product was purified by CombiFlash to afford tert-butyl (E)-4-(3-ethoxy-3-oxoprop-1-en-1-yl)piperidine-1-carboxylate (3.5 g, 52.7%).
49%	With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.5h;
	With sodium hydride In tetrahydrofuran at 0℃;
	In tetrahydrofuran; hexane	25.A Step A Step A 3-(1-(tert-Butoxycarbonyl)piperidin-4-yl)propionic acid Triethyl phosphonoacetate (1.40 g, 6.24 mmol) was added in one portion to a stirred suspension of sodium hydride (60% oil dispersion, 245 mg, 6.13 mmol) in THF (20 mL) cooled in an ice bath. After 15 min, the cooling bath was removed. After an additional 20 min, the clear solution was cooled in an ice bath, and 1-(tert-butoxycarbonyl)-4-piperidinecarboxaldehyde (1.19 g, 5.58 mmol, from Example 24, Step B) was added in THF (1.0 mL) with additional THF (2*1.0 mL) for rinsing. After 5 min, the cooling bath was removed and the reaction was stirred for 2.5 h at rt. The mixture was partitioned between ether (100 mL) and 2.5 N aq. NaOH (50 mL). The organic layer was washed with sat'd NaCl (50 mL), dried (Na2SO4), decanted, and evaporated. The crude product was purified by flash column chromatography on silica gel, eluding with 8-10% EtOAc in hexane, to give 1.18 g of 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)prop-2-enoic acid ethyl ester as a colorless oil.
	With sodium hydride In tetrahydrofuran
	Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 0.75h; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In tetrahydrofuran; mineral oil at 0 - 20℃; for 16.25h;	1 Step 1: tert-butyl (E)-4-(3-ethoxy-3-oxoprop-1-en-1-yl)piperidine-1- carboxylate. NaH (60% oil dispersion, 1.09 g, 28.5 mmol) was suspended in THF (20 mL) at 0 °C. A solution of triethyl phosphonoacetate (5.6 mL, 28.5 mmol) in THF (10 mL) was added dropwise over 15 min. The reaction was warmed to rt, stirred for 30 min and cooled to 0 °C. A solution of 1-Boc-piperidine-4-carboxaldehyde (5.00 g, 23.5 mmol) in THF (10 mL) was added dropwise over 15 min. The reaction was warmed to rt, stirred for 16 h, cooled to 0 °C and water added. The organic solvent was evaporated and the aqueous portion was extracted three times with EtOAc. The combined organic portions were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (6.79 g) the crude title compound. LCMS [M+H] 284.4.

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[2]Current Patent Assignee: PURDUE PHARMA L.P. - WO2010/114181, 2010, A1 Location in patent: Page/Page column 96
[3]Current Patent Assignee: AURANSA - WO2019/103897, 2019, A1 Location in patent: Page/Page column 84; 85; 99
[4]Current Patent Assignee: AURANSA - US2020/377510, 2020, A1 Location in patent: Paragraph 0344-0345; 0415-0416
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[8]Current Patent Assignee: MERCK & CO INC - US6399619, 2002, B1
[9]Current Patent Assignee: MERCK & CO INC - US2004/2504, 2004, A1 Location in patent: Page/Page column 24
[10]Current Patent Assignee: CURZA GLOBAL LLC; UNIVERSITY OF UTAH - WO2020/150385, 2020, A1 Location in patent: Paragraph 00332

4
[ 110-89-4 ]
[ 137076-22-3 ]
[ 184968-88-5 ]

Yield	Reaction Conditions	Operation in experiment
93%	Stage #1: piperidine; tert butyl 4-formylpiperidine-1-carboxylate With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane; 1,2-dichloro-ethane at 20℃; for 2h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water; 1,2-dichloro-ethane	36.B To 1,1-dimethylethyl 4-formyl-1-piperidinecarboxylate (1.02 g, 4.78 mmol) in 1,2-dichloroethane (50 mL) was added sequentially, HOAc (6.00 mL, 1M in DCM, 6.00 mmol), piperidine (1.0 mL, 10.1 mmol) and sodium triacetoxyborohydride (1.60 g, 7.55 mmol). The reaction was stirred at rt for 2 hours at which time HOAc (1.00 mL, 1M in DCM, 1.00 mmol) and sodium triacetoxyborohydride was added. When complete by TLC the reaction was quenched with saturated NaHCO3 (150 mL) and extracted with DCM. The combined organic layer was washed with H2O, dried (MgSO4) and concentrated to provide the title compound (1.25 g, 4.43 mmol, 93%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80-0.91 (m, 2H), 1.29-1.35 (m, 11H), 1.38-1.46 (m, 4H), 1.59 (d, J=10.6 Hz, 3H), 2.00 (d, J=6.8 Hz, 2H), 2.21 (br. s., 4H), 2.62 (br. s., 2H), 3.85 (d, J=12.6 Hz, 2H).
57%	Stage #1: piperidine; tert butyl 4-formylpiperidine-1-carboxylate With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 1h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water	2.2 (Step 2) 1-(Tert-butyloxycarbonyl)-4-formylpiperidine (3.81 g, 17.9 mmol) obtained in the Step 1 was dissolved in dichloromethane (40 mL) and the solution was added with piperidine (2.70 mL, 27.3 mmol) and triacetoxy sodium borohydride (5.30 g, 25.0 mmol) under ice bath, followed by stirring at room temperature for 1 hour. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. After washing with saturated brine, the organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane to chloroform/methanol (9:1)) to obtain 1-(tert-butyloxycarbonyl)-4-piperidinomethylpiperidine (2.88 g, 57 %) as a clear oily substance. 1H NMR (CDCl3, δppm): 1.36-1.48 (m, 12H), 1.48-1.76 (m, 8H), 2.11 (d, J = 6.6 Hz, 2H), 2.25-2.37 (m, 4H), 2.67 (t, J = 12.3 Hz, 2H), 4.06 (d, J = 12.3 Hz, 2H).
	With 2,2,2-trifluoroethanol; 3 A molecular sieve; sodium cyanoborohydride

With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane at 20℃; for 16h;

2.C C. Synthesis of fert-butyl 4-(piperidin-l-ylmethyl)piperidine-l-carboxylate; [0067] Crude tert-butyl 4-formylpiperidine-l-carboxylate (28.4 mmol assumed from example 2B) was stirred in dry DCM (100 mL) at rt. NaBH(OAc)3 (12 g, 56.8 mmol), AcOH (0.3 mL), and piperidine (2.8 mL, 28.4 mmol) were added and the reaction mixture was stirred at rt for 16 h. Additional DCM (50 mL) was added and the reaction mixture was washed with saturated sodium bicarbonate solution followed by H2O. The organic layer was separated, dried over MgSO4, concentrated and purified by column chromatography (5% MeOH/DCM) to give 2.0 g of desired product as a clear colorless oil.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2008/300242, 2008, A1 Location in patent: Page/Page column 59
[2]Current Patent Assignee: Kyowa Kirin (in: Kirin Holdings); KIRIN HOLDINGS CO., LTD. - EP1847530, 2007, A1 Location in patent: Page/Page column 173
[3]Ting, Pauline C; Lee, Joe F; Anthes, John C; Shih, Neng-Yang; Piwinski, John J [Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 4, p. 491 - 494]
[4]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - WO2008/31227, 2008, A1 Location in patent: Page/Page column 22

5
[ 110-91-8 ]
[ 137076-22-3 ]
[ 340962-93-8 ]

Yield	Reaction Conditions	Operation in experiment
75%		To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (1.00 g, 4.69 mmol) in MeOH (10 mL) was added morpholine (613 mg, 7.04 mmol). The resulting mixture was stirred for 6 hr, then NaBH3CN (444 mg, 7.07 mmol) was added. The resulting solution was stirred at room temperature overnight and quenched with H2O (1 mL). The resulting mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with 3% MeOH in DCM. This resulted in 1.0 g (75%) of tert-butyl 4-(morpholin-4-ylmethyl) piperidine-1-carboxylate as yellow oil. LCMS (Method 25) [M+H]+=285.0, RT=0.59 min.
		140 2-( 1 H-Indazol-4- yl)-4-morpholin-4- yl-6-(4-morpholin-4- ylmethyl-piperidin- 1 - ylmethyl)-thieno[3,2-d]pyrimidine.Via 2-chloro-4-morpholin-4-yl-6-(4-morpholin-4-ylmethyl-piperidin- 1 - ylmethyl)-thieno[3,2-d]pyrimidine, prepared from 4-piperidin-4-ylmethyl- morpholine. Amine preparation: To a solution of l-BOC-piperidine-4-ethyl ester (2.Og), stirring in dry DCM (3OmL), at -78C under a nitrogen atmosphere was added diisobutylaluminium hydride solution (1.0M in hexane; 8.OmL), the mixture was stirred at -78C for 2 h, then warmed to room temperature and quenched with MeOH (ImL). The mixture was extracted into DCM and dried (MgSO4), and the solvents removed in vacuo to give a residue which was purified using flash chromatography to give l-BOC-4-formyl-piperidine (457mg).To a solution of l-BOC-4-formyl-piperidine (210mg) in dry 1,2- dichloroethane (1OmL), was added morpholine (86mg) and glacial acetic acid (60muL) and stirred for 1 h at room temperature. To the mixture was added sodium triacetoxyborohydride (272 mg) and the mixture stirred for 12 h. The reaction mixture was extracted into DCM (25mL), washed with 50 % sodium bicarbonate solution (1OmL), brine (1OmL), and dried (MgSO-J.The solvents were removed in vacuo to give a residue which was purified by flash chromatography to give 4- mophiholine-4-ylmethyl-piperidine-l-carboxylic acid tert-butyl ester (120mg). Treatment with TFA yielded the desired amine which was isolated as the TFA salt. EPO <DP n="74"/>1H NMR (400 MHz, J6-DMSO) 1.13 (m, 2H), 1.50 (m, IH)5 1.67 (m, 2H), 2.04 (m, 2H), 2.10 (d, 2H, J=7.2 Hz), 2.28 (br s, 4H), 2.89 (m, 2H), 3.53 (m, 4H), 3.77 (m, 4H + CH2), 3.99 (m, 4H), 7.45 (t, 2H, J=9.8 Hz), 7.65 (d, IH, J=8.2 Hz), 8.21 (d, IH, J=6.8 Hz), 8.87 (s, IH), 13.15 (bs, IH); MS (ESI+) 534.3 (MH+).

Reference： [1]Patent: US2015/336962,2015,A1 .Location in patent: Paragraph 0840
[2]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 491 - 494
[3]Patent: WO2006/46031,2006,A1 .Location in patent: Page/Page column 71-72

6
[ 4606-65-9 ]
[ 137076-22-3 ]
[ 184969-11-7 ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; In 1,2-dichloro-ethane; at 20℃; for 48h;	Step a. Each well was charged with a mixture of DCE/AcOH, (9/1, v/v), 0.1 ml, N-Boc-4-piperidinylcarboxaldehyde, 0.1 ml of stock solution (2 muM/well), and amine, 0.06 ml of stock solution (2.4 muM/well). After that resin bound trimethylammonium cyanoborohydride was added, 1 mg per well (4 muM/well) and mixture was allowed to react for 48 h. At the end reactor block was filtered into collection plate, dried in SpeedVac.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 491 - 494
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5353 - 5357

7
[ 4138-26-5 ]
[ 137076-22-3 ]
[ 340962-96-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 491 - 494

8
[ 90965-06-3 ]
[ 137076-22-3 ]
[ 287192-97-6 ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium carbonate In methanol at 20℃; for 16h; Inert atmosphere;	1 tert-butyl 4-ethynylpiperidine-1-carboxylate To a stirred solution of tert-butyl 4-formylpiperidine-1-carboxylate (100 g, 469 mmol, 1 equiv) and dimethyl-1-diazo-2-oxopropylphosphonate (99.08 g, 515.8 mmol, 1.1 equiv) in MeOH (1000 mL) was added K2CO3 (97.20 g, 703 mmol, 1.5 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 hours at room temperature under nitrogen atmosphere. The reaction was monitored by TLC. The resulting mixture was filtered, the filter cake was washed with ethanol (2x150 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether/EtOAc (100:1 to 20:1) to afford tert-butyl 4-ethynylpiperidine-1-carboxylate (97 g, 98%) as a white solid.
98%	With potassium carbonate In methanol at 20℃; for 16h; Inert atmosphere;	1 tert-butyl 4-ethynylpiperidine-1-carboxylate To a stirred solution of tert-butyl 4-formylpiperidine-1-carboxylate (100 g, 469 mmol, 1 equiv) and dimethyl-1-diazo-2-oxopropylphosphonate (99.08 g, 515.8 mmol, 1.1 equiv) in MeOH (1000 mL) was added K2CO3 (97.20 g, 703 mmol, 1.5 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 hours at room temperature under nitrogen atmosphere. The reaction was monitored by TLC. The resulting mixture was filtered, the filter cake was washed with ethanol (2x150 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether/EtOAc (100:1 to 20:1) to afford tert-butyl 4-ethynylpiperidine-1-carboxylate (97 g, 98%) as a white solid.
96%	With potassium carbonate In methanol for 3h;

91%	With potassium carbonate In methanol at 5 - 20℃; Cooling with ice;	5.1 tert-butyl 4-ethynylpiperidine-1-carboxylate Dissolve 4-formylpiperidine-1-carboxylic acid tert-butyl ester (10g, 46.95mmol) in a 500mL single-neck round bottom flask with 200mL methanol, and cool down to 5-10 in an ice water bath.Add (1-diazo-2-oxopropyl) dimethyl phosphonate (12.46g, 56.34mmol) and potassium carbonate (25.92,187.8mmol) in sequence, warm to room temperature and stir for 3-4 hours, monitored by TLC The reaction is over. Dilute with 200mL ethyl acetate, filter with a sand core funnel, wash the filter cake with 100mL ethyl acetate, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain tert-butyl 4-ethynylpiperidine-1-carboxylate. Ester (5a), colorless oil (8.92g, yield: 91%).
88%	With potassium carbonate In methanol at 20℃;	23.3 At 0 C, to a stirred mixture of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (358 mg, 1.68 mmols) and potassium carbonate (464 rng, 3.36 mmols) in methanol (16 ml) was added dropwise a solution of (1-diazo-2-oxo-propyl)- phosphonic acid dimethyl ester (323 mg, 1.68 mmols) in methanol (2 ml). The resulting mixture was stirred at room temperature overnight, filtered and concentrated. The residue was chromatographed on silica gel using a solution of ethyl acetate in hexanes (1:5) to provide the title compound (308 mg, 88%) as colorless crystals. LCMS m/e (154, M - M3u + 2H). (J. Am. Chem. Soc. 2003, 125, 3714.)
88%	With potassium carbonate In methanol at 20℃;	18.3 At 0 C, to a stirred mixture of 4-formyl-piperidine-1-carboxylic acid fert-butyl ester (358 mg, 1.68 mmols) and potassium carbonate (464 mg, 3.36 mmols) in methanol (16 ml) was added dropwise a solution of (1-diazo-2-oxo-propyl)- phosphonic acid dimethyl ester (323 mg, 1.68 mmols) in methanol (2 ml). The resulting mixture was stirred at room temperature overnight, filtered and concentrated. The residue was chromatographed on silica gel using a solution of ethyl acetate in hexanes (1 :5) to provide the title compound (308 mg, 88%) as colorless crystals. LCMS m/e (154, M - f-Bu + 2H). (J. Am. Chem. Soc. 2003, 725, 3714.)
81%	With potassium carbonate In methanol at 20℃;
81%	With potassium carbonate In methanol at 20℃; for 18h;	General procedure for the synthesis of compound 9 A solution of compound 7 (0.1 g, 0.41 mmol) in methanolwas stirred at room temperature for 10 min. Then compound8 (95 mg, 0.49 mmol) and K2CO3 (113 mg, 0.82 mmol) were added and stirred at room temperature for 18 h. Thereaction mixture was filtered through a celite pad to removeK2CO3. The solvent was evaporated under vacuum. Thenwater was added and the product was extracted by ethylacetate (3 × 30 ml). The crude material was purified bycolumn chromatography to obtain product. Compound 9 Yield 81%, white solid powder; MS: [M+H]+ 210.09; 1H-NMR (400MHz, CDCl3-D) δ 3.72 (m, 2H),3.20 (m, 2H), 2.06 (s, 1H), 2.12 (d, J = 2.4 Hz, 1H), 1.81(m, 2H), 1.60 (m, 2H), 1.47 (s, 9H). 13C-NMR (100MHz,CDCl3-D) δ 154.8, 86.4, 79.5, 69.5, 31.2, 28.4, 26.7.
55%	With potassium carbonate In methanol for 20h;	124.A Example 124; Preparation of tert-butyl 4-(2-(7-(4-(1-(carbamoyl)cyclopropanecarboxamido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)ethynyl)piperidine-1-carboxylate; Step A: Preparation of tert-butyl 4-ethynylpiperidine-1-carboxylate; To a stirred suspension of tert-butyl 4-formylpiperidine-1-carboxylate (0.427 g, 2.00 mmol), K2CO3 (0.553 g, 4.00 mmol), and MeOH (25 mL) was added all at once the Bestman-Ohira reagent, dimethyl 2-oxo-1-diazo-propylphosphonate (0.461 g, 2.40 mmol, see Synthesis 2004, 1, 59-62). Stirring was continued for 20 hours under nitrogen. The reaction was diluted with Et2O (50 mL), washed with a 2:1 mixture of water and aqueous saturated NaHCO3 (20 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Yield: 253 mg (55%). 1H NMR (400 MHz, CDCl3) δ 3.72 (m, 2H), 3.19 (m, 2H), 2.58 (m, 1H), 2.10 (d, J=2 Hz, 1H), 1.77 (m, 2H), 1.61 (m, 2H), 1.46 (s, 9H).
	With potassium carbonate In methanol for 3h;
	Stage #1: 4-formyl-piperidine-1-carboxylic acid tert-butyl ester With potassium carbonate In methanol for 0.5h; Stage #2: dimethyl 1-(1-diazo-2-oxopropyl)phosphonate In methanol for 12h;	1.1D Example 1D tert-butyl 4-ethynylpiperidine-1-carboxylate Example 1D tert-butyl 4-ethynylpiperidine-1-carboxylate To a solution of Example 1C (1 g, 4.69 mmol) in methanol (20 mL) was added potassium carbonate (3.89 g, 28.1 mmol) and the mixture was stirred for 30 minutes. Dimethyl 1-diazo-2-oxopropylphosphonate (3.60 g, 18.76 mmol) was added and the mixture was stirred for 12 hours. The mixture was filtered through diatomaceous earth with methanol, concentrated and purified by column chromatography on silica gel (Isco, Redi-Sep column), eluting with 15% ethyl acetate in hexane to afford the title compound. LCMS: 110 (M+H-Boc)+.
	With potassium carbonate In methanol at 20℃;	21B tert-butyl 4-ethynylpiperidine-1-carboxylate To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (2.2 g, 10.4 mmol) and potassium carbonate (2.9 g, 20.8 mmol) in methanol (100 mL) was added Example 21A (2.0 g, 10.4 mmol) in methanol (20 mL) and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate (twice). The combined organic layers were washed with brine and concentrated. Purification by flash chromatography on silica gel (Teledyne CombiFlash Rf, 1:5 ethyl acetate/hexane) gave the title compound. MS (DCI/NH3) m/z 210 (M+H)+.
	With potassium carbonate In methanol at 0℃; for 5h;
	With potassium carbonate In methanol
	With potassium carbonate In methanol at 0 - 25℃; for 12h; Inert atmosphere;	45.1 Step 1: tert-Butyl 4-ethynylpiperidine-1-carboxylate To a mixture of tert-butyl 4-formylpiperidine-1-carboxylate (1 g, 4.69 mmol, 1 eq), K2CO3 (1.30 g, 9.38 mmol, 2 eq) in MeOH (15 mL) was added a solution of 1-diazo-1-dimethoxyphosphoryl-propan-2-one (901.00 mg, 4.69 mmol, 1 eq) in MeOH (5 mL) at 0° C. Then the mixture was stirred at 25° C. for 12 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with EtOAc (30 mL) and H2O (20 mL) and extracted with EtOAc (30 mL*2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 0-15% Ethyl acetate/Petroleum ether gradient 30 mL/min) to yield tert-butyl 4-ethynylpiperidine-1-carboxylate (1 g, 4.41 mmol, 93.9% yield, 92.2% purity) as colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.72 (d, J=6.8 Hz, 2H), 3.28-3.14 (m, 2H), 2.69-2.51 (m, 1H), 2.14 (d, J=2.2 Hz, 1H), 1.91-1.75 (m, 2H), 1.64 (d, J=4.0 Hz, 1H), 1.61-1.56 (m, 1H), 1.49 (s, 9H); ES-LCMS m/z 154.1 [M-t-Bu+H]+.
	With potassium carbonate In methanol for 3h;	FIGURE 86 shows the synthesis of IL-2 binding bifunctional molecule IL2-GN3.
	With potassium carbonate In methanol at 0 - 20℃; for 4h;	3 Synthesis of tert-butyl 4-ethynylpiperidine-1-carboxylate (Intermediate 5) K2CO3 (260 g) was added to a solution of N-Boc-piperidine-4-aldehyde (100 g) in MeOH (500 mL) at 0° C. Then dimethyl 1-diazoacetonylphosphonate (108 g) was slowly added at 0° C. After stirring at room temperature for 4 h, the mixture was quenched with water, then most of the MeOH was removed by rotary evaporation. The residue was extracted with ethyl acetate, and the organic layer washed with brine, dried with Na2SO4, and concentrated to give Intermediate 5 which was used in next step without further purification.
	With potassium carbonate In methanol for 3h;

Reference： [1]Current Patent Assignee: GOLDFINCH BIO INC - WO2022/11274, 2022, A1 Location in patent: Page/Page column 63
[2]Current Patent Assignee: GOLDFINCH BIO INC - WO2022/11274, 2022, A1 Location in patent: Page/Page column 63
[3]Braisted, Andrew C.; Oslob, Johan D.; Delano, Warren L.; Hyde, Jennifer; McDowell, Robert S.; Waal, Nathan; Yu, Chul; Arkin, Michelle R.; Raimundo, Brian C. [Journal of the American Chemical Society, 2003, vol. 125, # 13, p. 3714 - 3715]
[4]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - CN113527260, 2021, A Location in patent: Paragraph 0378-0386
[5]Current Patent Assignee: MERCK & CO INC - WO2007/97937, 2007, A1 Location in patent: Page/Page column 191
[6]Current Patent Assignee: MERCK & CO INC - WO2008/156739, 2008, A1 Location in patent: Page/Page column 222
[7]Dirat, Olivier; Clipson, Alex; Elliott, Jason M.; Garrett, Sasha; Brian Jones; Reader, Michael; Shaw, Duncan [Tetrahedron Letters, 2006, vol. 47, # 11, p. 1729 - 1731]
[8]Shi, YeHui; Zhang, Wei; Li, Lixin; Tong, ZhongSheng; Bai, CuiGai [Medicinal Chemistry Research, 2018, vol. 27, # 11-12, p. 2437 - 2445]
[9]Current Patent Assignee: PFIZER INC - US2007/197537, 2007, A1 Location in patent: Page/Page column 101
[10]Raimundo, Brian C.; Oslob, Johan D.; Braisted, Andrew C.; Hyde, Jennifer; McDowell, Robert S.; Randal, Mike; Waal, Nathan D.; Wilkinson, Jennifer; Yu, Chul H.; Arkin, Michelle R. [Journal of Medicinal Chemistry, 2004, vol. 47, # 12, p. 3111 - 3130]
[11]Current Patent Assignee: ABBVIE INC - US2014/275153, 2014, A1 Location in patent: Paragraph 0541
[12]Current Patent Assignee: ABBVIE INC - US2015/218165, 2015, A1 Location in patent: Paragraph 1175
[13]Lehmann; Vomacka; Esser; Nodwell; Kolbe; Rämer; Protzer; Reiling; Sieber [MedChemComm, 2016, vol. 7, # 9, p. 1797 - 1801]
[14]Current Patent Assignee: Helmholtz Association; TECHNICAL UNIVERSITY OF MUNICH; Leibniz Association - WO2017/194734, 2017, A1 Location in patent: Page/Page column 44
[15]Current Patent Assignee: IKENA ONCOLOGY INC - US2019/55218, 2019, A1 Location in patent: Paragraph 0498; 0499; 0500; 0501
[16]Current Patent Assignee: YALE UNIVERSITY - WO2019/199634, 2019, A1 Location in patent: Page/Page column 32
[17]Current Patent Assignee: UNIVERSITY OF MICHIGAN - US2020/109149, 2020, A1 Location in patent: Paragraph 0254-0255
[18]Current Patent Assignee: YALE UNIVERSITY - WO2021/72269, 2021, A1 Location in patent: Page/Page column 166; 167

9
[ 558-13-4 ]
[ 137076-22-3 ]
[ 203664-61-3 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: carbon tetrabromide With triphenylphosphine In dichloromethane at 0℃; for 0.416667h; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In dichloromethane at 0℃; for 0.833333h;	[00229] Step 1: tert-butyl 4-(2,2-dibromovinyl)piperidine-1-carboxylate [00230] carbon tetrabromide (11.6 g, 35.1 mmol) in DCM (150 mL) was cooled in an ice bath and triphenylphosphine (18.4 g, 70.2 mmol) added and stirring at 0oC continued for 25 mins then tert-butyl 4-formylpiperidine-1-carboxylate (5 g, 23.4 mmol) added in one portion. After stirring at ice bath temperature for 50 mins the mixture was evaporated to about 1/3 the original volume to give a suspension. Cyclopentylmethyl ether (150 mL) added causing more precipitation and the mixture filtered washing with more cyclopentylmethyl ether. The filtrate was washed with water (200 mL), 10% aqueous sodium bisulfite, dried over Na2SO4, filtered and evaporated. The residue was triturated with 40% EtOAc in Heptane and filtered through a pad of silica (washing with further 40% EtOAc in Heptane and filtrate evaporated to give tert- butyl 4-(2,2-dibromovinyl)piperidine-1-carboxylate (7.84 g, 90%) as a white solid.1H NMR (500 MHz, Chloroform-d) δ 6.23 (d, J = 8.9 Hz, 1H), 4.06 (s, 2H), 2.88 - 2.65 (m, 2H), 2.44 (tdt, J = 11.4, 8.9, 3.9 Hz, 1H), 1.75 - 1.67 (m, 2H), 1.46 (s, 9H), 1.37 - 1.27 (m, 2H).
81%	With triphenylphosphine In dichloromethane at 0℃; for 1h;
80%	With triphenylphosphine In dichloromethane at 0℃; for 1h;

77%	Stage #1: carbon tetrabromide With triphenylphosphine In dichloromethane at 0℃; for 0.5h; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In dichloromethane for 2h;
41%	Stage #1: carbon tetrabromide With triphenylphosphine In dichloromethane at 0℃; for 0.333333h; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In dichloromethane at 0 - 20℃; for 18h;
	With triphenylphosphine In dichloromethane
	With triphenylphosphine In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; ethyl acetate	1.3 1-(t-Butoxycarbonyl)-4-(2,2-dibromoethen-1-yl)-piperidine Step 3 1-(t-Butoxycarbonyl)-4-(2,2-dibromoethen-1-yl)-piperidine A solution of 48.615 g (146.6 mmole) carbon tetrabromide in 150 mL DCM was added dropwise with stirring to a solution of 76.895 g (293.2 mmole) triphenylphosphine in 150 mL DCM in a 1-L rb flask with ice bath cooling over 1.75 hours. After 40 minutes, a solution of 15.631 g (73.29 mmole) 1-(t-butoxycarbonyl)-4-formyl-piperidine (from Step 2 above) in 100 mL DCM was added to the resulting brown suspension with stirring and cooling over 40 minutes. After one hour, 200 mL ether and 400 mL hexanes was added. The top suspension was filtered through Celite, and the residue was resuspended in 150 mL DCM and treated with 300 mL ether. The mixture was filtered, and the solid was washed with hexanes till total filtrate was 2 L. The filtrate was filtered again through Celite and washed with hexanes. The filtrate was washed with 100 mL 5% NaHCO3, 300 mL water (2*), and 150 mL brine. The organic layer was dried over Na21SO4 and concentrated under vacuum to give crude product as a yellowish solid. Flash chromatography (FC) on 250 g silica gel (0~15% EtOAc in hexanes) gave title compound as a white solid. RF:0.57 (15% EtOAc in hexanes); 1H NMR (500 MHz) δ6.25 (d, J=8.9 Hz, 1H), 4.04~4.12 (m, 2H), 2.75~2.83 (m, 2H), 2.42~2.50 (m, 1H), 1.69~1.75 (m, 2H), (s, 9H), 1.29~1.37 (m, 2H).
42.54 g (75%)	With triethylamine; triphenylphosphine In dichloromethane	12.3 12.3 12.3 A solution of 160.86 g (613.3 mmol) of triphenylphosphine in 600 ml CH2Cl2 was treated with 101.7 g (306.6 mmol) of tetrabromomethane (the reaction heated up to 32° C.) and after 50 min at 20° C., 97.8 ml (705.3 mmol) of triethylamine was added (the reaction heated up to 35° C. and the color became dark violet). After cooling (0° C.), 32.7 g (153.4 mmol) of 4-Formyl-piperidine-1-carboxylic acid tert-butyl ester in 380 ml CH2Cl2 were added slowly (20 min). The solution was stirred over night at RT, evaporated and filtered through silica gel (deactivated with hexane/Et3N; with hexane and then hexane/ether 4:1 to 1:1) to give 42.54 g (75%) of 4-(2,2-dibromo-vinyl)-piperidine-1-carboxylic acid tert-butyl ester, mp: 82.3-83.9° C., MS: 368 (MH+, 2Br).
	With triphenylphosphine In dichloromethane	Ethyl[1-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)piperidin-4-yl]propiolate Ethyl[1-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)piperidin-4-yl]propiolate 200 ml of a solution of 19.7 g of triphenylphosphine and 12.4 g of carbon tetrabromide in dichloromethane was stirred under ice-cooling and 20 ml of a solution of 4.0 g of 1-(tert-butoxycarbonyl)piperidine-4-carbaldehyde in dichloromethane was dropped thereinto. After stirring for 1 hour, the reaction mixture was diluted with diethyl ether and filtered through celite to thereby remove the insoluble residue. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate/n-hexane) to thereby give 5.7 g of 4-(2,2-dibromovinyl)-1-(tert-butoxycarbonyl)piperidine as a colorless oily component.
	With triphenylphosphine In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; ethyl acetate	1.3 Step 3 Step 3 1-(t-Butoxycarbonyl)-4-(2,2-dibromoethen-1-yl)-piperidine A solution of 48.615 g (146.6 mmole) carbon tetrabromide in 150 mL DCM was added dropwise with stirring to a solution of 76.895 g (293.2 mmole) triphenylphosphine in 150 mL DCM in a 1-L rb flask with ice bath cooling over 1.75 hours. After 40 minutes, a solution of 15.631 g (73.29 mmole) 1-(t-butoxycarbonyl)-4-formyl-piperidine (from Step 2 above) in 100 mL DCM was added to the resulting brown suspension with stirring and cooling over 40 minutes. After one hour, 200 mL ether and 400 mL hexanes was added. The top suspension was filtered through Celite, and the residue was resuspended in 150 mL DCM and treated with 300 mL ether. The mixture was filtered, and the solid was washed with hexanes till total filtrate was 2 L. The filtrate was filtered again through Celite and washed with hexanes. The filtrate was washed with 100 mL 5% NaHCO3, 300 mL water (2*), and 150 mL brine. The organic layer was dried over Na2SO4 and concentrated under vacuum to give 53.458 g crude product as a yellowish solid. Flash chromatography (PC) on 250 g silica gel (0-15% EtOAc in hexanes) gave 21.595 g title compound as a white solid. RF: 0.57 (15% EtOAc in hexanes); 1H NMR (500 MHz) δ 6.25 (d, J=8.9 Hz, 1H), 4.04-4.12 (m, 2H), 2.75-2.83 (m, 2H), 2.42-2.50 (m, 1H), 1.69-1.75 (m, 2H), 1.47 (s, 9H), 1.29-1.37 (m, 2H).
	Stage #1: carbon tetrabromide With triphenylphosphine In dichloromethane at 0℃; for 2.41667h; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In dichloromethane for 0.166667h;	1.D.B.3; 5 A solution of 48.615 g (146.6 mmol) carbon tetrabromide in 150 mL DCM was added dropwise with stirring to a solution of 76.895 g (293.2 mmol) triphenylphosphine in 150 mL DCM in a 1-L rb flask with ice bath cooling over 1.75 h. After 40 min, a solution of 15.631 g (73.29 mmol) of the product of Step 2 above in 100 mL DCM was added to the resulting brown suspension with stirring and cooling over 40 min. After 1 h, 200 mL ether and 400 mL hexanes was added. The top suspension was filtered through Celite, and the residue was resuspended in 150 mL DCM and treated with 300 mL ether. The mixture was filtered, and the solid was washed with hexanes till total filtrate was 2 L. The filtrate was filtered again through Celite and washed with hexanes. The filtrate was washed with 100 mL 5% NaHCO3, 300 mL water (2*), and 150 mL brine. The organic layer was dried over Na2SO4 and concentrated under vacuum to give crude product as a yellowish solid. Flash chromatography (FC) on 250 g silica gel (0~15% EtOAc in hexanes) gave title compound as a white solid. RF: 0.57 (15% EtOAc in hexanes); 1H NMR (500 MHz) δ6.25 (d, J=8.9 Hz, 1H), 4.04~4.12 (m, 2H), 2.75~2.83 (m, 2H), 2.42~2.50 (m, 1H), 1.69~1.75 (m, 2H), 1.47 (s, 9H), 1.29~1.37 (m, 2H).
	With triphenylphosphine
	Stage #1: carbon tetrabromide With triphenylphosphine In dichloromethane at 0℃; for 0.416667h; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In dichloromethane at 0℃; for 0.833333h;	A Step A: ter -butyl 4-(2,2-dibromovinyl piperidine- 1 -carboxylateCarbon tetrabromide (2.332 g, 7.03 mmol) was dissolved in CH2C12 (30.2 ml, 469 mmol) and the solution was cooled in a 0°C bath. Triphenylphosphine (3.69 g, 14.07 mmol) was added, giving an orange colored solution as it dissolved. After 25 min tert-butyl 4-formylpiperidine-l- carboxylate (1 g, 4.69 mmol) was added in one portion to the 0°C solution. After 50 min, the solution was concentrated to about 1/3 the original volume, causing a precipitate.Cyclopentylmethyl ether was then added slowly, causing more precipitation. The suspension was filtered, rinsing with CPME. More precipitate appeared in the filtrate, so it was filtered again. The filtrate was partitioned with water. The aqueous layer was removed. The organic layer was washed with dilute aqueous sodium bisulfite followed by water. The final organic layer was concentrated to a mixture of solid and oil. The residue was triturated with 40% ethyl acetate/hexanes and filtered through a pad of silica. The filtrate was concentrated to yield the dibromoalkene as a white solid. 1H NMR (500 MHz, CDC13) δ 6.23 (d, J 8.9 Hz, 1H), 4.15-3.98 (m, 2H), 2.83-2.72 (m, 2H), 2.48-2.40 (m, 1H), 1.75-1.67 (m, 2H), 1.45 (s, 9H), 1.37-1.26 (m, 2H).
	With triphenylphosphine In dichloromethane Inert atmosphere;
	Stage #1: carbon tetrabromide With triphenylphosphine In dichloromethane at 0℃; for 0.416667h; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In dichloromethane at 0℃; for 0.833333h;
3.59 g	With triphenylphosphine In dichloromethane for 1h; Cooling with ice;	70.1 Reference Example 70 To a solution of carbon tetrabromide (12.5 g) and triphenylphosphine (19.7 g) in dichioromethane (200 mE) was added a solution of the Compound 1 (4.0 g) in dichloromethane (20 mE) under ice-cooling, and the resulting mixture was stirred at the same temperature for 1 hout To the reaction mixture was added diethyl ether (200 mE), and the resulting mixture was stirred, and then the resulting precipitates were removed by filtration, and the resulting filtrate was concentrated under reduced pressure. The resulting residues were purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 90:10) to give the Compound 2 (3.59 g) as a colorless powdet MS (APCI):mlz 368/370 [M+H]
3.59 g	With triphenylphosphine In dichloromethane for 1h; Cooling with ice;	70.1 (1) Carbon tetrabromide (12.5 g) and triphenylphosphine (19.7 g)Of dichloromethane (200 mL)Compound 1 (4.0 g) was added to the solution under ice cooling,Of dichloromethane (20 mL)The solution was added,The mixture was stirred at the same temperature for 1 hour.To the reaction mixture was added diethyl ether (200 mL)Was added and stirred,The precipitate was filtered off,The filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0 to 90: 10)Compound 2 (3.59 g) was obtained as a colorless powder.
	With triphenylphosphine In dichloromethane at -7 - 10℃; for 16h; Inert atmosphere; Large scale;	3.3 (3) Under the protection of nitrogen, open the vacuum of the 1000L glass-lined reaction kettle and draw in 80kg of the compound aldehyde (Y = N-Boc, piperidine ring) represented by formula (III); draw in 500kg of dichloromethane, and open the lid of the reaction kettle Put 164.1kg of carbon tetrabromide under stirring; turn on the frozen brine to reduce the temperature in the kettle to about -7 ° C; add 259.6kg of triphenylphosphine in batches while stirring to control the temperature in the kettle below 10 ° C. Incubate the reaction for 16h until the reaction is complete. The reaction system was centrifuged through a centrifuge, and the filter cake was washed with 150 kg of MTBE. The filtrate was desolvated to almost no flow. 800 kg of petroleum ether was pumped into the kettle, and 50 kg of MTBE was beaten and centrifuged. The mother liquor was desolvated to almost no flow to obtain 131.5 kg of a compound 1,1-dibromoolefin (Y = N-Boc, piperidine ring) represented by formula (IV). ), The yield is 95%; the compound represented by formula (IV) in the crude product is directly used in the next reaction;

Reference： [1]Current Patent Assignee: KALLYOPE - WO2021/71837, 2021, A1 Location in patent: Paragraph 00229-00230
[2]Kaneko, Toshihiko; Clark, Richard S. J.; Ohi, Norihito; Ozaki, Fumihiro; Kawahara, Tetsuya; Kamada, Atsushi; Okano, Kazuo; Yokohama, Hiromitsu; Ohkuro, Masayoshi; Muramoto, Kenzo; Takenaka, Osamu; Kobayashi, Seiichi [Chemical and Pharmaceutical Bulletin, 2004, vol. 52, # 6, p. 675 - 687]
[3]Liu, Feng; Tu, Jia-Lin; Zhu, Ze-Fan [Chemical Communications, 2019, vol. 55, # 76, p. 11478 - 11481]
[4]Bédard, Sandrine; Cavallo, Luigi; Falivene, Laura; Gauthier, Raphaël; Nolan, Steven P.; Paquin, Jean-François; Saab, Marina; Tzouras, Nikolaos V.; Van Hecke, Kristof; Zhang, Ziyun [Chemistry - A European Journal, 2022, vol. 28, # 4]
[5]Coffin, Aaron; Ready, Joseph M. [Organic Letters, 2019, vol. 21, # 3, p. 648 - 651]
[6]Shu, Min; Loebach, Jennifer L.; Parker, Kerry A.; Mills, Sander G.; Chapman, Kevin T.; Shen, Dong-Ming; Malkowitz, Lorraine; Springer, Martin S.; Gould, Sandra L.; DeMartino, Julie A.; Siciliano, Salvatore J.; Di Salvo, Jerry; Lyons, Kathy; Pivnichny, James V.; Kwei, Gloria Y.; Carella, Anthony; Carver, Gwen; Holmes, Karen; Schleif, William A.; Danzeisen, Renee; Hazuda, Daria; Kessler, Joseph; Lineberger, Janet; Miller, Michael D.; Emini, Emilio A. [Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 4, p. 947 - 952]
[7]Current Patent Assignee: MERCK & CO INC - US2002/193407, 2002, A1
[8]Current Patent Assignee: ROCHE HOLDING AG - US2002/68753, 2002, A1
[9]Current Patent Assignee: EISAI CO LTD - US6518423, 2003, B1
[10]Current Patent Assignee: MERCK & CO INC - US6248755, 2001, B1
[11]Current Patent Assignee: MERCK & CO INC - US2004/2504, 2004, A1 Location in patent: Page/Page column 19; 39
[12]Location in patent: scheme or table Szewczyk, Jason W.; Acton, John; Adams, Alan D.; Chicchi, Gary; Freeman, Stanley; Howard, Andrew D.; Huang, Yong; Li, Cai; Meinke, Peter T.; Mosely, Ralph; Murphy, Elizabeth; Samuel, Rachel; Santini, Conrad; Yang, Meng; Zhang, Yong; Zhao, Kake; Wood, Harold B. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 9, p. 2665 - 2669]
[13]Current Patent Assignee: MERCK & CO INC - WO2012/173917, 2012, A1 Location in patent: Page/Page column 39-40
[14]Liang, Tao; Nguyen, Khoa D.; Zhang, Wandi; Krische, Michael J. [Journal of the American Chemical Society, 2015, vol. 137, # 9, p. 3161 - 3164]
[15]Liu, Ping; Hu, Zhiyong; Dubois, Byron G.; Moyes, Christopher R.; Hunter, David N.; Zhu, Cheng; Kar, Nam Fung; Zhu, Yuping; Garfunkle, Joie; Kang, Ling; Chicchi, Gary; Ehrhardt, Anka; Woods, Andrea; Seo, Toru; Woods, Morgan; Van Heek, Margaret; Dingley, Karen H.; Pang, Jianmei; Salituro, Gino M.; Powell, Joyce; Terebetski, Jenna L.; Hornak, Viktor; Campeau, Louis-Charles; Lamberson, Joe; Ujjainwalla, Fez; Miller, Michael; Stamford, Andrew; Wood, Harold B.; Kowalski, Timothy; Nargund, Ravi P.; Edmondson, Scott D. [ACS Medicinal Chemistry Letters, 2015, vol. 6, # 8, p. 936 - 941]
[16]Current Patent Assignee: MITSUBISHI CHEMICAL HOLDINGS CORPORATION - US2018/258076, 2018, A1 Location in patent: Paragraph 0509
[17]Current Patent Assignee: MITSUBISHI CHEMICAL HOLDINGS CORPORATION - JP2018/199673, 2018, A Location in patent: Paragraph 0182
[18]Current Patent Assignee: HANGZHOU ALLSINO BIOTECHNOLOGY - CN110627827, 2019, A Location in patent: Paragraph 0024

10
[ 867-13-0 ]
[ 137076-22-3 ]
[ 162504-86-1 ]

Yield	Reaction Conditions	Operation in experiment
89%	Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With sodium hydride In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In tetrahydrofuran at 20℃; for 18h;	1 In the 0 °C conditions, to dissolved with 92 ml phosphoric acid and acetic acid ethyl three 250 ml THF adding 18g sodium hydride, stirring 1h after, a slow drip 49g II of compound 135 ml THF, and milling slowly after temperature to room temperature, the reaction 18h, TLC monitoring the reaction is complete, add 300 ml water, then 200 ml ethyl acetate extraction 4 times, the combined organic phase, rotary evaporation drying product is obtained after the crude, through column chromatography separation (PE: EA=10:1), to obtain 58g pure compound III, yield is 89%.
	With sodium hydride

Reference： [1]Current Patent Assignee: FIRST AFFILIATED HOSPITAL OF HENAN UNIVERSITY OF SCIENCE AND TECHNOLOGY - CN104829592, 2017, B Location in patent: Paragraph 0027; 0028
[2]Yamanaka, Toshio; Ohkubo, Mitsuru; Takahashi, Fumie; Kato, Masayuki [Tetrahedron Letters, 2004, vol. 45, # 13, p. 2843 - 2845]

11
[ 75-52-5 ]
[ 137076-22-3 ]
[ 301221-56-7 ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium <i>tert</i>-butylate In tetrahydrofuran; <i>tert</i>-butyl alcohol at 20℃; for 2h;	1013 To a solution of THF (15 ml) and t-BuOH (15 ml) was added compound 1013A (1.2 g, 5.6 mmol) and nitromethane (0.61 mL, 11.2 mmol) followed by addition of KOfBu (0.63 g, 5.6 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was adjusted to pH 6 using HOAc. The reaction mixture was diluted with EtOAc (30 mL), and was extracted with brine. The aqueous layer was extracted with EtOAc (30 mL x 2) The combined organic layers were washed with brine, dried, and concentrated to dryness. The crude material was purified via PTLC (25% EtOAc/Hexanes) to give 1.24 g (81%) of compound 1013B.
62%	With potassium <i>tert</i>-butylate In tetrahydrofuran; <i>tert</i>-butyl alcohol at 20℃; for 2h;
	With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran

	With potassium <i>tert</i>-butylate In tetrahydrofuran; <i>tert</i>-butyl alcohol at 0 - 20℃; Inert atmosphere;
	With potassium <i>tert</i>-butylate In tetrahydrofuran; <i>tert</i>-butyl alcohol at 20℃; for 2h;	I.a Step a :5 g (23.44 mmol) of 4-formylpiperidine-1-carboxylic acid tert-butyl ester were dissolved in 40 ml of THF and 40 ml of tert-butanol. 2.63 g (23.44 mmol) of potassium tert-butoxide and 2.51 ml (46.89 mmol) of nitromethane were added, and the reaction mixture was stirred at room temperature for 2 h. 1.6 ml of acetic acid was added, and the reaction mixture was diluted with ethyl acetate, washed 4 times with a saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness.7.2 g yellow oil, Rt.=2.91 min (method A), LCMS: 275 (M+H).
0.8 mg	With potassium <i>tert</i>-butylate In tetrahydrofuran; <i>tert</i>-butyl alcohol at 20℃; for 2h;	R Preparation R ferf-butyl 4-(1-hydroxy-2-nitroethyl)piperidine-1-carbox late [ XXV A = tert-but l-4-piperidine-1-carboxylate] Preparation R ferf-butyl 4-(1-hydroxy-2-nitroethyl)piperidine-1-carbox late [ XXV A = tert-but l-4-piperidine-1-carboxylate] erf-butyl 4-formylpiperidine-1-carboxylate (1.2 g, 5.6 mmol) and nitromethane (0.61 mL, 11.2 mmol) were added to a solution of THF (15 ml) and t-BuOH (15 ml) and addition of K-OtBu (0.63 g, 5.6 mmol) followed. The mixture was stirred at room temperature for 2 h. The reaction mixture was brought to pH 6 using HOAc, diluted with EtOAc (30 mL), and extracted with brine. The aqueous layer was extracted with EtOAc (30 mL x 2) The combined organic layers were washed with brine, dried, and concentrated to dryness. The crude material was purified via crystallization with diethyl ether and EtOAc, obtained 0.8g1H NMR (400 MHz, DMSO-d6) δ 5.38 (d, J = 6.35 Hz, 1 H), 4.69 - 4.76 (m, 1 H), 4.36 (dd, J = 9.70, 12.39 Hz, 1 H), 3.87 - 4.02 (m, 3H), 2.57 - 2.68 (m, 2H), 1.60 - 1.72 (m, 1 H), 1.44 - 1.60 (m, 2H), 1.36 - 1.42 (m, 9H), 1.04 - 1.21 (m, 2H).
	With potassium <i>tert</i>-butylate In tetrahydrofuran; <i>tert</i>-butyl alcohol at 0 - 20℃; for 13h; Inert atmosphere;

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2006/19768, 2006, A1 Location in patent: Page/Page column 140
[2]Di Lello, Paola; Pastor, Richard; Murray, Jeremy M.; Blake, Robert A.; Cohen, Frederick; Crawford, Terry D.; Drobnick, Joy; Drummond, Jason; Kategaya, Lorna; Kleinheinz, Tracy; Maurer, Till; Rougé, Lionel; Zhao, Xianrui; Wertz, Ingrid; Ndubaku, Chudi; Tsui, Vickie [Journal of Medicinal Chemistry, 2017, vol. 60, # 24, p. 10056 - 10070]
[3]Shankaran; Donnelly, Karla L.; Shah, Shrenik K.; Guthikonda, Ravindra N.; MacCoss, Malcolm; Mills, Sander G.; Gould, Sandra L.; Malkowitz, Lorraine; Siciliano, Salvatore J.; Springer, Martin S.; Carella, Anthony; Carver, Gwen; Hazuda, Daria; Holmes, Karen; Kessler, Joseph; Lineberger, Janet; Miller, Michael D.; Emini, Emilio A.; Schleif, William A. [Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 13, p. 3419 - 3424]
[4]Dirocco, Daniel A.; Rovis, Tomislav [Journal of the American Chemical Society, 2011, vol. 133, # 27, p. 10402 - 10405]
[5]Current Patent Assignee: MERCK KGAA - US2012/252815, 2012, A1 Location in patent: Page/Page column 60
[6]Current Patent Assignee: NERVIANO MEDICAL SCIENCES S.R.L. - WO2013/50448, 2013, A1 Location in patent: Page/Page column 64
[7]White, Nicholas A.; Dirocco, Daniel A.; Rovis, Tomislav [Journal of the American Chemical Society, 2013, vol. 135, # 23, p. 8504 - 8507]

12
[ 124443-68-1 ]
[ 137076-22-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	With diisobutylaluminium hydride In dichloromethane at -78℃; for 0.5h;	To a stirred solution of 1 -(/er/-butyl) 4-methyl piperidine- 1,4-dicarboxylate (10.5 g, 43.3 mmol) in CH2CI2 (200 mL) at -78 °C was added DIBAL-//(43.2 L, 43.3 mmol) slowly to the reaction mixture and stirred for 30 mins. Reaction was neutralized with saturated solution of sodium potassium tartatrate (50 mL) at same temperature, added CH2CI2 (100 mL) and allowed to stir reaction until layer separation at 23 °C. Organic layer was separated and aqueous layer was washed with CH2CI2 (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04, concentrated under vacuum, and purified with flash column chromatography to give tert- butyl 4-formylpiperidine-l-carboxylate (8.78 g, 95%) as a colorless oil.
	Stage #1: 1-tert-Butyl 4-methyl piperidine-1,4-dicarboxylate With diisobutylaluminium hydride In diethyl ether; toluene at -70℃; for 1.33333h; Stage #2: With ammonium carbonate In water; acetone	2.B B . Synthesis of fe/t-butyl 4-formylpiperidine- 1 -carboxylate; [0066] 1-tert-butyl 4-methyl piperidine-l,4-dicarboxylate (6.9 g, 28.4 mmol) was stirred under N2 in dry toluene (100 mL) at -7O0C. DIBALH (1 mmol solution in Et2O, 28.4 mL, 28.4 mmol) was added drop-wise over Ih maintaining the temperature below -70°C. The reaction was stirred for a further 20 min then H2O: Acetone (1:1, 20 mL) was added drop- wise over 30 min. Powdered (NFLO2CO3 was added and the reaction allowed to warm to rt. The reaction was filtered and the filtrate washed with brine, dried over MgSO4 and concentrated to yield crude product containing some starting material and alcohol as determined by TLC. The product was used in subsequent reactions without purification.
	Multi-step reaction with 2 steps 1.1: lithium aluminium tetrahydride / tetrahydrofuran / 0 °C 2.1: dimethyl sulfoxide; oxalyl dichloride / dichloromethane / 4 h 2.2: -78 °C

	Multi-step reaction with 2 steps 1.1: lithium aluminium tetrahydride / tetrahydrofuran / 0 °C 2.1: dimethylsulfide; oxalyl dichloride / dichloromethane / 4 h / -78 °C 2.2: -78 °C
	Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0 °C 2: oxalyl dichloride / dichloromethane; dimethyl sulfoxide / 4 h / -78 °C
	Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0 °C / Inert atmosphere 2: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 4 h / -78 °C
	Multi-step reaction with 2 steps 1: lithium borohydride / tetrahydrofuran / 0 °C / Reflux 2: pyridinium chlorochromate / dichloromethane / 0 - 25 °C

Reference： [1]Current Patent Assignee: HARVARD UNIVERSITY; ZIKANI THERAPEUTICS INC; ELOXX PHARMACEUTICALS INC - WO2020/106627, 2020, A1 Location in patent: Paragraph 00316
[2]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - WO2008/31227, 2008, A1 Location in patent: Page/Page column 21-22
[3]Current Patent Assignee: WUXI APPTEC CO., LTD.; MERCK & CO INC - WO2014/15495, 2014, A1
[4]Current Patent Assignee: WUXI APPTEC CO., LTD.; MERCK & CO INC - WO2014/18764, 2014, A1
[5]Current Patent Assignee: MERCK & CO INC - WO2015/17305, 2015, A1
[6]Current Patent Assignee: MERCK & CO INC - WO2016/60941, 2016, A1
[7]Current Patent Assignee: Gruenenthal Pharma GmbH & Co. Kommanditgesellschaft - US2010/113417, 2010, A1

13
[ 1774-47-6 ]
[ 137076-22-3 ]
[ 921199-39-5 ]

Yield	Reaction Conditions	Operation in experiment
99%	Stage #1: trimethylsulfoxonium iodide With sodium hydride In dimethyl sulfoxide at 0 - 20℃; for 1h; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In dimethyl sulfoxide at 20℃; Inert atmosphere;	9 To a suspension of trimethylsulfoxonium iodide (1.2 g, 5.6 mmol) in DMSO at 0oC was added NaH (250 mg, 6.1 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1h. Then tert-butyl 4-formylpiperidine-1-carboxylate (1.0 g, 4.7 mmol) was added. The reaction was stirred at room temperature under N2overnight. TLC test showed that the reaction was completed. The reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed by brine, dried over Na2SO4. Solvent was removed under vacuum and the resulting residue was used without further purification as yellow oil (1.0 g, yield: 99%)
61%	With sodium hydride In dimethyl sulfoxide at 20℃;
	Stage #1: trimethylsulfoxonium iodide With sodium hydride In dimethyl sulfoxide at 0 - 20℃; for 1h; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In dimethyl sulfoxide at 20℃; Inert atmosphere;	Representative procedure for synthesis of compound 210 [00214] To a suspension of trimethylsulfoxonium iodide (1.2 g, 5.6 mmol) in DMSO at 0 oC was added NaH (250 mg, 6.1 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1h. Then tert-butyl 4-formylpiperidine-1-carboxylate (1.0 g, 4.7 mmol) was added. The reaction was stirred at room temperature under N2 overnight. TLC test showed that the reaction was completed. The reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed by brine, dried over Na2SO4. Solvent was removed under vacuum and the resulting residue was used without further purification as yellow oil (1.0 g, yield: 99%).

Reference： [1]Current Patent Assignee: KURA ONCOLOGY, INC. - WO2016/40330, 2016, A1 Location in patent: Paragraph 00486
[2]Someya, Hidenori; Kondoh, Azusa; Sato, Akinori; Ohmiya, Hirohisa; Yorimitsu, Hideki; Oshima, Koichiro [Synlett, 2006, # 18, p. 3061 - 3064]
[3]Current Patent Assignee: KURA ONCOLOGY, INC. - WO2018/106818, 2018, A1 Location in patent: Paragraph 00214

14
[ 137076-22-3 ]
[ 301221-57-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3419 - 3424
[2]Patent: US2012/252815,2012,A1
[3]Patent: US2014/249146,2014,A1
[4]Journal of Medicinal Chemistry,2017,vol. 60,p. 10056 - 10070
[5]Patent: WO2006/113837,2006,A2
[6]Patent: WO2013/50448,2013,A1

15
[ 137076-22-3 ]
[ 301232-45-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: NaH / tetrahydrofuran / 0 °C 2: H₂ / Pd/C / methanol / 20 °C
	Multi-step reaction with 2 steps 1: tetrahydrofuran / 20 °C 2: palladium 10% on activated carbon; hydrogen / methanol
	Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 0.75 h / 0 - 20 °C 1.2: 16.25 h / 0 - 20 °C 2.1: palladium 10% on activated carbon; hydrogen / ethanol / 32 h

Reference： [1]Ogino, Yoshio; Ohtake, Norikazu; Kobayashi, Kensuke; Kimura, Toshifumi; Fujikawa, Toru; Hasegawa, Takuro; Noguchi, Kazuhito; Mase, Toshiaki [Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 13, p. 2167 - 2172]
[2]Rossi, Cristina; Porcelloni, Marina; D'Andrea, Piero; Fincham, Christopher I.; Ettorre, Alessandro; Mauro, Sandro; Squarcia, Antonella; Bigioni, Mario; Parlani, Massimo; Nardelli, Federica; Binaschi, Monica; Maggi, Carlo A.; Fattori, Daniela [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 8, p. 2305 - 2308]
[3]Current Patent Assignee: UNIVERSITY OF UTAH; CURZA GLOBAL LLC - WO2020/150385, 2020, A1

16
[ 137076-22-3 ]
[ 154775-43-6 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 2492 - 2502

17
[ 137076-22-3 ]
[ 162504-75-8 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 2492 - 2502

18
[ 581-45-3 ]
[ 137076-22-3 ]
[ 211937-26-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium cyanoborohydride; acetic acid; In methanol; at 20℃; for 3.5h;	To a solution of 1-(tert-butoxycarbonyl)-4-(formyl)piperidine (2.59 g) and 4-(4-pyridyl)piperidine (1.97 g) in methanol/acetic acid (99:1) (50 ml) was added sodium cyanoborohydride (2.29 g) portionwise over 30 minutes and the resultant suspension stirred at ambient temperature for 3 hours. The suspension was quenched by addition of saturated aqueous sodium bicarbonate and the resulting mixture extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated, The residue was purified by chromatography eluting with 5% methanol in dichloromethane to give 1-[1-tert-butoxycarbonyl(4-piperidinylmethyl)]-4-(4-pyridyl)piperidine (1.65 g) as a solid: NMR (CDCl3): 1.10 (m, 2H), 1.40 (s, 9H), 1.75 (m, 7H), 2.00 (dt, 2H), 2.20 (d, 2H), 2.45 (m, 1H), 2.70 (m, 2H), 3.00 (d, 2H), 4.10 (m, 2H), 7.20 (d, 2H), 8.50 (d, 2H); m/z 360 (M+1).

Reference： [1]Patent: US6335341,2002,B1 .Location in patent: Example 3
[2]Patent: US6391880,2002,B1 .Location in patent: Page column 16

19
[ 93246-53-8 ]
[ 137076-22-3 ]
[ 928300-13-4 ]

Yield	Reaction Conditions	Operation in experiment
72%	With sodium tris(acetoxy)borohydride; In dichloromethane; for 18h;	To a mixture of 3-fluoro-4- (4-morpholinyl)aniline D2(1.8g, 9.2mmol) and 1,1-dimethylethyl 4-formyl-1-piperidinecarboxylate (Wacker et al; Bioorg Med Chem Lett 2002,12 (13), 1785; 2.3g, 11 mmol) in anhydrous DCM (200ml) was added sodium triacetoxyborohydride (2.92 g; 13.8mmol). After stirring for 18h. the reaction mixture partitioned with NaHCO3(sat) and the organic phase separated, dried and evaporated in vacuo to give a yellow solid which was triturated with ether to afford the title product (1.96g, 54%). Further trituration of the mother liquors afforded additional title product (0.64g, 18%). Mass Spectrum (Electrospray LC/MS) : Found 394 (MH+). C21H32FN3O3 requires 393.
	With sodium tris(acetoxy)borohydride; In dichloromethane; for 18h;	To a mixture of 3-fluoro-4- (4-morpholinyl) aniline D2 (1.8g, 9. 2mmol) and 1, 1-dimethylethyl 4-formyl-1-piperidinecarboxylate (Wacker et al ; Bioorg Med Chem Lett 2002,12 (13), 1785; 2.3g, 11 mmol) in anhydrous DCM (200moi) was added sodium triacetoxyborohydride (2.92 g; 13. 8mmol). After stirring for 18h. the reaction mixture partitioned with NaHCO and the organic phase separated, dried and evaporated in vacuo to give a yellow solid which was triturated with ether to afford the title product (1.96g, 54%). Further trituration of the mother liquors afforded additional title product (0.64g, 18%). Mass Spectrum (Electrospray LC/MS): Found 394 (MH+). C21H32FN3O3 requires 393.

Reference： [1]Patent: WO2005/103000,2005,A1 .Location in patent: Page/Page column 37-38
[2]Patent: WO2005/58885,2005,A2 .Location in patent: Page/Page column 37

20
[ 109-04-6 ]
[ 137076-22-3 ]
[ 333986-05-3 ]

Yield	Reaction Conditions	Operation in experiment
65.41%	Stage #1: 2-bromo-pyridine With n-butyllithium In tetrahydrofuran at -78℃; for 0.0833333h; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In tetrahydrofuran at -78℃; for 1.5h;	124 Example 124; tert-Butyl 4-(hvdroxy(pyridm-2-vDme1hvDpiperidme- 1 -carboxylate; [00410] 2-Bromopyridine (13.89 g, 87.92 mmol) was added to THF (100 niL) and cooled to -78 °C. Butyl lithium (35.17 ml, 87.92 mmol) was added slowly and the reaction was stirred for 5 minutes. tert-Butyl 4-formylpiperidme-1-carboxylate (15.0 g, 70.33 mmol) in THF (50 mL) was added slowly to the above solution and the reaction mixture was stirred at -78 °C for 90 minutes.Ammonium chloride was added and the reaction mixture was extracted with dichloromethane. The reaction was concentrated and purified by silica gel chromatography (80-90% EtOAc in hexanes) to give the title compound (13.45 g, 65.41% yield). 1H NMR (DMSOd6) δ 8.48 (d, IH), 7.77 (dt, IH), 7.43 (d,IH), 7.24 (dd5 IH), 5.33 (d, IH), 4.39 (t, IH)3 3.92 (m, 2H)5 2.60 (m, 2H), 1.87(m, IH), 1.37 (m, HH), 1.18 (m, 2H).
62%	With n-butyllithium; sodium chloride; sodium hydrogencarbonate	R.48.1 1-tert-Butoxycarbonyl-4-[hydroxy(2-pyridyl)methyl]piperidine REFERENCE EXAMPLE 48-1 1-tert-Butoxycarbonyl-4-[hydroxy(2-pyridyl)methyl]piperidine To a solution of 2-bromopyridine (488 μL, 5 mmol) in ether (10 mL) was added dropwise butyl lithium (1.6M hexane solution, 3.125 mL, 5 mmol) at -78° C., and the mixture was stirred for 30 minutes. To the mixture was added dropwise a solution of 1-tert-butoxycarbonyl-4-formylpiperidine (1066 mg, 5 mmol) in ether (10 mL) at -78° C. The mixture was stirred for 18 hours while the temperature is elevated to room temperature. The reaction mixture was washed with saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (ethyl acetate:hexane=1:2) to give the titled compound as yellowish oily substance (913 mg). Yield 62%. 1H NMR (CDCl3) δ 1.20-1.49 (3H, m), 1.44 (9H, s), 1.66-1.93 (2H, m), 2.44-2.85 (2H, m), 4.01-4.23 (2H, m), 4.53 (1H, d, J=5.2Hz), 7.18-7.25 (2H, m), 7.69 (1H, dt, J=1.8, 7.2Hz), 8.55 (1H, dd, J=1.8, 5.4Hz); IR (KBr) 3418, 3024, 2922, 2854, 1732, 1694 cm-1.
	Stage #1: 2-bromo-pyridine With isopropylmagnesium chloride In tetrahydrofuran at 0℃; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In tetrahydrofuran at 0 - 20℃;

Reference： [1]Current Patent Assignee: PFIZER INC - WO2007/53345, 2007, A1 Location in patent: Page/Page column 146
[2]Current Patent Assignee: ABBVIE INC - US6562978, 2003, B1
[3]Location in patent: scheme or table Fish, Paul V.; Andrews, Mark D.; Jonathan Fray; Stobie, Alan; Wakenhut, Florian; Whitlock, Gavin A. [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 10, p. 2829 - 2834]

21
[ 675109-37-2 ]
[ 137076-22-3 ]
4-[(6-bromopyridin-2-ylmethyl)methylamino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; In dichloromethane; at 20.0℃; for 16.0h;	To a solution of (6-bromo- -2-ylmethyl)methylamine (Preparation 3, lOOmg, 0.50mmol) in CH2Cl2 (5mL) was added 4-formylpiperidine-l-carboxylic acid tert-butyl ester(117mg, 0.55mmol) then sodium triacetoxyborohydride (116mg, 0.55mmol). The reaction mixture was stirred for 16h at rt then partitioned between saturated aqueous NaHCO3 (3OmL) and CH2Cl2 (3OmL). The layers were separated and the aqueous extracted with CH2Cl2 (2x20mL). The combined organics were washed with brine (3OmL), dried (MgSO4), filtered and concentrated in vacuo. Purification via flash column chromatography (CH2Cl2 to2%MeOH/CH2Cl2) furnished the desired compound: deltaH (CDCl3): 0.95-1.08 (2H, m), 1.44 (9H, s), 1.54-1.69 (IH, m), 1.75 (2H, d), 2.21-2.26 (5H, m), 2.67 (2H, t), 3.61 (2H, s), 3.98-4.15 (2H, m), 7.33 (IH, d), 7.44 (IH, d), 7.51 (IH, t).

Reference： [1]Patent: WO2006/70208,2006,A1 .Location in patent: Page/Page column 19

22
[ 19493-09-5 ]
[ 137076-22-3 ]
[ 180307-56-6 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; hexanes; at -78 - 20℃; for 0.5h;	To a suspension of methyltriphenylphosphonium bromide (1.76 g, 4.93 mmol) in THF (30 ml), cooled to -78 C., was added n-BuLi (1.88 ml of 2.5M soln. in hexanes; 4.68 mmol), and the mixture was stirred at -78 C. for 30 min and then at 0 C. for 45 min. It was cooled back to -78 C., and a solution of aldehyde 6 (0.50 g, 2.34 mmol) in THF (5 ml) was added. The reaction mixture was stirred at -78 C. for 30 min and warmed up to rt. It was quenched with water, and the product was extracted with CH2Cl2. The organic layer was dried over Na2SO4 and purified by flash chromatography (0.5% MeOH/CH2Cl2) to provide 0.24 g of 20 as a clear oil. Step 2: BOC-deprotection and amide coupling steps as described in Example 2 were used to obtain the title compound MS (M+H): 347.

Reference： [1]Patent: US2007/10513,2007,A1 .Location in patent: Page/Page column 20

23
[ 187669-60-9 ]
[ 137076-22-3 ]
4-[4-(4-methanesulfonylphenyl)piperazin-1-ylmethyl]piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 17h;	Example 1; 4-[4-(4-Mcthancsulfonylphcnyl)pipcrazin-l -ylmcthyljpipcridinc-l -carboxylic acid tert-butyl ester; EPO <DP n="23"/>To a solution of l-(4-methanesulfonylphenyl)piperazine (0.41 mmol) and 4- formylpiperidine-1-carboxylic acid tert-mty ester (1.2 mmol) in DCM (3 mL) was added sodium triacetoxyborohydride (0.53 mmol). The resulting suspension was stirred at rt for 17 h. Polymer-supported isocyante scavenger resin (MP-NCO) (0.29 g, 1.44 mmol/g) was added and shaking continued until LCMS showed complete consumption of starting amine. The mixture was diluted with further DCM, shaken with water, and the organic layer separated using a hydrophobic frit. The crude mixture was purified via ion-exchange using an SCX column, to afford the title compound. deltaH (400 MHz, CHCl3) 1.14 (2H, m), 1.50 (9H, s), 1.70 (IH, m), 1.79 (2H, m), 2.26 (2H, d), 2.58 (4H, t), 2.74 (2H, m), 3.04 (3H, s), 3.38 (4H, t), 4.14 (2H, m), 6.96 (2H, d), 7.80 (2H, d).

Reference： [1]Patent: WO2007/3964,2007,A1 .Location in patent: Page/Page column 21-22

24
[ 868-59-7 ]
[ 137076-22-3 ]
[ 881197-94-0 ]

Yield	Reaction Conditions	Operation in experiment
75%	With triethylamine In toluene for 14h; Heating / reflux;	Synthesis of 4-(4-Ethoxycarbonyl-4,5-dihydro-thiazoI-2-yl)-piperidine-l-carboxylic acid t-butyl ester4-formyl-piperidine-l-carboxylic acid tert-butyl ester (1.0 eq, 13 mmol) was dissolved under inert conditions in 40 ml toluene. To this solution L-cystein ethylester hydrochloride (1.6 eq, 21 mmol) and Ixiethylamine (1.6 eq, 21 mmol) were added. The mixture was refluxed for 14 h. The generated water was removed with a Dean & Stark trap. The solvent was removed and the residue was dissolved in 100 ml ethylacetate. The organic layer was extracted 3 times with 50 ml 1 M citric acid, aqueous potassium hydrogen carbonate and 2 times with 50 ml brine, dried over MgSO4 and filtrated. The solvent was removed and the residue was purified by silica gel chromatography using a PE/ EA 4:1 gradient. Yield: 75%
75%	With triethylamine In toluene for 14h; Heating / reflux;	4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.0 eq, 13 mmol) was dissolved under inert conditions in 40 ml toluene. To this solution L-cystein ethylester hydrochloride (1.6 eq, 21 mmol) and triethylamine (1.6 eq, 21 mmol) were added. The mixture was refluxed for 14 h. The generated water was removed with a Dean & Stark trap. The solvent was removed and the residue was dissolved in 100 ml ethylacetate. The organic layer was extracted 3 times with 50 ml 1 M citric acid, aqueous potassium hydrogen carbonate and 2 times with 50 ml brine, dried over MgSO4 and filtrated. The solvent was removed and the residue was purified by silica gel chromatography using a PE/ EA 4:1 gradient. Yield: 75%
75%	With triethylamine In toluene for 14h; Heating / reflux;	4-forrnyl-piperidine-l-carboxylic acid tert-butyl ester (1.0 eq, 13 mmol) was dissolved under inert conditions in 40 ml toluene. To this solution L-cystein ethylester hydrochloride (1.6 eq, 21 mmol) and triethylamine (1.6 eq, 21 mmol) were added. The mixture was refluxed for 14 h. The generated water was removed with a Dean & Stark trap. The solvent was removed and the residue was dissolved in 100 ml ethylacetate. The organic layer was extracted 3 times with 50 ml 1 M citric acid, aqueous potassium hydrogen carbonate and 2 times with 50 ml brine, dried over MgSO4 and filtrated. The solvent was removed and the residue was purified by silica gel chromatography using a PE/ EA 4:1 gradient. Yield: 75%

75%	With triethylamine In toluene for 14h; Heating / reflux;	4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.0 eq, 13 mmol) was dissolved under inert conditions in 40 ml toluene. To this solution L-cystein ethylester hydrochloride (1.6 eq, 21 mmol) and triethylamine (1.6 eq, 21 mmol) were added. The mixture was refluxed for 14 h. The generated water was removed with a Dean & Stark trap.The solvent was removed and the residue was dissolved in 100 ml ethylacetate. The organic layer was extracted 3 times with 50 ml 1 M citric acid, aqueous potassium hydrogen carbonate and 2 times with 50 ml brine, dried over MgSO4 and filtrated. The solvent was removed and the residue was purified by silica gel chromatography using a PE/EA 4:1 gradient. Yield: 75%
75%	With triethylamine In toluene for 14h; Heating / reflux;	Synthesis of 4-(4-Ethoxycarbonyl-4,5-dihydro-thiazol-2-yl)-piperidine-1-carboxylic acid t-butyl ester Synthesis of 4-(4-Ethoxycarbonyl-4,5-dihydro-thiazol-2-yl)-piperidine-1-carboxylic acid t-butyl ester 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.0 eq, 13 mmol) was dissolved under inert conditions in 40 ml toluene. To this solution L-cystein ethylester hydrochloride (1.6 eq, 21 mmol) and triethylamine (1.6 eq, 21 mmol) were added. The mixture was refluxed for 14 h. The generated water was removed with a Dean & Stark trap. The solvent was removed and the residue was dissolved in 100 ml ethylacetate. The organic layer was extracted 3 times with 50 ml 1 M citric acid, aqueous potassium hydrogen carbonate and 2 times with 50 ml brine, dried over MgSO4 and filtrated. The solvent was removed and the residue was purified by silica gel chromatography using a PE/ EA 4:1 gradient. Yield: 75%

Reference： [1]Current Patent Assignee: BIONTECH AG - WO2007/16979, 2007, A2 Location in patent: Page/Page column 64
[2]Current Patent Assignee: 4 SC AG - EP1834954, 2007, A1 Location in patent: Page/Page column 20-21
[3]Current Patent Assignee: 4 SC AG - WO2009/37357, 2009, A1 Location in patent: Page/Page column 29-30
[4]Current Patent Assignee: 4 SC AG - US2008/241100, 2008, A1 Location in patent: Page/Page column 11-12
[5]Current Patent Assignee: 4 SC AG - EP1977759, 2008, A1 Location in patent: Page/Page column 15

25
[ 370864-67-8 ]
[ 137076-22-3 ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester With lithium aluminium tetrahydride In tetrahydrofuran at -50 - 0℃; for 4h; Stage #2: With water; citric acid In tetrahydrofuran at -78℃;	Synthesis of 4-Formyl-piperidine-1-carboxylic acid t-butyl ester Synthesis of 4-Formyl-piperidine-1-carboxylic acid t-butyl ester 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (1.0 eq, 16.4 mmol) was dissolved in 100 ml dry tetrahydrofurane under inert atmosphere. This solution was added dropwise over a period of 1 h to a suspension of lithiumalanate (3.0 eq, 49.6 mmol) in 70 ml dry tetrahydrofurane at -50° C. During the adding of the mixture, the temperature was held at -50° C. and then allowed to warm to 0° C. within 3 h. The mixture was cooled to -78° C. and quenched carefully with 100 ml 1 M citric acid. The mixture was warmed up to r.t. and diluted with 400 ml ethylacetate. The phases were separated and the aqueous phase was extracted 3 times with 70 ml ethylacetate. The combined organic layers were extracted 3 times with 100 ml 1 M citric acid, aqueous sodium carbonate and 2 times with 100 ml brine, dried over MgSO4 and filtrated. The solvent was removed and the residue was purified by distillation resulting in a yield of 85%

Reference： [1]Current Patent Assignee: 4 SC AG - US2007/219190, 2007, A1 Location in patent: Page/Page column 18

26
[ 137076-22-3 ]
[ 74-88-4 ]
[ 189442-92-0 ]

Yield	Reaction Conditions	Operation in experiment
43.8%	With potassium tert-butylate; In dichloromethane; at 0 - 20℃; for 2h;	Tert-butyl 4-formylpiperidine-l-carboxylate (35.0 g, 164.1 mmol) was dissolved in dichloromethane (200 mL) and cooled to 0 0C. Potassium tert-butoxide (23.9 g, 213 mmol) was added followed by addition of iodomethane (69.9 g, 492 mmol). The reaction was stirred at 0 0C for 30 minutes, and then warmed to ambient temperature and stirred for 1.5 hr. The reaction mixture was poured into brine (400 mL) and the organic layer was separated, dried, and filtered, and concentrated and purified by silica gel to provide tert-butyl 4-formyl-4- methylpiperidine-1-carboxylate (16.36 g, 72.0 mmol, 43.8 % yield
37.5%	With potassium tert-butylate; In dichloromethane; at 0 - 20℃; for 2h;	To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (4.5 g, 21.10 mmol) in CH2C12 (50 mL) at 0C was added t-BuOK (3.08 g, 27.4 mmol) followed by Mel (3.96 mL, 63.3 mmol) at 0 C. The resulting mixture was stirred 30 mm, and then warmed to room temp and stirred for 1.5 h. The reaction mixture was then poured into brine and themixture was extracted with dichloromethane, dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (0-20% EtOAc/hexane) to afford tert-butyl 4-formyl-4-methylpiperidine-1-carboxylate (1.8 g, 7.92 mmol, 37.5 % yield) as colorless oil. ?H NMR (500 MHz, CDC13) 9.48 (s, 1H), 3.7 1-3.66 (m, 2H), 3.19 - 3.05 (m, 2H), 1.93 (dt, J=13.7, 4.1 Hz, 2H), 1.47 (s, 9H), 1.46 - 1.37 (m,2H), 1.10 (s, 3H). LCMS (M+H) = 228.1.
37.5%	With potassium tert-butylate; In dichloromethane; at 0 - 20℃; for 2h;	To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (4.5 g, 21.10 mmol) in CH2Cl2 (50 mL) at 0C was added KOtBu (3.08 g, 27.4 mmol) followed by Mel (3.96 mL, 63.3 mmol) and the resulting mixture was stirred at 0C for 30 min, and then warmed to room temp and stirr for 1.5 h. The reaction mixture was then poured into brine and the mixture was extracted with dichloromethane, dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (0-20% EtOAc/hexane) to afford tert-butyl 4-formyl-4-methylpiperidine-1-carboxylate (1.8 g, 7.92 mmol, 37.5 % yield) as colorless oil. 1H NMR (500MHz, CDCl3) delta 9.48 (s, 1H), 3.71-3.66 (m, 2H), 3.19 - 3.05 (m, 2H), 1.93 (dt, J=13.7, 4.1 Hz, 2H), 1.47 (s, 9H), 1.46 - 1.37 (m, 2H), 1.10 (s, 3H). LCMS (M+H) = 228.1.

37.5%	With potassium tert-butylate; In dichloromethane; at 0 - 20℃; for 2h;	Prepared according to the procedure reported in W02008/118718. To a solution oftert-butyl4-formylpiperidine-1-carboxylate (4.5 g, 21.10 mmol) in CH2 Cb (50 mL) at ooc wasadded KOtBu (3.08 g, 27.4 mmol) followed by Mel (3.96 mL, 63.3 mmol) and the resulting mixture was stirred at 0 oc for 30 min, and then warmed to room temp and stirr for 1.5 h. The reaction mixture was then poured into brine and the mixture wasextracted with dichloromethane, dried (Na2 S04), filtered and concentrated. The residue was then purified by Biotage (0-20% EtOAc/hexane) to afford tert-butyl 4- formyl-4-methylpiperidine-1-carboxylate (1.8 g, 7.92 mmol, 37.5% yield) as colorless oil. 1H NMR (500MHz, CDCh) 8 9.48 (s, 1H), 3.71-3.66 (m, 2H), 3.19-3.05 (m, 2H), 1.93 (dt, J=13.7, 4.1 Hz, 2H), 1.47 (s, 9H), 1.46- 1.37 (m, 2H), 1.10 (s,3H). LCMS (M+H) = 228.1.
	With potassium tert-butylate; In dichloromethane; at 20℃;Cooling with ice;	Potassium tert-butoxide (2.80 g) and methyl iodide (3.60 mL) are added to an ice cold solution of 4-formyl-piperidine-1 -carboxylic acid tert-butyl ester (4.00 g) in dichloromethane (24 mL). The mixture is stirred in the cooling bath for 30 min and then at room temperature overnight. Brine is added and the resulting mixture is extracted with dichloromethane. The combined extracts are dried (MgSO4) and concentrated to give the crude title compound that is used without further purification.
	With potassium tert-butylate; In dichloromethane; at 20℃;Cooling with ice;	Step 1: 4-formyl-4-methyl-piperidine-1-carboxylic acid tert-butyl ester Potassium tert-butoxide (2.80 g) and methyl iodide (3.60 mL) are added to an ice cold solution of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (4.00 g) in dichloromethane (24 mL). The mixture is stirred in the cooling bath for 30 min and then at room temperature overnight. Brine is added and the resulting mixture is extracted with dichloromethane. The combined extracts are dried (MgSO4) and concentrated to give the crude title compound that is used without further purification.
	With potassium tert-butylate; In N,N-dimethyl-formamide; at 0 - 20℃;	To a solution of tert-butyl 4-formylpiperidine-i-carboxylate (3 g, 14.08 mmol) in DMF(30 mL) were added t-BuOK (1.56 g, 28 mmol, 2 eq) and methyl iodide (3.98 g, 28 mmol, 2 eq)at 0C. The reaction mixture was stirred at RT overnight. Progress of reaction was monitored byTLC. After completion, reaction mixture was diluted with brine (50 mL) and extracted EtOAc (2x 50 mL). Combine organic layer was washed with brine and dried over anhydrous sodiumsulfate. Removal of solvent under reduced pressure gave tert-butyl 4-formyl-4-methylpiperidine-1-carboxylate (3 g, 94 %) which was used in the next step without purification.LCMS: 228 [M+1]

Reference： [1]Patent: WO2008/118718,2008,A2 .Location in patent: Page/Page column 84
[2]Patent: WO2014/28384,2014,A1 .Location in patent: Page/Page column 112
[3]Patent: WO2014/164467,2014,A1 .Location in patent: Page/Page column 65
[4]Patent: WO2014/164428,2014,A1 .Location in patent: Page/Page column 61
[5]Patent: WO2013/127828,2013,A1 .Location in patent: Page/Page column 62
[6]Patent: US2013/225601,2013,A1 .Location in patent: Paragraph 0259
[7]Patent: WO2019/103897,2019,A1 .Location in patent: Page/Page column 172; 173

27
[ 18437-66-6 ]
[ 137076-22-3 ]
[ 416852-59-0 ]

Yield	Reaction Conditions	Operation in experiment
63%	Stage #1: N-(t-butoxycarbonyl)-4-chloroaniline With sec.-butyllithium In tetrahydrofuran; hexane at -50 - -40℃; for 1.5h; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In tetrahydrofuran; hexane at -50℃; for 2.75h;	21.1 To a solution of 93 (5.17 g, 22.7 mmol) in THF (100 mL) at -50°C was added S-BuLI (38.4 mL of a 1.3M solution in hexane, 49.9 mmol) dropwise. After 1.5h at -40°C, the reaction was recooled to -50°C and 95 (4.84 g, 22.7 mmol) in THF (20 mL) was added. After 2.75 h at -50°C, glacial acetic acid was added followed by saturated aqueous NH4Cl. The mixture was warmed to room temperature and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were dried (MgSO4) filtered and concentrated to provide a residue that was purified by flash column chromatography (1% to 3% MeOHZNH3 in CH2Cl2) to provide 95 (6.35 g, 63%).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2008/108957, 2008, A2 Location in patent: Page/Page column 63

28
[ 1076188-44-7 ]
[ 56553-60-7 ]
[ 64-19-7 ]
[ 137076-22-3 ]
4-(4-hydroxy-3-methylphenyl)-6-{2-methyl-4-[(piperidin-4-ylmethyl)amino]-phenyl}pyridin-2(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14%		[00611] In a round bottom flask was added 6-(4-amino-2-methylphenyl)-4-(4-hydroxy-3- methylphenyl)pyridin-2(lH)-one (76 mg, 0.25 mmol), 1 ,2 Dichloroethane (5.0 mL), acetic acid (0.1 mL), and N-Boc-4-Formyl piperidine (0.65 mg , 0.30 mmol). The reaction was stirred at room temperature for 15 minutes before adding sodium triacetoxy borohydride (85 mg, 0.40 mmol). Stirring was continued at room temperature for 10 min. The reaction was then concentrated down under reduced pressure. The resulting oil was then dissolved in 4N HCl/ dioxane (5.0 mL) and stirred at 45 0C for I h. The resulting slurry was cooled down to room temperature and the precipitate was filtered off. The resulting solid was then dissolved in MeOH and purified by preparatory HPLC (15-40 % gradient of NH4OAc/ACN) to give 4- (4-hydroxy-3-methylphenyl)-6-{2-methyl-4-[(piperidin-4-ylmethyl)amino]phenyI}pyridin- 2(lH)-one as the acetate salt (16 mg, 14% yield over 2 steps). 1H NMR (400 MHz, d6- DMSO) delta 7.47 (s, IH), 7.39 (dd, IH), 7.06 (d, IH), 6.85 (d, IH), 6.45 (m, 2H), 6.36 (s, IH), 6.27 (s, I H), 5.95 (t, IH), 2.98 (m, 2H), 2.91 (t, IH), 2.48 (m, 2H), 2.22 (s, 3H), 2.16 (s, 3H), 1.72 (m, 4H), 1.09 (m, 1 H); MS (EI) for C25H29N3O2: 404 (MH+).

Reference： [1]Patent: WO2008/133955,2008,A1 .Location in patent: Page/Page column 186

29
[ 1076188-18-5 ]
[ 56553-60-7 ]
[ 137076-22-3 ]
C₂₉H₃₆N₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		[00250] In a round bottom flask was added 6-(4-amino-2-methylphenyl)-4-(4-hydroxy-3- methylphenyl)pyrimidin-2(lH)-one (3) (30 mg, 0.10 mmol), 1,2 dichloroethane (2.0 mL), acetic acid (0.1 mL), and commercially available N-Boc-4-formyl piperidine (29 uL, 0.14 mmol). The reaction was stirred at room temperature for 15 minutes before adding sodium triacetoxy borohydride (30 mg, 0.14 mmol). Stirring was continued at room temperature overnight. The reaction was then quenched with saturated NaHCO3, extracted with EtOAc, dried over Na2SO4 and concentrated to dryness. The resultant oil was then dissolved in 4N HCl/ dioxane (1.0 mL) and allowed to sit at RT for 30 min. or until Boc deprotection was complete. The 4N HCl/ dioxane was decanted, and the residual solid product was rinsed with EtOAc 4X. The resulting orange solid was then dissolved in MeOH and purified by preparatory HPLC (5-85 % gradient of AmAc/ACN, 15 min.) to give the product 4-(4- hydroxy-3-methylphenyl)-6-{2-methyl-4-[(piperidin-4 ylmethyl)amino]phenyl}pyrimidin- 2(lH)-one as the acetate salt after lyopholyzation (24 mg, 59% yield).1H NMR (400 MHz, d6-DMSO) delta 7.91 (s, IH), 7.82 (dd, IH), 7.20 (d, IH), 6.84 (d, IH), 6.79 (s, IH), 6.50 (m, 2H), 6.19 (br t, IH), 2.99 (m, 4H), 2.48 (m, 2H), 2.33 (s, 3H), 2.20 (s, 3H), 1.82 (s, 3H), 1.73 (m, 4H), 1.10 (m, IH); MS (EI) for C24H28N4O2: 405.4 (MH+).

Reference： [1]Patent: WO2008/133955,2008,A1 .Location in patent: Page/Page column 107

30
[ 29898-32-6 ]
[ 137076-22-3 ]
[ 645378-86-5 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2,4-dichloro-1-iodo-benzene With iodine; magnesium In diethyl ether for 0.5h; Heating / reflux; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In diethyl ether at 0 - 23℃; for 0.5h;	39 Intermediate 39; [1.] 1-dimethylethyl [4-F (2. 4-DICHLOROPHENVL) (HVDROXY) METHVLL-1-PIPERIDINECARBOXVLATE] A solution of 2, 4-dichloroiodobenzene (2.23 mL) in anhydrous Et20 (8 mL) was dropped into a suspension of magnesium turning (0.395 [G)] and few crystals of iodine in anhydrous [ET20] (8 [ML)] under a Nitrogen atmosphere. The mixture was refluxed for 30 minutes, then it was allowed to cool to r. t. then cooled to [0°C] and a mixture of intermediate 3 (1.3 [G)] in anhydrous Et20 (8 mL) was added dropwise. At the end of the addition the mixture was allowed to warm to r. t. and stirred at [23°C] for 30 minutes. The mixture was quenched with ammonium chloride saturated solution, stirred for 10 minutes then extracted with DCM (3 x 50 mL). The combined organic extracts were concentrated in vacuo. The residue was purified by flash chromatography (CH/AcOEt from 95: 5 to 8: 2) to give the title compound (0.9 [G)] as a white foam. T. [I.] c.: CH/AcOEt 75: 25, Rf=0.35 MS (ES/+): m/z=360 [M+H] +.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2004/5255, 2004, A1 Location in patent: Page 35

31
[ 78593-40-5 ]
[ 137076-22-3 ]
[ 669075-72-3 ]

Yield	Reaction Conditions	Operation in experiment
		A suspension of lithium aluminum hydride (3.11 g, 0.082 mol) in [ET20] (250 mL) was cooled at-55 C under Argon. A solution of Compound 3b (18.5 g, 0.068 mol) in Et20 (75 [MLJ'WAS] added dropwise over a period of 15 min so that the temperature did not [EXCEED-50 C. THE] cooling bath was removed and the mixture was warmed up to [5 C,] cooled again to-35 C and celite (50 g) was added. The mixture was quenched slowly with bisulphate solution (15. [30] g in 43 mL [OF H20) WHILE] the temperature was kept at [- 30 C.] The resulting mixture was warmed to [0 C,] filtered over celite and the solid residue on the filter was washed with EtOAc (750 mL) and [H2O] (500 mL). The organic layer was separated, washed with [0.] 5N [HC1] (100 mL), saturated [NAHC03] (100 mL) and brine (100 mL). The aqueous layer was extracted with EtOAc (500 mL) and the combined organic layers were dried, filtered and evaporated. The resulting residue was purified by [KUGELROHR] distillation [(120-140 C] at 1.5-2 mm Hg) to yield Compound 13a as a colorless oil. A mixture of 3-bromoquinoline (10.40 g, 0.05 mol), trimethylsilylacetylene (8.48 mL, 0.06 mol), [CUPROUS] iodide (0.5 g) and trans-dichlorobis (triphenylphosphine) palladium [(1] g) and TEA (15 mL) was heated at [70 C] in a sealed tube for 1 h. H20 (150 mL) was added, followed by [ET2O] (300 mL). The organic layer was separated and the aqueous layer extracted with [ET20] (200 mL). The combined organic layers were dried [(NA2SO4)] and concentrated. The residue was purified by flash column chromatography (eluent: 100% DCM) to give [3- (TRIMETHYLSILYLETHYNYL)] quinoline as a brown oil. [3-(TRIMETHYLSILYLETHYNYL)] quinoline was dissolved in anhydrous MeOH (100 mL) and [K2CO3] (0.69 g, 5 mmol) was added. The mixture was stirred at rt for 1 h and DCM (250 mL) was added. The mixture was filtered over celite. The filtrate was evaporated and the residue was purified by flash column chromatography to give Compound 13b as an off-white solid. Butyllithium (2. 5M in hexane, 9.44 mL, 23.6 mmol) was added dropwise to a solution of Compound 13b [(3.] 62 g, 23.6 mmol) in THF (150 mL) under argon, such that the temperature did not [EXCEED-60 C,] then the mixture was cooled [TO-70 C.] The mixture was stirred at-70 C for 15 min and a solution of Compound 13a in THF (40 mL) was added dropwise while maintaining the temperature between-60 [AND-70 C.] After stirring at-70 C for 30 min, the mixture was warmed to [0 C] over a period of 20 min and [H2O] [(1] mL) was added'. The resulting mixture was dried over [K2C03,] 1 filtered and evaporated. The residue was purified by flash column chromatography (eluent gradient: DCM/MeOH : 100: 0 to 95 : 5) to yield Compound 13c as an oil. A mixture of Compound 13c (6.05 g) in pyridine (100 mL) was hydrogenated in the presence of [LINDLAR'S] catalyst [(1] g) at 1 psi of hydrogen for 7 h. The catalyst was removed by filtration over celite and the solvent was evaporated. The residue was purified by flash column chromatography (eluent gradient: [HEXANE/ETOAC] : 9: 1 to 1: 1) to yield Compound 13d as a solid. A solution of methyl 3-chloro-3-oxopropionate (1.24 mL, 11.53 mmol) in DCM (20 mL) was added dropwise over a period of 30 min to a solution of Compound 13d (4.25 g, 11.53 mmol) and TEA (1.81 mL, 13 mmol) in DCM (80 mL) at [0 C] under argon. The mixture was stirred overnight at rt. Aqueous NH4C1 solution (50 mL) and DCM (150 mL) were added. The organic layer was separated and washed with sat. [NAHC03] (100 mL) and brine (100 mL), dried [(NA2S04),] filtered and evaporated. The residue was purified by flash column chromatography (eluent gradient: [HEXANE/ETOAC] : 4: 1 to 1: 1) to yield Compound 13e as an oil. A solution of Compound 13e (4.45 g, 9.5 mmol) in THF (20 mL) was added dropwise to a flask containing sodium hydride (60% in mineral oil, 0.57 g, 14.25 mmol, triple washed with hexane (3 x 25 mL) ) at [60 C] under argon. The mixture was heated to 60 [C] for 15 min. Chlorotrimethylsilane (2.41 g, 19 mmol) was added via syringe and the mixture was heated for 4 h at [60 C. H20] (0.5 mL) was added and the mixture was stirred overnight at rt. The reaction mixture was evaporated, DCM (250 mL) was added and the mixture was'dried [(NA2S04).] After filtration and evaporation, the residue was heated at [130 C] for 2 h under vacuum. Purification by flash column chromatography (eluent: 1% MeOH in DCM) gave Compound 13f as a yellow oil. A solution of Compound [13F] (0.375 g, 0.88 mmol) in MeOH (50 mL) was hydrogenated in the presence of 10% palladium on carbon (120 mg) at 1 psi of hydrogen for 2 h. The catalyst was removed by filtration over celite and the solvent was evaporated to give a crude Compound 13g, which was used as such for the next reaction. TFA (10 mL) was added to a solution of Compound 13g (0.35 g, 0.82 mmol) [ ] in DCM (10 mL). The mixture was stirred at rt for 1 h and concentrated under vacuum to give crude Compound 13h, which was used as such for the next reaction. I...

Reference： [1]Patent: WO2004/20435,2004,A1 .Location in patent: Page 109

32
[ 30413-58-2 ]
[ 124-40-3 ]
[ 137076-22-3 ]
[ 1107617-19-5 ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) iodide; In water; for 2h;Sonographic reaction;	A mixture of <strong>[30413-58-2]2-ethynyl-6-methyl-pyridine</strong> (0.08 g, 0.7 mmol), 1-Boc-4-piperidinecarboxaldehyde (0.1 g, 0.47 mmol), CuI (0.001 g, 0.11 mmol) and 33% w/w aqueous dimethylamine (0.077 mL, 0.56 mmol) in water (3 mL) was sonicated for 2 h in a laboratory ultrasonic bath. Afterwards, it was extracted with EtOAc and the combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to give a crude, which was purified by automated flash liquid chromatography (Horizon-Biotage) eluting with EtOAc-Petroleum Ether 1:1 affording the title product (0.11 g).1H-NMR (CDCl3, delta): 1.25-1.48 (m, 2H), 1.51 (s, 9H), 1.65-1.73 (m, 1H), 2.05-2.11 (m, 2H), 2.23-2.40 (br, 6H), 2.66 (s, 3H), 2.69-2.77 (m, 2H), 3.21-3.39 (m, 1H), 4.09-4.21 (m, 2H), 7.09-7.11 (m, 1H), 7.27-7.30 (m, 1H), 7.53-7.56 (m, 1H).MS: [M+H]+=358.6

Reference： [1]Patent: US2009/42841,2009,A1 .Location in patent: Page/Page column 36

33
[ 30413-58-2 ]
[ 137076-22-3 ]
[ 1107617-18-4 ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of zinc trifluoromethanesulfonate (0.07 g, 0.19 mmol) and triethylamine (0.065 mL, 0.47 mmol) in anhydrous toluene (5 mL) was stirred at room temperature under nitrogen atmosphere. After 1 h, <strong>[30413-58-2]2-ethynyl-6-methyl-pyridine</strong> (0.13 g, 1.13 mmol) prepared as described in WO200544267 was added and after 15 min was dropped a solution of 1-Boc-4-piperidinecarboxaldehyde (0.2 g, 0.938 mmol) in toluene (1 mL): the resulting mixture was heated at 100 C. for 6 h. Afterwards, it was cooled to r.t., diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to give a crude, which was purified twice by automated flash liquid chromatography (Horizon-Biotage) eluting with CHCl3-MeOH 98-2 affording the title product (0.13 g) as a brown oil.1H-NMR (CDCl3, delta): 1.27-1.5 (m, 12H), 1.85-2.01 (m, 3H), 2.63 (s, 3H), 2.65-2.82 (m, 2H) 4.15-4.31 (m, 2H), 4.44-4.49 (m, 1H), 7.15-7.18 (m, 1H), 7.27-7.30 (m, 1H), 7.61-7.65 (m, 1H).MS: [M+H]+=331.6

Reference： [1]Patent: US2009/42841,2009,A1 .Location in patent: Page/Page column 36

34
[ 131543-46-9 ]
[ 137076-22-3 ]
4-(1H-imidazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With ammonium hydroxide In methanol; water at 20℃; for 1h;	1 Step 1: tert-butvl 4-(1 H-imidazol-2-yl)piperidine-1 -carboxylate Step 1: tert-butvl 4-(1 H-imidazol-2-yl)piperidine-1 -carboxylateA solution of tert-butyl 4-formylpiperidine-1 -carboxylate (99.0 g, 464.20 mmol) methanol (200 ml.) was treated with 30% aqueous ammonium hydroxide (500 ml_, 3.85 mol), followed by 40% aqueous glyoxal (53.50 ml_, 466.42 mmol). The contents were allowed to stir at room temp for 1 h before it rotary evaporated to remove methanol. The remains were treated with brine (500 ml.) and extracted with dichloromethane (1500 ml_). The organics were dried over sodium sulfate and concentrated to a yellow oil. The oil was seeded with authentic material to afford an off-white solid as the title compound that was dried under vacuum for 6 h (1 10.37 g, 439.16 mmol, 95%).
76%	Stage #1: tert butyl 4-formylpiperidine-1-carboxylate With ammonium hydroxide In methanol; water for 0.25h; Stage #2: Glyoxal In methanol; water at 20℃; for 16h;	94.b Add 28% ammonium hydroxide in water (372.66 mL, 5.0 eq) to a solution of tert- butyl 4-formylpiperidine-l-carboxylate (127 g, 595.47 mmol) in methanol (508 mL) and stir for 15 minutes. Add ethanedial (108.74 g, 1.0 eq) dropwise, maintaining the temperature of the mixture below 25°C with an ice/water bath. Stir for one hour. Add water (1.14 L) dropwise over 45 minutes and stir the resulting suspension for 16 hours at room temperature. Filter the suspension to give tert-butyl 4-(lH-imidazol-2- yl)piperidine-l-carboxylate as a white solid (113 g, 76%). Refilter the previous filtrate to obtain additional material (15 g, 10%). MS (ES) m/z = 252 [M]+.
45%	Stage #1: tert butyl 4-formylpiperidine-1-carboxylate With ammonium hydroxide In methanol for 0.0833333h; Stage #2: Glyoxal In methanol; water at 20℃; for 14h;	67.1 67.1 4-(1 H-lmidazol-2-yl)-piperidine-1 -carboxylic acid tert-butyl ester 4-Formylpiperidifle-1-CarbOxyliC acid tert-butyl ester (3.23 g; 15.145 mmol) was dissolved in methanol (6,74 ml; 11,000 aq.). Ammonium hydroxide solution (32%; 17.40 mL) and 5 mm later glyoxal (30% in water; 2.57 mL; 15.902 mol) was added and the solution was stirred at room temperature for14 h. The reaction was diluted with brine and water and extracted with dichioromethane. The combined organic layers were dried over sodium sulfate and evaporated to dryness. The oily residue was purified by flash chromatography (CombiFlashRF 200); yield: 1.73 g (45%).

With ammonia In methanol; water

Reference： [1]Current Patent Assignee: MERCK KGAA - WO2013/40059, 2013, A1 Location in patent: Page/Page column 35
[2]Current Patent Assignee: ELI LILLY & CO - WO2011/50016, 2011, A1 Location in patent: Page/Page column 106
[3]Current Patent Assignee: MERCK KGAA - WO2015/90496, 2015, A1 Location in patent: Page/Page column 108
[4]Location in patent: scheme or table Moss, Neil; Choi, Younggi; Cogan, Derek; Flegg, Adam; Kahrs, Andreas; Loke, Pui; Meyn, Orietta; Nagaraja, Raj; Napier, Spencer; Parker, Ashley; Thomas Peterson; Ramsden, Philip; Sarko, Christopher; Skow, Donna; Tomlinson, Josh; Tye, Heather; Whitaker, Mark [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 8, p. 2206 - 2210]

35
[ 137076-22-3 ]
[ 91419-52-2 ]

Yield	Reaction Conditions	Operation in experiment
93%	With hydroxylamine hydrochloride; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In ethyl acetate; N,N-dimethyl-formamide at 100℃;
90%	With O-(diphenylphosphinyl)hydroxylamine In toluene at 20 - 85℃; chemoselective reaction;
73%	With potassium hexafluorophosphate; tert.-butylnitrite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; oxygen; 1,1,1,3,3,3-hexamethyl-disilazane In acetonitrile at 30℃; for 8h;	23 Example 23: Preparation of N-Boc-4-piperidinecarbonitrile (Formula (2-8)) In a 100-ml flask, 30 mL of acetonitrile, 10 mmol of HMDS, 0.4 mmol of TEMPO, 0.4 mmol of KPF6 and 0.6 mmol of TBN were charged. The air was replaced with oxygen. The mixture was heated to 30 ° C in a preheated water bath and 4 mmol of N-Boc-4-piperidinecarboxaldehyde (as shown in formula (1-8)) was added slowly for 8 h. The reaction mixture was stirred with sodium thiosulfate solution and extracted with ether. The organic layer was separated, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography. The mixture was stirred at a volume ratio of ethyl acetate / petroleum ether of 1: 100 The eluent containing the title compound was collected and the solvent was evaporated to give N-Boc-4-piperidinecarbonitrile in an isolation yield of 70%.; The reaction procedure was the same as in Example 20, except that the amount of acetonitrile used was 80 mL, and the isolated yield of N-Boc-4-piperidinecarbonitrile was 73%.

70%	With potassium hexafluorophosphate; tert.-butylnitrite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; oxygen; 1,1,1,3,3,3-hexamethyl-disilazane In acetic acid; acetonitrile at 30℃; for 8h; Sealed tube;
58%	With tert.-butylhydroperoxide; ammonium acetate; iodine; sodium carbonate In ethanol at 50℃; for 8h; Green chemistry;
	Multi-step reaction with 2 steps 1: hydroxylamine hydrochloride / dimethyl sulfoxide / 70 °C 2: hydroxylamine hydrochloride; dimethyl sulfoxide / 70 °C
	Multi-step reaction with 2 steps 1: triethylamine; hydroxylamine hydrochloride / dichloromethane / 16 h / 20 °C / Inert atmosphere 2: ethanaminium,N-(difluoro-λ⁴-sulfanylidene)-N-ethyl-,tetrafluoroborate; triethylamine / ethyl acetate / 1 h / 20 °C / Inert atmosphere

Reference： [1]Location in patent: experimental part Augustine, John Kallikat; Atta, Rajendra Nath; Ramappa, Balakrishna Kolathur; Boodappa, Chandrakantha [Synlett, 2009, # 20, p. 3378 - 3382]
[2]Laulhe, Sebastien; Gori, Sadakatali S.; Nantz, Michael H. [Journal of Organic Chemistry, 2012, vol. 77, # 20, p. 9334 - 9337,4] Laulhé, Sébastien; Gori, Sadakatali S.; Nantz, Michael H. [Journal of Organic Chemistry, 2012, vol. 77, # 20, p. 9334 - 9337]
[3]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN105481624, 2016, A Location in patent: Paragraph 0041; 0042
[4]Fang, Chaojie; Li, Meichao; Hu, Xinquan; Mo, Weimin; Hu, Baoxiang; Sun, Nan; Jin, Liqun; Shen, Zhenlu [Advanced Synthesis and Catalysis, 2016, vol. 358, # 7, p. 1157 - 1163]
[5]Fang, Chaojie; Li, Meichao; Hu, Xinquan; Mo, Weimin; Hu, Baoxiang; Sun, Nan; Jin, Liqun; Shen, Zhenlu [RSC Advances, 2017, vol. 7, # 3, p. 1484 - 1489]
[6]Augustine, John Kallikat; Bombrun, Agnes; Atta, Rajendra Nath [Synlett, 2011, # 15, p. 2223 - 2227]
[7]Keita, Massaba; Vandamme, Mathilde; Paquin, Jean-François [Synthesis, 2015, vol. 47, # 23, p. 3758 - 3766]

36
[ 2107-69-9 ]
[ 137076-22-3 ]
[ 1020717-67-2 ]

Yield	Reaction Conditions	Operation in experiment
67%	Stage #1: 5,6-dimethoxy-1-indanone With N,N,N,N,N,N-hexamethylphosphoric triamide; n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; Inert atmosphere; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In tetrahydrofuran; hexane at -78 - 20℃; Inert atmosphere;	3.3 4-(5,6-Dimethoxy-1-oxo-indan-2-ylidenemethyl)-piperidine-1-carboxylic acid tent-butyl ester: At about 0° C. and under an atmosphere of argon, a solution of n-butyllithium in hexane (2.5 M, 3.7 mL, 1.12 equiv.) was added dropwise to a solution of diisopropylamine (930 mg, 9.19 mmol, 1.12 equiv.) in tetrahydrofuran (10 mL). The resulting solution was stirred at about 0° C. for about 10 minutes. After cooling the solution to about -78° C., a solution of 5,6-dimethoxyindan-1-one (1.5 g, 7.80 mmol, 1.00 equiv.) and hexamethylphosphoramide (1.6 g, 7.50 mmol, 1.12 equiv.) in tetrahydrofuran (10 mL) was added dropwise. The resulting solution was stirred at about -78° C. for about 15 minutes, and then a solution of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.6 g, 7.50 mmol, 1.00 equiv.) in tetrahydrofuran (10 mL) was added. After warming the solution to ambient temperature, the solution was stirred at ambient temperature for about 2 hours and then an aqueous solution of ammonium chloride (1%, 50 mL) was added. Standard extractive workup with ethyl acetate (2×50 mL), gave the title product as a yellow solid (2.0 g; yield=67%), which was used in the next step without further purification. LC-MS: m/z=388 (MH)+.
3.3 g	Stage #1: 5,6-dimethoxy-1-indanone With tetrabutylammomium bromide; sodium hydroxide In dichloromethane; water at 20℃; for 0.5h; Inert atmosphere; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In dichloromethane at 50℃; for 5h; Inert atmosphere;

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - US2010/143505, 2010, A1 Location in patent: Page/Page column 17
[2]Renou, Julien; Dias, José; Mercey, Guillaume; Verdelet, Tristan; Rousseau, Catherine; Gastellier, Anne-Julie; Arboléas, Mélanie; Touvrey-Loiodice, Mélanie; Baati, Rachid; Jean, Ludovic; Nachon, Florian; Renard, Pierre-Yves [RSC Advances, 2016, vol. 6, # 22, p. 17929 - 17940]

37
[ 5680-80-8 ]
[ 137076-22-3 ]
[ 1238759-94-8 ]

Yield	Reaction Conditions	Operation in experiment
84%	With 1,4-diaza-bicyclo[2.2.2]octane; N-chloro-succinimide In dichloromethane at 0 - 20℃; for 0.6h; Inert atmosphere;
83.6%	Stage #1: methyl (2S)-2-amino-3-hydroxypropanoate hydrochloride With 1,4-diaza-bicyclo[2.2.2]octane In dichloromethane at 20℃; for 0.333333h; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In dichloromethane at 20℃; for 0.5h; Stage #3: With N-chloro-succinimide In dichloromethane at 0 - 20℃; for 16h;	1 Step 1 To a suspension of methyl (2S)-2-amino-3-hydroxy-propanoate hydrochloride (CXIX) (3.21 g, 20.63 mmol) (1.1 eq) in DCM (40 mL) was added DABCO (6.31 g, 56.27 mmol) (3.0 eq). The reaction mixture was stirred at room temperature for 20 min before adding tert-butyl 4-formylpiperidine-1-carboxylate (CXVIII) (4.0 g, 18.76 mmol) (1.0 eq). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C., and 1-chloropyrrolidine-2,5-dione (2.75 g, 20.63 mmol) (1.1 eq) was added and stirred at the room temperature for 16 h. Saturated aqueous Na2S2O3 was added to the reaction mixture and extracted with DCM. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, and evaporated in vacuo. The crude product was purified by silica gel chromatography (0→50% EtOAc/Hexanes) to afford methyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2,5-dihydrooxazole-4-carboxylate (CXX) as a light brown oil (4.9 g, 15.7 mmol, 83.6% yield). ESIMS found for C15H24N2O5 m/z 213.1 (M+H-Boc).
83.6%	Stage #1: methyl (2S)-2-amino-3-hydroxypropanoate hydrochloride With 1,4-diaza-bicyclo[2.2.2]octane In dichloromethane at 20℃; for 0.333333h; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In dichloromethane at 20℃; for 0.5h; Stage #3: With N-chloro-succinimide In dichloromethane at 0 - 20℃; for 16h;	1 Step 1 To a suspension of methyl (2S)-2-amino-3-hydroxy-propanoate hydrochloride (XL) (3.21 g, 20.63 mmol) (1.1 eq) in DCM (40 mL) was added 1,4-diazabicyclo[2.2.2]octane (6.31 g, 56.27 mmol) (3.0 eq). The reaction mixture was stirred at room temperature for 20 min before adding tert-butyl 4-formylpiperidine-1-carboxylate (XXXIX) (4.0 g, 18.76 mmol) (1.0 eq). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C., and 1-chloropyrrolidine-2,5-dione (2.75 g, 20.63 mmol) (1.1 eq) was added and stirred at the room temperature for 16 h. Saturated aqueous Na2S2O3 was added to the reaction mixture and extracted with DCM. Organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, and evaporated in vacuo. The crude product was purified by silica gel chromatography (0→50% EtOAc/Hexanes) to afford methyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2,5-dihydrooxazole-4-carboxylate (XLI) as a light brown oil (4.9 g, 15.69 mmol, 83.6% yield). ESIMS found for C15H24N2O5 m/z 213.1 (M+H-Boc).

Reference： [1]Murai, Kenichi; Takahara, Yusuke; Matsushita, Tomoyo; Komatsu, Hideyuki; Fujioka, Hiromichi [Organic Letters, 2010, vol. 12, # 15, p. 3456 - 3459]
[2]Current Patent Assignee: BIOSPLICE THERAPEUTICS INC - US2019/127370, 2019, A1 Location in patent: Paragraph 0978-0979
[3]Current Patent Assignee: BIOSPLICE THERAPEUTICS INC - US2019/125740, 2019, A1 Location in patent: Paragraph 0554; 0555

38
[ 137076-22-3 ]
[ 1093759-68-2 ]

Yield	Reaction Conditions	Operation in experiment
	With diethylamino-sulfur trifluoride In dichloromethane at 0 - 20℃; for 18h;	4.2 To a solution of DAST (1.16 g, 7.20 mmol) in dichloromethane (30 mL) was added a solution of tert-butyl 4-formylpiperidine-l-carboxylate (0.51 g, 2.40 mmol) in dichloromethane (5 mL) at 0 0C. The reaction mixture was warmed to room temperature and stirred for 18 h. A 5% aqueous solution of sodium bicarbonate was added, the layers were separated, the organic layer was washed with saturated sodium bicarbonate, and brine, dried over sodium sulfate, filtered and concentrated to provide tert-butyl 4-(difiuoromethyl)piperidine-l- carboxylate. 1H NMR (400 MHz, CDCl3): 5.59 (m, IH), 4.20 (m, 2H), 2.69 (m, 2H), 1.91 (m, IH), 1.74 (m, 2H), 1.46 (s, 9H), 1.34 (m, 2H).
	With diethylamino-sulfur trifluoride In dichloromethane at 0 - 20℃;	6.2 To a solution of DAST (1.16 g, 7.20 mmol) in dichloromethane (30 niL) was added a solution of tert-butyl 4-formylpiperidine-l-carboxylate (0.51 g, 2.40 mmol) in dichloromethane (5 mL) at 0 0C. The reaction mixture was warmed to room temperature and stirred for 18 h. A 5% aqueous solution of sodium bicarbonate was added, the layers were separated, the organic layer was washed with saturated sodium bicarbonate, and brine, dried over sodium sulfate, filtered and concentrated to provide tert-butyl 4- (difiuoromethyl)piperidine-l-carboxylate. 1U NMR (400 MHz, CDCl3): 5.59 (m, IH), 4.20 (m, 2H), 2.69 (m, 2H), 1.91 (m, IH), 1.74 (m, 2H), 1.46 (s, 9H), 1.34 (m, 2H).
	With N-ethyl-N-(trifluoromethyl)ethanamine In dichloromethane at 0 - 20℃; for 18h;	6.2 To a solution of DAST (1.16 g, 7.20 mmol) in dichloromethane (30 mL) was added a solution of teri-butyl 4-formylpiperidine-l-carboxylate (0.51 g, 2.40 mmol) in dichloromethane (5 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 18 h. A 5% aqueous solution of sodium bicarbonate was added, the layers were separated, the organic layer was washed with saturated sodium bicarbonate, and brine, dried over sodium sulfate, filtered and concentrated to provide tert-butyl 4- (difluoromethyl)piperidine-l-carboxylate. NMR (400 MHz, CDC13): 5.59 (m, 1H), 4.20 (m, 2H), 2.69 (m, 2H), 1. 1 (m, IH), 1.74 (m, 2H), 1.46 (s, 9H), 1.34 (m, 2H).

With diethylamino-sulfur trifluoride In dichloromethane at 0 - 20℃;

Reference： [1]Current Patent Assignee: EXELIXIS INC - WO2010/138490, 2010, A1 Location in patent: Page/Page column 27
[2]Current Patent Assignee: EXELIXIS INC - WO2010/138487, 2010, A1 Location in patent: Page/Page column 120
[3]Current Patent Assignee: EXELIXIS INC - WO2012/71509, 2012, A2 Location in patent: Page/Page column 155
[4]Current Patent Assignee: RESEARCH TRIANGLE INSTITUTE - WO2018/53222, 2018, A1 Location in patent: Paragraph 00317

39
[ 75-16-1 ]
[ 137076-22-3 ]
[ 183170-69-6 ]

Yield	Reaction Conditions	Operation in experiment
97.7%	In tetrahydrofuran; at 0 - 20℃; for 1h;	To a stirred solution of t-butyl 4-formylpiperidine-1-carboxylate (0.5 g, 2.34 mmol) in THF (10 mL) was added MeMgBr (1.5M in THF) (3 mL, 4.68 mmol at 0 C. and reaction allowed to stir at room temperature for 1 h. Reaction was monitored by TLC. Reaction was quenched with aq. NH4Cl, extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to give 525 mg (97.7%) of t-butyl 4-(1-hydroxyethyl)piperidine-1-carboxylate. MS: 230.2[M++1]
		Preparation 4; 4-(1-Methanesulfonyloxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester1: 4-(1-Hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl esterTo a solution of N-tert-butoxycarbonyl-4-piperidinecarboxaldehyde (32.20 g, 151.45 mmol) in tetrahydrofuran at -78 C. is added methyl magnesium bromide (2 M in diethyl ether, 100.96 mL, 302.89 mmol). The reaction is stirred at -78 C. for 4.5 h, and then warmed to -50 C. for 30 min. The reaction is quenched with water at -50 C. and allowed to warm to room temperature for 16 h. The solvents are removed and the material is partitioned between diethyl ether and 0.1 M hydrochloric acid. The mixture is extracted with diethyl ether. The combined organic layers are washed with 0.1 M hydrochloric acid, saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated to dryness. The crude is purified by flash chromatography over silica gel to afford 16.90 g of the title compound as a colourless oil. MS (m/z) 229 (M+1).

Reference： [1]Patent: US2017/291910,2017,A1 .Location in patent: Paragraph 0308; 0309
[2]Patent: US2011/15199,2011,A1 .Location in patent: Page/Page column 6

40
[ 137076-22-3 ]
[ 199786-58-8 ]
[ 1304776-66-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2450 - 2455

41
[ 431-67-4 ]
[ 137076-22-3 ]
[ 1234710-04-3 ]

Yield	Reaction Conditions	Operation in experiment
88%	With ammonium hydroxide; In methanol; at 30℃;	Add sodium acetate (360.8 g, 2.0 eq) to water (3.54 L) at 30C. Add 1,1- dibromo-3,3,3-trifluoroacetone (653.01 g, 1.10 mol) dropwise. Heat the mixture at 90C under nitrogen for 1 hour. Add tert-butyl 4-formylpiperidine- 1 -carboxylate (470.00 g, 2.0 eq) to methanol (10 L) in another flask at 30C. Add a solution of 28% aqueous ammonium hydroxide (2.53 L, 8.18 eq) into the methanol solution. Cool the first mixture to 30C and add dropwise to the methanol solution over 45 minutes. Stir overnight under nitrogen. Remove solvent from the reaction mixture. Add water (2 L) anddichloromethane (6 L) and stir for 15 minutes at 25C. Extract the aqueous layer with dichloromethane three times (1 L x3). Wash the organics with saturated aqueous sodium chloride solution. Dry over anhydrous sodium sulfate and concentrate in vacuo. Add 5 L solution of 2% ethyl acetate in hexanes and stir at 30C for 30 minutes. Filter the solid, wash with hexanes, and concentrate in vacuo to give the title compound as a white solid (618.0 g, 88%). XH NMR (400 MHz, CDC13) delta 10.5 (s, 1H), 7.4 (s, 1H), 4.18 (s, 2 H), 2.98 (m, 1H), 2.80 (m, 2H), 2.01 (m, 2H), 1.71 (m, 2H), 1.45 (s, 9H).
60%	With ammonia; In methanol; at 0 - 25℃; for 2.5h;	tert-Butyl 4-formylpiperidine-1-carboxylate (2.0 g, 9.4 mmol) was dissolved in MeOH (lOmL)and followed by addition of 7M methanolic ammonia cooled at 0C for 30 mins followed byportion wise addition of 3,3-dibromo-1,1,1-trifluoropropan-2-one (5.07 g, 18.5 mmol). The resulting reaction mixture was stirred at 25C for 2 h, solvents were removed in vacuo and the residue was partitioned between H20 (80 mL) and EtOAc (50 mL), the aqueous layer was extracted with EtOAc (2 x 50 mL), organic layers were combined, dried (Na2SO4), solvent wasremoved in vacuo and residue was puiified by column chromatography (Activated basic Alumina at 0.5% MeOH in DCM) to give Intermediate 46, tert-butyl 4-(4-(trifluoromethyl)-1H- imidazol-2-yl)piperidine-1-carboxylate (1.80 g, 60%) as a white solid.

Reference： [1]Patent: WO2011/50016,2011,A1 .Location in patent: Page/Page column 40
[2]Patent: WO2015/118342,2015,A1 .Location in patent: Page/Page column 66

42
[ 626-60-8 ]
[ 137076-22-3 ]
[ 1334713-73-3 ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: 3-Chloropyridine With n-butyllithium; diisopropylamine In tetrahydrofuran; hexanes at -78 - 20℃; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In tetrahydrofuran; hexanes at 20℃; for 2h;	Diisopropylamine (1.82 mL, 12.9 mmol) was dissolved in THF (40 mL) and cooled to -78 °C. nBuLi (4.93 mL, 2.5 M in hexanes, 12.3 mmol) was added drop-wise and the solution was warmed to room temperature, stirred for 45 min and re -cooled -78 °C. A solution of 3-chloropyridine (1.40 g, 12.3 mmol) in THF (6 mL) was added and the reaction mixture was stirred at -78 °C for 4 h. A solution of tert-butyl 4-formylpiperidine-l-carboxylate (2.89 g, 13.6 mmol) in THF (6 mL) was added and the reaction mixture was warmed to r.t. and stirred for 2 h. The reaction mixture was quenched with water (60 mL) and extracted with DCM (100 mL and 2 x 30 mL). The combined organic fractions were dried (MgS04) and concentrated in vacuo. The residue was purified by normal phase column chromatography to give the title compound (2.94 g, 73%) as a yellow gum. LCMS (ES+): 271.0 (M+H-tBu)+.
73%	Stage #1: 3-Chloropyridine With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 4h; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In tetrahydrofuran; hexane at -78 - 20℃;	tert-Butyl 4-[(3-chloropyridin-4-yl)(hydroxy)methyl]piperidine-1-carboxylate Diisopropylamine (1.82 mL, 12.9 mmol) was dissolved in THF (40 mL) and cooled to -78° C. nBuLi (4.93 mL, 2.5 M in hexanes, 12.3 mmol) was added drop-wise and the solution was warmed to room temperature, stirred for 45 min and re-cooled -78° C. A solution of 3-chloropyridine (1.40 g, 12.3 mmol) in THF (6 mL) was added and the reaction mixture was stirred at -78° C. for 4 h. A solution of tert-butyl 4-formylpiperidine-1-carboxylate (2.89 g, 13.6 mmol) in THF (6 mL) was added and the reaction mixture was warmed to r.t. and stirred for 2 h. The reaction mixture was quenched with water (60 mL) and extracted with DCM (100 mL and 2*30 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography to give the title compound (2.94 g, 73%) as a yellow gum. LCMS (ES+): 271.0 (M+H-tBu)+.

Reference： [1]Current Patent Assignee: BENEVOLENTAI LIMITED - WO2011/113798, 2011, A2 Location in patent: Page/Page column 57-58
[2]Current Patent Assignee: BENEVOLENTAI LIMITED - US2013/102587, 2013, A1 Location in patent: Paragraph 0263; 0264

43
[ 179526-95-5 ]
[ 137076-22-3 ]
[ 1357575-08-6 ]

Yield	Reaction Conditions	Operation in experiment
43%		A heat-dried 50 ml round-bottom flask was charged, under nitrogen, with i-PrMgCl/LiCl complex (1.3 M in THF, 12.0 ml, 15.6 mmol). The flask was cooled to approximately -15 C.) and <strong>[179526-95-5]2-bromo-4'-chlorobiphenyl</strong> (INTERMEDIATE 9, 4.01 g, 14.99 mmol) was added. The resulting mixture was stirred at -15 C. for 1 hour, then at 0 C. for 2.5 hours and was then allowed to warm up to room temperature overnight. The reaction mixture cooled to 0 C. and tert-butyl 4-formylpiperidine-1-carboxylate (3.53 g, 16.35 mmol) in THF (5.0 ml) was added dropwise over approximately 5 minutes and the resulting mixture was allowed to stir for 90 minutes at this temperature. The reaction mixture was quenched by the addition of saturated aq. NH4Cl (30 ml) and extracted with EtOAc (4×60 ml). The organic layer was dried (MgSO4), filtered, and evaporated under reduced pressure. The concentrate was purified by column chromatography (ISCO, 120 g silica gel column, eluting with 100% hexanes?50% EtOAc/hexanes and subsequently with 0?3% MeOH/DCM) to give (R)-tert-butyl 4-((4'-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidine-1-carboxylate and (S)-tert-butyl 4-((4'-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidine-1-carboxylate, mixture of enantiomers (2.04 g, yield: 43%).1H NMR (400 MHz, DMSO-d6) delta ppm 0.61 (qd, 1H) 0.81-0.96 (m, 2H) 1.33 (s, 9 H) 1.50-1.63 (m, 1H) 1.74-1.85 (m, 1H) 3.63-3.78 (m, 1H) 3.81-3.93 (m, 1H) 4.28 (dd, 1 H) 5.21 (d, 1H) 7.12 (d, 1H) 7.26-7.38 (m, 3H) 7.41 (t, 1H) 7.50 (d, 2H) 7.56 (d, 1H).LCMS: (ESI) m/z 424 [M+Na]+

Reference： [1]Patent: US2012/35134,2012,A1 .Location in patent: Page/Page column 7; 34; 35

44
[ 137076-22-3 ]
[ 343338-28-3 ]
[ 1097880-26-6 ]

Yield	Reaction Conditions	Operation in experiment
86%	With titanium(IV) tetraethanolate In dichloromethane	27 Preparation of tert-butyl (S,E)-4-(((tert-butylsulfinyl)imino)methyl)piperidine-1 - carboxylate A solution of tert-butyl 4-formylpiperidine-1 -carboxylate (4.0 g, 18.8 mmol), (S)-2- methylpropane-2-sulfinamide (3.4 g, 28.1 mmol) and titanium tetraethoxide (8.6 g, 37.5 mmol) in DCM (40 ml) was stirred overnight before brine (20 ml) was added. The suspension was filtered through celite and the filtrate extracted with DCM. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated to give the crude product which was purified by flash chromatography (silica gel, 0-30% EtOAc in to afford the title compound (5.1 g, 86% yield). LCMS (ESI) m/z calcd for C15H28N2O3S: 316.18. Found: 317.28(M+1)+.
85%	With titanium(IV) tetraethanolate In tetrahydrofuran at 18 - 25℃; for 2h;	123 (S,E)-tert-butyl 4-((tert-butylsulfinylimino)methyl)piperidine-1-carboxylate A solution of (S)-2-methylpropane-2-sulfinamide (2.0 g, 16.50 mmol) in THF (8.0 ml) and titanium(IV) ethoxide (17.3 ml, 82.51 mmol) were added sequentially to a solution of tert-butyl 4-formylpiperidine-1-carboxylate (3.70 g, 17.33 mmol) in THF (8.0 ml). The resulting mixture was stirred at r.t for 2 hours. The reaction mixture was poured into ice/water and the suspension filtered. The filtrate was extracted with EtOAc and the organic layer was dried with MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was dried under vacuum to provide the title compound (4.45 g, yield: 85%). LCMS: (ESI) m/z 317 [M+H]+.
83%	With titanium(IV) tetraethanolate In dichloromethane at 20℃;	[00119] (S,E)-tert-butyl 4-(((tgrt-butylsulfinyl)imino)methyl)piperidine-l-carboxylate [00119] (S,E)-tert-butyl 4-(((tgrt-butylsulfinyl)imino)methyl)piperidine-l-carboxylate: A I L round bottom flask was charged with a magnetic stir bar, tert-butyl 4-formylpiperidine- 1-carboxylate (25 g, 1 17.22 mmol), (S)-2-methylpropane-2-sulfinamide (16.34 g, 134.8 mmol), DCM (200 mL) and tetraethoxytitanium (46.7 mL, 222.7 mmol) . The reaction was then allowed to stir overnight at ambient temperature. The reaction was quenched with 50 mL of brine and 10 mL of 10% HCl. A solid formed which was removed via vacuum filtration using a Buchner funnel. The resulting filter cake was washed with addtional DCM (~ 500 mL) and the filiate was dried with MgS04, filtered, and concentrated in vacuo to afford the title compound as a free flowing off-white solid (30.74 grams, 83%).

	With titanium(IV) tetraethanolate In dichloromethane at 20℃; for 3h;	26.1 Step 1: (5,E)tertbutyI 4((Qert4nityIsuIfinyI)imino)rnethyI)piperidine4carboxyIate: Step 1: (5,E)tertbutyI 4((Qert4nityIsuIfinyI)imino)rnethyI)piperidine4carboxyIate:To a round bottomed flask charged with a magnetic stir bar was added (5-2-methylropane2 sulfinamide (20.46 g, 169 nunol), tertbutyl 4ormylpiperidine1-carboxylate (30 g, 141 mmol), DCM (300 mL), and Ti(OEt)a (59.0 ml, 281 mmoi). The solution was stirred at room temperature for 3 h before it was quenched with brine (80 mE). The solution was stirred for 30 minutes before filtering. The filter cake was washed with DCM and the filtrate was placed in a scparatory funnel and washed with water, The organics layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue solidified to the title compound (29 g, 92 mrnol, 65.1 % yield) mIz 217.
	With titanium(IV) tetraethanolate In dichloromethane at 20℃; for 3h;	1.1 Step 1: (S,E)-tert-butyl 4-((Qert-butylsulfinyl)imino)methyl)piperidine-1-carboxylate Step 1: (S,E)-tert-butyl 4-((Qert-butylsulfinyl)imino)methyl)piperidine-1-carboxylate:(S)-2-methylpropane-2-sulfinamideTE4 To a round bottomed flask charged with a magnetic stir bar was added (S)-2-methylpropane- 2-sulfinamide (20.46 g, 169 mmol), tert-butyl 4-formylpiperidine-1-carboxylate (30 g, 141 mmol), DCM (300 mL), and Ti(OEt)4 (59.0 ml, 281 mmol). The solution was stined at room temperature for 3 h before it was quenched with brine (80 mL). The solution was stirred for 30 minutes before filtering. The filter cake was washed with DCM and the filtrate was placed in a separatory funnel and washed with water. The organics layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue solidified to the title compound (29 g, 92 mmol, 65.1 % yield) m/z 217.
	With copper(II) sulfate In dichloromethane at 30℃; for 12h;	3 Synthesis of compound 3-c 3-a (10.00g, 46.89mmol, 1.00eq), 3-b (5.97g, 49.23mmol, 1.05eq) and CuSO4 (18.718, 117.23mmol, 17.99mmol, 2.50eq) were dissolved in DCM (100.00mL) was stirred at 30 °C for 12 hours. The reaction was complete by TLC (PE:EtOAc = 3:1) and LC-MS. The mixture was filtered, and the obtained filtrate was dried over Na2SO4 reduced to yellow oily liquid 3-c.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2019/3141, 2019, A1 Location in patent: Page/Page column 47; 48
[2]Current Patent Assignee: ASTRAZENECA PLC - US2012/35134, 2012, A1 Location in patent: Page/Page column 75
[3]Current Patent Assignee: MORPHOSYS AG - WO2015/23915, 2015, A1 Location in patent: Paragraph 00118; 00119
[4]Current Patent Assignee: MORPHOSYS AG - WO2013/120104, 2013, A2 Location in patent: Page/Page column 90; 91
[5]Current Patent Assignee: MORPHOSYS AG - WO2014/124418, 2014, A1 Location in patent: Paragraph 0068
[6]Current Patent Assignee: WUXI APPTEC CO., LTD. - CN108929332, 2018, A Location in patent: Paragraph 0129; 0130; 0131

45
[ 138022-91-0 ]
[ 137076-22-3 ]

Yield	Reaction Conditions	Operation in experiment
87%	With cerium(III) chloride; sodium iodide In acetonitrile for 12h; Reflux;	4.1.18 4.1.12. tert-Butyl 4-formylpiperidine-1-carboxylate (14) To a solution of (methoxymethyl)triphenylphosphonium chloride (6.3 g, 18.3 mmol) in dry tetrahydrofuran (THF, 20 mL), sodium bis(trimethylsilyl)amide (1M in dry THF, 45 mmol) was added dropwise at 0 C. After 1 h, a solution of 13 (2.8 g, 14.1 mmol) in dry THF (20 mL) was slowly added at 0 C and the mixture kept at 25 C for 12 h. The solvent was removed in vacuo, H2O and EtOAc were added and the organic phase was separated, washed with an aqueous solution of HCl 1 N (1 5 mL) and with a saturated solution of sodium bicarbonate (1 5 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The crude reaction mixture was purified by flash chromatography on silica gel (2% EtOAc in petroleum ether) to give the enol ether intermediate tert-butyl 4-(methoxymethylene)piperidine-1-carboxylate as yellow oil (1.28 g,40%). 1H NMR (300 MHz, CDCl3) d 5.81 (s, 1H), 3.51 (s, 3H), 3.33 (t,J 6.3 Hz, 4H), 2.20 (t, J 6.0 Hz, 2H), 1.96 (t, J 6.0 Hz, 2H), 1.42 (s,9H); MS (ESI) m/z 250 [M Na]. To a solution of the above described compound (807 mg, 3.6 mmol) in CH3CN (20 mL), cerium chloride (530 mg, 1.4 mmol) and sodium iodide (160 mg, 1.1 mmol) were added. The reaction mixture was heated under reflux for 12 h.The solvent was removed in vacuo and the crude product was purified by flash chromatography on silica gel (10% MeOH, 1% NH4OH,in DCM) to give 14 as yellow oil (667 mg, 87%). 1H NMR (300 MHz,CDCl3) d 9.57 (s, 1H), 3.88 (d, J 13.3 Hz, 2H), 2.84 (t, J 10.9 Hz,2H), 2.39e2.28 (m, 1H), 1.80 (d, J 13.5, 2H), 1.49e1.41 (m, 2H), 1.36(s, 9H). MS (ESI) m/z 268 [M MeOH K].
77%	With cerium(III) chloride heptahydrate; sodium iodide In acetonitrile at 40℃;
	Acidic conditions; Heating;

58.9 kg

With formic acid In water at 30 - 35℃; for 3h; Inert atmosphere; Large scale;

3.2 (2) Under the protection of nitrogen, open the vacuum of the 500L glass-lined reactor, and draw in 80.0kg of the compound represented by formula (II) (Y = N-Boc, piperidine ring); draw in 80.0kg of tap water, 288kg of 90% formic acid, Under nitrogen protection, the temperature was raised to 30-35 ° C, and the reaction was performed for 3 hours until the reaction was completed. Solvent was removed at 30 to 35 ° C until the flow rate was small. Most of the formic acid was removed. 350 kg of dichloromethane and 80 kg of saturated brine were pumped into the layers. The brine phase was extracted twice with dichloromethane (350 kg x 2). The organic phases were combined. 80 kg of saturated saline was pumped in, 98 kg of sodium bicarbonate solid was added to adjust the pH to neutral, and the mother liquid was allowed to stand and separate. The organic phase was washed once with 80 kg of saturated saline, and dried with 50 kg of anhydrous sodium sulfate for half an hour. After filtration, the mother liquor was desolvated to almost no flow (about 30 ° C), and 58.9 kg of a compound of the formula (III) aldehyde (Y = N-Boc, piperidine ring) was obtained. The yield was 78.5%;

Reference： [1]Vallone, Alessandra; D'Alessandro, Sarah; Brogi, Simone; Brindisi, Margherita; Chemi, Giulia; Alfano, Gloria; Lamponi, Stefania; Lee, Soon Goo; Jez, Joseph M.; Koolen, Karin J.M.; Dechering, Koen J.; Saponara, Simona; Fusi, Fabio; Gorelli, Beatrice; Taramelli, Donatella; Parapini, Silvia; Caldelari, Reto; Campiani, Giuseppe; Gemma, Sandra; Butini, Stefania [European Journal of Medicinal Chemistry, 2018, vol. 150, p. 698 - 718]
[2]Brindisi, Margherita; Senger, Johanna; Cavella, Caterina; Grillo, Alessandro; Chemi, Giulia; Gemma, Sandra; Cucinella, Dora Mariagrazia; Lamponi, Stefania; Sarno, Federica; Iside, Concetta; Nebbioso, Angela; Novellino, Ettore; Shaik, Tajith Baba; Romier, Christophe; Herp, Daniel; Jung, Manfred; Butini, Stefania; Campiani, Giuseppe; Altucci, Lucia; Brogi, Simone [European Journal of Medicinal Chemistry, 2018, vol. 157, p. 127 - 138]
[3]Location in patent: scheme or table Calvo, Raul R.; Meegalla, Sanath K.; Parks, Daniel J.; Parsons, William H.; Ballentine, Shelley K.; Lubin, Mary Lou; Schneider, Craig; Colburn, Raymond W.; Flores, Christopher M.; Player, Mark R. [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 5, p. 1903 - 1907]
[4]Current Patent Assignee: HANGZHOU ALLSINO BIOTECHNOLOGY - CN110627827, 2019, A Location in patent: Paragraph 0024

46
[ 1192064-63-3 ]
[ 137076-22-3 ]
[ 1382137-33-8 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 584-[2-(2,5-Dichloro-pyrimidin-4-yl)-1 -hvdroxy-ethyl1-piperidine-1 -carboxylic acid tert- butyl esterN-butyllithium (1 .6 M in hexanes, 4.99 ml_) is added drop wise to diisopropylamine (1 .13 ml_) in tetrahydrofuran (20 ml_) at -50 to -60C under an argon atmosphere. The mixture is stirred for 30 min at this temperature, cooled to -70C, and 2,5- dichloro-4-methyl- pyrimidine (1.00 g) is added. After 1 h a solution of 4-formyl- piperidine-1 -carboxylic acid tert-butyl ester (1 .37 g) in tetrahydrofuran (10 ml_) is added and the resulting mixture is stirred for another hour. The reaction is quenched with acetic acid solution (1 % in ethanol, 10 mL) and the mixture is diluted with ethyl acetate. The organic phase is separated, washed with water and aqueous NaHC03 solution, dried over MgS04, and concentrated in vacuo. The residue ischromatographed on silica gel (cyclohexane/ethyl acetate 75:25? 30:70) to give the title compound. LC (method 7): tR = 1 .40 min; Mass spectrum (EST): m/z = 376[M+H]+.
		N-butyllithium (1.6 M in hexanes, 4.99 mL) is added drop wise to diisopropylamine (1.13 mL) in tetrahydrofuran (20 mL) at -50 to -60 C. under an argon atmosphere. The mixture is stirred for 30 min at this temperature, cooled to -70 C., and 2,5-dichloro-4-methyl-pyrimidine (1.00 g) is added. After 1 h a solution of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.37 g) in tetrahydrofuran (10 mL) is added and the resulting mixture is stirred for another hour. The reaction is quenched with acetic acid solution (1% in ethanol, 10 mL) and the mixture is diluted with ethyl acetate. The organic phase is separated, washed with water and aqueous NaHCO3 solution, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 75:25?30:70) to give the title compound. LC (method 7): tR=1.40 min; Mass spectrum (ESI+): m/z=376 [M+H]+.

Reference： [1]Patent: WO2012/80476,2012,A1 .Location in patent: Page/Page column 95-96
[2]Patent: US2012/322784,2012,A1 .Location in patent: Page/Page column 41

47
[ 1192064-63-3 ]
[ 137076-22-3 ]
[ 1382137-36-1 ]

Reference： [1]Patent: WO2012/80476,2012,A1
[2]Patent: US2012/322784,2012,A1

48
[ 372-47-4 ]
[ 137076-22-3 ]
[ 1038352-55-4 ]

Yield	Reaction Conditions	Operation in experiment
98%	Stage #1: 3-Fluoropyridine With n-butyllithium; diisopropylamine In tetrahydrofuran; cyclohexane at -78℃; for 0.833333h; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In tetrahydrofuran; cyclohexane at -78 - 20℃;	40 tert-butyl 4-[(3-fluoropyridin-4-yl)hydroxymethyl]piperidine-1-carboxylate Diisopropyl amine (0.66 ml, 4.69 mmol) was dissolved in THF (30 ml) and cooled to -78 °C. nBuLi (2.13 ml, 2.20 M in cyclohexane, 4.69 mmol) was added drop-wise and the reaction mixture was stirred at -78 °C for 10 min, at 0 °C for 30 min, and re -cooled to -78 °C. 3-Fluoro- pyridine (0.40 ml, 4.69 mmol) was added drop-wise over 5 min, and the reaction mixture was stirred for 45 min. A solution of N-Boc-4-piperidinecarboxaldehyde (1.00 g, 4.69 mmol) in THF (10 ml) was added and the reaction mixture was warmed to RT and stirred for 15 min. The reaction mixture was quenched with sat aq NH4OAC (10 mL), diluted with EtOAc (100 mL), washed with water (2 x 50 mL), dried (MgSO^.) and concentrated in vacuo to give the title compound as an orange oil (1.42 g, 98%). LCMS (ES+): 255.0 [MH-t-Bu]+.
98%	Stage #1: 3-Fluoropyridine With n-butyllithium; lithium diisopropyl amide In tetrahydrofuran; cyclohexane at -78℃; for 0.833333h; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In tetrahydrofuran; cyclohexane at 20℃; for 0.25h;	tert-Butyl 4-[(3-fluoropyridin-4-yl)(hydroxy)methyl]piperidine-1-carboxylate Diisopropylamine (0.66 ml, 4.69 mmol) was dissolved in THF (30 ml) and cooled to -78° C. nBuLi (2.13 ml, 2.20 M in cyclohexane, 4.69 mmol) was added drop-wise and the reaction mixture was stirred at -78° C. for 10 min, at 0° C. for 30 min, and re-cooled to -78° C. 3-Fluoro-pyridine (0.40 ml, 4.69 mmol) was added drop-wise over 5 min, and the reaction mixture was stirred for 45 min. A solution of N-Boc-4-piperidinecarboxaldehyde (1.00 g, 4.69 mmol) in THF (10 ml) was added and the reaction mixture was warmed to RT and stirred for 15 min. The reaction mixture was quenched with sat aq NH4OAc (10 mL), diluted with EtOAc (100 mL), washed with water (2*50 mL), dried (MgSO4) and concentrated in vacuo to give the title compound as an orange oil (1.42 g, 98%). LCMS (ES+): 255.0 [MH-t-Bu]+.

Reference： [1]Current Patent Assignee: BENEVOLENTAI LIMITED - WO2013/37411, 2013, A1 Location in patent: Page/Page column 32
[2]Current Patent Assignee: BENEVOLENTAI LIMITED - US2014/357623, 2014, A1 Location in patent: Paragraph 0131; 0132

49
[ 137076-22-3 ]
[ 1023595-19-8 ]

Reference： [1]Patent: WO2014/15495,2014,A1
[2]Patent: WO2015/17305,2015,A1
[3]Patent: WO2016/60941,2016,A1

50
[ 1003-21-0 ]
[ 137076-22-3 ]
[ 1599529-39-1 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of <strong>[1003-21-0]5-bromo-1-methyl-1H-imidazole</strong> (25.0 g, 155 mmol; dried over 3 A molecular sieves, then filtered) in DCM (310 mL) was stirred on an ice bath while iPrMgCl (72 mL, 2.01 M solution in THF, 145 mmol) was added rapidly dropwise under argon via pressure-equalizing addition funnel. Residual iPrMgCl was rinsed down with 50 mL THF, and the ice bath was removed and the reaction stirred for 25 minutes. A solution of tert-butyl 4-formylpiperidine-1-carboxylate (27.6 g, 130 mmol) (PharmaCore) in THF (65 mL) was added dropwise over ?5 minutes via pressure-equalizing addition funnel at room temperature. After stirring 1 hour at room temperature, the yellow mixture was quenched with 5 M aqueous NH4Cl (250 mL) in one portion. The organic layer was dried (Na2SO4), filtered, and concentrated to provide the crude title compound as a clear light amber oil.
		A solution of <strong>[1003-21-0]5-bromo-1-methyl-1H-imidazole</strong> (25.0 g, 155 mmol; dried over 3 MS, then filtered) in DCM (310 mL) was stirred on an ice bath while iPrMgCl (72 mL, 2.01 M solution in THF, 145 mmol) was added rapidly dropwise under argon via pressure-equalizing addition funnel. Residual iPrMgCl was rinsed down with 50 mL THF, and the ice bath was removed and the reaction stirred for 25 min. A solution of tert-butyl 4-formylpiperidine-1-carboxylate (27.6 g, 130 mmol) (PharmaCore) in THF (65 mL) was added dropwise over 5 min via pressure-equalizing addition funnel at room temperature. After stirring 1 hour at rt, the yellow mixture was quenched with 5 M NH4Cl (250 mL) in one portion. The organic layer was dried (Na2SO4), filtered, and concentrated to provide the crude title compound as a clear light amber oil.
		A solution of <strong>[1003-21-0]5-bromo-1-methyl-1H-imidazole</strong> (25.0 g, 155 mmol; dried over 3 A molecular sieves, then filtered) in DCM (310 mL) was stirred in an ice bath while iPrMgCl (72 mL, 2.01 M solution in THF, 145 mmol) was added rapidly dropwise under argon via pressure-equalizing addition funnel. Residual iPrMgCl was rinsed down with 50 mL THF, and the ice bath was removed and the reaction stirred for 25 minutes. A solution of tert-butyl 4-formylpiperidine-1-carboxylate (27.6 g, 130 mmol) in THF (65 mL) was added dropwise over ?5 minutes via pressure-equalizing addition funnel at room temperature. After stirring 1 hour at room temperature, the yellow mixture was quenched with 5 M aqueous NH4Cl (250 mL) in one portion. The organic layer was dried (Na2SO4), filtered, and concentrated to provide the crude title compound as a clear light amber oil.

		A solution of <strong>[1003-21-0]5-bromo-1-methyl-1H-imidazole</strong> (25.0 g, 155 mmol; dried over 3 A molecular sieves, then filtered) in DCM (310 mL) was stirred in an ice bath while iPrMgCl (72 mL, 2.01 M solution in THF, 145 mmol) was added rapidly dropwise under argon via pressure-equalizing addition funnel. Residual iPrMgCl was rinsed down with 50 mL THF, and the ice bath was removed and the reaction stirred for 25 minutes. A solution of tert-butyl 4-formylpiperidine-1-carboxylate (27.6 g, 130 mmol) in THF (65 mL) was added dropwise over ?5 minutes via pressure-equalizing addition funnel at room temperature. After stirring 1 hour at room temperature, the yellow mixture was quenched with 5 M aqueous NH4Cl (250 mL) in one portion. The organic layer was dried (Na2SO4), filtered, and concentrated to provide the crude title compound as a clear light amber oil.
		Intermediate 58: step a tert-butyl 4-(hydroxy(1-methyl-1H-imidazol-5-yl)methyl)piperidine-1-carboxylate A solution of 5-bromo-l -methyl- 1 /-/-imidazole (25.0 g, 155 rnmol; dried over 3 A molecular sieves, then filtered) in DCM (310 mL) was stirred in an ice bath while /FrMgCl (72 mL, 2.01 M solution in THF, 145 mmol) was added rapidly dropwise under argon via pressure-equalizing addition funnel. Residual PrMgCl was rinsed down with 50 mL THF, and the ice bath was removed and the reaction stirred for 25 minutes. A solution of iert-butyi 4-formylpiperidine-l- carboxylate (27.6 g, 130 mmol) in THF (65 mL) was added dropwise over ~5 minutes via pressure-equalizing addition funnel at room temperature. After stirring 1 hour at room temperature, the yellow mixture was quenched with 5 M aqueous NH4C1 (250 mL) in one portion. The organic layer was dried (NaaSO^, filtered, and concentrated to provide the crude title compound as a clear light amber oil.
		intermediate 1: step atert-butyl 4-(hydroxy(1-methyl-1H-imidazol-5-yl)methyl)piperidine-1-carboxylateA. solution of 5-bromo-l -methyl- IH-imidazole (25.0 g, 155 mmol; dried over 3.4 molecular sieves, then filtered) in DCM (310 mL) was stirred in an ice bath while /'PrMgCl (72 mL, 2.01 M solution in THF, 145 mmol) was added rapidly dropwise under argon via pressure-equalizing addition funnel . Residual /PrMgCl was rinsed down with 50 ml. THF, and the ice bath was removed and the reaction stirred for 25 minutes. A solution of eri-butyl 4-formylpiperidine-l - carboxylate (27.6 g, 130 mmol ) in THF (65 mL) was added dropwise over ~5 minutes via pressure-equalizing addition funnel at, room temperature. After stirring 1 hour at room temperature, the yellow mixture was quenched with 5 M aqueous NH C1 (250 mL) in one portion. The organic layer was dried (Na2S04), filtered, and concentrated to provide the crude title compound as a clear light amber oil.

Reference： [1]Patent: US2014/107094,2014,A1 .Location in patent: Paragraph 0577; 0578
[2]Patent: US2014/107097,2014,A1 .Location in patent: Paragraph 0438; 0439
[3]Patent: US2015/105404,2015,A1 .Location in patent: Paragraph 0188
[4]Patent: US2015/105366,2015,A1 .Location in patent: Paragraph 0481; 0482
[5]Patent: WO2015/57205,2015,A1 .Location in patent: Page/Page column 133
[6]Patent: WO2015/57203,2015,A1 .Location in patent: Page/Page column 48

51
[ 137076-22-3 ]
[ 49764-63-8 ]
5,6-dibromo-4-nitro-2-(piperidin-4-yl)-1-(piperidin-4-ylmethyl)-1H-1,3-benzodiazole trifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2014/96388,2014,A2

52
[ 137076-22-3 ]
[ 49764-63-8 ]
[ 1616359-51-3 ]

Yield	Reaction Conditions	Operation in experiment
20 mg	With 2,2,2-trifluoroethanol; for 1h;	3.11.11. Method 16A: tert-butyl 4-[5,6-dibromo- 1 -( { 1 -[(tert-butoxy)carbonyl]piperidin-4-yl}methyl)- 1H- 1,3- benzodiazo l-2-yl]piperidine- 1 -carboxylate ( 16 A) : 4,5-dibromobenzene-l,2-diamine (lOOmg, 0,38mmol) and tert-butyl 4-formylpiperidine-l- carboxylate (160mg, 0,76mmol) were stirred for 1 hour in 2,2,2trifiuoroethanol. Then Solvent was evaporated and product was purified on silica gel using EA/hex (l/l).Yield: 20mg. m/z 657,1 , rt. 4,2 min.

Reference： [1]Patent: WO2014/96388,2014,A2 .Location in patent: Page/Page column 140-141

53
[ 139512-70-2 ]
[ 137076-22-3 ]
[ 1613053-63-6 ]

Reference： [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 820 - 825

54
[ 137076-22-3 ]
[ 436799-32-5 ]
tert-butyl 4-(hydroxy(6-(trifluoromethyl)pyridin-3-yl)methyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of isopropylmagnesium chloride (2.0 M in THF, 40.3 mL, 80.6 mmol) was added dropwise by syringe to a solution of <strong>[436799-32-5]5-bromo-2-(trifluoromethyl)pyridine</strong> (19.5 g, 86.3 mmol) in dry THF (12 mL) at 2 C. After 30 minutes, tert-butyl 4-formylpiperidine-1-carboxylate (12.3 g, 57.3 mmol) was added to the Grignard solution at 2 C. as a solid. The reaction mixture was warmed to 10 C. over 1.5 hours after which it was quenched with saturated aqueous ammonium chloride solution. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate and washed with saturated aqueous NaCl solution. The organic phase was dried (MgSO4), filtered, and concentrated and used crude in the next step.
		A solution of isopropylmagnesium chloride (2.0 M in THF, 40.3 mL, 80.6 mmol) was added dropwise by syringe to a solution of <strong>[436799-32-5]5-bromo-2-(trifluoromethyl)pyridine</strong> (19.5 g, 86.3 mmol) in dry THF (12 mL) at 2 C. After 30 minutes, tert-butyl 4-formylpiperidine-1-carboxylate (12.3 g, 57.3 mmol) was added to the Grignard solution at 2 C. as a solid. The reaction mixture was warmed to 10 C. over 1.5 hours after which it was quenched with saturated aqueous ammonium chloride solution. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate and washed with saturated aqueous NaCl solution. The organic phase was dried (MgSO4), filtered, and concentrated to afford the title compound which was used without further purification in the next step.
		Intermediate 56: step a tert-butyl 4-(hydroxy(6-(trifluoromethyl)pyridin-3-yl)methyl)piperidine-1-carboxylate A solution of isopropylmagnesium chloride (2.0 M in THF, 40.3 mL, 80.6 mmol) was added dropwise by syringe to a solution of <strong>[436799-32-5]5-bromo-2-(trifluoromethyl)pyridine</strong> (19.5 g, 86.3 mmol) in dry THF ( 12 mL) at 2 C. After 30 minutes, tert-butyl 4-formylpiperidine-l -carboxylate (12.3 g, 57.3 mmol) was added to the Grignard solution at 2 C as a solid. The reaction mixture was warmed to 10 C over 1.5 hours after which it was quenched with saturated aqueous ammonium chloride solution. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate and washed with saturated aqueous NaCl solution.'The organic phase was dried (MgS04), filtered, and concentrated to afford the title compound which was used without further purification in the next step

intermediate 14: step atert-butyl 4-(hydroxy(6-(trifluoromethyl)pyridin-3-yl)methyl)piperidine-1-carboxylateA solution of isopropylniagnesium chloride (2.0 M in THF, 40.3 mL, 80,6 mmol) was added dropwise by syringe to a solution of 5-hromo-2-(t,rifluoromethyl)pyridine (19.5 g, 86.3 mmol) in dry THF (12 ml.) at 2 C. After 30 minutes, tert-butyl 4-formylpiperidine- 1 -carboxylate (12.3 g, 57.3 mmol) was added to the Grignard solution at 2 C as a solid. The reaction mixture was warmed to 10 C over 1.5 hours after which it, was quenched with saturated aqueous ammonium chloride solution. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate and washed with saturated aqueous NaCl solution. The organic phase was dried (MgS04), filtered, and concentrated and used crude in the next, step.

Reference： [1]Patent: US2015/105404,2015,A1 .Location in patent: Paragraph 0267
[2]Patent: US2015/105366,2015,A1 .Location in patent: Paragraph 0471; 0472
[3]Patent: WO2015/57205,2015,A1 .Location in patent: Page/Page column 130; 131
[4]Patent: WO2015/57203,2015,A1 .Location in patent: Page/Page column 68; 69

55
[ 106-95-6 ]
[ 137076-22-3 ]
tert-butyl 4-formyl-4-(prop-2-en-1-yl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With lithium tert-butoxide In N,N-dimethyl-formamide at 0℃; for 0.25h;	O.A Step A: A mixture of tert-butyl 4-formylpiperidine-1-carboxylate (30 g, 140.84 mmol), lithium tert-butoxide (13.4 g, 169 mmol) and allyl bromide (10.2 mL, 161.96 mmol) in DMF (288 mL) was stirred for 15 minutes at 0 °C. The mixture was poured into a separating funnel containing saturated aqueous NH4Cl:H2O (1:1, 160 mL), and it was extracted with EtOAc (5 X 60 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (gradient: 0-10% EtOAc/Hexane) to get tert-butyl 4-formyl-4-(prop-2-en-1- yl)piperidine-1-carboxylate (24 g, 67%) as a colorless oil. LCMS: 254.1 (M+H).
64.5%	With potassium <i>tert</i>-butylate In tetrahydrofuran at -25 - -15℃; for 0.75h;	26.1 Step 1: tert-Butyl 4-formyl-4-(prop-2-en-1-yl)piperidine-1-carboxylate The reaction mixture of tert-butyl 4-formylpiperidine-1-carboxylate (1200.0 g, 5.63 mol) in THF (10 L) was cooled to -25C, then allylbromide (816.5 g, 6.75 mol) was added, followed by t-BuOK (757.8 g, 6.75 mol) in portions. The reaction mixture was stirred at -25 C ~ -15 C for about 45min, then poured into ice NH4Cl (aq.8 L), extracted with EtOAc, washed by brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica column (pet.ether/EtOAc=50/1 to 20/1 to 10/1) to give the title compound (920.0 g, 64.5%) as colorless oil. 1H NMR (CDCl3): 9.49 (1H, s), 5.63 (1H, m), 5.09 (2H, m), 3.79 (2H, m), 2.96 (2H, m), 2.23 (2H, d), 1.93 (2H, m), 1.44 (10H, m).
60%	With potassium <i>tert</i>-butylate In tetrahydrofuran for 0.75h;	52.1 Step 1: tert-Butyl 4-formyl-4-(prop-2-en-1-yl)piperidine-1-carboxylate A solution of tert-butyl 4-formylpiperidine-1-carboxylate (300.0 g, 1.40 mol) in THF (3 L) was cooled to -25 oC, allylbromide (187.7 g, 1.55 mol) was added, then t-BuOK (173.0 g, 1.55 mol) in portions, then stirred at -25 °C ~ -15 °C for 45 min. The reaction mixture was poured into ice and NH 4Cl (aq. 3L), extracted with EtOAc (2 x 2L), washed with brine, dried over Na 2SO 4, concentrated in vacuo, purified by silica column (pet.ether/EtOAc=50/1 to 20/1 to 10/1) to give the product (210.0 g, 60%) as a colorless oil. 1H NMR (400 MHz, CDCl 3) δ: 9.48 (s, 1H), 5.58 (s, 1H), 5.03 (s, 2H), 3.76 (s, 2H), 2.90 (s, 2H), 2.21 (s, 2H), 1.89 (s, 2H), 1.43 (s, 9H).

52%	Stage #1: tert butyl 4-formylpiperidine-1-carboxylate With potassium hydroxide In N,N-dimethyl-formamide at -5℃; for 0.333333h; Stage #2: allyl bromide In N,N-dimethyl-formamide at -5 - 20℃;	13.1 Step 1) fey -butyl 4-allyl-4-formylpiperidine-l-carboxylate [370] To a solution of tert-butyl 4-formylpiperidine-l-carboxylate (10.66 g, 50.0 mmol) in DMF (100 mL) was added potassium hydroxide (15.00 g, 267.3 mmol) and the mixture was stirred at -5 °C for 20 min, then allyl bromide (12.10 g, 100.0 mmol) was added to the above suspension dropwise at -5 °C for 20 min. The resulting solution moved to room temperature and stirred overnight, then diluted in water (400 mL) and extracted with EtOAc (300 mL x 3). The combined organic phases were washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 30/1) to give the title compound as light yellow oil (6.60 g, 52%). MS (ESI, pos. ion) m z: 198 [(M-C4)+H]+; lU NMR (600 MHz, CDCI3): δ (ppm): 9.50 (s, 1H), 5.64 (m, 1H), 5.14-5.04 (m, 2H), 3.89-3.69 (m, 2H), 3.02- 2.89 (m, 2H), 2.26-2.22 (m, 2H), 1.97-1.90 (m, 2H), 1.82-1.74 (m, 1H), 1.69-1.60 (m, 1H), 1.45 (s, 9H).
52%	Stage #1: tert butyl 4-formylpiperidine-1-carboxylate With potassium hydroxide In N,N-dimethyl-formamide at -5℃; for 0.333333h; Stage #2: allyl bromide In N,N-dimethyl-formamide at -5 - 20℃;	14.1 Step 1) tert-butyl 4-allyl-4-formylpiperidine-l-carboxylate Step 1) tert-butyl 4-allyl-4-formylpiperidine-l-carboxylate [0400] To a solution of tert-butyl 4-formylpiperidine-l-carboxylate (10.66 g, 50.0 mmol) in DMF (100 mL) was added potassium hydroxide (15.00 g, 267.3 mmol), and stirring at -5 °C for 20 min, then allyl bromide (12.10 g, 100.0 mmol) was added to the above suspension dropwise at -5 °C in 20 min. The resulting mixture was stirred at room temperature overnight, then diluted in water (400 mL) and extracted with EtOAc (300 mL x 3). The combined organic phases were washed with brine (500 mL), then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 30/1) to give the title compound as light yellow oil (6.60 g, 52%). MS (ESI, pos. ion) m/z: 198 [M-C4H8+H]+; NMR (600 MHz, CDCb): δ (ppm) 9.50 (s, 1H), 5.64 (m, 1H), 5.14-5.04 (m, 2H), 3.89-3.69 (m, 2H), 3.02-2.89 (m, 2H), 2.26-2.22 (m, 2H), 1.97-1.90 (m, 2H), 1.82-1.74 (m, 1H), 1.69-1.60 (m, 1H), 1.45 (s, 9H).
52%	Stage #1: tert butyl 4-formylpiperidine-1-carboxylate With potassium hydroxide In N,N-dimethyl-formamide at -5℃; for 0.333333h; Stage #2: allyl bromide In N,N-dimethyl-formamide at 20℃;	14.1 Step 1) Tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (10.66 g, 50.0 mmol) in DMF (100 mL) was added potassium hydroxide (15.00 g, 267.3 mmol) and the mixture was stirred at -5 ° C for 20 minutes and then allyl bromide (12.10 g, 100.0 mmol) was added over 20 minutes. The reaction was stirred at room temperature overnight after addition, then diluted with water (400 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with saturated brine (500 mL), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was then subjected to silica gel column chromatography (PE / EtOAc (v / v) = 30/1) to give the title compound as a pale yellow oil (6.60 g, 52%).
52%	Stage #1: tert butyl 4-formylpiperidine-1-carboxylate With potassium hydroxide In N,N-dimethyl-formamide at -5℃; for 0.333333h; Stage #2: allyl bromide In N,N-dimethyl-formamide at 20℃;	13.1 Step 1) Tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate 1-tert-butoxycarbonylpiperidine-4-carbaldehyde (10.66 g, 50.0 mmol) was dissolved in N, N-dimethylformamide (100 mL) and potassium hydroxide (15.00 g, 267.3 mmol) was added thereto, and the mixture was stirred at -5 ° C for 20 minutes and then 3-bromopropene (12.10 g, 100.0 mmol) dropwise over 20 minutes and the resulting mixture was allowed to move to room temperature and stirred overnight before it was diluted with water (400 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic phases were washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 30/1) to give the title compound as a pale yellow oil (6.60 g, 52%).
48%	With lithium tert-butoxide In N,N-dimethyl-formamide at 0℃; for 1h;	10.1 Step 1: Tert-Butyl 4-allyl-4-formylpiperidine-1-carboxylate To a dry 1 L flask were added tert-butyl 4-formylpiperidine-1-carboxylate (35.0 g, 164 mmol), lithium tert-butoxide (15.77 g, 197 mmol) and allyl bromide (11.54 mL, 189 mmol) and DMF (328 mL), and the mixture was stirred at 0° C. for 1 hour. After the reaction was completed, the mixture was poured into a separating funnel charged with saturated aqueous NH4Cl solution and H2O (1:1, 500 mL), and extracted with Et2O (5*50 mL). The organic phases were combined, dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether with a gradient of 0 to 25%) to obtain tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate as a colorless oil (24 g, yield: 48%). 1H NMR (400 MHz, CDCl3) δ 9.52 (s, 1H), 5.53-5.76 (m, 1H), 4.96-5.19 (m, 2H), 3.80 (br.s., 2H), 2.97 (t, J=11.49 Hz, 2H), 2.26 (d, J=7.33 Hz, 2H), 1.95 (dt, J=13.71, 3.13 Hz, 2H), 1.38-1.58 (m, 11H) ppm.
42%	Stage #1: tert butyl 4-formylpiperidine-1-carboxylate With lithium tert-butoxide In N,N-dimethyl-formamide at 0℃; for 0.5h; Inert atmosphere; Stage #2: allyl bromide In N,N-dimethyl-formamide at 0℃; for 2h; Inert atmosphere;	143.1 Step 1: Preparation of tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate Lithium tert-butoxide (13.5 g, 16.9 mmol) was added to a solution of tert-butyl 4-formylpiperidine-1-carboxylate (30 g, 14.1 mmol) in N,N-dimethylformamide (300 mL) at 0°C, and the reaction solution was stirred for 30 minutes after completion of the addition. Allyl bromide (19 g, 16.2 mmol) was added, and the reaction solution was stirred at 0°C for 2 hours after completion of the addition. The reaction solution was poured into aqueous ammonium chloride solution (1 L), and extracted with ethyl acetate (1 L×2). The ethyl acetate layer was washed with saturated sodium chloride aqueous solution (500 mL), dried over anhydrous sodium sulfate, and purified by column chromatography [eluent: petroleum ether ∼ ethyl acetate/petroleum ether from 0% to 2%] to obtain the product tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate (15 g, yield: 42%) as a colorless oil.
42%	Stage #1: tert butyl 4-formylpiperidine-1-carboxylate With lithium hydroxide In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: allyl bromide In N,N-dimethyl-formamide at 0℃; for 2h;	35.1 Step 1: Preparation of tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate At 0, to tert-butyl 4-formylpiperidine-1-carboxylate (30g, 14.1mmol)N,N-Dimethylformamide (300mL)Add lithium tert-butoxide (13.5g, 16.9mmol),Stir for 30 minutes after adding,Add allyl bromide (19g, 16.2mmol),Stir at 0°C for 2 hours after adding.The reaction solution was poured into an aqueous ammonium chloride solution (1L), extracted with ethyl acetate (1L×2), the ethyl acetate layer was washed with a saturated aqueous sodium chloride solution (500mL), dried over anhydrous sodium sulfate and then column chromatography [ Eluent: petroleum ether ~ ethyl acetate/petroleum ether from 0% to 2%] Purify to obtain a colorless oily productTert-Butyl 4-allyl-4-formylpiperidine-1-carboxylate (15 g, yield 42%).
24 g	With lithium tert-butoxide In N,N-dimethyl-formamide at 0℃; for 1h;	a A mixture of fer?-butyl 4-formylpiperidine-l-carboxylate (35.0 g, 164 mmol), lithium fer?-butoxyde (15.77 g, 197 mmol), and allylbromide (11.54 mL, 189 mmol) in DMF (328 mL) was stirred for 1 h at 0 °C. The mixture was poured into a separation funnel containing sat. aq NH4C1:H20 (1 : 1 , 500 mL) and it was extracted with Et20 (5 x 50 mL). The combined organic phases were dried over MgS04, filtered, and the volatiles were removed under reduced pressure. The resulting residue was purified by silica chromatography (0 to 25% gradient of EtO Ac/heptane) to give fer?-butyl 4-allyl-4-formylpiperidine-l-carboxylate (24 g, 95 mmol) as colorless oil. NMR (400 MHz, CHLOROFORM-^ δ ppm 9.52 (s, 1 H), 5.53-5.76 (m, 1 H), 4.96-5.19 (m, 2 H), 3.80 (br. s., 2 H), 2.97 (t, J=11.49 Hz, 2 H), 2.26 (d, J=7.33 Hz, 2 H), 1.95 (dt, J=13.71, 3.13 Hz, 2 H), 1.38-1.58 (m, 11 H).
24 g	With lithium tert-butoxide In N,N-dimethyl-formamide at 0℃; for 1h;	2.a (a) A mixture of teri-butyl 4-formylpiperidine-l-carboxylate (35.0 g, 164 mmol), lithium teri-butoxyde (15.77 g, 197 mmol), and allylbromide (11.54 mL, 189 mmol) in DMF (328 mL) was stirred for 1 h at 0 °C. The mixture was poured into a separation funnel containing sat. aq NH^CLF^O (1 : 1, 500 mL) and it was extracted with Et20 (5 x 50 mL). The combined organic phases were dried over MgS04, filtered, and the volatiles were removed under reduced pressure. The resulting residue was purified by silica chromatography (0- 25% EtOAc/heptane eluent) to give teri-butyl 4-allyl-4-formylpiperidine-l-carboxylate (24 g, 95 mmol) as colorless oil. JH NMR (400 MHz, CHLOROFORM-
24 g	With lithium tert-butoxide In N,N-dimethyl-formamide at 0℃; for 1h;	a Step a: A mixture of tert-butyl 4-formylpiperidine- 1 -carboxylate (35.0 g, 164 mmol), lithium tert-butoxide (15.77 g, 197 mmol), and allylbromide (11.54 mL, 189 mmol) in DMF (328 mL) was stirred for 1 h at 0 °C. The mixture was poured into a separation funnel containing sat. aq. NH4C1/H20 (1/1, 500 mL) and it was extracted with Et20 (5 x 50 mL). The combined organic phases were dried over Mg504, filtered, and the volatiles were removed under reduced pressure. The resulting residue was purified by silica chromatography (0 to 25% gradient of EtOAc/heptane) to give tert-butyl 4-allyl-4-formylpiperidine- 1 -carboxylate (24 g, 95 mmol) as a colorless oil. ‘H NMR (400 MHz, Chloroform-d) ö ppm 9.52 (s, 1 H), 5.53-5.76 (m, 1 H), 4.96- 5.19 (m, 2 H), 3.80 (br. s, 2 H), 2.97 (t, J=11.49 Hz, 2 H), 2.26 (d, J=7.33 Hz, 2 H), 1.95 (dt, J=13.71, 3.13 Hz, 2 H), 1.38-1.58 (m, 11 H).
24 g	With lithium tert-butoxide In N,N-dimethyl-formamide at 0℃; for 1h;	a Step a Intermediates B-8 ferf-butyl l-oxo-8-azaspiror4.51dec-2-ene-8-carboxylate Step a: A mixture of ferf-butyl 4-formylpiperidine-l -carboxylate (35.0 g, 164 mmol), lithium ferf-butoxide (15.77 g, 197 mmol), and allylbromide (11.54 mL, 189 mmol) in DMF (328 mL) was stirred for 1 h at 0 °C. The mixture was poured into a separation funnel containing sat. aq. NH4CI/H2O (1/1, 500 mL) and it was extracted with Et20 (5 x 50 mL). The combined organic phases were dried over MgS04, filtered, and the volatiles were removed under reduced pressure. The resulting residue was purified by silica chromatography (0 to 25% gradient of EtO Ac/heptane) to give ferf-butyl 4-allyl-4-formylpiperidine-l -carboxylate (24 g, 95 mmol) as a colorless oil. NMR (400 MHz, Chloroform- ) δ ppm 9.52 (s, 1 H), 5.53-5.76 (m, 1 H), 4.96- 5.19 (m, 2 H), 3.80 (br. s, 2 H), 2.97 (t, 7=11.49 Hz, 2 H), 2.26 (d, 7=7.33 Hz, 2 H), 1.95 (dt, 7=13.71, 3.13 Hz, 2 H), 1.38-1.58 (m, 11 H).
24 g	With lithium tert-butoxide In N,N-dimethyl-formamide at 0℃; for 1h;	24.a tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate A mixture of tert-butyl 4-formylpiperidine-1 -carboxylate (35.0 g, 164 mmol), lithium tert-butoxide (15.77 g, 197 mmol), and allylbromide (11.54 mL, 189 mmol) in DMF (328 mL) was stirred for 1 h at 0° C. The mixture was poured into a separation funnel containing sat. aq NH4C1:H20 (1:1, 500 mL) and it was extracted with Et20 (5x50 mL). The combined organic phases were dried over Mg504, filtered, and the volatiles were removed under reduced pressure. The resulting residue was purified by silica chromatography (0 to 25% gradient of EtOAc/heptane) to give tert-butyl 4-allyl-4-formylpiperidine-1-car- boxylate (24 g, 95 mmol) as colorless oil. ‘H NMR (400 MHz, CHLOROFORM-d) ö ppm 9.52 (s, 1H), 5.53-5.76 (m, 1H), 4.96-5.19 (m, 2H), 3.80 (bt s., 2H), 2.97 (t, J=11.49 Hz, 2H), 2.26 (d, J=7.33 Hz, 2H), 1.95 (dt, J=13.71, 3.13 Hz, 2H), 1.38-1.58 (m, 11H).
24 g	With lithium tert-butoxide In N,N-dimethyl-formamide at 0℃; for 1h;	a (R)-3,3-Difluoro-8-azaspiror4.51decane-1-amine tert-butyl 1-oxo-8-azaspiro[4.5]dec-2-ene-8-carboxylate Step a: A mixture of ferf-butyl 4-formylpiperidine-l -carboxylate (35.0 g, 164 mmol), lithium ferf-butoxyde (15.77 g, 197 mmol), and allylbromide (11.54 mL, 189 mmol) in DMF (328 mL) was stirred for 1 h at 0 °C. The mixture was poured into a separation funnel containing sat. aq. NH4CI/H2O (1 : 1, 500 mL) and it was extracted with Et20 (5 x 50 mL). The combined organic phases were dried over MgS04, filtered, and the volatiles were removed under reduced pressure. The resulting residue was purified by silica chromatography (0-25 % EtOAc/heptane) to give ferf-butyl 4-allyl -4-formylpiperidine-l -carboxylate (24 g) as colorless oil. NMR (400 MHz, Chloroform- ) δ ppm 9.52 (s, 1 H), 5.53-5.76 (m, 1 H), 4.96-5.19 (m, 2 H), 3.80 (br. s., 2 H), 2.97 (t, / = 11.5 Hz, 2 H), 2.26 (d, / = 7.3 Hz, 2 H), 1.95 (dt, / = 13.7, 3.1 Hz, 2 H), 1.38-1.58 (m, 11 H).
7.01 g	Stage #1: tert butyl 4-formylpiperidine-1-carboxylate With lithium tert-butoxide In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: allyl bromide In N,N-dimethyl-formamide at 0℃; for 1h;	a Step a: To a 0 °C mixture of tert-butyl 4-formylpiperidine-1-carboxylate (15.00 g, 70.33 mmol) in DMF (60 mL) was added lithium 2-methylpropan-2-olate (6.75 g, 84.44 mmol) inportions. The resulting mixture was stirred for 30 mm at 0 °C. To the mixture was added3-bromoprop-1-ene (9.73 g, 80.44 mmol) dropwise at 0 °C and stirred for 1 h at this temperature. The reaction mixture was diluted with brine (100 mL), extracted with EA (3 x 200 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA: Hex = 1:20, v/v) to give tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate (7.01 g). MS: m/z 254 (M+H)+
7.01 g	Stage #1: tert butyl 4-formylpiperidine-1-carboxylate With lithium tert-butoxide In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: allyl bromide In N,N-dimethyl-formamide at 0℃; for 1h;	a Step a: 4-formylpiperidine-1-carboxylic acid tert-butyl ester (15.00 g, 70.33 mmol) at 0 °CLithium tert-butoxide (6.75 g, 84.44 mmol) was added portionwise to a solution of DMF (60 mL).The system was stirred at 0 ° C for 30 minutes.3-Bromopropene (9.73 g, 80.44 mmol) was added dropwise to the mixture at 0 ° C and stirred at this temperature for 1 h.The reaction was diluted with brine (100 mL) and EtOAc (EtOAc
	With lithium tert-butoxide In N,N-dimethyl-formamide at 0℃; for 1h;	Compound Q5b To a solution of Compound Q5a (125 g) in DMF (1.25 L) was added t-BuOLi (32.8 g) followed by dropwise addition of allyl bromide (50.6 mL) at 0° C. The resulting reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched with aq NH4Cl solution (1.2 L), extracted with EtOAc (2×500 mL). The combined organic layers were washed with saturated aqueous NaCl solution (250 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford Compound Q5b. 1H NMR (400 MHz, Chloroform-d) δ 9.50 (s, 1H), 5.63-5.60 (m, 1H), 5.12-5.05 (m, 2H), 3.78 (s, 2H), 2.98-2.92 (m, 2H), 2.24 (d, J=6.4 Hz, 2H), 1.95 (d, J=2.8 Hz, 2H), 1.58 (s, 9H), 1.49 (s, 1H), 1.48-1.46 (m, 1H).

Reference： [1]Current Patent Assignee: PFIZER INC - WO2020/81848, 2020, A1 Location in patent: Paragraph 00240
[2]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2021/33153, 2021, A1 Location in patent: Page/Page column 129
[3]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2020/22323, 2020, A1 Location in patent: Paragraph 0472; 0473
[4]Current Patent Assignee: CALITOR SCIENCES LLC; SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2015/94803, 2015, A1 Location in patent: Paragraph 370
[5]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD; CALITOR SCIENCES LLC - WO2016/190847, 2016, A1 Location in patent: Paragraph 0400
[6]Current Patent Assignee: CALITOR SCIENCES LLC; SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - CN104974163, 2017, B Location in patent: Paragraph 0752; 0753; 0754; 0755
[7]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD; CALITOR SCIENCES LLC - CN104672250, 2017, B Location in patent: Paragraph 0639; 0640; 0641; 0642; 0710; 0711; 0712; 0713
[8]Current Patent Assignee: BLUERAY THERAPEUTICS SHANGHAI - US2021/53989, 2021, A1 Location in patent: Paragraph 0432-0434
[9]Current Patent Assignee: HANSOH PHARMACEUTICAL GROUP CO LTD - EP3868742, 2021, A1 Location in patent: Paragraph 0109; 0753-0755
[10]Current Patent Assignee: HANSOH PHARMACEUTICAL GROUP CO LTD - CN113493440, 2021, A Location in patent: Paragraph 1033-1038
[11]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2015/107495, 2015, A1 Location in patent: Paragraph 00303
[12]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2016/203404, 2016, A1 Location in patent: Paragraph 00245
[13]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2016/203405, 2016, A1 Location in patent: Paragraph 00303
[14]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2016/203406, 2016, A1 Location in patent: Paragraph 00304
[15]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2017/15680, 2017, A1 Location in patent: Paragraph 0343; 0344
[16]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2017/216706, 2017, A1 Location in patent: Paragraph 00263
[17]Current Patent Assignee: JACOBIO PHARMACEUTICALS GROUP CO LTD - WO2018/172984, 2018, A1 Location in patent: Page/Page column 69
[18]Current Patent Assignee: JACOBIO PHARMACEUTICALS GROUP CO LTD - CN110143949, 2019, A Location in patent: Paragraph 0322
[19]Current Patent Assignee: GILEAD SCIENCES INC - US2020/108071, 2020, A1 Location in patent: Paragraph 0826-0827

56
[ 137076-22-3 ]
[ 1250994-14-9 ]

Reference： [1]Patent: WO2015/94803,2015,A1
[2]Patent: WO2016/190847,2016,A1
[3]Patent: CN104974163,2017,B
[4]Patent: CN104672250,2017,B

57
[ 137076-22-3 ]
[ 873924-08-4 ]

Reference： [1]Patent: WO2015/94803,2015,A1
[2]Patent: WO2015/148868,2015,A1
[3]Patent: CN105330698,2016,A
[4]Patent: WO2016/190847,2016,A1
[5]Patent: WO2017/44434,2017,A1
[6]Patent: CN106478607,2017,A
[7]Patent: US2010/113417,2010,A1
[8]Patent: WO2009/108827,2009,A1

58
[ 137076-22-3 ]
[ 160296-40-2 ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 6058 - 6080

59
[ 496-12-8 ]
[ 137076-22-3 ]
tert-butyl 4-(1,3-dihydro-2H-isoindol-2-ylmethyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃;	Sodium triacetoxyborohydride (0.47 g, 2.22 mmol) was added to a solution of <strong>[496-12-8]isoindoline</strong> (0.22 g, 1.85 mmol), tert-butyl 4-formyl-1-piperidinecarboxylate (0.40 g, 1.88mmol) and acetic acid (0.033 mL, 0.58 mmol) in dichloromethane (10 mL) and the resulting mixture was stirred overnight at room temperature. The reaction mixture was partitioned between excess of diethyl ether and water. The organic phase was separated, washed with diluted aqueous sodium hydroxide solution, dried over sodium sulfate and the solvent was evaporated to give the title compound (0.61 g, 83%)LRMS (mlz): 317 (M+1)+.

Reference： [1]Patent: WO2015/86693,2015,A1 .Location in patent: Page/Page column 79

60
[ 31166-44-6 ]
[ 137076-22-3 ]
[ 775288-80-7 ]

Yield	Reaction Conditions	Operation in experiment
87%	With sodium tris(acetoxy)borohydride In dichloromethane at 20℃;	30.a Benzyl 4-[I -(tert-butoxycarbonyl)pi peridi n-4-yI]methyl}pi perazi ne-I - carboxylate A mixture of tert-butyl 4-formylpiperidine-1-carboxylate (0.98 g, 4.60 mmol), benzyl piperazine-1-carboxylate (1.02 g, 4.61 mmol) and sodium triacetoxyborohydride (1.01 g, 4.76 mmol) in dichloromethane (30 mL) was stirred overnight at room temperature. The crude was washed with 2N aqueous solution of sodium hydroxide and 2N aqueoussolution of hydrogen chloride, dried over magnesium sulfate and the solvent was evaporated to yield the title compound (1 .68 g, 87%) as a white solid.LRMS (mlz): 418 (M+1).1H-NMR (300 MHz, CDCI3): 1.20- 1.35 (m, 3H), 1.45 (s, 9H), 1.80-2.20 (m, 3H), 2.60 - 2.90 (m, 6H), 3.50 (s, 2H), 3.77 - 4.58 (m, 6H), 5.15 (s, 2H), 7.32 -7.40 (m, 5H).
83.77%	With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 24h;	1D.1 Step 1: Synthesis of benzyl 4-[[l-(tert-butoxycarbonyl)piperidin-4-yl]methyl]iperazine-l- carboxylate To a stirred solution of tert-butyl 4-formylpiperidine-l-carboxylate (2.00 g, 9.38 mol, 1.00 equiv) and benzyl piperazine- 1-carboxylate (2065.60 mg, 9.38 mmol, 1.00 equiv) in THF (50.00 mL) was added NaBH(OAc)3 (1987.47 mg, 9.387 mmol, 1.00 equiv). The resulting mixture was stirred for 24 h at room temperature. After reaction, the reaction was quenched with sat.NELCl (20 mL) at 0 degrees C. The resulting mixture was extracted with EA (3x30 mL). The combined organic layers were washed with water (3x10 mL), dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE: EA = 1: 1 to afford benzyl 4-[[l-(tert-butoxycarbonyl)piperidin-4-yl]methyl]piperazine-l-carboxylate (3.28 g, 83.77%) as light yellow oil. LC/MS: mass calcd. For C23H35N3O4: 417.26, found: 418.30 [M+H]+.
76%	Stage #1: phenylmethyl 1-piperazinecarboxylate; tert butyl 4-formylpiperidine-1-carboxylate In methanol at 25℃; for 10h; Stage #2: With methanol; sodium cyanoborohydride at 25℃; for 2h;	3.1 Step 1: Preparation of benzyl 4-((l-(tert-butoxycarbonyl)pipendin-4- yl)methyi)piperazine-l -carboxylate To a solution of tert-butyl 4-formylpiperidine-l -carboxylate (10.00 g, 46.89 mmol, 1.00 eq) in methanol (20 mL) was added benzyl piperazine- 1 -carboxylate (10.33 g, 46.89 mmol, 9.06 mL, 1.00 eq) at 25 °C and stirred for 10 h. Then the mixture ws added sodium cyanoborohydride (4.42 g, 70.33 mmol, 1.50 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3/1) to give benzyl 4-[(l-tert-butoxycarbonyl-4- piperidyI)methyl]piperazine-l-carboxylate (15.00 g, 35.92 mmol, 76% yield) as a colorless oil. ' i-NXR (400MHz, CD Of)) 67.22 - 7.43 (m, 5H), 5.09 - 5.14 (m, 2H), 4.03 - 4.13 (m, 2H), 3.49 (s, 4H), 2.75 (s, 2.H), 2.39 (s, 4H), 2.20 (d, 7 6.4 Hz, 2H), 1.63 - 1.82. (m, 3H), 1.44 (s, 9H), 0.97 - 1.13 (m, 2.H).

53%	With sodium triacetoxyborohydride; acetic acid In dichloromethane Molecular sieve;	4.1; 15.1 first step:4-[(1-tert-Butoxycarbonyl-4-piperidinyl)methyl]piperazine-1-carboxylic acid benzyl ester (4b) Combine 1-tert-butoxycarbonylpiperidine-4-carbaldehyde (4a) (2.5g, 12mmol) andBenzyl 1-piperazinecarboxylate (2.8g, 13mmol) was dissolved in 60mL of dichloromethane,Add 5 grams of molecular sieves, acetic acid (1.1 g, 18 mmol), sodium triacetoxyborohydride (7.5 g, 35 mmol), and stir overnight.Add 30 mL of water, filter with diatomaceous earth, layer, dry,The residue is separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=50/1-20/1),4-[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]piperazine-1-carboxylic acid benzyl ester (4b) (2.6g, yield: 53%) was obtained.
53%	With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane Molecular sieve;	17.1 The first step: 4-[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]piperazine-1-carboxylic acid benzyl ester (17b) Add 1-tert-Butoxycarbonylpiperidine-4-carbaldehyde (17a) (2.5g, 12mmol)And benzyl 1-piperazinecarboxylate (2.8g, 13mmol)Dissolve in 60mL dichloromethane,Add 5 grams of molecular sieve,Acetic acid (1.1g, 18mmol), sodium triacetoxyborohydride (7.5g, 35mmol),Stir overnight.Add 30mL water, Diatomaceous earth filtration, layering, drying, the residue is separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=50/1-20/1) to obtain 4-[(1-tert-butyl Oxycarbonyl-4-piperidinyl)methyl]piperazine-1-carboxylic acid benzyl ester (17b) (2.6 g, yield: 53%).
693 mg	Stage #1: phenylmethyl 1-piperazinecarboxylate; tert butyl 4-formylpiperidine-1-carboxylate With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane at 20℃; Stage #2: With water; sodium hydrogencarbonate In dichloromethane	1 Step 1 : benzyl 4-((l-(tert-butoxycarbonyl)piperidin-4-yl)methyl)piperazine-l-carboxylate Step 1 : benzyl 4-((l-(tert-butoxycarbonyl)piperidin-4-yl)methyl)piperazine-l-carboxylate Sodium triacetoxyborohydride (1732 mg, 8.17 mmol) was added to a mixture of benzyl piperazine-l-carboxylate (600 mg, 2.72 mmol), tert-butyl 4-formylpiperidine-l-carboxylate (697 mg, 3.27 mmol) and acetic acid (156 uL, 2.72 mmol) in DCM (14 mL) at room temperature. After stirring at room temperature overnight, the mixture was quenched with sat. NaHCC , the aq. layer was CH2CI2 extraction (2X20 mL). The combined org. fractions were dried over Na2SC>4 and concentrated to dryness. The residue was purified by ISCO column chromatography (silica gel ISCO 24 g prepacked, eluting with 0-100% EtOAc/Hexane) to give the title compound (693 mg). LCMS m/z (M+H): Calc'd 418.2, found 418.4.

Reference： [1]Current Patent Assignee: ALMIRALL SA - WO2015/86693, 2015, A1 Location in patent: Page/Page column 74; 75
[2]Current Patent Assignee: DESIGN THERAPEUTICS - WO2021/158707, 2021, A1 Location in patent: Paragraph 00423; 001347; 001348; 001349
[3]Current Patent Assignee: ARVINAS - WO2021/127443, 2021, A1 Location in patent: Paragraph 0286-0288
[4]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - CN112010858, 2020, A Location in patent: Paragraph 0470-0478; 0800-0808
[5]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - CN112390785, 2021, A Location in patent: Paragraph 0724; 0728-0732
[6]Current Patent Assignee: MERCK & CO INC - WO2017/95758, 2017, A1 Location in patent: Page/Page column 48-49

61
[ 137076-22-3 ]
[ 711007-44-2 ]
tert-butyl 4-(4-carbamoyl-1H-benzimidazol-2-yl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With sodium hydrogensulfite; at 130℃; for 5h;	At room temperature, <strong>[711007-44-2]2,3-<strong>[711007-44-2]diaminobenzamide</strong></strong> (500 mg, 3.30 mmol) and 1-N-Boc-4-piperidinecarboxaldehyde (776 mg, 3.63 mmol) were initially charged in DMA (dimethylamide). With vigorous stirring, sodium bisulfite (585 mg, 5.62 mmol) was added at room temperature, and the reaction solution was then stirred at 130 C. for 5 h. After cooling to room temperature, water was added and the reaction mixture was repeatedly extracted thoroughly with dichloromethane The combined organic phases were then dried over magnesium sulfate, filtered off, concentrated under reduced pressure and then purified by column chromatography (gradient ethyl acetate/heptane). This gave tert-butyl 4-(4-carbamoyl-1H-benzimidazol-2-yl)piperidine-1-carboxylate (1.0 g, 88% of theory) in the form of a colorless solid. 1H-NMR (400 MHz, CDCl3 delta, ppm) 9.70 (br. s, 1H, NH), 8.10 (s, 1H), 7.60 (s, 1H), 7.30 (t, 1H), 5.90 (br. s, 1H, NH), 3.12 (m, 1H), 2.10 (m, 2H), 1.90 (m, 2H), 1.65 (m, 4H), 1.50 (s, 9H).

Reference： [1]Patent: US2015/216168,2015,A1 .Location in patent: Paragraph 0149; 0150

62
[ 137076-22-3 ]
[ 711007-44-2 ]
[ 272769-47-8 ]

Reference： [1]Patent: US2015/216168,2015,A1

63
[ 137076-22-3 ]
[ 345627-80-7 ]
tert-butyl 4-((4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)methyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃; for 16h;	To a solution of tert-butyl 4-formylpiperidine-l-carboxylate (100 mg, 0.46 mmol) and N- (5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)piperidine-4-carboxamide (178 mg, 0.46 mmol) in DCE (10 mL) was added sodium triacetoxyborohydride (293 mg, 1.38 mmol) portion wise and the reaction was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. The reaction mixture was diluted with DCM (30 mL) and washed with water (2 x 20 mL). The combined organic solvents were dried over Na2S04 and concentrated under vacuum to afford the title compound (200 mg, yield 74%) as an off white solid which was used directly in the next step without further purification. LCMS: [M+H]+ = 578.20 ; Rt = 2.29 min

Reference： [1]Patent: WO2015/154022,2015,A1 .Location in patent: Paragraph 232-234

64
[ 3607-17-8 ]
[ 137076-22-3 ]
tert-butyl 4-(cyclopropylidenemethyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: (3-Brompropyl)triphenylphosphoniumbromid With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 0.75h; Inert atmosphere; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	Piperidines 6, 9, 14, 15, and 21: General Procedure General procedure: Under argon, t-BuOK (27.0 g, 0.24 mol) was added in one portion to a stirred and cooled (0 °C) solution of the appropriate phosphonium salt 3a or 3b (0.12 mol) in anhyd THF (600 mL), and the mixture was stirred at 0 °C for 45 min. A solution of the appropriate ketone or aldehyde (0.10 mol) in anhyd THF (60 mL) was added dropwise to the stirred mixture, keeping the temperature at 0 °C (there was a very slight exothermic effect during the addition). The mixture was then warmed to r.t. and stirred overnight. Insoluble inorganic materials were removed by filtration, and the filtrate was evaporated in vacuo. The oily residue was triturated with hexane (300 mL), resulting in an abundant precipitate (Ph3PO). This was filtered off, and the filtrate was evaporated in vacuo to give crude alkene. Further distillation under reduced pressure afforded the pure compounds as oils, most of which solidified upon standing.

Reference： [1]Vyzir, Ivan I.; Iminov, Rustam T.; Tverdokhlebov, Anton; Tolmachev, Andrey A.; Shcherbatiuk, Andriy V.; Mykhailiuk, Pavel K.; Biitseva, Angelina V. [Synthesis, 2015, vol. 47, # 24, p. 3963 - 3971]

65
C₂₂H₂₃Br₂P [ No CAS ]
[ 137076-22-3 ]
tert-butyl 4-(cyclobutylidenemethyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: C₂₂H₂₃Br₂P With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 0.75h; Inert atmosphere; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	Piperidines 6, 9, 14, 15, and 21: General Procedure General procedure: Under argon, t-BuOK (27.0 g, 0.24 mol) was added in one portion to a stirred and cooled (0 °C) solution of the appropriate phosphonium salt 3a or 3b (0.12 mol) in anhyd THF (600 mL), and the mixture was stirred at 0 °C for 45 min. A solution of the appropriate ketone or aldehyde (0.10 mol) in anhyd THF (60 mL) was added dropwise to the stirred mixture, keeping the temperature at 0 °C (there was a very slight exothermic effect during the addition). The mixture was then warmed to r.t. and stirred overnight. Insoluble inorganic materials were removed by filtration, and the filtrate was evaporated in vacuo. The oily residue was triturated with hexane (300 mL), resulting in an abundant precipitate (Ph3PO). This was filtered off, and the filtrate was evaporated in vacuo to give crude alkene. Further distillation under reduced pressure afforded the pure compounds as oils, most of which solidified upon standing.

66
[ 137076-22-3 ]
[ 62718-31-4 ]

Reference： [1]Synthesis,2015,vol. 47,p. 3758 - 3766

67
[ 618-91-7 ]
[ 137076-22-3 ]
tert-butyl 4-(hydroxy(3-(methoxycarbonyl)phenyl)methyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With isopropylmagnesium chloride; In tetrahydrofuran; at -40 - 20℃;	[0282] To a stirred solution of methyl 3-iodobenzoate (3.0 g, 11.45 mmol) in anhydrous THF (100 mL) was added isopropyl magnesium chloride (6.27 mL, 12.59 mmol, 2M solution in THF) at -40 °C. tert-Butyl 4-formylpiperidine-l -carboxylate (2.68 g, 12.59 mmol) was added. The reaction was stirred at rt overnight. The reaction was quenched with saturated NH4C1 solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04 and concentrated under reduced pressure to obtain a crude residue which was purified by column chromatography to afford tert-butyl 4- (hydroxy(3-(methoxycarbonyl)phenyl)methyl)piperidine-l -carboxylate (2.91 g, 73 percent). LCMS: m/z = 350.15 (M+H)+.

Reference： [1]Patent: WO2016/40498,2016,A1 .Location in patent: Paragraph 0282

68
[ 610-81-1 ]
[ 137076-22-3 ]
tert-butyl 4-(6-hydroxy-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70.8%	With sodium dithionite; In ethanol; water; at 80℃; for 10h;	To a solution of compound 18 (200 mg, 0.94 mmol) in a mixed solvent,And Na2S2O4 (1.63 g, 9.38 mmol)(Ethanol: water = 2: 1, 15 mL) was added<strong>[610-81-1]4-Amino-3-nitrophenol</strong> (405 mg, 2.63 mmol) was added.The mixture was heated at 80 DEG C for 10 hours,And concentrated under reduced pressure. The solid product was washed with water and extracted with ethanol:Recrystallization from acetone yields compound19 (211 mg, 70.8% yield)

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 7410 - 7430
[2]Patent: KR2017/85170,2017,A .Location in patent: Paragraph 0287; 0288

69
[ 23132-21-0 ]
[ 75-16-1 ]
[ 137076-22-3 ]
C₁₃H₁₉N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(1) and at -78 for 1-Boc-4- piperidine aldehyde (1.87g) solution of tetrahydrofuran (18) was added dropwise a tetrahydrofuran solution (9.6) of 1.06M methyl magnesium bromide, It was stirred at room temperature for 0.5 hour. After the reaction terminated, it cooled to room temperature, and the addition of saturated aqueous ammonium chloride solution, followed by extracting with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation. Of the resulting residue at room temperature in ethyl acetate (18) was added a 4N hydrochloric acid / ethyl acetate solution (18), and stirred for 4 hours at the same temperature. After the reaction, hydrochloric acid was distilled off and the excess solvent. In addition, the obtained residue was purified by N, N- dimethylformamide (9.0) at room temperature was added <strong>[23132-21-0]2-bromo-3-methyl-5-nitropyridine</strong> (1.9g) and potassium carbonate (1.94g) was added and the on, 80 4 hours to stirring. After the reaction, it cooled to room temperature and, after addition of water, followed by extracting with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation.

Reference： [1]Patent: KR2015/2661,2015,A .Location in patent: Paragraph 0545; 0546; 0547

70
[ 56181-39-6 ]
[ 137076-22-3 ]
tert-butyl 4-[(4-chloropyrimidin-5-yl)(hydroxy)methyl]piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%		To a - 30 C solution of <strong>[56181-39-6]5-bromo-4-chloropyrimidine</strong> (1-112) (13 g, 0.07 mol) in anhydrous THF (130 ml_) was added in a dropwise manner a solution of /'-PrMgCI (50 ml_, 0.1 mol, 2M in THF). Then the resulting mixture was stirred at - 30 C for 30 min. A solution of tert-butyl 4-formylpiperidine-1 -carboxylate (15 g, 0.07 mol) in THF (20 ml_) was added to the above solution at - 30 C. After the addition, the mixture was allowed to room temperature, and stirred for a further 4 hr. TLC (petroleum ether/EtOAc 3:1 ) showed the reaction was complete. Saturated aq. NH4CI (200 ml_) was added to quench the reaction at 0 C. The mixture was extracted with EtOAc (2 x 200 ml_). The organic layers were dried over Na2S04 and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether/EtOAc from 10:1 to 3:1 ) to give tert-butyl 4-[(4-chloropyrimidin-5-yl)(hydroxy)methyl]piperidine-1 -carboxylate (1-113) (13.7 g, 60%) as a pale white solid .1H NMR (400 MHz, CDCI3) delta ppm 8.91 (s, 1 H), 8.83 (s, 1 H), 4.85 - 4.93 (m, 1 H), 4.14 (br. s., 2 H), 2.55 - 2.62 (m, 3 H), 1 .83 - 1 .92 (m, 1 H), 1 .41 - 1 .46 (m, 15 H).

Reference： [1]Patent: WO2016/97918,2016,A1 .Location in patent: Page/Page column 89

71
[ 137076-22-3 ]
[ 1181267-36-6 ]

Reference： [1]Patent: CN106146459,2016,A

72
[ 82891-99-4 ]
[ 137076-22-3 ]
tert-butyl 4-[(Z)-3-(1,3-dioxolan-2-yl)-2-nitro-prop-1-enyl]piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%		To a solution of commercially available 2-(2-bromoethyl)-1,3-dioxolane (40.73 g, 225 mmol) in anhydrous DMSO (350 mL) was added a solution of NaNO2 (27.95 g, 405 mmol) in anhydrous DMSO (350 mL) slowly at 0C and the resulting mixture was stirred at 18C for 6 hours under N2. Then, the reaction mixture was poured into water and extracted with MTBE. The combined organic phase was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was purified by silica gel column chromatography to give intermediate <strong>[82891-99-4]2-(2-nitroethyl)-1,3-dioxolane</strong> (12.50 g, 38%) as a yellow liquid . A mixture of this intermediate (3.97 g, 27 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (6.61 g, 31) in TEA (3.00 g, 30 mmol) was stirred at 18C for 8 hours. Then a solution of DMAP (330 mg, 2.70 mmol) in Ac2O (4.13 g, 40 mmol) was added and the reaction mixture was stirred at 18C for 7 hours. The reaction was quenched with water and then extracted with EtOAc. The combined organic phase was washed with saturated brine, dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography to afford intermediate tert-butyl 4-[(Z)-3-(1,3-dioxolan-2-yl)-2-nitro-prop-1-enyl]piperidine-1-carboxylate (5.64 g, 61%) as a yellow liquid. Finally, a stirred suspension of this intermediate (2.50 g, 7.30 mmol) in absolute EtOH (100 mL) and CHCl3 (8 mL) containing PtO2 (414 mg, 1.83 mmol) was placed under H2 (50 Psi) at 18C after 15 hours, the mixture was filtered through Celite and washed with EtOH. The filtrate was concentrated to dryness to give desired reagent R-04b (2.02 g, 88% crude) as a yellow syrup which was used for next step without further purification. ESI-MS (M+1): 315.3 calc. for C16H30N2O4: 314.2.

Reference： [1]Patent: WO2017/85053,2017,A1 .Location in patent: Page/Page column 55

73
[ 104-92-7 ]
[ 137076-22-3 ]
[ 856936-55-5 ]

Reference： [1]Journal of the American Chemical Society,2017,vol. 139,p. 11353 - 11356

74
[ 3466-32-8 ]
[ 137076-22-3 ]
tert-butyl 4-(4-(methylsulfonyl)benzoyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With Quinuclidine; 4,4'-di-tert-butyl-2,2'-bipyridine nickel(II) bromide; [Ir(C₆H₂F₂-C₅H₃NCF₃)₂(4,4′-di-tert-butyl-2,2′-dipyridyl)]; potassium carbonate In 1,4-dioxane at 20℃; for 20h; Inert atmosphere; Sealed tube; Irradiation;
69%	With 1,4-diaza-bicyclo[2.2.2]octane; Ir[dF(CF₃)ppy]2(dtbbpy)PF₆; sodium hydrogencarbonate; 4,4'-di-tert-butyl-2,2'-bipyridine In 1,4-dioxane at 20℃; for 20h; Inert atmosphere; Irradiation; Sealed tube;	3) General procedure for aldehyde arylation General procedure: To a 5mL glass vial were added NiBr2.DME (3.7 mg, 0.012 mmol, 0.11 equiv), 4,4'-ditert-butyl-2,2'-bipyridine (dtbbpy, 3.2 mg, 0.012 mmol, 0.11 equiv) as ligand and 3 mLof dry 1,4-dioxane. This precatalyst vial was sealed and sonicated for around 15 minutes, until its content became homogeneous. A separated 5 mL vial equipped with a magnetic stir bar was charged with the photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1.2 mg, 0.0011 mmol, 1 mol %), 1,4-diazabicyclo[2.2.2]octane (DABCO, 6.2 mg, 0.055 mmol, 0.5 equiv), NaHCO3 (13.9 mg,0.16 mmol, 1.5 equiv), the aryl bromide (0.11 mmol, 1 equiv) and the aldehyde (0.22mmol, 2 equiv). The volatile aldehydes were added after the sparging. The precatalyst was syringed into the reaction vial before sparging with argon for 15 minutes. The vial was sealed with parafilm and the reaction was magnetically stirred and irradiated for 20 h with a blue LED lamp 6 cm away from the vial with a cooling fan to keep the reaction at room temperature. After that time, the reaction was quenched by exposure to air and filtered through a pad of silica with ethyl acetate and dichloromethane. After concentration, the residue was purified by flash chromatography on silica gel to afford the desired product.The isolated yields reported are the average yield of four simultaneous and identical reactions.

Reference： [1]Zhang, Xiaheng; MacMillan, David W. C. [Journal of the American Chemical Society, 2017, vol. 139, # 33, p. 11353 - 11356]
[2]Cardozo, Thiago Messias; Da Silva Santos, Bruno Maia; Finelli, Fernanda Gadini; de Souza, Cauê Paula; dos Santos Dupim, Mariana [Beilstein Journal of Organic Chemistry, 2021, vol. 17, p. 2959 - 2967]

75
[ 1422-53-3 ]
[ 137076-22-3 ]
tert-butyl 4-(5-fluoro-2-methylbenzoyl)piperidine-1-carboxylate [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2017,vol. 139,p. 11353 - 11356

76
[ 100367-39-3 ]
[ 137076-22-3 ]
tert-butyl 4-(2-methoxyisonicotinoyl)piperidine-1-carboxylate [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2017,vol. 139,p. 11353 - 11356

77
[ 3699-66-9 ]
[ 137076-22-3 ]
(Z)-tert-butyl 4-(3-ethoxy-2-methyl-3-oxoprop-1-enyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48.2%	Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In tetrahydrofuran; mineral oil at 0 - 20℃;	70.1 Step-1 To a suspension of sodium hydride (60% in mineral oil, 0.487g, 12.81 mmol, 1.3 eq) in THF (50 mL) was added ethyl 2-(diethoxyphosphoryl)propanoate (2.23 g, 9.37 mmol, 1.0 eq)dropwise at 0°C and the mixture was allowed to stir at the same temperature for 30 minutes. To this mixture was added a solution of tert-butyl 4-formylpiperidine-1-carboxylate (2.0 g, 9.37 mmol, 1.0 eq) in THF (5 mL) and the resulting mixture was allowed to stir at RT for 2 h. Progress of reaction was monitored by TLC. After completion, reaction mixture was diluted with saturated aq. NH4C1 (100 mL) and extracted with ethyl acetate (3 x 50 mL). Combined organiclayer was washed with brine, dried over anhydrous Na2SO4 and evaporated to dryness under vacuum to afford crude which was purified by Combi-Flash on silica gel using ethyl acetatehexane system as eluent to afford (Z)-tert-butyl 4-(3-ethoxy-2-methyl-3-oxoprop-1- enyl)piperidine- 1 -carboxylate (1.34 g, 48.2 %).LCMS: 298 [M+1]
48.2%	Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In tetrahydrofuran; mineral oil at 20℃; for 2h;	70.1; 71.1 Step-1 To a suspension of sodium hydride (60% in mineral oil, 0.487 g, 12.81 mmol, 1.3 eq) in THF (50 mL) was added ethyl 2-(diethoxyphosphoryl)propanoate (2.23 g, 9.37 mmol, 1.0 eq) dropwise at 0° C. and the mixture was allowed to stir at the same temperature for 30 minutes. To this mixture was added a solution of tert-butyl 4-formylpiperidine-1-carboxylate (2.0 g, 9.37 mmol, 1.0 eq) in THF (5 mL) and the resulting mixture was allowed to stir at RT for 2 h. Progress of reaction was monitored by TLC. After completion, reaction mixture was diluted with saturated aq. NH4Cl (100 mL) and extracted with ethyl acetate (3*50 mL). Combined organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated to dryness under vacuum to afford crude which was purified by Combi-Flash on silica gel using ethyl acetate-hexane system as eluent to afford (Z)-tert-butyl 4-(3-ethoxy-2-methyl-3-oxoprop-1-enyl)piperidine-1-carboxylate (1.34 g, 48.2%).
	Stage #1: ethyl 2-diethoxyphosphorylpropionate With sodium t-butanolate In tetrahydrofuran at 0 - 20℃; for 1h; Inert atmosphere; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In tetrahydrofuran at 20℃; for 1h; Inert atmosphere;	16-1 (Z)-tert-butyl 4-(3-ethoxy-2-methyl-3-oxoprop-1-enyl)piperidine-1-carboxylate To a solution of t-BuONa (379 mg, 3.94 mmol) in anhydrous THF (20 mL) at 0 °C underN2 balloon was added ethyl2-(diethoxyphosphoryl)propanoate ( 871 mg, 3.66 mmol). And the10 mixture was stirred at room temperature for 1h. After cooling to 0°C, tert-butyl4-formylpiperidine-1-carboxylate (600 mg, 2.81 mmol) was added. The resulting mixture wasstirred at room temperature for 1h. LRMS showed the reaction was completed. The mixture wasquenched with sat. NH4Cl (20 mL), diluted with EtOAc (200 mL), washed with brine (30 mLx3),dried (Na2S04) and concentrated. The residue was purified by column chromatography (silica15 gel, PE/ EtOAc = 10/ 1 to 5/1) to give (Z)-tert-butyl4-(3-ethoxy-2-methyl-3-oxoprop-1-enyl)piperidine-1-carboxylate. LRMS m/z (M+Na), 320.2 found, 320.2 required.

Reference： [1]Current Patent Assignee: AURANSA - WO2019/103897, 2019, A1 Location in patent: Page/Page column 185; 186
[2]Current Patent Assignee: AURANSA - US2020/377510, 2020, A1 Location in patent: Paragraph 0803-0805; 0813-0815
[3]Current Patent Assignee: MERCK & CO INC - WO2018/68295, 2018, A1 Location in patent: Page/Page column 84

78
[ 638-94-8 ]
[ 137076-22-3 ]
(1S,2S,4R,6R,8S,9S,11S,12S,13R)-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-(piperidin-4-yl)-5,7-dioxapentacyclo[10.8.0.02'9.04'8.013'18]icosa-14,17-dien-16-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13%	With perchloric acid; In water; at 0 - 20℃;	This example demonstrates a method for making compound 7-4R in Table 1. This example refers to the compound numbering in FIG. 1. (1S,2S,4R,6R,8S,9S, 11S,12S, 13R)-1 l-Hydroxy-8-(2-hydroxyacetyl)-9, 13- dimethyl-6-(piperidin- -yl)-5,7-dioxapentacyclo[10.8.0.002'9.04'8.01 '18]icosa-14,17-dien- 16-one (7-4R). [0527] To a solution of <strong>[638-94-8]desonide</strong> (1, 0.10 g, 0.25 mmol) in nitropropane (5 mL) was added aqueous perchloric acid (70%, 0.11 g, 0.75 mmol) dropwise at 0 C, followed by the addition of l-Boc- -piperidinecarboxaldehyde (4-4, 64 mg, 0.30 mmol). After being stirred at RT overnight, the suspension was concentrated in vacuo. The residue was basified by the addition of ammonia solution in methanol (7 M, 10 mL). The resulting mixture was concentrated in vacuo and the crude product was purified by prep-HPLC twice (method B) to yield compound 7-4R (15 mg, yield 13%) as a white solid. ESI m/z: 472 (M + H)+. MR (MeOD^, 500 MHz) delta 7 '.47 (d, J = 10.0 Hz, 1H), 6.27 (dd, J= 10.0 Hz, 2.0 Hz, 1H), 6.03 (s, 1H), 4.90 (d, J= 4.0 Hz, 1H), 4.50 (d, J = 19.0 Hz, 1H), 4.46-4.43 (m, 1H), 4.41 (d, J= 4.0 Hz, 1H), 4.29 (d, J= 19.0 Hz, 1H), 3.13-3.09 (m, 2H), 2.71-2.60 (m, 3H), 2.42-2.38 (m, 1H), 2.27-2.13 (m, 2H), 1.99-1.96 (m, 1H), 1.85-1.64 (m, 7H), 1.52 (s, 3H), 1.51-1.38 (m, 2H), 1.14-0.99 (m, 2H), 0.96 (s, 3H) ppm. The stereochemical R-configuration for compound 7-4R was determined by 2D NMR

Reference： [1]Patent: WO2018/89373,2018,A2 .Location in patent: Paragraph 0525-0528

79
[ 67808-64-4 ]
[ 100-63-0 ]
[ 137076-22-3 ]
tert-butyl 1-((5-(methoxycarbonyl)thiophen-2-yl)methyl)spiro[indoline-3,4'-piperidine]-1'-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%		General procedure: To a solution of cyclohexanecarboxyaldehyde 6a (0.224 mL, 1.85 mmol) in acetic acid (6 mL) phenylhydrazine (7) was added (0.182 mL, 1.85 mmol) and the reaction mixture was then heated to 80 °C for 2 h. Then methyl 4-formylbenzoate 8a (0.359 g, 1.85 mmol) in 1,2-DCE (6 mL) was added at 0 °C and after 15 min NaBH(OAc)3 (0.943 g, 4.25 mmol) was added portionwise. Reaction mixture was stirred at 25 °C for 12 h. Solvents were removed under reduced pressure, residue was diluted with 10 mL of EtOAc and washed with a saturated solution of Na2CO3. The combined organic phases were dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography on silica gel (EtOAc/n-hexane 1:20) afforded the title compound as a yellow oil (yield 16percent).

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 157,p. 127 - 138

80
2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione [ No CAS ]
[ 137076-22-3 ]
tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3 -yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50.8%	Stage #1: 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione; tert butyl 4-formylpiperidine-1-carboxylate In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride In N,N-dimethyl-formamide at 50℃; for 3.5h;	1.1 A solution of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1 ,3-dione (A, 1.5 g, 4.4 mmol, 1.0 equiv) and tert-butyl 4-formylpiperidine-1-carboxylate (0.93 g, 4.4 mmol, 1.0 equiv) in DMF (20 ml_) was stirred at room temperature for 30 minutes. NaBH(OAc)3 (3.7 g, 17.5 mmol, 4.0 equiv) was then added and the resulting mixture stirred at 50 °C for 3.5 h. The mixture was cooled to RT, poured into water (100 ml_), extracted with EtOAc (50 ml_ x 3). The combined organic layers were concentrated and the residue was purified by preparative HPLC under the following conditions: C18 Spherical Column, 20- 35 urn, 330 g; mobile phase, phase A: water (0.16% NH4HCO3), B: ACN (Gradient B% 0%-70%, run time 40 min); Flow rate: 80 mL/min; Detector, UV detection at 254 nm. B (1 .2 g, 50.8%) was obtained from the purification as a yellow solid. LCMS (ESI) m/z: [M+H]+ = 540.
	With sodium acetate; sodium cyanoborohydride; acetic acid In methanol; dichloromethane
2.3 g	With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; for 48h; Inert atmosphere;

120 mg

Stage #1: 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione; tert butyl 4-formylpiperidine-1-carboxylate With sodium acetate; acetic acid In ethanol; dichloromethane at 40℃; for 1h; Stage #2: With sodium cyanoborohydride In ethanol; dichloromethane at 40℃; for 12h;

Step 2: Preparation of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate A mixture of tert-butyl 4-formylpiperidine-1-carboxylate (200 mg, 0.94 mmol), 2- (2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione (385 mg, 1.12 mmol), CH3COONa (38 mg, 0.42 mmol), CH3COOH (28 mg, 0.42 mmol) in DCM/EtOH (3 mL) was stirred at 40 for 1 hour. Then NaBH3CN (58.9 mg, 0.94 mmol) was added dropwise. The mixture was stirred at 40oC for 12 hours. After quenched with H2O (20 mL), the mixture was extracted with ethyl acetate (10 mL). The organic phase was concentrated under vacuum and purified by prep-TLC to afford the desired product (120 mg) as a yellow solid. LC/MS (ESI) m/z: 484.3 [M-55] +.

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155321, 2021, A2 Location in patent: Page/Page column 176-177
[2]Current Patent Assignee: ARVINAS - WO2018/140809, 2018, A1 Location in patent: Paragraph 00452
[3]Current Patent Assignee: BEIGENE LTD. - WO2021/58017, 2021, A1 Location in patent: Paragraph 0183; 0188-0189
[4]Current Patent Assignee: ARVINAS - WO2021/77010, 2021, A1 Location in patent: Paragraph 00477; 00478

81
[ 376608-71-8 ]
[ 137076-22-3 ]
C₂₀H₂₈F₂N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With sodium cyanoborohydride; acetic acid; In methanol; at 0℃; for 2h;	Compound 9c (2.3 g, 7.09 mmol) and compound 14 (commercially available, 1.7 g, 7.80 mmol) were dissolved in MeOH (20 mL). The solution was treated with HOAc (1.7 mL, 28.4 mmol), and then with NaBH3CN (891.5 mg, 14.2 mmol) batchwise. The mixture was stirred for 2 h under ice bath, diluted with ethyl acetate (50 mL), and washed with sat. aq. NaHCO3 and brine. The organic phase was dried over Na2SO4, evaporated to dryness, and purified with chromatography on silica gel (PE : EA = 1 : 1) to give product 15c (white powder, 1.2 g, 3.2 mmol, 45 %). Compound 15c: Rf 0.52 (1 : 1 : 0.01, PE - EA - TEA); HPLC tR 2.93 min; [alpha] D20 -44.26 (c 0.240 CH3OH); 1H NMR (400 MHz, Methanol-d4) delta 7.13 (dt, J = 10.6, 8.5 Hz, 1H, -ArH), 7.01 - 6.87 (m, 2H, 2 x -ArH), 4.09 (d, J = 14.1 Hz, 2H, 2 x piperidine-CH2), 2.85 - 2.68 (m, 2H, 2 x piperidine-CH2), 2.62 (d, J = 6.6 Hz, 2H, 2 x -CH2NH), 2.37 - 2.30 (m, 1H, cyclopropane-H), 1.95 (ddd, J = 9.1, 5.8, 3.2 Hz, 1H, cyclopropane-H), 1.76 (d, J = 14.7 Hz, 2H, 2 x piperidine-CH2), 1.73 - 1.64 (m, 1H, piperidine-CH), 1.47 (s, 9H, -C(CH3)3), 1.15 - 1.12 (m, 1H, cyclopropane-H), 1.11 - 1.04 (m, 2H, 2 x piperidine-CH2), 1.04 - 1.00 (m, 1H, cyclopropane-H), NH is missing; 13C NMR (126 MHz, Methanol-d4) delta 156.49 (-C=O), 151.55 (dd, J C-F = 214.8, 12.8 Hz, ArC), 149.61 (dd, J C-F = 213.0, 12.7 Hz, ArC), 141.22 (dd, J C-F = 5.8, 3.7 Hz, ArC), 123.20 (dd, J C-F = 6.0, 3.3 Hz, ArC), 117.93 (d, J C-F = 17.1 Hz, ArC), 115.48 (d, J C-F = 17.6 Hz, ArC), 80.89 (-C(CH3)3), 56.05 (-CH2NH-), 42.78 (cyclopropane-CH), 37.01 (piperidine-CH), 31.46 (2 x piperidine-CH2), 28.70 (3 x -C(CH3)3), 24.53 (cyclopropane-CH), 16.98 (cyclopropane-CH2), two signals missing; HRMS (ESI+) calcd. For C20H29F2N2O2+ 367.2192, found 367.2197.
45%	With sodium cyanoborohydride; acetic acid; In methanol; for 2h;Cooling with ice;	Compound 4b (2.3 g, 7.09 mmol)Compound 12a (1.7 g, 7.80 mmol 1) was dissolved in MueOH (20 mL).AcOH (1.7 mL, 28.4 mmol) was added dropwise and stirred under ice bath for five minutes;Another sodium cyanoborohydride (891.5 mg, 14.2 mmol),Divide it into three equal parts, and put one of them into the reaction solution every ten minutes;After all the materials were put on, they were stirred for two hours in an ice bath.The plate was confirmed to be completely reacted, and ethyl acetate (50 mL) was added to the reaction mixture.Saturated sodium bicarbonate solution (30 mL),Saturated saline solution (30 mL), and wash the reaction mixture.The organic phase was collected and dried over anhydrous sodium sulfate.The silica gel column (PE: EA, v: v = l: 1) was isolated and purified to give white solid 13b (1.2 g, 3.2 mmol).Yield: 45%.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 844 - 847
[2]Patent: CN110204551,2019,A .Location in patent: Paragraph 0121-0124

82
[ 356560-84-4 ]
[ 137076-22-3 ]
(x)C₂HF₃O₂*C₂₀H₂₁N₇ [ No CAS ]

Reference： [1]Patent: WO2019/195278,2019,A1

83
[ 356560-84-4 ]
[ 137076-22-3 ]
tert-butyl 4-(5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium acetate; In methanol; tert-butyl methyl ether; at 25℃; for 4h;	To a solution of 1 -(6-methyl -2-pyridyl)-2-([l, 2, 4]triazolo[l,5-a]pyridin-6-yl) ethane-l,2- dione (0.2 g, 751.16 umol, 1 eq ) and tert-butyl 4-formylpiperidine-l-carboxylate (160.20 mg, 751.16 umol, 1 eq) in MTBE (5 mL) and MeOH (10 mL) was added NH4OAc (289.51 mg, 3.76 mmol, 5 eq). The mixture was stirred at 25C for 4 hr. The reaction mixture was quenched by addition H20 20 mL, extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50mL x 1), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. Compound tert-butyl 4-(5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-(6- methylpyridin-2-yl)-lH-imidazol-2-yl)piperidine-l-carboxylate (0.3 g, crude) was obtained as a yellow solid.

Reference： [1]Patent: WO2019/195278,2019,A1 .Location in patent: Paragraph 0300-0301

84
[ 1099-45-2 ]
[ 137076-22-3 ]
[ 301232-45-1 ]

Yield	Reaction Conditions	Operation in experiment
62%	With N,N-dimethyl acetamide; palladium 10% on activated carbon; hydrogen In ethanol; water at 20℃; for 91h; chemoselective reaction;

Reference： [1]Devlin, Rory; Jones, David J.; Mcglacken, Gerard P. [Organic Letters, 2020, vol. 22, # 13, p. 5223 - 5228]

85
[ 5380-42-7 ]
[ 137076-22-3 ]
tert-butyl 4-(hydroxy(5-(methoxycarbonyl)thiophen-2-yl)methyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	Stage #1: thiophene-2-carboxylic acid methyl ester With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 0.25h; Stage #2: tert butyl 4-formylpiperidine-1-carboxylate In tetrahydrofuran; hexane at -78 - 20℃; for 18h;	tert-Butyl 4-(hydroxy(5-(methoxycarbonyl)thiophen-2-yl)methyl)piperidine-1-carboxylate A solution of diisopropylamine (2.16 mL, 15.8 mmol) in THF (20 mL, 7.03 mmol) at -78 °C was treated with n-BuLi in hexanes (6.19 mL, 15.5 mmol) over the course of 1 min. The solution was warmed to rt for 10 min and then re-cooled to -78 °C. Methyl thiophene-2-carboxylate (0.820 mL, 7.03 mmol) was added portionwise. The resulting mixture was stirred for 15 min at -78 °C before tert-butyl 4-formylpiperidine-1-carboxylate (1.88 g, 8.79 mmol) in THF (10 mL) was added portionwise. The reaction mixture was warmed to rt and left to stir for 18 hrs. The reaction mixture was quenched with sat. aq. NH4Cl (100 mL) and extracted with EtOAc (2 x 100 mL). Combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-50% EtOAc in iso-hexane) to afford the title compound (995 mg, 38% yield) as a pale brown glass.[M+H-Boc]+= 256.61H NMR (500 MHz, Chloroform-d) d 1.18 - 1.36 (m, 2H), 1.43 (d, J = 3.0 Hz, 1H), 1.46 (s, 9H), 1.81 (tdt, J = 11.3, 7.2, 3.6 Hz, 2H), 1.95 (dt, J = 13.1, 2.9 Hz, 1H), 2.67 (dtd, J = 20.0, 12.9, 2.9 Hz, 2H), 3.90 (s, 3H), 4.15 (dd, J = 30.8, 13.2 Hz, 2H), 4.70 (d, J = 7.0 Hz, 1H), 6.95 (d, J = 3.8 Hz, 1H), 7.69 (d, J = 3.8 Hz, 1H)

Reference： [1]Current Patent Assignee: KALVISTA PHARMACEUTICALS INC - WO2021/32938, 2021, A1 Location in patent: Page/Page column 117

86
3-(1-oxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)piperidine-2,6-dione [ No CAS ]
[ 137076-22-3 ]
C₂₆H₃₄N₄O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: 3-(1-oxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)piperidine-2,6-dione; tert butyl 4-formylpiperidine-1-carboxylate With acetic acid In 1,2-dichloro-ethane at 20℃; for 14h; Molecular sieve; Stage #2: With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; Molecular sieve;	24 Synthesis of 2-chloro-4-((3S)-8-(4-(4-((6-(2,6-dioxopiperidin-3-yl)-5-oxo-3,5,6,7- tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)piperidine-1-carbonyl)phenyl)-3- methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No.364) Compound 1 (1.0 eq) was dissolved in DCE (10 X), and compound 2 (2.0 eq) and AcOH (3 eq.) were added. The mixture was stirred at rt for 2 h. Molecular sieves (4 angstrom) (3X) were added, and the mixture was stirred for 12 h. NaB(OAc)3H (3.0 eq) was added, and the mixture was stirred at rt overnight. The reaction was concentrated and purified on a Combiflash chromatography system using MeOH/DCM as the eluent to give compound 3 in 90% yield. Compound 3 was dissolved in 10X DCM, and TFA (2X) was added. The reaction mixture was stirred at rt for 2 h. The solvent was distilled and the product was dried on a lyophilizer overnight to give compound 4.
90%	Stage #1: 3-(1-oxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)piperidine-2,6-dione; tert butyl 4-formylpiperidine-1-carboxylate With acetic acid In 1,2-dichloro-ethane at 20℃; for 2h; Stage #2: In 1,2-dichloro-ethane for 12h; Molecular sieve; Stage #3: With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃;	6 Synthesis of 3-(l-oxo-6-(piperidin-4-ylmethyl)-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol- 2(lH)-yl)piperidine-2,6-dione (Cpd. No. 843) Compound 1 (1.0 eq) was dissolved in DCE (10 X), and compound 2 (2.0 eq) and (0702) AcOH (3 eq.) were added. The mixture was stirred at rt for 2 h. Molecular sieves (4 angstrom) (3X) were added, and the mixture was stirred for 12 h. NaB(OAc)3H (3.0 eq) was added, and the mixture was stirred at rt overnight. The reaction was concentrated and purified on a Combiflash chromatography system using MeOH/DCM as the eluent to give compound 3 in 90% yield. Compound 3 was dissolved in 10X DCM, and TFA (2X) was added. The reaction mixture was stirred at rt for 2 h. The solvent was removed and the product was dried on the lyophilizer overnight to give Cpd. No. 843.

Reference： [1]Current Patent Assignee: UNIVERSITY OF MICHIGAN - WO2021/55756, 2021, A1 Location in patent: Paragraph 01109
[2]Current Patent Assignee: UNIVERSITY OF MICHIGAN - WO2021/41664, 2021, A1 Location in patent: Paragraph 0531

87
[ 867-13-0 ]
[ 137076-22-3 ]
[ 301232-45-1 ]

Yield	Reaction Conditions	Operation in experiment
46%	With lithium methanolate; ammonia; lithium perchlorate In N,N-dimethyl-formamide at 20℃; for 8h; Electrochemical reaction;

Reference： [1]Zhang, Xiaofeng; Jiang, Runze; Cheng, Xu [Journal of Organic Chemistry, 2021, vol. 86, # 22, p. 16016 - 16025]

88
[ 137076-22-3 ]
[ 188975-30-6 ]
tert-butyl 4-((3,6-dihydro-2H-pyran-4-yl)(hydroxy)methyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation;

Reference： [1]Hao, Erjun; Jin, Yunhe; Lin, Shuangjie; Liu, Yonghong; Shi, Lei; Song, Bingkun; Zhang, Dandan [Organic Letters, 2022]

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[ CAS No. 137076-22-3 ] {[proInfo.proName]}

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Aliphatic Heterocycles

Piperidines

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