169448-87-7|(R)-tert-Butyl 2-(hydroxymethyl)piperazine-1-carboxylate| Ambeed

Structure of 169448-87-7

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Quality Control of [ 169448-87-7 ] Purity: 97% SDS Specification

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Product Details of [ 169448-87-7 ]

CAS No. :	169448-87-7
Formula :	C₁₀H₂₀N₂O₃
M.W :	216.28
SMILES Code :	OC[C@@H]1N(C(OC(C)(C)C)=O)CCNC1
MDL No. :	MFCD07772092
InChI Key :	BCPPNDHZUPIXJM-MRVPVSSYSA-N
Pubchem ID :	24820219

Safety of [ 169448-87-7 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 169448-87-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	15
Num. arom. heavy atoms	0
Fraction Csp3	0.9
Num. rotatable bonds	4
Num. H-bond acceptors	4.0
Num. H-bond donors	2.0
Molar Refractivity	64.47
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	61.8 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.28
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	-0.16
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	-0.57
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.03
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	0.01
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.32

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-0.82
Solubility	33.0 mg/ml ; 0.153 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-0.68
Solubility	44.9 mg/ml ; 0.208 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-0.88
Solubility	28.2 mg/ml ; 0.131 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-7.73 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.91

Application In Synthesis of [ 169448-87-7 ]

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

Downstream synthetic route of [ 169448-87-7 ]

[ 169448-87-7 ] Synthesis Path-Downstream 1~35

1
[ 252990-05-9 ]
[ 169448-87-7 ]

Yield	Reaction Conditions	Operation in experiment
> 100%	With lithium aluminium tetrahydride; In tetrahydrofuran; at -40 - 20℃; for 1.0h;	Lithium aluminium hydride (1M in THF, 26 ml) was added to a solution of L-TERT- butyl 2-methyl (2R)-piperazine-1, 2-dicarboxylate (2. 55 g) in THF (70 ml) AT-40C, then the reaction was warmed to room temperature. The solution was stirred for 1 hour, then cooled to 0C and quenched by sequential addition of water (1 ml), sodium hydroxide (2N, 1 ml) and then water (2 ml). The resulting slurry was filtered and concentrated in vacuo to give TERT- butyl (2R)-2-(hydroxymethyl) piperazine-1-carboxylate (2.37 g, > 100%); NMR spectrum (DMSO-d6,373K) 1.40 (s, 9H), 2.58 (m, 1H), 2. 82 (M, 3H), 2. 92 (bs, 1H), 2.98 (d, 1H), 3.43 (m, 1H), 3.65 (M, 2H), 3.80 (M, 1H) ; Mass spectrum MH+ 217.

References: [1]Patent: WO2005/26152,2005,A1 .Location in patent: Page/Page column 136.

2
[ 169448-87-7 ]
[ 848482-33-7 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 4.0h;Heating / reflux;	Lithium aluminium hydride (1M in THF, 17.6 ml) was added to a solution OF TERT- butyl (2R)-2-(HYDROXYMETHYL) PIPERAZINE-1-CARBOXYLATE (1.27 g) in THF (40 ml) at 0C, then the reaction was warmed to room temperature. The solution was stirred for 3 hours, then heated at reflux for 1 hour, cooled to 0C and quenched by sequential addition of water (0.2 ml), sodium hydroxide (2N, 0.2 ml) and then water (0.4 ml). The resulting slurry was filtered and concentrated in vacuo to give [(2R)-1-methylpiperazin-2-yl]methanol (0.44 g) ; Mass spectrum MH+ 131.

References: [1]Patent: WO2005/26152,2005,A1 .Location in patent: Page/Page column 136-137.

3
[ 169448-87-7 ]
[ 1070294-74-4 ]
[ 1070294-93-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; In dichloromethane; for 16.0h;	A mixture of the product of Example 75 step i) (300mg), (f?>2-(hydroxymethyl)piperazine- 1-carboxylic acid, terf-butyl ester (465mg) and sodium triacetoxyborohydride (608mg) in dichloromethane (2OmL) was stirred under nitrogen for 16 hours. The reaction was partitioned between dichloromethane and water, the organics were then collected and concentrated to dryness. The residue was purified by HPLC to give the title compound (230mg) as a solid. <n="174"/>MS: APCI(+ve) 519 (M+H)+1H NMR DMSO-Cl6 8.54 (d, J = 4.2 Hz, 1 H), 8.35 (d, J = 8.3 Hz, 1 H), 7.97 (d, J = 1.5 Hz, 1 H), 7.69 - 7.64 (m, 2H), 7.54 (dd, J = 8.2, 1.4 Hz, 1 H), 7.49 (s, 1 H), 4.46 (t, J = 5.4 Hz, 1 H), 3.93 - 3.79 (m, 2H), 3.55 - 3.44 (m, 2H), 3.28 - 3.20 (m, 2H), 2.89 - 2.77 (m, 3H), 2.75 - 2.67 (m, 1H), 2.63 - 2.52 (m, 2H), 2.25 (d, J = 2.3 Hz, 3H), 2.07 - 1.87 (m, 2H), 1.67 - 1.58 (m, 1 H), 1.31 - 1.19 (m, 1H), 0.74 - 0.66 (m, 2H), 0.60 - 0.54 (m, 2H), 0.52 - 0.45 (m, 2H), 0.44 - 0.38 (m, 2H)

References: [1]Patent: WO2008/122765,2008,A1 .Location in patent: Page/Page column 172-173.

4
[ 169448-87-7 ]
[ 1220229-87-7 ]
[ 1220230-01-2 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; at 20℃;	To a solution of tert-butyl (2f?)-2-(hydroxymethyl)piperazine-1-carboxy.ate (0.479 g) and triethylamine (0.618 ml_) in THF (6 ml_) was added dropwise a solution of 6-bromo-1-oxo- 1 ,2-dihydroisoquinoline-4-sulfonyl chloride (Example 46a, 0.715 g) in THF (10 ml_). The reaction was stirred at room temperature for 20 min. The resulting solution was concentrated under reduced pressure before adding water and extracting into ethyl acetate. The combined organics were dried (MgSO4), filtered and evaporated under reduced pressure. Trituration with ethyl acetate gave the subtitle compound (0.855 g). MS: APCI(-ve) 500 / 504 (M-H)" 1H NMR delta (CDCI3) 8.34 (d, 1 H), 8.30 (d, 1 H), 8.05 (s, 1 H), 7.73 (dd, 1 H), 4.32 - 4.18 (m, 1H), 4.00 (d, 1 H), 3.88 (d, 1 H), 3.72 (d, 1 H), 3.63 (d, 2H), 3.10 - 2.96 (m, 1 H), 2.84 (td, 2H), 1.44 (s, 9H)

References: [1]Patent: WO2010/39079,2010,A1 .Location in patent: Page/Page column 110.

5
[ 169448-87-7 ]
[ 1220229-46-8 ]
[ 1220229-48-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 50℃; for 1.0h;Inert atmosphere;	A solution of 6-bromo-4-(bromomethyl)-2-(phenylsulfonyl)isoquinolin-1 (2H)-one (Examplei 1d, 1.75 g) in THF (20 mL) was treated with (f?)-tert-butyl ethyl(1-hydroxy-3- (methylamino)propan-2-yl)carbamate (0.98 g) and /V,Lambda/-diisopropylethylamine (0.80 mL) under nitrogen. The resulting solution was stirred at 50 C for 1 h. The reaction mixture20 was diluted with water (300 mL), and extracted with ethyl acetate (250 mL x 2). The combined organics were dried (MgSO4), filtered and evaporated. Triturated with diethyl ether / isohexane (1 :1) afforded the subtitle compound (2.30 g) as a solid. 1H NMR delta (CDCI3) 8.16 - 8.10 (m, 3H), 8.06 (s, 1H), 7.90 (s, 1H), 7.71 - 7.65 (m, 1H), 7.60 - 7.54 (m, 3H), 4.23 - 4.16 (m, 1 H), 3.84 (d, 2H), 3.59 - 3.45 (m, 2H), 3.21 - 3.02 (m, 2H),2S 2.89 - 2.79 (m, 1 H), 2.33 - 2.09 (m, 3H), 1.51 (s, 9H)

References: [1]Patent: WO2010/39079,2010,A1 .Location in patent: Page/Page column 73.

6
[ 169448-87-7 ]
[ 1175015-91-4 ]
C₂₄H₃₃ClN₄O₄ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5480 - 5486.

7
[ 169448-87-7 ]
[ 1401728-66-2 ]
[ 1401729-14-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 20℃; for 4.0h;	(E)-3-[4-(2-Ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-ylmethyl)-phenyl]-propenal (7) (100 mg, 0.313 mmol), <strong>[169448-87-7](R)-tert-butyl 2-(hydroxymethyl)piperazine-1-carboxylate</strong> (67.7 mg, 0.313 mmol), NaBH(OAc)3 (103 mg, 0.485 mmol) and DIPEA (0.063 ml, 0.363 mmol) were dissolved in 2 ml of dichlorethane and stirred for 4 h at rt. Then the mixture was diluted with EtOAc, washed with NaCl-solution and dried over Na2 SO4. Evaporation gave a yellow oil. The crude product was purified by chromatography (silica gel, ethyl acetate/methanol) to yield a white foam.

References: [1]Patent: US2012/252778,2012,A1 .Location in patent: Paragraph 0404-0405.

8
[ 169448-87-7 ]
[ 1442445-49-9 ]
[ 1442445-58-0 ]

Yield	Reaction Conditions	Operation in experiment
40%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃; for 18.0h;Inert atmosphere;	a) A mixture of (R)-6-bromo- l-(l-(2,4-dichlorophenyl)ethyl)- lH-indazole (prepared from Example 17 step c, 0.37 g, 1.0 mmol), (i?)-i-butyl 2- (bydroxymeihy])piperidirie~1 -carboxylase (0.22 g, 1.0 mmol), BetaGammaNuAlphaRho (0.093 g, 0.15 mmol), and CS2CO3 (0.65 g, 2.0 mmol) in toluene (1 mL) was purged with nitrogen for 5 min. Addition of Pd2(dba)3 (0.092 g, 0.10 mmol) was followed, and the mixture was purged with nitrogen for 1 min. The reaction was then heated at 100 C for 18 h. After cooling to room temperature, the mixture was filtered and washed with EtOAc (50 mL). The filtrate was concentrated in vacuo. The resulting crude mixture was purified by flash chromatography (S1O2, 40% ethyl acetate in hexanes) to afford the coupled product as a viscous oil (0.20, 0.40 mmol, 40%).

References: [1]Patent: WO2013/82429,2013,A1 .Location in patent: Paragraph 0178.

9
[ 169448-87-7 ]
[ 1442445-38-6 ]
[ 1442445-45-5 ]

Yield	Reaction Conditions	Operation in experiment
73%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 125℃; for 2.0h;	a) To a solution of (R)-N-(l-(2,4-dichlorophenyl)ethyl)-5-fluoro-2-nitroaniline (prepared from Example 14 step a, 1.6 g, 4.8 mmol) and i /' W- biuy 2- (hydroxymeihy])piperidirie-1 -carboxylase (0.99 g, 4.9 mmol) in anhydrous DMSO (10 mL) was added z'P^ Et (1.9 g, 14.6 mmol). The reaction mixture was heated at 125 C for 2 h. After cooling to room temperature, the mixture was diluted with deionized water. The aqueous layer was extracted with diethyl ether. The organic layer was dried (Na2S04), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (S1O2, 30-50% ethyl acetate in hexanes) to give the desired compound (1.9 g, 3.5 mmol, 73%).

References: [1]Patent: WO2013/82429,2013,A1 .Location in patent: Paragraph 0193.

10
[ 169448-87-7 ]
[ 24424-99-5 ]
[ 1159598-21-6 ]

Yield	Reaction Conditions	Operation in experiment
86%	With sodium carbonate; In 1,4-dioxane; water; at 0 - 20℃; for 18.0h;	Synthesis of (R)-2-Hydroxymethyl-piperazine-l,4-dicarboxylic acid di-tert-butyl ester [A031]. To a stirred solution of (R)-l-Boc-2-Hydroxymethyl-piperazine (1 g, 4.62 mmol) and a2C03 (990 mg, 9.25 mmol) in a mixture of dioxane (8 ml) and water (2 ml) at 0 C was added Di-tert-butyl dicarbonate and the reaction mixture warmed to room temperature. After 18 hours all solvents were removed in vacuo and the resulting residue partitioned between DCM and water. The DCM phase was passed through phase separation cartridge and evaporated to provide a white solid. Purification by column chromatography (0-50% EtOAc:cyclohexane) gave the title compound [A031] as a white solid (1.26g, 86%). 1H- NMR (1H, 300MHz, CDC13): 4.17 (2H, s, br), 3.93 (1H, s, br), 3.84 (1H, d, br), 3.59 (2H, s, br), 2.95 (3H, s, br), 1.46 (18H, s).

References: [1]Patent: WO2014/52699,2014,A1 .Location in patent: Page/Page column 231.

11
[ 169448-87-7 ]
[ 24424-99-5 ]
[ 216228-85-2 ]

References: [1]Patent: WO2014/52699,2014,A1 .

12
[ 169448-87-7 ]
[ 41803-59-2 ]
[ 1588951-42-1 ]

References: [1]Patent: WO2014/52699,2014,A1 .

13
[ 169448-87-7 ]
[ 41803-59-2 ]
C₂₃H₂₈N₆O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%		(R)-2-Benzyl-4-(5-methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-l- carboxylic acid tert-butyl ester [A046] To a solution of 2-Pyridin-4-yl-pyrido[2,3-d]pyrimidin-4-ol [A003] (0.2g, 0.78 mmol) in DMA 93 mL), 2,4,6-Triisopropylbenzenesulfonyl chloride (0.26 g, 0.86 mmol), Et3N (0.22 mL, 1.57 mmol) and DMAP (10 mg) were added successively. The mixture was stirred at rt for 2h and (R)-2-Hydroxymethyl-piperazine-l-carboxylic acid tert-butyl ester (0.2g, 0.94 mmol) was added. The reaction was stirred overnight and the solvent was removed under reduced pressure. The product was purified by flash chromatography using 0 to 8% MeOH / DCM to give the title compound [A046] (0.14g, 39% yield). LCMS method: 1, RT:4.41 min, MI 453.27 [M+H].

References: [1]Patent: WO2014/52699,2014,A1 .Location in patent: Page/Page column 242-243.

14
[ 169448-87-7 ]
(R)-[4-(2-ethyl-3-[4-(4-fluorophenyl)thiazol-2-yl](methyl)amino}imidazo[1,2-b]pyridazin-6-yl)piperazin-2-yl]methanol [ No CAS ]

References: [1]Patent: WO2014/202458,2014,A1 .

15
[ 169448-87-7 ]
N-(6-halo-2-ethylimidazo[1,2-b]pyridazin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine [ No CAS ]
(R)-4-(2-ethyl-3-[4-(4-fluorophenyl)thiazol-2-yl](methyl)amino}imidazo[1,2-b]pyridazin-6-yl)-2-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In butan-1-ol;Microwave irradiation; Heating;	[00316] To a solution of 6-halo-imidazo[l,2-b]pyridazin-3-ylamine or 6-halo-imidazo[l,2-a]pyrazin-3- ylamine derivative (1 eq.) in nBuOH are successively added the corresponding amine Gen- 10 (or commercially available products) (1.1 to 4 eq.), and DIPEA or TEA (1.5 to 5 eq). The reaction mixture is heated between 120C and 140C under microwave irradiation or under conventional thermal conditions until completion. After cooling to r.t., the crude product is concentrated in vacuo. The residue is directly purified by chromatography on silica gel or by preparative HPLC to afford the expected intermediate. Alternatively, the residue is partionned with DCM or EtOAc and water, the organic layer is separated, the aqueous layer is extracted with DCM or EtOAc twice. The combined organic layers are washed with water and brine, dried over Na2S04and concentrated in vacuo. The crude product is purified by chromatography on silica gel or by preparative HPLC to afford the expected intermediate

References: [1]Patent: WO2014/202458,2014,A1 .Location in patent: Paragraph 00316.

16
[ 169448-87-7 ]
[ 350-46-9 ]
(R)-tert-butyl 2-(hydroxymethyl)-4-(4-nitrophenyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃;Inert atmosphere;	A suspension of 1-fluoro-4-nitrobenzene (2.86 g, 20.30 mmol), (R)-tert-butyl 2-(hydroxymethyl)piperazine-1- carboxylate (4.39 g, 20.30 mmol) and potassium carbonate(4.21 g, 30.4 mmol) in anhydrous DMF (10 mL) was heated to 50 C under a nitrogen atmosphere overnight. The reaction mixture was allowed to cool to room temperature, diluted with water (30 mL) and stirred at room temperature for 15 minutes. The oily product wasextracted into ethyl acetate (50 mL) and washed with50:50 water:brine (3 x 50 mL) . The organic phase was then dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was slurried in a mixture of cyclohexane (20 mL) and diethyl ether (2 mL)to give the title compound as a yellow solid (4.78 g,70%) . ?H NMR (300 MHz, CDC13) : 3 8.11 (dt, 2H), 6.78 (dt,2H), 4.25 (br s, 1H), 3.87-4.03 (m, 2H), 3.62-3.80 (m,3H), 3.26-3.42 (m, 2H), 3.18 (ddd, 1H), 1.49 (s, 9H)LCMS (Method C) : = 1.39 mi m/z = 338 [M+H].
	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 140℃; for 24.0h;Inert atmosphere;	To a stirred solution of 1 -fluoro-4-nitrobenzene (1.1 g 8.0 mmol) in DMSO under a nitrogen atmosphere was added (R)-tert-butyl 2-(hydroxymethyl)piperazine- 1 -carboxylate (1.2 g, 9 mmol) followed by DIPEA (3 ml, 23 mmol), The mixture was stirred at 140 for 24 h, and then cooled to room temperature. The mixture was then poured into water and extracted with DOM. The combined organic layers were washed with brine, dried over magnesium sulfate, concentrated in vacuo to obtain (R)-tert-butyl 2-(hydroxym- ethyl)-4-(4-nitrophenyl)piperazine-1 -carboxylate.

References: [1]Patent: WO2015/92431,2015,A1 .Location in patent: Page/Page column 160; 161.
[2]Patent: US2016/96827,2016,A1 .Location in patent: Paragraph 1556.

17
[ 169448-87-7 ]
(R)-tert-butyl 2-(methoxymethyl)-4-(4-nitrophenyl)piperazine-1-carboxylate [ No CAS ]

References: [1]Patent: WO2015/92431,2015,A1 .

18
[ 169448-87-7 ]
(R)-tert-butyl 4-(4-aminophenyl)-2-(methoxymethyl)piperazine-1-carboxylate [ No CAS ]

References: [1]Patent: WO2015/92431,2015,A1 .

19
[ 169448-87-7 ]
[ 823-62-1 ]
(R)-5-amino-6-chloro-3-[4-Boc-3-(hydroxymethyl)piperazin-1-yl]-1,2,4-triazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With triethylamine; In 1,4-dioxane; at 95℃; for 2.5h;Microwave irradiation;	A vial was charged with 5-amino-3,6-dichloro-l ,2,4-triazine (573.3 mg, 3.47 mmol), triethylamine (1.5 mL, 10.76 mmol), (R)-tert-butyl 2-(hydroxymethyl)piperazine-l- carboxylate (791.3 mg, 3.55 mmol) in dioxane (10 mL). The mixture was heated at 95 C for 1.5 h using microwave. More of (R)-tert-butyl 2-(hydroxymethyl)piperazine-l-carboxylate (69.4 mg) was added. The mixture was heated at 95 C for another 1 h using microwave. The mixture was cooled to room temperature and transferred into a flask with dichloromethane, concentrated to remove the solvents. The residue was mixed with saturated potassium carbonate solution, extracted with dichloromethane (3 x 40 mL). The combined organic solution was dried over anhydrous sodium sulfate, concentrated. The residue was mixed with small amount of dichloromethane, filtered to collect the white solid as first batch of product (649.6 mg). The solution was concentrated and the residue was separated with flash column chromatography on silica gel using 1-5% methanol in dichloromethane to afford another batch of product (174.3 mg). The total yield was 69%. NMR (500 MHz, Chloroform-af) delta 5.32 (s, 2H), 4.71 (br, I H),, 4.47 (d, J= 12.5 Hz, 1 H), 4.24 (s, IH), 3.90 (s, IH), 3.54 (s, IH), 3.44 (s, IH), 3.15 (d, J = 14.0 Hz, IH), 3.05 (t, J = 12.0 Hz, IH), 2.95 (s, IH), 1.45 (s, 9H). MS for Ci3H2iClN603: 345.0 (MH+).

References: [1]Patent: WO2015/92819,2015,A2 .Location in patent: Paragraph 0608; 0609.

20
[ 169448-87-7 ]
5-(bromoacetyl)-4-fluoro-2-methoxybenzonitrile [ No CAS ]
tert-butyl (3R)-4-[5-cyano-2-fluoro-4-methoxyphenyl-2-oxoethyl]-3-(hydroxymethyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1.0h;	To a 250 mL flask was added 5-(bromoacetyl)-4-fluoro-2-methoxybenzonitrile (2.00 g, 7.35 mmol), <strong>[169448-87-7](R)-N-Boc-2-hydroxymethyl-piperazine</strong> (3.18 g, 14.7 mmol), DIEA (2.57 mL, 14.7 mmol) and THF (50 mL) and stirred at rt for1 h; LC analysis of the reaction mixture indicated completion of the reaction. The solution was treated with EtOAc(100 mL), washed with brine, dried (Na2SO4), filtered and concentrated to dryness. The residue was then purifiedover silica gel with the solvent systems of 5% MeOH in DCM to furnish the desired product. LC/MS: [(M+1)]+ =408

References: [1]Patent: EP2744499,2016,B1 .Location in patent: Paragraph 0166.

21
[ 169448-87-7 ]
5-[1-(2-cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoic acid [ No CAS ]
(R)-tert-butyl 4-(5-(1-(2-cyanophenyl)piperidin-4-ylamino)-2,4-dimethylbenzoyl)-2-(hydroxymethyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 17.0h;	A solution of amine (1.0 eq), acid (1.2 eq), HATU (1.05 eq) and DIPEA (3.0 eq) were dissolved in DMF and stirred at rt for 17 h. The mixture was extracted with EtOAc, the organic layer was concentrated. The residue was purified by column chromatography or prep-HPLC to obtain the target compounds.

References: [1]Patent: US2018/127370,2018,A1 .Location in patent: Paragraph 0352-0353; 0679; 0682.

22
[ 169448-87-7 ]
5-[1-(2-cyanophenyl)piperidin-4-yl]amino}-2,4-dimethylbenzoic acid [ No CAS ]
(R)-2-(4-(5-(3-(hydroxymethyl)piperazine-1-carbonyl)-2,4-dimethylphenylamino)piperidin-1-yl)benzonitrile [ No CAS ]

References: [1]Patent: US2018/127370,2018,A1 .

23
[ 930782-89-1 ]
[ 169448-87-7 ]

Yield	Reaction Conditions	Operation in experiment
	With palladium on activated charcoal; hydrogen; In methanol; at 20℃; for 4.0h;	Step 1: (R)-tert-Butyl-2-(hydroxyethyl)piperazine-1-carboxylate (R)-4-Benzyl 1-tert-butyl 2-(hydroxymethyl)piperazine-1,4-dicarboxylate (2.00 g, 4.85 mmol) was dissolved in MeOH (50.00 mL), Pd/C (480.00 mg, 3.95 mmol) was added and stirred at rt for 4 h under H2. The reaction mixture was filtered and the filtrate was concentrated to give crude (R)-tert-butyl-2-(hydroxymethyl)piperazine-1-carboxylate (900.00 mg, 4.16 mmol, 85%) as a colorless oil. ESI-MS (EI+, m/z): 217.3 [M+H]+.

References: [1]Patent: US2018/127370,2018,A1 .Location in patent: Paragraph 0681; 0679.

24
[ 169448-87-7 ]
[ 586-76-5 ]
tert-butyl (R)-4-(4-bromobenzoyl)-2-(hydroxymethyl)piperazine-1-carboxylate [ No CAS ]