130596-62-2|4,4-Dimethyl-1,4-azasilinane hydrochloride| Ambeed

Structure of 130596-62-2

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Quality Control of [ 130596-62-2 ] Purity: 95% SDS Specification

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Product Details of [ 130596-62-2 ]

CAS No. :	130596-62-2
Formula :	C₆H₁₆ClNSi
M.W :	165.74
SMILES Code :	C[Si]1(C)CCNCC1.[H]Cl
MDL No. :	MFCD28399395
InChI Key :	GAKCLWKKNFVTPB-UHFFFAOYSA-N
Pubchem ID :	67215837

Safety of [ 130596-62-2 ]

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

Computational Chemistry of [ 130596-62-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	9
Num. arom. heavy atoms	0
Fraction Csp3	1.0
Num. rotatable bonds	0
Num. H-bond acceptors	1.0
Num. H-bond donors	1.0
Molar Refractivity	50.39
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	12.03 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.0
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	2.39
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.72
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.	1.49
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	0.6
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.24

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.37
Solubility	0.702 mg/ml ; 0.00423 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.28
Solubility	0.862 mg/ml ; 0.0052 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	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	-1.88
Solubility	2.18 mg/ml ; 0.0132 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	Yes
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.	-5.61 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	2.0
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	1.0 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)	3.22

Application In Synthesis of [ 130596-62-2 ]

* 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 [ 130596-62-2 ]

[ 130596-62-2 ] Synthesis Path-Downstream 1~35

1
[ 214707-02-5 ]
[ 130596-62-2 ]
5-chloro-7-(4,4-dimethyl-[1,4]azasilinan-1-yl)-6-(2,4,6-trifluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;dmap; In ISOPROPYLAMIDE; at 20℃; for 2h;	d) 4,4-dimethyl-[1 ,4]azasilinane hydrochloride (120 mg, 0.7 mmol) is added to a suspension of 5>7-dichloro-6-(2,4,6)-trifluoro-phenyl)-[1 ,2,4]triazolo[1 ,5-a]pyrimidine(190 mg, 0.6 mmol), potassium carbonate anhydrous (200 mg, 1.5 mmol) and catalytic amounts of 4-(dimethylamino)pyridine in 4 ml of N.N-dimethylacetamide. This mixture is stirred 2 h at room temperature, then poured on icewater and extracted with ethyl acetate. The combined organic layer is washed with water and brine, dried over magnesium sulfate and evaporated. The residue is purified by chromatography on silica gel, using ethyl aceate and hexane as eluents, to deliver 100 mg of 5-chloro-7-(4,4-dimethyl-[1 ,4]azasilinan-1-yl)-6-(2,4,6-trifluoro-phenyl)- [1 ,2,4]triazolo[1 ,5-a]pyrimidine (Compound No.l.p.081).

References: [1]Patent: WO2006/66872,2006,A1 .Location in patent: Page/Page column 16.

2
[ 130596-61-1 ]
[ 130596-62-2 ]

Yield	Reaction Conditions	Operation in experiment
	With methanol;palladium on activated carbon; for 72h;	c) Preparation of 4,4-dimethyl-[1 ,4]azasilinane hydrochloride; A solution of 1-benzyl-4,4-dimethyl-[1 ,4]azasilinane hydrochloride (4.9 g, 19 mmol) in 75 ml of methanol is slowly added to a suspension of palladium (10 wt. % on activated carbon, 0.4 g) in 75 ml of methanol. This mixture is stirred for 72 h under argon. Subsequently the mixture is filtered through celite. The filtrate is evaporated, the residue is triturated with diethyl ether to yield 3 g of 4,4-dimethyl-[1 ,4]azasilinane hydrochloride as colourless cristalls.

References: [1]Patent: WO2006/66872,2006,A1 .Location in patent: Page/Page column 16.

3
[ 130596-62-2 ]
[ 937728-82-0 ]
[ 1112416-07-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 90℃;	1,1-dimethylethyl [2-([6-(4,4-dimethyl-l,4-azasilinan-l-yl)pyridin-3-yl]carbonyl}amino)-4-(2- thienyl)phenyl]carbamate. 1,1-dimethylethyl [2-[(6-chloropyridin-3-yl)carbonyl]amino}-4-(2- thienyl)phenyl]carbamate (300 mg, 0.698 mmol), 4,4-dimethyl-l,4-azasilinane hydrochloride (231 mg, <n="65"/>1.396 mmol) and DIPEA (0.487 mL, 2.79 mmol) were stirred in DMSO (3 mL) at 90 0C overnight. Room temperature was attained, water was added and the products extracted into EtOAc (x2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by MPLC (2-40% EtOAc-hexanes) followed by HPLC (50-100% MeCN-H2O) gave 1,1-dimethylethyl [2-([6-(4,4-dimethyl-l,4-azasilinan-l-yl)pyridin-3-yl]carbonyl}amino)-4-(2- thienyl)phenyl]carbamate as a beige solid. 1H NMR (d6-DMSO, 600 MHz) delta 9.67 (s, IH), 8.71 (d, J = 2.4 Hz, IH), 8.62 (s, IH), 8.01 (dd, J= 8.4 and 2.4 Hz, IH), 7.42 (d, J= 1.8 Hz, IH), 7.61 (d, J= 8.4 Hz, IH), 7.50 (dd, J= 4.8 and 1.2 Hz, IH), 7.47 (dd, J= 8.4 and 2.4 Hz, IH), 7.42 (dd, J= 3.6 and 1.2 Hz, IH), 7.10 (dd, J= 5.4 and 3.6 Hz, IH), 6.85 (d, J= 8.4 Hz, IH), 3.87 (m, 4H), 1.43 (s, 9H), 0.73 (m, 4H), 0.07 (s, 6H). MS: cal'd 523 (MH+), exp 523 (MH+).

References: [1]Patent: WO2009/20589,2009,A1 .Location in patent: Page/Page column 63-64.

4
[ 130596-62-2 ]
[ 953434-83-8 ]
[ 1112416-05-3 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; potassium iodide; In N,N-dimethyl-formamide; at 50℃;	1,1-dimethylethyl [2-[({4-[(4,4-dimethyl-l,4-azasiUnan-l-yl)methyl]phenyI}carbonyl)amino]-4-(2- thienyl)phenyl] carbamate. 1 , 1 -dimethyl ethyl [2-( { [4-(chloromethyl)phenyl]carbonyl } amino)-4-(2- thienyl)phenyl]carbamate (300 mg, 0.677 mmol), 4,4-dimethyl-l,4-azasilinane hydrochloride (123 mg, 0.745 mmol), DIPEA (0.260 mL, 1.490 mmol) and potassium iodide (22.49 mg, 0.135 mmol) were stirred <n="63"/>in DMF (2 mL) at 50 0C overnight. Room temperature was attained, H2O was added and the products extracted into EtOAc (x2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by MPLC (12-100% EtOAc-hexanes) gave 1,1- dimethylethyl [2-[( {4-[(4,4-dimethyl- 1 ,4-azasilinan- 1 -yl)methyl]phenyl} carbonyl)amino]-4-(2- thienyl)phenyl]carbamate as an orange gum. 1H NMR (d6-DMSO, 600 MHz) delta 9.86 (s, IH), 8.72 (s, IH), 7.91 (d, J= 8.4 Hz, 2H), 7.79 (d, J= 1.8 Hz, IH), 7.59 (d, J= 8.4 Hz, IH), 7.50 (m, 2H), 7.45 (d, J= 8.4 Hz, 2H), 7.43 (dd, J= 3.6 and 0.6 Hz, IH), 7.11 (dd, J= 5.4 and 3.6 Hz, IH), 3.57 (s, 2H), 2.62 (m, 4H), 1.43 (s, 9H), 0.69 (m, 4H), 0.03 (s, 6H). MS: cal'd 536 (MH+), exp 536 (MH+).

References: [1]Patent: WO2009/20589,2009,A1 .Location in patent: Page/Page column 61-62.

5
[ 130596-62-2 ]
[ 1003315-21-6 ]
[ 1112416-09-7 ]

Yield	Reaction Conditions	Operation in experiment
	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	1,1-dimethylethyl [2-[({4-[(4,4-dimethyl-l,4-azasilinan-l-yl)carbonyl]phenyl}carbonyl)amino]-4-(2- thienyl)phenyl] carbamate. 4-( { [2-( { [( 1 , 1 -dimethyl ethyl)oxy]carbonyl } amino)-5-(2- thienyl)phenyl]amino}carbonyl)benzoic acid (250 mg, 0.570 mmol), 4,4-dimethyl-l,4-azasilinane hydrochloride (104 mg, 0.627 mmol), BOP (303 mg, 0.684 mmol) and DEPEA (0.249 mL, 1.425 mmol) were stirred in DMF (2 mL) at room temperature overnight. Saturated NaHCO3 was added and the products extracted into EtOAc (x2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue twice by MPLC (6-50% EtOAc-hexanes) gave 1 , 1 -dimethylethyl [2-[( {4-[(4,4-dimethyl- 1 ,4-azasilinan-l -yl)carbonyl]phenyl} carbonyl)amino]-4- (2-thienyl)phenyl]carbamate as an orange gum. 1H NMR (d6-DMSO, 600 MHz) delta 9.95 (s, IH), 8.74 (s, IH), 8.01 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 1.8 Hz, IH), 7.62 (d, J= 8.4 Hz, IH), 7.52 (d, J= 8.4 Hz, 2H), 7.50 (m, 2H), 7.43 (dd, J= 3.6 and 1.2 Hz, IH), 7.11 (dd, J= 5.4 and 3.6 Hz), 3.76 (m, 2H), 3.41 (m, 2H), 1.43 (s, 9H), 0.82 (m, 2H), 0.65 (m, 2H), 0.11 (s, 6H). MS: cal'd 550 (MH+), exp 550 (MH+).

References: [1]Patent: WO2009/20589,2009,A1 .Location in patent: Page/Page column 66.

6
[ 130596-62-2 ]
[ 369-34-6 ]
[ 1430321-42-8 ]

Yield	Reaction Conditions	Operation in experiment
70%		To a solution of 4 (500 mg, 3.85 mmol) in ethylacetate, triethylamine (973 mg, 9.63 mmol) is added and stirred at 25 C for 10 min. The reaction mixture is cooled to 0 C and 3, 4- difluoronitrobenzene (612 mg, 3.85 mmol) is added dropwise and allowed to stir at 25 C for 6 h. Water is then added and the organic layer is separated. The aqueous layer is extracted with EtOAc and the solvent is removed. The product is purified by column chromatography using hexanes-EtOAc mixtures to obtain the product as a crystalline yellow solid 9 (721 mg) in 70% isolated yield. 1H NMR (50 MHz, CDC13): delta 7.93-7.84 (m, 2 H), 6.86 (t, J = 4 Hz, 1 H), 3.70-3.67 (m, 4 H), 0.91- 0.85 (m, 4 H), 0.12 (s, 6 H). 13C NMR (100 MHz, CDC13): delta 151.12 (d, J = 246.71 Hz), 144.43 (d, J = 7.13 Hz), 137.84 (d, J = 8.59 Hz), 121.45, 1 15.90 (d, J = 4.61 Hz), 113.18 (7 = 27.78 Hz), 49.44, 13.79, -2.85.
70%		To a solution of 4 (500 mg, 3.85 mmol) in ethylacetate, triethylamine (973 mg, 9.63 mmol) is added and stirred at 25 C. for 10 min. The reaction mixture is cooled to 0 C. and 3,4-difluoronitrobenzene (612 mg, 3.85 mmol) is added dropwise and allowed to stir at 25 C. for 6 h. Water is then added and the organic layer is separated. The aqueous layer is extracted with EtOAc and the solvent is removed. The product is purified by column chromatography using hexanes-EtOAc mixtures to obtain the product as a crystalline yellow solid 9 (721 mg) in 70% isolated yield. 1H NMR (50 MHz, CDCl3): delta 7.93-7.84 (m, 2H), 6.86 (t, J=4 Hz, 1H), 3.70-3.67 (m, 4H), 0.91-0.85 (m, 4H), 0.12 (s, 6H). 13C NMR (100 MHz, CDCl3): delta 151.12 (d, J=246.71 Hz), 144.43 (d, J=7.13 Hz), 137.84 (d, J=8.59 Hz), 121.45, 115.90 (d, J=4.61 Hz), 113.18 (J=27.78 Hz), 49.44, 13.79, -2.85.
28.1 g		4,4-Dimethyl azasilinane hydrochloride (19.3 g, 105.8 mmol) and triethylamine (48.2 g, 349.1 mmol) were dispersed in N,N-dimethylformamide (200 mL). The resulting mixture was stirred at room temperature for 10 min, and then transferred to an ice water bath and stirred. 3,4-Difluoronitrobenzene (16.8 g, 105.8 mmol) was added dropwise. After the completion of the dropwise addition, the resulting mixture was stirred for 30 min in an ice water bath, and then stirred at room temperature overnight. The reaction mixture was poured into 1 L of water, stirred for 10 min, suction-filtered, and washed with a large amount of water. The resulting solid was collected and dried to give 1-(2-fluoro-4-nitrophenyl)-4,4-dimethyl-1,4-azasilinane (28.1 g). 1H NMR (300 MHz, DMSO-d6): delta7.91-7.95 (m, 2H), 7.10-7.14 (m, 1H), 3.71-3.73 (m, 4H), 0.85-0.88 (m, 4H), 0.11 (s, 6H).

References: [1]Patent: WO2013/54275,2013,A1 .Location in patent: Page/Page column 19; 22.
[2]Patent: US2014/296133,2014,A1 .Location in patent: Paragraph 0077; 0094.
[3]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 1105 - 1110.
[4]Patent: US2020/17532,2020,A1 .Location in patent: Paragraph 0139; 0145-0147.

7
[ 130596-62-2 ]
[ 66684-58-0 ]
[ 1430321-66-6 ]

Yield	Reaction Conditions	Operation in experiment
63%		To a solution of 4,4-dimethyl- 1 ,4-azasilinane hydrochloride 4 (950 mg, 7.35 mmol) in EtOAc (15 mL), triethylamine (2.5 mL, 18.37 mmol) is added and stirred at 25 C for 10 min. The reaction mixture is cooled to 0 C and l,2,3-trifiuoro-5-nitrobenzene (1.29 g, 7.35 mmol) is added drop wise and allowed to stir at 25 C for 6 h. Water is then added and the organic layer is separated. The aqueous layer is extracted with EtOAc (2 X 10 mL) and the solvent is removed under reduced pressure. The product obtained is purified by column chromatography using hexane-EtOAc mixtures to give the product as a crystalline yellow solid 9a (1.32 g) in 63% yield. 1H NMR (400 MHz, CDC13): delta 7.77-7.69(m, 2H), 3.5 l(t, J=6.28 Hz, 4H), 0.90(t, J=6.28 Hz, 4H), 0.12(s, 6H). 13C NMR (50 MHz, CDC13): delta 155.05(dd, J=248.5 Hz, 8.40 Hz), 108.9(m), 138.96(d, J=10.98 Hz), 136.73(t, J=12.44 Hz), 51.04(t, J=4.02 Hz), 15.15, -3.07. IR: 1606, 1515, 1335, 1216, 1110, 758 cm 1.
63%		To a solution of <strong>[130596-62-2]4,4-dimethyl-1,4-azasilinane hydrochloride</strong> 4 (950 mg, 7.35 mmol) in EtOAc (15 mL), triethylamine (2.5 mL, 18.37 mmol) is added and stirred at 25 C. for 10 min. The reaction mixture is cooled to 0 C. and 1,2,3-trifluoro-5-nitrobenzene (1.29 g, 7.35 mmol) is added drop wise and allowed to stir at 25 C. for 6 h. Water is then added and the organic layer is separated. The aqueous layer is extracted with EtOAc (2*10 mL) and the solvent is removed under reduced pressure. The product obtained is purified by column chromatography using hexane-EtOAc mixtures to give the product as a crystalline yellow solid 9a (1.32 g) in 63% yield. 1H NMR (400 MHz, CDCl3): delta 7.77-7.69 (m, 2H), 3.51 (t, J=6.28 Hz, 4H), 0.90 (t, J=6.28 Hz, 4H), 0.12 (s, 6H). 13C NMR (50 MHz, CDCl3): delta 155.05 (dd, J=248.5 Hz, 8.40 Hz), 108.9 (m), 138.96 (d, J=10.98 Hz), 136.73 (t, J=12.44 Hz), 51.04 (t, J=4.02 Hz), 15.15, -3.07. IR: 1606, 1515, 1335, 1216, 1110, 758 cm-1.
31.2 g		4,4-Dimethyl azasilinane hydrochloride (20.6 g, 124.4 mmol) and triethylamine (51.6 g, 3373.0 mmol) were dispersed in N,N-dimethylformamide (200 mL). The resulting mixture was stirred at room temperature for 10 min, and then transferred to an ice water bath and stirred. 3,4,5-Trifluoronitrobenzene (20.0 g, 113.0 mmol) was added dropwise. After the completion of the dropwise addition, the resulting mixture was stirred for 30 min in an ice water bath, and then stirred at room temperature overnight. Then the reaction mixture was poured into 1 L of water, stirred for 10 min, suction-filtered, washed with water (10 mL*3), and dried to give 1-(2,6-difluoro-4-nitrophenyl)-4,4-dimethyl-1,4-azasilinane (31.2 g). 1H NMR (500 MHz, DMSO-d6): delta7.93 (dd, J=10.0 Hz, 1.0 Hz, 2H), 3.49-3.51 (m, 4H), 0.85-0.88 (m, 4H), 0.12 (s, 6H).

References: [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 1105 - 1110.
[2]Patent: WO2013/54275,2013,A1 .Location in patent: Page/Page column 31.
[3]Patent: US2014/296133,2014,A1 .Location in patent: Paragraph 0131.
[4]Patent: US2020/17532,2020,A1 .Location in patent: Paragraph 0139-0142.

8
[ 130596-60-0 ]
[ 130596-62-2 ]

Yield	Reaction Conditions	Operation in experiment
70%		To a solution of 3 (2.3 g, 10.5 mmol) in ethanol (EtOH), 6 N HC1 (10.5 mmol) is added and the solvent is removed under reduced pressure. The reaction mixture is co-evaporated with EtOH ( 2 X 10 mL ) and recrystallized from EtOH-diethyl ether. To a slurry of Pd/C in EtOH, an ethanolic solution of the HC1 salt is added dropwise and stirred at 25 C under hydrogen atmosphere for 20 h. The reaction mixture is filtered through celite, washed with 2 X 20 mL of Methanol. The filtrate is concentrated under reduced pressure to give a viscous oil which is titrated with diethyl ether to obtain the product 4 as a white solid (950 mg) in 70% yield. This compound was previously documented in WO 2006/ 066872.
70%		To a solution of 3 (2.3 g, 10.5 mmol) in ethanol (EtOH), 6 N HCl (10.5 mmol) is added and the solvent is removed under reduced pressure. The reaction mixture is co-evaporated with EtOH (210 mL) and recrystallized from EtOH-diethyl ether. To a slurry of Pd/C in EtOH, an ethanolic solution of the HCl salt is added dropwise and stirred at 25 C. under hydrogen atmosphere for 20 h. The reaction mixture is filtered through celite, washed with 220 mL of Methanol. The filtrate is concentrated under reduced pressure to give a viscous oil which is titrated with diethyl ether to obtain the product 4 as a white solid (950 mg) in 70% yield. This compound was previously documented in WO 2006/066872.
49.5%	With palladium on activated charcoal; hydrogen; In methanol; at 50℃;	The compound 1-benzyl-4,4-dimethyl-1,4-sipadipine (15.0 g, 68.36 mmol) was dissolved in dry methanol and palladium on charcoal (1.5 g) was added; To 50 C.TLC monitoring reaction is completed.Cooled to room temperature, suction filtered, the filtrate was added dropwise an ice-salt solution of isopropyl alcohol, pH was adjusted to about 1, no solid precipitation.Rotate the solvent to give orange salt.35mL ether beating, suction filtration, 5.6g pink powder.Yield 49.5%

References: [1]Patent: WO2013/54275,2013,A1 .Location in patent: Page/Page column 18-19; 22.
[2]Patent: US2014/296133,2014,A1 .Location in patent: Paragraph 0075; 0092.
[3]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 1105 - 1110.
[4]Patent: CN107266421,2017,A .Location in patent: Paragraph 0094; 0095; 0096.

9
[ 130596-62-2 ]
[ 2373-80-0 ]
[ 1622904-97-5 ]

Yield	Reaction Conditions	Operation in experiment
77%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 30℃; for 8h;	To a solution of (E)-3-(benzo[d][ l,3]dioxol-5-yl)acrylic acid (5), (300 mg, 1.56 mmol) in dry DCM, EDC.HC1 (315 mg, 2.0 mmol), HOBt (274 mg, 2.0 mmol) and ' diisopropylethylamine (0.8 mL, 4.7 mmol) was added at 0 C. Then the silapiperidine salt, 2 (285 mg, 1.7 mmol) was added and stirred at RT (30C) for' 8 h. The reaction was quenched by the addition of water and the organic layer was separated, washed with saturated NaHC03, IN HC1, dried over Na2S04 and concentrated under reduced pressure. This crude mixture was purified by column chromatography using pet ether- ethyl acetate (70:30) to give the title compound (360 mg, 77 % yield) as a crystalline white solid. H NMR (400 MHz, CDCI3) : delta 7.61 (d, J = 15.3 Hz, 1H), 7.05 (s, 1H), 7.01 (d, J= 8.0 Hz, 1H), 6.81-6.73 (m, 2H), 5.99 (s, 2H), 3.81 (t, J =6.3 Hz, 2H), 3.75 (t, J = 6.3 Hz, 2H), 0.90-0.83 (m, 4H), 0.12 (s, 6H); 13C NMR (100 MHz, CDC13): delta 165.5, 148.8, 148.1, 142.2, 129.9, 123.6, 1 15.5, 108.4, 106.3, 101.4, 45.5, 42.8, 15.6, 13.8, -3.0 (2C).

References: [1]Patent: WO2014/128724,2014,A1 .Location in patent: Page/Page column 10-11.

10
[ 130596-62-2 ]
[ 136-72-1 ]
[ 1622904-96-4 ]

References: [1]Patent: WO2014/128724,2014,A1 .

11
[ 130596-62-2 ]
[ 136-72-1 ]
[ 1622904-95-3 ]

Yield	Reaction Conditions	Operation in experiment
71%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 27℃; for 8h;	To a solution of (2£,4£)-5-(benzo[d][l,3]dioxol-5-yl)penta-2,4-dienoic acid, 1(188 mg, 0.86 mmol) in dry DCM, EDC.HC1 (215 mg, 1.1 mmol), HOBt (151 mg, 1.1 mmol) and diisopropylethylamine (0.45 mL, 2.6 mmol) at 0 C was added. Then the silapiperidine salt, 2 (171 mg, 1.0 mmol) was added and stirred at RT (i.e. 27C) for 8 h. The reaction was quenched by the addition of water and the organic layer was separated, washed with saturated NaHCC , IN HC1, dried over Na2S04 and concentrated under reduced pressure. This crude mixture was purified by column chromatography using pet ether- ethyl acetate (70:30) to give the title compound (200 mg, 71 % yield) as a yellow viscous liquid. IR Umax(film): cm 1 2925, 1635, 1591, 1490, 1446, 1252; NMR (400 MHz, CDC13): delta 7.44 (ddd, J = 14.2, 6.9, 2.8 Hz, 1H), 6.99 (s, 1H), 6.90 (d, J = 7.8 Hz, 1H), 6.79-6.75 (m, 3H), 6.46 (d, J= 14.7 Hz, 1H), 5.98 (s, 2H), 3.79 (t, J = 6.4 Hz, 2H), 3.71 (t, J = 6.2 Hz, 2H), 0.90-0.78 (m, 4H), 0.11 (s, 6H); i3C NMR (100 MHz, CDCI3) : delta 165.7, 148.3, 148.2, 142.8, 138.4, 131.1, 125.5, 122.6, 120.1, 108.6, 105.7, 101.4, 45.6, 42.8, 15.7, 13.9, -2.9 (2C).

References: [1]Patent: WO2014/128724,2014,A1 .Location in patent: Page/Page column 9.

12
[ 857855-71-1 ]
[ 130596-62-2 ]
1-((5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)methyl)-4,4-dimethyl-1,4-azasilinane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30 mg		NDS-100217 NDS-100218 To a solution of the compound NDS-100217 (80 mg, 0.22 mmol) in dry dichloromethane (DCM), was added Triethylamine (76 mu, 0.56 mmol) followed by Mesylchloride (19 mu^, 0.24 mmol) at 0C and stirred at the same temperature for 2 h. To the reaction mixture water was added and the organic layer was separated, dried over Na2S04 and concentrated under reduced pressure. This crude product was immediately taken to the next step. The compound was dissolved in dry dimethyl formamide (DMF), Triethylamine (0.12 mL, 0.87 mmol) and 4,4-dimethyl- 1 ,4-azasilinane hydrochloride (prepared according to the reported procedure) 71 mg, 0.44 mmol) was added at 0C and left to stir at RT for 2 h. To the reaction mixture water was added and the organic layer was separated, the aqueous layer was extracted using ethylacetate, dried over Na2S()4 and concentrated under reduced pressure. The crude was then purified by column chromatography to give the title compound NDS-100218 (30 mg) as a viscous liquid in 29 % yield over 2 steps. 1H NMR (400 MHz, CDC13): delta 7.50 (m, 1H), 7.38 (d, J - 8.3 Hz, 2H), 7.35 (m, 2H), 7.18 (d, J = 8.3 Hz, 2H), 3.79 (s, 2H), 2.93 (t, J = 6.0 Hz, 4H), 2.24 (s, 3H), 0.90 (t, J = 6.0 Hz, 4H), 0.15 (s, 6H). 13C NMR (125 MHz, CDC13): delta 141.3, 136.6, 135.0, 134.2, 133.3, 130.7, 130.6, 130.1 , 128.7, 128.4, 127.6, 1 15.0, 54.1, 52.3 (2C), 13.6 (2C), 8.8, -3.1 (2C).

References: [1]Patent: WO2014/181357,2014,A1 .Location in patent: Page/Page column 20; 21.

13
[ 191612-17-6 ]
[ 130596-62-2 ]
(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-(hydroxymethyl)-1H-pyrazol-3-yl)(4,4-dimethyl-1,4-azasilinan-1-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 6h;	To a solution of the compound NDS-100257 (100 mg, 0.25 mmol) in. dry dichloromethane, was added N-(3- Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HCI, 50 mg, 0.32 mmol), Hydroxybenzotriazole (HOBt, 44 mg, 0.32 mmol) and diisopropylethyl amine (0.13 mL, 0.75 mmol) at 0C. Then the amine 4,4-dimethyl-l ,4-azasilinane hydrochloride4 (50 mg, 0.30 mmol) was added and stirred at RT for 6 h. To the reaction mixture water was added and the organic layer was separated, washed with saturated NaHC03, IN HC1, dried over Na2S04 and concentrated under reduced pressure. This crude mixture was purified by column chromatography to give the title compound 13 (90 mg) as a white fluffy solid in 71% yield. NMR (400 MHz, CDC13): delta 7.50 (d, J = 2.3 Hz, 1 H), 7.33-7.25 (m, 3H), 7.17-7.13 (m, 3H), 4.48 (s, 2H), 4.13 (m, 2H), 3.93 (m, 2H), 0.95 (m, 4H), 0.14 (s, 6H) ); 13C NMR (100 MHz, CDCI3): delta 163.4, 147.2, 142.1, 135.8, 135.6, 135.3, 133.1 , 130.9 (2C), 130.36, 130.34, 129.0 (2C), 127.8, 126.4, 122.7, 54.7, 47.1 , 43.2, 15.4, 13.9, -3.0 (2C).

References: [1]Patent: WO2014/181357,2014,A1 .Location in patent: Page/Page column 22.

14
[ 130596-62-2 ]
ethyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylate [ No CAS ]
1-((4-(((tert-butyldimethylsilyl)oxy)methyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)methyl)-4,4-dimethyl-1,4-azasilinane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40 mg		l-((4-(((tcrt-butyldimcthylsiIyl)oxy)mcthyl)-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)- lH-pyrazol-3-yl)mcthyI)-4,4-dimcthyl-l,4-azasiIinane To a solution of lithium aluminium hydride (LAH 7.5 mg, 0.17 mmol) in dry tetrahydrofuran (THF), was added dropwise solution of Ethyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-(4- chlorophenyl)-l -(2,4-dichlorophenyl)-lH-pyrazole-3-carboxylate (95 mg, 0.17 mmol) in tetrahydrofuran at 0C and stirred at the same temperature for 2 h. To the reaction mixture quenched by careful addition of saturated solution of ammonium chloride (2 mL) then extracted with ethyl acetate the organic layer was separated, dried over Na2S04 and concentrated under reduced pressure. The compound obtained was dissolved in dry dichloromethane (DCM), was added Triethylamine (35 mu,, 0.25 mmol) followed by Mesylchloride (1 1 mu,, 0.15 mmol) at 0C and stirred at the same temperature for 2 h. To the reaction mixture water was added and the organic layer was separated, dried over Na2S04 and concentrated under reduced pressure. This crude product was immediately taken to the next step. The compound was dissolved in dry dimethyl formamide (DMF), Triethylamine (0.56 mL, 0.40 mmol) and 4,4-dimethyl-l,4-azasilinane hydrochloride (prepared according to the reported procedure) 33 mg, 0.20 mmol) was added at 0C and left to stir at RT for 2 h. To the reaction mixture water was added and the organic layer was separated, the aqueous layer was extracted using ethylacetate, dried over Na2S04 and concentrated under reduced pressure. The crude was then purified by column chromatography to give the title compound (40 mg) as a viscous liquid in 37 % yield over 3 steps. NMR (400MHz , CDC13) delta = 7.47 - 7.38 (m, 1 H), 7.34 - 7.15 (m, 6 H), 4.62 (s, 2 H), 3.80 (br. s., 2 H), 2.86 (br. s., 4 H), 0.92 (s, 9 PI), 0.82 (br. s., 4 H), 0.08 (s, 6 H), 0.06 (s, 6 H); 13C NMR (l O lMHz , CDC13) delta = 143.1 , 136.4, 135.3, 134.7, 133.4, 130.9, 130.7, 130.2, 128.6, 127.7, 1 19.1 , 77.0, 54.9, 54.2, 52.5, 25.9, 18.4, 13.6, -3.1, -5.3

References: [1]Patent: WO2014/181357,2014,A1 .Location in patent: Page/Page column 24; 25.

15
[ 130596-62-2 ]
(1,5-bis(4-chlorophenyl)-1H-pyrazol-3-yl)methanol [ No CAS ]
1-((1,5-bis(4-chlorophenyl)-1H-pyrazol-3-yl)methyl)-4,4-dimethyl-1,4-azasilinane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30 mg		To a solution of the compound (l ,5-bis(4-chlorophenyl)-lH-pyrazol-3-yl)methanol (NDS- 100530, prepared according to the reported procedure in patent US 6,350,892 B l) (100 mg, 0.31 mmol) in dry dichloromethane (DCM), was added Triethylamine (109 mu,, 0.78 mmol) followed by Mesylchloride (30 muIota 0.37 mmol) at 0C and stirred at the same temperature for 2 h. To the reaction mixture water was added and the organic layer was separated, dried over Na2S0 and concentrated under reduced pressure. This crude product was immediately taken to the next step. The compound was dissolved in dry dimethyl formamide (DMF), Triethylamine (0.132 mL, 0.94 mmol) and 4,4-dimethyl-l,4-azasilinane hydrochloride (prepared according to the reported procedure) 75 mg, 0.45 mmol) was added at 0C and left to stir at RT for 2 h. To the reaction mixture water was added and the organic layer was separated, the aqueous layer was extracted using ethylacetate, dried over Na2S04 and concentrated under reduced pressure. The crude was then purified by column chromatography to give the title compound (30 mg) as a viscous liquid in 29 % yield over 2 steps. lH NMR (400MI 1/ , CDC13) delta = 7.32 - 7.25 (m, 4 H), 7.22 - 7.18 (m, 2 H), 7.17 - 7.13 (m, 2 H), 6.54 (s, 1 H), 3.76 (s, 2 H), 2.89 (br. s., 4 H), 0.89 - 0.80 (m, 4 H), 0.06 (s, 6 H); 13C NMR (101MHz , CDC13) delta = 150.5, 142.6, 138.2, 134.4, 133.1 , 129.9, 129.1, 128.8, 128.6, 126.2, 108.5, 55.4, 52.5, 13.2, -3.2

References: [1]Patent: WO2014/181357,2014,A1 .Location in patent: Page/Page column 25; 26.

16
[ 10519-87-6 ]
[ 130596-62-2 ]