1306763-29-0|(R)-1-Amino-2,3-dihydro-1H-indene-4-carbonitrile hydrochloride| Ambeed

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Quality Control of [ 1306763-29-0 ] Purity: 97% SDS Specification

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Product Details of [ 1306763-29-0 ]

CAS No. :	1306763-29-0
Formula :	C₁₀H₁₁ClN₂
M.W :	194.66
SMILES Code :	N#CC1=CC=CC2=C1CC[C@H]2N.[H]Cl
MDL No. :	MFCD16295016
InChI Key :	NYCLSOKJNLLCHQ-HNCPQSOCSA-N
Pubchem ID :	52938552

Safety of [ 1306763-29-0 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 1306763-29-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	6
Fraction Csp3	0.3
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	53.45
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	49.81 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	1.73
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.98
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.	1.37
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	1.9
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.4

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.48
Solubility	0.647 mg/ml ; 0.00332 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.	-2.39
Solubility	0.789 mg/ml ; 0.00405 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	-2.71
Solubility	0.379 mg/ml ; 0.00195 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	Yes
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.	-6.26 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	1.0
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)	2.19

Application In Synthesis of [ 1306763-29-0 ]

* 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 [ 1306763-29-0 ]

[ 1306763-29-0 ] Synthesis Path-Downstream 1~17

1
[ 60899-34-5 ]
[ 1306763-29-0 ]

References: [1]Patent: WO2011/60389,2011,A1 .
[2]Patent: WO2018/64356,2018,A1 .

2
[ 24424-99-5 ]
[ 1306763-29-0 ]
[ 1306763-30-3 ]

Yield	Reaction Conditions	Operation in experiment
84%	With triethylamine; In dichloromethane; at 0 - 20℃; for 2.0h;	[0458] (R )-tert-butyl 4-cyano-2, 3-dihydro-lH-inden-l-ylcarbamate (INT-52)[0459] To (R)-l-amino-2,3-dihydro-lH-indene-l-yl)-4-carbonitrile HC1 INT-50 (11.6 g, 59.6 mmol) in DCM (100 mL) at 0C was added TEA (12.0 mL, 131.0 mmol). To the resulting solution was added a solution of Boc anhydride (14.3 g, 65.6 mmol) in DCM (30 mL) and the reaction mixture stirred at room temperature for 1.5 h. The reaction mixture was washed with brine, and the organic layers were dried over MgS04 and filtered. Additional DCM was added to a total volume of 250 mL and Norit (4.5 g) was added. The product was refluxed for 15 mins and the hot mixture filtered through a pad of celite / silica. The filtrate was concentrated and recrystallized from EA (50 mL) and hexane (150 mL) to produce 12.93 g (84%) of (R)-tert-butyl 4-cyano-2,3-dihydro-lH-inden-l-ylcarbamate INT-52 as an off-white solid. LCMS-ESI (m z) calculated for Ci5H18N202: 258.3; found 281.1 [M+Na]+, tR = 3.45 min. Elemental Analysis determined for Ci5H18N202; C calculated = 69.74%; found = 69.98%. H calculated = 7.02%; found = 7.14%. N calculated = 10.84%; found = 10.89%. NMR (400 MHz, CDC13) 6 7.64 - 7.49 (m, 2H), 7.34 (dt, J = 7.7, 3.8, 1H), 5.36 - 5.20 (m, 1H), 4.78 (d, J = 6.8, 1H), 3.20 (ddd, J = 16.9, 8.9, 3.3, lH), 3.02 (dt, J = 25.4, 8.4, 1H), 2.82 - 2.53 (m, 1H), 1.88 (dq, J = 13.2, 8.6, 1H), 1.55 - 1.44 (m, 9H). 13C NMR (101 MHz, DMSO) delta 155.52, 146.68, 146.32, 130.89, 128.70, 127.63, 117.51, 107.76, 77.98, 55.09, 31.88, 29.11, 28.19. Chiral HPLC: (R)-tert-butyl 4-cyano-2,3-dihydro-lH-inden-l- ylcarbamate was eluted using 2.5% EtOH in hexanes: >99.9% ee, tR = 19.36 min.
84%	With triethylamine; In dichloromethane; at 20℃; for 1.5h;	To (i?)-l-amino-2,3-dihydro-7H-indene-l-yl)-4-carbonitrile HCl INT-6 (1 1.6 g, 59.6 mmol) in DCM (100 mL) at 0C was added TEA (12.0 mL, 131.0 mmol). To the resulting solution was added a solution of Boc anhydride (14.3 g, 65.6 mmol) in DCM (30 mL) and the reaction mixture stirred at room temperature for 1.5 h. The reaction mixture was washed with brine, and the organic layers were dried over MgS04 and filtered. Additional DCM was added to a total volume of 250 mL and Norit (4.5 g) was added. The product was refluxed for 15 mins and the hot mixture filtered through a pad of celite / silica. The filtrate was concentrated and recrystallized from EA (50 mL) and hexane (150 mL) to produce 12.93 g (84%) of {R)-tert-bvXy 4-cyano-2,3-dihydro- iH-inden-l-ylcarbamate INT-8 as an off-white solid. LCMS-ESI (m/z) calculated for Ci5Hi8N202: 258.3; found 281.1 [M+Na]+, = 3.45 min. Elemental Analysis determined for Etaiota8Nu202; C calculated = 69.74%; found = 69.98%. H calculated = 7.02%; found = 7.14%. N calculated = 10.84%; found = 10.89%. 1H NMR (400 MHz, CDCI3) delta 7.64 - 7.49 (m, 2H), 7.34 (dt, J = 7.7, 3.8, 1H), 5.36 - 5.20 (m, 1H), 4.78 (d, J = 6.8, 1H), 3.20 (ddd, J = 16.9, 8.9, 3.3, 1H), 3.02 (dt, J = 25.4, 8.4, 1H), 2.82 - 2.53 (m, 1H), 1.88 (dq, J = 13.2, 8.6, 1H), 1.55 - 1.44 (m, 9H). 13C NMR (101 MHz, DMSO) delta 155.52, 146.68, 146.32, 130.89, 128.70, 127.63, 117.51 , 107.76, 77.98, 55.09, 31.88, 29.1 1 , 28.19. Chiral HPLC: (i?)-tert-butyl 4-cyano-2,3-dihydro-lH-inden- 1-ylcarbamate was eluted using 2.5%> EtOH in hexanes: >99.9%> ee, tR = 19.36 min. The (iS)-enantiomer INT-9 was prepared in an analogous fashion using (5)-l-amino- 2,3-dihydro-iH-indene-l-yl)-4-carbonitrile HC1. for (5)-enantiomer = 28.98 min.
84%	With triethylamine; In dichloromethane; at 0 - 20℃; for 1.5h;	To (R)- 1 -amino-2, 3 -dihydro-JH-indene- 1 -yl)-4-carbonitrile HC1 INT-6 (11.6 g, 59.6 mmol) in DCM (100 mL) at 0C was added TEA (12.0 mL, 131.0 mmol).To the resulting solution was added a solution of Boc anhydride (14.3 g, 65.6 mmol) in DCM (30 mL) and the reaction mixture stirred at room temperature for 1.5 h. The reaction mixture was washed with brine, and the organic layers were dried over MgSO4 and filtered. Additional DCM was added to a total volume of 250 mL and Norit (4.5 g) was added. The product was refluxed for 15 mins and the hot mixture filtered through apad of celite / silica. The filtrate was concentrated and recrystallized from EA (50 mL) and hexane (150 mL) to produce 12.93 g (84%) of (R)-tert-butyl 4-cyano-2,3-dihydro- JH-inden-1-ylcarbamate INT-8 as an off-white solid. LCMS-ESI (m/z) calculated for C,5H,8N202: 258.3; found 281.1 [M+Na], tR = 3.45 mm. Elemental Analysis determined for C,5H,8N202 C calculated = 69.74%; found = 69.98%. H calculated =7.02%; found = 7.14%. N calculated = 10.84%; found = 10.89%. ?H NMR (400 IVIHz, CDC13) 7.64 - 7.49 (m, 2H), 7.34 (dt, J= 7.7, 3.8, 1H), 5.36 - 5.20 (m, 1H), 4.78 (d, J = 6.8, 1H), 3.20 (ddd, J= 16.9, 8.9, 3.3, 1H), 3.02 (dt, J= 25.4, 8.4, 1H), 2.82-2.53 (m, 1H), 1.88 (dq, J = 13.2, 8.6, 1H), 1.55 - 1.44 (m, 9H). ?3C NIVIR (101 MHz, DMSO) 155.52, 146.68, 146.32, 130.89, 128.70, 127.63, 117.51, 107.76, 77.98,55.09, 31.88, 29.11, 28.19. Chiral HPLC: (R)-tert-butyl 4-cyano-2,3-dihydro-1H-inden-1-ylcarbamate was eluted using 2.5% EtOH in hexanes: >99.9% ee, tR = 19.36 mm.The ()-enantiomer INT-9 was prepared in an analogous fashion using (5)-i-amino-2,3-dihydro-JH-indene-1-yl)-4-carbonitrile HC1. tR for (5)-enantiomer = 28.98 mm.

References: [1]Patent: WO2011/60389,2011,A1 .Location in patent: Page/Page column 92-93.
[2]Patent: WO2015/66515,2015,A1 .Location in patent: Page/Page column 78-79.
[3]Patent: WO2018/64356,2018,A1 .Location in patent: Page/Page column 57.

3
[ 15115-60-3 ]
[ 1306763-29-0 ]

References: [1]Patent: WO2011/60389,2011,A1 .
[2]Patent: WO2018/64356,2018,A1 .

4
[ 1306763-27-8 ]
[ 1306763-29-0 ]

References: [1]Patent: WO2011/60389,2011,A1 .
[2]Patent: WO2018/64356,2018,A1 .

5
[ 1306763-28-9 ]
[ 1306763-29-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In 1,4-dioxane; at 20℃; for 1.5h;	[0455] ( R )-l-amino-2,3-dihydro-lH-indene-l-yl)-4-carbonitrile (INT -50)[0456] To crude (R)-N-((R)-4-cyano-2,3-dihydro-lH-inden-l-yl)-2-methylpropane-2- sulfmamide INT-49 (52.9 g, 0.20 mol) in MeOH (200 mL) was added 4N HC1 in dioxane (152.0 mL, 0.60 mol) and the resulting yellow suspension was stirred at room temperature for 1.5 h. The crude reaction mixture was diluted with MeOH (500 mL) and filtered to remove some Ti by-products. The filtrate was concentrated and the resulting solid was refluxed in acetonitrile (500 mL). The resulting white solid was collected to produce 13.0 g (31% over 3 steps) of the HC1 salt of (R)-l-amino-2,3-dihydro-lH-indene-l-yl)-4-carbonitrile INT-50. LCMS-ESI (m/z) calculated for C,0Hi0N2: 158.2; found 142.0 [M-NH2]+, tR = 0.84 min. lH NMR (400 MHz, DMSO) delta 8.61 (s, 3H), 7.96 (d, J = 7.7, 1H), 7.83 (d, J = 7.5, 1H), 7.52 (t, J = 7.7, 1H), 4.80 (s, 1H), 3.23 (ddd, J = 16.6, 8.7, 5.2, 1H), 3.05 (ddd, J = 16.6, 8.6, 6.3, 1H), 2.62 - 2.51 (m, 1H), 2.15 - 2.01 (m, 1H). 13C NMR (101 MHz, DMSO) delta 148.09, 141.15, 132.48, 130.32, 127.89, 117.27, 108.05, 54.36, 39.08, 29.64. The free base can be prepared by extraction with IN NaHC03 and DCM. LCMS-ESI (m/z) calculated for Ci0H10N2: 158.2; found 142.0 [M-NH2]+, tR = 0.83 min. NMR (400 MHz, CDC13) delta 7.52 - 7.38 (m, 2H), 7.23 (dd, J = 17.4, 9.8, 1H), 4.35 (t, J = 7.6, 1H), 3.11 (ddd, J = 16.8, 8.7, 3.2, 1H), 2.89 (dt, J = 16.9, 8.5, 1H), 2.53 (dddd, J = 12.8, 8.1, 7.3, 3.2, 1H), 1.70 (dtd, J = 12.8, 8.8, 8.0, 1H). 13C NMR (101 MHz, DMSO) delta 150.16, 146.67, 130.19, 128.74, 127.38, 117.77, 107.42, 56.86, 38.86, 29.14. Chiral HPLC: (R)-l-ammo-2,3-dmydro-lH-indene-l-yl)-4-carbonitrile was eluted using 5% EtOH in hexanes, plus 0.05% TEA: 95% ee, tR = 23.02 min.
13 g	With hydrogenchloride; In 1,4-dioxane; methanol; at 20℃; for 1.5h;	To crude (i?)-N-((i?)-4-cyano-2,3-dihydro-7H-inden-l-yl)-2- methylpropane-2-sulfinamide INT-5 (52.9 g, 0.20 mol) in MeOH (200 mL) was added 4N HCl in dioxane (152.0 mL, 0.60 mol) and the resulting yellow suspension was stirred at room temperature for 1.5 h. The crude reaction mixture was diluted with MeOH (500 mL) and filtered to remove some Ti by-products. The filtrate was concentrated and the resulting solid refluxed in acetonitrile (500 mL). The resulting white solid was collected to produce 13.0 g (31% over 3 steps) of the HCl salt of (i?)-l- amino-2,3-dihydro-7H-indene-l-yl)-4-carbonitrile INT-6. LCMS-ESI (m/z) calculated for CioHioN2: 158.2; found 142.0 [M-NH2]+, tR = 0.84 min. 1H NMR (400 MHz, DMSO) delta 8.61 (s, 3H), 7.96 (d, J = 7.7, 1H), 7.83 (d, J = 7.5, 1H), 7.52 (t, J = 7.7, 1H), 4.80 (s, 1H), 3.23 (ddd, J = 16.6, 8.7, 5.2, 1H), 3.05 (ddd, J = 16.6, 8.6, 6.3, 1H), 2.62 - 2.51 (m, 1H), 2.15 - 2.01 (m, 1H). 13C NMR (101 MHz, DMSO) delta 148.09, 141.15, 132.48, 130.32, 127.89, 1 17.27, 108.05, 54.36, 39.08, 29.64.
13 g	With hydrogenchloride; In 1,4-dioxane; at 20℃; for 1.5h;	To crude (R)-N-((R)-4-cyano-2,3 -dihydro-JH-inden- l-yl)-2-methylpropane-2-sulfinamide INT-5 (52.9 g, 0.20 mol) in MeOH (200 mL) was added4N HC1 in dioxane (152.0 mL, 0.60 mol) and the resulting yellow suspension was stirred at room temperature for 1.5 h. The crude reaction mixture was diluted with MeOH (500 mL) and filtered to remove some Ti by-products. The filtrate was concentrated and the resulting solid refluxed in acetonitrile (500 mL). The resultingwhite solid was collected to produce 13.0 g (31% over 3 steps) of the HC1 salt of (R)-1- amino-2, 3 -dihydro-JH-indene- 1 -yl)-4-carbonitrile INT-6. LCMS-ESI (m/z) calculated for C,0H,0N2: 158.2; found 142.0 [M-NH2], tR = 0.84 mm. ?H NMR (400 MHz, DMSO) 8.61 (s, 3H), 7.96 (d, J= 7.7, 1H), 7.83 (d, J 7.5, 1H), 7.52 (t, J 7.7, 1H), 4.80 (s, 1H), 3.23 (ddd, J= 16.6, 8.7, 5.2, 1H), 3.05 (ddd, J= 16.6, 8.6, 6.3, 1H), 2.62 -2.51 (m, 1H), 2.15 - 2.01 (m, 1H). ?3C NIVIR (101 IVIHz, DMSO) 148.09, 141.15,132.48, 130.32, 127.89, 117.27, 108.05, 54.36, 39.08, 29.64. The free base can beprepared by extraction with iN NaHCO3 and DCM. LCMS-ESI (m/z) calculated forC,0H,0N2: 158.2; found 142.0 [M-NH2], tR = 0.83 mm. ?H NIVIR (400 MHz, CDC13)7.52-7.38 (m, 2H), 7.23 (dd, J= 17.4, 9.8, 1H), 4.35 (t, J= 7.6, 1H), 3.11 (ddd, J=16.8, 8.7, 3.2, 1H), 2.89 (dt, J= 16.9, 8.5, 1H), 2.53 (dddd, J= 12.8, 8.1, 7.3, 3.2, 1H),1.70 (dtd, J = 12.8, 8.8, 8.0, 1H). ?3C NIVIR (101 MHz, DMSO) 150.16, 146.67,130.19, 128.74, 127.38, 117.77, 107.42, 56.86, 38.86, 29.14. Chiral HPLC: (R)-1- amino-2, 3 -dihydro-JH-indene- 1 -yl)-4-carbonitrile was eluted using 5% EtOH in hexanes, plus 0.05% TEA: 95% ee, tR = 23.02 mm. The (S)-enantiomer INT-7 wasprepared in an analogous fashion using ()-2-methylpropane-2-sulfinamide. tR for (5)- enantiomer= 20.17 mm.

References: [1]Patent: WO2011/60389,2011,A1 .Location in patent: Page/Page column 91-92.
[2]Patent: WO2015/66515,2015,A1 .Location in patent: Page/Page column 77-78.
[3]Patent: WO2018/64356,2018,A1 .Location in patent: Page/Page column 56.

6
[ 1306763-29-0 ]
[ 1213203-23-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In dichloromethane; water;	[0455] ( R )-l-amino-2,3-dihydro-lH-indene-l-yl)-4-carbonitrile (INT -50)[0456] To crude (R)-N-((R)-4-cyano-2,3-dihydro-lH-inden-l-yl)-2-methylpropane-2- sulfmamide INT-49 (52.9 g, 0.20 mol) in MeOH (200 mL) was added 4N HC1 in dioxane (152.0 mL, 0.60 mol) and the resulting yellow suspension was stirred at room temperature for 1.5 h. The crude reaction mixture was diluted with MeOH (500 mL) and filtered to remove some Ti by-products. The filtrate was concentrated and the resulting solid was refluxed in acetonitrile (500 mL). The resulting white solid was collected to produce 13.0 g (31% over 3 steps) of the HC1 salt of (R)-l-amino-2,3-dihydro-lH-indene-l-yl)-4-carbonitrile INT-50. LCMS-ESI (m/z) calculated for C,0Hi0N2: 158.2; found 142.0 [M-NH2]+, tR = 0.84 min. lH NMR (400 MHz, DMSO) delta 8.61 (s, 3H), 7.96 (d, J = 7.7, 1H), 7.83 (d, J = 7.5, 1H), 7.52 (t, J = 7.7, 1H), 4.80 (s, 1H), 3.23 (ddd, J = 16.6, 8.7, 5.2, 1H), 3.05 (ddd, J = 16.6, 8.6, 6.3, 1H), 2.62 - 2.51 (m, 1H), 2.15 - 2.01 (m, 1H). 13C NMR (101 MHz, DMSO) delta 148.09, 141.15, 132.48, 130.32, 127.89, 117.27, 108.05, 54.36, 39.08, 29.64. The free base can be prepared by extraction with IN NaHC03 and DCM. LCMS-ESI (m/z) calculated for Ci0H10N2: 158.2; found 142.0 [M-NH2]+, tR = 0.83 min. NMR (400 MHz, CDC13) delta 7.52 - 7.38 (m, 2H), 7.23 (dd, J = 17.4, 9.8, 1H), 4.35 (t, J = 7.6, 1H), 3.11 (ddd, J = 16.8, 8.7, 3.2, 1H), 2.89 (dt, J = 16.9, 8.5, 1H), 2.53 (dddd, J = 12.8, 8.1, 7.3, 3.2, 1H), 1.70 (dtd, J = 12.8, 8.8, 8.0, 1H). 13C NMR (101 MHz, DMSO) delta 150.16, 146.67, 130.19, 128.74, 127.38, 117.77, 107.42, 56.86, 38.86, 29.14. Chiral HPLC: (R)-l-ammo-2,3-dmydro-lH-indene-l-yl)-4-carbonitrile was eluted using 5% EtOH in hexanes, plus 0.05% TEA: 95% ee, tR = 23.02 min.
	With sodium hydrogencarbonate; In dichloromethane;	The free base can be prepared by extraction with IN NaHC03 and DCM. LCMS-ESI (m/z) calculated for CioHioN2: 158.2; found 142.0 [M-NH2]+, tR = 0.83 min. 1H NMR (400 MHz, CDC13) delta 7.52 - 7.38 (m, 2H), 7.23 (dd, J = 17.4, 9.8, 1H), 4.35 (t, J = 7.6, 1H), 3.1 1 (ddd, J = 16.8, 8.7, 3.2, 1H), 2.89 (dt, J = 16.9, 8.5, 1H), 2.53 (dddd, J = 12.8, 8.1 , 7.3, 3.2, 1H), 1.70 (dtd, J = 12.8, 8.8, 8.0, 1H). 13C NMR (101 MHz, DMSO) delta 150.16, 146.67, 130.19, 128.74, 127.38, 1 17.77, 107.42, 56.86, 38.86, 29.14. Chiral HPLC: (R)-l- amino-2,3-dihydro-7H-indene-l-yl)-4-carbonitrile was eluted using 5% EtOH in hexanes, plus 0.05% TEA: 95%> ee, tR = 23.02 min.
	With sodium hydrogencarbonate; In dichloromethane;	To crude (R)-N-((R)-4-cyano-2,3 -dihydro-JH-inden- l-yl)-2-methylpropane-2-sulfinamide INT-5 (52.9 g, 0.20 mol) in MeOH (200 mL) was added4N HC1 in dioxane (152.0 mL, 0.60 mol) and the resulting yellow suspension was stirred at room temperature for 1.5 h. The crude reaction mixture was diluted with MeOH (500 mL) and filtered to remove some Ti by-products. The filtrate was concentrated and the resulting solid refluxed in acetonitrile (500 mL). The resultingwhite solid was collected to produce 13.0 g (31% over 3 steps) of the HC1 salt of (R)-1- amino-2, 3 -dihydro-JH-indene- 1 -yl)-4-carbonitrile INT-6. LCMS-ESI (m/z) calculated for C,0H,0N2: 158.2; found 142.0 [M-NH2], tR = 0.84 mm. ?H NMR (400 MHz, DMSO) 8.61 (s, 3H), 7.96 (d, J= 7.7, 1H), 7.83 (d, J 7.5, 1H), 7.52 (t, J 7.7, 1H), 4.80 (s, 1H), 3.23 (ddd, J= 16.6, 8.7, 5.2, 1H), 3.05 (ddd, J= 16.6, 8.6, 6.3, 1H), 2.62 -2.51 (m, 1H), 2.15 - 2.01 (m, 1H). ?3C NIVIR (101 IVIHz, DMSO) 148.09, 141.15,132.48, 130.32, 127.89, 117.27, 108.05, 54.36, 39.08, 29.64. The free base can beprepared by extraction with iN NaHCO3 and DCM. LCMS-ESI (m/z) calculated forC,0H,0N2: 158.2; found 142.0 [M-NH2], tR = 0.83 mm. ?H NIVIR (400 MHz, CDC13)7.52-7.38 (m, 2H), 7.23 (dd, J= 17.4, 9.8, 1H), 4.35 (t, J= 7.6, 1H), 3.11 (ddd, J=16.8, 8.7, 3.2, 1H), 2.89 (dt, J= 16.9, 8.5, 1H), 2.53 (dddd, J= 12.8, 8.1, 7.3, 3.2, 1H),1.70 (dtd, J = 12.8, 8.8, 8.0, 1H). ?3C NIVIR (101 MHz, DMSO) 150.16, 146.67,130.19, 128.74, 127.38, 117.77, 107.42, 56.86, 38.86, 29.14. Chiral HPLC: (R)-1- amino-2, 3 -dihydro-JH-indene- 1 -yl)-4-carbonitrile was eluted using 5% EtOH in hexanes, plus 0.05% TEA: 95% ee, tR = 23.02 mm. The (S)-enantiomer INT-7 wasprepared in an analogous fashion using ()-2-methylpropane-2-sulfinamide. tR for (5)- enantiomer= 20.17 mm.

References: [1]Patent: WO2011/60389,2011,A1 .Location in patent: Page/Page column 91-92.
[2]Patent: WO2015/66515,2015,A1 .Location in patent: Page/Page column 78.
[3]Patent: WO2018/64356,2018,A1 .Location in patent: Page/Page column 56.

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