69535-85-9|2,2'-Dimethyl-[1,1'-biphenyl]-4-carboxylic acid| Ambeed

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Quality Control of [ 69535-85-9 ] Purity: 98% SDS Specification

COA

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NMR

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Product Details of [ 69535-85-9 ]

CAS No. :	69535-85-9
Formula :	C₁₅H₁₄O₂
M.W :	226.27
SMILES Code :	O=C(C1=CC=C(C2=CC=CC=C2C)C(C)=C1)O
MDL No. :	MFCD18318906
Boiling Point :	No data available
InChI Key :	ZGBAXFOVTPCBRW-UHFFFAOYSA-N
Pubchem ID :	21937303

Safety of [ 69535-85-9 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H319-H317
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 69535-85-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	17
Num. arom. heavy atoms	12
Fraction Csp3	0.13
Num. rotatable bonds	2
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	68.77
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	37.3 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.25
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	3.8
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.67
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.	3.67
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	3.89
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.46

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-4.03
Solubility	0.0213 mg/ml ; 0.0000939 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-4.28
Solubility	0.0119 mg/ml ; 0.0000528 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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	-5.07
Solubility	0.00193 mg/ml ; 0.00000851 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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.	-4.98 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.	0.56

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<2.0
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)	1.84

Application In Synthesis of [ 69535-85-9 ]

* 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 [ 69535-85-9 ]

[ 69535-85-9 ] Synthesis Path-Downstream 1~19

1
[ 909040-94-4 ]
[ 69535-85-9 ]

Yield	Reaction Conditions	Operation in experiment
97%		Step B. 2,2'-Dimethyl-biphenyl-4-carboxylic acid To a solution of methyl 2,2'-dimethyl-1,1'-biphenyl-4-carboxylate of Step A (24.7 g, 103 mmol) in tetrahydrofuran:methanol (5:1, 200 mL) was added 1N sodium hydroxide (108 mL, 108 mmol) and the reaction mixture was heated at reflux for 1 hour. The cooled reaction mixture was then concentrated in vacuo to remove organic solvents. The resulting aqueous solution was cooled to 0 C. and 2N hydrochloric acid (60 mL, 120 mmol) was added slowly followed by water (60 mL) to facilitate stirring of the precipitated product. The suspension was stirred for 1 hour at 0 C., then filtered to afford the title compound (22.6 g, 97%) as a white solid, m.p. 140-143 C. MS [(-)ESI, m/z]: 225 [M-H]-.
97%		Step B. 2,2'-Dimethyl-biphenyl-4-carboxylic acid; To a solution of methyl 2,2'-dimethyl-1,1'-biphenyl-4-carboxylate of Step A (24.7 g, 103 mmol) in 5:1 tetrahydrofuran:methanol (200 mL) was added 1 M sodium hydroxide (108 mL, 108 mmol) and the reaction mixture was heated at reflux for 1 hour. The cooled mixture was then concentrated in vacuo to remove organic solvents. The resulting aqueous solution was cooled to 0 C. and 2 M hydrochloric acid (60 mL, 120 mmol) added slowly followed by water (60 mL) to facilitate stirring of the precipitated product. The suspension was stirred for 1 hour at 0 C. then filtered to afford the title compound (22.6 g, 97%) as a white solid, m.p. 140-143 C. MS [(-)ESI), m/z]: 225 [M-H]-
95%		Sodium hydroxide (10% in water; 10 ml_) was added to a solution of intermediate 15 (15 g,62.24 mmol; 1 eq.) in THF (100 ml_) and the reaction mixture was stirred at 700C for 16 hours.The solvent was evaporated in vacuo and the aqueous residue washed with ethyl acetate. The aqueous layer was then acidified pH 2-3 with 3M HCI and extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo to afford the title compound (13.5 g, 95%) as a white solid.HPLC (Method B) : Rt 4.10 min (purity 99.6%). LC/MS : 227.0 (M+H)+. 1H NMR (DMSO,400MHz) delta 12.89 (1 H, bs), 7.89 (1 H, s), 7.82-7.80 (1 H, d), 7.32-7.23 (3H, m), 7.19-7.1 1 (1 H, d), 7.07-7.05 (1 H, d), 2.04 (3H, s),1.98 (3H, s).

95%		To a solution of methyl 2,2'-dimethyl-1 ,1 '-biphenyl-4-carboxylate, prepared in Step 1 (15 g, 62.2 mmol) in THF (100 mL) was added 10% sodium hydroxide (100 ml_) and the mixture was heated to 1000C overnight. THF was removed under reduced pressure and the aqueous residue was washed with EtOAc. The aqueous layer was then acidified with 3N HCI to pH 2- 3 and extracted with DCM. The organic phase was washed with water and dried over sodium sulfate and concentrated under reduced pressure to obtain get the title compound as a white solid (13.5 g, 95%). 1H NMR: (DMSOd6, 400 MHz) delta 12.89 (bs, 1 H), 7.89 (s, 1 H), 7.82-7.80 (d, 1 H), 7.32-7.23 (m, 3H), 7.19-7.1 1 (d, 1 H), 7.07-7.05 (d, 1 H), 2.04 (s, 3H), 1.98 (s, 3H). LC/MS (Method A): 227.0 (M+H) HPLC (Method B), Rt: 4.1 min (purity: 99.6%).
95%		2,2'-dimethyl-1 , 1 '-biphenyl-4-carboxylic acidTo a solution of methyl 2,2'-dimethyl-1 ,1 '-biphenyl-4-carboxylate, prepared in Step 1 (15 g, 62.2 mmol) in THF (100 mL) was added 10% sodium hydroxide (100 mL) and the mixture was heated at 1000C overnight. THF was removed under reduced pressure and the aqueous residue was washed with EtOAc. The aqueous layer was then acidified with HCI (3 N to pH 2-3) and extracted with DCM. The organic phase was washed with water and dried over sodium sulfate and concentrated under reduced pressure to obtain get the title compound as a white solid (13.5 g, 95%). 1H NMR: (DMSO-d6, 400 MHz) delta 12.89 (bs, 1 H), 7.89 (s, 1 H), 7.82-7.80 (m, 1 H), 7.32-7.23 (m, 3H), 7.19-7.1 1 (m, 1 H), 7.07-7.05 (m, 1 H), 2.04 (s, 3H), 1.98 (s, 3H). LC/MS (Method A): 227.0 (M+H)+. HPLC (Method B), Rt: 4.1 min (purity: 99.6%).
95%		To a solution of methyl 2,2'-dimethyl-1 ,1 '-biphenyl-4-carboxylate (15 g, 62.2 mmol) in THF (100 ml.) was added 10% sodium hydroxide (100 ml.) and the mixture was heated to 1000C overnight. THF was removed under reduced pressure and the aqueous residue was washed with EtOAc. The aqueous layer was then acidified with 3N HCI to pH 2-3 and extracted with DCM. The organic phase was washed with water and dried over sodium sulfate and concentrated under reduced pressure to obtain get the title compound as a white solid (13.5 g, 95%). 1H NMR (DMSOd6, 400 MHz) delta 12.89 (brs, 1 H), 7.89 (s, 1 H), 7.82-7.80 (d, 1 H), 7.32-7.23 (m, 3H), 7.19-7.11 (d, 1 H), 7.07-7.05 (d, 1 H), 2.04 (s, 3H), 1.98 (s, 3H). LC/MS, M+(ESI): 227.0.
		Step B. 2,2'-Dimethyl-biphenyl-4-carboxylic acid To a solution of methyl 2,2'-dimethyl-1,1'-biphenyl-4-carboxylate of Step A (24.7 g, 103 mmol) in 5:1 tetrahydrofuran:methanol (200 mL) was added 1 M aqueous sodium hydroxide (108 mL, 108 mmol). The reaction mixture heated at reflux for 1 hour, cooled and then concentrated in vacuo to remove organic solvents. The resulting aqueous solution was cooled to 0 C. and 2 M aqueous hydrochloric acid (60 mL, 120 mmol) added slowly followed by water (60 mL) to facilitate stirring of the precipitated product. The suspension was stirred for 1 h at 0 C. then filtered to afford the title compound (22.6 g) as a white solid, m. p. 140-143 C. MS [(+)ESI, m/z]: 225 [M-H]-.

References: [1]Patent: US2006/199806,2006,A1 .Location in patent: Page/Page column 19.
[2]Patent: US2006/287522,2006,A1 .Location in patent: Page/Page column 25.
[3]Patent: WO2009/43890,2009,A1 .Location in patent: Page/Page column 61.
[4]Patent: WO2009/43889,2009,A2 .Location in patent: Page/Page column 112-113.
[5]Patent: WO2010/69949,2010,A1 .Location in patent: Page/Page column 67-68.
[6]Patent: WO2010/100142,2010,A1 .Location in patent: Page/Page column 68.
[7]Patent: US2006/258645,2006,A1 .Location in patent: Page/Page column 28.
[8]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 3742 - 3745.
[9]ChemMedChem,2015,vol. 10,p. 688 - 714.

2
[ 69535-85-9 ]
[ 917373-55-8 ]

Yield	Reaction Conditions	Operation in experiment
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h;	Step C. (10,11-Dihydro-5H-pyrrolo[2,1-c](1,4]benzodiazepin-10-yl)-(2,2'-dimethyl-biphenyl-4-yl)-methanone To a suspension of <strong>[69535-85-9]2,2'-dimethyl-biphenyl-4-carboxylic acid</strong> of Step B (22.4 g, 99.0 mmol) in dry dichloromethane (500 mL) at room temperature under nitrogen was added dry N,N-dimethylformamide (5 mL) followed by the dropwise addition of a 2.0 M solution of oxalyl chloride in dichloromethane (60 mL, 120 mmol). The reaction mixture was stirred at room temperature for 2 hours, then concentrated in vacuo and the residue redissolved in dry dichloromethane (200 mL). The solution was concentrated in vacuo to afford the crude acid chloride as a brown oil. The acid chloride was dissolved in dichloromethane (500 mL), 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (21.9 g, 119 mmol) was added, followed by N,N-diisopropylethylamine (87 mL, 500 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 16 hours. The reaction mixture was then washed with 1N hydrochloric acid (5×1 L), 10% aqueous sodium hydroxide (1 L) and brine (500 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a dark foam. Purification by flash chromatography using a solvent gradient of 2.5 to 40% ethyl acetate in hexane gave a tan solid that was recrystallized from ethyl acetate/hexane to afford the title compound (12.4 g, 32%) as a pale orange solid. Purification of the mother liquors by flash chromatography yielded additional title compound (11.5 g, 30%) as a white solid, m.p. 145-148 C. MS [(+)ESI, m/z]: 393 [M+H]+.
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h;	Step C; (10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2,2'-dimethyl-biphenyl-4-yl)-methanone To a suspension of <strong>[69535-85-9]2,2'-dimethyl-biphenyl-4-carboxylic acid</strong> of Step B (22.4 g, 99.0 mmol) in dry dichloromethane (500 mL) at room temperature under nitrogen was added dry N,N-dimethylformamide (5 mL) followed by the dropwise addition of 2.0 M solution of oxalyl chloride in dichloromethane (60 mL, 120 mmol). The reaction mixture was stirred at room temperature for 2 hours then concentrated in vacuo and the residue redissolved in dry dichloromethane (200 mL). The solution was concentrated in vacuo to afford the crude acid chloride as a brown oil. The acid chloride was dissolved in dichloromethane (500 mL), 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (21.9 g, 119 mmol) was added followed by N,N-diisopropylethylamine (87 mL, 500 mmol) and the reaction mixture stirred at room temperature under nitrogen for 16 hours. The reaction mixture was then washed with 1 M aqueous hydrochloric acid (5×1 L), 10% aqueous sodium hydroxide (1 L) and brine (500 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a dark foam. Purification by flash chromatography using a solvent gradient of 2.5 to 40% ethyl acetate in hexane gave a tan solid that was recrystallized from ethyl acetate/hexane to afford the title compound (12.4 g) as a pale orange solid. Purification of the mother liquors by flash chromatography yielded additional title compound (11.5 g) as a white solid, m.p. 145-148 C. MS [(+)ESI, m/z]: 393 [M+H]+. Anal. Calcd for C27H24N2O: C, 82.62; H, 6.16; N, 7.14. Found: C, 82.26; H, 5.83; N, 6.50.
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 3h;	Under Argon atmosphere, Intermediate 3 (147.08 mg; 0.65 mmol) was stirred in anhydrous DCM (5 mL). Oxalyl chloride (57.75 muL; 0.68 mmol) was added followed by DMF (0.50 muL; 0.01 mmol). The reaction mixture was stirred 3 hours at RT. Solvents were evaporated to give 2,2'-dimethylbiphenyl-4-carbonyl chloride as a yellow oil. The latter was dissolved in anhydrous THF (3 mL), Intermediate 46 (136.62 mg; 0.65 mmol) and DIEA (221.08 muL; 1.30 mmol) were added under argon. The mixture was heated in the microwave at 15O0C for 15min. The reaction mixture was diluted in water and extracted with EtOAc, the organic phase was then washed with NH4CI, NaHCO3 and NaCI sat. solution. The organic layer was <n="213"/>then dried over magnesium sulfate, filtered and concentrated, the crude product was purified by flash chromatography (c-hex/EtOAc: 9.5/0.5), affording the title compound. LC/MS (Method A): 398.9 (M-H)", 400.8 (M+H)+. HPLC (Method A) Rt 6.37 min (Purity: 98.8%).

With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h;

Step C. (10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2,2'-dimethyl-biphenyl-4-yl)-methanone; To a suspension of <strong>[69535-85-9]2,2'-dimethyl-biphenyl-4-carboxylic acid</strong> of Step B (22.4 g, 99.0 mmol) in dry dichloromethane (500 mL) at room temperature under nitrogen was added dry N,N-dimethylformamide (5 mL) followed by the dropwise addition of a 2.0 M solution of oxalyl chloride in dichloromethane (60 mL, 120 mmol). The reaction mixture was stirred at room temperature for 2 hours then concentrated in vacuo and the residue redissolved in dry dichloromethane (200 mL). The solution was concentrated in vacuo to afford the crude acid chloride as a brown oil. The acid chloride was dissolved in dichloromethane (500 mL), and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (21.9 g, 119 mmol) was added followed by N,N-diisopropylethylamine (87 mL, 500 mmol). The reaction mixture stirred at room temperature under nitrogen for 16 hours. The mixture was then washed with 1 M hydrochloric acid (5×1 L), 10% aqueous sodium hydroxide (1 L) and brine (500 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a dark foam. Purification by flash chromatography using a solvent gradient of 2.5 to 40% ethyl acetate in hexane gave a tan solid that was recrystallized from ethyl acetate/hexane to afford the title compound (12.4 g, 32%) as a pale orange solid. Purification of the mother liquors by flash chromatography yielded additional title compound (11.5 g, 30%) as a white solid, m.p. 145-148 C. MS [+)ESI, m/z]: 393 [M+H]+

References: [1]Patent: US2006/199806,2006,A1 .Location in patent: Page/Page column 19.
[2]Patent: US2006/258645,2006,A1 .Location in patent: Page/Page column 28-29.
[3]Patent: WO2009/43889,2009,A2 .Location in patent: Page/Page column 211-212.
[4]Patent: US2006/287522,2006,A1 .Location in patent: Page/Page column 25.

3
[ 7697-28-1 ]
[ 16419-60-6 ]
[ 69535-85-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	With disodium hydrogenphosphate; disodium bis(2-aminopyrimidine-4,6-diolate)palladium acetate; In water; at 50 - 120℃; for 0.166667h;Microwave irradiation;	In a 35 mL microwave reaction vessel, commercially available 4-bromo-3- methylbenzoic acid (0.2 g, 0.93 mmol), o-tolylboronic acid (0.151 g, 1.12 mmol) and Na2HPO4 (0.66 g, 4.65 mmol) were sequentially added. H20 (6.0 mL) was added and the mixture stirred at 50 C to dissolve most of the materials. Bis-(disodium 2-aminopyrimidine-4,6-diolate) palladium acetate [prepared as described in I Am. Chem. Soc. 2009, 131, 16346-1 6347] (0.01 M in Pd(II),1.50 mL, 0.0 15 mmol) was added to the reaction and the tube was heated to 120 C under microwave irradiation for 10 mm, under vigorous stirring. After cooling to r.t., the reaction was partitioned between 1.0 M HC1 solution (100 mL) and EtOAc (100 mL). The organic layer was separated, dried over Na2504, filtered and concentrated affording a solid residue (0.304 g). Purification by typical silica gel flash chromatography (CH2C12) afforded the pure titlecompound (0. 20 g, 95%) as a white wax. R= 2.20 mm. MS (ESI) m/z: 225 [M-Hf. ?H NMR (DMSO-d6): oe 12.90 (s, 1H), 7.90 (d, 1H, J= 1.0 hz), 7.80 (dd, 1H, J= 7.9, 1.6 Hz), 7.35-7.23 (m, 3H), 7.19 (d, 1H, J= 7.9 Hz), 7.07 (dd, 1H, J= 7.5, 1.4 Hz), 2.04 (s, 3H), 1.99 (s, 3H).

References: [1]Journal of the American Chemical Society,2009,vol. 131,p. 16346 - 16347.
[2]Patent: WO2014/144836,2014,A2 .Location in patent: Paragraph 0562; 0563.

4
[ 69535-85-9 ]
[ 918967-55-2 ]
[ 1141474-66-9 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 3 (814 mg; 3.60 mmol; 1.20 eq.), Intermediate 1 (637 mg; 3 mmol; 1 eq.) and 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (690 mg; 3.60 mmol; 1.20 eq.) were dissolved in THF (10 mL) and CH3CN (10 mL) in a 20 mL microwave vial under N2. The <n="181"/>reaction mixture was stirred overnight at RT. Then n-ethyldiisopropylamine (DIEA) (1.22 ml 7.20 mmol; 2.40 eq.) was added and the mixture was heated in the microwave at 1500C for 30 min. The reaction mixture was evaporated to dryness. EtOAc (50 ml_) was added and the mixture was washed with HCI 0.1 N (2x 25ml_), a saturated aqueous solution of NaHCC>3 (25ml_) and dried over MgSO4. After evaporation of the solvents, the resulting crude product was purified by flash chromatography (c-hex/EtOAc: 9.5/0.5), affording the title compound as a white powder. 1H NMR (DMSO-d6, 300 MHz) delta 8.17-8.16 (m, 1 H), 8.12 (d, J = 7.2 Hz, 1 H), 8.29-8.04 (m, 2H), 7.98 (dd, J = 1 1.1 , 2.5 Hz, 1 H), 7.39-7.27 (m, 4H), 7.14-7.1 1 (m, 1 H), 3.91 (s, 3H), 2.13 (s, 3H), 2.03 (s, 3H). LC/MS (Method A): 403.0 (M+H)+. HPLC (Method A) Rt 6.23 min (Purity: 93.5%).

References: [1]Patent: WO2009/43889,2009,A2 .Location in patent: Page/Page column 179-180.

5
[ 69535-85-9 ]
1,3,3-trimethyl-6-azabicyclo<3.2.1>octane [ No CAS ]
C₂₅H₃₁NO [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 3742 - 3745.

6
[ 69535-85-9 ]
[ 22162-53-4 ]
[ 909040-95-5 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of 0.45 g (0.002 mole) of <strong>[69535-85-9]2,2'-dimethyl-1,1'-biphenyl-4-carboxylic acid</strong> in 50 mL of thionyl chloride was heated under reflux overnight. The excess thionyl chloride was stripped off in vacuo. To the residue was added 0.37 g (0.002 mole) of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 50 mL of 1,4-dioxane followed by 0.24 g (0.002 mole) of N,N-dimethylaniline. After standing for three hours, the reaction solution was poured into 300 mL of water to provide 0.6 g of title compound which was used directly in the next step after drying. MS [(+)ESI, m/z]: 393 [M+H]+.

References: [1]Patent: US2006/258644,2006,A1 .Location in patent: Page/Page column 38.

7
[ 69535-85-9 ]
[3-methyl-4-(o-tolyl)phenyl]methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With lithium aluminium tetrahydride; In tetrahydrofuran; diethyl ether; at 0 - 20℃; for 1h;Inert atmosphere;	Under nitrogen atmosphere, to a cooled (0 C) suspension of LiA1H4 (2.0 M in THF,1.77 mL, 3.54 mmol) in dry Et20 (11.0 mL), a solution of 3-methyl-4-(o-tolyl)-benzoic acid (0.2g, 0.88 mmol) in dry Et20 (6.0 mL) was added dropwise. The resulting mixture was stirred at r.t.for 1 h, then cooled to 0 C and H20 (0.15 mL) was slowly and cautiously added, followed by a3.0 M KOH solution (0.15 mL) and additional H20 (0.50 mL). The mixture was stirred at 0 Cfor 1 h, filtered and the organic phase dried over Na2504 and concentrated to dryness giving asolid residue (0.2 g). Purification by typical silica gel flash chromatography (Cy/EtOAc, 4:1)afforded the pure title compound (0.17 1 g, 92%), as a white solid. R= 2.57 mm. ?H NMR (DMSO-d6): oe 7.31-7.15 (m, 5H), 7.06-6.98 (m, 2H), 5.15 (t, 1H, J 5.7 Hz), 4.51 (d, 1H, J 5.7 Hz), 1.99 (s, 3H), 1.98 (s, 3H).

References: [1]Patent: WO2014/144836,2014,A2 .Location in patent: Paragraph 0564; 0565.

8
[ 69535-85-9 ]
[3-methyl-4-(o-tolyl)phenyl]methyl 2-pyridyl carbonate [ No CAS ]

References: [1]Patent: WO2014/144836,2014,A2 .

9
[ 69535-85-9 ]
[3-methyl-4-(o-tolyl)phenyl]methyl 2-oxopyridine-1-carboxylate [ No CAS ]

References: [1]Patent: WO2014/144836,2014,A2 .

10
[ 69535-85-9 ]
[3-methyl-4-(o-tolyl)phenyl]methyl N-[(3S)-2-oxoazetidin-3-yl]carbamate [ No CAS ]

References: [1]Patent: WO2014/144836,2014,A2 .

11
[ 148547-19-7 ]
[ 69535-85-9 ]