170229-98-8|4-Bromo-3-methylbenzamide| Ambeed

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Quality Control of [ 170229-98-8 ] Purity: 98% SDS Specification

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Product Details of [ 170229-98-8 ]

CAS No. :	170229-98-8
Formula :	C₈H₈BrNO
M.W :	214.06
SMILES Code :	O=C(N)C1=CC=C(Br)C(C)=C1
MDL No. :	MFCD00672914
InChI Key :	ZPFPOZMNEKPBIF-UHFFFAOYSA-N
Pubchem ID :	7020869

Safety of [ 170229-98-8 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P301+P312-P302+P352-P304+P340-P305+P351+P338

Computational Chemistry of [ 170229-98-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.12
Num. rotatable bonds	1
Num. H-bond acceptors	1.0
Num. H-bond donors	1.0
Molar Refractivity	47.2
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	43.09 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.68
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	2.09
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.86
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.	2.27
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	2.11
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.0

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.82
Solubility	0.323 mg/ml ; 0.00151 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.	-2.62
Solubility	0.508 mg/ml ; 0.00237 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	-3.23
Solubility	0.125 mg/ml ; 0.000585 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	Yes
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.	-6.12 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)	1.18

Application In Synthesis of [ 170229-98-8 ]

* 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 [ 170229-98-8 ]

[ 170229-98-8 ] Synthesis Path-Downstream 1~34

1
[ 872-36-6 ]
[ 170229-98-8 ]
[ 157672-20-3 ]

Yield	Reaction Conditions	Operation in experiment
36%	With polyphosphoric acid; at 170℃; for 3h;	A mixture of 4-Bromo-3-methyl-benzamide (1 g, 4.67 mmol) and vinylene carbonate (0.4 ml, 6.30 mmol) in PPA (15 ml) was heated to 170 C. for 3 h. Upon completion, the reaction was cooled, quenched with water, and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The crude material was purified by column chromatography to give 2-(4-Bromo-3-methyl-phenyl)-oxazole (400 mg, 36%).

References: [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 3111 - 3117.
[2]Patent: US2011/71150,2011,A1 .Location in patent: Page/Page column 30-31.

2
[ 170229-98-8 ]
[ 149104-92-7 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 1017 - 1022.

3
[ 170229-98-8 ]
[ 1008736-37-5 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 1017 - 1022.

4
[ 170229-98-8 ]
(S)-1-((R)-2-Amino-3,3-diphenyl-propionyl)-pyrrolidine-2-carboxylic acid 4-cyano-3-methyl-benzylamide [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 1017 - 1022.

5
[ 170229-98-8 ]
(S)-1-((R)-2-Methanesulfonylamino-3,3-diphenyl-propionyl)-pyrrolidine-2-carboxylic acid 4-cyano-3-methyl-benzylamide [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 1017 - 1022.

6
[ 170229-98-8 ]
(S)-1-((R)-2-Methanesulfonylamino-3,3-diphenyl-propionyl)-pyrrolidine-2-carboxylic acid 4-aminomethyl-3-methyl-benzylamide [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 1017 - 1022.

7
[ 170229-98-8 ]
{(R)-1-[(S)-2-(4-Cyano-3-methyl-benzylcarbamoyl)-pyrrolidine-1-carbonyl]-2,2-diphenyl-ethyl}-carbamic acid tert-butyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 1017 - 1022.

8
[ 170229-98-8 ]
[ 176961-43-6 ]

References: [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 3111 - 3117.

9
[ 170229-98-8 ]
[ 176961-42-5 ]

References: [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 3111 - 3117.

10
[ 170229-98-8 ]
N-(3,4-dimethyl-5-isoxazolyl)-2'-formyl-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 3111 - 3117.

11
[ 170229-98-8 ]
N-(3,4-dimethyl-5-isoxazolyl)-2'-(aminomethyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 3111 - 3117.

12
[ 170229-98-8 ]
N-(3,4-dimethyl-5-isoxazolyl)-2'-[(acetylamino)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 3111 - 3117.

13
[ 170229-98-8 ]
5-formyl-4'-oxazol-2-yl-biphenyl-2-sulfonic acid (3,4-dimethyl-isoxazol-5-yl)-(2-methoxy-ethoxymethyl)-amide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 3111 - 3117.

14
[ 170229-98-8 ]
(4-bromo-3-methylphenyl)methanamine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With hydrogenchloride; BH3; borane; In tetrahydrofuran; methanol; water;	(A)4-Bromo-3 -methylbenzylamine.HCl To a solution of borane (1.0 M BH3 in THF, 42 mL) was added a solution of <strong>[170229-98-8]4-bromo-3-methylbenzamide</strong> (1.3 g, 6.0 mmol) in anhydrous THF (20 mL) and the mixture stirred for 6 h at rt. To this was sequentially added dropwise 6N HCl (30 mL), water (30 mL), and MeOH (150 mL) and the mixture stirred for 12 h. After the resulting mixture was concentrated to 50 mL, the precipitates were filtered off and the filtrate concentrated in vacuo. The residue was purified by column chromatography (EtOAc: n-hexane, 1:4) to give the title compound as a yellow oil (0.81 g, 57%). 1H NMR (CD3OD) δ7.60 (d, 1H), 7.37 (s, 2H), 7.18 (d, 1H), 4.04 (s, 2H), 2.41 (s, 3H). FAB MS: 201 [M+1]+

References: [1]Chemical Science,2020,vol. 11,p. 1848 - 1854.
[2]Chemical Communications,2019,vol. 55,p. 11868 - 11871.
[3]Patent: US2002/169113,2002,A1 .

15
[ 1336-21-6 ]
[ 79-37-8 ]
[ 7697-28-1 ]
[ 170229-98-8 ]

Yield	Reaction Conditions	Operation in experiment
8.9g (89%)	In N-methyl-acetamide; methanol; dichloromethane; water;	EXAMPLE 21 N- (3, 4-Dimethyl-5-isoxazolyl) -2'-›(formylamino)[methyl]-4'-(2-oxazolyl)›1,1'-[biphenyl]-2-sulfonamide STR48 A. 4-Bromo-3-methylbenzamide To a solution of 10 g (46.5 mmol) of 4-bromo-3-methyl benzoic acid in 200 mL of dichloromethane under argon, 30 mL of 2M solution of oxalyl chloride in dichloromethane w as added. Four drops of dimethylformamide was then added and the mixture was stirred at room temperature for 1 hour. The soltion was evaporated and dried in vacuo. The residue was dissolved in 100 mL of methanol, and 25 mL of 28% aqueous ammonium hydroxide was added to the mixture. The solution was stirred at room temperature for 3 hours, and then diluted with 500 mL of water. The resulting white solid was filtered, washed with water and dried to afford 8.9g (89%) of compound A.

References: [1]Patent: US5827869,1998,A .

16
[ 41963-20-6 ]
[ 75-24-1 ]
[ 170229-98-8 ]

Yield	Reaction Conditions	Operation in experiment
6.8 g (100%)	With ammonium chloride; In methanol; dichloromethane; toluene;	A. 4-Bromo-3-methylbenzenecarboxamidamide To a suspension of 2.73 g (51.0 mmol) of ammonium chloride in 40 mL of toluene at 0 C., a 2.0M solution of trimethyl aluminum (25.5 mL) was added over 5 minutes. The mixture was then slowly warmed to room temperature and stirred for an additional 2 hrs. This mixture was then added to a solution of 5.0 g (25.5 mmol) of 4-bromo-3-methyl benzonitrile in 15 mL of toluene under argon, and the mixture was heated at 80 C. for 6 days. The mixture was then cooled to room temperature and added to a slurry of silica gel (100 g) in 200 mL of CH2 Cl2 and filtered. The silica was washed with 400 mL of methanol and the combined filtrate was evaporated to provide 6.8 g (100%) of the title compound of this step as a white solid.

References: [1]Patent: US5780473,1998,A .

17
4-(4'-amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxamidine bis-trifluoroacetate [ No CAS ]
[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester [ No CAS ]
tetrakis(triphenylphosine)palladium⁽⁰⁾ [ No CAS ]
{imino-[4-(4'-methoxymethoxy-[1,1';3',1']terphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-methyl}-carbamic acid tert-butyl ester [ No CAS ]
[ 25015-63-8 ]
[ 170229-98-8 ]
[4-(4'-Carbamoyl-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; triethylamine;PdCl2(PPh3)2; In 1,4-dioxane; ethyl acetate;	Example 225 3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2-methyl-biphenyl-4-carboxylic acid amide trifluoroacetate Following the same procedure as in Example 220, step a, reaction of 4-bromo-3-methyl-benzamide (200 mg, 0.93 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.41 mL, 2.8 mmol, Aldrich Chemical Company), PdCl2(PPh3)2 (65 mg, 0.093 mmol, Strem Chemicals Inc, Newburyport, Mass.), Et3N (700 μL, 46 mmol), and dioxane (5 mL) afforded 140 mg of a brown oil (58%) after purification (SiO2, flash elution: 30% EtOAc in hexanes. The above boronate ester (140 mg, 0.54 mmol) was reacted according to the procedure used in Example 1, step c, with [4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (88 mg, 0.18 mmol, as prepared in Example 27, step c), tetrakis(triphenylphosine)palladium(0) (52 mg, 0.05 mmol, Strem Chemicals Inc, Newburyport, Mass.), Na2CO3 (0.7 mL, 2 M), and toluene/EtOH mixture (2:1, 2.1 mL) to afford [4-(4'-Carbamoyl-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester after purification (preparative TLC, 1:3 EtOAc/hexanes, 3*1000μ SiO2 plate). ESI-MS (m/z): Calcd. for C25H27N3O5S3: 545.7; found: 446.1 (M-Boc).

References: [1]Patent: US2004/9995,2004,A1 .

18
[ 87199-17-5 ]
[ 170229-98-8 ]
[ 1027215-49-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 95℃; for 48h;	Preparation of Intermediate 4'-formyl-2-methylbiphenyl-4-carboxamide (l-4a):4-Bromo-3-methyl-benzamide (15.02 g), 70 mmol), 4-formylphenylboronic acid (14.03g, 91 mmol) and palladium tetrakis(triphenylphosphine) (5.03 g, 4 mmol) were combined in 1 ,2-dimethoxy ethane (5 ml) and 2M aqueous sodium carbonate (2.5 ml). After heating at 950C for 48 hours, the reaction mixture was cooled to ambient temperature and passed through a plug of Celite, rinsing with 1 ,2-dimethoxy ethane. The volatiles were removed under reduced pressure to yield 16g of the title compound (Ma) as a colorless solid.1H NMR (400 MHz, Chloroform-d) δ ppm 2.31 (s, 3 H), 5.66 (s, 1 H), 6.10 (s, 1 H), 7.30 (d, J=7.89 Hz, 1 H), 7.48 (d, J=8.10 Hz, 2 H), 7.67 (d, J=7.89 Hz, 1 H), 7.77 (s, 1 H), 7.95 (d, J^7.89 Hz, 2 H), 10.07 (s, 1 H). Mass Spec: (m/z+1 = 240)

References: [1]Patent: WO2008/59335,2008,A1 .Location in patent: Page/Page column 31.

19
[ 1108623-71-7 ]
[ 170229-98-8 ]
[ 1108613-19-9 ]

Yield	Reaction Conditions	Operation in experiment
30%	With tetrabutyl ammonium fluoride;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; ethanol;Heating / reflux;	A mixture of 5-Ethynyl-2-trifluoromethoxy-benzoic acid (3g), 4-Bromo-3-methylbenzamide (2.79 g), Pd(PPh3)2Cl2 (460 mg), TBAF (1M in THF, 39.11 ml) in THF (30 ml) and ethanol (15 ml) was stirred under reflux overnight. The reaction was cooled to ambient temperature, filtered and the solvent was evaporated. The residue was taken up in ethyl acetate / water and extracted with ethyl acetate. The combined organic layers were evaporated and the crude mixture was purified by flash chromatography to obtain the title compound in 30% yield. 1H-NMR (MeOD): 8.13 d (J = 2.1 Hz, 1H); 7.83 m (2H); 7.73 m (1H); 7.64 d (J = 8.1 Hz, 1H); 7.50 m (1H); 2.61 s (3H).

References: [1]Patent: EP2025669,2009,A1 .Location in patent: Page/Page column 44.

20
C₁₂H₁₃BrO₄ [ No CAS ]
[ 170229-98-8 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium hydroxide; at 0℃; for 0.0333333h;	General procedure: To 2-bromo-3-methylbenzoic acid (21, 159 g, 739 mmol) in dichloromethane (1000 mL) was added triethylamine (TEA, 119.7 mL, 813 mmol, 1.1 equiv) followed by iso-butyl chloroformate (101.5 mL, 813 mmol, 1.1 equiv) in dichloromethane (DCM, 200 mL) at 0 C over 10 min. Concentrated ammonia water (323 mL) was then added at 0 C over 2 min. The reaction mixture was poured into water (200 mL), cooled to rt and filtered. The solid was washed with water (2 × 300 mL), 0.5 N HCl (2 × 150 mL) and dried to give the amide as a solid (120 g, yield 76%). To the solution of the amide obtained (50 g, 233.6 mmol) in DMF (300 mL) was added 2,4,6-trichloro-1,3,5-triazine (64.6 g, 350.4 mmol, 1.5 equiv) dropwise at 0 C and the reaction was stirred at rt overnight. To the reaction was added 600 mL of water and the reaction was stirred for 30 min. All insoluble was removed by filtration and the solid was triturated with ethyl acetate (EA, 3 × 100 mL) for 40 min and filtered. The filtrate was washed with saturated sodium carbonate (3 × 200 mL), saturated sodium chloride (200 mL) and dried over anhydrous sodium sulfate.The solvent was removed under reduced pressure to give 22 as a solid (42 g, yield 87.3%). To a solution of 22 (20 g, 102.2 mmol, 1 equiv) in CCl4 (200 mL) was added NBS (18.2 g, 102.0 mmol, 1.0 equiv), Bz2O2 (0.15 g, 0.6 mmol, 0.006 equiv). The reaction was refluxed overnight under N2, cooled and filtered. The filtrate was crystallized at 0 C to provide the brominated intermediate (15 g, yield 53.6%). To a solution of the brominated intermediate (90 g, 327.3 mmol) in DMF (760 ml) was added KOAc (38.6 g, 393.1 mmol, 1.2 equiv). The reaction mixture was stirred at 80 C for 1 h, cooled and water (1 L) was added. The mixture was extracted with EA (1 L). The organic layer was washed with 0.5 N HCl (3 ×200 mL), 2% NaHCO3 (200 mL) and dried over anhydrous sodium sulfate. The solvent was removed to give 23 as a yellow solid (77.3 g, yield 92.9%). 1H NMR of 23 (500 MHz, CDCl3): δ 2.16 (s, 3H), 5.21 (s, 2H), 7.43-7.46 (t, 1H,), 7.63 (m, 2H) ppm. To a solution of 23 (20 g, 78.8 mmol) in 1,4-dioxane (400 mL) was added bis(pinacolato)diboron (30 g, 118.1 mmol, 1.5 equiv) and KOAc (33.2 g, 338.1 mmol, 4.3 equiv). After being de-gassed and backfilled with nitrogen, Pd(dppf)Cl2 (3.2 g, 3.935 mmol, 0.05 equiv) was added. The reaction was refluxed overnight under nitrogen, cooled and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography eluted with petroleum ether (PE)/EA = 5:1 to give 24 as red oil (29 g, crude yield 100% with 80% purity). 1H NMR of 24 (500 MHz, DMSO-d6): δ 1.42 (s, 12H), 2.20 (s, 3H), 5.25 (s, 2H), 7.44-7.49 (t, 1H), 7.57-7.64 (m, 2H) ppm. To a solution of 24 (29 g) in MeOH (100 mL) was added a solution of NaOH in MeOH (7.0 g/130 mL, 175.8 mmol, 2.3 equiv) and the reaction was stirred for 2 h at rt. The reaction mixture was concentrated under vacuum and the residue was dissolved in THF (150 mL) and 2 N HCl (138 mL, 69 mmol, 0.9 equiv). The reaction was stirred at rt for 50 min, concentrated and filtered. The solid was washed with water (3 × 20 mL) and petroleum ether (3 × 20 mL) to provide 25 (7.6 g, yield 62%). 1H NMR of 25 (500 MHz, DMSO-d6): δ 5.05 (s, 2H), 7.63-7.68 (t, 1H), 7.73-7.81 (m, 2H) ppm. To Raney Ni (0.849 g, 14.5 mmol, 2.3 equiv) in formic acid (10 mL) and water (2 mL) was added 25 (1 g, 6.29 mmol) at rt. The reaction was stirred at 100 C for 1 h, cooled and then filtered. The solvent was removed to give a solid that was purified by silica gel column chromatography eluted with CH2Cl2 to give 26 as a solid (0.714 g, yield 70%). 1H NMR of 26 (500 MHz, CDCl3): δ 10.03 (s, 1H), 8.08 (s, 1H), 7.86 (t, 1H), 7.63-7.71 (m, 2H), 5.20 (s, 2H) ppm. To a mixture of HCOOH (116.2 g, 10.0 equiv) and TEA (102.2 g, 4.0 equiv) were added 26 (40.9 g, 252.5 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (43.7 g, 1.2 equiv). The resulting mixture was refluxed for 15 h and cooled to rt. Hydrochloric acid (2 N, 320 mL) was added into the mixture that was then extracted with ethyl acetate twice (2 × 250 mL). The combined organic layer was washed with 2 N HCl (160 mL) and rotary evaporated to give the crude product that was recrystallized from DMF and 2 N HCl (34:204 mL) providing compound 1 as a white solid (15.6 g, yield 30%). An additional recrystallization from DMF and 2 N HCl (16:96 mL) was performed to give high purity product (12.9 g).