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Structure of 704-91-6

Chemical Structure| 704-91-6

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Product Details of [ 704-91-6 ]

CAS No. :704-91-6
Formula : C8H6N2O2
M.W : 162.15
SMILES Code : O=C(C1=CC2=C(C=C1)C=NN2)O
MDL No. :MFCD06804571
InChI Key :DNCVTVVLMRHJCJ-UHFFFAOYSA-N
Pubchem ID :16227938

Safety of [ 704-91-6 ]

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

Computational Chemistry of [ 704-91-6 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 9
Fraction Csp3 0.0
Num. rotatable bonds 1
Num. H-bond acceptors 3.0
Num. H-bond donors 2.0
Molar Refractivity 43.05
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

65.98 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

0.39
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

1.76
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

1.26
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

0.72
Log Po/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

1.38
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.1

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-2.44
Solubility 0.585 mg/ml ; 0.0036 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.

-2.76
Solubility 0.28 mg/ml ; 0.00173 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

-2.27
Solubility 0.863 mg/ml ; 0.00532 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.

-6.04 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.

0.56

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<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)

1.27

Application In Synthesis of [ 704-91-6 ]

* 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 [ 704-91-6 ]

[ 704-91-6 ] Synthesis Path-Downstream   1~35

  • 2
  • [ 478169-77-6 ]
  • [ 704-91-6 ]
YieldReaction ConditionsOperation in experiment
800 mg (97%) With potassium tert-butylate; In dimethyl sulfoxide; To a stirred solution of potassium tert-butoxide (8.1 g, 73 mmol) in DMSO (30 mL) was added a solution of 3-[(E)-(tert-butylthio)diazenyl]-4-methylbenzoic acid (1.9 g, 7.3 mmol) at RT. The mixture was stirred overnight, followed by the adition of ice water. The aqueous layer was extracted with ethyl acetate. The organic layer was dicarded. The pH of the aqueous layer was adjusted to 4-5 with aqueous 1N HCl. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford 800 mg (97percent) of 1H-indazole-6-carboxylic acid as a tan solid: 1H NMR (400 MHz. DMSO-d6) delta 13.4, 13.0, 8.2, 8.1, 7.9, 7.7.
  • 3
  • [ 704-91-6 ]
  • [ 6530-09-2 ]
  • [ 110-17-8 ]
  • N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-6-carboxamide fumarate [ No CAS ]
  • 5
  • [ 170487-40-8 ]
  • [ 704-91-6 ]
YieldReaction ConditionsOperation in experiment
Ca. 97% With water; lithium hydroxide; In tetrahydrofuran; methanol; at 20℃; for 16h; To a stirred solution of compound methyl lH-indazole-6-carboxylate (1.0 g, 5.676 mmol, leq) in tetrahydrofuran/rnethanol/H20 (1:1:1; lOmL) was added LIOH (476 mg, 11.353 mmol, 2 eq) at room temperature then stirred for 16h. The solvents were evaporated, residue diluted with water (lOmL) andacidified with 2N HCI (pH4-5) to get solid precipitate, filtered and dried to get compound 2 (900 mg,?97percent) as off white solid. TLC system: methanol/dichloromethane (1:9), Rf: 0.1.?H NMR (300 MHz, DMSO-d6): oe 13,36 (s, 1H), 13.04 (s, lH), 8.24?8.08 (m, 2H), 7.85 (dd, J 8.5, 0.9 Hz, I H), 7.67 (dd, J = 8.4, 1.3 Hz, I H).
87% With lithium hydroxide; water; In tetrahydrofuran; at 50℃; for 4h; b) A solution of compound 26e2 (5.0 g, 28.4 mmol) in THF (56 mL) was treated with LiOH (21 mL of a 2M aqueous solution, 42 mmol), and the reaction mixture is stirred at 50 °C. After 4 hours, the reaction mixture was cooled to room temperature and diluted with water. The basic aqueous layer was rinsed with diethyl ether, acidified to pH 3-4 by the addition of 1 M HCI, and extracted with ethyl acetate. The aqueous layer was extracted further with ethyl acetate, and the combined organic layers were rinsed with brine, dried over MgS04, and concentrated to afford 4.0 g (87percent yield) of compound 26. 3.'H NMR (CD30D) 8 7.79-7. 87 (m, 2H), 8.14 (s, 1H), 8.29 (s, 1H) ; ES (+) MS m/e = 163 (M+1).
85.6% With water; lithium hydroxide; In tetrahydrofuran; at 50℃; for 4h; A mixture of intermediate (12) (44.0g, 0.25mol) was dissolved in tetrahydrofuran (a 500 mL) was added 2NLiOH aqueous solution (200mL, 0.40mol), the reaction was stirred at 50 4h. Cooling to room temperature, the tetrahydrofuran was evaporated under reduced pressure, the residue was added distilled water (200 mL), washed with 1NHCl acidified to pH 3.5, added with ethyl acetate (3 × 500mL) extraction, the combined organic layer was washed with brine (a 500 mL), no over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a pale yellow solid intermediate (13) 34.7g, yield 85.6percent.
85.6% With water; lithium hydroxide; In tetrahydrofuran; at 50℃; for 4h; Intermediate (12) (44.0 g, 0.25 mol) was dissolved in tetrahydrofuran (500 mL), and an aqueous solution of 2N LiOH (200 mL, 0.40 mol) was added. The reaction mixture was stirred at 50°C for 4 h, and was then cooled to roomtemperature. Tetrahydrofuran was distilled off under reduced pressure, and the residue was diluted by adding distilledwater (200 mL). The resulting mixture was acidified to pH 3.5 with 1 N HCl, and was extracted with ethyl acetate (33500mL). The combined organic layer was washed with brine (500 mL), dried over anhydrous sodium sulfate, and filtered.The filtrate was concentrated under reduced pressure to obtain intermediate (13) as a light yellow solid (34.7 g, yield:85.6percent).MASS (ESI+) m/z = 163 (M+H)+.1 H NMR (400 MHz, CD3OD): 7.79-7.87 (m, 2H), 8.14 (s, 1H), 8.29 (s, 1H).
85.6% With water; lithium hydroxide; In tetrahydrofuran; at 50℃; for 4h; Methyl 1H-indazole-6-carboxylate (44.0 g, 0.25 mol) was dissolved in tetrahydrofuran (500 mL).2N LiOH aqueous solution (200 mL, 0.40 mol) was added.The reaction solution was stirred at 50 ° C for 4 h.After cooling to room temperature, tetrahydrofuran was evaporated under reduced pressure and the residue was diluted with distilled water (200 mL) and acidified to pH 3.5 with 1N HCl.Ethyl acetate (3 × 500 mL) was added for extraction.The mixed organic layer was washed with brine (500 mL).Dry over anhydrous sodium sulfate, filter,The filtrate was concentrated under reduced pressure to give a pale yellowColor solid intermediate (13) 34.7g,The yield was 85.6percent.

  • 6
  • [ 940877-16-7 ]
  • [ 704-91-6 ]
  • [ 940877-88-3 ]
YieldReaction ConditionsOperation in experiment
99% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); for 2h; d) A solution of compound 26. 3 (7.8 g, 20.8 mmol), compound 26. 4 (3. 4 g, 20.8 mmol), 1-hydroxybenzotriazole hydrate ("HOBt", 3.5 g, 22.3 mmol), and diisopropylethylamine ("DIEA", 14 mL, 83.3 mmol) in DMF (100 mL) was treated with EDCI (4.4 g, 22.3 mmol). After 2 h, the reaction mixture was treated with 1 M HC1 and extracted with ethyl acetate. The combined organic extracts were rinsed with NaHC03 (sat'd), rinsed with brine, rinsed with water, dried over MgS04, and concentrated to afford 8.4 g (99percent yield) of the title compound. ES (+) MS m/e = 404 (M+1).
  • 8
  • [ 704-91-6 ]
  • [ 104224-96-6 ]
  • [ 219507-11-6 ]
YieldReaction ConditionsOperation in experiment
B N2-(4-t-Butylbenzoyl)-N1-(6-indazolylcarbonyl)-4-methoxycarbonyl-1,2-benzenediamine By methods substantially equivalent to those described in Example 9-C, N2-(4-t-butylbenzoyl)-N1-(6-indazolylcarbonyl)-4-methoxycarbonyl-1,2-benzenediamine (0.1 g, 5percent) was prepared from 4-methoxycarbonyl-N2-(4-t-butylbenzoyl)-1,2-benzenediamine and <strong>[704-91-6]6-indazolecarboxylic acid</strong>. 1H NMR FD-MS, m/e 438.3 (M+) Anal. for C26H22N4O3: Calc: C, 68.92; H, 5.57; N, 11.91. Found: C, 68.94; H, 5.62; N, 11.79.
  • 9
  • [ 704-91-6 ]
  • [ 219492-28-1 ]
  • [ 219507-07-0 ]
YieldReaction ConditionsOperation in experiment
330 mg (26%) With 1,2-dichloro-ethane; In methanol; ethyl acetate; N,N-dimethyl-formamide; C N2-(4-t-Butylbenzoyl)-N1-(6-indazolylcarbonyl)-1,2-benzenediamine To a stirring solution of N2-(4-t-butylbenzoyl)-1,2-benzenediamine (830 mg, 3.1 mmol) and <strong>[704-91-6]6-indazolecarboxylic acid</strong> (European Pat. Appln. Pub. No. 242 167 A2, p 43) (500 mg, 3.1 mmol) in DMF (5 mL) was added EDC (1.19 g, 6.2 mmol). After 12 h, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate and washed twice with water and twice with brine. The organic phase was dried with MgSO4, filtered and concentrated in vacuo, then chromatographed over silica gel, eluding with a solvent gradient of dichloromethane through 5percent methanol/dichloromethane. The product containing fractions were combined and concentrated in vacuo to give 330 mg (26percent) of an off-white solid. 1H NMR FD-MS, m/e 412 (M+) Anal. for C24H24N4O2: Calc: C, 72.80; H, 5.87; N, 13.58. Found: C, 72.15; H, 5.80; N, 13.19.
  • 10
  • [ 704-91-6 ]
  • [ 74-89-5 ]
  • [ 906000-49-5 ]
YieldReaction ConditionsOperation in experiment
99% With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In methanol; N,N-dimethyl-formamide; at 0 - 20℃; General procedure: A DMF solution of 3-(5-amino-1H-indazol-3-yl)benzenesulfonamide 2,2,2-trifluoroacetate (1.0equiv), DIPEA (N,N-diisopropylethylamine, 3equiv) and RCO2H (1.05equiv) at 0°C was treated with TBTU (O-(Benzotriazol-1-yl)-N,N,N?,N?-tetramethyluronium tetrafluoroborate) (1.05equiv) added in one portion. The reaction was stirred allowing slowly to warm to rt. After several hours or overnight stirring the crude reaction was purified directly by preparative HPLC. Alternatively, a DMF solution of 3-(3-sulfamoylphenyl)-1H-indazole-5-carboxylic acid (1.0equiv), DIPEA (3equiv) and RR?NH (1.05equiv) at 0°C or rt was treated with TBTU (1.05equiv) added in one portion. The reaction was stirred allowing slowly to warm to rt. After several hours or overnight stirring the crude reaction was purified directly by prepHPLC.
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 23℃; for 14h; A mixture of <strong>[704-91-6]1H-<strong>[704-91-6]indazole-6-carboxylic acid</strong></strong> (4-1, 1.11 g, 6.85 mmol, 1 equiv), N,N- diisopropylethylamine (2.65 g, 20.5 mmol, 3.00 equiv), (1H-l,2,3-benzotriazol-1-yloxy)(tripyrrolidin-1- yl)rhohosphonium hexafluorophosphate (Pybop, 5.34 g, 10.3 mmol, 1.50 equiv) and methylamine (10.3 mL (2M in THF), 20.5 mmol, 3 .00 equiv) in DMF (10 mL) was stirred at 23 °C for 14 h. The reaction mixture was partitioned between a 1: 1 aqueous mixture of of sodium chloride solution and sodium bicarbonate solution and ethyl acetate (2 x 50 mL). The aqueous layer was then acidified to pH 5 and washed with ethyl acetate (2 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (hexanes initially, grading to EPO <DP n="64"/>100percent EtOAc, then 10percent MeOH in EtOAc) to give N-methyl-1H-indazole-6-carboxamide (4-2) as a light brown solid. LRMS m/z (M+H) 176.2 found, 176.1 required.
  • 11
  • [ 141290-59-7 ]
  • [ 704-91-6 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide; water; In ethanol; at 80℃; for 4h; A mixture of 1H-indazole-6-carbonitrile (1-3, 1.50 g, 10.5 mmol, 1.00 equiv), and sodium hydroxide ( 1.26 g, 31.4 mmol, 3 equiv) in a 1 : 1 mixture of ethanol and IN aqueous sodium hydroxide (5 mL) was heated to 80 °C for 4 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (4 x 50 mL). The organic layer was discarded and the aqueous layer was acidified to pH 5 and washed with ethyl acetate (2 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 1H-indazole-6-carboxylic acid (4- 1) as an off-white solid. The LRMS m/z (M+H ) 163.1 found, 163.0 required.
With sodium hydroxide; In ethanol; water; at 80℃; for 4h; A mixture of lH-indazole-6-carbonitrile (1-3, 1.50 g, 10.5 mmol, 1.00 equiv), and sodium hydroxide (1.26 g, 31.4 mmol, 3 equiv) in a 1:1 mixture of ethanol and IN aqueous sodium hydroxide (5 mL) was heated to 80 0C for 4 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (4 x 50 mL). The organic layer was discarded and the aqueous layer was acidified to pH 5 and washed with ethyl acetate (2 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated to give lH-indazole-6-carboxylic acid (4-1) as an off-white solid. The LRMS m/z (M+H ) 163.1 found, 163.0 required.
  • 12
  • [ 704-91-6 ]
  • 3-bromo-1H-indazole-6-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
99% With bromine; sodium hydrogensulfite; In acetic acid; (b) To a solution of 6-carboxyindazole (4.0 g) in acetic acid (140 ml) was added bromine (1.53 ml), and the mixture was stirred in the dark for 24 hours. After the addition of saturated sodium bisulfite (50 ml) and brine (100 ml), the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated. The resulting solid was powdered and vacuum dried to afford 3-bromo-6-carboxyindazole as a light brown solid (5.88 g, 99percent), mp >250°.
99% With bromine; sodium hydrogensulfite; In acetic acid; (b) To a solution of 6-carboxyindazole (4.0 g) in acetic acid (140 ml) was added bromine (1.53 ml), and the mixture was stirred in the dark for 24 hours. After the addition of saturated sodium bisulfite (50 ml) and brine (100 ml), the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated. The resulting solid was powdered and vacuum dried to afford 3-bromo-6-carboxyindazole as a light brown solid (5.88 g, 99percent), mp >250°.
With bromine; acetic acid; at 25℃; for 16h;in the dark; Bromine (0.385 mL, 7.48 mmol) was added dropwise to a solution of 1 H-<strong>[704-91-6]indazole-6-carboxylic acid</strong> (1 g, 5.98 mmol) in acetic acid (30 mL) and the reaction mixture was stirred for 16 h at 25°C in the dark. The reaction was quenched by addition of a saturated aqueous solution of Na2S03 (12 mL) and brine (25 mL) and extracted with EtOAc (x3). The combined organic extracts were washed with brine, dried (Na2S04), filtered and concentrated. The material thus obtained was used without further purification in the next step. MS (UPLC/MS): 239.1/241.1 [M-H]-, 481.3/483.3 [2M-H]-; tR (UPLC conditions f): 1.59 min.
  • 13
  • [ 540-80-7 ]
  • ethereal HCl [ No CAS ]
  • [ 2458-12-0 ]
  • [ 704-91-6 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; potassium acetate; trifluoroborane diethyl ether; In tetrahydrofuran; chloroform; ethyl acetate; acetone; (a) To a solution of boron trifluoride etherate (18 ml) in chloroform (450 ml, Al2 O3 treated) at -15° was added a solution of 3-amino-4-methylbenzoic acid (15.1 g) in tetrahydrofuran (150 ml) over 15 minutes and the resulting mixture was then stirred for an additional 5 minutes. To this mixture was added t-butyl nitrite (14 ml), and the reaction was warmed to 5°. After stirring for 1 hour, potassium acetate (49 g) and 18-crown-6 (2.65 g) were added. The reaction mixture was allowed to warm to room temperature and stirred for 72 hours. The reaction mixture was evaporated, and 3:7 acetone:ethyl acetate (500 ml) and 1N hydrochloric acid (150 ml) were added. After stirring for 2 hours, brine (150 ml) was added to the mixture and the mixture filtered. The aqueous filtrate was extracted with 3:7 acetone:ethyl acetate (2*100 ml). The combined organic extract was dried (MgSO4) and evaporated. The resulting residue was dissolved in hot acetic acid (250 ml) and 250 ml saturated ethereal HCl and 250 ml ether were added sequentially. After cooling to room temperature, the precipitate was filtered and treated with 3:7 acetone:ethyl acetate (500 ml) and brine (100 ml) for 1 hour. After the phases were separated, the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic extracts were washed with brine, dried (MgSO4) and evaporated to afford 6-carboxyindazole as a brown solid (9.8 g, 57percent), mp >250°.
With hydrogenchloride; potassium acetate; trifluoroborane diethyl ether; In tetrahydrofuran; chloroform; ethyl acetate; acetone; (a) To a solution of boron trifluoride etherate (18 ml) in chloroform (450 ml, Al2O3 treated) at -15° was added a solution of 3-amino-4-methylbenzoic acid (15.1 g) in tetrahydrofuran (150 ml) over 15 minutes and the resulting mixture was then stirred for an additional 5 minutes. To this mixture was added t-butyl nitrite (14 ml), and the reaction was warmed to 5°. After stirring for 1 hour, potassium acetate (49 g) and 18-crown-6 (2.65 g) were added. The reaction mixture was allowed to warm to room temperature and stirred for 72 hours. The reaction mixture was evaporated, and 3:7 acetone:ethyl acetate (500 ml) and 1N hydrochloric acid (150 ml) were added. After stirring for 2 hours, brine (150 ml) was added to the mixture and the mixture filtered. The aqueous filtrate was extracted with 3:7 acetone:ethyl acetate (2 x 100 ml). The combined organic extract was dried (MgSO4) and evaporated. The resulting residue was dissolved in hot acetic acid (250 ml) and 250 ml saturated ethereal HCl and 250 ml ether were added sequentially. After cooling to room temperature, the precipitate was filtered and treated with 3:7 acetone:ethyl acetate (500 ml) and brine (100 ml) for 1 hour. After the phases were separated, the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic extracts were washed with brine, dried (MgSO4) and evaporated to afford 6-carboxyindazole as a brown solid (9.8 g, 57percent), mp >250°.
  • 14
  • [ 704-91-6 ]
  • [ 170487-40-8 ]
YieldReaction ConditionsOperation in experiment
6.75 g (82%) With sulfuric acid; In methanol; water; 1.B 1H-Indazole-6-carboxylic acid methyl ester A mixture of 7.59 g (46.8 mmol, 1.0 equiv) <strong>[704-91-6]1H-<strong>[704-91-6]indazole-6-carboxylic acid</strong></strong> in 500 mL CH3OH and 1 mL conc. H2SO4 was heated to reflux for 8 hours, then allowed to stir at room temperature for 18 hours. The mixture was concentrated to ~200 mL, diluted with 1 L ethyl acetate, and washed 1*250 mL saturated aqueous NaHCO3, 1*250 mL H2O, 1*250 mL brine, and dried over Na2SO4. The aqueous washes were extracted with two portions of ethyl acetate to recover additional product. The organic layers were combined, concentrated, and dried to give 6.75 g (82percent) of a yellow-orange-tan solid: 1H NMR (300 MHz, CDCl3) delta 10.8 (br s, 1H), 8.28 (dd, 1H, J=0.9, 1.9 Hz), 8.15 (d, 1H, J=1.0 Hz), 7.8 (m, 2H), 3.97 (s, 3H): MS (Cl, NH3) m/z 177 (M+H+, base).
  • 15
  • [ 704-91-6 ]
  • [ 74-89-5 ]
  • [ 1379330-75-2 ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 23℃; for 14h; A mixture of lH-<strong>[704-91-6]indazole-6-carboxylic acid</strong> (4-1, 1.11 g, 6.85 mmol, 1 equiv), N,N-diisopropylethylamine (2.65 g, 20.5 mmol, 3.00 equiv), (lH-l,2,3-benzotriazol-l-yloxy)(tripyrrolidin-l-yl)phosphonium hexafluorophosphate (Pybop, 5.34 g, 10.3 mmol, 1.50 equiv) and methylamine (10.3 mL (2M in THF), 20.5 mmol, 3 .00 equiv) in DMF (10 mL) was stirred at 23 0C for 14 h. The reaction mixture was partitioned between a 1 : 1 aqueous mixture of of sodium chloride solution and sodium bicarbonate solution and ethyl acetate (2 x 50 mL). The aqueous layer was then acidified to pH 5 and washed with ethyl acetate (2 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (hexanes initially, grading to 100percent EtOAc, then 10percent MeOH in EtOAc) to give N-methyl-lH-indazole-6-carboxamide (4-2) as a light brown solid. LRMS m/z (M+H) 176.2 found, 176.1 required.
  • 16
  • [ 704-91-6 ]
  • [ 18107-18-1 ]
  • [ 170487-40-8 ]
YieldReaction ConditionsOperation in experiment
With methanol; In diethyl ether; toluene;Product distribution / selectivity; Step C - Synthesis of Compound 17 D; 17C 17D; A solution of lH-<strong>[704-91-6]indazole-6-carboxylic acid</strong> 17C (1.73 g; 10.70 mmol) in toluene (80 mL) and methanol (30 mL) was treated with a solution of TMS-diazomethane (2 M soln in ether) until evolution of gas stopped. The reaction mixture was concentrated in vacuo and the residue was adsorbed on silica gel. The product was purified on a Biotage 40-M silica gel column (gradient: 0 to 20 percent acetone in hexanes) to give the product 17D (950 mg; 50 percent for <n="113"/>two steps) as a slightly yellow solid. 1H-NMR (CDCl3; 400 MHz): delta 8.28 (IH, s), 8.16 (IH, s), 7.86 (IH, d, J = 8.54 Hz), 7.81 (IH, d, J = 8.54 Hz), 3.98 (3H, s). LR-MS (ESI): caldc for C9H9N2O2 [M+H]+ 177.07; found 177.20.
With methanol; In diethyl ether; toluene;Product distribution / selectivity; 19C 19D; A solution of lH-<strong>[704-91-6]indazole-6-carboxylic acid</strong> 19C (1.73 g; 10.70 mmol) in toluene (80 mL) and methanol (30 mL) was treated with a solution of TMS-diazomethane (2 M soln in ether) until evolution of gas stopped. The reaction mixture was concentrated in vacuo and the resulting residue was adsorbed on silica gel. The product was purified on a Biotage 40-M silica gel column (gradient: 0 to 20 percent acetone in hexanes) to provide the product 19D (950 mg; 50 percent for two steps) as a slightly yellow solid. 1H-NMR (CDCl3; 400 MHz): delta 8.28 (IH, s), 8.16 (IH, s), 7.86 (IH, d, J = 8.54 Hz), 7.81 (IH, d, J = 8.54 Hz), 3.98 (3H, s). LR-MS (ESI): caldc for C9H9N2O2 [M+H]+ 177.07; found 177.20.
  • 17
  • [ 521278-08-0 ]
  • [ 704-91-6 ]
YieldReaction ConditionsOperation in experiment
Step B - Synthesis of Compound 17 C; 17B 17C; To a stirred solution of potassium tert-butoxide (10.0 eq, 12.0 g) in DMSO (50 mL) was added a solution of t-butyldiazaenyl benzoic acid 17B (2.7 g; 10.70 mmol) in DMSO (30 mL). The mixture was stirred for 6 h and then diluted with ice and acidified with aqueous 1 M HCl until pH 5-6 was attained. The mixture was extracted with ethyl acetate (3 x 50 mL) and the combined organic layers were washed with water (20 mL) and brine (20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in rotavap to give the crude product 17C as a slightly yellow solid which was used without further purification.
Step B - Synthesis of Compound 19C; 19B 19C; To a stirred solution of potassium tert-butoxide (10.0 eq, 12.0 g) in DMSO (50 mL) was added a solution of t-butyldiazaenyl benzoic acid 19B (2.7 g; 10.70 mmol) in DMSO (30 mL). The mixture was allowed to stir for 6 h and then diluted with ice and acidified with aqueous 1 M HCl until pH 5-6 was attained. The mixture was extracted with ethyl acetate (3 x <n="187"/>50 mL) and the combined organic layers were washed with water (20 mL) and brine (20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in rotavap to provide the crude product 19C as a slightly yellow solid which was used without further purification.
With potassium tert-butylate; In dimethyl sulfoxide; for 6h; To a stirred solution of potassium tert-butoxide (10.0 eq, 12.0 g) in DMSO (50 mL) was added a solution of t-butyldiazaenyl benzoic acid 14B (2.7 g; 10.70 mmol) in DMSO (30 mL). The mixture was stirred for 6 h and then diluted with ice and acidified with aqueous 1 M HCl until pH 5-6 was attained. The mixture was extracted with ethyl acetate (3 x 50 mL) and the combined organic layers were washed with water (20 mL) and brine (20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in rotavap to provide the crude product 14C as a slightly yellow solid which was used without further purification.
  • 18
  • [ 67-56-1 ]
  • [ 704-91-6 ]
  • [ 170487-40-8 ]
YieldReaction ConditionsOperation in experiment
50% With diazomethyl-trimethyl-silane; In diethyl ether; toluene; A solution of IH-indazole-6-carboxyIic acid 14C (1.73 g; 10.70 ramol) in toluene (80 ml) and methanol (30 niL) was treated with a solution of TMS-diazomethaiie (2 M soln in ether) until evolution of gas stopped. The reaction mixture was concentrated in vacuo and the residue was adsorbed on silica gel. The product was purified on a Biotage 40-M silica gel column (gradient: 0 to 20 percent acetone in hexanes) to provide the product 14D (950 rag; 50 percent for two steps) as a slightly yellow solid. 1H-NMR (CDCl3; 400 MHz): delta 8.28 (IH, s), 8.16 (IH, s), 7.86 (IH, d, J = 8.54 Hz), 7.81 (IH, d, J = 8.54 Hz), 3.98 (3H, s). LR-MS (ESI): caldc for C9H9N2O2 [M+H]+ 177.07; found 177.20.
With sulfuric acid; Preparation of tert -butyl 5-(hydroxymethyl)-lH-indazole- l -carboxylateThe title compound was synthesized by esterification of <strong>[704-91-6]indazole-6-carboxylic acid</strong> using methanol in presence of cone, sulphuric acid followed by reduction of the ester group using lithium aluminium hydride and its subsequent reaction with di-ter/-butyl dicarbonate anhydride; NMR (300 MHz, DMSO-c 6) delta 1.64 (s, 9H), 4.67 (d, J = 5.1 Hz, l H), 5.43 (br s, I H), 7.29 (d, .] = 7.8 Hz, I H), 7.80 (d, J = 8.1 Hz, 1 H), 8.12 (s, 1 H), 8.36 (s, 1 H).
  • 19
  • [ 704-91-6 ]
  • [ 916902-55-1 ]
  • 20
  • [ 704-91-6 ]
  • [ 74-88-4 ]
  • [ 170487-40-8 ]
YieldReaction ConditionsOperation in experiment
90% With sodium carbonate; In N,N-dimethyl-formamide; at 20℃; To a solution of <strong>[704-91-6]1H-<strong>[704-91-6]indazole-6-carboxylic acid</strong></strong> (3.00 g, 18.5 mmol) in N,N-dimethylformamide (46 mL) was added sodium carbonate (2.06 g, 19.4 mmol), followed by iodomethane (2.75 g, 1.21 mL, 19.4 mmol) dropwise. The mixture was stirred at room temperature overnight. The mixture was poured into half saturated sodium bicarbonate and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown oil. This residue was purified by flash column chromatography (12-100percent ethyl acetate/heptanes) to afford methyl 1H-indazole-6-carboxylate as a yellow solid (2.95 g, 90percent). 1H NMR (400 MHz, CDCl3, delta): 10.40 (br. s., 1H), 8.26 (s, 1H), 8.13 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 3.96 (s, 3H).
90% With sodium carbonate; In N,N-dimethyl-formamide; at 20℃; Step 1.methyl 1H-indazole-6-carboxylateTo a solution of <strong>[704-91-6]1H-<strong>[704-91-6]indazole-6-carboxylic acid</strong></strong> (3.00 g, 18.5 mmol) in N,N-dimethylformamide (46 mL) was added sodium carbonate (2.06 g, 19.4 mmol), followed by iodomethane (2.75 g, 1.21 mL, 19.4 mmol) dropwise.The mixture was stirred at room temperature overnight.The mixture was poured into half saturated sodium bicarbonate and extracted with ethyl acetate three times.The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown oil.This residue was purified by flash column chromatography (12-100percent ethyl acetate/heptanes) to afford methyl 1H-indazole-6-carboxylate as a yellow solid (2.95 g, 90percent).1H NMR (400 MHz, CDCl3, delta): 10.40 (br. s., 1H), 8.26 (s, 1H), 8.13 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 3.96 (s, 3H).
  • 21
  • [ 704-91-6 ]
  • [ 885518-82-1 ]
  • 22
  • [ 704-91-6 ]
  • [ 1374258-29-3 ]
  • 23
  • [ 704-91-6 ]
  • [ 1374258-28-2 ]
  • 24
  • [ 704-91-6 ]
  • [ 1386457-24-4 ]
  • 25
  • [ 704-91-6 ]
  • [ 1386457-25-5 ]
  • 26
  • [ 704-91-6 ]
  • [ 1386457-26-6 ]
  • 27
  • [ 704-91-6 ]
  • [ 1403746-44-0 ]
  • 28
  • 5-(3-aminopyrrolidin-1-yl)-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine hydrochloride [ No CAS ]
  • [ 704-91-6 ]
  • [ 1401461-15-1 ]
YieldReaction ConditionsOperation in experiment
With 1-methyl-1H-imidazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 16h; Example 11 N-(1-(7-(3,4-Dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-yl)-1H-indazole-6-carboxamide Procedure:A mixture of 5-(3-aminopyrrolidin-1-yl)-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine hydrochloride (100 mg, 0.245 mmol), <strong>[704-91-6]1H-<strong>[704-91-6]indazole-6-carboxylic acid</strong></strong> (40 mg, 0.245 mmol), EDCI (97 mg, 0.49 mmol) and N-methylimidazole (60 mg, 0.735 mmol) in 10 mL of DCM was stirred at room temperature for 16 hours. The mixture was washed with water (5 mL), The organic layer was dried over Na2SO4. After filtration and concentration, the residue was purified by preparative HPLC (Gemini 5u C18 150.x.21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 25percent acetonitrile/75percent water (0.1percent TFA V/V) initially, and then proceed to 50percent acetonitrile/50percent water (0.1percent TFA V/V) in a linear fashion after just 9 min.) to give N-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-yl)-1H-indazole-6-carboxamide (45 mg, 36percent) as white solid. 1H NMR (300 MHz, DMSO): delta 9.69 (s, 1H), 8.84 (s, 1H), 8.74 (d, 1H, J=6.3 Hz), 8.14 (s, 1H), 8.06 (s, 1H), 7.89 (s, 1H), 7.81 (d, 1H, J=8.4 Hz), 7.63-7.44 (m, 2H), 6.92 (d, 1H, J=9.0 Hz), 4.62-4.25 (m, 2H), 3.96-3.66 (m, 10H), 2.35-2.11 (m, 3H). LC-MS: 516.9 [M+H]+, tR=1.38 min. HPLC: 100percent at 214 nm, 100percent at 254 nm, tR=5.76 min.
  • 29
  • [ 1401461-88-8 ]
  • [ 704-91-6 ]
  • [ 1401461-15-1 ]
YieldReaction ConditionsOperation in experiment
36% With 1-methyl-1H-imidazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 16h; A mixture of 5-(3-aminopyrrolidin-l-yl)-N-(3,4-dimethoxyphenyl)thiazolo[5,4- <i]pyrimidin-7-amine hydrochloride (100 mg, 0.245 mmol), lH-<strong>[704-91-6]indazole-6-carboxylic acid</strong> (40 mg, 0.245 mmol), EDCI (97 mg, 0.49 mmol) and N-methylimidazole (60 mg, 0.735 mmol) in 10 mL of DCM was stirred at room temperature for 16 hours. The mixture was washed with water (5 mL), The organic layer was dried over Na2S04. After filtration and concentration, the residue was purified by preparative HPLC (Gemini 5u C18 150 x 21.2 mm; inject volume: 3ml/inj, flow rate: 20ml/min; wavelength: 214nm and 254 nm; the gradient conditions are: 25percent acetonitrile/75percent water (0.1percentTFA V/V) initially, and then proceed to 50percent acetonitrile/50percent water (0.1percentTFA V/V) in a linear fashion after just 9 min.) to give N-(l-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-<JJpyrimidin-5- yl)pyrrolidin-3-yl)- lH-indazole-6-carboxamide (45 mg, 36 percent) as white solid. 1H NMR (300 MHz, DMSO): delta 9.69 (s, 1H), 8.84 (s, 1H), 8.74 (d, 1H, J = 6.3 Hz), 8.14 (s, 1H), 8.06 (s, 1H), 7.89 (s, 1H), 7.81 (d, 1H, = 8.4 Hz), 7.63 - 7.44 (m, 2H), 6.92 (d, 1H, = 9.0 Hz), 4.62 - 4.25 (m, 2H) , 3.96 - 3.66 (m, 10H), 2.35 - 2.11 (m, 3H). LC - MS: 516.9 [M + H]+, tR = 1.38 min. HPLC: 100 percent at 214 nm, 100 percent at 254nm, tR = 5.76 min.
  • 30
  • [ 5402-60-8 ]
  • [ 704-91-6 ]
  • 2,6-dimethylbenzyl 3-chloro-1-(2,6-dimethylbenzyl)-1H-indazole-6-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
195 mg To a solution of <strong>[704-91-6]1H-<strong>[704-91-6]indazole-6-carboxylic acid</strong></strong> (343 mg) in acetonitrile (10 mL) was addedN-chlorosuccinimide (313 mg), and the reaction mixture was stirred at 60°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and then acetone (10 mL), potassium carbonate (883 mg) and 2,6-dimethylbenzyl chloride (724 mg) were added and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was quenched with water, and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (195 mg) as a white solid. 1H-NMR (400 MHz, CDCl3) delta: 7.79 (1H, d, J = 8.8 Hz), 7.65 (2H, d, J = 8.1 Hz) 7.26-7.23 (1H, m), 7.14 (2H, d, J = 7.6 Hz), 7.06-7.02 (1H, m), 6.92 (2H, d, J = 7.6 Hz), 5.54 (2H, s), 5.40 (2H, s), 2.42 (6H, s), 2.25 (6H, s).
  • 31
  • tert-butyl (1R,5S)-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate [ No CAS ]
  • [ 704-91-6 ]
  • C20H26N4O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 12h; General procedure: The appropriate carboxylic acid (1 mmol) and N-tboc-bispidine 13 (248 mg, 1.1 mmol) were dissolved in dry CH2Cl2 (5 mL) and cooled to 0 °C. DMAP (6.1 mg, 0.05 mmol) and DCC (206 mg, 1 mmol) were added and the mixture was allowed to warm up and stir at rt. The precipitate was filtered off after 12 h and washed with cold CH2Cl2 (2 mL). The solvent of the filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography (silica gel, mixtures of CH2Cl2 and MeOH?40:1. 20:1 or 9:1).
  • 32
  • [ 704-91-6 ]
  • N-methyl-3-(3-sulfamoylphenyl)-1H-indazole-6-carboxamide [ No CAS ]
  • 33
  • [ 704-91-6 ]
  • [ 906000-50-8 ]
  • 34
  • [ 704-91-6 ]
  • [ 95-76-1 ]
  • N-(3,4-dichlorophenyl)-1H-indazole-6-carboxamide [ No CAS ]
  • 35
  • [ 704-91-6 ]
  • [ 626-43-7 ]
  • N-(3,5-dichlorophenyl)-1H-indazole-6-carboxamide [ No CAS ]
 

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