Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:6]2[O:10][B:9]([OH:11])[C:8]3[CH:12]=[C:13]([NH:16][C:17](=[O:28])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:29]C(F)(F)C1C=C(F)C=CC=1C(Cl)=O>>[CH:1]1([CH:6]2[O:10][B:9]([OH:11])[C:8]3[CH:12]=[C:13]([NH:16][C:17](=[O:28])[C:18]4[CH:23]=[CH:22][C:21]([F:29])=[CH:20][C:19]=4[C:24]([F:27])([F:25])[F:26])[CH:14]=[CH:15][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Nc1ccc2c(c1)B(O)OC2C1CCCC1)c1ccccc1C(F)(F)F
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Product: O=C(Nc1ccc2c(c1)B(O)OC2C1CCCC1)c1ccc(F)cc1C(F)(F)F

Procedure:
The title compound was prepared using a procedure similar to that of N-(3-cyclopentyl-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-trifluoromethyl-benzamide with 2-trifluoromethyl-4-fluorobenzoyl chloride replacing 2-trifluoromethylbenzoyl chloride. Data: LCMS (M/Z): 430 (M+23); 1H NMR (acetone) δ: 9.64 (br. s., 1H), 8.14 (d, J=1.9 Hz, 1H), 7.83 (dd, J=8.5, 5.4 Hz, 1H), 7.71 (dd, J=8.2, 2.0 Hz, 1H), 7.50-7.64 (m, 2H), 7.39 (d, J=8.2 Hz, 1H), 5.13 (d, J=4.8 Hz, 1H), 2.25-2.37 (m, J=8.2, 8.2, 8.2, 8.2, 4.8 Hz, 1H), 1.82-1.92 (m, 1H), 1.62-1.74 (m, 2H), 1.44-1.59 (m, 3H), 1.30-1.40 (m, 1H), 1.10-1.19 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-])=O)[CH:32]=5)=[CH:22][CH:21]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1>CCOC(C)=O.CCO.O=[Pt]=O>[NH2:37][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][O:29][CH2:28][CH2:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][CH2:18][N:14]2[CH2:13][C@@H:12]([C:10]3[CH:9]=[CH:8][C:6]4[O:7][C:2]([CH3:40])([CH3:1])[O:3][CH2:4][C:5]=4[CH:11]=3)[O:16][C:15]2=[O:17])=[CH:25][CH:24]=1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc([N+](=O)[O-])c5)cc4)C(=O)O3)ccc2O1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(N)c5)cc4)C(=O)O3)ccc2O1
Reaction time: 3 h
Yield: 86.2 %

Procedure:
(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[2-(4-{2-[(3-nitrobenzyl)oxy]ethoxy}phenyl)ethyl]-1,3-oxazolidin-2-one (1.22 g) in EtOAc (20 mL) and EtOH (15 mL) was hydrogenated over PtO2 (122 mg) at room temperature and atmospheric pressure for 3 h. The catalyst was then removed by filtration over Celite, washed with EtOAc and concentrated in vacuo to give the title compound (994 mg). LCMS RT=3.23 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4](Cl)[C:3]=1[Cl:11].O>[Cl-].C[N+](C)(C)C.CC(C)P([O-])(=O)[O-].[Zn]>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]([Cl:11])=[C:2]([Cl:1])[N:7]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: CC(C)P(=O)([O-])[O-]
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: O
Product: Clc1cc(Cl)c(Cl)nc1Cl
Temperature: 160 °C
Reaction time: 0.33 h
Yield: 83.9 %

Procedure:
A suspension of 8.22 g (0.075 mol) of tetramethylammonium chloride in 90 ml of dimethylmethanephosphonate is heated for 1 hour at 160° C. It is then cooled to 90° C., and 12.57 g (0.05 mol) of pentachloropyridine and 3 ml of water are added. There is subsequently added portionwise, in the course of 30 minutes, 4.1 g (0.063 gram atom) of zinc dust. After completion of the addition of the zinc dust, the mixture is firstly stirred for 20 minutes and then filtered. The filtrate is poured into a solution of 12.5 ml of concentrated hydrochloric acid in 500 ml of water, and stirring is maintained for 2 hours. After filtration, the filter residue is washed with water and dried to yield 9.1 g (83.9% of theory) of crude 2,3,5,6-tetrachloropyridine which has a melting point of 88° to 89° C. and which contains, according to gas-chromatographical analysis, 91.25% of 2,3,5,6-tetrachloropyridine, 2.66% of 2,3,5-trichloropyridine, 2.59% of 2,3,6-trichloropyridine and 0.5% of pentachloropyridine.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Br.[H-].[Na+]>CN(C)C=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:17]2[CH2:18][O:19]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCCCc1ccccc1
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CCCCCCCOCC2CO2)cc1

Procedure:
A procedure similar to that described in Preparation 46 was repeated, except that 2 g of 7-phenylheptyl alcohol, 1.7 ml of epibromohydrin, 0.44 g of sodium hydride (as a 55% by weight dispersion in mineral oil) and 50 ml of anhydrous dimethylformamide were used, to give 1.15 g of the title compound having an Rf value of 0.49 (on silica gel thin layer chromatography, using a 1:6 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: O.[OH-].[Li+].O.C[O:6][C:7]([C:9]1[CH:13]=[CH:12][N:11]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[N:19]3)[CH:10]=1)=[O:8]>O1CCCC1>[C:7]([C:9]1[CH:13]=[CH:12][N:11]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[N:19]3)[CH:10]=1)([OH:8])=[O:6]
Reactant: COC(=O)c1ccn(-c2cccc3ncccc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccn(-c2cccc3ncccc23)c1
Reaction time: 15 h
Yield: 89 %

Procedure:
0.36 g (8.58 mmol) of lithium hydroxide monohydrate and 20 mL of water are added to a solution at a temperature in the region of 22° C. of 0.5 g (1.98 mmol) of 3-methoxycarbonyl-1-(quinol-5-yl)-1H-pyrrole in 20 mL of tetrahydrofuran. After stirring at the reflux point of the solvent for 15 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is taken up in water. The resulting solution is adjusted to pH 7 using N hydrochloric acid and then it is extracted with ethyl acetate. The organic phase is washed with a saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 0.42 g of 3-carboxy-1-(quinol-5-yl)-1H-pyrrole is thus obtained in the form of a white solid. IR spectrum (KBr): 3423, 3105, 1665, 1536, 1275, 1188, 1107, 965 and 796 cm−1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[CH2:12]1[N:17]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=2[NH2:28])[CH2:16][CH2:15][O:14][CH2:13]1.P(Cl)(Cl)Cl.Cl>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1.[Cl-].[Na+].O.C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:28][C:19]1[CH:20]=[C:21]([C:24]([F:25])([F:26])[F:27])[CH:22]=[CH:23][C:18]=1[N:17]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:7]
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCOCC1
Reactant: Cc1ccc(C(=O)O)cc1O
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2cc(C(F)(F)F)ccc2N2CCOCC2)cc1O
Temperature: 130 °C
Reaction time: 0.75 h

Procedure:
3-Hydroxy-4-methylbenzoic acid (530 mg, 3.5 mmol), 3-amino-4-(4-morpholino)benzotrifluoride (890 mg, 3.6 mmol), and DMAP (150 mg, 1.3 mmol) were suspended in 20 mL dry toluene in a 2-neck flask with an attached Dean-Stark trap under N2. The mixture was stirred in a 130° C. oil bath and brought to a boil before PCl3 (0.18 mL, 2 mmol) was added dropwise by glass/Teflon syringe over 15 minutes. Heating was continued an additional 45 minutes. After cooling, the mixture was diluted with brine and ethyl acetate, and acidified with 1 N HCl. After extraction, the organic layer was dried with Na2SO4, concentrated, and purified by flash chromatography (2% MeOH in CH2Cl2). The isolated material was packed into a small filtration apparatus and rinsed with a small amount of CH2Cl2 to provide the title compound as a white solid. 1H NMR (Varian, 400 MHz, DMSO-d6) d: 9.83 (s, 1H), 9.50 (s, 1H), 8.45 (s, 1H), 7.48 (m, 1H), 7.43 (m, 1H), 7.34 (s, 1H), 7.31 (m, 1H), 7.25 (m, 1H), 3.78 (m, 4H), 2.90 (m, 4H), 2.18 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1>[CH3:13][S:14]([O:9][CH2:8][CH2:7][N:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=[C:2]1[CH3:1])(=[O:16])=[O:15]
Reactant: Cc1ncc([N+](=O)[O-])n1CCO
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1ncc([N+](=O)[O-])n1CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.9 %

Procedure:
Metronidazole (5.0 g, 29.2 mmol) was dissolved in pyridine (10 ml), and a pyridine solution (10 ml) of methanesulfonyl chloride (3.5 g, 30.7 mmol) was added dropwise to the solution. After the mixture was stirred at room temperature for 5 hours, the solvent was distilled off under reduced pressure, and the residue was washed with water-ethanol and dried to obtain 6.4 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C([Mg]Cl)(C)C.[F:14][C:15]([F:23])([F:22])[C:16]([C:18]([F:21])([F:20])[F:19])=[O:17]>C1COCC1>[Br:8][C:6]1[CH:7]=[C:2]([C:16]([OH:17])([C:18]([F:21])([F:20])[F:19])[C:15]([F:23])([F:22])[F:14])[CH:3]=[N:4][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC(c1cncc(Br)c1)(C(F)(F)F)C(F)(F)F
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3,5-dibromo pyridine 257 (1.09 g, 4.60 mmol) in dry THF cooled to 0° C., was added isopropyl magnesium chloride (2.4 mL, 4.8 mmol) drop wise while stirring for 10 min. Hexafluoroacetone (CF3—CO—CF3) 244 was added to the resulting reaction and continued stirring for another 2 h. After completion of the starting materials, the reaction was quenched with saturated ammonium chloride solution. The organic layer was separated and aqueous phase was extracted again with diethyl ether, the combined organic layer was dried over sodium sulphate and concentrated to get the crude 2-(5-bromopyridin-3-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol 258. The crude was purified through silica gel by using 100-200 mesh silica gel by eluting the compound at 20:5 ethyl acetate in hexane as thick oil of compound 258.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C:13](=[O:14])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:22]([Mg]Br)[CH:23]=[CH2:24]>C1COCC1>[OH:14][C@@:13]1([CH2:24][CH:23]=[CH2:22])[C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1
Reactant: C=CC[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CC(=O)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Solvent: C1CCOC1
Product: C=CC[C@@]1(O)CN(C(=O)OC(C)(C)C)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of tert-butyl (3S)-3-(tert-butyldimethylsilyl)oxy-4-oxopyrrolidine-1-carboxylate (1.2 g) in THF (5 mL) was added dropwise a 1M solution of allylmagnesium bromide in THF (3.8 mL), and the mixture was stirred for 30 min at 0° C. The reaction was quenched with saturated aqueous NH4Cl (5 mL) and the mixture was extracted with Et2O. The extract was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified with silica gel column chromatography (eluent: hexane/EtOAc=1/0˜50/50) to give tert-butyl (3R,4S)-3-hydroxy-4-(tert-butyldimethylsilyl)oxy-3-(prop-2-en-1-yl)pyrrolidine-1-carboxylate as a pale yellow foam.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.O>N1C=CC=CC=1.[O-2].[O-2].[O-2].[Cr+6]>[CH3:9][C:6]1[N:7]=[CH:8][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=1
Reactant: Cc1ccc(CO)cn1
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(C=O)cn1
Yield: 42.7 %

Procedure:
Chromium trioxide (11.5 g) is slowly added to 170 ml of pyridine at 20° C., and 10 g of the crude 5-hydroxymethyl-2-methylpyridine in 70 ml of pyridine is added in one portion to the complex. The temperature is raised to reflux temperature for 2 hours, and the mixture is refluxed for 1.5 hours. After cooling, 250 ml of water is added, and the mixture is extracted with five 150-ml portions of diethyl ether. The combined extracts are dried over magnesium sulfate and concentrated to give 4.2 g of crude 6-methyl-3-pyridinecarbaldehyde.
Reaction SMILES: C(OC([C:6]1[N:7]([CH2:19][CH:20]([NH:22][C:23]([O:25]C(C)(C)C)=O)[CH3:21])[N:8]=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1)=O)C.C([O-])([O-])=O.[Na+].[Na+]>Cl.O1CCOCC1.C(Cl)Cl>[CH3:21][CH:20]1[CH2:19][N:7]2[N:8]=[C:9]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=[C:6]2[C:23](=[O:25])[NH:22]1
Reactant: CCOC(=O)c1cc(COc2ccccc2)nn1CC(C)NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1Cn2nc(COc3ccccc3)cc2C(=O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.8 %

Procedure:
Rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (5.58 g, 5.53 mmol, 40% pure) was dissolved in a 4N solution of HCl in 1,4-dioxane (40 mL) under N2 at 0° C. The mixture was stirred at room temperature for 3 hours. The mixture was basified with a saturated solution of Na2CO3 and the mixture stirred at room temperature for 3 days. Then the mixture was diluted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 70/30). The desired fractions were collected and the solvents evaporated in vacuo to yield rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (1.52 g, 91% yield) as a white solid.
Reaction SMILES: [N+:1]([O-:4])([O-:3])=[O:2].[N+:5]([O-:8])([OH:7])=[O:6].[Cu:9]>>[N+:1]([O-:4])([O-:3])=[O:2].[Cu+2:9].[N+:5]([O-:8])([O-:7])=[O:6]
Reactant: [Cu]
Reactant: O=[N+]([O-])O
Agent: O=[N+]([O-])[O-]
Product: [Cu+2]

Procedure:
Preparing nitrate solution 100 may further comprise adding nitric acid solution to the at least one metal slurry 103. In applications, the nitric acid solution is added, with mechanical stirring, to the metal slurry or slurries drop wise. In embodiments, a portion of nitric acid solution is first combined with copper powder to dissolve the copper and form copper nitrate solution, the resultant copper nitrate solution is added dropwise to the iron powder/water slurry, and a second portion of nitric acid solution is added. The addition of nitric acid to metal slurry(ies) is slow. In applications, the nitric acid solution is added to the metal slurry(ies) at a rate of less than or in the range of from about 15 mL/min to about 20 mL/min. In this manner, the reaction temperature may be controlled to a temperature in the range of from about 30° C. to about 32° C. Desirably, the temperature does not fall below 30° C. and does not exceed 32° C. The dissolution reaction is exothermic and the nitric acid addition can be controlled based on reaction temperature. With intermittent cooling, when ˜80% of the nitric acid is added a dark green solution is formed. The combined nitric acid/metal slurry may be allowed to stir for a time. The combined nitric acid/metal slurry may be subjected to stirring (e.g. high speed stirring) for about 15 minutes with no heating.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH:8]=[CH:9][C:10]2[C:11]3[C:16]([N:17]=[C:18]4[C:23]=2[CH:22]=[CH:21][CH:20]=[CH:19]4)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:6][CH:5]=1)([O-])=O.[Sn](Cl)Cl>C(OCC)(=O)C.C(O)C>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([CH:8]=[CH:9][C:10]2[C:23]3[C:18]([N:17]=[C:16]4[C:11]=2[CH:12]=[CH:13][CH:14]=[CH:15]4)=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2c3ccccc3nc3ccccc23)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(C=Cc2c3ccccc3nc3ccccc23)cc1
Reaction time: 5 h

Procedure:
The 9-(4-nitrostyryl)acridine product (2.86 g, 10.0 mmol) is dissolved in ethyl acetate (250 ml) and then brought to reflux. A solution of tin(II) chloride dehydrate (9.0 g, 40 mmol) in hot ethanol (150 ml) is cooled and added to the solution of 9-(4-nitrostyryl)acridine. The mixture is reacted under reflux and with stirring for 5 hours. After cooling, the 9-(4-aminostyryl)acridine precipitates and is isolated by filtration under vacuum. The filtrate is dried by evaporation and taken up in water (500 ml) with stirring. The solution is basified (pH 13–14) with a sodium hydroxide solution. The 9-(4-aminostyryl)acridine fraction previously isolated, which contains a high proportion of tin salt, is also basified. The 9-(4-aminostyryl)acridine is separated by filtration, washed with water and dried. It is sufficiently pure for the following step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[C:22]([Cl:24])[C:21]([N+:25]([O-])=O)=[CH:20][C:19]=4[F:28])=[C:11]3[C:10]([CH3:29])=[N:9]2)=[CH:5][CH:4]=1>CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[C:19]([F:28])=[CH:20][C:21]([NH2:25])=[C:22]([Cl:24])[CH:23]=4)=[C:11]3[C:10]([CH3:29])=[N:9]2)=[CH:30][CH:31]=1
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4cc(Cl)c([N+](=O)[O-])cc4F)ccnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nc(C)c3c(Oc4cc(Cl)c(N)cc4F)ccnc32)cc1
Yield: 84.3 %

Procedure:
Prepared by process from Example 92, Step B, substituting 1-(4-methoxybenzyl)-4-(5-chloro-2-fluoro-4-nitrophenoxy)-3-methyl-1H-pyrazolo[3,4-b]pyridine (1.59 g, 3.59 mmol). The reaction mixture was diluted with EtOAc (250 mL) and saturated Na2CO3 (50 mL) was added. The solids were filtered through a celite plug and the organic layer was dried over sodium sulfate and concentrated to provide the desired product (1.25 g, 85%). The crude material was used in the next step without purification. LRMS M+1 (413.0) observed.
Reaction SMILES: CN(C)CCN(C)C.C([Li])(CC)C.[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[F:24])[C:18]([OH:20])=[O:19].[Cl:25]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1.C(OCC)C.O>[Cl:25][C:16]1[C:15]([F:14])=[C:23]([F:24])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)c1ccc(F)c(F)c1Cl
Temperature: -10 °C
Reaction time: 1 h
Yield: 36.1 %

Procedure:
A solution of N,N,N′,N′-tetramethylethylenediamine (39.6 ml, 264 mmol) in tetrahydrofuran (170 ml) was cooled under argon to −70° C. before the addition of sec-butyl lithium (205 ml, 288 mmol). To the mixture 3,4-difluorobenzoic acid (19 g, 120 mmol) was then added as a solution in tetrahydrofuran (80 ml) over a period of 40 minutes ensuring that the temperature of the mixture did not rise above −60° C. The mixture was then stirred at a temperature of −68° C. to −70° C. for 1 hr before adding a solution of hexachloroethane (100 g, 422 mmol) in tetrahydrofuran (170 ml) over a period of 35 minutes whilst keeping the temperature of the mixture below −60° C. The mixture was stirred at a temperature of −65° C. to −70° C. for 2 hrs. The mixture was allowed to warm to −10° C. and then water (500 ml) was added to quench the reaction. The mixture was diluted with diethyl ether (250 ml) and the two resulting layers were separated. The aqueous layer was acidified to pH1 using concentrated aqueous hydrogen chloride and then extracted with 2×500 ml aliquots of diethyl ether. The combined organic extracts were passed through a hydrophobic frit and reduced in vacuo to give a yellow solid. This was recrystallised from ethyl acetate to give two crops (8.35 g and 4.47 g) of pure 2-chloro-3,4-difluorobenzoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].Br[CH2:27][CH2:28][CH2:29][Cl:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:30][CH2:29][CH2:28][CH2:27][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: COc1ccc(Oc2ccnc3cc(O)c(OC)cc23)c(C(C)=O)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2ccnc3cc(OCCCCl)c(OC)cc23)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
1-{2-[(7-Hydroxy-6-methoxy-4-quinolyl)oxy]-5-methoxyphenyl}-1-ethanone (100 mg), 1-bromo-3-chloropropane (138 mg), and potassium carbonate (204 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (123 mg, yield 34%).
Reaction SMILES: [C:1](O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[NH:33][C:32]3[CH:34]=[CH:35][C:36]([C:38]([NH2:40])=[O:39])=[CH:37][C:31]=3[N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:1]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[CH2:20][CH2:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[NH:33][C:32]3[CH:34]=[CH:35][C:36]([C:38]([NH2:40])=[O:39])=[CH:37][C:31]=3[N:30]=2)=[CH:27][CH:28]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc2[nH]c(-c3ccc(OCCC4CCCCN4)cc3)nc2c1
Reactant: O=C(O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: NC(=O)c1ccc2[nH]c(-c3ccc(OCCC4CCCCN4C(=O)c4ccccc4)cc3)nc2c1
Reaction time: 18 h
Yield: 46.8 %

Procedure:
A solution of benzoic acid (75 mg, 0.62 mmol) and EDC (59 mg, 0.31 mmol) in DMF (1 mL) was stirred for 2 h and then was treated with 2-[4-(2-piperidin-2-yl-ethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide (75 mg, 0.21 mmol) and DMAP (65 mg, 0.53 mmol). The mixture was stirred for 18 h, and the crude material was purified by reverse phase HPLC (C18; H2O/CH3CN/0.01% TFA), providing 46 mg (66%) of the title compound. HPLC (Method C): Rt=5.15. MS (ESI+): mass calcd. for C28H28N4O3, 468.22; m/z found, 469.4 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.19 (s, 1H), 8.00-7.96 (m, 3H), 7.72 (d, J=8.6 Hz, 1H), 7.36-7.25 (m, 2H), 7.25-7.10 (m, 4H), 6.95-6.90 (m, 1H), 4.20-4.07 (m, 2H), 3.92-3.90 (m, 1H), 3.48-3.43 (m, 1H), 2.45-2.35 (m, 1H), 2.12-1.81 (m, 1H), 1.81-1.30 (m, 7H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].O>CC#N>[O:19]([CH2:18][CH2:17][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(C=O)cc1
Yield: 79.5 %

Procedure:
To a stirred suspension of 4-hydroxybenzaldehyde (0.500 g, 4.012 mmol) and anhydrous potassium carbonate (0.833 g, 6.019 mmol) in dry MeCN (15 ml) at room temperature was added 2-bromo-1-tert-butyldimethylsiloxyethane (83%, 1.730 g, 6.019 mmol), and the reaction mixture was heated under reflux for 20.5 h. Water (25 ml) was added and the reaction mixture was extracted with Et2O (4×25 ml). The combined organic extracts were washed with brine (50 ml), dried (Na2SO4), and the solvent was removed under reduced pressure to give a pale yellow oil that was purified by flash chromatography (3:1 Hexane/Et2O) to give the title compound (0.895 g, 79.5%) as a colourless oil.