Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.O>[Pd].CO>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Temperature: 30 °C
Reaction time: 0.25 h

Procedure:
A nitrogen-flushed, 2.5 L heavy-wall Parr bottle (pressure rated to 60 psi) is charged with 68 g (0.22 mol,) of tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate, (A2a), 6.8 g of 10% palladium on carbon, 50% water wet catalyst and 807 g (1020 mL) of methanol. The reaction vessel is inerted three times with nitrogen (ca. 30 psi), evacuating the atmosphere above the reaction mixture each time. The vessel is pressurized twice with hydrogen (ca. 30 psi), evacuating the atmosphere above the reaction mixture each time. The reaction vessel is pressurized to 45 psi with hydrogen. The shaker motor is started. The reaction is exothermic. A temperature rise from 19 to 54° C. over 15 min is observed after which time the hydrogen uptake stops. The mixture is allowed to cool to 30° C. over 1 h at which point the shaker is stopped. The hydrogen atmosphere is replaced with nitrogen as described above (Inert the reaction vessel). The catalyst is removed by filtration through a 10 g pad of filter cel. This entire process is repeated once more, both filtrates are combined and charged to a clean 3 L 4-neck round bottom flask.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O1CCCC1.[NH2:38][C:39]1[S:40][CH2:41][CH2:42][N:43]=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:38][C:39]3[S:40][CH2:41][CH2:42][N:43]=3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: NC1=NCCS1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)NC1=NCCS1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 9.3 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole), 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 3.5 hours with a stream of nitrogen bubbling through it. Solid 2-amino-2-thiazoline (2.67 g, 0.0261 mole) was added to the reaction mixture. The resulting suspension was allowed to stir at room temperature overnight. The solvent was evaporated under reduced pressure to give a white solid. The solid was triturated in water (200 ml), filtered, and the filter cake was rinsed twice more with water. The resulting solid was heated in boiling isopropyl alcohol to dissolve most of it, filtered while hot, and cooled to room temperature. A white precipitate formed. Water was added, and the white solid was filtered and rinsed once with isopropyl alcohol and twice with isopropyl ether. A 1.0-g sample of the resulting 3.3 g of white solid was dried at high vacuum to give 0.6 g (29%) of title compound, mp. 227°-229° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.Cl[CH2:10][CH:11]=O.C(=O)([O-])O.[Na+]>O.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:10]=[CH:11][N:8]=[C:4]2[CH:3]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Clc1ccn2ccnc2c1
Yield: 75 %

Procedure:
A stirred suspension of 4-chloropyridin-2-ylamine (6.20 g, 48.2 mmol), chloroacetaldehyde (11.4 g of a 50 wt % solution in water, 73 mmol) and sodium hydrogencarbonate (8.09 g, 96.4 mmol) in ethanol (70 ml) was heated under reflux for 6 h. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulphate and concentrated in vacuo to give an orange oil. This oil was purified by silica gel chromatography eluting with 50% ethyl acetate in isohexane to afford 7-chloroimidazo[1,2-α]pyridine (5.60 g, 75%) as a white crystalline solid. 1H NMR (400 MHz, CDCl3) δH 6.78 (1H, d, J 7), 7.56 (1H, s), 7.63 (2H, s), 8.05 (1H, d, J 7).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[CH3:15][C:16]1[O:22]C(C)(C)O[C:18](=[O:19])[CH:17]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[C:18]([O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14])(=[O:19])[CH2:17][C:16]([CH3:15])=[O:22]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: O=C1c2ccccc2C(=O)N1CCO
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OCCN1C(=O)c2ccccc2C1=O
Yield: 76.4 %

Procedure:
A solution of 10.0 g (52.3 mmol) of N-(2-hydroxyethyl)phthalimide, 8.84 ml (67.7 mmol) of 2,2,6-trimethyl-1,3-dioxen-4-one, and 10 mg of p toluenesulfonic acid in 50 ml of toluene is heated at reflux under N2 for 4 hr. The solvent is removed under vacuum and the dark-colored residue is flash chromatographed on silica gel (1:1 hexane-EtOAc). The resulting product is recrystallized from EtOAc to give 11.0 g of 2-phthalimidoethyl acetoacetate.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[N+:8]([C:7]1[C:2]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cccnc1Nc1ccccc1
Temperature: 25 °C

Procedure:
2-chloro-3-nitropyridine (structure 1 as shown in Scheme 1) was dissolved in THF (10 mL/mmol) in a round bottom flask. Aniline (1.0 eq.) (structure 2 as shown in Scheme 1) and diisopropylethylamine (1.05 eq.) were added. The reaction mixture was heated to the appropriate temperature for 4 to 36 hours. After cooling to room temperature the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (20 mL/mmol) and washed with water and brine (20 mL/mmol respectively). The organic phase was separated and dried over Na2SO4. After filtration the solvent was removed under reduced pressure. The crude product (red to brown solid) was solidified with hexane/ethyl acetate and collected by filtration. The product was carried on to the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)([CH3:17])[CH2:15][OH:16]
Reactant: CC(C)(C)OC(=O)N1CCN(C(C)(C)CO)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CO)N1CCNCC1
Reaction time: 3 h

Procedure:
To a solution of 4-(2-hydroxy-1,1-dimethylethyl)piperazine-1-carboxylic acid tert-butyl ester (110 mg, 0.43 mmol) in DCM (3 mL) was added TFA (1 mL) and the resulting mixture stirred for 3 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording the title compound as an off-white solid (62 mg, 91%). 1H NMR (CDCl3, 400 MHz): δ 3.32 (2 H, s), 2.90 (5 H, t, J=4.78 Hz), 2.38-2.13 (4 H, m), 1.03 (6 H, s)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][C:13](O)=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B#B.O>C1COCC1>[OH:14][CH2:13][CH2:12][CH:10]1[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)O)C1
Agent: B#B
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CCO)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
2-(1-(tert-Butoxycarbonyl)azetidin-3-yl)acetic acid (3.91 g) was dissolved in THF (18.17 ml) and cooled to 0° C. Diborane (1M in THF, 54.5 ml) was added dropwise and the reaction stirred for one hour. Water was added dropwise to quench unreacted borane and the mixture diluted with EtOAc (150 mL) and washed with water (100 mL). Organics were dried over sodium sulphate and solvent evaporated under reduced pressure to afford tert-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate (100% yield) as a clear oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][C:13](O)=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][CH2:13][OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)O)C1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CCO)C1
Temperature: 0 °C
Reaction time: 18 h
Yield: 96.5 %

Procedure:
A solution consisting of 3-carboxymethyl-azetidine-1-carboxylic acid tert-butyl ester (10.0 g, 46.5 mmol) and THF (15 mL) was cooled to 0° C. and treated with a 1 M solution of borane in THF (70 mL, 70 mmol), then slowly warmed to rt. After stirring for 18 h, the reaction mixture was quenched with 2 N NaOH (100 mL), diluted with H2O (100 mL), and extracted with Et2O (3×200 mL). The organic layers were combined, dried (MgSO4), and concentrated to give the title compound as a colorless oil (9.03 g, 97%). MS (ESI+): calcd. for C10H19NO3, 201.14. m/z found, 224.2 (M+Na)+. 1H NMR (d6-DMSO): 4.37 (t, J=5.1 Hz, 1H), 3.95-3.79 (m, 2H), 3.53-3.43 (m, 2H), 3.37 (dd, J=11.5, 6.2 Hz, 2H), 2.62-2.52 (m, 1H), 1.66 (dd, J=13.8, 6.4 Hz, 2H), 1.39-1.33 (m, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.N1C=CC=CC=1.[C:17](Cl)(=[O:19])[CH3:18]>O1CCCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:17](=[O:19])[CH3:18])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cn1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-5-nitropyridine (13.9 g, 100 mmol) and pyridine (24 ml, 300 mmol) in tetrahydrofuran (300 ml) was added dropwise acetyl chloride (10.7 ml, 150 mmol) with ice-cooling, the mixture was stirred at room temperature for 1 hour. To the mixture was added dropwise acetyl chloride (10.7 ml, 150 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice-water and the desired product (14.5 g, 80.1%) as a solid was collected by filtration.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)=[O:13])[CH3:10]>>[N:6]1[CH:7]=[CH:8][C:3]([C:18]2[CH:19]=[C:14]([CH:15]=[CH:16][CH:17]=2)[C:12]([O:11][CH2:9][CH3:10])=[O:13])=[CH:4][CH:5]=1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: Brc1ccncc1
Agent: Cl
Product: CCOC(=O)c1cccc(-c2ccncc2)c1
Yield: 92 %

Procedure:
Obtained in 92% yield by an analogous procedure to Example 605, starting from 4-bromopyridine hydrochloride and 3-(ethoxycarbonyl)phenylboronic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)CC)C>C1COCC1>[Si:10]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 3-hydroxybenzaldehyde (12.21 g, 100 mmol) in 600 mL THF was added tert-butyldimethylsilyl chloride (TBDMSCl, 18.84 g, 125 mmol). The solution was cooled to 0° C. and triethylamine (12.65 g, 17.4 mL, 125 mmol) was added dropwise. The reaction mixture was brought to room temperature and stirred 5 h. The mixture was filtered and the THF removed under reduced pressure. The oil was repeatedly dissolved in 200 mL portions of THF and evaporated, until no more triethylamine hydrochloride precipitated. The oil was then dissolved in 150 mL diethyl ether, filtered through a plug of neutral alumina and activated charcoal to remove the salt and the yellow color, and evaporated. The colorless, mobile oil was dried in vacuo overnight. Yield: 21.43 g (91%). IR: 1703, 1583, 1482, 1278, 1145, 840 cm-1. 1H NMR (CDCl3, TMS) δ 9.927 (s, 1H), 7.447 (d, J) 7.50 Hz, 1H), 7.379-7-335 (m, 2H), 7.096-7.074 (m, 1H), 0.994 (s, 9H), 0.215 (s, 6H). 13C NMR (CDCl3, TMS) δ 191.60, 156.34, 138.03, 130.03, 126.34, 123.46, 119.70, 25, 59, 18.12, −4.52. Anal. Calcd. for Cl3H20O2Si: C, 66.05; H, 8.53. Found: C, 66.13; H, 8.53.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:16](=[O:17])[CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([Mg]Br)[CH:26]=[CH2:27]>>[CH2:27]([C:16]1([OH:17])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:13][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1)[CH:26]=[CH2:25]
Reactant: C=CC[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CC(=O)[C@@H](NC(=O)OCc2ccccc2)C1
Product: C=CCC1(O)CN(C(=O)OC(C)(C)C)C[C@@H]1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 1.44 g of the ketone of step B in 20 mL of anhydrous T° F. cooled at 0° C. was added a solution of 6.2 mL of 1 M allyl magnesium bromide. The color turned dark right away. After being stirred at room temperature overnight, the reaction mixture was quenched with 50/50 mL of EtOAc/water. Water phase was extracted twice with EtOAc. The combined organic phase was dried over Na2SO4 and concentrated under vacuum. Column chromatography on silica gel using 3:1˜2:1 hexane/EtOAc as eluent provided 0.85 g of the title compound. MS (M+H)+ 377.
Reaction SMILES: [C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]\[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].II>C1COCC1>[C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[C:6]([OH:8])=[O:7]
Reactant: O=C(O)/C=C\C=C\C(=O)O
Agent: II
Solvent: C1CCOC1
Product: O=C(O)/C=C/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
cis,trans-Muconic acid (38.3 g, 269.7 mmol) is dissolved in THF (400 mL) at room temperature and a crystal of iodine (247 mg, 0.972 mmol) is added. The reaction mixture is allowed to stir at room temperature for 24 hours. The precipitate is obtained by filtration, washed with ice-cold tetrahydrofuran (2×) and dried under reduced pressure to yield 33.2 g (a 86 percent yield) of trans,trans-muconic acid. The reaction sequence is shown in FIG. 3.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH2:16][CH2:15]1.Cl>ClC(Cl)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCO2
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Product: O=C(O)CCC(=O)c1ccc2c(c1)CCO2
Temperature: 5 °C

Procedure:
A suspension, cooled to 0° C., of 120 g of 2,3-di-hydrobenzofuran and 128 g of aluminum chloride in 260 ml of dichloroethane is added to a mixture of 96 g of succinic anhydride and 260 g of aluminum chloride in 512 ml of dichloroethane. The temperature is maintained at approximately 5° C. The reaction medium, maintained for 2 hours at this temperature, is then poured into a solution of 3 liters of water containing 400 ml of concentrated hydrochloric acid. After separation following settling, and extraction with methylene chloride, the organic phase is exhaustively extracted with 1N sodium hydroxide. The combined basic phases are acidified in the cold with 6N hydrochloric acid and the oil formed is extracted with methylene chloride. The organic phase is washed to neutrality and then dried.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#N.CC(C[AlH]CC(C)C)C.C(O)(=[O:25])C.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:25]
Reactant: N#Cc1ccc(C(F)(F)F)nc1Cl
Reactant: CC(=O)O
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(C(F)(F)F)nc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 33.3 %

Procedure:
2-Chloro-6-(trifluoromethyl)nicotinonitrile (340 mg, 1.65 mmol) was diluted with toluene (2.0 mL), placed under nitrogen and cooled to −78° C. DIBAL-H (3292 μl, 3.29 mmol) was added dropwise and the reaction was stirred for 1 hour. The reaction was warmed to 0° C. and acetic acid (1 mL) was added followed by 5 mL of water. After stirring for 2 hours, the reaction was extracted twice with ethyl acetate, washed with Rochelle's salt, dried over MgSO4, filtered and concentrated. The material was loaded onto silica gel and eluted with 5% ethyl acetate/hexanes to 30% ethyl acetate/hexanes to yield the desired compound (115 mg, 0.549 mmol, 33.3% yield) as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[OH:55][CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>CN(C=O)C>[OH:55][CH:56]1[CH2:61][CH2:60][N:59]([C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:23][CH:22]=2)=[O:21])[CH2:58][CH2:57]1
Reactant: OC1CCNCC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCC(O)CC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (114 mg, 0.35 mmol), N,N-diisopropyl ethyl amine (275 μL, 1.6 mmol) and 4-hydroxypiperidine (1 M solution in MeOH, 354 μL, 0.35 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (93 mg, 73%) which was obtained as a white solid. MS: m/e=394.2 [M+H]+.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].I[CH:10]([CH3:12])[CH3:11].[OH-].[K+]>C(O)C.O>[CH:10]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)([CH3:12])[CH3:11]
Reactant: Oc1ccc(O)cc1
Reactant: CC(C)I
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Oc1ccc(O)cc1
Yield: 45.8 %

Procedure:
To a solution of hydroquinone (55.7 g, 0.5 mol) and 2-iodopropane (57.5 g, 0.33 mol) in ethanol was added a solution of potassium hydroxide (78.5 g, 0.5 mol) in water (100 mL). The dark brown solution was then refluxed for 16 hours. Ethanol was removed and the aqueous phase was acidified with 2N HCl and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to give over 70 g of crude material, which was triturated with dichloromethane and filtered. The filtrate was concentrated and purified on silica gel (5˜35% ethyl acetate/hexane) to give 23.0 g of product as a brown oil (46% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.30 (d, J=5.88 Hz, 6H) 4.30-4.50 (m, 1H) 4.78 (s, 1H) 6.66-6.86 (m, 4H). MS (ESI): m/z 151 (M−H). 1H NMR (300 MHz, CDCl3) δ ppm 8.31 (d, J=1.84 Hz, 1H) 7.99 (dd, J=8.46, 1.84 Hz, 1H) 7.77 (d, J=9.19 Hz, 1H) 7.20-7.34 (m, 2H) 6.89-7.01 (m, 2H) 4.48-4.62 (m, 1H) 2.65 (s, 3H) 1.37 (d, J=5.88 Hz, 6H). MS m/z (DCI) 405.1 (M+H)+.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[OH-].[Na+].[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Cl)=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH:4][CH2:3][CH2:1][OH:2])=[CH:10][CH:9]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: NCCO
Agent: [Na+]
Agent: [OH-]
Product: OCCNCc1ccc(Cl)cc1

Procedure:
Ethanolamine (56.9 g, 931 mmol) and sodium hydroxide (7.44 g, 186 mmol) were mixed in isopmpanol (50 ml) and 4-chlorobenzyl chloride (30 g, 186 mmol) was added at such a rate that a mild reflux was achieved. The mixture was then refluxed for another 30 min. Evaporation of the solvent was followed by the addition of methylene chloride (50 ml). The solids were filtered off and the solvent was evaporated from the filtrate. The residual oil was distilled under oil pump vacuum and the fraction at 125-126° C. (0.1 mm Hg) was collected. Yield 27 g, 78%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:13]O.S(=O)(=O)(O)O>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[C:9]([O:11][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)C(O)c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)C(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A mixture of 20 g (87 mmol) of (±)-4-bromo-α-hydroxyphenylacetic acid, 200 ml of methanol and 2 ml of concentrated sulfuric acid was stirred for 3 hours at room temperature. To the mixture 50 ml of water was added. After the solution was extracted with ethyl acetate, the organic extract was washed with a saturated aqueous solution of sodium bicarbonate and then with water, and it was dried on anhydrous magnesium sulfate. After removing the solvent, the residue was purified by chromatography (elution with toluene:ethyl acetate (2:1)), and 19.5 g of (±)-methyl 4-bromo-α-hydroxyphenylacetate was obtained (yield: 92%).
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[C:4]([F:12])[CH:3]=1.Cl[Sn]Cl.C(O)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[NH2:9][C:6]1[CH:5]=[C:4]([F:12])[CH:3]=[C:2]([Br:1])[C:7]=1[NH2:8]
Reactant: Nc1c(Br)cc(F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cc(F)cc(Br)c1N
Temperature: 25 °C

Procedure:
1,2-Diamino-3-bromo-5-fluorobenzene was prepared using an adaptation of the method of Bellamy et al., Tetrahedron Lett. 25:839 (1984). A mixture of 6-bromo-4-fluoro-2-nitroaniline (673 mg, 2.87 mmol) and SnCl2 2H2O (3.23 g, 14.3 mmol) dissolved in 6 mL ethyl acetate and 3 mL absolute ethanol was heated at 70° C. for 30 min. All the starting material had reacted as evidenced by TLC (silica gel, 2:1 hexanes:ethyl acetate). The reaction was allowed to cool to room temperature and poured into 20 mL crushed ice. Sufficient solid NaHCO3 was added to bring the pH to 7.5. The reaction mixture was then extracted with 3×20 mL ethyl acetate and the combined organic phases washed with sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a dark brown liquid 510 mg (86.7%). 1H NMR (CDCl3) δ3.64 (br s, 4H, 2(NH2)), 6.44 (dd, 1H, H5, J4-5 =2.7, JH-F =9.8), 6.72 (dd, 1H, H4, J4-5 =2.7, JH-F =8.4).