Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([CH:18]=[O:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:28])C(=O)OC(C)(C)C)[S:14]2)[C@@H:10]1[F:29])C1C=CC=CC=1.[CH3:30][Mg+].[Br-].B(Cl)(Cl)Cl>C1COCC1.C(Cl)Cl>[F:29][C@H:10]1[C@H:11]2[N:12]=[C:13]([NH:20][CH3:28])[S:14][C@H:15]2[O:16][C@H:17]([C@H:18]([OH:19])[CH3:30])[C@H:9]1[OH:8]
Reactant: C[Mg+]
Reactant: CN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@H](F)[C@H](OCc3ccccc3)[C@@H](C=O)O[C@@H]2S1
Agent: ClB(Cl)Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC1=N[C@@H]2[C@H](F)[C@H](O)[C@@H]([C@@H](C)O)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.8 %

Procedure:
To a solution of tert-butyl ((3aR,5S,6R,7S,7aR)-6-(benzyloxy)-7-fluoro-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.35 g, 0.83 mmol) in anhydrous THF (15 mL), at 0° C. and under N2, was added MeMgBr (1.4 M in THF/toluene, 3.0 mL, 4.2 mmol). After addition the mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated NaHCO3 aqueous solution (30 mL), and then extracted with EtOAc (30 mL) and DCM (3×30 mL). The combined extract was dried over anhydrous Na2SO4. After filtration the solvent was evaporated under reduced pressure, and the residue was dried under high vacuum. To the residue and PMB (0.50 g, 3.4 mmol) in dry DCM (8 mL) at −78° C. under N2, was added BCl3 (1.0 M in DCM, 3.0 mL, 3.0 mmol). The mixture was stirred for ˜3 h while the temperature of the cooling bath slowly warmed to room temperature. The reaction mixture was cooled at −78° C., quenched with mixed MeOH/DCM, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH/DCM, 1:10), affording (3aR,5R,6R,7S,7aR)-7-fluoro-5-((R)-1-hydroxyethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a white solid (0.039 g, 19%). 1H NMR (400 MHz, CD3OD) δ 6.40 (d, J=6.7 Hz, 1H), 4.78 (td, J=3.6, 49.3 Hz, 1H), 4.40 (ddd, J=3.6, 6.6, 18.0 Hz, 1H), 4.00-3.89 (m, 2H), 3.79 (dd, J=3.2, 8.0 Hz, 1H), 2.86 (s, 3H), 1.19 (d, J=6.6 Hz, 1H); 13C NMR (100 MHz, CD3OD) δ 165.99, 91.11 (d, J=5.31 Hz), 90.74 (d, J=184.1 Hz), 76.85 (q, J=3.7 Hz), 71.64 (d, J=16.4 Hz), 68.64, 68.22 (d, J=16.9 Hz), 30.55, 17.74; MS, (ES, m/z) [M+H]+ 251.1.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23](O)[CH:24]=2)[CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:23]1[CH:24]=[C:25]2[C:20]([CH:19]=[CH:18][CH:17]=[N:16]2)=[CH:21][CH:22]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc2cccnc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Oc1ccc2cccnc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
Trifluoromethanesulfonic anhydride (1.40 mL, 8.32 mmol) was added dropwise via a syringe to a solution of quinolin-7-ol (930 mg, 6.41 mmol), and pyridine (1.05 mL, 13.0 mmol) in anhydrous dichloromethane (50 mL) at 0° C. After addition the ice bath was removed and the reaction was allowed to warm to room temperature and stirred overnight. The reaction was concentrated and purified via flash chromatography using an Analogix SF25-40g column and eluant of ethyl acetate in heptane (0-40%) to afford the title compound as an orange-white solid (1.54 g, 86.7%). LC-MS m/z 278.4 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.42-7.57 (m, 2H) 7.95 (d, J=8.98 Hz, 1H) 8.05 (d, J=2.54 Hz, 1H) 8.20-8.29 (m, 1H) 8.97-9.06 (m, 1H).
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:21][F:22])[CH:8]=[C:7]([C:9](=[S:12])OC)[C:6]2[CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][C:5]=2[O:4]1.C1CC[N:31]2C(=[N:27][CH2:28][CH2:29][CH2:30]2)CC1.NCCC#N.C(OCC)(=O)C>O1CCCC1>[C:28]([CH2:29][CH2:30][NH:31][C:9]([C:7]1[C:6]2[CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][C:5]=2[O:4][C:3]([CH2:21][F:22])([CH2:2][F:1])[CH:8]=1)=[S:12])#[N:27]
Reactant: C1CCC2=NCCCN2CC1
Reactant: COC(=S)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Agent: N#CCCN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CCCNC(=S)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 1334.9 %

Procedure:
O-methyl 2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran-4-carbothioate (0.34 g) and DBU (10 mg) were dissolved in tetrahydrofuran (5 ml); to the solution, 3-aminopropionitrile (0.2 ml) was added at room temperature in a nitrogen atmosphere and the resulting mixture was stirred for 7 hours at room temperature. Ethyl acetate was added to the reaction mixture, which was washed with water, dilute HCl, aqueous sodium bicarbonate and a saturated aqueous solution of sodium chloride. The mixture was dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluent; methylene chloride) to give the titled compound (0.33 g), which was identical to the authentic sample.
Reaction SMILES: Cl.[N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]=1[CH2:11][CH2:12][C:13]([OH:15])=[O:14].[CH2:16](O)[CH3:17]>>[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCO
Reactant: O=C(O)CCc1nc2ccccc2[nH]1
Agent: Cl
Product: CCOC(=O)CCc1nc2ccccc2[nH]1

Procedure:
Hydrogen chloride gas is introduced into a suspension of 10 g (52.5 mmol) of 2-benzimidazole-propionic acid refluxing in 250 ml absolute ethanol over 1 hour. Then the mixture is concentrated by evaporation, the residue is dissolved in water and made alkaline with concentrated ammonia. Then it is extracted with ethyl acetate, the combined organic extracts are washed with water, dried and concentrated by evaporation.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[C:6]([CH:11]=1)[N:7]([CH3:10])[CH:8]=O.O.[OH-].[Na+]>C(O)(C)C>[F:1][C:2]1[CH:11]=[C:6]2[C:5]([C:12](=[O:18])[C:13]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][N:7]2[CH3:10])=[CH:4][CH:3]=1
Reactant: CN(C=O)c1cc(F)ccc1C(=O)CS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cn1cc(S(C)(=O)=O)c(=O)c2ccc(F)cc21

Procedure:
A mixture of 5'-fluoro-N-methyl-2'-methylsulphonylacetylformanilide (5.0 g), prepared in a similar manner to that described in Example 11, water (50 ml) and isopropyl alcohol (50 ml) was heated to 50°. Aqueous sodium hydroxide solution (1 M; 3 ml) was added and the mixture heated under reflux for 2.5 hours. The mixture was cooled in an ice bath and the product isolated by filtration, washed with water (10 ml), and then isopropyl alcohol (10 ml) to give the crude product (3.3 g). A sample of the crude product (2.0 g) was crystallised from industrial methylated spirit (112 ml) to give 7-fluoro-1-methyl-3-methylsulphonyl-4-quinolone, m.p 221.5°-223° (1.7 g). The product was heated at 90° with grinding to give 7-fluoro-1-methyl-3-methylsulphonyl-4-quinolone, m.p. 235°-236° (1.7 g).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5].[Cl:24][CH2:25][C:26](Cl)=O>C(O)(=O)C>[C:8]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:6]1[C:4](=[O:5])[C:3]2[C:2](=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:23])[N:1]=[C:26]1[CH2:25][Cl:24]
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc(Cl)c1C(=O)Nc1ccccc1-c1ccccc1
Solvent: CC(=O)O
Product: O=c1c2c(Cl)cccc2nc(CCl)n1-c1ccccc1-c1ccccc1
Yield: 60.9 %

Procedure:
Prepared according to Procedure B with 1i (2.0 g, 6.20 mmol) and chloroacetyl chloride (1.5 mL, 18.6 mmol) in acetic acid (30 mL). Purified by chromatography in CH2Cl21 followed by recrystallization from isopropanol to afford 1.44 g of an off-white solid (61%). 1H NMR (CDCl3) δ: 7.61-7.64 (m, 1H); 7.58-7.59 (m, 1H); 7.54-7.57 (m, 2H); 7.52-7.53 (m, 1H); 7.45-7.52 (m, 2H); 7.24 (s, 5H); 3.92-4.03 (m, 2H). MS (ES): m/z 381.0 (M+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1F>CN(C=O)C>[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1[N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: O=C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 90 °C
Yield: 46.6 %

Procedure:
To a stirred solution of 4-piperidinone (9.7 g, 63 mmol) and dry potassium carbonate (21.6 g, 157 mmol) in DMF (30 ml) was added 3,4-difluoro nitrobenzene (10 g, 63 mmol) and reaction mixture was heated to 90° C. for 3 h. The reaction mixture was poured into ice-water arid extracted with ethyl acetate (100 ml×2). Combined organic layer was washed with water followed by brine and dried over sodium sulfate. Evaporation of volatiles and purification of the resulting residue by silica gel column chromatography (ethyl acetate/pet. ether, 1:4) yielded the title compound (7 g, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:8][NH:9][C:10]2=O)=[CH:5][CH:4]=1.O.[OH-].[Na+].P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:8][N:9]=1
Reactant: COc1ccc2c(-c3ccccc3)n[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(-c3ccccc3)nnc(Cl)c2c1
Temperature: 80 °C

Procedure:
7-Methoxy-4-phenyl-2H-phthalazin-1-one (740 mg, 2.9 mmol) is dissolved in 7 mL of phosphoryl chloride. The solution is heated at 80° C. for 2 hours. The reaction medium is cooled to room temperature and then poured slowly into 200 mL of water with stirring. The mixture is then stirred at 5° C., basified with 35% sodium hydroxide solution and then extracted with dichloromethane. The organic phase is washed with water and then with brine and dried over anhydrous sodium sulfate. After filtration and evaporation under reduced pressure, 750 mg of product are obtained in the form of a beige-coloured powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[CH:6]=[C:5]([C:14]([O:16]C)=[O:15])[CH:4]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[CH:6]=[C:5]([C:14]([OH:16])=[O:15])[CH:4]=1
Reactant: COC(=O)c1cc2c(c(OC)c1)OC(C)(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)O)cc2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.2 %

Procedure:
To a solution of methyl 7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-carboxylate (40 g, 0.17 mol) in MeOH (200 mL) was added NaOH (34 g, 0.85 mol) in one portion. The mixture was stirred at room temperature for 24 h. TLC (EtOAc/petroleum ether=1/1) showed the reaction was complete. Then MeOH was removed under vacuum. The residue was dissolved in water (100 mL), and the solution was acidified with conc. HCl. The solid was filtered and the filter cake was dried in vacuo to give the title compound (25 g, 68%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.62 (s, 1H), 7.54 (s, 1H), 3.94 (s, 3H), 3.00 (s, 2H), 1.50 (s, 6H).
Reaction SMILES: [N+](=[CH2:3])=[N-].[O:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[N:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([C:21]([F:24])([F:23])[F:22])=[CH2:20])=[CH:16][CH:17]=2)[C:12]([C:25]2[N:30]=[C:29]([O:31][C@H:32]3[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37][CH2:36][C:33]43[CH2:35][CH2:34]4)[CH:28]=[N:27][CH:26]=2)=[N:11]1.CC(O)=O>C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[N:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]3([C:21]([F:24])([F:22])[F:23])[CH2:3][CH2:20]3)=[CH:16][CH:17]=2)[C:12]([C:25]2[N:30]=[C:29]([O:31][C@H:32]3[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37][CH2:36][C:33]43[CH2:35][CH2:34]4)[CH:28]=[N:27][CH:26]=2)=[N:11]1
Reactant: C=[N+]=[N-]
Reactant: C=C(c1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C1CCCCO1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(C5(C(F)(F)F)CC5)cc34)n2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
Diazomethane (˜0.25M in Et2O (prepared according to Aldrich Technical Bulletin AL-180, Aldrich, St. Louis, Mo.); 1.0 mL, 0.250 mmol) was added (dropwise) to a solution of (4R)-tert-butyl 4-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(3,3,3-trifluoroprop-1-en-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (41.8 mg, 0.070 mmol) and palladium(II) acetate (1.565 mg, 6.97 μmol) in DCM (1.0 mL) at 0° C., and the resulting solution was stirred at 0° C. for 30 min. Additional diazomethane (˜0.25M in Et2O; 2.0 mL, 0.500 mmol) was added, and the resulting solution was stirred at 0° C. for 30 min. Additional palladium(II) acetate (4.54 mg, 0.020 mmol) and diazomethane (˜0.25M in Et2O; 2×2.0 mL, 2×0.500 mmol) were sequentially added, and the reaction was stirred at 0° C. for 5 min. Additional diazomethane (˜0.25M in Et2O; 2.0 mL, 0.500 mmol) was added, the reaction was stirred at 0° C. for 5 min. HOAc (0.160 mL, 2.79 mmol) was added to quench excess diazomethane, and the resulting mixture was stirred at 25° C. for 12 h. The mixture was concentrated onto silica gel and chromatographically purified (ISCO, 12 g silica gel column, 0-60% EtOAc/hexanes, 15 min, 254 nm) to provide (4R)-tert-butyl 4-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(1-(trifluoromethyl)cyclopropyl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (25.2 mg, 0.041 mmol, 59% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ ppm 9.03 (1 H, s), 8.52 (1 H, s), 8.21 (1 H, br. s.), 7.63 (1 H, s), 7.53 (1 H, d, J=8.8 Hz), 5.80 (1 H, d, J=9.0 Hz), 4.69 (1 H, d, J=11.5 Hz), 4.44 (1 H, br. s.), 4.24-4.36 (1 H, m), 4.03 (1 H, d, J=11.5 Hz), 3.71-3.84 (1 H, m), 3.24 (1 H, d, J=14.7 Hz), 2.88-3.03 (1 H, m), 2.56-2.71 (1 H, m), 2.42-2.55 (1 H, m), 2.17-2.29 (1 H, m), 2.12 (1 H, d, J=7.8 Hz), 1.65-1.88 (5 H, m), 1.37-1.55 (9 H, m), 0.81-0.92 (2 H, m), 0.72 (1 H, br. s.), 0.48-0.63 (4 H, m). 19F NMR (377 MHz, CDCl3) δ ppm −70.26 (3 F, br. s.). MS (ESI, pos. ion) m/z: 614.3 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[C:9]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[C:23](=[O:27])[CH2:22][CH2:21]4)[CH:8]=2)[CH2:3][CH2:2]1.[Cl:28][C:29]1[CH:38]=[CH:37][C:32]([O:33][CH2:34][CH:35]=O)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:38]=[CH:37][C:32]([O:33][CH2:34][CH2:35][N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[O:11][C:10]([C:12]4[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=4)=[C:9]([C:18]4[CH:19]=[C:20]5[C:24](=[CH:25][CH:26]=4)[C:23](=[O:27])[CH2:22][CH2:21]5)[CH:8]=3)[CH2:5][CH2:6]2)=[CH:31][CH:30]=1
Reactant: O=C1CCc2cc(-c3cc(C4CCNCC4)oc3-c3ccncc3)ccc21
Reactant: O=CCOc1ccc(Cl)cc1
Product: O=C1CCc2cc(-c3cc(C4CCN(CCOc5ccc(Cl)cc5)CC4)oc3-c3ccncc3)ccc21
Yield: 65 %

Procedure:
The title compound (0.140 g, 65%) was prepared from the product of Example 31 Step 5 and (4-chlorophenoxy)acetaldehyde (Maguire et al, J. Chem. Soc., 1954, 3669) using the method of Example 32; MS(ES+) m/e 513 [M+H]+.
Reaction SMILES: C[C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[C:3]=1[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5].[CH2:17]([OH:19])C>>[NH2:14][C:10]1[C:11]([O:19][CH3:17])=[CH:12][CH:13]=[CH:2][C:3]=1[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5]
Reactant: C=CCOC(=O)c1c(C)cccc1[N+](=O)[O-]
Reactant: CCO
Product: C=CCOC(=O)c1cccc(OC)c1N

Procedure:
The above nitro compound was reduced by the method described in example 6 for the reduction of allyl 2-methyl-6-nitrobenzoate, except that the solvent was ethanol, to give allyl 2-amino-3-methoxybenzoate.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[C:18]([CH3:20])[N:19]=2)=[C:11]([O:27][CH3:28])[CH:10]=1)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[C:18]([CH3:20])[N:19]=2)=[C:11]([O:27][CH3:28])[CH:10]=1
Reactant: COc1cc(OCc2ccccc2)ccc1-c1nc(C)c(-c2cccnc2)[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(O)ccc1-c1nc(C)c(-c2cccnc2)[nH]1
Reaction time: 5 h
Yield: 28 %

Procedure:
To a solution of 2-(4-benzyloxy-2-methoxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (1.18 g) in methanol (12 ml) and tetrahydrofuran (6 ml) was added 10% palladium on carbon (wet ca. 50%, 0.30 g), and the mixture was stirred for 7 hours at ambient temperature under atmospheric pressure of hydrogen gas. The mixture was filtered, and the filtrate was evaporated. The residue was dissolved in methanol (20 ml), and hydrogenated again on palladium on carbon (wet, 0.50 g) for 5 hours. After the filtration, the filtrate was evaporated, and the residue was triturated in a mixture of diisopropyl ether and isopropanol (1:1 V/V) to give 2-(4-hydroxy-2-methoxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (0.25 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH:17]([C:22]3[CH:27]=[C:26]([Cl:28])[C:25]([Cl:29])=[C:24]([Cl:30])[CH:23]=3)[C:18]([F:21])([F:20])[F:19])=[CH:11][C:8]=2[C:9]#[N:10])[N:3]=1.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>C(Cl)Cl>[C:9]([C:8]1[CH:11]=[C:12](/[CH:15]=[CH:16]/[CH:17]([C:22]2[CH:23]=[C:24]([Cl:30])[C:25]([Cl:29])=[C:26]([Cl:28])[CH:27]=2)[C:18]([F:19])([F:20])[F:21])[CH:13]=[CH:14][C:7]=1[N:4]1[CH:5]=[N:6][C:2]([N:1]([C:34]([CH:31]2[CH2:33][CH2:32]2)=[O:35])[C:34]([CH:31]2[CH2:33][CH2:32]2)=[O:35])=[N:3]1)#[N:10]
Reactant: O=C(Cl)C1CC1
Reactant: N#Cc1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1-n1cnc(N)n1
Solvent: ClCCl
Product: N#Cc1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1-n1cnc(N(C(=O)C2CC2)C(=O)C2CC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
To a stirred solution of (E)-2-(3-amino-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzonitrile (0.1 g, 0.21 mmol) in CH2Cl2 at ambient temperature, was added cyclopropylcarbonyl chloride (0.045 g, 0.42 mmol) and the reaction mixture was stirred for 2 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 and washed with water and brine and dried over Na2SO4. Concentration under reduced pressure and purification by preparative HPLC afforded the title compound as a solid (0.09 g, 79%): mp 104-107° C.; 1H NMR (300 MHz, CDCl3) δ 8.78 (s, 2H), 7.83 (s, 1H), 7.80 (m, 2H), 7.42 (s, 2H), 6.65 (d, J=16.4 Hz, 1H), 6.51 (dd, J=7.6, 8.0 Hz, 1H), 4.17 (m, 1H), 2.16 (m, 2H), 1.25 (m, 4H), 1.00 (m, 4H); ESIMS m/z 609.98 ([M+H]+); IR (thin film) 2234, 1714, 1114, 807 cm−1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:40])[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)=[N:17][CH:16]=1.[N+:41]([O-])([OH:43])=[O:42].C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[O:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:40])[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:23][CH2:22]2)=[N:17][CH:16]=1)[N+:41]([O-:43])=[O:42]
Reactant: O=C(NCCCCCCCCCCCO)c1ccc(N2CCN(C(c3ccccc3)c3ccccc3)CC2)nc1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: O=C(NCCCCCCCCCCCO[N+](=O)[O-])c1ccc(N2CCN(C(c3ccccc3)c3ccccc3)CC2)nc1
Reaction time: 6 h
Yield: 57 %

Procedure:
0.66 g of N-(11-hydroxy-1-undecanyl)-6-(4-diphenylmethyl-1-piperazinyl)nicotinamide were dissolved in 15 ml of methylene chloride and to the solution was added dropwise under ice-cooling a mixed solution of 0.2 ml of fuming nitric acid and 0.5 ml of acetic anhydride and stirred for 6 hrs. This reaction mixture was poured into an aqueous sodium hydrogencarbonate solution, extracted with methylene chloride, washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 0.41 g (57%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].CS(O[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:25][CH2:24]2)=[CH:6][C:5]=1[C:11]([F:12])([F:13])[F:14])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Temperature: 90 °C

Procedure:
A 100 mL flask was charged with 4-nitro-3-(trifluoromethyl)phenol (commercially available from Acros; 0.31 g, 1.8 mmol), tert-butyl 4-(3-(methylsulfonyloxy)propyl)-piperazine-1-carboxylate (0.64 g, 2.0 mmol), cesium carbonate (1.2 g, 3.6 mmol) and DMA. The reaction mixture was heated to 90° C. for 15 hours. The reaction mixture was allowed to cool to room temperature, extracted with ethyl acetate and 10% aqueous lithium chloride solution. The organic solvent was removed on a rotary evaporator under reduced pressure to yield tert-butyl 4-(3-(4-nitro-3-(trifluoromethyl)phenoxy)propyl)piperazine-1-carboxylate that was used without further purification. MS (EI): 434 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:16][CH2:17][CH2:18][CH2:19][N:20](C(OC(C)(C)C)=O)[CH2:21][CH2:22][CH2:23][NH:24][C:25]2[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([OH:35])=[C:27]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:26]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[ClH:47]>>[ClH:47].[ClH:47].[ClH:47].[C:1]([C:5]1[CH:6]=[C:7]([NH:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]2[CH:26]=[C:27]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:28]([OH:35])=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:30]=2)[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(CCCNc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CCCNc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Product: CC(C)(C)c1cc(NCCCNCCCNc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O

Procedure:
Dissolve 1,9-bis[3,5-di-t-butyl-4-hydroxyphenyl]-5-(t-butyloxycarbonyl)-1,5,9-triazanonane (6.39 g, 10 mmol) in saturated methanolic hydrochloric acid (100 mL). Stir for several hours and evaporate the solvent in vacuo to give the title compound.