Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12]
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1Nc2c(cc(Br)cc2[N+](=O)[O-])C1=O
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a solution of 5-bromo-1H-indole-2,3-dione (5 g, 22.1 mmol) in conc. H2SO4 (22.5 mL) was added fuming nitric acid (1.45 mL) very slowly at −5 to 0° C. The reaction mixture was stirred at the same temperature for one hour. After completion of the reaction, the reaction mixture was poured on to crushed ice and the resulting precipitate was filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as yellow solid (5.5 g, 91.8%) which was used for the next step directly.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([CH2:15][CH2:16][CH2:17]Br)=[N:13][NH:12][C:11]=1[NH2:19].[NH2:20]C1NN=C(CCCO)C=1C1SC2C=CC=CC=2N=1.N>C(O)C>[NH2:20][CH2:17][CH2:16][CH2:15][C:14]1[C:10]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[C:11]([NH2:19])[NH:12][N:13]=1
Reactant: Nc1[nH]nc(CCCBr)c1-c1nc2ccccc2s1
Reactant: Nc1[nH]nc(CCCO)c1-c1nc2ccccc2s1
Agent: N
Solvent: CCO
Product: NCCCc1n[nH]c(N)c1-c1nc2ccccc2s1

Procedure:
The title compound (12 mg) was prepared using 130 mg (0.39 mmol) of 4-benzothiazol-2-yl-5-(3-bromopropyl)-2H-pyrazol-3-ylamine, which was derived from 3-(5-amino-4-benzothiazol-2-yl-1H-pyrazol-3-yl)-propan-1-ol, and a saturated solution of ammonia gas in ethanol. MS (m/z, ES+): 274.2 (M+1, 100%), 257.2 (M-NH2, 70%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]1([CH:14]([N:18]2[CH:22]=[C:21](B3OC(C)(C)C(C)(C)O3)[CH:20]=[N:19]2)[CH2:15][C:16]#[N:17])[CH2:13][CH2:12][CH2:11][CH2:10]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:21]2[CH:20]=[N:19][N:18]([CH:14]([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[CH2:15][C:16]#[N:17])[CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cnn(C(CC#N)C3CCCC3)c2)OC1(C)C
Reactant: Clc1ccnc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: N#CCC(C1CCCC1)n1cc(-c2ccnc(Cl)n2)cn1
Temperature: 100 °C
Yield: 67.3 %

Procedure:
A mixture of 2,4-dichloropyrimidine (0.28 g, 1.9 mmol), 3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile (0.500 g, 1.59 mmol), tetrakis(triphenylphosphine)palladium (100 mg, 0.1 mmol), and potassium phosphate (1.0 g, 4.8 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated at 100° C. overnight. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, concentrated. The residue was purified on silica gel, eluting with 0 to 80% EtOAc in hexanes, to give the desired product (323 mg, 67%). LCMS (M+H) 302.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[O-:24])[CH3:21])[CH:5]=[N:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=2[N:12]=1.CS(O[CH2:31][CH:32]1[CH2:34][C:33]1([F:36])[F:35])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:35][C:33]1([F:36])[CH2:34][CH:32]1[CH2:31][O:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:7]3[N:6]=[CH:5][C:4]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:24])[O:25][C:32]([CH3:34])([CH3:33])[CH3:31])[CH3:21])=[CH:3][C:2]=3[F:1])[O:9][C:10]=2[CH:16]=1
Reactant: CS(=O)(=O)OCC1CC1(F)F
Reactant: C[C@@H](COc1cnc(-c2nc3ccc(O)cc3o2)c(F)c1)NC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](COc1cnc(-c2nc3ccc(OCC4CC4(F)F)cc3o2)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Triethylamine (14.1 mL) was added to a solution of hexachloroethane (7.46 g) and triphenylphosphine (9.91 g) in acetonitrile (50 mL) at room temperature, and the mixture was stirred at room temperature for 10 min. Then a mixture of tert-butyl [(1S)-2-({6-[(2,4-dihydroxyphenyl)carbamoyl]-5-fluoropyridin-3-yl}oxy)-1-methylethyl]carbamate (5.31 g) and acetonitrile (50 mL) was added, and the mixture was stirred at room temperature for 2 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give tert-butyl [(1S)-2-{[5-fluoro-6-(6-hydroxy-1,3-benzoxazol-2-yl)pyridin-3-yl]oxy}-1-methylethyl]carbamate (10.7 g) as a mixture with impurities. A mixture of [(1S)-2-{[5-fluoro-6-(6-hydroxy-1,3-benzoxazol-2-yl)pyridin-3-yl]oxy}-1-methylethyl]carbamate (4.28 g, a mixture with impurities), (2,2-difluorocyclopropyl)methyl methanesulfonate (0.494 g), potassium carbonate (0.367 g), and DMF (30 mL) was stirred at 60° C. for 1 hr. Then additional (2,2-difluorocyclopropyl)methyl methanesulfonate (0.494 g) and potassium carbonate (0.367 g) were added, and the mixture was stirred at 60° C. for 1 hr. Then additional (2,2-difluorocyclopropyl)methyl methanesulfonate (0.494 g) and potassium carbonate (0.367 g) were added, and the mixture was stirred at 60° C. for 1 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.39 g) as a pale yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1C=CC=CC=1>[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1ccccc1
Yield: 137.2 %

Procedure:
10 mL of benzene was treated with benzoyl chloride (2.5 g, 20 mmol) in the presence of dry polystyrene polysulfonic acid catalyst (200 mg). The mixture was heated under reflux to obtain benzophenone (2.5 g, 68% yield). Similar reaction has been found effective for nitration, alkylation, halogenation and related electrophilic reactions.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([NH:9][CH:10]2[CH:17]3[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:19][CH:11]2[CH2:12]4)[CH2:16]3)=[O:8])[CH2:3]1.CCN(C(C)C)C(C)C.Cl[C:30]([O:32][CH3:33])=[O:31].Cl>C(Cl)Cl>[CH:17]12[CH2:16][CH:15]3[CH2:14][CH:13]([CH2:12][CH:11]([CH2:19]3)[CH:10]1[NH:9][C:7]([N:4]1[CH2:5][CH2:6][C@@H:2]([NH:1][C:30](=[O:31])[O:32][CH3:33])[CH2:3]1)=[O:8])[CH2:18]2
Reactant: N[C@@H]1CCN(C(=O)NC2C3CC4CC(C3)CC2C4)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@@H]1CCN(C(=O)NC2C3CC4CC(C3)CC2C4)C1
Yield: 49.1 %

Procedure:
A vial equipped with a flea stir bar was charged with (R)-3-amino-N-(2-adamantyl)pyrrolidine-1-carboxamide (25 mg, 0.095 mmol), i-Pr2NEt (0.07 mL, 0.38 mmol) and CH2Cl2. The solution was stirred and methyl chloroformate (0.009 mL, 0.11 mmol) was added. The mixture was stirred overnight at rt and applied to a 10-mL ChemElut cartridge prewetted with 5% aq HCl (6 mL). The cartridge was eluted with ether (20 mL). The eluate was evaporated to dryness and the residue was purified by preparative HPLC to afford (R)-methyl 1-(2-adamantylcarbamoyl)pyrrolidin-3-ylcarbamate (15 mg, 49%). LC-MS Method 1, tR=1.5 min, m/z=322; 1H NMR (CDCl3) 1.60-2.00 (15H), 2.20 (m, 1H), 3.26 (m, 1H), 3.46 (m, 2H), 3.63 (m, 1H), 3.69 (s, 3H), 3.96 (s, 1H), 4.30 (1H), 4.60 (1H), 4.89 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](#[N:12])[CH:10]=[CH2:11].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH2:10][C:9]#[N:12])=[CH:4][CH:3]=1
Reactant: C=CC#N
Reactant: Oc1ccc(Cl)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#CCCOc1ccc(Cl)cc1

Procedure:
A mixture of p-chlorophenol (25 g), acrylonitrile (30 ml) and a solution of benzyltrimethylammonium hydroxide (8 ml of a 40 wt % solution in methanol) were heated at reflux over the weekend. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extract was dried and evaporated to give 3-(4-chlorophenoxy)propionitrile.
Reaction SMILES: C([O:8][P:9]([CH2:19][CH:20]([CH2:31][CH2:32][C:33]([O:35]CC1C=CC=CC=1)=[O:34])[C:21]([O:23]CC1C=CC=CC=1)=[O:22])([O:11]CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1>[Pd].CO>[P:9]([CH2:19][CH:20]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:21]([OH:23])=[O:22])([OH:11])([OH:10])=[O:8]
Reactant: O=C(CCC(CP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)CCC(CP(=O)(O)O)C(=O)O
Reaction time: 24 h
Yield: 90.3 %

Procedure:
The benzyl pentanedioate 2(2.9 g, 4.9 mmol) was added to a mixture of 20 ml of methanol containing 0.29 g (6 mol %) of 10% Pd/C. This mixture was hydrogenated on a Parr hydrogenator at 40 psi for 24 hours, filtered and evaporated to give 3(1.0 g, 90%) as a clear slightly golden viscous oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH2:2]1.[Cl:25][C:26]1[CH:27]=[C:28]([N:33]=[C:34]=[O:35])[CH:29]=[CH:30][C:31]=1[Cl:32]>>[Cl:25][C:26]1[CH:27]=[C:28]([NH:33][C:34]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]3[N:15]=[C:14]([N:16]4[C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=5[N:18]=[CH:17]4)[CH:13]=[CH:12][N:11]=3)[CH3:8])[CH2:2]2)=[O:35])[CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCNC1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Product: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCN(C(=O)Nc2ccc(Cl)c(Cl)c2)C1

Procedure:
The title compound was prepared from 2-[1-(piperidin-3-yl)-ethylamino]-4-[benzimidazol-1-yl]pyrimidine and 3,4-dichlorophenylisocyanate according to the procedure described in EXAMPLE 29. Mass spectrum (ESI) 510.3 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(Br)c1
Reactant: C1CNCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Fc1cccc(N2CCNCC2)c1

Procedure:
1 g (5.71 mmol) of 3-fluorobromobenzene and 2.95 g (34.29 mmol) of piperazine are dissolved in 20 ml of toluene, and 0.77 g (8 mmol) of sodium tert-butoxide is added. In the presence of 0.11 g (0.17 mmol) of BINAP and 0.05 g (0.06 mmol) of tris(dibenzylideneacetone)dipalladium, the mixture is then stirred under reflux overnight. After cooling, ethyl acetate is added and the mixture is washed with water. The mixture is then extracted with 1N hydrochloric acid, and the aqueous phase is washed with ethyl acetate. The pH is adjusted to 8–9 and the mixture is then extracted with dichloromethane. The organic phase is dried over magnesium sulphate and the solvent is removed, giving the target compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[F:19])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:19][C:13]1[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=1[C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: C1COCCN1
Reactant: COC(=O)c1cc(Cl)nc(-c2ccc(C)cc2F)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(-c2ccc(C)cc2F)nc(N2CCOCC2)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 2-chloro-6-(2-fluoro-4-methylphenyl)isonicotinate (0.26 g, 0.94 mmol) in DMA (4 mL) were added morpholine (0.10 mL, 1.17 mmol), tris(dibenzylideneacetone)dipalladium(0) (21.4 mg, 0.02 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (33.5 mg, 0.07 mmol) and cesium carbonate (0.46 g, 1.41 mmol). The mixture was heated to 80° C. After 18 h, the mixture was filtered. The filtered cake was washed with methanol. The filtrate was concentrated to remove methanol. The solution in DMA was carried onto the next step.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][CH2:16][NH:15][C:14](=O)[C:13]=2[CH:20]=1.[OH-].[Na+]>O1CCCC1.O1CCOCC1>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][C:13]=2[CH:20]=1
Reactant: COc1ccc2c(c1)C(=O)NCCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CNCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To a solution of lithium aluminum hydride (3.07 g) in tetrahydrofuran (60 ml) was dropwise added a solution of 8-methoxy-2,3,4,5-tetrahydrobenz[c]azepin-1-one (4.42 g) in 1,4-dioxane (30 ml) with ice-cooling and the mixture was refluxed for 20 hours. After completion of the reaction, 20% aqueous sodium hydroxide solution was added dropwise with ice-cooling, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was filtrated, and the solvent was evaporated and the residue was dried under reduced pressure to give the title compound (4.05 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:15])=[C:4]([CH2:12][CH2:13][CH3:14])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:16][O:17][C:18](=[O:38])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][CH2:33]Br)[C:22]=1[CH2:35][CH2:36][CH3:37].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:16][O:17][C:18](=[O:38])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][CH2:33][O:15][C:3]2[C:2]([Br:1])=[CH:7][C:6]([C:8](=[O:10])[CH3:9])=[C:5]([OH:11])[C:4]=2[CH2:12][CH2:13][CH3:14])[C:22]=1[CH2:35][CH2:36][CH3:37]
Reactant: CCCc1c(O)c(Br)cc(C(C)=O)c1O
Reactant: CCCc1c(OCC(=O)OC)ccc(C(C)=O)c1OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(O)c(C(C)=O)cc(Br)c1OCCCOc1c(C(C)=O)ccc(OCC(=O)OC)c1CCC
Yield: 55.1 %

Procedure:
A mixture of 2 g (0.0073 mol) of 1-(5-bromo-2,4-dihydroxy-3-propylphenyl)ethanone, 2.84 g (0.0073 mol) of [4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]acetic acid methyl ester and 1.52 g (0.011 mol) of anhydrous potassium carbonate in 150 ml of anhydrous acetone was stirred at reflux for 20 hours. An additional 1 g of potassium carbonate was added and reflux was continued for a total of 35 hours. The hot reaction mixture was filtered and the filtrate was concentrated in vacuo to a oil which was dissolved in ethyl acetate and washed with 1N sodium hydroxide and sodium chloride solution. The crude product was purified by HPLC, eluting with 25% ethyl acetate in hexane to yield 2.33 g (55% yield) of [4-acetyl-3-[3-(4-acetyl-6-bromo-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]acetic acid methyl ester as a pale yellow oil.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:12])[C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH2:35]([NH2:42])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>C(Cl)Cl>[CH2:35]([NH:42][C:9](=[O:11])[C:8](=[O:12])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCN
Reactant: O=C(O)C(=O)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCCCCCNC(=O)C(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
A suspension of phenylpyruvic acid (2.1 g; 12.8 mmol) in DCM (50 ml) was cooled to 0° C. Then EDCl (3 g, 15.6 mmol) and HOBt (0.2 g, 1.5 mmol) were added successively. The resulted solution was cooled to −5° C. and then heptylamine (1.5 g, 13 mmol) was added dropwise at temperature below 0° C. Upon the addition the ice bath was removed and the reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into 1% aqueous hydrochloric acid solution (30 ml). The DCM phase was washed with water and concentrated in vacuum. The crude product was chromatographed on a silica gel column using ethylacetate/hexane (1:2) as eluent to provide the title compound (0.8 g, 24% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:7]1[C:12]([F:13])=[CH:11][C:10]([O:14][CH3:15])=[CH:9][C:8]=1[F:16])[OH:6])[CH3:2].[CH2:18](I)[CH3:19]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:7]1[C:12]([F:13])=[CH:11][C:10]([O:14][CH3:15])=[CH:9][C:8]=1[F:16])[O:6][CH2:18][CH3:19])[CH3:2]
Reactant: CCOC(=O)C(O)c1c(F)cc(OC)cc1F
Reactant: CCI
Solvent: Cc1ccccc1
Product: CCOC(=O)C(OCC)c1c(F)cc(OC)cc1F
Yield: 100.4 %

Procedure:
To a suspension of (RS)-(2,6-difluoro-4-methoxy-phenyl)-hydroxy-acetic acid ethyl ester (13.06 g) and Ag2O (24.58 g) in toluene (100 ml) was added ethyl iodide (24.81 g). The mixture was heated to reflux for 2.5 h. Ethyl iodide (24.81 g) and Ag2O (12.29 g) were added and the mixture was refluxed for a further 7 h. The solid was filtered off and the filtate was concentrated to give (RS)-(2,6-difluoro-4-methoxy-phenyl)-ethoxy-acetic acid ethyl ester (14.6 g). Light yellow oil. MS 274.1 ([M]+)
Reaction SMILES: [N+:1]([CH2:4][C@@:5]1([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:11][C@H:10]2[C@@H:6]1[CH:7]=[C:8]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:9]2)([O-])=O.[Cl-].[NH4+]>C(O)C.[Fe]>[NH2:1][CH2:4][C@@:5]1([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:11][C@H:10]2[C@@H:6]1[CH:7]=[C:8]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:9]2
Reactant: CC(C)(C)OC(=O)C[C@]1(C[N+](=O)[O-])C[C@@H]2CC(C3CCCC3)=C[C@@H]21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@]1(CN)C[C@@H]2CC(C3CCCC3)=C[C@@H]21
Reaction time: 4.5 h

Procedure:
Tert-butyl(±)-[(1S,5R,6R)-6-(nitromethyl)-3-cyclopentylbicyclo[3.2.0]hept-3-en-6-yl]acetate (3.30 g, 9.8 mmol) was dissolved in ethanol (60 mL). To the solution, iron powder (4.47 g, 80.0 mmol) and then an aqueous ammonium chloride (0.54 g, 10.0 mmol) solution (20 mL) were added, and the mixture was stirred for 4.5 hours under heating to reflux. The mixture was allowed to cool and then filtered through Celite to remove insoluble matter. The solution was concentrated, and the residue was diluted with ethyl acetate. The dilution was washed with a saturated aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound of interest as a colorless oil substance (2.00 g, 67%).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:10](F)(F)[C:11](OC(=O)C(F)(F)F)=[O:12].C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:11](=[O:12])[CH3:10])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C(C)=O)cc1
Yield: 78 %

Procedure:
Reference is made to the work of H. Burton and P. F. G. Praill (Journal of Chemical Society, April-1950, pp-1203-1206) wherein it is reported that Acetyl perchlorate formed in-situ from silver perchlorates and acetyl chloride, is an effective acylating agent and will convert anisole into p-methoxyacetophenone in about 70% yield. However, this process has disadvantages of using perchlorates which is hazardous chemical. Reference is made to the work of E. J, Bourne, et al. (Journal of Chemical Society, March-1951, pp-718-720) wherein trifluoroacetic anhydride catalyst is shown to promote, the condensation between suitably activated aromatic compound and carboxylic acid or sulphonic acid to give ketones or sulphones, respectively. In this process, reaction was done at room temperature. Anisole was added to a mixture of trifluroacetic anhydride and acetic acid. After three hours the solution was poured into the excess of sodium hydrogen carbonate solution and then extracted by chloroform The extract were dried, filtered and evaporated to dry syrup. After crystallization it gave 78% of p-methoxyacetophenone.
Reaction SMILES: Cl[C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].[CH3:18][OH:19]>>[CH3:18][O:19][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15]
Reactant: N#Cc1cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c1
Reactant: CO
Product: COc1c(C(F)(F)F)cc(C#N)cc1C(F)(F)F
Temperature: 30 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round-bottom flask, was placed methanol (10 mL) and cooled to 0° C. Na (337 mg, 14.65 mmol, 2.00 equiv) was added. When the Na was reacted completely, 4-chloro-3,5-bis(trifluoromethyl)benzonitrile (2.0 g, 7.31 mmol, 1.00 equiv) was added at 0° C. The resulting solution was stirred for 1 h at 30° C. The reaction progress was monitored by GCMS. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×20 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue could been used for the next step directly. This resulted in 1.33 g of 4-methoxy-3,5-bis(trifluoromethyl)benzonitrile as yellow oil. Mass spectrum (GC, m/z): Calcd. for C10H5F6NO, 269.0 (M). found 269.0.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[NH2:15][C:16]1[N:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[NH2:15][C:16]1[C:17]([C:18]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[CH:4]=2)=[O:19])=[CH:21][CH:22]=[CH:23][N:24]=1
Reactant: Nc1ncccc1C(=O)O
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: Nc1ncccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg) and 2-aminonicotinic acid to produce 2-amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamide. MS (Q1) 325.2 (M)+.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH2:7](O)/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[C:1]([O:6][CH2:7]/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)O
Reactant: CCCCCC/C=C/CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: CCCCCC/C=C/COC(=O)C(C)C
Yield: 64.2 %

Procedure:
Isobutyric acid (22.0 g, 0.25 mole), trans-2-nonen-1-ol (44.3 g, 0.25 mole), xylene (100 ml) and p-toluenesulfonic acid are heated to 145°C. The solution is refluxed for 5 minutes and 4.5 ml water is collected by distillation. The reaction mixture is cooled and first washed with water followed by 5% sodium carbonate. The washed solution is dried over sodium sulfate and distilled to yield 34.1 g of trans-2-nonenyl isobutyrate, b.p. 87° - 88°C/0.5 mm. An analytical sample is obtained for taste evaluation using gas chromatography.