Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:18])=[C:4]([C:8]([I:17])=[C:9]([N:12]([CH3:16])[C:13](=[O:15])[CH3:14])[C:10]=1[I:11])[C:5]([OH:7])=[O:6].[C:19]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21][CH2:20]1.S(=O)(=O)(O)O>O>[C:5]([C:4]1[C:3]([I:18])=[C:2]([C:10]([I:11])=[C:9]([N:12]([CH3:16])[C:13](=[O:15])[CH3:14])[C:8]=1[I:17])[NH:1][C:19](=[O:26])[CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])([OH:7])=[O:6]
Reactant: O=C1CCCC(=O)O1
Reactant: CC(=O)N(C)c1c(I)c(N)c(I)c(C(=O)O)c1I
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)N(C)c1c(I)c(NC(=O)CCCC(=O)O)c(I)c(C(=O)O)c1I

Procedure:
A mixture of 58.6 g. of 3-amino-5-(N-methylacetamido)-2,4,6-triiodobenzoic acid, 74 g. of glutaric anhydride and 8 ml. of concentrated sulfuric acid was heated on a steam bath for 5 hours. The reaction mixture was poured into water and the solid product collected by filtration. The product, consisting of 3-glutarimido-5-(N-methylacetamido)-2,4,6-triiodobenzoic acid (Example 1) was dissolved in excess dilute aqueous sodium hydroxide, and the solution warmed for thirty minutes, then cooled and 3N hydrochloric acid added slowly until precipitation was complete. The solid product was collected and recrystallized first from acetone, then from acetic acid, and finally from water to give 3'-carboxy-5'-(N-methylacetamido)-2',4',6'-triiodoglutaranilic acid, colorless prisms, m.p. 188.8°-196.0° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16](=[O:27])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[C:20]([Cl:26])[CH:19]=1)[CH3:14].I[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCCC1.CN1CCCN(C)C1=O>[CH2:13]([O:15][C:16](=[O:27])[CH:17]([C:18]1[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[C:20]([Cl:26])[CH:19]=1)[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[CH3:14]
Reactant: ICC1CCCC1
Reactant: CCOC(=O)Cc1ccc(SC)c(Cl)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC1CCCC1)c1ccc(SC)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
A solution of diisopropylamine (457 μL, 3.26 mmol) in tetrahydrofuran (5 mL) was cooled to −78° C. under a nitrogen atmosphere and then treated with a 2.5 M solution of n-butyllithium in hexanes (1.3 mL, 3.26 mmol). The mixture was stirred at −78° C. for 30 min, at which time, a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid ethyl ester (0.67 g, 2.75 mmol) in tetrahydrofuran (8 mL) was slowly added to the reaction mixture. The reaction mixture turned deep yellow in color. The reaction mixture was then further stirred at −78° C. for 30 min, at which time, a solution of iodomethylcyclopentane (0.65 g, 3.09 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (1 mL) was added via syringe. The reaction mixture was then allowed to warm to 25° C., where it was stirred for 16 h. The reaction mixture turned red in color during this time period. The reaction mixture was quenched with a 6 N aqueous hydrochloric acid solution (5 mL) and further diluted with water (20 mL). The reaction mixture was then extracted with methylene chloride (3×20 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 4/1 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid ethyl ester (0.50 g, 56%) as a light yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[NH2:11][C:12]1[CH:16]=[C:15]([CH3:17])[NH:14][N:13]=1.C[N:19](C=O)C>O>[CH3:17][C:15]1[C:16](=[N:19][NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:12]([NH2:11])=[N:13][N:14]=1
Reactant: CN(C)C=O
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: Cc1cc(N)n[nH]1
Solvent: O
Product: CC1=NN=C(N)C1=NNc1cccc([N+](=O)[O-])c1

Procedure:
5-methyl-4-[(3-nitrophenyl)hydrazono]-4H-pyrazol-3-ylamine was prepared from 3-nitroaniline (0.35 g, 2.5 mmol) and 3-amino-5-methylpyrazole (0.3 g, 3.1 mmol) according to the procedure described above except that the substituted aniline was initially dissolved in a mixture of water (3.6 mL) and DMF (2.0 mL) prior to being acidified. The product was isolated in a yield of 176 mg (29%) of the compound as a red solid and was not further purified. MS (m/z, ES+): 247.2 (M+1, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=O)[CH2:11][C:10](=[O:15])[CH2:9]1.C([O-])(=O)C.[NH4+:20].[CH3:21][C:22](=O)[C:23]#[CH:24]>C(O)C>[CH3:21][C:22]1[CH:23]=[CH:24][C:11]2[C:10](=[O:15])[CH2:9][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:13][C:12]=2[N:20]=1
Reactant: Cc1ccccc1C1CC(=O)CC(=O)C1
Reactant: [NH4+]
Reactant: C#CC(C)=O
Agent: CC(=O)[O-]
Solvent: CCO
Product: Cc1ccc2c(n1)CC(c1ccccc1C)CC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
A mixture of 5-(2-methylphenyl)cyclohexane-1,3-dione (1.3 g) and ammonium acetate (0.49 g) in ethanol (30 ml) was stirred at room temperature for 30 minutes, and to the mixture was added 3-butyn-2-one (0.44 g). The reaction solution was stirred at room temperature for 1.5 hours and refluxed for 27 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) to give colorless crystals of 2-methyl-7-(2-methylphenyl)-5,6,7,8-tetrahydroquinolin-5-one (0.88 g).
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([C:8]([OH:10])=O)=[C:5]([CH3:11])[CH:4]=1)=[O:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CN(C=O)C.C(OCC)(=O)C>[CH3:11][C:5]1[CH:4]=[C:3]([CH:1]=[O:2])[NH:7][C:6]=1[C:8]([N:30]1[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]1)=[O:10]
Reactant: Cc1cc(C=O)[nH]c1C(=O)O
Reactant: CN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cc(C=O)[nH]c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a solution of 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid (306.3 mg, 2 mmol) in DMF 5 mL was added HOBt (324.3 mg, 2.4 mmol), EDC (460.1 mg, 2.4 mmol) and then 1-methylpiperazine (0.27 mL, 2.4 mmol). The mixture was stirred at room temperature under nitrogen for overnight. The reaction was diluted with ethyl acetate and washed with sodium bicarbonate. The aqueous layer was extracted several times with ethyl acetate. The combined organic layer was washed with brine, dried, concentrated and column chromatographed (MeOH/DCM) to give 310 mg (66%) of 4-methyl-5-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde as a light yellow foam solid. 1H NMR (360 MHz, DMSO-d6) 12.20 (br s, 1H, NH), 9.47 (s, 1H, CHO), 6.80 (s, 1H), 3.58 (m, 4H, 2×CH2), 3.44 (m, 4H, 2×CH2), 2.03 (s, 3H, CH3).
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[CH:5][C:4]([N:7]([C:14]2[C:24]3[C:25]4[C:17]([CH2:18][CH2:19][C:20]=4[CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.[OH-:32].[Na+].[CH3:34]N(C)C=O>O>[CH:26]([C:1]1[CH:6]=[CH:5][C:4]([N:7]([C:14]2[C:24]3[C:25]4[C:17]([CH2:18][CH2:19][C:20]=4[CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:15]=2)[C:8]2[CH:9]=[CH:10][C:11]([CH3:34])=[CH:12][CH:13]=2)=[CH:3][CH:2]=1)=[O:32]
Reactant: CN(C)C=O
Reactant: [OH-]
Reactant: Cc1ccc(N(c2ccccc2)c2ccc3c4c(cccc24)CC3)cc1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1ccc(N(c2ccc(C=O)cc2)c2ccc3c4c(cccc24)CC3)cc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
4.7 g (0.014 mol) of the above prepared 5-[N-(4-tolyl)-N-phenylamino]acenaphthene was dissolved in 30 ml of N,N-dimethylformamide, and 3.22 g (0.021 mol) of phosphorus oxychloride was dropwise added thereto at room temperature for 10 minutes. After the temperature was raised to 50° C., and the mixture was stirred for 14 hours. The reaction was determined to be finished when disappearance of 5-[N-(4-tolyl)-N-phenylamino]acenaphthene was identified. The reaction product was poured into an aqueous solution having 10 g (0.23 mol) of 93% sodium hydroxide dissolved in 250 ml of water. The resultant mixture was cooled to precipitate a crystal, which was then filtrated, washed with water and dried to obtain 4.94 g (yield: 97.1%) of 5-[N-(4-formylphenyl)-N-(4-tolyl)amino]acenaphthene.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([C:18](OC)=[O:19])=[CH:14][C:13]3=[O:22])=[CH:8]2)=[N:3]1.[H-].C([Al+]CC(C)C)C(C)C.CO.O>ClCCl>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][C:13]3=[O:22])=[CH:8]2)=[N:3]1
Reactant: COC(=O)c1ccn(-c2ccc3nn(C)c(C)c3c2)c(=O)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Cc1c2cc(-n3ccc(CO)cc3=O)ccc2nn1C
Reaction time: 2 h
Yield: 54 %

Procedure:
To a solution of methyl 1-(2,3-dimethyl-2H-indazol-5-yl)-2-oxo-1,2-dihydropyridine-4-carboxylate (450 mg) in dichloromethane (40 ml) was added diisobutylaluminum hydride (1 M toluene solution, 7.5 ml) at −78° C., and the mixture was stirred at the same temperature for 2 hr. To the reaction mixture were added methanol and water at the same temperature, and the mixture was filtered through celite, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane/methanol) to give the title compound (220 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][C:28]4[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=4)[C:31]([O:33]C)=[O:32])[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][C:28]4[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=4)[C:31]([OH:33])=[O:32])[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: COC(=O)c1cccc(Cn2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(Cn2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.4 %

Procedure:
To a solution of methyl 3-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}benzoate (800 mg) in a mixed solvent of tetrahydrofuran (4.0 mL) and methanol (4.0 mL) was added 1N aqueous sodium hydroxide solution (4.0 mL), and the mixture was stirred at room temperature for 12 hrs. 1N Hydrochloric acid (4.0 mL) and water (15 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The resultant precipitate was collected by filtration, washed with water (10 mL×3) and diisopropyl ether (10 mL×3) and dried under reduced pressure (80° C.) to give the title compound (610 mg) as a white powder.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7](Cl)=[O:8].[NH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[O:8]
Reactant: O=C(Cl)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: NCc1ccccn1
Product: O=C(NCc1ccccn1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
In one aspect of the invention, a method of preparing a 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide is provided which comprises the following steps. Hydroquinone is contacted with 2,2,2-trifluoroethyl trifluoromethanesulfonate under conditions to yield 1,4-bis(2,2,2-trifluoroethoxy)benzene. Then, in the presence of a Lewis acid catalyst, the 1,4-bis(2,2,2-trifluoroethoxy)benzene is treated with an acetylation agent under conditions to create 2,5-bis(2,2,2-trifluoroethoxy)acetophenone. The methyl moiety of the acetophenone function of the 2,5-bis(2,2,2-trifluoroethoxy)acetophenone is thereafter replaced using hypochlorite to yield 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid. The 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid is then treated with an inorganic chloride to provide 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride. Subsequently, the resultant 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride is contacted with 2-aminomethylpyridine, whereby there is formed 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide. Finally, the 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide is treated with an agent capable of hydrogenation of the aromatic bond in the heterocyclic ring, whereby there is formed a 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([OH:8])[CH2:3]1.C(=O)(O)[O-].[Na+].Cl[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[CH2:15]([N:1]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([OH:8])[CH2:3]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: N[C@@H]1CCC[C@H](O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O[C@H]1CCC[C@@H](N(Cc2ccccc2)Cc2ccccc2)C1
Temperature: 75 °C
Yield: 91.3 %

Procedure:
To a suspension of (1S,3R)-3-aminocyclohexanol (5 g, 43.4 mmol; prepared as described in Tetrahedron: Asymmetry 15: 2051-2056 (2004)) and sodium bicarbonate (12.03 g, 143 mmol) in ethanol (100 mL) was added (chloromethyl)benzene (15.01 mL, 130 mmol) at room temperature. The reaction mixture was heated at 75° C. overnight. Upon completion of reaction as indicated by LCMS and TLC the reaction mixture was filtered and the filtrate was concentrated. The residue was then dissolved in DCM (250 mL) and washed with aqueous sodium hydroxide solution (1 N, 2×100 mL) and brine (1×100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, concentrated, and purified by silica gel chromatography (0%-80% ethyl acetate in hexanes) to yield (1S,3R)-3-(dibenzylamino)cyclohexanol (11.70 g, 91%) as a thick yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.26-7.37 (m, 8H), 7.17-7.22 (m, 2H), 4.56 (d, J=4.30 Hz, 1H), 3.57 (s, 4H), 3.16-3.26 (m, 1H), 2.41 (tt, J=3.17, 11.86 Hz, 1H), 1.99-2.06 (m, 1H), 1.72 (d, J=8.20 Hz, 2H), 1.63-1.69 (m, 1H), 1.18-1.28 (m, 2H), 0.98 (t, 2H); MS (ESI) m/z 296.4 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=O)[C@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[NH2:5].O[CH2:12][C@@H:13](N)[CH2:14]C(C)C.OCCN.C(=O)C(C)C>>[CH:13]([CH:1]1[NH:5][C@@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:3][O:2]1)([CH3:14])[CH3:12]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)C[C@H](N)CO
Agent: CC(C)C=O
Solvent: NCCO
Product: CC(C)C[C@H]1COC(C(C)C)N1

Procedure:
(L)-Leucine methyl ester was reduced to (1S)-1-(hydroxymethyl)-3-methylbutylamine according to Method B1b, Step 2. The 2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to afford (4S)-2-isopropyl-4-isobutyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give (1S)-1-(hydroxymethyl)-N-isobutyl-3-methylbutylamine. The substituted 2-hydroxyethylamine was reacted with SOCl2 according to Method B7b to give (1S)-1-(chloromethyl)-N-isobutyl-3-methylbutylamine. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-3,4-diisobutyl-1,3-oxazolidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[C:13]([NH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1ccnc(N)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)c1ccnc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
To a solution of ethyl 2-aminoisonicotinate (1.00 g, 6.02 mmol) in anhydrous pyridine (13 mL) was added benzoyl chloride (0.77 mL, 6.63 mmol) dropwise at 0° C. under nitrogen atmosphere. The resulting solution was warmed to ambient temperature, stirred for 18 hours and concentrated in vacuo. The residue was dissolved in ethyl acetate (75 mL), washed with 2 M aqueous hydrochloric acid solution (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The organic solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 10-50% ethyl acetate in hexanes to give ethyl 2-benzamidoisonicotinate as a colorless solid (1.35 g, 83%): 1H NMR (300 MHz, CDCl3) δ 8.94 (s, 1H), 8.84 (br s, 1H), 8.43 (d, J=5.1 Hz, 1H), 7.98-7.93 (m, 2H), 7.70-7.47 (m, 4H), 4.44 (q, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H); MS (ES+) m/z 271.5 (M+1).
Reaction SMILES: C([O:4][CH:5]1[C:11]2=[N:12][C:13]([CH3:21])=[C:14]([C:16](OCC)=[O:17])[CH:15]=[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6]1)(=O)C.Cl.[NH2:23][C:24]([NH2:26])=[NH:25]>>[OH:4][CH:5]1[C:11]2=[N:12][C:13]([CH3:21])=[C:14]([C:16]([NH:25][C:24]([NH2:26])=[NH:23])=[O:17])[CH:15]=[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: N=C(N)N
Reactant: CCOC(=O)c1cc2c(nc1C)C(OC(C)=O)CCCC2
Agent: Cl
Product: Cc1nc2c(cc1C(=O)NC(=N)N)CCCCC2O
Yield: 58.5 %

Procedure:
When the method of Inventive Example 1 was repeated using ethyl 9-acetoxy-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (450.0 mg, 1.55 mmol) and guanidine hydrochloride (2.67 g, 28.0 mmol), hydrolysis of the acetoxy group occurred at the same time, and the title compound (237.8 mg, 58.9%) was obtained as white powder.
Reaction SMILES: Cl[CH2:2][C@@H:3]([N:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][C:7]#[N:8])[CH3:4].[C-]#N.[Na+].[OH2:19].CCCC[CH2:24][CH3:25]>CS(C)=O>[C:24]([NH:8][C@@H:7]1[CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@@H:3]([CH3:4])[CH2:2]1)(=[O:19])[CH3:25]
Reactant: CCCCCC
Reactant: C[C@@H](CCl)N(CC#N)Cc1ccccc1
Reactant: O
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)N[C@H]1C[C@H](C)N(Cc2ccccc2)C1
Temperature: 60 °C
Reaction time: 21 h
Yield: 75.5 %

Procedure:
To 112.31 g (0.504 mol) of (S)-N-(1-chloro-2-propyl)-N-cyanomethylbenzylamine or the the mixture of compounds from step 1c, in 500 mL of anhdrous DMSO under nitrogen atmosphere was added 37.10 g (0.757 mol) of sodium cyanide. The reaction was stirred at 60° C. for 21 hours, slurried with water and extracted with ether. The extract was washed with brine, dried over magnesium sulfate, concentrated, and the residue chromatographed on silica gel, eluting with ethyl acetate:hexane in 1:4, 1:2, and 1:1 ratios to give 81.47 g (75.5% yield) of the title compound. MS M/Z: 231, 233 (M+NH4). NMR (CDCl3) δ: 1.41 (3H, d, J=6.5 Hz), 2.57 (1H, dd, J=6.5, J=16.5 Hz), 2.66 (1H, dd, J=6.5, J=16.5 Hz), 3.34 (1H, sextet, J=6.5 Hz), 3.48 (2H, s), 3.81 (2H, s), 7.36 (5H, m).
Reaction SMILES: C[C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]CC>C1C=CC=CC=1.CCOCC>[CH2:2]([O:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CC1(C)OCC(CO)O1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCOCC(O)CO
Temperature: 25 °C
Yield: 77.2 %

Procedure:
D-Acetone glycerol (4 grams) for synthesis of L-ALLE or L-Acetone glycerol for synthesis of D-ALLE, powdered potassium hydroxide (approximately 10 grams) and hexadecyl bromide (9.3 grams) in benzene (100 ml) were stirred and refluxed for 5 hours, while removing the water formed by azeotropic distillation (compare W. J. Baumann and H. K. Mangold, J. Org. Chem. 29: 3055, 1964 and F. Paltauf, Monatsh. 99:1277, 1968). The volume of the solvent was gradually reduced to about 20 ml, and the resulting mixture was cooled to room temperature and dissolved in ether (100 ml). The resulting solution was washed with water (2×50 ml), and the solvent was removed under reduced pressure. A 100 ml mixture of 90:10:5 methanol:water:concentrated hydrochloric acid was added to the residue and the mixture was refluxed for 10 minutes. The product was extracted with ether (200 ml) and was washed consecutively with water (50 ml), 10% sodium hydroxide (20 ml) and again with water (volumes of 20 ml) until neutral. The solvent was removed under reduced pressure and the product (8.8 grams) was crystallized from hexane to give 7.4 grams of pure 1-hexadecyl-glyceryl ether (compound I, FIG. 1) for synthesis of D-ALLE or 3-hexadecyl-glyceryl ether for synthesis of L-ALLE.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:13])=[CH:7][C:8]([F:12])=[C:9]([F:11])[CH:10]=2)[CH2:3][CH2:2]1.[OH:14][C:15]([C:18]1[CH:19]=[C:20]([C:24](O)=[O:25])[CH:21]=[N:22][CH:23]=1)([CH3:17])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH:1]1([NH:4][C:5]2[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=2[NH:13][C:24]([C:20]2[CH:21]=[N:22][CH:23]=[C:18]([C:15]([OH:14])([CH3:16])[CH3:17])[CH:19]=2)=[O:25])[CH2:3][CH2:2]1
Reactant: CC(C)(O)c1cncc(C(=O)O)c1
Reactant: Nc1cc(F)c(F)cc1NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)c1cncc(C(=O)Nc2cc(F)c(F)cc2NC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound from Step B (0.074 g, 0.40 mmol) in dichloromethane (2.1 mL) were added the title compound from Step C (0.080 g, 0.44 mmol), HATU (0.168 g, 0.442 mmol), HOAt (0.060 g, 0.44 mmol) and diisopropylethylamine (0.285 mL, 1.61 mmol). The reaction was stirred at room temperature for 1 hour, then diluted with dichloromethane, washed sequentially with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel (50-100% ethyl acetate in hexanes) provided the title compound: LCMS m/z 330.04 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.96 (s, 1 H), 8.90 (d, J=7.2 Hz, 1 H), 8.35 (s, 1 H), 7.66 (br s, 1 H), 7.31 (d, J=10.7 Hz, 1 H), 7.04-7.00 (m, 1 H), 4.31 (br s, 1 H), 2.80 (br s, 1 H), 2.44 (t, J=6.1, 3.1 Hz, 1 H), 1.66 (s, 6 H), 0.78-0.77 (m, 2 H), 0.53-0.51 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4](Cl)[N:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[NH2:1][C:2]1[N:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1nc(-c2ccccc2)cc(-c2ccccc2)n1
Yield: 76.7 %

Procedure:
2-Amino-4,6-dichloropyrimidine 9.5 g (58 mmol), phenylboronic acid 17 g (140 mmol) and tetrakis(triphenylphosphine)palladium 2.7 g (2.3 mmol) were dissolved in 120 mL of 1,2-dimethoxyethane. A 2.0M sodium carbonate aqueous solution 60 mL was added thereto, and the solution was refluxed for 8 hours under argon atmosphere by heating. After finishing the reaction, the aqueous layer was removed. The organic layer was dried on anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was refined by silica gel chromatography to obtain 11 g (yield: 77%) of 2-amino-4,6-diphenylpyrimidine.