Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)=O.[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:20]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1
Reactant: O=C(O)c1cccnc1
Reactant: CS(=O)(=O)OCCCCCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCCCCCCCOc1ccccc1)c1cccnc1
Temperature: 52.5 °C
Yield: 80.3 %

Procedure:
A solution of 7-(phenyloxy)-1-heptyl methanesulfonate (0.2 g, 0.699 mmol) and nicotinic acid (0.173 g, 1.41 mmol) in anhydrous dimethyl formamide (15 mL) was placed in a 25 mL round bottomed flask. Potassium carbonate (0.097 g, 0.702 mmol) was added to this solution and the reaction mixture was heated at 50-55° C. using an oil bath for a period of 16 hours. It was then allowed to attain room temperature diluted with ethyl acetate (40 mL) and quenched with saturated NH4Cl containing ice (20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with saturated NAHCO3 (3×10 mL), water (2×10 mL) and brine (2×10 mL). The organic layer was dried over Na2SO4. Removal of solvent from the dried extract under reduced pressure afforded the product 7-(phenyloxy)-1-heptyl nicotinate (0.176 g, 80.4%). The product ester from step C was analyzed yielding the following confirmatory data: 1H-NMR (CDCl3) δ 1.38-1.62 (m, 6H), 1.76-1.92 (m, 4H), 3.95 (t, 2H, J=6.45 Hz), 4.35 (t, 2H, J=6.64 Hz), 6.85-6.98 (m, 3H), 7.22-7.38 (m, 2H), 7.38 (dd, 1H, J1=7.93 Hz, J2=4.93 Hz), 8.29 (dt, 1H, J1=7.91 Hz, J2=1.92 Hz), 8.77 (dd, 1H, J1=4.83 Hz, J2=1.70 Hz) and 9.23 (d, 1H, J=2.00 Hz), 13C-NMR (CDCl3) δ 25.8, 25.9, 28.5, 28.9, 29.1, 65.4, 67.6, 114.3, 120.4, 123.2, 126.2, 129.3, 136.9, 150.8, 153.2, 158.9 and 165.2; IR (neat): 1712 cm−1; MS (ES+): 314 (M+1); Anal. Calcd. for C19H23NO3: C, 72.80; H, 7.40 and N, 4.47. Found: C, 72.94; H, 7.54 and N, 4.51.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[O:13][C:12](=[O:14])[O:11][C:10]=1[CH2:15][O:16][C:17](=[O:30])[C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1C(OC(C)(C)C)=O>C1(C)C=CC=CC=1>[CH3:8][C:9]1[O:13][C:12](=[O:14])[O:11][C:10]=1[CH2:15][O:16][C:17](=[O:30])[C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1
Reactant: Cc1oc(=O)oc1COC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1oc(=O)oc1COC(=O)[C@@H]1CCCN1
Reaction time: 0.75 h
Yield: 196.1 %

Procedure:
Trifluoroacetic acid (2.5 ml) was added to the compound (38) (360 mg, 1.1 mmol) under ice-cooling and the resulting mixture was stood for 45 min. To the reaction mixture was added toluene and the mixture was concentrated in vacuo to give 490 mg of the compound (39). This compound was used in the next reaction without purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[F:23][C:24](=[C:34]1[CH2:37][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:35]1)[S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26].N12CCCN=C1CCCCC2.C(#N)C>>[F:23][CH:24]([S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:26])=[O:27])[C:34]1([N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH:3]=[N:2]2)[CH2:35][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:37]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: CC(C)(C)OC(=O)N1CC(=C(F)S(=O)(=O)c2ccccc2)C1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC(C(F)S(=O)(=O)c2ccccc2)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
A mixture of 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.40 g, 1.3 mmol), tert-butyl 3-[fluoro(phenylsulfonyl)methylene]azetidine-1-carboxylate (0.56 g, 1.7 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.182 mL, 1.22 mmol) in acetonitrile (6 mL, 100 mmol) was stirred at rt for 3 h. After evaporation to dryness, the residue was purified on silica gel, eluting with 0 to 100% EtOAc in hexane, to give the desired product (820 mg, 100%). LCMS calculated for C30H40FN6O5SSi(M+H)+: m/z=643.3; Found: 643.4. 1H NMR (CDCl3, 300 MHz) δ 8.92 (1H, s), 8.55 (1H, s), 8.32 (1H, s), 7.87 (2H, m), 7.68 (1H, m), 7.55 (2H, m), 7.47 (1H, d, J=3.6 Hz), 6.84 (1H, d, J=3.6 Hz), 5.77 (1H, d, J=45.6 Hz), 5.74 (2H, s), 4.93 (1H, d, J=10.2 Hz), 4.73˜4.58 (3H, m), 3.60 (2H, t, J=8.1 Hz), 1.51 (9H, s), 0.98 (3H, t, J=8.1 Hz), 0.07 (9H, s) ppm. 19F NMR (CDCl3, 300 MHz) δ −181.84 (1F, d, J=48.6 Hz) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:15])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:7]=1[CH3:8].[CH2:16]([O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28](Cl)=[CH:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:35][CH3:36])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH2:16]([O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([O:15][C:4]3[C:5]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)=[CH:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:35][CH3:36])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cc(O)c(-c2ccccc2)nc1C
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccc3)ccnc2cc1OCc1ccccc1
Temperature: 140 °C
Reaction time: 4 h
Yield: 103.9 %

Procedure:
5,6-Dimethyl-2-phenyl-pyridin-3-ol (400 mg), 7-benzyloxy-4-chloro-6-methoxyquinoline (1.81 g), and 4-dimethylaminopyridine (736 mg) were suspended in o-dichlorobenzene (10 ml), and the suspension was stirred at 140° C. for 4 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (965 mg, yield 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:13]3([CH2:15][CH2:14]3)[C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[O:10][CH:9]([C:20]([O:22]C)=[O:21])[O:8][C:7]=2[C:24]=1[O:25][CH3:26].[OH-].[Na+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:13]3([CH2:15][CH2:14]3)[C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[O:10][CH:9]([C:20]([OH:22])=[O:21])[O:8][C:7]=2[C:24]=1[O:25][CH3:26]
Reactant: COC(=O)C1Oc2ccccc2C2(CC2)c2ccc(OC)c(OC)c2O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1OC)OC(C(=O)O)Oc1ccccc1C21CC1
Reaction time: 1.3 h

Procedure:
A solution of 76 mg (0.23 mmol) of methyl 3',4'-dimethoxyspiro(cyclopropane-1,12'(12'H)-dibenzo[d,g][1,3]dioxocin)-6'-carboxylate in 0.46 ml of tetrahydrofuran was combined with 0.172 ml (0.35 mmol) of 2N aqueous sodium hydroxide and the mixture stirred for 1.3 hour. The resulting mixture was diluted with 0.5 ml of water, extracted with ether, and then acidified with 1N aqueous hydrochloric acid. The resulting mixture was extracted 3 times with 1 ml portions of ether and the combined ethereal extracts were dried over magnesium sulfate and concentrated by evaporation under reduced pressure to obtain the title compound in quantitative yield as a white solid. The proton and carbon NMR and infrared spectra were consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].CO.O>Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([C:16]([F:19])([F:17])[F:18])(=[O:14])=[O:15])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(NS(=O)(=O)C(F)(F)F)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(NS(=O)(=O)C(F)(F)F)ccc1Cl
Yield: 81.5 %

Procedure:
A solution of methyl 2-chloro-5-{[(trifluoromethyl)sulfonyl]amino}benzoate (1.0 g, 3.15 mmol), sodium hydroxide (378 mg, 9.44 mmol), methanol (6 ml) and water (6 ml) was stirred for 1 hour. Removal of the volatiles by spin evaporation in vacuo gave a residue that was dissolved in 1 N aqueous hydrochloric acid. The aqueous solution was extracted with ethyl acetate (3 times) and the organic layers were combined, washed with water, and concentrated by spin evaporation in vacuo to give 2-chloro-5-{[(trifluoromethyl)sulfonyl]amino}benzoic acid as a crystalline solid (0.78 g, 82%). 1H-NMR (400 MHz, DMSO-d6): δ 7.63-7.60 (m, 1H), 7.59-7.54 (m, 1H), 7.40-7.35 (m, 1H). ES-LCMS m/z 304 (M+H).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[C:6]([O:10][C:11](=[O:29])[NH:12][C@H:13]([C:20](=[O:28])[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)([CH3:9])([CH3:8])[CH3:7]>CCO>[C:6]([O:10][C:11]([NH:12][C@H:13]([C:20](=[O:28])[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][S:3][C:1](=[O:4])[CH3:2])=[O:29])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCCBr)C(=O)Nc1ccccc1
Agent: [K+]
Solvent: CCO
Product: CC(=O)SCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Potassium thioacetate (9.7 mmol) was added to a solution of ((S)-6-bromo-1-phenylcarbamoyl-hexyl)-carbamic acid tert-butyl ester (6.5 mmol) in EtOH (40 ml). The reaction mixture was stirred at RT overnight. The solvent was removed under reduced pressure and the resulting precipitate was poured into water and extracted twice with AcOEt. The organic layer was washed with brine and dried over Na2SO4 before being evaporated to afford the desired adduct.
Reaction SMILES: [C:1]([OH:14])(=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH2:15](Br)[C:16]#[CH:17]>>[CH2:17]([O:13][C:1](=[O:14])[C:2]1[CH:3]=[C:4]([O:5][CH3:6])[C:7]([OH:8])=[C:9]([O:10][CH3:11])[CH:12]=1)[C:16]#[CH:15]
Reactant: COc1cc(C(=O)O)cc(OC)c1O
Reactant: C#CCBr
Product: C#CCOC(=O)c1cc(OC)c(O)c(OC)c1

Procedure:
By utilizing the procedure of Example 5, by reacting syringic acid and propargyl bromide, there is obtained syringic acid propargyl ester, F. P. 105°-106°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:11]([Si:14](Cl)([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])([CH3:13])[CH3:12]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:14]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:11]([CH3:13])[CH3:12])[CH:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
5-Bromoindole (2.5 g, 12.75 mmol) was dissolved in tetrahydrofuran (THF; 50 mL) and cooled to 0° C. and Sodium Hydride NaH (920 mg, 23 mmol, 60%) was added in portions. The mixture was allowed to warm to RT with stirring for 1 hour. The reaction mixture was again cooled to 0° C. and triisopropylsilyl chloride (TIPSCl; 2.78 mL, 13.1 mmol) was added dropwise. The mixture was allowed to warm to room temperature and was stirred overnight. The mixture was washed with 2.0 N H3PO4, and the organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by flash silica chromatography (100% Hexanes) to give compound 8 as an oil (4.3 g; 96% yield; M+1=353.4)
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH2:11].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH:11][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1ccccc1C(F)(F)F
Product: CC(=O)NCCc1ccccc1C(F)(F)F

Procedure:
In close analogy to the procedure described above, 2-(2-trifluoromethyl-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:9]2)[CH2:5][CH2:4]1)#N.Cl>>[C:17]1([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]3([CH2:5][CH2:4][NH:3][CH2:8][CH2:7]3)[CH2:9]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N#CN1CCC2(CC1)CN(c1ccccc1)c1ccccc12
Agent: Cl
Product: c1ccc(N2CC3(CCNCC3)c3ccccc32)cc1

Procedure:
A mixture of 1'-cyano-1-phenylspiro[indoline-3,4'-piperidine] (Example 8), is treated with 3 N hydrochloric acid under reflux to provide 1-phenylspiro[indoline-3,4'-piperidine].
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.C1CCN2C(=NCCC2)CC1.[C:30]([O:34][C:35](=[O:40])[NH:36][CH2:37][CH2:38]Br)([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[C:11]([O:10][C:8](=[O:9])[CH2:7][N:6]1[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=[C:2]1[S:1][CH2:38][CH2:37][NH:36][C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:40])([CH3:13])([CH3:14])[CH3:12]
Reactant: CC(C)(C)OC(=O)Cn1c(S)nc2ccccc21
Reactant: CC(C)(C)OC(=O)NCCBr
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)Cn1c(SCCNC(=O)OC(C)(C)C)nc2ccccc21
Reaction time: 2 h
Yield: 69.6 %

Procedure:
To a solution of tert-butyl (2-mercapto-benzoimidazol-1-yl)-acetate (Intermediate 3-I, 1.31 g, 4.97 mmol) in dry THF (2.6 ml) cooled to 0° C. is added a solution of DBU (756.6 mg, 742.5 μl, 0.47 mmol) in dry THF (1 ml). This yields a paste that is diluted with dry THF (2.5 ml). A solution of (2-bromo-ethyl)-carbamic acid tert-butyl ester (1.17 g, 5.22 mmol) in dry THF (2.6 ml) is then added and the resulting mixture is allowed to stir for 2 h. The solvent is removed under reduced pressure and saturated aqueous KH2PO4 solution (50 ml) is added. The product is extracted with AcOEt (150 ml), the organic phase is washed once with water and once with brine and dried over Na2SO4. The solvent is removed in vacuo and the crude mixture is purified by flash chromatography on silica-gel (AcOEt/heptane, 1:12), yielding the title compound (1.41 g) in 69% as a colourless oil: tR=2.35 min (LC-2), ESI-MS (pos.): m/z 408.27 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:9])=[C:6]([CH3:8])[CH:7]=1.O[CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].S(=O)(=O)(O)O.O>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([I:9])=[CH:4][C:3]=1[CH2:11][N:12]1[C:16](=[O:17])[C:15]2[C:14](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]1=[O:22]
Reactant: O=C1c2ccccc2C(=O)N1CO
Reactant: Cc1cc(Br)ccc1I
Agent: O=S(=O)(O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Br)c(CN2C(=O)c3ccccc3C2=O)cc1I
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 5-bromo-2-iodo toluene (512 mg, 1.72 mmol) in trifluoroacetic acid (5 mL) was added N-(hydroxymethy) phthalimide (305 mg, 1.72 mmol). The mixture developed a pink color. The solution was stirred at room temperature for 22 hours then concentrated sulfuric acid (1 mL) was added. The homogeneous solution was stirred for 18 hours at room temperature. Water was added and the precipitated solid collected by filtration and dried in a current of air (0.776 gm). This material, which by proton NMR analysis contained approximately 15% of an isomeric product, was carried forward to the following procedure without further purification. 1H NMR (400 MHz, CDCl3) δ7.85 (m, 2H) 7.76(m, 2H) 7.5 (s, 1H) 7.38(s, 1H) 4.84(s, 2H) 2.31(s, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+:11].CC(C)=O.[C:16](Cl)(=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>O>[C:16]([NH:1][C@H:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([O-:6])=[O:5])(=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[Na+:11].[Na+:11]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: CCCCCCCCCCCCCCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCC(=O)N[C@@H](CC(=O)[O-])C(=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a one L three-necked flask were placed 16.0 g (0.12 mol) of L-aspartic acid and an aqueous solution of 9.6 g (0.24 mol) of sodium hydroxide in 150 mL of water under stirring. After the L-aspartic acid was dissolved, 120 mL of acetone was added to the mixture in the flask. Then, to the resultant reaction liquid which had been cooled to 0° C. were added dropwise over a period of 30 minutes, 29.0 g (0.1 mol) of heptadecanoyl chloride and an aqueous solution of 4 g sodium hydroxide in 30 mL of water, while maintaining the reaction temperature at 0 to 5° C. and pH at 11 to 12. Thereafter, by gradually raising the temperature of the reaction liquid to room temperature (25° C.) under stirring over a period of 2 hours, a solution of disodium heptadecanoyl-L-aspartate was obtained. To the resultant solution was added 65 mL of 5N hydrochloric acid to lower the pH of the solution to 1. The crystal thus precipitated was separated from the solution by means of vacuum filtration, washed with water and dried under reduced pressure. The resultant crystal was washed with 500 mL of hexane, dried and recrystallized from a mixed solvent of ethanol/water (8:1). As a result 21.0 g (0.054 mol) of N-heptadecanoyl-L-aspartic acid was obtained in a yield of 54.3% based on the fed heptadecanoyl chloride. The physical properties of the objective N-heptadecanoyl-L-aspartic acid were as follows.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:8]=1)=O.[CH3:27][CH:28]([CH3:32])[CH2:29][NH:30][NH2:31]>CO>[CH3:27][CH:28]([CH3:32])[CH2:29][N:30]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=[N:31]1
Reactant: CC(C)CNN
Reactant: CN(C)C=CC(=O)c1nn(-c2ccc(N3CCOCC3)cc2)ccc1=O
Solvent: CO
Product: CC(C)Cn1nccc1-c1nn(-c2ccc(N3CCOCC3)cc2)ccc1=O
Yield: 14.9 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(4-morpholin-4-ylphenyl)pyridazin-4(1H)-one (300 mg, 0.85 mmol) in 20 mL of methanol, 2-methylpropylhydrazine (300 mg, 3.39 mmol) was added, the resulting mixture was refluxed for 4 hours, then concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1 M acetic acid aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (48 mg, 15% yield) as a yellow solid: NMR (400 MHz, CDCl3): δ 0.83 (6H, d, J=6.8 Hz), 2.17-2.25 (1H, m), 3.25-3.27 (4H, m), 3.89-3.92 (4H, m), 4.34 (2H, d, J=7.6 Hz), 6.72 (1H, d, J=8.0 Hz), 7.00-7.04 (2H, m), 7.33 (1H, d, J=2.4 Hz), 7.45-7.49 (2H, m), 7.59 (1H, d, J=2.0 Hz), 8.15 (1H, d, J=7.6 Hz); LCMS (mobile phase: from 90% water and 10% CH3CN to 5% water and 95% CH3CN in 6 min, finally under these conditions for 0.5 min.) purity is >95%, Rt=3.396 min; MS Calcd.: 379, MS Found: 380 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5]Br.[CH3:11][C:12]([CH3:14])=[O:13]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][C:12]([CH3:14])([OH:13])[CH3:11])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: Fc1ccc(CBr)cc1F
Reactant: CC(C)=O
Product: CC(C)(O)Cc1ccc(F)c(F)c1

Procedure:
From 23.0 g (111 mmol) of 3,4-difluorobenzyl bromide a Grignard is prepared, which is then reacted with 11.6 mL (158 mmol) of acetone. Slightly yellow oil. Yield: 9.7 g (47%); Rf value: 0.55 (ethyl acetate-petroleum ether (1:3)).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH2:15]([C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[CH2:24]O)[CH3:16]>>[CH2:15]([C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[CH2:24][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: CCc1cc(F)ccc1CO
Product: CCc1cc(F)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2-ethyl-4-fluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.23 (3H, t, J=7.6 Hz), 2.72 (2H, q, J=7.6 Hz), 5.20 (2H, s), 5.79 (1H, d, J=2.0 Hz), 6.89-7.00 (2H, m), 7.36-7.40 (2H, m), 7.59 (1H, d, J=2.0 Hz), 7.98 (1H, s), 8.67 (1H, d, J=5.2 Hz). [M+H] Calc'd for C18H15FN4O, 323. Found, 323.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=O.C(=O)(O)[O-].[Na+]>CCO>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([C:10]2[N:1]=[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]3[CH:9]=2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: Nc1ccccn1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(-c2cn3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
A mixture of 2-aminopyridine (0.20 g, 2.11 mmol) and 2-bromo-4′-nitroacetophenone (0.5 g, 2.05 mmol) in EtOH (25 ml) was heated under reflux for 18 h. The reaction mixture was allowed to cool and sodium bicarbonate (88 mg, 1.05 mmol) was added and heating was continued for 2 h. On cooling to room temperature, the solvent was removed under reduced pressure and the residue was dissolved in DCM (40 ml), washed with water (40 ml), and dried (Na2SO4). The solvent was removed under reduced pressure to give a brown solid which was purified by flash chromatography (15:1 DCM/MeOH) to give the title compound (0.27 g, 54%) as a yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH2:15])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=O)[C:24](=[N:30]O)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=1>N1C=CC=CC=1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[NH:15][C:14]([C:11]3[CH:10]=[CH:9][C:8]([CH2:7][N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[CH:13][CH:12]=3)=[N:30][C:24]=2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=1
Reactant: NCc1ccc(CN2CCOCC2)cc1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(-c2ccc(CN3CCOCC3)cc2)[nH]c1-c1ccc(Cl)cc1
Yield: 61.5 %

Procedure:
4-(Morpholinomethyl)phenylmethylamine (8 g) and ethyl 3-(4-chlorophenyl) -2-hydroxyimino-3-oxopropionate (8.26 g) were dissolved in pyridine (120 ml) and the mixture was refluxed under heating for 12 hr. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography to give the objective ethyl 5-(4-chlorophenyl)-2-[4-(morpholinomethyl)phenyl]imidazole-4-carboxylate (8.46 g), melting point 183-185° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[CH2:14]([O:16][C:17](=[O:24])[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:15]>CC(O)C>[CH2:14]([O:16][C:17]([CH:18]1[CH2:19][CH2:20][N:21]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:22][CH2:23]1)=[O:24])[CH3:15]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Brc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCOC(=O)C1CCN(c2ccccn2)CC1
Temperature: 120 °C

Procedure:
Potassium carbonate (52.5 g, 0.379 mol) was charged to a stirred solution of 2-Bromopyridine (60 g, 0.379 mol) and Ethylisonipecotate (59.7 g, 0.379 mol), at an ambient temperature before heating to 120° C. for 24 hours. The mixture was cooled to room temperature and propan-2-ol charged to the solution. The reaction mixture was then filtered and telescoped into preparation 1c.