Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[O:17])[N:14]([CH3:18])[C:13](=[N:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:29]C(C)([O-])C.[K+].CI.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH3:29])[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[N:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)[nH]2)cc1OC
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)n2C)cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a suspension of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (1.0 g) in N,N-dimethylformamide (10 ml) were added potassium tert-butoxide (0.38 g) and methyl iodide (0.33 ml) and the mixture was stirred at ambient temperature for 5 hours. To the reaction mixture were added additional potassium tertbutoxide (0.38 g) and methyl iodide (0.17 ml) and the mixture was stirred at ambient temperature for more 2 hours. The mixture was poured into water (100 ml) and the resulting precipitates were collected by filtration. The precipitate was recrystallized from a mixture of methanol and water (5:1) to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (0.83 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1O)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:20])=O>CN(C)C=O>[Br:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:15]2[Cl:20]
Reactant: CCOC(=O)c1cnc2ccc(Br)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2ccc(Br)cc2c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
Suspend 6-bromo-4-hydroxyquinoline-3-carboxylic acid ethyl ester (11 g, 37 mmol) in anhydrous dimethylformamide (148.6 mL) under nitrogen atmosphere. Add phosphoryl chloride (20.7 mL, 222 mmol, 6 eq.) via syringe over 5 minutes and stir vigorously at room temperature for 3 hours. Quench the reaction by pouring the mixture into ice water (1.5 L) and continue stirring until all the ice has melted. Obtain the solid formed by filtration, rinse with water and allow complete drying to afford the titled compound (11.4 g, 94%). MS (ESI) m/z (M+H)+314.0, 316.0.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([NH:5][C:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14](C(=O)C(F)(F)F)=[CH:13][CH:12]=2)[N:7]=1)=[O:4].ClCCl.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(N(CC)CC)C>[F:24][C:2]([F:1])([F:23])[C:3]([NH:5][C:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:7]=1)=[O:4]
Reactant: O=C(NC1=NN(c2ccc(C(=O)C(F)(F)F)cc2)CC1)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1=NN(c2ccccc2)CC1)C(F)(F)F
Reaction time: 0.5 h

Procedure:
A mixture of 5.0 g. of 3-amino-1-phenyl-2-pyrazoline (prepared as described in Example 8), 200 ml. of dichloromethane, 5.0 ml. of triethylamine and 7.0 ml. of trifluoroacetic anhydride is allowed to remain at room temperature for 30 minutes. The mixture is evaporated to dryness in vacuo, then water is added to separate a semi-solid. The solid is dissolved in dichloromethane. The solution is dried over anhydrous sodium sulfate, columnized and recrystallized as for Example 14 (B) to give 3.0 g. of the desired product as yellow-orange prisms, m,p. 163°-165° C.
Reaction SMILES: C(O)C.[CH2:4]([O:6][C:7]([CH:9]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23](OCC)=[NH:24])=[CH:17][CH:16]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8])[CH3:5].[CH2:28](N)[CH2:29][NH2:30].Cl>O>[CH2:13]([O:12][C:10]([CH:9]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]2[NH:24][CH2:28][CH2:29][N:30]=2)=[CH:19][CH:20]=1)[C:7]([O:6][CH2:4][CH3:5])=[O:8])=[O:11])[CH3:14]
Reactant: CCOC(=N)COc1ccc(C(C(=O)OCC)C(=O)OCC)cc1
Reactant: NCCN
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)c1ccc(OCC2=NCCN2)cc1
Yield: 54.8 %

Procedure:
With ice cooling and stirring, 40 ml of ethanol solution containing 3.6 g of ethyl 2-ethoxycarbonyl-2-[4-(2-ethoxy-2-iminoethoxy]phenyl]acetate obtained in the above step b) was added dropwise to a 10 ml ethanol solution containing 0.6 g of ethylenediamine, and the resulting mixture was stirred at room temperature for 1.5 hours, followed by refluxing under heating for 0.5 hours. After cooling, the resulting reaction solution was adjusted to an acidic pH with ethanol containing 13% (w/v) of hydrochloric acid, and then concentrated to dryness. The residue thus obtained was dissolved in water and washed with diethyl ether. Thereafter, the resulting water layer was adjusted to pH 9-10 with dilute sodium hydroxide aqueous solution, and crystals thus precipitated were collected by filtration. In this way, 1.83 g of the title compound was obtained in the form of colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])[C:5]2[N:11]=[CH:10]N=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[C:6]=2[N:7]=1.[C:27]1(C)C=CC(S(O)(=O)=O)=CC=1.C(NCCC)CC>O.CCOC(C)=O>[CH3:1][C:2]1[N:3]=[C:4]([N:20]([CH2:21][CH2:22][CH3:23])[CH2:24][CH2:25][CH3:26])[C:5]2[N:11]=[CH:10][CH:27]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[C:6]=2[N:7]=1
Reactant: CCCN(CCC)c1nc(C)nc2c(-c3ccc(Cl)cc3Cl)ncnc12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCNCCC
Product: CCCN(CCC)c1nc(C)nc2c(-c3ccc(Cl)cc3Cl)ccnc12
Temperature: 195 °C

Procedure:
A mixture of 4 (10 mg), p-toluenesulfonic acid (20 mg) and dipropylamine (50 ml) is stirred and heated to 195° C. in a sealed tube for 1.5 h. The solution is then allowed to cool to r.t., and dissolved in a mixture of water and EtOAc. This is extracted with EtOAc, the organic phase washed with brine, dried and concentrated. The product is purified by prep. TLC (SiO2) using ethyl acetate/hexane.
Reaction SMILES: [F:1][C:2]1[C:11]([OH:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N+:13]([O-])=O)[CH:3]=1.CO.[H][H]>[Pd].C1COCC1>[NH2:13][C:4]1[CH:3]=[C:2]([F:1])[C:11]([OH:12])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(O)c(F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(O)c(F)cc1N
Yield: 85 %

Procedure:
Palladium on carbon (2.5 wt. %, wet, 8.5 g, 0.005 eq) was charged into a 1 L Parr bomb. Then, methyl 4-fluoro-5-hydroxy-2-nitrobenzoate, 62 g, 0.29 mol, 1 eq) and MeOH (300 mL) were charged. The bomb was sealed, and pressurized/vented three times with hydrogen, and pressured with 100 psi hydrogen. The reaction mixture was stirred, until the hydrogen pressure was not dropping. The bomb was opened, and an HPLC sample showed that the reaction was complete. The mixture was diluted with 400 ml of THF and filtered through a Celite pad. The solution was concentrated under vacuum and solvent was switched to MeOH. To the thick suspension in MeOH, water (150 mL) was added in about 30 min. The slurry was filtered. The desired product, methyl 2-amino-4-fluoro-5-hydroxybenzoate, was obtained as off-white solid after drying under vacuum (45.5 g, 85% yield). NMR (DMSO-d6, 400 MHz) δ 9.05 (s, 1H), 7.28 (d, J=10.0 Hz, 1H), 6.54 (d, J=13.4 Hz, 1H), 6.30 (s, 2H), 3.74 (s, 3H). 13C NMR (DMSO-d6, 100 MHz) δ 167.0, 157.0, 154.5, 146.2, 146.1, 134.5, 134.4, 118.2, 104.7, 103.3, 51.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[CH:14]1[C:19](O)=[CH:18][CH:17]=[C:16]([CH3:21])[CH:15]=1>>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[CH:5]1[C:18]2[C:19](=[CH:14][CH:15]=[C:16]([CH3:21])[CH:17]=2)[O:8][C:7](=[O:9])[CH2:6]1
Reactant: COc1ccccc1C=CC(=O)O
Reactant: Cc1ccc(O)cc1
Product: COc1ccccc1C1CC(=O)Oc2ccc(C)cc21
Reaction time: 2 h

Procedure:
A mixture of 2-methoxycinnamic acid (178 g, 1.0 mol), p-cresol (108 g, 1.0 mol), and p-touenesulphonic acid monohydrate (47.5 g, 0.25 mol) was stirred on a boiling water-bath for about 2 h during which time the system was evacuated with a waterpump to remove formed water. The solid was then broken up and washed copiously with water. The granular material was then stirred with a large volume of saturated NaHCO3 solution containing some 10% acetone. The product was filtered off, washed dried and recrystallised from acetone affording 167 g (62,5%) white crystals of the desired lactone, m.p. 140°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C[Si]([C:27]#[N:28])(C)C.[OH-].[NH4+]>C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:27]#[N:28])([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([CH3:15])[CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Cc1cccc(N)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cccc(NC2(C#N)CCN(Cc3ccccc3)CC2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-benzyl-4-piperidone (18.9 g, 0.1 mol) and 3-methylaniline (10.7 g, 0.1 mol) in glacial acetic acid (100 mL), trimethylsilyl cyanide (6.7 mL, 0.1 mol; Journal of Organic Chemistry, vol.55, page 4207, year 1990) was added dropwise with the temp. of the reaction maintained <40° C. with a ice-water bath. After the addition was complete, the reaction mixture was stirred at room temp. for 30 min, and poured into a mixture of ice (140 g) and concentrated ammonium hydroxide (168 g). The resultant mixture was extracted with chloroform (3 times). The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residual oil was triturated with diisopropyl ether (300 mL) and stirred at room temp. overnight. The white solid precipitated was filtered to provide the title compound.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH3:25])=[O:5])C.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]=[C:34]=[O:35])[CH:28]=1>>[Cl:26][C:27]1[CH:28]=[C:29]([N:33]2[C:4](=[O:5])[C:6]3[CH:7]=[N:8][C:9]4[C:10]([O:24][CH3:25])=[CH:11][CH:12]=[CH:13][C:14]=4[C:15]=3[N:16]([CH:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)[C:34]2=[O:35])[CH:30]=[CH:31][CH:32]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCC(C)CC1
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCC(C)CC3)c12
Yield: 58.1 %

Procedure:
3-(3-Chloro-phenyl)-7-methoxy-1-(4-methyl-cyclohexyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (115 mg) was prepared from 8-methoxy-4-(4-methyl-cyclohexylamino)-quinoline-3-carboxylic acid ethyl ester (150 mg, 0.44 mmol) and 1-chloro-3-isocyanato-benzene (0.66 mmol) following general procedure C. LCMS: m/z 450 [M+1]+.
Reaction SMILES: [Cl-].[Cl-].C[Zr:4](C)(=[SiH2])(C1C2C(=C(C3C=CC=CC=3)C=CC=2)C=C1C)[CH:5]1[C:13]2[C:8](=C(C3C=CC=CC=3)C=CC=2)[CH:7]=[C:6]1C>C1(C)C=CC=CC=1>[CH-:5]1[CH:13]=[CH:8][CH:7]=[CH:6]1.[CH-:5]1[CH:13]=[CH:8][CH:7]=[CH:6]1.[Zr+2:4]
Reactant: CC1=Cc2c(-c3ccccc3)cccc2C1[Zr](C)(C)(=[SiH2])C1C(C)=Cc2c(-c3ccccc3)cccc21
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: [Zr+2]
Product: c1cc[cH-]c1
Temperature: -30 °C
Yield: 37.1 %

Procedure:
1.5 g of the solid prepared under aa) (106 mmol of Al) were suspended in 100 cm3 of toluene in a stirrable vessel and cooled to -30° C. At the same time, 155 mg (0.246 mmol) of rac-dimethyl-silanediylbis(2-methyl-4-phenylindenyl)zirconium dichloride were dissolved in 75 cm3 of toluene and added dropwise to the suspension in the course of 30 minutes. The mixture was warmed slowly to room temperature with stirring, during which time the suspension took on a red color. The mixture was subsequently stirred at 80° C. for 1 hour, cooled to room temperature and filtered, and the solid washed 3× with 100 cm3 of toluene in each case and once with 100 cm3 of hexane. The hexane-moist filter residue which remained was dried in vacuo, giving 12.9 g of free-flowing, pale red, supported catalyst. Analysis gave a content of 10.1 mg of zirconocene per gram of catalyst.
Reaction SMILES: [F:1][C:2]([C:5]([C:8]([F:11])([F:10])[F:9])=[N+:6]=[N-:7])([F:4])[F:3].[C:12]([C:14]#[CH:15])#[N:13]>>[F:1][C:2]([F:4])([F:3])[C:5]1([C:8]([F:9])([F:10])[F:11])[CH:15]=[C:14]([C:12]#[N:13])[N:7]=[N:6]1
Reactant: C#CC#N
Reactant: [N-]=[N+]=C(C(F)(F)F)C(F)(F)F
Product: N#CC1=CC(C(F)(F)F)(C(F)(F)F)N=N1
Temperature: 50 °C
Yield: 87.6 %

Procedure:
A sealed glass tube containing 36.2 g of bis(trifluoromethyl)diazomethane and 10.2 g of cyanoacetylene was heated at 50°C for 24 hours. The product was distilled to give 40.1 g of 3,3-bis(trifluoromethyl)-5-cyano-3H-pyrazole, bp 38°C/12 mm. The ultraviolet, infrared, and mass spectra as well as the proton and fluorine nuclear magnetic resonance spectra were consistent with the proposed structure.
Reaction SMILES: F[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[C:22]([N:24]3[CH:28]=[C:27]([CH2:29][CH2:30][OH:31])[N:26]=[N:25]3)[CH:21]=[CH:20][C:19]=2[CH3:32])=[O:17])=[C:12]([CH3:33])[CH:11]=1.BrC1C=C[C:38]([C:41](C2C=C(N3C=C(CCO)N=N3)C=CC=2C)=[O:42])=C(C)C=1.NC1C=C(C(=O)C)C=CC=1>>[OH:31][CH2:30][CH2:29][C:27]1[N:26]=[N:25][N:24]([C:22]2[CH:21]=[CH:20][C:19]([CH3:32])=[C:18]([CH:23]=2)[C:16]([C:13]2[CH:14]=[CH:15][C:10]([NH:9][C:3]3[CH:4]=[C:5]([C:41](=[O:42])[CH3:38])[CH:6]=[CH:7][CH:2]=3)=[CH:11][C:12]=2[CH3:33])=[O:17])[CH:28]=1
Reactant: Cc1cc(Br)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Reactant: Cc1cc(Nc2ccc(F)cc2F)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Agent: CC(=O)c1cccc(N)c1
Product: CC(=O)c1cccc(Nc2ccc(C(=O)c3cc(-n4cc(CCO)nn4)ccc3C)c(C)c2)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 148, using compound 452 (0.13 mmol) and 1-(3-amino-phenyl)-ethanone (0.13 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM/petroleum ether (40-60) 0:50:50, 0:100:0 and 5:95:0 as the eluent to afford the title compound as yellow solid. 13C NMR (CDCl3) δ 197.8, 197.1, 147.1, 146.3, 143.3, 142.3, 141.2, 138.5, 137.1, 135.3, 134.7, 132.3, 129.8, 128.5, 124.8, 123.2, 121.5, 120.0, 119.9, 119.6, 118.7, 111.8, 61.6, 28.7, 26.7, 22.2, 19.6
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.CC1(C)COB([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])(C)C)=[N:22][CH:23]=2)OC1.CO[C:36]1C=CC2N=C(C3C=NC(N)=NC=3)SC=2[CH:37]=1>>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][NH:25][C:26](=[O:32])[O:27][CH2:28][CH2:31][CH2:36][CH3:37])=[N:22][CH:23]=1
Reactant: CC1(C)COB(c2ccc(CNC(=O)OC(C)(C)C)nc2)OC1
Reactant: COc1ccc2nc(-c3cnc(N)nc3)sc2c1
Reactant: Clc1nc2ccccc2s1
Product: CCCCOC(=O)NCc1ccc(-c2nc3ccccc3s2)cn1
Reaction time: 1 h

Procedure:
2-Chlorobenzothiazole (31 μL, 0.25 mmol) and tert-butyl [5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)pyridin-2-yl]methylcarbamate (80 mg, 0.25 mmol) were reacted according to the procedure used for the preparation of 5-(6-methoxy-1,3-benzothiazol-2-yl)pyrimidin-2-amine. After 1 h at 80° C., the mixture was concentrated under reduced pressure and the residue was partitioned between DCM and H2O. The organic phase was concentrated. Flash chromatography (Heptane/EtOAc gradient) gave the product (53 mg) as a white solid. MS m/z (M+H) 342.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3].[CH3:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][C:31](O)=[O:32].CCCCCC>C(CC(C)(C)C)(C)C>[C:31]([O:11][CH2:10]/[CH:9]=[C:7](/[CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])\[CH3:8])(=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Reactant: CC(C)=CCC/C(C)=C/CO
Solvent: CCCCCC
Solvent: CC(C)CC(C)(C)C
Product: CCCCCCCCCC=CC=CC=CC=CC=CC(=O)OC/C=C(\C)CCC=C(C)C
Temperature: 60 °C
Reaction time: 24 h

Procedure:
There were dissolved, in 1 g of isooctane, 100 mg of geraniol and 900 mg of ethyl ester of eicosapentaenoic acid, followed by the addition of lipase in an amount of 1% relative to the total amount of the resulting solution and then stirring the mixture at 60° C. for 24 hours. After confirming whether the reaction system reached its equilibrium state or not by the GC technique, the reaction solution was diluted by the addition of hexane to the solution in an amount of 10 times the volume thereof, followed by the removal of the lipase from the reaction solution through filtration and then the removal of the hexane through distillation to thus give a crude reaction product. The crude product was purified by silica gel column chromatography to give 122 mg of geranyl eicosapentaenoate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3([CH2:30][C:31]([OH:33])=O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:18][CH2:17]2)[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>ClCCl.CN(C)C=O>[N:40]1([C:31](=[O:33])[CH2:30][C:24]2([CH2:23][CH2:22][N:19]3[CH2:20][CH2:21][CH:16]([N:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=4)[C:9]([C:11]4[O:12][CH:13]=[CH:14][CH:15]=4)=[O:10])[CH2:17][CH2:18]3)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CC(=O)O)CCCCC3)CC2)nc1
Reactant: C1COCCN1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CC(=O)N4CCOCC4)CCCCC3)CC2)nc1
Reaction time: 2 h
Yield: 17.4 %

Procedure:
To a solution of [1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetic acid (synthesized in Example 3A-3) (300 mg) in dichloromethane (4 mL) was added N,N-dimethylformamide (1 drop) dropwise and then oxalyl chloride (0.087 mL) under ice cooling. The solution was stirred under ice cooling for 2 hours. A 2 mL aliquot of the reaction solution was taken and it was added to a solution of morpholine (288 mg) in dichloromethane (4 mL) dropwise under ice cooling. The solution was stirred under ice cooling for 1.5 hours. NH silica gel was then added to the reaction solution and it was concentrated under reduced pressure. The residue was purified by chromatography [NH silica gel, hexane-ethyl acetate (1:1)] to give the title compound (60 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH3:13])([O-:3])=[O:2].[N:14]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1.N1CCCC1>>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1/[CH:13]=[CH:20]/[C:17]1[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccncc1
Reactant: Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: C1CCNC1
Product: O=[N+]([O-])c1ccc(/C=C/c2ccncc2)c([N+](=O)[O-])c1

Procedure:
1.4 g (7.7 mmol) of 2,4-dinitrotoluene, 0.82 g (7.7 mmol) of pyridine-4-carboxaldehyde and 0.2 mL of pyrrolidine were charged to a round-bottomed flask. The flask was fitted with a splash protector and then irradiated for 20 seconds in a domestic microwave oven (850 watt). The mixture was then allowed to cool, and the product was caused to precipitate by addition of 20 mL of acetone. Suction-filtration and drying at 40° C. under vacuum have 0.9 g of product (43% of the theoretical).
Reaction SMILES: [C:1]([C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)#[N:2].Cl.[NH2:9][OH:10].C([O-])([O-])=O.[K+].[K+]>C(O)C.O>[S:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[C:1](=[N:9][OH:10])[NH2:2]
Reactant: NO
Reactant: N#Cc1cccs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NC(=NO)c1cccs1
Yield: 78.8 %

Procedure:
To a solution of 21.8 g (0.20 mole) of 2-cyanothiophene in 500 ml of ethanol, 13.9 g (0.20 mole) of hydroxylamine HCl is added, followed by the addition of 13.8 g (0.10 mole) of K2CO3 in 50 ml of water. The mixture is refluxed for 16 hours, cooled and diluted with 200 ml of water. After removing the ethanol in vacuo, the product precipitates out of the aqueous residue. It is collected by filtration, washed with water and dried to yield 22.4 g (80%) of product, m.p. 70°-75°.
Reaction SMILES: [N:1]1([C:9](=[O:11])[CH3:10])[C:5]2[CH:6]=[CH:7][S:8][C:4]=2[CH:3]=[N:2]1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:12][C:7]1[S:8][C:4]2[CH:3]=[N:2][N:1]([C:9](=[O:11])[CH3:10])[C:5]=2[CH:6]=1
Reactant: CC(=O)n1ncc2sccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CC(=O)n1ncc2sc(Br)cc21
Temperature: 50 °C
Reaction time: 17 h
Yield: 84.2 %

Procedure:
A mixture of 1-(thieno[3,2-c]pyrazol-1-yl)-ethanone (5.00 g, 30.1 mmol), N-bromosuccinimide (16.1 g, 90.4 mmol), and chloroform (100 mL) was heated at 50° C. under nitrogen for 5 hours. The orange mixture was stirred at room temperature for an additional 17 hours. The red-orange mixture was filtered, the insolubles washed twice with dichloromethane (60 mL). The filtrate was washed with 10% aqueous NaHSO3 (60 mL) and then twice with water (60 mL), then dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 30% ethyl acetate/heptane to 50% ethyl acetate/heptane to give 1-(5-bromo-thieno[3,2-c]pyrazol-1-yl)-ethanone [6.21 g, 84%, Intermediate (51)] as an off-white solid. TLC Rf 0.50 (silica, 40% ethyl acetate/heptane). LC/MS: 244.93 (M+H), RT=3.10 minutes; 1H NMR [300 Mhz, (CD3)2SO]: δ 8.12 (s, 1H), 7.67 (s, 1H), 2.67 (s, 3H).
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][C:21]([CH:23]1[O:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[O:25][CH2:24]1)=[O:22].C(N(CC)CC)C.O>CN(C)C=O>[C:1]([NH:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:20][C:21]([CH:23]2[O:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[O:25][CH2:24]2)=[O:22])[CH2:15][CH2:14]1)=[O:11])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(=O)c1ccccc1)NC1CCNCC1
Reactant: O=C(CBr)C1COc2ccccc2O1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC(=O)c1ccccc1)NC1CCN(CC(=O)C2COc3ccccc3O2)CC1
Reaction time: 1 h
Yield: 76 %

Procedure:
1-Benzoyl-3-(piperid-4-yl)urea (2.46 g, 0.01 mol) and 2-bromoacetyl-1,4-benzodioxan (2.57 g, 0.01 mol) in dry dimethylformamide (40 mls) were stirred at room temperature. Triethylamine (1,1 g, 1.5 cm3) was added and the suspension stirred for 1 hour. Water was added and the solid filtered off (4.20 g, 100%). The solid was suspended in methanol (40 mls) and ethanolic hydrogen chloride added until the solution was acidic. The title compound was filtered off as the hydrochloride salt and dried (yield 3.51 gm 76% yield). Melting pt. 160°-161° C.