Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][C:14]([CH:22]=[N:23][OH:24])=[C:13]([CH2:25][O:26][CH3:27])[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrN1C(=O)C[CH2:31][C:30]1=O.C[Si](C#C)(C)C.[OH-].[Na+]>CN(C=O)C.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][C:14]([C:22]3[CH:31]=[CH:30][O:24][N:23]=3)=[C:13]([CH2:25][O:26][CH3:27])[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCc1c(C=NO)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Reactant: O=C1CCC(=O)N1Br
Agent: C#C[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCc1c(-c2ccon2)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.55 g (1.5 mmol) of 6-benzyloxy-4-methoxymethyl-β-carboline-3-carbaldehyde oxime is dissolved in 30 ml of dry DMF and combined with 0.3 g (1.7 mmol) of N-bromosuccinimide (dissolved in 5 ml of DMF). The reaction mixture is stirred for 10 minutes at room temperature and then 1.5 eq. of trimethylsilylacetylene and 1 ml of triethylamine are added. After 4 hours of agitation at room temperature, 5 ml of 1-molar sodium hydroxide solution is added and subsequently agitation is continued for another hour. The solution is poured into ice water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and the solvent drawn off. The resultant product is purified by column chromatography on silica gel with ethyl acetate as the eluent. Melting point: 123°-126° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=[O:6].O.[NH2:13][NH2:14].O>C(O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:13][NH2:14])=[O:6]
Reactant: COC(=O)c1cccc(I)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cccc(I)c1
Temperature: 25 °C

Procedure:
To Methyl 3-iodobenzoate (25.0 g, 95.41 mmol) in ethanol (120.0 ml) was added hydrazine hydrate (50.0 ml). The reaction mixture was reflux for 18 hours. Heating was stopped and then water (300.0 ml) was added. After cooling down to room temperature, white solid was appeared. The white product solid was collected by filtration. The product was washed with water and dried under vacuum. Final white pure product was obtained in 23.0 g (92.0%). 1H NMR (400 MHz, DMSO-d6, δ): 9.85 (s, br, 1H, NH), 8.14 (t, J=1.6 Hz, 1H), 7.85 (m, 1H), 7.82 (m, 1H), 7.25 (t, J=8.0 Hz, 1H), 4.50 (s, 2H, NH2). 13C NMR (100 MHz, CDCl3) δ: 168.54, 155.38, 129.54, 126.72, 125.57, 34.90, 31.07.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[O:6][C:7]1[N:12]=[C:11]([O:13][C:14]2[CH:15]=[C:16]([CH:22]=[C:23]([OH:25])[CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:10]([F:26])=[C:9]([CH3:27])[C:8]=1[F:28])#[N:2].[C:32](=O)([O-])[O-].[Cs+].[Cs+].IC>C(#N)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[O:6][C:7]1[N:12]=[C:11]([O:13][C:14]2[CH:15]=[C:16]([CH:22]=[C:23]([O:25][CH3:32])[CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:10]([F:26])=[C:9]([CH3:27])[C:8]=1[F:28])#[N:2]
Reactant: CCOC(=O)c1cc(O)cc(Oc2nc(Oc3cccc(C#N)c3)c(F)c(C)c2F)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: CCOC(=O)c1cc(OC)cc(Oc2nc(Oc3cccc(C#N)c3)c(F)c(C)c2F)c1
Reaction time: 15 h

Procedure:
To acetonitrile (5 mL) was added 3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-5-hydroxybenzoic acid, ethyl ester (0.20 g, 0.47 mmol), cesium carbonate (0.31 g, 0.94 mmol), and iodomethane (0.13 g, 0.94 mmol). After stirring for 15 hours the mixture was partitioned with ethyl acetate and water. The organic layer was dried (MgSO4) and the solvent was removed in vacuo to give 3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methyl-pyridin-2-yl)oxy]-5-methoxybenzoic acid, ethyl ester; NMR (CDCl3) 7.3 (m, 6), 6.8 (s, 1), 4.4 (q, 2), 3.8 (s, 3), 2.4 (s, 3), 1.4 (t, 3) ppm.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[N:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:23].C1CCC(N=C=NC2CCCCC2)CC1>COCCOC>[CH3:7][C:4]([CH3:5])([O:3][C:1]([NH:8][C@H:9]([C:13]([CH:19]1[CH2:20][C:21](=[O:22])[NH:17][C:18]1=[O:23])=[O:15])[CH:10]([CH3:11])[CH3:12])=[O:2])[CH3:6]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: COCCOC
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)C1CC(=O)NC1=O
Temperature: 5 °C
Reaction time: 6 h

Procedure:
To a cooled (icebath) stirred solution of BOC—L-valine (4.56 g, 0.021 mol), and N-hydroxysuccinimide (2.41 g, 0.021 mol) in DME (50 mL) was added DCC (4.75 g, 0.023 mol). The reaction was stirred for 6 h at 5° C. and then left to stand in the refrigerator over night. The reaction was then cold filtered, washing with Et2O, and conc to yield a solid which was crystallized from EtOAc/hexane to give the desired product as a white crystalline sold (4.59 g, 69.5%): mp 123-124° C.; 1H NMR (300 MHz, CDCl3) δ 5.00-4.95 (d, 1H, J=9.3 Hz), 4.62 (dd, 1H, J=4.97 Hz), 2.85 (s, 4H), 2.75-2.44 (m, 1H), 1.45 (s, 9H), 1.25-0.90 (m, 6H); 13C NMR (CDCl3) δ 168.6, 167.9, 155.1, 155.0, 80.4, 77.4, 77.2, 77.0, 76.6, 76.5, 57.0, 31.6, 31.1, 28.2, 28.1, 28.0, 27.99, 27.93, 25.5, 18.6, 17.3; MS (Cl/CH4) m/z 315 (MH+), 299, 287, 259, 241, 215 (base peak), 173, 172, 145, 144, 116, 100, 72. Anal. Calcd. for C14H22N2O6: C, 53.49; H, 7.05; N, 8.91. Found: C, 53.67; H, 7.06; N, 8.81.
Reaction SMILES: [C:1]([C:12]1[CH:27]=[CH:26][C:15]([O:16][CH2:17][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=2)=[C:14]([CH2:28][CH2:29][CH3:30])[C:13]=1[OH:31])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[S:32]1[CH2:38][C:36](=[O:37])[NH:35][C:33]1=[S:34].C(=O)C1C=CC=CC=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:1]([C:12]1[CH:27]=[CH:26][C:15]([O:16][CH2:17][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[C:38]3[S:32][C:33](=[S:34])[NH:35][C:36]3=[O:37])=[CH:20][CH:19]=2)=[C:14]([CH2:28][CH2:29][CH3:30])[C:13]=1[OH:31])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)c1ccc(OCc2ccc(C=O)cc2)c(CCC)c1O
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCCCCCCC(=O)c1ccc(OCc2ccc(C=C3SC(=S)NC3=O)cc2)c(CCC)c1O
Yield: 84 %

Procedure:
The 4-[(4-decanoyl-3-hydroxy-2-propylphenoxy)methyl]benzaldehyde thus obtained was coupled with the rhodanine by reacting equimolar amounts of the benzaldehyde and the rhodanine in the presence of sodium acetate and acetic acid as previously described to yield 1.6 g (84%) of the title product. mp 187.5°-188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([CH3:18])[C:10](=[O:17])[C:11]([CH3:16])([C:13]([OH:15])=[O:14])[O:12][C:7]=2[CH:6]=1.C1(NC2CCCCC2)CCCCC1.Br[CH2:43][C:44]([O:46][CH3:47])=[O:45].O>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([CH3:18])[C:10](=[O:17])[C:11]([CH3:16])([C:13]([O:15][CH2:43][C:44]([O:46][CH3:47])=[O:45])=[O:14])[O:12][C:7]=2[CH:6]=1
Reactant: COC(=O)CBr
Reactant: CN1C(=O)C(C)(C(=O)O)Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc21
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COC(=O)C1(C)Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2N(C)C1=O
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
7-(2-Chloro-4-trifluoromethylphenoxy)-2,4-dimethyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-2-carboxylic acid (Compound 23) (0.4 g) was dissolved in DMF (0.2 ml) and dicyclohexylamine (0.2 ml) was added thereto, followed by stirring at 60° C. for 15 minutes. Then methyl bromoacetate (0.2 g) was added, the mixture further stirred at 60° C. for 3 hours, to the reaction mixture was added water (20 ml), and the mixture was extracted twice with ethyl acetate (20 ml). The extract was washed with water and then with saturated aqueous sodium chloride, and then dried over magnesium sulfate, followed by an evaporation of the solvent under a reduced pressure. The residue was purified by silica gel chromatography (eluant: n-hexane/ethyl acetate=3/1) to give 0.3 g of the title compound (colorless crystals).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:26])[CH2:21][S:22][CH2:23][CH2:24][OH:25])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]([CH3:33])([CH3:32])[C:29](Cl)=[O:30]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:26])[CH2:21][S:22][CH2:23][CH2:24][O:25][C:29](=[O:30])[C:28]([CH3:33])([CH3:32])[CH3:27])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)(C)C(=O)OCCSCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 63 %

Procedure:
Following a procedure similar to that described in Example 7, but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide (prepared as described in Example 1) and 2,2-dimethylpropionyl chloride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a 63% yield.
Reaction SMILES: [F: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]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[N:16]1[CH:17]=[CH:18][C:13]([CH2:11][CH2:12][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: C=Cc1ccncc1
Reactant: Fc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: Fc1ccc2[nH]cc(CCc3ccncc3)c2c1
Temperature: 0 °C
Yield: 71 %

Procedure:
The starting product was prepared according to the same procedure as that described in the last paragraph of Example 2. 9.5 g of 5-fluoro-indole (U.S. Pat. No. 879,619) and 11 g 4-vinyl-pyridine were refluxed for 6 hours in 50 ml acetic acid. The mixture was then poured onto 300 g of crushed ice and alkalinized with a 20% potassium carbonate solution. A precipitate formed which was squeezed and washed in water several times. After drying under vacuum, 12 g of 3-[2-(4-pyridyl)-ethyl]-5-fluoro-indole were obtained which melted at 128° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][NH:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:36])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.Cl[C:38]([O:40][CH3:41])=[O:39].CCN(C(C)C)C(C)C>C1COCC1>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][C:27]([CH2:30][N:31]([CH2:32][CH2:33][O:34][CH3:35])[C:38](=[O:39])[O:40][CH3:41])=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:36])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1)C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.3 %

Procedure:
To a solution of compound 339 (220 mg, 0.433 mmol) and methyl chloroformate (50.2 μl, 0.65 mmol) in THF (4 ml) was added DIPEA (227 μl, 1.30 mmol) and the mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure, the residue was triturated with MeOH and the solid suspension was collected by filtration and purified via Biotage (linear gradient 0-20%, methanol/dichloromethane; Snap 25 g column) to afford compound 340 (123.1 mg, 0.218 mmol, 50.2% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.70 (s, 1H), 8.56-8.50 (m, 2H), 8.33 (s, 1H), 8.25 (d, J=8.0 Hz, 1H), 7.84-7.77 (m, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.2 Hz, 1H), 7.20 (dd, J=8.8, 1.2 Hz, 1H), 6.65 (d, J=5.6 Hz, 1H), 6.56 (d, J=2.8 Hz, 1H), 4.54 (s, 2H), 3.64 (s, 2H), 3.44 (s, 3H), 3.22 (s, 2H), 2.59-2.51 (m, 1H), 0.69-0.62 (m, 2H), 0.46-0.40 (m, 2H). MS (m/z): 566.4 (M+H).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].C(N(CC)CC)C>C(O)C>[N:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])=[CH:3][CH:4]=1
Reactant: Sc1ccncc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CCCCSc1ccncc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In 100 ml of ethanol were suspended 6.66 g of 4-mercaptopyridine and 16.9 g of N-(4-bromobutyl)phthalimide. To the suspension was added 9.09 g of triethylamine, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure. To the residue was added 300 ml of water, and the mixture was subjected to extraction twice with dichloromethane. The extract solutions were combined, washed with an aqueous saline solution, then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to a silica gel (500 g) column chromatography, using as the developer a mixture of hexane and ethyl acetate (1:2), followed by elution with ethyl acetate. The eluate was concentrated under reduced pressure. To the concentrate were added ethyl acetate and hexane. Resulting powders were collected by filtration to give N-[4-(4-pyridylthio)butyl]phthalimide as a colorless powdery product, m.p. 106.5°-107.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C.ClCCl>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[CH:7][C:2]=1[CH3:1]
Reactant: COc1ccccc1C
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Methylanisole (2.5 ml) in acetic acid (140 ml) and dichloromethane (150 ml) was cooled to 15° C. Concentrated nitric acid (20 ml) was added slowly keeping the temperature of the reaction below 40° C. The reaction was stirred at ambient temperature for 30 minutes and cooled to 0° C. before adding fuming nitric acid (50 ml) dropwise. The reaction mixture was allowed to warm to ambient temperature slowly and stirred for a further 4 days. The reaction mixture was poured onto ice water (600 ml) and the organic layer was washed with water (2×40 ml) and saturated sodium hydrogencarbonate (2×40 ml), dried over magnesium sulfate and concentrated. The residual deep red solid was subjected to flash silica chromatography on silica eluting with isohexane/ethyl acetate (9:1) to (7:3) to yield 1-methoxy-2-methyl-4-nitrobenzene (2.70 g) as an off white solid. LC-MS (Method J): RT 3.74 minutes, 168.27 (M+H)+.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH2:10][CH2:9][CH:8]2[CH2:13][OH:14])OCC1.[CH2:15](Br)[CH:16]=[CH2:17]>C1COCC1>[CH2:17]([O:14][CH2:13][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C:7]1=[O:3])[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: OCC1CCCCC12OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOCC1CCCCC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of NaH (1.14 g, 60% oil dispersion, 28.6 mmol) in dry THF (45 mL) at 0° C. was added 1,4-dioxaspiro[4.5]dec-6-ylmethanol (2.46 g, 14.3 mmol) in dry THF (5 mL). The mixture was allowed to warm to rt and stirred for 1 hr. The mixture was then cooled to 0° C. and allyl bromide (2.10 mL, 24.28 mmol) was added in one portion. The mixture was then allowed to warm to rt and stirred for 1 hr. The mixture was then heated to 60° C. overnight. It was cooled to 0° C. and quenched with 50 mL of 10% aq HCl. This mixture was stirred for 1 hr at rt. The resulting mixture was cooled to 0° C. and neutralized carefully with solid Na2CO3 and then extracted with Et2O. The combined organics were dried, filtered, and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3) δ 5.86-5.95 (m, 1H), 5.28 (d, 1H, J=1.7 Hz), 5.25 (d, 1H, J=1.5 Hz), 5.17 (d, 1H, J=10.5 Hz), 3.94-4.03 (m, 2H), 3.79 (dd, 1H, J=5.1 Hz, 9.8 Hz), 3.38 (dd, 1H, J=7.33 Hz, 9.53 Hz), 2.56-2.65 (m, 1H), 2.26-2.43 (m, 3H), 2.02-2.10 (m, 1H), 1.85-1.93 (m, 1H), 1.61-1.74 (m, 2H), 1.39-1.49 (m, 1H).
Reaction SMILES: C(O)(=O)C(O)=O.[CH3:7][O:8][C:9]1[C:26]([O:27][CH3:28])=[CH:25][C:12]2[CH:13]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][NH:15][CH2:16][CH2:17][C:11]=2[CH:10]=1.[O:29]([CH2:36][CH2:37][CH2:38]Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:7][O:8][C:9]1[C:26]([O:27][CH3:28])=[CH:25][C:12]2[CH:13]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][N:15]([CH2:38][CH2:37][CH2:36][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:16][CH2:17][C:11]=2[CH:10]=1
Reactant: BrCCCOc1ccccc1
Reactant: COc1cc2c(cc1OC)C(Oc1ccccc1)CNCC2
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C(Oc1ccccc1)CN(CCCOc1ccccc1)CC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
A mixture of 7,8-dimethoxy-1-phenoxy-2,3,4,5-tetrahydro-3-benzazepine of Example 35 (4.8 g, 16 mmole) and 3-phenoxypropyl bromide (4 g, 18 mmole) in 25 ml DMF containing potassium carbonate (milled, 4.4 g, 32 mmole) was stirred at 80° C. for two hours. After cooling, the mixture was stirred with 300 ml water and was extracted with ethyl acetate-ether. The organic extract was washed with water, saturated NaCl and was dried (anhydrous MgSO4), filtered and evaporated to 9 g of an oil. This oil was purified by HPLC (silica gel, 10% ethyl acetate/ dichloromethane) to give 4.7 g (68%) of 7,8-dimethoxy-3-(3-phenoxypropyl)-1-phenoxy-2,3,4,5-tetrahydro-3-benzazepine solid, m.p. 95°-100° C.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:17]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:24][C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:7]1)=[O:5])C.[OH-].[Na+].[Cl:33]CCl.Cl>C(O)C>[ClH:33].[CH:19]1[C:18]2[N:17]([CH2:16][CH2:15][O:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[S:24][C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCCN2c3ccccc3Sc3ccccc32)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOCCN2c3ccccc3Sc3ccccc32)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The above ester (0.8 g, 1.8 mmol) was dissolved in ethanol (15 ml) and a 4 N sodium hydroxide solution (2 ml) was added. The mixture was stirred vigorously at room temperature for 4 h. The solvent was evaporated in vacuo to give an oily residue. Dichloromethane (100 ml) was added and the mixture was cooled on an ice-bath. A concentrated hydrochloric acid solution (1 ml) was added. The mixture was stirred vigorously for a few minutes and the phases were separated. The organic phase was dried over sodium sulphate and the solvent was evaporated in vacuo. The residue was re-evaporated with dichloromethane, dissolved in dichloromethane and left overnight at 4° C. The solid formed was isolated by filtration to give 0.6 g of the title compound as a solid.
Reaction SMILES: Br[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4].[N-:20]=[N+:21]=[N-:22].[Na+].O>CN(C)C=O>[N:20]([CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCCCCCCCC(Br)C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCC(N=[N+]=[N-])C(=O)O
Temperature: 80 °C
Reaction time: 12 h
Yield: 82.3 %

Procedure:
To the solution of 2-bromohexadecanoic acid (1.00 g) in N,N-dimethylformamide (DMF, 15 ml) was added sodium azide (0.86 g), and the mixture was stirred at 80° C. for 12 hours. To the reaction mixture, after having been cooled to room temperature, was then added water. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was separated, washed twice with brine, dried over anhydrous sodium sulfate. The solvent was removed by distillation to give 2-azidohexadecanoic acid (0.73 g). To the solution of 2-azidohexadecanoic acid in DMF were added N-hydroxysuccinimide (74 mg) and N,N'-dicyclohexylcarbodiimide (146 mg), and the mixture was stirred for 12 hours. Precipitates produced was removed by filtration, and the filtrate was concentrated to give the active ester of 2-azidohexadecanoic acid. To the active ester in DMF were further added 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (246 mg) and triethylamine (0.72 ml), and the mixture was stirred for 12 hours. The solvent was removed by distillation, and the residue was subjected to chromatography on a silica gel column with an eluent system of chloroform-methanol (6:1) to give SPK229 in the yield of 185 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][NH:12][C:13]2[N:14]=[N:15][C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH:18]=2)=O)=[CH:4][CH:3]=1.[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC1C=CC=CC=1C1C(C2C=CC(Cl)=CC=2)=CC2N(C(CC3CCCCC3)=NN=2)N=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[N:14]3[N:15]=[C:16]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:32])[C:17]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[CH:18][C:13]3=[N:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)cc1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1
Agent: Clc1ccc(-c2cc3nnc(CC4CCCCC4)n3nc2-c2ccccc2Cl)cc1
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Clc1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(-c4ccccc4Cl)nn23)cc1
Yield: 53.7 %

Procedure:
The title compound (50 mg, 54%) as a white powder was prepared from 2-(4-chlorophenyl)-N′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)acetohydrazide (96 mg, 0.2 mmol) and triphenylphosphine dichloride (220 mg, 0.66 mmol) according to the procedures described for 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(cyclohexylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine (Example 7B), HPLC/MS (method A): retention time=4.12 min, (M+H)+=465.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH:11]1([Mg]Br)[CH2:13][CH2:12]1>O1CCCC1>[CH:11]1([C:8]([C:4]2[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=2)([OH:10])[CH3:9])[CH2:13][CH2:12]1
Reactant: Br[Mg]C1CC1
Reactant: CC(=O)c1cccc(O)c1
Solvent: C1CCOC1
Product: CC(O)(c1cccc(O)c1)C1CC1

Procedure:
By using 3′-hydroxyacetophenone (200 mg) and a 0.5 M solution of cyclopropylmagnesium bromide in tetrahydrofuran (8.8 ml) as starting materials, the title compound (176.6 mg) was obtained in the same manner as that of Reference Example 69.