Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][N:9]=[C:8](SC)[N:7]=2)=[CH:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2.[OH-:22].[Na+].Cl>O1CCOCC1>[S:1]1[C:5]([C:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][N:9]=[C:8]([OH:22])[N:7]=2)=[CH:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2
Reactant: CSc1ncc(C(F)(F)F)c(-c2cc3ccccc3s2)n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: Oc1ncc(C(F)(F)F)c(-c2cc3ccccc3s2)n1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
4-(Benzo[b]thiophen-2-yl)-2-(methylthio)-5-(trifluoromethyl)pyrimidine (0.45 g, 1.3 mmol) suspended in dioxane (3 mL) was treated with 5 N sodium hydroxide (3 mL) and the reaction heated to 75° C. After stirring overnight, there was still some starting material present in the reaction mixture by LC-MS. An additional 3 mL of 5 N sodium hydroxide was added to the reaction mixture and the temperature was increased to 90° C. After 6 h, the reaction was cooled to room temperature and acidified to pH 4 with 1 N hydrochloric acid. The precipitate that formed was collected by suction filtration, washed well with water and dried in a vacuum oven to give a white solid. Yield=0.31 g. MS (M+H)+ 297.
Reaction SMILES: C([Si](C)(C)[O:6][C@@H:7]([CH3:35])[C@@H:8]([NH:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=1)[C:9]1[O:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[N:12][N:13]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:11]2[O:10][C:9]([C@H:8]([NH:22][C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([C:31]([F:32])([F:34])[F:33])[CH:24]=3)[C@@H:7]([OH:6])[CH3:35])=[N:13][N:12]=2)=[CH:19][CH:18]=1)#[N:21]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)c1nnc(-c2ccc(C#N)cc2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a pre-cooled (−55° C.) solution of 4-((1R,2S)-2-(tert-butyldimethyl-silyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-(trifluoromethyl)benzo-nitrile (900 mg, 1.17 mmol) in THF (120 mL) was added TBAF (2.05 mL, 2.05 mmol, 1 M solution in THF) over 10 min. Upon complete addition the reaction mixture was allowed to warm to 0° C. over 1 h, then stirred at 0° C. for a further 30 min and quenched with sat. aq. NH4Cl (150 mL). The resulting mixture was partitioned between H2O (150 mL) and EtOAc (250 mL). The aqueous layer was extracted with EtOAc (100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography over silica gel (30-50% EtOAc in hexanes) to provided the title compound as a colourless oil (420 mg, 66%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.20 (dm, J=8.8 Hz, 2H), 8.01 (dm, J=8.8 Hz, 2H), 7.73 (d, J=8.6 Hz, 1H), 7.46 (d, J=2.4 Hz, 1H), 7.20 (dd, J=2.5, 8.8 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 5.23 (dd, J=3.5, 8.8 Hz, 1H), 4.62 (dq, J=3.5, 6.5 Hz, 1H), 1.40 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:37])[C:3]([O:5][C@@H:6]1[C@H:10]([O:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[C@@H:9]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[O:8][CH:7]1[N:22]1[CH:30]=[N:29][C:28]2[C:23]1=[N:24][CH:25]=[N:26][C:27]=2[NH:31][C@@H:32]1[CH2:36][CH2:35][O:34][CH2:33]1)=[O:4].[CH:38]1(C(O)=O)[CH2:42]C[CH2:40][CH2:39]1.C(OC(=O)C(C)C)(=O)C(C)C>>[CH3:1][CH:2]([CH3:37])[C:3]([O:5][C@@H:6]1[C@H:10]([O:11][C:12](=[O:16])[CH:13]([CH3:14])[CH3:15])[C@@H:9]([CH2:17][O:18][C:19]([CH:20]2[CH2:40][CH2:39][CH2:38][CH2:42]2)=[O:21])[O:8][CH:7]1[N:22]1[CH:30]=[N:29][C:28]2[C:23]1=[N:24][CH:25]=[N:26][C:27]=2[NH:31][C@@H:32]1[CH2:36][CH2:35][O:34][CH2:33]1)=[O:4]
Reactant: CC(=O)OC[C@H]1OC(n2cnc3c(N[C@@H]4CCOC4)ncnc32)[C@H](OC(=O)C(C)C)[C@@H]1OC(=O)C(C)C
Reactant: O=C(O)C1CCCC1
Agent: CC(C)C(=O)OC(=O)C(C)C
Product: CC(C)C(=O)O[C@@H]1[C@@H](COC(=O)C2CCCC2)OC(n2cnc3c(N[C@@H]4CCOC4)ncnc32)[C@@H]1OC(=O)C(C)C

Procedure:
Compound 17 was prepared in the manner of compound 15 utilizing cyclopentanecarboxylic acid under conditions B for introduction of the ester group at the 5′ hydroxyl group, and isobutyric anhydride under conditions A for the introduction of the 2′ and 3′ hydroxyl groups: 1H NMR(CDCl3) δ1.05-1.23 (m, 12H), 1.52-2.05 (m, 8H), 2.26-2.38 (m,1H), 2.49-2.63(m,2H), 2.71-2.79 (m, 1H), 3.75-3.87(m,2H), 3.94-4.06(m,2H), 4.34-4.45 (m, 3H), 4.78-4.86(m, 1H), 5.58 (dd, 1H), 5.81 (dd, 1H), 6.17 (d, 1H), 6.95 (br s, 1H), 7.97 (s,1H), 8.37(s,1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:14]([CH2:15][CH2:16][CH:17]=O)=[CH:13][C:12]([CH2:19][CH2:20][CH3:21])=[N:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:17][CH2:16][CH2:15][C:14]2[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[N:11]=[C:12]([CH2:19][CH2:20][CH3:21])[CH:13]=2)[CH2:31][CH2:30]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCCc1cc(CCC=O)n(-c2cccc([N+](=O)[O-])c2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2cccc([N+](=O)[O-])c2)n1

Procedure:
67 mg (83.6%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(3-nitrophenyl)-3-propyl-1H-pyrazol-5-yl)propanal (51 mg, 0.178 mmol), 1-(2-fluorophenyl)piperazine (42 mL, 0.266 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]2[C:15](=O)[C:14]3[C:13]([C:17]([O:19]CC)=O)=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][CH:7]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:2]1.O.[NH2:29][NH2:30]>CO>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]2[C:15]3=[N:29][NH:30][C:17](=[O:19])[C:13]4[CH:12]=[CH:11][CH:10]=[C:9]([C:14]=43)[NH:8][CH:7]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:2]1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccoc1)C(c1ccccc1)N2
Solvent: CO
Solvent: O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccccc1)C2c1ccoc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
A mixture of ethyl 3-(furan-3-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (80 mg) in 85% hydrazine monohydrate (10 mL) and methanol (10 mL) was stirred at 45° C. overnight. Methanol was removed under reduced pressure. The crude product was purified by prep-HPLC to give 9-(furan-3-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (5 mg, yield 7%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 4.19 (d, J=8.0 Hz, 1H), 4.67 (d, J=8.0 Hz, 1H), 6.26 (s, 1H), 7.07-7.21 (m, 7H), 7.30 (s, 1H), 7.27 (m, 1H), 7.41 (d, 1H), 7.51 (m, 1H); LC-MS (ESI) m/z: 330 (M+1)+.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[N:3]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C>[CH2:11]([NH:18][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[N:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: Fc1cc(F)c(F)nc1F
Solvent: CC#N
Product: Fc1cc(F)c(NCc2ccccc2)nc1F
Yield: 84.6 %

Procedure:
To 50 ml of acetonitrile were added 12.0 g of 2,3,5,6-tetrafluoropyridine and 18.0 g of benzylamine, and the mixture was stirred under reflux condition for 2 hours, and the solvent and the like were distilled off. To the residue was added 150 ml of ethyl acetate, and the mixture was washed twice with 150 ml of distilled water and 150 ml of 10% aqueous solution of citric acid. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 16.0 g of the title compound as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[C:17]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][NH:6]3)[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Brc1cccc2[nH]ccc12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)c1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 75 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
To a mixture of 4-bromoindole (3.00 g, 15.3 mmol), and 3-trifluoromethylphenylboronic acid (2.91 g, 15.3 mmol) in THF (52 mL)) were added Palladium catalyst Pd(PPh3)4 (530 mg, 0.46 mmol) and the freshly prepared sodium hydroxide solution (1.84 g, 45.9 mmol in 21 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for 16 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 3.55 g (89%) of the product 4-(3-trifluoromethyl-phenyl)-1H-indole.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:1]([N:17]1[C:13](=[O:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16]1=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CCCCCCCCCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCCCCCCCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a mixture of 10-undecen-1-ol (4.23 g, 24.8 mmol), phthalimide (3.65 g, 24.8 mmol) and triphenylphosphine (6.51 g, 24.8 mmol) in anhydrous tetrahydrofuran (30 ml), a solution of DEAD (3.9 ml, 24.8 mmol) in anhydrous tetrahydrofuran (10 ml) was slowly added while keeping the temperature below 8-10° C. After 2 hours further DEAD (1.0 ml, 6.37 mmol) and triphenylphosphine (1.3 g, 4.96 mmol) were added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was triturated with diethyl ether (50 ml). The solid was removed by filtration and washed with diethyl ether (2×50 ml). The combined filtrates were concentrated and the residue was triturated with hexane (50 ml) at 40° C. The resulting solid was removed by filtration and washed with hexane (2×50 ml). The combined filtrates were concentrated and the residue was purified by column chromatography eluting with 10:2 hexane:ethyl acetate mixture. The product was obtained as a low-melting white solid (4.9 g, 66% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([F:21])[CH:15]=3)=[CH:12][C:11]([C:22]([O:24]CC)=[O:23])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([F:21])[CH:15]=3)=[CH:12][C:11]([C:22]([OH:24])=[O:23])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1cc(-c2cc(C)cc(F)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: Cc1cc(F)cc(-c2cc(C(=O)O)nn2-c2ccc(F)c(Cl)c2)c1
Reaction time: 6 h

Procedure:
The preparation of the title compound takes place starting from the compound of Example 57A in analogy to the synthesis of the compound of Example 71A but with stiffing for 6 hours. 2.34 g of the title compound with 79% purity are obtained.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11](O)=[O:12])[CH:9]=2)[N:4]([S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:3]=1.[C:24]1([C:30]([NH:33][C:34]([NH:36][NH2:37])=S)([CH3:32])[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.O>CN(C=O)C.CCOC(C)=O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:12][C:34]([NH:33][C:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)([CH3:32])[CH3:31])=[N:36][N:37]=3)[CH:9]=2)[N:4]([S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)O)ccc32)cc1
Reactant: CC(C)(NC(=S)NN)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(NC(C)(C)c5ccccc5)o4)ccc32)cc1
Temperature: 25 °C
Yield: 22.7 %

Procedure:
A solution of 3-iodo-1-tosyl-1H-indole-5-carboxylic acid (1.330 g, 3.01 mmol), N-(2-phenylpropan-2-yl)hydrazinecarbothioamide (0.631 g, 3.01 mmol), and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (1.156 g, 6.03 mmol) (Sigma-Aldrich) in DMF (5.0 mL) was heated at 80° C. for 2 h. The solution was cooled to RT. Water (precipitate formed), EtOAc and Celite were added, and the solids were removed by filtration and washed with EtOAc (3×). The organic layer was evaporated to reduce solvent volume. The aqueous layer was then extracted with EtOAc (2×50 mL). The combined organic layers were concentrated in vacuo, and the crude material was purified by flash chromatography (20-100% EtOAc in Hex) to give 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(2-phenylpropan-2-yl)-1,3,4-oxadiazol-2-amine (408.1 mg, 0.682 mmol, 22.62%). MS (ESI, pos. ion) m/z: 599.0 (M+1).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:31]=[CH:30][C:21]([C:22]([O:24][CH:25]([C:27](Cl)=[O:28])[CH3:26])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.[CH3:33][NH:34][CH3:35]>N1C=CC=CC=1>[CH2:1]([NH:17][C:18]1[CH:31]=[CH:30][C:21]([C:22]([O:24][CH:25]([C:27](=[O:28])[N:34]([CH3:35])[CH3:33])[CH3:26])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CNC
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC(C)C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC(C)C(=O)N(C)C)cc1
Reaction time: 15 h

Procedure:
To a solution of 3 g. (6.32 m moles) 1-(chlorocarbonyl)ethyl 4-(hexadecylamino)benzoate in 25 ml. pyridine is added 0.6 g. (7.5 m moles) dimethylamine hydrochloride. The solution is stirred at 50°0 C. for 15 hours, then evaporated to dryness. The residue is partitioned between 50 ml. water and 50 ml. methylene chloride. The layers are separated, and the aqueous solution is washed once more with 50 ml. methylene chloride. The combined organic solutions are dried, condensed, and the residue is crystallized from acetonitrile to yield the title compound as colorless crystals.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:13]=[C:14](\[O:19][CH3:20])/[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[CH:10][C:11]=1I)[CH2:2][CH2:3][CH3:4].[CH3:21][NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:13]=[C:14](\[O:19][CH3:20])/[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[CH:10][C:11]=1[C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([NH:22][CH3:21])[CH:24]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(/C=C(\OC)C(=O)OC)ccc1I
Reactant: CNc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CCCCOc1cc(/C=C(\OC)C(=O)OC)ccc1-c1cccc(NC)c1
Temperature: 92.5 °C
Yield: 75.2 %

Procedure:
In a manner similar to that of Example 25c, 4 mg (0.018 mmol) of palladium acetate and then 13 mg (0.036 mmol) of 2-(dicyclohexylphosphino)biphenyl are added to a mixture of 0.7 g (1.8 mmol) of methyl (Z)-3-(3-butoxy-4-iodophenyl)-2-methoxyacrylate prepared as in Example 24c, 0.5 g (2.15 mmol) of methyl[3-(4,4,5,5-tetramethyl[1.3.2]dioxaborolan-2-yl)phenyl]amine and 1.8 mL of aqueous 2M potassium phosphate solution in 10 mL of dimethylformamide. The reaction mixture is heated at 90-95° C. for 1 hour. The reaction medium is hydrolyzed with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated off and the residue is purified by chromatography on a column of silica eluted with a 60/40 heptane/ethyl acetate mixture. 0.5 g (71%) of methyl (Z)-3-(2-butoxy-3′-methylaminobiphenyl-4-yl)-2-methoxyacrylate are obtained.
Reaction SMILES: P(Cl)(Cl)Cl.[CH:5]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1.[Br:13]Br>>[Br:13][C:5]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(O)C1CCCC1
Reactant: BrBr
Solvent: ClP(Cl)Cl
Product: O=C(O)C1(Br)CCCC1
Temperature: 85 °C
Reaction time: 12 h

Procedure:
Phosphorus trichloride (0.54 mL, 6.20 mmol) was added drop-wise to the mixture of cyclopentanecarboxylic acid (14.2 g, 124 mmol) and bromine (7.35 mL, 143 mmol). The mixture was then gradually heated to 85° C. and stirred at this temperature in a sealed vessel for 12 h. After cooling to ambient temperature, the mixture was partitioned between EtOAc and water. The organic portion was separated, washed with water and brine, and conc. in vacuo to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:34]([N+:37]([O-])=O)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CO.C(O)(=O)C.[Fe]>[NH2:37][C:34]1[CH:35]=[CH:36][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([CH:33]=1)[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc([N+](=O)[O-])ccc1OCc1ccccc1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 49.2 %

Procedure:
Iron powder (43 mg) was added to a solution mixture of tert-butyl 2-(2-(benzyloxy)-5-nitrobenzamido)-4-phenylbenzoate (0.14 g) in methanol (1.4 mL) and acetic acid (1.4 mL), followed by heating to reflux for 1 hour. The reaction mixture was cooled to room temperature, and iron powder (14 mg) was added thereto, followed by heating to reflux for 30 minutes. The reaction mixture was cooled to room temperature, and a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added thereto. The insoluble substance was removed by filtration. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 90-50% hexane/ethyl acetate] to obtain 0.065 g of tert-butyl 2-(5-amino-2-(benzyloxy)benzamido)-4-phenylbenzoate as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[C:27]([CH:29]=O)[CH:26]=[CH:25][N:24]=2)=[CH:19][CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH3:16])[CH2:29][C:27]2[CH:26]=[CH:25][N:24]=[C:23]([C:20]3[CH:19]=[CH:18][N:17]=[CH:22][CH:21]=3)[N:28]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccnc(-c2ccncc2)n1
Reactant: CNCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(Cc1ccnc(-c2ccncc2)n1)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-methylaminomethylpiperidine-1-carboxylic acid tert-butyl ester (37 mg, 0.16 mmol) in anhydrous CH2Cl2 (3 mL) was added 2-pyridin-4-yl-pyrimidine-4-carbaldehyde (Preparation 2, 30 mg, 0.16 mmol) followed by NaBH(OAc)3 (38 mg, 0.18 mmol). The mixture was stirred vigorously at rt for 24 h, before being partitioned between CH2Cl2 (30 mL) and H2O (20 mL). The aqueous phase was extracted with CH2Cl2 (20 mL), then the combined organics were washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. Flash column chromatography (EtOAc) gave the title compound. RT=2.36 min; m/z (ES+)=398 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][NH2:7])=[S:5])[CH3:2].[F:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[CH2:19][C:20]1[N:24]2[N:25]=[C:26]([C:29](=O)[CH3:30])[CH:27]=[CH:28][C:23]2=[N:22][CH:21]=1>>[CH2:1]([NH:3][C:4]([NH:6]/[N:7]=[C:29](/[C:26]1[CH:27]=[CH:28][C:23]2[N:24]([C:20]([CH2:19][C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][C:9]=3[F:8])[N:16]=[CH:15][CH:14]=[CH:13]4)=[CH:21][N:22]=2)[N:25]=1)\[CH3:30])=[S:5])[CH3:2]
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Reactant: CCNC(=S)NN
Product: CCNC(=S)N/N=C(\C)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Yield: 53 %

Procedure:
The title compound was prepared from N-ethylhydrazine carbothioamide and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 53% yield. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.83 (d, 1H), 8.30 (d, 1H), 8.24 (d, 1H), 7.93 (m, 2H), 7.69 (m, 2H), 7.48 (q, 1H), 4.67 (s, 2H), 3.74 (q, 2H), 2.39 (s, 3H), 1.26 (t, 3H). LCMS (method A): [MH]+=422, tR=5.43 min.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([O:6][CH:7]([CH3:32])[CH:8](N)[O:9][C:10](=[O:30])[NH:11][CH2:12][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][CH2:26][CH2:27][CH2:28][CH3:29])=[N:2]1.[Cl:33][CH2:34][CH2:35][CH2:36][S:37]([NH:40]CC(OC)CSCCCCCCCCCCCCCCCC)(=[O:39])=[O:38]>>[Cl:33][CH2:34][CH2:35][CH2:36][S:37]([NH:40][CH2:32][CH:7]([O:6][C:3]1[CH:4]=[CH:5][O:1][N:2]=1)[CH2:8][O:9][C:10](=[O:30])[NH:11][CH2:12][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][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:39])=[O:38]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OC(N)C(C)Oc1ccon1
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)Oc1ccon1

Procedure:
2-(3-Isoxazolyloxy)-1-octadecylcarbamoyloxypropylamine IVj2 is allowed to react and worked up by the same procedure as described in (4). m.p. 63.5°-65° C. The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: S(Cl)([Cl:3])=O.Cl.[NH2:6][CH2:7][C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12]>CN(C)C=O>[ClH:3].[NH2:6][CH2:7][C:8](=[O:14])[CH2:9][CH2:10][C:11]([O:13][CH2:11][CH2:10][CH2:9][CH:8]=[CH2:7])=[O:12]
Reactant: NCC(=O)CCC(=O)O
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Product: C=CCCCOC(=O)CCC(=O)CN
Yield: 47 %

Procedure:
To 1 ml of thionyl chloride (SOCl2) were added 3 drops of N,N-dimethylformamide (DMF) with stirring. Following the addition of 5-aminolevulinic acid hydrochloride (ALA.HCl, 200 mg, 1.19 mmol), the solution was stirred for 12 hours at room temperature. Concentration in a vacuum was conducted before the addition of 4-pentenol. Then, the reaction mixture was stirred for 1.5 hours at room temperature, followed by purification by silica gel chromatography to afford 4-pentenyl 5-aminolevulinate hydrochloride at a yield of 47%.