Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)CCCN=C=NCC.[O:12]=[C:13]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]1[CH:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([OH:22])=O.[Cl:27][C:28]1[CH:29]=[C:30]([CH:32]=[C:33]([Cl:35])[CH:34]=1)[NH2:31].O>O1CCCC1.CCCCCC.C(OCC)(=O)C>[O:18]=[C:15]1[CH:16]=[CH:17][C:13](=[O:12])[N:14]1[CH:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH:31][C:30]1[CH:29]=[C:28]([Cl:27])[CH:34]=[C:33]([Cl:35])[CH:32]=1)=[O:22]
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CC(C)CC(C(=O)O)N1C(=O)C=CC1=O
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)CC(C(=O)Nc1cc(Cl)cc(Cl)c1)N1C(=O)C=CC1=O
Reaction time: 0.5 h
Yield: 16.5 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide (3.5 g, 0.0182 mol) is added to a suspension of DL-2,5-dioxo-α-isobutyl-3-pyrroline-1-acetic acid (3.5 g, 0.0166 mol) in tetrahydrofuran. The reaction mixture is stirred for 30 minutes, treated with 3,5-dichloroaniline (2.69 g, 0.0166 mol) under nitrogen, stirred at room temperature for 12 hours and poured into water. The mixture is extracted with methylene chloride. The extracts are combined and concentrated in vacuo to give a residue. Flash chromatography using hexane/ethyl acetate (80/20) as eluent on silica gel of the residue yields the title compound as a pale yellow solid (0.97 g, 16%, mp 150.5° C.), identified by 1HNMR CIMS and IR analysis.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N+:8]([O-:12])=[CH:9]2)=[CH:4][N:3]=1.[CH:20]1([C:23]([NH2:25])=[O:24])[CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.ClCCl.CO>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:7]1[N+:8]([O-:12])=[CH:9][C:10]2[C:5]([CH:6]=1)=[CH:4][N:3]=[C:2]([NH:25][C:23]([CH:20]1[CH2:22][CH2:21]1)=[O:24])[CH:11]=2
Reactant: NC(=O)C1CC1
Reactant: [O-][n+]1cc2cc(Cl)ncc2cc1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(Nc1cc2c[n+]([O-])c(-c3ccccc3Cl)cc2cn1)C1CC1
Temperature: 90 °C
Yield: 84.1 %

Procedure:
A mixture of 7-chloro-3-(2-chlorophenyl)-2,6-naphthyridine 2-oxide (2.0 g, 7.0 mmol), cyclopropanecarboxamide (653 mg, 7.7 mmol), Chloro[2-(dicyclohexylphosphino)-3-,6-dimethoxy-2,4′-6′-tri-1-pr-1,1′-biphenyl)][2-(2-aminoethyl)Ph]Pd(II) (167 mg, 0.21 mmol), (dicyclohexylphosphino)-3-,6-dimethoxy-2,4′-6′-tri-1-pr-1,1′-biphenyl (281 mg, 0.52 mmol), and cesium carbonate (4.5 g, 13.9 mmol) in 1,4-dioxane (19 mL) was heated at 90° C. for 4 hours. The cooled reaction mixture was diluted with dichloromethane (200 mL) and methanol (100 mL), mixed with Celite, filtered, the solids washed with 15% methanol/dichloromethane (2×100 mL), and the filtrate was dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 40 g, ISCO, 0-10% methanol in dichloromethane) to afford the title compound as an off-white solid (2.0 g, 84%). 1H NMR (400 MHz, DMSO) δ 11.15 (s, 1H), 9.13 (s, 1H), 9.09 (s, 1H), 8.42 (s, 1H), 8.17 (s, 1H), 7.62 (m, 1H), 7.58-7.45 (m, 3H), 2.14-2.03 (m, 1H), 0.91-0.82 (m, 4H). LCMS (Method G): RT=8.18 min, M+H+=340.0.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(O)C>[CH:4]([C:3]1[C:6]([O:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:2]=1[O:1][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:5]
Reactant: CCOC(=O)CCCCCCBr
Reactant: COc1cccc(O)c1C=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CCCCCCOc1cccc(OC)c1C=O
Reaction time: 19 h

Procedure:
2-Hydroxy-6-methoxybenzaldehyde (3.04 g, 0.02 M), ethyl 7-bromoheptanoate (4.74 g, 0.02 M), anhydrous potassium carbonate (2.97 g), sodium iodide (0.12 g) and ethanol (27 ml) were refluxed with stirring for 19 hr. The cooled reaction mixture was filtered and the solid washed with ethanol. The filtrate was evaporated to dryness and the residue partitioned between ether (40 ml) and water (40 ml). The organic layer was separated and washed with ZN sodium hydroxide solution, water, dried (sodium sulphate) and evaporated to give ethyl 7-(2-formyl-3-methoxyphenoxy)heptanoate, 4.2 g, 68% as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[N:10]1([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)(=O)C>[CH3:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:19][CH:20]=2)=[N:3][CH:4]=1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: Cc1cnc(Cl)nc1N
Solvent: CC(=O)O
Product: Cc1cnc(Nc2ccc(OCCN3CCCC3)cc2)nc1N
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.50 g, 3.5 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (1.1 g, 5.3 mmol) in acetic acid (8 mL) was sealed in a microwave reaction tube and irradiated with microwave at 150° C. for 15 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (30 mL) and neutralized with 10% NaOH solution until pH˜10. The resulting aqueous layer was extracted with EtOAc (2×30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford the title compound as a grey solid (0.80 g, 73%). It was used in the next step without purification. MS (ES+): m/z 314 (M+H)+.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][C:7](=[O:9])[CH:6]([C:10](=[O:26])[CH2:11][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][CH3:25])[C:5](=[O:27])[CH2:4]1)=O.[NH2:28]OS(O)(=O)=O>O>[O:27]=[C:5]1[CH:6]([C:10](=[O:26])[CH2:11][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][CH3:25])[C:7](=[O:9])[CH2:8][CH:3]([C:1]#[N:28])[CH2:4]1
Reactant: CCCCCCCCCCCCCCCC(=O)C1C(=O)CC(C=O)CC1=O
Reactant: NOS(=O)(=O)O
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)C1C(=O)CC(C#N)CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
43 g (0.12 mol) of 5-formyl-2-palmitoylcyclohexane-1,3-dione were suspended in 150 ml of distilled water. To this were added 15.7 g (0.14 mol) of hydroxylamine-O-sulfonic acid dissolved in 50 ml of water. The heterogeneous reaction mixture was stirred at room temperature overnight. The resulting solid was filtered off with suction, washed with water and dried. 37.7 g (86% of theory) of 3,5-dioxo-4-palmitoylcyclohexanecarbonitrile were isolated (melting point 66° to 69° C).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:12])[NH:6][CH2:5]2.[H-].[Na+].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:19][CH:18]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH:31]1([CH:23]([C:20]2[CH:21]=[CH:22][C:17]([CH2:16][N:6]3[CH2:5][C:4]4[C:8](=[CH:9][C:10]([F:11])=[C:2]([F:1])[CH:3]=4)[C:7]3=[O:12])=[CH:18][CH:19]=2)[C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Reactant: O=C1NCc2cc(F)c(F)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(c1ccc(CN2Cc3cc(F)c(F)cc3C2=O)cc1)C1CCCC1
Reaction time: 0.5 h

Procedure:
At 0° C., 60 mg (0.355 mmol) of 5,6-difluoro-2,3-dihydro-1H-isoindol-1-one were added to 21.3 mg (0.53 mmol, 60% pure) of sodium hydride in 1 ml of DMF. The mixture was stirred for 30 min, and 125.3 mg (0.35 mmol) of tert-butyl(+/−)-[4-(bromomethyl)phenyl](cyclopentyl)acetate were then added at 0° C. The reaction mixture was stirred for a further 2 h, and water and ethyl acetate were then added. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1 to 2:1). This gave 30.0 mg (19.2% of theory) of the target compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH:5]=[C:6]([NH2:10])[CH:7]1[CH2:9][CH2:8]1)[CH3:2].[F:12][C:13]([F:31])([F:30])/[C:14](/O)=[CH:15]/[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)=O>>[CH2:1]([O:3][C:4](=[O:11])[C:5]1[C:14]([C:13]([F:12])([F:31])[F:30])=[CH:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=2)=[N:10][C:6]=1[CH:7]1[CH2:8][CH2:9]1)[CH3:2]
Reactant: CCOC(=O)C=C(N)C1CC1
Reactant: O=C(/C=C(\O)C(F)(F)F)c1ccc(OC(F)(F)F)cc1
Product: CCOC(=O)c1c(C(F)(F)F)cc(-c2ccc(OC(F)(F)F)cc2)nc1C1CC1

Procedure:
In analogy to the procedure described in example 152E], 3-amino-3-cyclopropyl-acrylic acid ethyl ester (J. P. Célérier, E. Deloisy, P. Kapron, G. Lhommet, P. Maitte, Synthesis 1981, 130–133) was reacted with (Z)-4,4,4-trifluoro-3-hydroxy-1-(4-trifluoromethoxy-phenyl)-but-2-en-1-one (example 152D]) to give the title compound as colorless oil.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[C:6]([O:15][CH2:16][CH:17]=C)=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:3].CSC.Cl.[NH2:23][CH2:24][C:25]1[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=1[CH3:31].C([BH3-])#N.[Na+]>ClCCl.CO>[CH3:31][C:30]1[CH:29]=[C:28]([CH3:32])[NH:27][C:26](=[O:33])[C:25]=1[CH2:24][NH:23][CH2:17][CH2:16][O:15][C:6]1[C:5]([O:4][CH:2]([CH3:1])[CH3:3])=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: C=CCOc1c(OC(C)C)cccc1C(=O)OC
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CSC
Product: COC(=O)c1cccc(OC(C)C)c1OCCNCc1c(C)cc(C)[nH]c1=O
Temperature: 25 °C
Reaction time: 14.5 h
Yield: 11.2 %

Procedure:
Ozone was bubbled through a cooled (−78° C.) solution of methyl 3-(propan-2-yloxy)-2-(prop-2-en-1-yloxy)benzoate (123d, 438.1 mg, 1.75 mmol) in dichloromethane (17.5 mL) until a persistent violet-blue color was obtained (about 5 minutes). Nitrogen was bubbled into the solution for 3 minutes, causing the color to fade, then dimethyl sulfide (1.0 mL, 13.5 mmol) was added and the mixture allowed to warm to room temperature for one hour. The solvents were evaporated and the residue partitioned between sodium carbonate solution (sat., aq., 10 mL) and ethyl acetate (2×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under vacuum to give the crude residue. This crude aldehyde was dissolved in methanol (10.0 mL) and treated with 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one hydrochloride (Cpd V, 334 mg, 1.87 mmol) at room temperature for five minutes, then sodium cyanoborohydride (332 mg, 4.50 mmol) was added and the mixture stirred at room temperature for 14.5 hours. The solvents were evaporated under vacuum and the residue partitioned between deionized water (10 mL) and ethyl acetate (2×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered, concentrated under vacuum, and purified by column chromatography (EtOH+5% NH4OH in ethyl acetate) to give methyl 2-(2-{[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]amino}ethoxy)-3-(propan-2-yloxy)benzoate (123e, 76 mg, 11% yield) as a colorless glass.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([CH3:14])([CH3:13])[C:6]([O:8]CC(C)C)=[O:7].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[O-:23].[Na+].C1(C)C=CC=CC=1>CS(C)=O>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[O:23][CH2:2][CH2:3][CH2:4][C:5]([CH3:14])([CH3:13])[C:6]([OH:8])=[O:7]
Reactant: CC(C)COC(=O)C(C)(C)CCCCl
Reactant: Cc1ccc(C)c([O-])c1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Cc1ccc(C)c(OCCCC(C)(C)C(=O)O)c1
Yield: 80 %

Procedure:
subsequently reacting said 2-methylpropyl 5-chloro-2,2-dimethylpentanoate with sodium 2,5-dimethylphenolate under reflux in a solvent comprising a mixture of from 10 parts (V/V) toluene/1 part (V/V) dimethylsulfoxide to 5 parts (V/V) toluene/1 part (V/V) dimethylsulfoxide, hydrolyzing the resulting ester, and thereafter acidifying the mixture and isolating 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid;
Reaction SMILES: Br[C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:10].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:17]1([B-](F)(F)F)[CH2:19][CH2:18]1.[K]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.I.C12(P(C34CC5CC(CC(C5)C3)C4)CCCC)CC3CC(CC(C3)C1)C2.O.C1(C)C=CC=CC=1>[CH:17]1([C:2]2[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[F:10])[CH2:19][CH2:18]1
Reactant: Nc1cc(F)c(Br)c(F)c1
Reactant: F[B-](F)(F)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1cc(F)c(C2CC2)c(F)c1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 82 %

Procedure:
To a pressure tube was added 4-bromo-3,5-difluoroaniline (1.0 g, 4.8 mmol), cesium carbonate (4.7 g, 14.4 mmol), toluene (10 mL) and water (1 mL). The solution was de-gassed with N2 gas for 30 minutes, followed by the addition of cyclopropyltrifluoro-borate, potassium salt (0.8 g, 5.3 mmol), di(1-adamantyl)-n-butylphosphine hydroiodide (0.07 g, 0.14 mmol) and palladium(II) acetate (0.02 g, 0.096 mmol). De-gassing was continued for 5 minutes, the tube was sealed and heated at 100° C. for 18 hours. The cooled solution was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4), and filtered. The filtrate was treated with 3-mercaptopropyl silica gel for 1 hour. The mixture was filtered and concentrated to give crude product which was purified by flash chromatography (0-30% EtOAc/hexane) to give the title compound (0.67 g, 4.0 mmol, 82%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[CH:7]=1.[F-].[Cs+].[CH3:22][N:23]([CH:25]=O)[CH3:24]>O>[C:12]([NH:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([C:16]3[CH:17]=[CH:18][C:13]([C:12]([NH:11][CH2:9][CH2:25][N:23]([CH3:22])[CH3:24])=[O:19])=[CH:14][CH:15]=3)=[CH:7][N:6]2[N:8]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Nc1nc2ccc(Br)cn2n1)c1ccccc1
Reactant: CN(C)C=O
Agent: [Cs+]
Agent: [F-]
Solvent: O
Product: CN(C)CCNC(=O)c1ccc(-c2ccc3nc(NC(=O)c4ccccc4)nn3c2)cc1
Temperature: 95 °C
Yield: 24 %

Procedure:
To a reaction vessel containing N-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-benzamide ((B5), 95 mg, 0.3 mmol, 1 mol eq.), N-(2-dimethylamino-ethyl)-4-boronic acid-benzamide (85 mg, 0.36 mmol, 1.2 mol eq.) and cesium fluoride (135 mg, 0.9 mmol, 3 mol eq.) in DMF (0.75 mL) and H2O (0.5 mL) was added bis-triphenylphosphine palladium dichloride (0.009 mmol, 3 mol %) in DMF (0.25 mL). The vessel was purged with nitrogen, capped and heated at 95° C. for approximately 18 hours. The reaction mixture was cooled to room temperature, filtered and the residue dissolved in DMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give the title compound as a white solid (30.4 mg, 24%). HPLC, Rt: 1.74 min (purity: 99%). LC/MS M+(ESI): 429.3, M−(ESI) 427.4.
Reaction SMILES: BrBr.[C:3]([O:6][C:7](Br)=[C:8]([Br:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=O)C.[CH3:18][OH:19]>C(Cl)(Cl)(Cl)Cl.O>[CH3:3][O:6][CH:7]([O:19][CH3:18])[CH:8]([Br:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCC(Br)=C(Br)OC(C)=O
Reactant: CO
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCCCCCCC(Br)C(OC)OC
Reaction time: 48 h

Procedure:
The oil is mixed with 200 ml of carbon tetrachloride and cooled in an ice bath. Bromine, diluted with an equal volume of carbon tetrachloride, is added slowly with agitation while maintaining the temperature below 10°C. Bromine addition is stopped when the bromine is no longer decolorized. To the brominated mixture, containing 1,2-dibromononen-1-yl acetate, is added 500 ml of methyl alcohol with shaking and cooling. The mixture is allowed to stand two days with occasional shaking and then diluted with 1.5 liters of water. The separated oil is washed with 5% sodium carbonate solution until free of acid and then fractionally distilled in the presence of a small amount of sodium carbonate to yield 2-bromo-nonanal dimethyl acetal.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C>[CH2:6]([NH:7][C:14]1[CH:15]=[CH:16][C:11]([C:10]#[N:17])=[CH:12][CH:13]=1)[C:5]1[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=1
Reactant: NCc1ccccc1
Reactant: N#Cc1ccc(F)cc1
Solvent: CC#N
Product: N#Cc1ccc(NCc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 72 h
Yield: 72 %

Procedure:
4-Fluorobenzonitrile (6.0 g, 49.5 mmol) was dissolved in acetonitrile (60 ml), and benzylamine (10.6 g, 98.9 mmol) was added thereto, followed by stirring at 100° C. for 3 days. To complete the reaction, benzylamine (21.2 g, 198 mmol) was further added thereto, followed by stirring at 100° C. for 1 day. The solvent was removed under reduced pressure, water was added to the resulting residue, and the mixture was extracted with chloroform. After the organic layer was dried (over anhydrous magnesium sulfate), the drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The resulting oily substances were purified by silica gel column chromatography (the substances were eluted with an increasing concentration of chloroform from chloroform/hexane=1/2 to chloroform/hexane=1/1) to give the title compound (7.42 g, 72%) as oily substances.
Reaction SMILES: O[C@@H:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([C:12]#[N:13])=[CH:6][CH:5]=[CH:4][C:3]1=2.C1C=CC(P([N:28]=[N+:29]=[N-:30])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:28]([C@H:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([C:12]#[N:13])=[CH:6][CH:5]=[CH:4][C:3]1=2)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: N#Cc1cccc2c1CCC[C@H]2O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1cccc2c1CCC[C@@H]2N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 72.6 %

Procedure:
A stirring solution of (R)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-1-carbonitrile INT-2 (3.00 g, 17.32 mmol) in toluene (16 mL) under N2, was cooled to 0° C. DPPA (9.53 g, 34.64 mmol) was added, followed by dropwise addition of DBU (3.16 mL, 20.78 mmol) over 20 min. The mixture was stirred at 0° C. for 4 h then slowly warmed to room temperature over 2 h and then concentrated. The resulting crude mixture was diluted with EA and washed with NaHCO3. The combined organic layers were washed with brine, dried over Na2SO4, and chromatographed (EA/hexane) to provide 2.49 g (72.6%) of (S)-5-azido-5,6,7,8-tetrahydronaphthalene-1-carbonitrile INT-6 as a white solid. LCMS-ESI (m/z) calculated for C11H10N4: 198.2; found 156.1 [M−N3]+, tR=3.65 min. 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J=7.6, 1.2 Hz, 1H), 7.56 (dd, J=7.8, 0.6 Hz, 1H), 7.33 (t, J=7.7 Hz, 1H), 4.59 (t, J=4.4 Hz, 1H), 3.08 (dt, J=18.0, 5.1 Hz, 1H), 2.99-2.83 (m, 1H), 2.15-1.96 (m, 3H), 2.00-1.81 (m, 1H). 13C NMR (101 MHz, DMSO) δ 141.05, 135.58, 133.47, 132.66, 126.58, 117.43, 113.21, 58.74, 28.28, 27.54, 18.27.
Reaction SMILES: [C:1]([CH:4]=[CH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)([OH:3])=[O:2].CCN(CC)CC.CN([P+](O[N:34]1[N:42]=[N:41][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[N:41]1([O:2][C:1]([CH:4]=[CH:5][C:6]2[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=2)=[O:3])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[N:42]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: COC(=O)c1ccc(C=CC(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C=CC(=O)On2nnc3ccccc32)cc1
Reaction time: 3 h
Yield: 83.6 %

Procedure:
To a stirred solution at room temperature of VII (264 mg, 1.28 mmol) in anhydrous DMF (10 ml) under nitrogen were added Et3N (196 μl, 1.41 mmol) and BOP reagent (680 mg, 1.1.54 mmol), respectively. After few min, a precipitate appeared. After 3 h, the reaction mixture was poured into a saturated aqueous solution of NH4Cl, and diluted with AcOEt. After separation, the organic layer was successively washed with sat NH4Cl, H2O and brine, concentrated a little bit, and hexane was added. The suspension was filtered off and rinsed with hexane. The solid was triturated in water, filtered off, rinsed with water, and dried to afford the title compound VIII (346 mg, 1.07 mmol, 84% yield) as a pale yellow solid (not stable on silica gel !). 1H NMR (300 MHz, CDCl3) δ(ppm): 8.56 (d, J=8.3 Hz, 1H), 8.21–8.02 (m, 3H), 7.90–7.72 (m, 4H), 7.62 (t, J=7.4 Hz, 1H), 3.97 (s, 3H).
Reaction SMILES: C1(C[O:5][C:6](=[O:33])[CH:7]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:15]([C:23]3[CH:24]=[CH:25][C:26]4[C:27]([CH:31]=3)=[N:28][O:29][N:30]=4)=[C:14]([Cl:32])[CH:13]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])CC1.[OH-].[K+]>CCO.O>[N:30]1[O:29][N:28]=[C:27]2[CH:31]=[C:23]([C:15]3[C:16]([O:18][CH2:19][CH:20]4[CH2:22][CH2:21]4)=[CH:17][C:12]([CH:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:6]([OH:33])=[O:5])=[CH:13][C:14]=3[Cl:32])[CH:24]=[CH:25][C:26]=12
Reactant: CC(C)CC(C(=O)OCC1CC1)c1cc(Cl)c(-c2ccc3nonc3c2)c(OCC2CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)CC(C(=O)O)c1cc(Cl)c(-c2ccc3nonc3c2)c(OCC2CC2)c1
Yield: 71.3 %

Procedure:
2-(4-Benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.11 g, 0.23 mmol) was dissolved in a mixture of EtOH/H2O (9 mL/1 mL) and KOH (0.1 g, 1.76 mmol) was added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5, and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4 and evaporated under reduced pressure to give 2-(4-benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid as a yellow oil (0.068 g, 70%). 1H NMR (300 MHz, CDCl3/TMS): δ 8.40 (br s, 1H), 7.70 (d, J=9.3 Hz, 1H), 7.62 (s, 1H), 7.19 (d, J=9.3 Hz, 1H), 6.97 (s, 1H), 6.73 (s, 1H), 3.67 (d, J=6.6 Hz, 2H), 3.52 (t, J=7.7 Hz, 1H), 1.90-1.81 (m, 1H), 1.62-1.53 (m, 1H), 1.50-1.39 (m, 1H), 0.98-0.68 (m, 1H), 0.81 (d, J=6.1 Hz, 6H), 0.37-0.31 (m, 2H), 0.15-0.10 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 179.1, 157.1, 149.1, 148.3, 141.0, 138.6, 135.3, 133.7, 126.8, 121.6, 117.4, 115.0, 110.9, 73.4, 49.4, 41.9, 25.9, 22.6, 22.3, 10.0, 3.1.
Reaction SMILES: C([O-])=O.[NH4+].[CH2:5]([P:9]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH3:8]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:14]([P:9]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:8][CH2:7][CH2:6][CH3:5])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:17][CH2:16][CH2:15][CH3:14])[CH2:15][CH2:16][CH2:17][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCP(CCCC)CCCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C[O-]
Solvent: C1CCOC1
Product: CCCCCCCCP(CCCCCCCC)CCCCCCCC
Yield: 62 %

Procedure:
EpB (30.0 mL), ammonium formate (24 g), tris(dibenzylideneacetone)dipalladium(0) (0.15 g) and tributylphosphine (0.50 mL) were added to 50 mL of THF solvent. This mixture was stirred at reflux for 1 hour and then filtered through silica gel to remove the palladium catalyst. The product was analyzed by GC and found to be nearly identical to the product obtained in Comparative Example 1 using trioctylphosphine, which consisted of 3-buten-1-ol/2-buten-1-ol in a mole ratio of >98:2), a small amount of crotonaldehyde, and a large amount of high boilers. This product was distilled through a Vigreux column to afford a product cut with 97.2% selectivity. The isolated yield was 62%. Formation of a white solid during this reaction resulted in a pressure buildup and a vapor release.