Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:14])=[C:9]([C:11](O)=[O:12])[N:10]=2)[CH:7]=1.C[N:16](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH4+].[Cl-]>CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:14])=[C:9]([C:11]([NH2:16])=[O:12])[N:10]=2)[CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1c(C(=O)O)nc2ccc(I)cn12
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(C(N)=O)nc2ccc(I)cn12
Temperature: 25 °C
Yield: 60.2 %

Procedure:
To a stirred solution of 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid (1.0 g) in DMF (15 ml) were added HATU (1.88 g) and triethylamine (1.38 ml) at 0° C. The mixture was allowed to warm to room temperature for 30 min, and then NH4Cl (725 mg) was added thereto. The resultant mixture was stirred at the same temperature for 18 h. The mixture was then concentrated in vacuo and diluted with DCM (100 ml). The DCM layer was successively washed with saturated aqueous NH4Cl solution, saturated aqueous NaHCO3 solution, water and brine. The DCM layer was then dried over Na2SO4 and concentrated in vacuo to give the title compound (600 mg) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:2].[Cl:13][C:14]([Cl:18])([Cl:17])[C:15]#[N:16].[Br-].[Al+3].[Br-].[Br-].[ClH:23]>>[Cl:13][C:14]([Cl:18])([Cl:17])[C:15]1[N:16]=[C:15]([C:14]([Cl:17])([Cl:13])[Cl:23])[N:16]=[C:1]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=2)[C:6]([O:8][CH3:9])=[O:7])[N:2]=1
Reactant: COC(=O)c1cccc(C#N)c1
Reactant: Cl
Reactant: N#CC(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Br-]
Product: COC(=O)c1cccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)c1

Procedure:
Methyl 3-cyanobenzoate (70 pw) are mixed with trichloroacetonitrile (376 pw) and aluminum bromide (13.9 pw) as described in Example 1, step 2, hydrogen chloride gas is added, the mixture is allowed to react and the reaction product is separated. Recrystallization from ethanol gives 160 pw=82% of white crystals of methyl 3-(4,6-bis(trichloromethyl)-s-triazin-2-yl)benzoate. M.p.: 115 to 117° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[CH:13][N:14]=[C:7]3[C:6]=2[CH:15]=1.[F:16][C:17]1[C:22](B(O)O)=[CH:21][CH:20]=[CH:19][N:18]=1.C([O-])(=O)C.[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:17]1[C:22]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[CH:13][N:14]=[C:7]4[C:6]=3[CH:15]=2)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: Brc1ccc2c(c1)-c1nccn1CCO2
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ncccc1-c1ccc2c(c1)-c1nccn1CCO2
Temperature: 100 °C

Procedure:
To 10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (140 mg, 0.53 mmol) in DMF (20 mL) and water (2 mL) was added 2-Fluoropyridine-3-boronic acid (89 mg, 0.632 mml), Potassium acetate (207 mg, 2.11 mmol) and Tetrakis(triphenylphosphine)palladium (30 mg, 0.0264 mmol). The reaction mixture was degassed for 5 minutes, and heated at 100° C. overnight. LCMS showed desired product peak. The reaction was allowed to cool to room temperature, diluted with EtOAc, and filtered through a thin pad of celite. The filtrate was washed with water followed by brine, dried over MgSO4 and concentrated. The crude residue was purified by Prep HPLC to provide 10-(2-fluoropyridin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine. LC/MS (ESI+): m/z 282 (M+H)
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]2=[CH:11][CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[N:7]2[N:6]=1)(=O)=O.[C-]#N.[K+].[CH3:25][N:26]1CCCC1=O.CCOC(C)=O>CO.C(Cl)Cl>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]1[N:7]2[C:8]([CH:9]=[N:10][C:5]([C:25]#[N:26])=[N:6]2)=[CH:11][CH:12]=1
Reactant: CN1CCCC1=O
Reactant: COc1ccccc1-c1ccc2cnc(S(C)(=O)=O)nn12
Agent: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: COc1ccccc1-c1ccc2cnc(C#N)nn12
Yield: 72.4 %

Procedure:
2-Methanesulfonyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (804 mg, 2.65 mmol) and Potassium cyanide (311 mg, 4.77 mmol) in N-Methylpyrrolidinone (8.0 mL, 84 mmol) was stirred under an atmosphere of Nitrogen at 80° C. for 7 h, reaching ˜90% conversion. Work up by partitioning between 50% brine (40 mL):EtOAc (60 mL); giving an emulsion, so DCM (20 mL) was added. The emulsion did not successfully break, so it was kept with the aq. The aq. and emulsion was ext. with EtOAc (3×40 mL), the emulsion was isolated by itself and solubilized with DCM:MeOH. Combining all the org. layers, the mix. was washed with satd. NaHCO3 (50 mL) and brine (2×50 mL), dried over sodium sulfate (two iterations) then conc. in vacuo. Purify on silica gel (ISCO 40 g, 0-40% EtOAc:Hex) to afford 7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine-2-carbonitrile (0.480 g, 72%). 1H-NMR (CDCl3): 8.95 (s, 1H), 7.73 (m, 1H), 7.48 (m, 1H), 7.42 (d, 1H, J=4.7 Hz), 7.1-7.2 (m, 3H), 3.87 (s, 3H).
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>ClCCl>[F:1][CH2:2][CH2:3][CH2:4][O:5][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCF
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCF)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
5 g of 3-fluoro-propanol (64.03 mmol) and 18 ml of triethylamine (129.32 mmol) were dissolved in 50 ml dichloromethane. At 0-5° C., 12.9 g toluene-4-sulfonylchloride (67.66 mmol) were added and the reaction mixture stirred at room temperature for 18 h. Standard work-up yielded 13.7 g of toluene-4-sulfonic acid 3-fluoro-propyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]([NH2:17])=O)[S:8][C:7]=3[C:6]=2[N:18]=1.[CH3:19]C(N(C)C)=O.CN(C=O)C.[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[NH:38][NH2:39]>C1(C)C=CC=CC=1.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:38]([C:32]5[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:31]=5[F:30])[N:39]=[CH:19][N:17]=4)[S:8][C:7]=3[C:6]=2[N:18]=1
Reactant: NC(=O)c1cc2c(s1)-c1nc(Cl)ccc1OCC2
Reactant: NNc1ccc(F)cc1F
Reactant: CC(=O)N(C)C
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
To a suspension of 9-Chloro-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene-2-carboxylic acid amide (22 g, 76.8 mmol) in dry toluene (250 mL) was added DMA-DMF (56.1 g, 471.4 mmol). The resulting mixture was heated to 90° C. for 2 h. After removal of the solvent and excess of DMA-DMF, the residue (13.6 g, 94.3 mmol) was dissolved in acetic acid (250 mL) and (2,4-difluorophenyl)hydrazine (16.6 g, 115.2 mmol) was added into the mixture. The mixture was stirred at 90° C. for 2 hours. After removal of the solvents, the residue was treated with EtOAc-water (500 mL, 5:1 (v/v)). The mixture was neutralized with sodium bicarbonate aqueous solution until pH=7. The suspension was filtered and the solid was washed with EtOAc (500 mL). The combined organic layers were washed with saturate sodium bicarbonate aqueous solution (300 mL), dried over sodium sulfate and filtered. The filtrate was concentrated to the crude product, which was purified by flash column (EtOAc/Hexanes=1:3) to give 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (21.4 g, yield: 67%)1H NMR (DMSO, 400 MHz): δ8.35 (s, 1H), 7.98-7.48 (m, 4H), 7.39 (d, J=8.8 Hz, 1H), 7.05 (s, 1H), 4.38 (t, J=4.4 Hz, 2H), 3.2 (t, J=4.4 Hz, 2H). LC-MS (ESI): m/z=417 [M+H]+
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH3:39])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[Cl:46])(C)(C)C.O>C1C=CC=CC=1>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH2:39][Cl:46])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OCl
Solvent: c1ccccc1
Solvent: O
Product: C=C(CCl)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 90 %

Procedure:
A 200 mg quantity of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-methyl-3-butenate was dissolved in 6 ml of benzene. To the solution was added with stirring 51 μl of t-BuOCl at room temperature and the mixture was further agitated for 1 hour. Water was added to the reaction mixture and the resulting mixture was subjected to the same subsequent procedure as in Example 12, giving 19.2 mg of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-chloromethyl-3-butenate in 90% yield.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:8][C:9]1[C:14]([C:15]2[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=2[F:23])=[C:13](Cl)[N:12]2[N:25]=[CH:26][CH:27]=[C:11]2[N:10]=1>C1COCC1.[Cu](I)I>[Cl:8][C:9]1[C:14]([C:15]2[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=2[F:23])=[C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[N:12]2[N:25]=[CH:26][CH:27]=[C:11]2[N:10]=1
Reactant: [Li]CCCCCC
Reactant: Fc1cc(F)c(-c2c(Cl)nc3ccnn3c2Cl)c(F)c1
Agent: I[Cu]I
Solvent: C1CCOC1
Product: CCCCCCc1c(-c2c(F)cc(F)cc2F)c(Cl)nc2ccnn12
Temperature: -70 °C
Reaction time: 0.75 h

Procedure:
Copper iodide (5 mmol) was suspended in THF (25 ml) under an inert gas atmosphere. The suspension was cooled to −70° C. and n-hexyllithium (5 ml,2M in hexanes) was added by syringe. The mixture was stirred for 45 minutes and 5,7-dichloro-6-(2,4,6-trifluoro-phenyl)-pyrazolo[1,5-α]pyrimidine (5 mmol, obtained from Example 3) was added as a solution in THF (10 min). The reaction mixture was stirred for 15 minutes at −70° C. The reaction mixture was then quenched with a mixture of aqueous saturated ammonium chloride/concentrated ammonia (9:1). The two phase mixture was separated. An oil was isolated from the organic layer which was subjected to chromatographic purification which yields the product as a crystalline residue.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:11])[C:9]#[CH:10])=[CH:4][CH:3]=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21](S(O)(=O)=O)=[CH:20][CH:19]=1.[C:29](=[O:32])(O)[O-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:11][C:20]3[CH:19]=[C:18]([C:28]4[CH:3]=[CH:4][C:5]([C:8]5[CH:12]=[CH:13][C:29]([OH:32])=[CH:10][CH:9]=5)=[CH:6][CH:7]=4)[C:23]4[C:22]([C:21]=3[CH:10]=[CH:9]2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:6][CH:7]=1
Reactant: C#CC(O)(c1ccccc1)c1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Oc1ccc(-c2ccc(-c3cc4c(c5ccccc35)C=CC(c3ccccc3)(c3ccc(F)cc3)O4)cc2)cc1

Procedure:
A solution of 4-(4′-hydroxy-4-biphenyl)-2-naphthol (16.14 g, 52 mmol), 1-(4-fluorophenyl)-1-phenylprop-2-yn-1-ol (11.7 g, 52 mmol) and toluene-4-sulphonic acid (0.05 g) in toluene (200 mL) was heated at reflux. After 2 h the mixture was poured into saturated sodium bicarbonate solution (400 mL), extracted with dichloromethane (DCM) (4×100 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was chromatographed on silica using EtOAc (10-30% in hexanes) to afford 3-(4-fluorophenyl)-6-(4′-hydroxybiphen-4-yl)-3-phenyl-3H-naphtho[2,1-b]pyran which was collected, the solvent removed under reduced pressure, the residue was filtered through a short plug of silica using DCM as eluent and the solvent removed under reduced pressure to give the title compound (19.37 g, 72%) as an orange solid which was used without further purification.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][CH:5]([NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:14]2[N:13]=[C:12](Cl)[C:11]=1[C:24]1[S:25][CH:26]=[CH:27][C:28]=1[CH3:29])[CH:6]([CH3:8])[CH3:7].O>CO>[CH3:4][CH:5]([NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:14]2[N:13]=[C:12]([O:2][CH3:1])[C:11]=1[C:24]1[S:25][CH:26]=[CH:27][C:28]=1[CH3:29])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)c1cnn2c(NC(C)C(C)C)c(-c3sccc3C)c(Cl)nc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cnn2c(NC(C)C(C)C)c(-c3sccc3C)c(OC)nc12
Temperature: 22 °C
Reaction time: 16 h

Procedure:
0.17 g (3 mmol) of sodium methoxide was dissolved in 10 ml of methanol, and 0.79 g (2 mmol) of methyl 7-(1,2-dimethylpropylamino)-5-chloro-6-(3-methylthiophen-2-yl)pyrazolo[1,5-α]-pyrimidine-3-carboxylate was added. The mixture was stirred at 22° C. for 16 hours. 10 ml of water were then added, the methanol was distilled off and 10 ml of dichloromethane were added to the residue. The organic phase was separated off, dried over sodium sulphate and concentrated under reduced pressure. This gave 0.35 g of methyl 7-(1,2-dimethylpropylamino)-5-methoxy-6-(3-methylthiophen-2-yl)pyrazolo[1,5-α]pyrimidine-3-carboxylate (logPs=4.60; content according to HPLC: 96%).
Reaction SMILES: [F:1][C:2]1(C#N)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.C(O)(C(F)(F)F)=O.[C:17](=[O:20])([O-])[O-:18].[Cs+].[Cs+].[O:23]1[CH2:25][CH:24]1[C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([C:37]3[O:41][N:40]=[C:39]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:38]=3[C:48]([F:51])([F:50])[F:49])[O:34][N:33]=2)=[CH:28][CH:27]=1>CC(O)C.CS(C)=O>[F:1][C:2]1([C:17]([OH:18])=[O:20])[CH2:7][CH2:6][CH2:5][N:4]([CH2:25][CH:24]([OH:23])[C:26]2[CH:31]=[CH:30][C:29]([C:32]3[N:36]=[C:35]([C:37]4[O:41][N:40]=[C:39]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:38]=4[C:48]([F:51])([F:50])[F:49])[O:34][N:33]=3)=[CH:28][CH:27]=2)[CH2:3]1
Reactant: N#CC1(F)CCCNC1
Reactant: O=C([O-])[O-]
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(C3CO3)cc2)no1
Agent: [Cs+]
Solvent: CC(C)O
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1(F)CCCN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Temperature: 80 °C

Procedure:
To a mixture of 3-fluoropiperidine-3-carbonitrile, TFA (55 mg, 0.227 mmol), and cesium carbonate (122 mg, 0.376 mmol) in 2-propanol (2 mL) and DMSO (0.5 mL) was added 3-(4-(oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole, Preparation 28C (30 mg, 0.075 mmol). The reaction mixture was heated at 80° C. over a weekend. The reaction mixture was purified by HPLC. The purified product was lyophilized and then was dissolved in MeCN/6N HCl and heated at 50° C. overnight. The mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 6 mgs of 3-fluoro-1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.14 (2H, d, J=7.91 Hz), 7.56-7.62 (4H, m), 7.44-7.56 (3H, m), 5.13-5.24 (1H, m), 3.86-4.28 (1H, m), 3.47-3.81 (2H, m), 3.25-3.41 (2H, m), 2.08-2.15 (3H, m), 1.87-2.02 (2H, m). MS (m+1)=547. HPLC Peak RT=3.32 minutes (Analytical Method A). Purity=98%.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]3)=[CH:19][C:18]=1[C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: OB(O)c1ccc(F)c(-c2ncccc2F)c1
Product: Fc1ccc(-c2ccnc3nc(C(F)(F)F)ccc23)cc1-c1ncccc1F
Yield: 49.2 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (100 mg, 0.43 mmol) was coupled to 4-fluoro-3-(3-fluoropyridin-2-yl)phenylboronic acid (131 mg, 0.56 mmol) as described in Example 3 part g), affording 5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-2-trifluoromethyl[1,8]-naphthyridine (82 mg, 49%). δH (360 MHz, CDCl3) 7.39-7.44 (2H, m), 7.55-7.63 (3H, m), 7.79 (1H, dd, J 2.3 and 6.5), 7.85 (1H, d, J 8.4), 8.55-8.60 (2H, m), 9.28 (1H, d, J 4.6). m/z (ES+) 388 [MH]+.
Reaction SMILES: [CH2:1]([Br:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:14][CH:15]=1>CC(C)=O>[Br-:8].[CH2:1]([N+:14]1[CH:15]=[C:10]([F:9])[CH:11]=[CH:12][C:13]=1[CH2:16][NH:17][C:18]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)cn1
Reactant: BrCc1ccccc1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(F)c[n+]1Cc1ccccc1
Product: [Br-]
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of benzyl bromide (4.21 mmol, 0.5 mL), tert-butyl (5-fluoropyridin-2-yl)methylcarbamate (3.49 mmol, 0.79 g) and acetone (4 mL) in a sealed tube was heated to 80° C. overnight. According to analytical HPLC, around 50% of the starting material remained. Additional benzyl bromide (33.68 mmol, 4.0 mL) was added and the reaction was continued for extra 8 h. The reaction mixture was concentrated in vacuo and loaded on a pad of silica which was rinsed with ether until benzyl bromide was gone. Then, the silica pad was rinsed with MeOH. Removal of MeOH in vacuo afforded desired product 1-benzyl-2-((tert-butoxycarbonylamino)methyl)-5-fluoropyridinium bromide as light orange solid in 43% yield. MS (ESI) 317 (M+H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[NH:4]N=1.[CH3:13]CN(CC)CC.[C:20]([C:22]1[CH:30]=[CH:29][C:25]([N:26]([CH3:28])[CH3:27])=[CH:24][CH:23]=1)#[CH:21]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:27][N:26]([CH3:28])[C:25]1[CH:29]=[CH:30][C:22]([C:20]#[C:21][C:2]2[C:10]3[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=3)[NH:4][CH:13]=2)=[CH:23][CH:24]=1
Reactant: C#Cc1ccc(N(C)C)cc1
Reactant: O=Cc1ccc2c(I)n[nH]c2c1
Reactant: CCN(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CN(C)c1ccc(C#Cc2c[nH]c3cc(C=O)ccc23)cc1
Temperature: 100 °C

Procedure:
To a solution of 3-iodo-1H-indazole-6-carbaldehyde (136 mg, 0.5 mmol), Pd(PPh3)2Cl2 (14 mg, 0.02 mmol) and CuI (7.6 mg, 0.04 mmol) in DMF (3 mL) was added Et3N (5 mL), followed by 4-ethynyl-N,N-dimethylaniline (109 mg, 0.75 mmol). The resulting mixture was heated at 100° C. (oil temp.) for 45 min. After removal of Et3N, the residue was loaded directly onto a silical gel column. Flash chromatography (eluent: hex to hex/ethyl acetate=5:1 to 1:1, to ethyl acetate) gave the crude 3-((4-(dimethylamino)phenyl)ethynyl)-1H-indole-6-carbaldehyde as greenish brown solid, which was redissolved in MeOH (20 mL). 2-Oxindole (53.2 mg, 0.4 mmol) and piperidine (10 drops) were added and the resulting mixture was refluxed (oil temp 75° C.) for 2 h. Additional 2-oxindole (13.3 mg) was added and the mixture was refluxed for another hour. After cooling to rt, the reaction mixture was suction filtered and the filter cake was rinsed with MeOH (10 mL). The filtrate was concentrated to about 0.5 mL and diluted with EtOAc (8 mL). Hexane (15 mL) was added and the resulting precipitate was collected by suction filtration to give the title compound (63 mg, 31% over 2 steps) as a golden solid (E:Z=9:1). 1H NMR (400 MHz, DMSO-d6) δ 13.40 (s, br, 1H), 10.64 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.91 (s, 1H), 7.79 (s, 1H), 7.57 (d, J=7.2 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.8 Hz, 2H), 7.24 (t, J=7.6 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H), 6.84 (t, J=7.4 Hz, 1H), 6.75 (d, J=8.8 Hz, 2H), 2.97 (s, 6H); MS ESI 405.2 [M+H]+, calcd for [C26H20N4O+H]+ 405.2.
Reaction SMILES: Cl[C:2]([Cl:12])(OC(=O)OC(Cl)(Cl)Cl)Cl.C[N:14](C)[NH:15][C:16]([NH:18][CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:22]=1)[CH3:20])=[O:17].[C:34](OCC)(=O)C>C(Cl)Cl>[Cl:12][C:2]1[N:18]([CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:22]=2)[CH3:20])[C:16](=[O:17])[N:15]([CH3:34])[N:14]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(NC(=O)NN(C)C)c1cccc(-c2ccccc2)c1
Reactant: CCOC(C)=O
Solvent: ClCCl
Product: CC(c1cccc(-c2ccccc2)c1)n1c(Cl)nn(C)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4.33 g (14.6 mmol) of triphosgene in 15 ml of methylene chloride was added dropwise a solution of 2.07 g (7.30 mmol) of 1,1-dimethyl-4-{1-(3-phenylphenyl)ethyl}semicarbazide (produced in the following Reference Production Example 7) in 20 ml of methylene chloride with ice-cooling. The mixture was removed from an ice bath, warmed to room temperature and heated under reflux for 4 hours. After allowing to cool to room temperature, the reaction mixture was poured into 150 ml of an about 5% aqueous solution of sodium bicarbonate, and the mixture was stirred for 1 hour. The organic layer was washed with water, dried and concentrated. The residue (1.93 g) was subjected to silica gel column chromatography (eluted with n-hexane:ethyl acetate=10:1 and then 5:1 and then 3:1) to obtain 418 mg (1.33 mmol) of 5-chloro-2-methyl-4-{1-(3-phenylphenyl)ethyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (the compound 12 of the present invention) as an oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)=[C:12]([C:27]#[N:28])[CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.C([O-])(O)=O.[Na+]>[NH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][N:18]=2)=[C:12]([CH:11]=1)[C:27]#[N:28]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(C(F)(F)F)cn2)c(C#N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(CCN)ccc1Oc1ccc(C(F)(F)F)cn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 92 %

Procedure:
Entire reaction was performed under argon atmosphere using syringe septa technique. {2-[3-cyano-4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (0.425 mmol, 1 eq) was dissolved in dichloromethane (1.5 ml) and stirred at 0° C. for 5 min. TFA (2.213 mmol, 5 eq) was added and stirring was continued for 2 hours. Reaction mixture was diluted with 10 ml NaHCO3 (sat.) and extraction with DCM (3×20 ml) followed. Organic layers were combined and evaporated in vacuo to give 5-(2-amino-ethyl)-2-(5-trifluoromethyl-pyridin-2-yloxy)benzonitrile (0.391 mmol, yield=92%, purity=80%). [M+H]+=308.29 1H NMR (300 MHz, CDCl3) δ/ppm 2.79 (br. s., 2H), 2.94-3.07 (m, 2H), 7.21 (br. s., 2H), 7.49 (d, J=8.9 Hz, 1H), 7.54 (br. s., 1H), 7.90-8.05 (m, 1H), 8.38 (br. s., 1H)