Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24](O)=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.CO>C1COCC1>[OH:25][CH2:24][CH:12]1[CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:15][CH2:16][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C(=O)O)C1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(CO)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.5 %

Procedure:
To 1-[(benzyloxy)carbonyl]-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (1 g) in anhydrous THF (11 ml) under argon, cooled to 0° C. was added 1M borane in THF (11 ml) and the mixture allowed to warm to room temperature over 3.5 hours. After cooling to 0° C., MeOH was added and stirring continued for 72 hours. The solvents were evaporated, saturated aqueous sodium bicarbonate and ethyl acetate added, the organic phase dried (MgSO4) and evaporated to give the title compound (0.88 g, 92%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].CC1(C)C(C)(C)OB([C:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH:22]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>COCCOC.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.C(OCC)(=O)C>[CH3:12][O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([C:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH:22]=2)[CH:3]=1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)C1
Reactant: COc1ccc([N+](=O)[O-])c(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc([N+](=O)[O-])c(C2=CC(C)(C)CC(C)(C)C2)c1
Temperature: 25 °C
Yield: 34.3 %

Procedure:
To a solution of 3-iodo-4-nitroanisole (4.21 g, 15.1 mmol) in 1,2-dimethoxyethane (50 mL) were added 4,4,5,5-tetramethyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)[1,3,2]dioxaborolane (4.78 g, 18.1 mmol) produced in Example (4b), tripotassium phosphate (4.81 g, 22.7 mmol) and water (3 mL). Then, tetrakis(triphenylphosphine)palladium(0) (870 mg, 0.755 mmol) was added to the mixture while stirring at room temperature under a nitrogen atmosphere. The mixture was then further stirred for 13 hours at an external temperature of 70° C. To the reaction mixture were added tetrakis(triphenylphosphine)palladium(0) (870 mg, 0.755 mmol) and water (3 mL), followed by stirring for 26 hours at an external temperature of 100° C. The reaction mixture was cooled, and then ethyl acetate was added and the mixture was filtered through Celite. The filtrate was concentrated to give a residue, which was subjected to extraction with ethyl acetate, and the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate and then the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/heptane) to give 1.5 g of the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19]([CH3:22])(=[O:21])=[O:20])[C:3]=1[CH3:23].[I:24][C:25]1[CH:33]=[C:32]2[C:28]([C:29]([CH3:35])([CH3:34])[CH2:30][NH:31]2)=[CH:27][CH:26]=1.Cl>CN1C(=O)CCC1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:31]3[C:32]4[C:28](=[CH:27][CH:26]=[C:25]([I:24])[CH:33]=4)[C:29]([CH3:35])([CH3:34])[CH2:30]3)=[C:3]([CH3:23])[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[S:19]([CH3:22])(=[O:21])=[O:20])=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)ccc2c1Cl
Reactant: CC1(C)CNc2cc(I)ccc21
Agent: Cl
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(I)cc21
Temperature: 150 °C

Procedure:
Prepared according to procedure L using 4-chloro-7-fluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline (102 mg, 0.29 mmol) (described herein), 6-iodo-3,3-dimethylindoline (80 mg, 0.29 mmol) (described herein), hydrochloric acid (70 μL, 0.29 mmol), and NMP (0.490 mL). The reaction mixture was heated in a microwave at 150° C. for 150 min. Purification afforded 7-fluoro-4-(6-iodo-3,3-dimethylindolin-1-yl)-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline as a yellow solid. Mass Spectrum (ESI) m/e=587 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.CCN(CC)CC.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[F:25]>CCOC(C)=O>[F:25][C:17]1[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:16]=1[N:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1
Reactant: OC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCC(O)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.5 %

Procedure:
To a solution of piperidin-4-ol (11.11 g, 0.11 mol) and Et3N (12.14 g, 0.12 mol) in EtOAc (500 mL) was added 1,2-difluoro-4-nitrobenzene (15.91 g, 0.10 mol). The mixture was stirred at rt for 24 h, and washed with water (200 mL×4). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as orange oil (19.35 g, 80%).
Reaction SMILES: [F:1][C:2]1([F:29])[C:4]2([CH2:9][CH2:8][N:7]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19](C(O)=O)[CH2:18][CH2:17]4)=[N:14][CH:15]=3)[CH2:6][CH2:5]2)[CH2:3]1.Cl>ClCCl.O1CCOCC1>[F:29][C:2]1([F:1])[C:4]2([CH2:9][CH2:8][N:7]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[NH:19][CH2:18][CH2:17]4)=[N:14][CH:15]=3)[CH2:6][CH2:5]2)[CH2:3]1
Reactant: O=C(O)N1CCN(c2ccc(N3CCC4(CC3)CC4(F)F)cn2)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: FC1(F)CC12CCN(c1ccc(N3CCNc4ccccc43)nc1)CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.48 g of tert-butyl ester of 4-[5-(1,1-difluoro-6-aza-spiro[2.5]oct-6-yl)-pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid is put in 16 mL of dichloromethane. 24 mL of 4M hydrochloric acid in dioxane is added at +4° C. The solution is stirred at room temperature for 4 h and evaporated to dryness. The residue is taken up in a saturated solution of sodium hydrogen carbonate to basic pH. The solution is extracted twice with dichloromethane, washed with water, dried over magnesium sulfate, filtered and evaporated to dryness. 1.4 g of 1-[5-(1,1-difluoro-6-aza-spiro[2.5]oct-6-yl)-pyridin-2-yl]-1,2,3,4-tetrahydroquinoxaline is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[Cl:25][C:26]1[CH:35]=[CH:34][C:29](/[CH:30]=[CH:31]/[CH:32]=O)=[CH:28][CH:27]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:25][C:26]1[CH:35]=[CH:34][C:29](/[CH:30]=[CH:31]/[C@H:32]2[O:21][CH2:20][C@H:19]([S:18][C@H:16]([CH3:17])[C@:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])([OH:24])[CH2:10][N:11]3[CH:15]=[N:14][CH:13]=[N:12]3)[CH2:22][O:23]2)=[CH:28][CH:27]=1
Reactant: O=C/C=C/c1ccc(Cl)cc1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/c2ccc(Cl)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
In 14 ml of methylene chloride were dissolved 294 mg (0.82 mmol) of (2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1 H-1,2,4-triazol-1-yl)-2-butanol as described in Reference example 2 and 191 mg (1.15 mmol) of trans-4-chlorocinnamaldehyde [Bull. Chem. Soc. Japan 52 555 (1979)], and 233 mg (1.23 mmol) of p-toluenesulfonic acid monohydrate and 1.5 g of molecular sieves 4A were added thereto, followed by stirring of the resulting mixture for 1 hour and 15 minutes. An aqueous sodium hydrogencarbonate solution was added to the reaction mixture and the mixture was stirred for 10 minutes, followed by removal of the molecular sieves by filtration. The organic layers were collected and dried to distil off the solvent under reduced pressure. The thus obtained oil was subjected to column chromatography using 15 g of silica gel and eluted with a mixed solvent hexane-ethyl acetate (3:2) to obtain 280 mg (yield: 67%) of the desired title compound, trans isomer (A) as an oil. Further, the oil was eluted with a mixed solvent of hexane-ethyl acetate (1:1) to obtain 35 mg (yield: 8%) of the cis isomer (B) as an oil.
Reaction SMILES: [CH:1]1([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[O:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[CH3:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:26][CH2:27][CH2:28][NH2:29]>>[F:25][C:24]1[C:19]([CH3:18])=[C:20]([CH2:26][CH2:27][CH2:28][NH:29][C@H:4]2[CH2:5][CH2:6][C@H:1]([C:8]3[CH:17]=[CH:16][C:11]4[NH:12][C:13](=[O:15])[O:14][C:10]=4[CH:9]=3)[CH2:2][CH2:3]2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Reactant: Cc1c(F)cccc1CCCN
Product: Cc1c(F)cccc1CCCN[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1

Procedure:
Coupling of ketone 5 and 3-(2-methyl-3-fluorophenyl)-1-propylamine, using the method given in Example 1, gave 6-{trans-4-[3-(3-fluoro-2-methylphenyl)propylamino]cyclohexyl}-3H-benzoxazol-2-one (1.4 g, 56%): 1H NMR (500 MHz, DMSO-d6): δ 7.16-7.10 (m, 2H), 7.01-6.93 (m, 4H), 2.65 (dd, J=8, 8 Hz, 2H), 2.60 (dd, J=7, 7 Hz, 2H), 2.49-2.39 (m, 2H), 2.18 (d, J=2 Hz, 3H), 1.98-1.93 (m, 2H), 1.81-1.75 (m, 2H), 1.68-1.61 (m, 2H), 1.45 (dddd, J=13, 13, 13, 3 Hz, 2H), 1.13 (dddd, J=13, 13, 13, 3 Hz, 2H).
Reaction SMILES: F[C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6].[H-].[Na+].[CH2:18]([SH:20])[CH3:19].Cl>CN(C)C=O>[CH2:18]([S:20][C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6])[CH3:19]
Reactant: CCS
Reactant: Cc1c(C(=O)O)ccc(C(F)(F)F)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSc1c(C(F)(F)F)ccc(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.00 g (13.5 mmol) of 3-fluoro-2-methyl-4-trifluoromethylbenzoic acid were initially charged in 50 ml of N,N-dimethylformamide. 1.68 g (purity 60% by weight, 41.9 mmol) of NaH were added a little at a time. Towards the end of the evolution of gas, 1.77 g (purity 95% by weight, 27.0 mmol) of ethanethiol were added dropwise. The mixture was stirred at RT for 2 h and then heated at 80° C. for 10 h. The reaction mixture was cooled and, for workup, poured into ice-water and then acidified with concentrated hydrochloric acid. The product precipitated out and was separated off by filtration. What was isolated were 3.7 g of the pure product.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:36])[NH:6][C@H:7]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15](=[O:29])[NH:16][CH2:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C:24]([NH2:28])=[N:23][CH:22]=[CH:21]2)=[O:9])(C)C.COC(N[C@@H](C1C=CC=CC=1)C(N1CCC[C@H]1C(O)=O)=O)=O>>[CH3:1][O:4][C:5](=[O:36])[NH:6][C@@H:7]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15](=[O:29])[NH:16][CH2:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C:24]([NH2:28])=[N:23][CH:22]=[CH:21]2)=[O:9]
Reactant: CC(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1)c1ccccc1
Agent: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1)c1ccccc1
Yield: 559.3 %

Procedure:
Using the procedure described for example 91d 0.110 g of 1-[(S)-methoxycarbonylamino-phenyl-acetyl]-pyrrolidine-2-(S)-carboxylic acid was converted into 0.58 g (36%) of the title compound. (+)-APCI-MS: 462 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([OH:9])=O)[CH2:5][C:4]([CH3:10])=[N:3]1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][C:33]=1[CH3:34])[O:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([NH:25][C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[N:24]=2)[N:21]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:28]1([C:26]([NH:25][C:23]2[N:24]=[C:19]3[CH:18]=[CH:17][C:16]([O:15][C:14]4[CH:31]=[CH:32][C:33]([CH3:34])=[C:12]([NH:11][C:7]([CH:6]5[N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH2:5]5)=[O:9])[CH:13]=4)=[N:21][N:20]3[CH:22]=2)=[O:27])[CH2:29][CH2:30]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: CC1=NN(C)C(C(=O)O)C1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1=NN(C)C(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)C1
Yield: 71.7 %

Procedure:
In the same manner as in Example 278 and using 1,3-dimethyl-4,5-dihydro-1H-pyrazole-5-carboxylic acid (120 mg, 0.87 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol), O-(7-azabenzotriazol-1-yl)-N,N′,N′-tetramethyluronium hexafluorophosphate (330 mg, 0.87 mmol), N,N-diisopropylethylamine (240 mg, 1.8 mmol) and N,N-dimethylformamide (7 mL) as starting materials, the title compound (199 mg, 72%) was obtained as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][CH2:12][CH:13]([N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])[CH2:14][CH2:15][CH2:16][OH:17].C(N(CC)CC)C>ClCCl.O>[F:11][CH2:12][CH:13]([N:18]1[C:19](=[O:28])[C:20]2=[CH:27][CH:26]=[CH:25][CH:24]=[C:21]2[C:22]1=[O:23])[CH2:14][CH2:15][CH:16]=[O:17]
Reactant: O=C1c2ccccc2C(=O)N1C(CF)CCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CCCC(CF)N1C(=O)c2ccccc2C1=O
Temperature: -60 °C
Reaction time: 0.75 h

Procedure:
To a solution at -60° C. of oxalylchloride (75.3 g, 0.59 mol) in dry dichloromethane (2 L) under nitrogen, was added a solution of dry DMSO (89.1 g, 1.14 mol) in dry dichloromethane (2 L). 5-Fluoro-4-phthalimidopentanol, 5a, (R=--CH2F) (135 g, 0.54 mol) in CH2Cl2 (2 L) was then added over 15 min. The mixture was stirred 45 min. at -60° C., a solution of triethylamine (352 g, 3.47 mol) in dry CH2Cl2 (2 L) was added slowly (exothermic). The solution was stirred overnight, cooled to -10° C. and water (2 L) added. The organic phase was separated, washed with 4 N HCl, followed by water (3×2 L). The organic phase was separated, dried over Na2SO4 and evaporated. The residue was dissolved in ether, washed with water (3×0.5 L) and dried over Na2SO4. Evaporation of the ether phase gave an oil which was heated at 70° C./0.1 mm Hg to remove traces of DMSO. The title compound (6, R=--CH2F) was obtained as a red oil: 136 g (100%). NMR (1H, CDCl3, 90 MHz).
Reaction SMILES: C([O-])(=O)C.[NH4+].[F:6][C:7]1[CH:23]=[CH:22][C:21]2[C:12]3[NH:13][C:14](=[O:20])[C:15]4[N:16]([CH:17]=[CH:18][N:19]=4)[C:11]=3[C:10](=[N:24]O)[C:9]=2[CH:8]=1.C(O)C.[ClH:29]>N.O.CO.[Zn]>[ClH:29].[NH2:24][CH:10]1[C:11]2[N:16]3[CH:17]=[CH:18][N:19]=[C:15]3[C:14](=[O:20])[NH:13][C:12]=2[C:21]2[CH:22]=[CH:23][C:7]([F:6])=[CH:8][C:9]1=2
Reactant: O=c1[nH]c2c(n3ccnc13)C(=NO)c1cc(F)ccc1-2
Agent: CC(=O)[O-]
Agent: Cl
Agent: N
Solvent: CO
Solvent: CCO
Solvent: O
Product: NC1c2cc(F)ccc2-c2[nH]c(=O)c3nccn3c21
Reaction time: 2 h

Procedure:
To a solution of 0.48 g of ammonium acetate in 120 ml of 28% aqueous ammonia solution are successively added 3.25 g of 8-fluoro-10-hydroxyimino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 120 ml of ethanol and 3.55 g of zinc powder. The mixture is stirred for 2 hours at boiling and for 16 hours at a temperature in the region of 20° C., followed by dropwise addition of 60 ml of aqueous 5N hydrochloric acid solution and the mixture is stirred for 16 hours at the same temperature. The insoluble material formed is removed by filtration and the filtrate is concentrated to dryness under reduced pressure (10 mmHg; 1.3 kPa) at 50° C. The product obtained (13.4 g) is stirred in suspension in 30 ml of distilled water and the insoluble material is separated out by filtration, washed twice with 4 ml in total of distilled water and dried under reduced pressure (10 mmHg; 1.3 kPa) at 50° C. The product obtained (1.35 g) is suspended for 10 minutes in 10 ml of boiling methanol. After cooling and storing for 16 hours at 5° C., the insoluble material is separated out by filtration, washed with 1 ml of methanol and resuspended for 10 minutes in 5 ml of boiling methanol. After cooling and storing for 6 hours at 5° C., the insoluble material is separated out by filtration, washed with 1 ml of methanol and dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 0.48 g of 10-amino-8-fluoro-5H,10H-imidazo[1,2-a]-indeno[1,2-e]pyrazin-4-one hydrochloride is thus obtained, decomposing without melting above 260° C. [N.M.R. spectrum: [200 MHz; (CD3)2SO d6 ; δ in ppm]: 5.69 (broad s, 1H: --CH-- 10); 7.44 (dt, J=8.5 and 2 Hz, 1H: --H7); 7.68 and 8.54 (2s, 1H each: --H of the imidazole); 7.93 (dd, J=8.5 and 2 Hz, 1H: --H9); 7.94 (dd, J=8.5 and 6 Hz, 1H: --H6); 9.30 (cplx, 3H: --NH3+Cl- ; 12.72 (wide cplx, 1H: --CONH--)].
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1)=[O:11].Cl[C:23]1[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1>>[Cl:29][C:26]1[CH:25]=[N:24][C:23]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][N:13]=2)=[O:11])=[N:28][CH:27]=1
Reactant: C[C@@H]1CCCN(C(=O)c2nccc3ccccc23)[C@@H]1CN
Reactant: Clc1cnc(Cl)nc1
Product: C[C@@H]1CCCN(C(=O)c2nccc3ccccc23)[C@@H]1CNc1ncc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(isoquinolin-1-yl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 396 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[NH:12][N:11]3[C:15](=[O:18])[NH:16][N:17]=[C:10]3[C:9]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[N:12]([CH2:32][C:33]3[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=3)[N:11]3[C:15](=[O:18])[NH:16][N:17]=[C:10]3[C:9]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]n2c(=O)[nH]nc2c(-c2ccncc2)c1-c1ccc(Cl)cc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2c(=O)c(-c3ccc(Cl)cc3)c(-c3ccncc3)c3n[nH]c(=O)n32)cc1
Reaction time: 0.25 h
Yield: 40.1 %

Procedure:
To the solution of 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3,6(2H,5H)-dione (8 mg, 0.023 mmol), prepared as described in Example 9 in DMF (0.3 ml) was added K2CO3 (5 mg, 0.036 mmol) followed by 4-(bromomethyl)benzonitrile (5 mg, 0.025 mmol). After 15 min, the reaction mixture was diluted with ethyl acetate. The resultant solution was then washed with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to give the title compound, 4-((7-(4-chlorophenyl)-3,6-dioxo-8-(pyridin-4-yl)-2,3-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-5(6H)-yl)methyl)benzonitrile, (4.2 mg, 32%) as a mono trifluoroacetate salt as a yellow foam. MS M+H=454; 1H (CD3OD) δ 8.68(2H), 7.71-7.65(6H), 7.28(2H), 7.20(2H), 5.94(2H).
Reaction SMILES: CN(C)C=O.N1C=CN=C1.[CH3:11][C:12]([Si:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)Cl)([CH3:14])[CH3:13].[Br:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>C1CCCCC1.CCOC(C)=O.CCCCC.C(OCC)(=O)C.O>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][Si:15]([C:12]([CH3:14])([CH3:13])[CH3:11])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:32][CH:31]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](Oc1ccc(Br)cc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
400 ml of dimethylformamide, 31.18 g of imidazole and 125.89 g of 1,1-dimethyl-ethyldiphenyl-chlorosilane are added under an inert atmosphere and at ambient temperature to 80.89 g of parabromophenol, then the solution obtained is agitated for 2 hours. The reaction medium is poured into 2 liters of water, precipitation is observed, the solid is solubilized with ethyl acetate and the aqueous phase is extracted with ethyl acetate, the combined organic phases are dried and evaporated under reduced pressure until an oil is obtained. Pentane is added and crystallisation is observed. After filtration and drying of the precipitate 179.24 g of expected product is obtained. Rf: 0.53 (thin layer chromatography, support: silica, eluant Cyclohexane/AcOEt 95/5).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH:9]=2)[CH:6]=1.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:19][C:16]2[CH:17]=[CH:18][C:13]([C:10]3[CH:9]=[C:8]([CH2:7][N:5]4[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]4)[O:12][N:11]=3)=[CH:14][CH:15]=2)=[CH:23][CH:22]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1cn(Cc2cc(-c3ccc(O)cc3)no2)cn1
Product: Cc1cn(Cc2cc(-c3ccc(OCc4ccc(F)cc4)cc3)no2)cn1

Procedure:
An experiment was performed in the same manner as in Example 139 to synthesize 4-[5-(4-methyl-imidazol-1-ylmethyl)-isoxazol-3-yl]-phenol as an intermediate, and then a synthesis was performed using 4-fluorobenzyl bromide in the same manner as in Example 142.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[C:18]([O:22][C:23](=[O:46])[C:24]([CH3:45])([CH3:44])[CH2:25][C:26]1[CH:43]=[CH:42][C:29]([CH2:30][N:31]([CH2:36][C:37]2[O:38][CH:39]=[CH:40][CH:41]=2)[CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=1)([CH3:21])([CH3:20])[CH3:19].[CH3:47][C:48]1[CH:54]=[C:53]([CH3:55])[CH:52]=[CH:51][C:49]=1[NH2:50]>CN(C)C1C=CN=CC=1.CN(C)C=O.O>[CH3:47][C:48]1[CH:54]=[C:53]([CH3:55])[CH:52]=[CH:51][C:49]=1[NH:50][C:33](=[O:34])[CH2:32][N:31]([CH2:30][C:29]1[CH:42]=[CH:43][C:26]([CH2:25][C:24]([CH3:44])([CH3:45])[C:23]([O:22][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:46])=[CH:27][CH:28]=1)[CH2:36][C:37]1[O:38][CH:39]=[CH:40][CH:41]=1
Reactant: Cc1ccc(N)c(C)c1
Reactant: CC(C)(C)OC(=O)C(C)(C)Cc1ccc(CN(CC(=O)O)Cc2ccco2)cc1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC(=O)CN(Cc2ccc(CC(C)(C)C(=O)OC(C)(C)C)cc2)Cc2ccco2)c(C)c1
Reaction time: 1 h
Yield: 90.7 %

Procedure:
At 0° C., 88 mg (0.648 mmol) of 1-hydroxy-1H-benzotriazole, 124 mg (0.648 mmol) of 1-ethyl-3-(3-dimethylamino)propylcarbodiimide hydrochloride, 151 mg (1.494 mmol) of N-methylmorpholine and 3 mg (0.025 mmol) of 4-dimethylaminopyridine are added to a solution of 200 mg (0.498 mmol) of N-[4-(3-tert-butoxy-2,2-dimethyl-3-oxopropyl)benzyl]-N-(2-furylmethyl)glycine (Example I-12) and 91 mg (0.747 mmol) of 2,4-dimethylaniline in 8 ml of dimethylformamide, and the solution is stirred at this temperature for 1 h. The mixture is then stirred at room temperature for 9 h and then admixed with 10 ml of water. The aqueous phase is extracted 2× with ethyl acetate and the combined organic phases are washed with 1 N hydrochloric acid, sat. NaHCO3 solution and sat. NaCl solution, dried over sodium sulphate and freed from the solvent under reduced pressure. Chromatographic purification of the residue on silica gel (cyclohexane/ethyl acetate 10:1→3:1) gives 228 mg (91%) of tert-butyl 3-(4-{[(2-(2,4-dimethylphenyl)amino-2-oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionate.