Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[C:19]=3[NH2:24])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH3:2].[F:26][C:27]([F:40])([F:39])[C:28]1[CH:29]=[C:30]([CH2:34][CH2:35][C:36](=O)[CH3:37])[CH:31]=[CH:32][CH:33]=1>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[C:19]=3[NH:24][CH:36]([CH3:37])[CH2:35][CH2:34][C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([C:27]([F:26])([F:39])[F:40])[CH:29]=3)=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3N)cc2)cc1
Reactant: CC(=O)CCc1cccc(C(F)(F)F)c1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(C)CCc3cccc(C(F)(F)F)c3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using [4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]acetic acid ethyl ester and 4-(3-trifluoromethyl-phenyl)-butan-2-one.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:12]([CH:26]([F:37])[C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[C:11]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[C:40]([F:45])[CH:39]=3)[C:10]1=2)(C(C)(C)C)(C)C.CO.O1CCCC1>Cl>[CH:21]1([C:13]2[C:12]([CH:26]([F:37])[C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)=[C:11]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[C:40]([F:45])[CH:39]=3)[C:10]3[CH:9]([OH:8])[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]=3[N:14]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC1(C)Cc2nc(C3CCCC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)c(F)c3)c2C(O[Si](C)(C)C(C)(C)C)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)Cc2nc(C3CCCC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)c(F)c3)c2C(O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.6 %

Procedure:
190 mg of 5-(tert-butyldimethylsilanyloxy)-2-cyclopentyl-4-(3,4-difluorophenyl)-3-[fluoro-(4-trifluoromethylphenyl)-methyl]-7,7dimethyl-5,6,7,8-tetra-hydroquinoline, in a mixture of 1.6 ml of 5 N hydrochloric acid, 2.3 ml of methanol and 1.5 ml of tetrahydrofuran, were stirred at RT for 1 hour and then at 40° C.-45° C. for 2 hours. Some of the compound precipitated out as a by-product. This gives 80 mg of m.p. 206-207° C. The mother liquor is admixed with saturated aqueous sodium bicarbonate solution and with ethyl acetate. The organic phase is once more washed with saturated aqueous sodium bicarbonate solution and then dried. The solvent is distilled off under reduced pressure and the residue is then purified over a silica gel column. Crystallization with heptane gives 40 mg of the base of m.p. 149-150° C.
Reaction SMILES: [Br-].[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C[O-].[Na+]>CO>[C:10]1([CH2:9][N:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]2=[NH:2])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cccc[n+]1Cc1ccccc1
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Product: N=c1ccccn1Cc1ccccc1
Yield: 96.6 %

Procedure:
To a solution of 2-amino-1-(phenylmethyl)pyridinium bromide (94.5 g) in 700 ml of methanol is added, portionwise, a total of 38.5 g of sodium methoxide. The mixture is stirred and heated under reflux conditions for 2.5 hours. Workup yields 63.4 g of the title compound, melting point 52°-54°C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH:5]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:3]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.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>[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:2]2[N:7]=[C:6]([CH2:8][N:9]3[C:17](=[O:18])[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10]3=[O:19])[CH:5]=[C:4]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[N:3]=2)[CH:31]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Reactant: OB(O)c1cccnc1
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: COCCOC
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccnc2)n1
Temperature: 80 °C
Yield: 33.2 %

Procedure:
To a solution of 2-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-ylmethyl]-isoindole-1,3-dione (0.30 g, 0.72 mmol) in DME (4 mL) and H2O (1 mL) was added 3-pyridine boronic acid (0.09 g, 0.72), Pd(PPh3)4 (0.04 g, 0.04 mmol), and K3PO4 (0.21 g, 1.01 mmol) at rt. The resulting mixture was heated to 80° C. for 12 hours then allowed to cool to rt. At which time the mixture was partitioned between H2O (5 mL) and EtOAc (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×5 mL). The organic layers were combined, dried over Na2SO4, filtered, concentrated and purified by FCC to afford the title compound as a colorless solid (0.11 g, 33%). MS (ESI): mass calcd. for C25H15F3N4O2, 460.1; m/z found, 461.2 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:12])(C)(C)C.Cl>O1CCOCC1>[CH3:19][C:17]([CH3:18])([CH3:20])[CH2:16][CH2:15][NH:14][C:13](=[O:21])[C@H:11]([CH3:12])[CH2:10][C@H:9]([OH:22])[C@@H:8]([NH2:7])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCCC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NCCC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
[(1S,2S,4R)-1-Benzyl-4-(3,3-dimethylbutylcarbamoyl)-2-hydroxypentyl]-carbamic acid t-butyl ester (D1) (264 mg, 0.63 mmol) was treated with 4M HCl in dioxane (5 ml) and the resulting solution was stirred at room temperature for 1 h. It was then evaporated to dryness and the residue was partitioned between satd. aq. sodium carbonate and ethyl acetate. The aqueous layer was separated and extracted with further ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated to afford product (179 mg, 89%).
Reaction SMILES: [NH2:1][C:2]([CH3:31])([CH3:30])[C:3]([N:5]1[CH2:10][CH2:9][N:8]2[C:11]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:13]=[C:7]2[CH2:6]1)=[O:4]>O=[Mn]=O>[F:29][C:24]1[CH:23]=[C:22]([NH:21][C:11]2[N:8]3[C:7]([C:6]4[N:5]([C:3](=[O:4])[C:2]([CH3:31])([CH3:30])[N:1]=4)[CH2:10][CH2:9]3)=[N:13][C:12]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:27]=[CH:26][C:25]=1[F:28]
Reactant: CC(C)(N)C(=O)N1CCn2c(nc(-c3ccc(F)cc3)c2Nc2ccc(F)c(F)c2)C1
Agent: O=[Mn]=O
Product: CC1(C)N=C2c3nc(-c4ccc(F)cc4)c(Nc4ccc(F)c(F)c4)n3CCN2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Example 645 was prepared from Example 29 by the following method: to a stirred solution of Example 29 (12 mg, 0.03 mmol) was added MnO2 (52 mg, 0.60 mmol). The reaction mixture was stirred at room temperature for 2 hours. LC/MS test showed that Example 29 was almost gone and the desired product ([M+1]=526) was detected as one of the major peaks. Solid was filtered off and solvent was removed. The residue was subjected to a mass-triggered HPLC purification to give Example 645.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([N:13]2[C:17]([CH2:18][F:19])=[N:16][N:15]=[C:14]2[SH:20])=[CH:5][CH:4]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](=[O:41])(=[O:40])[NH2:39])=[CH:34][C:33]=1[Cl:42])=[O:30].O>CN(C=O)C>[Cl:42][C:33]1[CH:34]=[C:35]([S:38](=[O:41])(=[O:40])[NH2:39])[CH:36]=[CH:37][C:32]=1[NH:31][C:29](=[O:30])[CH2:28][S:20][C:14]1[N:13]([C:6]2[C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=3[C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[C:17]([CH2:18][F:19])=[N:16][N:15]=1
Reactant: CCc1ccc(-n2c(S)nnc2CF)c2c1CCCC2
Reactant: NS(=O)(=O)c1ccc(NC(=O)CCl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(-n2c(CF)nnc2SCC(=O)Nc2ccc(S(N)(=O)=O)cc2Cl)c2c1CCCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.8 %

Procedure:
In a solution of 4-(4-ethyl-5,6,7,8-tetrahydro-naphthalen-1-yl)-5-fluoromethyl-4H-[1,2,4]triazole-3-thiol (85 mg, 0.29 mmol), K2CO3 (44.4 mg, 0.32 mmol) in DMF (2.0 mL) was added 2-chloro-N-(2-chloro-4-sulfamoyl-phenyl)-acetamide (82.6 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for 16 h. Upon the completion of the reaction, H2O (2.0 mL) was added to the reaction and stirred til precipitation occurred and filtered to give solid (73.0 mg, 47% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:23][C:24](OC(C)=O)=[O:25]>N1C=CC=CC=1>[CH3:22][C:3]1[C:2]([NH:1][C:24](=[O:25])[CH3:23])=[N:11][C:10]2[C:5]([N:4]=1)=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]1[NH:20][C:19]2[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=2[CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C
Temperature: 50 °C

Procedure:
A mixture of 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (126) (0.30 g, 1.01 mmol) and ammonia (4.05 mL, 8.10 mmol) in DMSO (5 mL) was heated at 90° C. in a sealed tube for 16 h. The reaction mixture was cooled to RT, treated with water, and extracted with DCM (3×). The extracts were dried over Na2SO4, concentrated. The residue was purified by silica gel chromatography (0-10% MeOH/DCM) to give 2-(3-amino-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (445a, 235 mg, 79%). m/z (ESI, +ve) 294 (M+H)+. A mixture of 2-(3-amino-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (445a, 50 mg, 0.17 mmol) and Ac2O (0.016 mL, 0.17 mmol) in pyridine (2 mL) was heated at 50° C. for 16 h. It was concentrated under reduced pressure. The residue was purified by reverse phase HPLC. The pure fractions were combined and concentrated to dryness. The solid was dissolved in MeOH and neutralized by pass through Stratosphere SPE (PL-HCO3 MP-Resin) to give N-(3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxalin-2-yl)acetamide as a tan solid (445) (10 mg, 17%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.21 (1H, br. s.), 10.22 (1H, s), 8.07-8.20 (1H, m), 7.71 (1H, dd, J=8.2, 1.2 Hz), 7.63 (1H, t, J=7.8 Hz), 7.09 (1H, d, J=2.3 Hz), 6.99 (1H, br. s.), 3.41-3.51 (2H, t, J=6.8 Hz), 2.94 (2H, t, J=6.8 Hz), 2.75 (3H, s), 2.36 (3H, s). m/z (ESI, +ve) 336 (M+H)+.
Reaction SMILES: [NH2:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([C:12](Cl)=[O:13])([CH2:5]3)[CH2:3]1)[CH2:9]2.[NH2:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:17]1>>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:21][N:18]2[CH2:19][CH2:20][CH:16]([NH:15][C:12]([C:4]34[CH2:10][CH:8]5[CH2:9][C:2]([NH2:1])([CH2:11][C@@H:6]([CH2:7]5)[CH2:5]3)[CH2:3]4)=[O:13])[CH2:17]2)=[CH:24][CH:25]=1
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Reactant: NC12CC3CC(C1)CC(C(=O)Cl)(C3)C2
Product: NC12CC3C[C@H](C1)CC(C(=O)NC1CCN(CCc4ccc(F)cc4)C1)(C3)C2

Procedure:
1-Aza-5-methyladamantane-3-carbonyl chloride and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-aza-5-methyladamantane-3-carboxamide.
Reaction SMILES: [C:1]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:14]([O: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][CH2:29][CH2:30][CH2:31][CH3:32])=[O:15].C(N(CC)CC)C>C(OCC)C>[CH2:17]([O:16][C:14]([O:12][C:10]([CH3:11])=[CH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCCCOC(=O)Cl
Reactant: CC(=O)CC(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCOC(=O)OC(C)=CC(=O)c1ccccc1
Yield: 80.6 %

Procedure:
The preparation is carried out as described in Example 1, using 17.8 g (0.11 mole) of benzoylacetone, 30.5 g (0.1 mole) of n-hexadecyl chloroformate and 100 ml of diethyl ether as well as 11 g (0.11 mole) of triethylamine. The crude product (34.7 g) obtained is recrystallised from a mixture of 85 ml of isopropanol and 10 ml of water. The white crystals melt at 31° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[S:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)=[O:6].C([C:28]1[C:29]([N:35]=[CH:36][N:37]([CH3:39])C)=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=1)#N>>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:15]=[CH:16][C:17]([S:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[C:2]([NH:1][C:39]3[C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[N:30][C:29]=4[N:35]=[CH:36][N:37]=3)[CH:3]=2)=[CH:9][CH:10]=1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Reactant: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Product: Cc1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cc4)ccc3Sc3ccc(O)cc3)ncnc2n1
Yield: 51 %

Procedure:
The product of Example 28A was reacted with the product of Example 9B using the procedure of Example 22C substituting the product of Example 28A for the product of Example 22B and substituting the product of Example 9B for the product of Example 8E to provide the crude title compound which was purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title product (24 mg, 51%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.68 (s, 3 H) 6.85 (d, J=8.46 Hz, 2 H) 6.89-7.00 (m, 1 H) 7.31 (d, J=8.82 Hz, 2 H) 7.45-7.64 (m, 3 H) 7.67-7.88 (m, 3 H) 7.97 (s, 1 H) 8.58 (s, 1 H) 8.70-8.92 (m, 1 H) 9.96 (s, 1 H) 10.19 (s, 1 H) 10.29 (s, 1 H); MS (ESI+) m/z 558/560 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:9][C:10]1[NH:11][CH:12]=[CH:13][N:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH3:9])=[N:6][CH:7]=1
Reactant: Cc1ncc[nH]1
Reactant: Clc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1nccn1-c1ccc(Br)cn1
Temperature: 150 °C

Procedure:
A mixture of 5-bromo-2-chloro-pyridine (Aldrich, Buchs, Switzerland, 392 mg, 2.04 mmol), 2-methyl-1H-imidazole (Aldrich, Buchs, Switzerland, 251 mg, 3.06 mmol) and cesium carbonate (1.33 g, 4.08 mmol) in DMA (10 ml) was heated by microwave irradiation for 20 min at 100° C. and 2.5 h at 150° C. The reaction mixture was quenched with diluted brine (200 ml) and cooled. The precipitate was filtered, washed with water and dried to give the title compound as off-white solid. (HPLC: tR 2.03 min (Method A); M+H=238, 240 MS-ES).
Reaction SMILES: C([O:3][C:4]([C:6](=[N:10][NH:11][C:12]1[C:13]([O:27][CH3:28])=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([OH:26])=[O:25])[CH:19]=2)[CH:15]=[CH:16][CH:17]=1)[C:7](=O)[CH3:8])=O)C.Cl.[CH3:30][C:31]1[CH:32]=[C:33]([NH:38][NH2:39])[CH:34]=[CH:35][C:36]=1[CH3:37].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:30][C:31]1[CH:32]=[C:33]([N:38]2[C:4](=[O:3])[C:6](=[N:10][NH:11][C:12]3[C:13]([O:27][CH3:28])=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([OH:26])=[O:25])[CH:19]=4)[CH:15]=[CH:16][CH:17]=3)[C:7]([CH3:8])=[N:39]2)[CH:34]=[CH:35][C:36]=1[CH3:37]
Reactant: Cc1ccc(NN)cc1C
Reactant: CCOC(=O)C(=NNc1cccc(-c2cccc(C(=O)O)c2)c1OC)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1c(NN=C2C(=O)N(c3ccc(C)c(C)c3)N=C2C)cccc1-c1cccc(C(=O)O)c1

Procedure:
A solution of 3′-{-2-[1-(ethoxycarbonyl)-2-oxopropylidene]hydrazino}-2′-methoxybiphenyl-3-carboxylic acid (3.5 g) prepared as in Example 7, and 3,4-dimethylphenylhydrazine hydrochloride (1.72 g) and sodium acetate(0.9 g) in glacial acetic acid (120 mL) was stirred and heated to about reflux temperature for about 4 hours. The mixture was cooled to about room temperature and stirred for about 1 hour. It was filtered, washed with water (25 mL) and dried in an oven at about 55° C. to about 60° C. for about 12 hours to an orange solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@H:10]([NH2:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[O:33]=[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]1[C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C@H:10]([NH:25][C:44](=[O:45])[C:43]2[CH:42]=[CH:41][C:40]([N:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]3=[O:33])=[CH:48][CH:47]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(-n2ccccc2=O)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](N)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](NC(=O)c2ccc(-n3ccccc3=O)cc2)C1
Reaction time: 8 h
Yield: 66.1 %

Procedure:
Cis-3-amino-4-benzyloxycarbonylamino-piperidine-1-carboxylic acid tert-butyl ester (332.1 mg, 0.95 mmol), from Example 112 Part F, was mixed with 10 mL of CH2Cl2 and 96 mg (0.95 mmol) of triethylamine. The resulting solution was cooled with an ice-water bath. Freshly prepared 4-(2-oxopyridin-1(2H)-yl)benzoyl chloride (222 mg, 0.95 mmol), from part A, was added portion wise. Stirring was continued at rt overnight. CH2Cl2 (10 mL) was added, and the solution was washed with water (3×3 mL). The organic phase was dried over MgSO4, filtered, and evaporated to yield cis-4-Benzyloxycarbonylamino-3-[4-(2-oxo-2H-pyridin-1-yl)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (343.2 mg) as a crude oil, which was further purified by flash chromatography (ISCO system; 10 g cartridge Eluent AcOEt/Hexane 20%). 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J=8.4 Hz, 2H), 7.42–7.24 (m, 8H), 7.06 (d, J=6.5 Hz, 1H), 6.62 (d, J=9.1 Hz, 1H), 6.27 (t, 1H), 5.06 (s, 2H), 4.34 (bs, 1H), 4.08 (bs, 1H), 3.87 (m, 1H), 3.16 (d, J=13.4 Hz, 1H), 2.98 (t, 1H), 1.85 (bs, 1H), 1.65 (m, 1H), 1.39 (m, 9H), ppm. LC-MS (ESI) 569.24 [M+Na]+, tR=6.331 min (Shimadzu Phenomenex S5 ODS 4.6 ×50 mm Luna flow rate 2.5 mL/mn; detection at 220 nM; Gradient elution 0% to 100% B over 8 min; (A=10% MeOH, 90% H2O, 0.2% H3PO4& B=90% MeOH, 10% H2O, 0.2% H3PO4)).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([NH:11]C(OC(C)(C)C)=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[C:5]1([CH:4]([NH2:11])[CH2:3][CH2:2][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)NC(CCBr)c1ccccc1
Reactant: C1CCNCC1
Product: NC(CCN1CCCCC1)c1ccccc1

Procedure:
The procedure given in Example 2 except for the formation of salts was followed using 3-bromo-1-(tert-butoxycarbonyl)amino-1-phenyl propane and piperidine as reactants, instead of d-1-bromo-2-(tert-butoxycarbonyl)amino-3-phenyl propane and hexamethyleneimine to give 1-Phenyl-3-(1-piperidinyl)-n-propylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[C:18](Cl)(=O)C(Cl)=O>CN(C)C=O.ClCCCl>[N+:1]([C:4]1[CH:12]=[C:11]([O:13][C:14]([F:15])([F:16])[F:17])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH3:18])=[O:7])([O-:3])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 48 h

Procedure:
2-Nitro-4-trifluoromethoxybenzoic acid (4.7 g) was heated under reflux conditions for 2 hours with oxalyl chloride (1.95 ml) and 1,2-dichloroethane (25 ml) containing N,N-dimethylformamide (2 drops). The solvents were evaporated to dryness, the residue dissolved in drv dichloromethane and added to a solution of triethylamine (2.08 g) in dry methanol. After 2 days, the solvent was evaporated and the residue partitioned between dichloromethane and sodium bicarbonate solution. The organic phase was dried (magnesium sulphate), evaporated and the residue purified by chromatography, eluting with dichloromethane/hexane to give methyl 2-nitro-4-trifluoromethoxybenzoate (4.9 g) as a yellow liquid, NMR (CDCl3) 3.9(s,3H), 7.5(m,1H), 7.75(brs, 1H), 7.85(d,1H).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:13]1([CH2:19][CH2:20][NH2:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:20]([NH:21][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: NCCc1ccccc1
Product: CCCCCCC/C=C/C(=O)NCCc1ccccc1

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 2-phenylethaneamine as starting materials to give the aimed compound. Compound 29 was obtained by the purification using silica gel column chromatography.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[CH2:29]([O:31][CH2:32][CH2:33][C:34](=[N:36]O)[NH2:35])[CH3:30]>>[CH2:29]([O:31][CH2:32][CH2:33][C:34]1[N:36]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][S:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:27][N:35]=1)[CH3:30]
Reactant: CCOCCC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Product: CCOCCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 6A, 600 mg (1.434 mmol) of the compound from Example 25A and 307 mg (approx. 1.864 mmol) of 3-ethoxy-N′-hydroxypropanimidamide were reacted Yield: 403 mg (55% of theory)
Reaction SMILES: [C:1]([C:5]1[CH:35]=[CH:34][C:8]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([O:32]C)=[C:25]([C:27]4[O:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([OH:32])=[C:25]([C:27]4[O:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)=[N:12][N:11]=2)=[CH:34][CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ncc(Cc2nnc(Nc3ccc(C(C)(C)C)cc3)c3ccccc23)cc1-c1ccco1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc(Nc2nnc(Cc3cnc(O)c(-c4ccco4)c3)c3ccccc23)cc1

Procedure:
In analogy to Ex. 3, treatment of a solution of 1-(4-tert-butyl-anilino)-4-[5-(furan-2-yl)-6-methoxy-(pyridin-3-yl)-methyl]phthalazine in CHCl3 with Me3Sil, followed by hydrolysis gives the title compound. ES-MS: (M+H)+451; HPLC(Grad20-100) tRet=12.6.