Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]([CH3:18])[C:13](=O)[CH2:12][CH2:11]2.C1(=O)C2C(=CC=CC=2)CCC1.[ClH:31]>C1(C)C=CC=CC=1.C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[ClH:7].[ClH:31].[CH3:18][C@@H:14]1[C:15]2[C:10](=[CH:9][C:8]([Cl:7])=[CH:17][CH:16]=2)[CH2:11][CH2:12][C@@H:13]1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: CC1C(=O)CCc2cc(Cl)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C1CCCc2ccccc21
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[C@@H]1c2ccc(Cl)cc2CC[C@@H]1N1CCNCC1
Reaction time: 23 h

Procedure:
To 15 g of 4A molecular sieves in 250 ml of dry toluene were added piperazine (6.37 g) and 6-chloro-1-methyl-2-tetralone (8.6 g). Using a Dean-Stark water trap, the mixture was stirred and heated at reflux under a nitrogen atmosphere. After 23 hours, NMR analysis of a sample of the reaction solution showed the presence of tetralone. Fifty mg of p-toluenesulfonic acid were added, and the mixture was stirred and refluxed for an additional 26 hours. An additional 10 g of 4A sieves was added, and reflux was continued for an additional 10 hours. The sieves were filtered, and toluene was evaporated from the filtrate. The residue was dissolved in a mixture of 200 ml of THF and 20 ml of methanol. To the resulting solution, stirred under nitrogen and with ice bath cooling, was added sodium cyanoborohydride (2.68 g). Gaseous HCl was added to the solution, in portions, until the solution remained acidic. After stirring overnight at room temperature, solvents were removed on a rotary evaporator, and the residue was partitioned between ether and dilute hydrochloric acid. The acidic solution was separated and made basic in the cold with sodium hydroxide. The oil which separated was extracted with ether, and the ether solution was dried (MgSO4). Removal of the ether left 8.1 g of an oil. The oil was combined with 1 g of the product from a previous small scale reaction. A solution of the total in ethanol was treated with excess gaseous HCl. The crystals which separated were filtered and digested on the steam bath with 100 ml of methanol. The several crops of crystals obtained from the methanol were combined and recrystallized from ethanol to provide 6.3 g of the title compound. When dried at 120° C. in vacuo, the dihydrochloride lost one mol of hydrogen chloride and gave the following:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][C:3]=1[O:10][CH3:11].[C-:12]#[N:13].[K+]>C(O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:12]#[N:13])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: [C-]#N
Reactant: COc1cc(CCl)ccc1Br
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1cc(CC#N)ccc1Br

Procedure:
4-Bromo-3-methoxybenzyl chloride (23.5 g, 0.1 m) dissolved in ethanol (500 ml) is treated with potassium cyanide (13 g, 0.2 m) dissolved in water. The mixture is warmed and stirred to give 4-bromo-3-methoxyphenylacetonitrile.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH:12]([CH3:16])C(O)=O)=O.[CH:17]([NH:20][S:21]([C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2)(=[O:23])=[O:22])([CH3:19])[CH3:18].N1CCCCC1.[C:40]([OH:43])(=[O:42])C>C(O)C>[CH:17]([NH:20][S:21]([C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[C:27]2=[CH:1][C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:16][C:40]([OH:43])=[O:42])(=[O:23])=[O:22])([CH3:19])[CH3:18]
Reactant: CC(C(=O)O)c1c(C=O)[nH]c2c1CCCC2
Reactant: CC(C)NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CC(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)NS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]c3c(c1CCC(=O)O)CCCC3)C(=O)N2
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of (2-Formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (5.4 g), 5.7 g of 5-isopropylaminosulfonyl-2-oxindole and 2.7 g of piperidine in 25 mL of ethanol was refluxed for 4 hours. Upon addition of acetic acid (8 mL), a precipitate formed. The mixture was refluxed for 5 minutes and cooled to ambient temperature. The precipitate was collected by vacuum filtration and washed with 20 mL of ethanol. The solids were slurry-washed in 30 mL of reflushing ethanol, cooled, collected by vacuum filtration, washed with 30 mL of ethanol and vacuum dried to give 8.1 g (80% yield) of 3-[2-(5-isopropylaminosulfonyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid as an orange solid.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[NH:9][C:8](=[O:14])[C:7]3[S:15][CH:16]=[CH:17][C:6]=3[C:5]=2[C:4]=1[C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]([CH3:35])[CH2:25][N:26](C)C(=O)OC(C)(C)C)=[CH:20][CH:19]=1.B(Br)(Br)[Br:37]>>[BrH:37].[NH2:26][CH2:25][C@@H:24]([C:21]1[CH:20]=[CH:19][C:18]([C:4]2[C:5]3[C:6]4[CH:17]=[CH:16][S:15][C:7]=4[C:8](=[O:14])[NH:9][C:10]=3[C:11]([CH3:13])=[CH:12][C:3]=2[OH:2])=[CH:23][CH:22]=1)[CH3:35]
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)CN(C)C(=O)OC(C)(C)C)cc1
Reactant: BrB(Br)Br
Product: Br
Product: Cc1cc(O)c(-c2ccc([C@@H](C)CN)cc2)c2c1[nH]c(=O)c1sccc12
Yield: 73.2 %

Procedure:
Following General Procedure F, (R)-tert-butyl 2-(4-(8-methoxy-6-methyl-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propyl(methyl)carbamate (2.20 g, 4.60 mmol) was treated with BBr3 (1.0 M in CH2Cl2, 50 mL, 50 mmol) to afford the desired product as a yellow solid (1.50 g, 73%): 1H NMR (500 MHz, CD3OD) δ 7.58 (d, J=5.4 Hz, 1H), 7.55 (dd, J=7.9, 1.8 Hz, 1H), 7.45 (dd, J=7.8, 1.9 Hz, 1H), 7.35 (dd, J=7.9, 1.7 Hz, 1H), 7.30 (dd, J=7.7, 1.6 Hz, 1H), 7.08 (d, J=0.8 Hz, 1H), 6.17 (d, J=5.4 Hz, 1H), 3.36-3.19 (m, 3H), 2.57 (d, J=0.6 Hz, 3H), 1.50 (d, J=6.4 Hz, 3H); ESI MS m/z 365 [C21H20N2O2S+H]+; HPLC 98.3% (AUC), tR=8.64 min.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[C:11]3[S:15][C:14](=S)[NH:13][C:12]3=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CCO.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[C:11]3[S:15][C:14](=[N:31][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[NH:13][C:12]3=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C1NC(=S)SC1=Cc1ccc2c(c1)OCO2
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1NC(=NCc2ccccc2)SC1=Cc1ccc2c(c1)OCO2
Reaction time: 0.5 h

Procedure:
5-Benzo[1,3]dioxol-5-ylmethylene-2-thioxo-thiazolidin-4-one (100 mg, 0.37 mmol) were dissolved in EtOH/water, followed by 60 mg of Na2CO3. The reaction was stirred for 30 min and benzylamine (122 μl, 3 eq.) was added. The reaction mixture was refluxed for 2 h. and the solvents were evaporated. The crude was purified by Parallel Flex chromatography.
Reaction SMILES: C1N=CN([C:6]([N:8]2[CH:12]=[N:11]C=C2)=[O:7])C=1.[OH:13][CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33](=[O:37])[CH2:34][O:35][CH3:36])[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1.C(=O)(O)O.[NH2:42]C(N)=N.[C:46]([OH:55])(=[O:54])[C@@H:47]([C@H:49]([C:51]([OH:53])=[O:52])[OH:50])[OH:48]>CC#N.O.CN(C=O)C>[C:51]([C@@H:49]([C@H:47]([C:46]([OH:55])=[O:54])[OH:48])[OH:50])([OH:53])=[O:52].[C:12]([NH:8][C:6](=[O:7])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33](=[O:37])[CH2:34][O:35][CH3:36])[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:16]=1)(=[NH:11])[NH2:42]
Reactant: N=C(N)N
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COCC(=O)N1CCN(c2ncc(-c3cccc(CO)c3)cn2)CC1
Agent: O=C(O)O
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: COCC(=O)N1CCN(c2ncc(-c3cccc(COC(=O)NC(=N)N)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
CDI (225 mg) was added to a mixture of 1-(4-{5-[3-(hydroxymethyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)-2-methoxyethanone (216 mg) and DMF (6 ml), followed by stirring at room temperature for 2 hours. Then, guanidine carbonate (220 mg) was added to the mixture, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and evaporated under reduced pressure. A mixture obtained by dissolving L-tartaric acid (59 mg) in a mixed solvent (1 ml) of MeCN and water at 9:1 was added to a mixture of the obtained residue (166.9 mg) in a mixed solvent (4 ml) of MeCN and water at 9:1, followed by stirring at room temperature. The precipitated solid was collected by filtration to obtain 3-{2-[4-(methoxyacetyl)piperazin-1-yl]pyrimidin-5-yl}benzyl carbamimidoylcarbamate L-tartrate (177 mg) as a colorless solid.
Reaction SMILES: C[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[N:5][CH:6]=[N:7]2.[N-:18]=[C:19]=O.[N-:21]=[C:22]=[S:23]>>[N:18]1[CH:19]=[CH:11][CH:2]=[C:3]([CH2:8][NH:21][C:22]([N:15]2[CH2:14][CH2:13][N:12]([C:4]3[C:3]4[C:8](=[CH:9][CH:10]=[CH:11][CH:2]=4)[N:7]=[CH:6][N:5]=3)[CH2:17][CH2:16]2)=[S:23])[CH:4]=1
Reactant: Cc1cccc2ncnc(N3CCNCC3)c12
Reactant: [N-]=C=O
Reactant: [N-]=C=S
Product: S=C(NCc1cccnc1)N1CCN(c2ncnc3ccccc23)CC1

Procedure:
In the following Examples 287 and 288, substantially the same procedure as in Example 1 was repeated, except that 5-methyl-4-(1-piperazinyl)quinazoline was used in place of 6,7-dimethoxy-4-(1-piperazinyl)quinazoline, and the corresponding isocyanate or isothiocyanate was used in place of phenyl isocyanate, to give the desired compound.
Reaction SMILES: [CH3:1][NH:2][O:3][CH3:4].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[CH2:18][CH2:19][O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([Cl:34])=[C:28]([C:31](O)=[O:32])[CH:29]=2)[NH:24][C:23](=[O:35])[C:22]=1[C:36]1[CH:41]=[C:40]([CH3:42])[CH:39]=[C:38]([CH3:43])[CH:37]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[CH2:18][CH2:19][O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([Cl:34])=[C:28]([C:31](=[O:32])[N:2]([O:3][CH3:4])[CH3:1])[CH:29]=2)[NH:24][C:23](=[O:35])[C:22]=1[C:36]1[CH:37]=[C:38]([CH3:43])[CH:39]=[C:40]([CH3:42])[CH:41]=1)=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: CNOC
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(C(=O)O)c(Cl)cc3[nH]c2=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c(-c3cc(C)cc(C)c3)c(=O)[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 36 h
Yield: 81.1 %

Procedure:
To a solution of N,O-dimethylhydroxylamine (1.14 g in 50 mL dry methylene chloride) was added 1.5 mL triethylamine followed by 4-[2-(1 -tert-butoxycarbonylpiperidin-2-yl)-ethoxy]-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinoline-6-carboxylic acid (EXAMPLE 4.1, Step F, 1.35 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 1.35 g) and 4-dimethylaminopyridine (400 mg) and the mixture stirred at room temperature. After 36 hours, the mixture was concentrated in vacuo and the residue purified by flash chromatography on silica gel (ethyl acetate) to give the title compound (1.18 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].[CH3:16][CH2:17]O>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCO
Reactant: O=C(O)Cc1cc([N+](=O)[O-])c(F)cc1F
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc([N+](=O)[O-])c(F)cc1F
Temperature: 0 °C
Yield: 89 %

Procedure:
A solution of (2,4-difluoro-5-nitro-phenyl)acetic acid (16 g, 74 mmol) in EtOH (200 mL) and 98% H2SO4 (14 mL) was refluxed at 80′C for 2.5 h under a N2 atmosphere. The reaction mixture was poured into ice water, and the resultant solution was extracted with Et2O. The combined organic extracts were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by silica gel chromatography to give ethyl 2-(2,4-difluoro-5-nitrophenyl)acetate (16 g, 89% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.22 (t, J=8.1 Hz, 1H), 7.55 (t, J=11.1 Hz, 1H), 4.06 (m, 2H), 3.77 (s, 2H), 1.13 (t, J=6.9 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@@H:13]([OH:27])[C@@H:14]([N+:24]([O-])=O)[CH2:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[CH2:11][O:10][C:9]1([CH3:29])[CH3:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO.[Ni](Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@@H:13]([OH:27])[C@@H:14]([NH2:24])[CH2:15][C:16]2[CH:17]=[C:18]([F:23])[CH:19]=[C:20]([F:22])[CH:21]=2)[CH2:11][O:10][C:9]1([CH3:29])[CH3:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)[N+](=O)[O-])COC1(C)C
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)COC1(C)C
Reaction time: 0.33 h
Yield: 87.9 %

Procedure:
Combine (R)-4-[(1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-2-nitropropyl]-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (1.13 g, 2.71 mmol) and nickel (II) chloride (0.58 g, 4.485 mmol) in dry methanol (30 ml) and add sodium borohydride (0.454 g, 12 mmol) over 1 minute. Stir the resulting mixture for 20 minutes and then add water (3 mL). Concentrate and dissolve the residue in ethyl acetate. Filter the black solution through a pad of Celite® and wash the filter cake with ethyl acetate. Wash the filtrate with water (twice), saturated aqueous sodium chloride, dry (magnesium sulfate), filter, and concentrate to give the desired compound as a white solid (920 mg, 95%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[CH3:13][C:14]([C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)([CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[CH3:15].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.C(Cl)CCl>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([C:14]([CH3:15])([CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)[CH3:13])=[CH:24][CH:25]=1)=[O:8])([O-:3])=[O:2]
Reactant: CN1CCC(C(C)(C)c2ccc(N)cc2)CC1
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(C(C)(C)c2ccc(NC(=O)c3ccccc3[N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-nitrobenzoic acid (400 mg), 4-[1-methyl-1-(1-methylpiperidin-4-yl)-ethyl]phenylamine (Preparation IV (aw)) (600 mg) and DIEA (0.6 mL) in CH2Cl2 (80 mL) was added EDC (600 mg) and HOBt (350 mg). The reaction was stirred at RT overnight and washed with saturated NaHCO3 (30 mL), H2O (50 mL) and brine (30 mL). The organic layer was dried over Na2SO4 and evaporated to give 2-nitro-N-{4-[1-methyl-1-(1-methylpiperidin-4-yl)ethyl]phenyl}benzamide which was used in the next step without further purification.
Reaction SMILES: [C:1]1(=[O:13])[O:10][C:8](=[O:9])[CH:7]2[CH2:11][CH2:12][C:2]1([C:4]2([CH3:6])[CH3:5])[CH3:3].Cl.[CH3:15][NH2:16]>CN(C1C=CN=CC=1)C>[CH3:3][C@@:2]1([C:1]([OH:10])=[O:13])[CH2:12][CH2:11][C@H:7]([C:8](=[O:9])[NH:16][CH3:15])[C:4]1([CH3:6])[CH3:5]
Reactant: CN
Reactant: CC12CCC(C(=O)OC1=O)C2(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CNC(=O)[C@H]1CC[C@@](C)(C(=O)O)C1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 40% aqueous methylamine (70 mL) and camphoric anhydride (5 g) was stirred at room temperature for 30 minutes. To this N,N-dimethyl-4-aminopyridine (DMAP) (0.67 g, 5.4 mmol) was added and stirred further for 24 hours. The reaction mixture was allowed to cool to room temperature and acidified with con. HCl at 0-5° C. White precipitate formed was filtered and dried (5.2 g). m/z (M+H): 214.1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:5]=1[C:6](Cl)=[O:7])[CH3:2].[NH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31]([C:37]([F:40])([F:39])[F:38])[CH:30]=1.C(N(CC)CC)C>ClCCl>[C:33]([C:32]1[CH:35]=[CH:36][C:29]([NH:28][C:6](=[O:7])[C:5]2[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:10][CH:11]=[CH:12][C:4]=2[O:3][CH2:1][CH3:2])=[CH:30][C:31]=1[C:37]([F:38])([F:39])[F:40])#[N:34]
Reactant: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)Cl
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
2-ethoxy-6-pentadecyl-benzoyl chloride was condensed with 4-Amino-2-trifluromethyl benzonitrile in dichloromethane in presence of triethylamine as acid scavenger to, yield N-(4-Cyano-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [NH2:1][C@H:2]([C:18]([OH:20])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[NH2:21][C@H:22]([C:35]([OH:37])=[O:36])[CH2:23][CH2:24][C:25](=[O:34])[O:26]CC1C=CC=CC=1>>[NH2:21][C@H:22]([C:35]([OH:37])=[O:36])[CH2:23][CH2:24][C:25](=[O:26])[OH:34].[CH:15]1[CH:16]=[CH:17][C:12]([CH2:11][O:10][C:8]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[NH:1][C:25](=[O:26])[O:20][C:18]2=[O:19])=[O:9])=[CH:13][CH:14]=1
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O
Product: O=C(NCCCCC1NC(=O)OC1=O)OCc1ccccc1

Procedure:
H-Lys(Z)—OH and H-Glu(OBn)-OH were purchased from Chem-Impex International (Des Plaines, Ill.) and used as received. Glu-NCA and Lys-NCA were prepared by following previously reported procedures (Lu, H.; Cheng, J. J. Am. Chem. Soc. 2007, 129, 14114-14115).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:16][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:9][C:5]=2[C:4](=O)[CH2:3]1.O.[NH2:20][NH2:21].CC(O)=O.C([O-])(O)=O.[Na+]>CCO>[CH3:1][C:2]1([CH3:18])[CH2:16][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:9][C:5]=2/[C:4](=[N:20]/[NH2:21])/[CH2:3]1
Reactant: NN
Reactant: CC1(C)CC(=O)c2sc(N3CCOCC3)nc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC1(C)C/C(=N\N)c2sc(N3CCOCC3)nc2C1
Yield: 35.7 %

Procedure:
To a stirred solution of Example 48 (0.27 g, 1.00 mmol) in EtOH (10 mL) was added hydrazine monohydrate (0.05 g, 0.05 mL, 1.00 mmol) and a catalytic amount of AcOH. The reaction mixture was then heated to reflux for 8 h. Upon cooling, the reaction mixture was poured into aqueous sat. NaHCO3 (50 mL) and extracted with DCM (2×50 mL). The combined organic fractions were dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a white solid (0.10 g, 35%). δH (DMSO-d6) 5.93 (2H, br. s), 3.68 (4H, t, J 4.9 Hz), 3.36 (4H, t, J 4.9 Hz), 2.42 (2H, s), 2.22 (2H, s), 1.00 (6H, s). LCMS (ES+) 281.2 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[C:5](=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])C(O)=O.N[C:19]([NH2:21])=[O:20].C[N:23]1CCCC1=O>C(OCC)(=O)C>[NH2:23][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:19](=[O:20])[NH:21][C:15]2=[O:17]
Reactant: CN1CCCC1=O
Reactant: NC(N)=O
Reactant: O=C(O)c1cc(F)c(C(F)(F)F)cc1C(=O)O
Solvent: CCOC(C)=O
Product: Nc1cc2c(cc1C(F)(F)F)C(=O)NC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2.14 mmol 4-fluoro-5-trifluoromethyl-phthalic acid in 7 ml N-methylpyrolidone was added 4.28 mmol urea and the mixture was at 140° C. for 2 h, and then at 160° C. for 4 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate and washed sequentially with water and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was triturated in ether/penane (1/1) to yield the title compound as a yellow solid. MS (m/e): 229.1 ([M−H]−, 100%)
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](Cl)=[O:15].C(Cl)(Cl)Cl.[NH2:21][C:22]1[CH:34]=[CH:33][C:32]([O:35][C:36]2[CH:37]=[N:38][C:39]([C:42]3[N:46]=[C:45]([CH3:47])[O:44][N:43]=3)=[CH:40][CH:41]=2)=[CH:31][C:23]=1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][C:26]1=[O:30]>O>[CH3:47][C:45]1[O:44][N:43]=[C:42]([C:39]2[N:38]=[CH:37][C:36]([O:35][C:32]3[CH:33]=[CH:34][C:22]([NH:21][C:14]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=4)=[O:15])=[C:23]([CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][C:26]4=[O:30])[CH:31]=3)=[CH:41][CH:40]=2)[N:46]=1
Reactant: Cc1nc(-c2ccc(Oc3ccc(N)c(CN4CCCC4=O)c3)cn2)no1
Reactant: O=C(Cl)c1ccccn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1nc(-c2ccc(Oc3ccc(NC(=O)c4ccccn4)c(CN4CCCC4=O)c3)cn2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
With cooling with ice, 0.33 ml of triethylamine and 210 mg of picolinic acid chloride were added to a chloroform (2 ml) solution of 144 mg of 1-(2-amino-5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl]oxy}benzyl)pyrrolidin-2-one, and stirred at room temperature for 1 hour. Water was added to it, extracted with chloroform, the organic layer was dried, the solvent was removed, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=9/1 to 2/8) to obtain 117 mg of N-{4-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl]oxy}-2-[(2-oxopyrrolidin-1-yl)methyl]phenyl}pyridine-2-carboxamide as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[CH3:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[F:25][C:4]1[CH:3]=[C:2]([N:29]2[CH2:30][CH2:31][N:27]([CH3:26])[C:28]2=[O:32])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: CN1CCNC1=O
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3F)CC2)nc1C
Yield: 8 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (203 mg) described in Preparation Example 128 and 1-methylimidazolidin-2-one (60 mg) and by the reaction and treatment in the same manner as in Example 511, the title compound (17 mg) was obtained.
Reaction SMILES: [CH:1]([NH:3][CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])=O.P(Cl)(Cl)([Cl:20])=O.CO>C(#N)C>[ClH:20].[CH3:17][O:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[CH:1]=[N:3][CH2:4][CH:5]2[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)C(CNC=O)c1cccc(OC)c1
Solvent: CC#N
Solvent: CO
Product: COC(=O)C1CN=Cc2ccc(OC)cc21
Product: Cl
Temperature: 60 °C

Procedure:
The compound obtained in Step C (8.03 g; 0.03 mol) is dissolved in 100 ml of acetonitrile, and then the reaction mixture is heated to approximately 60° C. Phosphorus oxychloride (16 ml; 0.17 mol) is added to the solution, which is then heated at reflux for 6 hours with stirring and subsequently evaporated under reduced pressure. The residue obtained is taken up twice with methanol and evaporated under reduced pressure, and then taken up in a minimum of acetone. The precipitate formed is then suction-filtered off to yield the title product in the form of a white solid.