Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:28][C:27]=2[O:38][CH3:39])[C:22]([Cl:40])=[CH:21][N:20]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C(O)(C)C>[Cl:40][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:28][C:27]=2[O:38][CH3:39])=[N:24][C:19]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)C(C)(C)CCC(=O)N2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCOCC4)cc3OC)n1)C(C)(C)CCC(=O)N2
Yield: 41.2 %

Procedure:
7-Amino-8-methoxy-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (59 mg, 0.25 mmol), (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (89 mg, 0.25 mmol), and 10-Camphorsulfonic acid (59 mg, 0.25 mmol) in Isopropyl alcohol (4 mL) were irradiated at 120° C. for 40 min in a CEM microwave. The sample was cooled, treated with MP-carbonate resin, filtered and conc. in vacuo. Silica gel chromatography afforded 7-[5-Chloro-4-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-2-ylamino]-8-methoxy-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as a white solid (57 mg, 41%). MP: 246-248° C., LCMS: 553 (M+H); 1H-NMR, CDCl3: 8.39 (s, 1H), 8.26 (d, 1H, J=8.8 Hz), 8.08 (s, 1H), 7.60 (s, 1H), 7.25 (m, 1H), 7.06 (s, 1H), 6.55 (s, 1H), 6.47 (m, 1H), 6.45 (s, 1H), 3.94 (s, 3H), 3.89 (m, 7H), 3.14 (m, 4H), 2.40 (t, 2H, J=7.0 Hz), 2.10 (t, 2H, J=7.0 Hz), 1.32 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C:11]2=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:20][N:21]1[CH2:25][CH2:24][CH2:23][C:22]1=O>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[C:22]3[CH2:23][CH2:24][CH2:25][N:21]3[CH3:20])[C:11]2=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CN1CCCC1=O
Reactant: COc1ccc(N2C(=O)Cc3ccccc32)cc1F
Solvent: CCOC(C)=O
Product: COc1ccc(N2C(=O)C(=C3CCCN3C)c3ccccc32)cc1F

Procedure:
By the procedure of Example B5, except to use ethyl acetate as eluant, 1-(3-fluoro-4-methoxyphenyl)-(1H,3H)-indolone (2.0 g, 7.8 mmoles) and 1-methyl-2-pyrrolidone (1.5 ml, 15.6 mmole) were converted to title product, 0.32 g, m.p. 68°-71°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:33]([NH2:35])=[O:34])=[C:24]([NH:27][C:28]([NH:30][CH2:31][CH3:32])=[O:29])[NH:25][CH:26]=2)=[CH:18][CH:17]=1>O1CCCC1>[CH2:31]([NH:30][C:28](=[O:29])[NH:27][C:24]1[NH:25][CH:26]=[C:22]([C:19]2[CH:20]=[CH:21][C:16]([NH:15][C:13]([NH:12][C:3]3[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=3[F:1])=[O:14])=[CH:17][CH:18]=2)[C:23]=1[C:33]([NH2:35])=[O:34])[CH3:32]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: CCNC(=O)Nc1[nH]cc(-c2ccc(N)cc2)c1C(N)=O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1[nH]cc(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c1C(N)=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 200.2 %

Procedure:
0.031 cm3 (0.0213 mmol) of 2-fluoro-5-trifluoromethylphenyl isocyanate is added at a temperature in the region of 25° C. to 0.056 g (0.194 mmol) of 4-(4-aminophenyl)-2-(3-ethylureido)-1H-pyrrole-3-carboxamide in solution in 20 cm3 of tetrahydrofuran. After stirring for 16 hours at a temperature in the region of 60° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is then diluted in 40 cm3 of ethyl acetate and then washed with twice 30 cm3 of water. The organic solution is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is purified by flash chromatography [eluent: dichloromethane/methanol/acetonitrile (95/2.5/2.5 by volume)]. After concentrating the fractions under reduced pressure, 0.021 g of 2-(3-ethylureido)-4-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrole-3-carboxamide is obtained in the form of a yellow solid. ES+: m/z=494 (MH+).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:12]([C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8])(=O)[CH3:2]>[OH-].[Na+]>[CH3:2][C:1]1[N:9]=[C:7]([OH:8])[C:6]2[C:5](=[CH:13][C:12]([C:14]3[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:11][CH:10]=2)[N:4]=1
Reactant: CC(=O)Nc1cc(-c2ncccc2C(F)(F)F)ccc1C(N)=O
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(O)c2ccc(-c3ncccc3C(F)(F)F)cc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Suspend 2-acetylamino-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide in 20 ml of 20% NaOH, stir for 30 minutes at room temperature. Filter, acidify to pH=6, extract with EtOAc, and concentrate under vacuum to give 2-methyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-ol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C@@H:6]([NH:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:16](Cl)[C:15]=1[N+:22]([O-])=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C@@H:6]([NH:13][C:14]1[C:15]([NH2:22])=[CH:16][N:17]=[C:18]([CH3:20])[CH:19]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](Nc1cc(C)nc(Cl)c1[N+](=O)[O-])c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C[C@@H](Nc1cc(C)ncc1N)c1ccccc1
Reaction time: 3 h
Yield: 110.1 %

Procedure:
To a solution of (R)-3-(2-chloro-6-methyl-3-nitro-pyridin-4-ylamino)-3-phenyl-propionic acid ethyl ester (650 mg, 1.79 mmol) in MeOH (20 ml) was added slurry of Pd/C (500 mg) in MeOH (2 mL). The reaction mixture was degassed using house vacuum. The flask was saturated with H2 and stirred under a H2 balloon for 3 hours. When the reaction was complete, the mixture was filtered through a pad of celite and the filtrate was concentrated to afford 590 mg (100%) of the title compound. The resulting light brown oily residue was used for the next reaction without further purification. LCMS, M++1, m/z: 300.92.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:29]1[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=1.FC(F)(F)C(O)=O>C(O)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:35][C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([C:25]5[NH:26][CH:27]=[CH:28][N:24]=5)[CH:30]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cccc(-c2ncc[nH]2)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4cccc(-c5ncc[nH]5)c4)ncnc3[nH]2)CC1
Temperature: 80 °C

Procedure:
Into a sealed tube were added 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (368 mg, 1.0 mmol), 3-(1H-imidazol-2-yl)-phenylamine (210 mg, 1.32 mmol), trifluoroacetic acid (847 μL, 11.0 mmol) and 1-butanol (10 mL). The above mixture was heated at 80° C. for 24 h. After that time, the mixture was concentrated in vacuo, and the residue was dissolved in DMSO for submission for MS-directed purification to obtain brown oil, which was purified again to give the title compound. 1H NMR (CD3OD, 400 MHz): δ=1.52 (s, 9H), 2.58 (brs, 2H), 3.68 (brs, 2H), 4.14 (brs, 2H), 6.30 (brs, 1H), 6.68 (s, 1H), 7.16 (s, 2H), 7,45 (t, 1H, J=8.0 Hz), 7.57-7.60 (m, 1H), 7.76-7.79 (m, 1H), 8.21 (t, 1H, J=1.6 Hz), 9.26 (s, 1H). MS (ES+): m/z 458.06 (100) [MH+]. HPLC: tR=2.17 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH2:1]([O:3][C:4]1[O:5][C@H:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C@H:7]2[N:8]=1)[CH3:2].[NH2:16][C:17]1[CH:30]=[CH:29][C:20]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C1C=CC=CC=1>[C:21]([C:20]1[CH:19]=[CH:18][C:17]([NH:16][C@@H:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C@H:7]2[NH:8][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:30][CH:29]=1)(=[O:22])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC1=N[C@@H]2Cc3ccccc3[C@@H]2O1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Nc1ccc(C(=O)c2ccccc2)cc1
Temperature: 80 °C
Yield: 76 %

Procedure:
A solution of (±) cis-2-ethoxy-3a,8b-dihydro-4H-indeno[2,1-d]oxazole (2.50 g, 0.012 mol) in dry toluene (40 ml) was treated with 4-aminobenzophenone (2.43 g, 0.012 mol) and a catalytic amount of p-toluenesulfonic acid (0.25 ml of an anhydrous 0.1M solution of p-toluenesulfonic acid in benzene). The mixture was heated under nitrogen at 80° C. overnight. The reaction was worked up as described in Preparation 5. Purification on a silica gel column using a graded eluant of 5-40% ethyl acetate in petroleum ether 40/60 afforded the title compound as a yellow foam (3.65 g).
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH:10]1[CH3:23])C1C=CC=CC=1.C([O-])=O.[NH4+]>CCO.[Pd]>[NH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH:10]1[CH3:23]
Reactant: CC1CC(CNc2ccccc2)CCC1NCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC1CC(CNc2ccccc2)CCC1N

Procedure:
(4-Benzylamino-3-methyl-cyclohexylmethyl)-phenyl-amine (160 mg, 0.52 mmol) and ammonium formate (164 mg, 2.60 mmol) in EtOH (5 mL) is treated with 10% Pd/C (30 mg) and heated at reflux for 2 hours. The Pd/C is removed by filtration and washed with MeOH. The filtrate is concentrated in vacuo to afford the title compound which is used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH:14]([C:25](OC)=[O:26])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Ca+2].[Cl-].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(O)C>[CH2:1]([O:8][C:9]([N:11]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH:12]1[CH2:13][CH:14]([CH2:25][OH:26])[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:17]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CC(N(CC(C)C)C(=O)OCc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)CN(C(=O)OCc1ccccc1)C1CC(CO)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A solution of 1-tert-butyl 3-methyl 5-{[(benzyloxy)carbonyl](2-methylpropyl)amino}piperidine-1,3-dicarboxylate (13.0 g) in THF (100 ml) was added to a solution of calcium chloride (6.5 g) and sodium borohydride (4.5 g) in ethanol (100 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 4 with 10% aqueous citric acid solution, and concentrated under reduced pressure to a half volume. The residue was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (5:95-80:20) was concentrated under reduced pressure to give the object compound (8.04 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([NH:12]C(=O)OCC)=S)=[N:7][CH:8]=1.[Cl-].O[NH3+].C([N:24](CC)C(C)C)(C)C.C(O)C>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([N:24]=[C:10]([NH2:12])[N:9]=2)[CH:8]=1
Reactant: CCOC(=O)NC(=S)Nc1ccc(OC)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CCO
Solvent: CO
Product: COc1ccc2nc(N)nn2c1
Yield: 91.7 %

Procedure:
In the same manner as in the below-mentioned Example 23-1 and using ethyl {[(5-methoxypyridin-2-yl)amino]carbonothioyl}carbamate (1.34 g, 5.25 mmol), hydroxylammonium chloride (2.55 g, 36.7 mmol), N,N-diisopropylethylamine (4.57 mL, 26.2 mmol), ethanol (15 mL) and methanol (15 mL) as starting materials, the title compound (790 mg, 92%) was obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14](C)[C:15](=O)OC(C)(C)C)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>C(Cl)Cl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([NH:14][CH3:15])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.1 %

Procedure:
Tert-butyl N-[1-(4-chlorophenyl)piperidin-4-yl]-N-methylcarbamate (4.71 g, 14.5 mmol) prepared in Reference Example 165 was dissolved in methylene chloride (30 ml), to which trifluoroacetic acid (20 ml) was added dropwise, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was then dissolved in methylene chloride. The solution was neutralized with sodium hydroxide aqueous solution, and the mixture was extracted with methylene chloride. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to afford N-[1-(4-chlorophenyl)piperidin-4-yl]-N-methylamine (3.1 g, yield 95%) as a pale brown oil.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][O:41][C:42]([N:44]2[CH2:49][CH2:48][N:47](C(OC(C)(C)C)=O)[CH2:46][CH2:45]2)=[O:43])=[CH:36][CH:35]=1)=[O:32])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:30])[NH2:29])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14].FC(F)(F)C(O)=O.C(OCC)C>ClCCl>[O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:31]([NH:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:40][O:41][C:42]([N:44]2[CH2:45][CH2:46][NH:47][CH2:48][CH2:49]2)=[O:43])=[CH:38][CH:39]=1)=[O:32])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:30])[NH2:29])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14]
Reactant: CC(C)[C@H](NC(=O)CCCCCN1C(=O)C=CC1=O)C(=O)N[C@@H](CCCNC(N)=O)C(=O)Nc1ccc(COC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)CCCCCN1C(=O)C=CC1=O)C(=O)N[C@@H](CCCNC(N)=O)C(=O)Nc1ccc(COC(=O)N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 104.2 %

Procedure:
Step 2 The intermediate 59 (22.0 mg) was treated with trifluoroacetic acid (327 mg, 2.87 mmol) in anhydrous dichloromethane (0.12 ml). The reaction mixture was stirred at room temperature for 15 minutes, until disappearance of the starting material (HPLC-MS analysis). After that, the reaction mixture was treated with diethyl ether (20 ml) and the residue thus obtained was rinsed with diethyl ether (2×10 ml): the product N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N5-carbamoyl-N-(4-{[(piperazin-1-ylcarbonyl)oxy]methyl}phenyl)-L-ornithinamide 60 (white wax, 20.0 mg) was thus isolated and used without further purification in the next step. MS (ESI): 685 [M+H]+. Retention time=2.97 min (method 1).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2C=O)=[CH:4][CH:3]=1.[Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[O:43]1[CH2:47]C[CH2:45][CH2:44]1.CC(C)([O-])C.[K+]>O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2([CH:45]=[CH:44][O:43][CH3:47])[CH:17]=[CH:16][CH:15]=[CH:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: O=Cc1ccccc1-c1ccc(Br)c2ccccc12
Agent: CC(C)(C)[O-]
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: O
Product: COC=CC1(c2ccc(Br)c3ccccc23)C=CC=CC1
Temperature: 25 °C
Yield: 99 %

Procedure:
Under an argon atmosphere, 170 g of the resulting 1-bromo-4-(2-formylphenyl)naphthalene, 207 g of methoxymethyl triphenylphosphonium chloride and 2.0 L of tetrahydrofuran (THF) were placed in a flask. During stirring at room temperature, 73.6 g of potassium t-butoxide was added to the flask. After further stirring at room temperature for 2 hours, 1.5 L of water was added. The reaction solution was extracted with diethyl ether. An aqueous phase was removed and an organic phase which had been separated was washed with water and saturated brine, and then dried with magnesium sulfate. After the magnesium sulfate was filtered out, the organic phase was concentrated. The resulting residue was purified by means of silica gel column chromatography, whereby 180 g (yield: 99%) of 1-bromo-4-[1-(2-methoxyvinyl)phenyl]naphthalene was obtained.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[Cl:8][C:9]1[CH:14]=CC(O)=[CH:11][CH:10]=1.[OH-].[Na+]>S(=O)(=O)(O)O>[C:5]([O:4][C:1]1[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:2]=1)(=[O:7])[CH3:6]
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Oc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 17 h
Yield: 97.7 %

Procedure:
Acetic anhydride (80.1 g, 0.78 mol) and one drop of concentrated sulfuric acid were added to 4-chlorophenol [compound (6-1)] (100 g, 0.78 mol) at room temperature, and the mixture was stirred for 17 hours. The resultant mixture was added to ice-water, and converted to alkaline by the addition of sodium hydroxide (20% aqueous solution), followed by extraction with diethyl ether. The organic layer was washed with water, dried over magnesium sulfate. Subsequently, the solvent was removed under reduced pressure, and then the residue was subjected to distillation under reduced pressure (81° C./1.5 mmHg), to thereby yield 4-chlorophenyl acetate as a colorless oily product (130 g, yield: 98.0%).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH3:16].Cl>>[NH2:16][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: N
Reactant: CS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1Cl
Agent: Cl
Product: CS(=O)(=O)c1cc(C(=O)O)c(N)cc1Cl

Procedure:
50 g of 2,4-dichloro-5-methylsulphonylbenzoic acid [obtainable in accordance with Ex. 2] are heated in an autoclave, at 180° and under a pressure of 30 bar for 12 h, together with 500 ml of a 32% aqueous solution of ammonia. The reaction mixture is then poured onto ice, acidified with conc. HCl and extracted by boiling with methanol. 2-Amino-4-chloro-5-methylsulphonylbenzoic acid is obtained, m.p. 284°-286°.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[N:8][OH:9])[NH2:7])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[C:20]1[NH:24][C:23](=[O:25])[N:22]([C:26]2[CH:33]=[CH:32][C:29]([C:30]#N)=[CH:28][CH:27]=2)[N:21]=1>CN(C=O)C.[Cl-].[Cl-].[Zn+2]>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[C:20]1[NH:24][C:23](=[O:25])[N:22]([C:26]2[CH:27]=[CH:28][C:29]([C:30]3[O:9][N:8]=[C:6]([C:5]4[CH:10]=[CH:11][C:2]([F:1])=[CH:3][CH:4]=4)[N:7]=3)=[CH:32][CH:33]=2)[N:21]=1
Reactant: NC(=NO)c1ccc(F)cc1
Reactant: N#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(-c2nc(-c3ccc(F)cc3)no2)cc1
Temperature: 100 °C
Yield: 17.8 %

Procedure:
To a solution of 4-fluoro-N′-hydroxybenzimidamide (Intermediate-18, 0.073 g, 0.47 mmol) in dry DMF (3 mL) under nitrogen atmosphere was added 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzonitrile (step-4 of Intermediate-17, 0.100 g, 0.31 mmol) and ZnCl2 (0.0087 g, 0.06 mmol). The reaction mass was heated at 100° C. for 8-10 h. The reaction mass was quenched with water, extracted in DCM and column purified to afford 0.025 g of desired product. 1HNMR (DMSO-d6): δ 7.02 (br s, 1H), 7.33 (t, 1H), 7.45-7.54 (m, 2H), 7.61 (d, 1H), 7.70 (m, 1H), 7.83 (t, 1H), 8.09-8.17 (m, 2H), 8.26-8.30 (m, 2H), 12.81 (br s, 1H). MS (m/z): 452.05 [M+H]+.
Reaction SMILES: S([O-])(OC(C)(C)S(OC1C=CC(O)=CC=1)(=O)=O)(=O)=O.[C:20]([OH:43])(=O)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=[CH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:59][C@@H:60]([C:62]([OH:64])=[O:63])[CH3:61].C(N(CC)CC)C>C(#N)C.O>[C:20]([NH:59][C@@H:60]([C:62]([OH:64])=[O:63])[CH3:61])(=[O:43])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=[CH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)O
Reactant: C[C@@H](N)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(OS(=O)(=O)[O-])S(=O)(=O)Oc1ccc(O)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)N[C@H](C)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
4-hydroxyphenyldimethylsulfomethyl sulfate 2.66 g (0.01 mol) was heated and dissolved in 40 ml of acetonitrile. Docosahexaenoic acid 3.28 g (0.01 mol) was added to the solution obtained in a stream of nitrogen, and the mixture was stirred at 0° C. To the mixture solution, dicyclohexyl carbodiimide 2.06 g (0.01 mol) was added little by little, and the solution was stirred for 2 hours at 0° C. and then for 2 hours at room temperature. The solution reacted was filtered to remove dicyclohexyl urea, and the filtrate was distilled in vacuo to obtain oily residue. D-alanine 0.89 g (0.01 mol) and triethyl amine 1.4 ml (0.01 mol) were added to 10 ml of water. An acetonitrile solution of the above oily residue was added to the mixture with stirring, and stirred for 10 hours at room temperature. After reaction, the reaction mixture was concentrated under reduced pressure. The concentrate was adjusted to pH 2 or 3 with 6N-HCl, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium acetate, and freed of solvent in vacuo. The oily residue obtained was purified by column chromatography (column: 2.5×15 cm) on 50 g of silica gel and N-docosahexaenoyl-D-alanine 1.6 g was obtained.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[C:19]([C:22]([OH:24])=[O:23])[CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:25]([O:27]C)=O.Cl>CO>[O:27]=[C:25]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10][NH:9]1
Reactant: COC(=O)c1nc2ccc(C(=O)O)cc2n1CCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)c1ccc2nc3n(c2c1)CCCNC3=O
Yield: 29.4 %

Procedure:
Triethylamine (14.3 g, 141.7 mmol) is added to a solution of the crude 1-(3-aminopropyl)-2-(methoxycarbonyl)-1H-benzimidazole-6-carboxylic acid hydrochloride (20 g, 47.2 mmol) in methanol (100 mL) and reaction mixture is refluxed for 1 h. The reaction mixture is cooled and acidified with 1M HCl. The solvent is evaporated and water is added. The resultant solid is collected by filtration and purified by acid-base neutralization using sodium bicarbonate and conc. HCl to afford the title compound (3.4 g, 30%) as a solid.