Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([O:14][CH2:13][CH2:12][O:11]1)[C:9]1[CH:8]=[CH:7][CH:6]=[C:5](N)[C:4]=1[CH2:3][CH2:2]2.[C:15](O)(=O)C.C=O.[C:21]([BH3-])#[N:22].[Na+]>CN(C)C=O>[CH3:15][N:22]([CH3:21])[C:5]1[C:4]2[CH2:3][CH2:2][C:1]3([O:14][CH2:13][CH2:12][O:11]3)[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Reactant: Nc1cccc2c1CCC21OCCO1
Agent: C=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1cccc2c1CCC21OCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 25 (100 mg, 0.52 mmol) in N,N-dimethylformamide (1 mL) was added acetic acid (0.1 mL) and a 37% aqueous solution of formaldehyde (0.5 mL, 5.23 mmol) and the mixture was stirred at room temperature for about 1 hour. Then sodium cyanoborohydride (330 mg, 5.23 mmol) was added and stirring at room temperature was continued overnight. The reaction was quenched by addition of saturated aqueous sodium bicarbonate and the mixture was extracted with dichloromethane. The combined organic extracts were dried (MgSO4), filtered, and concentrated under vacuum to provide the desired product. MS (ESI): m/z 220 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=1.[CH3:13]CN(CC)CC.CI.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)[CH:6]=1
Reactant: CCN(CC)CC
Reactant: Brc1cnn(C2CCNCC2)c1
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(n2cc(Br)cn2)CC1
Reaction time: 0.08 h
Yield: 63.1 %

Procedure:
To a solution of 4-(4-bromo-pyrazol-1-yl)-piperidine (375 mg, 1.63 mmol) in DMF (3.26 mL) was added NEt3 (230 μL, 1.63 mmol) and stirred for 5 minutes. Methyliodide (MeI) (1.63 mL, 1M MeI in DMF, freshly made) was added and the reaction was stirred overnight at room temperature. Water was added and the solution was extracted with EtOAc (4×10 mL). The organic solution was washed with brine, dried with Na2SO4, concentrated, and dried in vacuo to afford 4-(4-bromo-pyrazol-1-yl)-1-methyl-piperidine (251 mg, 63% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:53][CH3:54])=[C:6]([CH:52]=1)[CH2:7][C@@H:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@@H:19]([C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28]C(C)(C)C)=[O:27])=[C:24]([N+:35]([O-])=O)[CH:23]=2)[CH2:20][CH3:21])=[O:17])[CH2:12][C:11](=[O:38])[N:10](CC2C(OC)=CC(OC)=CC=2OC)[CH2:9]1.O>Cl.C(OCC)(=O)C.[Zn]>[C:26]([OH:28])(=[O:27])[CH3:25].[NH2:35][C:24]1[CH:23]=[C:22]([C@H:19]([NH:18][C:16]([N:13]2[C:14](=[O:15])[C@@H:8]([CH2:7][C:6]3[CH:52]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:53][CH3:54])[CH2:9][NH:10][C:11](=[O:38])[CH2:12]2)=[O:17])[CH2:20][CH3:21])[CH:34]=[CH:33][C:25]=1[C:26]([OH:28])=[O:27]
Reactant: CC[C@@H](NC(=O)N1CC(=O)N(Cc2c(OC)cc(OC)cc2OC)C[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)O
Product: CC[C@@H](NC(=O)N1CC(=O)NC[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)O)c(N)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 178.3 %

Procedure:
Tert-butyl 4-[(1R)-1-({[(6S)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepan-1-yl]carbonyl}amino) propyl]-2-nitrobenzoate (9.5 g) was dissolved in 4N solution of hydrochloric acid in an ethyl acetate (170 ml), and the mixture stirred at room temperature for 16 hours. Next, sandy zinc (9g) was added to the reaction solution, and the mixture was stirred at 40° C. for 20 hours. Water was added to the reaction solution to wash it, then the organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. Then 20% hydrous isopropyl alcohol (60 ml) was added to the obtained residue, and the resultant mixture was heated to dissolve the residue at 50° C., and acetic acid (30 ml) and water (90 ml) were added to the solution. The mixture was cooled down to room temperature, and stirred for 2 hours. The precipitated crystals were collected by filtration and dried to obtain a crude product of the title compound (6.2 g) as a colorless crystal. The obtained crude product (6g) was heated to dissolve at 55° C. in 20% hydrous isopropyl alcohol (40 ml), then acetic acid (20 ml) was added to the solution, and the mixture was stirred at that temperature for 1 hour 30 minutes. After water was added to the solution, the resulting mixture was gradually cooled down to room temperature and then stirred for 3 hours. The precipitated crystals were collected by filtration and dried to obtain the title compound (5.6 g) as a colorless crystal.
Reaction SMILES: [N+:1]([C:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[NH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:20][C:21]1[C:26]([CH3:27])=[C:25]([O:28][CH3:29])[N:24]=[CH:23][N:22]=1.O>CN(C=O)C>[CH3:29][O:28][C:25]1[N:24]=[CH:23][N:22]=[C:21]([CH2:20][N:6]2[C:7]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5]2)[C:26]=1[CH3:27]
Reactant: O=[N+]([O-])c1c[nH]c2cccnc12
Reactant: COc1ncnc(CCl)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncnc(Cn2cc([N+](=O)[O-])c3ncccc32)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
To a stirred suspension of 3-Nitro-1H-pyrrolo[3,2-b]pyridine (25b) (0.5 g, 3.04 mmol) and K2CO3 (0.5 g, 9.12 mmol) in DMF (10 mL) was added 4-(chloromethyl)-6-methoxy-5-methylpyrimidine (0.7 g, 6.09 mmol) and the resulting mixture was stirred for 16 h at room temperature. Then the reaction mixture was poured in to water (50 mL) and extracted with dichloromethane (2×50 mL). The combined organic layer was washed with brine and the solvent was evaporated under reduced pressure to yield 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-3-nitro-1H-pyrrolo[3,2-b]pyridine (25c) [300 mg (33%)] as a pale yellow solid.
Reaction SMILES: [CH:1]1([O:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[S:23][CH:22]=[N:21][C:20]=2[CH3:24])[C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].C(O)C>[CH:1]1([O:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[S:23][CH:22]=[N:21][C:20]=2[CH3:24])[C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C(CCCC/C=C/c1scnc1C)OC1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C(CCCCCCc1scnc1C)OC1CCCCC1
Yield: 97 %

Procedure:
To a solution of (E)-methyl 2-(cyclohexyloxy)-8-(4-methylthiazol-5-yl)oct-7-enoate (560 mg, 1.58 mmol) and ethanol (40 mL) was added 10% palladium on carbon (82 mg) and the resulting mixture was hydrogenated at 1 atm H2 overnight. The resulting mixture was then filtered through CELITE and concentrated in vacuo to yield methyl 2-(cyclohexyloxy)-8-(4-methylthiazol-5-yl)octanoate (97%) which was used in the next step without further purification. A solution of methyl 2-(cyclohexyloxy)-8-(4-methylthiazol-5-yl)octanoate (563 mg, 1.58 mmol), methanol (8.6 mL), and p-toluenesulfonic acid (14.8 mg, 0.086 mmol) was stirred at room temperature for 1 h. Solvent was removed in vacuo to yield methyl 2-hydroxy-8-(4-methylthiazol-5-yl)octanoate which was used in the next step without further purification. A mixture of 2-hydroxy-8-(4-methylthiazol-5-yl)octanoic acid (590 mg, 2.17 mmol), tetrahydrofuran (21 mL), water (54 mL) and lithium hydroxide (78.1 mg, 3.26 mmol) was stirred at room temperature for 2 h. The resulting mixture was acidified with 1N HCl and concentrated in vacuo. An excess amount of acetonitrile was added to the residue and the mixture was concentrated. The process was repeated twice to yield 2-hydroxy-8-(4-methylthiazol-5-yl)octanoic acid which was used in the next step without further purification. MS (ES+) 258 (M+1).
Reaction SMILES: [H-].[Na+].C1(C)C=CC(S([CH2:12][N+:13]#[C-:14])(=O)=O)=CC=1.[F:16][C:17]([F:25])([F:24])/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21].CCOCC.CS(C)=O>CCOCC.CCOC(C)=O>[F:16][C:17]([F:25])([F:24])[C:18]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:12][NH:13][CH:14]=1
Reactant: COC(=O)/C=C/C(F)(F)F
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1c[nH]cc1C(F)(F)F
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
In a round-bottomed flask was added sodium hydride (3.24 mmol, 78 mg) in Et2O (5 mL). A mixture of p-toluenesulfonylmethyl isocyanide (3.24 mmol, 634 mg) and (E)-methyl 4,4,4-trifluorobut-2-enoate (3.24 mmol, 500 mg) were added in a 2:1 mixture of Et2O/DMSO (22.5 mL). The reaction mixture was stirred for a further 30 min then quenched with H2O (10 mL) and extracted with Et2O (×3). The Et2O layers were combined and washed with brine, dried over MgSO4, filtered and the solvent removed to give a yellow/orange solid. Purification by flash chromatography (1:4 EtOAc:Hept) the desired product (154 mg, 0.80 mmol, 24.6%). 1H NMR (400 MHz, CD3OD) δ 3.79 (s, 3H) 7.20 (s, 1H) 7.50 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:29])([F:28])[C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[N:24]=[CH:23][CH:22]=[CH:21]5)=[N:15][N:16]=3)[N:13]=2)[CH:5]=[CH:4][N:3]=1.[CH3:30][N:31](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:28][C:17]([F:29])([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2)[C:14]1[N:12]2[N:13]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:30]#[N:31])[CH:7]=3)[CH:9]=[CH:10][C:11]2=[N:16][N:15]=1
Reactant: CN(C)C=O
Reactant: FC(F)(c1ccc2ncccc2c1)c1nnc2ccc(-c3ccnc(Cl)c3)nn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(-c2ccc3nnc(C(F)(F)c4ccc5ncccc5c4)n3n2)ccn1

Procedure:
A mixture of 6-{[6-(2-Chloro-pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-difluoro-methyl}-quinoline (see Example 100b) (50 mg, 0.122 mmol) in DMF (4 mL) and Zn(CN)2 (43 mg, 0.367 mmol) was degassed with house vacuum for ˜5 min, and tetrakis(triphenylphosphine)palladium (13.4 mg, 0.012 mmol) were then added. The mixture was microwaved at 190° C. for 20 min. Following the aqueous work up, solvent was removed by vacuo. The target compound, 21 mg (41%), was obtained by column purification. 1H NMR(CDCl3) δ 9.04 (dd, J=4.2, 1.6 Hz, 1H), 8.95 (d, J=5.12 Hz, 1H), 8.41 (d, J=9.8 Hz, 1H), 8.22-8.35 (m, 4H), 8.00-8.05 (m, 2H), 7.70 (d, J=9.8 Hz, 1H), 7.54 (dd, J=8.2, 3.8 Hz, 1H); MS (ES) m/z 400.3 (M+H+).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:13])[C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1.[Cl:14][C:15]1[C:16](=[O:26])[N:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[N:18]=[CH:19][C:20]=1Cl>>[Cl:14][C:15]1[C:16](=[O:26])[N:17]([C:22]([CH3:24])([CH3:23])[CH3:25])[N:18]=[CH:19][C:20]=1[NH:10][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH3:13])[CH3:3])=[CH:6][CH:7]=1
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Reactant: CN(C)c1ccc(CN)cc1
Agent: Cl
Product: CN(C)c1ccc(CNc2cnn(C(C)(C)C)c(=O)c2Cl)cc1

Procedure:
The compounds as identified in Table 9 were prepared in the synthetic manner and after-treatment similar to those in Example 2 except that the benzylamine dihydrochlorides with Y1, Y2, Y3 and R3 as identified in Table 9 were used instead of the starting 4-dimethylaminobenzylamine dihydrochloride used in Example 2, and the 4,5-di(chloro or bromo)-2-alkyl-3(2H)pyridazinones with R1 and R2 as identified in Table 8 were used instead of the starting 4,5-dichloro-2-t-butyl-3(2H)pyridazinone. In the NMR data, only the characteristic absorptions are given in Table 9.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[N:8][C:7]([NH2:10])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH3:11][C:12]1[C:16]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[C:15]([CH3:29])[O:14][N:13]=1>N1C=CC=CC=1>[CH:1]1([C:4]2[N:9]=[N:8][C:7]([NH:10][S:25]([C:22]3[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]4[C:12]([CH3:11])=[N:13][O:14][C:15]=4[CH3:29])=[CH:24][CH:23]=3)(=[O:26])=[O:27])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc(C2CC2)nn1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)Nc2ccc(C3CC3)nn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.4 %

Procedure:
To a solution of 6-cyclopropylpyridazin-3-amine (50 mg, 0.370 mmol) in pyridine (1 mL), stirred under nitrogen at room temperature, was added 4-((3,5-dimethylisoxazol-4-yl)methoxy)benzene-1-sulfonyl chloride (346 mg, 1.147 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was evaporated and purified by solid phase extraction (SPE) using an aminopropyl (NH2) cartridge with sequential solvents methanol then 2M ammonia/methanol. The appropriate fractions were combined and evaporated in vacuo to give the crude product. The crude was further purified by mass directed autoprep (formic acid modifier). The relevant fractions were removed under a stream of nitrogen to give the title product (51 mg). LCMS (2 min, formic) Rt 0.86 min, m/z (ES+) 401 (M+H).
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][N:12]=2)[C:7]([OH:14])=[C:6]([C:15]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[S:17](=[O:26])(=[O:25])[N:16]=2)[C:5]1=[O:27])[CH:2]=[CH2:3].C[N+]1([O-])CC[O:32]CC1.C1COCC1.S(=O)(O)[O-].[Na+].[OH2:46]>[Os](=O)(=O)(=O)=O>[OH:46][CH:2]([CH2:3][OH:32])[CH2:1][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][N:12]=2)[C:7]([OH:14])=[C:6]([C:15]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[S:17](=[O:25])(=[O:26])[N:16]=2)[C:5]1=[O:27]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2cccnc21
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2cccnc2n1CC(O)CO

Procedure:
The product of Example 55B (1.08 g, 0.028 mol) was reacted with osmium tetroxide (0.0007 mol) and N-methylmorpholine N-oxide (4.96 g, 0.043 mol) in a 1:1 mixture of water and THF (50 mL) at room temperature for 18 hours. The reaction mixture was treated with sodium bisulfite and diluted with water. The product precipitated from the aqueous mixture and was collected by vacuum filtration to give the title compound as a a white solid (1.09 g, 93%). MS (DCI/NH3) m/z 417 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 3.33 (m, 2H), 3.87 (m, 1H), 4.37 (m, 2H), 4.52 (t, J=6.07 Hz, 1H), 4.78 (d, J=5.52 Hz, 1H), 7.17 (dd, J=7.72, 4.78 Hz, 1H), 7.29 (m, 2H), 7.56 (m, 1H), 7.67 (d, J=6.99 Hz, 1H), 8.40 (dd, J=7.72, 1.84 Hz, 1H), 8.53 (dd, J=4.78, 1.84 Hz, 1H), 15.80 (m, 1H).
Reaction SMILES: NC1C=CSC=1C(OC)=O.[F:11][C:12]([F:26])([F:25])[C:13]([NH:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]([O:23][CH3:24])=[O:22])=[O:14].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([Li])CCC.[Br:45]CCBr>>[Br:45][C:19]1[S:18][C:17]([C:21]([O:23][CH3:24])=[O:22])=[C:16]([NH:15][C:13](=[O:14])[C:12]([F:11])([F:25])[F:26])[CH:20]=1
Reactant: COC(=O)c1sccc1NC(=O)C(F)(F)F
Reactant: BrCCBr
Agent: COC(=O)c1sccc1N
Agent: [Li]CCCC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1sc(Br)cc1NC(=O)C(F)(F)F

Procedure:
In reaction scheme 5 the synthesis of compound B53 is described. The intermediate 3-amino-5-bromo-thiophene-2-carboxylic acid methyl ester (compound B54b) is obtained according to a procedure described in literature (Bioorganic & Medicinal Chemistry Letters 17 (2007) 2535-2539) by conversion of methyl 3-aminothiophene-2-carboxylate to methyl 3-[(trifluoroacetyl)amino]thiophene-2-carboxylate with trifluoroacetic acid anhydride followed by a lithiation/bromination sequence using n-butyllithium and 1,2-dibromoethane to give methyl 5-bromo-3-[(trifluoroacetyl)amino]thiophene-2-carboxylate which is hydrolysed under basic conditions using potassium carbonate to obtain 3-amino-5-bromo-thiophene-2-carboxylic acid methyl ester (compound B54b).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O.CCOCC.CCCCCC>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc(N)cc1
Solvent: CCCCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(N)c(Br)c1

Procedure:
To a stirred solution of 48.96 g 4'-aminoacetophenone in 490 ml of toluene was added 64.5 g of solid N-bromosuccinimide in portions over 30 minutes, such that the temperature did not exceed 40° C. Fifteen minutes later, the warm solution was washed with water, dried with sodium sulfate and evaporated in vacuo, giving a dark brown oil, which became crystalline when treated with 20 ml of ether and 80 ml of hexane. The brown crystals were collected, giving 70.5 g of the desired compound, mp 59°-62° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[Cl:20])=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: NCc1ccccc1Cl
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCc1ccccc1Cl
Yield: 83 %

Procedure:
The compound prepared in Example 3 was reacted with 2-chloro-benzylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 83%).
Reaction SMILES: [CH3:1][O:2][NH:3][CH:4]([CH3:16])[CH2:5][CH2:6][C:7]1[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=1[Cl:15].C(N(CC)CC)C.[F:24][CH:25]([F:35])[C:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][N:28]([CH3:34])[N:27]=1>ClCCl.O>[CH3:1][O:2][N:3]([CH:4]([CH3:16])[CH2:5][CH2:6][C:7]1[C:8]([Cl:15])=[CH:9][C:10]([Cl:14])=[CH:11][C:12]=1[Cl:13])[C:31]([C:30]1[C:26]([CH:25]([F:35])[F:24])=[N:27][N:28]([CH3:34])[CH:29]=1)=[O:32]
Reactant: CONC(C)CCc1c(Cl)cc(Cl)cc1Cl
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)CCc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.3 %

Procedure:
To a solution of O-Methyl-N-[1-methyl-3-(2,4,6-trichloro-phenyl)-propyl]-hydroxylamine (0.6 g, 2.1 mmol) prepared as described in example P23d, in dichloromethane (6 ml), was added triethylamine (0.73 ml, 5.2 mmol) followed by drop wise addition of a solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.415 g, 2.1 mmol) in dichloromethane at 0° C. After complete addition of acid chloride, the reaction mixture was stirred for 18 hours at ambient temperature. When the TLC confirmed completion of the reaction, the reaction mass was diluted with water and extracted with dichloromethane (3×60 ml). The combined dichloromethane layer was washed with 2N HCl, followed by sat NaHCO3 then water and finally brine solution, dried over sodium sulfate and solvent was evaporated off under reduced pressure. The resulting crude mass was purified by column chromatography using 60-120μ mesh silica gel and product collected at 30% ethyl acetate in hexane as eluent to give 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid methoxy-[1-methyl-3-(2,4,6-trichloro-phenyl)-propyl]amide (0.53 g, 57%) as a gum like mass.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C(OP([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])(OCC)=O)C.C1(C)C=CC=CC=1.[O-]CC.[Na+]>C(O)C.O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(-c2ccc(C=O)cc2)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCc1ccc(-c2ccc(CCC(=O)OCC)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
4′-Propyl-4-formyl-1,1′-biphenyl (s56) (30.0 g), ethyl diethylphosphonoacetate (36.0 g) and toluene (300 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to 0° C. Sodium ethoxide in ethanol solution (20%; 54.6 g) was added at the same temperature, and the stirring was continued for another 2 hours. After the reaction mixture had been returned to 25° C., the stirring was continued for another 2 hours. The reaction mixture was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography with a mixed solvent of toluene and heptane (toluene:heptane=2:1 by volume) as an eluent and silica gel as a stationary phase powder. The purified product was dissolved in 2-propanol (300 ml), to which Pd/C (1.5 g) was added. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed, and then solvent was distilled off. The residue was purified by column chromatography with a mixed solvent of toluene and heptane (toluene:heptane=2:1 by volume) as an eluent and silica gel as a stationary phase powder to give ethyl 3-(4′-propyl-1,1′-biphenyl-4-yl)propionate (s57) (29.8 g). The yield based on the compound (s56) was 75.2%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[NH:11][C:10]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(N)=C(C(C[C@H](N)C(O)=O)=O)C=1.Br[CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]([CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:10]1=[O:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(=O)c2ccccc2NC1=O
Agent: Nc1ccccc1C(=O)C[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-(S)-t-butyloxycarbonylamino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2,5-dione (12.5 g) prepared from L-kynurenine as described in Australian J. Chemistry Vol. 33, 633-40 (1980), and t-butyl bromoacetate (10.1 g) in acetone (700 ml) was stirred at room temperature under a dry nitrogen atmosphere. Potassium carbonate (12.5 g) was added in one portion and the resulting suspension was stirred at room temperature for 16 hours. The potassium salts were filtered off and the filtrate evaporated to dryness. The residue was partitioned between ethyl acetate (250 ml) and H2O (250 ml). The layers were separated and the organic phase dried (sodium sulfate). The residue was triturated with petroleum ether (350 ml; bp 30°-60°) to give 3-(S)-t-butyloxycarbonylamino-1-t-butyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2,5-dione, m.p. 75°-77° C., [alpha]D =-172° (C=0.96 in DMF).
Reaction SMILES: C([C:5]1[C:13]([CH2:14][NH:15][C:16](=[O:24])[CH:17]([CH3:23])[CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:12]([NH2:25])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(C)(C)C.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[NH2:25][C:12]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:13]=1[CH2:14][NH:15][C:16](=[O:24])[CH:17]([CH3:23])[CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C(=O)NCc1c(N)ccc(C(=O)O)c1C(C)(C)C)C1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C(=O)NCc1cc(C(=O)O)ccc1N)C1CCCC1
Reaction time: 12 h

Procedure:
To a stirred solution of t-butyl-4-amino-3-[(2-cyclopentyl-N-methylacetylamino)methyl]benzoic acid (0.75 g, 2.16 mmole) in CH2Cl2 (20 mL) at RT was added TFA (20 mL). After 12 hr, the reaction contents were evaporated, washed with hexanes and dried under high vacuum overnight affording the title compound (0.63 g, 2.16 mmol) as an orange oil. This product was used without further purification: MS (ES) m/e 292 (M+H-TFA)+.