Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.[CH:21]([NH:24][CH2:25][CH2:26][NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29])([CH3:23])[CH3:22]>C(N(CC)CC)C>[C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([N:24]([CH2:25][CH2:26][NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH:21]([CH3:22])[CH3:23])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)NCCNC(C)C)cc1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NCCN(C(=O)c2ccccc2C(=O)c2ccccc2)C(C)C)cc1

Procedure:
A solution of 37 grams of ψ-acid chloride of 0-benzoyl benzoic acid in 60 ml. of dichloromethane was added dropwise to a stirred solution of 38.5 grams of N-[2-(isopropylamino) ethyl]-p-toluenesulfonamide, 200 ml. of dichloromethane and 25 ml. of triethylamine. The mixture was refluxed for 3.5 hours. After cooling, the solution was extracted successively with water, 10% hydrochloric acid, and saturated sodium carbonate solution. The dichloromethane solution was dried over magnesium sulfate and the solvent evaporated in vacuo to a solid residue. On recrystallization from ethyl acetate there was obtained 2-benzoyl-N-[2-(p-toluenesulfonamido)ethyl]-N-isopropylbenzamide, m.p. 135°-137°C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]=[O:12])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[C:4]([F:26])[CH:3]=1.[CH3:27][Mg]Br.O>O1CCCC1>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]([OH:12])[CH3:27])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[C:4]([F:26])[CH:3]=1
Reactant: C[Mg]Br
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3cc(C=O)oc23)c1=O
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
4.0 g (10.2 mmol) of 3-(4-chloro-6-fluoro-2-formylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil was dissolved in 20 ml of tetrahydrofuran, and 12.3 ml of methyl magnesium bromide (1.0M tetrahydrofuran solution) was dropwise added thereto at -65° C. After stirring at room temperature for 1 hour, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 2.3 g (yield: 55.3%) of the desired product as pale yellow crystals. Melting point: 154-157° C.
Reaction SMILES: [I-:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N+:10]([CH3:16])=[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:8]=[C:7]2SC.[I-].[CH3:26][C:27]1[S:28][C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[N+:31]=1[CH3:32].C(N(CC)CC)C>CN(C)C=O>[I-:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH3:16])[C:9]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[N:8][C:7]2=[CH:26][C:27]1[S:28][C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[N+:31]=1[CH3:32]
Reactant: Cc1sc2ccccc2[n+]1C
Reactant: COc1cc2c(SC)nc(-c3ccccc3)[n+](C)c2cc1OC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)N(C)C(c1ccccc1)=NC2=Cc1sc2ccccc2[n+]1C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
500 mg (1.10 mmol) 6,7-Dimethoxy-1-methyl-4-methylsulfanyl-2-phenyl-quinazolin-1-ium iodide and 320 mg (1.10 mmol) 2,3-Dimethyl-benzothiazol-3-ium iodide were dissolved in 200 ml dimethylformamide and 445 mg (0.61 ml, 4.40 mmol) triethylamine were added. The solution was stirred for 1 h at 80° C., filtrated and the residue is washed with water and methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1B1OC(C)(C)C(C)(C)O1)[C:5]([NH2:7])=[O:6].Br[C:21]1[N:26]2[CH:27]=[CH:28][N:29]=[C:25]2[C:24]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)=[CH:33][CH:32]=2)=[N:23][CH:22]=1>O1CCOCC1.CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+].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:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:21]1[N:26]2[CH:27]=[CH:28][N:29]=[C:25]2[C:24]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([N:37]3[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]3)=[CH:35][CH:36]=2)=[N:23][CH:22]=1)[C:5]([NH2:7])=[O:6]
Reactant: CN1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1
Reactant: CC1(C)OB(c2ccc(C(N)=O)cc2F)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(Nc3ncc(-c4ccc(C(N)=O)cc4F)n4ccnc34)cc2)CC1

Procedure:
In the same way as described for Compound 127, step 4, using 3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamide (82 mg, 0.31 mmol), (5-bromoimidazo[1,2-a]pyrazin-8-yl)-(4-(4-methylpiperazin-1-yl)phenyl)amine (60 mg, 0.155 mmol) and Pd(PPh3)4 (45 mg, 0.038 mmol) in dioxane (0.68 mL), DMF (1.52 mL) and 1.5M Na2CO3 (0.83 mL). The residue is chromatographed on silica gel, eluting with DCM followed by 95:5 DCM:NH3 (7M in MeOH), and the fractions containing the desired product are combined and evaporated. The title compound is isolated as a solid. HPLC (254 nm): Rt 1.92 min (95.0%); m/z (APCI) 446 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)=[O:10].[C:18](OC(=O)C)(=[O:20])[CH3:19]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18](=[O:20])[CH3:19])=[C:3]([C:9](=[O:10])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[CH:4]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1cccc(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(Br)cc1C(=O)c1cccc(Cl)c1
Yield: 120.2 %

Procedure:
A solution of intermediate 2 (0.328 mol) and acetic acid anhydride (0.656 mol) in toluene (1200 ml) was stirred and refluxed for one night. The mixture was evaporated and the product was used without further purification, yielding 139 g (quant.) of N-[4-bromo-2-(3-chlorobenzoyl)phenyl]-acetamide (intermediate 3).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH2:11](O)[CH3:12].S(Cl)(Cl)=O>CN(C)C=O>[CH2:11]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[N:3][CH:4]=1)[CH3:12]
Reactant: CCO
Reactant: Nc1ccc(C(=O)O)cn1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(N)nc1
Temperature: 80 °C

Procedure:
6-Aminonicotinic acid, 40 g (or 6-aminonicotinic acid phosphoric salt, 62 g), was mixed with anhydrous ethanol 500 ml. The mixture was externally cooled by an ice water bath. Thionyl chloride, 50 ml, was slowly added into the mixture. (N,N-Dimethylformamide, 50 ml, may be added to dissolve any still undissolved phosphoric salt.) The reaction mixture was heated to 80° C. for 5 hours and was then evaporated to a syrupy reside which crystallized on addition of acetone. These crystals were separated by filtration and were redissolved in 400 g of ice water. 4N KOH was added to the solution to adjust the pH to 8. The white crystals thus formed were separated again by filtration and were washed with water. The yield of practically pure 6-aminonicotinic acid ethyl ester was 41.8 g. This product had an Rf value of 0.79 on thin-layer chromatogram using a solvent system of benzene:methanol, 1:1.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CC1(C)C=CC(=O)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)CCC(=O)CC1
Yield: 93.8 %

Procedure:
A solution of 4,4-dimethyl-cyclohex-2-enone (3 mmol) in ethyl acetate is hydrogenated overnight at room temperature using Pd/C (0.05 mmol) with hydrogen under normal pressure. Filtration over celite and then concentration by evaporation produces 4,4-dimethyl-cyclohexanone (355 mg) in a yield of 94% (J. Org. Chem. 2001, 66 (3), 733-738).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[C:11]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([O:9][CH3:11])=[CH:6][C:7]=1[F:8]
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(F)c(Br)cc1F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(F)c(Br)cc1F
Temperature: 45 °C
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged with 20 mL of DMF. To the stirred solvent were added 4-Bromo-2,5-difluorophenol (2.0 g, 9.6 mmol), K2CO3 (3.98 g, 28.8 mmol) and methyl iodide (1.63 g, 11.53 mmol), stirred at 45° C. for 15 minutes under nitrogen atmosphere. The RM was quenched with water, extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as white color solid (1.2 g, yield: 56.07%).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH2:25]([O:27][CH2:28][CH2:29][CH2:30]Br)[CH3:26].C([O-])([O-])=O.[K+].[K+]>C(O)(C)C>[CH2:25]([O:27][CH2:28][CH2:29][CH2:30][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:23][CH:24]=1)[CH3:26]
Reactant: CCOCCCBr
Reactant: Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCOCCCNc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
11 g of 1-(4-aminobenzoyl)-4-[2-(4-chlorophenyl)ethyl]piperazine and 5.7 g of 3-ethoxypropyl bromide are suspended in 150 ml of isopropanol and dissolved at 100°. 9.4 g of potash are added thereto, and the mixture is boiled under reflux for 20 hours. Concentration by evaporation and chromatography over silica gel yield an oil, which is crystallised from methylene chloride and petroleum ether, yielding 1-[4-(3-ethoxypropylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]piperazine having a melting point of 87°-89°.
Reaction SMILES: C(C1C=CC(C(N[C:12]2[CH:27]=[CH:26][CH:25]=[CH:24][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)=[O:15])=O)=C(OC2CCNCC2)C=1)(C)(C)C.N=C=N.C(Cl)(Cl)Cl>C(O)(C)(C)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14](=[O:15])[C:13]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:12]=2)=[N:18][CH:19]=1
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCNCC2)c1
Agent: N=C=N
Solvent: ClC(Cl)Cl
Solvent: CC(C)(C)O
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-[4-(tert-butyl)-2-(piperidin-4-yloxy)benzoylamino]-N-(5-chloropyrdin-2-yl)benzamide (30 mg, 59 pmnol) in a 4 mL screw cap vial is added polymer-supported carbodiimide (P-EPC, 280 mg @0.85 mmol/g, 4 eq) and a carboxylic acid of choice (120 micromoles, 2 eq), followed by 3 mL of 4:1 (amylene stabilized) chloroform:tert-butyl alcohol. Where acid hydrochloride salts are used, piperidinomethyl polystyrene resin (100 mg @2.6-2.8 mmol/g) is added to effect reaction. The vial is capped, shaken overnight at room temperature, then the mixture is filtered. Retentates are washed with amylene stabilized chloroform (3 mL), and the combined filtrate and wash are concentrated in vacuo to afford the amide derivative of the compound of Example 202.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH:9]1[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[C:13]([S:16][CH2:17][CH:18]([CH3:22])[C:19](O)=[O:20])(=[O:15])[CH3:14].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:12])[CH2:7][N:8]([C:19](=[O:20])[CH:18]([CH3:22])[CH2:17][S:16][C:13](=[O:15])[CH3:14])[CH:9]1[CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)SCC(C)C(=O)O
Reactant: CC(C)(C)OC(=O)CNC1CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)C1CC1
Temperature: 25 °C

Procedure:
To a solution of N-(cyclopropyl)glycine t-butyl ester (12 g, 0.0702 mol) and 3-acetylthio-2-methylpropionic acid (8.1 g, 0.050 mol) in methylene chloride (200 ml) chilled in an ice bath was added dicyclohexylcarbodiimide (14.4 g, 0.070 mol). The resulting mixture was stirred for sixteen hours at room temperature. The dicyclohexylurea was removed by filtration and washed with diethyl ether. Evaporation of the filtrate yielded the crude product as a pale yellow oil which was used without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][C:4](C1C=C2C(=CC=1)NC(C(O)=O)=C2)=[O:5].[CH2:19]([O:21][C:22]([C:24]1[NH:25][C:26]2[C:31]([C:32]=1[Br:33])=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH3:20].[Al+3].[Cl-].[Cl-].[Cl-].C(Cl)(=O)CC(C)C>[N+](C)([O-])=O>[CH2:19]([O:21][C:22]([C:24]1[NH:25][C:26]2[C:31]([C:32]=1[Br:33])=[CH:30][C:29]([C:4](=[O:5])[CH2:3][CH:2]([CH3:18])[CH3:1])=[CH:28][CH:27]=2)=[O:23])[CH3:20]
Reactant: CC(C)CC(=O)c1ccc2[nH]c(C(=O)O)cc2c1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Br
Agent: CC(C)CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CCOC(=O)c1[nH]c2ccc(C(=O)CC(C)C)cc2c1Br
Temperature: 0 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
Preparation of 5-(3-Methyl-butyryl)-1H-indole-2-carboxylic acid (Froshauer, S. A.; Goldstein, S. W.; Stirtan, W. G. U.S. Pat. No. 5,981,762): 3-Bromo-1H-indole-2-carboxylic acid ethyl ester (536 mg, 2.0 mmol), prepared as previously described (Elliott, J. D.; Leber, J. D.; Thompson, S. K.; Halbert, S. M. U.S. Pat. No. 5,684,032) was dissolved in nitromethane (10 mL) and cooled to 0° C. AlCl3 was added to the flask. Then a solution of isovaleryl chloride (0.295 mL, 2.4 mmol) in nitromethane (2 mL) was added dropwise to the flask. The mixture was allowed to come to room temperature and stirred for 18 hours. The mixture was then cooled to 0° C. 20 mL ice-water was added and extracted with CH2Cl2 (4×20 mL). The combined organic phase was washed with saturated brine (20 mL), 1N NaHCO3 (20 mL) and saturated brine (2×20 mL), Dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give yellow solid. It was then purified by flash column chromatography eluted with hexane:ethyl acetate (6:1) to give 3-Bromo-5-(3-methyl-butyryl)-1H-indole-2-carboxylic acid ethyl ester (468 mg, 67%) as light yellow solid.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]([NH:1][CH:2]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=2)[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=2)[OH:4])=[O:35])=[CH:26][CH:25]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(F)c1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (274 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (412 mg, 2.15 mmol) and 1-hydroxy-1H-benzotriazole (221 mg, 1.44 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (573 mg, 82%).
Reaction SMILES: [N+](C1C=CC(OC2C=CC([N+]([O-])=O)=CC=2)=CC=1)([O-])=O.[CH2:20]([O:27][C:28]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([OH:34])=O)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH2:38][C@H:39]([C:47]([OH:49])=[O:48])[CH2:40][CH2:41][CH2:42][NH:43][C:44](=[NH:46])[NH2:45]>O1CCOCC1.O>[CH2:20]([O:27][C:28]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([NH:38][C@H:39]([C:47]([OH:49])=[O:48])[CH2:40][CH2:41][CH2:42][NH:43][C:44](=[NH:45])[NH2:46])=[O:34])=[O:29])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: O=[N+]([O-])c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
To a solution of 37 g (0.1 mol) of p-nitrophenyl ether of benzyloxycarbonylproline in 360 ml of dioxane there is added a solution of 16 g (0.09 mole) of arginine in 160 ml of water under vigorous stirring. After two hours the solvent is evaporated and the residue is dissolved in 100 ml of dimethylformamide. The solution is stirred at room temperature (25° C.) for 72 hours and then poured into 1 liter of ethylacetate. After residence of the reaction mixture for 12 hours in a cooler the resulting precipitate is filtered-off, washed on the filter with ethylacetate and diethyl ether. After recrystallization of the product from a mixture of ethanol-diethyl ether (1:5) there are obtained 35 g (96%) of benzyloxycarbonyl-prolyl-arginine having the following properties: melting point 137°-140° C., [L]D20 -46.6° (c 1.0; H2O); Rf 0.53 (A, "Eastman"); 0.66 (B, "Eastman"), Ehis 0.56 (pH 2.4).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C1([Mg]Br)C=CC=CC=1.[CH:20](=[O:24])[CH:21]([CH3:23])[CH3:22]>C1COCC1>[I:8][C:5]1[CH:6]=[CH:7][C:2]([CH:20]([OH:24])[CH:21]([CH3:23])[CH3:22])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(I)ccc1I
Reactant: CC(C)C=O
Agent: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)C(O)c1ccc(I)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.9 %

Procedure:
To a solution of 1,4-diiodo-2-nitrobenzene (2.24 g, 6.0 mmol) in anhydrous THF (20 mL) at minus 40° C. under a nitrogen atmosphere, phenylmagnesium bromide (2 M in THF, 3.2 mL, 6.4 mmol) was added dropwise at a rate that the temperature would not exceed minus 35° C. Upon completion of the addition the mixture was stirred for 5 minutes, followed by addition of isobutyraldehyde (0.726 mL, 8.0 mmol). The mixture was gradually warmed up to room temperature, quenched with saturated NH4Cl (8 mL), then poured into water (100 mL). The mixture was extracted three times with ethyl acetate (150 mL), and the combined organic phase was washed with brine (100 mL), dried over Na2SO4, concentrated in vacuo and purified by silica gel column chromatography to yield racemic (RS)-1-(4-Iodo-2-nitrophenyl)-2-methyl-1-propanol (1.54 g, 80%) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.18 (d, 1H, J=1.7 Hz, Ph-H), 7.93 (dd, 1H, J=1.7 and 8.3 Hz, Ph-H), 7.50 (d, 1H, J=8.3 Hz, Ph-H), 5.04 (m, 1H, Ph-CH), 2.17 (d, 1H, J=4.4 Hz, OH), 1.98 (m, 1H, CH), 0.93 (d, 3H, J=4.4 Hz, CH3), 0.92 (d, 3H, J=4.4 Hz, CH3); 13C NMR (100 MHz, CDCl3): δ 148.62 (C), 141.81 (CH), 138.57 (C), 132.72 (CH), 130.49 (CH), 91.51 (C), 73.48 (CH), 34.22 (CH), 19.62 (CH3), 16.71 (CH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26]>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2([OH:26])[C:4]1[CH:5]=[C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(-c2ccccc2)cc1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Product: COc1ccc(-c2ccccc2)cc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 50 %

Procedure:
With 18.4 g of 4-methoxybiphenyl and 15.1 g of 5-chloroisatin as starting materials, 15.2 g of the title compound (yellow solid) was obtained by a similar method to Step 245-1.
Reaction SMILES: C([O:5][C:6](=[O:52])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17](=[O:51])[NH:18][CH:19]1[C:25](=[O:26])[N:24]([C:27]([CH:37]([CH3:39])[CH3:38])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28](=[O:30])[NH2:29])[C:23]2[CH:40]=[CH:41][CH:42]=[CH:43][C:22]=2[N:21]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:20]1=[O:50])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:37]([C:27]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:28](=[O:30])[NH2:29])[N:24]1[C:25](=[O:26])[CH:19]([NH:18][C:17]([C:9]2[N:8]([CH2:7][C:6]([OH:52])=[O:5])[C:16]3[C:11]([CH:10]=2)=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:51])[C:20](=[O:50])[N:21]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:22]2[CH:43]=[CH:42][CH:41]=[CH:40][C:23]1=2)([CH3:39])[CH3:38]
Reactant: CC(C)C(C(N)=O)(c1ccccc1)N1C(=O)C(NC(=O)c2cc3ccccc3n2CC(=O)OC(C)(C)C)C(=O)N(c2ccccc2)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(C(N)=O)(c1ccccc1)N1C(=O)C(NC(=O)c2cc3ccccc3n2CC(=O)O)C(=O)N(c2ccccc2)c2ccccc21
Yield: 75.5 %

Procedure:
To a solution of {2-[1 -(Isopropyl-phenyl-carbamoylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1 H-benzo[b][1,4]diazepin-3-ylcarbamoyl]-indol-1-yl}-acetic acid tert-butyl ester (0.072 g) in dichloromethane (4 ml) at ambient temperature was added trifluoroacetic acid (1.5 ml) gradually with stirring. After the reaction was stirred 30 minutes, the dichloromethane and trifluoroacetic acid were evaporated under reduced pressure to afford a clear glass. The glass was purified by purified RP-HPLC on a C-18 column with a gradient elution of 45-55% acetonitrile in water with 0.1% trifluoroacetic acid buffer over a 30 minute period at a rate of 100 ml/min. Fractions containing the desired material were combined, frozen and lyophilized to afford the title compound (0.050 g) as a white powder. 1H NMR (300 MHz, CDCl3): d 1.07 (d, J=4.4 Hz, 3H), 1.10 (d, J=4.4 Hz, 3H), 4.23 (d, J=16.6 Hz, 1H), 4.40 (d, J=16.6 Hz, 1H), 5.01 (m, 1H), 5.06 (s, 2H), 5.44 (d, J=7.1 Hz, 1H), 7.03 (dd, J=1.2, 8.1 Hz, 1H), 7.17-7.52 (m, 17H), 7.67 (d, J=8.1 Hz, 1H), 7.74 (d, J=7.1 Hz, 1H); MS (ES): m/z=644.2 (MH+); TLC (CH2Cl2 /CH3OH(19:1)): Rf =0.15; RP-HPLC (Vydac C-18, 25 cm×4.6 mm; 45-55% CH3CN in H2O with 0.1% TFA buffer;, 30 minutes; 1 ml/min): tf =22 min (to =3 min).