Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][OH:27])[CH:20]=1>ClCCl>[C:9]1([CH3:8])[CH:14]=[CH:13][C:12]([S:15]([O:27][CH2:26][CH2:25][C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: OCCc1cccnc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
6.62 mL (47.26 mmol) of triethylamine and 8.26 g (43.32 mmol) of 4-methylbenzenesulfonyl chloride are added at 0° C. to a solution of 5 g (39.38 mmol) of 2-pyrid-3-ylethanol in 300 mL of dichloromethane. After allowing the reaction medium to warm to room temperature and stirring overnight, it is washed with water and with saturated NaCl solution. The organic phase is dried over magnesium sulfate and evaporated to dryness. After purification by chromatography on silica gel (eluent: 4/6 heptane/EtOAc), 8 g of 2-pyrid-3-ylethyl toluene-4-sulfonate were obtained, corresponding to the following characteristics:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.[Cl-].[NH3+:45][C:46]([CH3:65])([CH3:64])[CH2:47][O:48][C:49]1[CH:58]=[CH:57][CH:56]=[C:55]2[C:50]=1[C:51]([NH3+:63])=[C:52]([C:60]([OH:62])=[O:61])[C:53]([CH3:59])=[N:54]2.[Cl-]>CN(C=O)C>[NH2:63][C:51]1[C:50]2[C:55](=[CH:56][CH:57]=[CH:58][C:49]=2[O:48][CH2:47][C:46]([NH:45][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([CH3:65])[CH3:64])[N:54]=[C:53]([CH3:59])[C:52]=1[C:60]([OH:62])=[O:61]
Reactant: Cc1nc2cccc(OCC(C)(C)[NH3+])c2c([NH3+])c1C(=O)O
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc2cccc(OCC(C)(C)NC(=O)CCCCCNC(=O)OC(C)(C)C)c2c(N)c1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.4 %

Procedure:
A solution of 6-(tert-butoxycarbonylamino)hexanoic acid (0.21 g, 0.90 mmol) in dry DMF (10 mL) was treated with triethylamine (0.46 g, 4.51 mmol, 0.63 mL) and N,N,N′,N′-tetramethyl-O—(N-succinimidyl)uronium tetrafluoroborate (TSTU) (0.30 g, 0.99 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature over 3 h and then a solution of 5-(2-ammonio-2-methylpropoxy)-3-carboxy-2-methylquinolin-4-aminium chloride (Example 20b) (0.33 g, 0.90 mmol) and triethylamine (0.46 g, 4.51 mmol, 0.63 mL) in dry DMF was added dropwise at room temperature. The obtained mixture was stirred at room temperature over 3 days and the solvent was evaporated. The residue was dissolved in a mixture of MeOH and H2O (50 mL, 1:1) and the product was isolated by preparative HPLC (RPC18, H2O→CH3CN gradient). The appropriate fractions were collected and evaporated under reduced pressure. The residue was dried in a dessicator over phosphorus pentoxide to give 0.21 g (45%) of 4-amino-5-(2-(6-(tert-butoxycarbonylamino)hexanamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylic acid as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.95-12.65 (m, 1H), 12.45-11.95 (m, 1H), 9.05-8.60 (m, 1H), 7.84 (s, 1H), 7.67 (t, J=8.0 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H), 7.02 (d, J=8.1 Hz, 1H), 6.71 (t, J=5.6 Hz, 1H), 4.36 (s, 2H), 2.78 (s, 3H), 2.70 (q, J=6.4 Hz, 2H), 2.05 (t, J=7.3 Hz, 2H), 1.45-1.34 (m, 2H), 1.36 (s, 3H), 1.34 (s, 3H), 1.30-1.19 (m, 2H), 1.14-1.03 (m, 2H). MS 503 (MH+).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(P(C(C)(C)C)C(C)(C)C)C=CC=CC=1.Cl[C:25]1[CH:26]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:29][CH:30]=1.C1(C(N)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CC(N(C)C)=O>[F:32][C:31]([F:34])([F:33])[C:27]1[CH:26]=[C:25](/[CH:1]=[CH:2]/[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: FC(F)(F)c1cccc(Cl)c1
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1)C(C)(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: FC(F)(F)c1cccc(/C=C/c2ccccc2)c1
Reaction time: 4 h

Procedure:
0.745 g (7.2 mmol) of styrene, 38.7 mg (120 μmol) of NBu4Br, 6.7 mg (30 μmol) of palladium acetate and 26.7 mg (120 μmol) of phenyldi(t-butyl)phosphine are weighed into a Schlenk vessel. 1.08 g (6 mmol) of 3-chlorobenzotrifluoride and 1.53 ml (7.2 mmol) of dicyclohexylmethylamine and also 3.5 ml of dimethylacetamide are then added. The Schlenk vessel is placed in a heating bath at 130° C. and the contents are stirred. After 4 hours, the contents are poured into 30 ml of water and the product is extracted by shaking with t-butyl methyl ether. After drying the organic phase over MgSO4, the solvent is removed under reduced pressure and the product is isolated. Yellowish, crystalline solid, yield: 1.43 g (96% of theory).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[N:10]([CH3:13])[C:8](=[O:9])[C:4]2[NH:5][CH:6]=[N:7][C:3]1=2.CN1C(=O)N(C)[C:21](=O)[C:17]2NC=N[C:16]1=2.C(N)CN.N1(C(=O)C2NC=NC=2N(C)C1=O)C.C(N)CN>>[CH2:1]([N:2]1[C:3]2[N:7]=[CH:6][NH:5][C:4]=2[C:8](=[O:9])[N:10]([CH3:13])[C:11]1=[O:12])[CH:17]([CH3:21])[CH3:16]
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Solvent: NCCN
Product: CC(C)Cn1c(=O)n(C)c(=O)c2[nH]cnc21

Procedure:
Aminophylline {adduct of Theophylline and 1,2-ethanediamine (2:1)}.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[N:4]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:3]=1.C([Mg]Cl)(C)C.[C:27]([O:31][C:32](=[O:52])[N:33]([C:43]1[CH:44]=[N:45][C:46]([O:49][CH2:50][CH3:51])=[CH:47][CH:48]=1)[C:34]1[CH:39]=[CH:38][C:37]([CH:40]=[O:41])=[C:36]([F:42])[N:35]=1)([CH3:30])([CH3:29])[CH3:28].O>O1CCCC1>[C:27]([O:31][C:32](=[O:52])[N:33]([C:43]1[CH:44]=[N:45][C:46]([O:49][CH2:50][CH3:51])=[CH:47][CH:48]=1)[C:34]1[CH:39]=[CH:38][C:37]([CH:40]([OH:41])[C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([CH3:11])[CH:9]=3)[N:4]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:3]=2)=[C:36]([F:42])[N:35]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CCOc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C=O)c(F)n2)cn1
Reactant: Cc1cnc2c(c1)c(I)cn2[Si](C(C)C)(C(C)C)C(C)C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncc(C)cc34)c(F)n2)cn1
Temperature: -5 °C
Yield: 83.2 %

Procedure:
To a solution of 3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (8, 0.43 g, 1.0 mmol) in 5 mL of tetrahydrofuran at −40° C. under nitrogen, isopropylmagnesium chloride (0.51 mL, 2.00 M in tetrahydrofuran, 1.0 mmol) is added slowly. The reaction is allowed to warm to −5° C. over 60 minutes, then cooled to −45° C., followed by addition of (6-ethoxy-pyridin-3-yl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (69, 0.06 g, 0.2 mmol) in 2.0 mL of tetrahydrofuran. The reaction is allowed to warm to room temperature over 2 hours, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (70, 108.1 mg).
Reaction SMILES: C(COC)OC.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[Na+].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)CCC>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([O:19][CH3:18])[CH:21]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=S([O-])c1ccc(Cl)cc1
Reactant: COc1cccc(CCl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCCCO
Solvent: COCCOC
Product: COc1cccc(CS(=O)(=O)c2ccc(Cl)cc2)c1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A dimethoxyethane (10 ml) suspension of sodium 4-chlorobenzenesulfinate (210 mg, 1.06 mmol) and 3-methoxybenzyl chloride (154 μl, 1.06 mmol) was stirred at 70° C. for 16 hours. After cooling to room temperature, butanol (2 ml) and tetrabutylammonium bromide (45 mg) were added and the resulting mixture was stirred further at 70° C. for 16 hours. After cooling the reaction mixture to room temperature, the solvent was concentrated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed successively with water and brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate (=5:1) eluate was concentrated under reduced pressure, whereby the title compound (216 mg, 69%) was obtained as a white solid.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[O:15][C:14]([C:16]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[N:30]=[CH:29][C:28]([CH2:31][C:32]([O:34]C)=[O:33])=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)=[O:17])=[N:13][N:12]=1.Cl>CO>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[O:15][C:14]([C:16]([NH:18][CH:19]2[CH2:20][CH2:21][N:22]([C:25]3[N:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=[O:33])=[CH:27][CH:26]=3)[CH2:23][CH2:24]2)=[O:17])=[N:13][N:12]=1
Reactant: COC(=O)Cc1ccc(N2CCC(NC(=O)c3nnc(Nc4ccccc4F)o3)CC2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1ccc(N2CCC(NC(=O)c3nnc(Nc4ccccc4F)o3)CC2)nc1
Reaction time: 16 h
Yield: 2.5 %

Procedure:
A mixture of 2M NaOH (0.09 mL, 0.18 mmol) and methyl (6-{4-[({5-[(2-fluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]piperidin-1-yl}pyridin-3-yl)acetate (Intermediate 102) (41 mg, 0.09 mmol) in MeOH (1 mL) was stirred for 16 h then acidified with 2M HCl and concentrated by evaporation. The residue purified by preparative HPLC to give the title compound (1 mg) as a gum; 1H NMR (CD3OD) δ 1.78-1.63 (m, 3H), 2.11-2.00 (m, 2H), 3.35-3.25 (m, 2H), 3.55 (s, 2H), 4.23-4.07 (m, 3H), 7.07-6.99 (m, 1H), 7.15-7.07 (m, 2H), 7.30-7.23 (m, 1H), 7.79 (s, 1H), 7.89-7.83 (m, 1H), 7.99-7.91 (m, 1H); MS m/e MH+ 441.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[CH2:21][CH2:22]O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:44]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[CH2:21][CH2:22][Br:44])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(CCO)C1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(CCBr)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
In methylene chloride (70 ml) were dissolved 1,4-bis(tert-butoxycarbonyl)-2-(2-hydroxyethyl)piperazine (2.01 g) and triphenylphosphine (1.98 g). Under ice cooling, carbon tetrabromide (3.07 g) was added to the resulting solution, followed by stirring at room temperature for 2.5 hours. The reaction mixture was extracted with a 10% aqueous solution of sodium thiosulfate. The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate an distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (hexane:ethyl acetate=4:1) using as a carrier silica gel, whereby the title compound (2.20 g) was obtained as colorless powder.
Reaction SMILES: [CH:1]1([C:7]([NH:9][CH:10]([C:17]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)=[O:18])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[O:18][C:17]([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)=[C:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(NC(=O)C1CCCCC1)C(=O)c1ccco1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1nc(C2CCCCC2)oc1-c1ccco1
Yield: 69.9 %

Procedure:
5.0 g of ethyl 3-cyclohexylcarbonylamino-3-(2-furylcarbonyl)propionate, 30 ml of chloroform and 16.0 g of phosphorus oxychloride are treated in the same manner as described in Example 2. 3.3 g of ethyl 2-[2-cyclohexyl-5-(2-furyl)-4-oxazolyl]acetate are thereby obtained as an oil. Yield: 70.0%
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C:2]1=[O:7].[H-].[Na+].[C:10]([O:14][C:15]([N:17]1[CH2:22][C@H:21]([CH2:23]Cl)[N:20]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:19][C@H:18]1[CH3:32])=[O:16])([CH3:13])([CH3:12])[CH3:11]>CN(C=O)C>[C:10]([O:14][C:15]([N:17]1[CH2:22][C@H:21]([CH2:23][N:1]2[CH2:6][CH2:5][O:4][CH2:3][C:2]2=[O:7])[N:20]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:19][C@H:18]1[CH3:32])=[O:16])([CH3:11])([CH3:12])[CH3:13]
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Reactant: O=C1COCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](CN2CCOCC2=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
Morpholin-3-one (896 mg, 8.87 mmol) was added to a slurry of NaH (60% in mineral oil, 355 mg, 8.87 mmol) in DMF (10 mL) under N2. The suspension was stirred for 30 minutes at room temperature and then a solution of (2R,5R)-4-benzyl-5-chloromethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (2.0 g, 5.9 mmol) in DMF (10 mL) was slowly added. The resulting mixture was stirred at 65° C. for 2 h. The reaction was cooled to room temperature and partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase was dried over MgSO4 and concentrated in vacuo. Chromatography (50% EtOAc in petrol) gave the title compound (1.76 g) as a pale yellow gum. MS: [M+H]+=404.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)=[O:4].[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1>O1CCOCC1>[Br:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)c1cccc(Br)c1
Reactant: c1c[nH]cn1
Solvent: C1COCCO1
Product: O=C(Cn1ccnc1)c1cccc(Br)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of 2-bromo-1-(3-bromophenyl)ethanone (120 mg, 0.432 mmol) in dioxane (2 mL) was added imidazole (58.8 mg, 0.864 mmol) and the reaction mixture was stirred for 1 h at 80° C. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography using MeOH:CH2Cl2 (6:94) as eluent to give the sub-title compound in 68% yield (77.9 mg, 0.293 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH:14]([CH3:20])[C:15]([O:17]CC)=[O:16])=[CH:10][C:9]=2[CH3:21])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH:14]([CH3:20])[C:15]([OH:17])=[O:16])=[CH:10][C:9]=2[CH3:21])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)c1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(C)C(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1

Procedure:
An ethanol solution of 2.9 g. (0.0087 mole) of ethyl 5-(p-chlorobenzoyl)1,4,α-trimethylpyrrole-2-acetate is added to 17.5 ml. 0.5 N sodium hydroxide solution, and the mixture is heated under reflux for one hour. The ethanol is evaporated in vacuo and the solution poured into dilute hydrochloric acid. The precipitated solid is collected by filtration and recrystallized from ether-cyclohexane to give 5-(p-chlorobenzoyl)-1,4,α-trimethylpyrrole-2-acetic acid as a white solid, m.p. 153-154° C. Anal. Calcd. for C16H16ClNO3 : C, 62.85; H, 5.29; N, 4.58%. Found: C, 62.74; H, 5.22; N, 4.47%.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1)(=O)=O.[C-:19]#[N:20].[Na+]>C(#N)C.C(OCC)(=O)C.[Cu](I)I.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>[C:13]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[CH:7][C:8]=1[C:19]#[N:20])([CH3:16])([CH3:15])[CH3:14]
Reactant: [C-]#N
Reactant: CC(C)(C)c1cccc(OS(=O)(=O)C(F)(F)F)c1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cccc(Cc2ccccc2C#N)c1
Yield: 151.3 %

Procedure:
To a solution of 3-tert-butylphenyl trifluoromethanesulfonate (6.17 g, 21.9 mmol) in acetonitrile (80 ml) were added sodium cyanide (2.15 g, 43.8 mmol) and copper iodide (0.42 g, 2.19 mmol). To the mixture was added tetrakis(triphenylphosphine)palladium (1.27 g, 1.10 mmol) under nitrogen stream and the mixture was heated under reflux for 5 hrs. The mixture was diluted with ethyl acetate, and insoluble material was filtered off with celite. The filtrate was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ether=1:0, 20:1) to give 3-tert-butylbenzylbenzonitrile (4.13 g) as a colorless transparent oil. The compound included impurities, but was directly used in the next reaction.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([CH2:18]O)[CH:13]=[C:14]([Br:17])[CH:15]=2)[CH:10]=[C:9]1[O:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:28]([O:30][C:31](=[O:47])[CH2:32][CH:33]([N:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[NH:39][C:38]1=[O:46])[CH2:34][CH2:35][CH3:36])C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([CH2:18][N:39]3[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[N:37]([CH:33]([CH2:32][C:31]([O:30][CH3:28])=[O:47])[CH2:34][CH2:35][CH3:36])[C:38]3=[O:46])[CH:13]=[C:14]([Br:17])[CH:15]=2)[CH:10]=[C:9]1[O:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Reactant: CC(C)(C)OC(=O)Oc1cc2c(CO)cc(Br)cc2n1C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(CC(=O)OC)n1c(=O)n(Cc2cc(Br)cc3c2cc(OC(=O)OC(C)(C)C)n3C(=O)OC(C)(C)C)c2ccccc21
Temperature: 0 °C
Yield: 56 %

Procedure:
6-Bromo-2-tert-butoxycarbonyloxy-4-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester (220 mg, 0.50 mmol) is and 3-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-hexanoic acid ethyl ester (151 mg, 0.55 mmol) is taken up in 5 mL of tetrahydrofuran and then triphenyl phosphine is added (157 mg, 0.6 mmol). The reaction is stirred at 0° C. and diisopropyl azodicarboxylate (116 □L, 0.6 mmol) is added drop wise to the reaction. The reaction is stirred at room temperature for 4 hours and then the solvent evaporated in vacuo. Product is purified by preparative TLC 3% methanol in dichloromethane to give the title compound (200 mg 0.28 mmol 57%). LCMS (ESMS): m/z 687.7 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].[CH:16](O)=O>>[N+:13]([C:10]1[C:11]2[N:12]=[CH:16][NH:1][C:2]=2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=1)([O-:15])=[O:14]
Reactant: COC(=O)c1cc(N)c(N)c([N+](=O)[O-])c1
Reactant: O=CO
Product: COC(=O)c1cc([N+](=O)[O-])c2nc[nH]c2c1
Temperature: 25 °C
Yield: 110 %

Procedure:
A solution of methyl 3,4-diamino-5-nitrobenzoate (D245) (1.3 g, 6.16 mmol, 1 equiv) in HCOOH (20 ml) was stirred at 100° C. for 1 h then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt and a 2N aqueous NaOH solution and the layers were separated. The organic phase was dried over MgSO4 and concentrated in vacuo to give methyl 4-nitro-1H-benzimidazole-6-carboxylate (D250) (1.5 g, 110%) as a light brown solid which was used in the next step without further purification. [M+H]+=222.3, RT=2.29 min.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(N(CC)CC)C.C(Cl)Cl.CO>ClCCl>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:27](=[O:28])[O:29][CH2:30][CH3:31])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Temperature: 20 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
To a solution of 100 mg (0.30 mmole) of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3), in 5 mL of dichloromethane, 57 μL of ethyl chloroformate and 85 μL (2 eq) of triethylamine were added. The mixture was magnetically stirred at 20° C. during 4 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 97:3 volume ratio) to provide 111 mg (yield: 83%) of the desired product (formula below) as an orange powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([O:17]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:39][C@H:40]([C:53]([O:55]CC1C=CC=CC=1)=[O:54])[CH2:41][CH2:42][C:43]([O:45]CC1C=CC=CC=1)=[O:44]>>[CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([NH:39][C@H:40]([C:53]([OH:55])=[O:54])[CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[O:17])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(CCC(=O)Oc2ccc([N+](=O)[O-])cc2)=C(C)C1=O
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC1=C(OC)C(=O)C(CCC(=O)N[C@@H](CCC(=O)O)C(=O)O)=C(C)C1=O
Yield: 25.6 %

Procedure:
Using p-nitrophenyl 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)propionate (187 mg, 0.5 mmol) and dibenzyl L-glutamate p-toluenesulfonate (250 mg, 0.5 mmol) and following the procedure of Example 4, there was obtained 3-(2,3-dimethoxy-5-methylbenzoquinon-6-yl)propionyl-L-glutamic acid (49 mg).
Reaction SMILES: C(OC[N:9]1[C:13]2[CH:14]=[C:15]([Br:18])[CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[S:19][CH2:20][CH3:21])(=O)C(C)(C)C.C(OCN1C2C=CC(Br)=CC=2N=C1SCC)(=O)C(C)(C)C>>[Br:18][C:15]1[CH:16]=[CH:17][C:12]2[N:11]=[C:10]([S:19][CH2:20][CH3:21])[NH:9][C:13]=2[CH:14]=1
Reactant: CCSc1nc2ccc(Br)cc2n1COC(=O)C(C)(C)C
Agent: CCSc1nc2cc(Br)ccc2n1COC(=O)C(C)(C)C
Product: CCSc1nc2ccc(Br)cc2[nH]1

Procedure:
11.8 g mixture of [6-bromo-2-(ethylsulfanyl)-1H-benzo[d]imidazol-1-yl]methyl pivalate and [5-bromo-2-(ethylsulfanyl)-1H-benzo[d]imidazol-1-yl]methyl pivalate in a ratio of 1:1 was obtained as pale yellow solid by the same method as in Production Example 64 from 8.1 g 6-bromo-2-(ethylsulfanyl)-1H-benzo[d]imidazole obtained in Production Example 72. 7.2 g of the title compound was obtained as a colorless amorphous by the same method as in Production Example 65 from 6.9 g of the above product and 10 g 3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolylboronic acid (compound in Production Example 25).