Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[C:5]([I:13])=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl[CH2:24][C:25]1[C:26]2[C:31]([CH:32]=[C:33]3[C:38]=1[CH:37]=[CH:36][CH:35]=[CH:34]3)=[CH:30][CH:29]=[CH:28][CH:27]=2.C1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.CN(C=O)C>[CH:27]1[C:26]2[C:31](=[CH:32][C:33]3[C:38]([C:25]=2[CH2:24][O:1][C:2]2[C:3]4[O:16][N:15]=[C:14]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[C:4]=4[C:5]([I:13])=[N:6][C:7]=2[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1nc(I)c2c(-c3ccccc3)noc2c1O
Reactant: ClCc1c2ccccc2cc2ccccc12
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(I)c2c(-c3ccccc3)noc2c1OCc1c2ccccc2cc2ccccc12
Temperature: 55 °C
Reaction time: 3 h
Yield: 45.6 %

Procedure:
Ethyl 7-hydroxy-4-iodo-3-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (300 mg, 0.73 mmol), 9-chloromethylanthracene (249 mg, 1.10 mmol), 18-crown-6 (29 mg, 0.11 mmol) and K2CO3 (152 mg, 1.10 mmol) were added to DMF, and the mixture was stirred at 55° C. for 3 h. EtOAc (50 mL) was added and the organic layer was washed with brine and dried over MgSO4. Solvent was removed in vacuo and the crude product was purified twice by flash chromatography (0-30% EtOAc/hexanes) to give 200 mg of the title compound. 1H NMR (CDCl3, 200 MHz): δ=8.65-8.80 (m, 2H), 8.18 (s, 1H), 7.70-7.80 (m, 2H), 7.40-7.55 (m, 3H), 7.18-7.30 (m, 6H), 6.30 (s, 2H), 3.95 (q, 2H, J=7.0 Hz), 0.72 (t, 3H, J=7.2 Hz).
Reaction SMILES: CO[C:3](=O)[C:4]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)(=[O:11])=[O:10])=[CH:5][O:6]CC.[N+:21]([C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27])([O-:23])=[O:22]>>[F:19][C:14]1[CH:13]=[C:12]([S:9]([C:4]2[CH:3]=[N:27][C:26]3[C:28]([C:5]=2[OH:6])=[CH:29][CH:30]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=3)(=[O:10])=[O:11])[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: CCOC=C(C(=O)OC)S(=O)(=O)c1ccc(F)c(F)c1
Reactant: Nc1cccc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1ccc2c(O)c(S(=O)(=O)c3ccc(F)c(F)c3)cnc2c1

Procedure:
The title compound was prepared applying the procedure described in Example 4 from 2-(3,4-difluoro-benzenesulfonyl)-3-ethoxy-acrylic acid methyl ester (3.49 g, 11.4 mmol) and 3-nitroaniline (1.57 g, 11.4 mmol). The yield was 1.6 g (38.3%).
Reaction SMILES: [CH2:1]([C:3]1[CH2:4][CH2:5][C@@H:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([C@@H:3]1[NH:7][C@H:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCC(CC)=N1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC[C@H](CC)N1

Procedure:
Ethyl(2S)-5-ethyl-3,4-dihydro-2H-pyrrole-2-carboxylate dissolved in ethanol (32 mL) was stirred with 0.30 g of 10% Pd/C and under hydrogen (60 psi) for 16 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to provide the titled compound. MS (CI) m/z 172 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24](=O)[CH2:25][CH3:26]>>[CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][N:14]([CH2:24][CH2:25][CH3:26])[CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cn2nc(-c3ccccc3)c3c2CCNCC3)cc1
Reactant: CCC=O
Product: CCCN1CCc2c(-c3ccccc3)nn(Cc3ccccc3)c2CC1

Procedure:
The title compound (0.05 g) was prepared from 1-benzyl-3-phenyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 44, 0.09 g) and 23 μL of propionaldehyde as in Example 35. MS (ESI): exact mass calculated for C23H27N3, 345.22. found, m/z 346.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.56-7.54 (m, 2H), 7.47-7.28 (m, 6H), 7.21-7.19 (m, 2H), 5.44 (s, 2H), 3.70-3.66 (m, 2H), 3.41-3.07 (m, 8H), 1.86-1.76 (m, 2H), 1.03 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].FS([C:20]([F:25])([F:24])C(O)=O)(=O)=O.C(=O)([O-])O.[Na+]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:20]([F:25])[F:24])=[N:6][CH:7]=1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: O=c1ccc(Br)c[nH]1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: FC(F)Oc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
5-Bromopyridin-2(1H)-one (17.4 g, 100 mmol) was mixed with sodium sulfate (1.42 g, 10 mmol) and 2-(fluorosulfonyl)difluoroacetic acid (11.4 ml, 100 mmol) in acetonitrile, and stirred overnight at room temperature. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction solution, and the solvent was concentrated under reduced pressure. The residue was dissolved in diethyl ether, washed with saturated saline, the organic layer was dried with sodium sulfate, and the solvent was evaporated off under reduced pressure. The residue was purified through silica gel column chromatography (eluate: ethyl acetate/hexane=20/80 to 50/50) to obtain the entitled compound (18.75 g, 84%) as a pale yellow oily substance.
Reaction SMILES: [CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]=1[O:29][CH2:30][CH2:31][NH2:32])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C1C2C(COC([NH:50][CH2:51][C:52](Cl)=[O:53])=O)C3C(=CC=CC=3)C=2C=CC=1>C(Cl)Cl>[CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]=1[O:29][CH2:30][CH2:31][NH:32][C:52](=[O:53])[CH2:51][NH2:50])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC[C@H](NC(=O)c1c(OCCN)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reactant: O=C(Cl)CNC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Product: CC[C@H](NC(=O)c1c(OCCNC(=O)CN)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 17.5 %

Procedure:
3.0 g (7.1 mmol) of (S)-N-(α-ethylbenzyl)-3-(2-aminoethoxy)-2-phenylquinoline-4-carboxamide (compound of Description 4) were dissolved, under nitrogen atmosphere, in 60 ml of CH2Cl2 and 1.2 ml (8.5 mmol) of TEA were added; the solution was cooled to 0° C. and 2.7 g (8.5 mmol) of (9-fluorenylmethoxy carbonyl)glycinyl chloride (FMOC-glycinyl chloride), dissolved in 60 ml of CH2Cl2, were added dropwise. The reaction mixture was stirred at room temperature for 3 hours and then washed with sat. sol. NaCl, 20% citric acid, sat. sol. NaHCO3, sat. sol. NaCl, dried over Na2SO4 and evaporated in vacuo to dryness. The crude product was purified by gradient flash column chromatography on 230-400 mesh silica gel, utilising a mixture of hexane/EtOAc 1:1 as starting eluent and a mixture of EtOAc/MeOH 9:1 as final eluent. The product (5.0 g) was dissolved in 100 ml of a 10% solution of diethylamine in DMF and stirred at room temperature for 30 minutes. The reaction mixture was then evaporated in vacuo and purified by gradient flash column chromatography on 230-400 mesh silica gel, utilising a mixture of EtOAc/MeOH 9:1 as starting eluent and a mixture of EtOAc/MeOH 7:3 as final eluent, to yield 0.6 g of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([O:23]C)=[O:22])=[CH:11][CH:10]=2)[C:6]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:5][C:4]=1[Cl:29].[OH-].[K+].Cl>O.CO>[NH2:1][CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([OH:23])=[O:22])=[CH:13][CH:14]=2)[C:6]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:5][C:4]=1[Cl:29]
Reactant: CCCCc1nc(Cl)c(CN)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCc1nc(Cl)c(CN)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 111.1 %

Procedure:
5-Aminomethyl-2-butyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-4-chloroimidazole (1.64 g. 3.98 mmol, 1 eq), 0.5N KOH in methanol (11.96 mL, 5.98 mmol, 1.5 eq), water (1.0 mL) and methanol (20 mL) were mixed and refluxed under N2 overnight. The solution was then brought to neutrality with 1N HCl and the solvents removed in vacuo. The residue was taken up in DMF and the salts filtered off. The DMF was then removed in vacuo to yield 1.76 g of a glass. NMR (200 MHz, DMSO-d6) δ 7.50 (d, 1H, J=7 Hz); 7.40-7.18 (m, 5H); 6.92 (d, 2H, J=8 Hz); 6.50 (bm, 3H); 5.26 (s, 2H); 3.60 (s, 2H); 2.55 (t, 2H, J=7 Hz); 1.51 (t of t, 2H, J=7,7 Hz); 1.27 (t of q, 2H, J=7,7 Hz); 0.81 (t, 3H, J=7 Hz).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C@@H:11]1[C:17](=[O:18])[N:16]2[C@H:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:21][CH2:22][N:15]2[C:14](=[O:30])[CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([NH:10][C@@H:11]1[C:17](=[O:18])[N:16]2[C@H:19]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:20][CH2:21][CH2:22][N:15]2[C:14](=[O:30])[CH2:13][CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](N)C(=O)N12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](NC(=O)c3ccccc3)C(=O)N12
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
A solution of benzoyl chloride (1.61 g, 11.47 mmol) in CH2Cl2 (15 ml) was added dropwise to a stirred ice cold mixture of (1S, 9S) t-butyl 9-amino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate (GB 2,128,984; 3.1 g, 10.43 mmol), dry CH2Cl2 (20 ml) and diisopropylethylamine (4.54 ml, 26.06 mmol). The mixture was kept cold for 1 h then left at room temperature for 0.5 h. The mixture was diluted with CH2Cl2, washed twice with brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (0-5% methanol in CH2Cl2) to afford 211e (4.0 g, 96%) of a colourless glass: mp 74°-76 ° C.; [α]D+ -75.0° (c 0.12, CH2Cl2). IR (KBr) 3350, 2979, 2938, 1736, 1677, 1662, 1536, 1422, 1276, 1250, 1155; 1H NMR (CDCl3) δ8.72 (2H, m), 7.53-7.40 (3H, m), 7.07 (1H, d, J=7.2), 5.30 (1H, dd, J=3.0, 5.8), 5.12 (1H, m), 4.66 (1H, m), 3.51 (1H, m), 2.90 (2H, m), 2.38 (1H, dd, J 13.2, 6.8), 2.25 (1H, m), 1.9 (2H, m), 1.70 (1H, m). Anal. Calcd for C21H27N3O5 0.5H2O: C, 61.45; H, 6.88; N, 10.24. Found C, 61.69; H, 6.71; N, 10.18.
Reaction SMILES: [CH3:1][C@H:2]1[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1>>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:4]2[C:3](=[O:8])[C@@H:2]([CH3:1])[NH:6][C:5]2=[O:7])=[CH:13][CH:12]=1
Reactant: COc1ccc(CCl)cc1
Reactant: C[C@H]1NC(=O)NC1=O
Product: COc1ccc(CN2C(=O)N[C@H](C)C2=O)cc1

Procedure:
Using (R)-5-methylimidazolidine-2,4-dione (2.00 g) and 4-methoxybenzyl chloride (2.85 mL) and by the reaction and treatment in the same manner as in Preparation Example 51, the title compound (2.95 g) was obtained.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[S:3]([NH:6][C:7]1[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][O:12][C:11]1=[O:16])(=[O:5])=[O:4].C(=O)([O-])O.[Na+].Cl[C:29]([O:31][CH2:32][CH2:33][CH3:34])=[O:30].O>C(#N)C>[CH2:32]([O:31][C:29]([N:6]([C:7]1[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][O:12][C:11]1=[O:16])[S:3]([C:2]([F:1])([F:21])[F:22])(=[O:5])=[O:4])=[O:30])[CH2:33][CH3:34]
Reactant: O=C1OCCCN1Cc1ccccc1NS(=O)(=O)C(F)(F)F
Reactant: CCCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCCOC(=O)N(c1ccccc1CN1CCCOC1=O)S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Yield: 68.2 %

Procedure:
3-[2-(Trifluoromethanesulfonylamino)benzyl]-[1,3]-oxazinan-2-one (0.13 g, 0.38 mmol) and sodium hydrogen carbonate (0.06 g, 0.71 mmol) was suspended in acetonitrile (15 ml), added with propyl chloroformate (0.09 g, 0.77 mmol) and heated to reflux for six hours. After cooling to room temperature, the reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with a saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:4) to obtain 3-{2-[N-(propoxycarbonyl)-N-(trifluoromethanesulfonyl)amino]benzyl)-[1,3]-oxazinan-2-one (0.11 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13](Cl)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:18][C:19]([C:21]1[CH:26]=[CH:25][N:24]=[C:23](Cl)[CH:22]=1)=[O:20].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:18][C:19]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([N:14]2[CH2:15][CH2:16][CH2:11][CH2:12][CH2:13]2)[CH:22]=1)=[O:20]
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccnc(Cl)c2)c1)c1ccnc(Cl)c1
Reactant: C1CCNCC1
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccnc(N3CCCCC3)c2)c1)c1ccnc(N2CCCCC2)c1
Yield: 96 %

Procedure:
Using an analogous procedure to that described in Example 21, N-[2-chloro-5-(2-chloropyrid-4-ylcarbonylamino)phenyl]-2-chloropyridine-4-carboxamide was reacted with piperidine to give the title compound in 96% yield; NMR Spectrum: (DMSOd6) 1.6 (m, 12H), 3.58 (m, 8H), 7.01 (m, 2H), 7.24 (d, 2H), 7.54 (d, 1H), 7.73 (d, 1H), (m, 2H), 10.09 (br s, 1H), 10.44 (br s, 1H); Mass Spectrum: M+H+ 519.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7](Br)[C:6]([F:11])=[C:5]([F:12])[C:3]=1[NH2:4].[CH3:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[F:1][C:2]1[C:8]([F:9])=[C:7]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([O:14][CH3:13])[CH:20]=2)[C:6]([F:11])=[C:5]([F:12])[C:3]=1[NH2:4]
Reactant: Nc1c(F)c(F)c(Br)c(F)c1F
Reactant: COc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: COc1cccc(-c2c(F)c(F)c(N)c(F)c2F)c1
Temperature: 90 °C

Procedure:
2,3,5,6-Tetrafluoro-4-bromoaniline (7.5 g, 30.7 mmol) is dissolved in DME (150 mL) and treated with 3-methoxyphenylboronic acid (4.7 g, 30.7 mmol), a catalytic amount of tetrakistriphenylphosphine palladium(0) (0.70 g, 0.6 mmol) and triphenylphosphine (0.66 g, 2.5 mmol). Potassium carbonate (8.5 μg in 50 mL of water) is added and the reaction mixture stirred and heated to 90° C. for 24 hours. After cooling to room temperature most of the DME is removed by rotary evaporator under high vacuum. The resulting material is partitioned between EtOAc (200 mL) and water (250 mL). The organic layer is washed with brine, dried (Na2SO4) and concentrated by rotary evaporator. The crude reaction product is purified by flash chromatography (9:1 hexanes/EtOAc, then 6:4 hexanes/EtOAC) to give 2,3,5,6-tetrafluoro-4-(3′-methoxyphenyl)aniline (m.p. 94–96° C.).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:16]([N:23]3[CH2:31][C:30]4[C:25](=[C:26]([N+:32]([O-])=O)[CH:27]=[CH:28][CH:29]=4)[C:24]3=[O:35])[CH2:17][C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[C:24](=[O:35])[N:23]([CH:16]([C:8]1[CH:9]=[CH:10][C:11]([O:12][CH:13]([F:14])[F:15])=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH:7]=1)[CH2:17][C:18]([N:20]([CH3:21])[CH3:22])=[O:19])[CH2:31]2
Reactant: [H][H]
Reactant: CN(C)C(=O)CC(c1ccc(OC(F)F)c(OCC2CC2)c1)N1Cc2cccc([N+](=O)[O-])c2C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C)C(=O)CC(c1ccc(OC(F)F)c(OCC2CC2)c1)N1Cc2cccc(N)c2C1=O
Yield: 97.4 %

Procedure:
To a solution of 3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-N,N-dimethyl-propionamide (330 mg, 0.67 mmol) in ethyl acetate (100 ml) was added 10% Pd on carbon (100 mg). The suspension was shaked under about 50 psi hydrogen atmosphere at room temperature overnight. The suspension was filtered through a pad of celite. The solvent was removed and the resulted oil was purified by HPLC (CH3CN:water=40:60) to give 3-(7-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-N,N-dimethyl-propionamide as a white solid (300 mg, 65%): mp 70-72° C.; 1H NMR (CDCl3): δ 0.31-0.37 (m, 2H), 0.58-0.65 (m, 2H), 1.21-1.28 (m, 1H), 2.90 (s, 3H), 3.05 (dd, J=6.3, 15.8 Hz, 1H), 3.09 (s, 3H), 3.52 (dd, J=8.5,15.3 Hz, 1H), 3.85 (d, J=7 Hz, 2H), 4.20 (d, J=16.8 Hz, 1H), 4.35 (d, J=16.8 Hz, 1H), 5.20 (broad, 2H), 5.56 (dd, J=6.3, 8.5 Hz, 1H), 6.52-6.63 (m, 2H), 6.59 (t, JH-F=75 Hz, 1H), 6.90-6.98 (m, 1H), 7.09-7.26 (m, 3H); 13C NMR (CDCl3): δ 10.8, 36.2, 37.0, 38.1, 49.8, 54.3, 114.0, 114.9, 116.3, 116.9, 120.1, 121.0, 123.3, 133.4, 139.4, 140.5, 143.4, 146.6, 151.3, 170.4, 170.9; Anal. Calcd. for C24H27F2N3O4+0.18H2O: C, 62.30; H, 5.96; N, 9.08; H2O, 0.7; Found: C, 62.30; H, 5.89; N, 9.02; H2O, 0.7.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([O-:6])=[C:3]1[OH:4].[Na+].[OH-].[Na+]>O.CO.CO>[O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4]
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O

Procedure:
Except that 200 ml of 0.1 w/v% solution of sodium ascorbate in water-methanol (water/methanol-1/100) was used in place of 200 ml of the solution of sodium hydroxide in methanol in Example 1, a similar treatment to that in Example 1 gave 190 g of ascorbic acid powder of 100 mesh pass. The powder contained about 30 ppm of sodium ascorbate.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl.Cl.[CH3:26][N:27]([CH3:34])[CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(Cl)(Cl)Cl>[CH3:26][N:27]([CH3:34])[CH:28]1[CH2:33][CH2:32][N:31]([S:20]([C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:7]3[C:6]4[C:11](=[CH:12][C:3]([Cl:2])=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH2:30][CH2:29]1
Reactant: CN(C)C1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(C)C1CCN(S(=O)(=O)c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11.3 Grams of 4-(7-chloro-4-quinolylamino)-benzenesulphonyl chloride hydrochloride [prepared as in Example 1(b)] were added in portions to a stirred mixture of 5.83 grams of 4-dimethylamino-piperidine dihydrochloride and 32 grams of sodium carbonate in 100 milliliters of water and 75 milliliters of chloroform. After stirring overnight at room temperature the mixture was filtered, the resultant solid washed with water, dried and recrystallised from ethanol/water to give 6.28 grams of the title compound. Melting point 230°--231°C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19]>ClCCl.C(N(CC)CC)C>[CH3:1][S:2]([O:6][CH2:7][CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1c2ccccc2C(=O)N1CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.7 %

Procedure:
After methanesulfonyl chloride (12.7 g) was added to a solution of N-(2-hydroxyethyl)phthalimide (19.1 g) in anhydrous dichloromethane (200 ml), triethylamine (20 ml) was added dropwise to the mixture in an ice bath. The mixture was stirred at ambient temperature for 4 hours. At the end of this time the reaction mixture was concentrated under reduced pressure. The residual solid was washed with ethyl acetate and water and then recrystallized from ethyl acetate to afford the desired compound (18.2 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3]1.I[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2)[CH3:18]
Reactant: Cn1ccc2cccc(O)c21
Reactant: CCOC(=O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2ccn(C)c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 85 %

Procedure:
To a solution of 1-methyl-1-H-indol-7-ol (Chemstep, CAS: 47577-334, 2.5 g, 17 mmol) and ethyl iodoacetate (Fluka, CAS: 623-48-3, 4.58 g, 21 mmol) in DMF abs. (25 mL) was added potassium carbonate (4.23 g, 31 mmol). The reaction mixture was stirred at rt for 20 h, quenched with ice/water, and extracted with ethyl acetate. The organics were washed, dried and concentrated, the residue was chromatographed on silica gel using heptanelethyl acetate as eluent to obtain the desired compound (3.37 g) as a creamy solid. MS (ISP): m/e 234.1 (M+H)+
Reaction SMILES: CN(C=O)C.Br[C:7]1[C:27]([O:28][CH3:29])=[CH:26][C:10]2[N:11]([CH3:25])[C:12](=[O:24])[CH2:13][N:14]=[C:15]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])[C:9]=2[CH:8]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.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>[CH3:29][O:28][C:27]1[C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:8][C:9]2[C:15]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])=[N:14][CH2:13][C:12](=[O:24])[N:11]([CH3:25])[C:10]=2[CH:26]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cc2c(cc1Br)C(c1cccc(C#N)c1)=NCC(=O)N2C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1-c1ccccc1)C(c1cccc(C#N)c1)=NCC(=O)N2C
Temperature: 120 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
To 5 mL of degazed DMF were added 3-(7-bromo-8-methoxy-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 9 (200 mg, 0.52 mmol), benzene boronic acid (160 mg, 1.32 mmoles), tripotassium phosphate (300 mg, 1.42 mmol), Pd(PPh3)4 (30 mg, 0.03 mmoles). The mixture was stirred for 16 hours at 120° C. under nitrogen atmosphere. The working solution was diluted ten times with water and extracted three times with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated until dryness. The residue was chromatographied: eluant: CH2Cl2/Et2O: 1/1. The obtained compound was crystallised from ether/pentane to afford the title compound (118 mg): white solid, (yield=60%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]([C@@H:9]3[O:26][CH2:25][C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]3[O:11][C:12](=[O:14])[CH3:13])[CH:7]=[N:8][C:4]=2[CH:3]=1.[Br:29]N1C(=O)CCC1=O>O1CCCC1>[Br:29][C:7]1[N:6]([C@@H:9]2[O:26][CH2:25][C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[C:5]2[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1cnc2cc(Cl)ccc21
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1c(Br)nc2cc(Cl)ccc21
Yield: 75.6 %

Procedure:
The title compound was prepared according to General Procedure IV using 5-chloro-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole (0.17 g, 0.41 mmol), 30 ml tetrahydrofuran (Aldrich Sure Seal, Milwaukee), and a total of 2.6 g (7.0 mmol) of N-bromosuccinimide that was added over 2 h. The product from work-up by General Procedure IV was purified on a silica gel column (2.5×20 cm, 230-400 mesh) with dichloromethane containing 1.0% methanol to give 2-Bromo-5-chloro-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole (0.15 g, 0.31 mmol, 76%); MS (ES+): m/z (rel. intensity) 511 (0.25, M+23 (Na)) 1H NMR (DMSO-d6) δ8.02-8.00 (d,1H, J=8.7), 7.68 (d, 1H, J=2.1 Hz), 7.30-7.27 (dd, 1H, J=1.9 Hz, J=8.9 Hz), 5.96-5.93 (d, 1H, J=8.9 Hz), 5.67-5.62 (m, 2H), 5.55-5.45 (m,1H), 4.20-3.90 (m, 2H), 2.20 (s, 3H), 1.99 (s, 3H), 1.73 (s, 3H).