Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH2:38])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C:32]([CH3:35])([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.CN1CCOCC1.[CH3:46][O:47][C:48]([NH:50][C@H:51]([C:56](O)=[O:57])[C@H:52]([CH2:54][CH3:55])[CH3:53])=[O:49].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C>CN(C=O)C>[S:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][N:13]([NH:38][C:56](=[O:57])[C@H:51]([C@H:52]([CH2:54][CH3:55])[CH3:53])[NH:50][C:48]([O:47][CH3:46])=[O:49])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C:32]([CH3:34])([CH3:35])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1)C(C)(C)C
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Under an argon atmosphere, 292 mg of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane (Example 2d) and 165 μl (1.5 mmol) of NMM in 4.8 ml of DMF are added to 113 mg of N-methoxycarbonyl-(L)-iso-leucine and 149 mg (0.50 mmol) of TPTU in 2.5 ml of DMF, and the mixture is stirred at room temperature for 14 hours and worked up analogously to Example 3, yielding the title compound: m.p: 139-141° C.; TLC: Rf =0.7 (methylene chloride/methanol 10:1); HPLC20-100 : tRet =14.6; FAB MS (M+H)+ =711.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:8])([CH3:7])[CH:5]([CH2:9][CH:10]=[O:11])[CH2:4][CH:3]=1.[H][H]>[Pd]>[CH3:8][C:6]1([CH3:7])[CH:2]([CH3:1])[CH2:3][CH2:4][CH:5]1[CH2:9][CH:10]=[O:11]
Reactant: [H][H]
Reactant: CC1=CCC(CC=O)C1(C)C
Agent: [Pd]
Product: CC1CCC(CC=O)C1(C)C
Temperature: 80 °C
Reaction time: 5 h
Yield: 90.7 %

Procedure:
A three liter autoclave with a stirrer is charged with 830 g of campholenic aldehyde and 56 g of catalyst Pd(5%)/C. Hydrogen is introduced until the pressure reaches 30 bars. The mixture is heated up to 80° C. with stirring for five hours. The calculated amount of hydrogen is now absorbed. The catalyst is separated by filtration and washed with ethanol. The solvent is removed by vacuum evaporation and 815 g of crude saturated aldehyde are obtained (purity: 95%, GC). The vacuum distillation of the crude through a Widmer column gives 763 g of pure product (purity 95%); bp20 85° C.; nD20 : 1,4553;
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH:11](I)([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:11]([O:10][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][CH:7]=1)([CH3:13])[CH3:12]
Reactant: CC(C)I
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1cccc([N+](=O)[O-])c1
Yield: 85.9 %

Procedure:
3-Nitrophenol (50.0 g, 360 mmol), isopropyl iodide (76.19 g, 450 mmol), and potassium carbonate (60 g) were combined and refluxed under nitrogen overnight in 400 ml of acetone. The reaction mixture was cooled, and the solvent was removed in vacuo . The reaction was combined with about 300 ml of water and thereafter extracted with four 100 ml portions of ethyl acetate. The ethyl acetate extracts were combined and washed twice with 1N sodium hydroxide and brine, dried over anhydrous sodium sulfate, and evaporated to provide 56 g (86%) of 3-isopropoxynitrobenzene as a clear yellow oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)=O.[OH:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[OH:31][C:32]1[CH:33]=[C:34]([C:7]2[C:16]3[C:11](=[C:12]([C:17]([F:19])([F:18])[F:20])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:28])[CH:35]=[CH:36][CH:37]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1OS(=O)(=O)C(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Yield: 86 %

Procedure:
A solution of 3-benzoyl-8-(trifluoromethyl)quinolin-4-yl trifluoromethanesulfonate (1.6 g, 3.6 mmol), 3-hydroxyphenylboronic acid (0.60 g, 4.3 mmol), and K3PO4 (3.0 g) in dioxane (50 ml) was heated to reflux. After, 4 hr, the reaction was cooled, filtered, concentrated to give a solid which was triturated with 10% EtOAc/hexane to give a white solid (1.2 g Yield=86%); MS (ESI) m/z 394 ([M+H]+; 1H NMR (DMSO) δ 9.54 (s, 1H), 9.11 (s, 1H), 8.339 (d, 1h, J=7.0 Hz), 8.01(d, 1H, J=8.0 Hz), 7.83-7.79 (m, 1H), 7.64-7.61 (m, 2h), 7.55-7.51 (m, 1H), 7.39 (t, 2H, J=7.8 Hz), 7.13 (t, 1H, =7.8 Hz), 6.72-6.68 (m, 3H); Anal. Calcd for C23H14F3NO2: C, 70.23; H, 3.59; N, 3.56. Found: C, 69.67; H, 3.43; N, 3.51.
Reaction SMILES: [CH2:1](I)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:11]([NH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(C)=O>[CH2:11]([N:19]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)[CH2:1][CH2:2][CH3:3])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCI
Reactant: COc1cccc(CCNCCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCN(CCc1ccccc1)CCc1cccc(OC)c1
Reaction time: 5 h

Procedure:
1.1 ml of propyl iodide and 1.1 g of potassium carbonate were added to a solution of 1.1 g of the product of Step A in 15 ml of acetone and the mixture was refluxed with stirring for 5 hours. The acetone was distilled under reduced pressure and 50 ml of water were added thereto. The mixture was extracted 3 times with 20 ml of methylene chloride and the combined organic phases were washed with 70 ml of aqueous sodium chloride solution. The organic phases were dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure to obtain 1.25 g of N-phenethyl-N-propyl-3-methoxyphenethylamine in the form of an orange oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([OH:13])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:14])[N:5]=[C:4]2[S:15][C:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[C:3]=12.C(O[C:26]([CH3:29])([CH3:28])[CH3:27])(=O)C.Cl(O)(=O)(=O)=O>>[Cl:1][C:2]1[C:7]([CH:8]([O:13][C:26]([CH3:29])([CH3:28])[CH3:27])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:14])[N:5]=[C:4]2[S:15][C:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[C:3]=12
Reactant: COC(=O)C(O)c1c(C)nc2sc3c(c2c1Cl)CCCC3
Reactant: CC(=O)OC(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1Cl)CCCC3
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.8 %

Procedure:
To a solution of methyl 2-[4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-hydroxyacetate (0.100 g, 0.307 mmol) in tert-butyl acetate (1.5 mL; 11.23 mmol) under a nitrogen atmosphere was added perchloric acid 70% (0.029 mL; 0.338 mmol). The reaction was stirred at room temperature for 5 h and quenched by adding a saturated solution of sodium bicarbonate. The mixture was diluted with dichloromethane and the phases were separated. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethylacetate (5-40%) in heptane furnished 0.069 g (59%) of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[C:8](=O)(OCC)[O:9]CC>C(O)C>[OH:4][CH2:3][C:2]1([CH3:7])[CH2:5][O:6][C:8](=[O:9])[NH:1]1
Reactant: CC(N)(CO)CO
Reactant: CCOC(=O)OCC
Solvent: CCO
Product: CC1(CO)COC(=O)N1
Temperature: 25 °C

Procedure:
A Dean-Stark trap was fitted to a flask containing 2-amino-2-methyl-1,3-propanediol (21.62 g, 205.6 mmol) suspended in diethyl carbonate (40 ml, 330 mmol). The suspension was heated to 150° C. for 6 h, during which time approximately 12 ml of ethanol was distilled. The solution was cooled to RT overnight, and the resulting crystals were filtered and washed with cold ethanol. The crude material (˜90% purity) was used without further purification (24.82 g, 189.0 mmol, 92%). 1H NMR (CDCl3, 400 MHz) δ 1.36 (s, 3H), 2.2 (br s, 1H), 3.57 (m, 2H), 4.06 (d, 1H, J=8.8 Hz), 4.33 (d, 1H, J=8.8 Hz), 5.2 (br s, 1H). LRMS (ESI/APCI): 132 [M+H]+.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])[NH2:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+]>O.CO>[CH2:19]([NH:13][C@H:12]([C:14]([OH:16])=[O:15])[CH2:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@H](N)C(=O)O
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCC[C@H](NCc1ccccc1)C(=O)O
Reaction time: 1 h

Procedure:
A solution of Nδ-Boc-ornithine (7.0 g), 2M sodium hydroxide (20 ml), benzaldehyde (3.2 ml) and methanol (10 ml) was cooled to 0° C. and sodium borohydride (2.7 g) was added. After 1 hr at 0° C., the mixture was kept at 25° C. for 12 h. Water (100 ml) was added and the mixture extracted with ether (2×60 ml). The combined organic extract was washed with sat. sodium bicarbonate (ca. 150 ml) and water, and dried over anhydrous sodium sulfate. After concentration in vacuo, the desired product (4.5 g) was obtained as a white solid: 1H NMR (400 MHz, CD3OD) δ1.42 (s, 9H), 1.60 (m, 2H), 1.84 (m, 2H), 3.03 (m, 2H), 3.50 (t, J=7.4 Hz, 1H), 4.11 (d, J=11.9 Hz, 1H), 4.21 (d, J=11.9 Hz, 1H), 7.41 (m, 3H), and 7.49 (m, 2H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][NH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:13]=[N:14][N:15]([CH:17]4[CH2:20][O:19][CH2:18]4)[CH:16]=3)[CH:8]=2)[N:3]1[C:21](=[O:23])[CH3:22].[CH3:24][CH:25]([CH3:30])[CH2:26][C:27](Cl)=[O:28].N1C=CC=CC=1>ClCCl>[C:21]([N:3]1[C:4]2[C:9](=[CH:8][C:7]([C:12]3[CH:13]=[N:14][N:15]([CH:17]4[CH2:20][O:19][CH2:18]4)[CH:16]=3)=[CH:6][CH:5]=2)[N:10]([C:27](=[O:28])[CH2:26][CH:25]([CH3:30])[CH3:24])[CH2:11][C@@H:2]1[CH3:1])(=[O:23])[CH3:22]
Reactant: CC(C)CC(=O)Cl
Reactant: CC(=O)N1c2ccc(-c3cnn(C4COC4)c3)cc2NC[C@@H]1C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1c2ccc(-c3cnn(C4COC4)c3)cc2N(C(=O)CC(C)C)C[C@@H]1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
A 100-mL round-bottom flask was charged with (S)-1-(2-methyl-6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (50 mg, 0.16 mmol), 3-methylbutanoyl chloride (93 mg, 0.77 mmol), pyridine (63 mg, 0.80 mmol, 5.00 equiv) and dichloromethane (30 mL). The resulting solution stirred for 30 min at 0° C. in a water/ice bath and an additional 3 h at room temperature. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluting with 2-50% ethyl acetate-petroleum ether) to afford (S)-1-(4-acetyl-3-methyl-7-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-yl)-3-methylbutan-1-one (26.7 mg, 42%) of as light yellow oil. 1H NMR (300 MHz, CD3OD) δ ppm 079 (br s, 3 H), 0.93 (d, J=6.60 Hz, 3 H), 1.18 (d, J=6.30 Hz, 3 H), 1.90-2.10 (m, 1 H), 2.42 (s, 3 H), 2.35-2.43 (m, 1 H), 2.48-2.50 (m, 1 H), 2.51-2.89 (m, 1 H), 4.80-4.95 (m, 2 H), 5.08 (d, J=6.90 Hz, 4 H), 5.55-5.65 (m, 1 H), 7.38-7.45 (m, 1 H), 7.55-7.75 (m, 2 H), 8.03 (s, 1 H), 8.24 (s, 1 H). MS (ESI, pos. ion) m/z 425 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[N:8](C)[CH:9]=[O:10].[CH3:12][O:13][C:14]([C:16]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19](C(O)=O)[N:18]([CH2:27][CH2:28][O:29][CH2:30][CH3:31])[N:17]=1)=[O:15]>ClCCl>[C:9]([C:19]1[N:18]([CH2:27][CH2:28][O:29][CH2:30][CH3:31])[N:17]=[C:16]([C:14]([O:13][CH3:12])=[O:15])[C:20]=1[N+:21]([O-:23])=[O:22])(=[O:10])[NH2:8]
Reactant: CN(C)C=O
Reactant: CCOCCn1nc(C(=O)OC)c([N+](=O)[O-])c1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCOCCn1nc(C(=O)OC)c([N+](=O)[O-])c1C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (1.2 mL, 13.76 mmol) and N,N-dimethylformamide (39 μL) were added to a solution of the carboxylic acid of Step 2 (1.33 g, 4.63 mmol) in dichloromethane (20 mL) and the reaction mixture stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and azeotroped from dichloromethane (3×50 mL). The product was dissolved in tetrahydrofuran (50 mL), cooled in an ice bath, treated with 0.88 ammonia solution (10 mL) and stirred for 18 hours at room temperature. The mixture was concentrated in vacuo and the residue partitioned between dichloromethane (200 mL) and water (50 mL). The organics phase was dried over magnesium sulphate and concentrated in vacuo to yield the title product.
Reaction SMILES: O[CH:2]([CH3:27])[CH2:3][CH2:4][C:5](=[O:26])[CH2:6][PH:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:28][B-:29]([F:32])([F:31])[F:30].C([O+](CC)CC)C>C(Cl)Cl.C(=O)=O.CC(C)=O>[F:28][B-:29]([F:32])([F:31])[F:30].[C:8]1([P+:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[C:5]2[CH2:4][CH2:3][CH:2]([CH3:27])[O:26]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(O)CCC(=O)C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC1CCC(=C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.5 g of (5-hydroxy-2-oxohexyl)triphenylphosphorane was dissolved in 20 ml of methylene chloride under a nitrogen atmosphere, cooled in dry ice/acetone bath and 15 ml of triethyloxonium tetrafluoroborate as a 1 M solution in methylene chloride was added. The reaction mixture was stirred at about -78 C. for 0.5 hour and allowed to warm to room temperature over about 2 hours, decanted into ice water and stirred vigorously with the addition of an additional 30 ml of methylene chloride. The extraction was repeated twice, the extracts combined, and solvent removed to afford the desired product, m.p. 118.5°-122° C. and having the formula ##STR8##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[N:25]1([CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]2)[CH2:29][CH2:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:33]1[CH2:34][CH2:35][CH2:36][CH:31]([CH2:30][N:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:32]1)=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: C1CNCC(CN2CCCC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)N2CCCC(CN3CCCC3)C2)c(Cl)c1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, 3-(pyrrolidin-1-ylmethyl)piperidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.05 minutes; C26H29Cl2N5O2 (514.45); mass spectrum: (M+H)+=514.2.
Reaction SMILES: [OH:1][CH:2]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].CCN(C(C)C)C(C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH:2]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(O)c1cccs1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C(OS(C)(=O)=O)c1cccs1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 2-hydroxy-2-(thiophen-2-yl)acetate (I26) (4.58 g, 24.6 mmol) was dissolved in dry DCM (125 ml) and cooled at 0° C. DIPEA (5.15 ml, 29.5 mmol) and methanesulphonyl chloride (2.11 ml, 27.1 mmol) were added, and the resulting solution was stirred at room temperature for 1 hour. DIPEA (0.86 ml, 4.92 mmol) and methanesulphonyl chloride (0.19 ml, 2.46 mmol) were added again. After 1 additional hour, a third portion of DIPEA (0.43 ml, 2.46 mmol) and methanesulphonyl chloride (77 ul, 0.98 mmol) was added. After 1 hour, the reaction was completed. The mixture was diluted with DCM, washed with sat. NaHCO3, water and brine, dried (Na2SO4), filtered, and evaporated. The resulting oil was used for the next step without any further purification.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])SC)#[N:2].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[C:1]([N:3]=[C:4]([NH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])[NH:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)#[N:2]
Reactant: NCc1ccccc1
Reactant: COC(=O)c1cccc(NC(=NC#N)SC)c1
Solvent: CCO
Product: COC(=O)c1cccc(NC(=NC#N)NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
A stirred mixture of the compound from Example D (1.0 g) and benzylamine (440 mg) in ethanol (15 ml) was heated at reflux under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature. On standing overnight at room temperature a white solid was obtained and isolated by filtration (720 mg). The crude filtrate was further purified by chromatography on silica (eluant; ethyl acetate/hexane, 1:1) to afford the title compound (550 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=[N:7][C:6]=2[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].[CH:28]([NH2:32])([CH2:30][CH3:31])[CH3:29]>>[CH:28]([NH:32][C:2]1[C:10]2[NH:9][C:8]([C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=[N:7][C:6]=2[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25])([CH2:30][CH3:31])[CH3:29]
Reactant: CCC(C)N
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c2[nH]c(C(F)(F)C(F)(F)C(F)(F)F)nc12
Product: CCC(C)Nc1c(C(F)(F)F)cc([N+](=O)[O-])c2nc(C(F)(F)C(F)(F)C(F)(F)F)[nH]c12

Procedure:
4-Chloro-7-nitro-5-trifluoromethyl-2-heptafluoropropylbenzimidazole is reacted with sec-butylamine to obtain 4-sec-butylamino-7-nitro-5-trifluoromethyl-2-heptafluoropropylbenzimidazole, m.w., 470.3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:21][C:22](=[O:30])[CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][CH2:18][CH2:19][OH:20])[CH2:13]1)[CH:6]=[CH:5]2.[C:31]([O:35][C:36](=O)[O:37]C(C)(C)C)([CH3:34])([CH3:33])[CH3:32]>ClCCl.CO>[CH3:32][C:31]([O:35][C:36](=[O:37])[N:17]([CH:14]1[CH2:15][CH2:16][N:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[C:3]=3[NH:21][C:22](=[O:30])[CH2:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[N:8]=2)[CH2:13]1)[CH2:18][CH2:19][OH:20])([CH3:34])[CH3:33]
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CC[C@H](NCCO)C3)ccc12
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCO)C1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.5 %

Procedure:
To a stirred solution of N-[6-chloro-2-[(3S)-3-[(2-hydroxyethyl)amino]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide (Example 36) (1 g) in dichloromethane (5 mL) and methanol (2 mL) was added di-tert-butyl-carbonate (1 g). The mixture was stirred at room temperature for 18 hours and absorbed onto silica. Purification (SiO2, methanol:dichloromethane 5:95 as eluant) gave the title compound as a solid (400 mg).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH:5]=[CH:4][NH:3]1.[C:21]([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C=O)C>[CH3:21][N:3]1[CH:4]=[CH:5][C:6]([CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:7][C:2]1=[O:1]
Reactant: O=C1c2ccccc2C(=O)N1CCc1cc[nH]c(=O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1ccc(CCN2C(=O)c3ccccc3C2=O)cc1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 74.1 %

Procedure:
A mixture of 2-(2-(2-oxo-1,2-dihydropyridin-4-yl)ethyl)isoindoline-1,3-dione (300 mg, 1.1 mmol) CH3I (1.0 g, 7 mmol) and K2CO3 (700 mg, 5 mmol) in 30 mL of DCM and 10 mL of DMF was stirred at room temperature for 3 days. 30 mL of DCM was added. The mixture was washed with H2O (3×30 mL), dried over anhydrous sodium sulfate, concentrated under reduce pressure to give 2-(2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)isoindoline-1,3-dione (230 mg, 73%) as a white solid. LC-MS: 283 [M+H]+, tR=1.29 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH:63]([CH:66]1[CH2:70][CH2:69][CH2:68][NH:67]1)([CH3:65])[CH3:64]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:67]1[CH2:68][CH2:69][CH2:70][CH:66]1[CH:63]([CH3:65])[CH3:64])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(C)C1CCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCCC3C(C)C)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-isopropyl-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.OP(O)(O)=O.[C:20]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)(=O)[CH2:21][CH3:22].[NH:30]([C:32]1C=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=1)N>O>[N:27]1[CH:28]=[CH:29][C:24]([C:20]2[NH:30][C:32]3[C:22]([CH:21]=2)=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=3)=[CH:25][CH:26]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CCC(=O)c1ccncc1
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: O=C(O)c1ccc2[nH]c(-c3ccncc3)cc2c1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
20 g of P2O5 were admixed with 12.5 ml of H3PO4 (85%), resulting in a strong increase of the temperature of the reaction mixture. The reaction mixture was then cooled to 60° C., and 8.90 g (65.84 mmol) of 4-propionylpyridine and 4.20 g (27.60 mmol) of 4-hydrazinobenzoic acid were added. The mixture was then stirred at 145° C. for 45 min. The reaction mixture was poured into water, resulting in the precipitation of the yellow product 2-pyridin-4-yl-1H-indole-5-carboxylic acid. This precipitate was filtered off with suction and washed with water until neutral. The 2-pyridin-4-yl-1H-indole-5-carboxylicacid, which was obtained by this method in quantitative yield, was used without further purification for coupling with amino acid derivatives.