Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:19]([O:21][C:22](=[O:32])[CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:20].C(OCC)(=O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:19]([O:21][C:22](=[O:32])[CH2:23][N:24]([C:16](=[O:18])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:20]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)CNCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C

Procedure:
CBZ-L-Valine (12.6g, 0.05mol) was dissolved in CH2Cl2 (250mL) and the following reagents were added in equal molar amounts in the stated order; 4-Dimethylaminopyridine (DMAP), ethyl-N-(benzyl)glycinate and WSCDI. The reaction mixture was allowed to stir at room temperature over night. Evaporation of the solvent yielded a viscous semisolid which was treated with ethyl acetate and then IN HCl and separated. The organic extract was washed with 1N HCl followed by 5% aqueous Na2CO3 and saturated aqueous NaCl-solution. After drying over MgSO4, filtration and evaporation under reduced pressure afforded an oil (17.6 g) which ws used as is for saponification.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:44])[CH2:7][C:8]1[CH:13]=[C:12]([C:14]2[N:18]([CH:19]([CH3:21])[CH3:20])[C:17]3[CH:22]([C:34]4[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=4)[N:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=4[F:33])[C:24](=[O:25])[C:16]=3[CH:15]=2)[C:11]([O:42][CH3:43])=[CH:10][N:9]=1)C.Cl>CO.C1COCC1.O>[Cl:32][C:28]1[C:27]([F:33])=[C:26]([N:23]2[C:24](=[O:25])[C:16]3[CH:15]=[C:14]([C:12]4[C:11]([O:42][CH3:43])=[CH:10][N:9]=[C:8]([CH2:7][C:6]([OH:44])=[O:5])[CH:13]=4)[N:18]([CH:19]([CH3:21])[CH3:20])[C:17]=3[CH:22]2[C:34]2[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)Cc1cc(-c2cc3c(n2C(C)C)C(c2ccc(C#N)cc2)N(c2cccc(Cl)c2F)C3=O)c(OC)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cnc(CC(=O)O)cc1-c1cc2c(n1C(C)C)C(c1ccc(C#N)cc1)N(c1cccc(Cl)c1F)C2=O
Reaction time: 0.5 h

Procedure:
2N Aqueous NaOH (0.906 mmol) was added to a solution of {4-[5-(3-chloro-2-fluoro-phenyl)-6-(4-cyano-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-2-yl]-5-methoxy-pyridin-2-yl}-acetic acid ethyl ester (Step 84.1) (0.227 mmol) in MeOH (0.4 mL) and THF (0.4 mL) at 0° C. After stirring for 30 min, the reaction mixture was diluted with H2O, acidified to pH 3-4 with 1N aqueous HCl and then extracted with EtOAc (2×). The combined organic layers were dried (MgSO4), filtered and concentrated. The title compound was obtained as a white solid. tR: 4.51 min (HPLC 4); ESI-MS: tR=0.99 min, [M+H]+ 559/561 (LC-MS 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][C:8]2[O:9][CH:10]=[C:11]([C:13]([OH:15])=O)[N:12]=2)=[CH:5][CH:4]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:28]2([CH2:33][NH:34]C(C3N=C(CC4C=CC(OC)=CC=4)SC=3)=O)[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:28]2([CH2:33][NH:34][C:13]([C:11]3[N:12]=[C:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=4)[O:9][CH:10]=3)=[O:15])[CH2:29][CH2:30][CH2:31][CH2:32]2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(Cc2nc(C(=O)NCC3(c4ccc(OC)c(OC)c4)CCCC3)cs2)cc1
Reactant: COc1ccc(Cc2nc(C(=O)O)co2)cc1
Product: COc1ccc(Cc2nc(C(=O)NCC3(c4ccc(OC)c(OC)c4)CCCC3)co2)cc1
Yield: 66 %

Procedure:
Starting from 2-(4-Methoxy-benzyl)-oxazole-4-carboxylic acid (25 g, 0.1 mmol) and [2-(3,4-Dimethoxy-phenyl)-2-methyl]-propylamine (47 mg, 0.2 mmol) following a similar procedure reported for the preparation of 2-(4-Methoxy-benzyl)-thiazole-4-carboxylic acid[1-(3,4-dimethoxy-phenyl)-cyclopentylmethyl]-amide, the amide (30 mg, 66%) was obtained as a white solid. ESI-MS m/z calc. 450.5, found 451.2 (M+1)+. Retention time of 3.51 minutes 1H NMR (400 MHz, CDCl3) δ 1.68-2.19 (m, 8H), 3.50 (d, J=6.3 Hz, 2H), 3.81 (s, 3H), 3.88 (s, 3H), 3.92 (s, 3H), 4.00 (s, 2H), 6.73-6.88 (m, 6H), 7.20 (d, J=8.7 Hz, 2H), 8.07 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[CH:12][NH:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:18]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: NC1=CC(=O)CCC1
Product: CCOC(=O)C(=CNC1=CC(=O)CCC1)C(=O)OCC
Temperature: 130 °C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
A mixture of 3-amino-cyclohex-2-enone (3.3 g, 29.7 mmol) and diethyl 2-(ethoxymethylene)malonate (6.7 g, 31.2 mmol) was stirred at 130° C. for 4 h. The reaction mixture was concentrated under reduced pressure and the resulting oil was purified by column chromatography (silica gel, ethyl acetate) to give 2-[(3-oxo-cyclohex-1-enylamino)-methylene]-malonic acid diethyl ester (7.5 g, 90%).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:29])[N:5]([C:9]([NH:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:27][CH3:28])=[C:20]([S:23](=[O:26])(=[O:25])[NH2:24])[CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2].[CH2:30]([N:33]=[C:34]=[S:35])[CH2:31][CH3:32]>>[CH2:1]([C:3]1[C:4](=[O:29])[N:5]([C:9]([NH:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:27][CH3:28])=[C:20]([S:23]([NH:24][C:34]([NH:33][CH2:30][CH2:31][CH3:32])=[S:35])(=[O:25])=[O:26])[CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2]
Reactant: CCC1=C(C)CN(C(=O)NCC2CCOc3cc(OC)c(S(N)(=O)=O)cc32)C1=O
Reactant: CCCN=C=S
Product: CCCNC(=S)NS(=O)(=O)c1cc2c(cc1OC)OCCC2CNC(=O)N1CC(C)=C(CC)C1=O

Procedure:
4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-(n-propylaminothiocarbonylaminosulfonyl)-7-methoxychroman ##STR49## 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-(n-propylaminothiocarbonylaminosulfonyl)-7-methoxychroman is prepared as described in Example 14 from 4-((3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-sulfamoyl-7-methoxychroman and n-propyl isothiocyanate. Melting point: 96°-98° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[S:9][C:10]([CH3:24])=[CH:11][C:12]=1[C:13](=O)[C:14]([C:16]1[CH:20]=[C:19]([CH3:21])[S:18][C:17]=1[CH3:22])=O.[CH:25]1[CH:30]=CC=[CH:27][CH:26]=1>>[CH3:7][C:8]1[S:9][C:10]([CH3:24])=[CH:11][C:12]=1[C:13]1[CH:30]=[CH:25][CH2:26][CH2:27][C:14]=1[C:16]1[CH:20]=[C:19]([CH3:21])[S:18][C:17]=1[CH3:22]
Reactant: Cc1cc(C(=O)C(=O)c2cc(C)sc2C)c(C)s1
Reactant: c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1cc(C2=C(c3cc(C)sc3C)CCC=C2)c(C)s1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 25 %

Procedure:
Potassium t-butoxide (163 mg, 1.45 mmol) was added to a suspension of 1,4-butanebis(triphenylphosphonium)dibromide (537 mg, 0.725 mmol) in benzene (50 mL). The reaction was stirred for 45 min at room temperature. The resulting orange solution was heated to reflux and treated drop-wise with a solution of 1,2-bis(2,5-dimethyl-3-thienyl)ethanedione 23 (202 mg, 0.72 mmol) in benzene (25 mL). The reaction mixture was stirred at reflux for 20 min, at which point the heating mantle was removed and the reaction was allowed to cool to room temperature. The reaction was quenched by the addition of water (50 mL) and extracted with Et2O (3×50 mL). The organic extracts were combined, washed with brine, dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography through silica (1:9 EtOAc:hexanes) to yield 55 mg (25%) of 25 as a white solid. Mp=55-57° C. 1H NMR (CDCl3): δ=6.13 (s, 2H), 5.88 (m, 2H), 2.26 (m, 10H), 2.14 (s, 6H); 13C NMR (CDCl3) δ=137.8, 134.4, 133.9, 131.6, 127.4, 126.7, 22.7, 15.1, 14.0. MS (EI): m/z=300 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:7]=1.CC(C)([O-])C.[K+].O>C(O)(C)(C)C>[C:18]1([CH3:21])[CH:19]=[CH:20][C:15]([C:5]2[N:4]=[C:3]3[CH:22]=[C:23]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[NH:1][C:2]3=[N:7][C:6]=2[C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:16][CH:17]=1
Reactant: Cc1ccc(-c2nc(N)c(C#CCCCCC(=O)O)nc2-c2ccc(C)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1ccc(-c2nc3cc(CCCCC(=O)O)[nH]c3nc2-c2ccc(C)cc2)cc1

Procedure:
7-(3-Amino-5,6-di-p-tolylpyrazin-2-yl)hept-6-ynoic acid (step 1) (137 mg, 0.343 mmol) in tert-BuOH (3 ml) was treated with potassium tert-butoxide (154 mg, 1.372 mmol) and stirred at reflux for 3 hours. The mixture was added to water (50 ml) and extracted with DCM (×3). The organic solvent was removed under reduced pressure and the crude material was dissolved in EtOH (minimal) and excess of water was added. The resulting suspension was sonicated and filtered, rinsing the filter cake with water (×3). Purification of crude product by chromatograpy on silica eluting with 0-1% MeOH in DCM afforded the titled compound; LC-MS Rt 1.10 mins MS m/z 400.2 [M+H]+; Method 2 minLC_v003
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.O>C(Cl)Cl>[C:1]12([CH:11]=[O:12])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: O=CC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
To a solution of 1-adamantanemethanol (1.66 g, 10 mmol) in CH2Cl2 was added PCC (4.3 g, 20 mmol) at 0° C. The resulting mixture was stirred at the same temperature for 10 mins before warming to ambient temperature. Stirring was continued for 1.5 hrs until the disappearance of starting material as checked by TLC. Water was added and extracted with CH2Cl2 for 3 times. The combined organic phase was dried over MgSO4, filtrated and concentrated in vacuo. The crude mixture was separated by flash chromatography (50%-100% CH2Cl2/Hexane) to give 49 as white solid (1.36 g, Yield: 83%). 1H-NMR (360 MHz, CDCl3) δ 9.32 (s, 1H), 2.07 (br s, 3H), 1.77 (br s, 6H), 1.72 (br s, 6H); 13C-NMR (90 MHz, CDCl3) δ 206.07, 45.03, 37.25, 36.10, 27.61; ESI-MS: Calculated for C11H16O (M+H)+ 165.2. Found: 165.5.
Reaction SMILES: [CH:1]1([O:6][N:7]=[C:8]([C:42]2[N:43]=[C:44]([NH:47]C=O)[S:45][CH:46]=2)[C:9]([NH:11][CH:12]2[C:40](=[O:41])[N:14]3[C:15]([C:37]([OH:39])=[O:38])=[C:16]([CH2:19][S:20][C:21]4[N:25]([CH2:26][CH2:27][CH2:28][NH:29]C(OC(C)(C)C)=O)[N:24]=[N:23][N:22]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1.Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CO.O>[CH:1]1([O:6][N:7]=[C:8]([C:42]2[N:43]=[C:44]([NH2:47])[S:45][CH:46]=2)[C:9]([NH:11][CH:12]2[C:40](=[O:41])[N:14]3[C:15]([C:37]([OH:39])=[O:38])=[C:16]([CH2:19][S:20][C:21]4[N:25]([CH2:26][CH2:27][CH2:28][NH2:29])[N:24]=[N:23][N:22]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)NCCCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC3C=CCC3)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: NCCCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC3C=CCC3)c3csc(N)n3)[C@H]2SC1
Yield: 21.5 %

Procedure:
To a solution of 7-[2-(2-cyclopenten-1-yl)oxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[1-[3-(N-tertbutoxycarbonylamino)propyl]-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(1.75 g) in methanol (13 ml) was added conc. hydrochloric acid (1.0 g) with stirring and the mixture was stirred for 3 hours at room temperature. After the evaporation of the resulting mixture, to the residue was added methanol (20 ml) to give a homogeneous solution and then the solution was evaporated. Solution and evaporation were repeated three times and to the resulting reaction mixture were added ethyl acetate and water. After the mixture was adjusted to pH 7.5 with sodium bicarbonate, the aqueous layer was separated, washed with ethyl acetate and the remaining ethyl acetate was distilled off. The resulting aqueous layer was adjusted to pH 3.8 with 1N hydrochloric acid and then filtered. The precipitates thus collected were washed with water and dried over phosphorus pentoxide under reduced pressure to give 7-[2-(2-cyclopenten-1 -yl)oxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(0.31 g).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([CH3:11])=[CH:6][C:5]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14]>C(=O)(OC)OC>[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([CH3:11])=[CH:6][C:5]=1[CH:12]([C:13]([O:15][CH3:16])=[O:14])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)Cc1cc(C)c(C)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: COC(=O)OC
Product: COC(=O)C(C(=O)OC)c1cc(C)c(C)cc1C
Temperature: 80 °C
Yield: 164.9 %

Procedure:
18.6 g (0.62 mol, 80% pure) of sodium hydride were initially introduced into 384 ml of dimethyl carbonate and the mixture was heated to about 80° C. 48 g (0.25 mol) of methyl 2,4,5-trimethylphenylacetate, dissolved in 100 ml of dimethyl carbonate, were then added dropwise and the mixture was heated under reflux for 4 hours. It was cooled to room temperature, the excess sodium hydride was destroyed with ethanol and the mixture was then poured into 1500 ml of ice-water. A pH of 4 to 5 was established with 6 N hydrochloric acid and the organic phase was taken up in toluene. The organic phase was separated off, dried and concentrated and the residue was employed in the next stage without further purification. 51.6 g of dimethyl 2-(2,4,5-trimethylphenyl)-malonate were obtained as an oil.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4]([C:6]1([NH:9]C(=O)OC(C)(C)C)[CH2:8][CH2:7]1)=[O:5].[H-].[Na+].FC(F)(F)S(O[CH2:25][C:26]([F:29])([F:28])[F:27])(=O)=O.[ClH:32]>C(Cl)Cl.CCOCC.O.CN(C=O)C>[ClH:32].[NH2:9][C:6]1([C:4]([N:3]([O:2][CH3:1])[CH2:25][C:26]([F:29])([F:28])[F:27])=[O:5])[CH2:7][CH2:8]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CONC(=O)C1(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CON(CC(F)(F)F)C(=O)C1(N)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A dry 50 mL 3 neck round bottom flask was charged with tert-butyl (1-(methoxycarbamoyl)cyclopropyl)carbamate (0.82 g, 3.56 mmol) and 20 mL of dry DMF. The reaction mixture was cooled in an ice-water bath and 60% NaH (0.16 g, 3.92 mmol) was added in one portion. The reaction mixture was stirred at RT for 1.5 h after which time, 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.87 g, 3.74 mmol) was added neat drop wise and the resulting reaction mixture was stirred at RT for 18 h. The reaction mixture was added to H2O and extracted 3× with ether. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give 0.92 g of crude product as a white solid. This material was taken up in 5 mL of DCM and cooled in an ice water bath. 2M HCl in ether (4 mL) was added and the reaction mixture was allowed to warm toward RT and stirred for 18 h. The reaction mixture was evaporated to give a solid. This material was washed several times with 10% ether/hex to afford 0.70 g of the title compound. This material was carried forward without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][C:28]=3[CH3:32])[NH:23][C:22]2=[O:33])[CH2:17][CH2:16]1.[CH2:34](I)[CH2:35][CH3:36]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:16][CH2:17][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][C:28]=3[CH3:32])[N:23]([CH2:34][CH2:35][CH3:36])[C:22]2=[O:33])[CH2:19][CH2:20]1
Reactant: CCCI
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5cccc(C)c5c4=O)CC3)c2cc1OC
Product: CCCn1c(=O)n(C2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)c(=O)c2c(C)cccc21
Yield: 73 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.67 mmol) of Compound 100 was used in place of Compound 24 and propyl iodide was used in place of methyl iodide. As a result, 238.8 mg (yield: 73%) of Compound 58 was obtained as white crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([CH3:16])=[CH2:15])[C:6]1=[O:17].[C:18]1([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[CH3:16][C:14]([N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:5]([CH2:4][CH2:3][CH2:2][N:28]2[CH2:29][CH2:30][N:25]([CH2:24][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:26][CH2:27]2)[C:6]1=[O:17])=[CH2:15]
Reactant: C=C(C)n1c(=O)n(CCCCl)c2ccccc21
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: C=C(C)n1c(=O)n(CCCN2CCN(Cc3ccccc3)CC2)c2ccccc21

Procedure:
A mixture of 60.5 parts of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one, 31.68 parts of 1-(phenylmethyl)piperazine, 21.2 parts of sodium carbonate, 0.1 parts of potassium iodide and 400 parts of 4-methyl-2-pentanone is stirred and refluxed for 20 hours with water-separator. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated, yielding 1,3-dihydro-1-(1-methylethenyl)-3-{3-[4-(phenylmethyl)-1-piperazinyl]propyl}-2H-benzimidazol-2-one as a residue.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32].[N:33]1([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.[I-].[Na+]>COCCOC>[N:33]1([CH:39]2[CH2:44][CH2:43][N:42]([CH2:2][CH2:3][O:4][C:5]3[CH:14]=[C:13]4[C:8]([C:9]([NH:17][C:18]5[CH:23]=[CH:22][C:21]([O:24][C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)=[CH:20][CH:19]=5)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]4)=[CH:7][C:6]=3[O:31][CH3:32])[CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COc1cc2c(Nc3ccc(Oc4ccccc4)cc3)c(C#N)cnc2cc1OCCCl
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(Nc3ccc(Oc4ccccc4)cc3)c(C#N)cnc2cc1OCCN1CCC(N2CCCCC2)CC1
Temperature: 137.5 °C
Yield: 47.7 %

Procedure:
A mixture of 222.5 mg (0.5 mmol) of 7-(2-chloroethoxy)-6-methoxy-4-(4-phenoxyphenylamino)quinoline-3-carbonitrile, 841.4 mg (5.0 mmol) of 4-piperidinopiperidine and 49.5 mg (0.33 mmol) of sodium iodide in 6.0 mL of ethylene glycol dimethyl ether are heated in a sealed tube at 135-140° C. for 17 hours to yield the crude product. Solvents are removed in vacuo. Purification of the oily residue is carried out by preparative thin layer chromatography (eluting with 85:15 dichloromethane/methanol) to provide 137.7 mg of 7-(2-[1,4′]bipiperidinyl-1′-yl-ethoxy)-6-methoxy-4-(4-phenoxy-phenylamino)-quinoline-3-carbonitrile as a light yellow solid, mp 141° C. (decompose).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[NH:10][C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[NH2:4].[CH3:22][CH2:23]N(C(C)C)C(C)C.C(Cl)(=O)C>C(#N)C.C(=O)(O)[O-].[Na+]>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:11]([NH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:3]2[N:4]=[C:22]([CH3:23])[O:1][N:2]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: COc1ccc(CC(=O)Nc2sccc2C(N)=NO)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CC#N
Product: COc1ccc(CC(=O)Nc2sccc2-c2noc(C)n2)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of N-(3-(N′-hydroxycarbamimidoyl)thiophen-2-yl)-2-(4-methoxyphenyl)-acetamide (104 mg, 0.341 mmol) in acetonitrile (2 mL) was added DIPEA (127 mg, 0.987 mmol) and acetyl chloride (48 μL, 0.681 mmol). The resulting solution was stirred at 60° C. for 18 h and was subsequently diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phases were combined, dried (Na2SO4), filtered, concentrated under vacuum and purified by preparative HPLC to give 2-(4-methoxyphenyl)-N-(3-(5-methyl-1,2,4-oxadiazol-3-yl)thiophen-2-yl)acetamide. Retention time (min)=6.733, method [7], MS(ESI) 330.1 (M+H); 1H NMR (300 MHz, CDCl3) δ 10.63 (s, 1H), 7.30-7.35 (m, 3H), 7.00 (d, J=9.2 Hz, 2H), 6.89 (d, J=6.2 Hz, 1H), 3.86 (s, 3H), 3.80 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:31]I>C1COCC1.CN(C=O)C>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[N:23]2[CH3:31])[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN1C(=O)OC[C@@]1(C)c1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.5 %

Procedure:
To a solution of (R)-4-[6-(4-tert-butyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (73 mg, 0.19 mmol) in THF (1 mL) and DMF (1 mL) was added sodium hydride (60% in mineral oil, 12 mg, 0.29 mmol). After the mixture was stirred at room temperature for 2 hrs, methyl iodide (60 μL, 0.96 mmol) was added. The mixture was stirred at room temperature for 3 hrs. LCMS showed about 30% of conversion. Additional sodium hydride (60% in mineral oil, 50 mg) was added. After the mixture was stirred at room temperature overnight, the mixture was partitioned between NH4Cl aq and EtOAc. The organic phase was washed with water, dried over anhydrous MgSO4, filtered, and concentrated to give 80 mg of crude product, 106%. ESI-MS (M+H)+: 396.20, room temperature 2.53 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:26][C:27](=[O:29])[CH3:28])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Cl:37])C(=O)C1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:26][C:27](=[O:29])[CH3:28])=[C:8]2[C:16]([Cl:37])=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(OC)cc2)c1OC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2Cc2ccc(OC)cc2)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 124(b) from 4-acetoxy-7-cyano-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and NCS in MeCN. The title compound, ESI MS (m/z): 428 (M+H)+.