Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]([C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1)[S:6]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17])(=[O:8])=[O:7].[CH2:30]([OH:33])[CH:31]=[CH2:32].C(=O)(O)[O-].[Na+].O>CN(C)C=O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CC([O-])=O.CC([O-])=O.[Pd+2].C(OCC)(=O)C>[Cl:1][C:2]1[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]([C:18]1[CH:23]=[CH:22][C:21]([CH2:32][CH2:31][CH:30]=[O:33])=[CH:20][CH:19]=1)[S:6]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17])(=[O:8])=[O:7]
Reactant: Cc1cc(C)c(S(=O)(=O)N(Cc2ccc(O)cc2Cl)c2ccc(I)cc2)c(C)c1
Reactant: C=CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2ccc(O)cc2Cl)c2ccc(CCC=O)cc2)c(C)c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 91.8 %

Procedure:
To a solution of N-(2-chloro-4-hydroxy-benzyl)-N-(4-iodo-phenyl)-2,4,6-trimethyl-benzenesulfonamide (0.652 g, 1.20 mmol) in 6 mL dimethylformamide was added allyl alcohol (0.204 mL, 3.01 mmol), Pd(OAc)2, sodium bicarbonate (0.253 g, 3.01 mmol), and tetrabutylammonium chloride (0.333 g, 1.20 mmol). The reaction mixture was stirred at 50° C. for 6 hr. and at room temperature overnight. Additional allyl alcohol (0.100 mL, 1.47 mmol), was added and the reaction mixture was stirred at 50° C. for an additional 4 hr. The reaction mixture was allowed to cool, water and ethyl acetate were added, and the mixture was filtered through diatomaceous earth. The filtrate was washed several times with water and the combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried (magnesium sulfate) and concentrated. Medium pressure silica gel chromatography of the residue (2:1 hexanes:ethyl acetate) afforded 0.52 g (92%) of the title compound.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[O:24]([CH2:23][CH2:22][CH2:21][N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCCCOc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of n-Boc-piperazine (1.08 g, 5.80 mmol) in dry DMF (10 mL) were added anhydrous potassium carbonate (4.01 g, 29.04 mmol) and compound 26 (1.5 g, 6.97 mmol). The reaction mixture was stirred at RT for 8 h. The potassium carbonate was removed by suction filtration and the solvent was removed under reduced pressure. The residue was dissolved with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed by evaporation. The crude product was purified by column chromatography using ethyl acetate:hexane (8:2) to give compound 28 (1.58 g, 85%). 1H NMR (400 MHz, CDCl3) δ 1.39 (s, 9H), 1.92 (s, 2H), 2.36 (s, 4H), 2.48 (s, 2H), 3.39 (s, 4), 3.95 (m, 2), 6.83 (m, 2H), 7.19 (m, 3H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:8])[NH:4][N:5]=[CH:6][CH:7]=1.[B:9]1(B2OC(C)(C)C(C)(C)O2)[O:13]C(C)(C)C(C)(C)[O:10]1.CC([O-])=O.[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[O:8]=[C:3]1[C:2]([B:9]([OH:13])[OH:10])=[CH:7][CH:6]=[N:5][NH:4]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: O=c1[nH]nccc1Cl
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: O=c1[nH]nccc1B(O)O
Temperature: 110 °C
Yield: 51.7 %

Procedure:
Step b—A microwave vial was charged with 75 (0.400 g, 3 mmol), bis-(pinacolato)diboron (0.934 g, 4 mmol), dicyclohexyl[2′,4′,6′-tris(1-methylethyl)[1,1′-biphenyl]-2-yl]-phosphine (X-Phos, 0.058 g, 0.12 mmol), Pd2(dba)3 (0.056 g, 0.061 mmol) and KOAc (0.902 g, 9 mmol) and the flask was evacuated and back-filled with Ar and sealed. Dioxane (6 mL) was added and the reaction heated at 110° C. overnight. The reaction mixture was cooled to RT and extracted with EtOAc (120 mL). The organic extract was washed sequentially with H2O (10 mL) and brine (10 mL), dried (Na2SO4), filtered and evaporated. The crude product was triturated with Et2O to afford 0.217 g of 78.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Br:6][C:7]1[S:11][C:10]([N-:12][CH2:13][CH2:14][C:15](=O)[CH3:16])=[N:9][N:8]=1>C(=O)([O-])[O-].[Na+].[Na+]>[Br:6][C:7]1[S:11][C:10]2=[N:12][C:13](=[O:2])[CH:14]=[C:15]([CH3:16])[N:9]2[N:8]=1
Reactant: CC(=O)CC[N-]c1nnc(Br)s1
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(=O)nc2sc(Br)nn12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To concentrated sulfuric acid (10 ml) heated to 60° C. was added the compound (1.3 g) obtained in Step 2 in divided portions, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was poured into ice (100 g), and the mixture was neutralized with an aqueous solution (100 ml) of sodium carbonate (20 g). The organic layer was extracted with chloroform (50 ml), and dried to give the title compound (810 mg).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:5]=1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)=[C:9]([N+:26]2C=CC=CC=2)[C:8]1=[O:32].NN>C(O)C>[NH2:26][C:9]1[C:8](=[O:32])[N:7]([CH2:6][C:5]2[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:4]=2[O:3][CH3:2])[C:16]2[C:11]([C:10]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2
Reactant: COc1ccc(Cn2c(=O)c(-[n+]3ccccc3)c(-c3cccc(F)c3)c3cc(OC)ccc32)c(OC)c1
Agent: NN
Agent: [Cl-]
Solvent: CCO
Product: COc1ccc(Cn2c(=O)c(N)c(-c3cccc(F)c3)c3cc(OC)ccc32)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-[1-(2,4-dimethoxybenzyl)-4-(3-fluorophenyl)-6-methoxy-2-oxo-1,2-dihydroquinolin-3-yl]pyridinium chloride (225 mg, 0.422 mmol) and hydrazine (0.133 mL, 4.22 mmol) in 3 mL of ethanol was heated to reflux. After one hour, the reaction was cooled to room temperature. The reaction was partitioned between EtOAc and saturated NaHCO3 solution, and the organic layer dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography through SiO2 (0-5% MeOH/CH2Cl2) to provide the titled product as a white foam. 1H-NMR (500 MHz, CDCl3) δ 7.55 (m, 1H), 7.18 (d, J=8.5 Hz, 2H), 7.12 (m, 1H), 6.81 (dd, J=9.2, 2.7 Hz, 1H), 6.76 (d, J=8.5 Hz, 1H), 6.52 (br s, 1H), 6.34 (dd, J=8.5, 2.2 Hz, 1H), 5.57 (s, 2H), 3.96 (s, 3H), 3.76 (s, 3H), 3.65 (s, 3H) ppm. HRMS (ES) exact mass calculated for C25H23FN2O4 (M+H+): 435.1715. Found 435.1732.
Reaction SMILES: C([NH:8][CH:9]([CH2:20][CH2:21][CH2:22][CH3:23])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH:9]([CH2:20][CH2:21][CH2:22][CH3:23])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: CCCCC(NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCC(N)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 151.1 %

Procedure:
To N-Boc-aminocaproic acid, benzyl ester (1.125 g, 3.50 mmol) in dichloromethane (4 ml) was added trifluoroacetic acid (8 ml) and the mixture stirred at room temperature for 10 minutes. The solvents were removed in vacuo to give the title compound (1.17 g, 100%) as an oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([O:6]/[N:7]=[C:8](/[C:14](=[O:16])[CH3:15])\[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1=[O:17].S(Cl)([Cl:21])(=O)=O>C(Cl)Cl>[NH:1]1[CH2:5][CH2:4][C@H:3]([O:6]/[N:7]=[C:8](/[C:14](=[O:16])[CH2:15][Cl:21])\[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1=[O:17]
Reactant: CCOC(=O)/C(=N\O[C@H]1CCNC1=O)C(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)/C(=N\O[C@H]1CCNC1=O)C(=O)CCl
Reaction time: 20 h

Procedure:
2.4 g of ethyl (Z)-2-[((3S)-2-pyrrolidon-3-yl)-oxyimino]-3-oxo-n-butyrate are dissolved in 15 ml of methylene chloride, and 1.6 g of sulfuryl chloride are added thereto. The mixture is stirred at 15° to 25° C. for 20 hours. Then, the mixture is concentrated under reduced pressure to remove solvent. The residue is dissolved in chloroform, and the solution is washed with water. The chloroform solution is dried and concentrated under reduced pressure to dryness. Ethyl (Z)-2-[((3S)-2-pyrrolidon-3-yl)oxyimino]-3-oxo-4-chloro-n-butyrate is thereby obtained as crude product. The crude product thus obtained is dissolved in 20 ml of ethanol, and one g of thiourea and 1.2 g of N,N-dimethylaniline are added thereto. The mixture is stirred at 20° to 25° C. for 2 hours. Then, the mixture is concentrated under reduced pressure to remove solvent. The residue is dissolved in chloroform, and the solution is washed with water and an aqueous sodium bicarbonate solution, successively. The chloroform solution is dried and concentrated under reduced pressure to remove solvent. The residue is crystallized with isopropanol, and the crystals are collected by filtration. 1.2 g of ethyl (Z)-2-(2-aminothiazol-4-yl)-2-[((3S)-2-pyrrolidon-3-yl)oxyimino]acetate are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([CH3:31])[CH2:17][N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20](C(C)=C)[C:19]3=[O:30])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C(O)C.Cl>CC(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH:16]([CH3:31])[CH2:17][N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[O:30])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: C=C(C)n1c(=O)n(CC(C)CN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c2ccccc21
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: CC(CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)Cn1c(=O)[nH]c2ccccc21

Procedure:
A stirred solution of 8 parts of 1-[3-{4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}-2-methylpropyl]-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one in 120 parts of ethanol is acidified with 2-propanol, previously saturated with gaseous hydrogen chloride. The whole is stirred and refluxed for 5 minutes. The reaction mixture is evaporated. The residue is taken up in water and the whole is alkalized with a concentrated ammonium hydroxide solution. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 1-[3-{4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}-2-methylpropyl]-1,3-dihydro-2H-benzimidazol-2-one; mp. 176° C.
Reaction SMILES: [CH2:1]([NH2:8])C1C=CC=CC=1.CN.[C:11]([C:14]1[S:18][C:17]([N:19]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][CH:26]=3)[C:20]2=[O:34])=[N:16][C:15]=1[CH3:35])(=[O:13])[CH3:12]>>[C:11]([C:14]1[S:18][C:17]([N:19]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:29]([NH:8][CH3:1])=[O:31])=[CH:32][CH:33]=3)[C:20]2=[O:34])=[N:16][C:15]=1[CH3:35])(=[O:13])[CH3:12]
Reactant: CC(=O)c1sc(N2CCN(Cc3ccc(C(=O)O)cc3)C2=O)nc1C
Reactant: NCc1ccccc1
Agent: CN
Product: CNC(=O)c1ccc(CN2CCN(c3nc(C)c(C(C)=O)s3)C2=O)cc1
Yield: 43 %

Procedure:
Following the procedure as describe in Example 8, making variations as required to replace benzylamine with methylamine to react with 4-((3-(5-acetyl-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoic acid, the title compound was obtained as a white powder in 43% yield: mp 173-175° C. (ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 6.12 (br s, 1H), 4.52 (s, 2H), 4.12-4.06 (m, 2H), 3.49-3.43 (m, 2H), 3.00 (d, J=4.2 Hz, 3H), 2.67 (s, 3H), 2.46 (s, 3H); MS (ES+) m/z 373.2 (M+1).
Reaction SMILES: [CH2:1]([S:3][CH:4]([CH2:20][C:21]([O-:23])=[O:22])[C:5](=O)[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[O:7])[CH3:2].S(Cl)([Cl:26])=O>ClCCCl>[Cl:26][C:5]1([C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)=[O:7])[CH:4]([S:3][CH2:1][CH3:2])[CH2:20][C:21](=[O:22])[O:23]1
Reactant: O=S(Cl)Cl
Reactant: CCSC(CC(=O)[O-])C(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: ClCCCl
Product: CCSC1CC(=O)OC1(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
In 4 ml of 1,2-dichloroethane was dissolved 170 mg of the Compound (39) obtained in Example 39. To the solution was added 0.30 ml of thionyl chloride. The mixture was heated for 3.5 hours under reflux. The solvent was evaporated off, and the residue was subjected to a column chromatography using Florisil (Floridin Inc. U.S.A.), followed by elution with hexane and hexane-ethyl acetate (3:1) to give 79 mg of the subject Compound (40) as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][CH:5]([NH:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25]C(OC(C)(C)C)=O)=[CH:17][CH:16]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].[ClH:34]>>[ClH:34].[ClH:34].[CH3:1][O:2][C:3](=[O:33])[CH2:4][CH:5]([NH:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])=[CH:19][CH:20]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)CC(CC(=O)OC)NCCOc1ccc(CCCCNC(=O)OC(C)(C)C)cc1
Agent: Cl
Product: COC(=O)CC(CC(=O)OC)NCCOc1ccc(CCCCN)cc1
Yield: 88 %

Procedure:
3-{2-[4-(4-tert-Butoxycarbonylaminobutyl)phenoxy]ethylamino}pentanedioic acid dimethyl ester (2) (0.57 g, 1.22 mmol) and saturated methanolic HCl were stirred together at ambient temperature for 3 hours. Subsequent evaporation of the solvent followed by further drying under high vacuum for 12 hours afforded the compound 18 (0.47 g, 88% yield) as a viscous oil: 1H NMR (500 MHz, CDCl3) δ 1.46-1.52 (m, 2H), 1.55-1.64 (m, 2H), 2.56-2.58 (m, 4H), 2.64-2.65 (m, 2H), 2.72-2.79 (m, 2H), 2.88-2.93 (m, 2H), 3.74 (d, 6H), 3.88-3.93 (m, 1H), 4.44-4.49 (m, 2H), 6.40 (br, 1H), 6.85 (d, 2H), 7.09 (d, 2H), 8.27 (br, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][O:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][S:17][C:18]3[NH:22][C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[N:19]=3)[C:11]=2[CH3:27])[O:4][CH2:3]1.ClC1C=CC=C(C(OO)=[O:37])C=1.C(=O)([O-])O.[Na+]>CO.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:28])[CH2:7][O:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][S:17]([C:18]3[NH:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)=[O:37])[C:11]=2[CH3:27])[O:4][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(OCC2OCC(C)(C)CO2)ccnc1CSc1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1c(OCC2OCC(C)(C)CO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Temperature: -50 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
The 2-(((4-((5,5-dimethyl-1,3-dioxan-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (599 mg, 1.5 mmol) obtained by the step (1e) was mixed with methanol (5 ml) and toluene (15 ml), and the mixture was cooled to −50° C. 3-chloroperbenzoic acid (358 mg, 1.35 mmol, as the content was regarded as 65%) dissolved in a solvent mixture of methanol and toluene was slowly added dropwise to the mixture, and stirred at −47° C. to −70° C. for 3 hours. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over potassium carbonate, and the solvent was distilled off. The residue was purified with silica gel column chromatography (NH silica gel: 40 g, elution solvent: dichloromethane/heptane=7/3→methanol/dichloromethan=3/97 to 1/9). To the obtained product, heptane (20 ml) and diethyl ether (2 ml) were added, the precipitate was obtained by filtration. In this manner, the title compound (475 mg, yield: 76.2%) was obtained as a light orange solid.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][C:9]1[C:14]([O:15][C:16]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:17]=2[C:18]([OH:20])=O)=[CH:13][CH:12]=[CH:11][N:10]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][C:54]1[CH:55]=[C:56]([S:60]([NH2:63])(=[O:62])=[O:61])[CH:57]=[CH:58][CH:59]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:8][C:9]1[C:14]([O:15][C:16]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:17]=2[C:18]([NH:53][C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([S:60](=[O:62])(=[O:61])[NH2:63])[CH:55]=2)=[O:20])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Cc1ncccc1Oc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: Nc1cccc(S(N)(=O)=O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1cccc(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(2-methylpyridin-3-yloxy)-4-(trifluoromethyl)benzoic acid TFA salt (54 mg, 0.13 mmol) and HATU (50 mg, 0.13 mmol) in DMF (1 mL) was stirred at room temperature 3 min. To this solution was added 3-amino-benzenesulfonamide (23 mg, 0.13 mmol) and triethylamine (46 μL, 0.33 mmol). The reaction was stirred at room temperature for 16 h and purified by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give 2-(2-methylpyridin-3-yloxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide. LC/MS: m/z 452.3 (M+H)+ at 1.07 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:47]=[CH:46][C:12]([C:13]([O:28][CH2:29][C@H:30]2[O:34][C@@H:33]([N:35]3[CH:42]=[C:41]([CH3:43])[C:39](=[O:40])[NH:38][C:36]3=[O:37])[C@H:32]([OH:44])[C@@H:31]2[OH:45])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.[Si:48](Cl)([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49]>C1COCC1.[N+]([O-])([O-])=O.[Ag+]>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([O:28][CH2:29][C@H:30]2[O:34][C@@H:33]([N:35]3[CH:42]=[C:41]([CH3:43])[C:39](=[O:40])[NH:38][C:36]3=[O:37])[C@H:32]([O:44][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[C@@H:31]2[OH:45])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:12]2[CH:46]=[CH:47][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.8 %

Procedure:
Anhydrous pyridine (9.9 mL) was added to a solution of 5′-O-(4,4′-dimethoxitrityl)-5-methyluridine (6.9 g) and AgNO3 (2.51 g) in dry THF (123 mL) and stirred at room temperature for 20 min under an argon atmosphere. Followed by addition of tert-butyldimethylsilyl chloride (2.51 g) in dry THF (6 mL) and stirred at the same temperature for 2-3 h. The solids were filtered off and the filtrate was concentrated to a crude residue which was applied to a column of silica gel eluted with hexane-ethyl acetate (3:1) to give a pure title compound (7.04 g) as an amorphous solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:23])[CH2:7][NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=3)[N:12]=[N:11][CH:10]=2)[CH2:2]1.[OH:24][CH:25]([CH:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1)[CH2:26][CH3:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(CC)CC)C>ClCCl>[OH:24][CH:25]([CH:28]1[CH2:33][CH2:32][CH:31]([N:1]2[CH2:2][CH:3]([NH:5][C:6](=[O:23])[CH2:7][NH:8][C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]([F:21])([F:20])[F:22])[CH:17]=4)[N:12]=[N:11][CH:10]=3)[CH2:4]2)[CH2:30][CH2:29]1)[CH2:26][CH3:27]
Reactant: O=C(CNc1cnnc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: CCC(O)C1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(O)C1CCC(N2CC(NC(=O)CNc3cnnc4ccc(C(F)(F)F)cc34)C2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of N-(azetidin-3-yl)-2-(6-(trifluoromethyl)cinnolin-4-ylamino)acetamide (as prepared in the previous step, 450 mg, 1.38 mmol, 1.00 equiv) in dichloromethane (30 mL), 4-(1-hydroxypropyl)cyclohexanone (as described in Example 25, Step B) (216 mg, 1.38 mmol, 1.00 equiv), NaBH(OAc)3 (877 mg, 4.14 mmol, 3.00 equiv) and triethylamine (418 mg, 4.14 mmol, 3.00 equiv). The reaction mixture was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product (500 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-5): Column, SunFire Prep C18, 5 μm, 19×100 mm; mobile phase, Water and CH3CN (30% CH3CN up to 40% in 13 min, up to 100% in 0.1 min, hold 100% in 2 min, down to 30% in 0.1 min, hold 30% in 1.4 min); Detector, UV 220&254 nm. The title compound was obtained as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH3:10])[C:8]3=[N:11][C:12]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:13]([CH2:14][C:15]([OH:17])=O)[N:7]3[C:6]=2[CH:24]=1.[NH3:25]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH3:10])[C:8]3=[N:11][C:12]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:13]([CH2:14][C:15]([NH2:25])=[O:17])[N:7]3[C:6]=2[CH:24]=1
Reactant: N
Reactant: Cc1ccc2c(c1)n1c(CC(=O)O)c(-c3ccccc3)nc1n2C
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)n1c(CC(N)=O)c(-c3ccccc3)nc1n2C
Reaction time: 2 h

Procedure:
A suspension of 1.5 g (0.0047 mol) of 6,9-dimethyl-2-phenyl-9H-imidazo[1,2-a]benzimidazole-3-acetic acid is prepared in 50 ml of dry tetrahydrofuran. 1.22 g (0.0075 mol) of N,N'-carbonyldiimidazole are added thereto and the mixture is stirred for 2 h at 40°-45° C. The solution obtained is then treated with an excess of dry ammonia and stirred for 2 h. The solvent is evaporated under reduced pressure. The residue is washed with water and dried. The product obtained is purified by silica gel column chromatography, eluting with a chloroform/acetone 95/5 mixture and 0.71 g of product is isolated. Melting point: 247°-249° C. (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][C:5]1([OH:19])[CH2:10][CH2:9][CH2:8][CH:7]([NH:11]C(=O)OC(C)(C)C)[CH2:6]1.[ClH:24]>O1CCOCC1>[ClH:24].[NH2:11][CH:7]1[CH2:8][CH2:9][CH2:10][C:5]([CH2:4][C:3]2[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=2[F:1])([OH:19])[CH2:6]1
Reactant: CC(C)(C)OC(=O)NC1CCCC(O)(Cc2ccccc2F)C1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCCC(O)(Cc2ccccc2F)C1

Procedure:
tert-Butyl 3-(2-fluorobenzyl)-3-hydroxycyclohexylcarbamate was stirred in a solution of HCl in dioxane (4 M) at room temperature for one hour. The product, HCl salt of 3-amino-1-(2-fluorobenzyl)cyclohexanol, was obtained after evaporation of solvent.