Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[CH2:6][CH2:5]2.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH:20]=O>>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1/[CH:20]=[C:6]1/[C:7](=[O:12])[C:8]2[C:4]([CH2:5]/1)=[CH:3][C:2]([CH3:1])=[C:10]([CH3:11])[CH:9]=2
Reactant: O=Cc1ccncc1Br
Reactant: Cc1cc2c(cc1C)C(=O)CC2
Product: Cc1cc2c(cc1C)C(=O)/C(=C/c1ccncc1Br)C2

Procedure:
The title compound 92 is prepared according to the procedure reported in Example 35.3 with 5,6-dimethyl-1-indanone (0.40 g, 2.5 mmol) and 3-bromo-4-pyridinecarboxaldehyde (0.45 g, 2.5 mmol) as reactants. Yellow solid. (Yield 0.48 g, 58%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[CH2:18][C@H:17](OC(OCC)=O)[CH:16]=[CH:15]2)=[C:7]([NH:25][C@H:26]([CH2:34][OH:35])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:6]=1)=[O:4].[NH:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.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]>[CH3:1][O:2][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[CH2:18][C@H:17]([N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])[CH:16]=[CH:15]2)=[C:7]([NH:25][C@H:26]([CH2:34][OH:35])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:6]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(N[C@H](CO)Cc4ccccc4)nc(C(=O)OC)nc32)C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1nc(N[C@H](CO)Cc2ccccc2)c2ncn([C@H]3C=C[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C3)c2n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
9-((1R,4S)-4-Ethoxycarbonyloxy-cyclopent-2-enyl)-6-((S)-1-hydroxymethyl-2-phenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester (Intermediate WB) (1 eq.), di-tert-butyl iminodicarboxylate (1.1 eq.), triphenylphosphane (0.15 eq.) and TEA are dissolved in THF (deoxygenated & dry).) Tris(dibenzylideneacetone)dipalladium(0) (0.05 eq.) is added and the reaction mixture is stirred at 50° C. for 1 hour. The reaction mixture is removed in vacuo and the title compound is obtained by column chromatography.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[NH:5][N:4]=1)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH3:20][O:21][CH2:22][CH2:23]Br.C(Cl)Cl>C1COCC1.O>[CH2:1]([C:3]1[N:4]([CH2:23][CH2:22][O:21][CH3:20])[N:5]=[C:6]([C:11]([NH2:13])=[O:12])[C:7]=1[N+:8]([O-:10])=[O:9])[CH3:2]
Reactant: COCCBr
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CCc1c([N+](=O)[O-])c(C(N)=O)nn1CCOC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (2.5 kg, 13.6 Mol), sodium carbonate (1.8 Kg, 17.0 Mol) and 2-bromoethyl methyl ether (1.98 kg, 14.2 Mol) in THF (22.5 L) and water (2.5 L) was heated under reflux and stirred for 20 hours. The mixture was cooled to ambient temperature and CH2Cl2 (67.5 L) and water (22.5 L) were added. The resultant organic and aqueous layers were separated. The aqueous phase was extracted with CH2Cl2 (22.5 L) and the combined organic solution was distilled under atmospheric pressure and replaced with ethyl acetate (33 L) to a final volume of 17 L. The cooled mixture was granulated at ambient temperature for 2 hours, filtered and washed with ethyl acetate (2.5 L). This afforded 5-ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamide as a white crystalline solid, 2.10 kg, 57%. m.p.=140° C. Found: C, 44.46; H, 5.79; N, 23.01. C9H14N4O4 requires C, 44.63; H, 5.79; N, 23.14%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.CN(C)C=O.[C:32](Cl)(=[O:34])[CH3:33]>O.CC1C=CC=CC=1>[OH:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:32](=[O:34])[CH3:33])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccc(N2CCN(c3ccc(O)cc3)CC2)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(N2CCN(c3ccc(O)cc3)CC2)cc1
Reaction time: 1 h
Yield: 42.5 %

Procedure:
To a stirred solution of 10.8 parts of 4-[4-(4-aminophenyl)-1-piperazinyl]phenol in 3.2 parts of pyridine and 90 parts of N,N-dimethylformamide was added dropwise a solution of 3.1 parts of acetyl chloride in 27 parts of methylbenzene at 20° C. (exothermic reaction). Upon completion, stirring was continued for 1 hour at 20° C. The reaction mixture was poured into water while stirring. The product was filtered off, washed with water and dissolved in a mixture of trichloromethane and methanol (3:1 by volume). The whole was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The second fraction was collected and the eluent was evaporated. The residue was crystallized from a mixture of ethanol and methylbenzene (1:1 by volume)+(activated charcoal). The produce was filtered off and dried yielding 5.3 parts (42.5%) of N-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]acetamide; mp. 256.2° C. (compound 1.03).
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]([N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)=[CH:11][NH:10]2)[CH:4]=1.Cl.[F:21][C:22]1([F:26])[CH2:25][NH:24][CH2:23]1.C(N(C(C)C)C(C)C)C>O1CCCC1>[F:21][C:22]1([F:26])[CH2:25][N:24]([C:3]2[N:8]=[CH:7][N:6]=[C:5]([N:9]3[C:13](=[O:14])[C:12]([N:15]4[CH:19]=[CH:18][N:17]=[N:16]4)=[CH:11][NH:10]3)[CH:4]=2)[CH2:23]1
Reactant: FC1(F)CNC1
Reactant: O=c1c(-n2ccnn2)c[nH]n1-c1cc(Cl)ncn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=c1c(-n2ccnn2)c[nH]n1-c1cc(N2CC(F)(F)C2)ncn1

Procedure:
100 mg (0.3 mmol) of the compound from Example 12A, 52 mg (0.4 mmol) of 3,3-difluoroazetidine hydrochloride and 174 ml (130 mg, 1.0 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are initially charged in 2 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 30 min. After concentration under reduced pressure, the residue is taken up in acetonitrile/water and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 36 mg (34% of theory)
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])[CH:15]=[CH:16][CH:17]=3)=[CH:10][N:11]=[C:5]2[CH:4]=1)=[O:2].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S([CH2:43][N+:44]#[C-:45])(=O)=O)=CC=1>CO>[O:2]1[C:1]([C:3]2[CH:8]=[CH:7][N:6]3[C:9]([C:12]4[CH:13]=[C:14]([NH:18][C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])[CH:15]=[CH:16][CH:17]=4)=[CH:10][N:11]=[C:5]3[CH:4]=2)=[CH:45][N:44]=[CH:43]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnco4)ccn23)c1
Yield: 37.4 %

Procedure:
A solution of 1-[3-(7-Formyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (15 mg, 0.04 mmol), potassium carbonate (11 mg, 0.08 mmol) and TosMic (9.7 mg, 0.05 mmol) were heated in MeOH (2 ml) at 80° C. for 3 h. The reaction mixture was purified using a C18 SPE cartridge, washing with water and eluting the desired compound with MeOH. Removal of the solvent in vacuo afforded the title compound (6 mg). MS: [M+H]+=402
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:11]=[C:10]([C:12](OC)=[O:13])[CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>C(O)C>[CH2:1]([O:5][C:6]1[N:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cccc(C(=O)OC)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCOc1cccc(CO)n1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
Methyl 6-butoxypyridine-2-carboxylate (2.46 g, 11.8 mmol, obtained from Example 17(b)) was dissolved in absolute ethanol (112 mL) and sodium borohydride (1.78 g, 47.0 mmol, 4 equiv.) was added. After refluxing for 1 h, another 2 equivalents of sodium borohydride were added and then after 2 h more an additional 2 equivalents more sodium borohydride were added. After another 3 h the reaction was cooled to r.t. and concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo producing 1.92 g (91% yield, 10.7 mmol) of the title compound as a clear liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[C:13]([O-])(O)=O.[Na+]>CO.OS(O)(=O)=O>[CH3:13][O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(O)c(F)c1
Temperature: 25 °C
Yield: 181.5 %

Procedure:
To a solution of (3-fluoro-4-hydroxy-phenyl)-acetic acid (20 g, 117.5 mmol) in MeOH (150 mL), was H2SO4 (3 drops) added. The reaction mixture was heated to reflux and maintained for 2 hours. The reaction was cooled to room temperature and 5 g of NaHCO3 was added portionwise. The reaction was concentrated under vacuum and dissolved in ether (200 mL). The ether layer was washed with sat. NaHCO3. The ether layer was dried over MgSO4, and concentrated under vacuum to afford the desired compound (19.9 g, 92%) as an oil. The crude compound was used for the next step without further purification. 1H NMR (400 Mz, DMSO-d6) δ 9.92 (s, 1H), 7.01-7.20 (m, 2H), 3.62 (s, 2H), 3.61 (s, 3H). LCMS 185.1 [MH+].
Reaction SMILES: [OH:1][C@H:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].N1C=CN=C1.[CH:15]([Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16].O>CN(C)C=O>[CH:15]([Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:1][C@H:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])([CH3:17])[CH3:16]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CCOC(=O)C[C@@H](C)O
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](C)O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 0 °C

Procedure:
0.077 mol (10.0 g) of ethyl(R)-3-hydroxybutyrate is dissolved in 90 ml of dimethylformamide and 0.151 mol (10.3 g) of imidazole is added. The mixture is cooled to 0° C. under protective gas in an ice bath and 0.083 mol (16.05 g) of triisopropylsilyl chloride is added dropwise over 5 min. The mixture is stirred at room temperature for a further 5 hours, hydrolyzed with water, the product is extracted with tert-butyl methyl ether, and the organic phase is dried using Na2SO4 and concentrated under reduced pressure on a rotary evaporator.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:23])[NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([O:26][C:27]1[C:28](=O)[C:29](=[O:34])[C:30]=1[O:31]CC)[CH3:25]>>[C:1]1([CH2:7][O:8][C:9](=[O:23])[NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:28]2[C:29](=[O:34])[C:30](=[O:31])[C:27]=2[O:26][CH2:24][CH3:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)CNCCCNC(=O)OCc1ccccc1
Reactant: CCOc1c(OCC)c(=O)c1=O
Product: CCOc1c(N(CCCNC(=O)OCc2ccccc2)CC(=O)OC(C)(C)C)c(=O)c1=O
Yield: 90.6 %

Procedure:
An ethanolic solution (60 mL) of [3-[[(1,1-dimethylethyloxycarbonyl)methyl]amino]propyl]carbamic acid phenylmethyl ester (4.49 g, 13.9 mmol) under nitrogen was added to 3,4-diethoxy-3-cyclobutene-1,2-dione (2.0 mL, 13 mmol) in the same solvent (60 mL) over 1 hour. After 3.5 more hours, the reaction mixture was preadsorbed onto silica gel and purified by flash chromatography (7.5 cm diameter, gradient elution with 30 to 60% ethyl acetate in petroleum ether) to afford [3-[[(1,1-dimethylethyloxycarbonyl)methyl]-(2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)amino]propyl]carbamic acid phenylmethyl ester as a viscous colorless oil (5.26 g, 91%); MS (+CI): 447 (MH+, 100), 391 (38); 1H NMR (CDCl3, 400 MHz): δ 7.35 (m, 5H), 5.55, 4.97 (br m, NH), 5.10 (s, 2H), 4.75, 4.73 (q, J=7 Hz, 2H), 4.29, 3.99 (s, 2H), 3.74, 3.49 (t, J=6.5 Hz, 2H), 3.29-3.22 (m, 2H), 1.84-1.75 (m, 2H), 1.48, 1.47 (s, 9H), 1.45-1.40 (m, 3H).
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:31])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[CH:26][C:27]([C:29]#[CH:30])=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1.[N:33]([CH2:36][C:37](OCC)=[O:38])=[N+:34]=[N-:35].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[BH4-].[Na+]>CC(O)(C)C.O.CO.[O-]S([O-])(=O)=O.[Cu+2]>[F:32][C:2]1([F:1])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:31])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[CH:26][C:27]([C:29]6[N:35]=[N:34][N:33]([CH2:36][CH2:37][OH:38])[CH:30]=6)=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: C#Cc1ccn2c(C(=O)Nc3cc(-c4noc(C5CC(F)(F)C5)n4)ccc3C)cnc2c1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CO
Solvent: CC(C)(C)O
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2cc(-c3cn(CCO)nn3)ccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-7-ethynylimidazo[1,2-a]pyridine-3-carboxamide (53) (20 mg, 0.046 mmol), ethyl 2-azidoacetate (5.9 mg, 0.046 mmol), CuSO4(4 μL of 0.5M aqueous solution, 0.002 mmol) and sodium ascorbate (2.8 mg, 0.014 mmol) in tBuOH/H2O (1 mL, 2:1) was stirred at room temperature overnight. Then the reaction mixture was diluted and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated to afford a residue which was dissolved in MeOH (2 mL). NaBH4(17 mg, 0.46 mmol) was added and the reaction mixture was stirred for 30 minutes. The above mixture was purified by HPLC to give N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-7-(1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (F66). 1H NMR (400 MHz, d4-MeOH) δ 9.70 (m, 1H), 8.60-8.80 (m, 2H), 8.33 (s, 1H), 8.16 (d, J=1.6 Hz, 1H), 7.96 (m, 1H), 7.85 (d, J=7.2 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 4.62 (t, J=4.8 Hz, 2H), 4.02 (t, J=4.8 Hz, 2H), 3.79 (m, 1H), 3.13 (m, 4H), 2.44 (s, 3H). MS m/z 521.1 (M+1)+.
Reaction SMILES: [Mg].Cl[CH2:3][CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6].BrC(Br)C.[OH:13][C:14]1[C:15](=[O:25])[C:16]2[C:21]([C:22](=[O:24])[CH:23]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2>O1CCCC1.C(OCC)(=O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:6][C:5]([CH3:8])([CH3:7])[CH2:4][CH2:3][C:15]1([OH:25])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22](=[O:24])[CH2:23][C:14]1=[O:13]
Reactant: CC(C)(C)CCCl
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Agent: [Ti+4]
Agent: CC(Br)Br
Agent: CC(C)[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)CCC1(O)C(=O)CC(=O)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
To a suspension of magnesium turnings (2.90 g, 0.12 mol) in tetrahydrofuran (150 mL) was added 1-chloro-3,3-dimethylbutane (14.2 g, 0.12 mol). The mixture was cooled to 0° C. and dibromoethane (2.5 mL, 29 mmol) was added portion wise over 15 min. The mixture was allowed to warm to room temperature and stirred for 1 h. After which, an additional equivalent of dibromoethane (2.5 mL, 29 mmol) was added portion wise over 15 min and stirred at room temperature for 72 h. The mixture was diluted with tetrahydrofuran (50 mL) cooled to −78° C., and treated with titanium(IV) isopropoxide (33.9 mL, 0.11 mol). The reaction mixture was stirred at −78° C. for 1 h and a solution of 2-hydroxy-1,4-naphthoquinone (5.0 g, 29 mmol) in tetrahydrofuran (80 mL) pre-cooled to 0° C. was added via a cannula. After addition, the solution was warmed to room temperature and stirred for 18 h. The solution was diluted with ethyl acetate (250 mL) and washed with aqueous 1 N HCl (2×100 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. Column chromatography on florisil (dichloromethane→1%→3→%5% methanol/dichloromethane) followed by second column chromatography on silica (30%→50% ethyl acetate/hexane) afforded the title compound as an orange amorphous solid (2.06 g, 28%). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.33-0.52 (m, 1H), 0.68 (s, 9H), 0.77-0.92 (m, 1H), 1.67-1.84 (m, 1H), 1.88-2.11 (m, 1H), 5.56 (s, 1H), 7.36-7.45 (m, 1H), 7.57 (t, J=6.99 Hz, 1H), 7.62-7.68 (m, 1H), 7.82 (d, J=6.62 Hz, 1H); MS m/z 261.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:19][O:20][C:21](=[O:33])[C:22]1[CH:27]=[C:26]([OH:28])[CH:25]=[C:24]([O:29][CH2:30][O:31][CH3:32])[CH:23]=1.[Cl-].[NH4+]>CN(C)C=O.C(OC(=O)C)C>[CH3:19][O:20][C:21](=[O:33])[C:22]1[CH:23]=[C:24]([O:29][CH2:30][O:31][CH3:32])[CH:25]=[C:26]([O:28][C:2]2[CH:7]=[N:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH:27]=1
Reactant: COCOc1cc(O)cc(C(=O)OC)c1
Reactant: CCS(=O)(=O)c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1ccc(Oc2cc(OCOC)cc(C(=O)OC)c2)cn1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 92 %

Procedure:
After adding 178 mg (0.71 mmol) of 5-bromo-2-ethanesulfonylpyridine and 232 mg (0.71 mmol) of cesium carbonate to a solution of 100 mg (0.47 mmol) of 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester in N,N-dimethylformamide (1.0 ml), the mixture was stirred at 100° C. for 2.5 hours under a nitrogen atmosphere. Acetic acid ethyl ester and aqueous ammonium chloride were added to the reaction mixture, the aqueous layer was extracted with acetic acid ethyl ester, and then the organic layer was washed with brine, dried and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:acetic acid ethyl ester=1:1) to obtain 165 mg of 3-(6-ethanesulfonyl-pyridin-3-yloxy)-5-methoxymethoxybenzoic acid methyl ester (yield: 91%) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][NH:21][C:22]([C:24]1[C:28]([CH3:29])=[C:27]([CH:30]=O)[NH:26][C:25]=1[CH3:32])=[O:23]>>[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][NH:21][C:22]([C:24]1[C:28]([CH3:29])=[C:27]([CH:30]=[C:11]2[C:10]3[C:14](=[CH:15][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)[NH:13][C:12]2=[O:16])[NH:26][C:25]=1[CH3:32])=[O:23]
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN(C)C
Product: Cc1[nH]c(C=C2C(=O)Nc3cc(-c4ccccc4)ccc32)c(C)c1C(=O)NCCN(C)C
Yield: 37.9 %

Procedure:
6-Phenyl-1,3-dihydroindol-2-one (0.17 g, 0.8 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)amide (0.2 g) to give 0.13 g (36%) of the title compound as a yellow-orange solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[S:12](Cl)(=[O:14])=[O:13].S([O-])([O-])=O.[Na+:20].[Na+].C(=O)([O-])O.[Na+]>O1CCOCC1.O>[Na+:20].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[S:12]([O-:14])=[O:13]
Reactant: CC(=O)Cc1ccc(F)c(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Cc1ccc(F)c(S(=O)[O-])c1
Temperature: 70 °C

Procedure:
To a stirred solution of 2-fluoro-5-(2-oxo-propyl)-benzenesulfonyl chloride (AG1) (16.25 g, 86.36 mmol) in dioxane (200 ml) is added dropwise a solution of sodium sulfite (16.38 g, 130 mmol) and sodium hydrogen carbonate (10.92 g, 130 mmol) in water (200 ml). The reaction mixture is heated to 70° C. for 20 minutes and then allowed to cool to room temperature. The solvent is removed in vacuo and the resultant residue is used crude in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[F:15][C:16]([F:32])([F:31])[C:17]1[CH:30]=[CH:29][C:20]([CH2:21][O:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.O>CN(C=O)C>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([CH3:14])([OH:12])[CH2:13][N:26]2[CH2:25][CH2:24][CH:23]([O:22][CH2:21][C:20]3[CH:29]=[CH:30][C:17]([C:16]([F:15])([F:31])[F:32])=[CH:18][CH:19]=3)[CH2:28][CH2:27]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: FC(F)(F)c1ccc(COC2CCNCC2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@](O)(CN1CCC(OCc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 88.6 %

Procedure:
(R)-2-Chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (700 mg, 3.22 mmol) and 4-(4-trifluoromethylbenzyloxy)piperidine (1.09 g, 4.86 mol) in DMF (10 ml) were stirred at 70-75° C. for 4 hours. The reaction mixture was allowed to return to room temperature, poured into water and extracted with ethyl acetate. The extract was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) to afford (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethylbenzyloxy)piperidin-1-yl]propan-2-ol (1.36 g, yield 87%) as a yellow oil.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[C:11]1([CH2:17][CH2:18][NH2:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN1CCOCC1.Cl.[CH3:28][N:29]([CH3:46])[C:30]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:35][CH2:34][CH:33]([CH2:36][C:37]([OH:39])=O)[CH2:32][CH2:31]1.C1(N=C=NC2CCCCC2)CCCCC1.[OH-].[Na+]>CN(C)C=O.O>[CH3:46][N:29]([CH3:28])[C:30]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:31][CH2:32][CH:33]([CH2:36][C:37]([NH:19][CH2:18][CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:39])[CH2:34][CH2:35]1
Reactant: NCCc1ccccc1
Reactant: CN(C)C1(c2ccccc2)CCC(CC(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CN(C)C1(c2ccccc2)CCC(CC(=O)NCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 13.4 %

Procedure:
1-Hydroxybenzotriazole (273 mg, 2.0 mmol), 2-phenylethylamine (0.125 ml, 1.0 mmol) and N-methylmorpholine (0.222 ml, 2.0 mmol) were added to a solution of (4-dimethylamino-4-phenylcyclohexyl)acetic acid hydrochloride (298 mg, 1.0 mmol) in dry dimethylformamide under argon. Dicyclohexylcarbodiimide (417 mg, 2.0 mmol) was added at 0° C. and the mixture was stirred at RT for 5 d. The urea which had precipitated out was filtered off with suction and the filtrate was introduced into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Still further urea thereby precipitated out as a mixture with the product (349 mg) and was separated off. The filtrate obtained was diluted with water (300 ml), 5 M sodium hydroxide solution (8 ml, 40 mmol) was added and the mixture was stored at 5° C. for 16 h. Further product thereby precipitated out as a colourless solid (172 mg). After purification of the fraction contaminated with dicyclohexylurea by chromatography on silica gel with methanol, further product (49 mg) was obtained. The product was isolated in a total yield of 61% (221 mg) with an m.p. of 182-186° C.