Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH3:9].[C:10]([C:14]1[CH:15]=[CH:16][C:17]([OH:23])=[C:18]([CH:22]=1)[C:19]([OH:21])=[O:20])([CH3:13])([CH3:12])[CH3:11].[CH3:24][C:25](=O)CC>>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([O:23][CH2:8][CH3:9])=[C:18]([CH:22]=1)[C:19]([O:21][CH2:24][CH3:25])=[O:20])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1ccc(O)c(C(=O)O)c1
Reactant: CCI
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cc(C(C)(C)C)ccc1OCC
Temperature: 80 °C
Yield: 81 %

Procedure:
Potassium carbonate (9.4 g, 68.0 mmol) and iodoethane (3.3 mL, 41.3 mmol) were added to a stirred solution of 5-tert-butyl-2-hydroxy-benzoic acid (1.3 g, 6.8 mmol) in 2-butanone (50 mL). The resulting mixture was heated at 80° C. (oil bath) for 16 h and then allowed to cool. The solution was concentrated and redisolved in methylene chloride. The organic phase was washed with water, brine, and dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was concentrated. Purification of the crude residue by flash chromatography (silica gel, eluting with 5-10% ethyl acetate in hexanes) gave ethyl 5-tert-butyl-2-ethoxy-benzoate (1.2 g, 81%) as a yellow oil.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:23]([OH:25])=[O:24])[CH2:20][CH2:21][CH3:22])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].S(Cl)(Cl)=O.[CH3:30]O>C(OC(=O)C)C>[NH:18]([C:1]([O:3][CH2:4][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:2])[C@H:19]([C:23]([O:25][CH3:30])=[O:24])[CH2:20][CH2:21][CH3:22]
Reactant: CCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CO
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: CCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC

Procedure:
To a chilled solution of the commercially available Fmoc-norvaline (25 g, 73.75 mmol) in anhydrous methanol (469 ml) was added thionyl chloride (53.76 ml, 737.5 mmol) over one hour. TLC in ethylacetate taken an hour later confirmed the completion of the reaction (Rf=0.85). The reaction mixture was concentrated and the remaining residue was dissolved in ethylacetate. The organic layer was washed with several 200 ml portions of saturated sodium bicarbonate followed by brine. The organic layer was dried, filtered and concentrated to afford Fmoc-norVal-OMe) as a white solid (26.03 g) in quantitative yield. NMR δ ppm (CD3OD): 7.7 (m, 2H), 7.6 (m, 2H), 7.4 (m, 2H), 7.3 (m, 2H), 4.3 (m, 2H), 4.1 (m, 2H), 3.7 (s, 3H), 1.7 (m, 1H), 1.6 (m, 1H), 1.4 (m, 2H), 0.95 (t, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:24]=[C:23]([CH3:25])[C:18]([O:19][CH2:20][CH2:21][OH:22])=[C:17]([CH2:26][CH3:27])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:28])[N:5]=1)[CH3:2].CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl.CCOC(C)=O>[CH2:29]([N:3]([CH2:1][CH3:2])[C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:24]=[C:23]([CH3:25])[C:18]([O:19][CH2:20][CH2:21][O:22][S:39]([CH3:38])(=[O:41])=[O:40])=[C:17]([CH2:26][CH3:27])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:28])[N:5]=1)[CH3:30]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)n3)n2)cc(C)c1OCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)n3)n2)cc(C)c1OCCOS(C)(=O)=O
Temperature: 5 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a solution of 2-{4-[5-(2-diethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-ethanol (895 mg, 2.44 mmol) in DCM (20 mL) is added Et3N (0.47 mL, 3.41 mmol). The reaction mixture is cooled down to 5° C. before adding methanesulfonylchloride (0.23 mL, 2.92 mmol) and stirring is continued at rt for 2 h. The mixture is then diluted with EtOAc and the org. solution is washed with sat. aq. NaHCO3 followed by brine, is dried over MgSO4, filtered and concentrated to give methanesulfonic acid 2-{4-[5-(2-diethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-ethyl ester as a brown oil (1.07 g); LC-MS: tR=1.19 min; [M+H]+=489.89.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[CH2:29]([C:31]1[NH:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH3:30]>>[CH2:29]([C:31]1[N:32]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH3:30]
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Reactant: CCc1nc2ccccc2[nH]1
Product: CCc1nc2ccccc2n1Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2C(F)(F)F)cc1
Yield: 63 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 2-ethylbenzimidazole, the title compound was isolated as a yellow solid in 63% yield (96% purity by HPLC).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:22][C:21]([C:23]([O:25][CH3:26])=[O:24])=[CH:20][C:9]=3[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]=[CH2:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:29](Br)[CH:30]=[CH2:31]>CN(C=O)C>[CH2:31]([N:10]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]=[CH2:19])=[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]2[S:22][C:21]([C:23]([O:25][CH3:26])=[O:24])=[CH:20][C:9]1=2)[CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: C=Cc1ccccc1-c1[nH]c2cc(C(=O)OC)sc2c1C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(-c2ccccc2C=C)c(C2CCCCC2)c2sc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a 0.1M solution of methyl 6-cyclohexyl-5-(2-vinylphenyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate in dry DMF, 60% NaH (1.2 eq.) in mineral oil was added; when gas evolution had ceased, allyl bromide (1.3 eq.) was added, and the suspension was stirred at RT for 1 h. All volatiles were evaporated and the title compound was isolated by chromatography (PE/Et2O 20:1). Yield: 98%. 1H-NMR (400 MHz, CDCl3, 300K, δ) 7.73 (d, 1H, J 7.6), 7.70 (s, 1H), 7.47 (t, 1H, J 7.6), 7.36 (t, 1H, J 7.6), 7.25 (d, 1H, J 7.6), 6.48 (dd, 1H, J 17.8, 11.4), 5.72 (d, 1H, J 17.8), 5.80-5.69 (m, 1H), 5.20 (d, 1H, J 11.4), 5.09 (dd, 1H, J 10.3, 1.1), 4.97 (dd, 1H, J 17.1, 1.1), 4.36 (dd, 1H, J 16.2, 5.6), 4.23 (dd, 1H, J 16.2, 5.6), 3.92 (s, 3H), 2.35-2.24 (m, 1H), 1.75-1.16 (m, 10H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.[NH:7]1[CH2:12][CH2:11][CH2:10][C@@H:9]([NH:13][C:14]2[C:19](=[O:20])[NH:18][CH:17]=[C:16]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH:15]=2)[CH2:8]1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([N:7]1[CH2:12][CH2:11][CH2:10][C@@H:9]([NH:13][C:14]2[C:19](=[O:20])[NH:18][CH:17]=[C:16]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH:15]=2)[CH2:8]1)=[O:4]
Reactant: O=c1[nH]cc(-c2ccncc2)cc1N[C@@H]1CCCNC1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCC[C@@H](Nc2cc(-c3ccncc3)c[nH]c2=O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
Chloroacetyl chloride (0.021 mL, 0.26 mmol) was added to a solution of (R)-5-(piperidin-3-ylamino)-[3,4′-bipyridin]-6(1H)-one hydrochloride (100 mg, 0.26 mmol) and triethylamine (0.17 mL, 1.2 mmol) in dichloromethane (5.0 mL) at 0° C. The solution was stirred at 0° C. for 30 min and was concentrated. The residue was diluted with water and extracted with 5% methanol in ethyl acetate. The organic layer was dried over sodium sulphate, filtered, and concentrated. The residue was purified on silica gel eluting with 10% methanol in dichloromethane to provide 20 mg of the title compound: 1H NMR (300 MHz, DMSO-d6) 11.80-11.95 (m, 1H), 8.45-8.60 (m, 2H), 7.60-7.70 (m, 2H), 7.20-7.35 (m, 1H), 6.70-6.95 (m, 1H), 5.50-5.80 (m, 1H), 4.20-4.50 m, 1H), 3.45-3.95 (m, 1H), 2.95-3.40 (m, 2H), 2.65-2.90 (m, 1H), 1.35-2.15 (m, 2H); MS (ES) m/z 347 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2[CH2:18]O)=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=1[SH:40].C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl>[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=1[S:40][CH2:18][C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=1
Reactant: Sc1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1cnc(CO)n1-c1ccc(F)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(CSc2c(Cl)cccc2Cl)n1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 1-(4-fluorophenyl)-2-(hydroxymethyl)-1H-imidazole-5-carboxylate (15) (1.25 g, 4.7 mmol) and triethylamine (0.95 g, 9.4 mmol) in CH2Cl2 (30 mL) was added methanesulfonyl chloride (0.65 g, 5.64 mmol) at 0° C. and the reaction was stirred at 0° C. After 3 hours, 2,6-dichlorobenzenethiol (0.84 g mg, 4.7 mmol) and cesium carbonate (2.28 g, 7 mmol) were added and the reaction was stirred at room temperature for 1 hour. The mixture was filtered by vacuum filtration, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford ethyl 2-(((2,6-dichlorophenyl)thio)methyl)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (72).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][N:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][O:48][C@@H:49]1[CH2:53][CH2:52][NH:51][CH2:50]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][N:37]([CH2:40][C:41]([N:51]4[CH2:52][CH2:53][C@@H:49]([O:48][CH3:47])[CH2:50]4)=[O:42])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CO[C@@H]1CCNC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CC[C@@H](OC)C2)CC1

Procedure:
In a manner analogous to the method described in example 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid was coupled with (R)-3-methoxy-pyrrolidine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C40H51Cl2N6O4 [(M+H)+] 749.3344, observed 749.3337.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:4]=1[CH:5]=[O:6].[CH2:16]([Mg]Br)[CH:17]=[CH2:18]>C1COCC1>[CH3:1][O:2][C:3]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:4]=1[CH:5]([OH:6])[CH2:18][CH:17]=[CH2:16]
Reactant: COc1c(C)c(C)c(OC)c(C=O)c1C
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCC(O)c1c(C)c(OC)c(C)c(C)c1OC
Reaction time: 0.25 h

Procedure:
A stirred solution of 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde (6.34 g) in 125 mL THF was cooled to 0° C. and treated with 34 mL 1.0 M allyl magnesium bromide (1.0 M in THF, 1.1 equiv.) slowly over 0.25 h via dropping funnel. The solution was stirred for and additional 0.25 h and quenched by the addition of 40 mL 1.0 M aqueous citric acid and stirring until the layers clarified. The layers were separated and the aqueous layer extracted 3×50 mL EtOAc. The combined organics were washed 2×25 mL saturated aqueous NaCl, dried over Na2SO4 and concentrated to yield 9.8 g of 1-(2,5-dimethoxy-3,4,6-trimethylphenyl)but-3-en-1-ol as a brown oil. M+−H2O=233.4 m/z; 1H NMR (400 MHz, CDCl3) δ=5.90 (m, 1H), 5.15 (m, 1H), 5.10 (m, 1H), 4.98 (m, 1H), 3.78 (s, 3H), 3.65 (s, 3H), 2.66 (s, 1H), 2.48 (s, 1H), 2.25 (s, 3H), 2.18 (s, 6H) ppm.
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][NH:5]1)#[N:2].[H-].[Na+].[H][H].[C:13](Cl)(=[O:16])[CH2:14][CH3:15].Cl>CN(C)C=O.ClCCl>[C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][N:5]1[C:13](=[O:16])[CH2:14][CH3:15])#[N:2]
Reactant: N#CN=C1NCCN1
Reactant: CCC(=O)Cl
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(=O)N1CCNC1=NC#N
Temperature: 25 °C
Yield: 42.2 %

Procedure:
2.2 g of 2-cyanoimino-imidazolidine is dissolved in 20 ml of dry dimethyl formamide. To this solution were portionwise added 1.7 g of 60% oil dispersed sodium hydride at a temperature of at most 0° C. The reaction mixture was stirred at 0° C. until the evolution of hydrogen had ceased. To the reaction mixture were dropwise added 1.9 g of propionyl chloride while the reaction mixture was kept at a temperature lower than 0° C. After this addition, the reaction mixture was stirred at room temperature for a short period of time. The reaction mixture was poured into ice water, and neutralized with hydrochloric acid. An extraction operation was carried out by using dichloromethane, and the extractant was concentrated, so that the aimed product was precipitated as a crystalline material. The precipitated product was separated by filtration, and washed in ether, 1.4 g of 2-cyanoimino-1-propionyl-imidazolidine were obtained. mp. 208°-210° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[C@@H:10]([CH3:16])[NH:11][O:12][CH2:13][CH:14]=[CH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[Br:25][CH2:26][C:27](Br)=[O:28]>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:17])[C@@H:10]([CH3:16])[N:11]([C:27](=[O:28])[CH2:26][Br:25])[O:12][CH2:13][CH:14]=[CH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCON[C@H](C)C(=O)OCc1ccccc1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCON(C(=O)CBr)[C@H](C)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
To a solution of (R)-N-allyloxyalanine benzyl ester (2a) (2.59 g, 11 mmol) and Et3N (1.11 g, 11 mmol) in dry CH2Cl2 (30 mL), a solution of bromoacetyl bromide (2.22 g, 11 mmol) in dry CH2Cl2 (20 mL) was added dropwise with cooling (−25˜−30° C.) and stirring. The reaction mixture was stirred for 1 h at 0˜+5° C. and allowed to warm up to RT. After dilution with CH2Cl2 (ca. 30 mL), the mixture was washed with water (2×30 mL), 1N HCl (30 mL), sat. aq. NaHCO3 (30 mL), and dried over MgSO4. Removal of the solvent afforded 3.90 g (99%) of the product 3 as a yellowish oil. 1H NMR (100 MHz) in CDCl3 (J, Hz): δ 1.60 (3H, d, 3J=7.3, MeCH), 4.08 (2H, CH2Br), 4.49 (2H, dt, 3J=6.1, 4J=0.9, OCH2CH═CH2), 4.98 (1H, q, MeCH, 3J=7.3), 5.16-5.48 (2H, m, CH═CH2), 5.20 (2H, CH2Ph), 5.76-6.15 (1H, m, 3J=6.1, 3Jcis=10.0, 3Jtrans=17.3, CH═CH2), 7.29-7.41 (5H, m, Ph). IR (film), cm−1: 1746, 1678, 1455, 1214. MS (CI, isobutane), m/Z: 357 (M++1), 356 (M+).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[F:26][C:27]([F:34])([C:30]([F:33])([F:32])[F:31])[CH2:28][NH2:29]>>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:29][CH2:28][C:27]([F:34])([F:26])[C:30]([F:33])([F:32])[F:31])=[O:2])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1
Reactant: NCC(F)(F)C(F)(F)F
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3F)noc2C)nc1
Product: Cc1onc(-c2ccccc2F)c1COc1ccc(C(=O)NCC(F)(F)C(F)(F)F)cn1
Yield: 75 %

Procedure:
As described for example 84f, 6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.292 mmol) was converted, using 2,2,3,3,3-pentafluoropropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (100 mg, 75%) which was obtained as a white solid. MS: m/e=460.1 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][C:6]([C:8]1[S:9][C:10]([CH3:13])=[CH:11][CH:12]=1)=[O:7].[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.[Hg]>[CH3:1][Si:2]([CH3:14])([CH3:15])[CH2:3][CH2:4][O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][Br:16])=[CH:11][CH:12]=1)=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)OCC[Si](C)(C)C)s1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Hg]
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](C)(C)CCOC(=O)c1ccc(CBr)s1

Procedure:
A solution of the title A compound, 5-methyl-thiophene-2-carboxylic acid 2-trimethylsilanyl-ethyl ester (34.15 g, 141 mmol) in CCl4 (200 mL) is treated with N-bromosuccinimide (NBS, 25.08 g, 141 mmol) and 2,2′-azobisisobutyronitrile (1.0 g, 6 mmol). The mixture is irradiated with a 450 W mercury lamp for 3 h. An additional 2.5 g of NBS is added and the mixture is further irradiated for 2 h. The mixture is filtered through Celite and a plug of silica gel. The solvent is evaporated to give 5-bromomethyl-thiophene-2-carboxylic acid 2-trimethylsilanyl-ethyl ester as a yellow liquid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.[OH-].[Na+]>C(OCC)C>[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(O)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: C=Cc1ccc(OC2CCCCO2)cc1
Reaction time: 20 h

Procedure:
In a 250 ml round-bottomed flask, 15 g (125 mmol) of 4-hydroxystyrene and 0.4 g (2.3 mmol) of p-toluenesulfonic acid monohydrate are dissolved in 120 ml of diethyl ether. Then, at 5° C., 11.6 g (137 mmol) of 3,4-dihydro-2H-pyran are added dropwise over a period of 10 minutes. The mixture is allowed to reach room temperature and is further stirred for 20 hours. 1N NaOH solution is then added and the organic phase is washed twice with water, dried over magnesium sulfate and concentrated to yield 23.3 g (114 mmol, 90% of the theoretical yield) of 4-tetrahydropyran-2-yloxystyrene in the form of a colourless oil that can be used for the copolymerisation without being further purified. 1H-NMR (CDCl3, 100 mHz): δ7.37/d (J=9 Hz)/2H, 7.02/d (J=9 Hz)/2H, 6.52/dd (J1 =18 Hz, J2 =11 Hz)/1H, 5.50/dd (J1 =18 Hz, J2 =2 Hz)/1H, 5.41/m/1H, 5.11/dd (J1 =11 Hz, J2 =2 Hz)/1H, 4.0-3.7/m/1H, 3.7-3.4/m/1H, 2.2-1.2/m/6H.
Reaction SMILES: [I:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.C(OC(O[CH2:19][CH3:20])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:32][NH:33][CH2:34]C>C1CCCCC1.C(OCC)(=O)C>[I:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([N:6]=[CH:32][N:33]([CH2:19][CH3:20])[CH3:34])=[C:4]([CH3:10])[CH:3]=1
Reactant: CCNC
Reactant: CCOC(OCC)OCC
Reactant: Cc1cc(I)c(C)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CCN(C)C=Nc1cc(C)c(I)cc1C
Temperature: 40 °C
Reaction time: 16 h
Yield: 84.6 %

Procedure:
To a mixture of 12.3 g (50 mmol) of 4-iodo-2,5-dimethylaniline and 83 ml (500 mmol) of triethoxymethane 0.48 g (2.50 mmol) of p-toluene sulfonic acid were added. The reaction mixture was refluxed for 16 hrs and concentrated in vacuo. The crude product was dissolved in 100 ml of dichloromethane and 5.91 g (100 mmol) N-methylethanamine were added. The reaction mixture was stirred for 16 hrs at 40° C. The reaction mixture was concentrated in vacuo. Column chromatographie (cyclohexane/ethyl acetate 3:1) yielded 13.4 g (42.3 mmol) 85% of N′-(4-iodo-2,5-dimethylphenyl)-N-ethyl-N-methylimidoformamide; log P (pH 2.3)=1.21.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2)=[CH:5][C:4]=1[CH:22]([CH3:24])[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:44]N1C(=O)CCC1=O>>[Br:44][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2)=[CH:5][C:4]=1[CH:22]([CH3:24])[CH3:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(CO)c(C(C)C)c2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)Cc1ccc(C#Cc2ccc(CBr)c(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of methyl [4-(4-hydroxymethyl-3-isopropyl-phenylethynyl)-phenyl]-acetate (Compound 123, 180.0 mg, 0.56 mmol) and triphenylphosphine (190.0 mg, 0.73 mmol) in 5 mL CH2C2 was cooled to 0° C. and N-bromosuccinimide (130.0 mg, 0.73 mmol) was added in 5 portions over 20 minutes. The solution was warmed to 25° C. and stirred for 17 hours. The reaction was quenched by the addition of dilute aqueous NaHCO3. The resulting mixture was extracted with Et2O and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (Na2SO4) and concentrated under reduced pressure. The title compound, 212.0 mg (98%), was isolated by column chromatography (5-10% EtOAc-hexanes) as a pale-yellow oil.
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][CH:7]=[C:6]2[O:15][C:16]1[C:17]([OH:26])=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2.C(=O)([O-])[O-].[K+].[K+].[CH:33]1(Br)[CH2:37][CH2:36][CH2:35][CH2:34]1.O>CN(C)C=O>[CH:33]1([O:26][C:17]2[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3O)c2cc1OC
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3OC3CCCC3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
6,7-Dimethoxy-4-(2-hydroxy-quinolin-3-yloxy)-quinoline (19 mg) was dissolved in N,N-dimethylformamide (4 ml) to prepare a solution. Potassium carbonate (180 mg) and cyclopentyl bromide (0.1 ml) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography using acetone-chloroform to give the title compound (14 mg, yield 60%).
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1.OS(O)(=O)=O.[CH2:15](O)[CH3:16]>>[SH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:15][CH3:16])=[O:8])[N:6]=1
Reactant: CCO
Reactant: O=C(O)c1csc(S)n1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1csc(S)n1

Procedure:
To 2-mercaptothiazole-4-carboxylic acid (Ex. 19b, 4.2 g) in 50 mL ethyl alcohol was added 2 mL conc. H2SO4. The mixture was heated to reflux for 8 h and cooled. The solvent was removed under reduced pressure and the residue was poured onto 50 mL ice water. The solid was collected, washed with water and dried under vacuum. The crude product was recrystallized from 8 mL ethyl alcohol to afford ethyl 2-mercaptothiazole-4-carboxylate (2.3 g) as a yellow solid.