Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][C:10]([CH3:19])([CH3:18])[C:11]([OH:17])([CH3:16])[CH2:12][CH2:13][CH:14]=[CH2:15])=[CH:6][CH:5]=1.N1C2C(=CC=CC=2)C=CC=1>C(Cl)(Cl)Cl>[Br:1][CH2:15][CH:14]1[CH2:13][CH2:12][C:11]([C:10]([CH3:19])([CH3:18])[CH2:9][O:8][C:7]2[CH:20]=[CH:21][C:4]([Cl:3])=[CH:5][CH:6]=2)([CH3:16])[O:17]1
Reactant: BrBr
Reactant: C=CCCC(C)(O)C(C)(C)COc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccc2ncccc2c1
Product: CC(C)(COc1ccc(Cl)cc1)C1(C)CCC(CBr)O1
Yield: 90.4 %

Procedure:
16 g (0.1 mole) of bromine are added dropwise to 28.2 g (0.1 mole) of 7-(4-chlorophenoxy)-5-hydroxy-5,6,6-trimethyl-hept-1-ene in 200 ml of absolute chloroform at room temperature, with stirring, followed by 13 g (0.1 mole) of quinoline, at -10° C. with cooling. The reaction mixture is stirred at room temperature for a further 2 hours and concentrated in vacuo, the residue is taken up in ether, the mixture is filtered and concentrated again in vacuo and the residue is stirred at 95° C. on a water-bath for 1 hour. The resulting mixture is taken up in ether and filtered and the filtrate is washed with 15% strength hydrochloric acid and then with water, dried over sodium sulphate and freed from the solvent in vacuo. 32.7 g (90% of theory) of 2-bromomethyl-5-[1-(4-chlorophenoxy)-2-methylprop-2-yl]-5-methyl-tetrahydrofuran are obtained as an oil, which can be used in the next stage without further purification. ##STR142##
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:33])[C:13]2[O:19][C:18]3[C:20]([Cl:29])=[CH:21][C:22]([NH:24][C:25](=[O:28])[CH2:26]Cl)=[CH:23][C:17]=3[CH2:16][S:15](=[O:31])(=[O:30])[C:14]=2[CH:32]=1)=[O:9]>CN(C=O)C>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:33])[C:13]2[O:19][C:18]3[C:20]([Cl:29])=[CH:21][C:22]([NH:24][C:25](=[O:28])[CH2:26][N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)=[CH:23][C:17]=3[CH2:16][S:15](=[O:31])(=[O:30])[C:14]=2[CH:32]=1)=[O:9]
Reactant: c1c[nH]cn1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CCl)cc(Cl)c1O2
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)Cn3ccnc3)cc(Cl)c1O2
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
Imidazole (0.215 g, 3.16 mmol) was added to a solution of Example 133 (0.7 g, 1.58 mmol) in DMF (15 mL) and the reaction mixture was stirred at 120° C. for 2.5 h. It was concentrated, treated with water and the solid that precipitated was filtered, washed with water and purified using flash chromatography (silica gel, 4% methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.4 g, (53.33%); 1H NMR (DMSO-d6): δ 2.66 (s, 3H, CH3), 3.9 (s, 3H, OCH3), 4.97 (s, 2H, CH2), 5.4 (s, 2H, CH2), 6.9 (s, 1H, Ar), 7.2 (s, 1H, Ar), 7.64 (s, 1H, Ar), 7.7 (d, 1H, Ar), 7.9 (d, 1H, Ar), 8.12 (s, 1H, Ar), 8.2 (s, 1H, Ar), 10.72 (bs, 1H, NH); MS: m/e (ES+) 476 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([NH:12][C:13](=[N:21]Cl)[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:5]=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:21]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:12][C:6]=2[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)=[O:23]
Reactant: COC(=O)c1ccc(OC)c(NC(=NCl)c2ccc(Cl)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(OC)c2[nH]c(-c3ccc(Cl)cc3)nc12
Temperature: 25 °C
Yield: 52 %

Procedure:
3-[(4-chloro-N-chloro-benzimidoyl)-amino]-4-methoxy-benzoic acid methyl ester (5.5 g, 15.63 mmol) obtained in step 1 was dissolved in 40 ml of 50% methanol and Na2CO3 (3.53 g, 33.26 mmol) was added dropwise thereto at room temperature and refluxed for 5 min. The resulting solution was cooled to room temperature, extracted with ethyl acetate, the extract was concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (2.57 g, 8.13 mmol) in a yield of 52%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:14]([CH3:23])[C:13](=[N:24][C:25]3[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=3[CH3:33])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[F:41][C:42]1[CH:50]=[CH:49][C:45]([C:46](Cl)=[O:47])=[CH:44][CH:43]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([N:17]3[CH2:18][CH2:19][N:20]([C:46](=[O:47])[C:45]4[CH:49]=[CH:50][C:42]([F:41])=[CH:43][CH:44]=4)[CH2:21][CH2:22]3)[N:14]([CH3:23])[C:13](=[N:24][C:25]3[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=3[CH3:33])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(N3CCNCC3)n2)cc1OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(N3CCN(C(=O)c4ccc(F)cc4)CC3)n2)cc1OC
Temperature: 25 °C

Procedure:
To a suspension of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-2-(1-piperazinyl)-4-(2,4,6-trimethylphenylimino)pyrimidine (0.31 g) in tetrahydrofuran (10 ml) were added triethylamine (0.11 ml) and 4-fluorobenzoyl chloride (0.69 ml). The mixture was stirred at ambient temperature for an hour and the reaction was quenched by adding methanol (5 ml). After evaporation of the solvent, the residue was dissolved in ethyl acetate. The solution was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel using a mixture of chloroform and methanol (95:5) to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-2-[4-(4-fluorobenzoyl)piperazin-1-yl]-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (0.34 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C@@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:13][CH2:12][C@H:11]([CH3:14])[CH2:10][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: Oc1cccc(F)c1
Reactant: C[C@@H](CCl)CBr
Product: C[C@@H](CCl)COc1cccc(F)c1

Procedure:
Prepared by Procedure U and Scheme AK using 3-fluorophenol and (2S)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[C:11]2[CH3:28])=[CH:4][CH:3]=1.[C:30]1([CH3:40])[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37](Cl)=[O:38]>>[CH3:28][C:11]1[N:10]([CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:37](=[O:38])[CH2:36][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH3:40])=[CH:7][CH:6]=2)=[O:29])[C:14](=[O:15])[C:13]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=1
Reactant: Cc1ccccc1CC(=O)Cl
Reactant: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(N)cc1
Product: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(NC(=O)Cc2ccccc2C)cc1

Procedure:
Synthesis in analogy to Example 8 starting from 3-[2-(4-amino-phenyl)-2-oxo-ethyl]-2-methyl-5,5-diphenyl-3,5-dihydro-imidazol-4-one and o-tolyl-acetyl chloride to yield N-{4-[2-(2-methyl-5-oxo-4,4-diphenyl-4,5-dihydro-imidazol-1-yl)-acetyl]-phenyl}-2-o-tolyl-acetamide. LC/MS at 254 nm; [M+H] 516; Rt 3.526 min.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[C:32]([OH:39])[CH:31]=1)(=[O:29])=[O:28]>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][S:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[C:32]([OH:39])[CH:31]=2)(=[O:29])=[O:28])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(CCc2c(Cc3ccccc3)sc3ccccc23)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: O=C(O)c1ccc(S(=O)(=O)Oc2ccc(CCc3c(Cc4ccccc4)sc4ccccc34)cc2)cc1O

Procedure:
The title compound was prepared according to the procedure in Example 4 using 4-[2-(2-benzyl-benzo[b]thiophen-3-yl)-ethyl]-phenol (0.400 g, 1.16 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.550 g, 2.32 mmol). Purification on 2% H3PO4 /MeOH treated silica gel, eluting with 20% EtOAc/hexane gave the title compound as an off white solid, mp 57-59° C. 1H NMR (DMSO-d6) δ 2.74 (t, 2 H), 3.09 (t, 2 H), 4.00 (s, 2 H), 6.97 (d, 2 H), 7.19-7.23 (m, 5 H), 7.27-7.38 (m, 6 H), 7.76 (d, 1 H), 7.83 (dd, 1 H), 7.98 (d, 1 H). IR (KBr) 3400, 2950, 1675, 1390 and 1190 cm-1. mass spectrum (-ESI) m/z 543 (M-H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([OH:12])(=[O:11])=[O:10].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>[Cu]>[N:13]1([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[S:9]([OH:12])(=[O:11])=[O:10])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: Cc1ccc(F)c(S(=O)(=O)O)c1
Reactant: C1CNCCN1
Agent: [Cu]
Product: Cc1ccc(N2CCNCC2)c(S(=O)(=O)O)c1
Yield: 65.4 %

Procedure:
According to the method described in Example 1 of the Japanese Patent Unexamined Publication (KOKAI) No.(Hei)3-7263/1991, 2-fluoro-5-methylbenzenesulfonic acid (0.76 g) and piperazine (3.44 g) were reacted in a sealed tube in the presence of cuprous iodide (0.76 g) and copper powder (0.26 g) at 160° C. for 8 hours, and then the reaction product was purified by silica gel chromatography (eluent: chloroform: methanol: acetic acid=100:100:3) to give anhydrous crystals of 2-(1-piperazinyl)-5-methylbenzenesulfonic acid (0.67 g, yield: 65.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8]Cl)=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:12][C:13]1[C:18]([NH:19][CH2:8][CH:7]=[CH:6][C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: Nc1cccnc1N
Reactant: ClCC=Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncccc1NCC=Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 50 h
Yield: 42.2 %

Procedure:
7.71 g of p-chlorocinnamyl chloride and 13.5 g of 2,3-diaminopyridine were dissolved in 220 ml of dimethylformamide, and to the solution was added 8.6 g of potassium carbonate, and the mixture was stirred at a room temperature for 50 hours, and after adding 300 ml of water, extracted twice with 200 ml of chloroform. The extract was dried over magnesium sulfate and concentrated under a reduced pressure, and resulting residue was applied to a silica gel column and eluted with chloroform/methanol (100:1 to 50:1), to obtain 4.52 g of the title compound as yellow crystals.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](\[C:10]([NH:12][C@@H:13]1[C:16](=[O:17])[N:15]2[C:18]([C:27]([OH:29])=[O:28])=[C:19]([CH2:22][O:23][C:24]([NH2:26])=[O:25])[CH2:20][S:21][C@H:14]12)=[O:11])/[C:5]1[O:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:37][O:38][C:39](=[O:45])[C:40]([O:43][CH3:44])([CH3:42])[CH3:41].O>CN(C)C=O>[C:24]([O:23][CH2:22][C:19]1[CH2:20][S:21][C@@H:14]2[C@H:13]([NH:12][C:10](=[O:11])/[C:4](/[C:5]3[O:9][CH:8]=[CH:7][CH:6]=3)=[N:3]\[O:2][CH3:1])[C:16](=[O:17])[N:15]2[C:18]=1[C:27]([O:29][CH2:37][O:38][C:39](=[O:45])[C:40]([O:43][CH3:44])([CH3:42])[CH3:41])=[O:28])(=[O:25])[NH2:26]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reactant: COC(C)(C)C(=O)OCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)OC)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 0.58 h
Yield: 69.1 %

Procedure:
Cefuroxime (1.697 g) and powdered potassium carbonate (276 mg) were stirred in anhydrous N,N-dimethylformamide (20 ml) at 22° for 1 hour and the resulting solution was cooled in an ice/salt bath to -8°. A solution of crude 2-methoxy-2-methylpropanoic acid iodomethyl ester (1.52 g) in anhydrous N,N-dimethylformamide (6 ml) was added and the solution was stirred for 35 mins. Water (75 ml) was added and the mixture was extracted with ethyl acetate (2×100 ml). The combined organic layers were washed successively with 50 ml each of 2N hydrochloric acid (3×), water, saturated aqueous sodium bicarbonate, water, 10% aqueous sodium metabisulphite, water (2×) and saturated brine, dried over magnesium sulphate and concentrated under vacuum to ca 10 ml. The solution was added dropwise to stirred petroleum ether (100 ml) to give a precipitate which was filtered off, washed with petroleum ether and dried under reduced pressure to give the title ester (1.532 g); λmax (ethanol 277) nm E11 323; νmax (CHBr3) 3520 and 3400 (NH and NH2), 1788 (β-lactam C=O); 1735 (ester and carbamate C=O) and 1685 and 1510 cm-1 (amide C=O).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[CH:10][C:9]([C:12]([OH:14])=O)=[CH:8][CH:7]=1.S(Cl)([Cl:17])=O>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[CH:10][C:9]([C:12]([Cl:17])=[O:14])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(-c2cccs2)nc1
Product: O=C(Cl)c1ccc(-c2cccs2)nc1

Procedure:
A mixture of 1.8 g of 6-(2-thienyl)pyridine-3-carboxylic acid in 50 ml of thionyl chloride is refluxed under dry conditions for 1 hour. The reaction mixture is evaporated to dryness and evaporated again from 50 ml of carbon tetrachloride to a residue. The residue is dissolved in 60 ml of methylene chloride and used further reactions.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C@H:9]([O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)/[CH:10]=[CH:11]/[C@@H:12]2[C@@H:24]3[C@@H:15]([O:16][C:17](=[O:25])[CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH2:23]3)[CH2:14][C@H:13]2[O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:40]([NH2:42])[CH3:41].Cl>O1CCCC1.O>[CH2:40]([NH:42][C:17](=[O:25])[CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][C@H:24]1[C@@H:15]([OH:16])[CH2:14][C@@H:13]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C@@H:12]1/[CH:11]=[CH:10]/[C@@H:9]([O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:41]
Reactant: O=C1CCCC=CC[C@@H]2[C@@H](/C=C/[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Reactant: CCN
Agent: Cl
Agent: O=C1CCC/C=C\C[C@@H]2[C@@H](/C=C/[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@H](CCc2ccccc2)OC2CCCCO2)[C@H](OC2CCCCO2)C[C@@H]1O
Temperature: 40 °C
Yield: 73.8 %

Procedure:
A solution of (6Z,8aR,9R,10R,11aS)-4,5,8,8a,9,10,11,11a-octahydro-9-((S,E)-5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)pent-1-enyl)-10-(tetrahydro-2H-pyran-2-yloxy)cyclopenta[b]oxecin-2(3H)-one (3.0 g, 5.57 mmol) in 15 mL tetrahydrofuran (THF) was treated with 2 M ethylamine (31 ml) in THF. This mixture was stirred and heated at 40° C. over 18 hours under an atmosphere of nitrogen. The mixture was diluted with 50 mL water and the pH was adjusted to 6 with 1N HCl. The layers were separated and the aqueous layer was extracted with 20 mL ethyl acetate twice. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. Then, the crude product was purified by column chromatography providing 2.4 g of the title compound (73.8% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]1[CH2:8][CH2:7][CH:6]=[CH:5][CH:4]=1.[C:10]1(=[O:16])[NH:14][C:13](=[O:15])[CH:12]=[CH:11]1>O1CCOCC1>[CH3:1][N:2]([CH3:9])[C:3]12[CH2:8][CH2:7][CH:6]([CH:5]=[CH:4]1)[CH:12]1[CH:11]2[C:10](=[O:16])[NH:14][C:13]1=[O:15]
Reactant: CN(C)C1=CC=CCC1
Reactant: O=C1C=CC(=O)N1
Solvent: C1COCCO1
Product: CN(C)C12C=CC(CC1)C1C(=O)NC(=O)C12

Procedure:
9 g (73 mmol) of 1-dimethylaminocyclohexa-1,3-diene and 6.4 g (66 mmol) of maleimide are stirred in 100 ml of absolute dioxane at room temperature overnight. The mixture is concentrated and the residue is recrystallized from isopropanol.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:5][C:6]=1[CH:7]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[CH2:8][CH:9]([CH3:11])[CH3:10].[CH3:32][NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37]>>[CH3:1][C:2]1[O:3][C:4]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:26][CH:27]=2)=[CH:5][C:6]=1[CH:7]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([N:33]([CH3:32])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:18])=[CH:15][CH:14]=1)[CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(CC(C)C)Oc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CCNC
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(CC(C)C)Oc1ccc(C(=O)N(C)CCC(=O)O)cc1
Yield: 86.9 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-(1-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}-3-methylbutoxy)benzoic acid (99 mg) as well as ethyl 3-(methylamino)propanoate (37 mg) to give the title compound (103 mg, 87%) as an amorphous compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH2:13])=[O:12])[C:6](=[O:14])[CH2:5]2.[CH3:15][S:16][C:17]1[O:21][C:20](C(Cl)=O)=[N:19][N:18]=1>CN(C1C=CN=CC=1)C.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH2:13])=[O:12])[C:6](=[O:14])[CH:5]2[C:20]1[O:21][C:17]([S:16][CH3:15])=[N:18][N:19]=1
Reactant: CSc1nnc(C(=O)Cl)o1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CSc1nnc(C2C(=O)N(C(N)=O)c3ccc(Cl)cc32)o1
Yield: 44.2 %

Procedure:
Using the procedure of Example 32, a 30 ml N,N-dimethylformamide solution of 958 mg (4.55 mmoles) of 5-chloro-2-oxindole-1-carboxamide and 1.50 g (12.28 mmoles) of 4-(N,N-dimethylamino)pyridine was reacted with 975 mg (5.46 mmoles) of 5-methylthio-1,3,4-oxadiazol-2-carbonyl chloride (U.S. Pat. No. 4,001,238). After acidic workup a crude orange solid (1.25 g, 78% yield) was obtained. Suspension in hot glacial acetic acid followed by filtration furnished the pure title compound (710 mg, 2.01 mmole, 44%) as a bright yellow solid, m.p. 297-9° C.
Reaction SMILES: C(O[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1)=[O:5])C.[CH3:27][C:28]1([CH3:38])[O:33][CH2:32][C:31]([CH3:37])(C(O)=O)[CH2:30][O:29]1>>[CH2:23]([O:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([CH2:12][C:9]2([C:28]([O:29][CH2:30][CH3:31])=[O:33])[CH2:10][CH2:11][N:6]([C:4]([C:31]3([CH3:37])[CH2:30][O:29][C:28]([CH3:27])([CH3:38])[O:33][CH2:32]3)=[O:5])[CH2:7][CH2:8]2)(=[O:14])=[O:15])=[CH:21][CH:20]=1)[C:24]#[C:25][CH3:26]
Reactant: CC1(C)OCC(C)(C(=O)O)CO1
Reactant: CC#CCOc1ccc(S(=O)(=O)CC2CCN(C(=O)OCC)CC2)cc1
Product: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCN(C(=O)C3(C)COC(C)(C)OC3)CC2)cc1
Yield: 131.8 %

Procedure:
Ethyl 4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-1-[(2,2,5-trimethyl-1,3-dioxan 5-yl)carbonyl]-4-piperidinecarboxylate was prepared according to the general method as outlined in Example 30 (step 8). Starting from 4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]piperidinecarboxylic acid ethyl ester (0.333 g, 0.8 mmol) and 2,2,5-trimethyl-(1,3)dioxane-5-carboxylic acid (0.168 g, 0.96 mmol), 0.339 g (79%) of the desired product was isolated as a white solid. Electrospray Mass Spec: 536.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8]([C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])[C:9](=[O:16])[C:10]#[C:11][Si](C)(C)C)=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8]([C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])[C:9](=[O:16])[C:10]#[CH:11])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#CC(=O)C(c1ccc(Cl)nn1)c1c(F)cccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: C#CC(=O)C(c1ccc(Cl)nn1)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 132 %

Procedure:
To a solution of 1-(6-chloropyridazin-3-yl)-1-(2,6-difluorophenyl)-4-(trimethylsilyl)but-3-yn-2-one (9.6 g, 26.4 mmol) in THF (200 mL) was added TBAF (32.9 mL, 32.9 mmol) at 0° C. After stirring at 0° C. for 15 min, the reaction was poured into aqueous NH4Cl, and extracted with EtOAc. The combined organic layers were washed with 1N HCl, brine, dried over MgSO4, and concentrated to an oil. The crude product was purified by silica gel chromatography (hexanes/CH2Cl2) to give title compound (10.2 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[C:4]([CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]=1F)[C:5]([OH:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[CH3:22][Si:23]([CH3:28])([CH3:27])[CH2:24][CH2:25][SH:26].[NH4+].[Cl-]>CCO.O>[Cl:1][C:2]1[C:3]([F:15])=[C:4]([CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]=1[S:26][CH2:25][CH2:24][Si:23]([CH3:28])([CH3:27])[CH3:22])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)c(Cl)c1F
Reactant: C[Si](C)(C)CCS
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCSc1c([N+](=O)[O-])cc(C(=O)O)c(F)c1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a mixture of 3.52 g (16.96 mmol) of 3-chloro-2,4-difluoro-5-nitro-benzoic acid (prepared as described in WO 03/077914) in 70 mL of EtOH, is added 6.56 g (47.48 mmol, 2.8 eq.) of K2CO3 dissolved in 30 mL of H2O. Then, 2.67 mL (16.96 mmol) of 2-(trimethylsilyl)ethanethiol are added in 10 minutes. The mixture is stirred at 50° C. during 1 h and then cooled to ambient temperature. After addition of a saturated NH4Cl aqueous solution, the product is extracted with EtOAc (3 times). The regrouped organic phases are dried with Na2SO4, filtered and evaporated. The crude 3-chloro-2-fluoro-5-nitro-4-(2-trimethylsilanyl-ethylsulfanyl)-benzoic acid is contaminated by 3-chloro-5-nitro-2,4-bis-(2-trimethylsilanyl-ethylsulfanyl)-benzoic acid. NMR integrals indicated a ratio 74:26 in favour of the desired compound. 1H-NMR of 3-chloro-2-fluoro-5-nitro-4-(2-trimethylsilanyl-ethylsulfanyl)-benzoic acid (CDCl3, 300 MHz): 0.04 (s, 9H), 0.76-0.81 (m, 2H), 2.90-2.94 (m, 2H), 7.93 (d, 1H) ppm. The mixture is used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:34])([F:33])[O:21][C:22]1[CH:23]=[C:24](/[CH:28]=[CH:29]/[C:30](O)=[O:31])[CH:25]=[CH:26][CH:27]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30](=[O:31])/[CH:29]=[CH:28]/[C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:33])([F:34])[F:19])[CH:23]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)/C=C/c1cccc(OC(F)(F)F)c1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3cccc(OC(F)(F)F)c3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(3-trifluoromethoxy-phenyl)-acrylic acid.