Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:21][S:20][C@@H:5]2[C@H:6]([NH:9][C:10]([C@H:12]([NH2:19])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:11])[C:7](=[O:8])[N:4]2[C:3]=1[C:22]([OH:24])=[O:23].O.C(=O)([O-])[O-].[K+].[K+].[CH2:32]([N:34]1[CH2:39][CH2:38][N:37]([C:40](Cl)=[O:41])[C:36](=[O:43])[C:35]1=[O:44])[CH3:33]>C(OCC)(=O)C>[CH3:1][C:2]1[CH2:21][S:20][C@@H:5]2[CH:6]([NH:9][C:10](=[O:11])[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:19][C:40]([N:37]3[CH2:38][CH2:39][N:34]([CH2:32][CH3:33])[C:35](=[O:44])[C:36]3=[O:43])=[O:41])[C:7](=[O:8])[N:4]2[C:3]=1[C:22]([OH:24])=[O:23]
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)[C@H](N)c3ccccc3)[C@H]2SC1
Reactant: CCN1CCN(C(=O)Cl)C(=O)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCN1CCN(C(=O)NC(C(=O)NC2C(=O)N3C(C(=O)O)=C(C)CS[C@H]23)c2ccccc2)C(=O)C1=O
Yield: 55.1 %

Procedure:
Cephalexin (696 mg., 2 mmoles) was dissolved in 10 ml. of water at 5° C. by the action of potassium carbonate (304 mg., 2.2 mmoles). Ethyl acetate (5 ml.) was added and then 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride (450 mg., 2.2 mole) was added over a period of 15 minutes at 0°-5° C. After addition was complete, the reaction mixture was stirred for an additional 30 minutes, at which time the ethyl acetate layer was separated and the aqueous phase washed with an additional portion of ethyl acetate. The aqueous phase was adjusted to 2.5 and the product extracted into several portions of fresh ethyl acetate. The acidic ethyl acetate extracts were combined, back-washed with water, washed with brine, dried over anhydrous magnesium sulfate, evaporated to dryness in vacuo, and the residue crystallized from methylene chloride to yield 3-methyl-7-[2-phenyl-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)acetamido]ceph-3-em-4-carboxylic acid (568 mg., m.p. 199°-200° C.).
Reaction SMILES: C(OC(=O)[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19](Cl)[N:18]=2)[CH:12]=1)[CH2:8][CH3:9])(C)(C)C.[F:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33][NH2:34])[CH:29]=[CH:30][CH:31]=1>>[CH2:8]([NH:7][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:34][CH2:33][CH2:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=3)[N:18]=2)[CH:14]=[CH:15][CH:16]=1)[CH3:9]
Reactant: CCN(Cc1cccc(-c2ccnc(Cl)n2)c1)C(=O)OC(C)(C)C
Reactant: NCCc1cccc(F)c1
Product: CCNCc1cccc(-c2ccnc(NCCc3cccc(F)c3)n2)c1

Procedure:
Intermediate 37 was coupled with 2-(3-fluoro-phenyl)-ethylamine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 351. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 9.5 (s, 2H) 8.5 (m, 2H) 8.2 (d, 1H) 7.8 (d, 1H) 7.6 (m, 1H) 7.5 (ms, 1H) 7.3 (m, 1H) 7.1 (m, 2H) 7.0 (m, 1H) 4.2 (s, 2H) 3.8 (m, 2H) 2.9 (m, 4H) 1.2 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][NH:11][N:10]=1.C(N(CC)CC)C.[Cl:29][CH2:30][C:31](Cl)=[O:32]>C1COCC1>[Cl:29][CH2:30][C:31]([N:11]1[N:10]=[C:9]([CH2:8][C:7]2[C:6]([Cl:21])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12]1)=[O:32]
Reactant: COc1ccc2c(c1)CNN=C2Cc1c(Cl)cncc1Cl
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CN(C(=O)CCl)N=C2Cc1c(Cl)cncc1Cl
Temperature: 25 °C
Yield: 110.5 %

Procedure:
At room temperature, under N2 and stirring, a solution of 1-[4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-1H-phthalazine (1.9 g, 5.9 mmoles), prepared as described in example 22, in dry THF (70 ml) was added with triethylamine (2.05 ml, 14.7 mmoles) and cooled at 0° C. Chloroacetyl chloride (0.56 ml, 7.07 mmoles) was dropwise added and a precipitate formed. After 1 night further 50% of triethylamine and chloroacetyl chloride was added, and after 20 hours at room temperature the mixture was poured into water/ice, concentrated and extracted more times with CH2Cl2. The organic phase was washed with water, anhydrified and brought to dryness to give 2.6 g of the title compound (quantitative yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[N:4][S:5][C:6]=1[C:7]([NH2:9])=[O:8].[N:18]([O-])=O.[Na+]>C(O)(=O)C.Cl.O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:3]2[C:2]3[N:1]=[N:18][NH:9][C:7](=[O:8])[C:6]=3[S:5][N:4]=2)=[CH:11][CH:12]=1
Reactant: O=N[O-]
Reactant: COc1ccc(-c2nsc(C(N)=O)c2N)cc1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2nsc3c(=O)[nH]nnc23)cc1
Reaction time: 1 h
Yield: 78.5 %

Procedure:
1 g of 4-amino-3-(4-methoxyphenyl)-5-isothiazolecarboxamide in 10 ml of glacial acetic acid and 3 ml of concentrated hydrochloric acid was stirred at 0° C. during the addition of a solution of 416 mg of sodium nitrite in 5 ml of water. The cooling bath was removed, the mixture was stirred for 1 hour and the precipitated product was removed by filtration. Recrystallization from aqueous dimethylformamide gave 820 mg of 7-(4-methoxyphenyl)-isothiazolo[4,5-d]-1,2,3-triazin-4(3H)-one as an off-white solid of melting point 213° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[N+:23]([O-])=O)[NH:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[N:16][N:15]([CH3:18])[C:14]=2[CH:19]=1)=[O:9])([O-])=O.[CH3:26][N:27]([CH3:36])[C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1>>[CH3:26][N:27]([CH3:36])[C:28]1[CH:35]=[CH:34][C:31]([C:32]2[NH:23][C:22]3[CH:21]=[CH:20][C:6]([NH:7][C:8]([C:10]4[CH:11]=[CH:12][C:13]5[N:17]=[N:16][N:15]([CH3:18])[C:14]=5[CH:19]=4)=[O:9])=[CH:5][C:4]=3[N:1]=2)=[CH:30][CH:29]=1
Reactant: Cn1nnc2ccc(C(=O)Nc3ccc([N+](=O)[O-])c([N+](=O)[O-])c3)cc21
Reactant: CN(C)c1ccc(C=O)cc1
Product: CN(C)c1ccc(-c2nc3cc(NC(=O)c4ccc5nnn(C)c5c4)ccc3[nH]2)cc1

Procedure:
Compound 190 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(1-methyl-6-benzotriazolylcarbonyl)aniline and 4-dimethylaminobenzaldehyde. 1H NMR (500 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.78 (s, 1H), 8.43 (d, J=1.5 Hz, 1H), 8.16 (dd, J=1, 8.5 Hz, 1H), 8.10 (d, J=9 Hz, 2H), 8.01 (d, J=8.5 Hz, 2H), 7.84 (dd, J=2, 9 Hz, 1H), 7.72 (d, J=9 Hz, 1H), 6.96 (d, J=9 Hz, 2H), 4.39 (s, 3H), 3.10 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][S:8](=[O:11])(=[O:10])[N:7]([CH3:12])[C:6]=2[CH:13]=1.C([O-])([O-])=O.[K+].[K+].[CH3:20][Si:21]([CH2:24][CH2:25][O:26][CH2:27]Cl)([CH3:23])[CH3:22]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH2:27][O:26][CH2:25][CH2:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[S:8](=[O:11])(=[O:10])[N:7]([CH3:12])[C:6]=2[CH:13]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CN1c2cc(Br)ccc2NS1(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1c2cc(Br)ccc2N(COCC[Si](C)(C)C)S1(=O)=O
Temperature: 75 °C
Reaction time: 4 h

Procedure:
To a solution of 6-bromo-1-methyl-1,3-dihydrobenzo[c][1,2,5]thiadiazole 2,2-dioxide (557 mmol, 2.10 mmol, as prepared above) in DMF (5 mL), K2CO3 (1.00 g, 7.23 mmol) and SEM-Cl (0.560 mL, 3.20 mmol) were added. The resulting mixture was stirred at 75° C. for 4 h and allowed to cool to rt. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3×20 mL). The combined DCM layers were dried over Na2SO4, filtered, concentrated and the resulting residue was purified by flash column chromatography on silica gel (0-50% hexane/EtOAc) to obtain compound 39a. 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.12-7.17 (m, 2H), 6.60 (d, J=8.6 Hz, 1H), 5.14 (s, 2H), 3.68-3.74 (m, 2H), 3.25 (s, 3H), 0.93-0.99 (m, 3H), 0.01 (s, 9H).
Reaction SMILES: FC(F)(F)S(O[C@@H:7]1[C:11]([CH3:13])([CH3:12])[CH2:10][O:9][C:8]1=[O:14])(=O)=O.[N-:17]=[N+:18]=[N-:19].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCOCC>[N:17]([C@H:7]1[C:11]([CH3:13])([CH3:12])[CH2:10][O:9][C:8]1=[O:14])=[N+:18]=[N-:19]
Reactant: CC1(C)COC(=O)[C@@H]1OS(=O)(=O)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1(C)COC(=O)[C@H]1N=[N+]=[N-]
Reaction time: 5 h

Procedure:
To a solution containing the product from Example 174A (4.6 g, 17.56 mmol) in toluene (80.0 mL) was added tetra-n-butylammonium azide (5.0 g, 17.57 mmol) at room temperature, and the mixture was stirred for 5 hours. The reaction was diluted with ether and washed with water, dilute NaHCO3, 10% citric acid and brine. The organic layer was dried over MgSO4, filtered and concentrated to give the crude product, which was used without further purification (2.79 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[NH:10]2)[CH:6]=[CH:7][CH:8]=1.[F:16][C:17]([F:25])([F:24])[C:18](=[O:23])[C:19]([O:21][CH3:22])=[O:20]>C(Cl)(Cl)Cl>[CH3:22][O:21][C:19](=[O:20])[C:18]([OH:23])([C:17]([F:25])([F:24])[F:16])[C:12]1[C:13](=[O:14])[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:10][C:11]=1[CH3:15]
Reactant: COc1cccc(-n2[nH]c(C)cc2=O)c1
Reactant: COC(=O)C(=O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)C(O)(c1c(C)[nH]n(-c2cccc(OC)c2)c1=O)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a chloroform solution (5 ml) of 1-(3-methoxyphenyl)-3-methyl-5-pyrazolone (102 mg, 0.5 mmol), methyl trifluoropyruvate (78 mg, 0.5 mmol) was added at room temperature and the mixture was stirred at 80° C. for 2 hours. After removing the solvent under reduced pressure, the title compound was obtained as a pale yellow solid (180 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[CH2:10][CH2:9][N:8]([C@@H:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]([O:14]C(C)(C)C)=[O:13])[C:7]1=[O:23].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[CH2:10][CH2:9][N:8]([C@@H:11]([C:19]([CH3:20])([CH3:21])[CH3:22])[C:12]([OH:14])=[O:13])[C:7]1=[O:23]
Reactant: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2cccc(F)c2)C1=O)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2cccc(F)c2)C1=O
Yield: 74 %

Procedure:
A solution of Example 137B in dichloromethane (1.5 mL) was treated with trifluoroacetic acid (1.5 mL) at 25° C. for 16 h. The solvents were evaporated, and the crude residue was purified using reverse phase chromatography eluting with a gradient of 95% water (0.1% trifluoroacetic acid)/5% acetonitrile to 100% acetonitrile to give the title compound (0.14 g, 74%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:13][O:14][C:15](=[O:22])[C:16]([N:19]=[C:20]=[O:21])([CH3:18])[CH3:17]>>[CH3:13][O:14][C:15](=[O:22])[C:16]([CH3:18])([CH3:17])[NH:19][C:20](=[O:21])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: COC(=O)C(C)(C)N=C=O
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Product: COC(=O)C(C)(C)NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
9.75 g. of 5-amino-2-chlorobenzotrifluoride and 7.15 g. of 2-isocyanato-2-methylpropionic acid methyl ester are melted at 80° and the melt is kept at this temperature for 30 minutes. The product which has crystallized out during this process is recrystallized from isopropanol/methylene chloride and dried under greatly reduced pressure at 50° for 20 hours. N-[(3-trifluoromethyl-4-chlorophenyl)-carbamoyl]-2-methylalanine methyl ester, which melts at 141°-142° is obtained.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[CH3:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>ClCCl.CO>[CH3:15][O:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:20]1[CH2:21][CH2:22][CH:17]([CH3:16])[CH2:18][CH2:19]1
Reactant: CC1CCNCC1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Solvent: ClCCl
Solvent: CO
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCC(C)CC1

Procedure:
Prepared analogously to Example 1.1 C. from 1-(2-bromoethoxy)-2-methoxy-4-nitrobenzene and 4-methylpiperidine. Yield: 0.7 g (88.2% of theory); C15H22N2O4 (M=294.35); calc.: molecular ion peak (M+H)+: 295; found: molecular ion peak (M+H)+: 295; Rf value: 0.5 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH3:7])[CH:4]=[O:5])[CH3:2].[CH2:8](O)[CH:9]=[CH:10][CH2:11][OH:12].C1CCCCC1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH3:2][CH2:1][CH:3]([CH:4]1[O:12][CH2:11][CH:10]=[CH:9][CH2:8][O:5]1)[CH2:6][CH3:7]
Reactant: CCC(C=O)CC
Reactant: OCC=CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCCCC1
Product: CCC(CC)C1OCC=CCO1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a one liter flask equipped with heating jacket, agitator and condenser fitted with a Dean-Stark trap was charged 100 grams (1.0 mole), 2-ethyl-butanal, 97 grams(1.1 mole) 2-butene-1,4-diol, 80 grams cyclohexane and 0.2 grams p-toluenesulfonic acid monohydrate. The mixture was heated with vigorous agitation at reflux (84° - 99°C.) until water no longer continued to be distilled from the reaction mixture (1.2 hours). The reaction mixture was cooled to room temperature and the p-toluenesulfonic acid neutralized by washing with reaction mixture with a 5% aqueous solution of sodium hydroxide. The reaction mixture was then washed neutral with water and distilled to remove the cyclohexane. The oil was vacuum distilled to obtain 146 grams (86% of theoretical) of 4,7-dihydro-2-(3-pentyl)-1,3-dioxepin having a boiling point of 47°C. at a pressure of 1.0 millimeter of mercury, (refractive index, ND20 = 1.457). Analysis for carbonyl content of IR showed 0.0% carbonyl and VPC analysis showed the compound to have a purity of 100%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[N:2]1.C(=O)([O-])[O-].I[CH:19]([CH3:21])[CH3:20]>CN(C)C=O>[CH:19]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[N:2]1)([CH3:21])[CH3:20]
Reactant: CC(C)I
Reactant: COC(=O)c1ccc2cn[nH]c2c1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cnn(C(C)C)c2c1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 55.9 %

Procedure:
A solution of methyl 1H-indazole-6-carboxylate (1.92 g, 10.9 mmol) and cessium carbonate (7.12 g, 21.8 mmol) in N,N-dimethylformamide (21.8 mL) under argon was heated to 60° C. for 10 min. 2-Iodopropane (1.09 mL, 10.9 mmol) was added dropwise. The mixture was stirred at 60° C. for 1.5 h. The mixture was cooled to ambient temperature and quenched with saturated aqueous sodium bicarbonate (30 mL). The mixture was extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with saturated aqueous ammonium chloride (3×20 mL), saturated aqueous sodium chloride (1×20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (100% hexanes→70% hexanes/ethyl acetate) gave the title compound (1.33 g): LC-MS [M+1]=219.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: C1CCNC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example B5) (6.81 g, 20 mmol) and pyrrolidine (8.27 mL, 100 mmol) in DMSO (70 mL) at 23° C. according to the general procedure C. Obtained as a yellow solid (7.35 g).
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:14]/[C:15]1[NH:16][CH:17]=[C:18]([C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])[C:19]=1[CH3:20])/[C:5](=[O:13])[NH:6]2.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.[Pd]>[CH3:12][O:11][C:10]1[C:2]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:3]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5](=[O:13])/[C:4]/2=[CH:14]\[C:15]1[NH:16][CH:17]=[C:18]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])[C:19]=1[CH3:20]
Reactant: COc1ccc2c(c1Br)/C(=C/c1[nH]cc(C(=O)N3CCOCC3)c1C)C(=O)N2
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc2c(c1-c1ccccc1)/C(=C/c1[nH]cc(C(=O)N3CCOCC3)c1C)C(=O)N2
Temperature: 85 °C
Reaction time: 8 h
Yield: 9.5 %

Procedure:
To a mixture of 4-bromo-5-methoxy-3-[1-[3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one (223 mg, 0.5 mmol) and phenylboronic acid (73 mg, 0.6 mmol) in DME/water (5 mL) were added Palladium catalyst Pd(PPh3)2Cl2 (10.5 mg) and sodium carbonate (106 mg, 1 mmol). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 85° C. oil bath for overnight. TLC showed some de-bromination of the starting material. The degass procedure was repeated for three more times and the heating was continued for 3 more days. The mixture was cooled to room temperature, the unreacted starting material was filtered off and the mother liquor was concentrated. The residue was purified on a silica gel column to give 21 mg of 5-methoxy-3-[1-[3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-phenyl-1,3-dihydro-indol-2-one.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:15][C:14]=3[CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:26]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:15][C:14]=3[CH:24]=2)=[CH:4][CH:3]=1)[CH2:27][CH3:28]
Reactant: CC(=O)NC(C)c1cc2cc(CCc3ccc(O)cc3)ccc2o1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(CCc2ccc3oc(C(C)NC(C)=O)cc3c2)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 78.1 %

Procedure:
A suspension of N-(1-{5-[2-(4-hydroxyphenyl)ethyl]-1-benzofuran-2-yl}ethyl)acetamide (333 mg, 1.03 mmol) obtained in Example 157, bromopropane (1.08 g, 6.37 mmol) and potassium carbonate (924 mg, 6.68 mmol) in DMF (10 mL) was stirred at 80° C. for 2 days. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solution was applied to silica gel column chromatography (hexane:ethyl acetate=9:11 to 0:1), and recrystallized from hexane-ethyl acetate to give the title compound (294 mg, yield 78%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1
Reactant: Nc1ccccc1Br
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccccc2Br)cc1
Temperature: 40 °C

Procedure:
To a suspension of 2-bromoaniline (7.3 mL) and pyridine (13.5 mL) in toluene (110 mL) was added 4-methoxybenzoyl chloride (11 mL) and the mixture was heated at 40° C. for 2.5 hours. The solid was filtered, washed with diethyl ether and water and dried to afford the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[C:16](O)(=[O:19])[CH:17]=[O:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>ClCCCl>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]2[O:15][C:17](=[O:18])[CH:16]([OH:19])[C:7]=2[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: O=CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O

Procedure:
A mixture of 21.2 g (0.10 mol) of 2,4-di-tert-butylphenol (97%), 16.3 g (0.11 mol) of 50% aqueous glyoxylic acid and 0.05 g (0.26 mmol) of p-toluenesulfonic acid monohydrate in 30 ml of 1,2-dichloroethane is refluxed under nitrogen for 3.5 hours on a water separator. Afterwards the reaction mixture is concentrated on a vacuum rotary evaporator. The residue is taken up in 80 ml of hexane and washed three times with water. The aqueous phases are separated in the separating funnel and further extracted with 30 ml of hexane. The organic phases are combined, dried over magnesium sulfate and concentrated on a vacuum rotary evaporator. The residue yields 26.23 g (~100%) of analytically pure 5,7-di-tert-butyl-3-hydroxy-3H-benzofuran-2-one in the form of a thick yellowish resin (compound (101 ), Table 1).
Reaction SMILES: [C:1](O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[N:25]1([C:31]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[NH:38][C:37](=[O:42])[CH2:36]3)=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CN(C=O)C>[C:1]([N:28]1[CH2:29][CH2:30][N:25]([C:31]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[NH:38][C:37](=[O:42])[CH2:36]3)=[O:32])[CH2:26][CH2:27]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Cc2cc(C(=O)N3CCNCC3)ccc2N1
Reactant: O=C(O)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Cc2cc(C(=O)N3CCN(C(=O)c4ccccc4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.8 %

Procedure:
To a solution of 3.2 g of benzoic acid and 4 ml of triethylamine in 50 ml of DMF was added dropwise a solution of 3.87 g of isobutyl chloroformate in 2 ml of DMF. After stirring the mixture for 30 minutes at room temperature, a solution of 8.8 g of 5-(1-piperazinylcarbonyl)oxindol in 3 ml of DMF was added dropwise thereto, and the mixture was stirred for 30 minutes at room temperature and then for 1 hour at 50° to 60° C. The reaction mixture was poured into a large amount of a saturated saline solution, extracted with chloroform, washed with water and dried. The solvent was distilled off, and the residue was recrystallized from methanol to give 1.9 g of 5-(4-benzoyl-1-piperazinylcarbonyl)oxindol.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][NH:8][C@@H:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[O:4].C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][N:8]([S:33]([C:30]2[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=2)(=[O:35])=[O:34])[C@@H:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CCN[C@@H](C(=O)OC(C)(C)C)C1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCN(S(=O)(=O)c2ccc(OC)cc2)[C@@H](C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred, cold (0° C.) solution of (2R,4R)-piperidine-2,4-dicarboxylic acid 2-tert-butyl ester 4-methyl ester (2.7 g, 11.1 mmol) and triethylamine (4.6 ml, 33.3 mmol) in 30 mL of methylene chloride was added 4-methoxy-benzenesulfonyl chloride (2.3 g, 11.1 mmol). The mixture was warmed to ambient temperature and stirred for 4 hours. The reaction was quenched by the addition of aqueous ammonium chloride and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, and the organic mixture was dried over sodium sulfate. After filtration and concentration of the filtrate, the resulting crude product was purified by silica gel chromatography (elution with 3:8 ethyl acetate/hexanes) to provide (2R,4R)-1-(4-methoxy-benzenesulfonyl)-piperidine-2,4-dicarboxylic acid 2-tert-butyl ester 4-methyl ester.