Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[N+:14]([C:17]1[CH:23]=[CH:22][C:21](Cl)=[CH:20][C:18]=1[NH2:19])([O-:16])=[O:15]>CN(C)C=O>[NH2:19][C:18]1[CH:20]=[C:21]([O:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[CH:22]=[CH:23][C:17]=1[N+:14]([O-:16])=[O:15]
Reactant: Oc1ccncc1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccncc2)ccc1[N+](=O)[O-]
Temperature: 17.5 °C
Reaction time: 2 h

Procedure:
A 2-liter round-bottomed flask is charged with 35.2 g (0.369 mol) of 4-hydroxypyridine and 250 ml of anhydrous dimethylformamide (DMF). Under nitrogen, 42 g (0.369 mol) of potassium tert-butylate are added portionwise while the temperature is maintained at 15-20° C. with a water/ice bath. After the addition, the mixture is stirred for 2 hours and a pale yellow solution is obtained. 60 g (0.358 mol) of 2-nitro-5-chloroaniline are then added and an intense red coloration is obtained. The mixture is brought to 100° C. for 6 hours and then allowed to cool overnight. The DMF is evaporated off and water is then added; a precipitate is obtained, which is filtered off and washed with isopropanol in the heated state and then dried.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH:6]([C:19]([OH:28])([CH2:24][C:25]([CH3:27])=[CH2:26])[C:20]([F:23])([F:22])[F:21])[NH:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[N:11][C:12]([CH3:18])=[N:13]3)=[C:4]([O:31][CH3:32])[CH:3]=1.C(OCC)(=O)C.C(N(CC)CC)C>CO.[Pd].[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:30]=[CH:29][C:5]([CH:6]([C:19]([OH:28])([CH2:24][CH:25]([CH3:26])[CH3:27])[C:20]([F:22])([F:21])[F:23])[NH:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[N:11][C:12]([CH3:18])=[N:13]3)=[C:4]([O:31][CH3:32])[CH:3]=1
Reactant: C=C(C)CC(O)(C(Nc1cccc2nc(C)ncc12)c1ccc(F)cc1OC)C(F)(F)F
Agent: [Mn+4]
Agent: [Pd]
Agent: [O-2]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(F)ccc1C(Nc1cccc2nc(C)ncc12)C(O)(CC(C)C)C(F)(F)F
Yield: 16.6 %

Procedure:
17 mg (0.04 mmol) of (rac.) 2-{4-fluoro-alpha-[(2-methylquinazolin-5-yl)amino]-2-methoxybenzyl}-1,1,1-trifluoro-4-methylpent-4-en-2-ol is shaken in 2 ml of methanol, 2 ml of ethyl acetate and 0.05 ml of triethylamine with 20 mg of palladium on carbon (10%) for 5 hours under hydrogen atmosphere. The reaction mixture is mixed with 200 mg of activated manganese dioxide and filtered through Celite after 10 minutes. It is concentrated by evaporation, and 3 mg of the desired product is obtained after preparative thin-layer chromatography on silica gel (cyclohexane/ethyl acetate 50%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:25]4[CH2:30][CH2:29][N:28]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:26]4)=[N:21][NH:22]3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46]Cl)=[CH:44][CH:43]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:25]4[CH2:26][CH2:27][N:28]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:30]4)=[N:21][N:22]3[CH2:46][C:45]3[CH:48]=[CH:49][C:42]([Cl:41])=[CH:43][CH:44]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN1CCC(c2n[nH]c3cc(/C=C/C4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCC(c2nn(Cc3ccc(Cl)cc3)c3cc(/C=C/C4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
A solution of 4-{2-[3-(1-tert-butoxycarbonylmethyl-piperidin-4-yl)-1H-indazol-6-yl]-(E)-vinyl}-piperidine-1-carboxylic acid tert-butyl ester (0.29 g, 0.553 mmol) in dry DMF (5 ml) was stirred under nitrogen and treated with sodium hydride (0.024 g, 0.608 mmol, 60% dispersion in oil). The mixture was stirred for 0.5 h and a solution of 4-chlorobenzyl chloride (0.090 g, 0.559 mmol; Aldrich) in DMF (5 ml) was added). The mixture was stirred at 23° for 16 h, evaporated in vacuo, treated with water (10 ml) and extracted with dichloromethane (3×20 ml). The extracts were evaporated in vacuo and purified by flash chromatography on silica gel (Merck 9385), eluant ether:cyclohexane:triethylamine (50:50:2 to 100:0:2), to give the title compound as a colourless gum (0.157 g, 44%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](OC(=O)C)(=[O:12])[CH3:11]>O1CCCC1>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:10](=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(I)cc1F
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(I)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.7 %

Procedure:
A solution of 2-fluoro-4-iodoaniline (4.74 g, 20 mmol) in dry tetrahydrofuran (20 mL) was cooled to 0° C. and then treated with acetic anhydride (8.2 g, 80 mmol). The reaction mixture was stirred for 10 min at 0° C. and then was allowed to warm to 25° C. where it was stirred for 2 h. After this time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to afford a crude residue. The residue precipitated from diethyl ether (50 mL) and hexanes (50 mL). The solid was collected by filtration and washed with hexanes to afford N-(2-fluoro-4-iodo-phenyl)-acetamide (5.12 g, 92%) as a white crystalline solid: mp 152-154° C.; EI-HRMS m/e calcd for C8H7FINO (M+) 278.9556, found 278.9559.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B(O)O)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Br[C:15]1[N:16]([CH3:21])[CH:17]=[C:18]([Br:20])[N:19]=1.O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:20][C:18]1[N:19]=[C:15]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[N:3]=[CH:4]3)[N:16]([CH3:21])[CH:17]=1
Reactant: Cn1ncc2cc(B(O)O)ccc21
Reactant: Cn1cc(Br)nc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(Br)nc1-c1ccc2c(cnn2C)c1
Temperature: 110 °C

Procedure:
In a 10-20 mL reaction vial, the 1-methyl-1H-indazol-5-ylboronic acid (169 mg, 0.966 mmol) and the 2,4-dibromo-1-methyl-1H-imidazole (300 mg, 1.25 mmol) were dissolved in dioxane (4 mL) and water (1 mL) under argon atmosphere. The mixture was bubbled with argon for 5 min and then potassium carbonate (400 mg, 2.895 mmol) and Pd(PPh3)4 (167 mg, 0.145 mmol) were added sequentially. The resulting reaction mixture was then sealed and heated in oil bath at 110° C. for 1.5 h. Reaction was then partitioned between EtOAc (30 mL) and water (30 mL).The organic phase was washed with water (3×20 mL) and was concentrated. Residue was purified on silica gel column with 0-50% EtOAc/Hex to afford the desired product. LCMS-ESI+: calc'd for: C12H11BrN4: 291.0, 293.0 (M+H+); found: 291.0, 293.0 (M+H+)
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]([CH3:20])([CH3:19])[O:10][C:9]2=[O:21])=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:24]=[C:25](B(O)O)[C:26]([F:29])=[N:27][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Br:22][C:23]1[CH:24]=[C:25]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C@@H:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:11]([CH3:20])([CH3:19])[O:10][C:9]3=[O:21])=[CH:4][CH:3]=2)[C:26]([F:29])=[N:27][CH:28]=1
Reactant: CC1(C)OC(=O)N(c2ccc(I)cc2)[C@H]1c1ccccc1
Reactant: OB(O)c1cc(Br)cnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)OC(=O)N(c2ccc(-c3cc(Br)cnc3F)cc2)[C@H]1c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
A microwave vial was charged with (S)-3-(4-iodophenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (Intermediate C)(0.200 g, 0.509 mmol), 5-bromo-2-fluoropyridine-3-boronic acid (0.224 g, 1.017 mmol)(commercially available from Alfa Aesar, Ward Hill, Mass.), sodium carbonate (0.162 g, 1.526 mmol), dioxane (3.0 mL), and water (0.600 mL). Tetrakis(triphenylphosphine)palladium(0) (0.059 g, 0.051 mmol) was added, the system was purged with argon, and the tube was sealed. The mixture was then stirred at 100° C. in the microwave for 1 hour. The resulting reaction mixture was filtered through Celite® brand filter aid and the filtrate was concentrated to afford a yellow oil. The residual oil was purified by column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-25% EtOAc-hexane) to afford (S)-3-(4-(5-bromo-2-fluoropyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (0.104 g, 0.236 mmol, 46% yield) as a pale tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (s, 3H), 1.64 (s, 3H), 5.52 (s, 1H), 7.07-7.47 (m, 5H), 7.51-7.75 (m, 4H), 8.15-8.44 (m, 2H). m/z (ESI) 441, 443 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]1([N:9]=[C:10]=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.Br[CH2:14][C:15](=[O:26])[CH2:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]>O1CCOCC1>[O:26]=[C:15]1[CH2:14][O:11][C:10]([NH:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[C:16]1[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]
Reactant: O=C(CBr)CC(=O)Nc1ccccc1
Reactant: O=C=Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1COC(Nc2ccccc2)=C1C(=O)Nc1ccccc1
Reaction time: 5 h

Procedure:
Under a nitrogen atmosphere, sodium hydride (97%; 0.633 g, 25.61 mmol) was weighed into a dry reaction vessel and covered with 55 ml of anhydrous dioxane. A solution of phenyl isocyanate (1.39 ml, 12.81 mmol) in 5 ml of anhydrous dioxane was then added over a 5-10 minute period at room temperature (cooling with cold water). Next, the 4-bromoacetoacetanilide (3.28 g, 12.8 mmol) was added portionwise over a 20-minute period. The reaction mixture was stirred at 20°-25° C. for 5 hours, filtered under nitrogen atmosphere, and poured into 300 ml of ice-cold water. After acidifying (pH 5-6) with several drops of concentrated hydrochloric acid, the crude product was filtered off and crystallized from ethanol to provide 2.8 g. of amide product, m.p. 182°-184° C.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].[C:19]([O:23][C:24]([N:26]1[CH:30]=[C:29](I)[CH:28]=[C:27]1[C:32]([O:34][CH3:35])=[O:33])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([N:26]1[CH:30]=[C:29]([C:2]#[C:1][CH:3]([OH:4])[C:5]2[CH:14]=[CH:13][C:12]3[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=3[CH:6]=2)[CH:28]=[C:27]1[C:32]([O:34][CH3:35])=[O:33])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)c1cc(I)cn1C(=O)OC(C)(C)C
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: COC(=O)c1cc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cn1C(=O)OC(C)(C)C
Yield: 99.5 %

Procedure:
Following the basic procedure of Example 11(d), by reacting 2 g (8.2 mmol) of α-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol with 3 g (8.5 mmol) of methyl N-tert-butoxycarbonyl-4-iodo-2-pyrrolecarboxylate, 3.8 g (98%) of the expected ester were obtained in the form of a brown oil.
Reaction SMILES: C([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]1[CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(OCC)=O.[OH-].[K+]>C(O)C.O>[C:23]1([CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:7]2[C:8](=[O:15])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[NH:6]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)n1c2ccccc2c(=O)n1C(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=c1c2ccccc2[nH]n1C(c1ccccc1)c1ccccc1
Temperature: 80 °C
Yield: 53.1 %

Procedure:
A solution of 1,2-dihydro-1-carboethoxy-2-diphenylmethyl-3H-indazol-3-one (1.4 g) in ethanol (15 ml) containing potassium hydroxide (820 mg) was heated at 80° C. for 30 minutes. The reaction mixture was diluted with water (50 ml) and extracted with ether. The extracts were discarded. The aqueous phase was acidified to pH2 with 2M hydrochloric acid and extracted with methylene chloride. These extracts were dried (MgSO4) and evaporated. The residue was recrystallised from acetone/ether to give 1,2-dihydro-2-diphenylmethyl-3H-indazol-3-one as a solid (0.6 g), m.p. 179-181° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:8]([S:10]([OH:13])(=[O:12])=[O:11])[CH:9]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:8]([S:10]([OH:13])(=[O:11])=[O:12])[CH:9]=1
Reactant: O=[N+]([O-])c1ccc(N2CCCC2)c(S(=O)(=O)O)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCCC2)c(S(=O)(=O)O)c1

Procedure:
72.4 Grams 2-chloro-5-nitrobenzenesulfonic acid was added in portions to 134 ml pyrrolidine, while keeping the temperature below 65° C. After the addition, the reaction was heated at reflux temperature with stirring for 7 hours and allowed to stand overnight at room temperature. The reaction was poured into 800 ml ice water and the solution made strongly acidic with concentrated HCl until light yellow crystals separated. The product was filtered, washed with a little dilute HCl and the moist cake was recrystallized from about 800 ml water to give 70.7 grams 5-nitro-2-pyrrolidinylbenzenesulfonic acid. m.p. = 178°-179° C. The nitro compound was reduced catalytically in ethanol with 5% palladium on carbon catalyst to give 5-amino-2-pyrrolidinyl-benzenesulfonic acid. m.p. = 255°-256° C.
Reaction SMILES: [ClH:1].[NH:2]1[C:10]23[CH2:11][CH2:12][CH2:13][CH2:14][C:5]2([CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=23)[CH2:4][CH2:3]1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[ClH:1].[C:20]1([CH2:19][N:2]2[C:10]34[CH2:11][CH2:12][CH2:13][CH2:14][C:5]3([CH2:6][CH2:7][C:8]3[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=34)[CH2:4][CH2:3]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc2c(c1)CCC13CCCCC21NCC3
Reactant: O=Cc1ccccc1
Agent: Cl
Product: c1ccc(CN2CCC34CCCCC23c2ccccc2CC4)cc1
Yield: 42 %

Procedure:
In a manner similar to that described in Example 32, the product from Example 23 (0.34 g, 1.50 mmol) and benzaldehyde are reacted. Workup, followed crystallization from ether and HCl gave the title compound (0 22 g, 42%) as a white solid mp 235-237° C.
Reaction SMILES: Cl.[CH:2]([O:5][C:6]([C:8]1([C:31]([O:33]C(C)C)=[O:32])[O:12][C:11]2[CH:13]=[CH:14][C:15]([CH2:17][CH:18]([NH:20][CH2:21][CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[OH:23])[CH3:19])=[CH:16][C:10]=2[O:9]1)=[O:7])([CH3:4])[CH3:3].[OH-].[Na+]>CC(O)C>[CH:2]([O:5][C:6]([C:8]1([C:31]([OH:33])=[O:32])[O:12][C:11]2[CH:13]=[CH:14][C:15]([CH2:17][CH:18]([NH:20][CH2:21][CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[OH:23])[CH3:19])=[CH:16][C:10]=2[O:9]1)=[O:7])([CH3:3])[CH3:4]
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)OC(C)C)(C(=O)OC(C)C)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)OC(C)C)O2)NCC(O)c1cccc(Cl)c1
Temperature: 23 °C
Reaction time: 72 h
Yield: 39 %

Procedure:
To a stirred solution of 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-isopropyl ester hydrochloride salt (3.0 g, 5.53 mmol) and 20 mL of i-PrOH was added was added 1N NaOH (11.1 mL, 11.1 mmol). After stirring at 23° C. for 3 days, the mixture was concentrated to dryness, dissolved in 10% MeOH/CH2Cl2, and filtered through a small pad of silica gel. The filtrate was concentrated to a colorless gum, and triturated with Et2O to give 1.0 g (39%) of 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid isopropyl ester as a white solid; 1H NMR (300 MHz, CDCl3): δ 0.93 (d, J=6.1 Hz, 3H), 1.17 (d, J=6.3 Hz, 6H), 2.30-2.53 (m, 2H), 2.67-2.80 (m, 2H), 2.85-3.00 (m, 1H), 4.65-4.75 (brs, 1H), 4.91 (hept, J=6.3 Hz, 1H), 6.52-6.80 (complexm, 3H), 7.17-7.45 (complexm, 4H); MS (ES) m/z (relative intensity): 464 (M+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O>>[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2/[CH:26]=[CH:14]/[C:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: O=Cc1c[nH]c2ccc(F)cc12
Product: COc1cc(C(=O)/C=C/c2c[nH]c3ccc(F)cc23)cc(OC)c1OC
Yield: 59.2 %

Procedure:
Substantially the same procedure as in Example 12 was repeated using 3',4',5'-trimethoxyacetophenone (2.1 g) and 5-fluoroindole-3-carboxaldehyde (1.63 g) to give Compound 29 (2.1 g).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:12]=1[CH:13]=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].CSC.P([O-])(O)(O)=[O:25].[Na+].Cl([O-])=O.[Na+]>C1COCC1.O>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:12]=1[C:13]([OH:25])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=P([O-])(O)O
Reactant: CC(C)(C)OC(=O)c1sc(-c2ccccc2)cc1C=O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1sc(-c2ccccc2)cc1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
A solution of 3-Formyl-5-phenyl-thiophene-2-carboxylic acid tert-butyl ester (300 mg, 1.04 mmol) in dry THF (20 ml), at 0° C., under nitrogen, was treated with methyl sulfide (10% w/w in THF, 3.8 ml, 5.2 mmol) followed by sodium dihydrogenphosphate (30% aqueous solution, 9.56 ml, 2.05 mmol). After 0.5 h, the solution was treated with sodium chlorite (30% w/w aqueous solution, 1.9 ml, 2.08 mmol) added over 1 min via a syringe. The pale yellow solution was stirred for 1.5 h at 0° C., then diluted with water (20 ml) and extracted with EtOAc (4×40 ml). The aqueous phase was separated, extracted with more EtOAc (40 ml) and the combined extracts were washed with brine dried and concentrated to give 316 mg (100%) of 5-Phenyl-thiophene-2,3-dicarboxylic acid 2-tert-butyl ester as a pale brown solid. NMR 1H (CD3CO; 400 MHz): 7.87 (s, 1H); 7.83-7.81 (m, 2H); 7.17-7.53 (m, 3H); 1.65 (bs, 9H).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].I[C:13]1[CH:17]=[CH:16][S:15][CH:14]=1.Cl>N1C2C(=CC=CC=2)C=CC=1.[Cu]Br.O>[S:15]1[CH:16]=[CH:17][C:13]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:14]1
Reactant: COC(=O)CC(=O)OC
Reactant: Ic1ccsc1
Agent: [Cu]Br
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: COC(=O)C(C(=O)OC)c1ccsc1
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
In the way described before 5.3 g (=0.040 mole) dimethyl malonate were mono-deprotonated with 0.040 mole NaH in 75 ml quinoline. Then 6.7 g (=0.032 mole) 3-iodothiophene and 4.6 g (=0.032 mole) copper (I) bromide were added. The resulting mixture was stirred under N2 atmosphere during a period of 4.5 hours at a temperature of 80° C. and then poured out into a mixture of 75 ml water and 75 ml concentrated HCl. The precipitated copper salts were collected on a Buchner funnel and washed with chloroform. Extraction of the filtrate occured likewise with chloroform. Both chloroform layers were joined and dried over magnesium sulphate. After removal of the solvent 11.0 g of an oily product remained in which by GLC analysis the presence was demonstrated of 1.93 g 3-iodothiophene and 1.32 g di-methyl 3-thienylmalonate (=0.006 mole or 19% calculated to the 3-iodothiophene started from). The product was identified in the same way as described in Example 5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:4][C:3]=1[C:24]1[S:28](=[O:30])(=[O:29])[N:27](C(C)(C)C)[C:26](=[O:35])[CH:25]=1>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][C:3]=1[C:24]1[S:28](=[O:29])(=[O:30])[NH:27][C:26](=[O:35])[CH:25]=1
Reactant: CC(C)(C)N1C(=O)C=C(c2ccc(CC(C(=O)c3ccccc3)c3ccccc3)cc2Br)S1(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1C=C(c2ccc(CC(C(=O)c3ccccc3)c3ccccc3)cc2Br)S(=O)(=O)N1
Yield: 64.1 %

Procedure:
A solution of 1.36-B (12 mg, 22 μmol) in trifluoroacetic acid (2.5 mL) was heated at 150° C. in a microwave for 30 sec. The reaction mixture was concentrated to a crude residue which was purified by preparative LCMS to yield the desired product (7 mg, 65%). 1H NMR (400 MHz, CDCl3): δ 7.91 (d, J=7.2 Hz, 2H), 7.75 (d, J=8.0 Hz, 1H), 7.52–7.47 (m, 2H), 7.37 (dd, J=7.8, 7.6 Hz, 2H), 7.32–7.21 (m, 6H), 7.00 (s, 1H), 4.79 (dd, J=7.4, 7.2 Hz, 1H), 3.57 (dd, J=13.7, 7.6 Hz, 1H), 3.10 (dd, J=13.9, 6.8 Hz, 1H); LCMS found for C24H19BrNO4S (M+H)+: m/z=496.
Reaction SMILES: [CH3:1][C:2]1([OH:16])[CH2:5][N:4]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=2)[CH2:3]1>CO.[Pd]>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][N:4]2[CH2:3][C:2]([CH3:1])([OH:16])[CH2:5]2)=[N:8][CH:9]=1
Reactant: CC1(O)CN(Cc2ccc([N+](=O)[O-])cn2)C1
Agent: [Pd]
Solvent: CO
Product: CC1(O)CN(Cc2ccc(N)cn2)C1

Procedure:
To a stirred solution of 53 (0.35 g, 2.2 mmol) in MeOH (6 mL) was added 10% Pd/C (50 mg) and hydrogenated using a balloon for 2 h at rt. The reaction mixture was filtered through a pad of Celite and concentrated to give the desired amine A4-18 (0.3 g, 69%) as a gummy liquid. Rf: 0.1 (10% MeOH/DCM); (m/z): 194 [MH]+; 1H NMR (400 MHz, DMSO-d6): δ 7.82 (1H, d, J=2.8 Hz), 6.95 (1H, d, J=8.4 Hz), 6.86 (1H, dd, J=8.4, 2.4 Hz), 5.12-5.10 (2H, m), 4.08 (1H, br s), 3.48 (2H, s), 3.16-3.14 (4H, m), 1.33 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[O:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[O:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20]
Reactant: CCOC(=O)C=Cc1ccc(O)c(OCCCOC)c1
Solvent: CCO
Product: CCOC(=O)CCc1ccc(O)c(OCCCOC)c1
Yield: 76.4 %

Procedure:
Ethyl 3-[4-hydroxy-3-(3-methoxypropoxy)phenyl]acrylate (16 g, 57 mmol) was dissolved in ethanol (190 mL) in a Parr apparatus. Nitrogen was bubbled for 15 minutes and Pd/C 10% (0.8 g) was added. The reaction mixture was submitted to hydrogenation under H2 atmosphere (3 bars) until the end of H2 consumption. The palladium was then filtered and the solvent was evaporated under reduced pressure to yield 12.3 g (76%) of the desired product as a colorless oil.
Reaction SMILES: [CH:1]1([C:6]2[N:7]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=3)[S:9][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]1(=[O:31])[O:26][C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]2[CH2:21]1.C1(C)C=CC=CC=1>O1CCCC1>[CH:1]1([C:6]2[N:7]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:14]=[C:15]([NH:19][C:20](=[O:31])[CH2:21][C:22]4[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=4[C:24]([OH:26])=[O:25])[CH:16]=[CH:17][CH:18]=3)[S:9][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cccc(/C=C/c2nc(C3CCCC3)cs2)c1
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1C(=O)O)Nc1cccc(/C=C/c2nc(C3CCCC3)cs2)c1

Procedure:
A solution of 2.7 g of (E)-3-[2-[4-(cyclopentyl)-2-thiazolyl]ethenyl]benzeneamine, 1.78 g of homophthalic anhydride and 40 ml of toluene was heated to reflux for 0.5 hr. Cooling and filtration yielded 3.75 g of (E)-2-[2-[3-[2-[4-(cyclopentyl)-2-thiazolyl]ethenyl]phenyl=amino]-2-oxoethyl]benzoic acid; m.p. 209°-210° C. from tetrahydrofuran.