Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[CH3:7])(=O)=O.[C:21]([O-:24])(=[S:23])[CH3:22].[K+].CS(C)=O>CCOCC>[C:21]([S:23][CH:6]([CH:8]1[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:12][CH2:13]1)[CH3:7])(=[O:24])[CH3:22]
Reactant: CC([O-])=S
Reactant: CC(OS(C)(=O)=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(=O)SC(C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 84.4 %

Procedure:
To a 500 ml round bottom flask was added tert-butyl 4-{1-[(methylsulfonyl)oxy]ethyl}piperidine-1-carboxylate (19 g, 61.8 mmol), potassium thioacetate (8.47 g, 74.2 mmol) and 90 ml dimethyl sulfoxide. The resulting reaction mixture was heated at 60° C. under nitrogen for 2 hours then at 45° C. for 18 hours. After cooling to room temperature, the reaction mixture was diluted with 300 ml ether, washed with 400 ml water and then 150 ml brine. The organics were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel column eluted with 1:20 to 1:10 ethyl acetate/hexane to give 15 g tert-butyl 4-[1-(acetylthio)ethyl]piperidine-1-carboxylate as dark yellow sticky material. This material was dissolved in 100 ml MeOH. A solution of KOH (17.3 g, 309 mmol) in 150 ml water was added. The reaction mixture was flushed with nitrogen and stirred at 50° C. for 2 hours. After cooling to room temperature, the volume of reaction was reduced to 150 ml. Hexane (300 ml) was added. The layers were separated, and the aqueous portion was poured into an Erlenmyer flask with 250 ml saturated NH4Cl, and pH of the mixture was adjusted to 7 by addition of 3N HCl. This solution was extracted with 250 ml ether. The extracts were washed with 100 ml brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel column eluted with 1:20 to 1:9 ethyl acetate/hexane to give 8.3 g desire product as light yellow sticky material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23](O)=[O:24])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[N:38]1C(C)=C[CH:41]=[CH:40][C:39]=1C.C(N)C=C>C(Cl)Cl>[CH2:39]([NH:38][C:23]([CH2:22][CH2:21][N:18]1[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:26][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)=[N:17]1)=[O:24])[CH:40]=[CH2:41]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Reactant: Cc1cccc(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C=CCN
Product: C=CCNC(=O)CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.1 %

Procedure:
To a solution containing 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid (prepared in example 9, 50 mg, 0.11 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (59 μL, 0.12 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (17 μL, 0.14 mmol) was added to the solution at 0° C. After 1 h, allylamine (9 μL, 0.11 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford N-[1-(2-allylcarbamoyl-ethyl)-1H-pyrazol-3-yl]-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (9 mg, 16%) as a white solid: ESI-LRMS m/e calcd for C23H29ClN4O4S [M+] 506.19, found 507.34 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.06-1.20 (m, 2H, CH2), 1.42-1.94 (m, 8H, 4×CH2), 2.12-2.30 (m, 1H, CH), 2.65 (t, J=6.3 Hz, 2H, COCH2), 3.26 (s, 3H, SO2CH3), 3.54 (t, J=7.5 Hz, 1H, CH), 3.79-3.84 (m, 2H, CONCH2), 4.31 (t, J=6.3 Hz, 2H, NCH2), 5.02-5.07 (m, 1H, vinylic), 5.06-5.09 (m, 1H, vinylic), 6.55 (brm, 1H, NH), 5.67-5.78 (m, 1H, vinylic), 6.60 (d, J=2.3 Hz, 1H, Ar), 7.30 (d, J=2.3 Hz, 1H, Ar), 7.46 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.59 (d, Jm=1.7 Hz, 1H, Ar), 8.02 (s, 1H, NH), 8.09 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=2[F:15])[N:4]=1.[CH2:16]([N:18]1[C:22]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[N:21][NH:20][C:19]1=[S:28])[CH3:17].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[F:15][C:9]1[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=1[C:5]1[N:4]=[C:3]([CH2:2][S:28][C:19]2[N:18]([CH2:16][CH3:17])[C:22]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[N:21][N:20]=2)[O:7][N:6]=1
Reactant: CCn1c(-c2cccs2)n[nH]c1=S
Reactant: Fc1ccc(F)c(-c2noc(CCl)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c(SCc2nc(-c3cc(F)ccc3F)no2)nnc1-c1cccs1
Yield: 49.3 %

Procedure:
5-Chloromethyl-3-(2,5-difluoro-phenyl)-[1,2,4]oxadiazole (23 mg, 0.10 mmol) and 4-ethyl-5-thiophen-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione (23 mg, 0.11 mmol) was dissolved in anhydrous DMF (1 ml) and potassium carbonate (21 mg, 0.15 mmol) was added. After stirring for 22 h ethyl acetate was added, the resulting mixture was washed twice with water and once with brine, dried over MgSO4 and evaporated. Flash chromatography using heptane:ethyl acetate 1:1 yielded the title compound (20 mg, 50%). 1H NMR (CDCl3) d (ppm): 7.64 (m, 1H), 7.45 (d, 1H), 7.39 (d, 1H), 7.10 (m, 3H), 4.70 (s, 2H), 4.08 (q, 2H), 1.32 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]=C)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[BH4-].[Na+].C[OH:15]>C(Cl)Cl>[F:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:15])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C=Cc1ccc(C#N)c(F)c1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(CO)cc1F

Procedure:
Into a cooled solution (−78° C.) of 2-fluoro-4-vinylbenzonitrile (1.3 g, 8.8 mmol; see step (i) above) in 40 mL of CH2Cl2 and 5 mL of methanol was to bubbled ozone (50 L/h, 29 g/m3) for 30 min. Argon was subsequently bubbled through to remove excess ozone. Sodium borohydride (0.67 g, 0.018 mol) was added and the cooling bath was removed. The mixture was stirred and allowed to react for 1 h. The mixture was evaporated and 2M HCl was added. The mixture was extracted twice with diethyl ether and the combined ether fraction was dried (Na2SO4) and evaporated. The crude product crystallised. Yield: 1.1 g (81%).
Reaction SMILES: [CH3:1][C@@:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6]C(=O)N[C:3]1=[O:8].[OH2:15].N>C(OCC)(=O)C>[NH2:6][C@:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:1])[C:3]([OH:15])=[O:8]
Reactant: C[C@@]1(c2ccccc2)NC(=O)NC1=O
Reactant: O
Agent: N
Solvent: CCOC(C)=O
Product: C[C@@](N)(C(=O)O)c1ccccc1
Temperature: 160 °C

Procedure:
22 g (0.115 mol) of (+)-(5S)-5-methyl-5-phenylhydantoin, 100 ml of water and 100 ml of 28% aqueous ammonia are introduced successively into a 1 liter autoclave. The medium is heated at 160° C. for 15 hours. After cooling to room temperate, the solution is concentrated under reduced pressure. The white solid obtained is treated with 100 ml of ethyl acetate for 2 hours and then filtered and dried under vacuum at 80° C.
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:2]([C:15]([OH:17])=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[N:60]1[CH:65]=[CH:64][C:63]([N:66]2[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]2)=[CH:62][CH:61]=1.CCN(C(C)C)C(C)C>CN(C)C=O>[C:22]1([CH2:21][O:20][C:18]([NH:1][C@H:2]([C:15]([N:69]2[CH2:70][CH2:71][N:66]([C:63]3[CH:64]=[CH:65][N:60]=[CH:61][CH:62]=3)[CH2:67][CH2:68]2)=[O:17])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])=[O:19])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCN(c2ccncc2)CC1

Procedure:
To a mixture of 100 g (0.263 mol) of Z-Lys(Boc)-OH, 86.1 g (0.268 mol) of TBTU and 36.3 g (0.263 mol) of HOBt in 600 ml of dimethylformamide were added 43.0 g (0.263 mol) of 1-(4-pyridinyl)-piperazine and 47.2 ml (0.268 mol) of DIEA with stirring and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated down in vacuo and the residue divided between ethyl acetate and aqueous saturated sodium hydrogen carbonate solution. The aqueous phase was extracted twice more with a mixture of ethyl acetate/methanol (10/1, v/v) and the combined organic phases were washed once with saturated sodium hydrogen carbonate solution. The organic phase was, after drying over sodium sulphate, evaporated down in vacuo and the residue was taken up in 750 ml of ethyl acetate and washed four times with 100 ml of water, six times with 100 ml of 1% potassium hydrogen sulphate solution, once with 100 ml of water, twice with 100 ml of 3% aqueous ammonia solution and twice with 100 ml of water. The organic phase was evaporated down after drying over sodium sulphate. 120 g (87% of theory) of the desired product were obtained as an oil, which was used without further purification for the subsequent reactions.
Reaction SMILES: C(O[CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])[CH2:6]1)C=C.I([O-])(=O)(=O)=O.[Na+].[C:32]([O:36]C)(C)(C)[CH3:33]>C(OCC)C.O.[Os](=O)(=O)(=O)=O>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:15]2[O:16][C:17]([CH3:18])=[C:13]([CH2:12][O:11][CH:7]3[CH2:8][CH2:9][CH2:10][CH:5]([CH2:33][CH:32]=[O:36])[CH2:6]3)[N:14]=2)=[CH:24][CH:23]=1
Reactant: C=CCOC1CCCC(OCc2nc(-c3ccc(F)cc3)oc2C)C1
Reactant: COC(C)(C)C
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCOCC
Product: Cc1oc(-c2ccc(F)cc2)nc1COC1CCCC(CC=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.0 g of 4-(3-allyloxycyclohexyloxymethyl)-2-(4-fluorophenyl)-5-methyloxazole are dissolved in 50 ml of diethyl ether, and 3.8 g of sodium periodate, dissolved in 50 ml of water, are added. At 0° C., 1 ml of an osmium tetroxide solution (2.5% by weight in tert-butanol) is added, and the mixture is stirred vigorously at room temperature. After 8 h, 100 ml of methyl tert-butyl ether are added and the mixture is washed with a saturated sodium thiosulfate solution. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified on silica gel (n-heptane:ethyl acetate=1:1→1:5). This gives 1.4 g of [3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl]-acetaldehyde as a yellow-brown oil. C20H25NO4 (343.42), MS(ESI): 344 (M+H+), Rf(n-heptane:ethyl acetate=1:1)=0.25.
Reaction SMILES: [F-].[K+].[Si]([C:7]([F:10])([F:9])[F:8])(C)(C)C.[CH2:11]([O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26](I)[CH:27]=2)[N:22]=[N:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN1CCCC1=O.[Cu]I>[CH2:11]([O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:7]([F:10])([F:9])[F:8])[CH:27]=2)[N:22]=[N:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Ic1ccc2nncc(OCc3ccccc3)c2c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccc2nncc(OCc3ccccc3)c2c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Into a 500 mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed CuI (6.4 g, 33.68 mmol, 1.20 equiv), a solution of KF (1.97 g, 33.97 mmol, 1.20 equiv) in 1-methylpyrrolidin-2-one (250 mL), TMS-CF3 (4.828 g, 34.00 mmol, 1.20 equiv) and 4-(benzyloxy)-6-iodocinnoline (as prepared in the previous step, 10.2 g, 28.18 mmol, 1.00 equiv). The reaction mixture was stirred for 24 h at 50° C. in an oil bath. The reaction was then quenched by the addition of 30 mL of ammonia and 300 mL H2O. The resulting solution was extracted with 3×300 mL of ether, and the combined ether portions was washed with 2×200 mL of brine, dried (Na2SO4), and concentrated under vacuum. The title compound was obtained as a brown solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:13]O>C(O)(=O)C>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N+:8]=2[O-:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OO
Reactant: c1ccc(-c2ccccn2)cc1
Solvent: CC(=O)O
Product: [O-][n+]1ccccc1-c1ccccc1
Yield: 72 %

Procedure:
The N-oxide was prepared by modifying the method outlined by Zhang et al.25 using 2-phenylpyridine (5.00 g, 32.2 mmol) and 30% H2O2 in glacial acetic acid to yield the title compound as a light yellow solid (4.00 g, 72%), m.p. 154-157° C. (lit.26 m.p. 155-155.5° C.). The spectral data were consistent with literature data.27
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([NH:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][CH2:19][C:17]3=[O:18])=[CH:12][CH:11]=2)=[O:9])=[CH:5][CH:4]=1.[H-].[Na+].[CH2:31](Br)[CH3:32]>CN(C)C=O>[CH2:31]([N:7]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][C:17]2=[O:18])=[CH:12][CH:11]=1)=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=1)[CH3:32]
Reactant: CCBr
Reactant: COc1ccc(NC(=O)c2ccc(N3C(=O)CCc4ccccc43)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)c1ccc(N2C(=O)CCc3ccccc32)cc1)c1ccc(OC)cc1
Yield: 55.8 %

Procedure:
To a solution of 1-[4-(4-methoxyanilinocarbonyl)-phenyl]-3,4-dihydrocarbostyril (0.2 g) in dimethylformamide (15 ml) is added 60% sodium hydride (24 mg) with stirring under ice cooling and the mixture is stirred at room temperature for 0.5 hour. Then, thereto is added a solution of ethyl bromide (64 mg) in dimethylformamide (DMF, 1 ml) and the mixture is refluxed with heating for 1 hour. DMF is distilled off under reduced pressure and water is added to the residue and the mixture is extracted with dichloromethane. The extract is washed with water and dried with magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography to give 1-[4-(N-ethyl-4-methoxyanilinocarbonyl)phenyl]-3,4-dihydrocarbostyril (0.12 g).
Reaction SMILES: [CH2:1]1[C:9]2[C:5]([S:6][C:7]3[C:8]=2[C:10]2[C:15]([C:16]=3[OH:17])=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=[CH:2]1.C[O:19][C:20](=[O:42])[C@H:21]([CH2:40]O)[NH:22]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O.OS(O)(=O)=O>FC(F)(F)C(O)=O>[CH:1]1[C:9]2[C:8]3[C:10]4[C:15]([CH:16]([O:17][CH2:40][C@@H:21]([C:20]([OH:42])=[O:19])[NH2:22])[C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:14][CH:13]=[CH:12][CH:11]=4
Reactant: COC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: OC1=c2sc3c(c2-c2ccccc21)CC=CC=3
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](COC1c2ccccc2-c2c1sc1ccccc21)C(=O)O

Procedure:
from benzo[b]indeno[1,2-d]thiophen-6-ol (prepared by NaBH4 reduction of benzo[b]indeno[1,2-d]thiophen-9-one (Example i, Starting Fluorenones)) and Nα -(9-fluorenylmethoxycarbonyl)-L-serine methyl ester following method A, using trifluoroacetic acid as catalyst in place of H2SO4.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>C(#N)C>[N:11]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(CCl)cc1
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CN=[N+]=[N-])cc1

Procedure:
A mixture of 1-(chloromethyl)-4-methoxybenzene (20.0 g, 128 mmol) and sodium azide (12.5 g, 192 mmol) in acetonitrile (255 mL) was refluxed for 5 h under N2 atmosphere. The mixture was filtered and concentrated in vacuo. The residue was diluted in DCM, washed with H2O and brine, dried over Na2SO4 and concentrated in vacuo to afford crude 1-(azidomethyl)-4-methoxybenzene. The residue was used for the next reaction without further purification.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:16][CH:15]([NH:17][C:18]([CH2:20][NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[O:19])[CH2:14]3)[CH2:9][CH2:8]2)[CH:6]=1.[Si:34]([C:38]#[CH:39])([CH3:37])([CH3:36])[CH3:35].CCN(CC)CC>CN(C=O)C.[Cu]I>[F:30][C:29]([F:32])([F:31])[C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[C:22]([NH:21][CH2:20][C:18](=[O:19])[NH:17][CH:15]1[CH2:16][N:13]([CH:10]2[CH2:11][CH2:12][CH:7]([N:5]3[CH:6]=[C:2]([C:39]#[C:38][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:3]=[N:4]3)[CH2:8][CH2:9]2)[CH2:14]1)=[O:33]
Reactant: C#C[Si](C)(C)C
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3cc(I)cn3)CC2)C1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnn(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
A solution of N-({1-[4-(4-Iodo-pyrazol-1-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (as prepared in Example 28, 120 mg, 0.20 mmol), TMS-acetylene (Fluka, 20 mg, 0.40 mmol), Pd(Cl2)dppf (Aldrich, 16 mg, 0.02 mmol), CuI (Aldrich, 3.8 mg, 0.02 mmol) and Et3N (56 uL, 0.40 mmol) in DMF (5 mL) was heated to 80° C. overnight. The reaction was purified column chromatography purification (0-100% ethyl acetate in hexanes with NH3 in MeOH) resulting in the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18]([O:20][C:21]([Sn](CCCC)(CCCC)CCCC)=[CH2:22])[CH3:19]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:18]([O:20][CH2:21][CH3:22])=[CH2:19])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2sccc2n1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(OCC)c1nc(Cl)nc2ccsc12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
To a solution of Example 2 (3.0 g, 14.6 mmol) in 1,4-dioxane (200 mL) was added a solution of K2CO3 (4.0 g, 29.3 mmol) in water (40 mL). The almost clear solution was placed under nitrogen atmosphere and (1-Ethoxyvinyl)-tributylstannane (5.0 mL, 14.6 mmol) and PdCl2(PPh3)2 (500 mg, 0.731 mmol). The mixture was heated to 100° C. and stirred at 100° C. for 30 min under nitrogen atmosphere. After cooling to room temp. the 1,4-dioxane was removed i. vac. The residue was re-dissolved in DCM (100 mL) and water (50 mL) and transferred to a separating funnel. The aqueous layer was extracted with DCM (30 mL), the combined organic layers were washed with water (50 mL) and sat. brine (30 mL), dried over Na2SO4 and evaporated to dryness i. vac. The residue was purified by flash column chromatography (50 g SiO2 Isolute® pre-wetted with 1CV DCM) eluting with neat DCM collecting 12 mL fractions. Desired product eluted in fractions 10 to 20 with Rf=0.31 (DCM). By-products eluted in fractions 6 to 9 (Rf=0.59 in DCM) and fractions 21-31 ((Rf=0.14 in DCM). Fractions 10 to 20 were combined and evaporated to dryness i. vac. providing 2.28 g (65% yield) 2-chloro-4-(1′-ethoxy-vinyl)-thieno[3,2-d]pyrimidine as yellow powder of 95% purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5](/[CH:10]=[CH:11]/[C:12]([CH2:14][C:15](/[CH:17]=[CH:18]/[C:19]2[CH:27]=[C:24]([O:25][CH3:26])[C:22]([OH:23])=[CH:21][CH:20]=2)=[O:16])=[O:13])[CH:4]=1.C(N(CC)CC)C.[C:35]1(=[O:42])[O:41][C:39](=[O:40])[CH2:38][CH2:37][CH2:36]1.CC[O:45]CC>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:26][O:25][C:24]1[C:22]([OH:23])=[CH:21][CH:20]=[C:19](/[CH:18]=[CH:17]/[C:15]([CH2:14][C:12](/[CH:11]=[CH:10]/[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([OH:9])=[CH:7][CH:6]=2)=[O:13])=[O:16])[CH:27]=1.[C:35]([O-:41])(=[O:42])[CH2:36][CH2:37][CH2:38][C:39]([O-:45])=[O:40]
Reactant: CCOCC
Reactant: O=C1CCCC(=O)O1
Agent: CN(C)c1ccncc1
Agent: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C([O-])CCCC(=O)[O-]
Temperature: 80 °C

Procedure:
In a 500 mL round bottom flask curcumin (3.00 g), DMAP (168 mg) and triethyl amine (4 ml) were taken in 150 mL of THF. Glutaric anhydride (2.35 ml) in 15 mL of THF was added drop-wise under anhydrous conditions. The mixture was refluxed for 20 hours at 80° C. The solution was evaporated in a rotovop. The thick residue was taken in 150 mL of ethyl acetate, washed with 50 mL of 0.5 N HCl. The HCl wash was extracted with 50 mL of ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous sodium sulfate and was concentrated under vacuum to get 4.80 g. This was co-evaporated with ether several times to get a solid, 2.5 g. NMR was consistent with the structure.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH:29]=[CH2:30].O>CN(C)C=O>[CH2:30]([N:19]1[CH2:20][CH2:21][N:16]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH2:17][CH2:18]1)[CH:29]=[CH2:28]
Reactant: c1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN1CCN(c2nn(-c3ccccc3)c3ccccc23)CC1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of 5.0 g of 1-phenyl-3-(1-piperazinyl)-1H-indazole and 2.7 g of potassium carbonate in 50 ml of dimethylformamide was added 2.4 g of allyl bromide. The reaction mixture was stirred at 70° C. for 16 hours, poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated to yield 3-[4-(2-propenyl)-1-piperazinyl]-1-phenyl-1H-indazole as an oil. The oil was diluted with diethyl ether and filtered. Treatment of the filtrate with ethereal hydrogen chloride precipitated the hydrochloride salt. Recrystallization from ethanol/diethyl ether gave 2.0 g (21%) of 3-[4-(2-propenyl)-1-piperazinyl]-1-phenyl-1H-indazole hydrochloride, mp 234°-236°.
Reaction SMILES: [C:1]([OH:13])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[CH:14]1[C:19]([CH2:20][CH2:21]O)=[CH:18][C:17]([OH:23])=[C:16]([OH:24])[CH:15]=1.C1C(CCO)=CC=C(O)C=1>>[C:1]([O:13][CH2:21][CH2:20][C:19]1[CH:14]=[CH:15][C:16]([OH:24])=[C:17]([OH:23])[CH:18]=1)(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Reactant: OCCc1ccc(O)c(O)c1
Agent: OCCc1ccc(O)cc1
Product: O=C(/C=C/c1ccc(O)c(O)c1)OCCc1ccc(O)c(O)c1

Procedure:
The protocol derived from Example 14 above is applied with caffeic acid and 3-hydroxytyrosol instead of caffeic acid and tyrosol; the compound obtained is 2-(3,4-dihydroxyphenylethyl) trans-caffeoate (formula IVb2).