Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.[Ce:3].[NH2:4][C@H:5]([C:9]([OH:11])=[O:10])[C@@H:6]([CH3:8])[OH:7]>>[NH2:4][CH:5]([C:9]([OH:11])=[O:10])[CH:6]([CH3:8])[OH:7].[Ce:3]
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Agent: OO
Agent: [Ce]
Product: CC(O)C(N)C(=O)O
Temperature: 80 °C

Procedure:
Into a 600 ml glass beaker containing a magnetic stir bar was introduced 500 ml of high purity (HP) water. A 2.743 gm quantity of DL-threonine was dissolved in this volume. A 5.0 gm quantity of Ce(NO3)3·6(H2O) was added, thereby forming an equimolar ratio of L-threonine to cerium ion. Then a 10 ml solution containing 2.40 gm of 50% H2O2 (3.0 molar ratio of H2O2 to cerium ion) was added slowly to the cerium and threonine solution mixture. The pH was further adjusted to about 3.5. The reaction product was then heated to 80° C. for 1 hour.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.O1CCOCC1.CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O.[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OCC)(=O)C>[C:33]1([NH:32][C:2]2[C:7]([C:8](=[O:10])[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Nc1ccccc1
Reactant: CC(=O)c1cccnc1Cl
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)c1cccnc1Nc1ccccc1
Temperature: 75 °C
Reaction time: 3 h
Yield: 35.8 %

Procedure:
A solution of 1-(2-chloro-pyridin-3-yl)-ethanone (6.42 g, 41.3 mmol) and 1,4-dioxane (70 mL, 0.59M) in a large sealed tube vessel was treated with DL-10-camphorsulfonic acid (23.96 g, 103 mmol). The vessel was tightly sealed, placed behind a blast shield, and warmed to 75° C. At this time, the reaction vessel was removed from the oil bath, carefully opened, treated quickly with aniline (5.6 mL, 61.5 mmol), resealed, and lowered back into the oil bath. The reaction was then warmed to 80° C., where it was stirred for 3 h. At this time, the reaction was cooled to 25° C., diluted with ethyl acetate (250 mL) and washed with a saturated aqueous sodium bicarbonate solution (3×250 mL), water (150 mL) and a saturated aqueous sodium chloride solution (150 mL). The organics were dried over magnesium sulfate, filtered, rinsed with ethyl acetate, and concentrated in vacuo. Flash chromatography (AnaLogix Intelliflash 280, 220 g silica gel column, 1-20% ethyl acetate/hexanes) afforded 1-(2-phenylamino-pyridin-3-yl)-ethanone (3.14 g, 36%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C1COCC1>[NH:17]1[CH2:22][CH2:21][N:20]([C:14]([CH2:13][CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:16])[CH2:19][CH2:18]1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: O=C(NCCC(=O)N1CCNCC1)OCc1ccccc1
Yield: 86.2 %

Procedure:
2.23 g of N-benzyloxycarbonyl-β-alanine was coupled with 2.58 g of piperazine. The evaporation residue was suspended in THF, the undissolved material was filtered off and the filtrate was evaporated. Chromatography of the residue on silica gel RP 18 using water/methanol (2-5%) gave 2.51 g of benzyl [2-(4-piperazinylcarbonyl)ethyl]carbamate, MS: 291 (M+).
Reaction SMILES: C(N(CC)CC)C.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](Cl)=O.Cl.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([NH:28][NH2:29])=[N:20][N:19]=1>O1CCOCC1>[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2=[N:28][N:29]=[C:13]([C:9]3[O:8][CH:12]=[CH:11][CH:10]=3)[N:20]2[N:19]=1
Reactant: NNc1nnc(Cl)c2ccccc12
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Clc1nn2c(-c3ccco3)nnc2c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.2 %

Procedure:
Triethylamine (1.46 ml, 10.5 mmol) and 2-furoyl chloride (1.03 ml, 10.4 mmol) were added to a stirred solution of 1-chloro-4-hydrazinophthalazine hydrochloride (2.0 g, 8.7 mmol) in dioxane (200 ml) at room temperature under nitrogen. The mixture was stirred at room temperature for 2 h and then heated at reflux for 6 h. The mixture was cooled to room temperature, the solvent evaporated in vacuo and the residue partitioned between dichloromethane (800 ml) and water (200 ml). The organic layer was separated, washed further with water (4×200 ml) and brine (x 1), dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel, eluting with a 0.5-2% methanol/dichloromethane gradient, to afford the title-product (0.665 g, 28%); 1H NMR (250 MHz, CDCl3) 6.68 (1H, q, J=1.7 Hz, Ar—H), 7.56 (1H, m, Ar—H), 7.73 (1H, m, Ar—H), 7.91 (1H, m, Ar—H), 8.05 (1H, m, Ar—H), 8.31 (1H, d, J=7.5 Hz, Ar—H), 8.76 (1H, m, Ar—H).
Reaction SMILES: C1(S([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[CH:21][C:20]=4[CH:28]=3)[CH2:12][CH2:11]2)(=O)=O)C=CC=CC=1.Br.Cl>C(O)(=O)C.OC1C=CC(C(O)=O)=CC=1>[N:13]1([C:16]2[CH:17]=[CH:18][C:19]3[O:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[CH:21][C:20]=3[CH:28]=2)[CH2:12][CH2:11][NH:10][CH2:15][CH2:14]1
Reactant: COC(=O)c1cc2cc(N3CCN(S(=O)(=O)c4ccccc4)CC3)ccc2o1
Agent: Br
Agent: Cl
Agent: O=C(O)c1ccc(O)cc1
Solvent: CC(=O)O
Product: COC(=O)c1cc2cc(N3CCNCC3)ccc2o1
Temperature: 27.5 °C
Reaction time: 0.08 h
Yield: 82.1 %

Procedure:
Methyl 5-[4-(benzenesulfonyl)-1-piperazinyl]benzofuran-2-carboxylate (30 g) was added to a solution of hydrobromic acid in acetic acid (180 ml) and 4-hydroxybenzoic acid (24 g). The resulting mixture was stirred for 5 minutes at 25-30° C., followed by heating the mixture to 80-85° C. and maintaining for 6 hours at the same temperature. The reaction mass was poured into methanolic HCl (1000 ml), followed by heating to reflux and then stirring for 6 hours under reflux. The resulting mass was cooled to 0-5° C. and then stirred for 1 hour at the same temperature. The separated solid was filtered and washed with chilled methanol (100 ml). The wet solid was added to methanolic HCl (500 ml) and then heated to reflux for 4 hours. The resulting mass was cooled to 0-5° C. and then stirred for 1 hour at the same temperature. The separated solid was filtered, washed with chilled methanol (100 ml) and then dried at 60-65° C. The resulting solid was added to toluene (500 ml) at 25-30° C., followed by purging ammonia gas slowly for 7 hours. After completion of the ammonia gas purging, the reaction mass was stirred for 15 minutes at 25-30° C. The resulting mass was filtered and the filtrate was distilled to produce 16 g of methyl 5-(1-piperazinyl)benzofuran-2-carboxylate (Purity by HPLC: 99.5%; Yield: 82.5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:19])[CH2:15][C:16](N)=[O:17])=[CH:10][CH:9]=1.[CH3:20][Mg]I.[Mg].CI.S(=O)(=O)(O)O>C(Cl)Cl.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:19])[CH2:15][C:16](=[O:17])[CH3:20])=[CH:10][CH:9]=1
Reactant: CC(CC(N)=O)c1ccc(-c2ccccc2F)cc1
Reactant: C[Mg]I
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CI
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)CC(C)c1ccc(-c2ccccc2F)cc1
Temperature: 0 °C

Procedure:
A solution of 25.7 gm (0.1 mol) of 3-(2'-fluoro-4-biphenylyl)-butyramide in 750 ml of dry methylene chloride was added dropwise over a period of one hour to a methyl magnesium iodide solution which was prepared from 12.2 gm (0.5 mol) of magnesium and 71 gm (0.5 mol) of methyl iodide in a total of 400 ml of anhydrous ether, and the resulting mixture was refluxed for 6 hours to make the reaction go to completion. After cooling, the reaction mixture was stirred into a mixture consisting of 2 kg of ice and 100 ml of concentrated sulfuric acid. The ethereal phase was separated, washed twice with water, once with an aqueous saturated sodium bicarbonate solution, and again with water, dried over anhydrous magnesium sulfate and evaporated in vacuo. The solid residue was recrystallized twice from gasoline (b.p. range 60° to 80°C), yielding 22.0 gm (86% of theory) of the colorless crystalline compound, m.p. 60°-61°C, of the formula ##SPC22##
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:25])[CH:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:13][S:14]2)=[CH:9][CH:8]=1.CC(C)([O-])C.[K+].O>CS(C)=O>[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:25])[C:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)([CH2:3][CH:2]=[CH2:1])[CH2:13][S:14]2)=[CH:9][CH:8]=1
Reactant: COc1ccc(C2CSc3cc(OC)ccc3C2=O)cc1
Reactant: C=CCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCC1(c2ccc(OC)cc2)CSc2cc(OC)ccc2C1=O
Temperature: 10 °C
Reaction time: 15 h
Yield: 78.7 %

Procedure:
Allyl bromide (5.7 ml, 66.56 mmol) was added dropwise to a solution of 7-methoxy-3-(4-methoxyphenyl)thiochroman-4-one (2 g, 6.64 mmol) in dimethyl sulfoxide (34 ml). To this mixture, a solution of potassium tert-butoxide (5.22 g, 46.55 mmol) in dimethyl sulfoxide (70 ml) was slowly added dropwise at 10° C., followed by stirring for 2 hours at 10° C. and for 15 hours at room temperature. Water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent:ethyl acetate/hexane=1/9) to give 7-methoxy-3-(4-methoxyphenyl)-3-(2-propenyl)thiochroman-4-one (1.78 g, Yield 79%) as a colorless oil.
Reaction SMILES: CC([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]2)[CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:15])=[N:10][CH:9]=1)(C)C(O)=O.C1(O)C=CC=CC=1.C([O:43][C:44](=[O:56])[C:45]([CH3:55])([CH3:54])[CH2:46]SC1SC(N)=NC=1)C>>[CH3:46][C:45]([CH3:55])([CH2:54][S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]2)[CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:15])=[N:10][CH:9]=1)[C:44]([OH:56])=[O:43]
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCCOc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: CCOC(=O)C(C)(C)CSc1cnc(N)s1
Solvent: Oc1ccccc1
Product: CC(C)(CSc1cnc(NC(=O)N(CCCOc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-(3-phenoxy -propyl)-ureido]-thiazol -5-ylsulfanyl}-propionic acid using phenol and 3-(2-amino-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:27][OH:28])[CH:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:18][C:17]3[CH:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=[CH:22][C:16]=3[N:15]=2)=[CH:10][CH:9]=1.[Mn]([O-])(=O)(=O)=[O:30].[K+]>N1C=CC=CC=1.O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[NH:18][C:17]4[CH:19]=[C:20]([C:23]([F:25])([F:26])[F:24])[CH:21]=[CH:22][C:16]=4[N:15]=3)=[CH:10][CH:9]=2)=[N:6][CH:5]=[C:4]([CH:3]=1)[C:27]([OH:30])=[O:28]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: OCc1cnc(-c2ccc(-c3nc4ccc(C(F)(F)F)cc4[nH]3)cc2)c(Cl)c1
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)c1cnc(-c2ccc(-c3nc4ccc(C(F)(F)F)cc4[nH]3)cc2)c(Cl)c1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
0.40 g of {5-chloro-6-[4-(6-trifluoromethyl-1H-benzoimidazol-2-yl)-phenyl]-pyridin-3-yl}-methanol (28) (0.99 mmol) prepared in Example 16 was dissolved in 4 mL of pyridine and 2 mL of distilled water. 0.59 g of potassium permanganate (3.71 mmol) was added thereto, and reacted at 110° C. for 4 hours. Then, 0.59 g of potassium permanganate (3.71 mmol) and 2 mL of distilled water were added thereto, and reacted at 110° C. for 18 hours. The resultant was cooled to room temperature, and concentrated under reduced pressure. The aqueous layer was washed with ethyl acetate, pH 1 was adjusted with concentrated hydrochloric acid, and extracted with ethyl acetate several times. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=10/1) to obtain 0.32 g of 5-chloro-6-[4-(6-trifluoromethyl-1H-benzoimidazol-2-yl)-phenyl]-nicotinic acid (yield 77%).
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].C(O)=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Br:22])[CH:18]=2)[CH:13]=1>C1C=CC=CC=1>[Br:22][C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([NH:11][S:2](=[O:4])(=[O:3])[NH2:5])[CH:13]=2)[CH:18]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Nc1ccc2cc(Br)ccc2c1
Solvent: c1ccccc1
Solvent: O=CO
Product: NS(=O)(=O)Nc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 19.5 h

Procedure:
A solution of chlorosulfonyl isocyanate (870 μl, WAKO) in benzene (10 ml) was added dropwise with formic acid (377 μl, WAKO) under ice cooling, warmed to room temperature, stirred for 19.5 hours, then heated to 40° C. and further stirred for 4 hours. The reaction mixture was added dropwise with a solution (5 ml) of 2-amino-6-bromonaphthalene (443 mg) in benzene under ice cooling, warmed to room temperature and stirred for 21.5 hours. The reaction mixture was filtered, and the obtained solid was added with ethyl acetate and mixed. The mixture was filtered again, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=2:1) to obtain the title compound (Intermediate 28, 158 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.Cl[CH2:12][C:13]([OH:15])=[O:14]>C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][O:8][CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Cl)cc1
Reactant: O=C(O)CCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(O)COCCc1ccc(Cl)cc1
Yield: 105.4 %

Procedure:
3.15 g of 4-chlorophenethyl alcohol were reacted with 2.2 g of chloroacetic acid in a manner analogous to that described in Example 1(a) to give 4.55 g (91%) of 2-(4-chlorophenyl)ethoxyacetic acid of melting point 75°-77° C. (from ethyl acetate/hexane).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[CH:20]([C:22]1[CH:23]=[CH:24][C:25]([OH:32])=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28])=[O:21].CN(C)C=O>O>[CH:20]([C:22]1[CH:23]=[CH:24][C:25]([O:32][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[O:10][CH:11]=[CH:12][CH:13]=3)[O:6][C:7]=2[CH3:8])=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28])=[O:21]
Reactant: COC(=O)c1cc(C=O)ccc1O
Reactant: Cc1oc(-c2ccco2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 90 °C
Reaction time: 15 h
Yield: 91.5 %

Procedure:
A mixture of 4-chloromethyl-2-(2-furyl)-5-methyl-1,3-oxazole (7.13 g), potassium carbonate (3.84 g), methyl 5-formyl-2-hydroxybenzoate (5.0 g) and N,N-dimethylformamide (100 mL) was stirred at 90° C. for 15 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give methyl 5-formyl-2-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzoate as pale-brown crystals (8.67 g, 91%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 121-122° C.
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([O:19][CH2:20][CH3:21])=[N:16][N:15]=3)=[CH:12][C:8]([C:9](N)=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.N([O-])=[O:24].[Na+]>C(O)(C(F)(F)F)=O>[CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([O:19][CH2:20][CH3:21])=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([OH:24])=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCOc1nnc(-c2cc(C(N)=O)c(C)cc2C2CCC2)[nH]1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOc1nnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzamide (219.8, 0.1 g, 0.33 mmol) in TFA (5 ml) was added NaNO2 (0.046 g, 0.66 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour then at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated to give a clear oil. Yield: 0.1 g, 100%. m/z (ES−) 300 (M−H)−.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([CH:6]([CH2:10][CH2:11][CH2:12][C@H:13]1[C@@H:21]2[C@@H:16]([NH:17][C:18]([NH:20]2)=[O:19])[CH2:15][S:14]1)[C:7](=[O:9])[OH:8])=[O:5].[CH3:22]O>>[CH3:1][N:2]([CH3:22])[CH2:3][C:4]([CH:6]([CH2:10][CH2:11][CH2:12][C@H:13]1[C@@H:21]2[C@@H:16]([NH:17][C:18]([NH:20]2)=[O:19])[CH2:15][S:14]1)[C:7](=[O:8])[OH:9])=[O:5]
Reactant: CO
Reactant: CNCC(=O)C(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(=O)O
Product: CN(C)CC(=O)C(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(=O)O

Procedure:
N-methyl-glycyl-biotin is esterified in refluxing methanol containing gaseous HCl to give the methylester, methyl-(N-methyl)glycyl-biotin. This methyl ester is dissolved in ethylene diamine and stirred at 23° C. for 14 hours to afford biotinyl-N-methyl-glycyl-ethylene diamine monoamide. The solvent (ethylene diamine) is evaporated under vacuum. The amino group of biotinyl-N-methyl-glycyl-ethylene diamine monoamide is acylated with N-hydroxysuccinimidyl iodoacetate (prepared from iodoacetic acid available from Aldrich Chemical Co., N-hydroxysuccinimide and dicyclohexylcarbodiimide (DCC)) in DMF with triethylamine to form an acylated iodinated biotin derivative. Troc-NH-palytoxin prepared as set forth above is deprotonated with 1.0 equivalents of sodium hydride and O-alkylated with the iodo-biotin derivative, N-(iodoacetyl)-ethylene-diamine-N'-(N-methyl)glycylbiotin, to afford the ether, N-(trichloroethoxycarbonyl)-palytoxin-mono-oxo-N-acetamido-ethylenediamine-N'-(N-methyl)glycylbiotin. The trichloro-carbamate group of the ether is cleaved with zinc in aqueous THF, pH 5.5-7.2, to afford the final product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]#[C:16][Si](C)(C)C)[CH:12]=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]C.[F-].[K+]>>[C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:10]=1)#[CH:16]
Reactant: CCCCCCCOc1cccc(C#C[Si](C)(C)C)c1
Agent: [F-]
Agent: [K+]
Product: C#Cc1cccc(OCCCCCC)c1

Procedure:
According to the method of Example S117b, ((3-(heptyloxy)phenyl)ethynyl)trimethyl silane (575 mg, 2.1 mmol) was reacted with potassium fluoride (429 mg, 7.4 mmol) to give the title compound as a clear oil following silica gel purification (hexane) (390 mg, 93%). 1H NMR (400 MHz, CDCl3) 1H NMR (400 MHz, CDCl3) δ 7.22 (t, 1H, J=7.6 Hz), 7.08 (d, 1H, J=7.2 Hz), 7.02 (s, 1H), 6.90 (d, 1H, J=7.0 Hz), 3.95 (t, 2H, J=6.4 Hz), 3.06 (s, 1H) 1.80-1.75 (m, 2H), 1.48-1.30 (m, 6H), 0.92 (t, 3H, J=6.8 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32]>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][CH3:32])[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: COc1ccccc1CBr
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Product: COc1ccccc1CN1C(=O)N(c2cnn(Cc3c(C)noc3C)c2)C(=O)C1(C)C
Yield: 53 %

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 1-(bromomethyl)-2-methoxybenzene. Yield 53%, white solid. 1H NMR (DMSO-d6, 400 MHz): s, 6H), 2.16 (s, 3H), 2.42 (s, 3H), 3.83 (s, 3H), 4.50 (s, 2H), 5.20 (s, 2H), 6.91 (dt, J=1.2, 7.6 Hz, 1H) 7.00 (dd, J=0.8, 8.0 Hz, 1H), 7.27 (m, 2H), 7.82 (d, J=0.8 Hz, 1H), 8.20 (d, J=0.8 Hz, 1H). MS 424 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.08 μM.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:8]=[C:9]([C:12]#[N:13])[S:10][CH:11]=1.C(=O)=O.CC(C)=O.[Cl:21][CH2:22][C:23](N(OC)C)=[O:24].Cl>O1CCCC1>[Br:6][C:7]1[CH:8]=[C:9]([C:12]#[N:13])[S:10][C:11]=1[C:23](=[O:24])[CH2:22][Cl:21]
Reactant: CON(C)C(=O)CCl
Reactant: N#Cc1cc(Br)cs1
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: N#Cc1cc(Br)c(C(=O)CCl)s1
Temperature: 25 °C
Yield: 21.7 %

Procedure:
Butyllithium (2.5 M solution in hexanes; 14.5 mL, 36.3 mmol) was added under nitrogen over approximately 5 min to a solution of 4-bromo-thiophene-2-carbonitrile (5.95 g, 31.6 mmol) in 300 mL of anhydrous tetrahydrofuran at dry ice-acetone temperature. After the addition, the reaction was stirred at dry ice-acetone temperature for 30 min. 2-Chloro-N-methoxy-N-methyl acetamide (4.80 g, 32.7 mmol) in 40 mL of anhydrous tetrahydrofuran was then added dropwise over 30 min. After the addition, the reaction was stirred at dry ice-acetone temperature for 4 h. 6 M HCl (36 mL) was added and the reaction allowed to warm to room temperature. The reaction was concentrated under reduced pressure to remove the tetrahydrofuran. The residue was partitioned between ethyl acetate and water. Saturated sodium chloride was added to aid in the separation of an emulsion. The organic layer was separated, washed with water, saturated sodium chloride, dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was purified on 800 g of silica gel (230-400 mesh) using a gradient of 30% methylene chloride in hexane to 60% methylene chloride in hexane as the eluent. Isolation of the major component gave 4-bromo-5-(chloroacetyl)thiophene-2-carbonitrile (1.81 g, 22%) as a white solid, mp 126-128° C.; MS (ESI) m/z 262.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](=O)[CH2:8]Br)=[CH:5][CH:4]=1)#[N:2].[F:13][C:14]([F:21])([F:20])[CH2:15][NH:16][C:17]([NH2:19])=[S:18].C(=O)(O)[O-].[Na+]>C(O)C>[F:13][C:14]([F:21])([F:20])[CH2:15][NH:16][C:17]1[S:18][CH:8]=[C:7]([C:6]2[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:19]=1
Reactant: NC(=S)NCC(F)(F)F
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(-c2csc(NCC(F)(F)F)n2)cc1
Temperature: 25 °C
Yield: 95.3 %

Procedure:
Slurry 4-cyanophenacyl bromide (1.4 g, 6.3 mmol), 2,2,2-trifluoroethyl-thiourea (1.0 g, 6.3 mmol) and sodium bicarbonate (529 mg, 6.3 mmol) in absolute ethanol (30 mL). Stir the mixture at reflux for 1 h under a nitrogen atmosphere. Cool to room temperature and concentrate in vacuo. Partition the residue between DCM (100 mL) and water (20 mL). Dry the organic layer over Na2SO4 and concentrate in vacuo to obtain the desired intermediate (1.7 g, 95%). MS (ES+) m/z: 284 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.C([O:15][B:16](OC(C)C)[O:17]C(C)C)(C)C.C([Li])CCC.Cl>O.C1COCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([B:16]([OH:17])[OH:15])=[CH:3][C:4]=1[O:10][CH3:11])#[N:7]
Reactant: COc1cc(Br)ccc1C#N
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(B(O)O)ccc1C#N
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
A 3-necked 1 L round-bottomed flask was equipped with an overhead stirrer, and a nitrogen line. The flask was charged with 45.56 g (215 mmol) of 4-bromo-2-methoxybenzonitrile, 64 mL (277 mmol) of tri-isopropylborate and 500 mL of THF. The solution was cooled to −78° C. in a dry-ice/acetone bath. n-Butyllithium (2.5M, 110 mL, 275 mmol) was added dropwise via addition funnel. The mixture was stirred for 30 minutes and 2N HCl was added. The mixture was stirred for an hour and poured into water. The mixture was extracted with Et2O. The organic solution was backextracted with 1N NaOH. The aqueous layer was washed with Et2O and acidified with conc. HCl. The mixture was extracted with Et2O. The organic extract was dried (MgSO4) and evaporated in vacuo to afford 20.77 g (55%) of the product as a white solid. 1H NMR (500 MHz, d6-DMSO) δ 7.68 (d, 1H), 7.59 (s, 1H), 7.47 (d, 1H), 3.95 (s, 3H).