Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(/C=C/C([O:11][C@H:12]2[C@H:17]([OH:18])[C@H:16]([OH:19])[CH2:15][C@@:14](O)([C:20]([OH:22])=[O:21])[CH2:13]2)=O)=CC(O)=C(O)C=1.[K]>O>[C:20]([OH:22])(=[O:21])[C:14]1[CH:15]=[C:16]([OH:19])[C:17]([OH:18])=[C:12]([OH:11])[CH:13]=1
Reactant: O=C(/C=C/c1ccc(O)c(O)c1)O[C@@H]1C[C@](O)(C(=O)O)C[C@@H](O)[C@H]1O
Agent: [K]
Solvent: O
Product: O=C(O)c1cc(O)c(O)c(O)c1

Procedure:
After 20 g of commercially available instant coffee (Nescafe Gold Blend with Red Label) was dissolved in 1400 mL of distilled water (the solution thus obtained will hereinafter be called “Coffee P”), 30 g of activated carbon “Shirasagi WH2c 28/42” (product of Japan EnviroChemicals, Ltd.) was added to the resulting solution. The resulting mixture was stirred for one hour and then, filtered through a membrane filter (0.45 μm) to yield a filtrate (which will hereinafter be called “Coffee Q”). The resulting filtrate was freeze dried, whereby 15.8 g of brown powder was obtained. The resulting brown powder was dissolved in distilled water and amounts of chlorogenic acids and HHQ were determined by HPLC analysis as in Example 1. As a result, the chlorogenic acid content was 4.12 wt. %, while the HHQ content was below the detection limit (in accordance with the analysis conditions B). In addition, the potassium content was measured by ICP emission spectrometry. The potassium content in each of the raw material instant coffee and coffee treated with activated carbon was about 4.2 wt. %. Analysis results of coffee P, coffee Q and gallic acid by HPLC are shown by the respective charts in FIGS. 5 and 6. In coffee Q, a peak in the vicinity of a retention time of 6.8 minutes disappears and there exists no peak substantially. In FIG. 5, a represents the chart of coffee P, b represents the chart of coffee Q and c represents a chart of gallic acid. In FIG. 6, b represents the chart of coffee P, c represents the chart of coffee Q and a represents the chart of gallic acid.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([C:18](=[O:22])[CH2:19][CH2:20][CH3:21])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].Cl.[CH3:24]NC.C=O.C(O)(=O)C>CN(C)C=O>[Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([C:18](=[O:22])[C:19](=[CH2:24])[CH2:20][CH3:21])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCCC(=O)c1ccc(OCCCCCC(=O)O)c(Cl)c1Cl
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C=C(CC)C(=O)c1ccc(OCCCCCC(=O)O)c(Cl)c1Cl
Temperature: 0 °C

Procedure:
A mixture of 6-(2,3-dichloro-4-butyrylphenoxy)hexanoic acid (9.5 g, 0.026 mole), dimethylamine hydrochloride (15 g, 0.184 mole), paraformaldehyde (2.8 g, 0.09 equiv.) and acetic acid (1 ml) were united and stirred and heated on a steam bath for two hours. The reaction mixture was treated with N,N-dimethylformamide (30 ml) and stirring and heating continued for another hour. The reaction mixture was poured into ice water and the solid that separated was removed by filtration, washed with water and dried. The yield was 9.2 g after recrystallization from butyl chloride the 6-[2,3-dichloro-4-(2-methylenebutyryl)phenoxy]hexanoic acid melted at 106°-107° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([CH3:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[O:41][N:40]=[C:39]([CH3:42])[CH:38]=2)[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)[C:11]([CH3:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[O:41][N:40]=[C:39]([CH3:42])[CH:38]=2)[CH:32]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1N1CCCC1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(N4CCCC4)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-4-methyl-5-pyrrolidin-1-yl-phenyl)-carbamic acid tert-butyl ester (Example J39) (291 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (330 mg, 64%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[C:26]([CH3:27])=[CH:25][C:23]([NH2:24])=[C:22]([CH3:28])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]=[C:40]=[O:41]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[C:26]([CH3:27])=[CH:25][C:23]([NH:24][C:40]([NH:39][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[O:32][CH3:31])=[O:41])=[C:22]([CH3:28])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(Oc3cc(C)c(N)cc3C)ccnc2cc1OCc1ccccc1
Reactant: COc1ccccc1N=C=O
Solvent: ClC(Cl)Cl
Product: COc1ccccc1NC(=O)Nc1cc(C)c(Oc2ccnc3cc(OCc4ccccc4)c(OC)cc23)cc1C
Temperature: 70 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2,5-dimethylaniline (300 mg) was dissolved in chloroform (5 ml). 2-Methoxyphenyl isocyanate (0.24 ml) was then added to the solution, and the mixture was stirred at 70° C. overnight. The reaction solution was purified by chromatography on silica gel by development with chloroform/acetone (75/25) to give 365 mg (yield 89%) of the title compound. 1H-NMR (CDCl3, 400 MHz): δ 2.17 (s, 3H), 2.28 (s, 3H), 3.83 (s, 3H), 4.07 (s, 3H), 5.33 (s, 2H), 6.26 (s, 3H), 6.29 (d, J=5.4 Hz, 1H), 6.86-7.06 (m, 4H), 7.12 (s, 1H), 7.30-7.41 (m, 3H), 7.46 (s, 1H), 7.50-7.56 (m, 3H), 7.61 (s, 1H), 8.11-8.16 (m, 1H), 8.43 (d, J=5.4 Hz, 1H)
Reaction SMILES: C([O:3][C:4](=[O:42])[CH2:5][N:6]([CH2:36][C:37]([O:39]CC)=[O:38])[C:7](=[O:35])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:11]=1)=[O:9])C.[OH-].[Na+]>CO>[C:4]([CH2:5][N:6]([C:7](=[O:35])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:11]=1)=[O:9])[CH2:36][C:37]([OH:39])=[O:38])([OH:42])=[O:3]
Reactant: CCCCCCCCCCCCCCCCCCOc1cccc(C(=O)C(=O)N(CC(=O)OCC)CC(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOc1cccc(C(=O)C(=O)N(CC(=O)O)CC(=O)O)c1
Yield: 92 %

Procedure:
A solution of 1.3 g (2.2 mmol) of N-(2-ethoxy-2-oxoethyl)-N-[2-[3-(octadecyloxy)phenyl]-1,2-dioxoethyl]glycine ethyl ester and 1.8 ml (11 mmol) of 6N NaOH in 100 ml of methanol was stirred at reflux under argon for 3 hours. The solvent was removed at reduced pressure, the residue was acidified and the product was extracted with ethyl acetate. The dried extract was concentrated at reduced pressure to a solid which was recrystallized from acetone-hexane to give 1.08 g (91% yield, mp 126°-128°) of N-(carboxymethyl)-N-[2-[3-(octadecyloxy)phenyl]-1,2-dioxoethyl]glycine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:40][N:41]([CH2:58][CH2:59][C:60]1[S:61][CH:62]=[CH:63][CH:64]=1)[C:42](=[O:57])[C@H:43]([NH:55][CH3:56])[CH2:44][C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:55]([CH3:56])[C@@H:43]([C:42](=[O:57])[N:41]([CH3:40])[CH2:58][CH2:59][C:60]1[S:61][CH:62]=[CH:63][CH:64]=1)[CH2:44][C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCc1cccs1)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.8 %

Procedure:
(2E)-5-tert-Butoxycarbonylamino-5-methylhex-2-enoic acid (380 mg, 1.56 mmol) was dissolved in N,N-dimethylformamide (2 ml) and dichloromethane (2 ml). 1-Hydroxy-7-azabenzotriazole (299 mg, 1.56 mmol) was added as a solid. The solution was cooled to 0° C. N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (380 mg, 1.56 mmol) was added. The solution was stirred for 15 min. at 0° C. A solution of (2R)-N-methyl-2-(methylamino)-3-(2-naphthyl)-N-(2-(2-thienyl)ethyl)propionamide (500 mg, 1.42 mmol) in dichloromethane (2 ml) was added. Ethyldiisopropylamine (0.25 ml, 1.42 mmol) was added. The solution was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (70 ml) and washed with 1 N hydrochloric acid (100 ml). The organic layer was washed with saturated sodium hydrogen carbonate solution (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (150 g), using ethyl acetate/heptane (1:1) as eluent, to give 679 mg of (3E)-1,1-dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enylcarbamic acid tert-butyl ester.
Reaction SMILES: [Na+].[NH:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15]([O-:18])(=[O:17])=[O:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(#N)C>[NH:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:16])=[O:17])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)([O-])CCCCCCNc1ccccc1
Agent: [Na+]
Solvent: CC#N
Product: O=S(=O)(O)CCCCCCNc1ccccc1

Procedure:
6-Anilino 1-hexanesulfonic acid sodium salt (11.2 g, 0.5 mol) is dissolved in aqueous 0.5M HCLO4 solution (30 mL) and acetonitrile (400 mL) is added to the solution. The solution is filtered and the filtrate is kept in a refrigerator overnight to obtain 6-anilino-1-hexanesulfonic acid as a precipitate.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH:8]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1)=[O:4].[Li+].[OH-].Cl>O>[CH2:12]([O:11][C:9]1[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH:8]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(-c2cccc(F)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(OCc2ccccc2)cc(-c2cccc(F)c2)c1
Temperature: 55 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
To a solution of 5-benzyloxy-3′-fluoro-biphenyl-3-carboxylic acid methyl ester (4.2 g) was added a solution of LiOH (2.9 g) in water (50 mL) and the resulting mixture was stirred at 55° C. overnight. The reaction mixture was acidified with 3 N HCl and the white precipitate was collected by filtration. It was washed with water and dried on air to yield the title compound (3.8 g, 94% yield).
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[O:15]1[CH2:18][C:17](=[O:19])[CH2:16]1>C1COCC1.C(OCC)(=O)C>[Cl:9][C:3]1[CH:4]=[C:5]([Cl:8])[N:6]=[CH:7][C:2]=1[C:17]1([OH:19])[CH2:18][O:15][CH2:16]1
Reactant: Clc1cc(Cl)c(Br)cn1
Reactant: O=C1COC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC1(c2cnc(Cl)cc2Cl)COC1
Temperature: -15 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a solution of 5-bromo-2,4-dichloropyridine (CAN 849937-96-8, 15 g, 66.1 mmol) in dry THF (300 ml) cooled down to −15° C. under an argon atmosphere was added isopropyl magnesium chloride, lithium chloride complex (53.4 ml, 69.4 mmol) and the mixture was stirred at −15° C. for 1 hour. Then oxetan-3-one (5.24 g, 72.7 mmol) was added neat to the reaction mixture cooled at −15° C., reaction mixture was stirred and let to warm up to room temperature overnight. Reaction was quenched by addition of water and stirred for 5 minutes. Reaction was diluted with ethyl acetate and was transferred into a separatory funnel. The organic phase was extracted with a saturated aqueous solution of ammonium chloride and the organic phase was collected. The aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (10.5 mg, 72%). MS (ESI, m/z): 220.4 (M+H+)
Reaction SMILES: Br.[NH:2]=[C:3]1[N:7]([CH2:8][C:9]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[NH:14][C:15](=[O:17])[CH3:16])=[O:10])[CH2:6][CH2:5][S:4]1.[BH4-].[Na+].[ClH:23].CC(C)=O>C(O)C>[ClH:23].[OH:10][CH:9]([C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[NH:14][C:15](=[O:17])[CH3:16])[CH2:8][N:7]1[CH2:6][CH2:5][S:4][C:3]1=[NH:2]
Reactant: CC(=O)Nc1cccc(C(=O)CN2CCSC2=N)c1
Agent: Br
Agent: Cl
Agent: [BH4-]
Solvent: CCO
Solvent: CC(C)=O
Product: CC(=O)Nc1cccc(C(O)CN2CCSC2=N)c1
Reaction time: 0.67 h

Procedure:
To a stirred slurry of 63.47 g. (0.177 mole) of 3'-[ (2-imino-3-thiazolidinyl)acetyl]acetanilide hydrobromide (Example 3) in 1 liter of 95% ethanol, maintained at 5°C., is added 5.70 g. (0.15 mole) of sodium borohydride. After stirring 40 minutes an additional 4.10 g. of sodium borohydride is added and the mixture is acidified with hydrochloric acid and evaporated under reduced pressure. The residue is partitioned between chloroform and dilute aqueous ammonium hydroxide. Two further chloroform extracts are combined with the original, washed with brine, dried (sodium sulfate) and evaporated to give an oil. Treatment with acetone gives 26.77 g. (48%) of white crystalline hydrochloride, which has melting point 235°-237°C. Anal: Calcd. for C13H18ClN3O2S:x Calcd: C, 49.44; H, 5.74; Cl, 11.23; N, 13.31; S, 10.15. found: C, 49.87; H, 5.27; Cl, 11.51; N, 13.25; S, 10.40.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[C:21]3[CH2:20][CH2:19][C:18]4[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=4[C:16](=[O:26])[C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:27][C:28]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:29]=1[NH2:30].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C1(C)C=CC=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)(C)(C)C>[F:27][C:28]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:29]=1[NH:30][C:23]1[CH:24]=[CH:25][C:17]2[C:16](=[O:26])[C:15]3[CH:21]=[C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH:12]=[CH:13][C:14]=3[CH2:20][CH2:19][C:18]=2[CH:22]=1
Reactant: O=C1c2ccccc2CCc2c(OCCCN3CCOCC3)cccc21
Reactant: Nc1ccc(F)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: O=C1c2ccc(Nc3ccc(F)cc3F)cc2CCc2ccc(OCCCN3CCOCC3)cc21
Yield: 43 %

Procedure:
In accordance with general method AA, 0.67 g (1.8 mmol) of 2-chloro-7-(3-morpholin-4-yl-propoxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one (36i), 0.25 g (1.9 mmol) of 2,4-difluoroaniline, 0.05 g (0.22 mmol) of Pd(OAc)2, 0.10 g (0.21 mmol) of 2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.60 g (6.2 mmol) of Na—O-tert-butylate, 5 ml of toluene and 1 ml of tert-BuOH are used. Reaction time: 1 h. Purification is carried out via flash chromatography (SiO2, hexane/ethyl acetate 7+3). C28H28F2N2O3 (Mr=478.54); yield 43%; m.p. 114° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([S:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Reactant: Sc1ccccc1
Product: COc1ccc(-c2cc(Sc3ccccc3)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (352.5 mg, 1.08 mmol) and thiophenol were reacted as starting materials at 100° C. for 7 hours and post-treatment was then conducted, whereby the title compound was obtained as a colorless crystalline powder (55.8 mg, 12.9%). Melting point: 176.9-177.8° C. (chloroform-diethyl ether)
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])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Cl.[CH3:22][O:23]C(=O)[C@H](CO)N.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH:16]([CH2:22][OH:23])[NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)NC(CO)C2=O)cn1
Temperature: 25 °C
Yield: 5.5 %

Procedure:
4-((4-isocyanato-1H-pyrazol-1-yl)methyl)-3,5-dimethylisoxazole (example 10-1) (784 mg, 3.6 mmol), serine methyl ester hydrochloride (672 mg, 4.32 mmol) and triethylamine (1 mL, 7.2 mmol) were refluxed in toluene (16 mL) for 8 hours. The reaction was allowed to cool to room temperature and then the solution was concentrated on the rotovap. The product was purified by reverse phase HPLC (5 to 95% acetonitrile in H2O: 16 minute gradient) to afford 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5-(hydroxymethyl)imidazolidine-2,4-dione as a white solid (60 mg, 25%). 1H NMR (CDCl3, 400 MHz): δ(s, 3H), 2.40 (s, 3H), 3.13-3.07 (m, 1H), 3.94-3.93 (d, J=4 Hz, 2H), 4.21-4.19 (t, J=4 Hz, 1H), 5.03 (s, 2H), 6.68 (bs, 1H), 7.87 (s, 1H), 7.99 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 3 μM.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:34])[NH:10][C@@H:11]([CH2:28][C:29]2[N:30]=[CH:31][S:32][CH:33]=2)[C:12]([NH:14][CH2:15][C:16]2[N:17]=[N:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:20]=2)=[O:13])[O:7]1)=[O:5])C.[Li+].[OH-]>>[F:27][C:24]1[CH:23]=[CH:22][C:21]([N:19]2[CH:20]=[C:16]([CH2:15][NH:14][C:12](=[O:13])[C@@H:11]([NH:10][C:9]([C@H:8]3[O:7][C@@H:6]3[C:4]([OH:5])=[O:3])=[O:34])[CH2:28][C:29]3[N:30]=[CH:31][S:32][CH:33]=3)[N:17]=[N:18]2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cscn1)C(=O)NCc1cn(-c2ccc(F)cc2)nn1
Agent: [Li+]
Agent: [OH-]
Product: O=C(NCc1cn(-c2ccc(F)cc2)nn1)[C@H](Cc1cscn1)NC(=O)[C@H]1O[C@@H]1C(=O)O
Yield: 7.7 %

Procedure:
Followed general procedure using: the corresponding peptidomimetic epoxide ethyl ester 39 (25 mg, 0.51 mmol); LiOH (1.3 mg, 0.06 mmol); after extraction afforded the desired product as a white solid (18 mg, 76.2%). 1H NMR (DMSO-d6, 400 MHz): δ 8.98 (s, 1H); 8.72-8.70 (t, 1H); 8.57-8.55 (d, 1H, J=8.06); 8.48 (s, 1H); 7.93-7.90 (q, 2H); 7.48-7.44 (t, 2H); 7.34 (s, 1H); 4.70-4.65 (q, 1H); 4.40-4.38 (d, 2H; J=5.52); 3.66 (s, 1H); 3.54-3.06 (m, 3H). 13C NMR (DMSO-d6, 100 MHz): 170.62, 165.75, 163.24, 160.80, 154.06, 153.32, 146.40, 133.62, 122.81, 122.72, 121.76, 117.33, 117.10, 53.24, 53.01, 52.94, 34.77, 33.50. HRMS-ESI: m/z [M+H+] calculated for C19H17FN6O5S: 461.1043, observed: m/z 461.1049 (M+H+): HPLC Method 2: Rt=17.9 min; purity=97.2%.
Reaction SMILES: [C:1]([C:6]1[CH:17]=[CH:16][C:9]2[N:10]3[CH2:15][CH2:14][CH2:13][C:11]3=[N:12][C:8]=2[CH:7]=1)([O:3]CC)=[O:2].C(O)(=O)C>C(O)C.[OH-].[Na+]>[C:1]([C:6]1[CH:17]=[CH:16][C:9]2[N:10]3[CH2:15][CH2:14][CH2:13][C:11]3=[N:12][C:8]=2[CH:7]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)c1ccc2c(c1)nc1n2CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc1n2CCC1

Procedure:
A solution of 5 g of 6-carbethoxy-2,3-dihydro-1H-pyrrolo [1,2-a]benzimidazole (1A06) in 15 cm3 of ethanol and 25 cm3 of 2,5 N sodium hydroxide are refluxed for 5 min. After cooling the reaction mixture is slightly acidified with diluted acetic acid and the precipitate formed is sucked off and washed with water and ethanol. Yield: 4 g. Melting point: 300°c.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:14]=2[C:15]#[N:16])[CH2:9][CH2:8]1.C(N(CC)CC)C.[F:29][C:30]1[CH:31]=[C:32]([CH:37]2[C:42]([C:43](O)=[O:44])=[C:41]([CH3:46])[NH:40][C:39](=[O:47])[N:38]2[CH3:48])[CH:33]=[CH:34][C:35]=1[F:36].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.CCOCC>[C:15]([C:14]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:13]=1[CH:10]1[CH2:11][CH2:12][N:7]([CH2:6][CH2:5][CH2:4][NH:3][C:43]([C:42]2[CH:37]([C:32]3[CH:33]=[CH:34][C:35]([F:36])=[C:30]([F:29])[CH:31]=3)[N:38]([CH3:48])[C:39](=[O:47])[NH:40][C:41]=2[CH3:46])=[O:44])[CH2:8][CH2:9]1)#[N:16]
Reactant: CC1=C(C(=O)O)C(c2ccc(F)c(F)c2)N(C)C(=O)N1
Reactant: N#Cc1cc(F)ccc1C1CCN(CCCN)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: O
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)NCCCN2CCC(c3ccc(F)cc3C#N)CC2)C(c2ccc(F)c(F)c2)N(C)C(=O)N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-[1-(3-Amino-propyl)-piperidin-4yl]-5-fluoro-benzonitrile dihydrochloride (85.0 mg, 0.254 mmol), triethylamine (108 μl, 0.774 mmol), (−)-4-(3,4-difluorophenyl)-3,6-dimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid (75.0 mg, 0.266 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide Hydrochloride (50.9 mg, 0.266 mmol), and 1-hydroxybenzotriazole hydrate (35.9 mg, 0.266 mmol) were combined in dimethylformamide (5 ml) and stirred 24 hr at room temperature After removal of the solvent in vacuo, the residue was treated with saturated sodium bicarbonate (aq.) and extracted with ethyl acetate (3X). The extracts were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give a crude oil (140 mg). Flash chromatography on silica gel (133/10/1 of methylene chloride/methanol/conc. ammonium hydroxide) gave the product as a white solid from ether ([αD]=−78.4°, c=0.125 MeOH).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH2:14])=[N:2]1.C(N(C(C)C)CC)(C)C.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([Cl:24])=[CH:26][CH:27]=2)=[N:2]1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NCCCNc1nsc2ccccc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCCNc1nsc2ccccc12)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N1-(Benzo[d]isothiazol-3-yl)propane-1,3-diamine (100 mg, 0.48 mmol) was dissolved in anhydrous dichloromethane (5 mL) with diisopropylethylamine (92 μL, 0.53 mmol). The solution was cooled on an ice-water bath and then a solution of 4-chlorobenzoyl chloride (68 μL, 0.53 mmol) in dichloromethane (0.5 mL) was added dropwise. The reaction mixture was allowed to stir for 2 h while warming to room temperature. The solution was washed with water, then dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with a mixture of 20% ethyl acetate in hexanes and selected fractions were combined and concentrated under reduced pressure to yield N-(3-(benzo[d]isothiazol-3-ylamino)propyl)-4-chlorobenzamide as a white solid, (73 mg). 1H NMR (300 MHz, DMSO-d6): 8.6 (broad s, 1H), 8.1 (d, 1H), 7.8 (m, 3H), 7.4 (m, 5H), 3.5 (m, 2H), 3.3 (m, 2H), 1.9 ppm (m, 2H). MW=346 confirmed by LC-MS, tr=3.97 min (Method B) MH+=347.