Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC(C)C[C:4]([CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]=[CH:8][CH:7]1[CH3:14])=O.C(N(CC)CC)C.[OH:23][C:24]1[CH:29]=[C:28]([OH:30])[CH:27]=[CH:26][C:25]=1[CH:31]=[CH:32][C:33]([OH:35])=[O:34].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.CN(C=O)C>[CH3:14][C:7]([O:34][C:33](=[O:35])[CH:32]=[CH:31][C:25]1[CH:26]=[CH:27][C:28]([OH:30])=[CH:29][C:24]=1[OH:23])([CH:6]=[CH2:4])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12]
Reactant: O=C(O)C=Cc1ccc(O)cc1O
Reactant: CC(N)CC(=O)C1C(C)C=CCC1(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(C)(CCC=C(C)C)OC(=O)C=Cc1ccc(O)cc1O
Reaction time: 1 h

Procedure:
To a solution of 3-amino-1-(2,6,6-trimethyl-cyclohex-3-enyl)-butan-1-one (2.38, 11.3 mmol, 10) and triethylamine (2.30 g, 22.6 mmol) in anhydrous THF (150 mL) stirred for 5 min at 22° C. is added 3-(2,4-dihydroxyphenyl)-acrylic acid (2.04 g, 11.3 mmol). To this heterogeneous solution is added BOP Reagent (5.00 g, 11.3 mmol; Aldrich #22,608-4) in DMF (10 mL), and the subsequent homogeneous reaction mixture is stirred for 1 h. The reaction mixture is partitioned between ether (200 mL) and water (400 mL); the organic layer is removed and washed with ether (200 mL). The combined organic layers are washed sequentially with saturated sodium bicarbonate solution (200 mL) and brine (200 mL). The organic layer is dried over anhydrous magnesium sulfate, vacuum filtered and concentrated to give 3-(2,4-dihydroxy-phenyl)-acrylic acid 1,5-dimethyl-1-vinyl-hex-4-enyl ester as an oil that is purified by flash chromatography to give 11 as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7](CC)[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:27]=2[C:28]([NH2:30])=[O:29])[C:22]([Cl:36])=[CH:21][N:20]=1>>[Cl:36][C:22]1[C:23]([NH:25][C:26]2[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:27]=2[C:28]([NH2:30])=[O:29])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Reactant: Cc1cccc(C(N)=O)c1Nc1nc(Cl)ncc1Cl
Product: Cc1cccc(C(N)=O)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-methyl-benzamide to yield an off-white solid (2.4%). LCMS: m/z=465.15 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.05 (s, 1H), 7.46 (m, 4H), 7.20 (m, 2H), 7.04 (s, 1H), 6.74 (d, 1H, J=8.6 Hz), 6.23 (bs, 1H), 5.81 (bs, 1H), 2.36 (m, 2H), 2.27 (s, 3H), 2.06 (m, 2H), 1.36 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH3:20])[N:3]=1.[OH-].[K+]>CCO.[Pd]>[Cl-:1].[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH:2]=[NH+:3][C:4]([CH3:20])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc2c(Cl)nc(C)c(-c3ccccc3)c2c1
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c[nH+]c(C)c(-c3ccccc3)c2c1
Product: [Cl-]
Reaction time: 20 h

Procedure:
1-chloro-6-methoxy-3-methyl-4-phenylisoquinoline (0.55 g) in 25 mL EtOH was treated with 120 mg KOH and 30 mg Pd—C (10%). The reaction was shaken under an H2 atmosphere (50 psi) for 20 h. The reaction was filtered through celite and concentrated to dryness, then dissolved in isopropanol and treated with excess HCl. Crystallization from isopropanol/diethyl ether gave the titled compound.
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([O:8][NH:9][C:10](=[O:12])[CH3:11])=[O:7])([CH3:4])[CH3:3].[CH3:13][N:14]=[C:15]=[O:16]>C(N(CC)CC)C.C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:13][NH:14][C:15]([N:9]([O:8][C:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C:10](=[O:12])[CH3:11])=[O:16]
Reactant: CN=C=O
Reactant: CC(=O)NOC(=O)NC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)N(OC(=O)NC(C)(C)C)C(C)=O

Procedure:
N-((((1,1-dimethylethyl)amino)carbonyl)oxy)acetamide (8.7 grams), methyl isocyanate (3.2 grams), and a few drops of triethylamine were stirred at room temperature in 150 ml of methylene chloride for about 12 hours. The solvent was then removed under vacuum leaving an oily residue which was dissolved in hot toluene. Upon cooling, a white crystalline material separated and was collected by filtration. The white crystals were recrystallized from toluene leaving a residue which was mixed with about 50 ml of water for two hours. This mixture was then filtered, and the insoluble material was dried in a vacuum leaving the desired N-((methylamino)carbonyl)-N-((((1,1-dimethylethyl)amino)carbonyl)oxy)acetamide, m.p. 142°-144° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]=[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)[CH3:7])[CH3:2].[CH:20]([C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1)=O.[C:30](#[N:34])[CH2:31][C:32]#[N:33].N1CCCCC1>C(O)C>[NH2:34][C:30]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:18])[F:17])[CH:10]=2)[C:6]([CH3:7])=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:19])[CH:20]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[C:31]=1[C:32]#[N:33]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: N#CCC#N
Reactant: CCOC(=O)C=C(C)Nc1cccc(C(F)(F)F)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(N)=C(C#N)C1c1ccc(C#N)cc1

Procedure:
The compound is prepared as described for Example 14A with 100 mg (0.37 mmol) of the compound of Example 1A, 48 mg (0.37 mmol) 4-formylbenzonitrile, 24.18 mg (0.37 mmol) malononitrile and 3.12 mg (3.6 μl, 0.04 mmol) piperidine in 2 ml ethanol. The product is purified by HPLC.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[CH:14]=[C:15]([NH:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C(#N)C>C(=O)([O-])[O-].[K+].[K+].O.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>[CH2:24]([NH:23][C:21]([NH:20][C:15]1[CH:16]=[CH:17][C:18]([F:19])=[C:13]([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:30]4[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=4)[CH:3]=3)[NH:8][CH:9]=2)=[O:12])[CH:14]=1)=[O:22])[CH2:25][CH2:26][CH3:27]
Reactant: OB(O)c1cccnc1
Reactant: CCCCNC(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1
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: O
Solvent: CC#N
Product: CCCCNC(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1
Temperature: 120 °C
Yield: 61 %

Procedure:
To 1-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-3-butyl-urea (P-1637, 14.0 mg, 0.0000323 mol), 3-pyridylboronic acid (5.96 mg, 0.0000485 mol), and Tetrakis(triphenylphosphine)palladium(0) (0.820 mg, 7.09E-7 mol) were mixed in 1.00 M potassium carbonate in water (1.00 mL) and acetonitrile (2.00 mL, 0.0383 mol). The resulting mixture was heated at 120° C. in the microwave for 40 minutes. The reaction was extracted with ethyl acetate and water twice, and the combined organic layers were washed with 1M sodium bicarbonate followed by brine and the organic layer was dried over magnesium sulfate and filtered. The organic layer was concentrated and purified by reverse phase HPLC (acetonitrile and water with 0.1% formic acid) to give the compound as a white solid (P-1637, 8.5 mg, 61%). MS (ESI) [M+H+]+=432.3.
Reaction SMILES: C(=O)([O-])N.[Cl:5][C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:7].[CH3:17][NH:18][CH2:19][CH2:20][N:21](C(C)(C)C)C(=O)[O-]>>[ClH:5].[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6](=[O:7])[N:18]([CH3:17])[CH2:19][CH2:20][NH2:21])=[CH:10][CH:11]=1
Reactant: COc1ccc(OC(=O)Cl)cc1
Reactant: CNCCN(C(=O)[O-])C(C)(C)C
Agent: NC(=O)[O-]
Product: COc1ccc(OC(=O)N(C)CCN)cc1
Product: Cl

Procedure:
This carbamate, m.p. 152.5°-154.5°, was prepared from 4-methoxyphenyl chloroformate and N-[2-(methylamino)ethyl]tert.-butylcarbamate by the procedure of Example 1.
Reaction SMILES: [CH3:1][C:2]#[CH:3].C(=O)=O.[CH2:7]([O:14][CH2:15][CH:16]([CH3:20])[CH2:17][CH:18]=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl-].[NH4+]>CCCCCC.CCOCC.O1CCCC1>[CH2:7]([O:14][CH2:15][CH:16]([CH3:20])[CH2:17][CH:18]([OH:19])[C:1]#[C:2][CH3:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(CC=O)COCc1ccccc1
Reactant: C#CC
Agent: O=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC#CC(O)CC(C)COCc1ccccc1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
A mixture of 72.8 ml. (0.146 mole) of 2 M n-butylithium solution in hexane and 420 ml. of anhydrous tetrahydrofuran was stirred and cooled to -50° C. while 112 ml. of liquified methylacetylene was added dropwise from a dry ice cooled addition funnel. After the addition was complete, the reaction mixture was allowed to warm to reflux temperature (8° C.) (dry ice condenser) and stirred at this temperature for 1 hour. The white slurry was then cooled to 0° C. and stirred while a solution of 14 g. (0.0728 mole) of rac. 4-benzyloxy-3-methylbutanal in 125 ml. of anhydrous tetrahydrofuran was added dropwise. After stirring at 0° C. for 1 hour, the mixture was slowly warmed to 40° C. and stirred at this temperature for 1 hour whereupon the reaction mixture was treated with saturated aqueous ammonium chloride. The product was isolated by ether extraction and worked up as in Example 1. There was obtained 15.4 g. of crude material which was chromatographed on 400 g. of silica gel. Elution with 2:1 parts by volume and 1:1 parts by volume hexane: ether afforded rac. 1-benzyloxy-2-methylhept-5-yn-4-ol as a yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:13]([CH2:16][S:17]([OH:20])(=[O:19])=[O:18])[CH2:14][NH2:15].[CH2:21]([OH:23])C>O1CCOCC1.[OH-].[Na+].O>[NH2:15][C@H:14]([C:21]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:23])[CH2:13][C:16]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:10]=1.[CH2:13]([CH2:16][S:17]([OH:20])(=[O:19])=[O:18])[CH2:14][NH2:15]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCO
Agent: NCCCS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N—BOC-L-phenylalanine-N-hydroxusuccinimide ester (400 mg, 1.1 mmol) in a mixture of ethanol (6 mL) and 1,4-dioxane (4 mL) was added to a solution of L-Phe-Homotaurine (273 mg, 1.0 mmol) in 1N NaOH (1.05 mL), water (3 mL) and ethanol (4 mL). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the solid (601.9 mg) was suspended in a mixture of acetone (8 mL) and isopropanol (0.2 mL) and stirred overnight at room temperature. The mixture was heated under refluxed for 30 minutes and then was cooled to room temperature. The white solid was collected by filtration, washed with ether, then dried in the vacuum oven for 45 minutes. The resulting solid (423.1 mg) was dissolved in a mixture of water/tert-butanol (7:3, 5 mL) and treated with Amberlite IR-120 plus (washed, 15 g dry weight) for 2 minutes at room temperature. The resin was removed by filtration and washed 3 times with the mixed solvents of water and tert-butanol (10 mL). Concentrated HCl (4 mL) was added. The solvents were removed under reduced pressure, and the resulting solid was dried in vacuum. The compound was purified by recrystallization from a mixed solvent of THF and MeOH. The resulting solid was heated under reflux in methanol (about 3 mL) to remove the yellowish color. The solid was dried in vacuo. Compound X was obtained as white solid (84.4 mg, 20%). The 1H and 13C NMR were consistent with the structure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]=O)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][N:28]3[CH2:29][CH2:30][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=CCCc1cc(-c2cccc([N+](=O)[O-])c2)no1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(-c2cc(CCCN3CCN(c4ccccc4)CC3)on2)c1
Reaction time: 22 h
Yield: 51.2 %

Procedure:
About 3 min after dissolving 3-[3-(3-nitrophenyl)isoxazol-5-yl]propanal (20 mg, 0.09 mmol) and 1-phenylpiperazine (13.4, 0.09 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (56 mg, 0.26 mmol) and molecular sieves (5 beads). After the reaction was carried out for about 22 hr, the reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 solution saturated sodium chloride solution. After drying the organic layer over anhydrous MgSO4, the solvent was removed under reduced pressure. After dissolving the residue with 1 mL of diethyl ether, HCl ether solution was slowly dropped to precipitate a white hydrochloric acid salt which was collected by filtration or centrifugation, and it was washed several times with diethyl ether. After drying the same under reduced pressure, was obtained 18.1 mg (56.8%) of the target compound.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH:27]2[O:45][C:30]3=[CH:31][N:32]=[C:33]([C:35]4[CH:40]=[CH:39][C:38]([C:41](=O)[NH2:42])=[CH:37][C:36]=4[F:44])[CH:34]=[C:29]3[CH2:28]2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH:27]2[O:45][C:30]3=[CH:31][N:32]=[C:33]([C:35]4[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][C:36]=4[F:44])[CH:34]=[C:29]3[CH2:28]2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(C(N)=O)cc4F)ncc3O2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(C#N)cc4F)ncc3O2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic anhydride (50 mL) is added to a mixture of 4-[5-(4-carbamoyl-2-fluoro-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (50 mg) and triethylamine (100 mL) in dichloromethane (3 mL) and the reaction mixture is stirred at room temperature for 1 h. Aqueous NaHCO3 solution is added and the mixture is extracted with dichloromethane. The combined extracts are washed with brine, dried over MgSO4, and concentrated in vacuo. The residue is triturated with diethyl ether, stirred for 1 h, filtered off, and dried to give the title compound. LC (method 7): tR=1.47 min; Mass spectrum (ESI+): m/z=424 [M+H]+.
Reaction SMILES: C[S:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=CC=1.Br[CH:11]([OH:13])[CH3:12].[C:14](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:14][C:8]1[CH:7]=[C:6]([O:9][CH:11]([OH:13])[CH3:12])[S:2][CH:3]=1
Reactant: CC(O)Br
Reactant: O=C([O-])[O-]
Reactant: CSc1ccc(O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1csc(OC(C)O)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 74.9 %

Procedure:
Under a nitrogen atmosphere, 4-(methylthio) phenol (4.2 g) and bromoethanol (5.6 g) were dissolved in dimethylformamide solution (60 ml), potassium carbonate (12.4 g) was added, and the mixture was heating under stirring at 100° C. After 3 hours, the mixture was cooled to room temperature, then the organic layer was separated by adding diethyl ether and water thereto. The resulting organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the mixture was evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system), to give (4-methylthiophenoxy) ethanol (3.55 g, 64%) as white crystals. The product (1.0 g) was dissolved in dichloromethane (50 ml), the mixture was cooled on a methanol-dry ice bath, methachloroperbenzoic acid (3.6 g) was added, and the mixture was stirred. After cooling naturally to room temperature over 2 hours, a 1N aqueous sodium bicarbonate and 1N Na2S2O3 were added. After stirring, the mixture was extracted with dichloromethane, and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the mixture was evaporated. The residue was dissolved in acetonitrile (18 ml), triethylamine (2.3 ml) and methanesulfonyl chloride (0.5 ml) were added, and the mixture was stirred at room temperature. After 1.5 hours, sodium iodide (4.9 g) and tert-butyl-1-piperazinecarboxylate (1.2 g) were added, and the mixture was heated under stirring at 60° C. After stirring for 4.5 hours, the organic layer was separated by adding ethyl acetate and water. The resulting organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filtering the drying agent, the mixture was evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system), to give tert-butyl-2-(4-methylthiophenoxy)ethyl-1-piperazinecarboxylate (1.15 g) as white crystals. The product (1.15 g) was dissolved in methanol (10 ml), and the solution was added to a 4N hydrochloric acid-ethyl acetate solution (30 ml) in an ice bath. After stirring at room temperature overnight, the resulting white crystals were collected by filtration and washed with diethyl ether. A 1N aqueous sodium hydroxide and dichloromethane were added to the crystals, to separate the organic layer. The resulting organic layer was evaporated, to give the title compound as a yellow oil (820 mg, 53%; 3 steps).
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.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1>>[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][N:15]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[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: Fc1cccc(CBr)c1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(F)c3)C2=O)cn1
Yield: 27 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 1-(bromomethyl)-3-fluorobenzene. Yield 27%. MS M+H calculated 384.1. found 384.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.06 uM.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:59])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[CH:46]([OH:58])[CH2:45]2)[CH:7]([CH3:60])[CH2:6][CH2:5][C:4]1=[O:61])[CH3:2].[CH2:62](OC(=N)C(Cl)(Cl)Cl)[CH:63]=[CH2:64].FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:59])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:52])[CH3:53])[CH:46]([O:58][CH2:64][CH:63]=[CH2:62])[CH2:45]2)[CH:7]([CH3:60])[CH2:6][CH2:5][C:4]1=[O:61])[CH3:2]
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"(tert-butyldimethylsiloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (186 mg in 6 ml 33% methylene chloride in cyclohexane) allyltrichloroacetimidate (62 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (5 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 24 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×5 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:4)+1% methanol) gave the title compound (80 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[C:9]2[C:5]([C:6]3[CH:15]=[C:14]([CH3:16])[CH:13]=[N:12][C:7]=3[NH:8]2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH2:26][CH3:27])(=[O:25])=[O:24])[CH:18]=2)[CH:3]=1.[CH2:28]([O:35]CCCO)[C:29]1C=CC=C[CH:30]=1>[Pd].[H][H]>[Cl:1][C:2]1[C:10]([O:11][CH2:30][CH2:29][CH2:28][OH:35])=[C:9]2[C:5]([C:6]3[CH:15]=[C:14]([CH3:16])[CH:13]=[N:12][C:7]=3[NH:8]2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH2:26][CH3:27])(=[O:24])=[O:25])[CH:18]=2)[CH:3]=1
Reactant: [H][H]
Reactant: CCS(=O)(=O)c1cccc(-c2cc(Cl)c(O)c3[nH]c4ncc(C)cc4c23)c1
Reactant: OCCCOCc1ccccc1
Agent: [Pd]
Product: CCS(=O)(=O)c1cccc(-c2cc(Cl)c(OCCCO)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was synthesized from Compound 247 and 3-(benzyloxy)propan-1-ol using an analogous procedure to that outlined in the preparation of Compound 210 followed by debenzylation using Pd/C—H2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (t, J=7.33 Hz, 3H) 1.99-2.06 (m, 2H) 2.25 (s, 3H) 3.41 (q, J=7.58 Hz, 2H) 3.71 (br. s., 2H) 4.26 (t, J=6.44 Hz, 2H) 4.81 (br. s., 1H) 7.23 (s, 1H) 7.46 (s, 1H) 7.87 (t, J=7.71 Hz, 1H) 8.03 (t, J=7.20 Hz, 2H) 8.11 (s, 1H) 8.31 (s, 1H) 12.27 (br. s., 1H); [M+H] calc'd for C23H24ClN2O4S, 459.1; found, 459.3.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:18][NH2:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]2[N:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[O:33][N:32]=2)[CH:30]=1)[C:25](O)=[O:26])#[N:21]>>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]2[N:35]=[C:34]([C:36]([F:38])([F:39])[F:37])[O:33][N:32]=2)[CH:30]=1)[C:25]([NH:19][CH2:18][C:12]1([C:9]2[S:10][CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)=[O:26])#[N:21]
Reactant: NCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Reactant: N#Cc1cc(C(=O)O)cc(-c2noc(C(F)(F)F)n2)c1
Product: N#Cc1cc(C(=O)NCC2(c3nc(-c4ccccc4)cs3)CCOCC2)cc(-c2noc(C(F)(F)F)n2)c1
Yield: 30 %

Procedure:
This compound was synthesized from (4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-cyano-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (25 mg, yield 30%): 1H NMR (400 MHz, MeOD) δ 8.63 (t, J=1.6 Hz, 1H), 8.52 (t, J=1.5 Hz, 1H), 8.25 (t, J=1.6 Hz, 1H), 7.87-7.85 (m, 2H), 7.81 (s, 1H), 7.32-7.28 (m, 2H), 7.25-7.21 (m, 1H), 3.97-3.92 (m, 2H), 3.71 (s, 2H), 3.62-3.58 (td, J=11.4 Hz, 2.1 Hz, 2H), 2.48-2.44 (d, J=13.3 Hz, 2H), 2.11-2.04 (ddd, J=14.3 Hz, 10.5 Hz, 4.3 Hz, 2H). MS (ESI) m/z: Calculated for C26H20F3N5O3S: 539.12. found: 540.0 (M+H)+.