Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[C:15]([Cl:24])[CH:14]=1.C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.CN(C)C=O>[Cl:24][C:15]1[CH:14]=[C:13]([C:2]#[C:1][C:3]2([OH:11])[CH:8]3[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]3)[CH2:4]2)[CH:18]=[CH:17][C:16]=1[O:19][CH2:20][CH2:21][O:22][CH3:23]
Reactant: COCCOc1ccc(Br)cc1Cl
Reactant: C#CC1(O)CN2CCC1CC2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCOc1ccc(C#CC2(O)CN3CCC2CC3)cc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 51.7 %

Procedure:
A mixture of 3-ethynyl-3-hydroxyquinuclidine (453 mg), methoxyethyl 4-bromo-2-chlorophenyl ether (0.97 g), bis(triphenylphosphine)palladium (II) chloride (105 mg), copper (I) iodide (55 mg), triethylamine (5 ml) and dimethylformamide (10 ml) was stirred at 70° C. under an atmosphere of argon for 2 hours. The triethylamine and dimethylformamide were removed by evaporation. The residue was purified by flash column chromatography on silica gel (Merck Art. No. 9385) using a mixture of 10% methanol in dichloromethane containing 1% ammonia (density, 0.880 g/cm3) as eluent. The residue was crystallised from acetonitrile to give 3-[2-(3-chloro-4-(2-methoxyethoxy)phenyl)ethynyl]quinuclidin-3-ol (0.52 g) as a colourless solid, m.p. 138-139° C.; microanalysis, found: C, 64.1; H, 6.7; N, 4.1%; C18H22ClNO3 requires: C, 63.9; H, 6.6; N, 4.1%; NMR ([CD3 ]2SO): 7.5(1H,d), 7.3(1H,d of d), 7.1(1H,d), 5.5(1H,s), 4.2(2H,m), 3.7(2H,m), 3.3(3H,s), 2.8(2H,m), 2.7(4H,m), 2-1.8(3H,m), 1.6(1H,m) and 1.3(1H,m); m/z 336(M+H).
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[C:5](CC)(CC)[C:6]#[N:7].[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>C1COCC1>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH:5][C:6]#[N:7])=[CH:17][CH:16]=1
Reactant: CCC(C#N)(CC)O[PH](=O)[O-]
Reactant: O=Cc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC=Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 60% suspension of NaH in mineral oil (2.16 g, 54.1 mmol) was suspended in THF (50 ml) and cooled to 0° C. under nitrogen. Diethyl-cyanomethyl phosphonate (8.74 ml, 54.1 mmol) was added dropwise and the whole stirred at 0° C. for 30 min. 4-bromobenzaldehyde (10 g, 54.1 mmol) was then added dropwise as a solution in 20 ml THF, and the mixture allowed to warm to room temperature overnight. The reaction was quenched with water, extracted with EtOAc (3×50 ml), dried (MgSO4) and then filtered and evaporated to a yellow oil. This oil was taken up in a 9:1 mixture of pentane:EtOAc from which the title product crystallised (5.8 g, 52%); 1HNMR (400 MHz, CDCl3) δ: 5.82 (d, 1H), 7.21-7.28 (m, 3H), 7.50 (d, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:11]2[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[CH:23]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)([O-])=O.P(OCC)(OCC)(OCC)=O>O>[CH:21]1[C:22]2[C:23]3[NH:1][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[C:10]=3[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1ccccc1-c1cc2ccccc2c2ccccc12
Solvent: CCOP(=O)(OCC)OCC
Solvent: O
Product: c1ccc2c(c1)[nH]c1c3ccccc3c3ccccc3c21
Temperature: 150 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
Next, a mixed solution of 2.0 g of 9-(2-nitrophenyl)phenanthrene and 40 ml of triethyl phosphate was heated and stirred under a nitrogen gas stream at 150° C. for 8 hours. After cooling to room temperature, 50 ml of water was poured into the solution, followed by extraction with 50 ml of toluene. The organic layer was washed twice with 50 ml of water, dried over magnesium sulfate and then concentrated by evaporation. The concentrate was purified by silica gel chromatography and then vacuum-dried to obtain 840 mg of 13H-13-azaindeno[1,2-l]phenanthrene.
Reaction SMILES: [N+]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][CH2:9][O:10][N:11]2[N:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[NH:12]2)=[CH:6][CH:5]=1)([O-])=O.COC1C=C(OC)C=CC=1C=O.C(O)CC1C=CC=CC=1.N1C(C)=CC(C)=CC=1C>>[CH2:9]([O:10][N:11]1[N:12]=[C:13]([Cl:18])[CH:14]=[C:15]([Cl:17])[NH:16]1)[CH2:8][C:7]1[CH:6]=[CH:5][CH:4]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(CCON2N=C(Cl)C=C(Cl)N2)cc1
Agent: COc1ccc(C=O)c(OC)c1
Solvent: Cc1cc(C)nc(C)c1
Solvent: OCCc1ccccc1
Product: ClC1=CC(Cl)=NN(OCCc2ccccc2)N1
Yield: 52 %

Procedure:
In a manner exactly analogous to the preparation of compound 35, using 4.4 g (0.0024 mole) of cyanuric chloride (1), 2.9 g (0.0024 mole) of phenethyl alcohol and 3.2 ml of collidine, 3.37 g (52% yield) of the desired compound 46 was obtained after plug filtration of the crude product on silica gel using methylene chloride.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.ClCCl.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31](Cl)=[O:32])[CH:27]=[CH:28][CH:29]=1>C(N(CC)CC)C>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([CH:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:7]([CH3:9])[CH3:8])=[CH:11][C:12]=2[N+:17]([O-:19])=[O:18])=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: O=C(Cl)Cc1cccc(Cl)c1
Reactant: CC(C)C(c1ccc(N)c([N+](=O)[O-])c1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(c1ccc(NC(=O)Cc2cccc(Cl)c2)c([N+](=O)[O-])c1)n1ccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a stirred solution of 13 parts of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-2-nitrobenzenamine in 195 parts of dichloromethane was added a solution of 19 parts of 3-chlorobenzeneacetyl chloride in 65 parts of dichloromethane. After stirring for 4 hours at room temperature, 10.1 parts of N,N-diethylethanamine were added. The reaction mixture was washed with water, dried, filtered and evaporated, yielding 39 parts (100%) of 3-chloro-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-2-nitrophenyl]-benzeneacetamide as an oily residue (interm. 100).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]3)=[CH:10][CH:11]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[NH:35]([CH2:39][CH2:40][OH:41])[CH2:36][CH2:37][OH:38].O>C(#N)C>[OH:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][OH:41])[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]3)=[CH:10][CH:11]=1)=[O:4]
Reactant: O=C(CCl)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: OCCNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(CN(CCO)CCO)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]acetamide (177 mg) in acetonitrile was added potassium carbonate (118 mg) and diethanolamine (65 μl). The mixture was stirred at room temperature. Water was added to the reaction mixture. Solution was extracted with ethyl acetate. Organic extract was dried and evaporated. 2-[Bis(2-hydroxyethyl)amino]-N-[6-(2-phenyl-chroman-6-yloxy)pyridin-3-yl]acetamide was purified by column chromatography using 10% methanol in methylenechloride as eluant. 1H-NMR (400 MHz; d6-DMSO) δ: 10.1 (s, 1H), 8.31 (d, 1H, J 2.7 Hz), 8.07 (dd, 1H, J 2.7, 8.8 Hz), 7.46-7.31 (m, 5H), 6.95 (d, 1H, J 8.8 Hz), 6.86-6.84 (m, 3H), 5.11 (dd, 1H, J 2.1, 10.0 Hz), 4.71 (t, 2H, J 5.4 Hz), 3.50 (q, 4H, J 5.4 Hz), 2.97-2.92 (m, 1H), 2.74-2.70 (m, 1H), 2.67 (t, 4H, J 5.4 Hz), 2.18-2.14 (m, 1H), 2.02-1.97 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N+:3]=1[O-].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:14]>>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([CH2:9][OH:14])[CH:5]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(C)[n+]([O-])c(C)c1
Product: Cc1cc(C)nc(CO)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 50 %

Procedure:
Trifluoroacetic anhydride (20 mL) was added to 2,4,6-trimethyl-pyridine-1-oxide (2.0 g, 14.6 mmol) at 0° C., then the mixture was stirred at room temperature for 5 h. The mixture was concentrated in vacuo, diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate and concentrated to afford a residue which was purified by column chromatography on silica gel (60-120 mesh), eluting with 25% ethyl acetate/hexane, to afford (4,6-dimethyl-pyridin-2-yl)-methanol (1.0 g, 50%)-s a dark brown liquid
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[C:11]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:16]=[CH:15][C:14]([CH2:17][C@@H:18]([NH:27]C(OC(C)(C)C)=O)[CH2:19][C@:20]([CH2:25][OH:26])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:13][CH:12]=1.CCN(CC)CC>CC(C)=O>[N:5]1([C:3](=[O:4])[CH2:2][O:23][C:21](=[O:22])[C@@:20]([CH2:25][OH:26])([CH3:24])[CH2:19][C@H:18]([NH2:27])[CH2:17][C:14]2[CH:15]=[CH:16][C:11]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:12][CH:13]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: O=C(CCl)N1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OCC(=O)N1CCOCC1

Procedure:
4-(2-chloroacetyl)morpholine (63 mg, 387 μmol) was added to a mixture of (2S,4R)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (100 mg, 242 μmol) and Et3N (35 μL, 254 μmol) in acetone (10 mL). The mixture was refluxed for 24 hours and the reaction monitored for completion. When the reaction was complete, the product was purified ((Interchim reverse phase chromatography column) the solvent was removed under vacuum to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 2-morpholin-4-yl-2-oxo-ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.[CH3:15][CH:16](O)[CH:17]=[CH2:18]>COC(OC)(C)C.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:15]([CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]1=[O:14])[CH:16]=[CH:17][CH3:18]
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2cc(OC)c(OC)cc2C1=O
Yield: 26.5 %

Procedure:
A solution of 20 g of 5,6-dimethoxy-1-indanone, 21.5 ml (0.25 mol) of 3-buten-2-ol and 200 mg of p-toluenesulfonic acid in 21.5 ml of 2,2-dimethoxypropane and 200 ml of anhydrous toluene was boiled under reflux for 24 hours. The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/ethyl acetate 3:2). 6.8 g (27%) of (RS)-2-(2-buten-1-yl)-5,6-dimethoxy-1-indanone were obtained as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O[CH2:14][C:15]1([CH3:19])[CH2:18][O:17][CH2:16]1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:14][C:15]1([CH2:19][O:11][C:10](=[O:12])[CH2:9][C:7]2[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)[CH2:18][O:17][CH2:16]1
Reactant: CC(=O)c1ccc(CC(=O)O)s1
Reactant: CC1(CO)COC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(CC(=O)OCC2(C)COC2)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
(5-Acetyl-thiophen-2-yl)-acetic acid (2 g, 10.8 mmol), 3-hydroxymethyl-3-methyloxetane (1.07 mL, 10.8 mmol), and dimethylaminopyridine (221 mg, 1.08 mmol) were dissolved in 5 mL of dry THF and cooled to 0° C. Dicyclohexylcarbodiimide (2.24 g, 10.8 mmol) was added and the mixture was stirred at 0° C. for 1 hr, then warmed to room temperature and stirred overnight. The mixture was cooled to 0° C. and filtered. The white solid was washed with cold THF and the combined filtrates were concentrated. The crude product was purified via flash chromatography (hexanes/ethyl acetate gradient) to give 2.3 g of (5-Acetyl-thiophen-2-yl)-acetic acid 3-methyl-oxetan-3-ylmethyl ester (8.5 mmol, 79%). The product was dissolved in 20 mL DCM and cooled to −5° C. Boron trifluoride diethyletherate (121 μL, 1 mmol) was added dropwise, the mixture was slowly warmed to room temperature and stirred for 30 minutes. The reaction was quenched with triethylamine, concentrated and purified via flash chromatography (hexanes/ethyl acetate gradient) to give 1.44 g of 1-[5-(4-Methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-ylmethyl)-thiophen-2-yl]-ethanone (4.1 mmol, 38% over two steps).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17]CC)=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:36][C:37]([F:40])([F:39])[F:38])=[C:32]([CH:35]=1)[C:33]#[N:34]>CN(C=O)C>[C:33]([C:32]1[CH:35]=[C:28]([CH:29]=[CH:30][C:31]=1[O:36][C:37]([F:38])([F:40])[F:39])[CH2:27][O:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1)#[N:34]
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Reactant: N#Cc1cc(CCl)ccc1OC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cc(COc2ccc3[nH]c4c(c3c2)CCC4CC(=O)O)ccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24.1 %

Procedure:
Ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (0.100 g, 0.386 mmol) and cesium carbonate (0.138 g, 0.424 mmol) were dissolved in DMF (1.0 mL), stirred at room temperature for 10 min, followed by addition of 5-(chloromethyl)-2-(trifluoromethoxy)benzonitrile (0.100 g, 0.424 mmol) in DMF (0.300 mL) at 0° C. This mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water and extracted with ethylacetate (2×50 mL). The organic phase was washed with brine and concentrated. The residue was taken up in dioxane (4 mL) before aqueous 1 N LiOH (1.3 mL) was added. The mixture was stirred at room temperature for 2.5 h before it was quenched with water and acidified to pH 3 using aqueous 3 N HCl. The mixture was purified by HPLC to give the title compound (0.040 g). LCMS m/z=431.2 [M+H]+, 1H NMR (500 MHz, DMSO-d6) δ ppm 2.00-2.20 (m, 1H), 2.01-2.21 (m, 1H), 2.23-2.43 (m, 1H), 2.55-2.83 (m, 4H), 3.33-3.57 (m, 1H), 5.16 (s, 2H), 6.73 (dd, J=8.83, 2.52 Hz, 1H), 6.94 (s, 1H), 7.21 (d, J=8.83 Hz, 1H), 7.69 (dd, J=8.67, 1.42 Hz, 1H), 7.94 (dd, J=8.67, 2.05 Hz, 1H), 8.09 (s, 1H), 10.40 (s, 1H).
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.[CH2:21](Br)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][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]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: BrCCc1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CCc3ccccc3)C2=O)cn1
Yield: 37 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and phenethylbromide. Yield: 37%. 1H NMR (DMSO-d6, 400 MHz): δ2.11 (s, 3H), 2.38 (s, 3H), 2.83 (t, J=6.4 Hz, 2H), 3.55 (t, J=7.4 Hz, 2H), 4.03 (s, 2H), 5.17 (s, 2H), 7.18-7.30 (m, 5H), 7.73 (s, 1H), 8.13 (s, 1H). MS M+H calculated 380.2. found 380.1. Melting point: 95-96° C. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.14 μM.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH3:13].[CH3:14][O:15][P:16]([O:19]C)[O:17][CH3:18]>>[CH3:13][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:2][P:16](=[O:19])([O:17][CH3:18])[O:15][CH3:14]
Reactant: COP(OC)OC
Reactant: Cc1ccc2ccccc2c1CCl
Product: COP(=O)(Cc1c(C)ccc2ccccc12)OC
Yield: 59.1 %

Procedure:
A solution of 1-chloromethyl-2-methylnaphthalene (9.50 g, 0.050 M) in trimethylphosphite (15 mL, 15.8 g, 0.13 M) is heated at reflux temperature for 48 hours. Excess trimethylphosphite is removed under reduced pressure, giving a yellow oil which is chromatographed over silica gel (40-63 μ, 400 g, 50 mL fractions) using ethyl acetate for elution of the column. Fractions 18-21 are pooled and after concentration gave a white solid (7.78 g). Recrystallization from ether-pentane gave title compound (6.94 g) as colorless crystals, mp 54°-57° C.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][C:4](=[O:16])[C:3]=1[S:17][C:18]#[N:19].O>CN(C)C=O>[NH2:19][C:18]1[S:17][C:3]2[C:4](=[O:16])[N:5]=[C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[NH:7][C:2]=2[N:1]=1
Reactant: N#CSc1c(N)[nH]c(SCc2ccccc2)nc1=O
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc2[nH]c(SCc3ccccc3)nc(=O)c2s1

Procedure:
The product of step (a) (7.35 g) was heated at 120° C. in dimethylformamide (40 mL) and water (10 mL) for 10 hours. After cooling, the resulting solid was filtered off, washed with water, ether and ethyl acetate to give the title compound containing 0.4 moles of dimethylformamide.
Reaction SMILES: [CH:1]([O:4][C:5]([O:7][CH2:8][CH2:9]Cl)=[O:6])([CH3:3])[CH3:2].[I-:11].[Na+]>[Cl-].[Zn+2].[Cl-].C(Cl)(Cl)(Cl)Cl>[CH:1]([O:4][C:5]([O:7][CH2:8][CH2:9][I:11])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)OCCCl
Reactant: [I-]
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)OC(=O)OCCI
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.2 %

Procedure:
A mixture of isopropoxycarbonyloxyethyl chloride (=2-chloroethyl isopropylcarbonate) (1.67 g), carbon tetrachloride (10 ml), sodium iodide (2.10 g) and anhydrous zinc chloride (0.08 g) is stirred at room temperature for 2 hours, and thereafter, ice water is added to the mixture. The organic layer is separated, and the aqueous layer is extracted twice with carbon tetrachloride. The combined organic layers are washed, dried and evaporated under reduced pressure to give isopropoxycarbonyloxyethyl iodide (=2-iodoethyl isopropylcarbonate) (1.48 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[NH:5][CH2:6][CH2:7][CH2:8][CH3:9].Br[CH2:15][C:16]1[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:18]([CH3:29])[CH:17]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Br:1][C:2]1[C:3]([CH3:13])=[C:4]([N:5]([CH2:15][C:16]2[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:18]([CH3:29])[CH:17]=2)[CH2:6][CH2:7][CH2:8][CH3:9])[CH:10]=[CH:11][CH:12]=1
Reactant: CCCCNc1cccc(Br)c1C
Reactant: CCOC(=O)COc1ccc(CBr)cc1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1C
Yield: 57.8 %

Procedure:
To a solution of 3-bromo-N-butyl-2-methylaniline (700 mg, 2.89 mmol) in dry acetonitrile (75 mL) was added ethyl [4-(bromomethyl)-2-methylphenoxy]acetate (830 mg, 2.89 mmol) and N,N-diisopropylethylamine (331 μL, 1.9 mmol). The resultant mixture was heated at 80° C. for 3 h. The reaction mixture was cooled and the solvents removed in vacuo, diluted with water (50 mL) and extracted with CH2Cl2 (2×100 mL). The organic solution was dried (Na2SO4) and the solvents removed in vacuo. Purification by SPE (silica, 20 g) eluted with 100:2 to 100:5 cylclohexane:EtOAc afforded the title compound as a colourless oil (749 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:33]=[CH:32][C:9]2[N:10]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([N:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[CH:17][CH:18]=3)[S:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35].C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[N:19]1([C:16]2[N:15]=[CH:14][C:13]([C:11]3[S:12][C:8]4[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:33]=[CH:32][C:9]=4[N:10]=3)=[CH:18][CH:17]=2)[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]1
Reactant: CCOC(=O)c1ccc2nc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)sc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2nc(-c3ccc(N4CCNCC4)nc3)sc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2-[6-[4-[(1,1-Dimethylethoxy)carbonyl]-1-piperazinyl]-3-pyridinyl]-6-benzothiazolecarboxylic acid ethyl ester (0.42 g, 0.90 mmol) was dissolved in DCM (35 mL) and TFA (2 mL) was added. The reaction was stirred at r.t. for 3 days. Sat. sodium hydrogencarbonate was added to the mixture. The precipitate was collected, followed by washing with DCM and water, before drying in vacuo over P2O5 to give the title compound (0.34 g) as a yellow solid. 1H NMR δ 8.82-8.93 (m, 3H) 8.76 (s, 1H) 8.27 (dd, 1H) 8.07 (d, 2H) 7.11 (d, 1H) 4.37 (q, 2H) 3.84-3.95 (m, 4H) 3.23 (br. s., 4H) 1.36 (t, 3H); MS m/z (M+H) 369.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+:20].[K+]>CO>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:14]#[N:15])=[CH:2][C:1]([O-:5])=[O:4])=[CH:9][CH:8]=1.[K+:20]
Reactant: N#CCc1ccc(Cl)cc1
Reactant: O=CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N#CC(=CC(=O)[O-])c1ccc(Cl)cc1
Temperature: 35 °C
Reaction time: 6 h

Procedure:
133 g (0.9 mol) of 50% strength aqueous glyoxylic acid was added dropwise with stirring to 91.2 g (0.6 mol) of (4-chlorophenyl)acetonitrile and 210 g (1.5 mol) of potassium carbonate in 1.2 1 of methanol such that the reaction temperature increased to 35° C. The mixture was stirred at room temperature for 6 h and then filtered, and the residue was washed with methylene chloride and dried under reduced pressure. At room temperature, the crude product was stirred with 3 1 of water for 1.5 h, and the residue was filtered off, washed with water and dried. Yield: 138 g of a solid of m.p. 241-242° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37](=O)[C:36]([C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1)([CH3:42])[CH2:35][CH2:34]2.[Cl-].[NH4+]>C(OCC)C.CCCCCC>[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37](=[CH:2][O:3][CH3:4])[C:36]([C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1)([CH3:42])[CH:35]=[CH:34]2
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C2(C)CCc3cc(OC)ccc3C2=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: COC=C1c2ccc(OC)cc2C=CC1(C)c1ccc(OC)cc1

Procedure:
A suspension of (methoxymethyl)triphenylphosphonium chloride (25.7 g) in diethyl ether (400 ml) was stirred under an argon atmosphere and cooled in an ice-bath while a solution of n-butyl-lithium in hexane (1.6M, 46 ml) was added slowly over 10 minutes. The reaction mixture was then stirred at that temperature for 1 hour. A solution of 6-methoxy-2-(4-methoxyphenyl)-2-methyltetralone (8.9 g ) in diethyl ether 150 ml) was added to the reaction, and it was then stirred at room temperature for 16 h, saturated ammonium chloride solution (300 ml) was added to the reaction mixture and the organic layer was separated. The aqueous layer was extracted twice with diethyl ether (200 ml). The organic extracts were combined, dried and evaporated to dryness. The resulting gum was subjected to flash column chromatography on silica (K60) using toluene as eluting solvent to give 6-methoxy-1-methoxymethylene-2-(4-methoxyphenyl)-2-methylnaphthalene as a colourless oil.