Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN(C=O)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([NH:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:14]
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cnc2ccccc2c1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1c[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.4 %

Procedure:
To a solution of 4-hydroxy-quinoline-3-carboxylic acid (A-1) (19 mg, 0.1 mmol), HATU (38 mg, 0.1 mmol) and DIEA (34.9 μL, 0.2 mmol) in DMF (1 mL) was added aniline (18.2 μL, 0.2 mmol) and the reaction mixture was stirred at room temperature for 3 h. The resulting solution was filtered and purified by HPLC (10-99% CH3CN/H2O) to yield 4-oxo-N-phenyl-1H-quinoline-3-carboxamide (215) (12 mg, 45%). 1H NMR (400 MHz, DMSO-d6) δ 12.97 (s, 1H), 12.50 (s, 1H), 8.89 (s, 1H), 8.34 (dd, J=8.1, 1.1 Hz, 1H), 7.83 (t, J=8.3 Hz, 1H), 7.75 (m, 3H), 7.55 (t, J=8.1 Hz, 1H), 7.37 (t, J=7.9 Hz, 2H), 7.10 (t, J=6.8 Hz, 1H); HPLC ret. time 3.02 min, 10-99% CH3CN, 5 min run; ESI-MS 265.1 m/z (MH+).
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.[C:27]([O:30][CH2:31][CH3:32])(=O)C>CN(C)C=O.O>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:1][C:2]2[C:9]([O:10][CH2:6][C:3]3[CH:4]=[CH:32][C:31]([O:30][CH3:27])=[CH:9][CH:2]=3)=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:21][CH:20]=1
Reactant: COc1ccc(CBr)cc1
Reactant: O=Cc1cccc(O)c1O
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cccc(C=O)c2OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
To a solution of 2,3-dihydroxybenzaldehyde (1) (6.91 g; 50 mMol.) in N, N-dimethylformamide (70 ml) cooling at 0° C. are added potassium carbonate power (17.97 g; 2.6 Eq.) and p-methoxybenzyl bromide (26.14 g; 2.6 Eq.), and the mixture is stirred at room temperature for 4 hours. ##STR12## The reaction mixture is dilued with ethyl acetate and water. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue is crystallized from a mixture of ether and hexane to give 2,3-di(p-methoxybenzyloxy)benzaldehyde (2) (16.43 g).
Reaction SMILES: [C:1]1([CH:7]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:24][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27]>C(OCC)(=O)C>[Cl-:24].[O:27]=[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:25][N+:13]12[CH2:18][CH2:17][CH:16]([CH2:15][CH2:14]1)[C@@H:11]([O:10][C:8](=[O:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:12]2
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)N1CCCC1
Reactant: O=C(CCl)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(c1ccccc1)N1CCCC1)C2)c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 84 h
Yield: 58.6 %

Procedure:
(R)-Quinuclidin-3-yl 2-phenyl-2-(pyrrolidin-1-yl)acetate (51 mg, 0.16 mmol) was dissolved in ethyl acetate (1.6 ml) and 2-chloro-1-phenylethanone (25.1 mg, 0.16 mmol) was added. The solution was stirred at room temperature for 3.5 days. The suspension was evaporated and the residue was purified by flash chromatography (DCM/MeOH=9/1 to 85/15) to obtain (3R)-1-(2-oxo-2-phenylethyl)-3-(2-phenyl-2-(pyrrolidin-1-yl)acetoxy)-1-azoniabicyclo[2.2.2]octane chloride (44 mg, 57.8% yield) as a yellow vitreous solid.
Reaction SMILES: C([O:4][C@H:5]([C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11])[CH2:6][C:7]([OH:9])=[O:8])(=O)C.[C:18](OC(CC(N1CCOCC1)=O)C(O)=O)(=O)C.O1CCOCC1.C([O-])(O)=O.[Na+]>CO>[CH3:18][O:9][C:7](=[O:8])[CH2:6][C@H:5]([OH:4])[C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11]
Reactant: CC(=O)O[C@@H](CC(=O)O)C(=O)N1CCOCC1
Reactant: CC(=O)OC(CC(=O)N1CCOCC1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)C[C@H](O)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of (S)-3-Acetoxy-4-morpholin-4-yl-4-oxo-butyric acid and 2-Acetoxy-4-morpholin-4-yl-4-oxo-butyric acid (11 g, 44.8 mmol) in dry methanol (30 mL) HCl in dioxane (4M, 7.3 ml, 29.16 mmol) was added and stirred at room temperature for 5 hrs. The reaction mixture was neutralized with solid NaHCO3, filtered through a mixture of Celite/Na2SO4 (1:1) and concentrated under reduced pressure. Column chromatography on silica eluting with a mixture of ethyl acetate and methylene chloride gave (S)-3-Hydroxy-4-morpholin-4-yl-4-oxo-butyric acid methyl ester (6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]2[C:6]([C@@:7]3([CH3:24])[C@H:16]([CH2:17][S:18]2)[C@:15]2([CH3:21])[C@H:10]([C:11]([CH3:23])([CH3:22])[CH2:12][CH2:13][CH2:14]2)[CH2:9][CH2:8]3)=[C:5]([C:25]([OH:27])=O)[CH:4]=1.[CH3:28][N:29](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:20]=[C:19]2[C:6]([C@@:7]3([CH3:24])[C@H:16]([CH2:17][S:18]2)[C@:15]2([CH3:21])[C@H:10]([C:11]([CH3:23])([CH3:22])[CH2:12][CH2:13][CH2:14]2)[CH2:9][CH2:8]3)=[C:5]([C:25]([NH:29][CH3:28])=[O:27])[CH:4]=1
Reactant: COc1cc2c(c(C(=O)O)c1)[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(OC)cc2c1[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
A solution of (1R,10R,11S,16S)-5-methoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carboxylic acid (74) (0.13 g, 0.33 mmol) in anhydrous THF (10 mL) and anhydrous DMF (0.7 mL), was prepared under N2. To the solution, HATU (0.15 g, 0.40 mmol) and Hunig's base (0.08 mL, 0.4 mmol) were added. The mixture was stirred at room temperature for 1 h. MeNH2 (2 M in THF, 2.0 mL, 4.0 mmol) was added and the flask was sealed and stirred at room temperature for 24 h. The reaction mixture was concentrated, and the residue was dissolved in CH2Cl2 and washed with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with CH2Cl2. The combined organic extracts were washed with brine and concentrated to dryness. The crude product was purified by flash chromatography on silica gel (CH2Cl2/EtOAc, 5:1) to yield (1R,10R,11S,16S)-5-methoxy-N,1,11,15,15-pentamethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carboxamide (75) (0.08 g, 59%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.[Mg].II.[Cl:14][C:15]1[CH:16]=[C:17]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH:24]=[O:25]>C1COCC1.O>[Cl:14][C:15]1[CH:16]=[C:17]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH:24]([OH:25])[CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(CBr)c1
Reactant: O=Cc1nccn1Cc1cc(Cl)cc(Cl)c1
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(CC(O)c2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Yield: 304.8 %

Procedure:
A mixture of 3-methoxy-benzylbromide (40 mg, 0.2 mmol), magnesium turnings (172 mg, 7.1 mmol) and a small crystal of iodine in dry THF (0.6 mL) was heated at 40° C. until an exothermic reaction to initiated. A solution containing a mixture of 1-(3,5-dichloro-benzyl)-1H-imidazole-2-carbaldehyde (255 mg, 1.0 mmol) and 3-methoxy-benzylbromide (241 mg, 1.2 mmol) in THF (2.5 mL) was then added dropwise to the stirred reaction mixture. After the addition was complete, the mixture was poured into cold water (20 mL) and extracted with CH2Cl2 (2×30 mL). The combined CH2Cl2 extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 20:1 CH2Cl2/iPrOH) to provide the desired 1-[1-(3,5-dichloro-benzyl)-1H-imidazol-2-yl]-2-(3-methoxy-phenyl)-ethanol (230 mg, 61%) as an off-white solid: ESI MS m/z 377 [C19H18Cl2N2O2+H]+.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:12]1([C:4]2[CH:3]=[C:2]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:6][C:5]=2[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1oc(Br)cc1-c1ccccc1
Product: CCOC(=O)c1oc(-c2ccccc2)cc1-c1ccccc1
Yield: 103.5 %

Procedure:
Using ethyl 5-bromo-3-phenyl-2-furancarboxylate (1.18 g) and phenylboronic acid (0.98 g), a reaction and treatment was carried out in the same manner as in Reference Example 2, thereby giving 1.21 g of ethyl 3,5-diphenyl-2-furancarboxylate.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][OH:6])[CH3:2].[N+:7]([O-:10])([OH:9])=[O:8]>CCOC(C)=O.CCCCCC>[N+:7]([O-:10])([O-:9])=[O:8].[CH2:1]([NH2+:3][CH2:4][CH2:5][O:6][N+:7]([O-:9])=[O:8])[CH3:2]
Reactant: CCNCCO
Reactant: O=[N+]([O-])O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC[NH2+]CCO[N+](=O)[O-]
Product: O=[N+]([O-])[O-]
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
Ethyl(2-(hydroxy)ethyl)amine (5 g, 56 mmol) in EtOAc (60 mL) was added drop-wise to a mixture of fuming HNO3 (17.7 g, 11.8 mL, 280 mmol) and Ac20 (45.8 g, 42.3 mL, 448 mmol) at −10° C. The reaction mixture was stirred at −10° C. for 30 minutes and diluted with EtOAc and hexane. The oil layer was separated and dried in high vacuo to give the title compound (8.4 g, 76% yield) as a pale green oil. 1H NMR (300 MHz, d6-DMSO) δ 8.60-8.95 (bs, 2H), 4.84 (m, 2H), 3.37-3.49 (m, 2H), 3.02-3.16 (m, 2H), 1.24 (t, J=7.2 Hz, 3H). 13C NMR (75 MHz, d6-DMSO) δ 69.1, 43.6, 42.6, 11.0. Mass spectrum (API-TIS) m/z 135 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[C].[Pd]>[N:10]1([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:12]=[CH:11]1
Reactant: O=[N+]([O-])c1ccc(-n2cnc3cnccc32)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-n2cnc3cnccc32)cc1

Procedure:
In 20 mL of methanol, 33 mg (0.1237 mmol) of 1-(4-nitrophenyl)-1H-imidazo[4,5-c]pyridine prepared in Step A was dissolved and the solution was stirred on 5 mg of 10% palladium carbon in a hydrogen atmosphere at room temperature at normal pressures for one hour. After removal of the palladium carbon by filtration, the solvent was distilled under reduced pressure, and the obtained product was vacuum dried to obtain 4-(imidazo[4,5-c]-pyridin-1-yl)aniline as a white solid. This product was used in process C without further purification.
Reaction SMILES: [C:1]([S:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:16][CH2:17][CH2:18][OH:19]>CC(C)=O>[I-:16].[OH:19][CH:18]([N+:12]1[CH:13]=[CH:14][CH:15]=[C:10]([S:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:11]=1)[CH3:17]
Reactant: OCCI
Reactant: O=C(Sc1cccnc1)c1ccccc1
Solvent: CC(C)=O
Product: CC(O)[n+]1cccc(SC(=O)c2ccccc2)c1
Product: [I-]

Procedure:
5.3 g of 3-benzoylthiopyridine was dissolved in 30 ml of acetone, and 9.4 ml of 2-iodoethanol was added thereto and reacted for 16 hours, while heated under reflux. After the reaction, the reaction solution was concentrated and the remaining residue was washed with ether and then with a mixture solution of methylene chloride/ether (=2/1) and dried to obtain 5.3 g of 1-hydroxyethyl-3-benzoylthiopyridinium iodide.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH:20]([CH3:22])[CH3:21].O>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)CBr
Reactant: O=C1CCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)COc1ccc2c(c1)C(=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a mixture of 6-hydroxy-2,3-dihydro-1H-inden-1-one (5.0 g, 33.8 mmol) in DMF (170 mL) was added K2CO3 (9.33 g, 67.5 mmol) and 1-bromo-2-methylpropane (5.50 mL, 50.6 mmol). The resulting orange mixture was stirred at r.t. overnight and was then heated to 60° C. for 2 days. The mixture was cooled to r.t., water was added and the mixture was extracted with EtOAc (×4). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography using 0-20% EtOAc in heptane as eluent afforded 4.98 g (72% yield) of the title compound: 1H NMR (500 MHz, CDCl3) δ ppm 1.03 (d, 6H), 2.10 (dt, 1H), 2.69-2.75 (m, 2H), 3.04-3.11 (m, 2H), 3.75 (d, 2H), 7.17-7.22 (m, 2H), 7.37 (d, 1H); MS (ES+) m/z 205 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH2:12][C:13]([OH:15])=[O:14])(=[O:3])[CH3:2].S(=O)(=O)(O)O.[CH3:21]O>>[CH3:21][O:14][C:13](=[O:15])[CH2:12][C:5]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CO
Reactant: COc1ccc(C(C)=O)c(CC(=O)O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cc(OC)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a solution of (2-acetyl-5-methoxy-phenyl)-acetic acid (5.00 g, 24.0 mmol) in methanol (50 mL) was added concentrated sulfuric acid (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours after which it was concentrated to a low volume. Dichloromethane (50 mL) was added and the solution was washed with 1N sodium hydroxide (50 mL). The layers were separated and the organic layer was dried over magnesium sulfate, filtered, and concentrated to an oil which solidified on standing to afford (2-acetyl-5-methoxy-phenyl)-acetic acid methyl ester (4.70 g, 88%). M.p. 74-76° C. 1H NMR (300 MHz, CDCl3) δ2.58 (s, 3), 3.74 (s, 3), 3.89 (s, 3), 3.95 (s, 2), 6.78 (d, 1, J=2.6), 6.89 (dd, 1, J=8.7, 2.6), 7.89 (d, 1, J=8.6). 13C NMR (75 MHz, CDCl3) δ29.65, 42.35, 53.11, 56.69, 113.17, 120.00, 130.52, 134.39, 138.90, 163.54, 173.23, 200.35. IR 1739, 1665, 1605, 1568, 1321, 1247, 1165 cm−1. Analysis calculated for C12H14O4: C, 65.85; H, 6.35. Found: C, 64.87; H, 6.44.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5](C(O)=O)=[CH:4][C:3]=1O.[CH:12]([O:17]C)(OC)[O:13]C.[CH3:19][OH:20]>>[O:20]1[C:3]2[CH:4]=[CH:5][C:9]([C:12]([OH:17])=[O:13])=[CH:10][C:2]=2[N:1]=[CH:19]1
Reactant: COC(OC)OC
Reactant: Nc1ccc(C(=O)O)cc1O
Reactant: CO
Product: O=C(O)c1ccc2ocnc2c1
Temperature: 100 °C
Yield: 27 %

Procedure:
A mixture of 4-amino-3-hydroxybenzoic acid (1.0 g, 6.5 mmol) and trimethyl orthoformate (2.0 mL, 18.3 mmol) is heated in an oil bath at 100° C. for 30 h. The mixture is cooled to rt and diluted with MeOH. The resulting solution is filtered through a pad of Celite, and the filtrate is concentrated in vacuo to give 1,3-benzoxazole-5-carboxylic acid as a brown solid (290 mg, 27%): 1H NMR (DMSO-d6) δ 13.0, 8.9, 8.3, 8.1, 7.9.
Reaction SMILES: C1(C[N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:21][C:22]2[CH:23]=[N:24][C:25](OCC)=[CH:26]C=2)CC1.[CH2:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=O)=[CH:36][CH:35]=1)[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.NC1C=C(C=CC=1NCC1C=CN=CC=1)C(N(CC)CC)=O>>[CH2:31]([O:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:40][C:41]2[N:5]([CH2:6][C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)[C:9]3[CH:10]=[CH:11][C:12]([C:14]([N:16]([CH2:17][CH3:18])[CH2:19][CH3:20])=[O:15])=[CH:13][C:8]=3[N:7]=2)=[CH:38][CH:39]=1)[CH3:32]
Reactant: CCOc1ccc(Cc2nc3cc(C(=O)N(CC)CC)ccc3n2CC2CC2)cn1
Reactant: CCOc1ccc(CC(=O)O)cc1
Agent: CCN(CC)C(=O)c1ccc(NCc2ccncc2)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(Cc2nc3cc(C(=O)N(CC)CC)ccc3n2Cc2ccncc2)cc1
Yield: 36 %

Procedure:
Following general 13B, (4-ethoxyphenyl)acetic acid (0.0364 g, 0.202 mmol), HATU (0.0768 g, 0.202 mmol), DIPEA (0.048 mL, 0.28 mmol), and 3-amino-N,N-diethyl-4-[(4-pyridinylmethyl)amino]benzamide (0.0548 g, 0.184 mmol) were combined. The crude product was purified by reverse phase MPLC (gradient 10–50% CH3CN in H2O) to provide the title compound (0.0459 g, 36%) as its TFA salt. This material was lyophilized from H2O/dioxane to produce a white solid. 1H-NMR (CD3OD): δ 8.60 (br s, 2H), 7.87 (s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.52 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 7.42 (d, J=5.6 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 6.71 (d, J=9.6 Hz, 2H), 6.06 (s, 2H), 4.54 (s, 2H), 3.93 (q, J=7.2 Hz, 2H), 3.59 (br s, 2H), 3.31 (br s, 2H), 1.35 (t, J=6.8 Hz, 3H), 1.38–1.04 (2×br s, 6H). MS (ESI) (M+H)+443. Anal. Calcd for C27H30N4O2.2.1 TFA. 0.8H2O: C, 53.81; H, 4.88; N, 8.04. Found: C, 53.74; H, 4.89; N, 8.07.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[N:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[C:17](=O)([O-])O.[Na+]>CO>[CH3:17][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:14]([Cl:16])=[N:15][C:7]=1[NH2:6]
Reactant: O=C([O-])O
Reactant: Nc1nc(Cl)ccc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(Cl)nc1N
Temperature: 70 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
Concentrated sulfuric acid (25 mL) and 2-amino-6-chloro-nicotinic acid (4.3 g, 25 mmol) described in Manufacturing Example 26-1-1 were added to methanol (50 mL) on an ice bath, and stirred at 70° C. for 5 hours. The reaction mixture was cooled and then neutralized by addition of aqueous sodium hydrogen carbonate (90 g) solution. The precipitated solids were filtered to obtain the title compound (3.2 g, 17 mmol, 68%).
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.[CH3:21][O:22][C:23]1[N:28]=[C:27]([CH2:29]O)[CH:26]=[CH:25][CH:24]=1.C(P(CCCC)CCCC)CCC>C1COCC1.[Cl-].[Na+].O>[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]([CH2:29][C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH3:21])[N:28]=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: COc1cccc(CO)n1
Agent: CCCCP(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(CN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 3.2 %

Procedure:
3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (100 mg, 0.4 mmol), (6-methoxy-pyridin-2-yl)-methanol (example 10-75a) (101 mg, 0.7 mmol), tributylphosphine (147 mg, 0.7 mmol), and 1,1″″-azobis(N,N-dimethylformamide) (125 mg, 0.7 mmol) were dissolved in THF (5 mL) and stirred at room temperature for 15 hours. The reaction was diluted with brine (100 mL) and extracted with ethyl acetate (2×, 100 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated on the rotovap. The residue was taken up in methanol (5 mL) and purified by reversed phase HPLC (5 to 95% acetonitrile in H2O: 25 minute gradient). The pure fractions were combined, concentrated then re-dissolved in ethyl acetate/hexane (1:9). The solution was cooled at 5° C. for 15 hrs, where a white solid formed. The precipitate was collected to afford 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-((6-methoxypyridin-2-yl)methyl)imidazolidine-2,4-dione (5 mg, 4%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ2.11 (s, 3H), 2.37 (s, 3H), 3.74 (s, 3H), 4.17 (s, 2H), 4.54 (s, 2H), 5.17 (s, 2H), 6.69 (d, J=7.6 Hz, 1H), 6.96 (d, J=6.8 Hz, 1H), 7.67 (d, J=6.8 Hz, 1H), 7.76 (s, 1H), 8.17 (s, 1H). MS M+H calculated 397.2; found 397.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.23 μM.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:18])[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH2:11])[CH:5]=[CH:4][C:3]=1[O:19][CH3:20].S(=O)(=O)(O)O>C(Cl)Cl>[C:12]1([CH:10]2[CH2:11][C:5]3[C:6](=[C:7]([Cl:8])[C:2]([Cl:1])=[C:3]([O:19][CH3:20])[CH:4]=3)[C:9]2=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=C(C(=O)c1ccc(OC)c(Cl)c1Cl)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccccc1)C2
Reaction time: 0.5 h
Yield: 56 %

Procedure:
2,3-Dichloro-4-(2-phenylacryloyl)anisole (8.2 g., 26.8 mmol) in 215 ml. of methylene chloride is added dropwise over a 4.5 hr. period to a stirred solution of 107 ml. of sulfuric acid in 107 ml. of methylene chloride at 0°-5° under an atmosphere of argon. Following addition, the reaction mixture is stirred for 0.5 hr., poured over about 300 g. of crushed ice and the aqueous-organic phases separated. The aqueous phase is extracted with methylene chloride and the combine methylene chloride solutions sequentially washed with water and then dried over magnesium sulfate. Removal of the solvent affords 8.52 g. of solid which crystallized from benzene-cyclohexane provides 4.59 g. (56% yield) of 2-phenyl-5-methoxy-6,7-dichloro-1-indanone, m.p. 193.5°-196.5°.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].ClCCl.[C:14]12(O)[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.S(=O)(=O)(O)O>O>[C:14]12([C:7]3[C:8]([OH:10])=[CH:9][C:2]([OH:1])=[C:3]([CH:6]=3)[CH:4]=[O:5])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: O=Cc1ccc(O)cc1O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: O=Cc1cc(C23CC4CC(CC(C4)C2)C3)c(O)cc1O
Temperature: 25 °C

Procedure:
40 g (0.29 mol) of 2,4-dihydroxybenzaldehyde, 600 ml of dichloromethane and 46.4 g (0.34 mol) of 1-adamantanol were introduced into a round-bottomed flask and 24 ml of concentrated sulfuric acid were added. The reaction medium was stirred at room temperature for twelve hours and was then poured into water. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a column of silica, eluted with dichloromethane. 50.8 g (64%) of the expected aldehyde, having a melting point of 259°-61° C., were recovered.