Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:1][CH:2]([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:3]([OH:5])=[O:4])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: NC(CCCc1ccccc1)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(CCCc1ccccc1)NS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of (±)-2-amino-5-phenyl-pentanoic acid (0.188 g, 0.000973 mol), 4-fluoro-benzenesulfonyl chloride (0.189 g, 0.000971 mol), and sodium carbonate (0.208 g, 0.00196 mol) in water (4 mL) was stirred at room temperature for 4 days. The mixture was heated briefly on a steam bath to give a cloudy solution. The solution was gravity filtered hot, and the filtrate allowed to cool. The resulting solid that crystallized was filtered off, washed with water, and dried in vacuo; yield 0.131 g, (38%). 1H-NMR (DMSO-d6): δ 7.81 (m, 2H), 7.37 (t, 2H), 7.25 (t, 2H), 7.14 (m, 4H), 3.34 (br s, H2), 3.04 (t, 1H), 2.46 (m, 2H), 1.6-1.4 (m, 4H).
Reaction SMILES: C(NC([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:19][C:20](=O)C)[C:13]=2[CH2:15][CH:16]2C[O:17]2)[CH:8]=[N:7]1)=O)C.C(=O)([O-])[O-].[K+].[K+].O.Cl>CO>[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[O:19][CH2:20][CH:16]([OH:17])[CH2:15][C:13]3=2)[CH:8]=[N:7]1
Reactant: CCNC(=O)n1ncc2ccc(OC(C)=O)c(CC3CO3)c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: OC1COc2ccc3cn[nH]c3c2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the product of Step E (1.44 g, 4.75 mmol) in methanol (100 mL) was added saturated aqueous potassium carbonate (10 mL) and the mixture stirred for 18 h at ambient temperature. Water (200 mL) was added to the reaction mixture and the pH adjusted to 7 with conc HCl followed by extraction ethyl acetate (5×100 mL). The combined extracts were dried (MgSO4) and evaporated to tan solid (0.84 g, 93%): 1H NMR (DMSO-d6) δ 12.77 (s, 1H), 7.94 (s, 1H), 7.49 (d, J=6.0 Hz, 1H), 6.66 (d, J=6.0 Hz, 1H), 5.02 (t, J=6.0 Hz, 1H), 4.85-4.95 (m, 1H), 3.62 (m, 2H), 2.9-3.4 (m, 2H); LC/MS (+APCI) m/z 191 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].C(OC([N:35]1[CH2:39][CH2:38]OS1(=O)=O)=O)(C)(C)C.Cl>CN(C=O)C.O>[NH2:35][CH2:39][CH2:38][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:15][CH2:14]2)=[O:12])=[CH:7]1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCN(c2ccccc2F)CC1
Reactant: CC(C)(C)OC(=O)N1CCOS1(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NCCn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone in dry DMF under argon at 0° C. was added (1.1 eq) NaH. The reaction mixture was stirred for 1 h at 0° C. 2,2-Dioxo-2λ6-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (1.1 eq) (described in WO 2003037327) was added, and the reaction mixture was stirred for 2 h at RT. After evaporation of DMF, redissolution in dioxan, addition of 5 eq. of HCl (4.0M solution in dioxane) and a few drops of water, the reaction mixture was stirred for 2 h at 50° C.; LC-MS showed complete conversion to the crude product.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][PH:11](=[O:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH3:23][O:24][C:25](=[O:42])[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:29]=1)=[CH2:27]>C(Cl)Cl>[CH3:23][O:24][C:25](=[O:42])[CH:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:29]=1)[CH2:27][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:12])=[O:13]
Reactant: C=C(C(=O)OC)c1cccc(NC(=O)OC(C)(C)C)c1
Reactant: O=[PH](O)CCCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(CP(=O)(O)CCCCc1ccccc1)c1cccc(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To 4-phenylbutylphosphinic acid (357 mg, 1.8 mmol) in methylene chloride at 0° C. was added DIEA (0.66 mL, 3.8 mmol), followed by TMSCI (0.47 mL, 3.8 mmol). After 1 hour, 2-(3-(t-butoxycarbonylamino)phenyl)propenoic acid methyl ester (0.5 g, 1.8 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After 5 hours, the reaction was partitioned between methylene chloride and saturated NaHCO3 solution. The organic layer was washed with 0.1 N sulfuric acid and concentrated in vacuo. The residue was dissolved in 10 mL 3:1 THF:methanol for 18 hours. The reaction was concentrated to provide 2-(3-(t-butoxycarbonylamino)phenyl)-3-((4-phenylbutyl)(hydroxy)phosphinoyl)propanoic acid methyl ester (845 mg) as a white foam.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:21]=[C:20]([N:22]([CH3:24])[CH3:23])[CH:19]=[CH:18][C:6]=1[C:7]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=O)(=[O:3])[CH3:2].[CH3:25][N:26]([CH3:36])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([CH3:35])[CH3:34])[CH:28]=1>>[CH3:34][N:33]([CH3:35])[C:29]1[CH:28]=[C:27]([N:26]([CH3:36])[CH3:25])[CH:32]=[CH:31][C:30]=1[C:7]1([C:6]2[CH:18]=[CH:19][C:20]([N:22]([CH3:24])[CH3:23])=[CH:21][C:5]=2[NH:4][C:1](=[O:3])[CH3:2])[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[O:13])[O:12]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: CC(=O)Nc1cc(N(C)C)ccc1C(=O)c1ccccc1C(=O)O
Product: CC(=O)Nc1cc(N(C)C)ccc1C1(c2ccc(N(C)C)cc2N(C)C)OC(=O)c2ccccc21

Procedure:
Condensation of 2-(2-acetamido-4-(dimethylamino)benzoyl)benzoic acid and N,N,N',N'-tetramethyl-m-phenylenediamine by the method of part B of Example 1 affords 3-(2,4-bis(dimethylamino)phenyl)-3-(2-acetamido-4-(dimethylamino)phenyl)phthalide, the compound of part A of this example.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[Cl:9][C:10]1[CH:11]=[C:12]([N:16]=[C:17]=[O:18])[CH:13]=[CH:14][CH:15]=1>CN(C)C=O>[Cl:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]([N:8]=[C:7]2[NH:6][C:4](=[O:5])[CH2:3][N:2]2[CH3:1])=[O:18])[CH:13]=[CH:14][CH:15]=1
Reactant: CN1CC(=O)N=C1N
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: CN(C)C=O
Product: CN1CC(=O)NC1=NC(=O)Nc1cccc(Cl)c1
Reaction time: 2 h

Procedure:
To a suspension of creatinine (5.66 g, 0.05 mole) in 150 ml. of dry dimethylformamide (DMF) is added 7.68 g. (0.05 mole) of m-chlorophenylisocyanate. The mixture is stirred for two hours and heated on a steam bath for 30 minutes. During this time the solution becomes clear (yellow). The solution is filtered and the filtrate cooled. Ice and ice-water are added to the filtrate. A light yellow solid precipitates and is filtered off. After recrystallizations from acetone-methanol and tetrahydrofuran-ether, the pure product, 1-m-chlorophenyl-3-(1-methyl-4-oxo-2-imidazolidinylidene)urea, is obtained, mp 180°-180.5° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36](O)=[O:37])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36]([N:6]2[CH2:5][C@H:4]3[C@H:8]([CH2:9][CH:2]([CH3:1])[CH2:3]3)[C@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])=[O:37])=[CH:28][CH:29]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2ccc(F)cc2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)(Cl)Cl)[CH:5]=[CH:6][CH:7]=1.[F:18][C:19]1[CH:24]=[C:23]([OH:25])[C:22]([OH:26])=[CH:21][C:20]=1[C:27]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[O:25][C:23]3[CH:24]=[C:19]([F:18])[C:20]([C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:28])=[CH:21][C:22]=3[O:26]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1cc(O)c(O)cc1F)N1CCOCC1
Reactant: Clc1cccc(C(Cl)(Cl)c2cccc(Cl)c2)c1
Product: O=C(c1cc2c(cc1F)OC(c1cccc(Cl)c1)(c1cccc(Cl)c1)O2)N1CCOCC1

Procedure:
This compound was prepared from bis-(3-chloro-phenyl)-dichloromethane and (2-fluoro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone according to Example 276b; viscous brown oil, MS: m/e=474 ([M+H]+).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH:9]1[CH:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1.C(OCC)C>ClCCl>[C:1]([NH:8][CH:9]1[CH:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: NC1CN(C(=O)OCc2ccccc2)CC1O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)NC1CN(C(=O)OCc2ccccc2)CC1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
3.24 g acetic anhydride was added to 7.1 g benzyl 3-amino-4-hydroxypyrrolidine-1-carboxylate in 100 mL dichlormethane at 0-5° C. The mixture was stirred 2 h at RT, 100 mL diethylether was added and the mixture was stirred for 15 min. The precipitate was filtered to give 7.6 g of the desired product.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)=[N:9][C:10](=[O:17])[N:11]2[CH:14]([CH3:16])[CH3:15])=[CH:6][CH:5]=1)([OH:3])=[O:2].Cl.[CH3:27]O>>[C:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)=[N:9][C:10](=[O:17])[N:11]2[CH:14]([CH3:16])[CH3:15])=[CH:6][CH:5]=1)([O:3][CH3:27])=[O:2]
Reactant: COc1cccc(-c2nc(=O)n(C(C)C)c3cc(C(=O)O)ccc23)c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc2c(-c3cccc(OC)c3)nc(=O)n(C(C)C)c2c1
Reaction time: 7 h

Procedure:
Into a flask containing 7.0 g. of 7-carboxy-1-isopropyl-4-(m-methoxyphenyl)-2(1H)-quinazolinone dissolved in anhydrous methanol is introduced hydrogen chloride gas until the temperature reaches 50° C. The flask is then equipped with a stopper and the reaction mixture allowed to stand under ambient conditions for 7 hours. The resulting mixture is evaporated to dryness, the residue taken up in benzene, washed with water, followed by evaporation to dryness and crystallization of the residue from methanol to obtain 7-carbomethoxy-1-isopropyl-4-(m-methoxyphenyl)-2(1H)-quinazolinone, m.p. 164°-167° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][CH2:16][C:17]([N:19]([C:21]2[C:22]([Cl:38])=[C:23]([C:34]([Cl:37])=[CH:35][CH:36]=2)[CH2:24][O:25][C:26]2[C:27]([NH2:33])=[C:28]([CH:30]=[CH:31][CH:32]=2)[NH2:29])[CH3:20])=[O:18])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:39](OC)(OC)(OC)[O:40][CH3:41]>C(O)(=O)C>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][CH2:16][C:17]([N:19]([C:21]2[C:22]([Cl:38])=[C:23]([C:34]([Cl:37])=[CH:35][CH:36]=2)[CH2:24][O:25][C:26]2[C:27]3[N:33]=[C:39]([O:40][CH3:41])[NH:29][C:28]=3[CH:30]=[CH:31][CH:32]=2)[CH3:20])=[O:18])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(/C=C/C(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc(N)c3N)c2Cl)cn1
Reactant: COC(OC)(OC)OC
Solvent: CC(=O)O
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(NC(C)=O)nc4)c3Cl)cccc2[nH]1
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of 3-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-aminoaniline (735 mg) in acetic acid (7.4 ml) was added tetramethyl orthocarbonate (215 mg) at ambient temperature, and the mixture was stirred for 8 hours at the same temperature. The solvent was removed, and the residue was dissolved in chloroform. The solution was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (chloroform-methanol) to give 4-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1H-benzimidazole (654 mg).
Reaction SMILES: [O:1]1[C@@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[CH2:4][NH:3][C:2]1=[O:13].Br[C:15]1[CH:16]=[C:17]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[S:18][CH:19]=1>[Cu]I>[N:23]1[CH:22]=[CH:21][C:20]([C:17]2[S:18][CH:19]=[C:15]([N:3]3[CH2:4][C@:5]4([CH:10]5[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]5)[CH2:6]4)[O:1][C:2]3=[O:13])[CH:16]=2)=[CH:25][CH:24]=1
Reactant: O=C1NC[C@@]2(CN3CCC2CC3)O1
Reactant: Brc1csc(-c2ccncc2)c1
Agent: [Cu]I
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1csc(-c2ccncc2)c1

Procedure:
The title compound was prepared by a method analogous to that described in Preparation 3 from (S)-spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 4-bromo-2-(4-pyridyl)thiophene using 2 equivalents of copper (I) iodide. The title compound (1.70 g) was obtained as a pale-yellow solid, m/z 342 (MH+).
Reaction SMILES: CO.[N+:3]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[NH:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21])([O-])=O>[Pd].O1CCCC1>[NH2:3][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[NH:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21]
Reactant: N#Cc1cccc(Nc2ccc3ccccc3c2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cccc(Nc2ccc3ccccc3c2N)c1
Reaction time: 4 h
Yield: 73.9 %

Procedure:
To a methanol (10 mL) and an anhydrous tetrahydrofuran (50 mL) solution of 3-(1-nitro-2-naphthylamino)benzonitrile (1.60 g, 5.53 mmol) was added 10% palladium-active carbon (160 mg), and the mixture was hydrogenated for 4 hours at room temperature under atmospheric pressure. After removal of the catalyst by filtration, the solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3) to obtain the titled compound as a pale brown powder (1.06 g, yield 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[F:12][C:13]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:15]/[C:14]2[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:13]=2[F:12])/[C:9]#[N:10])=[C:4]([F:11])[CH:3]=1
Reactant: O=Cc1cccc(F)c1F
Reactant: N#CCc1ccc(Cl)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1cccc(F)c1F)c1ccc(Cl)cc1F
Yield: 89.7 %

Procedure:
In a manner similar to the method described in Example 1b, 4-chloro-2-fluorophenylacetonitrile (4.5 g, 26 mmol) was reacted with 2,3-difluorobenzaldehyde (Aldrich) (4.5 g, 32 mmol), methanolic solution (25 wt %) of sodium methoxide (6.3 g, 29 mmol) in methanol (135 mL) at 50° C. for 3 h to give (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(2,3-difluoro-phenyl)-acrylonitrile as a white powder (6.85 g, 88%).
Reaction SMILES: Cl[C:2]1[C:13]2=[C:14]3[N:9]([CH2:10][CH2:11][CH2:12]2)[CH:8]=[C:7]([C:15]([OH:17])=[O:16])[C:6](=[O:18])[C:5]3=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CS(C)=O.Cl>[OH-].[Na+]>[N:19]1([C:2]2[C:13]3=[C:14]4[N:9]([CH2:10][CH2:11][CH2:12]3)[CH:8]=[C:7]([C:15]([OH:17])=[O:16])[C:6](=[O:18])[C:5]4=[CH:4][CH:3]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: O=C(O)c1cn2c3c(c(Cl)ccc3c1=O)CCC2
Reactant: C1CNCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1cn2c3c(c(N4CCNCC4)ccc3c1=O)CCC2
Yield: 28.5 %

Procedure:
19.2 g of 8-chloro-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid and 35.5 g of piperazine were added to 350 ml of anhydrous dimethyl sulfoxide and the mixture was heated on an oil bath at 170° to 180° C. for 6 hours while stirring. After completion of the reaction, the solvent was removed under reduced pressure. 500 ml of water was added to the residue and the pH value of the mixture was adjusted to a pH of 2 followed by filtering water-insoluble materials. The filtrate was concentrated to 100 ml under reduced pressure and rendered alkaline (pH=9) with a 10% aqueous sodium hydroxide solution. After extracting the aqueous alkali solution with chloroform to thereby remove chloroform-soluble materials, the aqueous alkali solution layer was allowed to stand to precipitate crystals which were filtered. The crude crystals thus-obtained were dissolved in 10 ml of a 10% aqueous sodium hydroxide solution and the solution was treated with activated carbon and adjusted to a pH of 8 with a 10% aqueous hydrochloric acid solution to precipitate crystals which were filtered and washed with water sufficiently. Recrystallization of the crystals from dimethylformamide gave 6.5 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white needles having a melting point of 267° to 268° C. 6.4 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid thus-obtained was suspended in 50 ml of water and 15 ml of a 10% aqueous hydrochloric acid solution was added to the resulting solution. After removing the insoluble materials by filtration, the water was distilled off to obtain 5.7 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride as white amorphous crystals having a melting point of 300° C. or more.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:10]2([CH2:15][O:16][C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)=[C:19]([CH3:34])[CH:18]=3)[CH2:14][CH:13]=[CH:12][CH2:11]2)=[CH:8][CH:9]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1>[CH3:34][C:19]1[CH:18]=[C:17]([O:16][CH2:15][C:10]2([C:7]3[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH:12]=[CH:13][CH2:14]2)[CH:22]=[C:21]([CH3:23])[C:20]=1[C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(C2(COc3cc(C)c(-c4ccc(C(F)(F)F)cc4)c(C)c3)CC=CC2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(OCC2(c3ccc(C(=O)O)s3)CC=CC2)cc(C)c1-c1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
A solution of 5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxymethyl)-cyclopent-3-enyl]-thiophene-2-carboxylic acid methyl ester (0.239 g, 0.492 mmol) in THF (5.0 mL) is treated with LiOH (1N aqueous, 5.0 mL, 5.0 mmol), warmed to 70° C., and stirred overnight. The reaction mixture is cooled to rt, acidified with HCl (1N aqueous, 5.2 mL), and extracted with EtOAc (3×10 mL). The combined extracts are dried over MgSO4, filtered, and concentrated to provide 5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxymethyl)-cyclopent-3-enyl]-thiophene-2-carboxylic acid (0.210 g, 90%) as a yellow foam. MS (ES): 471.2 [M−H]−.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[C:23]([CH3:26])[CH:24]=2)[N:19]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[C:18]1=[O:34])[CH3:16].[H-].[Na+]>CN(C=O)C>[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[C:23]([CH3:26])[CH:24]=2)[N:19]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:29][CH:28]=2)[C:18]1=[O:34])[CH3:16]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(C)cc21
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncc(C)cc21
Temperature: 150 °C
Reaction time: 2 h
Yield: 17.4 %

Procedure:
To a solution of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (156 mg) and 1-ethyl-3-(4-hydroxyphenyl)-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (166 mg) in DMF (3 mL) was added NaH (30 mg) at room temperature, and the mixture was stirred at 150° C. under microwave irradiation for 2 h. The mixture was partitioned between water and AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (dry charge, NH silica gel, eluted with 50%-100% AcOEt in hexane) and column chromatography (dry charge, silica gel, eluted with 50%-100% AcOEt in hexane), and recrystallized from MeOH to give 1-ethyl-6-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (43 mg) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:29](I)[CH3:30]>CN(C=O)C.C(OCC)(=O)C>[CH2:29]([N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=1)[S:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH3:30]
Reactant: COc1ccc(CNS(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(C(=O)O)cc1
Temperature: 165 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
4-(N-(4-methoxybenzyl)sulfamoyl)benzoic acid (Example 5-1b) (160 mg, 0.5 mmol) and Cesium Carbonate (325 mg, 1 mmol) were placed in a microwave vial and dissolved in 2 mL DMF. Ethyl iodide (155 mg, 1 mmol) was added into the reaction mixture. The reaction was placed in a microwave reactor and heated at 165° C. for 5 minutes. The reaction mixture was dissolved in Ethyl Acetate and washed with water. The organic layer was dried over sodium sulfate and evaporated under vacuum. The crude product was dissolved in 4/1 solution of 6N NaOH(aq)/tetrahydrofuran (3 mL) and stirred at ambient temperature for 6 hours. The solution was acidified with 3N HCl (aq) to a pH of ˜3 and the product was extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate and concentrated under vacuum. The residue was taken up in methanol (3 mL) and purified by reverse phased HPLC (5-95% acetonitrile in H2O gradient: 25 minutes). The compound was known to inhibit the hT2R14 with IC50 of 20 μM. Yield 35%. MS M+H calculated 350.11, found 350.0.
Reaction SMILES: [OH:1][N:2]=[C:3]([CH:6]=O)[C:4]#[N:5].[OH:8][CH2:9][CH2:10][NH:11][NH2:12]>CO>[OH:8][CH2:9][CH2:10][NH:11][N:12]=[CH:6][C:3](=[N:2][OH:1])[C:4]#[N:5]
Reactant: N#CC(C=O)=NO
Reactant: NNCCO
Solvent: CO
Product: N#CC(C=NNCCO)=NO
Temperature: 5 °C
Yield: 99 %

Procedure:
In a similar apparatus used in Example 1 were charged 0.98 g (10 mmol) of 2-hydroxyimino-3-oxopropionitrile synthesized by the same method as in Example 1 and 6 ml of methanol, and the mixture was cooled to 5° C. while stirring. Then, 0.80 g (10 mmol) of 95% by weight 2-hydroxyethylhydrazine was added to the mixture at the same temperature, and reacted at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, hexane was added to the concentrate, the resulting mixture was filtered and dried under reduced pressure to give 1.55 g (isolation yield: 99%) of 3-(2-hydroxyethyl)hydrazono-2-hydroxyiminopropionitrile as dark brownish solid.