Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][C:20](Cl)=[O:21]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC#N>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:11][CH2:19][C:20](=[O:21])[NH:1][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: O=C(Cl)CCl
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Product: O=C1COc2ccc([N+](=O)[O-])cc2N1
Temperature: 80 °C
Yield: 94 %

Procedure:
To a solution of 2-amino-4-nitrophenol (114.0 g, 740 mmol), K2CO3 (306.2 g, 2220 mmol) and tetrabutyl ammonium bromide (23.8 g, 74 mmol) in MeCN (1.50 L) at 0° C. was added 2-chloroacetyl chloride (83.6 mL, 1110 mmol) dropwise. The reaction mixture was heated at 80° C. for 1 h. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was dissolved in water (500 mL) and extracted with EtOAc (3×150 mL). The combined organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated in vacuo to give 6-nitro-2H-benzo[1,4]oxazin-3-one as a white solid (135.0 g, 94%). 1H NMR (DMSO-d6, 400 MHz): δ 7.83 (dd, J=2.8 Hz, J=9.2 Hz, 1H), 7.75 (d, J=2.8 Hz, 1H), 7.15 (d, J=9.2 Hz, 1H), 4.78 (s, 2H). The amide proton was not observed in DMSO-d6.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([CH3:13])=[CH:8][CH:9]=[C:10]([NH:11][NH2:12])[C:4]=2[O:3]1.C(N(CC)C(C)C)(C)C.Cl[C:24]([O:26][CH3:27])=[O:25]>C1COCC1>[CH3:27][O:26][C:24]([NH:12][NH:11][C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[C:7]([CH3:13])=[CH:8][CH:9]=1)=[O:25]
Reactant: Cc1ccc(NN)c2c1CC(C)O2
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NNc1ccc(C)c2c1OC(C)C2
Temperature: -5 °C
Reaction time: 2 h

Procedure:
15.6 g of 1E was mixed with 150 ml of THF and 11.3 g of N,N-diisopropylethylamine. The mixture was cooled to -5° C. and 9.1 g of methyl chloroformate was added drop-by-drop to the stirred mixture, stirred at 0° C. for two hours, then poured over ice water and extracted with ether. The extract was dried (MgSO4) and the solvent was evaporated. The residue was column chromatographed on silica gel, using a 1:4:20 v:v:v mixture of tetrahydrofuran, ethyl acetate and hexane as eluent, to give 2-(2,3-dihydro-2,4-dimethylbenzofuran-7-yl)hydrazinecarboxylic acid methyl ester (1F), as a tan solid, m.p.: 90°-92° C.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[NH:11][C:12](=[O:14])[CH3:13]>C1C=CC=CC=1>[C:12]([NH:11][C:10]1[CH:9]=[C:8]([CH:17]=[CH:16][CH:15]=1)[NH:7][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: C=C1CC(=O)O1
Solvent: c1ccccc1
Product: CC(=O)CC(=O)Nc1cccc(NC(C)=O)c1
Yield: 91.6 %

Procedure:
20.1 g of diketene were added to a solution of 35 g of m-aminoacetanilide in 150 ml of benzene and after stirring for an hour, the mixture was evaporated to dryness under reduced pressure. The residue was added to acetone and the mixture was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was added to ether. The mixture was vacuum filtered and the precipitate was washed and dried to obtain 50 g of m-acetamido-acetylacetanilide melting at 107° C. which was used as is for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[C:18]([CH3:39])=[N:19][N:20]4[CH:25]=[CH:24][C:23]([CH2:26][NH:27]CC5C=CC(OC)=CC=5OC)=[CH:22][C:21]=34)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:4][CH:3]=1.FC(F)(F)S(O)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.FC(F)(F)C(O)=O.CO.CCOCC.CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[C:18]([CH3:39])=[N:19][N:20]4[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][C:21]=34)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:40][CH:41]=1
Reactant: COc1ccc(CNCc2ccn3nc(C)c(-c4nc(Cc5ccc(Cl)cc5)c(-c5nnc[nH]5)s4)c3c2)c(OC)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: Cc1nn2ccc(CN)cc2c1-c1nc(Cc2ccc(Cl)cc2)c(-c2nnc[nH]2)s1
Temperature: 60 °C
Yield: 3.6 %

Procedure:
1-{3-[4-(4-chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridin-5-yl}-N-(2,4-dimethoxybenzyl)methanamine (0.257 g, 0.438 mmol) was dissolved in methylene chloride (6.0 mL) and trifluoroacetic acid (6.0 mL). Trifluoromethanesulfonic acid (0.050 mL, 0.56 mmol) was added and the mixture was heated to 60° C. for 6 days. The mixture was evaporated in a rotary evaporator, azeotroped with EtOAc (3×), and evaporated to give a crude residue. The residue was suspended in ˜1 mL of MeOH and diluted with ˜20 mL of Et2O. The resulting powder was collected by filtration and dried under high vacuum to afford a pale pink solid product. The solid was taken up in EtOAc/water (20 mL/10 mL) and adjusted to ˜pH 8 with NaHCO3 solution. The layers were separated and the aqueous layer was extracted with EtOAc (2×30 mL). The combined EtOAc solutions were washed with water, brine, dried over Na2SO4, and filtered. The filtrate was concentrated to ˜5 mL volume and the precipitated solid was collected by filtration to give a pure crop of product (0.0069 g). The filtrate was evaporated then dried under high vacuum to afford a second crop of solid product (0.171 g, yield for 2 crops 89.9%). LCMS: (FA) ES+ 436, 438; ES− 434, 436. 1H NMR (400 MHz, d4-methanol) δ: 8.33-8.35 (d, J=7.29 Hz, 1H), 8.24 (s, 1H), 8.09 (s, 1H), 7.31-7.33 (d, J=8.78 Hz, 2H), 7.20-7.22 (d, J=8.53 Hz, 2H), 6.98-7.00 (m, 1H), 4.59 (s, 2H), 4.06 (s, 2H), 2.67 (s, 3H).
Reaction SMILES: [CH:1]1([C:6]([OH:31])([CH2:21][C:22]2[O:23][C:24]([CH3:30])([CH3:29])[O:25][C:26](=[O:28])[CH:27]=2)[C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:19])([CH3:18])[C:16]#[N:17])=[C:11]([F:20])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(O)(CC2OC(C)(C)OC(=O)C=2)C#CC2C=CC(C3(C#N)CC3)=C(F)C=2)CCCC1>>[CH:1]1([C:6]([OH:31])([CH2:21][C:22]2[O:23][C:24]([CH3:30])([CH3:29])[O:25][C:26](=[O:28])[CH:27]=2)[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:19])[C:16]#[N:17])=[C:11]([F:20])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C(C)(C)C#N)c(F)c2)C2CCCC2)O1
Agent: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C3(C#N)CC3)c(F)c2)C2CCCC2)O1
Product: CC1(C)OC(=O)C=C(CC(O)(CCc2ccc(C(C)(C)C#N)c(F)c2)C2CCCC2)O1

Procedure:
The desired product was prepared analogously to example A(86), Step 6, substituting 2-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-2-methyl-propionitrile (1.25 g, 2.9 mmol) from Step 2 above in place of 1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile. Yield: 1.23 g, 99%. MS (ESI): 428 (M−H).
Reaction SMILES: [CH:1]#[C:2][CH3:3].[CH3:4][O:5][C:6](=[O:16])[C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9](I)[C:8]=1[NH2:15]>C(N(CC)CC)C.[Cu]I.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>[CH3:4][O:5][C:6](=[O:16])[C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([C:1]#[C:2][CH3:3])[C:8]=1[NH2:15]
Reactant: C#CC
Reactant: COC(=O)c1cc(Cl)cc(I)c1N
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC#Cc1cc(Cl)cc(C(=O)OC)c1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Propyne (excess ca 3 ml) was condensed onto a cold (−78° C.) solution of 2-amino-5-chloro-3-iodobenzoic acid methyl ester (500 mg, 1.61 mmol) in triethylamine (10 ml) in a Parr pressure reaction vessel. To this solution was added copper (I) iodide and bis(triphenylphosphine)palladium (II) chloride and the pressure tube was then sealed and stirred at rt for 4 h. The solvent was then removed in vacuo and the residue was purified by flash column chromatography (9:1 cyclohexane:EtOAc) to give 2-amino-5-chloro-3-prop-1-ynylbenzoic acid methyl ester (340 mg, 95%) as an off white solid. 1H NMR (CDCl3, 300 MHz): δ 7.76 (d, J=2.5 Hz, 1H), 7.33 (d, J=2.5 Hz, 1H), 6.37 (br s, 2H), 3.87 (s, 3H), 2.13 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:18]=[C:11]2[N:12]=[C:13]([CH3:17])[NH:14][C:15](=[O:16])[N:10]2[N:9]=1.[I:19]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:18]([I:19])=[C:11]2[N:12]=[C:13]([CH3:17])[NH:14][C:15](=[O:16])[N:10]2[N:9]=1
Reactant: Cc1nc2cc(-c3ccccc3Cl)nn2c(=O)[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: Cc1nc2c(I)c(-c3ccccc3Cl)nn2c(=O)[nH]1
Reaction time: 5 h
Yield: 90.9 %

Procedure:
To a suspension of 7-(2-chlorophenyl)-2-methyl-3H-pyrazolo[1,5-a]-[1,3,5]triazin-4-one (I-1A-1c; 18.9 g, 72.6 mmol) in methylene chloride (290 ml) cooled in an ice bath was added N-iodosuccinimide (18.0 g, 79.9 mmol). The mixture became homogeneous orange solution within 5 minutes. After stirring for 5 hours, the mixture was washed with 50% saturated aqueous NH4OH (160 ml), 1 M aqueous Na2S2O3 (120 ml), and brine (120 ml). The solution was concentrated, in vacuo, and then concentrated again from MTBE (150 ml). Additional MTBE (75 ml) was added and stirred for 1 hour. The resulting solid precipitate was collected by vacuum filtration in a course sintered glass funnel, washed with MTBE (50 ml) and then dried, in vacuo, to afford product I-1A-1d as a solid (25.5 g, 91%): +APcI MS (M+1) 387.3; 1H NMR (400 MHz, CD3OD) δ 7.54 (d, J=7.1 Hz, 1H), 7.51-7.39 (m, 3H), 2.45 (S, 3H).
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][NH:15][C:16]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[O:17])[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:44]2[C@H:45]([CH3:68])[C@H:46]3[C@@H:63]([C@H:64]([OH:66])[CH3:65])[C:62](=[O:67])[N:47]3[C:48]=2[C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=2)=[O:50])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[S:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[C:16]([NH:15][CH2:14][C:12]1[N:13]=[C:9]([N:7]2[CH2:6][CH:5]([S:4][C:44]3[C@H:45]([CH3:68])[C@@H:46]4[C@@H:63]([C@H:64]([OH:66])[CH3:65])[C:62](=[O:67])[N:47]4[C:48]=3[C:49]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=3)=[O:50])[CH2:8]2)[S:10][CH:11]=1)=[O:17]
Reactant: CC(=O)SC1CN(c2nc(CNC(=O)c3cccs3)cs2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(CNC(=O)c5cccs5)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 3-acetylthio-1-{4-[(thiophene-2-carbonylamino)methyl]-1,3-thiazol-2-yl}azetidine (490 mg, 1.52 mmol) (obtained as described in Reference Example 66) in dimethylformamide (15 ml) was added hydrazine acetate (169 mg, 1.83 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.09 g, 1.83 mmol) in acetonitrile (30 ml) was added dropwise into the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (1.06 ml, 0.68 mmol). The mixture was stirred for 2.5 hours while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: ethyl acetate) to afford p-nitrobenzyl (1R,5S,6S)-2-(1-{4-[(thiophene-2-carbonylamino)methyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (997 mg, yield 100%) as a pale yellow solid.
Reaction SMILES: C(O)(=O)C1C=CC=CC=1.Cl[C:11]1[C:12](Cl)=[C:13](Cl)[C:14](Cl)=[C:15]2[C:20](=[O:21])[O:19][C:17](=O)[C:16]=12.N[C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:35]=1[N:34]=[C:33]([CH3:36])[CH:32]=[CH:31]2.[OH-].[Na+]>O>[CH:28]1[CH:29]=[C:30]2[CH:31]=[CH:32][C:33]([CH:36]3[C:17](=[O:19])[C:16]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:20]3=[O:21])=[N:34][C:35]2=[CH:26][CH:27]=1
Reactant: Cc1ccc2cccc(N)c2n1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: O=C(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1c2ccccc2C(=O)C1c1ccc2ccccc2n1
Temperature: 140 °C
Reaction time: 2 h
Yield: 249.8 %

Procedure:
270 g of benzoic acid were placed in a stirred reaction vessel and melted. At from 125° to 130° C., there were added to the melt 82 g of tetrachlorophthalic anhydride followed by 19 g of 8-aminoquinaldine. The mixture was heated to 140° C. and stirred at that temperature for 2 hours and then heated to 160° C. and stirred for a further 2 hours. The reaction mixture was then cooled to 130° C. and there was added thereto a mixture of 400 ml of water and 160 g of 50% w/w caustic soda solution. The pigment suspension was filtered in vacuo, washed to neutrality with water and dried. There were obtained 82 g (98%) of quinophthalone of the formula ##STR5##
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[CH3:10][S:11](Cl)(=[O:13])=[O:12].N1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:10][S:11]([O:9][CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)(=[O:13])=[O:12]
Reactant: OC1CN2CCC1CC2
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN2CCC1CC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.8 %

Procedure:
Quinuclidin-3-ol (10.0 g, 0.0787 mol) was dissolved under N2 in dry dichloromethane (200 ml) and cooled in an ice bath to 0° C. Methanesulphonyl chloride (7.3 ml, 10.8 g, 0.094 mol, 1.2 eq) and dry pyridine (7.64 ml, 7.46 g, 0.094 mol, 1.2 eq) were added and the mixture stirred at 0° C. for 20 min. The solution was then warmed to r.t. and stirred under N2 for 1 h. Saturated aqueous potassium carbonate solution (150 ml) was added, and the organic layer extracted and collected. The aqueous layer was re-extracted with EtOAc (3×200 ml), the organic solutions dried (Na2SO4), filtered, and evaporated to dryness under reduced pressure to yield a pale yellow oil which was pumped under high vacuum to remove any last traces of pyridine to yield the title compound (D8) (15.8 g, 98%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:22][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)=[N:7][C:2]([NH:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[N:3][CH:4]=1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Reactant: Nc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3cccnc3)ncc2Cl)CC1
Temperature: 120 °C
Yield: 24.8 %

Procedure:
A suspension of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide (A14) (100 mg, 297 μmol), Cs2CO3 (291 mg, 892 μmol) and 3-aminopyridine (56.0 mg, 595 μmol) in 1,4-dioxane (2.0 mL) was sonicated for 10 minutes. To this Xantphos (6.88 mg, 11.9 μmol) and Pd(OAc)2 (1.33 mg, 5.95 μmol) were added and the resulting mixture heated under microwave irradiation for 20 minutes at 120° C. The resulting mixture was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-50% MeOH in EtOAc) to yield a tan solid. This was sonicated for 10 min in water (50 mL) and filtered to give the title compound 6 as a green solid (29 mg, 25%); 1H NMR (400 MHz, CDCl3) δ 8.80-8.74 (d, J=2.5 Hz, 1H), 8.33 (s, 1H), 8.32-8.28 (dd, J=4.7, 1.3 Hz, 1H), 8.18-8.12 (m, 1H), 7.47-7.42 (d, J=7.2 Hz, 1H), 7.38-7.34 (m, 3H), 7.34-7.25 (m, 2H), 5.56 (s, 1H), 5.37 (s, 1H), 3.34-3.14 (m, 4H), 1.78 (s, 2H), 1.16 (s, 2H). LCMS-A: rt 4.502 min; m/z 394 [M+H]+.
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.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[CH:21](=[C:16]1/[C:17](=[O:18])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:20])[CH:12]=2)[C:14](=[O:19])[NH:15]/1)\[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1noc(C)c1Cn1cc(N2C(=O)N/C(=C\c3ccccc3)C2=O)cn1
Yield: 47.6 %

Procedure:
3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) (275 mg, 1 mmol), benzaldehyde (140 mg, 1.3 mmol), and sodium acetate (205 mg, 2.5 mmol), in glacial acetic acid (3 mL) were irradiated in the microwave reactor for 7 hours at 185° C. Upon cooling the mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (3×, 50 mL). The combined organic extracts were washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate, filtered and concentrated. the solid product was triturated with ethyl acetate/hexanes (1/1) and dried under high vacuum to afford (Z)-5-benzylidene-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (173 mg, 48%) as a light yellow solid. 1H NMR (DMSO-d6, 400 MHz): δ 2.14 (s, 3H), 2.40 (s, 3H), 6.59 (s, 1H), 5.20 (s, 2H), 7.33-7.40 (m, 3H), 7.66 (s, 2H), 7.81 (s, 1H), 8.21 (s, 1H), 11.01 (bs, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.34 μM.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:22][OH:23])[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(CO)cc(Br)cc3c2C1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2oc3c(COS(C)(=O)=O)cc(Br)cc3c2C1
Temperature: 25 °C
Yield: 94.7 %

Procedure:
To a mixture of the product of Example 74, step E (300 mg, 0.78 mmol) in dichloromethane (4 mL) at 0° C. was added triethylamine (93 mg, 0.92 mmol) followed by methanesulfonyl chloride (100 mg, 0.88 mmol). The reaction mixture was allowed to warm to ambient temperature over 2 h, then treated with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic extracts were dried over sodium sulphate, filtered, and concentrated in vacuo. Purification by flash chromatography (SiO2, 95:5 hexanes/ethyl acetate) provided tert-butyl 8-bromo-6-((methylsulfonyloxy)methyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (340 mg, 94%) as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 7.59 (s, 1H), 7.44 (s, 1H), 5.47 (s, 2H), 4.52 (s, 2H), 3.83 (t, J=5.1 Hz, 2H), 3.02 (s, 3H), 2.88 (s, 2H), 1.51 (s, 9H).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:14]([F:25])[CH:13]=2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][C:37]([C:38]([NH2:40])=[O:39])=[CH:36][CH:35]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[F:25][C:14]1[CH:13]=[C:12]([NH:11][C:5]2[C:6]3[N:7]([CH:8]=[CH:9][N:10]=3)[C:2]([C:34]3[CH:42]=[CH:41][C:37]([C:38]([NH2:40])=[O:39])=[CH:36][CH:35]=3)=[CH:3][N:4]=2)[CH:17]=[CH:16][C:15]=1[N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1
Reactant: CC1(C)OB(c2ccc(C(N)=O)cc2)OC1(C)C
Reactant: CN1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cc2F)CC1
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: [Na+]
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(Nc3ncc(-c4ccc(C(N)=O)cc4)n4ccnc34)cc2F)CC1
Yield: 16.5 %

Procedure:
In the same way as described for Compound 178, step 4, using (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-[3-fluoro-4-(4-methyl-piperazin-1-yl)-phenyl]-amine (60.0 mg, 0.15 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (49.5 mg, 0.30 mmol), Pd(PPh3)4 (43.0 mg, 0.038 mmol) and 1.5 M Na2CO3 (0.80 mL, 1.20 mmol) in dioxane (3 mL). The crude material is purified by silica gel column chromatography eluting with 95:5 and 90:10 DCM:MeOH to afford the title compound (11 mg, 16%). LCMS: Rt 1.86 min (96%), m/z (ES+) 446 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.26 (3H, s), 2.52 (4H, m), 3.01 (4H, m), 7.05 (1H, t), 7.52 (1H, br s), 7.59 (1H, s), 7.75 (1H, s), 7.79-7.85 (3H, m), 8.04 (1H, s), 8.09-8.11 (3H, m), 8.15 (1H, br s), 9.86 (1H, s).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:3]1.[Cl:13][C:14]1[CH:23]=[C:22]([C:24](Cl)=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1>C(Cl)(Cl)Cl>[CH:7]1([N:4]2[CH2:5][CH2:6][CH:2]([NH:1][C:24]([C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:14]([Cl:13])[CH:23]=3)=[O:25])[CH2:3]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(Cl)c1cc(Cl)nc2ccccc12
Reactant: NC1CCN(C2CCCCC2)C1
Solvent: ClC(Cl)Cl
Product: O=C(NC1CCN(C2CCCCC2)C1)c1cc(Cl)nc2ccccc12

Procedure:
To 3.16 gm. (0.0195 mole) of 3-amino-1-cyclohexylpyrrolidine in 50 ml. of chloroform was added dropwise a solution of 3.5 gm. (0.015 mole) of 2-chloro-4-quinolinecarbonyl chloride in 50 ml. of chloroform. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate containing 10% isopropyl ether and dilute hydrochloric acid. The separated acid layer was made basic with dilute sodium hydroxide solution and extracted with chloroform. The chloroform solution was dried over sodium sulfate, concentrated and the residue recrystallized twice from isopropyl ether-ethyl acetate. The product (0.7 gm.; 13%) melted at 127°-219° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:18](OC)=[O:19].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[CH2:18][OH:19]
Reactant: COCCOCOc1c(C(=O)OC)ccc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COCCOCOc1c(CO)ccc2ccccc12

Procedure:
In an analogous manner to that described in Example 5 (b)-(c), from methyl 1-(2-methoxy-ethoxymethoxy)-naphthalene-2-carboxylate by reduction by means of lithium aluminium hydride there was obtained [1-(2-methoxy-ethoxymethoxy)-naphthalen-2-yl]-methanol, which was then converted into 2-chloromethyl-1-(2-methoxy-ethoxymethoxy)-naphthalene; MS: 280 (M)+.