Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14](B4OC(C)(C)C(C)(C)O4)=[CH:15][CH:16]=3)[CH2:11][N:10]([CH3:27])[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:29]1[N:34]=[N:33][C:32]([N:35]([CH3:43])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([C:29]4[N:34]=[N:33][C:32]([N:35]([CH3:43])[C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[CH:31][CH:30]=4)=[CH:15][CH:16]=3)[CH2:11][N:10]([CH3:27])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(Cl)nn1
Reactant: CN1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C(c2ccc(F)cc2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2cc(-c3ccc(N(C)C(=O)OC(C)(C)C)nn3)ccc2C(c2ccc(F)cc2)C1
Temperature: 85 °C
Yield: 89.8 %

Procedure:
To a mixture of 4-(4-fluorophenyl)-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (1.13 g, 3.08 mmol), and tert-butyl 6-chloropyridazin-3-yl(methyl)carbamate (751 mg, 3.08 mmol) in DMF (15 mL) and water (3 mL) was added cesium carbonate (4.01 g, 12.3 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg, 0.06 mmol). The reaction flask was evacuated and back filled with nitrogen. After heating the reaction mixture at 85° C. for 4 hours, it was cooled to ambient temperature then partitioned between ethyl acetate (300 mL) and water (150 mL). The organic layer was washed with water and brine then dried over sodium sulfate. Concentration in vacuo gave the crude material which was purified by flash column chromatography to give tert-butyl 6-(4-(4-fluorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridazin-3-yl(methyl)carbamate (1.24 g, 90%) as an orange/brown foam: 1H NMR (CDCl3, 500 MHz) δ 8.12 (d, J=9.5 Hz, 1H), 7.88 (d, J=1.5 Hz, 1H), 7.75-7.70 (m, 2H), 7.19 (dd, J=8.8 Hz, 5.0 Hz, 2H), 7.01-6.97 (m, 3H), 4.30 ((brs, 1H), 3.82 (d, J=14.5 Hz, 1H), 3.71 (d, J=14.5 Hz, 1H), 3.61 (s, 3H), 3.08-3.05 (m, 1H), 2.59 (dd, J=11.5 Hz, 8.0 Hz, 1H), 2.46 (s, 3H), 1.56 (s, 9H); ESI MS m/z 449 [M+H]+.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]([NH2:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].Br[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21].FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)/C=C/c1ccccc1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)c1coc(/C=C/c2ccccc2)n1
Temperature: 0 °C
Reaction time: 10 h

Procedure:
A mixture of (2E)-3-phenylprop-2-enamide (2.00 g, 13.6 mmol) and sodium bicarbonate (4.57 g, 54.4 mmol) in tetrahydrofuran (48 mL) was cooled to 0° C. Ethyl 3-bromo-2-oxopropanoate (3.16 mL, 25.2 mmol) was added drop-wise, and the reaction mixture was heated at reflux for 4 hours, whereupon it was filtered through diatomaceous earth and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (33 mL), cooled to 0° C., and treated drop-wise with trifluoroacetic anhydride (14.8 mL, 105 mmol). The reaction mixture was stirred at room temperature for 10 hours, then cooled to 0° C. and quenched via addition of saturated aqueous sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Chromatography on silica gel (Gradient: 0% to 30% ethyl acetate in heptane) provided partially purified product; this was crystallized from heptane/ethyl acetate to afford the product as pale yellow needles. Yield: 1.52 g, 6.25 mmol, 46%. LCMS m/z 244.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.63 (d, J=16.4 Hz, 1H), 7.51-7.56 (m, 2H), 7.34-7.43 (m, 3H), 6.97 (d, J=16.5 Hz, 1H), 4.42 (q, J=7.1 Hz, 2H), 1.41 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:31][CH3:32])[CH:3]=1.[CH:33](=O)[CH3:34].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:33][CH3:34])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:31][CH3:32])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCNCc2ccccc2)CC1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccccc1

Procedure:
4-Amino-N-((1-(4-benzylaminobutyl)piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide (0.5 g) as starting compound, acetaldehyde (0.07 ml) and sodium cyanoborohydride (0.15 g) were reacted and treated in the same manner as in Example 136 to give 0.35 g of 4-amino-5-chloro-N-((1-(4-(N-ethyl-N-benzylamino)butyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][CH:8]2[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][OH:32])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>ClCCl.B(F)(F)F.CCOCC>[OH:13][CH:8]([C:7]([O:32][CH2:31][CH2:30][C:24]1[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COc1ccc(CCO)cc1OC
Reactant: COC(=O)C1OC1(c1ccccc1)c1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C(O)C(OCCc1ccc(OC)c(OC)c1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
7 g (27.5 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate and 5.5 g (30.2 mmol) of 2-(3,4-dimethoxyphenyl)ethanol were dissolved in 20 ml of dichloromethane and, at room temperature, 5 drops of boron trifluoride etherate were added. The solution was stirred for 2 hours. The solvent was then distilled off, and the residue (10.7 g, 89%) was immediately reacted further.
Reaction SMILES: [Si:1]([O:8][CH:9]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)/[CH:10]=[CH:11]/[CH:12]1[CH2:19][CH2:18][CH:17]2[CH:13]1[CH2:14][CH2:15][C:16]2=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[CH3:35][O:36][C:37]([CH2:39][CH2:40][CH2:41][CH:42]=O)=[O:38].C(O)(=O)C>C(OCC)C.O>[Si:1]([O:8][CH:9]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)/[CH:10]=[CH:11]/[CH:12]1[CH2:19][CH2:18][CH:17]2[CH:13]1[CH2:14]/[C:15](=[CH:42]\[CH2:41][CH2:40][CH2:39][C:37]([O:36][CH3:35])=[O:38])/[C:16]2=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)CCCC=O
Reactant: CC(C)(C)[Si](C)(C)OC(/C=C/C1CCC2C(=O)CCC12)C1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)CCC/C=C1\CC2C(/C=C/C(O[Si](C)(C)C(C)(C)C)C3CCCCC3)CCC2C1=O
Temperature: -70 °C
Yield: 16.2 %

Procedure:
(E)-2-(3-tert-Butyldimethylsilyloxy-3-cyclohexylprop-1-enyl)bicyclo[3,3,0]octan-6-one (57 mg), prepared as described in Reference Example 14 and in the form of (±)-(E)-2β-(3α-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-enyl)bicyclo[3,3,0]octan-6-one, was dissolved in dry diethyl ether (0.6 ml). The solution was cooled to -70° C. under an atmosphere of argon and treated with a solution of lithium diisopropylamide in diethyl ether (0.132 ml; 1.3M) with stirring, and the mixture was stirred at -70° C. for 10 minutes. 4-Methoxycarbonylbutanal (29.6 mg) was then added to the mixture, which was stirred for a further period of 10 minutes at -70° C. The mixture was then treated with a solution of glacial acetic acid (0.05 ml) in diethyl ether (1 ml) and the mixture was allowed to warm to ambient temperature. Water and diethyl ether were added and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined diethyl ether and ethyl acetate solutions were washed with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The resulting residue was dissolved in dry benzene (0.6 ml). The solution was treated with methanesulphonyl chloride (0.015 ml) with stirring at the ambient temperature, and then with triethylamine (0.0255 ml), and was stirred for a further period of 2 hours. The mixture was then treated with 1,8-diazabicyclo[5,4,0]undec-7-ene (137 mg) and stirred for 16 hours at ambient temperature. The crude mixture was then subjected to medium pressure, short column chromatography on silica gel, eluting with a mixture of ethyl acetate and hexane (1:9 by volume), to give (E)-6-(3-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-enyl)-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one (12 mg), in the form of (±)-6β-[(E)-3α-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one, otherwise known as (±)-methyl (5E,13E)-(9S,15S)-6a-oxo-6,9-methano-15-tert-butyldimethylsilyloxy-15-cyclohexyl-16,17,18,19,20-pentanorprosta-5,13-dienoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:24])[C:5]([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH2:17])[CH2:12][CH2:11]3)[CH:7]=1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:36](O)=[O:37])[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30](=[O:31])[NH:32][C:33]1([C:36](=[O:37])[NH:17][C@@H:13]2[C:14]3[C:10](=[CH:9][C:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([F:24])[C:5]=4[C:18]4[N:22]=[C:21]([CH3:23])[O:20][N:19]=4)=[CH:16][CH:15]=3)[CH2:11][CH2:12]2)[CH2:34][CH2:35]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3N)no1
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(NC(=O)OC(C)(C)C)CC2)no1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], (S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-ylamine (intermediate A-11) was coupled with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid to yield the title compound as light yellow amorphous solid. MS: 527.2 (MH+, 1Cl).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(OC(N(C)C)=[N+](C)C)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2N=N1.NC1C=CC=CC=1.[C:32]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]([C:43]1[S:47][N:46]=[C:45]([CH3:48])[N:44]=1)[C:40](O)=[O:41])#[N:33].C(N(CC)CC)C>ClCCl>[C:12]1([NH:8][C:40](=[O:41])[CH:39]([C:43]2[S:47][N:46]=[C:45]([CH3:48])[N:44]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][C:32]#[N:33])[CH:11]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1nsc(C(CCCCCC#N)C(=O)O)n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nsc(C(CCCCCC#N)C(=O)Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a stirred mixture of O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.63 g, 1.64 mmol) and aniline (0.14 g, 1.5 mmol) in dichloromethane (10 mL) was added over 5 min the crude solution of 7-cyano-2-(3-methyl[1,2,4]thiadiazol-5-yl)heptanoic acid (2021052) and triethylamine. The resultant reaction mixture was then stirred at room temperature overnight before being quenched with citric acid (5 g) in water (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic fractions were dried (MgSO4) and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (3:1 hexane/ethyl acetate followed by 1:1 hexane/ethyl acetate) to afford 7-cyano-2-(3-methyl[1,2,4]thiadiazol-5-yl)heptanoic acid phenylamide (2021044) (440 mg, 73% over two steps) as a yellow oil.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([CH2:14][CH2:15][CH3:16])=[C:12]([CH2:17][CH2:18][CH3:19])[C:11]([CH2:20][CH2:21][CH3:22])=[C:6]([C:7](OC)=[O:8])[C:5]=1[C:23](OC)=[O:24])[CH2:2][CH3:3].C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].OS(O)(=O)=O>O>[OH:8][CH2:7][C:6]1[C:11]([CH2:20][CH2:21][CH3:22])=[C:12]([CH2:17][CH2:18][CH3:19])[C:13]([CH2:14][CH2:15][CH3:16])=[C:4]([CH2:1][CH2:2][CH3:3])[C:5]=1[CH2:23][OH:24]
Reactant: CCCc1c(CCC)c(CCC)c(C(=O)OC)c(C(=O)OC)c1CCC
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(CO)c(CO)c(CCC)c(CCC)c1CCC
Temperature: 25 °C
Yield: 83.2 %

Procedure:
Dimethyl 3,4,5,6-tetrapropylphthalate (5.22 g, 14.4 mmols) was added at 0° C. to a 50 ml THF solution of LiAlH4 (1.20 g, 31.7 mmols). After stirring at room temperature for an hour, water was added for hydrolysis. The mixture was treated with 2N H2SO4 followed by extraction with diethyl ether. Subsequently, the extract was washed with brine and dried over anhydrous magnesium sulfate. Column chromatography was performed using silica gel as the packing material to give the title compound (3.67 g) as a white solid. The isolation yield was 91%.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([Cl:15])[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1OB(O)O>>[Cl:15][C:4]1[CH:3]=[C:2]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[Cl:16])[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)COc1ccc(Br)cc1Cl
Reactant: OB(O)Oc1ccccc1Cl
Product: CCOC(=O)COc1ccc(-c2ccccc2Cl)cc1Cl

Procedure:
Prepared analogously to Example 130a from ethyl (4-bromo-2-chloro-phenoxy)-acetate (Z26) and 2-chlorophenylboric acid.
Reaction SMILES: [C:1]([O:4][C:5]([C:7]([F:21])([F:20])[C@@:8](C(=O)C)([C@@H:10]([CH:12]([C:14](=[O:16])[CH3:15])[OH:13])[OH:11])[OH:9])=[O:6])(=[O:3])[CH3:2].CC(C)([O-])C.[K+].C(O)(=O)C>O1CCCC1>[C:1]([O:4][C:5]([C:7]([F:20])([F:21])[C@@H:8]([C@@H:10]([CH:12]([C:14](=[O:16])[CH3:15])[OH:13])[OH:11])[OH:9])=[O:6])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(=O)C(F)(F)[C@@](O)(C(C)=O)[C@H](O)C(O)C(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)OC(=O)C(F)(F)[C@H](O)[C@H](O)C(O)C(C)=O
Temperature: -65 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
To a solution of 0.995 g (2.6 mmol) of 1-(acetoxy)-3,5-bis(acetyl)-2-deoxy-2,2-difluororibose in tetrahydrofuran (10ml) at -65° C. were added 5.1 ml of a 1M solution of potassium t-butoxide in tetrahydrofuran (5.1 mmol) dropwise over 10 minutes. The reaction mixture was stirred 3 hours at -65° C. and then 0.58 ml of glacial acetic acid (10.2 mmol) were added to quench the reaction. The reaction mixture was then allowed to warm to room temperature and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. Organics were dried with sodium sulfate and concentrated under reduced pressure. The residue was triturated with diethyl ether (10 ml) and the resulting solid was dried under reduced pressure at 40° C. to give 0.63 g of 1-(acetoxy)-5-(acetyl)-2-deoxy-2,2-difluororibose.
Reaction SMILES: [CH3:1][CH:2]([S:4][C:5]1[NH:6][C:7]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:9]=1)[CH3:3].ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)Cl>[CH3:3][CH:2]([S:4]([C:5]1[NH:6][C:7]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[N:9]=1)=[O:32])[CH3:1]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc(SC(C)C)[nH]c2-c2ccncc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)C(C)C)[nH]c2-c2ccncc2)cc1
Reaction time: 0.25 h

Procedure:
The 2-isopropylthioimidazole from Example 9 (11.1 g, 35 mmole) was suspended in 300 ml of methylene chloride and placed in an ice-bath. m-Chloroperbenzoic acid (7.5 g) was added in 100 ml. of methylene chloride over the period of 40 minutes. The solution was stirred for an additional 15 minutes and organic solution extracted with sodium bicarbonate (5%). The aqueous alkaline extract was discarded and the organic layer was dried and evaporated to give a semi-solid which was recrystallized from methylene chloride-ether yielding 7.5 g of a crystalline solid which was further purified by chromatography (alumina). The pure product was obtained from chloroform elution: 180°-181.5°.
Reaction SMILES: [CH2:1]([C:5]1[NH:9][C:8]([CH:10]=[O:11])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.C1C(=O)N([Br:24])C(=O)C1>>[Br:24][C:7]1[N:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[NH:9][C:8]=1[CH:10]=[O:11]
Reactant: CCCCc1ncc(C=O)[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCCCc1nc(Br)c(C=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
2-Butyl-3H-imidazole-4-carbaldehyde (30.0 g, 197 mmol) was dissolved in DMF (220 mL, 2.8 mol). NBS (36.8 g, 207 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was then concentrated and taken up in EtOAc and water. The aqueous layer was extracted three times with EtOAc, and the combined organic extracts washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated. The mixture was purified by silica gel chromatography (0-50% EtOAc:hexanes) to obtain 7.8 g of the title compound as a gray solid. MS m/z: [M+H+] calcd for C8H11BrN2O, 232.09. found 233.0. 1H-NMR (DMSO): 13.3 (1H, br), 9.48 (1H, s), 2.66 (2H, t), 1.59 (2H, m), 1.25 (2H, m), 0.85 (3H, t).
Reaction SMILES: CN1CCOCC1.[CH2:8]([O:15][C:16](=[O:31])[CH:17]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:19][C:20]([OH:22])=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN([C:35]([O:39][N:40]1N=NC2C=CC=N[C:41]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CNOC>CN(C)C=O>[CH2:8]([O:15][C:16](=[O:31])[CH:17]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:19][C:20](=[O:22])[N:40]([O:39][CH3:35])[CH3:41])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)NC(CCC(=O)O)C(=O)OCc1ccccc1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CON(C)C(=O)CCC(NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Yield: 100.6 %

Procedure:
4-Methylmorpholine (9.77 mL, 88.9 mmol) was added to a suspension of 2-tert-butoxycarbonylamino-pentanedioic acid 1-benzyl ester (6 g, 17.7 mmol), and HATU (8.11 g, 21.3 mmol) in dimethylformamide (20 mL). After 5 minutes N,O-dimethylhydroxylamine hydrochloride (2.60 g, 26.7 mmol), was added to the solution. After 1 hour the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (150 mL), and washed with water (100 mL), aqueous hydrogen chloride (0.5 N, 2×100 mL), saturated sodium bicarbonate (100 mL), and saturated sodium chloride (100 mL). The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography with eluent of ethyl acetate and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to yield 2-tert-butoxycarbonylamino-4-(methoxy-methyl-carbamoyl)-butyric acid benzyl ester (6.8 g, 17.8 mmol, 99%). C19H28N2O6 calculated 380.2 observed [M+1]+ 381.2; rt=2.48 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1.[F:31][C:32]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][C:33]=1[C:34](O)=[O:35]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:34](=[O:35])[C:33]2[CH:37]=[C:38]([C:41]([F:42])([F:43])[F:44])[CH:39]=[CH:40][C:32]=2[F:31])[CH:25]=1
Reactant: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(N)c2)c1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Product: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3cc(C(F)(F)F)ccc3F)c2)c1

Procedure:
In a manner similar to that described in Example 25, methyl 5-[N-({6-amino-5-[(3-aminophenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoate and 2-fluoro-5-(trifluoromethyl)benzoic acid were coupled to give the title compound as a white foam (74 mg).
Reaction SMILES: [CH3:1][C:2]1([C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])=[O:12])[CH2:6][CH2:5][CH:4]([C:7]([CH3:9])=[CH2:8])[C:3]1=[CH2:10]>[Pd]>[CH3:1][C:2]1([C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])=[O:12])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:8])[CH3:9])[CH:3]1[CH3:10]
Reactant: C=C(C)C1CCC(C)(C(=O)C2CCCC2=O)C1=C
Agent: [Pd]
Product: CC(C)C1CCC(C)(C(=O)C2CCCC2=O)C1C
Yield: 17.4 %

Procedure:
9.6 g of 2-[1-methyl-2-methylene-3-(prop-1-en-2-yl)-cyclopentylcarbonyl]-cyclopentanone are treated in 100 ml of absolute alcohol with 1 g of 5% palladium-on-carbon and the mixture is hydrogenated at normal pressure. After completion of the hydrogen uptake (8 hours), the mixture is filtered, the filtrate is concentrated and the residue is chromatographed on a hundred-fold amount of silica gel with toluene/ethyl acetate (1:2). There are obtained 1.7 g of 2-(1,2-dimethyl-3-isopropyl-cyclopentylcarbonyl)-cyclopentanone, which are contaminated with a small amount (<5%) of 2-(1,2-dimethyl-3-isopropyl-cyclopent-2-en-1-yl-carbonyl)-cyclopentanone or 2-(1,2-dimethyl-3-isopropylidenecyclopentyl carbonyl)-cyclopentanone.
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][N:15]([CH2:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=4)[C:23]([OH:25])=O)[C:14]3=[O:29])[CH:10]=[N:9]2)=[C:5]([CH3:30])[O:4][N:3]=1.[CH2:31]([N:33](CC)CC)C.C(Cl)CCl>C(#N)C.Cl>[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]([CH2:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=4)[C:23]([NH:33][CH3:31])=[O:25])[C:14]3=[O:29])[CH:10]=[N:9]2)=[C:5]([CH3:30])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(C(=O)O)c3)C2=O)cn1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCCl
Solvent: CC#N
Product: CNC(=O)c1cccc(CN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)c1
Yield: 24.7 %

Procedure:
3-((3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,4-dioxoimidazolidin-1-yl)methyl)benzoic acid (100 mg, 0.24 mmol) (example 10-8), methylamaine hydrochloride (67 mg, 1 mmol), triethylamine (155 mg, 1.5 mmol), and EDC (57 mg, 0.3 mmol) in acetonitrile (3 mL) were irradiated in the microwave reactor at 80° C. for 10 minutes. The reaction was cooled, diluted with aqueous 1N HCl (100 mL) and extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The crude product was dissolved in MeOH (3 mL) and purified by reversed phase HPLC (5 to 95% acetonitrile in H2O: 25 minute gradient) to afford 3-((3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,4-dioxoimidazolidin-1-yl)methyl)-N-methylbenzamide (25 mg, 25%) as white solid. MS M+H calculated 423.17; found 423.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.14 μM.