Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].[CH3:17][C:18]1([CH3:25])[C:22]([CH3:24])([CH3:23])[O:21][BH:20][O:19]1.C(N(CC)CC)C>C(Cl)Cl.[H-].[Cl-].C1([Zr+2]C2C=CC=C2)C=CC=C1>[CH3:17][C:18]1([CH3:25])[C:22]([CH3:24])([CH3:23])[O:21][B:20](/[CH:3]=[CH:2]/[CH2:1][CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)[O:19]1
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC1(C)OBOC1(C)C
Agent: C1=CC([Zr+2]C2C=CC=C2)C=C1
Agent: [Cl-]
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C/C=C/B2OC(C)(C)C(C)(C)O2)CC1
Temperature: 25 °C
Yield: 51.8 %

Procedure:
A solution of tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (0.162 g, 0.725 mmol) synthesized in Example B58, Step 1 in methylene chloride (1 mL) was added with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.139 g, 1.09 mmol) and triethylamine (0.00734 g, 0.0725 mmol), and the mixture was stirred at room temperature. The reaction mixture was added with bis(cyclopentadienyl)zirconium(IV) chloride hydride (0.0281 g, 0.109 mmol), and the mixture was stirred at room temperature for 40 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (E)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl]piperidine-1-carboxylate (0.132 g, 52%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[Br:17]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>CCCCCC>[Br:17][C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1
Reactant: c1ccc2c(c1)OCCO2
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCCCCC
Product: Brc1ccc2c(c1)OCCO2
Reaction time: 1 h

Procedure:
To a mixture of 1,4-benzodioxane (5.0 g) and sodium carbonate (5.9 g) in hexane (100 ml) was added dropwise at room temperature a solution of bromine (1.9 ml) in hexane (20 ml) for 1 hour and the mixture was stirred for 1 hour. To the mixture was added an aqueous solution of sodium thiosulfate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give orange oil of 6-bromo-2,3-dihydro-1,4-benzodioxine (7.48 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH2:11](O)[CH3:12].Cl>O1CCOCC1>[CH2:11]([O:9][C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=1)=[O:10])[CH3:12]
Reactant: CCO
Reactant: O=C(O)c1ccc(F)cn1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(F)cn1
Yield: 49.3 %

Procedure:
5-Fluoro-pyridine-2-carboxylic acid (200 mg, 1.13 mmol) was mixed with ethanol (6 mL) and 4 M HCl in dioxane (0.5 mL) at 90° C. for 20 h. The mixture was concentrated and mixed with saturated sodium carbonate and dichloromethane. The dichloromethane layer was washed with brine, dried to give 94 mg (49.3%) of 5-fluoro-pyridine-2-carboxylic acid ethyl ester.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)=[CH:2][CH3:3].C1(S([O-])=O)C=CC=CC=1.[Na+].Cl.C1(C)C=CC=CC=1>C1COCC1>[CH:1](/[CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[C:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)=[CH:2]\[CH3:3]
Reactant: CC=CC1CCC(c2ccc(C#Cc3ccc(C)cc3)cc2)CC1
Agent: Cl
Agent: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C/C=C/C1CCC(c2ccc(C#Cc3ccc(C)cc3)cc2)CC1
Reaction time: 4 h

Procedure:
26.0 g of 1-propenyl-4-(4-p-tolylethynylphenyl)cyclohexane from Example 9, 10.34 g of sodium benzenesulphinate, 100 ml of 2 N hydrochloric acid solution, 175 ml of toluene and 87 ml of THF were combined and heated to reflux. After 4 hours, the reaction mixture was allowed to cool, and the aqueous phase was removed. A further 10.34 g of sodium benzenesulphinate and 100 ml of 2 N hydrochloric acid solution were then added, and the mixture was refluxed for a further 2 hours, the aqueous phase was again removed after cooling, and a further 10.34 g of sodium benzenesulphinate and 100 ml of 2 N hydrochloric acid solution were added, the mixture was refluxed overnight, and subsequently subjected to conventional work-up, giving 1-E-propenyl-4-(4-p-tolylethynylphenyl)cyclohexane in the form of a colourless solid.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)[CH2:2][CH3:3].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[CH2:16][CH2:15][CH:14]([O:17][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)[CH2:2][CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCCOC1CCC(C2CCC(O)CC2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOC1CCC(C2CCC(OS(C)(=O)=O)CC2)CC1
Reaction time: 3 h

Procedure:
To a solution of 4′-propoxybicyclohexyl-4-ol (1 g) and triethylamine (0.81 ml) in dichloromethane (10 ml) was added dropwise methanesulfonyl chloride (0.39 ml) at 0-5° C., and stirred for 3 hours. The reaction mixture was washed with water and brine, and dried, and evaporated under reduced pressure to give 4′-propoxy-4-methylsulfonyloxy-1,1′-bicyclohexane (1.44 g).
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.O[CH:10]1[C:16]([OH:40])([C:17]2[S:18][C:19]([C:22]3[CH:27]=[C:26]([NH:28][C:29]4[N:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=4)[CH:25]=[C:24]([CH3:39])[CH:23]=3)=[CH:20][N:21]=2)[CH2:15][CH2:14][NH:13][C:12](=[O:41])[CH2:11]1>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[OH:40][C:16]1([C:17]2[S:18][C:19]([C:22]3[CH:27]=[C:26]([NH:28][C:29]4[N:34]=[C:33]([C:35]([F:36])([F:38])[F:37])[CH:32]=[CH:31][N:30]=4)[CH:25]=[C:24]([CH3:39])[CH:23]=3)=[CH:20][N:21]=2)[CH:15]([OH:5])[CH2:14][NH:13][C:12](=[O:41])[CH2:11][CH2:10]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCNC(=O)CC3O)s2)c1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCC(=O)NCC3O)s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
The 70:30 mixture of products from Step 1 (100 mg, 0.22 mmol) was dissolved in acetone (1 mL) and water (125 μL). Osmium tetroxide (4% in H2O, 548 μL, 0.09 mmol) and 4-methylmorpholine N-oxide (105 mg, 0.90 mmol) were added and the suspension was stirred for 1 h at room temperature. The reaction was quenched with 5% aqueous sodium thiosulfate and stirred for 15 minutes. The mixture was washed with ethyl acetate (3×), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a mixture of 4,5-dihydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2-one and 5,6-dihydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2-one (70:30, 40 mg, 0.084 mmol 37% yield) as a brownish-yellow solid. MS ESI: [M+H]+ m/z 480.1. 1H NMR (600 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.80 (d, J=4.9, 1H), 7.93 (s, 1H), 7.90 (s, 1H), 7.53-7.36 (m, 2H), 7.23 (d, J=4.9, 1H), 7.11 (s, 1H), 5.92 (s, 1H), 5.86 (s, 1H), 5.12-5.01 (m, 1H), 4.04-3.99 (m, 1H), 3.58-3.36 (m, 1H), 3.19-3.09 (m, 1H), 2.96-2.75 (m, 1H), 2.30 (s, 3H), 2.04-1.82 (m, 2H) rhSYK activity=+++
Reaction SMILES: ClC1C=CC(C2NC(C3C=CC([O:19]C)=CC=3OCC)=NC2CC)=CC=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[N:37]([C:38]([N:40]3[CH2:45][CH2:44][N:43](C)[CH2:42][CH2:41]3)=[O:39])[C:36]([C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=3[O:55][CH2:56][CH3:57])=[N:35][CH:34]2[CH2:58][CH:59]2CCCC2)=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([CH:33]2[N:37]([C:38]([N:40]3[CH2:41][CH2:42][NH:43][C:44](=[O:19])[CH2:45]3)=[O:39])[C:36]([C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=3[O:55][CH2:56][CH3:57])=[N:35][CH:34]2[CH2:58][CH3:59])=[CH:31][CH:32]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC)C(c2ccc(Cl)cc2)N1
Product: CCOc1cc(OC)ccc1C1=NC(CC)C(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
4-[5-(4-Chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-ethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one was prepared from 5-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-ethyl-4,5-dihydro-1H-imidazole (Example 20) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 485.1959, calculated for C25H30N4O3Cl [(M+H)+]485.1950.
Reaction SMILES: [C:1]([C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:13])[CH2:10][CH:11]=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[Na]>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:11][CH2:10][C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH2:30][CH2:29]1
Reactant: CC(CC=O)(C(=O)c1ccccc1)c1ccccc1
Reactant: COc1ccccc1N1CCNCC1
Agent: [Na]
Product: COc1ccccc1N1CCN(CCC(C)(C(=O)c2ccccc2)c2ccccc2)CC1
Yield: 23.4 %

Procedure:
Following the procedures described in the Example 1, Step C, the reaction of 3-benzoyl-3-phenylbutyraldehyde (0.32 g) and 1-(2-methoxyphenyl)piperazine (0.23 g) with sodium triacetoxyboranehydride (0.33 g) gave pure product 1-(2-methoxyphenyl)-4-[3-(benzoyl)-3-(phenyl)butyl]piperazine (0.12 g). The oxalate salt was prepared as described above.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([NH2:20])[CH2:16][CH2:15]3)=[O:13])[C:6]=2[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][N:17]([NH:20][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:18][CH2:19]3)=[O:13])[C:6]=2[CH:21]=1
Reactant: NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 33.7 %

Procedure:
A mixture of 5-chloro-3-[(4-amino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone (0.85 g), anhydrous potassium carbonate (430 mg), dichloromethane (40 ml), dioxane (10 ml) and ethyl chloroformate (339 mg) was stirred for 1.5 hours at room temperature. The insoluble materials were filtered off and the filtrate was concentrated under reduced pressure. The residue was recrystallized from a mixture of chloroform and dioxane to give colorless crystals of 5-chloro-3-[(4-ethoxycarbonylamino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone (0.35 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH2:6][CH:7]([NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([CH:21]3[CH2:23][CH2:22]3)[N:19]=2)[N:14](COCC[Si](C)(C)C)[CH:13]=1)=[O:11])[CH3:8])=[O:5])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([NH:3][C:4]([CH2:6][CH:7]([NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([CH:21]3[CH2:22][CH2:23]3)[N:19]=2)[NH:14][CH:13]=1)=[O:11])[CH3:8])=[O:5])[CH3:2]
Reactant: CCNC(=O)CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(C3CC3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)CC(C)NC(=O)c1c[nH]c2ncc(C3CC3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.2 %

Procedure:
To a solution of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-ethylcarbamoyl-1-methyl-ethyl)-amide (0.114 g, 0.25 mmol) in CH2Cl2 (8 mL) was added trifluoroacetic acid (1.0 mL). The reaction mixture was stirred at room temperature overnight then concentrated. The residue was dissolved in MeOH (7 mL) and H2O (0.5 mL) and Et3N (1 mL) were added. The reaction mixture was stirred at room temperature overnight then concentrated. The residue was purified by SiO2 chromatography (4% MeOH/CH2Cl2) to afford 0.012 g (16%) of 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-ethylcarbamoyl-1-methyl-ethyl)-amide as a white solid. MS: (M+H)+=316; mp=182.0-184.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[CH:17][C:10]=12)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([S:22]([CH3:21])(=[O:24])=[O:23])[CH:16]=[CH:17][C:10]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCc1ccnc2[nH]ccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccnc2c1ccn2S(C)(=O)=O
Reaction time: 0.25 h

Procedure:
To a stirred solution of (1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-carbamic acid tert-butyl ester (400 mg, 1.62 mmol) in DMF (10.0 mL) was added powdered KOH (143 mg, 1.88 mmol). After 15 minutes, methanesulfonyl chloride (137 μL, 1.78 mmol) was added. After 15 hours, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (25 mL), dried over magesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-50% ethyl acetate in heptane to afford (1-methanesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [N:1]1([CH:6]2[CH2:9][N:8]([CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:20]>C(OCC)C.O1CCOCC1>[ClH:20].[ClH:20].[N:1]1([CH:6]2[CH2:9][N:8]([CH2:10][CH2:11][NH2:12])[CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)NCCN1CC(N2CCCC2)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NCCN1CC(N2CCCC2)C1

Procedure:
460 mg of tert-butyl {2-[3-(pyrrolidin-1-yl)azetidin-1-yl]ethyl}carbamate (Example 220A, 1.7 mmol, 1 equivalent) were initially charged in 8.54 ml of 2 N hydrochloric acid in diethyl ether and 1 ml of dioxane, and the mixture was stirred at RT overnight. The precipitated solid was filtered off, washed with diethyl ether and dried under reduced pressure. This gave 390 mg (94% of theory) of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.Cl.[CH3:15][NH:16][OH:17]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N+:16]([O-:17])[CH3:15])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: CNO
Reactant: O=C(Cn1ccnc1)c1cccs1
Agent: Cl
Product: C[N+]([O-])=C(Cn1ccnc1)c1cccs1

Procedure:
As illustrated in the following diagram, the thienyl compounds of this invention can be prepared by an initial bromination of 2-acetylthiophene 1, and reacting the resulting bromo derivative 2 with imidazole to produce the 1-(2-thienyl)-2-(1H-imidazol-1-yl)ethanone 3. Reaction of compound 3 with N-methylhyroxylamine hydrochloride provides the 1-(2-thienyl)-2-(1H-imidazol-1-yl)-N-methylethanimine N-oxide 4 which is included in the subject matter of our co-pending application Ser. No. 900,856 filed Aug. 27, 1986 entitled "α-Substituted Ketonitrone Derivatives" whose disclosure is incorporated herein by reference. The nitrone compound 4 is then treated with styrene or an appropriate styrene (or allyl phenyl ether or alkyl phenyl thioether) derivative 5 to give a diastereomeric mixture of the desired cis- and trans-5-(phenyl, phenoxymethyl or phenylthiomethyl)-3-(2-thienyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine 6. ##STR3##
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[CH:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29](O)=[O:30])([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([O:34][CH3:35])[N:4]=1.[CH:36]1([S:39]([NH2:42])(=[O:41])=[O:40])[CH2:38][CH2:37]1.CCN=C=NCCCN(C)C.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[CH:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29]([NH:42][S:39]([CH:36]5[CH2:38][CH2:37]5)(=[O:41])=[O:40])=[O:30])([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([O:34][CH3:35])[N:4]=1
Reactant: COc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)nc(OC)n1
Reactant: NS(=O)(=O)C1CC1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)nc(OC)n1
Yield: 52.1 %

Procedure:
The acid 18g (1.2 g, 2 mmol) was reacted with cyclopropane sulfonamide (73 mg, 0.6 mmol), EDAC (115 mg, 0.6 mmol) and DBU (215 mg, 1.4 mmol) in dry DCM (3 ml) according to the procedure described in Example 13 step f. Purification by column chromatography on silica gel eluted with diethyl ether-ethyl acetate gave the title compound, (185 mg, 70%), (M+H)+592.
Reaction SMILES: [CH3:1][C@@:2]12[C:11]3[C:12]([S:18]([C:21]4[C:26]([CH:27]([CH3:29])[CH3:28])=[CH:25][C:24]([CH:30]([CH3:32])[CH3:31])=[CH:23][C:22]=4[CH:33]([CH3:35])[CH3:34])(=[O:20])=[O:19])=[CH:13][CH:14]=[C:15]4[NH:16][CH:17]=[C:9]([C:10]=34)[CH2:8][C@H:3]1[NH:4][CH2:5][CH2:6][O:7]2.C(=O)([O-])[O-].[Na+].[Na+].[Cl:42][CH2:43][C:44](Cl)=[O:45]>C(OCC)(=O)C>[Cl:42][CH2:43][C:44]([N:4]1[C@@H:3]2[CH2:8][C:9]3[C:10]4[C:15]([NH:16][CH:17]=3)=[CH:14][CH:13]=[C:12]([S:18]([C:21]3[C:22]([CH:33]([CH3:35])[CH3:34])=[CH:23][C:24]([CH:30]([CH3:32])[CH3:31])=[CH:25][C:26]=3[CH:27]([CH3:29])[CH3:28])(=[O:20])=[O:19])[C:11]=4[C@@:2]2([CH3:1])[O:7][CH2:6][CH2:5]1)=[O:45]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)c2ccc3[nH]cc4c3c2[C@@]2(C)OCCN[C@@H]2C4)c(C(C)C)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)c2ccc3[nH]cc4c3c2[C@@]2(C)OCCN(C(=O)CCl)[C@@H]2C4)c(C(C)C)c1
Yield: 89 %

Procedure:
To a solution of trans-4,6,6a,8,9,10a-hexahydro-10a-methyl-1-(2,4,6-triisopropylphenylsulfonyl)-7H-indolo[3,4-gh][1.4]benzoxazine (106 mg, 0.21 mmol) in ethyl acetate (10 ml) was added a saturated aqueous solution of sodium carbonate (2 ml). To the mixture was added, while stirring vigorously, chloroacetyl chloride (1.2 equivalent). After completion of the reaction, the organic layer was separated, washed with an aqueous saline solution and dried (anhydrous Na2SO4). The solvent was distilled off under reduced pressure, and the residue was subjected to a silica gel column chromatography, eluting with n-hexane-ethyl acetate (4:1) to afford 109 mg (89%) of the title compound as an amorphous crystalline product.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.Cl[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)=[O:15].C(N(C(C)C)CC)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[O:6]=[C:4]1[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1](=[O:11])[N:5]1[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CN2C(=O)c3ccccc3C2=O)CC1
Yield: 66.5 %

Procedure:
Phthalimide (33 mg, 0.23 mmol) was treated with tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate (80.5 mg, 0.32 mmol), tetrabutylammonium iodide (TBAI, 84 mg, 2.3 mmol), diisopropylethylamine (DIEA, 0.20 mg, 1.14 mmol) in anhydrous CH2Cl2 (10 mL) for 24 h at 40° C. The mixture was partitioned between CH2Cl2 and water. The organic phase was separated, dried over MgSO4, filtered, concentrated, and purified by flash chromatography on a silica gel column with elution of EtOAc/hexane (1:1) to give the title compound (57.1 mg, 67% yield). C19H23N3O5; white solid; TLC (EtOAc/hexane=1:1) Rf=0.2; 1H NMR (400 MHz, CDCl3) δ 7.85-7.87 (2H, m), 7.70-7.72 (2H, m), 4.49 (2H, s), 3.51-3.57 (6H, m), 3.44 (2H, d, J=5.2 Hz), 1.46 (9H, d, J=4.8 Hz).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Na][Na].Cl.[C:26]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:17]1([CH2:16][C@@H:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:35]3[CH2:36][CH2:37][CH:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:33][CH2:34]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[C:13]([OH:15])=[O:14])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccc(F)cc1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cl
Agent: [Na][Na]
Product: O=C(O)[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1

Procedure:
In a manner similar to Example 3(b), (R)-2-(4-fluoro-benzenesulfonylamino)-3-phenyl-propionic acid, disodium salt was condensed with 4-phenyl-piperidine hydrochloride to give the title compound, mp=168-170° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][CH2:22][C:23](=[O:26])[CH2:24]Br)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=[O:29])C.[K+].Cl.C(Cl)Cl>C(O)(=O)C>[CH2:1]([N:8]([CH2:21][CH2:22][C:23](=[O:26])[CH2:24][OH:29])[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)CCN(Cc1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(CO)CCN(Cc1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 112.5 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
A mixture of N-benzyl-N-(4-bromo-3-oxobutyl)-2-nitrobenzenesulfonamide (16 g, 36.3 mmol) and potassium acetate (8.90 g, 91 mmol) in acetic acid (130 ml) was heated to 110-115° C. (slow reflux visible) and stirred for 1 hour (complete by HPLC). Cooled, acetic acid (80 ml) removed under reduced pressure, the residue distributed between DCM (120 ml) and water (120 ml). The organic phase was washed with water, evaporated to half of the volume, diluted with 2-propanol (65.0 ml), the rest of DCM removed. Water (18.20 ml) was added followed by concentrated hydrochloric acid (2.102 ml, 25.4 mmol), residual DCM was distilled off at atmospheric pressure until head temperature reached 77° C., then stirred under reflux for 3 hours. Diluted with water (65 ml), 2-propanol removed at 60° C./180 mbar, to the biphasic residue EA (80 ml) was added followed by sodium bicarbonate with stirring until evolution of gas stopped. The organic phase was dried (MgSO4), evaporated to dryness to give N-benzyl-N-(4-hydroxy-3-oxobutyl)-2-nitrobenzenesulfonamide (13.2 g, 34.9 mmol, 96% yield).
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.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30]>>[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]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:30])([F:31])[F:32])[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3ccccc3C(F)(F)F)C2=O)cn1
Yield: 37 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 1-(bromomethyl)-2-(trifluoromethyl)benzene. Yield: 37%. MS M+H calculated 434.1; found 434.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.2 uM.