Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](Cl)(C)C.[C:6]1(=[O:13])[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[CH2:7]1.[CH:14]([C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1)=O.[F:24][C:25]([F:37])([F:36])[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]([NH2:35])=[O:34])[CH:27]=1>CN(C)C=O.C(#N)C.O>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([CH:14]([C:7]2[C:8](=[O:12])[CH2:9][CH2:10][CH2:11][C:6]=2[OH:13])[NH:35][C:33]([NH:32][C:28]2[CH:27]=[C:26]([C:25]([F:36])([F:24])[F:37])[CH:31]=[CH:30][N:29]=2)=[O:34])=[CH:17][CH:18]=1)#[N:21]
Reactant: NC(=O)Nc1cc(C(F)(F)F)ccn1
Reactant: O=C1CCCC(=O)C1
Reactant: N#Cc1ccc(C=O)cc1
Agent: C[Si](C)(C)Cl
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(NC(=O)Nc2cc(C(F)(F)F)ccn2)C2=C(O)CCCC2=O)cc1
Temperature: 50 °C

Procedure:
Trimethylsilyl chloride (125 μL, 0.982 mmol) is added to a solution of cyclohexane-1,3-dione (100 mg, 0.892 mmol), 4-formylbenzonitrile (117 mg, 0.892 mmol) and 1-(4-(tri-fluoromethyl)pyridin-2-yl)urea (183 mg, 0.892 mmol) in a mixture of N,N-dimethylformamide (670 μL) and acetonitrile (1.2 mL), and the mixture is heated at 50° C. for 1 h. The reaction mixture is cooled to room temperature and poured into a mixture of water and ice. The mixture is filtered, and the precipitate is washed with water and dried under reduced pressure. Yield: 293 mg; ESI mass spectrum [M+H]+=431, Retention time HPLC: 0.63 min (V011_S01).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[O-:11]CC.[K+].[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)=O.Cl>CCOCC>[CH2:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([CH:16]([CH:15]=[O:11])[C:2](=[O:4])[C:1]([O:8][CH2:9][CH3:10])=[O:7])=[CH:19][CH:20]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Product: CCOC(=O)C(=O)C(C=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
Diethyl oxalate (17.7 g) is added in one portion to a stirred suspension of potassium ethoxide (10.2 g) in anhydrous ether (1000 mL). The stirred mixture is cooled to 0° C., treated with 4-benzyloxyacetophenone (25 g) portionwise, and stirring continued for 3 hours. After standing at room temperature for 18 hours the reaction mixture is poured onto 1 N hydrochloric acid (500 mL) and the organic phase separated. The organic phase is washed with water, dried over magnesium sulphate and evaporated to give ethyl 4-benzyloxypheyl-2,4-dioxobutanoate (35 g).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:25](Cl)[C:26]#[CH:27]>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:27][C:26]#[CH:25])[N:13]=2)=[CH:23][CH:22]=1
Reactant: C#CCCl
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: C#CCn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Yield: 24.5 %

Procedure:
The title compound (0.014 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 2-propynyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C16H16ClN3, 285.10; found, m/z 286.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.38-7.32 (m, 4H), 7.13 (t, J=6.4 Hz, 1H), 5.48 (d, J=6.4 Hz, 2H), 2.93-2.91 (m, 4H), 2.84-2.81 (m, 2H), 2.68-2.65 (m, 2H).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([CH:7]([NH:15][CH3:16])[CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1.[Cl:23][C:24]1[C:25]([Cl:38])=[CH:26][C:27]2[O:32][CH2:31][CH2:30][N:29]([CH2:33][C:34]([OH:36])=O)[C:28]=2[CH:37]=1.CN([P+]([O:49]N1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:2]=[CH:3][C:4]([CH:7]([N:15]([CH3:16])[C:34](=[O:36])[CH2:33][N:29]2[C:28]3[CH:37]=[C:24]([Cl:23])[C:25]([Cl:38])=[CH:26][C:27]=3[O:32][CH2:31][C:30]2=[O:49])[CH2:8][N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:5][CH:6]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)CN1CCOc2cc(Cl)c(Cl)cc21
Reactant: CNC(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Yield: 59.3 %

Procedure:
To a solution of [1-(4-biphenylyl)-2-(4-morpholinyl)ethyl]methylamine (3.67 g, 12.4 mmol) and (6,7-dichloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetic acid (3.42 g, 12.4 mmol) in DMF (50 mL) was added BOP Reagent (8.23 g, 18.6 mmol) followed by triethylamine (3.76 g, 37.2 mmol). The resultant mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure, diluted with ethyl acetate (150 mL), and extracted with 5% NaHCO3 (100 mL) and brine (100 mL). The organic layer was dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (330 g redisep column, silica 40 um, 60 A, 100 ml/min, A: MeOH, B: CH2Cl2, A: 1% for 30 min) to give 4.08 g (59%) of title compound as a white solid. MS (ES) m/e 554.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:13](=[O:14])[CH2:12][CH2:11][C:10]2=[O:15])=[C:4]([CH3:16])[CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].IC>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH3:16])[C:5]([C:9]2[C:13](=[O:14])[CH2:12][CH2:11][C:10]=2[O:15][CH3:17])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(F)cc(C)c1C1C(=O)CCC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COC1=C(c2c(C)cc(F)cc2C)C(=O)CC1
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
To a solution of 2-(4-fluoro-2,6-dimethylphenyl)-cyclopentane-1,3-dione (2.9 g, 13.3 mmol) in tetrahydrofuran (290 ml) is added anhydrous potassium carbonate (22 g, 159 mmol) and iodomethane (22.6 g, 159 mmol. The resulting mixture is stirred at 25-30° C. for 16 hours. The organic layer is evaporated, reaction mixture is quenched with water (150 ml) and extracted with ethylacetate (3×100 ml). The combined organic extracts are combined, washed with water and brine, dried over anhydrous sodium sulphate, filtered and the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel to give 2-(4-fluoro-2,6-dimethylphenyl)-3-methoxy-cyclopent-2-enone (2 g).
Reaction SMILES: C([C:3]([CH2:10][CH3:11])([CH2:8][CH3:9])[C:4]([O-:7])([O-:6])[O-])C.[CH2:12]([C:16]1C=CC=CC=1C(O)=O)[CH:13]([CH3:15])[CH3:14].[C:25]1(C)C=CC=C[CH:26]=1>>[CH2:12]([C:16]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH2:25][CH3:26])=[O:7])=[CH:10][CH:11]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: Cc1ccccc1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: CC(C)Cc1ccccc1C(=O)O
Product: CCOC(=O)c1ccc(CC(C)C)cc1
Temperature: 115 °C
Reaction time: 24 h
Yield: 97 %

Procedure:
Triethylorthoacetate (15.4 mL, 84.2 mmol) was added slowly to a solution of isobutyl benzoic acid (5.0 g, 28.1 mmol) and toluene (60 mL) at room temperature. The resulting heterogeneous solution was heated to 115° C. and stirred for 24 hours. The reaction mixture was cooled to room temperature and quenched with 1N HCl (60 mL). The organic layer was separated, washed with saturated NaHCO3 (1×30 mL) and brine (1×30 mL), dried (MgSO4), filtered and concentrated in vacuo to obtain the title compound (5.59 g, 97% yield) as a clear oil.
Reaction SMILES: [CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH2:20])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>ClCCCl.CO>[CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH:20][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Reactant: COc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CN[C@H]2CC[C@@H](C(c3ccccc3)c3ccccc3)OC2)cc1
Yield: 78.3 %

Procedure:
Trans-5-amino-2-diphenylmethyl-tetrahydropyran 15 (0.15 g, 0.56 mmol) was reacted with 4-methoxybenzaldehyde (0.078 g, 0.56 mmol) in the presence of glacial acetic acid (0.033 g, 0.56 mmol) in 1,2-dichloroethane (20 ml), and NaCNBH3 (0.042 g, 0.67 mmol) in methanol (5 ml) (Procedure D) to give compound 16e (0.17 g, 78%) as an oil.
Reaction SMILES: [C:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14])#[C:2][CH3:3].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.[CH2:36]=O>O1CCOCC1.S([O-])([O-])(=O)=O.[Cu+2]>[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[N:30]2[CH2:31][CH2:32][N:33]([CH2:36][C:3]#[C:2][CH2:1][N:4]3[C:12](=[O:13])[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]3=[O:14])[CH2:34][CH2:35]2)=[CH:20][CH:21]=1
Reactant: C=O
Reactant: CC#CN1C(=O)c2ccccc2C1=O
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1CC#CCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
15 g (81 mmol) 2-propinyl-isoindolin-1,3-dione, 15 g (52 mmol) [bis-(4-fluorophenyl)-methyl]-piperazine, 2:5 g (81 mmol) paraformaldehyde and 0,2 g copper sulfate are stirred for three hours in 200 ml dioxane at 100° C. The cool solution is concentrated under vacuum and the residue is distributed between acetic acid ethyl ester and saturated NaCl solution. The organic phase is dried over sodium sulfate and concentrated under vacuum until dry. The residue is chromatographically purified over silica gel with acetic acid ethyl ester/petroleum ether (1/1): Yield 23.4 g (93%) yellow amorphous solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[NH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:10][O:9][C:7]([C:4]1[S:3][C:2]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][NH2:11])[CH2:15][CH2:16]2)=[N:6][CH:5]=1)=[O:8]
Reactant: COC(=O)c1cnc(Br)s1
Reactant: NCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cnc(N2CCN(CCN)CC2)s1
Temperature: 80 °C
Yield: 65.1 %

Procedure:
To a solution of methyl 2-bromothiazole-5-carboxylate 1 (222 mg, 1.00 mmol) in acetonitrile (20 mL) were added N-(2-amino ethyl)piperazine 14d (155 mg, 1.20 mmol) and potassium carbonate (152 mg, 1.10 mmol) under a N2 atmosphere. The reaction mixture was heated to reflux at 80° C. for 10 h. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 15d (176 mg, 65.2%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[CH3:10][CH2:11][O:12][C:13]([CH:15]([C:19]([CH3:21])=O)[C:16]([CH3:18])=O)=[O:14]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:19]([CH3:21])=[C:15]([C:13]([O:12][CH2:11][CH3:10])=[O:14])[C:16]([CH3:18])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: NNc1ccc(F)cc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2ccc(F)cc2)c1C
Yield: 96.2 %

Procedure:
4-Fluorophenylhydrazine (7.75 g) and ethyl diacetoacetate (10.6 g) were added to ethanol (30 ml) and the mixture was refluxed for 3 h. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-diisopropyl ether to give ethyl 1-(4-fluorophenyl)-3,5-dimethylpyrazole-4-carboxylate (15.5 g), melting point: 59–60° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8](CC#N)=[C:7]([CH3:15])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[OH-:17].[Na+].[CH2:19]([OH:22])[CH2:20]O>O>[C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:20][C:19]([OH:22])=[O:17])=[C:7]([CH3:15])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CC#N
Reactant: OCCO
Agent: [Na+]
Solvent: O
Product: Cc1cc(C(C)(C)C)c(O)c(C)c1CC(=O)O
Temperature: 50 °C

Procedure:
65.1 grams of the compound of Example 3 was added with stirring to a solution of 36 grams of sodium hydroxide in 40 ml of ethylene glycol and 66 ml of water. The reaction mixture became homogeneous at about 116° to 117° and was heated at this temperature for two hours. The reaction mixture was cooled by the addition of chopped ice and cold water to the reaction mixture to make a total volume of one liter. After clarifying the reaction mixture by filtration, the filtrate was made acid with concentrated aqueous hydrochloric acid, yielding a white precipitate, which was filtered, washed with cold water and dried. The product was then treated with rapid stirring at 50° C. with about 800 ml of 6% sodium bicarbonate solution until carbon dioxide evolution stopped. The turbid solution was filtered free of a white solid-by-product. (A). The clarified filtrate was made acid with concentrated hydrochloric acid while cooling, and the resulting white precipitate filtered. After washing with hot water and drying the product was obtained as a white powder melting at 161° to 165°.
Reaction SMILES: Br[C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:17]2[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH:18]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[F:8][C:3]1[C:2]([C:17]2[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH:18]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Fc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)N1CC=C(c2cccnc2F)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 20.5 %

Procedure:
To a round-bottomed flask was added 3-bromo-2-fluoropyridine (0.54 g, 3.1 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone (0.96 g, 3.8 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (0.17 g, 0.25 mmol), and sodium carbonate (0.97 g, 9.2 mmol) in DME (7.5 mL) and Water (2.5 mL). The reaction mixture was stirred at 100° C. for 16 h. After cooling to RT, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3×50 mL). The organic extract was washed with water, brine, dried with Na2SO4, filtered, and concentrated. The crude product was chromatographed through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 10% to 100% EtOAc in hexane, to provide 1-(4-(2-fluoropyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone (0.14 g, 21% yield) as a yellow oil. MS (ESI, pos. ion) m/z: 221.0 (M+1).
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH:11]([Cl:13])[CH3:12])=[O:9].[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])(=[O:17])[CH:15]=[CH2:16]>ClCCl>[C:8](=[O:9])([O:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:14](=[O:17])[CH:15]=[CH2:16])[O:10][CH:11]([Cl:13])[CH3:12]
Reactant: CC(Cl)OC(=O)Cl
Reactant: C=CC(=O)OCCCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC(=O)OCCCCOC(=O)OC(C)Cl
Reaction time: 0.25 h
Yield: 90.2 %

Procedure:
Pyridine (0.89 ml, 11.00 mmol) is added dropwise to a solution of 1-chloroethyl chloroformate (1.20 ml, 11.00 mmol) and 4-hydroxybutyl acrylate (1.38 ml, 10.00 mmol) in dichloromethane (12 ml) at 3° C. under a dry N2 atmosphere. After 15 min. at 3° C. and 17 hours at 20° C. the reaction mixture is transferred to a separating funnel with the aid of dichloromethane (10 ml). The reaction mixture is washed with hydrochloric acid (1.00M, 10 ml), saturated aqueous sodium hydrogen carbonate (10 ml) and water (2×10 ml). The organic phase is dried (MgSO4) and the solvent evaporated under reduced pressure to give 2.26 g (90%) of the title product. 1H NMR (60 MHz, CDCl3): δ 1.80 (4 H, m, CH2 --CH2), 1.86 (3 H, d, J=5 Hz, CH3), 4.24 (4 H, m, 2×CH2 --O), 5.7-6.6 (4 H, m, CH=CH2 and CH).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[I:15])=[CH:5][CH:4]=1.[CH2:16]([C:20]1[NH:21][C:22]([CH:26]=[O:27])=[C:23]([Cl:25])[N:24]=1)[CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:16]([C:20]1[N:21]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[I:15])=[CH:5][CH:4]=2)[C:22]([CH:26]=[O:27])=[C:23]([Cl:25])[N:24]=1)[CH2:17][CH2:18][CH3:19]
Reactant: BrCc1ccc(-c2ccccc2I)cc1
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2I)cc1
Reaction time: 24 h

Procedure:
A solution of 4-(bromomethyl)-2'-iodobiphenyl (9.23 g; preparable as described in Example 2(b)) in dry dimethylformamide (50 ml) was added to a stirring mixture of 2-butyl-4-chloro-1H-imidazole-5-carboxaldehyde (preparable as described in Drugs of the Future (1991), Vol. 16, p 305), anhydrous potassium carbonate (6.9 g) and dry dimethylformamide (100 ml), at ambient temperature. Stirring was continued at ambient temperature for 24 hours. Water (200 ml) was added and the resulting mixture was extracted with diethyl ether (500 ml then 200 ml). The combined extracts were washed with water (2×100 ml) and dried over magnesium sulphate. The organic solvent was evaporated and the residual orange oil was purified by flash chromatography on silica gel (eluting with 5% then 30% ethyl acetate in petroleum ether (b.p. 60°-80° C.)) to give the intermediate compound 2-butyl-4-chloro-1-(2'-iodobiphenyl-4-ylmethyl)-1H-imidazol-5-carboxaldehyde as a yellow oil (8.06 g).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([NH:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH2:9][C:10]1[CH:22]=[CH:21][C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18](O)=[O:19])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:40](C(C)C)CC)(C)C.CN(C(O[N:54]1N=NC2[CH:57]=[CH:58][CH:59]=[N:60][C:55]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1.N1CCCN=C1N>[C:1]([O:5][C:6](=[O:7])[C@@H:8]([NH:23][S:24]([C:27]1[CH:28]=[CH:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=1)(=[O:25])=[O:26])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18](=[O:19])[NH:40][C:55]2[NH:54][CH2:57][CH2:58][CH2:59][N:60]=2)=[CH:21][CH:22]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)O)cc1)NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1=NCCCN1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 8 h

Procedure:
56 mg of 4-{4-[(2S)-2-tert-butoxycarbonyl-2-(4-trifluoromethylbenzenesulfonylamino)-ethyl]-phenoxy}-butyric acid were dissolved in tetrahydrofuran and 12.5 mg of 1,4,5,6-tetrahydropyrimidin-2-ylamine, 68 mg of diisopropylethylamine and 44 mg of HATU were added. The reaction mixture was stirred overnight, and the solvent was removed in vacuo. The residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on reversed-phase (C-18) silica gel eluting with a gradient of 10-90% acetonitrile in water. Yield 37.3 mg. MS (FAB+): m/e=613.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F:24][C:25]([F:38])([F:37])[CH:26]1[CH2:31][CH2:30][CH:29](OS(C)(=O)=O)[CH2:28][CH2:27]1.ClCCl>CC(O)(C)C.CC(=O)CC>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH:29]3[CH2:30][CH2:31][CH:26]([C:25]([F:38])([F:37])[F:24])[CH2:27][CH2:28]3)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)OC1CCC(C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Solvent: CCC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(OC3CCC(C(F)(F)F)CC3)ccc21
Temperature: 100 °C
Yield: 37.1 %

Procedure:
A mixture of 5-hydroxy-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (0.33 g, 1.4 mmol), cesium carbonate (0.93 g, 2.8 mmol), and methanesulfonic acid 4-trifluoromethyl-cyclohexyl ester (0.70 g, 2.8 mmol) in t-BuOH (5 mL) and 2-butanone (2.5 mL) was heated in a sealed vial at 100° C. overnight. The mixture was treated with dichloromethane to form precipitate. The solid was filtered off and the filtrate was concentrated. The residue was treated with minimum of amount dichloromethane to form solid during 2 days. The solid was filtered and washed with ether to give desired product (200 mg, yield: 40%). ESI-MS: 408.20 (M+23)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4][CH:3]1C(OCC)=O.[OH-].[Na+].Cl>O1CCOCC1.O>[O:1]=[C:2]1[CH2:3][CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
To a solution 1-tert-butyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate (compound 82.1, 19.0 g, 66.6 mmol) in 1,4-dioxane (190 mL) was added drop-wise a solution of sodium hydroxide (4.00 g, 100 mmol) in water (100 mL). The resulting mixture was stirred at room temperature overnight. The pH was then adjusted to 4-5 with hydrogen chloride (aq. 3 M) and the resulting solution was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (2×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:3) as the eluent to furnish 11 g (77%) of the title compound as a yellow oil.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)C=CC=CC=1.C([O:33][C:34](=O)[CH2:35][NH:36][CH:37]([CH3:39])[CH3:38])C.O1CCOCC1>CN(C)C1C=CN=CC=1.O>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:13]3[CH:12]=[CH:11][C:10]([N:9]4[C:34](=[O:33])[CH2:35][N:36]([CH:37]([CH3:39])[CH3:38])[C:8]4=[O:30])=[CH:15][CH:14]=3)[CH2:17][CH2:18]2)=[CH:23][CH:24]=1
Reactant: COc1ccc(N2CCN(c3ccc(NC(=O)Oc4ccccc4)cc3)CC2)cc1
Reactant: CCOC(=O)CNC(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(c3ccc(N4C(=O)CN(C(C)C)C4=O)cc3)CC2)cc1
Yield: 73 %

Procedure:
A mixture of 5 parts of phenyl[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]carbamate, 3 parts of ethyl[(1-methylethyl)amino]acetate, 1 part of N,N-dimethyl-4-pyridinamine and 100 parts of 1,4-dioxane was stirred and refluxed overnight. The warm solution was saturated with water and allowed to cool. The solution was poured onto water and extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by filtration over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The filtrate was evaporated and the residue was crystallized from methylbenzene, yielding 3.7 parts (73%) of 3-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-1-(1-methylethyl)-2,4-imidazolidinedione; mp. 193.7° C. (38).