Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].ON1C2C=CC=CC=2N=N1.[NH2:27][C:28]1[CH:36]=[CH:35][C:31]2[NH:32][N:33]=[N:34][C:30]=2[CH:29]=1.C1(N=C=NC2CCCCC2)CCCCC1.O>CN(C)C=O>[NH:32]1[C:31]2[CH:35]=[CH:36][C:28]([NH:27][C:12](=[O:14])[CH2:11][O:10][C:9]3[CH:8]=[CH:7][C:6]([NH:5][NH:4][C:1](=[O:3])[CH3:2])=[CH:16][CH:15]=3)=[CH:29][C:30]=2[N:34]=[N:33]1
Reactant: CC(=O)NNc1ccc(OCC(=O)O)cc1
Reactant: Nc1ccc2[nH]nnc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NNc1ccc(OCC(=O)Nc2ccc3[nH]nnc3c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4-(2-acetylhydrazino)phenoxyacetic acid (1.1 g), N-hydroxybenzotriazole (1.0 g) and 5-aminobenzotriazole (0.67 g, 0.005 mole) in dry dimethylformamide (10 ml) was stirred at 0° under dry nitrogen. Dicyclohexylcarbodiimide (1.1 g) in dry dimethylformamide (5 ml) was added dropwise over 15 minutes and the reaction mixture was stirred for 1 hour at 0° and 4 hours at room temperature. The dicyclohexylurea which precipitated was filtered and dried (0.7 g) and the filtrate was stirred at 60° overnight, under nitrogen. The reaction mixture was cooled and an additional precipitate of dicyclohexylurea was filtered off (0.3 g). The filtrate was evaporated, the residue was triturated with boiling methanol (50 ml) and the solid which precipitated was filtered off and dried (0.7 g). The filtrate was cooled at 5° overnight and the solid which crystallized out was filtered off and dried (0.6 g). The two precipitates, which were identical by IR, were combined and recrystallized from methanol:acetonitrile to give the product was a beige-colored powder (1.0 g). NMR analysis indicates the presence of ca 0.3 mole of H2O.
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:33])=[O:5])[S:12][CH:13]=2)=[CH:27][CH:28]=1
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 101.1 %

Procedure:
2-[(4-{2-[(4-Chlorophenyl)(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (1.1 g) obtained in Example 286-3 was dissolved in dichloromethane (20 mL), trifluoroacetic acid (4.0 mL) was added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:1 to 1:1) to give the title compound (0.99 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1([F:34])[CH2:6][C@H:5](/[CH:7]=[CH:8]/[C@@H:9]([OH:21])[C@@H:10]([CH3:20])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]([CH2:22][CH2:23][CH2:24][C:25]2[S:29][C:28]([C:30]([OH:32])=[O:31])=[CH:27][CH:26]=2)[C:3]1=[O:33].[H][H]>C(O)C.[Pd]>[F:34][C:2]1([F:1])[CH2:6][C@H:5]([CH2:7][CH2:8][C@@H:9]([OH:21])[C@@H:10]([CH3:20])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]([CH2:22][CH2:23][CH2:24][C:25]2[S:29][C:28]([C:30]([OH:32])=[O:31])=[CH:27][CH:26]=2)[C:3]1=[O:33]
Reactant: [H][H]
Reactant: C[C@@H](CCCc1ccccc1)[C@H](O)/C=C/[C@H]1CC(F)(F)C(=O)N1CCCc1ccc(C(=O)O)s1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](CCCc1ccccc1)[C@H](O)CC[C@H]1CC(F)(F)C(=O)N1CCCc1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.1 %

Procedure:
To a solution consisting of 5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic acid (15.2 mg, 0.031 mmol) in ethanol (12 mL) and covered with an atmosphere of nitrogen was added palladium (12 mg, 10% on activated carbon). The nitrogen atmosphere was replaced with hydrogen and the reaction mixture was stirred vigorously for 5 hours at room temperature. The hydrogen was replaced with nitrogen and mixture was filtered through a small pad of celite which was washed with ethanol. The combined filtrate was concentrated under vacuum and the residue was purified by silica gel chromatography eluting with ethyl acetate-heptane-acetic acid (45:55:0.4 v/v/v) to give 9.5 mg (62%) of the title compound as a colorless oil; TLC Rf 0.29 (solvent system: 45:55:1 v/v/v ethyl acetate-heptane-acetic acid); MS (ESI−) m/z 492.2 (M−H)−; 1H NMR (CD3OD) δ 7.47 (d, J=3.66 Hz, 1H), 7.18-7.01 (m, 5H), 6.80 (d, J=3.30 Hz, 1H), 3.72-3.63 (m, 1H), 3.16-3.03 (m, 1H), 2.79 (t, J=7.32 Hz, 2H), 2.61-2.45 (m, 3H), 2.19-2.05 (m, 1H), 1.98-1.78 (m, 2H), 1.78-1.57 (m, 2H), 1.53-1.39 (m, 4H), 1.34-1.14 (m, 5H), 1.10-1.00 (m, 1H), 0.81-0.76 (m, 3H); 19F NMR (CD3OD) δ−103.2 (ddd, 1F), −105.9 (ddd, 1F).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([NH:12][C:13](=[O:15])[CH3:14])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[C:19](=O)([O-])[O-:20].[Cs+].[Cs+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH3:19][O:20][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([NH:12][C:13](=[O:15])[CH3:14])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: CC(=O)Nc1c([N+](=O)[O-])cc(F)cc1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: COc1cc([N+](=O)[O-])c(NC(C)=O)c(C(F)(F)F)c1
Temperature: 100 °C

Procedure:
A well stirred mixture of 3.00 g (11.2 mmol) N-(4-fluoro-2-nitro-6-trifluoromethyl-phenyl)-acetamide and 6.00 g (18.4 mmol) caesium carbonate in 90 mL methanol was heated for 10 min at 100° C. in the microwave. After cooling the solvent was eliminated i.vac. and the residue remaining was combined with 100 mL water. The aqueous phase was acidified with 10% citric acid and the product was extracted with 100 mL ethyl acetate. The organic phase was dried and evaporated down i.vac. The residue obtained was purified by flash chromatography. The fractions containing product were combined and evaporated down i.vac.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:32][C:33]([O:35]CC)=[O:34])[CH:5]=[CH:6][C:7]=1[N:8]1[C:16](=[O:17])[C:15]2[C:14]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[C:13]3[CH:24]=[CH:25][CH:26]=[CH:27][C:12]3=[C:11]([O:28][CH2:29][CH3:30])[C:10]=2[C:9]1=[O:31].C(O)(=O)C.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:32][C:33]([OH:35])=[O:34])[CH:5]=[CH:6][C:7]=1[N:8]1[C:16](=[O:17])[C:15]2[C:14]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])=[C:13]3[CH:24]=[CH:25][CH:26]=[CH:27][C:12]3=[C:11]([O:28][CH2:29][CH3:30])[C:10]=2[C:9]1=[O:31]
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC(F)(F)F)c4ccccc4c3OCC)C2=O)c(Cl)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCOc1c2c(c(OCC(F)(F)F)c3ccccc13)C(=O)N(c1ccc(CC(=O)O)cc1Cl)C2=O

Procedure:
Ethyl (3-chloro-4-{4-(ethyloxy)-1,3-dioxo-9-[(2,2,2-trifluoroethyl)oxy]-1,3-dihydro-2H-benzo[f]isoindol-2-yl}phenyl)acetate (0.060 g, 0.11 mmol) was heated to 100° C. in a 1:1 mixture of acetic acid:HCl (2N) (6 ml) for 1.25 hours. On addition of water, the resulting white solid was collected by filtration and washed with water (0.047 g, 0.09 mmol). LC/MS: Rt=3.44, [MH]+ 508.
Reaction SMILES: [Na].[Cl:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:4]=1[NH:11][S:12]([C:15]1[N:19]=[C:18]([NH2:20])[NH:17][N:16]=1)(=[O:14])=[O:13].[C:21](OC)(=[O:27])[CH2:22][C:23](OC)=[O:24]>C(O)C>[Cl:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:4]=1[NH:11][S:12]([C:15]1[N:19]=[C:18]2[N:20]=[C:21]([OH:27])[CH:22]=[C:23]([OH:24])[N:17]2[N:16]=1)(=[O:14])=[O:13]
Reactant: COC(=O)CC(=O)OC
Reactant: Cc1ccc(Cl)c(NS(=O)(=O)c2n[nH]c(N)n2)c1Cl
Agent: [Na]
Solvent: CCO
Product: Cc1ccc(Cl)c(NS(=O)(=O)c2nc3nc(O)cc(O)n3n2)c1Cl
Reaction time: 72 h

Procedure:
Sodium (3.11 g, 135 mmol) was added to 250 ml of absolute ethanol in a 500 ml round bottom flask and allowed to react under nitrogen. N-(2,6-dichloro-3-methylphenyl)-5-amino-1,2,4-triazole-3-sulfonamide (14.5 g, 45 mmol) and then dimethyl malonate (11.9 g, 90 mmol) were added and the mixture heated at reflux with stirring for about three days. The mixture was then cooled with an ice bath and filtered to collect the solids. These were washed with hexane and dissolved in about 75 ml of cold water and the resulting solution was acidified to about pH 2 with conc. hydrochloric acid. The precipitate that formed was collected by filtration and dried to obtain 13.55 g (77.1 percent of theory) of the title compound as a white powder, which decomposes above 200° C. This was shown to be the title compound by NMR.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([C:13]1[C:18]([F:19])=[CH:17][N:16]=[CH:15][N:14]=1)[CH3:12].[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:28](=[O:35])[CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1.C(O)(=O)C>C1COCC1>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:28]([OH:35])([CH:11]([C:13]1[C:18]([F:19])=[CH:17][N:16]=[CH:15][N:14]=1)[CH3:12])[CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1
Reactant: O=C(Cn1cncn1)c1ccc(F)cc1F
Reactant: CCc1ncncc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(c1ncncc1F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: -65 °C
Reaction time: 3 h

Procedure:
To THF (20 ml) was added sodium bis(trimethylsilyl)amide (79 ml) of a 1.0M solution in THF) and the solution cooled to -65° C. under nitrogen. A solution of 4-ethyl-5-fluoropyrimidine (10 g) (see Preparation 8) in THF (100 ml) was added over 30 minutes. After stirring for 3 hours at -65° C. the thin slurry was treated with a solution of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (17.7 g) in THF (100 ml), dropwise over 30 minutes. The solution was stirred for a further 1 hour at -65° C. and then treated with acetic acid (20 ml). After warming to -20° C. the solution was washed with water (200 ml) and the organic layer separated and combined with an ethyl acetate (200 ml) back extract of the aqueous phase. The combined organic layers were concentrated under reduced pressure to provide a solid that was triturated with diethyl ether (230 ml) and filtered. The filtrate was concentrated under reduced pressure and chromatographed on silica with 1:1 diethyl ether/ethyl acetate as the eluent. The fractions containing the title compound were combined, concentrated under reduced pressure and the residue chromatographed on silica with 1:1 ethyl acetate/hexane as the eluent. The appropriate fractions were combined and evaporated under reduced pressure to provide the purified title compound (0.82 g), m.p. 125°-127° C. Found: C,54.89; H,4.06; N,19.66; C16H14F3N5O requires: C,55.01; H,4.01; N,20.05%.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:16]>CN(C=O)C>[C:8]([NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:16]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 4 °C
Reaction time: 8 h

Procedure:
To N-TeocT4 (0.017 g, 17 μmol) in 1 mL dry DMF was added dicyclohexylcarbodiimide (0.004 g, 18 μmol). After stirring for 30 minutes N-dimethyl-4-aminopyridine (0.004 g, 36 μmol) and Gly18 (0.017 g, 17 μmol) were added and the reaction stirred overnight. The cloudy solution was poured into 20 mL H2O and extracted twice with 10 mL CH2Cl2. The aqueous component was acidified to pH 3 with 1 N HCl and chilled to 4° C. The material was isolated by centrifugation and the pellet washed 3 times with 8 mL H2O. The pellet was dried in vacuum to yield dicyclohexylurea and N-TeocT4-Gly18.(SEQ ID NO: 6)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([O:14]C)=[CH:13][C:7]=2[CH:6]=1)=[O:4].B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2cc(OC)ccc2s1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1cc2cc(O)ccc2s1
Temperature: 0 °C
Yield: 77.8 %

Procedure:
The above prepared 5-methoxy-benzo[b]thiophene-2-carboxylic acid methyl ester (0.199 g, 0.895 mmol) was dissolved in 6 mL of CH2Cl2, cooled to 0° C., and treated with BBr3 (1.79 mL of 1M solution in CH2Cl2, 2 eq.). After 2 additional h at 0° C., the reaction mixture was carefully poured onto crashed ice, twofold extracted with AcOEt, washed with water, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=7/3) yielded 0.145 g of the title compound as off-white solid.
Reaction SMILES: [OH-].[K+].[CH:3]1([C:6]2[O:10][N:9]=[C:8]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[C:7]=2[CH2:19][O:20][CH:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[CH:40]=[CH:39][C:31]4[C:32]([C:35]([O:37]C)=[O:36])=[N:33][S:34][C:30]=4[CH:29]=3)[CH2:23][CH2:22]2)[CH2:5][CH2:4]1>C(O)C.O1CCCC1>[CH:3]1([C:6]2[O:10][N:9]=[C:8]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[C:7]=2[CH2:19][O:20][CH:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[CH:40]=[CH:39][C:31]4[C:32]([C:35]([OH:37])=[O:36])=[N:33][S:34][C:30]=4[CH:29]=3)[CH2:23][CH2:22]2)[CH2:5][CH2:4]1
Reactant: COC(=O)c1nsc2cc(N3CCCC(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)CC3)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1nsc2cc(N3CCCC(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)CC3)ccc12
Temperature: 60 °C
Reaction time: 24 h
Yield: 51.7 %

Procedure:
Potassium hydroxide (0.118 g, 2.10 mmol) is added to a solution of methyl 6-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)azepan-1-yl)benzo[d]isothiazole-3-carboxylate (0.30 g, 0.52 mmol) in ethanol (2 ml) and tetrahydrofuran (6 mL). The mixture is stirred at 60° C. for 24 h and concentrated in vacuo. The residue is dissolved in water (8 ml), acidified to pH˜5 with 1 N HCl and extracted with dichloromethane (2×10 ml). The organic extracts are dried over sodium sulfate and the solvent is evaporated in vacuo to give 0.15 g (51.0%) of the title compound as an off white solid. ES/MS m/z 558.06 (M+1).
Reaction SMILES: C([O:5][C:6]([NH:8][CH2:9][C:10]([N:12]([CH:25]([C:31]1[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[CH:33][C:32]=1[O:39][CH3:40])C(OCC)=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)=[O:11])=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[CH3:38][O:37][C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([O:39][CH3:40])[C:31]=1[CH:25]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=2)[C:10](=[O:11])[CH2:9][NH:8][C:6]1=[O:5]
Reactant: CCOC(=O)C(c1c(OC)cccc1OC)N(Cc1ccc(OC(F)(F)F)cc1)C(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cccc(OC)c1C1C(=O)NCC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A cooled (0° C.) solution of ethyl 2-(2-((tert-butoxycarbonyl)amino)-N-(4-(trifluoromethoxy)-benzyl)acetamido)-2-(2,6-dimethoxyphenyl)acetate (900 mg; 1.57 mmol) in anh. DCM (18 ml) was treated dropwise with 4 M HCl in dioxane (6.00 ml; 24.00 mmol), and the resulting mixture was further stirred at rt, under nitrogen, for 2.5 h. The reaction mixture was concentrated to dryness under reduced pressure, the resulting residue was treated with aq. sat. NaHCO3 (7.5 ml) and AcOEt (7.5 ml), and stirring at rt was then continued for 17 h. The separated aq. layer was extracted with AcOEt (20 ml), and the mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 6-(2,6-dimethoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)-piperazine-2,5-dione as a slightly orange solid. LC-MS (conditions D): tR=0.94 min.; [M+H]+: 424.88 g/mol.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:20]([NH2:22])=[O:21].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](Cl)=O)=[CH:27][CH:26]=1>>[OH:19][CH:17]([CH:7]([N:6]1[C:2]2[N:1]=[C:32]([CH2:31][C:28]3[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)[NH:22][C:20](=[O:21])[C:3]=2[CH:4]=[N:5]1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:18]
Reactant: CC(O)C(CCCc1ccccc1)n1ncc(C(N)=O)c1N
Reactant: COc1ccc(CC(=O)Cl)cc1
Product: COc1ccc(Cc2nc3c(cnn3C(CCCc3ccccc3)C(C)O)c(=O)[nH]2)cc1

Procedure:
Starting from 1 g (3.31 mmol) of 5-amino-1-[1-(1-hydroxy-ethyl)-4-phenyl-butyl]-1H-pyrazole-4-carboxamide and 1.52 g (8.26 mmol) of 4-methoxyphenylacetyl chloride, the title compounds are prepared analogously to the protocol of Example 13. This gives 240 mg (17%) of the diastereomer which elutes more rapidly, M.p.: 41° C., and 134 mg (9%) of the diastereomer which elutes more slowly, M.p.: 48° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4](F)[CH:3]=1.[CH2:12]([Mg]Br)[CH3:13]>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH2:12][CH3:13])[CH:3]=1
Reactant: CC[Mg]Br
Reactant: O=C(O)c1ccc(Br)cc1F
Solvent: C1CCOC1
Product: CCc1cc(Br)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 4-bromo-2-fluorobenzoic acid (2.0 g, 9.17 mmol) in THF (16 mL), was added 1.0 M ethyl magnesium bromide in THF (32 mL, 32.0 mmol) dropwise at 0° C. and the resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was quenched with 2 N HCl and extracted with EtOAc. The combined EtOAc layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude 4-bromo-2-ethylbenzoic acid as a colorless liquid that was used in the next step without purification (0.4 g): 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J=8.4 Hz, 1H), 7.47 (m, 1H), 7.43 (m, 1H), 2.95 (q, J=4.0 Hz, 2H), 1.32 (t, J=4.0 Hz, 3H); ESIMS m/z 228.97 ([M+H]+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:20])([F:19])[C:9]([C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)([F:11])[F:10])=[CH:4][CH:3]=1.[CH2:21]([OH:27])[CH2:22][O:23][CH2:24][CH2:25][OH:26]>>[OH:27][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:20])([F:19])[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:27][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])=[CH:14][CH:13]=2)([F:11])[F:10])=[CH:4][CH:3]=1
Reactant: OCCOCCO
Reactant: Fc1ccc(C(F)(F)C(F)(F)c2ccc(F)cc2)cc1
Product: OCCOCCOc1ccc(C(F)(F)C(F)(F)c2ccc(OCCOCCO)cc2)cc1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
700 ml of diethylene glycol and 65 g of 1,2-bis(4-fluorophenyl)-1,1,2,2-tetrafluoroethane* are heated to 130° C. in a stirred flask and 57 g of potassium tert.-butylate are added in portions. The mixture is then heated to 150° C. and stirred at this temperature for 2 hours. The mixture is cooled, poured onto 4 liters of ice-water and mixed thoroughly with a homogenizer (Ultraturax), until crystals precipitate. The precipitate is filtered off with suction, stirred again with 3 liters of water, acidified with hydrochloric acid, filtered off with suction again, dried and recrystallized from toluene.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])[CH3:2].[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)#[CH:19].C(N(CC)CC)C>CN(C)C=O.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:19]#[C:18][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])[CH3:2]
Reactant: C#Cc1cccc(F)c1
Reactant: CCOC(=O)COc1ccc(Br)cc1[N+](=O)[O-]
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C#Cc2cccc(F)c2)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 51.6 %

Procedure:
To a solution of (4-bromo-2-nitro-phenoxy)-acetic acid ethyl ester (2.95 g, 9.70 mmol, 1 equiv) and 1-ethynyl-3-fluorobenzene (1.34 mL, 11.6 mmol, 1.2 equiv) in dimethylformamide (15 mL) in a microwave reactor vessel was added triethylamine (4.05 mL, 29.1 mmol, 3 equiv), copper iodide (55 mg, 0.29 mmol, 0.03 equiv) and trans-dichlorobis(tri-o-tolylphosphine) palladium(II) (152 mg, 0.19 mmol, 0.02 equiv). The reaction was placed under an argon atmosphere then heated to 80° C. in a microwave reactor for 30 min. The reaction mixture was then partitioned between ethyl acetate:heptane (1:1) and 1.0 N aqueous hydrochloric acid (100 mL each). The organic layer was separated and washed successively with saturated aqueous sodium bicarbonate, 1:1 saturated aqueous sodium bicarbonate:saturated aqueous ammonium chloride, saturated brine solution (100 mL each) then dried (MgSO4), filtered and concentrated. The product was purified using an Isco CombiFlash automated chromatography system. The residue was loaded onto a 120 g silica gel column as a solution in dichloromethane (5 mL) then eluted with ethyl acetate in heptane (0-40% ethyl acetate linear gradient over 16 column volumes at a flow rate of 85 mL/min) to give 1.72 g (5.01 mmol, 52%) of the title compound as a brown oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:31][C:32]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][NH:34][N:33]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[Si:24]([O:23][CH2:22][C:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:36]5[C:32]([CH3:31])=[N:33][NH:34][CH:35]=5)=[CH:3][CH:4]=4)[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1n[nH]cc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO[Si](C)(C)C(C)(C)C)C4)CC2)cc1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A solution of the compound (300 mg, 0.59 mmol) obtained in Example 16-4), 3-methyl-1H-pyrazole-4-boronic acid pinacol ester (135 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (68 mg, 0.06 mmol), and potassium carbonate (163 mg, 1.18 mmol) in 1,2-dimethoxyethane (3 mL) and water (1.5 mL) was stirred at 120° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature, water (3 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=30:70) to obtain the title compound (213 mg, 71%) in an orange oily form.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=3)[CH2:22][CH2:21]2)[CH:12]=[CH:11]1>>[CH3:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:19][N:20]2[CH2:21][CH2:22][CH:23]([C:26]3[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:29]=[CH:30][CH:31]=3)[CH2:24][CH2:25]2)[CH:12]=[CH:11]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4cc[nH]c34)CC2)c1
Reactant: Cc1cccc(I)c1C
Product: Cc1cccc(-n2ccc3cccc(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)c32)c1C

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-2,3-dimethylbenzene and N-{3-[1-(1H-indol-7-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 480.0 (M+H)+.