Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:5][CH2:6][CH2:7][C@@H:8]([C:13]2[O:14][CH:15]=[C:16]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[N:17]=2)[CH2:9][C:10](O)=[O:11])[CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:40][NH2:41]>O1CCCC1.CO>[CH:1]1([CH2:5][CH2:6][CH2:7][C@@H:8]([C:13]2[O:14][CH:15]=[C:16]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[N:17]=2)[CH2:9][C:10]([NH:41][OH:40])=[O:11])[CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)ON
Reactant: CN(C)C(=O)c1coc([C@H](CCCC2CCC2)CC(=O)O)n1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C(=O)c1coc([C@H](CCCC2CCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
A solution of (3R)-6-cyclobutyl-3-{4-[(dimethylamino)carbonyl]-1,3-oxazol-2-yl}hexanoic acid (Preparation 121) (155 mg, 0.50 mmol) and N-methylmorpholine (90 μl, 0.82 mmol) in anhydrous tetrahydrofuran (8 ml) was cooled to 0° C., treated with isobutyl chloroformate (90 μl, 0.70 mmol) and stirred under a nitrogen atmosphere for 2 hours. O-(Trimethylsilyl)hydroxylamine (200 μl, 1.63 mmol) was added and the mixture was stirred for 18 hours, being allowed to warm to room temperature over this time. The mixture was then treated with methanol (2 ml) and stirred at room temperature for 10 minutes. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a gradient system of 98:2 (dichloromethane:methanol) gradually changing to 90:10 (dichloromethane:methanol). The solid was triturated with diethyl ether, filtered and dried under reduced pressure to afford the title compound as a white solid (64 mg).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:29])[NH:18][C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.O.ClCCl>[N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[C:19]([NH:18][C:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][CH2:9][CH2:10]3)=[O:29])[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)Nc3cnc4ccccc4c3)ccc21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cnc2ccccc2c1)c1ccc2c(c1)CCN2
Yield: 99.2 %

Procedure:
A solution of 5-(Quinolin-3-ylcarbamoyl)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1.4 g, 3.59 mmol) in trifluoroacetic acid (9 mL), water (1 mL) and dichloromethane (20 mL) was stirred at room temperature for 18 hours. The solvents were evaporated in vacuo and the residue was triturated in aqueous sodium bicarbonate. The product was collected by filtration and washed with water, to give an off white solid 1.03 g (99%). MS: m/z 290 (MH+). 1H NMR (DMSO-d6): δ 3.02 (t, 2 H), 3.56 (t, 2 H), 6.27 (br s, 1 H), 6.54 (d, 1 H), 7.56 (t, 1 H), 7.64 (t, 1 H), 7.71-7.76 (m, 2 H), 7.94 (m, 2 H), 8.82 (d, 1 H), 9.14 (d, 1 H) and 10.23 (s, 1 H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].S1C=CC=C1S(NN)(=O)=O.O.C(Cl)(Cl)Cl.[Br:25]Br>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([Br:25])(=[O:8])=[O:7]
Reactant: BrBr
Reactant: O=S(=O)(Cl)c1cccs1
Agent: NNS(=O)(=O)c1cccs1
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Br)c1cccs1
Temperature: 15 °C

Procedure:
In the reaction, excess hydrazine in the presence of a solvent, advantageously a lower alkanol, is reacted with the 2-thiophenesulfonyl chloride to form a 2-thiophenesulfonyl hydrazine. In the reaction, the 2-thiophenesulfonyl chloride is gradually added to the hydrazine solution which is maintained at a low temperature, advantageously between about 5° and up to about 15° C. The reaction mixture is then allowed to warm to room temperature, the solvent is removed in vacuo and a mixture of a heavy oil and a fluffy solid results. This mixture is treated with water and the solid is dissolved and the oil separated therefrom. This mixture of oil and water, which contains the hydrazine hydrochloride from the first reaction, is then placed in a flask containing a bromine solvent, advantageously chloroform, crushed ice is added thereto and to the resulting slurry bromine is added at such a rate that the reaction temperature remains below about 10° C. After the bromine has been added and the bromine color has dissipated, the layers are separated, the chloroform layer is dried over an appropriate desiccant, advantageously anhydrous magnesium sulfate, and the chloroform removed in vacuo to leave a yellow oil which crystallizes on addition of hexane to give the 2-thiophenesulfonyl bromide.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][CH:10]2[CH:5]3[CH2:6][CH:7]4[CH:9]2[CH:8]4[CH:4]13.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[S:21])=[CH:15][CH:14]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[S:21])[NH:2][CH:3]2[CH2:11][CH:10]3[CH:5]4[CH2:6][CH:7]5[CH:9]3[CH:8]5[CH:4]24)=[CH:15][CH:14]=1
Reactant: NC1CC2C3CC4C2C4C13
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: S=C(Nc1ccc(Cl)cc1)NC1CC2C3CC4C2C4C13

Procedure:
8-Aminotetracyclo[4,3,0,02,4,03,7 ]nonane hydrochloride (0.5 g.) (prepared as described in U.K. Patent Specification No. 1,180,749) was dissolved in a mixture of chloroform (25 ml.) and triethylamine (0.33 g.). To this solution was added p-chlorophenylisothiocyanate (0.5 g.) and the mixture refluxed for 16 hours. The chloroform solution, after cooling, was washed successively with 10 ml. portions of 2N HCl, water and saturated brine, and then dried over anhydrous MgSO4. After filtration, the solvent was evaporated in vacuo and the residue crystallised from toluene/cyclohexane (1:2 v/v) to give 8-[3-(p-chlorophenyl)thioureido]tetracyclo[4,3,0,02,4,03,7 ]-nonane, m.p. 168°-170°.
Reaction SMILES: [CH2:1]([Br:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]([NH:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)(=[O:12])[CH3:11].CCOCC>C(O)C>[Br-:9].[CH2:1]([N+:17]1[CH:18]=[CH:19][C:14]([NH:13][C:10](=[O:12])[CH3:11])=[CH:15][CH:16]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCCc1ccccc1
Reactant: CC(=O)Nc1ccncc1
Solvent: CCOCC
Solvent: CCO
Product: CC(=O)Nc1cc[n+](CCc2ccccc2)cc1
Product: [Br-]
Reaction time: 8 h

Procedure:
A solution of phenethyl bromide and 4-acetamidopyridine in absolute ethanol was heated under reflux, cooled, treated with ether and allowed to stand overnight to give 1-phenethyl-4-acetamidopyridinium bromide.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[C:6]([C:24]([F:27])([F:26])[F:25])[CH:5]=1)([O-:3])=[O:2].Cl>C(Cl)Cl.O1CCOCC1.CCOC(C)=O>[N+:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[C:6]([C:24]([F:27])([F:25])[F:26])[CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(OC2CCNCC2)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A solution of tert-butyl 4-(4-nitro-2-(trifluoromethyl)phenoxy)piperidine-1-carboxylate (1.4 g, 1.0 eq, 3.6 mmol) in CH2Cl2 (25 mL) was cooled to 0° C. while stifling. 4N HCl in dioxane (15 mL) was added to the above solution and stirred at 0° C. for 30 minutes and brought to room temperature for 2 hours. The volatiles were removed under vacuum to leave a crude solid. The crude mixture was dissolved in EtOAc (100 mL) and partitioned with 1N aqueous NaOH solution (50 mL). Organic layers were separated and the aqueous layer was washed with EtOAc (50 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to give the desired product in 90% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:27](O)=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[CH:27]=[O:28]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: C1N2CN3CN1CN(C2)C3
Product: Cc1ccc(-c2ccc(C=O)c(Cl)c2)cc1
Reaction time: 0.25 h

Procedure:
A mixture of 4.76 g of 3-chloro-4'-methylbiphenyl, 2.94 g of hexamethylenetetramine and 30 ml of trifluoroacetic acid is heated to boiling under reflux for 5 days. The reaction mixture is then concentrated and treated with ice-water, whereupon it is stirred for 15 minutes, made basic with sodium carbonate and extracted with ether. After evaporation of the ethereal extracts and chromatography of the residue on silica gel with methylene chloride/methanol 9:1 as the eluent, there is obtained 2-chloro-4-(4'-methylphenyl)benzaldehyde, b.p. 210°-215°C./25 Pa.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH:12]=O)=[CH:6][NH:7]2.[CH3:14][C:15]1([CH3:23])[O:22][C:20](=[O:21])[CH2:19][C:17](=[O:18])[O:16]1.N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH:12]=[C:19]1[C:20](=[O:21])[O:22][C:15]([CH3:23])([CH3:14])[O:16][C:17]1=[O:18])=[CH:6][NH:7]2
Reactant: COc1cccc2[nH]cc(C=O)c12
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COc1cccc2[nH]cc(C=C3C(=O)OC(C)(C)OC3=O)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.5 %

Procedure:
4-MethoxyIndole-3-carboxaldehyde (5.0 g) and Meldrum's acid (2,2-Dimethyl-[1,3]dioxane-4,6-dione, 4.11 g) were mixed in toluene (200 ml). To this mixture was added 0.6 ml each of piperidine and acetic acid. The reaction mixture was stirred at room temperature for four hours. The precipitate was filtered and washed with toluene to afford 4.25 g of crude 5-(4-methoxy-1H-indol-3-ylmethylene)-2,2-dimethyl-[1,3]dioxane-4,6-dione as an orange solid which was used without further purification.
Reaction SMILES: [C:1]([OH:11])(=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CS([N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[N:17]1)(=O)=O.C(N(CC)CC)C>O1CCCC1.C(#N)C>[N:16]1([C:1](=[O:11])/[CH:2]=[CH:3]/[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[N:17]1
Reactant: CS(=O)(=O)n1nnc2ccccc21
Reactant: O=C(O)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccccc1)n1nnc2ccccc21

Procedure:
1.42 g (0.01 mol) of trans-cinnamic acid (compound of formula IV) and 1.97 g (0.01 mol) of 1-(methylsulfonyl)benzotriazole are stirred at room temperature in 50 ml of tetrahydrofuran, followed by dropwise addition of 0.014 mol of triethylamine. The solution is then refluxed for 24 hours, and then evaporated under reduced pressure. The residue is taken up in 60 ml of water and extracted with 70 ml of ethyl acetate. The organic phase is dried, filtered and then concentrated under vacuum. The powder obtained is taken up in 50 ml of acetonitrile and filtered off by suction.
Reaction SMILES: [CH2:1]([CH:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4].[OH:26]O.[OH-].[Na+]>CO>[CH2:1]([C:5]1([OH:26])[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:7]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: OO
Reactant: CCCCC1C(=O)N(c2ccccc2)N(c2ccc(OC)cc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC1(O)C(=O)N(c2ccccc2)N(c2ccc(OC)cc2)C1=O

Procedure:
Prepared from 4-(1-butyl)-1-(4-methoxyphenyl)-2-phenyl-3,5-pyrazolidinedione (1.35 g; 3.8 mmol), 35% H2O2 (4.3 ml; 50 mmol), 2 M NaOH (0.35 ml; 0.7 mmol), and methanol (50 ml) using the procedure of Example 7. Purified by flash chromatography on a 110×65 mm silica gel 60 column eluted with ethyl acetate-heptane (1:1) to give 0.7 g (52%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=1[CH2:23][S:24][C:25]1[CH2:29][C:28]([CH3:31])([CH3:30])[O:27][N:26]=1.[OH2:32]>C(Cl)(Cl)Cl>[Cl:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[C:14]=1[CH2:23][S:24]([C:25]1[CH2:29][C:28]([CH3:31])([CH3:30])[O:27][N:26]=1)(=[O:9])=[O:32]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O
Reactant: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(C)C2)c1Cl
Solvent: ClC(Cl)Cl
Product: Cn1nc(C(F)(F)F)c(CS(=O)(=O)C2=NOC(C)(C)C2)c1Cl
Reaction time: 1 h
Yield: 95.1 %

Procedure:
16.87 g of m-chloroperbenzoic acid (purity: 70%, 68.4 mmoles) was added, with ice-cooling, to a solution of 8.97 g (27.4 mmoles) of 3-(5-chloro-1-methyl-3-trifluoromethylpyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline dissolved in 300 ml of chloroform. The mixture was stirred for 1 hour and then at room temperature over one night to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution, water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The solid thus obtained was washed with n-hexane to obtain 9.36 g (yield: 95.1%) of 3-(5-chloro-1-methyl-3-trifluoromethylpyrazol-4-ylmethanesulfonyl)-5,5-dimethyl-2-isoxazoline as white powder (melting point: 115.0 to 116.0° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:12]2OS(C(F)(F)F)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:12]2[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[F:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COC(=O)c1c(-c2ccccc2F)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
A mixture of methyl 6-benzyloxy-2-isobutyl-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate (10.50 g, 20 mmol), 2-fluorophenylboronic acid (3.36 g, 24 mmol) and sodium carbonate (5.30 g, 50 mmol) in toluene (50 mL), ethanol (10 mL) and water (10 mL) was stirred under an argon atmosphere at room temperature for 30 min. To the obtained mixture was added tetrakis(triphenylphosphine)palladium (1.16 g, 1 mmol) and the mixture was refluxed under heating under an argon atmosphere for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 6-benzyloxy-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (6.06 g, 65.9%) as crystals.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@@H:28]([OH:32])[CH:29]([CH3:31])[CH3:30])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[CH:35]([C:37]1([C:44]([OH:46])=[O:45])[CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38]1)=[CH2:36].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:32][C@@H:28]([CH:29]([CH3:31])[CH3:30])[C:27]([NH:26][C@@H:24]([CH3:25])[C:23]([N:19]1[CH2:20][CH2:21][CH2:22][C@@H:17]([C:15]([NH:14][C@@H:12]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2](/[CH:36]=[CH:35]/[C:37]4([C:44]([OH:46])=[O:45])[CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38]4)=[CH:3][CH:4]=3)[N:9]=2)[CH3:13])=[O:16])[NH:18]1)=[O:34])=[O:33]
Reactant: C=CC1(C(=O)O)COCCOC1
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(/C=C/C4(C(=O)O)COCCOC4)cc3n2)N1
Temperature: 50 °C

Procedure:
A mixture of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (68 mg, 0.128 mmol), 6-vinyl-[1,4]dioxepane-6-carboxylic acid (22 mg, 0.128 mmol), triethylamine (39 mg, 54 μL, 0.384 mmol) and tri(o-tolyl)phosphine (8 mg, 0.026 mmol) in 1,4-dioxane (2 mL) was deoxygenated by bubbling nitrogen through for 5 minutes and then warmed to 50° C. under nitrogen with stirring. Tris(dibenzylideneacetone)dipalladium(0) (12 mg, 0.013 mmol) was added and the mixture was refluxed for 40 minutes and then allowed to cool. The suspension was filtered and the filtrate was evaporated to give crude title compound which was used directly in the next stage. LCMS (m/z) 626.2 [M+H], Tr=1.67 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]4[CH2:29][O:28]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:30]([OH:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:28])[CH2:29][O:37][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C4CO4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)COCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 1-[4′-(3-methyl-4-oxiranyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and benzyl alcohol.
Reaction SMILES: BrC1C=C(F)C([C:8]2[CH:13]=[CH:12][C:11]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=NC=1.[Si](OC1C=CC([C:57]2[C:62]([F:63])=[CH:61][C:60]([OH:64])=[CH:59][N:58]=2)=CC=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:65](O)[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72]>>[Si:15]([O:14][C:11]1[CH:10]=[CH:9][CH:8]=[CH:13][C:12]=1[C:57]1[C:62]([F:63])=[CH:61][C:60]([O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])=[CH:59][N:58]=1)([C:28]([CH3:30])([CH3:31])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCCCCCCO
Reactant: CC(C)(C)[Si](Oc1ccc(-c2ncc(Br)cc2F)cc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](Oc1ccc(-c2ncc(O)cc2F)cc1)(c1ccccc1)c1ccccc1
Product: CCCCCCCCOc1cnc(-c2ccccc2O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(F)c1

Procedure:
5-bromo-2-(4-tert-butyldiphenylsilyloxyphenyl)-3-fluoropyridine is converted analogously to Example 2 into 2-(4-tert-butyldiphenylsilyloxyphenyl)-3-5-hydroxypyridine. ##STR32## 2-(4-tert-butyldiphenylsilyloxyphenyl)-3-fluoro-5-hydroxypyridine and octanol are reacted analogously to Example 2 to give 2-(tert-butyldiphenylsilyloxyphenyl)-3-fluoro-5-octyloxypyridine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH2:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C[O:29][C:30](=O)[C:31]([F:34])([F:33])[F:32].O>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH:15][C:30](=[O:29])[C:31]([F:34])([F:33])[F:32])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(F)(F)F
Reactant: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: O=C(O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)C(F)(F)F

Procedure:
112.5 g (0.41 mmol) of O-benzyltyrosine is suspended in 1 liter of dry methanol and mixed at room temperature with 58.9 ml (0.42 mol) of triethylamine. After addition of 67 ml (0.53 mol) of trifluoroacetic acid methyl ester, it is stirred for 130 hours at room temperature with exclusion of water. The unreacted initial material is separated and the leaving components are removed by shaking with ethyl acetate/aqueous hydrochloric acid. The ethyl acetate phase is decolored with activated carbon. After evaporation of the solvent, 120.7 g (80% of theory) of colorless crystals is obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:17][CH2:16]3)[N:10]=2)=[CH:5][CH:4]=1.[CH2:26]([CH:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH2:29][CH3:30])[CH3:27]>>[ClH:1].[ClH:1].[ClH:1].[CH2:26]([CH:28]([N:31]1[CH2:36][CH2:35][N:34]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[O:13][N:12]=[C:11]([CH2:14][CH:15]4[CH2:20][CH2:19][N:18]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:17][CH2:16]4)[N:10]=3)=[CH:5][CH:4]=2)[CH2:33][CH2:32]1)[CH2:29][CH3:30])[CH3:27]
Reactant: CCC(CC)N1CCC(Cc2noc(-c3ccc(CCl)cc3)n2)CC1
Reactant: CCC(CC)N1CCNCC1
Product: CCC(CC)N1CCC(Cc2noc(-c3ccc(CN4CCN(C(CC)CC)CC4)cc3)n2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 23, starting from 4-[5-(4-(chloromethyl)phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-1-(1-ethylpropyl)piperidine and 1-(1-ethylpropyl)piperazine. HPLC: Rt=6.50 min.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([C:18]([OH:20])=[O:19])=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:23])=[N-]>CCOC(C)=O.CCOCC>[C:1]1([C:7]2[S:8][C:9]([C:18]([O:20][CH3:23])=[O:19])=[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1sc(-c2ccccc2)nc1-c1ccccc1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(-c2ccccc2)nc1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 106.9 %

Procedure:
To a pre-cooled (0° C.) solution of 2,4-Diphenyl-1,3-thiazole-5-carboxylic acid 72 (400 mg, 1.422 mmol) in EtOAc (7.109 ml) was added a 0.5 M solution of diazomethane (5.69 ml, 2.84 mmol) in Et2O (freshly prepared) (c.a. 5 mL) and the resulting white suspension was stirred at 0° C. for 1 h. TLC showed completion. Then, the small amount of white solid left was filtered off and the filtrate was concentrated in vacuo to afford methyl 2,4-diphenylthiazole-5-carboxylate 73 (0.449 g, 107% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2C=N[CH:14]=[CH:13][N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].ClC1[N:23]=[C:22]([O:24][CH3:25])C=CN=1>>[CH3:25][O:24][C:22]1[CH:14]=[CH:13][N:12]=[C:11]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=2[C:7]([OH:9])=[O:8])[N:23]=1
Reactant: COc1ccnc(Cl)n1
Reactant: Cc1ccc(-c2cnccn2)c(C(=O)O)c1
Product: COc1ccnc(-c2ccc(C)cc2C(=O)O)n1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(pyrazin-2-yl)benzoic acid in Example A19, starting from 2-chloro-4-methoxypyrimidine. ESI-MS (m/z): 245 [M+1]+.