Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[O:7][N:6]=[C:5]([NH:8]C(=O)C)[CH:4]=1.Cl>C(O)CO>[F:1][C:2]([F:13])([F:12])[C:3]1[O:7][N:6]=[C:5]([NH2:8])[CH:4]=1
Reactant: CC(=O)Nc1cc(C(F)(F)F)on1
Agent: Cl
Solvent: OCCO
Product: Nc1cc(C(F)(F)F)on1

Procedure:
The reaction was carried out according to the same procedure as described in Example 50 except that 5-trifluoromethyl-3-acetylaminoisoxazole (2.21 g, 11.4 mmole), 36% hydrochloric acid (2.89 g, 28.5 mmole) and ehtylene glycol (11.4 ml) were used. The product was then purified by column chromatography on silica gel and further distilled under reduced pressure to give the title compound. Yield: 1.22 g (70.4%), b.p. 84°-85° C./13.0 mmHg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].CS(O[CH:14]1[CH2:18][CH2:17][N:16]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[CH2:15]1)(=O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:14]1[CH2:18][CH2:17][N:16]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[CH2:15]1
Reactant: Oc1ccccc1Br
Reactant: CS(=O)(=O)OC1CCN(CC2CC2)C1
Product: Brc1ccccc1OC1CCN(CC2CC2)C1

Procedure:
The title compound was prepared from 2-bromophenol and 1-(cyclopropylmethyl)pyrrolidin-3-yl methanesulphonate in a similar manner to Example 134 (b) except that the compound was purified by cation exchange chromatography eluting with ammonia/methanol mixtures.
Reaction SMILES: C([NH:8][C:9]1[C:10]([CH3:32])=[C:11]([CH3:31])[C:12]2[O:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:19][CH:18]=3)[C:13]=2[C:29]=1[CH3:30])C1C=CC=CC=1>CCCCCC>[C:20]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:21]=[CH:22][C:17]([CH:14]2[C:13]3[C:29]([CH3:30])=[C:9]([NH2:8])[C:10]([CH3:32])=[C:11]([CH3:31])[C:12]=3[O:16][CH2:15]2)=[CH:18][CH:19]=1
Reactant: Cc1c(C)c2c(c(C)c1NCc1ccccc1)C(c1ccc(-c3ccccc3)cc1)CO2
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1N)C(c1ccc(-c3ccccc3)cc1)CO2
Yield: 89 %

Procedure:
Using N-benzyl-3-(biphenyl-4-yl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 279, the title compound was synthesized in the same manner as in Reference Example 30. Yield 89%. Melting point: 149-150° C. (hexane).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:11]2[CH:12]=[C:13]3[C:19]([NH:20][C:21](=[O:42])[C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)=[CH:24][C:23]=4[NH:35][CH:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[N:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:5]=[C:6]([F:8])[CH:7]=1>O1CCCC1.CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:19]([NH:20][C:21](=[O:42])[C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[CH:24][C:23]=3[NH:35][CH:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)=[N:18][NH:17][C:14]2=[N:15][CH:16]=1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ncc(C#Cc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ncc(CCc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.5 %

Procedure:
10 mg of 10% Pd/C is added to 100 mg (0.175 mmol) of N-(5-((3,5-difluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide in solution in a mixture of 10 ml of tetrahydrofuran and 5 ml of methanol before placing the reaction medium under an atmosphere of hydrogen. The reaction mixture is stirred for 12 hours at room temperature and then filtered on Celite and concentrated. 62 mg (yield=60%) of N-(5-(3,5-difluorophenethyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide are isolated in the form of a white solid. LCMS (EI, m/z): (M+1) 576.23.
Reaction SMILES: [Na].[CH3:2][C:3]([C:5]1[N:6]([CH3:15])[C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[C:16](OCC)(=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[CH3:15][N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[O:14][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:2][C:3](=[O:4])[C:5]1=2
Reactant: CC(=O)c1c(O)c2ccccc2n1C
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2c(o1)c1ccccc1n2C

Procedure:
To a solution of 6.0 g (0.26 mole) of sodium metal in 600 ml ab. ethanol was added 18.0 g (0.095 mole) of 3-hydroxy-1-methyl-1H-indol-2-yl methyl ketone, followed by 37.6 g (0.26 mole) of diethyl oxalate, added over 10 min. The mixture was stirred and heated at reflux for 17 hours, cooled and the red di-sodium salt was filtered and washed with cold hexane. The crude salt was added to a solution of 28 ml conc. HCl and 120 ml ab. ethanol, heated at reflux for 30 min., and the mixture was filtered while hot. Cooling the filtrate gave the crude product, which was filtered and then dissolved in 400 ml of chloroform. The chloroform solution was washed 3 times with dilute aqueous NaHCO3, 1 time with water, dried (MgSO4) and evaporated to leave a grey residue. Recrystallization from 15% CHCl3 in hexane gave yellow needles of mpt. 160°-162°.
Reaction SMILES: C[CH:2]([CH3:4])[O-:3].[Al+3].CC(C)[O-:8].CC(C)[O-].[S:14]([C:18]1C=[C:22]([C:23]([OH:25])=[O:24])[C:21](C(O)=O)=[CH:20][CH:19]=1)([OH:17])(=[O:16])=[O:15].[O-]CC.[Mg+2:33].[O-]CC>O>[S:14]([C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([C:23]([O-:25])=[O:24])[C:4]=1[C:2]([O-:8])=[O:3])([OH:17])(=[O:16])=[O:15].[Mg+2:33]
Reactant: O=C(O)c1ccc(S(=O)(=O)O)cc1C(=O)O
Reactant: CC(C)[O-]
Agent: CC[O-]
Agent: [Al+3]
Agent: [Mg+2]
Solvent: O
Product: O=C([O-])c1cccc(S(=O)(=O)O)c1C(=O)[O-]
Temperature: 60 °C

Procedure:
The same classes of materials were also prepared by using appropriate metal alkoxides and hydroxysulfonic or sulfocarboxylic acids in water. Thus, aluminum isopropoxide was mixed with 5-sulfophthalic acid in 2:3 molar ratio and the mixture was heated to about 60° C. for about ½ hr. Aluminum isopropoxide was hydrolyzed and the salt was obtained as aqueous solution and was used as such for inkjet coatings. Magnesium ethoxide was similarly hydrolyzed from its mixture with the same acid in 1:2 molar ratio to obtain magnesium sulfophthalate in aqueous solution.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][S:10][C:11]2[NH:12][C:13]3[CH:19]=[C:18]4[O:20][CH2:21][O:22][C:17]4=[CH:16][C:14]=3[N:15]=2)[C:4]=1[CH3:23].ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][S:10]([C:11]2[NH:15][C:14]3[CH:16]=[C:17]4[O:22][CH2:21][O:20][C:18]4=[CH:19][C:13]=3[N:12]=2)=[O:32])[C:4]=1[CH3:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccnc(CSc2nc3cc4c(cc3[nH]2)OCO4)c1C
Solvent: ClC(Cl)Cl
Product: COc1ccnc(CS(=O)c2nc3cc4c(cc3[nH]2)OCO4)c1C

Procedure:
A solution of 330 mg of 6-[[(4-methoxy-3-methyl-2-pyridyl)methyl]thio]-5H-1,3-dioxolo[4,5-f]benzimidazole in 5 ml of chloroform was treated portionwise with 200 mg of m-chloroperbenzoic acid while cooling with ice and stirring. After 15 minutes the reaction mixture was extracted with 10% sodium carbonate solution, dried and concentrated. The residue was chromatographed on silica gel with methylene chloride/methanol (8.5:1.5) as the elution agent, the medium pressure flash chromatography method being used and the pressure being produced with nitrogen. By recrystallization from ether there was obtained 6-[[(4-methoxy-3-methyl-2-pyridyl)methyl]sulfinyl]-5H-1,3-dioxolo[4,5-f]benzimidazole of melting point 185°-186° (decomposition).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[F:18][C:15]([F:16])([F:17])[C:13]1[CH:12]=[CH:11][C:7]2[C:8](=[O:10])[O:9][C:1](=[O:2])[NH:5][C:6]=2[CH:14]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2c(=O)o1
Reaction time: 2 h

Procedure:
A solution of phosgene (9.9 g) in toluene (100 ml) was added dropwise to a stirred solution of 2-amino-4-trifluoromethylbenzoic acid (6.9 g) and sodium carbonate (3.2 g) in water (100 ml) cooled in ice. Coolant was removed, the mixture was stirred for 2 hours, and the resulting solid was collected by filtration. The solid was dissolved in ethyl acetate and the solution was dried over anhydrous magnesium sulphate and then evaporated under reduced pressure. The resulting solid was crystallised from ethyl acetate to give the novel compound 7-trifluoromethyl-1H-3,1-benzoxazine-2,4-dione, m.p. 243°-245° (dec.)
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1.I[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1>>[OH:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COCOc1cccc(B(O)O)c1
Reactant: CCOC(=O)Cc1ccc(I)cc1
Product: CCOC(=O)Cc1ccc(-c2cccc(O)c2)cc1

Procedure:
In a manner similar to that of Example 1(h), by reaction of 543 mg (3.6 mmol) of 3-methoxymethoxyphenylboronic acid with 700 mg (2.4 mmol) of ethyl 4-iodophenylacetate, 630 mg (68%) of the expected ethyl ester are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[CH:11][S:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])[C:5](Cl)=[N:6][CH:7]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>COCCOC>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:5]2[C:4]([C:9]3[N:10]=[CH:11][S:12][C:13]=3[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=3[Cl:21])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc(CN)cc1
Reactant: Clc1cccc(-c2scnc2-c2cc(Br)cnc2Cl)c1Cl
Solvent: COCCOC
Product: COc1ccc(CNc2ncc(Br)cc2-c2ncsc2-c2cccc(Cl)c2Cl)cc1
Yield: 85 %

Procedure:
A solution of 5-bromo-2-chloro-3-(5-(2,3-dichlorophenyl)thiazol-4-yl)pyridine (520 mg, 1.24 mmol) and p-methoxybenzyl amine (373 mg, 2.72 mmol) in DME (12 mL) was stirred at 80° C. for 48 hours. The reaction mixture was concentrated and the residue purified by silica gel chromatography (0-25% EtOAc/hexanes) to give N-(4-methoxybenzyl)-5-bromo-3-(5-(2,3-dichlorophenyl)thiazol-4-yl)pyridin-2-amine as a pale yellow solid [631 mg, 85% yield; LC-MS, M+H=519.9; 1H-NMR (300 MHz, CDCl3) 8.85 (1 H, s), 8.00 (1 H, d, J=2.3 Hz), 7.45 (1H, dd, J=1.9, 7.6 Hz), 7.10-7.17 (4 H, m), 7.01 (1 H, d, J=2.4 Hz), 6.77 (1 H, t, J=6.7 Hz)].
Reaction SMILES: [Si]([O:8][C@@H:9]([CH3:42])[C@H:10]([C:22]1[O:26][C:25]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:29][CH:28]=2)=[N:24][N:23]=1)[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([Cl:20])[C:13]=1[CH3:21])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:20][C:14]1[C:13]([CH3:21])=[C:12]([NH:11][C@@H:10]([C:22]2[O:26][C:25]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:41])[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:29][CH:28]=3)=[N:24][N:23]=2)[C@@H:9]([OH:8])[CH3:42])[CH:17]=[CH:16][C:15]=1[C:18]#[N:19]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(NC(=O)c4ccccc4)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(NC(=O)c4ccccc4)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 11.2 %

Procedure:
To a pre-cooled (−55° C.) solution of N-(4-(5-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-cyano-2-methylphenylamino)propyl)-1,3,4-oxadiazol-2-yl)phenyl)benzamide (100 mg, 0.17 mmol) in THF (10 mL) was added TBAF (20 μL, 0.20 mmol, 1 M solution in THF) over 5 minutes. Upon complete addition the reaction mixture, was allowed to warm to room temperature over 1.5 h and stirred for a further 20 minutes before being quenched with sat. aq. NH4Cl (10 mL). The resulting mixture was partitioned between H2O (15 mL) and EtOAc (25 mL). The aqueous layer was extracted with EtOAc (25 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to provide a pale yellow oil, which was purified by flash chromatography over silica gel (60-100% EtOAc in hexanes) to provided the title compound as a colourless solid (9.3 mg, 11%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.86 (s 1H), 8.09-7.91 (m, 6H), 7.64-7.42 (m, 4H), 6.88 (d, J=8.8 Hz, 1H), 5.69 (d, J=6.6 Hz, 1H), 5.11 (dd, J=3.7, 8.2 Hz, 1H), 4.83 (br s, 1H), 4.62 (dq, J=3.5, 5.9 Hz, 1H), 2.41 (s, 3H), 1.41 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][NH:9][C@H:10]1[CH2:15][NH:14][C@H:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:30]=[C:31](Cl)OC(Cl)(Cl)Cl>C(#N)C.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][N:9]1[C:31](=[O:30])[N:14]2[CH2:15][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
To a solution of (2S,5R)-tert-butyl 5-(benzyloxyamino)piperidine-2-carboxylate (4.14 g, 13.51 mmol) in dehydrated acetonitrile (615 mL) was added triethylamine (4.9 mL) under an argon atmosphere at 0° C., followed by adding dropwise diphosgene (1.18 mL) for 5 minutes, and stirring at the same temperature for 10 minutes. To this solution was added 4-dimethylaminopyridine (182 mg), followed by raising the temperature to room temperature and allowing to react for 3 hours. The reaction mixture was concentrated under reduced pressure to the volume of one tenth thereof, the resulting concentrated solution was diluted with ethyl acetate, followed by washing with water, 5% citric acid aqueous solution, 6.5% sodium bicarbonate aqueous solution, and saturated brine sequentially, then drying over anhydrous magnesium sulfate, and distilling off the solvent under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane/ethyl acetate=2/1) to afford 3.09 g of the title compound (yield 69%). The resulting solid was recrystallized from ethyl acetate-hexane, the generated precipitate was filtered off. The wet crystal was washed with hexane, followed by drying at room temperature under reduced pressure, and the title compound was afforded as a colorless crystalline powder. Enantiomeric excess 99.4% ee (CHIRALPAK AD-H, 4.6×150 mm, hexane/ethanol=2/1, UV 210 nm, flow rate 1 mL/min., retention time 8.0 min.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][C:19](=[CH:22][CH2:23][CH3:24])[CH2:18][CH2:17]3)=[CH:12][C:11]=2[F:25])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[FH:26].C(=O)([O-])O.[Na+]>ClCCl.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:17][CH2:18][C:19]([F:26])([CH2:22][CH2:23][CH3:24])[CH2:20][CH2:21]3)=[CH:12][C:11]=2[F:25])[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: CCC=C1CCC(c2ccc(-c3cc(F)c(F)c(F)c3)c(F)c2)CC1
Reactant: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC1(F)CCC(c2ccc(-c3cc(F)c(F)c(F)c3)c(F)c2)CC1
Temperature: -25 °C
Reaction time: 1 h

Procedure:
8.0 g of 3,4,5,2'-tetrafluoro-4'-(4-propylidenecyclohexyl)biphenyl in 16 ml of dichloromethane were introduced into a Teflon apparatus and cooled to -25° C. 80 ml of a 70% solution of hydrogen fluoride in pyridine were then added dropwise with stirring, and the mixture was stirred for 30 minutes at -25° C. and then for a further 1 hour at room temperature. The reaction solution was poured into a suspension of 10 g of sodium hydrogencarbonate and 200 g of ice-water. The mixture was then extracted with 3×80 ml of hexane. The combined organic extracts were washed once with 50 ml of sodium chloride solution, dried using sodium sulfate, filtered and evaporated to a residue. The crude product was purified by means of a silica-gel frit and the eluate was evaporated to a residue, giving 3,4,5,2'-tetrafluoro-4'-(4-fluoro-4-propylcyclohexyl)-biphenyl (C 73 N (48.8) I, Δε=15.3, Δn=+0.111).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][C@@H:15]([C:28]2[N:29]=[N:30][N:31](CC3C=CC(OC)=CC=3)[CH:32]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][N:17]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)(C(F)(F)F)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([NH:14][C@@H:15]([C:28]2[N:29]=[N:30][NH:31][CH:32]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:25])[F:26])=[CH:18][N:17]=2)=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cn2cc([C@H](NC(=O)Cc3ccc(C(C)(C)C)cc3)c3ccc(OCC(F)(F)F)cn3)nn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(CC(=O)N[C@H](c2ccc(OCC(F)(F)F)cn2)c2c[nH]nn2)cc1
Temperature: 65 °C
Yield: 93.5 %

Procedure:
2-(4-tert-butylphenyl)-N-{(S)-[1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}acetamide (0.064 g, 0.11 mmol) was dissolved in TFA (1.0 mL) and heated at 65° C. for 6 h. The solvent was removed by N2 and the residue was purified by reverse-phase HPLC to give the product (0.046 g, 91%). 1H NMR (CDCl3, 400 MHz) δ 8.30 (d, J=2.8 Hz, 1H), 7.94 (d, J=6.8 Hz, 1H), 7.49 (s, 1H), 7.45 (d, J=8.8 Hz, 1H), 7.39 (dd, J=2.8, 8.8 Hz, 1H), 7.34 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 6.39 (d, J=6.8 Hz, 1H), 4.41 (q, J=8.0 Hz, 2H), 3.63 (s, 2H), 1.30 (s, 9H). HRMS (ES) [M+1]+ calcd for C22H24F3N5O2: 448.1955. Found: 448.1976.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:16][C:17]1([CH3:24])[CH2:20][N:19]([CH2:21][CH2:22]Cl)[CH2:18]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][N:10]([CH2:22][CH2:21][N:19]3[CH2:20][C:17]([CH3:24])([CH3:16])[CH2:18]3)[C:9]2=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CN(CCCl)C1
Reactant: O=C1NCCN1c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CN(CCN2CCN(c3cccc(Cl)c3)C2=O)C1
Temperature: 25 °C

Procedure:
A solution of 5 g. of 1-(m-chlorophenyl)-2-imidazolidinone in 30 ml. of dimethylformamide is added at room temperature to a mixture of 1.5 g. of 50% NaH (as a mineral oil emulsion) in 30 ml. of dimethylformamide. The reaction mixture is stirred for an hour at room temperature and 4.5 g. of 3,3-dimethyl-1-(2-chloroethyl)azetidine is added thereto. The mixture is then stirred at room temperature for an additional two hours, then heated for five hours at 80°-85° C. The by-product salts are filtered off and the solvent is removed under vacuum. The residue is taken up with 8 ml. of aqueous 18% HCl and 16 ml. of water and extracted with ether. The water solution is alkalinized by adding aqueous 15% sodium carbonate and extracted with diethyl ether. By evaporation of the organic layer, a residue is obtained that is triturated in light petroleum. Yield 7.24 g., m.p. 84°-85° C. (from hexane). The hydrochloride melts at 191°- 192° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C:33](=[O:59])[CH2:34][C:35]([O:37][C@H:38]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C:39]([OH:52])([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:36])[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C@@H:33]([OH:59])[CH2:34][C:35]([O:37][C@H:38]([C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:39]([OH:52])([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[O:36])[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CCC(=O)CC(=O)O[C@H](c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)CC(=O)O[C@H](c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 940.6 %

Procedure:
A solution of 5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-3-oxo-1-pentanoic acid, (R)-2-hydroxy-1,2,2-triphenylethyl ester (0.1 g, 0.127 mmol., 7) in 6 ml of THF/MeOH (1:2, v/v) was cooled to −78° C. To this solution was added sodium borohydride (20 mg) in two portions over a period of 0.5 h. The resulting reaction mixture was stirred at −78° C. for an additional 1 hour under nitrogen and then quenched with aqueous saturated NH4Cl solution and extracted with dichloromethane (10 mL×2). The combined dichloromethane layers were washed with brine (5 mL×2), dried (Na2SO4) and evaporated to give a white crystalline solid (0.94 g, 94%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([N:17](C(OC(C)(C)C)=O)[CH3:18])=[CH:9][CH:8]=1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([NH:17][CH3:18])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccc(N(C)C(=O)OC(C)(C)C)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(NC)c2ccccc12

Procedure:
To 3.90 g (10.9 mmol) of the above prepared [4-(tert-butoxycarbonyl-methyl-amino)-naphthalen-1-yloxy]-acetic acid ethyl ester, dissolved in 110 ml of CH2Cl2, was added via dropping funnel within 15 Min. 27.9 ml of TFA. After additional 30 Min. at RT, the bulk of the solvents was removed i. V. and the residue distributed between NaHCO3 and AcOEt. Washing with cold water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=8/2), gave 2.25 g of the title compound as off-white crystals.
Reaction SMILES: [CH3:1][C:2](O)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C[Si]([Br:24])(C)C>ClCCl.C(OCC)C>[C:13]1([C:2]([Br:24])([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:1])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCCCCCCCCC(C)(O)c1ccccc1
Reactant: C[Si](C)(C)Br
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCCCCCCC(C)(Br)c1ccccc1
Reaction time: 1 h

Procedure:
0.942 g (3.6 mmol) of 1-methyl-1-phenylundecyl alcohol was dissolved in 5 ml of dichloromethane, 1 ml of trimethylsilyl bromide (7.2 mmol) was added and the mixture stirred for 1 h under protection from moisture. The solution was diluted with 15 ml of diethyl ether, washed with water (3×10 ml), 15 ml brine, dried and evaporated to give 1.18 of crude 2-phenyl-2-bromododecane. 795 mg of silver trifluoroacetate (3.6 mmol) was dissolved in 5 ml THF. To the crude bromide was added 500 mg of 1-methyl-1-phenylundecyl hydroperoxide (1.8 mmol) dissolved in 10 ml THF. This mixture was cooled in ice-salt bath to −15° C. and the silver trifluoroacetate solution added with a pipette. 2 ml of brine was then added, followed by 10 ml conc. NaHCO3. The reaction mixture was stirred and filtered. The reaction flask and the filter cake were rinsed with 15 ml diethyl ether. The aqueous phase was separated and the organic phase washed with conc. NaHCO3, 15 ml water, 15 ml brine, dried and evaporated to give 1.40 g of a yellowish oil. Purification was done using a 1:9 ether:pentane mixture as eluent. The yield was 409 mg (43%). 13C-NMR (CDCl3) δ 14.33, 22.91, 23.96, 24.06, 24.19, 29.55, 29.72, 29.82, 30.24, 32.13, 40.68, 40.97, 84.18, 126.16, 126.69, 127.86, 145.59, 145.71