Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si:4]1([C:11]2[CH:16]=[CH:15]C=CC=2)[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)CC.Br[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:29])=[C:26]([F:28])[F:27])=[C:20]([F:30])[CH:19]=1>>[CH2:11]([Si@H:4]1[CH2:5][CH2:6][C@H:7]([C:18]2[CH:23]=[CH:22][C:21]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:29])=[C:26]([F:28])[F:27])=[C:20]([F:30])[CH:19]=3)=[C:20]([F:30])[CH:19]=2)[CH2:8][CH2:9]1)[CH2:16][CH3:15]
Reactant: FC(F)=C(F)Oc1ccc(Br)cc1F
Reactant: CCC[Si]1(c2ccccc2)CCC(=O)CC1
Product: CCC[Si@H]1CC[C@H](c2ccc(-c3ccc(OC(F)=C(F)F)c(F)c3)c(F)c2)CC1

Procedure:
The general procedure of Example 36 was repeated using 4-propyl-4-phenyl-4-silacyclohexanone instead of 4-pentyl-4-phenyl-4-silacyclohexanone and 4-bromo-2-fluoro-1-(1,2,2-trifluorovinyloxy)benzene instead of 4-bromo-2,6-difluoro-1-(1,2,2-trifluorovinyl)benzene, thereby obtaining the intended compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:18])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])[C@@H:7]([CH3:17])[CH2:6][CH2:5]2.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[Br:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])[C@@H:7]([CH3:17])[CH2:6][CH2:5]2
Reactant: C[C@H]1CCc2c(ccc(Br)c2O)N1C(=O)C1CC1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H]1CCc2c(ccc(Br)c2Oc2ccccc2)N1C(=O)C1CC1
Temperature: 40 °C
Reaction time: 24 h
Yield: 70.2 %

Procedure:
A 100-mL round-bottom flask equipped with a balloon filled with air was charged with (5)-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.800 g, 2.58 mmol), phenylboronic acid (0.937 g, 7.68 mmol), pyridine (0.83 mL, 10.30 mmol), dichloromethane (50 mL), and copper (II) acetate (0.934 g, 5.14 mmol). The resulting mixture stirred at 40° C. for 1 day. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum, and the residue was purified via column chromatography on silica gel (gradient elution with 5-10% ethyl acetate/petroleum ether) to afford (S)-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.700 g, 70%) as a white solid. MS (ESI, pos. ion) m/z 386, 388 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[C:12](O)=[N:11][C:10]([NH:22][C:23]1[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=1)=[CH:9]2.O=P(Cl)(Cl)[Cl:31]>>[Cl:31][C:12]1[C:13]2[C:8](=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:14]=2)[CH:9]=[C:10]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1
Reactant: COCCOc1cc2cc(Nc3cc(C)[nH]n3)nc(O)c2cc1OCCOC
Reactant: O=P(Cl)(Cl)Cl
Product: COCCOc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OCCOC
Temperature: 170 °C
Yield: 37.6 %

Procedure:
A mixture of 6,7-Bis-(2-methoxy-ethoxy)-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ol (1.8 g, 4.64 mmol) in POCl3 (15 ml) was sealed in microwave process vial (20 ml). The mixture was heated at 170° C. for 30 minutes under microwave irradiation. After removal of solvent, the ice water was added to the residue, and the mixture was neutralized by 2M NaOH, extracted by EtOAc. The organic layer was concentrated and the residue was purified by flash column chromatography to give product as a solid (0.7 g, 37.6%). LC-MS: m/e 408 (MH+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]([CH:17]1[CH2:22][O:21][CH2:20][CH2:19][O:18]1)=[O:16].[CH:23](=[O:25])[CH3:24]>O1CCCC1>[CH3:13][O:14][C:15]([C:17]1([CH:23]([OH:25])[CH3:24])[CH2:22][O:21][CH2:20][CH2:19][O:18]1)=[O:16]
Reactant: CC=O
Reactant: COC(=O)C1COCCO1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(C(C)O)COCCO1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
A solution of N,N-diisopropylamine (1.67 g, 2.3 mL, 16.5 mmol) in anhydrous tetrahydrofuran (10 mL) was stirred at −78° C. under nitrogen. n-Butyllithium (6.6 mL, 16.5 mmol, 2.5 M solution in hexane) was added dropwise and the reaction mixture was stirred at −78° C. for 30 minutes. A solution of [1,4]dioxane-2-carboxylic acid methyl ester (1.61 g, 11 mmol) in tetrahydrofuran (10 mL) was added and the reaction mixture was stirred at −78° C. for 30 minutes. Acetaldehyde (1.45 g, 1.8 mL, 33 mmol) was added in one portion. The cooling bath was removed and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to 5° C. and ice-cold 1 M hydrochloric acid was added to acidify the reaction mixture to pH 2. Sodium chloride was added to saturate the solution and the mixture was extracted with diethyl ether (4×). The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 1:1 to 0:1 to afford the title compound (1.49 g, 71%), as an oil, and as a 3:1 mixture of diastereoisomers. LCMS (m/z) 213.2 [M+H], Tr=0.62 min.
Reaction SMILES: [CH:1]([Si:3](Cl)(Cl)Cl)=[CH2:2].[C:7]([OH:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.ClCl>CCCCCC>[CH:1]([Si:3]([O:15][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O:14][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[O:14][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:2]
Reactant: O=C(O)c1ccccc1
Reactant: C=C[Si](Cl)(Cl)Cl
Agent: ClCl
Solvent: CCCCCC
Product: C=C[Si](OC(=O)c1ccccc1)(OC(=O)c1ccccc1)OC(=O)c1ccccc1
Reaction time: 20 h

Procedure:
A six-liter three-necked flask is placed in a mushroom heating hood, and equipped with a stirrer, a reflux condenser and a dropping funnel whose nozzle bore amounts to 1 cm. 808 g (5 moles) of vinyltrichlorosilane and 1000 ml of hexane are introduced into the flask. The outlet from the reflux condenser is shielded with nitrogen. After the liquid has been heated until an intensive refluxing is taking place at the condenser, 1855 g (15.2 mol) of benzoic acid is added in 30-gram portions. The addition is completed in about 20 hours. The reaction is allowed to run, with refluxing and vigorous stirring, until the analytically determined contents of hydrolyzable chlorine amount to less than 100 parts per million.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4]([OH:6])=O.[Cl:8][C:9]1[CH:10]=[C:11]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[O:34][C@@H:35]([CH3:39])[CH2:36][NH:37][CH3:38])[N:27]=[CH:26][N:25]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[Cl:8][C:9]1[CH:10]=[C:11]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[O:34][C@@H:35]([CH3:39])[CH2:36][N:37]([CH3:38])[C:4](=[O:6])[CH2:3][N:2]([CH3:7])[CH3:1])[N:27]=[CH:26][N:25]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: CN(C)CC(=O)O
Reactant: CNC[C@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: C[C@@H](CN(C)C(=O)CN(C)C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 27 %

Procedure:
The procedure described in Example 1 was repeated using N,N-dimethylglycine and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(1S)-1-methyl-2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described for the R-antipode in Example 2.3, preparation of starting materials) to give the title compound in 27% yield; NMR spectrum (DMSO-d6) 1.37 (d, 3H), 2.06 (s, 6H), 3.08 (s, 3H), 3.23 (dd, 1H), 3.25 (s, 2H), 4.26 (dd, 1H), 5.10 (m, 1H), 5.29 (s, 2H), 7.23 (m, 2H), 7.30 (d, 1H), 7.35 (m, 1H), 7.56 (s, 1H), 7.68 (m, 2H), 7.87 (dt, 1H), 8.13 (d, 1H), 8.44 (s, 1H), 8.58 (d, 1H), 9.90 (s, 1H); Mass Spectrum MH+ 535.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12](O)(=O)CC(O)=O>>[O:5]=[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])[CH3:12]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: O=C(O)CC(=O)O
Product: CC(=O)c1ccccc1C(=O)O

Procedure:
(i) Using the method of Preparation 3, phthalic anhydride and malonic acid gave 2-(1'-oxoethyl)benzoic acid (m.p. 110°) and thence 1-hydroxymethyl-2-(1'-hydroxyethyl)benzene (oil)
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([NH:8][C:9](=[O:18])[C:10]([CH3:17])([CH3:16])[CH:11]([OH:15])[CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1.I[CH3:22]>CN(C)C(=O)C.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:8][C:9](=[O:18])[C:10]([CH3:16])([CH3:17])[CH:11]([O:15][CH3:22])[CH:12]([CH3:13])[CH3:14])=[CH:19][CH:20]=1
Reactant: CC(C)C(O)C(C)(C)C(=O)Nc1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(C(C)C)C(C)(C)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 44.7 %

Procedure:
To a stirred suspension of sodium hydride (0.25 g of a 60% dispersion in mineral oil, 5.1 mmol) in N,N-dimethylacetamide is added dropwise a solution of 4′-chloro-3-hydroxy-2,2,4-trimethylvaleranilide (1.5 g, 5.6 mmol) in N,N-dimethylacetamide. After stirring for 40 minutes at room temperature, iodomethane (1.58 g, 11.1 mmol) is added. The reaction mixture is stirred at room temperature for 18 hours, diluted with water, and extracted with ether. The combined organic extracts are washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a semisolid. Flash column chromatography of the semi-solid using silica gel and an ethyl acetate/hexanes solution (1:10) gives the title product as a white solid (0.71 g, mp 103-107° C.) which is identified by 1H NMR spectral analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.Br[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1.[Pd](Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:12]2[C:13]([C:14]#[N:15])=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: N#Cc1ccccc1Br
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
4-methoxyphenylmagnesium bromide (280 g, 15% solution in tetrahydrofuran) is added dropwise over seven hours to a refluxing solution of 2-bromobenzonitrile (32 g), palladium (II) chloride (1.3 g) and triphenylphosphine (3.8 g) in tetrahydrofuran (210 ml). [HPLC: yield 94-95%]. After cooling to room temperature and the addition of water (50 ml), tetrahydrofuran is removed under vacuum. The residue is extracted with toluene (230 ml). Insoluble material is filtered off and the solvent distilled off. The crude product is recrystallised from ethanol to give 4'-methoxybiphenyl-2-carbonitrile as a solid, m.pt. 82-83° C. 1H NMR (CDCl3): 3.90(s,3H), 7.02(d,2H), 7.36-7.52(m,4H), 7.59-7.65(m,1H), 7.74(d,1H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C@@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])[CH2:5][C@H:4]([C:15]([O:17][CH3:18])=[O:16])[CH2:3]1.[CH3:19]I.[H-].[Na+].Cl>CN(C)C=O>[CH3:19][C:4]1([C:15]([O:17][CH3:18])=[O:16])[CH2:3][C:2](=[O:1])[N:6]([C@@H:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])[CH2:5]1
Reactant: CI
Reactant: COC(=O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(C)CC(=O)N([C@H](C)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl (3R)-5-oxo-1-[(R)-1-phenylethyl]pyrrolidin-3-yl-carboxylate (49.5 g, 200 mmol) and methyl iodide (37.4 mL, 600 mmol) in dimethylformamide (1 L), sodium hydride (in oil; content, 55%; 11.35 g: 260 mmol) was gradually added in 5 minutes at room temperature. After stirring at room temperature for 2 hours, methyl iodide (24.9 mL, 400 mmol) and sodium hydride (in oil; content, 55%; 6.11 g; 140 mmol) were further added, and the mixture was stirred for another 4 hours. The reaction mixture was added to 0.5N hydrochloric acid (1 L) in an ice bath, and extracted with ethyl acetate (2 L+1 L). The organic layers were combined and washed with water (1 L×2) and saturated aqueous solution of sodium chloride (1 L), and dried with anhydrous sodium sulfate. After removing the dessicating agent by filtration, the solvent was removed by distillation under reduced pressure. The thus obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate, 80:20→67:33→50:50→33:67) to obtain stereoisomers at position 3 of the title compound (stereoisomer A: 19.86 g (76.0 mmol, 38%) as a pale yellow oil, stereoisomer B: 20.22 g (77.4 mmol, 39%) as a pale yellow solid, and a mixture of stereoisomers A and B: 9.69 g (37.1 mmol, 19%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:20]=1)[CH2:16]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C=O)C>[CH2:1]([O:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:20]=1)[CH2:16][N:33]=[N+:34]=[N-:35])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCOc1cc(CCl)cc(OCCCCCCCCCCC)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCOc1cc(CN=[N+]=[N-])cc(OCCCCCCCCCCC)c1
Reaction time: 1 h
Yield: 97.1 %

Procedure:
3,5-diundecoxybenzyl chloride (13.5 g, 30.1 mmol) was dissolved in DMF (50 mL) in a 250 mL RBF. Sodium azide (3.94 g, 60.2 mmol) and a magnetic stir bar were added to the RBF. A heating mantel was used to gently heat the reaction mixture. After 1 hour, thin layer chromatography indicated that no starting material was present. The contents of the RBF were transferred to a separatory funnel. Ether (250 mL) and distilled H2O (250 mL) were added to the funnel. The aqueous layer was washed 2 times with ether (250 mL). The ether layers were combined and washed 2 times with saturated ammonium chloride solution (125 mL) and once with saturated sodium chloride solution (125 mL). The ether layer was then dried with magnesium sulfate, gravity filtered and concentrated using rotary evaporation. The resulting light yellow oil was then placed under high vacuum where it solidified. This produced a 13.3 g yield or a 97.1% yield of the derivative. The NMR characterization data for the derivative is as follows. 1NMR (300 MHz, CDCl3): 0.88 (t, J=6.3, 6H, CH2CH3), 1.21-1.44 (m, 32H, CH2(CH2)7), 1.77 (p, J=6.6, 4H, OCH2CH2), 3.93 (t, J=6.6, 4H, OCH2), 4.24 (s, 2H, ArCH2Cl), 6.41-6.43 (m, 2H, ArH). 13C NMR (75 MHZ, CDCl3): 14.22, 22.79, 26.13, 29.33, 29.44, 29.49, 29.68, 32.00, 55.00, 68.16, 101.07, 106.50, 137.45, 160.68.
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[C:7]([N+:16]([O-:18])=[O:17])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Oc1cccc2c1OC(C)(C)C2
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1cc([N+](=O)[O-])cc2c1OC(C)(C)C2
Reaction time: 1 h

Procedure:
2,3-Dihydro-2,2-dimethyl-7-benzofuranol (16.4 g, 0.1 mol) was dissolved in 100 ml of an aqueous solution of sodium hydroxide (6.0 g, 0.15 mol), and 12.8 g of acetic anhydride was dumped into the solution and thoroughly mixed, whereby a white solid substance was precipitated. This substance was collected by filtration and dried, whereby 19.5 g of 7-acetoxy-2,3-dihydro-2,2-dimethylbenzofuran was obtained. The melting point of this product was 48.5°-49.5° C. This phenol acetate was dissolved in 400 ml of chloroform, and 60 ml of 70% nitric acid was dropwise added at -5° C. Then, the stirring was continued at 10° C. for one hour. The reaction solution was washed with water, then dried over anhydrous sodium sulfate and concentrated. The solid substance thereby obtained was recrystallized from benzene-cyclohexane, whereby 19.6 g of 7-acetoxy-2,3-dihydro-2,2-dimethyl-5-nitrobenzofuran was obtained. The melting point of this product was 141°-142° C. The structure was confirmed by 1H-NMR spectrum and IR spectrum. Then, the product was added to a solution containing 35 g of sodium hydroxide in 200 ml of water and 50 ml of methanol, and heated at 40° C. for 15 minutes to complete hydrolysis. The reaction solution was neutralized by concentrated hydrochloric acid, and then extracted with ether. The extracted solution was washed with water, then dried over anhydrous sodium sulfate and concentrated, whereby 13.0 g of substantially pure 2,3-dihydro-2,2-dimethyl-5-nitro-7-benzofuranol was obtained. The melting point of this product was 97°-97.5° C. The phenol thus obtained, was reacted with O-ethyl-S-n-propyl-thiophosphoryl chloride in the same manner as in Example 1, whereby the compound (No. 4) identified in Table 1 was obtained as oily substance.
Reaction SMILES: [OH-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:13]=[C:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])[O:11][N:10]=1>CO>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:13]=[C:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[O:11][N:10]=1
Reactant: CCOC(=O)CCCCCCCc1nc(-c2ccccn2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCCCCc1nc(-c2ccccn2)no1
Reaction time: 3 h

Procedure:
Add 2 N sodium hydroxide (20 mL) to a solution of ethyl 8-(3-pyridin-2-yl[1,2,4]oxadiazol-5-yl)octanoate in methanol (100 mL) at room temperature under nitrogen and stir the mixture for 3 hours. Remove the solvent under reduced pressure, dilute the residue with water and wash with diethyl ether. Adjust the aqueous layer to pH 1 with 2 N HCl and collect the solids by vacuum filtration to afford the title compound. APCI mass spectrum m/z 288 [C15H19N3O3—H]−.
Reaction SMILES: [K].C([O-])(C)(C)C.[O:7]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:21]([N:23]([CH2:30][CH3:31])[C:24](=[O:29])[CH:25](Cl)[CH2:26][CH3:27])[CH3:22].C(OCC)C>CS(C)=O>[CH2:21]([N:23]([CH2:30][CH3:31])[C:24](=[O:29])[CH2:25][CH2:26][CH2:27][O:20][C:17]1[CH:16]=[CH:15][C:14]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:19][CH:18]=1)[CH3:22]
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CCC(Cl)C(=O)N(CC)CC
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCN(CC)C(=O)CCCOc1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
17 g of potassium-tert.-butanolate is added at 10° C to a solution of 28 g of 4-phenoxy-phenol in 100 ml of anhydrous dimethylsulphoxide. After the base has completely dissolved, an addition is made dropwise in the course of 2 hours, with stirring, of 26.5 g of chlorobutyric acid diethylamide dissolved in 20 ml of dimethylsulphoxide and the whole is further stirred overnight at room temperature. For further processing, the reaction mixture is poured into ice water, and extraction is repeatedly performed with diethyl ether. The combined ether phases are washed four times with cold 10% potassium hydroxide solution and subsequently repeatedly with water; they are then dried by means of sodium sulphate. After the ether has been distilled off, there is obtained crude 4-[(4-phenoxy)-phenoxy]-butyric acid diethylamide, which is purified by chromatography on silica gel (eluant: ether/hexane 1:3), and recrystallised from isopropanol/hexane, M.P. 73°-74° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[S:16][CH3:17])[C:10](O)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[S:16][CH3:17])[C:10]([Cl:20])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: CSc1ccc(C(=O)O)cc1OC1CCCC1
Solvent: Cc1ccccc1
Product: CSc1ccc(C(=O)Cl)cc1OC1CCCC1

Procedure:
3-Cyclopentyloxy-4-(methylthio)benzoic acid (0.7 g) is dissolved in toluene (20 mL) and heated at 80° C. for 1 hour 30 minutes in the presence of thionyl chloride (5 mL). The reaction mixture is concentrated to give 3-cyclopentyloxy-4-(methylthio)benzoyl chloride (0.76 g), in the form of a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:22][CH2:23][OH:24]>CO>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:22][CH2:23][OH:24])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCBr
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(CCO)CC1

Procedure:
To a solution of piperidin-4-yl-carbamic acid tert-butyl ester 3 (10 g, 50 mmol) in 100 ml of methanol are added sodium carbonate (21.2 g, 200 mmol) and 2-bromoethanol (7.1 ml, 100 mmol). The mixture is stirred over night. The solvents are then evaporated and the residue is triturated with DCM, filtered and evaporated again. The crude product is purified by chromatography using EtOAc/MeOH (saturated with ammonia): 9/1.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[N:39][C:40]([N:43]2[CH2:46][C:45]([F:48])([F:47])[CH2:44]2)=[N:41][CH:42]=1>>[F:48][C:45]1([F:47])[CH2:46][N:43]([C:40]2[N:39]=[CH:38][C:37]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:42][N:41]=2)[CH2:44]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: FC1(F)CN(c2ncc(Br)cn2)C1
Product: C[C@@H](c1ccc(-c2cnc(N3CC(F)(F)C3)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared following a procedure analogous to Example 31 using (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one and 5-bromo-2-(3,3-difluoroazetidin-1-yl)pyrimidine. LC (method 5): tR=1.7 min; Mass spectrum (ESI+): m/z=523 [M+H]+; 1H NMR (CD3OD) δ 0.94 (s, 3H), 1.25 (s, 3H), 1.54 (d, 3H), 2.14 (s, 2H), 2.20 (m, 1H), 2.46 (m, 2H), 3.03 (m, 1H), 4.51 (m, 4H), 5.57 (q, 1H), 7.07 (d, 2H), 7.25-7.40 (m, 7H), 8.60 (s, 2H).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:26][C:27]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=2)[O:29][N:28]=1>C(#N)C>[CH3:41][C:38]([C:35]1[CH:34]=[CH:33][C:32]([C:30]2[O:29][N:28]=[C:27]([CH2:26][N:5]3[C:6]4[C:11](=[C:10]([C:13]([F:15])([F:16])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH2:1][CH2:2][CH3:3])[N:31]=2)=[CH:37][CH:36]=1)([CH3:39])[CH3:40]
Reactant: CC(C)(C)c1ccc(-c2nc(CBr)no2)cc1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2ccc(C(C)(C)C)cc2)n1
Yield: 157 %

Procedure:
To a solution of 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 153A) (0.100 g, 0.396 mmol) in anhydrous acetonitrile (20 mL) was added Cs2CO3 (1.30 g, 4.00 mmol) and 3-(bromomethyl)-5-[4-(1,1-dimethylethyl)phenyl]-1,2,4-oxadiazole (0.176 g, 0.596 mmol). The mixture was heated under N2, for 2 h. Upon cooling, the mixture was partitioned between EtOAc and water. The organic phase was separated, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc-hexanes gradient) to afford a pure product (0.29 g, 16% yield): MS (ES) m/z 466 (M+).