Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:12])=[CH:6][CH:7]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: CCOC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
4-(4-Ethoxycarbonylphenoxy)piperidine-1-carboxylic acid tert-butyl ester was prepared from 4-hydroxybenzoic acid ethyl ester and 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester using the procedure described in Example 103 step 1; Mp 76-78° C.; MS m/z 350 (M+H).
Reaction SMILES: Cl.CC1C(CN2C=C(N)C=N2)=C(C)[O:5]N=1.Br[CH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21].C(N(CC)CC)C>CN(C=O)C.O>[C:20]1(=[O:5])[C:19]2[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][NH:21]1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: N#Cc1ccccc1CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCc2ccccc21
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 145.1 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine-hydrochloride (100 mg, 0.44 mmol), 2-(bromomethyl)benzonitrile (115 mg, 0.6 mmol), and triethylamine (0.5 mL, 3.5 mmol) in DMF (3 mL) were irradiated and stirred in the microwave reactor at 80° C. for 10 minutes. The reaction was cooled, diluted with H2O (50 mL) and extracted with ethyl acetate (3×, 30 mL). The combined organic extracts were dried over sodium sulfate and concentrated on the rotovap. The residue was dissolved in ethanol (70 mL), H2O (3 mL) and acetic acid (1 mL) and the mixture was refluxed for 2 hours. The solution was concentrated on the rotovap, taken up in methanol (3 mL) and purified by reversed phase HPLC in 3-1 mL aliquots (5 to 95% acetonitrile in H2O: 16 minute gradient). The pure fractions were combined and concentrated on the rotovap. The residue was triturated with ethyl acetate/hexanes (1/9) to afford 2-(1-(3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)isoindolin-1-one (85 mg, 61%) as a pure white solid. 1H NMR (DMSO-d6, 400 MHz): δ2.18 (s, 3H), 2.43 (s, 3H), 4.97 (s, 2H), 5.18 (s, 2H), 7.58-7.68 (m, 3H), 7.77 (s, 1H), 8.10 (d, J=8 Hz, 1H), 8.27 (s, 1H), 9.19 (bs, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 value greater than 30 μM.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[OH-].[K+].[CH3:23]I>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH3:23])[C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([NH2:20])=[O:19])[C:11]=3[N:10]=2)=[CH:5][CH:4]=1
Reactant: CI
Reactant: COc1ccc(-c2nc3cccc(C(N)=O)c3[nH]2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1ccc(-c2nc3c(C(N)=O)cccc3n2C)cc1

Procedure:
2-(4′-Methoxyphenyl)benzimidazole-4-carboxamide (NU1076 from Example 5) (105.3 mg, 0.394 mmol) and powdered potassium hydroxide (22 mg, 0.394 mmol) were suspended in acetone (4 ml) and stirred until all the solids had dissolved. Methyl iodide (24.6 μll, 0.394 mmol) was added and the reaction stirred at room temperature overnight. The solvent was removed under reduced pressure and the white solid residue purified by column chromatography with dichloromethane/methanol 95:5 to give fine white crystals of the title compound. (33.2 mg, 30%) mp 289-292° C.; Found C 68.62 H 5.36 N 14.67 C16Hl5N3O2 Requires C 68.33 H 5.34 N 14.95; vmax(cm−1) 3309.23, 3141.44, 1671.29, 1605.30, 1255.08, δH 3.95 (3H, s), 4.02 (3H, s), 7.22-7.27 (2H, d), 7.44-7.52 (1H, t), 7.86-8.00 (5H, m), 9.4 (1H, br s, NH); m/z (EI) 281 (M+), 264, 250.
Reaction SMILES: [N:1]([C:4]1[C:5]([C:7]2[C:12]([C:13](=[O:15])[CH:14]=1)=[CH:11][C:10]([CH3:16])=[C:9]([CH3:17])[CH:8]=2)=[O:6])=[N+]=[N-].S(=O)(=O)(O)O.C1(C2C(=CC=CC=2)CO1)=O>>[C:4]([CH:14]=[C:13]1[C:12]2[C:7](=[CH:8][C:9]([CH3:17])=[C:10]([CH3:16])[CH:11]=2)[C:5](=[O:6])[O:15]1)#[N:1]
Reactant: Cc1cc2c(cc1C)C(=O)C(N=[N+]=[N-])=CC2=O
Agent: O=C1OCc2ccccc21
Agent: O=S(=O)(O)O
Product: Cc1cc2c(cc1C)C(=CC#N)OC2=O
Temperature: 3 °C
Reaction time: 0.17 h

Procedure:
2-Azido-6,7-dimethyl naphtho-1,4-quinone (2.0 g) was added in small portions (10 mg) to cold (0°-5° C.), vigorously stirred concentrated sulphuric acid (30 ml. over 11/2 hours and the red solution stirred a further 10 minutes at 3° C. until nitrogen evolution ceased. Poured onto ice-water (400 g) whereby the phthalide separated as a whitish solid. After recrystallisation from ethanol in the presence of charcoal the white solid had m.p. 165°-181° C. (mixture of E and Z isomers). (Found; C, 72.10; H, 4.77; N, 6.91; C12H9NO2 requires; C, 72.35; H, 4.55; N, 7.03%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:28]=[CH:29][CH:30]=1>>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:28]=[CH:29][CH:30]=1)#[N:7]
Reactant: CNCCc1cccc(CC(=O)OC)c1
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Product: COC(=O)Cc1cccc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)c1

Procedure:
Reaction of 1f with 2o produced 3at. MS found M+H=467. The oxalate salt of 3at was recrystallized from ethyl acetate; mp 77-82° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.Cl[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([O:8][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:6][N:7]=1
Reactant: Cc1cc(Cl)ncc1O
Reactant: Fc1ccc(CCl)cc1
Product: Cc1cc(Cl)ncc1OCc1ccc(F)cc1
Yield: 96 %

Procedure:
The title compound is prepared in 96% yield (3.38 g, white solid) from 6-chloro-4-methylpyridin-3-ol (2.00 g, 13.9 mmol) and 1-(chloromethyl)-4-fluorobenzene (3.22 g, 22.3 mmol) in a similar manner to Step-1 of Amine-49.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8]COC)[CH:5]=[CH:4][C:3]=1[C:12](=[O:23])[CH2:13][CH2:14][C:15]1[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>CC#N.O>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:12](=[O:23])[CH2:13][CH2:14][C:15]1[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1
Reactant: COCOc1ccc(C(=O)CCc2ccc(OC)nc2)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(CCC(=O)c2ccc(O)cc2O)cn1
Reaction time: 8 h
Yield: 35.8 %

Procedure:
To a solution of 1-(2-hydroxy-4-(methoxymethoxy)phenyl)-3-(6-methoxypyridin-3-yl)propan-1-one (1.62 g, 5.11 mmol) in CH3CN (30 ml) at room temperature was added TFA (2 ml) dropwise, two drops of water. The reaction was stirred at same temperature for 8 h. Aqueous 1N NaOH was added to the reaction mixture until pH=7. The aqueous was extracted with 100 ml EtOAc, and the organic layers were combined. The organic layer was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (15% EtOAc/Hexane) to provide 0.5 g (35%) of white solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6](/[C:10](=[N:21]/[O:22][CH3:23])/[CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:24]([CH:26]([C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[CH2:27][C:28]([O:30]C)=[O:29])#[N:25]>>[C:24]([CH:26]([C:32]1[CH:37]=[CH:36][C:35]([O:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11]/[C:10](/[C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[CH2:1][CH2:2][CH2:3]4)=[N:21]\[O:22][CH3:23])=[CH:14][CH:15]=2)=[CH:34][CH:33]=1)[CH2:27][C:28]([OH:30])=[O:29])#[N:25]
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccc2c(c1)CCC2
Reactant: COC(=O)CC(C#N)c1ccc(O)cc1
Product: CO/N=C(\COc1ccc(COc2ccc(C(C#N)CC(=O)O)cc2)cc1)c1ccc2c(c1)CCC2
Yield: 38.4 %

Procedure:
Compound 103 was synthesized from (4-{[(2Z)-2-(2,3-dihydro-1H-inden-5-yl)-2-(methoxyimino)ethyl]oxy}phenyl)methanol (0.25 g, 0.8 mmol) and methyl 3-cyano-3-(4-hydroxyphenyl)propanoate (0.214 g, 1.04 mmol) by following the procedure described in scheme 5 (0.008 g, yield: 38.4%); Purity: 95.42%.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH3:22])[C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][N:34]([C:2]2[N:7]=[C:6]3[N:8]([CH3:22])[C:9]4[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=4[C:5]3=[CH:4][CH:3]=2)[C:33](=[O:37])[CH:32]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cn1c2c(c3ccc(Br)nc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)nc31)CN(C(=O)OC(C)(C)C)CC2
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
tert-Butyl 2-bromo-9-methyl-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (0.73 g, 2.0 mmol), 4-benzyloxy pyridinone (0.44 g, 2.2 mmol), and Cs2CO3 (0.72 g, 2.2 mmol) were suspended in DMSO (12 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (87 mg, 0.60 mmol) and copper iodide (0.49 g, 2.6 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with 5.0:3.5:1.5 NH4Cl(aq.)/NH4OH/H2O (70 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH2Cl2 (30 mL) and washed with 5.0:3.5:1.5 NH4Cl(aq.)/NH4OH/H2O (2×30 mL). The resulting organic solution was dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. Flash chromatography (40 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 2 column volumes, increased to 50:50 over 12 column volumes and held for 5 column volumes; increased to 0:100 over 10 column volumes and held for 5 column volumes) gave the title compound (0.51 g, 52%) as a yellow foam: 1H NMR (500 MHz, DMSO-d6) δ 8.00 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.50-7.36 (m, 5H), 7.29 (d, J=8.0 Hz, 1H), 6.15 (dd, J=8.0, 2.5 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 5.16 (s, 2H), 4.57 (s, 2H), 3.75 (t, J=5.5 Hz, 2H) 3.67 (s, 3H), 2.88 (t, J=5.5 Hz, 2H), 1.42 (s, 9H); ESI MS m/z 487 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([OH:18])=O)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.CN(C(O[N:27]1N=N[C:29]2[CH:30]=[CH:31][CH:32]=[N:33][C:28]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][C:11]([CH:14]=[CH:15][C:16]([NH:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:33]=3)=[O:18])=[CH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C=Cc1cnc(-c2ccc(F)cc2)nc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(C=Cc1cnc(-c2ccc(F)cc2)nc1)Nc1ccccn1

Procedure:
The N-substituted 3-[2-(4-fluoro-phenyl)-pyrimidin-5-yl]-acrylamides of the formula Ik, which are listed in Table 8, were prepared as described in Example 116(d) from 110 mg (0.45 mmol) of 3-[2-(4-fluoro-phenyl)-pyrimidin-5-yl]-acrylic acid, 0.9 mmol of the respective amine, 171 mg (0.45 mmol) of HATU and 136.7 mg (1.35 mmol) of triethylamine.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[C:12]1[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[N:13]=1>CN(C)C=O>[C:4]1([CH2:3][S:10][C:12]2[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[C:14]([C:22]([F:23])([F:25])[F:24])[N:13]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(F)(F)F)nc1Br
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(F)(F)F)nc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of 0.28 g (0.008 mol) of 60% sodium hydride (in mineral oil, then washed with hexanes) in 7 mL dry dimethylformamide under nitrogen at 0° C. was added 0.8 mL (0.0067 mol) of benzyl mercaptan while maintaining the temperature below 10° C. The suspension was warmed to room temperature and stirred another 45 minutes before cooling back to 0° C. A solution of 2.0 g (0.0067 mol) of the product from Example 2a or 2b in 5 mL dry dimethylformamide was added dropwise and stirred 30 minutes at 0° C. The reaction was poured into ice water and extracted with ether. The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated to afford 2.3 g (100%). 1H NMR (CDCl3) δ, 3.94 (3H, s), 4.43 (2H, s), 7.2-7.6 (6H, m), 8.38 (1H, d, J=8Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=2)O1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Brc1cc(I)ccn1
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: CCO
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2ccnc(Br)c2)cc1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
To a sealed tube were added 2-bromo-4-iodopyridine 203-1 (568 mg, 2.0 mmol), ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate 203-2 (580 mg, 2.0 mmol), Pd(PPh3)4 (116 mg, 0.1 mmol), Na2CO3 (636 mg, 6.0 mmol), toluene (4 mL), H2O (4 mL) and ethanol (1 mL). The reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 80° C. for 10 hours. After cooling to room temperature, the solvents were evaporated and the residue was redissolved in water (5 ml) and extracted with ethyl acetate (5 mL×3). The combined organic phases were dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography and eluted with 15% ethyl acetate in hexane to give ethyl 2-(4-(2-bromopyridin-4-yl)phenyl)acetate 203-3. MS m/z 320.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:20]([O:18][C:17](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 63 h
Yield: 82.4 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-L-phenylalanine (30.0 g, 113 mmol) and benzyl alcohol (14.0 mL, 136 mmol) in methylene chloride (200 mL), were added successively 4-dimethylaminopyridine (1.38 g, 11.3 mmol) and WSCI.HCl (26.0 g, 136 mmol) under ice-cooling, and the mixture was stirred for 63 hr while gradually raising the temperature to room temperature. The solvent was distilled away from the reaction solution under reduced pressure, and water (200 mL) was added to the residue. The mixture was extracted with ethyl acetate (400 mL). The obtained extract solution was washed with 0.5N hydrochloric acid, water, saturated aqueous sodium hydrogencarbonate solution, water and saturated brine (each 200 mL), and dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. The obtained residue was recrystallized from hexane to give the title compound (33.1 g, 82%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1.I[CH:17]([CH3:19])[CH3:18]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:17]([CH3:19])[CH3:18])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1
Reactant: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Reactant: CC(C)I
Product: Cc1cc(CC(C)C)nc(-n2c(C)ccc2C)c1

Procedure:
By analogy to Example 71, Step A, the anion of 4,6-dimethyl-2-(2,5-dimethylpyrrol-1-yl)pyridine was alkylated with 2-iodopropane to give 4-methyl-6-(2-methylpropyl)-2-(2,5-dimethylpyrrol-1-yl)pyridine.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=O)C.C(OC(C1N=NC(OCC2[C:41]([C:46]3[CH:51]=[CH:50]C=C(F)C=3)=[N:42]OC=2C)=CC=1)=O)C.NCC1CC1>>[CH:46]1([CH2:41][NH:42][C:4]([C:6]2[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]3[C:15]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[N:16][O:17][C:18]=3[CH3:19])=[CH:10][CH:11]=2)=[O:3])[CH2:51][CH2:50]1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nn1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C)nn1
Agent: NCC1CC1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NCC2CC2)nn1
Yield: 26 %

Procedure:
As described for example 50, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (143 mg, 0.4 mmol), instead of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester, was converted, using aminomethylcyclopropane instead of methylamine, to the title compound (39 mg, 26%) which was obtained as a white solid. MS: m/e=383.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)=[O:4].[I-].[K+].C(N(CC)CC)C.[CH2:25]([CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C>[CH2:25]([CH:32]1[CH2:37][CH2:36][N:35]([CH2:2][C:3]([NH:5][C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:15])[CH2:9]3)=[O:4])[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(CCl)Nc1ccc2c(c1)CC(=O)N2
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(CN1CCC(Cc2ccccc2)CC1)Nc1ccc2c(c1)CC(=O)N2
Yield: 64.2 %

Procedure:
A mixture of 0.9 g (4 mmol) of 2-chloro-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide, 0.7 g (4 mmol) of potassium iodide, 0.6 ml (4 mmol) of triethylamine, 0.53 ml (3 mmol) of 4-benzyl-piperidine and 50 ml of acetonitrile is refluxed for 20 hours. The reaction mixture is concentrated and 30 ml of water and 30 ml of chloroform are added to the residue. The organic layer is separated and the water phase is extracted three times with 10 ml of chloroform. The combined organic layers are dried over sodium sulfate, concentrated and the residue is treated with diethylether and the precipitated crystals are filtered off to yield 0.7 g (64%) of the title compound. Melting Point: 176-180° C. (diethylether)
Reaction SMILES: [CH2:1]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]([C:23]3[C:24]([C:30]4[CH:35]=[CH:34][C:33]([O:36]C)=[CH:32][CH:31]=4)=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(O)(=O)C.I>O>[CH2:1]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]([C:23]3[C:24]([C:30]4[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=4)=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1ccc(-c2ccccc2-c2cccc(C)c2-c2ccc(OC)cc2)cc1
Agent: I
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCCCc1ccc(-c2ccccc2-c2cccc(C)c2-c2ccc(O)cc2)cc1
Temperature: 25 °C

Procedure:
4-decyl-3″-methyl-4′″-methoxyquaterphenyl of Intermediate 4 was mixed with 100 ml of acetic acid and 5 ml of 59% aqueous hydroiodic acid. The mixture was refluxed for twelve hours, cooled down to room temperature and poured into water. The product was twice extracted with methylene chloride. The combined organic layers were washed by diluted solution of sodium thiosulphate, water and dried over magnesium sulphate. After removing the solvent, the product was recrystallised from toluene-heptane mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([C:16]2([C:27]#[N:28])[CH2:25][CH2:24][C:23]3[N:22]=[CH:21][NH:20][C:19](=[O:26])[C:18]=3[CH2:17]2)=[CH:5][CH:4]=1.Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[C:27]([C:16]1([C:6]2[C:7]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[O:9][C:8]=3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:25][CH2:24][C:23]2[N:22]=[CH:21][N:20]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:19](=[O:26])[C:18]=2[CH2:17]1)#[N:28]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(C2(C#N)CCc3nc[nH]c(=O)c3C2)c2c1oc1ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cnc2c(c1=O)CC(C#N)(c1ccc(OC)c3oc4ccccc4c13)CC2

Procedure:
To a solution of the compound obtained in example 13 (170 mg, 0.46 mmol) in 5 ml of dry DMF was added ethyl bromoacetate (84.5 mg, 0.5 mmol) and cesium carbonate (195.6 mg, 0.6 mmol) at room temperature for 1 hr. Once the reaction has completed, the reaction mass was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, followed by brine, and concentrated under vacuum. The crude product was purified by column chromatography to get 175 mg (83.2% yields) of the product. MP-106.2-125.1° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([N:12]2[CH2:16][CH:15]([C:17]([F:20])([F:19])[F:18])[CH:14]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:13]2)=[O:11])[CH:3]=[CH:2]1.[CH2:35]1OCCOCCOCCOCCOCCOC1.CC([O-])(C)C.[K+].CI>CCOCC>[CH3:35][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([N:12]2[CH2:16][CH:15]([C:17]([F:19])([F:20])[F:18])[CH:14]([CH2:21][N:22]3[CH2:23][CH2:24][CH:25]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH2:26][CH2:27]3)[CH2:13]2)=[O:11])[CH:3]=[CH:2]1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: O=C(c1cccc2cc[nH]c12)N1CC(CN2CCC(c3ccc(F)cc3)CC2)C(C(F)(F)F)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CI
Product: Cn1ccc2cccc(C(=O)N3CC(CN4CCC(c5ccc(F)cc5)CC4)C(C(F)(F)F)C3)c21
Reaction time: 0.08 h

Procedure:
To a solution of 0.033 g (0.07 mmol) of 1-(7-indolecarbonyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(trifluoromethyl)pyrrolidine and 0.022 g (0.084 mmol) of 18-Crown-6 ether in 2 mL of ether at rt was added 0.084 mL of KOt-Bu (1M in t-BuOH). After stirring for 5 min, 0.006 mL (0.098 mmol) of MeI was added and the reaction was stirred for 1 h. The reaction mixture was concentrated and the residue was purified by chromatography (silica, acetone:hexanes, 1:3) to give the title compound. 1H NMR (CDCl3) δ (key peaks) 7.68-7.70 (m, 1H), 7.10-7.21 (m, 4H), 7.06 (t, 1H, J=3.0 Hz), 6.97-7.03 (m, 2H), 6.55 (d, 1H, J=3.0 hz); Mass Spectrum (ESI) m/e 488 (M+1).