Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:17][C:18]1[N:19]=[C:20]([NH2:23])[S:21][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:23][C:20]3[S:21][CH:22]=[C:18]([CH3:17])[N:19]=3)[CH:7]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(Oc2ccnc(Cl)c2)cc1
Reactant: Cc1csc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(Oc2ccnc(Nc3nc(C)cs3)c2)cc1
Yield: 48.4 %

Procedure:
Using the method of Example 3, Step B, 2-chloro-4-(4-methoxyphenoxy)pyridine (2.952 g, 12.53 mmol), 4-methylthiazol-2-amine (28.47 mL, 11.39 mmol), potassium phosphate (2.417 g, 11.39 mmol), Pd2(dba)3, (0.2607 g, 0.2847 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.1812 g, 0.3131 mmol) were reacted in toluene (30 mL) and water (8 mL) to provide 4-(4-methoxyphenoxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine (1.726 g, 44.50% yield) as yellow solid. 1H NMR (CDCl3) δ 8.10 (d, 1H), 6.96 (m, 2H), 6.87 (m, 2H), 6.42 (dd, 1H), 6.26 (d, 1H), 6.18 (d, 1H), 3.80 (s, 3H), 2.15 (s, 3H); Mass spectrum (esi) m/z=314 (100) (+H).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:27][CH3:28])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].P(Br)(Br)([Br:32])=O>CC#N>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:32])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:27][CH3:28])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Br)(Br)Br
Reactant: CCCCOC(=O)c1nc(O)c2ccc(Oc3c(C)cccc3CC)cc2c1O
Solvent: CC#N
Product: CCCCOC(=O)c1nc(Br)c2ccc(Oc3c(C)cccc3CC)cc2c1O
Reaction time: 1 h
Yield: 34.7 %

Procedure:
A mixture of 6-(2-Ethyl-6-methyl-phenoxy)-1,4-dihydroxy-isoquinoline-3-carboxylic acid butyl ester (2.83 mmol, 1.12 g), POBr3 (11 mmol, 3.19 g), MeCN (20 mL) was refluxed gently with stirring for 1 h before it was concentrated in vacuo. The residue was dissolved in CHCl3 (50 mL). Water (10 mL) and subsequently small portions of NaHCO3 (6 g) were added with stirring. The mixture was stirred for 30 min at ambient temperature before it was filtered through a pad of celite. The filtrate was dried over MgSO4. Concentration and purification of the residue by flash column chromatography on silica gel using CH2Cl2 as the eluent gave the title compound as a tan oil (450 mg); MS-(+)-ion: M+1, 79Br/81Br=458.4 and 460.6.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]([C:38](O)=[S:39])=[C:32]2[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[NH2:47][CH2:48][C:49]1[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=1.C(N(CC)CC)C>CN(C)C=O>[N:51]1[CH:52]=[CH:53][CH:54]=[C:49]([CH2:48][NH:47][C:38]([C:33]2[NH:34][C:35]3[C:31]([C:32]=2[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:30][C:29]([Cl:28])=[CH:37][CH:36]=3)=[S:39])[CH:50]=1
Reactant: NCc1cccnc1
Reactant: OC(=S)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: S=C(NCc1cccnc1)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorphosphate (0.73 g, 1.6 mmol) was added to a solution of 5-chloro-3-phenylthio-indole-2-carboxylic acid (0.50 g, 1.6 mmol), 3-aminomethylpyridine (0.35 g, 3.2 mmol) and triethylamine (0.50 mL, 3.2 mmol) in degassed dimethylformamide (25 mL). The reaction was stirred at room temperature overnight. The precipitated product was filtered and the filter cake washed well with water. The solid was triturated with 30% ethyl acetate in hexane, filtered and dried at 60° C. in vacuo for 72 h. The title compound was obtained as an off-white solid, mp 240°-241° C. Anal. Calc. for C21H16ClN3OS.0.25 H2O: C, 63.31; H, 4.17; N, 10.54. Found: C, 63.34; H, 4.06; N, 10.71. NMR (DMSO-d6): δ12.54 (1H, s), 8.91 (1H, t, J=6 Hz), 8.51 (1H, s), 8.42 (1H, d, J=5 Hz), 7.58 (2H, m), 7.45 (1H, m), 7.25 (4H, m), 7.15 (1H, t, J=7 Hz), 7.04 (2H, d, J=8 Hz), 4.58 (2H, d, J=6 Hz).
Reaction SMILES: C1(O)C=CC=CC=1.BrCCCCCCCCCO.[O:19]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O(CCCCCCCCC(O)=O)C1C=CC=CC=1.Cl.Cl.[CH2:56]([O:63][C:64](=[O:72])[CH2:65][C@@H:66]([NH2:71])[CH2:67][N:68]([CH3:70])[CH3:69])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>>[CH2:56]([O:63][C:64](=[O:72])[CH2:65][C@@H:66]([NH:71][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:67][N:68]([CH3:69])[CH3:70])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: OCCCCCCCCCOc1ccccc1
Agent: Cl
Agent: O=C(O)CCCCCCCCOc1ccccc1
Agent: OCCCCCCCCCBr
Solvent: Oc1ccccc1
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCOc1ccccc1

Procedure:
The title compound, m/e=379.4 ([M+H]+), was produced in analogy with example 18, steps 1 to 4. Thus, phenol was alkylated in step 1 with 9-bromo-1-nonanol, leading to 9-phenoxy-nonan-1-ol, which was oxidized in step 2 to 9-phenoxy-nonanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-[9-phenoxy-nonanoylamino]-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2([CH2:27][NH2:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2([CH2:27][NH:28][C:9](=[O:11])[CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:23][CH2:24][CH2:25][CH2:26]2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(C2(CN)CCCC2)cc1OC
Reactant: O=C(O)CCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C2(CNC(=O)CCc3ccccc3)CCCC2)cc1OC
Reaction time: 16 h
Yield: 25.9 %

Procedure:
3-Phenyl-propionic acid (30.0 mg, 0.200 mmol) and C-[1-(3,4-Dimethoxy-phenyl)-cyclopentyl]-methylamine (47.1 g, 0.200 mmol) were dissolved in acetonitrile (1 mL) containing triethylamine (83.6 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (76.0 mg, 0.200 mmol) was added and the solution was allowed to stir for 16 hours. The mixture was then purified by reverse phase preparative liquid chromatography to yield the pure product (19.0 mg, 0.0517 mmol, 25.8%) ESI-MS m/z calc. 367.2, found 367.5 (M+1)+. Retention time of 3.05 minutes.
Reaction SMILES: [C:1]([Si:5]([CH3:13])([CH3:12])[O:6][CH2:7][CH2:8][CH2:9][S:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[O-:14]I(=O)(=O)=O.[Na+]>O.CO>[C:1]([Si:5]([CH3:12])([CH3:13])[O:6][CH2:7][CH2:8][CH2:9][S:10]([CH3:11])=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSCCCO[Si](C)(C)C(C)(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)CCCO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A solution of tert-butyldimethyl(3-(methylthio)propoxy)silane (0.1 mol) in water/MeOH (3:2, 500 mL) at 0° C. was added sodium (meta)periodate (˜30 g). The reaction mixture was stirred first at 0° C. for 20 hours, then at room temperature for 3 hours. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure to remove the most of the organic solvent. The aqueous residue was then extracted with CHCl3 (2×) and the combined organic extracts were dried with anhydrous sodium sulfate. The organic phase was decanted and concentrated to yield the title compound as an oil which solidified to provide a white solid upon standing (17.65 g).
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([O:8][C:9]2[C:17]3[O:16][CH:15]=[CH:14][C:13]=3[CH:12]=[C:11]([N+:18]([O-])=O)[CH:10]=2)[CH2:6][CH2:5][N:4]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:3]1.O.NN>C1COCC1.C(O)C.[Ni]>[NH2:18][C:11]1[CH:10]=[C:9]([O:8][C@H:7]2[CH2:6][CH2:5][N:4]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:3][C@H:2]2[F:1])[C:17]2[O:16][CH:15]=[CH:14][C:13]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2cc([N+](=O)[O-])cc3ccoc23)[C@H](F)C1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2cc(N)cc3ccoc23)[C@H](F)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl cis-3-fluoro-4-[(5-nitro-1-benzofuran-7-yl)oxy]piperidine-1-carboxylate (200 mg, 0.526 mmol; Intermediate 50) dissolved in THF (10 mL) and ethanol (40 mL), was added Raney-nickel (as a slurry in ethanol) and hydrazine hydrate (0.2 mL). The mixture was stirred at room temperature for 30 min and then filtered through Celite and evaporated. The residue was re-dissolved in toluene and evaporated again. This material was used directly in the subsequent experiment.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH2:44][CH2:45][CH2:46][NH:47]C(=O)OC(C)(C)C)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[N:18](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:19]=[C:20]([C:21]([F:24])([F:23])[F:22])[C:13]=34)[CH:11]=2)[CH2:5][CH2:4]1)#[N:2].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:47][CH2:46][CH2:45][CH2:44][C:8]1[CH:7]=[C:6]([C:3]2([C:1]#[N:2])[CH2:5][CH2:4]2)[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]3[NH:18][N:19]=[C:20]([C:21]([F:23])([F:24])[F:22])[C:13]=23)[CH:9]=1
Reactant: CC(C)(C)OC(=O)NCCCc1cc(-c2ccnc3c2c(C(F)(F)F)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc(C2(C#N)CC2)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1(c2cc(CCCN)cc(-c3ccnc4[nH]nc(C(F)(F)F)c34)c2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
tert-Butyl 3-(3-(1-cyanocyclopropyl)-5-(3-(trifluoromethyl)-1-trityl-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)propylcarbamate (72 mg, 0.09893 mmol) was dissolved in DCM (3 mL) and cooled to 0° C. Triethylsilane (46.01 mg, 63.20 μL, 0.3957 mmol) was added followed by TFA (0.5 mL). The reaction was stirred at 0° C. for 1 hour then the solvent removed under reduced pressure. The crude product was dissolved in DMSO and purified by FractionLynx. The fractions were passed through bicarbonate cartridges to obtain free base and lyophilised to give 1-(3-(3-aminopropyl)-5-(3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)cyclopropanecarbonitrile as a white solid (22 mg, 57%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]4[O:25][CH2:24]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:4]([F:26])[CH:3]=1.OC1C=C2C(C(NC3C=CC([Br:45])=CC=3F)=NC=N2)=CC=1OC.BrCC1OC1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:45][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]4[O:25][CH2:24]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:4]([F:26])[CH:3]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCC1CO1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Agent: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCC1CO1
Yield: 26 %

Procedure:
Using a similar procedure to the one described in Example 2 for the preparation of 4-(4-chloro-2fluorophenylamino)-7-(2,3-epoxypropoxy)-6-methoxyquinazoline, 7-hydroxy-6-methoxy-4-(2-fluoro-4-bromophenylamino)quinazoline (6 g, 16.5 mmol) was reacted with 1-bromo-2,3-epoxypropane (1.7 ml, 19.8 mmol) in DMF (50 ml) in the presence of potassium carbonate (4.55 g, 3.3 mmol) and purified as described to give 4-(4-bromo-2-fluorophenylamino)-7-(2,3-epoxypropoxy)-6-methoxyquinazoline (1.8 g, 26%).
Reaction SMILES: [C:1]([S:5]([O:8][K])(=[O:7])=[O:6])([F:4])([F:3])[F:2].[OH:10][S:11]([OH:14])(=[O:13])=[O:12]>>[S:11](=[O:12])(=[O:10])([OH:14])[OH:13].[C:1]([S:5]([OH:8])(=[O:7])=[O:6])([F:4])([F:3])[F:2]
Reactant: O=S(=O)(O[K])C(F)(F)F
Agent: O=S(=O)(O)O
Product: O=S(=O)(O)C(F)(F)F

Procedure:
That is, CH3SO2F is subjected to electrolytic fluorination using HF to obtain CF3SO2F. The resultant CF3SO2F is subjected to hydrolysis using KOH to obtain CF3SO3K. The CF3SO3K obtained is subjected to acid decomposition with the use of concentrated H2SO4 and if necessary, additionally fuming sulfuric acid at elevated temperature and under reduced pressure to obtain a CF3SO3H-containing reaction product. The reaction product obtained is subjected to simple distillation at a temperature of from 120° to 200° C. and under condition of reduced pressure of from 50 to 10 Torr to obtain a distillate of CF3SO3H. Thus, there is obtained a crude product of CF3SO3H. This CF3SO3H product still contains a certain amount of those impurities as above described.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1.[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.[K].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[S:16]1[CH:17]=[CH:18][C:14]([C:10]2[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=2)[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]2[C:22](=[O:24])[C:21]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]3[C:19]2=[O:29])=[CH:15]1
Reactant: BrCCCCCOc1cccc(-c2ccsc2)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCCCOc1cccc(-c2ccsc2)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 46.3 %

Procedure:
0.65 g of 3-[3-(5-bromopentyloxy)phenyl]thiophene, 0.37 g of potassium phthalimide and 0.14 g of potassium carbonate were dissolved in 5 ml of dimethylformamide, and the mixture was heated at 50° C. with stirring for 5 hours. Ethyl acetate and water were added, and the organic layer separated was worked up in a customary manner. The product was purified by silica gel column chromatography [hexane/ethyl acetate=7/1→5/1] to give 0.36 g of N-[5-[3-(3-thienyl)-phenoxy]pentyl]phthalimide as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30]>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=3)[N:14]=2)(=[O:26])=[O:27])=[CH:21][C:20]=1[C:29]([F:32])([F:30])[F:31]
Reactant: O=S(=O)(Cl)c1ccc(F)c(C(F)(F)F)c1
Reactant: Nc1cccc(COCc2ccc(F)cc2)n1
Product: O=S(=O)(Nc1cccc(COCc2ccc(F)cc2)n1)c1ccc(F)c(C(F)(F)F)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(4-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.07 g) and 4-fluoro-3-(trifluoromethyl)-benzenesulfonyl chloride (0.087 g) as alight yellow gum (0.11 g). MS (ESI−): 457.2 ([M−H]−).
Reaction SMILES: C[Mg]I.[Mg].[CH3:5]I.[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([F:16])[CH:9]=1>C(OCC)C>[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]([OH:13])[CH3:5])=[C:10]([F:16])[CH:9]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CI
Agent: C[Mg]I
Agent: [Mg]
Solvent: CCOCC
Product: CC(O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a ice-cold solution of methyl magnesium iodide prepared from magnesium (1.7 g, 73.88 mmoles) and methyl iodide (4.58 ml, 73.88 mmoles) in diethyl ether (50 ml), 4-bromo-2-fluorobenzaldehyde (5 g, 24.62 mmoles) in diethyl ether (10 ml) was added and warmed to room temperature. After 12 h, the reaction mixture was cooled to 0° C., quenched with dilute HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as red colour liquid (5 g, 94% yield). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 7.40 (t, J=8.2 Hz, 1H), 7.30 (dd, J=8.3, 1.7 Hz, 1H), 7.21 (dd, J=9.9, 1.9 Hz, 1H), 5.17 (q, J=6.4 Hz, 1H), 1.49 (d, J=6.5 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].II.[CH:11]([C:13]1[C:21]2[O:20][CH2:19][CH:18]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[C:17]=2[C:16]([CH3:31])=[C:15]([NH:32][C:33](=[O:39])[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:14]=1[CH3:40])=[O:12]>C1COCC1>[OH:12][CH:11]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:13]1[C:21]2[O:20][CH2:19][CH:18]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[C:17]=2[C:16]([CH3:31])=[C:15]([NH:32][C:33](=[O:39])[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:14]=1[CH3:40]
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: Brc1ccccc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1C(O)c1ccccc1)OCC2c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.6 %

Procedure:
A solution of bromobenzene (770 mg, 4.91 mmol) in THF (10 mL) was added under an argon atmosphere to a mixture of magnesium (119 mg, 4.91 mmol) and a catalytic amount of iodine, and the resulting mixture was stirred at room temperature for 20 minutes. To the reaction solution was added dropwise a solution of N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (400 mg, 0.98 mmol) obtained in Example 20 in THF (5 mL) and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution was added to ice and the product was extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 512 mg (yield: 99%) of the title compound. Yield: 99%. Oily matter.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O-:19])=[O:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+].C(O)C.S(O[CH:35]([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])(C1C=CC(C)=CC=1)(=O)=O>O>[CH:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:41])=[O:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])Cc1ccc(NCCC2CCCCC2)cc1
Reactant: CCOC(=O)C(C)OS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)OC(=O)Cc1ccc(NCCC2CCCCC2)cc1

Procedure:
To a warm mixture of 7 g. sodium 4-(2-cyclohexylethylamino)phenylacetate in 100 ml. ethanol is added 4.7 g. ethyl 2-tosyloxypropionate. After 17 hours at reflux, the cooled solution is diluted with an equal volume of water and the resultant precipitate is filtered. After washing with cold ethanol and drying, the product is crystallized from acetonitrile to yield 1-(ethoxycarbonyl)ethyl 4-(2-cyclohexylethylamino)phenylacetate as colorless crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:15][CH3:16])[CH2:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[O:6]1)=[O:4].[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([CH3:28])([CH3:27])[CH2:25][CH3:26])[CH:21]=[CH:20][C:19]=1[O:29][CH2:30][CH2:31][CH2:32]I>>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:28])[CH2:25][CH3:26])[CH:21]=[CH:20][C:19]=1[O:29][CH2:30][CH2:31][CH2:32][O:14][C:11]1[CH:12]=[CH:13][C:7]2[O:6][C:5]([CH2:15][CH3:16])([C:3]([OH:2])=[O:4])[CH2:9][C:8]=2[CH:10]=1
Reactant: CCC(C)(C)c1ccc(OCCCI)c(Cl)c1
Reactant: CCC1(C(=O)OC)Cc2cc(O)ccc2O1
Product: CCC1(C(=O)O)Cc2cc(OCCCOc3ccc(C(C)(C)CC)cc3Cl)ccc2O1

Procedure:
The title compound was prepared following the general procedure described in Example 1, Step 4 employing the phenol prepared in Example 4, Step 1 and the iodide prepared in Step 1.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH3:19])[C:3]=1[I:20].C(ON=O)(C)(C)C>O1CCCC1>[Cl:13][C:12]1[CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=[C:8]([Cl:18])[C:7]=1[N:6]1[CH:2]=[C:3]([I:20])[C:4]([CH3:19])=[N:5]1
Reactant: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1I
Temperature: 25 °C

Procedure:
To a stirred solution of 5-amino -1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodo-3-methylpyrazole (2.85 g) in tetrahydrofuran (35 ml) at 0° C. was added dropwise t-butylnitrite (2.33 ml). The reaction mixture was allowed to warm to room temperature and then heated under reflux for 1.5 hours. The reaction mixture was evaporated and the residue purified by column chromatography on silica gel eluted with dichloromethane: hexane (1:1). Combination and evaporation of suitable fractions provided a yellow oil which was further purified by column chromatography on silica gel eluted with dichloromethane: hexane (1:2). Combination and evaporation of suitable fractions provided the title compound as a white solid, m.p. 118.5-119.4° C.
Reaction SMILES: [Cl-:1].[NH2:2][N+:3]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[C:4]=1[CH2:21][CH3:22].[CH3:23][N:24]([CH3:33])[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1>C(O)(=O)C>[Cl-:1].[CH2:21]([C:4]1[N:5]([CH2:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:6]=[CH:7][N+:3]=1[N:2]=[CH:29][C:28]1[CH:31]=[CH:32][C:25]([N:24]([CH3:33])[CH3:23])=[CH:26][CH:27]=1)[CH3:22]
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CCc1n(Cc2cc(OC)c(OC)c(OC)c2)cc[n+]1N
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCc1n(Cc2cc(OC)c(OC)c(OC)c2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 52 h

Procedure:
(ii.c) 1.9 g of 1-amino-2-ethyl-3-(3,4,5-trimethoxybenzyl)imidazolium chloride are dissolved in 38 ml of glacial acetic acid, whereupon the solution is treated with 0.86 g of p-dimethylaminobenzaldehyde and stirred at room temperature for 52 hours and the solution is evaporated. The product is recrystallized from ethanol/ether. There is obtained 2-ethyl-1-[[p-(dimethylamino)benzylidene)amino]-3-(3,4,5-trimethoxybenzyl)imidazolium chloride of melting point 211°.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][C:4]=1[CH3:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[C:58]([C:59](O)=[O:60])=[CH:57][O:56][N:55]=2)=[CH:50][CH:49]=1>CN(C=O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([C:59]([C:58]3[C:54]([C:51]4[CH:52]=[CH:53][C:48]([CH3:47])=[CH:49][CH:50]=4)=[N:55][O:56][CH:57]=3)=[O:60])[CH2:10]2)=[CH:5][C:4]=1[CH3:15]
Reactant: Cc1ccc(-c2nocc2C(=O)O)cc1
Reactant: Cc1cc(C2(O)CCNC2)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nocc2C(=O)N2CCC(O)(c3ccc(F)c(C)c3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
A solution of 3-(4-fluoro-3-methylphenyl)pyrrolidin-3-ol hydrochloride (9 mg, 0.039 mmol), TBTU (15 mg, 0.047 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.079 mmol, 2 equ.) in DMF (0.3 mL) was added to 3-(4-methylphenyl)isoxazole-4-carboxylic acid (8 mg, 0.039 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (12 mg). MS (ESI, pos. ion) m/z calcd for C22H21FN2O3: 380.1536, found 380.1532.