Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:3][CH:2]([CH3:4])[C:1]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:12]=1)=[O:5]
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCNCC1
Reaction time: 2 h
Yield: 78.5 %

Procedure:
Into a solution of tert-butyl 4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidinecarboxylate (335 mg, 0.930 mmol) in CH2Cl2 (10.0 mL) was added TFA (10.0 mL) at room temperature. The reaction mixture was stirred for 2 h and concentrated in vacuo. The residue was dissolved in 20 mL of CHCl3/i-PrOH (3:1) and was basified with 5% KOH solution (10 mL). The aqueous layer was extracted with CHCl3/i-PrOH (3:1, 3×10 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 2-methyl-N-[4-methyl-3-(4-piperidinyl)phenyl]propanamide (190 mg, 78%): ESMS m/e: 261.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][CH:11](O)[C:12]([F:15])([F:14])[F:13])[CH3:9]>C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:8]([O:10][CH:11]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:12]([F:15])([F:14])[F:13])[CH3:9]
Reactant: Nc1ccccc1
Reactant: CCOC(O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(Nc1ccccc1)C(F)(F)F
Yield: 86.7 %

Procedure:
A solution of aniline (2 mL, 21.9 mmol), trifluoroacetaldehyde ethyl hemiacetal (2.6 mL, 21.9 mmol) and p-toluenesulfonic acid monohydrate (220 mg, 1.16 mmol) in ethanol (25 mL) was heated to reflux for 3 h under continuous stirring. The reaction mixture was cooled, the solvent was removed under reduced pressure and the residue was dissolved in EtOAc. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to afford title compound 325 (4.16 g, crude) as a yellow oil which was used directly for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[C:12]([CH2:18][OH:19])[C:11]=2[CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[CH3:34][N:35]=[C:36]=[O:37]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[C:12]([CH2:18][O:19][C:36](=[O:37])[NH:35][CH3:34])[C:11]=2[CH2:20][C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CN=C=O
Reactant: CC(C)n1nc(CO)c(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)OCc1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1Cc1ccncc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution containing 45 mg of 5-(3,5-dichlorophenylthio)-1-isopropyl-4-[(4-pyridyl)methyl]-1H-pyrazole-3-methanol in 4 ml of anhydrous dichloromethane under nitrogen at room temperature was treated with 0.017 ml of triethylamine and 0,007 ml of methyl isocyanate. The mixture was stirred at room temperature for 1 h. The mixture was partitioned between ethyl acetate and water then extracted with dichloromethane three times. The combined extracts were washed with brine then dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using methanol/dichloromethane (0:1 to 1:49) for the elution to give 36 mg of methylcarbamic acid [5-(3,5-dichlorophenylthio)-1-isopropyl-4-[(4-pyridyl)methyl]-1H-pyrazol-3-yl]methyl ester as a yellow gum. Mass spectrum (ESI) m/z 465 [M+H]+. 1H NMR (DMSO) 1.30 (d, 6H), 2.55 (d, 3H), 3.90 (s, 2H), 5.05 (s, 2H), 6.77 (s, 2H), 7.05 (d, 2H), 7.12 (m, 1H), 7.37 (s, 1H), 8.30 (d, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:25]=[CH:24][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:26][CH3:27])[CH:4]=1.[CH2:28]([C:30]1[S:31][CH:32]=[C:33](/[CH:35]=[CH:36]/[C:37]2[C:38]([OH:48])=[N:39][N:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:41]=2)[N:34]=1)[CH3:29].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:28]([C:30]1[S:31][CH:32]=[C:33](/[CH:35]=[CH:36]/[C:37]2[C:38]([O:48][CH2:2][C:3]3[CH:25]=[CH:24][C:6]([O:7][CH2:8][C:9]4[N:10]=[C:11]([C:15]5[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=5)[O:12][C:13]=4[CH3:14])=[C:5]([O:26][CH3:27])[CH:4]=3)=[N:39][N:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:41]=2)[N:34]=1)[CH3:29]
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2cccc([N+](=O)[O-])c2)oc1C
Reactant: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2O)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4cccc([N+](=O)[O-])c4)oc3C)c(OC)c2)cs1
Temperature: 90 °C
Reaction time: 2 h
Yield: 38.1 %

Procedure:
A mixture of 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-2-(3-nitrophenyl)-1,3-oxazole (1.17 g), 4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol (0.892 g), potassium carbonate (0.415 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with acetone-hexane (1:5-1:4-1:3, v/v) to give {4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-2-(3-nitrophenyl)-1,3-oxazole (0.742 g, yield 38%) as colorless crystals. Recrystallization from ethyl acetate-diethyl ether gave pale-yellow prism crystals. melting point: 127-129° C.
Reaction SMILES: [CH2:1]([C@@H:5]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:13])[C@@H:6](O)[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)[F:36])(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH2:1]([C@@H:5]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:13])[C@H:6]([F:36])[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)[C@@H](O)C(=O)OC
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC[C@@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)[C@H](F)C(=O)OC
Temperature: -20 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To methyl 3-(R)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-1-ylcarbonyl)-2-(R)-hydroxypropionate H-3 (8.7 mmol) in DCM (10 mL) was added pyridine (25 mmol), the reaction was cooled to −20° C., then triflic anhydride (12.5 mmol) was added. The solution was stirred for 1 hour, then worked up as described above. The intermediate triflate was resuspended in DCM and cooled to −50° C. Tris(dimethylamino)sulfur (trimethylsilyl)difluoride (TAS-F) was added (8.7 mmol) and the solution allowed to warm to rt. The reaction mixture was washed with aqueous sodium bicarbonate and brine, dried (Na2SO4) and concentrated, then purified on silica gel (ethylacetate/hexanes) to afford 4.3 mmol (50%) of methyl 3-(S)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-1-yl-carbonyl)-2-(S)-fluoropropionate H-4.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[NH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]1[NH2:26]>N1C=CC=CC=1>[NH2:19][C@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[NH:26][C:10]1[CH:11]=[C:12]2[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]2[CH2:1][CH3:2])=[CH:8][C:9]=1[F:14]
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N[C@@H]3CCCC[C@@H]3N)cc21
Yield: 69.1 %

Procedure:
A mixture of 2.53 g of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 4.6 g of cis-1,2-diaminocyclohexane in 10 ml of pyridine was heated as described in Example 1 giving 2.4 g of the desired product, m.p. 225°-227°C.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[C:19]2[NH:20][C:21]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:22][O:23][C:18]=2[CH:17]=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[O:4]=[C:2]1[N:20]2[C:21]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:22][O:23][C:18]3=[C:19]2[C:14](=[CH:15][CH:16]=[CH:17]3)[NH:13]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(=O)NCC1(c2ccccn2)COc2cccc(N)c2N1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)NCC1(c2ccccn2)COc2cccc3[nH]c(=O)n1c23
Reaction time: 1 h
Yield: 176.2 %

Procedure:
Triphosgene (20 mg, 0.07 mmol) was added to a mixture of N-[(5-amino-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-3-yl)methyl]acetamide (50 mg, 0.2 mmol), tetrahydrofuran (5 mL) and N,N-diisopropylethylamine (60 μL) at room temperature. The reaction was stirred for 1 h then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude N-[(2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl)methyl]acetamide (0.040 g. 70%). LCMS calculated for C17H17N4O3 (M+H)+: m/z=325.1. found: 325.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:39]=[CH:38][S:37][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20](/[C:24](/[F:36])=[CH:25]/[C:26]4[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=4)[CH:21]=[CH:22][CH:23]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+].Cl>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:39]=[CH:38][S:37][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20](/[C:24](/[F:36])=[CH:25]/[C:26]4[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=4)[CH:21]=[CH:22][CH:23]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(/C=C(\F)c2cccc(-c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Nc2nc(-c3cccc(/C(F)=C/c4ccc(C(=O)O)cc4)c3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
To a stirred solution of (Z)-methyl 4-(2-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)phenyl)-2-fluorovinyl)benzoate (50 mg, 0.09 mmol) in 3 mL of 1,4-dioxane and 3 mL of H2O was added NaOH (140 mg, 3.5 mmol) at room temperature. Then the reaction was stirred at room temperature overnight and then treated by conc. HCl until pH=3-4. The solvent was removed under reduce pressure the residue was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1% TFA V/V) initially, and then proceed to 55% acetonitrile/45% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give (Z)-4-(2-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)phenyl)-2-fluorovinyl)benzoic acid (25 mg, 51%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 12.94 (brs, 1H, exchangeable by D2O), 10.18 (s, 1H, exchangeable by D2O), 9.40 (s, 1H), 8.54-8.49 (m, 2H), 7.82-7.74 (m, 3H), 7.41-7.31 (m, 5H), 6.90-6.78 (m, 2H), 3.80 (s, 6H). LC-MS: 529 [M+H]+, 527 [M−H]−, tR=1.71 min. HPLC: 96.85% at 214 nm, 95.49% at 254 nm, tR=5.08 min.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=[O:7].[CH2:8]([C:11]1[C:19]2[O:18][N:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=2[CH:14]=[CH:13][C:12]=1[O:24][CH2:25][CH2:26][CH2:27]Br)[CH2:9][CH3:10]>>[CH2:8]([C:11]1[C:19]2[O:18][N:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[C:15]=2[CH:14]=[CH:13][C:12]=1[O:24][CH2:25][CH2:26][CH2:27][N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=[O:7])[CH2:9][CH3:10]
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Reactant: O=C1CCC(=O)N1
Product: CCCc1c(OCCCN2C(=O)CCC2=O)ccc2c(C(F)(F)F)noc12

Procedure:
1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-pyrrolidine-2,5-dione was prepared as for Example 10 from pyrrolidine-2,5-dione and the bromide from Example 7. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=3)=[O:22])=[C:7]([CH:18]([CH3:20])[CH3:19])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C([O:35][C:36](=O)[CH2:37][CH2:38][CH2:39]Br)C>CN1C(=O)CCC1.CCOC(C)=O>[CH2:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([N:1]3[CH2:39][CH2:38][CH2:37][C:36]3=[O:35])[CH:10]=2)[C:6]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=2)=[O:22])=[C:7]1[CH:18]([CH3:19])[CH3:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(N)cc2n1Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(N3CCCC3=O)cc2n1Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 6-amino-1-benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 125, 20 mg, 0.046 mmol) and ethyl4-bromobutanoate (13 μl, 0.092 mmol) in NMP (1 ml) was heated at 168° C. for 16 h, cooled to room temperature, diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.C(N(CC)CC)C.[C:15]1([C:21](Cl)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[C:15]1([C:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:1]2[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 15 °C
Reaction time: 19 h

Procedure:
To a stirred suspension of 4-imidazole carboxaldehyde (from Maybridge Chemicals, United Kingdom) (35.0 g, 364 mmol) and triethylamine (55.8 mL; 400 mmol) in dichloromethane (2 L), was added a solution of triphenylmethyl chloride in dichloromethane (600 mL) while maintaining the reaction temperature at approximately 15° C. with a cooling bath. The resultant solution was warmed to room temperature and stirred for 19 h. Washed the reaction solution with a solution of saturated brine and water (1:3.5; 3×600 mL), followed by brine (1×800 mL). Dried over sodium sulfate; filtered to remove drying agent; and removed solvent under vacuum to obtain the desired tritylated product (7) as an off-white solid. MP 186.5-194° C. [Trituration of this product with ether yielded a cream-colored powder with mp 195-197° C.]
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][N:12]1[CH3:17])[CH3:10].[C:18](Cl)(=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH:9]([CH3:10])[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[CH3:17])=[O:27])=[CH:20][CH:21]=1
Reactant: CC(Cc1ccccc1N)C1CCCCN1C
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2ccccc2CC(C)C2CCCCN2C)cc1

Procedure:
Reaction of 2-[2-(2-aminophenyl)-1-methylethyl]-1-methylpiperidine with anisoyl chloride, according to the procedure of Example 25, provides 4-methoxy-2'-[2-methyl-2-(1-methyl-2-piperidyl)ethyl]benzanilide as a 72:28 mixture of diastereoisomers (according to nmr), m.p. 125.5°-136.5° C. (corr.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:13](=[O:17])[CH:14]([CH3:16])[CH3:15]>>[Cl:12][C:5]1[CH:4]=[CH:3][C:2]([CH:13]([OH:17])[CH:14]([CH3:16])[CH3:15])=[CH:7][C:6]=1[C:8]([F:11])([F:10])[F:9]
Reactant: CC(C)C=O
Reactant: FC(F)(F)c1cc(Br)ccc1Cl
Product: CC(C)C(O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Prepared analogously to the method described for Example 1a) from 2.3 mL (15 mmol) of 5-bromo-2-chlorobenzotrifluoride and 1.3 mL (14 mmol) isobutyraldehyde. Yellow oil. Yield: 2.0 g (53%).
Reaction SMILES: [Si:1]([O:8][CH:9]([CH:23]([CH3:25])[CH3:24])[C:10](=[O:22])[CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO[CH:28](OC)[N:29]([CH3:31])[CH3:30]>C1(C)C=CC=CC=1>[Si:1]([O:8][CH:9]([CH:23]([CH3:25])[CH3:24])[C:10](=[O:22])/[C:11](=[CH:28]/[N:29]([CH3:31])[CH3:30])/[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CC(C)C(O[Si](C)(C)C(C)(C)C)C(=O)CC(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)C(O[Si](C)(C)C(C)(C)C)C(=O)/C(=C/N(C)C)C(=O)OCc1ccccc1
Temperature: 110 °C
Reaction time: 18 h
Yield: 29.9 %

Procedure:
To a solution of benzyl 4-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-3-oxohexanoate (0.39 g, 1.06 mmol) in toluene (5.3 mL) were added 1,1-dimethoxy-N,N-dimethylmethanamine (0.21 mL, 1.59 mmol). The mixture was heated to 110° C. After 18 h, excess amount of 1,1-dimethoxy-N,N-dimethylmethanamine was added and the mixture was concentrated. Purification by silica gel chromatography (75% hexanes/ethyl acetate 25% hexanes/ethyl acetate) gave the title compound (0.133 g).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C-]#N.[Na+].C[C:17](O)=[O:18]>CO.O=[Mn]=O>[CH2:1]([C:5]1[NH:6][C:7]([C:11]([O:18][CH3:17])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Agent: O=[Mn]=O
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: CCCCc1nc(Cl)c(C(=O)OC)[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-Butyl-4-chloro-5-formylimidazole (4.9 g, 26 mMol) in methanol (350 ml) were added NaCN (12.98 g, 0.26 Mol), glacial AcOH (2.5 ml) and MnO2 (57.6 g, 0.663 Mol), and the mixture was stirred at room temperature for 72 h. The reaction was filtered through a pad of celite and concentrated in vacuo. The residue obtained was partitioned between EtOAc (150 ml) and water (50 ml), and the organic phase was washed with brine and then dried over sodium sulfate. The crude product (5.73 g), obtained after removal of the solvent under reduced pressure, was purified by flash-chromatography on silica-gel using EtOAc-hexane (1:5). Yield 4.5 g (80%, white solid). The product was crystallized from ethylacetate-hexane to give fine needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([F:12])=[C:7]([CH:11]=1)[CH2:8][C:9]#[N:10].[O-]CC.[Na+].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[F:12][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][C:7]=1[C:8](=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]#[N:10]
Reactant: COc1ccc(F)c(CC#N)c1
Reactant: O=Cc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(F)c(C(C#N)=Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
To a solution of 5-methoxy-2-fluorobenzylcyanide (8 g, 48.4 mmol) in 200 ml ethanol was added sodium ethoxide 21% in ethanol (19.89 ml, 53.3 mmol) and benzaldehyde (4.92 ml, 48.4 mmol). The reaction mixture was stirred at room temperature over night and concentrated to ½ volume, filtered and washed with small amount of ether, and dried under high vacuum to obtain yellow crystals.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.Br[CH2:12][CH2:13][C:14](OCC)=[O:15].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].C(OC(C)C)(C)C>CC(C)=O>[S:1]1[CH:5]=[C:4]([O:6][CH2:12][CH2:13][CH2:14][OH:15])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2
Reactant: CCOC(=O)CCBr
Reactant: O=C1CSc2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)OC(C)C
Solvent: CC(C)=O
Product: OCCCOc1csc2ccccc12
Yield: 1.3 %

Procedure:
A mixture of benzo[b]thiophen-3-one (30 g), ethyl 3-bromopropionate (73 g), potassium carbonate (55 g), potassium iodide (1.3 g) and acetone (600 ml) was refluxed for 18 h. Filtration and removal of solvent in vacuo a red oil which was dissolved in ether (200 ml) and dried over magnesium sulfate. The ether solution was added dropwise to a suspension of lithium aluminium hydride (5 g) in ether (100ml) followed by reflux for 1 h. Usual work-up gave a viscous oil which was applied to a silica gel column (eluent: isopropyl ether) giving 3-(benzo[b]thiophen-3-yloxy)-1-propanol (0.54 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:10]2[CH:15]=[CH:14][C:13]([N:16]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:17]3[CH:27]=[CH:26][C:20]([O:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>CN(C)C1C=CN=CC=1>[CH3:51][S:52]([O:25][CH2:24][CH2:23][CH2:22][O:21][C:20]1[CH:26]=[CH:27][C:17]([N:16]([C:13]2[CH:12]=[CH:11][C:10]([N:9]([C:36]3[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=3)[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[CH:15][CH:14]=2)[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[CH:18][CH:19]=1)(=[O:54])=[O:53]
Reactant: COc1ccc(N(c2ccc(OC)cc2)c2ccc(N(c3ccc(OC)cc3)c3ccc(OCCCO)cc3)cc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: COc1ccc(N(c2ccc(OC)cc2)c2ccc(N(c3ccc(OC)cc3)c3ccc(OCCCOS(C)(=O)=O)cc3)cc2)cc1
Reaction time: 0.17 h
Yield: 73.5 %

Procedure:
To a dry schlenk flask was added 3-(4-((4-(bis(4-methoxyphenyl)amino)phenyl)(4-methoxyphenyl)amino)phenoxy)propan-1-ol (1.16 g, 2.01 mmol) and 4-dimethylaminopyridine (0.012 g, 0.100 mmol. The flask was evacuated under vacuum and filled with nitrogen before addition of anhydrous tetrahydrofuran (2.0 mL). The mixture was placed in an ice bath and allowed to stir for 10 minutes. Triethylamine (0.712 g, 7.04 mmol) was added and the reaction was allowed to stir for 10 minutes. Added methanesulfonyl chloride (0.691 g, 6.03 mmol) and allowed mixture to stir for 5 minutes. The ice bath was removed and the mixture was stirred at room temperature while being monitored by thin layer chromatography (1:2 hexanes:ethyl acetate). Upon disappearance of the starting material the reaction mixture was poured into a separatory funnel containing 100 mL of cold water. The product was extracted using 3×50 mL ether. The organic layers were combined and washed with 3×50 mL of water, sodium bicarbonate solution, and sodium chloride solution. The resulting ether layers were dried over MgSO4. The drying agent was removed by filtration and the solvent was removed under reduced pressure. The residual solvent was removed in vacuo. The material was purified by flash chromatography (silica gel, 4:2 toluene:ethyl acetate) to yield an off-white solid (0.967 g, 73.3%). 1H NMR (400 MHz, C3D6O) δ 6.96 (m, 8H), 6.85 (m, 8H), 6.80 (s, 4H), 4.43 (t, J=6.3 Hz, 2H), 4.09 (t, J=6.0 Hz, 2H), 3.74 (s, 9H), 3.09 (s, 3H), 2.19 (q, J=6.2 Hz, 2H). 13C{1H} NMR (400 MHz, C3D6O) δ 156.42, 156.39, 155.30, 143.73, 143.49, 142.62, 142.26, 142.22, 126.33, 126.28, 126.00, 123.91, 123.69, 116.14, 115.41, 67.94, 64.61, 55.63, 36.97, 29.87. HRMS-EI (m/z): [M]− calcd for C37H38N2O7S, 654.24. found, 654.1). Anal. Calcd for C37H38N2O7S: C, 67.87; H, 5.85; N, 4.28. Found: C, 67.61; H, 5.77; N, 4.26.