Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8](=[O:19])[NH:9][O:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[CH:4][CH:3]=1.Cl.O1CCOCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:19])[NH:9][O:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)CONC(=O)NCc1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CONC(=O)NCc1ccc(Cl)cc1
Yield: 100.5 %

Procedure:
According to the procedure described in the synthesis method of Compound VI-9, tert-butyl 2-(3-(4-chlorobenzyl)ureidooxy)acetate (Compound V-6) (47.2 mg, 0.15 mmol) was reacted with 4N HCl/dioxane (2 ml) to obtain the title compound (39 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[NH:4][C@@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[NH:8][C@H:7]([CH2:19][CH3:20])[CH2:6]1.N1C=CC=CC=1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(Cl)Cl>[CH2:32]([O:31][C:29]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=2)[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:21])[CH2:6][C@H:7]1[CH2:19][CH3:20])=[O:30])[CH3:33]
Reactant: CCOC(=O)Cl
Reactant: CC[C@@H]1C[C@H](NC(=O)OC)c2cc(C(F)(F)F)ccc2N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@@H](NC(=O)OC)C[C@H]1CC
Temperature: -10 °C
Reaction time: 20 h
Yield: 88.2 %

Procedure:
A clean, dry and nitrogen gas purged 100 L glass tank was charged with (2R, 4S)-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid methyl ester (5191 g, 17.17 mol), methylene chloride (21 L), and pyridine (4.16 L, 51.4 mol). The reaction vessel was cooled to −10° C. Ethyl chloroformate (4.10 L, 42.9 mol) was slowly added at such a rate that the internal temperature did not exceed −5° C. The reaction solution was brought to 0° C. and held for 20 hours. The reaction was quenched by adding to a mixture of diisopropyl ether (IPE) (36 L), methylene chloride (6.2 L) and 1.5M hydrochloric acid solution (52 L). The resulting phases were separated and the organic layer was extracted with 1M sodium hydroxide solution (15 L). The resulting phases were separated and the organic layer was washed with saturated aqueous sodium chloride NaCl (15 L). The resulting phases were separated and the organic layer was concentrated by distillation to a volume of 40 L. Crystallization initiated at lower volume. The methylene chloride was displaced with IPE by distilling the mixture and periodically adding IPE to maintain a constant volume at 40L until a temperature of 68° C. was maintained (46 L total IPE used). The mixture was cooled and allowed to granulate with stirring at room temperature for 19 hours. The solids were filtered, rinsed with IPE (8 L), and dried under vacuum at 40° C. to afford 5668 g of the title compound (88%).
Reaction SMILES: CO[C:3]([O:12][CH3:13])(OC)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18]([C:23]2[O:27][CH2:26][C:25]([CH3:29])([CH3:28])[C:24]=2[C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:17]C=1O.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>S(O)(C1C=CC(C)=CC=1)(=O)=O.O.O>[C:30]([C:24]1[C:25]([CH3:29])([CH3:28])[CH2:26][O:27][C:23]=1[C:18]1[CH:19]=[C:20]([O:21][CH3:22])[C:15]2[N:14]=[C:3]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[O:12][C:13]=2[CH:17]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: COc1cc(C2=C(C(C)(C)C)C(C)(C)CO2)cc(O)c1N
Reactant: COC(OC)(OC)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C2=C(C(C)(C)C)C(C)(C)CO2)cc2oc(-c3ccccc3)nc12
Temperature: 150 °C
Yield: 78.3 %

Procedure:
To 1.00 mL (5.82 mmol) of trimethyl orthobenzoate was added 204 mg (0.70 mmol) of 5-(4-amino-3-hydroxy-5-methoxyphenyl)-4-t-butyl-3,3-dimethyl-2,3-dihydrofuran (Compound [61]), and the mixture was refluxed for 1.5 hours at 150° C. To this reaction mixture, 2.0 ml of ethyl acetate, and 0.2 ml of H2O, and 10.1 mg (0.05 mmol) of TsOH H2O was added and the mixture was refluxed for 1 hours at 97° C. The resulting mixture was poured in saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried with magnesium sulfate anhydride, and concentrated. The residue was applied to a silica gel column and the elution was carried out with the mixture of hexane and ethyl acetate (hexane:ethyl acetate=10:1) to obtain 207 mg of 4-t-butyl-5-(4-methoxy-2-phenylbenzo[d]oxazol-6-yl)-3,3-dimethyl-2,3-dihydrofuran (Compound [62]). Yield 78.4%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:9])[C:5]([Cl:8])=[N:6][CH:7]=1.C([Li])CCC.C[O:16]B(OC)OC.[OH-].[Na+].OO.S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>CCCCCC.C1(C)C=CC=CC=1>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([OH:16])=[CH:3][C:4]=1[F:9]
Reactant: COB(OC)OC
Reactant: Fc1cc(Br)cnc1Cl
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: OO
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Oc1cnc(Cl)c(F)c1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
Under an argon atmosphere, to a mixture of 5-bromo-2-chloro-3-fluoropyridine (4.45 g) and toluene (50 mL) was added dropwise a hexane solution (1.6 M, 15.8 mL) of n-butyllithium at −78° C., and the obtained mixture was stirred at −78° C. for 5 min. To the reaction mixture was added trimethoxyborane (2.84 mL), and the obtained mixture was stirred at −78° C. for 15 min, and then at room temperature overnight. The reaction mixture was cooled to 0° C., 8M aqueous sodium hydroxide solution (3.17 mL) and 30% aqueous hydrogen peroxide (20 mL) were added thereto, and the obtained mixture was stirred at room temperature for 2 hr. The reaction mixture was cooled to 0° C., and saturated aqueous sodium thiosulfate solution was added thereto. The mixture was neutralized with 1M hydrochloric acid, and extracted with ethyl acetate. The combined organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.20 g).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[N:12]1([CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:4][CH2:3][OH:2])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1
Reactant: COC(=O)CC(c1ccccc1)n1ccc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC(c1ccccc1)n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-indol-1-yl-3-phenyl-propionic acid methyl ester (0.2 g, 0.71 mmol) in THF (5 mL) at 0° C. was added 1M LiAlH4 in THF (0.71 mL), and the mixture was stirred for 0.5 hours at room temperature. The reaction mixture was quenched by the cautious addition of Na2SO4.10H2O and the reaction mixture was stirred for another 1 h at room temperature. The mixture was filtered and the solvent was removed under vacuum. 3-Indol-1-yl-3-phenyl-propan-1-ol was obtained as a clear oil (0.166 g, 92% yield).
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[N:22]=[C:21]([CH:23]=[N:24][C:25]2[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=2[CH3:33])[CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].[BH3-]C#N.[Na+].O>CO.C(O)=O>[C:1]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[N:22]=[C:21]([CH2:23][NH:24][C:25]2[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=2[CH3:33])[CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)c(N=Cc2cccc(-c3c(CNC(C)(C)C)ccc4ccccc34)n2)c(C)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O=CO
Solvent: O
Product: Cc1cc(C)c(NCc2cccc(-c3c(CNC(C)(C)C)ccc4ccccc34)n2)c(C)c1

Procedure:
To a solution of 1.75 g (4.10 mmol) of N-[(6-{2-[(tert-butylamino)methyl]-1-naphthyl}pyridin-2-yl)methylene]-2,4,6-trimethylaniline in 20 ml of methanol, 0.42 g (6.70 mmol) of NaBH3CN was added in one portion followed by addition of three drops of 88% formic acid. The reaction mixture was refluxed under inert atmosphere for 1 hour and then poured into 50 ml of water. The crude product was extracted with 3×20 ml of ether. The organic extract was washed with water, dried over K2CO3, and then evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um; eluent: dichloromethane-methanol-triethylamine=100:10:1, vol.). Yield 1.60 g (90%) of orange oil. Anal. calc. for C30H35N3: C, 82.34; H, 8.06; N, 9.60. Found: C, 82.56; H, 8.21; N, 9.59. 1H NMR (CDCl3): 7.89 (d, J=8.5 Hz, 1H, 4-H in naphthyl), 7.86 (m, 1H, 8-H in naphthyl), 7.77 (m, 1H, 4-H in Py), 7.65 (d, J=8.5 Hz, 3-H in naphthyl), 7.43 (m, 1H, 7-H in naphthyl)), 7.87 (m, 1H, 3-H in Py), 7.30-7.35 (m, 3H, 5-H in Py and 5,6-H in naphthyl), 6.80 (s, 2H, 3,5-H in mesityl), 4.35 (m, 2H, CH2NHtBu), 3.55 (m, 2H, CH2NMes), 2.94 (br. s, 2H, NH), 2.24 (s, 6H, 2,6-Me in mesityl), 2.22 (s, 3H, 4-Me in mesityl), 0.96 (s, 9H, tBu).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[N+:19]([O-])=O)=[CH:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].CO>[Pd].O1CCCC1>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[NH2:19])[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C2=CCC(C(C)(C)C)CC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C2CCC(C(C)(C)C)CC2)c(N)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 1-(4-t-butylcyclohex-1-enyl)-4-methoxy-2-nitrobenzene (2.89 g, 10.0 mmol) prepared in Example (12a), 10% palladium on carbon (1.0 g, wet), methanol (15 mL) and tetrahydrofuran (15 mL) was stirred for 12 hours under hydrogen atmosphere at atmospheric pressure and room temperature.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:10][C:9](=[CH:11]/[CH:12]=[CH:13]/[CH2:14][CH2:15][CH2:16][C:17]([CH3:39])([CH3:38])[CH2:18]/[CH:19]=[CH:20]\[C:21]([O:30][Si](CC)(CC)CC)([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])[CH2:8][C@@H:7]([O:40]C(=O)C)[CH2:6]1)(=O)C.C([O-])([O-])=O.[K+].[K+]>O>[F:23][C:22]([F:24])([F:25])[C:21]([OH:30])([C:26]([F:28])([F:29])[F:27])/[CH:20]=[CH:19]\[CH2:18][C:17]([CH3:39])([CH3:38])[CH2:16][CH2:15][CH2:14]/[CH:13]=[CH:12]/[CH:11]=[C:9]1[CH2:10][C@@H:5]([OH:4])[CH2:6][C@H:7]([OH:40])[CH2:8]1
Reactant: CC[Si](CC)(CC)OC(/C=C\CC(C)(C)CCC/C=C/C=C1C[C@@H](OC(C)=O)C[C@H](OC(C)=O)C1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C/C=C\C(O)(C(F)(F)F)C(F)(F)F)CCC/C=C/C=C1C[C@@H](O)C[C@H](O)C1
Reaction time: 8 h

Procedure:
To a solution of 50 mg of acetic acid (1R,3R)-3-acetoxy-5-[(2E,9Z)-12,12,12-trifluoro-7,7-dimethyl-11-triethylsilanyloxy-11-trifluoromethyl-dodeca-2,9-dienylidene]-cyclohexyl ester in 1.5 ml of CH3 1OH was added at 22° a solution of 37 mg of K2CO3 in 0.25 ml of water and stirring, was continued for 8 h after which time t.l.c. indicated completion of the reaction. The mixture was evaporated and the residue was partitioned between dichloromethane and aqueous sat. NaCl, the organic layer was dried over MgSO4 and evaporated. The residue was chromatographed on silica with hexane/AcOEt 2:1 to give 34 mg of the pure (t.l.c.) title compound as a colorless resin. IR (neat): 3345s (OH), 1661 w and 1622 w (C═C); MS (EI): 444/10 (M), 426/8 (M—H2O).
Reaction SMILES: [F:1][C:2]1[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[N:18]=[C:17]([NH:19][C:20]3[CH:24]=[CH:23][N:22](COCC[Si](C)(C)C)[N:21]=3)[CH:16]=[N:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5].O>FC(F)(F)C(O)=O>[F:1][C:2]1[C:36]([C:37]([F:39])([F:38])[F:40])=[CH:35][CH:34]=[CH:33][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[N:18]=[C:17]([NH:19][C:20]3[CH:24]=[CH:23][NH:22][N:21]=3)[CH:16]=[N:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: C[Si](C)(C)CCOCn1ccc(Nc2cncc(CN3CCN(C(=O)c4cccc(C(F)(F)F)c4F)CC3)n2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(c1cccc(C(F)(F)F)c1F)N1CCN(Cc2cncc(Nc3cc[nH]n3)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.49 g of 6-((4-(2-fluoro-3-(trifluoromethyl)benzoyl)piperazin-1-yl)methyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazin-2-amine was dissolved in 25 ml of trifluoroacetic acid and 2.5 ml of water followed by stirring at room temperature for 2 hours. The reaction solution was concentrated in vacuo, diluted with ethyl acetate, and then washed with saturated sodium bicarbonate, water and brine. The resulting organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform to chloroform/methanol=5/1) to give the title compound as a solid. The resulting solid was dissolved in ethanol by heating to 80° C. The solution was charged with heptane, and heating was stopped. Then the solution was cooled slowly to room temperature. After heptane was further added, the precipitate was filtered and dried to give a crystal of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:9]=[O:10].C[Li].C([Li])CCC.[CH:18]1([CH:21]2[CH2:24][CH2:23][C:22]2=[O:25])[CH2:20][CH2:19]1.[Cl-].[NH4+]>O1CCCC1.C(OCC)C.C(OCC)(=O)C>[CH:18]1([CH:21]2[CH2:24][CH2:23][C:22]2([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][CH:9]=[O:10])[OH:25])[CH2:20][CH2:19]1
Reactant: O=CNc1ccccc1Br
Reactant: O=C1CCC1C1CC1
Agent: [Cl-]
Agent: [Li]C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=CNc1ccccc1C1(O)CCC1C1CC1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
In a sulfonation flask, 7.8 g (0.039 mol) N-(2-bromophenyl)formamide was dissolved in a mixture of 150 ml dry tetrahydrofuran and 150 ml dry diethyl ether. The solution was cooled to −70° C. and 25.6 ml (0.041 mol) methyllithium solution (1.6M in diethyl ether) added in 30 minutes in such a manner that the internal temperature remained constant at −70° C. Then the resulting solution was cooled to −100° C. and 25.6 ml (0.041 mol) of n-butyllithium solution (1.6M in hexane) was added in such a manner that the internal temperature remained constant at −100° C. (±2° C.). After stirring for 2 hours at −70 to −75° C., the solution was again cooled to −100° C. and 4.54 g (0.041 mol) 2-cyclopropylcyclobutan-1-one (prepared as described in Example 2) dissolved in 30 ml of dry tetrahydrofuran, was added slowly (20 minutes) at an internal temperature of −100° C. After stirring for 3 hours at −75° C., the temperature was elevated to 0° C. in ca. 30 minutes. After the addition of concentrated ammonium chloride solution, ethyl acetate was added and the organic phase was washed several times with water. After drying and evaporation of the solvent in a water jet vacuum, the crude material was obtained. Purification was achieved by flash chromatography over silica gel (eluant: hexane/ethyl acetate 1:1). Yield: 3.4 g (38% of theory) of N-[2-(2-cyclopropyl-1-hydroxycyclo-butyl)-phenyl]formamide in the form of a slightly yellow liquid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH2:21]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH2:21][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12]
Reactant: Clc1ccc(Br)c(CBr)c1
Reactant: O=C1CCCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CCCc2c(OCc3cc(Cl)ccc3Br)cccc21
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a stirred solution of 5-hydroxy-1-tetralone (2.0 g, 12.3 mmol) and 1-bromo-2-(bromomethyl)-4-chlorobenzene (3.6 g, 12.7 mmol) in dimethylformamide (125 mL) was added potassium carbonate (3.5 g, 25.1 mmol). The reaction was stirred under argon for 1 hour then diluted with ethyl acetate (1 L). The organics were washed three times with water and once with brine. The organic layer was then dried with magnesium sulfate, filtered and concentrated. To the resulting oil was added methanol (100 mL) and the suspension was agitated for thirty minutes. 5-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one (4.25 g, 94% yield) was isolated by filtration.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21](=[O:26])[NH:22][CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=1[O:37][CH3:38]>>[Si:1]([O:18][CH2:19][C:20]1[C:21](=[O:26])[N:22]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=2[O:37][CH3:38])[CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc([N+](=O)[O-])ccc1F
Reactant: CC(C)(C)[Si](OCc1ccc[nH]c1=O)(c1ccccc1)c1ccccc1
Product: COc1cc([N+](=O)[O-])ccc1-n1cccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O

Procedure:
Analogously to Example 4A, 5.00 g (13.8 mmol) of the compound from Example 3A are reacted with 2.59 g (15.1 mmol) of 1-fluoro-2-methoxy-4-nitrobenzene. The product is purified by chromatography on silica gel (mobile phase pentane/ethyl acetate=5:1), giving 2.70 g (38% of theory) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:17]([F:20])([F:19])[F:18])=[N:8][C:9]([C:13]([Cl:16])([F:15])[F:14])=[CH:10][C:11]=1[OH:12])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].I[CH:28]([CH3:30])[CH3:29]>CC(C)=O>[Cl:16][C:13]([F:14])([F:15])[C:9]1[N:8]=[C:7]([C:17]([F:20])([F:18])[F:19])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([O:12][CH:28]([CH3:30])[CH3:29])[CH:10]=1
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)Cl)nc1C(F)(F)F
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(OC(C)C)cc(C(F)(F)Cl)nc1C(F)(F)F
Yield: 88.9 %

Procedure:
A mixture of 15.0 g (0.047 mol) of product of Example 3, 6.5 g (0.047 mol) of K2CO3 and 5.2 ml (0.052 mol) of 2-iodopropane in 100 of acetone was stirred at reflux for 64 hours. The cooled reaction mixture was concentrated in vacuo. The residue was dissolved in ether, washed with H2O, dried (MgSO4), and concentrated in vacuo to a brown oil which was kugelrohr distilled at 68 Pa, pot temperature 90° C., affording 15.11 g (88.9%) of product as a clear oil, nD25 1.4405.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]3[S:21][CH:22]=[C:23]([CH2:25][C:26](OCC)=[O:27])[N:24]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.C(O)(=O)C(C(C(O)=O)O)O.[Na]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]3[S:21][CH:22]=[C:23]([CH2:25][CH2:26][OH:27])[N:24]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1csc(NC(=O)N2CCC(N3CCc4ccc(F)cc43)CC2)n1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [Na]
Solvent: ClCCl
Product: O=C(Nc1nc(CCO)cs1)N1CCC(N2CCc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of ethyl 2-(2-(4-(6-fluoroindolin-1-yl)piperidine-1-carboxamido)thiazol-4-yl)acetate (86.4 mg, 0.2 mmol, 1 equiv) in dried CH2Cl2 (3 mL) under N2 at room temperature was then slowly added DIBAL-H (1M in CH2Cl2, 1 mL, 1 mmol, 5 equiv). The resulting mixture became a clear solution and was stirred at room temperature for 1 h. The resulting mixture was slowly poured into a vigorously stirred mixture of CH2Cl2/10 wt % sodium tartaric acid (aq) (10 mL/10 mL). The resulting mixture was stirred for 1 h and the layers were separated. The aqueous layer was extracted with CH2Cl2 (30 mL×2). The combined organic layer was dried (Na2SO4) and filtered. The solvent was removed by roto-evaporator and the resulting residue purified by column using 80-90% EtOAc/hexane as the eluent to yield 4-(6-fluoroindolin-1-yl)-N-(4-(2-hydroxyethyl)thiazol-2-yl)piperidine-1-carboxamide.
Reaction SMILES: [OH-].[K+].Cl.NO.[CH3:6][N:7]([CH3:23])[C:8]([C:10]1[N:11]([CH3:22])[N:12]=[C:13]([N:15]2C(C)=CC=C2C)[CH:14]=1)=[O:9]>O.C(O)C>[CH3:6][N:7]([CH3:23])[C:8]([C:10]1[N:11]([CH3:22])[N:12]=[C:13]([NH2:15])[CH:14]=1)=[O:9]
Reactant: Cc1ccc(C)n1-c1cc(C(=O)N(C)C)n(C)n1
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CN(C)C(=O)c1cc(N)nn1C
Temperature: 25 °C

Procedure:
A solution of potassium hydroxide (1.1 g, 19.5 mmol) in water (30 mL) and ethanol (30 mL) is added to a slurry of hydroxylamine hydrochloride (2.7 g, 39 mmol) in ethanol (50 mL). 5-(2,5-dimethyl-pyrrol-1-yl)-2-methyl-2H-pyrazole-3-carboxylic acid dimethylamide (1.6 g, 6.5 mmol) is added and the mixture is refluxed for 48 hours. The contents of the flask are then concentrated under reduced pressure and the residue is suspended in DCM. The suspension is heated to reflux and then cooled down to room temperature, filtered and the filtrate is concentrated to give crude product. MS (ESI) m/z 169.3 (M+1).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[CH2:16]([O:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[O:26]CCBr)[C:17]1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[ClH:1].[OH:26][C:25]1[CH:30]=[CH:31][CH:32]=[CH:33][C:24]=1[O:23][CH2:16][CH2:17][N:11]1[CH2:12][CH2:13][CH:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([CH3:2])=[CH:15][CH:14]=2)[CH2:9][CH2:10]1
Reactant: BrCCOc1ccccc1OCc1ccccc1
Reactant: Cc1ccc(CC2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(CC2CCN(CCOc3ccccc3O)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-methylbenzyl)piperidine hydrochloride (294 mg, 1.30 mmol), 2-(2-benzyloxyphenoxy)ethyl bromide (399 mg, 1.3 mmol) and potassium carbonate (449 mg, 3.2 mmol) in two steps as white-off solid (240 mg): mp 225-227° C. 1H NMR (CD3OD) 1.436 (m, 2 H), 1.758 (d, J=12.9 Hz, 3 H), 2.135 (s, 3 H), 2.443 (d, J=6.3 Hz, 2 H), 2.900 (m, 2 H), 3.388 (m, 2 H), 3.503 (m, 2 H), 4.172 (t, J=5.7 Hz, 2 H), 6.651-6.739 (m, 3 H), 6.818 (m, 1 H), 6.928 (m, 4 H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[C:6]=1[CH2:7][OH:8]>CCO.C(O)(=O)C.[Fe]>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:5]2[C:6]([CH2:7][OH:8])=[C:2]([Cl:1])[N:3]=[C:4]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][CH:14]=1
Reactant: CCCCCCCc1nc(Cl)c(CO)n1Cc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCCCCc1nc(Cl)c(CO)n1Cc1ccc(N)cc1
Yield: 88.2 %

Procedure:
To a solution of 4-chloro-2-heptyl-5-hydroxymethyl-1-(4-nitrobenzyl)imidazole (1.00 g, 2.7 mmol) in EtOH (30 mL) and glacial acetic acid (5 mL) was added iron powder (2.5 g, 44.8 mmol). The mixture was stirred while being refluxed for 20 minutes. The solution was cooled, the iron was removed by filtration, and the solution was partitioned between EtOAc and 20% aq. K2CO3 (150 mL each). The organic phase was washed with saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to afford 0.8 g yellow-orange oil. Flash chromatography (silica gel, 25 g; EtOAc/hexanes, 1:1) gave 0.74 g (80%) of yellow-orange oil. NMR (200 MHz, CDCl3) δ 6.80-6.60 (ABq, 4H, 7Hz,32Hz; 5.10 (s, 2H); 4.45 (s, 2H); 3.75-3.60 (m, 2H); 2.55 (t, 2H, 5Hz); 1.75-1.65 (m, 2H); 1.30-1.15 (m, 8H); 0.90-0.80 (m, 3H). Mass Spec. 335.