Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1CCNCC1.[NH2:8][N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1.C([O:30][C@@H:31]1[C@H:35]([O:36]C(=O)C2C=CC=CC=2)[C@@H:34]([CH2:45][O:46]C(=O)C2C=CC=CC=2)[O:33][C@H:32]1[N:55]1[CH:63]=[N:62][C:61]2[C:56]1=[N:57][C:58]([Cl:65])=[N:59][C:60]=2Cl)(=O)C1C=CC=CC=1.N>>[Cl:65][C:58]1[N:59]=[C:60]([NH:8][N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[C:61]2[N:62]=[CH:63][N:55]([C:56]=2[N:57]=1)[C@@H:32]1[O:33][C@H:34]([CH2:45][OH:46])[C@@H:35]([OH:36])[C@H:31]1[OH:30]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: NN1CCC(Oc2ccccc2)CC1
Agent: N
Agent: OC1CCNCC1
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CCC(Oc5ccccc5)CC4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Yield: 56.1 %

Procedure:
This compound was prepared from 4-hydroxypiperidine using the methodology described in Example 16. 1-Amino-4-phenoxypiperidine (0.96 g, 5.0 mmol) was reacted with 9-(2',3',5'-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.50 g, 4 mmol), followed by debenzoylation of the purified product using methanolic ammonia. This provided the title 2-chloro-N-(4-phenoxy-1-piperidinyl)adenosine (1.07 g, 57%) as a foam, 1H NMR (DMSO-d6) δ 3.52-3.60 (1H, m, H-5'a), 3.63-3.70 (1H, m, H-5'b), 3.95 (1H, q, H-4'), 4.14 (1H, q, H-3'), 4.43-4.54 (2H, m, H-2' and --C--H), 5.07 (1H, t, 5'-0H), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.84 (1H, d, H-1'), 6.90-7.33 (5H, 2m, Ar--H), 8.42 (1H, s, H-8), 9.49 (1H, s, N--H).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10](=[N:20]OS(C2C=CC(C)=CC=2)(=O)=O)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[N:8]=[C:7]([CH3:32])[CH:6]=1)(=[O:3])[CH3:2].C1CCN2C(=NCCC2)CC1.Cl>CS(C)=O.O>[C:1]([N:4]1[C:5]2=[CH:6][C:7]([CH3:32])=[N:8][N:9]2[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[N:20]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(C)nn1C(=NOS(=O)(=O)c1ccc(C)cc1)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(=O)n1nc(-c2cccc([N+](=O)[O-])c2)n2nc(C)cc12
Temperature: 25 °C
Yield: 90.1 %

Procedure:
800 mg (1.75 mmol) of 5-acetamido-3-methyl-1-(O-tosyl-3-nitro-benzohydroximoyl)-pyrazole are suspended in 10 ml of DMSO, treated with 0.8 ml DBU with stirring at room temperature, diluted with water and acidified with 2N hydrochloric acid. The precipitate obtained is filtered under suction, washed with water, a little methanol and a little ethyl acetate and recrystallised from methyl glycol. 450 mg (90%) of 1-acetyl-6-methyl-3-(3-nitro-phenyl)pyrazolo[5,1-c][1,2,4]triazole with a m. pt. of 207°-210° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]=[CH:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)=[O:4].[NH2:19][CH:20]([CH3:24])[CH2:21][C:22]#[N:23]>C(#N)C>[CH3:1][O:2][C:3]([NH:5][CH:6]=[CH:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH:20]([CH3:24])[CH2:21][C:22]#[N:23])=[CH:10][CH:9]=1)=[O:4]
Reactant: COC(=O)NC=Cc1ccc(OCC2CO2)cc1
Reactant: CC(N)CC#N
Solvent: CC#N
Product: COC(=O)NC=Cc1ccc(OCC(O)CNC(C)CC#N)cc1
Reaction time: 20 h

Procedure:
3.0 g (0.012 mol) of 1-[p-(2-methoxycarbonylaminovinyl)-phenoxy]-2,3-epoxypropane are dissolved in 25 ml of acetonitrile and added dropwise to a boiling stirred solution of 0.96 g (0.011 mol) of β-aminobutyronitrile in 20 ml of acetonitrile. The mixture is stirred for 20 hours under reflux, the solvent is removed by distillation under reduced pressure and the oil which remains is partitioned between 150 ml of 0.1 N hydrochloric acid and 100 ml of ethyl acetate. The hydrochloric acid extract is separated off, rendered alkaline with sodium carbonate and extracted four times with 50 ml of ethyl acetate at a time. The organic phases are dried over sodium sulphate and evaporated under reduced pressure. The resulting oil solidifies on cooling to give crystals of 1-[p-(2-methoxycarbonylaminovinyl)-phenoxy]-2-hydroxy-3-(2-cyano-1-methylethyl-amino)-propane of melting point 122°-123° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[C:4](=[O:12])[N:3]1[C:13]1[CH2:14][O:15][C:16](=[O:18])[CH:17]=1.F[C:20](F)(F)S(OC1COC(=O)C=1C)(=O)=O>>[CH3:1][CH:2]1[CH2:6][C:5]2([CH2:7][CH2:8][NH:9][CH2:10][CH2:11]2)[C:4](=[O:12])[N:3]1[C:13]1[CH2:14][O:15][C:16](=[O:18])[C:17]=1[CH3:20]
Reactant: CC1=C(OS(=O)(=O)C(F)(F)F)COC1=O
Reactant: CC1CC2(CCNCC2)C(=O)N1C1=CC(=O)OC1
Product: CC1=C(N2C(=O)C3(CCNCC3)CC2C)COC1=O

Procedure:
The title compound was prepared in two steps in an analogous fashion to that described for 3-methyl-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-22), except starting from 4-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (I-9). LC-MS (IE, m/z): 265 (M+1)+.
Reaction SMILES: CC1(C)[O:6][CH:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13](=O)[CH2:14][CH2:15][C:16](=O)[CH:17]([C:25]3[CH:30]=[CH:29][C:28]([S:31][CH3:32])=[C:27]([F:33])[CH:26]=3)[CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:11][CH:12]=2)[CH2:4][O:3]1.C([O-])(=O)C.[NH4+:41].Cl>C(O)(=O)C.C(OCC)(=O)C.O1CCCC1>[F:33][C:27]1[CH:26]=[C:25]([CH:17]([C:16]2[NH:41][C:13]([C:10]3[N:11]=[CH:12][C:7]([CH:5]([OH:6])[CH2:4][OH:3])=[CH:8][CH:9]=3)=[CH:14][CH:15]=2)[CH2:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:30]=[CH:29][C:28]=1[S:31][CH3:32]
Reactant: [NH4+]
Reactant: CSc1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccc(C3COC(C)(C)O3)cn2)cc1F
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CSc1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(C(O)CO)cn3)[nH]2)cc1F
Temperature: 110 °C
Reaction time: 0.75 h

Procedure:
To a solution of 1-[5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-2-yl]-5-[3-fluoro-4-(methylsulfanyl)phenyl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (500 mg) in acetic acid (5 mL) was added ammonium acetate (1.20 g), and the mixture was stirred at 110° C. for 45 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated to give a crude product (400 mg). To a solution of the obtained crude product (400 mg) in tetrahydrofuran (5 mL) was added 1M hydrochloric acid (5 mL), and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give the title compound (367 mg, quantitatively) as a pale-brown amorphous solid. MS: 457 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:26])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[CH:14][CH:13]=2)[CH:9]=1)=[O:4]>O1CCCC1>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][C:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[O:6][C:7]=2[CH3:26])=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc(COc2ccc(-c3ccccc3OC)cc2)c(C)o1
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccc(OCc2cc(C(=O)O)oc2C)cc1
Reaction time: 16 h
Yield: 77.9 %

Procedure:
A solution of 4-(2′-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester (125) (40 mg, 0.11 mmoles) in dry tetrahydrofuran (25 ml) was treated with potassium trimethylsilanoate (73 mg, 0.56 mmoles) and the mixture stirred under an argon atmosphere for 16 h. After evaporation of the solvent the residue was acidified to pH=2 with 0.1M aqueous hydrochloric acid and the mixture extracted with ethyl acetate. The dried extracts were evaporated and the residue pumped under high vacuum at 40° C. to afford compound 126 (29 mg) as an off-white solid. LC/MS System D; Rt=8.30 mins, m/z (ES+) 339 (M+H for C20H18O5).
Reaction SMILES: [Cl:1][C:2]1([C:14]([OH:16])=O)[N:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][NH:3]1.C(N(CC)CC)C.N1C(F)=NC(F)=NC=1[F:26]>ClCCl>[Cl:1][C:2]1([C:14]([F:26])=[O:16])[N:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][NH:3]1
Reactant: Fc1nc(F)nc(F)n1
Reactant: O=C(O)C1(Cl)N=C(NC2CCCC2)C=CN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(F)C1(Cl)N=C(NC2CCCC2)C=CN1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
To a suspension of 5.24 (21.68 mmol) of the product prepared in step 3.1 in 140 mL of dichloromethane are added 3.02 mL (21.68 mmol) of triethylamine and then 2.75 mL (35.52 mmol) of cyanuric fluoride. The mixture is stirred at room temperature for 4 hours and the solution is diluted with 150 mL of dichloromethane. The organic phase is washed three times with 200 mL of ice-cold aqueous NaHCO3, dried over MgSO4, filtered and concentrated under vacuum. 5.2 g of the expected product are obtained in the form of an orange solid. Yield=98%.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].OS(O)(=O)=O.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([NH2:19])[CH3:18])=[CH:13][CH:12]=1.[OH-].[Na+]>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([NH2:19])[CH3:18])=[CH:13][C:12]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CC(N)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(N)c1ccc(F)c([N+](=O)[O-])c1
Yield: 98 %

Procedure:
Fuming HNO3 (0.48 ml, 10.8 mmol) was added carefully to ice bath cooled concentrated H2SO4 (3.6 ml, 68.2 mmol). To the mixture was added 1-(4-fluorophenyl)ethanamine (1.0 g, 7.2 mmol) dropwise. The reaction mixture was stirred with cooling for 50 minutes. The reaction mixture was poured into ice and basified with 3M NaOH solution (24 ml, 72.00 mmol) to about pH8.0. The alkaline solution was extracted with DCM twice. The combined organic layer was dried over Na2SO4 and evaporated to afford title compound (1.3 g, yield: 96%). 1H-NMR (400 MHz, CDCl3) δ 1.41 (d, 6H) 4.25 (q, 1H) 7.21-7.26 (m, 1H) 7.67 (ddd, 1H) 8.10 (dd, 1H)
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[C:5]([NH:12][C@H:13]([C:22]([OH:24])=O)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]>ClCCl.CN(C=O)C>[C:8]([O:7][C:5](=[O:6])[NH:12][C@H:13]([C:22](=[O:24])[N:3]([CH3:4])[CH3:2])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C

Procedure:
Dimethylamine hydrochloride (79 mmol) and Boc-L-tyrosine (66 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 12:1 dichloromethane/DMF reaction solvent, 60 hour reaction time) and the product purified by chromatography on silica gel eluted with 10, 20, 30, 50 and 70% ethyl acetate in hexanes. Yield 20.6 g, 102%; HPLC (60/40) 3.21 minutes (96%).
Reaction SMILES: Cl[CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.[CH2:10]([SH:13])[CH2:11][SH:12].C(N(CC)CC)C>CN(C=O)C>[SH:12][CH2:11][CH2:10][S:13][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1
Reactant: CC1(CCl)COC(=O)N1
Reactant: SCCS
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(CSCCS)COC(=O)N1
Temperature: 90 °C

Procedure:
To a solution of 4-(chloromethyl)-4-methyloxazolidin-2-one (1.85 g, 12.4 mmol) in DMF (5 ml) was added 1,2-ethanedithiol (10.0 ml, 119 mmol). Triethylamine (2.0 ml, 14 mmol) was added, and the solution heated to 90° C. for 2 h, then cooled to RT and concentrated in vacuo. Purification of the residue by flash chromatography (30%→80% EtOAc in hexanes) afforded a mixture of the title compound and various EDT disulfide adducts which was used without further purification. ESI/APCI expected for C7H13NO2S2: 207.04. Found: 208 (MH+), 300 (MH++EDT), 414 (MNa++2 EDT).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.NC(N)=[S:16].N.Cl>C(O)C>[C:8]1([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][SH:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NC(N)=S
Reactant: BrCCCCCCc1ccccc1
Agent: Cl
Agent: N
Solvent: CCO
Product: SCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
15.0 g (62.2 mmol) 1-bromo-6-phenyl-hexane (described in the unexamined laid-open patent application of the int. Appl. PCT/EP95/04413) dissolved in 40 ml ethanol was added under a nitrogen atmosphere to a solution of 7.10 g (93.3 mmol) thiourea in 30 ml ethanol. After boiling for 7 hours at reflux temperature, it was allowed to cool to room temperature, admixed with 33 ml concentrated ammonia and heated for 4 h to reflux. Subsequently it was acidified to pH 1 with 15 ml concentrated HCl. It was extracted three times with 200 ml ether each time, washed with water and saturated sodium chloride solution, dried over magnesium sulfate and the solvent was removed in a vacuum. The residue was taken up in dichloromethane, the solid was suction filled, rewashed with dichloromethane and the filtrate was evaporated in a vaccum. 9.80 g (82%) 13 as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.C1(O)C=CC=CC=1.[CH2:26]([N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)[CH3:27]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:34][CH:31]1[CH2:32][CH2:33][N:28]([CH2:26][CH3:27])[CH2:29][CH2:30]1)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: CCN1CCC(N)CC1
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Solvent: Oc1ccccc1
Solvent: ClCCl
Product: CCN1CCC(Nc2c3ccc(Cl)cc3nc3ccc(OC)cc23)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 6,9-dichloro-2-methoxyacridine (100 mg, 0.36 mmol) and phenol (approximately 1.5 g) was heated to 100° C. under nitrogen atmosphere and stirred for 1 hour. 1-Ethylpiperidin-4-amine (92 mg, 0.72 mmol) was added to the mixture. The reaction was stirred at 100° C. for 5 hours, cooled to 20-25° C., and diluted with dichloromethane. The mixture was washed twice with sodium hydroxide solution (1 N) and twice with ammonium chloride solution. The phases were separated, and the organic layer was dried and concentrated. The residue was purified by Biotage column chromatography using triethylamine (5%) and methanol (5 to 15%) in dichloromethane to give the title compound; MS (Found: M+1=370).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6](/[CH:7]=[CH:8]/[S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6](/[CH:7]=[CH:8]/[S:9]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([F:15])=[CH:17][CH:18]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: Nc1ccc(F)cc1
Reactant: COc1ccc(/C=C/S(=O)(=O)Cl)cc1
Product: COc1ccc(/C=C/S(=O)(=O)Nc2ccc(F)cc2)cc1
Yield: 60.3 %

Procedure:
A solution of (E)-4-methoxystyrylsulfonyl chloride (10 mmol) and 4-fluoroaniline (10 mmol) was subjected to General Procedure 1, part B. The title compound was obtained in 60.3% yield.
Reaction SMILES: Br[SiH3].[F:3][C:4]([F:22])([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[CH2:5][CH2:6][Si:7](Br)([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9].[C:23]([Mg]Br)#[CH:24]>C1COCC1>[F:3][C:4]([F:22])([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[CH2:5][CH2:6][Si:7]([C:23]#[CH:24])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)[Si](Br)(CCC(F)(F)C(F)(F)C(F)(F)F)C(C)C
Reactant: C#C[Mg]Br
Agent: [SiH3]Br
Solvent: C1CCOC1
Product: C#C[Si](CCC(F)(F)C(F)(F)C(F)(F)F)(C(C)C)C(C)C
Temperature: 40 °C
Yield: 90 %

Procedure:
In an oven dried round bottom flask, (3,3,4,4,5,5,5-heptafluoropentyl)diisopropylsilane (10 g, 32 mmol) was dissolved in allyl bromide (20 mL) and the flask was flushed with N2. PdCl2 (40 mg) was added and the solution was heated to 60° C. for 12 hr. Solvent was removed on a rotary evaporator to yield a brown suspension that was taken up in pentane and filtered. Solvent removal yielded the bromosilane as a brown liquid (12.1 g). The bromosilane, (3,3,4,4,5,5,5-heptafluoropentyldiisopropylsilyl)bromide, was treated with ethynylmagnesium bromide (70 mL, 35 mmol, 0.5 M in THF) in anhydrous THF (20 mL) and heated to 40° C. for 4 hr. After cooling, the reaction was quenched by the slow addition of water (20 mL) and dilute sulfuric acid sufficient to dissolve the magnesium salts. Pentane was added and the organic layer was separated. The aqueous layer was extracted with pentane an additional time, then the organic layers were combined, washed with water (5×10 mL) and brine, dried over MgSO4, and filtered. Solvent was removed and the crude product was taken up in hexane and rinsed through a thin pad of silica. Solvent removal yielded the product as a colorless liquid (9.7 g, 29 mmol, 90%). Analysis of the product provided the following data: 1H-NMR (400 MHz, CDCl3) δ=2.4 (s, 1H), 2.2 (m, 2H), 1.0 (m, 14H), 0.8 (m, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14].Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:16])[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N+:13]([O-:15])=[O:14])[CH2:29][CH2:28]2)=[O:26])=[CH:23][CH:24]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: O=C(NCCCBr)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=C(NCCCN1CCC(C(=O)c2ccc(F)cc2)CC1)c1ccccc1[N+](=O)[O-]
Yield: 87 %

Procedure:
A mixture of 14.4 parts of N-(3-bromopropyl)-2-nitrobenzamide, 12.2 parts of (4-fluorophenyl) (4-piperidinyl)methanone hydrochloride, 16 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 3 hours using a water-separator. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 18 parts (87%) of N-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]-propyl]-2-nitrobenzamide as an oily residue.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:23][C@@H:24]([CH3:27])[CH2:25][OH:26])=[C:7]([CH:22]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:9])#[N:2].[H-].[Na+].F[C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:23][C@@H:24]([CH3:27])[CH2:25][O:26][C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)=[C:7]([CH:22]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:9])#[N:2]
Reactant: N#Cc1ccc(F)cc1
Reactant: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)CO)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)COc2ccc(C#N)cc2)cc1OC
Reaction time: 0.33 h
Yield: 33.7 %

Procedure:
To a solution of (S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)benzamide (177 mg) in dimethylformamide (4 mL) was added sodium hydride (19.2 mg) at ambient temperature. After stirring for 20 minutes, 4-fluorobenzonitrile (63.8 mg) was added to the mixture. After stirring for an hour at 60° C., the mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with the mixture of chloroform and ethyl acetate (9:1) to give (S)-5-cyano-2-[2-(4-cyanophenoxy)-1-methylethylamino]-N-(3,4-dimethoxybenzyl)benzamide (76 mg) as a solid substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[C:20](=[O:21])[C:19]3[C:14](=[C:15]([CH3:26])[C:16]([O:22]C(=O)C)=[CH:17][CH:18]=3)[O:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].N1C=CN=C1.O>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[C:20](=[O:21])[C:19]3[C:14](=[C:15]([CH3:26])[C:16]([OH:22])=[CH:17][CH:18]=3)[O:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2COc3c(ccc(OC(C)=O)c3C)C2=O)cc1OC
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCO
Product: COc1ccc(C2COc3c(ccc(O)c3C)C2=O)cc1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Acetic acid 3-(3,4-dimethoxy-phenyl)-8-methyl-4-oxo-chroman-7-yl ester (1.1 g, 3.2 mmol) and imidazole (3.2 g, 47 mmol) were refluxed in EtOH (100 ml). The reaction was complete after 90 minutes and allowed to cool to room temperature before pouring into stirred H2O (800 ml). A fine white precipitate was filtered off and 1H NMR in d-CDCl3 indicated the solid was 3-(3,4-Dimethoxy-phenyl)-7-hydroxy-8-methyl-chroman-4-one in >95% purity (0.31 g, 30%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[CH2:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:15].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:14]([N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:15]
Reactant: CCNc1ccccc1
Reactant: Oc1ccc(OCCCCBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCN(CCCCOc1ccc(O)cc1)c1ccccc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 6.9 %

Procedure:
To a solution of compound 12a (250 mg, 1.02 mmol) and N-ethylaniline (0.24 mL, 2.04 mmol) in acetonitrile (5.0 mL), diisopropylethylamine (0.42 mL, 3.05 mmol) was added dropwise. After the addition was complete, the reaction was stirred at 60° C. for 12 hours. The reaction mixture was concentrated and purified by column chromatography to isolate the compound 12 as a colorless oil (20 mg, 0.07 mmol, 12% yield). MS (ESI, positive) m/z calcd. for C18H24NO2 [M+H]+: 286.18, found: 286.18. 1H NMR (400 MHz, Chloroform-d) δ 7.23 (t, J=8 Hz, 1H), 6.65-6.81 (m, 8H), 4.71 (bs, 1H), 3.95 (t, J=5.2 Hz, 2H), 3.33-3.52 (m, 4H), 1.27-1.33 (m, 4H), 1.17 (t, J=6.8 Hz, 3H).
Reaction SMILES: [H-].[Na+].[C:3]([N:8]1[C:16]2[C:11](=[C:12]([CH3:19])[C:13]([OH:18])=[C:14]([CH3:17])[CH:15]=2)[CH:10]([CH3:20])[CH2:9]1)(=[O:7])[CH:4]([CH3:6])[CH3:5].[CH3:21]I>O1CCCC1>[C:3]([N:8]1[C:16]2[C:11](=[C:12]([CH3:19])[C:13]([O:18][CH3:21])=[C:14]([CH3:17])[CH:15]=2)[CH:10]([CH3:20])[CH2:9]1)(=[O:7])[CH:4]([CH3:6])[CH3:5]
Reactant: CI
Reactant: Cc1cc2c(c(C)c1O)C(C)CN2C(=O)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1c(C)cc2c(c1C)C(C)CN2C(=O)C(C)C
Temperature: 0 °C
Yield: 90 %

Procedure:
Sodium hydride (7 mg, 0.18 mmol) contained in a round-bottom flask was washed using dry hexanes and tetrahydrofuran (2 mL) was added, and the suspension was stirred at 0° C. under nitrogen atmosphere. A solution of N-isobutyryl-5-hydroxy-3,4,6-trimethylindoline (11 b, 42 mg 0.17 mmol) dissolved in tetrahydrofuran (2 mL) was added dropwise using a syringe. Methyl iodide (0.2 mL) was added to the cold solution in one portion, and the mixture was heated under reflux for 17 h. The reaction mixture was cooled, quenched with saturated aq. ammonium chloride solution and extracted with ether. The combined extracts were washed with brine and dried (MgSO4). Removal of solvents gave a viscous liquid which was purified by flash column chromatography using 1:4 ethyl acetate:hexanes as eluent, to afford N-isobutyryl-5-methoxy-3,4,6-trimethylindoline (13, 40 mg, 90% yield) as a viscous liquid. Spectral data: 1H NMR: δ 1.20-1.35 (m, 9H), 2.22 (s, 3H), 2.27 (s, 3H), 2.74 (quintet, 1H, J=6.5 Hz), 3.30 (t, 1H, J=6.5 Hz), 3.65 (s, 3H), 3.76 (dd, 1H, J=10, 1 Hz), 4.15 (t, 1H, J=9 Hz), 8.0 (s, 1H).