Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH2:18]([S:34](Cl)(=[O:36])=[O:35])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>O1CCCC1>[CH2:18]([S:34]([NH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1)(=[O:36])=[O:35])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CC(=O)c1cccc(N)c1
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCS(=O)(=O)Nc1cccc(C(C)=O)c1
Reaction time: 2 h

Procedure:
To a mechanically stirred solution of 31.2 g (0.23 M) of m-aminoacetophenone and 35.4 ml (0.254 M) of triethylamine in 1 liter of tetrahydrofuran was added 75 g (0.23 M) of 1-hexadecanesulfonyl chloride at room temperature. The mixture was stirred for 2 hours and the suspended salt was removed. The filtrate was treated on a rotary evaporator to give a solid which was recrystallized from hexane: mp 95.5°-100° C.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([S:13](/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:15])=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:24][OH:25]>C1COCC1>[OH:25][NH:24][CH:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:16][S:13]([N:10]1[CH2:9][CH2:8][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)(=[O:15])=[O:14]
Reactant: O=S(=O)(/C=C/c1ccccc1)N1CCN(c2ccccc2)CC1
Reactant: NO
Solvent: C1CCOC1
Product: O=S(=O)(CC(NO)c1ccccc1)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-phenyl-4-(trans-b-styrenesulfonyl)piperazine (108 mg) in THF (3 ml) was added hydroxylamine (0.45 ml, 50% aqueous solution). The mixture was stirred at ambient temperature for 18 hours. Solvent was removed in vauo and the residue dissolved in dichloromethane, washed with water, dried (Na2SO4) and evaporated to give the product 1-[2-(hydroxyamino)-2-phenylethanesulfonyl]-4-phenylpiperazine as a foam (120 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.[OH-].[Na+].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.O>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([O:8][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:7]=1
Reactant: OCc1ccc(Cl)cc1O
Reactant: Fc1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCc1ccc(Cl)cc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a solution of 5-chloro-2-(hydroxymethyl)phenol (943 mg, 5.95 mmol) and NaOH (3.5 mL, 6.54 mmol, 2M in water) in ethanol (10 mL) was added 4-(bromomethyl)-1-fluorobenzene (1.13 g, 5.95 mmol) slowly, the mixture was then stirred at room temperature overnight. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic phase was collected and washed with water, brine, and dried with anhydrous Na2SO4. The solvent was removed to give 900 mg of the title compound (57%). 1H NMR (400 MHz, CDCl3): δ 2.08 (1H, t, J=6.4 Hz), 4.67 (2H, d, J=6.4 Hz), 5.05 (2H, s), 6.93 (1H, d, J=1.2 Hz), 6.96 (1H, dd, J=1.6 Hz, 8.0 Hz), 7.07-7.11 (2H, m), 7.25 (1H, d, J=6.0 Hz), 7.37-7.40 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1)=[O:5].[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[S:23]([Cl:26])(=[O:25])=[O:24]>>[ClH:26].[NH:13]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[NH:1][S:23]([C:19]1[S:18][CH:22]=[CH:21][CH:20]=1)(=[O:25])=[O:24]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Nc1ccccc1C(=O)NCCc1ncc[nH]1
Product: Cl
Product: O=C(NCCc1ncc[nH]1)c1ccccc1NS(=O)(=O)c1cccs1
Yield: 36.8 %

Procedure:
The titled compound was prepared substantially in accordance with the method detailed in Example 6B using 1.50 g (0.00651 mol) of 2-amino-N-[2-(1H-imidazol-2-yl)ethyl]benzamide, prepared as in Example 6A, and 1.62 g (0.00847 mol) of 2-thiophenesulfonyl chloride, with the exception that after removing ethyl acetate, the resultant residue was dissolved in methanol containing hydrochloric acid and diethyl ether. The resulting solution was reduced to dryness under reduced pressure and the product was recrystallized from water and dried for approximately 8 hours at 100° C. under reduced pressure to provide 0.99 g of the desired titled compound (m.p. 210°-213° C.).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](Cl)(Cl)=[S:16].CCCCCC.CCOC(C)=O>CC(C)=O>[O:1]([C:8]1[CH:9]=[C:10]([N:11]=[C:15]=[S:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Oc2ccccc2)c1
Reactant: S=C(Cl)Cl
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: S=C=Nc1cccc(Oc2ccccc2)c1

Procedure:
To a stirring solution of 3-phenoxyaniline (185 mg, 1.0 mmol) in acetone (4.0 mL) at 0° C. was added thiophosgene (0.23 mL, 3.0 mmol) and the resulting reaction maintained for 30 min. The reaction determined complete by TLC (4:1 hexane/EtOAc). The reaction was concentrated, azeotroped with toluene and taken on without further purification.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7]([OH:22])(=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>[Pd]>[CH2:20]([O:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7].[CH3:2][CH2:3][O:22][CH2:7][CH3:8]
Reactant: CCCCCCCCCCCCCC(=O)O
Reactant: OCC(O)CO
Agent: [Pd]
Product: CCCCCCCCCCCCCCOCC(O)CO
Product: CCOCC
Temperature: 120 °C
Yield: 41 %

Procedure:
A stirred autoclave was charged, at room temperature, with 65.41 g (710 mmol) of glycerol, 4.01 g (17.6 mmol) of myristic acid, 0.40 g (10 wt %) of AMBERLYST® (a polymer based catalyst) 35 resin and 0.39 g (1.0 mol %) of Pd/C at 5%. The autoclave was then pressurized at 50 bar of dihydrogen gas H2, and then it was heated at 120° C. for 16 h, stirring vigorously. After 16 h of reaction, the reaction mixture was brought back to room temperature. The catalyst was filtered on a MILLIPORE® filter (a membrane filter) (0.1 μm) and was rinsed with absolute ethanol. The solvents were evaporated and the organic products were extracted from the glycerol phase by extraction with CH2Cl2 (3×50 ml). The organic phase was washed with water (2×30 ml) and the CH2Cl2 was then evaporated at reduced pressure. The crude reaction product was purified on a flash silica column (eluent: cyclohexane/ethyl acetate=5:1˜1:1). 1-O-tetradecanyl-glycerol ether was obtained at an isolated yield of 41%.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([OH:27])=[CH:20][C:13]=3[C:14]=2[C:15]([O:17]CC)=[O:16])=[CH:6][CH:5]=1>CCO.C1COCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][C:12]3[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([OH:27])=[CH:20][C:13]=3[C:14]=2[C:15]([OH:17])=[O:16])=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(O)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(O)cc12
Temperature: 64 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
Excess NaOH (11 ml, 11.00 mmol, 1M aq) was added to a stirring solution of ethyl 2-(4-fluorophenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylate (1.9 g, 5.50 mmol) in EtOH (55 ml) and THF (55 ml) and was allowed to stir at 64° C. overnight. The mixture was concentrated and diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the titled compound (1.7 g, quant.). 1H NMR (300 MHz, DMSO-D6) δ ppm 7.31-7.48 (m, 2H) 7.71 (s, 1H) 8.00-8.14 (m, 2H) 8.29 (s, 1H) 10.80 (s, 1H) 13.35 (s, 1H). LC-MS retention time: 0.99 min; m/z (MH−): 416. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=1)=[CH:13][C:12]([C:27]#[N:28])=[CH:11][C:10]=2[CH2:29][CH3:30])=O)C.C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].C1COCC1>C1COCC1>[Cl:26][C:20]1[CH:19]=[C:18]([CH2:17][NH:16][C:15]2[C:14]3[C:9](=[C:10]([CH2:29][CH3:30])[CH:11]=[C:12]([C:27]#[N:28])[CH:13]=3)[N:8]=[CH:7][C:6]=2[CH2:4][OH:3])[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: CCOC(=O)c1cnc2c(CC)cc(C#N)cc2c1NCc1ccc(OC)c(Cl)c1
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cc(C#N)cc2c(NCc3ccc(OC)c(Cl)c3)c(CO)cnc12
Yield: 83.2 %

Procedure:
To a suspension of 100 mg (0.236 mmol) of 4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethylquinoline-3-carboxylic acid ethyl ester in 2.8 mL anhydrous THF under nitrogen, was added 1.2 mL (5.0 eq) of 1M lithium tri-t-butoxyaluminohydride/THF. The resulting mixture was refluxed overnight with stirring. The reaction was quenched with 1 mL of MeOH and partitioned between 75 mL 1M NaOH and 100 mL CH2Cl2. The organic phase was washed with 1M NaOH (2×30 mL) and dried over MgSO4. Removal of the solvent under reduced pressure gave 75 mg (84% yield) of the title compound as a light yellow solid. The analytical sample was obtained by trituration in ether: mp: 188-189° C. LC: 3.15′; MH+: 382.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:22][CH3:23])[C:4]1[CH:21]=[CH:20][C:7](/[CH:8]=[N:9]/[C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][O:13][C:14]3=[O:19])=[CH:6][CH:5]=1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH3:32][O-:33].[Na+]>C(OCC)(=O)CC>[CH3:23][O:22][CH:3]([O:2][CH3:1])[C:4]1[CH:21]=[CH:20][C:7]([CH:8]2[CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:32](=[O:33])[C:11]3[C:15]([C:14]([O:13][CH3:12])=[O:19])=[CH:16][CH:17]=[CH:18][C:10]=3[NH:9]2)=[CH:6][CH:5]=1
Reactant: COC(OC)c1ccc(/C=N/c2cccc3c2COC3=O)cc1
Reactant: C[O-]
Reactant: O=Cc1ccccc1
Agent: [Na+]
Solvent: CCOC(=O)CC
Product: COC(=O)c1cccc2c1C(=O)C(c1ccccc1)C(c1ccc(C(OC)OC)cc1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
To a solution of (E)-4-(4-(dimethoxymethyl)benzylideneamino)isobenzofuran-1(3H)-one (600 mg, 1 mmol) and benzaldehyde (616 mg, 3 mmol) in ethyl propionate (20 mL), sodium methanolate (414 mg, 7.6 mmol) were added and the mixture was stirred at room temperature overnight. Then the resulting mixture was evaporated under reduced pressure and extracted with ethyl acetate (100 mL×4) and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate 20:1 to 5:1) to obtain a white solid of methyl 2-(4-(dimethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (120 mg, yield 22%). LC-MS (ESI) m/z: 432 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH:9]([CH3:11])[CH2:8][CH:7]([C:12]([O:14]C)=[O:13])[CH2:6]1.[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH:9]([CH3:11])[CH2:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6]1
Reactant: COC(=O)C1CC(C)CN(Cc2ccccc2F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1CC(C(=O)O)CN(Cc2ccccc2F)C1
Reaction time: 8 h

Procedure:
To methyl 1-(2-fluorobenzyl)-5-methylpiperidine-3-carboxylate (0.5 mmol), LiOH (1 mmol) in 2 ml THF/H2O (1:1) was added. The reaction was stirred overnight. The solvent was removed under vacuo. The crude product was progressed to the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)C(=O)[N:3]1[CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]=O)=[CH:15][CH:14]=1.[C:25]([O-:28])([O-])=O.[K+].[K+].O1CCOC[CH2:32]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:23]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([CH2:12][N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:25]2=[O:28])=[CH:14][CH:15]=1)=[CH2:32]
Reactant: O=Cc1ccc(CN2C(=O)c3ccccc3C2=O)c2ccccc12
Reactant: O=C([O-])[O-]
Reactant: C1COCCO1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Product: C=Cc1ccc(CN2C(=O)c3ccccc3C2=O)c2ccccc12
Temperature: 100 °C
Yield: 67 %

Procedure:
To a stirred solution of 4-((1,3-dioxoisoindolin-2-yl)methyl)-1-naphthaldehyde (9 g, 28.5 mmol) in 1,4-dioxane (100 mL) were added K2CO3 (6 g, 42.8 mmol) and methyl triphenyl phosphonium bromide (15.3 g, 35.7 mmol) at ambient temperature. The reaction mixture was heated at 100° C. for 14 h and then was cooled to ambient temperature. The reaction mixture was filtered, and the obtained filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 20% EtOAc in petroleum ether) afforded the title compound as a white solid (6 g, 67%): mp 146-147° C.; 1H NMR (400 MHz, CDCl3) δ 8.35 (m, 2H), 7.95 (m, 4H), 7.65 (m, 4H), 7.39 (m, 1H), 5.81 (m, 1H), 5.45 (m, 1H), 5.21 (s, 2H); ESIMS m/z 314.13 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][OH:14])[C@H:10]([C:15]([CH3:23])([CH3:22])[O:16][SiH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OC(C)(C)C)=O.CC#N.O>C(Cl)Cl.O.CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH:13]=[O:14])[C@H:10]([C:15]([CH3:23])([CH3:22])[O:16][SiH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CO)[C@H](C(C)(C)O[SiH2]C(C)(C)C)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)(C)OC=O
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](C=O)[C@H](C(C)(C)O[SiH2]C(C)(C)C)C1

Procedure:
The title compound is prepared in a similar manner as described for Example 9/reaction step E, from (3S*,4S*)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (10.4 g, 58.9 mmol) and Dess-Martin periodinane (25.0 g, 58.9 mmol) in CH2Cl2 (150 mL), slowly wet CH2Cl2 (1.17 mL of water in 150 mL of CH2Cl2) as colorless oil. MS: 244.2 [M+H-Boc]+. tR (HPLC, C18 column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 6.46 min.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[C:15]2[CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:14]=2[CH:13]=[CH:12][CH:11]=1)(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[C:10]1([CH2:9][OH:8])[C:15]2[CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc2c1C=CCCCC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cccc2c1C=CCCCC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl(5,6,7,8-tetrahydrobenzo[a]cycloocten-1-ylmethoxy)dimethylsilane (10.94 g, 36.16 mmol) in tetrahydrofuran (100 ml) was added a solution (43.4 ml, 43.4 mmol) of 1.0 M tetrabutylammonium fluoride in tetrahydrofuran at room temperature and the mixture was stirred at room temperature for 15 min. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1−3/1) to give the objective substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[C:17](=O)[NH:16][CH2:15][CH:14]2[CH2:13][CH2:12][CH2:11][CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8].B.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]2[CH2:15][NH:16][CH2:17]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NCC2CCCCC12c1ccc(Cl)c(Cl)c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: Clc1ccc(C23CCCCC2CNC3)cc1Cl
Yield: 25.1 %

Procedure:
7a-(3,4-Dichlorophenyl)octahydro-1H-isoindol-1-one (65 mg, 0.2287 mmol) was diluted in THF (2 mL) and borane (0.7 mL, 1 M in THF, 3 eq) and heated in the microwave for 15 minutes (max temp=100° C.). After cooling, the mixture was stirred with 6N HCl for thirty minutes and washed with MTBE. The aqueous layer was basicified with KOH and extracted with MTBE. The organic phase was evaporated and filtered (aminopropyl cartridge) to give 3a-(3,4-dichlorophenyl)octahydro-1H-isoindole (15.5 mg, 24%) as a clear oil. A further portion was later found in the organic wash and separated by silica gel filtration to give 19 mg (26%) additional product. LCMS Rt=7.60 min, m/z=270 (M+1). 1H NMR (CDCl3, δ): 7.43 (d, J=2.3 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.19 (dd, J=2.3, 8.5 Hz, 1H), 3.1 (m, 2H), 2.9 (m, 1H), 2.6 (m, 2H), 2.0-1.2 (m, 8H). 13C NMR (CDCl3, δ, mult): 146.7(0), 132.3(0), 130.1(1), 129.7(0), 128.9(1), 126.2(1), 59.9(2), 49.6(2), 47.9(0), 41.0(1), 32.8(2), 24.2(2), 22.0(2), 21.4(2).
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([Cl:9])[CH:6]=[CH:7][CH:8]=1.[C:10](#N)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(=O)(=O)(O)[OH:19]>O1CCCC1>[Cl:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:19]
Reactant: O=S(=O)(O)O
Reactant: Clc1cccc(Br)c1
Reactant: N#Cc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1cccc(Cl)c1
Temperature: 0 °C

Procedure:
To a suspension of 6.4 g. (0.266 mole) of magnesium turnings in 50 ml. of tetrahydrofuran was added dropwise 51 g. (0.268 mole) of 3-bromochlorobenzene in 100 ml. of dried tetrahydrofuran and the mixture refluxed for one hour. The cooled reaction mixture was added to 27.4 g. (0.266 mole) of benzonitrile in 100 ml. of tetrahydrofuran and refluxed for one hour. The reaction mixture was poured carefully into 100 ml. of ice/water and 10 ml. of concentrated sulfuric acid and heated on a steam bath for 30 minutes. The solution was cooled, extracted with ether, washed with water and 5% sodium bicarbonate solution, dried, evaporated and chromatographed to give 3-chlorobenzophenone (recrystallized from methanol), m.p. 83° C.
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:18][NH:19][C:20]([CH3:34])([CH3:33])[CH2:21][C:22]2[CH:23]=[C:24]([CH2:28][C:29]([O:31]C)=[O:30])[CH:25]=[CH:26][CH:27]=2)=[CH:13][C:12]=1[CH2:43][OH:44])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1.CO>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:37])[CH3:38])[CH2:18][NH:19][C:20]([CH3:34])([CH3:33])[CH2:21][C:22]2[CH:23]=[C:24]([CH2:28][C:29]([OH:31])=[O:30])[CH:25]=[CH:26][CH:27]=2)=[CH:13][C:12]=1[CH2:43][OH:44])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)Cc1cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c(CO)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(Cc1cccc(CC(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c(CO)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
Lithium hydroxide solution (1M in water, 16.2 mL, 16.2 mmol) was added to a solution of methyl (3-{2-[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methylpropyl}phenyl)acetate (preparation 147), (4.80 g, 8.1 mmol) in tetrahydrofuran (49 mL) and methanol (17 mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was diluted with water and acidified to pH 7 with 1M hydrochloric acid. The resulting precipitate was filtered off and washed with water to afford the title compound as a pale yellow solid in 94% yield, 4.37 g 1H NMR (400 MHz, DMSO-d6) δ: 7.45-7.38 (6H, m), 7.31 (2H, m), 7.13 (1H, m) 7.02 (3H, m), 5.04 (3H, m), 4.52 (2H, d), 3.52 (2H, d), 2.43 (2H, d), 3.37 (2H, d), 1.24 (6H, m), 0.78 (9H, s), 0.02 (3H, s), -0.92 (3H, s) ppm; LRMS ESI m/z 659 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][N:4]([CH3:9])[N:3]=1.[H-].[Na+].Cl[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21].O>O1CCCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([NH:1][C:2]2[C:6]([C:7]#[N:8])=[CH:5][N:4]([CH3:9])[N:3]=2)=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: Cn1cc(C#N)c(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(C#N)c(Nc2ccc(Cl)cc2[N+](=O)[O-])n1
Reaction time: 0.17 h

Procedure:
3-Amino-1-methylpyrazole-4-carbonitrile (Helv. Chim. Acta (1959) 42 763) (3.66 g) was stirred in dry tetrahydrofuran (40 ml). Sodium hydride (50% oil dispersion, 2.28 g) was added and the mixture was stirred for 10 minutes. 2,5-Dichloronitrobenzene (5.76 g) was added and the solution stirred under nitrogen for 20 hours. Water was added dropwise to destroy any excess sodium hydride, then the solution was poured on to a mixture of ice and dilute hydrochloric acid. After standing for 1 hour the brick-red precipitate was filtered, washed with water and dried. Crystallization from ethanol-ethyl acetate afforded the product m.p. 205° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:28][C@@H:29]1[NH:34][CH2:33][CH2:32][N:31]([C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=2)[CH2:30]1>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:34]2[CH2:33][CH2:32][N:31]([C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:36]=3)[CH2:30][C@@H:29]2[CH3:28])[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: C[C@H]1CN(c2ccc3ccccc3n2)CCN1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Product: C[C@H]1CN(c2ccc3ccccc3n2)CCN1CCCCC1(C(=O)NCC(F)(F)F)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-[(S)-3-methyl-piperazin-1-yl]-quinoline
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH:11](C(OCC1C=CC=CC=1)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)Cc1ccc(N)cc1F
Yield: 60.3 %

Procedure:
Ethyl phenylmethyl (2-fluoro-4-nitrophenyl)propanedioate (3.86 g, 10.6 mmol) dissolved in ethanol, was treated with ammonium formate (6.7 g, 10.6 mmol) and palladium on carbon 10% paste (380 mg) was added under argon. The reaction mixture was refluxed for 3 hours, cooled and filtered. Evaporated and purified by chromatography on silica gel eluting with ethyl acetate/hexane (1:1) to give the title compound as a yellow oil (1.26 g). LC/MS: Rt=2.10, [MH]+ 198.