Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.CC1C=CC(C(C)C)=CC=1.CC1C=CC(C(C)C)=CC=1.Cl[Ru]Cl.Cl[Ru]Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(F)cc1
Agent: Cl[Ru]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccc(C(C)C)cc1
Solvent: C1COCCO1
Product: CC(O)c1ccc(F)cc1
Temperature: 105 °C
Reaction time: 1 h

Procedure:
Dichloro(p-cymene)ruthenium(II) dimer (1.2 mg, 2 μmol, 0.5 mol %) and a chiral ligand (M=Ru, R=i-Pr, Ar=C6H5—, 2.6 μmol, 0.65 mol %) were dissolved in 1,4-dioxane (3 mL) under nitrogen atmosphere, and then heated and stirred for 1 h at 105° C. After the mixture was cooled to room temperature, p-fluoroacetophenone (0.4 mmol), 1,4-dioxane (2 mL) and a solution of sodium carbonate in 1,4-dioxane (0.8 mL, 0.2 M) were added thereto. Thereafter, the reaction system was placed in an autoclave, and stirred for 24 h under H2 (5 atm) at 10° C. The solvent was removed under reduced pressure, and the resultants were separated by column chromatography (silica gel column; eluent: ethyl acetate/petroleum ether=1/5). Accordingly, pure 1-(p-fluorophenyl)ethanol was obtained and the ee value (ee=98%) was measured by GC analysis.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]([CH3:12])[CH2:10][C:9](=[O:13])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.Cl.[N:17]1([CH2:22][CH2:23][N:24]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:26]=[C:25]2[CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:21][CH2:20][CH2:19][CH2:18]1.CN1CCCC1=O.C(N(C(C)C)CC)(C)C>O>[CH3:12][CH:11]1[C:3]2[C:2]([N:36]3[CH2:35][CH2:34][CH:33]([C:25]4[N:24]([CH2:23][CH2:22][N:17]5[CH2:18][CH2:19][CH2:20][CH2:21]5)[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[N:26]=4)[CH2:38][CH2:37]3)=[N:7][CH:6]=[N:5][C:4]=2[NH:8][C:9](=[O:13])[CH2:10]1
Reactant: CC1CC(=O)Nc2ncnc(Cl)c21
Reactant: FC(F)(F)c1cn(CCN2CCCC2)c(C2CCNCC2)n1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CC(=O)Nc2ncnc(N3CCC(c4nc(C(F)(F)F)cn4CCN4CCCC4)CC3)c21
Temperature: 200 °C

Procedure:
Add 4-chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (0.22 g, 1.11 mmol), 4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine trihydrochloride (0.57 g, 1.2 eq), N-methylpyrrolidinone (10 mL) and diisopropylethylamine (1.16 mL, 6.0 eq) in a microwave tube. Seal the tube and heat in a microwave reactor at 200° C. for 30 minutes. Dilute the reaction mixture with water and extract with ethyl acetate. Wash with saturated aqueous sodium chloride. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by normal phase chromatography, eluting with a 1-10% methanol/dichloromethane gradient, to give 5-methyl-4-(4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-1-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one as a racemate (0.19 g, 36%). MS (ES) m/z=478 [M]+. Chiral separation (Chiralpak AD-H, 30% ethanol/70% CO2 w/0.2% isopropylamine) provides enantiomer 1 (>99% ee) and (R)-5-methyl-4-(4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-1-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one as enantiomer 2 (>99% ee). MS (ES) m/z=478 [M]+ for both compounds.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][C:24](C)([O-:26])C.[K+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]2[C@H:10]([N:14]([C@@H:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:16])[C:24](=[O:26])[CH2:23][O:13]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[O-]
Reactant: C[C@@H](N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1O)c1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C(=O)CO[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3.14 g of trans-1-tert-butoxycarbonyl -4-hydroxy-3-[(1R)-1-phenylethylamino]pyrrolidine 8a in 200 of tetrahydrofuran was added 1 g of potassium tert-butoxide. The mixture was stirred at room temperature for 20 minutes. The solvent was removed under reduced pressure and a residue was subjected to silica gel column chromatography. From an eluant of a mixture of hexane and ethyl acetate (1:1 by volume), the titled compound 9a weighing 2.45 g was obtained as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.[C:14]([Cl:24])(=[O:23])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[ClH:24].[CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:14](=[O:23])[CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][CH:7]=1
Reactant: CN(C)CCOc1ccc(N)cc1
Reactant: O=C(Cl)C=Cc1ccccc1
Product: CN(C)CCOc1ccc(NC(=O)C=Cc2ccccc2)cc1
Product: Cl
Yield: 100.3 %

Procedure:
The reaction between 27.0g of 4-[2-(dimethylamino)-ethoxy]benzenamine and 24.9g of cinnamoyl chloride (using the procedure of Example 4, part b) gives 52.0g of crystals, melting point 257°-259° C, dec. Crystallization from a solution of 500 ml of methanol and 30 ml of water yields 43.1g of product, melting point 263°-265° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][O:10][C:11]3[CH:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][C:12]=3[CH:13]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[CH3:45][N:46]([CH2:53][C@H:54]1[CH2:59][CH2:58][C@H:57]([NH2:60])[CH2:56][CH2:55]1)[CH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][O:10][C:11]3[CH:17]=[CH:16][C:15]([C:18]([NH:60][C@H:57]4[CH2:56][CH2:55][C@H:54]([CH2:53][N:46]([CH3:45])[CH:47]5[CH2:52][CH2:51][O:50][CH2:49][CH2:48]5)[CH2:59][CH2:58]4)=[O:19])=[CH:14][C:12]=3[CH:13]=2)=[CH:6][CH:7]=1
Reactant: CN(C[C@H]1CC[C@H](N)CC1)C1CCOCC1
Reactant: Cc1ccc(C2=Cc3cc(C(=O)O)ccc3OC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(C2=Cc3cc(C(=O)N[C@H]4CC[C@H](CN(C)C5CCOCC5)CC4)ccc3OC2)cc1
Reaction time: 2 h

Procedure:
Into a suspension of 3-(4-methylphenyl)-2H-1-benzopyran-6-carboxylic acid (150 mg) and 1-hydroxybenzotriazole (114 mg) in acetonitrile (15 ml) was added at room temperature 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (162 mg), and the resulting mixture was stirred for 2 hours. Into the reaction mixture was added a solution of trans-4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexylamine dihydrochloride (253 mg), 1,8-diazabicyclo[5,4,0]-7-undecene (257 mg) and triethylamine (0.16 ml) in acetonitrile (20 ml), and the resulting mixture was stirred for 4 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with chloroform. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After the resulting organic layer was concentrated under reduced pressure to remove the solvent, the residue was subjected to purification using column chromatography (ethanol/ethyl acetate 1:2) and to recrystallization (ethanol) to obtain trans-3-(4-methylphenyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexyl]-2H-1-benzopyran-6-carboxamide (compound 68) (190 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:23]([OH:24])[C@@H:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:21]([CH2:33][O:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[O:20][C@H:10]1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:47](OC(=O)C)(=[O:49])[CH3:48]>C1(C)C=CC=CC=1>[C:47]([O:24][C@H:23]1[C@@H:22]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:21]([CH2:33][O:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[O:20][C@@H:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C@@H:9]1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:49])[CH3:48]
Reactant: CCCCCCCCO[C@@H]1O[C@H](COC(=O)C(C)(C)C)[C@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCO[C@@H]1O[C@H](COC(=O)C(C)(C)C)[C@H](OCc2ccccc2)[C@H](OC(C)=O)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 17 (10 mg, 18.0 μmol) was dissolved by addition of pyridine (1 mL). Acetic anhydride (0.5 mL) was added to the solution, and the mixture was stirred at the room temperature for 2 hours. The solvent was subjected to azeotropy with toluene, and the residue was purified with Sephadex LH-20 (CHCl3:MeOH=1:2) to obtain Compound 18 (11 mg, qu.).
Reaction SMILES: [C:1]([C:3]1[NH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:11]([O:13][CH3:14])=[O:12])=[CH:6][N:7]=1)#[N:2].CN(C=O)C.C1C(=O)N([Cl:31])C(=O)C1>C(Cl)(Cl)Cl>[Cl:31][C:6]1[N:7]=[C:3]([C:1]#[N:2])[NH:4][C:5]=1[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(C)c(-c2cnc(C#N)[nH]2)c1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(C)c(-c2[nH]c(C#N)nc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(2-cyano-1H-imidazol-5-yl)-4-methylbenzoate (compound 234.3, 290 mg, 1.20 mmol) in a solvent mixture of DMF and CHCl3 (4/20 mL). NCS (161 mg, 1.21 mmol, 1.00 equiv) was added to the above reaction mixture. The reaction mixture was stirred overnight at room temperature, then was concentrated under reduced pressure. The residue was diluted with 30 mL of EtOAc, then was washed with 3×15 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/10-1/7) as eluent to furnish 160 mg (48%) of the title compound as light yellow oil.
Reaction SMILES: [CH:1]([Mg]Cl)([CH2:3][CH3:4])[CH3:2].[CH3:7][Si:8]([O:11][CH3:12])(Cl)Cl.[Cl-].[NH4+]>>[CH:1]([Si:8]([CH:1]([CH2:3][CH3:4])[CH3:2])([CH3:7])[O:11][CH3:12])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)[Mg]Cl
Reactant: CO[Si](C)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CCC(C)[Si](C)(OC)C(C)CC
Yield: 80 %

Procedure:
The sec-butyl magnesium chloride as prepared above was added dropwise to the methylmethoxydichlorosilane solution as obtained in Example 7, in the same manner as in Example 3(c), to effect the Grignard reaction. The resulting Grignard reaction solution was post-treated with the saturated aqueous ammonium chloride solution as used in Example 3(c) in a reduced amount of 80 ml, instead of the 120 ml. The organic layer was separated and was subjected to a fractional distillation, thereby to afford 31 g of di-sec-butyl methylmethoxysilane as a fraction boiling at 76° C.-78° C./16 mmHg (yield; 80%).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][O:15][C:16]([C:18]1[O:19][C:20]([CH3:25])=[C:21]([CH2:23][OH:24])[CH:22]=1)=[O:17]>CC(C)=O.C(OCC)C>[CH3:14][O:15][C:16]([C:18]1[O:19][C:20]([CH3:25])=[C:21]([C:23]([OH:3])=[O:24])[CH:22]=1)=[O:17]
Reactant: CC(C)=O
Reactant: COC(=O)c1cc(CO)c(C)o1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COC(=O)c1cc(C(=O)O)c(C)o1
Reaction time: 5 h

Procedure:
Jones' reagent (Prepared according to Fieser and Fieser, Reagents for Organic Synthesis, Volume 1, page 142, 1967) was added drop-wise to a stirred solution of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (100 mg) in acetone (10 mL) until the orange colouration just remained. Stirring was continued for a further 5 hours then the reaction mixture was diluted with diethyl ether (20 mL) and filtered. The filtrate was dried and concentrated in vacuo to afford compound 23 as a buff coloured solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([C:14]#[N:15])=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[N:28]([Sn](C)(C)C)=[N+:29]=[N-:30].O.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([C:14]2[NH:30][N:29]=[N:28][N:15]=2)=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1C#N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1-c1nnn[nH]1
Temperature: 70 °C
Reaction time: 168 h

Procedure:
A mixture of 0.682 g (1.73 mM) of 2-cyano-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation XV, and 1.24 g (6.05 mM) of azidotrimethyltin in 10 ml of toluene is prepared and this mixture is stirred at 70° C. for 7 days. After cooling, the reaction medium is poured onto a mixture of water and ethyl acetate and brought to pH 1 by addition of an N hydrochloric acid solution. The aqueous phase is extracted, brought to pH 5 by addition of a dilute sodium hydroxide solution and extracted with ethyl acetate. This organic phase is separated, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The crude product obtained is purified by chromatography on silica gel, elution being carried out with a dichloromethane/methanol mixture (95/5;v/v). The expected compound is thus obtained in the form of a white foam (yield=30%).
Reaction SMILES: C([O-])(=O)C.[Bi+3:5].C([O-])(=O)C.C([O-])(=O)C.[C:14]([OH:22])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[C:14]([O-:22])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Bi+3:5].[C:14]([O-:22])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:14]([O-:22])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Bi+3]
Solvent: Cc1ccccc1
Product: O=C([O-])c1ccccc1
Temperature: 110 °C

Procedure:
5.79 grams of bismuth acetate (Aldrich) and three equivalents, 5.49 grams, of benzoic acid (Aldrich) were added to a 500 milliliter one neck round bottom flask. Toluene (300 milliliters) was then added as the solvent. A distillation head with 500 milliliters catch flask was attached to the reaction flask. The mixture was stirred vigorously and heated to reflux (about 110° C.). The mixture never completely dissolved (white cloudy mix). After about 5 hours of refluxing (while stirring), the toluene was slowly distilled off. When about 50 milliliters were left in the reaction flask, the heat was turned off and the reaction was allowed to cool to room temperature. A white powder precipitated and was separated by filtration. The resulting white powder was rinsed with about 1 liter of hexane, collected and dried overnight in vacuo at 50° C. The yield was 7.2 grams.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH2:7][C:6]([CH2:10][CH2:11][CH2:12][C:13]#[C:14][Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])([OH:9])[CH2:5][CH2:4]1.I[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-2](Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:28][N:2]([CH3:1])[C:3]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:8][CH2:7][C:6]([CH2:10][CH2:11][CH2:12][C:13]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:14]=2[Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])([OH:9])[CH2:5][CH2:4]1
Reactant: CC[Si](C#CCCCC1(O)CCC(c2ccccc2)(N(C)C)CC1)(CC)CC
Reactant: INc1ccccc1
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-2](Cl)c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC[Si](CC)(CC)c1[nH]c2ccccc2c1CCCC1(O)CCC(c2ccccc2)(N(C)C)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 4-dimethylamino-4-phenyl-1-(5-triethylsilanyl-pent-4-inyl)cyclohexanol (504 mg, 1.26 mmol), iodoaniline (331 mg, 1.51 mmol), [1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene]-(3-chloropyridyl)palladium(II)-chloride (PEPPSI, 171 mg, 0.25 mmol) and sodium carbonate (668 mg, 6.3 mmol) was evacuated for 30 min (oil pump). It was then flushed with argon and absolute N,N-dimethylformamide (5 mL, previously flushed for 1 h with argon) was added by syringe via a Schlenk tube. The mixture was stirred for 18 h at 100° C. and changed colour to dark brown during this. The reaction mixture was then concentrated to low volume in a vacuum, the residue taken up several times in toluol (3×10 mL) and concentrated to low volume again in each case, distributed between water and ethyl acetate (20 mL each) and the phases separated again. The aqueous phase was extracted with ethyl acetate (2×30 mL), the combined organic phases were washed with 1 M sodium thiosulphate solution (30 mL) and saturated sodium chloride solution (50 mL), dried with sodium sulphate and concentrated to low volume in a vacuum. The raw product (750 mg) was purified by means of flash chromatography (38 g, 20×2.5 cm) with chloroform/methanol (97:3). The mixed fractions (489 mg) obtained were purified once again by means of MPLC [LiChroprep Si60 (15-25 μm), 130 g, 46×2.6 cm] also with chloroform/methanol (97:3).
Reaction SMILES: [F:1][CH:2]([O:7][C:8]1[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)[C:3]([F:6])([F:5])[F:4].[N+:15]([O-])([OH:17])=[O:16].S(=O)(=O)(O)O>C(O)(=O)C>[N+:15]([C:13]1[CH:12]=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=1[O:7][CH:2]([F:1])[C:3]([F:4])([F:5])[F:6])([O-:17])=[O:16]
Reactant: Cc1cccc(OC(F)C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1ccc([N+](=O)[O-])c(OC(F)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
20.8 g (0.10 moles) 3-tetrafluoroethoxytoluene is placed in 25 ml glacial acetic acid and nitrated at 5° C. with a mixture of 30 ml concentrated nitric acid and 35 ml concentrated sulfuric acid. The solution turns yellow as the nitrating acid is added dropwise. When the addition is terminated the cooling bath is removed and the solution is agitated for 31/2 hours at room temperature. The solution is then poured onto ice, the precipitated oil separated and the aqueous solution is extracted with ethyl acetate. After drying over sodium sulfate and distilling the solvent, a yellow oil remains in quantitative yield, which according to the NMR spectrum, involves the 4-nitro-3-tetrafluoroethoxytoluene.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:2]([Cl:1])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)cccc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(Cl)cccc1CBr
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A mixture of methyl 2-chloro-6-methylbenzoate (3.0 g, 16.2 mmol), N-bromosuccinimide (3.0 g, 17.0 mmol), and benzoyl peroxide (catalytic) in anhydrous carbon tetrachloride (50 mL) was stirred at reflux overnight. Dichloromethane (50 mL) was added after cooling to room temperature. The mixture was extracted with 1 N NaOH (2×100 mL). The organic layer was recovered, dried over MgSO4, filtered, and evaporated, and the residue was dried in vacuo, affording methyl 2-(bromomethyl)-6-chlorobenzoate (4.06 g, 95% yield), which was used without further purification.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].S(Cl)(Cl)=O.[C:15]([NH2:24])(=O)[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[OH:18]>C1(C)C(C)=CC=CC=1>[OH:18][C:17]1[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=1[C:15]1[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1](=[O:10])[N:24]=1
Reactant: NC(=O)c1ccccc1O
Reactant: O=C(O)c1ccccc1O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1C
Product: O=c1nc(-c2ccccc2O)oc2ccccc12
Temperature: 37.5 °C
Reaction time: 0.5 h

Procedure:
Xylene (1.5 L) and salicylic acid (1 Kg.) was added to a 5 L 4-neck round bottom flask equipped with a mechanical stirrer and thermocouple. Thionyl chloride (1.29 kg) was added at 10° C. to 15° C. After addition of thionyl chloride reaction mass is stirred at 10° C. to 15° C. for 30 minutes. Reaction mass is heated at 35-40° C. for 1 hr. Salicylamide solution (0.891 kg in 2.0 lit of Xylene) was added in reaction mass at 25° C.-30° C. After addition reaction mass was gradually heated at 80° C.-126° C. and stirred for 2 hrs. After the completion of reaction excess of Xylene was distilled out. Methanol was added in the reaction mass at 70° C.-80° C. and stirred for 1 hr. gradually cooled the reaction mass at 25-30° C. Filtered the solid and washed with Methanol and sucked it dry. Dry the obtained solid at 55-60° C. under vacuum tray drier.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][CH:21]=1)[O:8][C:9]([CH3:18])([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C.[S:29](Cl)([CH3:32])(=[O:31])=[O:30].Cl>C(Cl)Cl>[CH3:32][S:29]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][CH:21]=1)[O:8][C:9]([CH3:18])([CH3:17])[C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCCO)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCCOS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
tert-Butyl 2-[3-(3-hydroxypropyl)phenoxy]-2-methylpropionate (10.1 g, 34.3 mmol) was dissolved in methylene chloride (50 mL). Subsequently, triethylamine (6.94 g, 68.6 mmol) was added thereto. Mesyl chloride (4.71 g, 41.2 mmol) was added dropwise under ice-cooling, and the mixture was stirred for five hours at room temperature. Diluted hydrochloric acid was added thereto, the resultant mixture was extracted with chloroform. The reaction mixture was subjected to drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (n-hexane/ethyl acetate=4/1), whereby the target compound was obtained (7.8 g, 61%).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[CH2:39]([O:38][C:36]([N:13]1[CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9][C@@H:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:37])[CH3:40]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Reaction time: 2 h
Yield: 34.2 %

Procedure:
A solution of (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (Example 2) (73 mg, 0.2 mmol) in THF (0.5 mL) at room temperature was treated with triethylamine (28.4, 0.2 mmol) followed by ethyl chloroformate (19 μL, 0.2 mmol). The reaction mixture was stirred for 2 h then diluted with EtOAc (2 mL) followed by a saturated aqueous NaHCO3 solution (1 mL). The organic phase was isolated and further washed with an additional portion of a saturated aqueous NaHCO3 solution (1 mL) followed by a brine solution (1 mL). The organic component was dried over MgSO4, filtered, and evaporated to an oil which was purified by silica gel flash chromatography with 10% then 30% EtOAc/hexane as eluant to afford product as an oil (30 mg, 34%). 1H NMR (CDCl3) 1.25 (t, J=7.2, 3H), 1.60-1.65 (m, 2H), 1.79-1.89 (m, 3H), 1.92-2.00 (m, 2H), 2.60-2.72 (m, 2H), 2.95 (dd, J=12.9, 4.8, 1H), 3.20-3.28 (m, 2H), 3.33-3.42 (m, 2H), 3.79 (s, 3H), 4.08-4.13 (m, 3H), 4.40 (br s, 1H), 4.69-4.72 (m, 1H), 6.39 (dd, J=8.6, 2.4, 1H), 6.47 (s, 1H), 6.77 (d, J=8.6, 1H), 7.22-7.34 (m, 5H) LC/MS 7.81 min, [M+1]+ 439.