Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([O:15][CH2:16][CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([O:24][CH2:25][C:26]#[N:27])[C:5]2=3)[CH:14]=1>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([O:15][CH2:16][CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([O:24][CH2:25][CH2:26][NH2:27])[C:5]2=3)[CH:14]=1
Reactant: Cc1cc2c3c(c1)c1c(OCC#N)cccc1n3C(c1ccccc1)CO2
Solvent: C1CCOC1
Product: Cc1cc2c3c(c1)c1c(OCCN)cccc1n3C(c1ccccc1)CO2
Temperature: 85 °C
Yield: 66.6 %

Procedure:
To a mixture of 2-[(5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]acetonitrile (0.66 g, 1.86 mmol) in dry THF (120 mL) is added borane-methylsulfide complex (0.53 mL, 5.6 mmol). The mixture is refluxed at 85° C. for 18 h. The mixture is removed from heat and methanol is slowly added until gas evolution ceased. The solvents are removed under vacuum and methanol (5 mL) is added and again removed. The residue is dissolved in CH2Cl2/CH3OH (1:2 15 mL). Conc. HCl (2 mL) is added and the mixture heated at 65° C. for 1 h. The mixture is removed from heat and neutralized with aqueous potassium carbonate then partitioned between water and CH2Cl2. The organic layer is washed with water, dried over magnesium sulfate, and concentrated. Column chromatography (70 g silica gel) using CH3OH/CH2Cl2 (4:96) as eluent gave 0.444 g (67%) of the title compound;
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[CH:29]1([CH:35]=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(OC)(OC)OC.[BH4-].[Na+]>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:35][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: NCCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: O=CC1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: O=C(NCCCCNCC1CCCCC1)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (50.6 mg) obtained in Example 3-2 was dissolved in anhydrous methanol (2.0 ml) and added with cyclohexane carboxaldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.0240 ml) and trimethyl orthoformate (0.0430 ml), followed by stirring at room temperature for 30 minutes. Then, the solution was added with sodium borohydride (14.8 mg), followed by stirring at room temperature for 15 minutes. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (42.0 mg) of the subject compound as a white solid.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[S:8][CH:7]=[N:6][C:5]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=1)[CH3:3].CN(C)CCN(C)C.C([Li])CCC.[F:30][C:31]([F:39])([F:38])[C:32]([C:34]([F:37])([F:36])[F:35])=[O:33]>O1CCCC1>[CH3:3][CH:2]([C:4]1[S:8][C:7]([C:32]([C:34]([F:37])([F:36])[F:35])([C:31]([F:39])([F:38])[F:30])[OH:33])=[N:6][C:5]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=1)[CH3:1]
Reactant: CSc1ccc(-c2ncsc2C(C)C)cc1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc(-c2nc(C(O)(C(F)(F)F)C(F)(F)F)sc2C(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of 4.50 g (18.0 mmol) of 5-(1-methylethyl)-4-(4-methylthiophenyl)thiazole and 3.15 ml (20.9 mmol) of tetramethylethylenediamine in 85 ml of tetrahydrofuran at -78° C. was added dropwise 20.0 ml (32.0 mmol) of n-butyl lithium (1.6M in hexane). The resulting solution was stirred for 1 hour at -78° C., and then 5.6 ml (50 mmol) of hexafluoroacetone was added dropwise. The mixture was stirred for 1 hour at -78° C. and then quenched by the rapid addition of 50 ml of sodium bicarbonate solution. After warming to 25° C., the organic and aqueous phases were separated and the aqueous phase was extracted with tetrahydrofuran. The combined organic phases were then washed with brine, dried over anhydrous potassium carbonate, filtered, and concentrated. The residue was dissolved in a mixture of 150 ml of ethanol and 30 ml of 4N hydrochloric acid; and the solution was stirred overnight at 25° C. The solution was concentrated in vacuo to remove the ethanol and the resulting aqueous mixture was extracted with diethyl ether. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (elution-benzene) to provide 5.9 g of 5-(1-methylethyl)-4-(4-methylthiophenyl)-α,α-bis(trifluoromethyl)thiazole-2-methanol as a light orange oil.
Reaction SMILES: C[Si]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)(C)C.[Mg].[CH3:14][O:15][CH2:16][O:17][C:18]1[CH:38]=[CH:37][C:21]2[C:22](=[O:36])[CH:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=3)[CH2:24][O:25][C:20]=2[CH:19]=1>O1CCCC1>[OH:5][C:6]1[CH:7]=[C:8]([C:22]2([OH:36])[C:21]3[CH:37]=[CH:38][C:18]([O:17][CH2:16][O:15][CH3:14])=[CH:19][C:20]=3[O:25][CH2:24][CH:23]2[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: C[Si](C)(C)Oc1cccc(Br)c1
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2=O)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2cccc(O)c2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
Under nitrogen atmosphere 3-bromomagnesium phenyl trimethylsilyl ether was prepared from 3-bromophenyl trimethylsilyl ether (629 mg, 2.1 mmol) and magnesium turning (52 mg, 2.1 mmol) in dry tetrahydrofuran (1.5 ml) and then cooled to -78° C. 7-Methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-2,3-dihydro-benzopyran-4-one (250 mg, 0.7 mmol) dissolved in dry tetrahydrofuran (2 ml) was slowly added dropwise thereto and then stirred for one hour. The reaction solution was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to remove the organic solvent. The concentrate was separated by column chromatography (n-hexane:ethyl acetate=4:1) to obtain 283 mg (yield: 92%) of the title compound as a foam.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([SH:10])[CH2:8][CH3:9].CN1CCCC1=O.F[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27]>O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([S:10][CH2:7][CH2:8][CH3:9])=[C:20]([N+:26]([O-:28])=[O:27])[CH:21]=1
Reactant: CCCS
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCSc1ccc(F)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Potassium carbonate (5.0 g, 36.2 mmol) and 1-propanethiol (2.7 g, 35.5 mmol) were added to a N-methylpyrolidone (NMP) solution (15 ml) of 2,5-difluoronitrobenzene (5.0 g, 31.4 mmol), and the mixture obtained was stirred at 90° C. for 2 hours. After the reaction mixture was cooled to room temperature, water (50 ml) was added, and the reaction product was extracted with ethyl acetate (100 ml). The organic layer was washed with water, and then dried over anhydrous magnesium sulfate. The resulting dry product was concentrated under reduced pressure to thereby obtain 6.7 g of powdery yellow 4-fluoro-2-nitro-1-propylsulfanylbenzene (yield: 99%).
Reaction SMILES: [O:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]([CH2:13][N:14]2[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]2=[O:24])[CH2:5][N:4]3[CH2:3][CH2:2]1.[I:25]I>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[I:25][C:9]1[CH:8]=[C:7]2[C:12]3=[C:11]([O:1][CH2:2][CH2:3][N:4]3[CH2:5][CH:6]2[CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH:10]=1
Reactant: O=C1c2ccccc2C(=O)N1CC1CN2CCOc3cccc1c32
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1CC1CN2CCOc3cc(I)cc1c32
Reaction time: 68 h

Procedure:
To a suspension of (rac)-2-(2,3,5,6-tetrahydro[1,4]oxazino[2,3,4-hi]indol-6-ylmethyl)-1H-isoindole-1,3(2H)-dione (0.081 g, 0.253 mmol) and silver trifluoroacetate (0.059 g, 0.266 mmol) in CHCl3 (2.0 mL) was added a solution of iodine (0.067 g, 0.266 mmol) in CHCl3 (8.0 mL) dropwise at rt. The mixture was stirred for 68 h. Silver trifluoroacetate (0.03 g, 0.136 mmol) and solution of iodine (0.035 g, 0.136 mmol) in CHCl3 (6.0 mL) were added. The mixture was stirred at rt for 4 h and added again silver trifluoroacetate (0.02 g, 0.09 mmol) and solution of iodine (0.025 g, 0.10 mmol) in CHCl3 (5.0 mL). After stirring for another 2 h, the mixture was filtered through a pad of celite and washed with CHCl3. The filtrate was washed with Na2SO3 solution and dried (MgSO4). After filtration, the filtrate was concentrated in vacuo to dryness and the residue was subjected to prep TLC (EtOAc/hexane, 1:2) to give 0.046 g (41%) of light yellow oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.81-7.78 (m, 2 H), 7.69-7.65 (m, 2 H), 6.98 (s, 1 H), 6.86 (s, 1 H), 4.34-4.29 (m, 2 H), 3.91-3.80 (m, 2 H), 3.62-3.58 (m, 1 H), 3.24-3.14 (m, 2 H), 3.04-3.00 (m, 1 H), 2.97-2.92 (m, 1 H); MS (EI) m/z 447 (M++H).
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:3]([OH:5])=[O:4].Cl.[NH2:12][CH2:13][C:14]([NH2:16])=[O:15].[OH-].[Na+].O>>[C:3]([C:2]1([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[NH:16][C:14](=[O:15])[CH2:13][NH:12]1)([OH:5])=[O:4]
Reactant: O=C(O)CCC(=O)C(=O)O
Reactant: NCC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCC1(C(=O)O)NCC(=O)N1
Yield: 42.9 %

Procedure:
A solution of 2-oxoglutaric acid (10 g, 0.068 mol), glycinamide hydrochloride (8.3 g, 0.075 mol) and sodium hydroxide (8.2 g, 0.205 mol) in water (120 mol) was refluxed for 4 hours. After cooling the solution was adjusted to pH 2.5 and the resulting precipitate was collected and dried under vacuum at 60° C. to afford 5.9 g (43%) of the title compound, m.p. 202°-205° C. NMR (DMSO-d6): deltaH =8.5 (s, 1H, CONH); 7.00-4.00 (b.s., 3H, NH, COOH); 3.22 and 3.18 (ABq, J=16 Hz, 2H, NHCH2CO); 2.40-1.75 (c.a., 4H, CH2CH2COOH). MS (E.I., 70 eV, 1.5 mA) m/z=140 (M-H2O-COOH)+, 84 (C3H4N2O)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](I)[CH2:22][CH2:23][CH3:24]>CN(C=O)C>[CH2:21]([N:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCI
Reactant: c1ccc2c(c1)CCC21CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCN1CCC2(CCc3ccccc32)CC1
Yield: 53.1 %

Procedure:
In the same way as that described in Example 1, step 5, the title compound was prepared using spiro[indane-1,4'-piperidine] (77 mg, 0.41 mmol), DMF (10 ml), potassium carbonate (68 mg, 0.49 mmol), and n-butyl iodide (0.05 ml, 0.45 mmol). The crude residue was chromatographed using 5:95 methanol: dichloromethane, to give 1'-n-butylspiro[indane-1,4'-piperidine] (53 mg, 53%) as a beige solid.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][N:10]([CH:11]([CH3:13])[CH3:12])[C:6]=2[CH:5]=[C:4]([Cl:14])[N:3]=1.[NH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1>CC(O)CC>[Cl:14][C:4]1[N:3]=[C:2]([NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:7]2[N:8]=[CH:9][N:10]([CH:11]([CH3:13])[CH3:12])[C:6]=2[CH:5]=1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)cc21
Reactant: NCCc1ccc(O)cc1
Solvent: CCC(C)O
Product: CC(C)n1cnc2c(NCCc3ccc(O)cc3)nc(Cl)cc21
Temperature: 140 °C

Procedure:
A mixture of 4,6-dichloro-1-isopropyl-1H-imidazo[4,5-c]pyridine (b) (40 mg, 0.17 mmol), tyramine (120 mg, 0.86 mmol), and 2-butanol (2 mL) was heated under microwave irradiation at 140° C. for 8 hr. The mixture was concentrated and the residue was purified by reverse-phase HPLC (C18 column, eluting with ACN—H2O 0.05% TFA) to afford the title compound as an off-white solid. MS m/z 331.1 (M+1).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].O[C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[CH3:32])[CH:28]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:27][CH2:26]2>ClCCl>[F:7][C:8]([F:21])([F:20])[S:9]([O:12][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[CH3:32])[CH:28]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:27][CH2:26]2)(=[O:11])=[O:10]
Reactant: COC(=O)CC1CCc2cc(O)c(C)cc21
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CC1CCc2cc(OS(=O)(=O)C(F)(F)F)c(C)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
To a solution of pyridine (0.13 mL, 1.61 mmol) in dichloromethane (1.0 mL) cooled to 0° C. trifluoromethanesulfonic anhydride (0.25 mL, 1.47 mmol) was added. The resultant mixture was stirred for 5 min and methyl (5-hydroxy-6-methylindan-1-yl)acetate (295 mg, 1.34 mmol, from Step D) was added as a solid. The reaction mixture was warmed to ambient temperature, stirred for 30 min and diluted with dichloromethane. The organic layer was washed with H2O, brine and dried over MgSO4. The mixture was filtered and concentrated in vacuo. Purification by flash chromatography (10% EtOAc/hexanes) on SiO2 gave 405 mg of the title compound as a pale yellow liquid: 1H NMR (500 MHz, CDCl3) δ 1.69-1.91 (m, 1H), 2.33 (s, 3H), 2.38-2.56 (m, 2H), 2.69-2.79 (m, 1H), 2.79-3.01 (m, 2H), 3.49-3.65 (m, 1H), 3.76 (s, 3H), 7.09 (s, 2H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]2C2CCCCO2)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4].[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>CO>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[NH:12]2)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Temperature: 25 °C

Procedure:
To a solution of 2-butoxy-8-methoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (7.34 g) in methanol (100 mL) was added trifluoroacetic acid (10 mL). The mixture was stirred at ambient temperature over the weekend to give a suspension. The reaction mixture was concentrated to a small volume (thick slurry) before being diluted with ethyl acetate (50 mL). The resultant slurry was filtered and washed with a small volume of ethyl acetate until the filtrate was colourless. The solid remaining was dried by air and then in vacuo to give the title compound as a solid (6.20 g). The filtrate obtained previously was concentrated to give a slurry which was diluted with a small volume of ethyl acetate (10 mL) and then filtered and dried as above. This second crop was isolated as a white solid (0.276 g). Both crops were identical by NMR.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([O:32][CH2:33][CH3:34])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][O:16][CH:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH:28]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH:17]([O:16][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH:5]([O:32][CH2:33][CH3:34])[C:4]([OH:35])=[O:3])=[CH:12][CH:11]=3)[C:18]=2[CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCOC2c3ccccc3CCc3ccccc32)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(Cc1ccc(OCCOC2c3ccccc3CCc3ccccc32)cc1)C(=O)O

Procedure:
3-(4-[2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)-ethoxy]-phenyl)-2-ethoxy -propanoic acid ethyl ester (example 8) (1.5 g, 3.2 mmol) was dissolved in ethanol (30 ml) and 20% sodium hydroxide (3 ml) was added. After 3 days ethanol was evaporated in vacuo, water (50 ml) and hydrochloric acid (2 ml) were added and the mixture was extracted with dichloromethane. The organic phase was dried (MgSO4) and the solvent evaporated in vacuo. The residue (1.1 g, 78%) was dissolved in ethanol and treated with (L)-lysine monohydrate (0.41 g). Ethanol was evaporated and the residue triturated with diethyl ether. The crystalline product was filtered off and dried in the air. This afforded 1.45 g of the title compound as salt with (L)-lysine (dihydrate). M.p. 148-150° C. 1H NMR (250 MHz, DMSO-d6 δ7.00-7.35 (m, 10 H); 6.75 (bd, J=8.2 Hz, 2 H); 6.26 (bs, 8 H); 5.91 (t, J=6.6 Hz, 1 H); 4.02 (t, J=6.2 Hz, 2 H); 3.76 (m, 1 H); 3.59 (m) +3.31 (m), 2 H; 3.07 (bs (4 H); 2.70-2,95 (m, 4 H); 2.51 (bq, 2 H); 1.66 (bm, 6 H); 1.03 (t, J=7.2 Hz, 3 H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([OH:12])(=[O:11])=[O:10].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>[Cu](I)I.[Cu]>[N:13]1([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[S:9]([OH:12])(=[O:11])=[O:10])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: Cc1ccc(F)c(S(=O)(=O)O)c1
Reactant: C1CNCCN1
Agent: I[Cu]I
Agent: [Cu]
Product: Cc1ccc(N2CCNCC2)c(S(=O)(=O)O)c1
Yield: 65.4 %

Procedure:
After the reaction was carried out between 0.76 g of 2-fluoro-5-methylbenzenesulfonic acid and 3.44 g of piperazine in the co-presence of 0.76 g of copper iodide and 0.26 g of copper powder in a sealed tube at 160° C. for 8 hours, the reaction product was purified by silica gel column chromatography (eluant:chloroform:methanol:acetic acid =100:100:3) to give 0.67 g (yield: 65.0%) of the above title product having the following physical property.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([OH:14])[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C.[Ni]>[Si:1]([O:8][C@@H:9]1[CH2:10][CH2:11][C@H:12]([OH:14])[CH2:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@@H](O)C1
Agent: [Ni]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](O)C1
Temperature: 0 °C
Reaction time: 5.25 h
Yield: 87.3 %

Procedure:
Dissolve (-)-cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol (28.85 g, 135 mmol, prepared in example 10) in ethanol (75 mL) and treated with Raney nickel (1.85 g, 32 mmol, previously washed with water (2×50 mL) and ethanol (2×50 mL)). Charge the atmosphere with hydrogen at 50 psi (344.74 kPa) and shake the mixture. After 5.25 hours, filter the reaction. Cool the filtrate to 0° C. and treat with sodium borohydride (0.54 g, 14.3 mmol). After stirring for 2 hours, concentrate the solution under vacuum and distill the resulting oil by Kugelrohr distillation (40°-60° C., 1 mmHg) to provide the title compound (25.5 g, 87%) as a colorless oil, [α]20D =-3.9°, (c=0.99, chloroform); 1H NMR (CDCl3) δ 4.4 (m, 1 H), 4.3 (m, 1 H), 3.03 (d, 1 H, J=10.5 Hz), 1.9-1.6 (m, 6 H), 0.89 (s, 9 H), 0.07 (s, 6 H); 13C NMR (CDCl3) δ 74.9, 74.1, 44.4, 34.2, 34.1, 25.8, 17.9, -4.9, -5.0; IR (neat) νmax 3405, 2957, 2932, 2888, 2858, 1256, 1091, 1069, 1038, 1026 cm-1 ; CIMS m/e (% relative intensity) 217 (M+H+, 81), 199 (M+H+ --H2O, 37), 67 (100). This (-)-enantiomer (title compound) could not be separated from the (+)-enantiomer (antipode) using the previously described chiral column.
Reaction SMILES: [N@:1]1([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3][CH:2]1[C:4]([O:6][CH3:7])=[O:5].B(F)(F)F.[CH3:22][CH2:23][O:24]CC.C(O)C>ClCCl>[CH2:11]([O:10][C:8]([NH:1][C@H:2]([C:4]([O:6][CH3:7])=[O:5])[CH2:3][O:24][CH2:23][CH3:22])=[O:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOCC
Reactant: COC(=O)C1CN1C(=O)OCc1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCO
Product: CCOC[C@H](NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 25 °C

Procedure:
To a stirred solution of (S)-1-benzyl 2-methyl aziridine-1,2-dicarboxylate (prepared according to the literature procedure: Org. Biomol. Chem., 2005, 3, 3357, 2.7 g, 11.4 mmol) in dichloromethane (30 mL), boron trifluoride etherate (0.01 mL, 0.11 mmol) was added at 0° C. followed by absolute ethanol (1.05 g, 22.9 mmol). The reaction mixture was stirred at room temperature for an hour, after which the solution was quenched with saturated bicarbonate solution (2 mL), extracted with dichloromethane (3×25 mL), organic layers were washed with water (25 mL), brine solution (25 mL) and dried over sodium sulfate. The removal of solvents afforded crude product, which was purified by silica gel column chromatography using a gradient of ethyl acetate in pet. ether. Yield: 2.0 g (63%). 1H NMR (400 MHz, DMSO-d6) δ: 1.08 (t, 3H), 3.38-3.46 (m, 2H), 3.57-3.63 (m, 2H), 3.70 (s, 3H), 4.26-4.31 (m, 1H), 5.04 (s, 2H), 7.30-7.39 (m, 5H), 7.73 (d, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[O:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1.CO>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][O:11][CH:12]([C:14]2[CH:15]=[CH:16][C:17]([Br:20])=[CH:18][CH:19]=2)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COC(c2ccc(Br)cc2)CN1Cc1ccccc1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a solution of 4-benzyl-6-(4-bromo-phenyl)-morpholin-3-one (21.3 g; 62 mmol) in THF (350 mL) was added BH3.THF in THF (1M, 155 mL; 155 mmol) dropwise, at 0° C. After 1 hour the mixture was allowed to warm to RT and stirred for another 2 hours. To the reaction mixture was added MeOH (300 mL), at 0° C., the resulting mixture was stirred at RT for 3 days, and subsequently concentrated in vacuo. The residue was partitioned between EtOAc and 1 M aqueous NaOH-solution. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo to afford 4-benzyl-2-(4-bromo-phenyl)-morpholine (20.1 g), which was used as such in the next step.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[CH2:3][Mg]Br.[CH3:8][S:9][C:10]1[N:15]=[C:14]([CH3:16])[C:13]([C:17]2[C:22]([F:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=2[F:25])=[C:12](Cl)[N:11]=1>C1(C)C=CC=CC=1>[CH3:8][S:9][C:10]1[N:15]=[C:14]([CH3:16])[C:13]([C:17]2[C:22]([F:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=2[F:25])=[C:12]([CH2:1][CH:2]([CH3:3])[CH2:6][CH3:7])[N:11]=1
Reactant: CSc1nc(C)c(-c2c(F)cc(F)cc2F)c(Cl)n1
Reactant: CCC(C)C[Mg]Br
Solvent: Cc1ccccc1
Product: CCC(C)Cc1nc(SC)nc(C)c1-c1c(F)cc(F)cc1F
Reaction time: 2 h

Procedure:
At 50° C., 70 ml (0.035 mol) of a 0.5 M solution of 2-methylbutylmagnesium bromide (in tetrahydrofuran) were added to 9.1 g (30 mmol) of 2-methylthio-4-methyl-5-(2,4,6-trifluorophenyl)-6-chloropyrimidine (Example 1.1.) and about 200 mg of bisdiphenylphosphinoferrocenepalladium dichloride in 90 ml of toluene. After about 2 hours, an additional about 200 mg of bisdiphenylphosphinoferrocenepalladium dichloride and, a little at a time, a further 50 ml of a 0.5 M solution of 2-methylbutyl-magnesium bromide (in tetrahydrofuran) were added. The reaction was monitored by HPLC.