Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH3:16])=[N:4][N:5]([CH3:15])[C:6]=1[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[F:14].C([Li])CCC.[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH:25]=[O:26]>O1CCCC1.[Cl-].[NH4+]>[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH:25]([C:2]1[C:3]([CH3:16])=[N:4][N:5]([CH3:15])[C:6]=1[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[F:14])[OH:26]
Reactant: O=Cc1ccc(F)cc1F
Reactant: Cc1nn(C)c(-c2c(F)cccc2F)c1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nn(C)c(-c2c(F)cccc2F)c1C(O)c1ccc(F)cc1F
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 4-bromo-5-(2,6-difluorophenyl)-1,3-dimethyl-1H-pyrazole (i.e. the product of Step C) (500 mg, 1.7 mmol) in tetrahydrofuran (15 mL) at −78° C. was added dropwise n-butyllithium (2.0 M in hexanes, 0.76 mL, 1.9 mmol). The reaction mixture was stirred at −78° C. for about 20 minutes, and then a solution of 2,4-difluorobenzaldehyde (153 μL, 1.4 mmol) in tetrahydrofuran (1 mL) was added dropwise. After the addition was complete, the reaction mixture was stirred at about −78° C. for about 15 minutes, and then diluted with saturated aqueous ammonium chloride solution (1 mL) and allowed to warm to room temperature. The resulting mixture was poured onto a solid phase extraction tube (Varian Chem Elute®, prepacked with diatomaceous earth) eluting with ethyl acetate (50 mL). The ethyl acetate eluant was concentrated under reduced pressure and the resulting material was purified by MPLC (20 to 50% gradient of ethyl acetate in hexanes as eluant) to provide the title compound, a compound of the present invention, as a solid (560 mg).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19](O)=[O:20])[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.C(N(C(C)C)CC)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.[CH3:71][NH:72][C@@H:73]([C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[CH3:74]>CN(C=O)C>[CH3:71][N:72]([C@@H:73]([C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[CH3:74])[C:19](=[O:20])[C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([CH:13]2[CH2:12][CH2:11][N:10]([C:8](=[O:9])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:25]([F:28])([F:27])[F:26])=[N:5]3)[CH2:15][CH2:14]2)[CH:17]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2cccc(C(=O)O)c2)CC1
Reactant: CN[C@H](C)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2cccc(C(=O)N(C)[C@H](C)c3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.5 %

Procedure:
To a solution of 3-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-benzoic acid (320 mg, 0.80 mmol) in DMF (8 mL) was added diisopropylethylamine (1.01 mL, 4.85 mmol), followed by 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (0.41 g, 0.89 mmol) at RT. After stirring for 15 min. at RT, Methyl-((R)-1-phenyl-ethyl)-amine (0.132 g, 0.80 mmol) was added to the reaction mixture. After stirring for 2 h at RT, solvent was evaporated and the resulting brown oil was dissolved in ethylacetate (20 mL), washed with aq. sat. sodium bicarbonate solution (30 mL) and the aqueous phase was re-extracted with ethylacetate (20 mL). The combined organic layers were washed with 1M HCl solution (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and evaporated under reduce pressure. The crude mixture was purified by column chromatography on silica gel (ethylacetate/cyclohexane 1:1 to 8:2) to give N-methyl-3-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-N—((R)-1-phenyl-ethyl)-benzamide (170 mg, 41%). 1H-NMR (400 MHz, d6-DMSO): δ=1.55 (d, 3H), 1.62-1.71 (m, 1H), 1.82-1.89 (m, 2H), 1.99 (s, 3H), 2.22 (s, 3H), 2.54-2.73 (m, 3H), 2.81-2.90 (m, 1H), 3.12-3.21 (m, 1H), 3.99-4.04 (m, 1H), 4.46-4.52 (m, 1H), 5.19-5.38 (m, 2H), 6.50 (s, 1H), 7.12-7.41 (m, 9H). MS: m/z=513 (M+1)
Reaction SMILES: [F:1][C:2]([F:34])([O:6][C:7]1[CH:33]=[CH:32][C:10]([CH:11]=[N:12][NH:13][C:14]([NH:16][N:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])=[CH:21][CH:20]=2)=[NH:15])=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].C(N(C(C)C)CC)(C)C.[CH3:44][N:45]([CH3:49])[C:46](Cl)=[O:47]>C(#N)C>[F:1][C:2]([F:34])([O:6][C:7]1[CH:33]=[CH:32][C:10]([CH:11]=[N:12][NH:13][C:14](=[NH:15])[N:16]([N:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])=[CH:21][CH:20]=2)[C:46]([N:45]([CH3:49])[CH3:44])=[O:47])=[CH:9][CH:8]=1)[CH:3]([F:4])[F:5]
Reactant: CN(C)C(=O)Cl
Reactant: N=C(NN=Cc1ccc(OC(F)(F)C(F)F)cc1)NN=Cc1ccc(OC(F)(F)C(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(C)C(=O)N(N=Cc1ccc(OC(F)(F)C(F)F)cc1)C(=N)NN=Cc1ccc(OC(F)(F)C(F)F)cc1
Yield: 92.9 %

Procedure:
A solution of 1,3-bis{[p-(1,1,2,2-tetrafluoroethoxy)benzylidene]amino}guanidine (29.84 g, 0.06 mol), diisopropylethylamine (15.51 g, 0.12 mol) and dimethylcarbamoyl chloride (129.2 g, 0.12 mol) in acetonitrile (200 mL) is stirred at reflux for 22 hours. The reaction mixture is cooled, and the acetonitrile is evaporated under reduced pressure. The residue is dissolved in ethyl acetate (250 mL), and the organic solution is washed with water, saturated NaCl and dried over Na2SO4. The solvent is evaporated under reduced pressure, and the residue is crystallized from benzene-hexanes to give the desired product as a yellow solid, mp 141.5°-143.5° C. in 92.9% yield.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][N:19]([C@@H](C3C=CC=CC=3)C)[CH2:18][C@@H:17]2[OH:30])=[CH:12][CH:11]=1)C1C=CC=CC=1>CO.O.[C].[Pd]>[ClH:1].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][NH:19][CH2:18][C@@H:17]2[OH:30])=[CH:12][CH:11]=1
Reactant: C[C@H](c1ccccc1)N1CC[C@H](c2ccc(OCc3ccccc3)cc2)[C@@H](O)C1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: Oc1ccc([C@H]2CCNC[C@@H]2O)cc1
Reaction time: 6 h
Yield: 99.6 %

Procedure:
The reaction flask was charged under argon with 250 mg of 10% carbon-palladium (Degussa E-101 N/D), then a solution of 5 g (11.8 mmol) of (3R,4R)-4-(4-benzyloxy-phenyl)-1-((R)-1-phenyl-ethyl)-piperidin-3-ol hydrochloride in 50 mL of methanol and 5 mL water was added. After hydogenation during 6 h at room temperature and normal pressure the catalyst was separated by filtration and washed with methanol. The filtrate was concentrated and the remaining water was azeotropically removed at the rotary evaporator using toluene (3×100 mL) to give 2.7 g of (3R,4R)-4-(4-hydroxy-phenyl)-piperidin-3-ol hydrochloride as white crystals.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]2Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([CH2:1][NH2:2])[C:15]([N+:21]([O-:23])=[O:22])=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN
Reactant: O=[N+]([O-])c1cnc2ccc(OCc3ccccc3)cc2c1Cl
Solvent: O
Product: NCc1nc2ccc(OCc3ccccc3)cc2cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
Methylamine (available as a 40% solution in water, 24 mL, 0.28 mol) was added to a solution of 6-benzyloxy-4-chloro-3-nitroquinoline (15.0 g, 48.5 mmol), prepared as described in Parts A-D of Example 2, in distilled water (300 mL), and the reaction was stirred at 100° C. for 1.5 hours. The reaction was allowed to cool to ambient temperature and stirred for four hours. A precipitate formed, which was isolated by filtration and washed with distilled water (3×60 mL). The solid was combined with material from another run and recrystallized from 2-propanol. The crystals were isolated by filtration, washed twice with cold hexanes, and dried for three days under high vacuum to provide 24.10 g of (6-benzyloxy-3-nitroquinolinyl)methylamine as yellow crystals.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N:10]12[CH2:17][CH2:16][CH2:15][C:14]1([CH2:18][CH2:19][NH2:20])[CH2:13][CH2:12][CH2:11]2.N1C=CC=CC=1>O>[N:10]12[CH2:17][CH2:16][CH2:15][C:14]1([CH2:18][CH2:19][NH:20][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH2:13][CH2:12][CH2:11]2
Reactant: N#Cc1ccccc1F
Reactant: NCCC12CCCN1CCC2
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1ccccc1NCCC12CCCN1CCC2
Yield: 95.8 %

Procedure:
2-Fluorobenzonitrile (1.00 g, 8.26 mmol) and 2-(1-azabicyclo[3.3.0]octan-5-yl)ethylamine (3.15 g, 20.4 mmol) were added into anhydrous pyridine (10.0 ml) to react the mixture in a sealed tube for 10.5 hours at 180° C. After addition of water subsequent to concentration in vacuo, the reaction mixture was extracted by ethyl acetate, dried over anhydrous sodium sulfate, concentrated in vacuo, and refined by column chromatography to afford the desired compound (2.02 g, 95.8%), as a colorless liquid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:20])(C)(C)C.CC1(C)O[C:27]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])=[CH:26][C:25](=[O:37])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:37]=[C:25]1[CH2:26][C:27]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[NH:20]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccncc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(-c4ccncc4)cc3NC(=O)C2)c1

Procedure:
Prepared from (2-amino-4-pyridin-4-yl-phenyl)-carbamic acid tert.-butyl ester (Example G28) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a red-brown solid (25 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C:13]([N:15]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@H:16]1[CH2:21][C@@H:20]([C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:19][N:18]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:17]1)=[O:14].C(N(CC)CC)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>C1COCC1.C(=O)(O)[O-].[Na+]>[CH3:39][CH:38]([CH3:40])[CH2:37][N:15]([C:13]([C:5]1[N:4]([CH2:3][CH2:2][O:1][S:49]([CH3:48])(=[O:51])=[O:50])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=1)=[O:14])[C@H:16]1[CH2:21][C@@H:20]([C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:19][N:18]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:17]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CN(C(=O)c1nc2ccccc2n1CCO)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCOS(C)(=O)=O)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (3S,5R)-3-[[[1-(2-hydroxyethyl)-1H-benzimidazol-2-yl]carbonyl](2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (223 mg) and triethylamine (84 μl) in THF (5 ml) was added dropwise methanesulfonyl chloride (37 μl) at room temperature. The reaction mixture was stirred at room temperature for 3 hr, diluted with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object product (288 mg).
Reaction SMILES: Cl[CH2:2][SiH:3]([CH3:5])[CH3:4].[Mg].[CH3:7][SiH:8](Cl)Cl.O>O1CCCC1>[CH3:4][SiH:3]([CH2:2][SiH:8]([CH3:7])[CH2:2][SiH:3]([CH3:5])[CH3:4])[CH3:5]
Reactant: C[SiH](C)CCl
Reactant: C[SiH](Cl)Cl
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: C[SiH](C)C[SiH](C)C[SiH](C)C
Temperature: 25 °C
Yield: 91.4 %

Procedure:
A solution of 70 g of chloromethyldimethylsilane in 400 ml of anhydrous tetrahydrofuran (THF) was added dropwise to 20 g of magnesium powder in a flask equipped with a mechanical stirrer and a condenser. The rate of addition was regulated to maintain reflux for the Grignard solution. To this Grignard reagent solution was then added dropwise 37 g of methyldichlorosilane in 300 ml THF. The resultant mixture was stirred overnight with gentle reflux. After cooled down to room temperature, the reaction was worked up by adding water. The organic phase was separated and dried over anhydrous sodium sulfate. Solvent (THF) was removed by atmospheric pressure distillation. Vacuum distillation at 85° C./20 mm yielded 56 g of 2,4,6-trimethyl-2,4,6-trisila-heptane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[C:12]([CH2:18][OH:19])[C:11]=2[CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[CH3:34][N:35]=[C:36]=[O:37]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[C:12]([CH2:18][O:19][C:36](=[O:37])[NH:35][CH3:34])[C:11]=2[CH2:20][C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)n1nc(CO)c(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)OCc1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1Cc1ccncc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution containing 45 mg of 5-(3,5-dichlorophenylthio)-1-isopropyl-4-[(4-pyridyl)methyl]-1H-pyrazole-3-methanol in 4 ml of anhydrous dichloromethane under nitrogen at room temperature was treated with 0.017 ml of triethylamine and 0,007 ml of methyl isocyanate. The mixture was stirred at room temperature for 1 h. The mixture was partitioned between ethyl acetate and water then extracted with dichloromethane three times. The combined extracts were washed with brine then dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using methanol/dichloromethane (0:1 to 1:49) for the elution to give 36 mg of methylcarbamic acid [5-(3,5-dichlorophenylthio)-1-isopropyl-4-[(4-pyridyl)methyl]-1H-pyrazol-3-yl]methyl ester as a yellow gum. Mass spectrum (ESI) m/z 465 [M+H]+. 1H NMR (DMSO) 1.30 (d, 6H), 2.55 (d, 3H), 3.90 (s, 2H), 5.05 (s, 2H), 6.77 (s, 2H), 7.05 (d, 2H), 7.12 (m, 1H), 7.37 (s, 1H), 8.30 (d, 2H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(O)C>[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[CH2:16][CH2:15]1
Reactant: OCCN1CCNCC1
Reactant: CSc1ccc(CCl)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CSc1ccc(CN2CCN(CCO)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.6 %

Procedure:
A mixture of 4-(methylthio)benzyl chloride (28.6 g), 1-(2-hydroxyethyl)piperazine (21.6 g), triethylamine (16.8 g), and ethanol (250 ml) is stirred at room temperature for 5 hours. The ethanol is then removed in vacuo and water added to the residue. The product is extracted with ether, dried, and the ether evaporated to give 31.6 g of 1-(2-hydroxyethyl)-4-[4-(methylthio)benzyl] piperazine as an orange oil, suitable for use in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([O:8][CH3:9])=[CH:6][S:5][CH:4]=1.[CH2:10](O)[CH:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]CC>>[CH2:10]([CH:1]1[O:2][C:3]2=[CH:4][S:5][CH:6]=[C:7]2[O:8][CH2:9]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: COc1cscc1OC
Reactant: CCCCCCCCCCC(O)CO
Product: CCCCCCCCCCC1COc2cscc2O1

Procedure:
Racemic 2-n-decyl-2,3-dihydro-thieno[3,4-b][1,4]dioxine was synthesized by transetherification of 3,4-dimethoxythiophene with racemic 1,2-dodecanediol as described in EXAMPLE 1. It was characterized by GC-MS and H-NMR-spectroscopy, and exhibited no optical rotation.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:42])[C@H:15]([CH2:19][S:20](N1CCN(C2N=CC(C3C=CC(F)=CC=3)=CN=2)CC1)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[Cl:45][C:46]1[CH:47]=[C:48]([C:53]2[CH:54]=[N:55][C:56]([N:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)=[N:57][CH:58]=2)[CH:49]=[CH:50][C:51]=1[Cl:52].C([C@@H]1COC(=O)N1C(=O)[C@H](CS(Cl)(=O)=O)C(C)C)C1C=CC=CC=1>>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:42])[C@H:15]([CH2:19][S:20]([N:62]1[CH2:61][CH2:60][N:59]([C:56]2[N:57]=[CH:58][C:53]([C:48]3[CH:49]=[CH:50][C:51]([Cl:52])=[C:46]([Cl:45])[CH:47]=3)=[CH:54][N:55]=2)[CH2:64][CH2:63]1)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2cnc(N3CCNCC3)nc2)cc1Cl
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(Cl)c(Cl)c3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 39 %

Procedure:
Prepared according to the method for the preparation of 4-(R)-benzyl-3-(2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methyl-butyryl)oxazolidin-2-one, from 5-(3,4-dichlorophenyl)-2-piperazine-1-yl-pyrimidine, dihydrochloride (0.52 g) and 4-(R)-benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methylbutyryl)oxazolidin-2-one (0 67 g), to yield the title compound as a white solid (0.51 g, 39%).
Reaction SMILES: [NH:1]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([N:17]1[CH2:31][CH2:30][CH2:29][C@H:18]1[C:19]([O:21]CC1C=CC=CC=1)=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]>C(O)CCC.C(O)C.[Pd]>[NH:1]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([N:17]1[CH2:31][CH2:30][CH2:29][C@H:18]1[C:19]([OH:21])=[O:20])=[O:16])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCCCO
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 3 h
Yield: 94.4 %

Procedure:
Substance [2] (76.98 g, 145 mM) was dissolved in n-butanol (20 ml) and ethanol (300 ml). 5% Pd/C (15 g) was added thereto and catalytic hydrogenation was allowed to proceed for 3 hours. After removing the catalyst, the mother liquor was concentrated in vacuo. Diethyl ether (300 ml) was added to the residue, which was then extracted successively with 500 ml and 200 ml of 5% aqueous sodium bicarbonate. The extract was adjusted to pH 4 by adding 1 N HCl with ice cooling to precipitate the product continuously, which was extracted with ethyl acetate and washed twice with water. After drying with anhydrous sodium sulfate, the solution was concentrated in vacuo. The residue was solidified by adding ether-hexane. Recrystallization was effected with ethyl acetate-ether-hexane to obtain the substance [3] (60.33 g, yield: 94.2%).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][C:9]([CH:12]=O)=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([BH3-])#N.[Na+]>CO>[C:1]1([N:7]2[CH:11]=[CH:10][C:9]([CH2:12][N:24]3[CH2:25][CH2:26][CH:21]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:22][CH2:23]3)=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=Cc1ccn(-c2ccccc2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(CC2CCN(Cc3ccn(-c4ccccc4)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 171 mg of 1-phenyl pyrrole-3-carboxaldehyde in 1 mL of methanol was added 525 mg of 4-benzylpiperidine, 175 mg of 4-benzylpiperidine. HCl and 63 mg of sodium cyanoborohydride. The reaction mixture was stirred overnight at room temperature under an atmosphere of nitrogen. The methanol was removed by evaporation under reduced pressure and the residue was extracted into 50 mL of ethyl acetate, then washed successively with 50 mL aliquots of 10% sodium hydroxide and water. The ethyl acetate extract was dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure to yield 1-phenyl-3[(4-benzylpiperidin-1-yl)methyl]pyrrole, which was purified by chromatography on silica gel using 5% methanol in dichloromethane as elvent. On evaporation of the solvent, the free base was dissolved in ethanol and treated with 1 equivalent of maleic acid. The 1-phenyl-3[(4-benzyl-piperidin-1-yl)methyl]pyrrole maleate salt (compound 7) had a melting point of 159°-161° C.
Reaction SMILES: C(O)(=O)C.Br.C(OP([N:14]1[CH2:27][CH2:26][N:25]([S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N+:37]([O-:39])=[O:38])(=[O:30])=[O:29])[CH2:24][CH2:23][CH2:22][C:21]([F:41])([F:40])[CH2:20][CH2:19][CH2:18][N:17]([S:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[N+:51]([O-:53])=[O:52])(=[O:44])=[O:43])[CH2:16][CH2:15]1)(=O)OCC)C>C(OCC)C>[F:41][C:21]1([F:40])[CH2:22][CH2:23][CH2:24][N:25]([S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N+:37]([O-:39])=[O:38])(=[O:30])=[O:29])[CH2:26][CH2:27][NH:14][CH2:15][CH2:16][N:17]([S:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[N+:51]([O-:53])=[O:52])(=[O:43])=[O:44])[CH2:18][CH2:19][CH2:20]1
Reactant: CCOP(=O)(OCC)N1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCCC(F)(F)CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCCC(F)(F)CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.3 %

Procedure:
Acetic acid (10 ml), saturated with anhydrous hydrogen bromide (gas) was added to [11,11-difluoro-1,7-bis(2-nitro-benzenesulfonyl)-1,4,7-triaza-cyclotetradec-4-yl]-phosphonic acid diethyl ester (311 mg, 0.41 mmol) contained in round-bottomed flask closed by glass stopper. The resulting mixture was allowed to stir for 18 hours at room temperature and then diethyl ether (50 ml) was added. The white precipitate which formed was allowed to settle to the bottom of the flask and the diethyl ether solution was decanted off. This white solid was re-dissolved in methanol, stirred with K2CO3 (solid) for 30 mins and the mixture was diluted with 100-ml ethyl acetate. The solids were removed by filtration and the filtrates were evaporated to give the title compound (239 mg, 94%) as white form.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].ClCCl.[CH:17]1(O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CC(OC)(C)C>[CH:17]1([O:9][C:8](=[O:10])[C:7]([CH3:12])([CH3:11])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:13])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: OC1CCCCC1
Reactant: CC(C)(C)OC(=O)C(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)C(=O)OC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2,2-dimethylmalonic acid mono-t-butyl ester [CAS No. 143688-40-8] (800 mg), DMAP (104 mg), and dichloromethane (8 mL), cyclohexanol (0.494 mL) and WSC (976 mg) were sequentially added at 0° C. The resulting mixture was stirred overnight at room temperature, and TBME (50 mL) was added thereto. The resulting mixture was sequentially washed with water (30 mL) and saturated aqueous sodium chloride solution (30 mL), and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate) to obtain the captioned compound (817 mg).