Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][NH:32][CH3:33]>>[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][N:32]([CH3:33])[C:23]([C:22]1[CH:21]=[CH:20][C:19]([C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:16][CH2:15]2)=[O:18])=[CH:27][CH:26]=1)=[O:24]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Reactant: CNCCN(C)C
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N(C)CCN(C)C)cc2)CC1
Yield: 80 %

Procedure:
By the same procedure as described in the example 46, synthesis was carried out starting with 4-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid and using N,N,N'-trimethylethylenediamine. Then, the product was recrystallized using isopropanol and ether to give the desired compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@@H:11]([OH:22])[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CS(Cl)(=O)=O.Cl.[N-:29]=[N+:30]=[N-:31].[Na+].[Cl-].[Na+]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.C(OCC)(=O)C.CCCCCC>[N:29]([CH:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[C@H:11]([OH:22])[CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H](O)C(O)c1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OCC[C@@H](O)C(N=[N+]=[N-])c1ccc(Cl)c(Cl)c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
32.07 g (87.8 mmole) of 4-t-butyldimethylsilyloxy-(2R)-(3,4-dichlorophenyl)butane-1,2-diol [prepared as described in step (c) above] and 1.07 g (8.76 mmole) of 4-dimethylaminopyridine were dissolved in 320 ml of pyridine, and 10.19 ml (0.132 mole) of methanesulfonyl chloride was slowly added dropwise, whilst ice-cooling. The mixture was then stirred under a nitrogen atmosphere at the same temperature for 2 hours. The reaction mixture was then poured into 1500 ml of ice-cooled 10% w/v aqueous hydrochloric acid and then extracted three times, each time with 200 ml of ethyl acetate. The combined organic extracts were washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was dried under reduced pressure. The residue was then dissolved in 300 ml of anhydrous dimethylformamide, and 11.41 g (0.18 mole) of sodium azide were added. The mixture was then heated under a nitrogen atmosphere at 120° C. for 4 hours. At the end of this time, the reaction mixture was cooled to room temperature, poured into 1000 ml of a saturated aqueous solution of sodium chloride and then extracted three times, each time with 500 ml of ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel flash column chromatography, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 10:1 to 5:1 by volume as the eluent, to obtain 29.3 g (yield 85%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:13][CH2:14][N:15]([CH2:28][CH2:29]Cl)[C:16]([N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1)=[O:17].O>O1CCCC1.C(OCC)(=O)C>[N:18]1([C:16]([N:15]2[CH2:28][CH2:29][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:8]#[N:9])[CH2:13][CH2:14]2)=[O:17])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: O=C(N(CCCl)CCCl)N1CCCc2ccccc21
Reactant: N#CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: N#CC1(c2ccccc2)CCN(C(=O)N2CCCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.29 ml of phenylacetonitrile in 6 ml of tetrahydrofuran is introduced into a 25 ml three-necked flask. 0.38 g of sodium hydride is subsequently added at 0° C. The reaction medium is stirred at ambient temperature for 30 min and then, at 0° C., 0.5 g of N,N-bis(2-chloroethyl)-3,4-dihydroquinoline-1(2H)-carboxamide is added. The reaction mixture is brought to reflux for 3 h and then ice, water and ethyl acetate are added. The aqueous phase is extracted with ethyl acetate and then the organic phases are combined, washed with water and dried over sodium sulfate and then the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel with a heptane/methanol gradient from 1/0 to 95/5. 2.91 g of 1-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)-4-phenylpiperidine-4-carbonitrile are obtained.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]([Cl:6])[CH2:4][Cl:5].[CH3:7][N:8]([CH3:10])[CH3:9].C[P:12](C)C>>[CH3:7][N:8]([CH3:10])[CH3:9].[PH3:12].[CH2:1]=[CH:2][CH:3]([Cl:6])[CH2:4][Cl:5]
Reactant: CP(C)C
Agent: C=CC(Cl)CCl
Agent: CN(C)C
Product: P

Procedure:
A process for producing 4-chloro-2-butenyl trimethyl ammonium or phosphonium chloride which comprises reacting 3,4-dichlorobutene-1 with trimethyl amine or trimethyl phosphine, in a molar ratio of trimethyl amine or phosphine to 3,4-dichlorobutene-1 of about 2:1 to about 0.5:1 in a solvent at a temperature of from about 0°C to about 50°C, for a period of time sufficient to yield the desired product.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1.[CH3:35][N:36](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:35]([C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:22]=[N:21][C:20]([N:23]3[CH2:24][CH2:25][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:27][CH2:28]3)=[N:19][CH:18]=2)[CH:3]=1)#[N:36]
Reactant: CN(C)C=O
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(C#N)c2s1
Temperature: 100 °C
Yield: 100 %

Procedure:
Ethyl 1-[5-[7-bromo-2-(ethylcarbamoylamino)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (600 mg, 0.658 mmol), zinc cyanide (96 mg, 0.822 mmol) and Pd(PPh3)4 (76 mg, 0.066 mmol) were suspended in DMF (10 mL) and degassed/purged (×3) with Ar. The reaction mixture was then heated at 100° C. under microwave irradiation for 40 mins, cooled to rt, diluted with EtOAc (50 mL), washed with water, brine and separated. The organic fraction was dried (Na2SO4) and concentrated under reduced pressure and the resulting solid purified by flash column chromatography (40 g GraceResolv silica cartridge—dry loaded), eluting with 0-10% MeOH/CH2Cl2. The resulting residue was washed with MeOH to afford desired compound (327 mg, ˜100%) as an off-white solid. MS: 494.14 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[CH2:10][CH2:11][C:12](C(O)=O)([C:27]([OH:29])=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:33])[CH2:10][CH2:11][CH:12]([C:27]([OH:29])=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCCCC(CCC(=O)OCc1ccccc1)(C(=O)O)C(=O)O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCC(CCC(=O)OCc1ccccc1)C(=O)O

Procedure:
A solution of benzyl-4,4-dicarboxyoctadecanoate 36 (1.14 g, 2.5 mmol) in moist DMF (100 mL DMF; 1 mL H2O) was stirred for 2 days (100°-105° C.) then solvent was removed by rotary evaporation. Crystallization from hexane yielded product 8 as a white solid (950 mg, 91%), mp 62°-63° C. High resolution FAB MS: C26H43O4 (M+H); Theor. 419.3161353. Found 419.3144060. Anal. C26H42O4 :C,H.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:12]=[C:13]([Cl:28])[C:14]=1[CH2:15][C@@H:16]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:17]1=[O:27].[CH3:36][S:37](Cl)(=[O:39])=[O:38].C(N(CC)CC)C>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[CH:12]=[C:13]([Cl:28])[C:14]=1[CH2:15][C@@H:16]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][N:24]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:23][CH2:22]2)[C:17]1=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1[C@H](Cc2c(Cl)cc(-c3ccc(F)cc3)cc2Cl)CCN1C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(F)cc4)cc3Cl)C2=O)CC1
Yield: 73.8 %

Procedure:
Treat a solution of (R)-3-(3,5-Dichloro-4′-fluoro-biphenyl-4-ylmethyl)-1-piperidin-4-yl-pyrrolidin-2-one trifluoroacetic acid (Preparation 29) (0.10 g, 0.19 mmol) in CH2Cl2 (3 mL) with methanesulfonyl chloride (0.02 mL, 0.28 mmol) and triethylamine (0.07 mL, 0.48 mmol) and stir the reaction for 1 hr at room temperature. Quench the reaction with 1N HCl and extract with Et2O. Wash the organic with brine, dry over MgSO4, and filter. Remove the solvent to afford 0.07 g (73%) of product. MS (m/e): 500 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:28]C(=O)C)([CH3:27])[CH3:26])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[OH:8])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO.O>[CH2:1]([N:3]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:28])([CH3:27])[CH3:26])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:11][CH:10]=1)[OH:8])[CH3:2]
Reactant: CCN(CCCCCC(C)(C)OC(C)=O)CCCC(O)c1ccc(NS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCN(CCCCCC(C)(C)O)CCCC(O)c1ccc(NS(C)(=O)=O)cc1
Reaction time: 42.5 h
Yield: 89.6 %

Procedure:
A stirred solution of the product from Example 13 (1.35 g, 0.00296 mol) in methanol (80 ml) was treated with a solution of K2CO3 (2.04 g, 0.0148 mol) in water (5.9 ml) and the mixture was refluxed for 21.5 hours. It was kept at ambient temperature for 42.5 hours and concentrated to an aqueous residue which was mixed with water (10 ml) and CH2Cl2, acidified to pH 8.5-9 with 6 NHCl, saturated with NaCl and extracted with CH2Cl2. The extract was dried (MgSO4), concentrated and the residue chromatographed on silica gel with 0.5% NH4OH-9% MeOH--CH2Cl2 to give 1.1 g of the titled compound which is a compound of Formula I'. The high resolution mass spectrum had m/z 414(M+). Theory for C21H38N2O4S: 414.2552; measured: 414.2560.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:19]2[CH:18]=[C:17]3[CH:20]([CH2:23][C:24]([OH:26])=O)[CH2:21][O:22][C:16]3=[CH:15][C:14]=2[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([N:29](CC)[CH2:30]C)C.ClC(OCC)=O>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[C:19]2[CH:18]=[C:17]3[CH:20]([CH2:23][C:24]([N:29]([CH3:30])[CH3:27])=[O:26])[CH2:21][O:22][C:16]3=[CH:15][C:14]=2[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)CC1COc2cc3c(cc21)N(C(=O)OCc1ccccc1)CC3
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: CN(C)C(=O)CC1COc2cc3c(cc21)N(C(=O)OCc1ccccc1)CC3
Reaction time: 2 h
Yield: 46.3 %

Procedure:
5-(Benzyloxycarbonyl)-2,3,6,7-tetrahydrofuro[2,3-f]indol-3-ylacetic acid (D22, 0.89 g, 2.5 mmol) and triethylamine (0.7 ml, 5 mmol) were stirred in dichloromethane (80 ml) under Ar at 0° C. as ethyl chloroformate (0.27 ml, 92.8 mmol) was added. The mixture was stirred for 2 h, and dimethylamine gas was then bubbled through the solution for 10 min. It was then washed with water, K2CO3 solution and brine, dried (Na2SO4) and evaporated. Chromatography of the crude product on silica, eluting with 75% ethyl acetate/petroleum ether (b.p. 60-80° C.) gave the title compound (0.44 g, 46%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([OH:29])=O)[C:24]3[C:19](=[C:20]([O:30][CH3:31])[CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.Cl.[N:65]1([CH2:70][CH2:71][C@H:72]2[CH2:77][CH2:76][C@H:75]([NH2:78])[CH2:74][CH2:73]2)[CH2:69][CH2:68][CH2:67][CH2:66]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([NH:78][C@H:75]3[CH2:76][CH2:77][C@H:72]([CH2:71][CH2:70][N:65]4[CH2:69][CH2:68][CH2:67][CH2:66]4)[CH2:73][CH2:74]3)=[O:29])[C:24]3[C:19](=[C:20]([O:30][CH3:31])[CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N[C@H]1CC[C@H](CCN2CCCC2)CC1
Reactant: COc1cccc2c1-c1ccccc1N(S(=O)(=O)c1ccc(Cl)c(Cl)c1)C2CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc2c1-c1ccccc1N(S(=O)(=O)c1ccc(Cl)c(Cl)c1)C2CC(=O)N[C@H]1CC[C@H](CCN2CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of [5-(3,4-dichloro-benzenesulfonyl)-10-methoxy-5,6-dihydro-phenanthridin-6-yl]-acetic acid (Example 17/d) (0.163 g, 0.34 mmol), triethylamine (0.3 mL, 2.1 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (0.152 g, 0.4 mmol) in dry dimethyl formamide (10 mL) was stirred at room temperature for five minutes before trans-4-(2-pyrrolidin-1-yl-ethyl)-cyclohexylamine dihydrochloride (Reference Example 4) (0.09 g, 0.34 mmol) was added. The pH of the reaction mixture was adjusted to 8 by addition of triethylamine, the so obtained mixture was stirred at room temperature overnight, then concentrated in vacuo. The residue was treated with saturated sodium hydrogencarbonate solution (30 mL), the precipitated crystals were filtered off, washed with water and dried. The crude product was purified by column chromatography using Kieselgel 60 (0.040-0.063 mm) (Merck) as adsorbent, and chloroform:methanol:NH4OH=9:1:0.1 as eluent. The product was crystallized with diethyl ether to yield 0.135 g (60%) of the title compound. MS (EI) 657.2 (MH+).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:13]=[C:14]=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:14](=[O:15])[NH:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=C=Nc1ccccc1C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(OC(=O)Nc2ccccc2C2CCCCC2)CC1

Procedure:
A solution of the product of step (a) (˜9.8 mmol) and 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (2.4 g, 11.8 mmol) in DMF (19.7 mL) was stirred at room temperature for 24 h and then the solvent was removed under reduced pressure. The resulting residue was dissolved in ethyl acetate (20 mL) and this mixture was washed with 1N hydrochloric acid (2×10 mL), 1N aqueous sodium hydroxide (2×10 mL) and brine (10 mL), and then dried (MgSO4), filtered and the solvent removed under reduced pressure. The resulting residue was purified by column chromatography to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.Cl.[NH2:16][OH:17]>N1C=CC=CC=1>[OH:17][N:16]=[C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[N:5][N:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NO
Reactant: Cn1cnnc1C(=O)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: Cn1cnnc1C(=NO)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
To a solution of (4-methyl-4H-1,2,4-triazol-3-yl)(phenyl)methanone (2.4 g, 12.82 mmol, 1 eq.) in 100 ml of pyridine was added hydroxylamine hydrochloride (3.56 g, 51.28 mmol, 4.0 eq.). The temperature was raised to 50° C. and the reaction stirred overnight. The solvent was then evaporated and the residue dissolved in DCM and washed with H2O. The organic layer was washed with 0.1N HCl and dried over MgSO4. The solvent was evaporated to give N-hydroxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)-1-phenylmethanimine (2.51 g, 89% yield) as a white solid.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([Cl:44])[CH:38]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:36])[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=2[O:34][CH3:35])[CH2:21]1)(=O)=O.C(#N)C>>[Cl:44][C:39]1[CH:38]=[C:37]([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][CH:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:36])[C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=3[O:34][CH3:35])[CH2:21]2)[CH:42]=[CH:41][C:40]=1[Cl:43]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COc1ccc(C(=O)N2CC[C@](CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)c(OC)c1
Solvent: CC#N
Product: COc1ccc(C(=O)N2CC[C@@](CCN3CCC(N4CCCCC4)CC3)(c3ccc(Cl)c(Cl)c3)C2)c(OC)c1

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-(2,4-dimethoxybenzoyl)pyrrolidine (3.17 g), prepared essentially as described, supra, is mixed with an equimolar amount of 4-(piperidin-1-yl)piperidine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum and the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: [ClH:1].[CH:2]1[C:12]2[C:11](=[C:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[CH2:15][CH2:14]3)[C:10]3[CH:28]=[CH:29][CH:30]=[CH:31][C:9]=3[CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[ClH:1].[CH:2]1[C:12]2[C:11](=[C:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:15][CH2:14]3)[C:10]3[CH:28]=[CH:29][CH:30]=[CH:31][C:9]=3[CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCCN1CCC(=C2c3ccccc3COc3ccccc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCN1CCC(=C2c3ccccc3COc3ccccc32)CC1
Yield: 99.7 %

Procedure:
A mixture of 4.20 g of ethyl 4-(dibenz[b,e]oxepin-11(6H)-ylidene)-1-piperidinevalerate hydrochloride, 14.5 ml of 2N sodium hydroxide aqueous solution and 40 ml of methanol was refluxed for 1 hr and concentrated. Water was added to the residue, adjusted to pH 2 with 10% hydrochloric acid. The precipitate was collected by filtration and washed with water and ether to give 3.92 g of colorless crystals, which were recrystallized from water to give 3.08 g of colorless prisms, mp 304°-306° C. (dec.).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]1)=[O:5].C(N(C(C)C)CC)(C)C.[CH2:21]([O:28][C:29](ON1C(=O)CCC1=O)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH3:2][O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[C:29]([O:28][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:30])=[O:5]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: COC(=O)[C@@H]1CCCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred suspension of (S)-piperidine-2-carboxylic acid methyl ester hydrochloride salt (5.0 g, 27.8 mmol) in dichloromethane (DCM) (35 mL ) at 0° C. was added diisopropylethylamine (DIPEA) (10.1 mL, 58.4 mmol) followed by N-(benzyloxycarbonyloxy)succinimide (7.63 g, 30.6 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The residue was diluted with DCM and washed with 1.0-M HCl. The organic layer was washed with brine, dried(Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (20% ethyl acetate in hexane) to afford the title compound as a pale yellow oil (7.72, 100%): 1H NMR (400 MHz, CD3OD) δ 1.19–1.88 (5H, m), 2.15–2.28 (1H, m), 2.91–3.12 (1H, m), 3.70–3.73 (3H, 2s), 4.00–4.07 (1H, m), 4.82–4.87 (1H, m), 5.03–5.21 (2H, m), 7.24–7.39 (5H, m); 13C NMR (100 MHz, CD3OD) δ 22.0, 22.1 (CH2), 26.0, 26.1 (CH2), 28.1 (CH2), 43.4, 43.5 (CH2), 53.1 (CH3), 56.2, 56.5 (CH), 68.8, 68.9 (CH2), 129.2 (CH), 129.5 (CH), 129.9 (CH), 138.4 (C), 167.0 (CO), 173.7 (CO).
Reaction SMILES: [CH2:1]([CH:6]([CH2:9][OH:10])[CH2:7][OH:8])[CH2:2][CH2:3][CH:4]=[CH2:5].[CH2:11]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[CH2:12][CH:13]=[CH2:14]>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[CH2:11]([O:15][C:16]1[CH:17]=[CH:18][C:19]([C@H:20]2[O:10][CH2:9][C@H:6]([CH2:1][CH2:2][CH2:3][CH:4]=[CH2:5])[CH2:7][O:8]2)=[CH:22][CH:23]=1)[CH2:12][CH:13]=[CH2:14]
Reactant: C=CCCCC(CO)CO
Reactant: C=CCCOc1ccc(C=O)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: C=CCCC[C@H]1CO[C@H](c2ccc(OCCC=C)cc2)OC1
Reaction time: 2.5 h

Procedure:
A mixture of 3.6 g of 2-(4-pentenyl)-1,3-propanediol, 4,4 of p-(3-butenyl)oxybenzaldehyde, 75 ml of toluene and 3 drops of 10 percent sulphuric acid is heated to boiling for 2.5 hours, whereby about 50 ml of wet solvent are distilled off and are replaced by the dropwise addition of 50 ml of fresh toluene. Thereafter, the mixture is neutralized with 4 drops of triethylamine and, after cooling, is washed with 5 percent sodium hydrogen carbonate solution and water. The organic phase is dried over sodium sulphate and concentrated. Chromatographic separation of the residue on silica gel with hexane/ethyl acetate and recrystallization from hexane gives trans-2-[p-(3-butenyl)oxyphenyl]-5-(4-pentenyl)-m-dioxane with m.p. (C-I) 17.8° C. and cl.p. (N-I) 7.3° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10]([C:21](=[O:23])[CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10]([C@H:21]([OH:23])[CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(Cl)c1
Reaction time: 1 h

Procedure:
To a solution of 1-[(3R,4S)-1-benzyl-4-(3-chloro-4-fluoro-phenyl)-pyrrolidin-3-yl]-ethanone (191 mg, 0.57 mmol) in THF (7 mL) at 0° C. were added portion wise LiAlH4 (19 mg, 0.50 mmol). Stirring was continued for one hour, and the reaction mixture was carefully quenched by addition of aq. NH4Cl, concentrated under vacuo and the product extracted with EtOAC. The combined organic phases were dried on Na2SO4 and concentrated under vacuo. The two diastereoisomeres were separated by column chromatography (SiO2, EtOAc/H, 1:1) to yield (R)-1-[(3R,4S)-1-benzyl-4-(3-chloro-4-fluoro-phenyl)-pyrrolidin-3-yl]-ethanol (X-B-5) 81 mg (42%) as a white solid ES-MS m/e: 334.2 (M+H+) and (S)-1-[(3R,4S)-1-benzyl-4-(3-chloro-4-fluoro-phenyl)-pyrrolidin-3-yl]-ethanol (X-A-5) 43 mg (22%) as a white solid ES-MS m/e: 334.2 (M+H+).