Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:16]>CCCCCC>[C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][Br:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrP(Br)Br
Reactant: OCc1cccc(-c2ccccc2)c1
Solvent: CCCCCC
Product: BrCc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 198.5 %

Procedure:
To a solution of 5.57 g (30 mmol) of 3-phenylbenzylalcohol in n-hexane was added dropwise 4.06 g (13.5 mmol) of phosphorous tribromide with ice-cooling. The mixture was removed from an ice bath and stirred at room temperature for 3.5 hours. To the reaction mixture were added ice water and tert-butyl methyl ether and the mixture was stirred for 30 minutes and separated. The organic layer was washed twice with water, dried and concentrated to obtain 6.62 g (26.8 mmol) of 3-phenylbenzylbromide.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1)(C)C.[OH-].[K+].CC(O)=O>CO>[C:6]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1)#[CH:5]
Reactant: CC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: C#Cc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a stirring solution of compound 1.9 (19 g, 88 mmol) in MeOH (200 mL) was added a solution of KOH (2.46 g, 44 mmol) in MeOH (20 mL) at 10° C. and the mixture was stirred at room temperature for 1 hr. AcOH was added until the pH was 7, and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL), washed with 5% aqueous NaHCO3 (100 mL), brine (100 mL), dried, and concentrated under reduced pressure to give compound 1.10 as a white solid (12 g, 95%). 1H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J=8, 2H), 7.62 (d, J=8, 2H), 4.49 (s, 1H), 2.59 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[CH2:20][N:21]3[CH2:26][CH2:25][C@@H:24]([NH:27]C(=O)OCC=C)[C@H:23]([C:34](=[O:37])[NH:35][CH3:36])[CH2:22]3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.N(C)C>C1COCC1.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>[NH2:27][C@@H:24]1[CH2:25][CH2:26][N:21]([CH2:20][C:18]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:19]=2[C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:11][CH:12]=[N:13]3)[CH2:22][C@H:23]1[C:34]([NH:35][CH3:36])=[O:37]
Reactant: C=CCOC(=O)N[C@@H]1CCN(Cc2cccc3ncnc(Nc4cccc(OC)c4)c23)C[C@H]1C(=O)NC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CNC
Solvent: C1CCOC1
Product: CNC(=O)[C@@H]1CN(Cc2cccc3ncnc(Nc4cccc(OC)c4)c23)CC[C@H]1N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 15E (27 mg, 0.054 mmol) in THF (3 ml) was degassed and purged with N2. To this was added 2N Me2NH in THF (95 μl, 0.19 mmol), followed by Pd(PPh3)4 (9 mg, 0.0078 mmol). The mixture was stirred at room temperature for 1.5 h. Concentration in vacuo followed by purification using preparative HPLC gave, after concentration and lyophilization, a TFA salt of 15F (20.3 mg, 70%) as a solid. The compound has an analytical HPLC retention time=1.307 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) and a LC/MS M++H=421+.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10]>C1(C)C=CC=CC=1.N1CCCN2CCCN=C12>[O:6]=[C:1]1[CH2:5][CH2:4][CH:3]([CH:8]([C:7]([O:14][CH3:15])=[O:13])[C:9]([O:11][CH3:12])=[O:10])[CH2:2]1
Reactant: O=C1C=CCC1
Reactant: COC(=O)CC(=O)OC
Agent: C1CN=C2NCCCN2C1
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)C1CCC(=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.3 %

Procedure:
Tetrahedron Letters 2005, 46, 6875-6878. To a solution of cyclopent-2-enone (99.82 g, 1216 mmol) and dimethyl malonate (560 mL, 4887 mmol) in dry toluene (1000 mL) was added 2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (5.10 g, 36.6 mmol). The reaction was stirred at room temperature under nitrogen for 16 hrs, then concentrated under reduced pressure to ˜½ volume. The crude product was filtered through a short path of silica gel (3.5×4 cm), eluting with ethyl acetate. The filtrate was concentrated under vacuum pump rotary evaporation (70-75° C. water bath) for 2 hrs, affording the target compound (247.7 g, 1098 mmol, 90% yield). 1H NMR (500 MHz, CDCl3) δ ppm 3.76 (3 H, s), 3.74 (3 H, s), 3.37 (1 H, d, J=9.46 Hz), 2.80-2.91 (1 H, m), 2.49 (1 H, dd, J=18.31, 7.63 Hz), 2.29-2.37 (1 H, m), 2.15-2.28 (2 H, m), 2.00 (1 H, ddd, J=18.46, 10.99, 1.37 Hz), 1.58-1.71 (1 H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH3:26])([CH3:25])[C:17](=[O:24])[N:18]2[CH:21]2[CH2:23][CH2:22]2)=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH3:26])([CH3:25])[C:17](=[O:24])[N:18]2[CH:21]2[CH2:22][CH2:23]2)=[CH:14][CH:13]=1)=[O:6]
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(N)ccc21
Reactant: O=C(O)c1ccncc1Cl
Product: CC1(C)C(=O)N(C2CC2)c2cc(NC(=O)c3ccncc3Cl)ccc21

Procedure:
Prepared in analogy to example 26 from 3-chloroisonicotinic acid and 6-amino-1-cyclopropyl-3,3-dimethyl-1,3-dihydro-indol-2-one (example 14c). The title compound was obtained as white foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:9]([OH:20])[CH2:8][NH:7]1)=[O:5])[CH3:2].[C:21]([O:24][CH2:25][CH3:26])(=[O:23])C>C(=O)([O-])[O-].[Na+].[Na+].ClC(OCC1C=CC=CC=1)=O>[CH3:2][CH2:1][O:3][C:4]([C@@H:6]1[CH2:11][C@H:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[C@@H:9]([OH:20])[CH2:8][N:7]1[C:21]([O:24][CH2:25][C:26]1[CH:6]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:23])=[O:5]
Reactant: CCOC(=O)[C@@H]1C[C@H](c2ccc(OC)cc2)[C@@H](O)CN1
Reactant: CCOC(C)=O
Agent: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)[C@@H]1C[C@H](c2ccc(OC)cc2)[C@@H](O)CN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 1.2 g (2S,4R,5R)-5-hydroxy-4-(4-methoxy-phenyl)-piperidine-2-carboxylic acid ethyl ester in 40 ml of ethyl acetate, 20 ml of saturated aqueous sodium carbonate solution and 0.42 ml of benzyl chlorformate is stirred for 1 hour at 0° C., diluted with ethyl acetate and the organic phase is dried over sodium sulfate. The organic phase is concentrated under reduced pressure and the residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a yellow oil. Rf=0.3 (EtOAc-heptane 1:1); Rt=4.34.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[N:17]2[C:26]=1I)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[N:17]2[C:26]=1[C:31]1[CH:32]=[N:33][CH:34]=[C:29]([F:28])[CH:30]=1)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc2nc([C@H](C)NC(=O)OCc3ccccc3)c(I)n12
Reactant: OB(O)c1cncc(F)c1
Product: COC(=O)c1cccc2nc([C@H](C)NC(=O)OCc3ccccc3)c(-c3cncc(F)c3)n12

Procedure:
Prepared according to Step C3b in General Procedure C using (S)-methyl 2-(1-(benzyloxycarbonylamino)ethyl)-3-iodoimidazo[1,2-a]pyridine-5-carboxylate (0.350 g, 0.730 mmol) and 5-fluoropyridin-3-ylboronic acid (0.154 g, 1.10 mmol) to give (S)-methyl 2-(1-(benzyloxycarbonylamino)ethyl)-3-(5-fluoropyridin-3-yl)imidazo[1,2-a]pyridine-5-carboxylate as a tan solid. LC-MS (ESI) m/z 449.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]([O:19]CC2C=CC=CC=2)=[O:18])=[CH:8]1)=[O:5])[CH3:2]>[Pd].O1CCCC1>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]([OH:19])=[O:18])=[CH:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cn1cc(CC(=O)OCc2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1cc(CC(=O)O)c2ccccc21
Yield: 60 %

Procedure:
Prepared analogously to Example 45f), but using tetrahydrofuran instead of ethanol as solvent, from phenylmethyl 1-(ethoxycarbonylmethyl)-1H-indole-3-acetate by catalytic hydrogenation in the presence of palladium/activated charcoal in a yield of 60% of theory. Colourless crystal, Mp. 138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C:8]1([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17])=[O:6].[C:29]1([CH2:35][CH2:36][CH2:37]Br)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C:8]1([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:37][CH2:36][CH2:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]1=[O:17])=[O:6]
Reactant: BrCCCc1ccccc1
Reactant: CCOC(=O)CCC1(NC(=O)c2ccc(Cl)c(Cl)c2)C(=O)Nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCC1(NC(=O)c2ccc(Cl)c(Cl)c2)C(=O)N(CCCc2ccccc2)c2ccccc21
Yield: 92.1 %

Procedure:
A mixture of 1.06 g of ethyl 3-[3-(3,4-dichlorobenzoylamino)-2,3-dihydro-2-oxo-1H-indol-3-yl]propionate, 1.0 g of 3-phenylpropyl bromide, 1.10 g of potassium carbonate and 16 ml of acetone was refluxed overnight. The solvent was removed by evaporation. The residue was extracted with ethyl acetate, washed with water and dried. After removal of solvent, the residual solid was crystallized from isopropyl ether-hexane to afford 1.25 g of ethyl 3-[3-(3,4-dichlorobenzoylamino)-2,3-dihydro-2-oxo-1-(3-phenylpropyl)-1H-indol-3-yl]propionate as a colorless solid. Melting point: 119.5° to 121.5° C., IR (Nujol) (cm-1): 3320, 1730, 1700, 1660, 1615, FAB-MS (m/z): 541 & 539 (MH+).
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][CH:13]3[NH:19][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:10][O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH3:26][O+](C)C>>[CH3:26][O:20][C:18]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]([CH2:12][C:11]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][O:9][CH:10]=2)[N:19]=1
Reactant: O=C1CCCCC(Cc2conc2-c2ccccc2)N1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Product: COC1=NC(Cc2conc2-c2ccccc2)CCCC1

Procedure:
The title product of Example 126 is reacted with trimethyloxonium tetrafluoroborate by the method of Example 3 to generate the title compound.
Reaction SMILES: CC(O)=O.OS(O)(=O)=O.[CH2:10]([N:12]([CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)[CH3:11].ClC[C:37]([NH:39]CO)=O>O>[NH2:39][CH2:37][C:21]1[CH:20]=[C:19]([CH:16]2[CH2:17][CH2:18][CH:13]([N:12]([CH2:10][CH3:11])[CH2:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:14][CH2:15]2)[CH:24]=[CH:23][C:22]=1[OH:25]
Reactant: CCN(CCCc1ccccc1)C1CCC(c2ccc(O)cc2)CC1
Reactant: O=C(CCl)NCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCN(CCCc1ccccc1)C1CCC(c2ccc(O)c(CN)c2)CC1
Temperature: 10 °C
Reaction time: 16 h
Yield: 33.5 %

Procedure:
A mixture of HOAc and H2SO4 (1 mL, 9:1, v:v) was cooled to 10° C. 4-{4-[ethyl(3-phenylpropyl)amino]cyclohexyl}phenol (200 mg, 0.53 mmol) and 2-chloro-N-(hydroxymethyl)acetamide (66 mg, 0.53 mmol) were added portionwise. The reaction mixture was warmed to room temperature and stirred for 16 hours. The mixture was poured onto ice (1 g) and water (10 mL) was added. After concentration under reduced pressure, a mixture of EtOH and HCl (6.5 mL, 10:3, v:v) was added, and the mixture was heated under reflux for 1.5 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. Purification by flash chromatography (silica, 90:10:0.5 CH2Cl2:MeOH:NH4OH), followed by formation of the HCl salt, gave 2-aminomethyl-4-{4-[ethyl(3-phenylpropyl)amino]cyclohexyl}phenol (65 mg, 28%), as a yellow solid: mp 168-173° C.; IR (KBr): 2940, 1510, 1453 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 10.16 (br s, 1H), 9.96 (s, 1H), 8.1 (br s, 2H), 7.35-7.17 (m, 6H), 7.06 (dd, J=8 Hz, 1H), 6.85 (d, J=8 Hz, 1H), 3.90 (br d, J=5 Hz, 2H), 3.45-2.98 (m, 4H), 2.71-2.65 (m, 2H), 2.52-2.39 (m, 2M), 2.19-2.10 (m, 2H), 2.10-2.05 (m, 2H), 1.90-1.83 (m, 2H), 1.70-1.49 (m, 4H), 1.27 (t, J=7 Hz, 3H) API-MS (methane) (m/z): 367 [M+H]+; HRMS-API (m/z): [M+H]+ Calcd for C24H34N2O, 367.2749. found: 367.2741. Anal. Calcd for C24H34N2O.02HCl.H2O: C, 64.93; H, 8.29; N, 6.31. Found: C, 64.90; H, 8.53; N, 6.09.
Reaction SMILES: [CH3:1][N:2]([C@H:21]([CH3:26])[C:22]([O:24]C)=[O:23])[C:3](=[O:20])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH3:5].[Li+].[OH-].Cl.CCOC(C)=O>C1COCC1>[CH3:1][N:2]([C@H:21]([CH3:26])[C:22]([OH:24])=[O:23])[C:3](=[O:20])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH3:5]
Reactant: COC(=O)[C@@H](C)N(C)C(=O)C(C)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C(=O)N(C)[C@H](C)C(=O)O)c1ccc(OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To a solution of methyl 2-[N-methyl-N-((R/S)-α-methyl-4-benzyloxyphenylacetyl)amino]-(R)-propionate 45c (380 mg, 1.1 mmol) in THF (10 mL) was added 1 N LiOH (2 mL). The solution was stirred for 1 h and acidified with 1 N HCl to pH 3. EtOAc was added and the organic layer was separated, washed with brine, dried (MgSO4) and concentrated to afford the carboxylic acid (360 mg, 98%) as a solid. MS (CI—NH3): (M+H)+=342.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]2[N:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6]2.[N:17]([O-])=[O:18].[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH3:1][S:2][C:3]1[C:4]([N:17]=[O:18])=[C:5]2[N:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6]2
Reactant: CCOC(=O)c1c(SC)cc2ccccn12
Reactant: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(SC)c(N=O)c2ccccn12
Yield: 87 %

Procedure:
A solution of 470 mg (2 mmol) of ethyl 2-(methylsulphanyl)-3-indolizinecarboxylate 9 in 10 ml of acetic acid, stirred at 0° C., was admixed dropwise over 10 minutes with a solution of 165 mg of sodium nitrite in 5 ml of water. The reaction mixture was then left with stirring for a further hour. The acidic phase was basified with a solution of 2N NaOH, and then extracted with dichloromethane (25 ml×3). The organic phase was dried over magnesium sulphate, filtered and then concentrated under vacuum to give ethyl 2-(methylsulphanyl)-1-nitroso-3-indolizinecarboxylate 10 (460 mg). m.p: 134-135° C. 1H NMR (CDCl3): δ 9.58 (d, J=6.8 Hz, 1H), 8.45 (d, J=8.5 Hz, 1H), 7.70 (t, J=8.2 Hz, 1H), 7.20 (td, J=7.0, 1.1 Hz, 1H), 4.50 (q, J=7.1 Hz, 2H), 3.05 (s, 3H), 1.52 (t, J=7.1 Hz, 3H). 13C NMR (CDCl3): 161.2, 156.9, 143.4, 135.7, 127.2, 123.7, 118.7, 118.0, 112.9, 61.2, 19.4, 14.4.
Reaction SMILES: [N+:1]([C:4]1[O:19][C:7]([CH:8]=[C:9]2[N:13]=[C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([NH2:18])[C:11]3=[N:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:20][C:21]1[CH:22]=[C:23]([N:27]=[C:28]=[O:29])[CH:24]=[CH:25][CH:26]=1>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]([N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([NH2:18])[C:11]=3[NH:10][C:9]2=[CH:8][C:7]2[O:19][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:29])[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1cccc2c1=NC(=Cc1ccc([N+](=O)[O-])o1)N=2
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Nc1cccc2c1NC(=Cc1ccc([N+](=O)[O-])o1)N2C(=O)Nc1cccc(Cl)c1
Yield: 65.6 %

Procedure:
51.2 g of 2-(5-nitro-furfurylidene)-amino-benzimidazole are dissolved in a mixture of 120 ml of chloroform and 80 ml of dimethylformamide, whereupon 30.6 g (0.2 moles) of 3-chlorophenyl-isocyanate are slowly added. The crystalline reaction mixture is stirred at room temperature for 7 hours while a mixture of 40 ml of dimethylformamide and 60 ml of chloroform are added. The precipitated crystals are filtered off, washed with 100 ml of chloroform and dried in vacuo at 40° C. to 60° C. Thus 54 g of 1-(3'-chlorophenyl-carbamoyl)-2-(5-nitro-furfurylidene)-amino-benzimidazole are obtained. Mp.: 210°-212° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].[CH3:10][C:11]([CH3:13])=O.[BH4-].[Na+]>CO>[CH:11]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9])([CH3:13])[CH3:10]
Reactant: CC(C)=O
Reactant: Cc1cccc(N)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(NC(C)C)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 12 g of 2,3-xylidine, 60 ml of acetone and 30 g of type 5A sieves (alumino silicate) are placed in a flask and stirred overnight at room temperature. The mixture is filtered and the filtrate concentrated in vacuo to yield an oily residue. This residue is taken up in 100 ml of methanol, treated with 4.0 g of sodium borohydride and warmed to above 15° C. The mixture is made acidic, then basic, and finally extracted with ether to yield 11.4 g of N-isopropyl-2,3-xylidine which is verified by infra-red spectra and NMR.
Reaction SMILES: [CH3:1]/[C:2](=[CH:12]\[S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)/[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.S(Cl)(Cl)=O.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[SH:31].[H-].[Na+]>CN(C=O)C.O.C1(C)C=CC=CC=1>[CH3:1][C:2](=[CH:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([S:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH3:24])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C/C(=C\Sc1ccccc1)C(=O)Nc1ccccc1
Reactant: Cc1ccccc1S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=CSc1ccccc1)C(=Nc1ccccc1)Sc1ccccc1C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 82.5 %

Procedure:
A mixture of 0.5 g (1.85 mmol) of (E)-2-methyl-N-phenyl-3-(phenylthio)-2-propenamide, 0.4 ml of thionyl chloride, 5 mg of DMF, and 10 ml of toluene was refluxed for 1 hour and then concentrated. The residue was dissolved in 5 ml of DMF and cooled to 0° C. To a solution of 277 mg (2.23 mmol) of 2-methylthiophenol in 5 ml of DMF was added 90 mg of sodium hydride (60% in oil) under ice cooling and stirred for 5 minutes. The solution was added portionwise to the above-described DMF solution of the residue under ice cooling and stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with tert-butyl methyl ether (three times). The combined organic layer was washed sequentially with water and a saturated NaCl solution, dried over anhydrous MgSO4, and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1) to obtain 573 mg of 2-methylphenyl 2-methyl-N-phenyl-3-(phenylthio)-2-propenimidothioate (hereinafter referred to as the present compound 21).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[CH3:6][C:7]1([CH3:44])[O:12][C:11]2[CH:13]=[CH:14][C:15]([C@H:17]3[O:21][C:20](=[O:22])[N:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]4[CH:35]=[C:36]([S:40]([NH2:43])(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=4)[CH2:18]3)=[CH:16][C:10]=2[CH2:9][O:8]1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:6][C:7]1([CH3:44])[O:12][C:11]2[CH:13]=[CH:14][C:15]([C@H:17]3[O:21][C:20](=[O:22])[N:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]4[CH:35]=[C:36]([S:40]([NH:43][C:4]([NH:3][CH2:1][CH3:2])=[O:5])(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=4)[CH2:18]3)=[CH:16][C:10]=2[CH2:9][O:8]1
Reactant: CCN=C=O
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCCCc4cccc(S(N)(=O)=O)c4)C(=O)O3)ccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCNC(=O)NS(=O)(=O)c1cccc(CCCCOCCCCCCN2C[C@@H](c3ccc4c(c3)COC(C)(C)O4)OC2=O)c1
Yield: 54.1 %

Procedure:
Ethyl isocyanate (0.015 g) was added to a stirred mixture of 3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide (0.11 g) and K2CO3 (0.055 g) in acetone (2 ml). The mixture was heated at reflux for 2 h then ethyl isocyanate (0.005 g) was added. After 0.5 h the reaction mixture was cooled and quenched with water (1 ml). The mixture was partitioned between EtOAc (20 ml) and H2O (20 ml). The aqueous phase was extracted with EtOAc (20 ml). The combined EtOAc phases were washed with brine (10 ml) then dried (Na2SO4) and concentrated. The residue was purified by SPE (silica 5 g) with CH2Cl2 (2×15 ml), Et2O (2×15 ml) and EtOAc (2×15 ml), evaporation of the EtOAc fractions afforded the title compound (0.067 g). ES+ve 632 (MH)+
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][C:10]1([F:16])[F:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].C(N(CC)CC)C.Cl[CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1>>[CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:11][C:10]1([F:16])[F:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC1(F)CNCCC1NCc1ccccc1
Reactant: Fc1ccc(OCCCCl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Fc1ccc(OCCCN2CCC(NCc3ccccc3)C(F)(F)C2)cc1
Temperature: 120 °C
Reaction time: 30 h
Yield: 48.1 %

Procedure:
In a 100 mL flask, a mixture of 1.22 g (5.4 mmol) of benzyl-(3,3-difluoro-piperidin-4-yl)amine 14, 0.81 g (5.4 mmol; 1 equiv) of sodium iodide, 2.73 g (27.0 mmol; 5 equiv) of triethylamine and 1.05 g (5.4 mmol; 1 equiv) of 1-(3-chloropropoxy)-4-fluorobenzene in 70 mL was stirred at 120° C. during 30 hours. Another portion of 2.73 g (27.0 mmol; 5 equiv) of triethylamine was added and the mixture stirred at 120° C. during 16 hours. Then 1.05 g (5.4 mmol; 1 equiv) of 1-(3-chloropropoxy)-4-fluorobenzene was added and the mixture was stirred at 120° C. during 54 hours until the reaction was completed. The solvent was removed under vacuum and the crude oil was redissolved in 100 mL of EtOAc and washed with brine and dried over MgSO4. Filtration of the solids and evaporation of the solvent resulted in a crude oil which was purified via flash chromatography (hexane/EtOAc 1:1, Rf=0.19-0.38) yielding 1.00 g (2.6 mmol; 49% yield) of benzyl-{3,3-difluoro-1-[3-(4-fluoro-phenoxy)propyl]piperidin-4-yl}amine 15 as a brown oil.