Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[N:10]12[CH2:17][CH2:16][C:13]([C:18]([O:20]CC)=O)([CH2:14][CH2:15]1)[CH2:12][CH2:11]2>C1COCC1>[N:10]12[CH2:11][CH2:12][C:13]([C:18]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[CH:7]=3)([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[CH:7]=3)[OH:20])([CH2:14][CH2:15]1)[CH2:16][CH2:17]2
Reactant: CCOC(=O)C12CCN(CC1)CC2
Reactant: Cc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: Cc1cccc(C(O)(c2cccc(C)c2)C23CCN(CC2)CC3)c1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
A solution of 3-methylphenylmagnesiumbromide (1.0 M in THF, 3.3 mL, 3.3 mmol) was chilled down to 0° C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.1484 g, 0.810 mmol) in THF (4 mL) was slowly added to the reaction mixture at 0° C. over 20 min. The reaction was allowed to warm up to room temperature and then heated at 60° C. for 16 h. The reaction was chilled in an ice bath, quenched with saturated NH4Cl, and concentrated under vacuum. The resulting residue was treated with H2O and extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum to yield the desired product (0.1806 g, 69.4%). EI-MS m/z 322 (M+H+) Rt (1.54 min).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]=[C:30]=[O:31])[CH:24]=1>>[F:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]([NH:21][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([NH:10][C@H:1]2[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]2)[CH:20]=[CH:19]3)=[O:31])[CH:26]=[CH:27][CH:28]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Product: O=C(Nc1cccc(F)c1)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
The title compound, MS: m/e=413.7 (M+H+), was prepared in accordance with the general method 4 of example 16 from (R)—N2-indan-1-yl-quinoline-2,6-diamine and 1-fluoro-3-isocyanato-benzene.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][CH:5]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:15])[CH2:13][CH3:14])[CH2:6][CH:7]=O.CN(C)[CH:18]=[O:19]>O>[CH3:6][C:5](/[CH:9]=[CH:7]\[CH2:6][CH:5]([CH3:4])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:15])[CH2:13][CH3:14])=[CH:4][C:1]([O:19][CH3:18])=[O:2]
Reactant: CCC(C)CCCC(C)CC=O
Reactant: C[O-]
Reactant: CN(C)C=O
Agent: [Na+]
Solvent: O
Product: CCC(C)CCCC(C)C/C=C\C(C)=CC(=O)OC
Reaction time: 1 h

Procedure:
Sodium methoxide (from 200 mg. sodium and 12 ml. methanol) is added dropwise to a stirred solution of 1.8 g. of trans diethyl 3-ethoxycarbonyl-2-methylprop-2-enyl phosphonate (II; R = ethyl, R1 = methyl and R6 = ethoxy) and 1 g. of 3,7-dimethyl-1-nonanal in 50 ml. of dimethylformamide under nitrogen. The reaction mixture is left for one hour at room temperature and then water is added followed by extraction with ether. The ethereal extracts are washed with brine, dried and evaporated to yield trans/cis methyl 3,7,11-trimethyltrideca-2,4-dienoate. The isomeric mixture can be chromatographed on silica or distilled for purification. The isomeric mixture is predominantly trans at C-2,3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=O)=[CH:16][CH:15]=2)[CH:10]([O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:36][CH2:37][C:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:39].C(N(CC)CC)C.F[B-](F)(F)F.O=C1C=CC=CN1OC(N(C)C)=[N+](C)C>CN(C)C=O>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][O:24][CH:10]1[CH:11]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C:21](=[O:23])[NH:36][CH2:37][C:38](=[O:39])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:18][CH:19]=2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CC(=O)O)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: NCC(=O)c1ccccc1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CC(=O)NCC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.3 %

Procedure:
A solution of 150 mg (0.32 mmol) of (3RS,4RS)-[4-(1-tert-butoxycarbonyl-3-naphthalen-2-ylmethoxy-piperidin-4-yl)-phenyl]-acetic acid and 55 mg (0.32 mmol) of 2-amino-1-phenyl-ethanone in 5 ml of dimethylformamide was treated in sequence with 44.6 μl (0.32 mmol) of triethylamine and 96 mg (0.32 mmol) of O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TPTU) and the mixture was stirred at room temperature for 18 hours. For the working-up, the reaction was evaporated in an oil pump vacuum, the residue was taken up in 20 ml of methylene chloride and washed with 5 ml of water. The organic phase was dried over sodium sulphate and evaporated under reduced pressure. For purification, the crude material was chromatographed on silica gel using a 95:5 mixture of methylene chloride and methanol as the eluent. There were obtained 120 mg (64% of theory) of tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-{4-[(2-oxo-2-phenyl-ethylcarbamoyl)-methyl]-phenyl}-piperidine-1-carboxylate as a colourless oil; MS: 615 (M+Na)+.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[N:10]=[CH:11][N:12]([CH3:14])[CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1C=C(S(Cl)(=O)=O)N=C1.C(N)(C)(C)C.C1C[O:33][CH2:32]C1>>[C:1]([NH:5][S:6]([C:9]1[N:10]=[C:11]([CH:32]=[O:33])[N:12]([CH3:14])[CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: Cn1cnc(S(=O)(=O)NC(C)(C)C)c1
Agent: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: CC(C)(C)N
Product: Cn1cc(S(=O)(=O)NC(C)(C)C)nc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Step A) Preparation of N-(tert-butyl)-1-methyl-1H-imidazole-4-sulfonamide: A solution of 5.2 gm (29 mmol) 1-methyl-1H-imidazole-4-sulfonyl chloride in 30 mL THF was cooled in ice water while 7 mL tert-butylamine was added dropwise. The solution was warmed to room temperature and stirred overnight. Solids were filtered and rinsed with additional THF. The filtrate was concentrated to give a white solid that was recrystallized from water and dried in vacuo to give 4.8 gm of the subtitle compound, 1H NMR (d6-DMSO) δ 7.75 (s, 1H), 7.65 (s, 1H), 7.2 (s, 1H), 3.7 (s, 3H), 1.1 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:5]([NH2:16])[CH:4]=1.[CH3:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1/[CH:23]=[CH:24]/[C:25](Cl)=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:51]([OH:56])(=[O:55])[C:52]([OH:54])=[O:53]>C(OCC)(=O)C>[C:51]([OH:56])(=[O:55])[C:52]([OH:54])=[O:53].[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[C:25](/[CH:24]=[CH:23]/[C:19]3[S:20][CH:21]=[CH:22][C:18]=3[CH3:17])=[N:16][C:5]=2[CH:4]=1
Reactant: Cc1ccsc1/C=C/C(=O)Cl
Reactant: COc1ccc(Nc2ccccn2)c(N)c1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)nc(/C=C/c1sccc1C)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-methoxy-2-amino-N-(2-pyridyl)aniline and (E)-3-(3-methyl-2-thienyl)acryloyl chloride (Sekiya, T.; Hiranuma, H.; Hata, S.; Mizogami, S.; Hanazuka, M.; Yamada, S. J. Med. Chem., 1983, 26, 411) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl MeOH/n-hexane yielded the titled compound. MW: 437.48; mp: 192.5-193.5° C.; 1H-NMR (DMSO) δ: 8.65 (1H, dd, J=4.9, 1.8 Hz), 8.07 (1H, td, J=7.8, 1.9 Hz), 7.87 (1H, d, J=15.6 Hz), 7.62 (1H, d, J=8.1 Hz), 7.52 (1H, dd, J=7.4, 4.9 Hz), 7.37 (1H, d, J=5.1 Hz), 7.24 (1H, d, J=8.9 Hz), 7.16 (1H, d, J=2.3 Hz), 6.86 (1H, d, J=4.9 Hz), 6.79 (1H, dd, J=8.9,2.5 Hz), 6.67 (1H, d, J=15.6 Hz), 3.72 (3H, s), 2.22 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[C:15](\[C:22]2[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=2)/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][C:7]=1[CH3:29].[C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)#[CH:32].ClCCl>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[C:15](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)\[C:22]2[CH:27]=[CH:26][C:25]([C:32]#[C:31][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[CH:24][CH:23]=2)=[CH:8][C:7]=1[CH3:29]
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccccc2)c2ccc(I)cc2)cc1C
Reactant: C#Cc1ccccn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(/c2ccccc2)c2ccc(C#Cc3ccccn3)cc2)cc1C

Procedure:
A solution of (Z)-{4-[3-(4-iodo-phenyl)-3-phenyl-allyloxy]-2-methyl-phenoxy}-acetic acid methyl ester (283 mg, 0.55 mmol), 2-Ethynyl-pyridine (0.167 ml, 1.65 mmol), bis(triphenylphosphine) palladium(II) chloride (0.015 g, 0.022 mmol), copper(I) iodide (0.31 mg, 0.002 mmol) in dry triethylamine (4 ml) were heated to 120° C. by microwave irradiation for 20 min. The cooled reaction mixture was added dichloromethane (20 ml) and silica gel Fluka 60 (10 g) and evaporated in vacuo. The residue was purified by ISCO combiflash 16 (silica gel, hexane/ethyl acetate 85:15) yielding {2-Methyl-4-[(Z)-3-phenyl-3-(4-pyridin-2-ylethynyl-phenyl)-allyloxy]-phenoxy}-acetic acid methyl ester as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[C:6]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=2)[N:5]=[C:4]([S:25][CH3:26])[N:3]=1.[NH2:27][NH2:28].O.[CH3:30]CO>>[CH3:26][S:25][C:4]1[N:3]2[CH:30]=[N:27][N:28]=[C:2]2[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[C:6]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=2)[N:5]=1
Reactant: CCO
Reactant: NN
Reactant: CSc1nc(Cl)c(-c2cccc(C(F)(F)F)c2)c(-c2ccnc(Cl)c2)n1
Solvent: O
Product: CSc1nc(-c2ccnc(Cl)c2)c(-c2cccc(C(F)(F)F)c2)c2nncn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloro-6-(2-chloro-4-pyridyl)-2-methylthio-5-(3-(trifluoromethyl)-phenyl)pyrimidine (0.873 g, 2.1 mmol) and 16.5 ml of NH2NH2—H2O in 90 ml EtOH in a 150-ml r.b.flask with a stir bar was stirred at 70° C. The reaction was cooled to room temperature. The solvents were evaporated in vacuo. The residue was dried by addition and removal of toluene in vacuo and further dried under vacuum at 50° C. overnight. The resulting light yellow solid was mixed with 40 ml of DCM, 20 ml of CH(OCH3)3, and 10 ml of TFA in a 150-ml r.b.flask with a stir bar. The reaction solution was stirred at RT overnight. The acidic reaction solution was neutralized to pH 8 by sat'd NaHCO3. The DCM layer was washed with brine (3×20 ml) and dried over Na2SO4. After removal of the DCM in vacuo, crude product (MS m/z 421.8 (M+H)+) was obtained as a dark brown oil, which was used directly in the next step.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[O:16]([C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccccc1
Reactant: N#Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1Oc1ccccc1
Temperature: 130 °C
Reaction time: 10 h
Yield: 93 %

Procedure:
To a suspension of 2-fluorobenzonitrile (10.0 g, 82.6 mmol) and phenol (7.7 g, 5.1 mmol) in DMF (80 mL) was added K2CO3 (22.8 g, 165 mmol) at rt. The reaction was stirred at 130° C. for 10 h. The reaction mixture was diluted with water, extracted with EtAOAc (100 mL×3), washed with brine (100 mL), dried (Na2SO4), and concentrated to give 15.0 g, (93%) of the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 6.85 (1H, d, J=8.4 Hz), 7.07-7.14 (3H, m), 7.22 (1H, t, J=7.2 Hz), 7.40 (2H, t, J=8.0 Hz), 7.47 (1H, td, J=2.0, 8.4 Hz), 7.65 (1H, dd, J=1.2, 8.0 Hz).
Reaction SMILES: [C-:1]#[N:2].[Na+].O.Cl[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]2[N:16]=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[S:18][CH:19]=2)=[CH:9][CH:8]=1>CN(C=O)C>[C:1]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]2[N:16]=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[S:18][CH:19]=2)=[CH:9][CH:8]=1)#[N:2]
Reactant: [C-]#N
Reactant: CC(=O)Nc1nc(CCc2ccc(CCl)cc2)cs1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(CCc2ccc(CC#N)cc2)cs1
Temperature: 25 °C
Reaction time: 19 h
Yield: 67 %

Procedure:
NaCN (115 mg), KI (130 mg) and water (1.8 ml) were combined, and then a solution of N-(4-{2-[4-(chloromethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (230 mg) in DMF (7 ml) was added dropwise to the mixture at 0° C. The reaction mixture was stirred at r.t. for 19 hours, poured into water, and extracted with CHCl3. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residual solid was washed with ethyl ether to give N-(4-{2-[4-(cyanomethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (149.1 mg) as a colorless solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:17])[CH2:6][C:7](=O)[CH2:8][NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH3:3].C(O)(C)(C)C.[C:23]([S-:25])#[N:24].[K+]>O>[CH2:2]([O:4][C:5](=[O:17])[CH2:6][C:7]1[NH:24][C:23](=[S:25])[N:9]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:8]=1)[CH3:3]
Reactant: CCOC(=O)CC(=O)CNC1CCCCC1
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)Cc1cn(C2CCCCC2)c(=S)[nH]1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
200 g (0.758 mol) 4-Cyclohexylamino-3-oxo-butyric acid ethyl ester hydrochloride were dissolved in 360 ml water and 120 ml tert-butanol and were heated to 90° C. Then 88.4 g (0.91 mol) KSCN were added and the mixture was heated for 20 s, thereby a phase separation occurred. After cooling to RT, the phases were separated and the aqueous layer was extracted with AcOEt. The combined organic layers were washed with Brine, dried with MgSO4 and concentrated. The solid was digested in MTBE and filtered to yield 192 g (0.715 mol, 94%) of (1-Cyclohexyl-2-thioxo-2,3-dihydro-1H-imidazol-4-yl)-acetic acid ethyl ester as a beige solid. HPLC: tR=1.16 min (YMC J′ sphere ODS H 80 20×2.1 mm, 4 μm, A: H2O+0.05% TFA, B: MeCN, 4%→95% B in 2 min, 1 ml/min, 30° C.); Mass (ES+) (C13H20N2O2S): calculated. 268. found 269 [M+H]+.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12]1([CH2:18][O:19][C:20](=[O:60])[CH2:21][N:22]2[CH2:33][CH2:32][N:31]([CH2:34][C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[CH2:30][CH2:29][N:28]([CH2:45][C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:27][CH2:26][N:25]([CH2:56][C:57]([OH:59])=[O:58])[CH2:24][CH2:23]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Br[CH2:62][C:63]([N:65]([CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH3:101])[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83])=[O:64]>C1(C)C=CC=CC=1>[C:12]1([CH2:18][O:19][C:20](=[O:60])[CH2:21][N:22]2[CH2:23][CH2:24][N:25]([CH2:56][C:57]([O:59][CH2:62][C:63]([N:65]([CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83])[CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH3:101])=[O:64])=[O:58])[CH2:26][CH2:27][N:28]([CH2:45][C:46]([O:48][CH2:49][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)=[O:47])[CH2:29][CH2:30][N:31]([CH2:34][C:35]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[O:36])[CH2:32][CH2:33]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)CN1CCN(CC(=O)OCc2ccccc2)CCN(CC(=O)OCc2ccccc2)CCN(CC(=O)OCc2ccccc2)CC1
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)CBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COC(=O)CN1CCN(CC(=O)OCc2ccccc2)CCN(CC(=O)OCc2ccccc2)CCN(CC(=O)OCc2ccccc2)CC1
Yield: 68 %

Procedure:
DBU (820 μL; 5.5 mmol) was added to a suspension of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid tris(phenylmethyl)ester (prepared according to Step E3 of Example 17) (3.71 g; 5.5 mmol) in toluene (350 mL) obtaining a clear solution, then 2-bromo-N,N-dioctadecylacetamide (prepared according to Example 5, Step A) (3.9 g; 6.05 mmol) dissolved in toluene (50 mL) was added dropwise. After 2 h the reaction mixture was filtered and the solvent was evaporated. The crude was suspended in CH3CN (50 mL) and the insoluble was filtered off with a paper filter. The solution was evaporated obtaining the desired product (4.63 g; 3.74 mmol). Yield 68%. The 13C-NMR, MS and IR spectra were consistent with the structure.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:11]([CH2:14][CH2:15][NH2:16])([CH3:13])[CH3:12]>C(O)C>[CH3:12][N:11]([CH3:13])[CH2:14][CH2:15][NH:16][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(C)CCN
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCO
Product: CN(C)CCNc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 61 %

Procedure:
A solution of 2-chloro-3-nitropyridine (1.76 g, 20.0 mmol) in ethanol is treated with Me2NCH2CH2NH2 (3.17 g, 20.0 mmol), stirred at ambient temperature for 17 h, heated to reflux temperature for 7 h, cooled to room temperature and concentrated in vacuo. The resulting solid residue is triturated with ethanol and suction filtered. The filtercake is air-dried to give the title compound as a yellow solid, 3.20 g (61% yield),. mp 202-203° C., identified by NMR and mass spectral analyses.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:3]=1.[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.C(OCC)(=O)C>[N:27]1([C:2]2[N:7]=[CH:6][N:5]=[C:4]([N:8]3[CH2:13][CH2:12][CH:11]([CH:14]4[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]4)[CH2:10][CH2:9]3)[CH:3]=2)[CH:31]=[N:30][CH:29]=[N:28]1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cc(Cl)ncn3)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cc(-n4cncn4)ncn3)CC2)CC1
Temperature: 140 °C

Procedure:
The tert-butyl 1′-(6-chloropyrimidin-4-yl)-4,4′-bipiperidine-1-carboxylate (190 mg, 0.50 mmol), 1,2,4-triazole (69 mg, 1.0 mmol), cesium carbonate (488 mg, 1.5 mmol) were added in NMP (5 mL) and heated to 140° C. for 1.5 hours. The reaction crude were cooled down to r.t. and diluted with ethyl acetate (10 mL), washed with water (5 mL, ×1) and brine (5 mL, ×1). The organic phase was dried over magnesium sulfate, filtered and concentrated on rotavapor. The crude mixture was purified by preparative TLC with 50% ethyl acetate:hexane to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10]CC(C)(C)N=2)=[CH:5][C:4]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].CN(C=[O:26])C.C([Li])CCC.CS[S:34][CH3:35]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:10])=[O:26])=[C:5]([S:34][CH3:35])[C:4]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCOc1cc(C2=NC(C)(C)CO2)ccc1OC
Reactant: CSSC
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Product: CCCCCOc1c(OC)ccc(C(=O)O)c1SC
Reaction time: 1 h
Yield: 74 %

Procedure:
2-(4-Methoxy-3-pentyloxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole (500 mg, 1.76 mmol) and DMF (8 ml) were mixed, and this solution was cooled to -60° C. n-Butyllithium (1.6M hexane solution, 2.42 ml, 3.87 mmol) was added and the mixture was stirred for 1 hour. Dimethyl disulfide (0.35 ml, 3.87 mmol) was added to this solution, and the mitxure was stirred at room temperature for 1 hour. Water (5 ml) was added, and the aqueous layer was extracted 3 times with ethyl acetate (10 ml). The organic layers were combined and concentrated under reduced pressure. A 3N hydrochloric acid (4 ml) was added to the obtained residue and the mixture was under heating for 3 hours. A 10N aqueous sodium hydroxide solution (4 ml) was added and the mixture was refluxed under heating for 2 hours. A concentrated hydrochloric acid (3 ml) was added to make the reaction mixture acidic, and the aqueous layer was extracted 4 times with ethyl acetate (20 ml). The organic layers were combined, washed 3 times with saturated brine (10 ml) and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained crude crystals were purified by washing with hexane to give 4-methoxy-2-methylthio-3-pentyloxybenzoic acid (370 mg, 74%) as pale-brown crystals.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[NH:17])C1C=CC=CC=1.C.C(O)(=O)C>CO.[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][S:19]([C:22]1[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=1)(=[O:21])=[O:20])=[NH:17]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCCCCCOCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCCCCCO)cc1
Reaction time: 1 h
Yield: 100.2 %

Procedure:
3.20 g (7.9 mmol) of N—(N-(6-(benzyloxy)hexyl)carbamimidoyl)-4-methylbenzenesulfonamide were dissolved under nitrogen in MeOH. A few mg of 10% Palladium over activated charcoal were added. 1 mL of acetic acid was added. 3 vacuo hydrogen flush were done before stirring vigorously the reaction under a H2 atmosphere. The reaction was vigorously stirred at room temperature for 3 hours and checked by TLC. No conversion was found and 2 mL of acetic acid were added. After 1 hour, the TLC showed no conversion and more 10% Palladium over activated charcoal were added. After 3 days, the TLC showed a complete conversion and the solution was filtered over celite and the solvent evaporated to afford 2.480 g of N—(N-(6-hydroxyhexyl)carbamimidoyl)-4-methylbenzenesulfonamide as slightly yellow oil was obtained (yield=100%).
Reaction SMILES: [Li+].[OH-].O.[OH:4][C@@:5]1([C:17]([O:19]CC)=[O:18])[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]1=[O:16]>C1COCC1.O>[OH:4][C@@:5]1([C:17]([OH:19])=[O:18])[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]1=[O:16]
Reactant: CCOC(=O)[C@]1(O)CCN(c2ccccc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@]1(O)CCN(c2ccccc2)C1=O
Reaction time: 4 h

Procedure:
LiOH/H2O (750 mg) is added to a solution of ethyl (S)-3-hydroxy-2-oxo-1-phenylpyrrolidine-3-carboxylate (1.5 g) in THF/H2O=3:1, and the mixture is stirred for 4 h. The solvent is then removed in vacuo, and the batch is acidified using 1.5N HCl. The aqueous phase is extracted with ethyl acetate, and the combined organic phases are dried over sodium sulfate, giving (S)-3-hydroxy-2-oxo-1-phenylpyrrolidine-3-carboxylic acid;
Reaction SMILES: [Se:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=1)=O.[CH2:18]([NH:25][NH2:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N1C2C=C[Se]C=2C(C2OC(C(OC)=O)=CC=2)=N1)C1C=CC=CC=1>C(O)(=O)C>[CH2:18]([N:25]1[C:3]2[CH:4]=[CH:5][Se:1][C:2]=2[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[N:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(C(=O)c2ccc[se]2)cc1
Reactant: NNCc1ccccc1
Agent: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3cc[se]c23)o1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3cc[se]c23)cc1

Procedure:
Compound 63 (5.86 g, 0.02 mole), benzylhydrazine 50 (4.88 g, 0.04 mole) and glacial acetic acid (1.5 ml) were allowed to react as in the preparation of compound 55 to afford compound 67. Yield: 2.49 g (31.4%); white crystals; mp 150-153° C.