Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)[CH2:3][C:4]#[N:5].[N:16]([O-])=[O:17].[Na+]>C(O)(=O)C.O>[OH:17][N:16]=[C:3]([C:2](=[O:1])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:14])[F:15])[CH:7]=1)[C:4]#[N:5]
Reactant: N#CCC(=O)c1cccc(C(F)(F)F)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#CC(=NO)C(=O)c1cccc(C(F)(F)F)c1
Temperature: 15 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of 30.0 g of the title compound of Step A in 200 mL of glacial acetic acid was added dropwise a solution of 11.7 g of sodium nitrite in 35 mL of water while maintaining the reaction temperature at about 15° C. with external cooling. Following addition, the external cooling was removed and the suspension was stirred at room temperature overnight and then poured into excess water (about 400 mL). The aqueous suspension was acidified by dropwise addition of concentrated hydrochloric acid (until red to litmus paper) and then extracted with methylene chloride. The organic solution was dried (MgSO4), filtered and concentrated to give 32.5 g of the title compound of Step B as an oil. 1H NMR (CDCl3): δ 8.3 (s,1H), 8.2 (m,1H), 7.9 (m,1H), 7.65 (m,1H); IR (neat) 1670.2 cm-1.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:18][C@H:17]2[C@H:13]([N:14]=[C:15]([N:19]([CH2:27][CH2:28][F:29])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[S:16]2)[C@@H:12]([OH:30])[C@@H:11]1[OH:31])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C)C=O>[CH2:35]([O:31][C@@H:11]1[C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[O:18][C@H:17]2[C@H:13]([N:14]=[C:15]([N:19]([CH2:27][CH2:28][F:29])[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[S:16]2)[C@H:12]1[O:30][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N(CCF)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCF)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Reaction time: 0.25 h
Yield: 25.2 %

Procedure:
A solution of tert-butyl (3aR,5R,6S,7R,7aR)-5-((tert-butyldimethylsilyloxy)methyl)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(2-fluoroethyl)carbamate (2.0 g, 4.2 mmol) in N,N-dimethylformamide (30 mL) was treated with sodium hydride (510 mg, 21 mmol) for 10 min at 10° C. in a nitrogen atmosphere, and followed by addition of 1-(bromomethyl)benzene (2.2 g, 13 mmol). After stirred for 15 min, the reaction was quenched with saturated aqueous NH4Cl and extracted with dichloromethane (3×30 mL). The organic layers were dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column, eluting with 1.5-3% ethyl acetate in petroleum ether to provide compound 70 as a yellow oil (0.7 g, 25%). (ES, m/z) [M+H]+ 660.8; 1H NMR (300 MHz, CDCl3) δ 7.28-7.43 (m, 10H), 6.11-6.13 (d, J=6.3 Hz, 1H), 4.60-4.74 (m, 4H), 4.30-4.41 (m, 6H), 3.73-3.75 (m, 3H), 3.37-3.44 (m, 1H), 1.54 (s, 9H), 0.90 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: [H-].[Na+].Br[C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([C:18]#[N:19])=[CH:6][N:5]=1.[CH3:20][N:21]([CH3:34])[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH:32]=[O:33])=[CH:24][CH:23]=1.[I-].C[N+]1C=CN(C)C=1>CN(C=O)C.C(Cl)Cl.CCOC(C)=O.O>[CH3:20][N:21]([CH3:34])[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]([C:4]2[C:13]3[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3)[C:7]([C:18]#[N:19])=[CH:6][N:5]=2)=[O:33])=[CH:24][CH:23]=1
Reactant: COc1cc2c(C#N)cnc(Br)c2cc1OC
Reactant: CN(C)c1ccc(C=O)c2ccccc12
Agent: Cn1cc[n+](C)c1
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc2c(C#N)cnc(C(=O)c3ccc(N(C)C)c4ccccc34)c2cc1OC
Reaction time: 1 h
Yield: 44.3 %

Procedure:
Sodium hydride (11 mg, 0.26 mmol) was added to a stirred mixture of 1-bromo-6,7-dimethoxy-isoquinoline-4-carbonitrile (see example 1) (50 mg, 0.17 mmol), 4-dimethylamino-1-naphthaldehyde (51.8 mg, 0.26 mmol), 1,3-dimethylimidazolium iodide (16 mg, 0.26 mmol) in DMF (2 mL). The reaction mixture became dark color. After 1 h, water (4 mL) was added to the above mixture, and extracted with chloroform (6 mL). The extract was washed with water (4 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford a solid. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 0–40% EtOAc in methylenechloride in 30 min) afforded 1-(4-dimethylamino-naphthalene-1-carbonyl)-6,7-dimethoxy-isoquinoline-4-carbonitrile (31 mg, 41%) as a white solid. LC-MS m/e calcd for C21H18N2O5 (MH+) 379. found 379.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11](=[O:25])[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].CC(C)=[O:28].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11](=[O:25])[C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:17]=2)[CH:7]=[CH:6][C:3]=1[C:4]([OH:28])=[O:5]
Reactant: CCCCCCCc1ccc(C(=O)Oc2ccc(C=O)c(Cl)c2)cc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CCCCCCCc1ccc(C(=O)Oc2ccc(C(=O)O)c(Cl)c2)cc1
Reaction time: 1 h

Procedure:
The resulting, crude 2-chloro-4-[(p-heptylbenzoyl)oxy]benzaldehyde is dissolved in 350 ml of acetone. Within 40 minutes there are added dropwise thereto 30 ml of Jones' reagent, the mixture warming slightly. The mixture is stirred for a further 1 hour, precipitated inorganic material is then filtered off under suction, the filtrate is diluted with 300 ml of water (the product precipitating), concentrated on a rotary evaporator to about 300 ml and the suspension obtained in suction filtered. The suction filter material is washed three times with 50 ml of 10% aqueous acetone, dried and recrystallized from about 60 ml of benzene. There are obtained 13.8 g of 2-chloro-4-[(p-heptylbenzoyl)oxy]benzoic acid, m.p. 108° C. (nematic).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[N:16]=[C:15]([O:26][CH3:27])[CH:14]=2)=[CH:9][CH:8]=1)(=O)=O.CCOC(C)=O.O.[CH3:37][N:38](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Pd].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.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>[CH3:27][O:26][C:15]1[CH:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:37]#[N:38])=[CH:8][CH:9]=2)[N:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:16]=1
Reactant: COc1ccc(-n2nc(OC)cc2-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)cc1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-n2nc(OC)cc2-c2ccc(C#N)cc2)cc1
Temperature: 85 °C
Reaction time: 5 h

Procedure:
A mixture of 4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenyl trifluoromethanesulfonate (679 mg), zinc cyanide (279 mg), and tetrakis(triphenylphosphine)-palladium(0) (183 mg) in DMF (4 ml) was stirred at 85° C. for 5 hours. The reaction mixture was cooled to ambient temperature and AcOEt and H2O were added. Unsoluble matter was filtered off through a celite pad. The filtrate was partitioned, and the organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated invacuo. The residue was purified by silica gel column chromatography eluted with AcOEt/n-hexane=20%. The pure fractions were collected and concentrated in vacuo to give 4-[3-methoxy-1-(4-methoxy-phenyl) -1H-pyrazol-5-yl]benzonitrile (326 mg) as a powder.
Reaction SMILES: [O:1]=[C:2]([C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)[CH2:3][NH:4]C(=O)OC(C)(C)C.[ClH:17]>CCOCC>[ClH:17].[NH2:4][CH2:3][C:2]([C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)NCC(=O)c1ccsc1
Agent: Cl
Solvent: CCOCC
Product: NCC(=O)c1ccsc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a mixture of tert-butyl 2-oxo-2-(thiophen-3-yl)ethylcarbamate (776 mg, 3.21 mmol) in Et2O (3 mL) was added a HCl solution (4.0 M in dioxane, 6 mL) at 0° C. After stirring at 0° C. for 10 min, the resulting mixture was allowed warmed up to room temperature and stirred for 2 h. The reaction mixture was evaporated under vacuum to provide the titled compound (570 mg, quantitative) as a white solid. MH+142.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([Br:17])[CH:12]=1)[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].[CH3:19]I.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O>[C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([Br:17])[CH:12]=1)[CH2:9][O:10][CH3:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)c1ccnc(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC[C@H](NC(=O)OC(C)(C)C)c1ccnc(Br)c1
Reaction time: 1 h

Procedure:
To a solution of [(R)-1-(2-bromo-pyridin-4-yl)-2-hydroxy-ethyl]-carbamic acid tert-butyl ester (180 mg, 0.568 mmol), methyl iodide (177 μL, 2.84 mmol) and tetrabutylammonium hydrogen sulfate (192 mg, 0.568 mmol) in THF (4.0 mL) was added 50% aqueous solution of sodium hydroxide (2.5 mL). After 1 hour, the reaction mixture was diluted with water (50 mL) and extracted with ethyl ether (3×50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0-30% ethyl acetate in heptane to afford [(R)-1-(2-bromo-pyridin-4-yl)-2-methoxy-ethyl]-carbamic acid tert-butyl ester as oil which solidified upon standing.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH2:15])(=[O:14])=[O:13])[C:2](=[O:4])[CH3:3].[CH2:16](O)[CH2:17][OH:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:3][C:2]1([CH2:1][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12]([NH2:15])(=[O:14])=[O:13])[O:18][CH2:17][CH2:16][O:4]1
Reactant: OCCO
Reactant: CC(=O)COc1ccccc1S(N)(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(COc2ccccc2S(N)(=O)=O)OCCO1

Procedure:
A mixture of 4.58 g of 2-(2-propanon-1-yloxy)phenylsulfonamide, 2 ml of ethylene glycol, 0.02 g of p-toluenesulfonic acid and 30 ml of toluene is heated for 7 hours to reflux while simultaneously separating the water of reaction. The cooled solution is taken up in 80 ml of ethyl acetate and the organic phase is washed with saturated sodium bicarbonate solution and water, dried and concentrated, affording 5 g of 2-(2-methyl-1,3-dioxolan-2-yl-methoxy)phenylsulfonamide in the form of a yellow viscous oil which can be further used without purification.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>CC(O)C>[NH:22]([C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[CH:4][CH:3]=1)[NH2:23]
Reactant: NN
Reactant: Cn1cc(-c2cc(Oc3ccc(F)nc3)ccn2)cn1
Solvent: CC(C)O
Solvent: O
Product: Cn1cc(-c2cc(Oc3ccc(NN)nc3)ccn2)cn1
Temperature: 80 °C
Reaction time: 12 h
Yield: 87.1 %

Procedure:
4-((6-Fluoropyridin-3-yl)oxy)-2-(1-methyl-1H-pyrazol-4-yl)pyridine (0.99 g, 3.66 mmol) was dissolved in 2-propanol (7.3 mL) in a screw-cap reaction vessel. Hydrazine hydrate (64%) (0.9 mL, 18.3 mmol) was added, the vessel was sealed, and the reaction mixture was stirred at 80° C. for 12 h. The mixture was partitioned between sat. aqueous NaHCO3 (aq) (30 mL) and EtOAc (30 mL). The organic phase was collected and the aqueous phase was extracted with EtOAc (4×30 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford 4-((6-hydrazinylpyridin-3-yl)oxy)-2-(1-methyl-1H-pyrazol-4-yl)pyridine (0.9 g, 87%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.29 (s, 1H), 8.33 (d, J=5.7 Hz, 1H), 8.23 (s, 1H), 8.00 (d, J=2.9 Hz, 1H), 7.93 (s, 1H), 7.48 (dd, J=9.0, 2.9 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 6.62 (dd, J=5.7, 2.4 Hz, 1H), 4.10 (d, J=4.5 Hz, 2H), 3.84 (s, 3H); MS (ESI) m/z: 283.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].[F:10][CH:11]([C:17]([CH3:19])=O)[C:12](OCC)=[O:13].S(=O)(=O)(O)O.O>O1CCOCC1>[F:10][C:11]1[C:12](=[O:13])[O:4][C:3]2[C:5]([C:17]=1[CH3:19])=[CH:6][CH:7]=[C:8]([OH:9])[C:2]=2[CH3:1]
Reactant: CCOC(=O)C(F)C(C)=O
Reactant: Cc1c(O)cccc1O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(F)c(=O)oc2c(C)c(O)ccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
A solution of 2-methylresorcinol (3.23 g, 26.02 mmoles), ethyl 2-fluoro-acetoacetate [E. B. Banks, N. J. Lawrence, A. L. Popplewell, J. Chem. Soc., Chem. Commun, 343 (1994)] (3.85 g, 25.99 mmoles) in 0.5 mL of 1,4-dioxane was added dropwise, at 0° C. and under an inert atmosphere, to 25 mL of concentrated sulfuric acid. The reaction mixture was stirred for 1.5 hours, while the temperature was increased to 25° C. Cold water (100 mL) was added, the reaction mixture was stirred for 15 minutes and the resulting precipitate was collected by suction filtration, dried in vacuo, affording 4.56 g (84% yield) of 3-fluoro-4,8-dimethyl-7-hydroxycoumarin as a white solid. An analytical sample was obtained by recrystallisation from methanol:water: mp 260° C. (decomp.).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]2[O:8][C:9]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:6]=2[CH:5]=1)([O-])=O>[Ni].C(O)C>[CH:5]1[C:6]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:9]=3[O:8][C:7]=2[CH:17]=[CH:18][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccc2oc3c(c2c1)CCCCCC3
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 76.3 %

Procedure:
The core molecule was synthesized by the following procedure. Potassium t-butoxide (5.9 g, 53 mmol) was added in portions to a cooled (5° C.) solution of cycloheptanone oxime (7.5 g, 53 mmol) in DMF (100 mL). The cooled reaction mixture was stirred for 50 minutes and then 1-chloro-4-nitrobenzene (7.9 g, 50 mmol) in DMF (25 mL) was added over 5 minutes. The reaction mixture was stirred at ˜10° C. for 30 minutes and then allowed to warm to room temperature and stirred for an additional 4 hours. The reaction mixture was concentrated under reduced pressure and the crude material was dissolved in ether and washed with water and brine. The organic phase was dried (Na2SO4) and concentrated to provide cyclooctanone O-(4-nitro-phenyl)-oxime (5.7 g). Cyclooctanone O-(4-nitro-phenyl)-oxime (5.3 g, 20 mmol) was dissolved in warm isopropanol (120 mL) and 12 N hydrochloric acid (6.8 mL) was added. The reaction mixture was heated to reflux for 5 hours and then cooled in an ice bath. The solid was collected by filtration, washed with water and cold isopropanol, and dried in an oven. The crude solid was purified by flash column chromatography (elution with 2% ethyl acetate-hexanes) to give 2-nitro-6,7,8,9,10,11-hexahydro-benzo[b]-cycloocta[d]furan (3.5 g, 14 mmol). A mixture of 2-nitro-6,7,8,9,10,11-hexahydro-benzo[b]-cycloocta[d]furan (3.4 g, 14 mmol) and Raney nickel (-4.1 g wet weight) in ethanol (170 mL) was hydrogenated at 50 PSI on a Parr shaker overnight. The mixture was filtered through Celite® and the filtrate was concentrated. The crude solid was purified by flash column chromatography (elution with 20% ethyl acetate-hexanes) to give 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (2.3 g). Mp 97-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:21])=O)[C:13]=3[N:12]=[C:11]2[C:22](=[O:33])[NH:23][CH:24]2[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]2)=[CH:4][CH:3]=1.[OH:34][CH:35]1[CH2:38][NH:37][CH2:36]1>>[CH:30]([N:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:22]([C:11]2[N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([N:37]4[CH2:38][CH:35]([OH:34])[CH2:36]4)=[O:21])[C:13]=3[N:12]=2)=[O:33])[CH2:25][CH2:26]1)([CH3:31])[CH3:32]
Reactant: OC1CNC1
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)cccc3n2CCc2ccc(Cl)cc2)CC1
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)N4CC(O)C4)cccc3n2CCc2ccc(Cl)cc2)CC1

Procedure:
1-[2-(4-Chloro-phenyl)-ethyl]-4-(3-hydroxy-azetidine-1-carbonyl)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 150 mg (0.29 mmol) 1-[2-(4-Chloro-phenyl)-ethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid and 23.4 mg (0.32 mmol) 3-hydroxy-azetidine. The title compound was obtained as its formiate in form a white amorphous solid.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)=[O:4].C1N2CN3CN(C2)C[N:22]1C3.[Br-].[NH4+].C(O)(C)C>O>[Cl:20][C:17]1[CH:18]=[CH:19][C:6]2[NH:5][C:3](=[O:4])[CH2:2][N:22]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]=2[CH:16]=1
Reactant: O=C(CBr)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: [Br-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1

Procedure:
Reflux 1.76 g. (0.005 moles) of 2-(2-bromoacetamido)-5-chlorobenzophenone, 2.80 g. (0.02 moles) of hexamethylenetetramine and 1.96 g. (0.020 moles) of ammonium bromide in 14 ml. of 85% (v/v) aqueous isopropyl alcohol for 2 hours. Pour the reaction mixture into water and extract with benzene. Dry the benzene solution over anhydrous sodium sulfate. Filter and evaporate to dryness. After recrystallization, 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one is obtained. In thin layer chromatography the product shows a single spot (silica gel GF plates, benzene-ethyl acetate-acetic acid=18:3:1), m.p. 213°-215° C.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].Cl.[CH3:12][NH:13][OH:14].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N+:13]([CH3:12])[O-:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: CNO
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[N+]([O-])=Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
A mixture of 4-cyanobenzaldehyde (3.3 g, 25.2 mmol), N-methylhydroxyamine hydrogen chloride and sodium bicarbonate (4.23 g, 50.4 mmol) in dry methylene chloride (80 ml) was stirred at rt for 5 hrs. The solid portion was filtered off and the filtrate was concentrated to give the product as white solid (98% yield). 1H NMR (300 MHz, CDCl3) δ3.94(s, 3H), 7.46(s, 1H), 7.72(d, J=8 Hz, 2H), 8.32(d, J=8 Hz, 2H). MS (NH3-CI) Calc. for (M+1)+: 161. Found: 161.
Reaction SMILES: C(O[C:4]([CH:6]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=2[N:11]=[C:10]1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:5])C.CO.[CH3:37][NH2:38]>>[CH3:37][NH:38][C:4]([CH:6]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=2[N:11]=[C:10]1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:5]
Reactant: CCOC(=O)C(CCn1c(COc2ccc(Cl)cc2)nc2c(C)cccc21)Cc1ccccc1
Reactant: CN
Solvent: CO
Product: CNC(=O)C(CCn1c(COc2ccc(Cl)cc2)nc2c(C)cccc21)Cc1ccccc1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
In methylamine (40% in water, 10 ml), 1-[3-(ethoxycarbonyl)-4-phenylbutyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (1.0 g, 2.5 mmol) was placed. To this mixture 10 ml of methanol were added, to enhance solubility. The resulting mixture was stirred at room temperature for about 64 hours, after which time the reaction mixture was concentrated in vacuo. The residue was taken up in 200 ml of methylene chloride. The organic fraction was washed once with 200 ml of water. The organic fraction was dried over potassium carbonate and the solvents were removed in vacuo to yield 0.967 grams of a viscous oil. The crude material was further purified by flash silica gel chromatography, eluting with a gradient of methylene chloride to a 1:1 methylene chloride:ethyl acetate mixture. The fractions containing the desired material were combined and concentrated under reduced pressure to yield 305 mg (26%) of the desired title product as a crystalline material.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][S:6][CH2:5][C:4]1=[O:9].I[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1>[Cu]Br.CN(C=O)C>[Cl:17][C:14]1[CH:15]=[C:16]([N:3]2[CH2:8][CH2:7][S:6][CH2:5][C:4]2=[O:9])[CH:11]=[CH:12][C:13]=1[Cl:18]
Reactant: O=C1CSCCN1
Reactant: Clc1ccc(I)cc1Cl
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CSCCN1c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 81 %

Procedure:
Under a nitrogen atmosphere in a flame-dried flask, sodium hydride (72 mg, 1.79 mmol, 60% oil dispersion) was washed with hexanes and then treated with 6 mL of anhydrous DMF, and cooled to 0° C. Thiomorpholin-3-one (200 mg, 1.71 mmol) was added in one portion with stirring. After gas evolution had stopped (ca. 30 min), 4-iodo-1,2-dichlorobenzene (700 mg, 2.56 mmol) was added, followed after 5 minutes by copper (I) bromide (490 mg, 3.42 mmol). After heating at 75° C. overnight, the mixture was partitioned between ethyl acetate and 1N lithium chloride, filtered through diatomaceous earth and combined with additional ethyl acetate washes of the diatomaceous earth filter cake. The organic layers were washed with additional 1N lithium chloride, brine (saturated sodium chloride) and dried over calcium sulfate (CaSO4). Concentration in vacuc gave 363 mg of light brown oil which was flash chromatographed (30-50% ethyl acetate in hexanes) to give a white solid, 108 mg.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([C:14](=O)[C:15]([OH:17])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19][O:20][CH:21]([S:29][CH3:30])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11](/[C:14](=[N:19]/[O:20][CH:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:29][CH3:30])/[C:15]([OH:17])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)O)ns1
Reactant: CSC(ON)C(=O)OC(C)(C)C
Solvent: CO
Product: CSC(O/N=C(\C(=O)O)c1nsc(NC(=O)OC(C)(C)C)n1)C(=O)OC(C)(C)C
Yield: 49.2 %

Procedure:
2-(5-Tert-butyloxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-oxoacetic acid (3.0 g) was dissolved in methanol (30 ml). To this solution a solution of tert-butyl 2-aminooxy-2-(methylthio)acetate (2.12 g) in methanol (20 ml) was added dropwise. The resultant mixture was stirred for 1 hr. at the room temperature, and then the solvent was evaporated to give (Z)-2-(5-tert-butyloxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-[[(tert-butoxycarbonyl)(methylthio)methoxy]imino]acetic acid (2.42 g).