Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH2:10][NH:11][C:12](=O)/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[C:17]([O:27][CH3:28])[CH:16]=2)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:35].C(OCC)(=O)C.O.C(=O)(O)[O-].[Na+]>C(O)(=O)C.C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[N:35]=[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]4)=[C:17]([O:27][CH3:28])[CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(/C=C/C(=O)NCC(=O)Cc2ccc(F)cc2)ccc1-n1cnc(C)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(/C=C/c2nc(Cc3ccc(F)cc3)c[nH]2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 31.7 %

Procedure:
A solution of (E)-N-[3-(4-fluorophenyl)-2-oxopropyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide (43 mg) and ammonium acetate (163 mg) in acetic acid (1 mL) and xylene (5 mL) was heated under reflux for 16 hours. The reaction solution was left to cool to room temperature. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: ethyl acetate->ethyl acetate:methanol=5:1) to obtain 13 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1.CS(C)=O.C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:1]=[CH:2][CH2:3][C:4]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCOC(CCO)(c2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCOC(CC=O)(c2ccccc2)C1
Reaction time: 2 h
Yield: 52.9 %

Procedure:
To a 0° C. solution of tert-butyl 2-(2-hydroxyethyl)-2-phenylmorpholine-4-carboxylate (428 mg, 1.4 mmol), dimethyl sulfoxide (4.0 mL, 56.4 mmol) and diisopropylethylamine (1.3 mL, 7.2 mmol) in 8 mL CH2Cl2 was added SO3.pyr (1.4 g, 8.8 mmol) and the reaction mixture was stirred for 2 h. After the addition of saturated aqueous NaHCO3, the solution was extracted with CHCl3, and passed through a plug of silica gel flushing with 2:1 hex:EtOAc to provide tert-butyl 2-(2-oxoethyl)-2-phenylmorpholine-4-carboxylate (226 mg, 53%) as a clear oil. 1H NMR (400 MHz, CDCl3), δ 9.60 (br. s, 1H), 7.54-7.44 (br., 2H), 7.42-7.37 (m, 2H), 7.30 (m, 1H), 4.25-4.01 (br., 1H), 3.80-3.23 (m, 5H), 3.00-2.81 (m, 2H), 2.73 (br., 1H), 1.47 (br., 9H); ESI-MS 328 (M+H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]1([S:29]([N:32]2[C:36]3=[N:37][CH:38]=[CH:39][CH:40]=[C:35]3[CH:34]=[C:33]2[CH:41]([OH:46])[CH2:42][CH:43]([CH3:45])[CH3:44])(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[C:23]1([S:29]([N:32]2[C:36]3=[N:37][CH:38]=[CH:39][CH:40]=[C:35]3[CH:34]=[C:33]2[C:41](=[O:46])[CH2:42][CH:43]([CH3:44])[CH3:45])(=[O:30])=[O:31])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)CC(O)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)CC(=O)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
A solution of Dess-Martin periodinane reagent (3.3 g, 7.8 mmol) in dichloromethane (50 mL) at 25° C. was treated with 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-butan-1-ol (1.4 g, 4.1 mmol). The reaction was stirred at 25° C. for 3 h. At this time, the reaction was quenched by the addition of a saturated aqueous sodium bicarbonate solution. The resulting solution was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (20% ethyl acetate/petroleum ether) afforded 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-butan-1-one as a white solid (1.2 g, 82.1%): 1H NMR (300 MHz, d6-DMSO): δ ppm 8.54 (d, 1H, J=4.5 Hz), 8.27 (d, 2H, J=7.8 Hz), 8.17 (d, 1H, J=7.8 Hz), 7.76-7.66 (m, 3H), 7.58 (s, 1H), 7.42-7.38 (m, 1H), 2.91 (d, 2H, J=6.9 Hz), 2.23-2.18 (m, 1H), 1.01 (s, 3H), 0.99 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9](O)[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([C:25]([NH2:27])=[O:26])=[CH:24][C:18]=4[N:17]=3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].N>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([C:25]([NH2:27])=[O:26])=[CH:24][C:18]=3[N:17]=2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(C(O)c2ccc(-c3nc4cc(C(N)=O)ccc4[nH]3)cc2)cc1C
Agent: N
Solvent: CO
Product: Cc1ccc(Cc2ccc(-c3nc4cc(C(N)=O)ccc4[nH]3)cc2)cc1C

Procedure:
The title compound was prepared as described in Example 35 from 2-{4-[(3,4-dimethyl-phenyl)-hydroxy-methyl]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide (Example 27, 14 mg, 0.03 mmol). Purification by chromatography (silica gel, 1% methanol saturated with ammonia/9% methanol/CH2Cl2) afforded 11.1 mg (83%) of the title, compound. TLC (silica, 1% methanol saturated with ammonia/9% methanol/CH2Cl2): Rf=0.39. HPLC (Method A): Rt=8.11. MS (ESI+): mass calculated for C23H21N3O, 855.2; m/z found, 356.1 [M+H]+. 1H NMR (500 MHz, CD3OD): δ 8.17 (s, 1H), 8.04 (d, J=8.2 Hz, 2H), 7.81 (br d, J=8.2 Hz, 1H), 7.63 (br s, 1H), 7.40 (d, J=8.2 Hz, 2H), 7.05 (d, J=7.71 Hz, 1H), 7.02 (s, 1H), 6.96 (d, J=7.6 Hz, 1H), 3.97 (s, 2H), 2.22 (d, J=4.1 Hz, 6H).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)[N:10]=[N:9][C:8]=1[C:23]([NH:25][CH:26]1[CH2:28][CH2:27]1)=[O:24])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[S-:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Na+]>C(O)C.C(OCC)(=O)C.CCCCCC>[CH:26]1([NH:25][C:23]([C:8]2[N:9]=[N:10][N:11]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:17]=3)[C:7]=2[CH2:6][S:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:24])[CH2:28][CH2:27]1
Reactant: [S-]c1ccccc1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CSc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
(4-[(Cyclopropylamino)carbonyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazol-5-yl)methyl methanesulfonate (310 mg, 0.761 mmol) obtained in Example 126a), potassium carbonate (52.6 mg, 0.380 mmol, 0.5 eq.) and sodium thiophenoxide (168 mg, 1.14 mmol, 1.5 eq.) were dissolved in ethanol (6.0 ml), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (30 ml) and hexane (2 ml), washed twice with 2% aqueous sodium carbonate solution and with saturated brine, dried over anhydrous sodium sulfate and concentrated. Diethyl ether was added and the precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (290 mg, 0.688 mmol, 90.4%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])=[CH:29][CH:28]=1)(C(C)(C)C)(C)C.[NH4+].[Cl-].CCOCC>C1COCC1>[Si:35]([O:34][CH2:33][C:30]1[CH:31]=[CH:32][C:27]([OH:26])=[CH:28][CH:29]=1)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(O)cc1
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
Tetrabutylammonium fluoride (1 M THF, 44 mL, 44 mmol) was added to a 0° C. solution of 1-(tert-butyldimethylsilyloxy)-4-((tert-butyldimethylsilyloxy)methyl)benzene (14 g, 40 mmol) in THF (400 mL). The reaction was stirred for 30 minutes, then poured into a mixture of saturated NH4Cl and Et2O. The layers were separated and the aqueous phase was extracted twice with Et2O. The organics were combined, washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was chromatographed (1:9 EtOAc/hexanes) to provide the product as a colorless oil (8.0 g, 85%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)=[CH:10][CH:11]=1.[CH3:19][S:20]SC.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:19][S:20][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)=[CH:10][CH:11]=1
Reactant: Brc1cccc(-c2ccc(Br)s2)c1
Reactant: CSSC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ccc(-c2cccc(Br)c2)s1
Reaction time: 0.17 h

Procedure:
A 2.5M solution of n-butyllithium (2.2 mL; 5.5. mM) was slowly added to a solution of 2-bromo-5-(3'-bromophenyl)thiophene (1.59 g; 5 mM) in 10 mL of tetrahydrofuran at -78° under nitrogen. The mixture was stirred 10 mins. and dimethyldisulfide (1.35 mL; 15 mM) was added slowly. This mixture was stirred overnight at R.T. after which 5 mL of sat'd. ammonium chloride and 15 mL of ethyl acetate were added. The organic phase was separated, washed with 2×5 mL of sat'd. sodium chloride, and dried over anhyd. magnesium sulfate. Solvent removal and purification on silica gel with hexane as solvent gave 2-methylthio-5-(3'-bromophenyl)thiophene as a colorless oil boiling at 142°-5°/0.5 mm.
Reaction SMILES: ClC(OC=C)=O.[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([CH:16]2[CH2:22][CH:21]3[N:23](C)[CH:18]([CH2:19][CH2:20]3)[CH2:17]2)=[N:8]1.C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([CH:16]2[CH2:22][CH:21]3[NH:23][CH:18]([CH2:19][CH2:20]3)[CH2:17]2)=[N:8]1
Reactant: CN1C2CCC1CC(c1nsc3ccccc13)C2
Agent: C=COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: c1ccc2c(C3CC4CCC(C3)N4)nsc2c1
Yield: 101 %

Procedure:
Vinyl chloroformate (4.4 g) was added dropwise to a solution of 3-(1,2-benzisothiazol-3-yl)-8-methyl-8-azabicyclo[3.2.1]octane (8.9 g) and potassium carbonate (4.76 g) in 250 ml of 1,2-dichloroethane. The resulting suspension was heated at reflux for 3 hours, and then the solution was cooled, and the solvent was removed in vacuo. The residue was suspended in isopropyl alcohol and acidified with HCl in isopropanol (to about a pH of 1), and the mixture was heated at reflux for 1 hour. The mixture was cooled, made basic, and then the product was extracted into dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated to provide 8.5 g of 3-(1,2-benzisothiazol-3-yl)-8-azabicyclo[3.2.1]octane which was used subsequently without purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:35][C:36]([OH:38])=[O:37])[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14](C1C=CC=CC=1)(=[O:16])=[O:15].[O:39]1[CH2:44][CH2:43][N:42](S(C2C=CC=CC=2C=O)(=O)=O)[CH2:41][CH2:40]1>>[CH3:1][C:2]1[N:3]([CH2:35][C:36]([OH:38])=[O:37])[C:4]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:5]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:42]1[CH2:43][CH2:44][O:39][CH2:40][CH2:41]1)(=[O:16])=[O:15]
Reactant: O=Cc1ccccc1S(=O)(=O)N1CCOCC1
Reactant: Cc1c(Cc2ccccc2S(=O)(=O)c2ccccc2)c(-c2ccccc2)c(-c2ccccc2)n1CC(=O)O
Product: Cc1c(Cc2ccccc2S(=O)(=O)N2CCOCC2)c(-c2ccccc2)c(-c2ccccc2)n1CC(=O)O

Procedure:
2-(2-methyl-3-(2-(morpholinosulfonyl)benzyl)-4,5-diphenyl-1H-pyrrol-1-yl)acetic acid was synthesized according to 2-(2-methyl-4,5-diphenyl-3-(2-(phenylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetic acid using 2-(morpholinosulfonyl)benzaldehyde in the general procedure X (step 1). 1H NMR (CDCl3/400 MHz) δ (ppm) 7.95 (d, 1H), 7.52 (t, 1H), 7.37-7.24 (m, 5H), 7.19-7.15 (m, 2H), 7.08-7.04 (m, 3H), 6.95-6.91 (m, 2H), 4.65 (s, 2H), 4.23 (s, 2H), 3.52 (t, 4H), 3.02 (t, 4H), 2.09 (s, 3H). MS m/z: 531.35 (M+1).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:50]1[CH2:55][CH2:54][CH:53]([CH2:56][NH2:57])[CH2:52][CH2:51]1.O>CN(C=O)C>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:57][CH2:56][CH:53]3[CH2:54][CH2:55][O:50][CH2:51][CH2:52]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: NCC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1-c1ccc(F)cc1
Yield: 58.8 %

Procedure:
A solution of 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid (60 mg, 0.17 mmol), HATU (76 mg, 0.20 mmol), DEIA (0.035 mL, 0.20 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (0.023 mL, 0.20 mmol) in DMF (1 mL) was stirred at room temperature for 1 day. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20→100% ethyl acetate/hexane0→5% methanol/ethyl acetate) to give the title compound (44 mg, 0.100 mmol, 60%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:30]([O:31][CH3:32])=[CH:29][C:6]2[CH2:7][C:8](=[O:28])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:27])[CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([NH2:25])=[C:20]([Cl:26])[CH:19]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[Se](=O)=[O:34]>>[CH3:1][O:2][C:3]1[C:30]([O:31][CH3:32])=[CH:29][C:6]2[C:7](=[O:34])[C:8](=[O:28])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:27])[CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([NH2:25])=[C:20]([Cl:26])[CH:19]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1cc(Cl)c(N)c(Cl)c1)CC2
Reactant: O=[Se]=O
Product: COc1cc2c(cc1OC)C(=O)C(=O)N(CCCN(C)CCc1cc(Cl)c(N)c(Cl)c1)CC2

Procedure:
This compound was prepared analogous to Example 5(b) from 1-[7,8dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl]-3-[N-methyl-N-(2-{4-amino-3,5-dichloro-phenyl}-ethyl)-amino]-propane and selenium dioxide.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9](Cl)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([N:26]3[CH2:25][CH2:24][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:28][CH2:27]3)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)C1CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)C3CC3)cc2[N+](=O)[O-])CC1
Yield: 98 %

Procedure:
Method 1 was followed using 4-chloro-3-nitrophenyl cyclopropyl ketone (1.0 eq), 1-Boc-piperazine (1.2 eq), and TEA (1.5 eq) at 55° C. for 48 hours yielding tert-butyl 4-(4-(cyclopropanecarbonyl)-2-nitrophenyl)piperazine-1-carboxylate (98%). LCMS (m/z): 376.1 (MH+); LC Rt=3.33 min.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.Br[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:18][O:17][C:15](=[O:16])[C:14]1[CH:19]=[CH:20][C:11]([CH2:10][C:2]2[N:3]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(Cc2nc3ccccc3[nH]2)cc1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(Cc2nc3ccccc3n2CCc2ccccc2)cc1
Temperature: 100 °C
Yield: 30 %

Procedure:
A solution of methyl 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoate (200 mg, 0.75 mmol) in acetonitrile was treated with (2-bromoethyl)benzene (209 mg, 1.13 mmol) and potassium carbonate (143 mg, 0.90 mmol). The reaction mixture was heated with microwave irradiation at 100° C. for 2 h. The solvent was removed under reduced pressure and the residue was partitioned between water and dichloromethane. The organic phase was separated, dried over sodium sulfate and concentrated in vacuo. Purification of the resultant residue by flash column chromatography (silica, petroleum ether:ethyl acetate 8:2 to 1:1) afforded 4-(1-phenethyl-1H-benzoimidazol-2-ylmethyl)-benzoic acid methyl ester (30%). [M+H] 371.2.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:15][CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C>[Si:18]([O:17][CH2:16][CH2:15][N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCN1CCc2ccc([N+](=O)[O-])cc2C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
7-Nitro-tetrahydroisoquinoline (5.0 g; 28.0 mmol) was dissolved in DMF (150 ml). This solution was treated with (2-bromoethoxy)-tert-butyl-dimethylsilane (12.0 ml; 56.0 mmol), and stirred at 80° C. overnight. The mixture was cooled to room temperature and the solvent removed in vacuo. Purification by column chromatography through SiO2, eluting with 50% diethyl ether/petroleum ether gave the title compound (4.2 g, 44%).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>O.C(O)C>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14](=[N:2][OH:3])[NH2:15]
Reactant: NO
Reactant: COc1ccccc1C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccccc1C(N)=NO
Reaction time: 1.5 h
Yield: 30.9 %

Procedure:
To a solution of hydroxylamine hydrochloride (245 g.) and sodium carbonate (170 g.) in water (2.6 l.) was added a solution of 2-methoxybenzonitrile (127.5 g.) in ethanol (1.25 l.), and the mixture refluxed with stirring for 1.5 hours. The solution was concentrated in vacuo to low bulk and the resultant oil crystallised on standing. The solid was filtered off, washed with water to remove inorganic salts, dried at 60° C., and recrystallised from benzene to give 2-methoxybenzamidoxime (49.2 g.), m.p. 117°-119° C. Further material (21.2 g., m.p. 119°-120° C.) was obtained by concentration of the recrystallisation mother liquor.
Reaction SMILES: [CH2:1]([N:3]([CH3:12])[C:4]1([CH2:10][NH2:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:2].[CH2:13]([O:17][C:18]1[C:26]([O:27][CH3:28])=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][C:19]=1[O:29][CH3:30])[CH2:14][CH2:15][CH3:16]>>[CH2:13]([O:17][C:18]1[C:19]([O:29][CH3:30])=[CH:20][C:21]([C:22]([NH:11][CH2:10][C:4]2([N:3]([CH2:1][CH3:2])[CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)=[O:23])=[CH:25][C:26]=1[O:27][CH3:28])[CH2:14][CH2:15][CH3:16]
Reactant: CCN(C)C1(CN)CCCCC1
Reactant: CCCCOc1c(OC)cc(C(=O)Cl)cc1OC
Product: CCCCOc1c(OC)cc(C(=O)NCC2(N(C)CC)CCCCC2)cc1OC

Procedure:
Synthesised from [1-(ethylmethylamino)cyclohexyl]methylamine and 4-butyloxy-3,5-dimethoxybenzoyl chloride V, following procedure described in Example 1 and purified by LCMS to obtain the product as a trifluoroacetate salt. 1H NMR (CDCl3) δ: 0.94 (t, 3H, J=4 Hz), 1.15 (m, 1H), 1.48 (m, 3H), 1.58 (t, 3H, J=4 Hz), 1.65 (m, 3H), 1.73 (m, 3H), 1.81 (m, 3H), 2.09 (d, 2H, J=4 Hz), 2.77 (d, 2H, J=2 Hz), 2.82 (m, 1H), 3.54 (m, 1H), 3.96 (s, 6H), 4.01 (t, 2H, J=4 Hz), 4.06 (m, 1H), 4.20 (dd, 1H, J=3 Hz), 7.57 (s, 2H), 9.05 (m, 1H), 11.62 (s, 1H). LCMS m/z 407.4 (MH+; 98.8%). HRMS (FAB) calc. 407.2898, found 407.2910.
Reaction SMILES: O.[Cl-].[NH4+].[N+:4]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])[CH:8]=1)([O-])=O>C(O)C.[Fe]>[NH2:4][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])[CH:8]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1N1CCOC1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(N)cc1N1CCOC1=O
Yield: 85.7 %

Procedure:
To a mixture of methyl 2-bromo-4-nitrobenzoate (2 g), oxazolidin-2-one (0.67 g), potassium carbonate (2.06 g), copper(I) iodide (0.73 g) and N,N′-dimethylethylenediamine (0.83 mL) was added toluene (16 mL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give methyl 4-nitro-2-(2-oxo-oxazolidin-3-yl)benzoate (960 mg). To a solution of ethanol (24 mL) and water (5 mL) were added ammonium chloride (0.11 g) and iron (0.79 g), and a solution of the obtained methyl 4-nitro-2-(2-oxooxazolidin-3-yl)benzoate (960 mg) in ethanol (19 mL) was added while stirring at 60° C.-70° C. After completion of the reaction, the insoluble material was collected by filtration, and the filtrate was concentrated. To the obtained residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer to give methyl 4-amino-2-(2-oxooxazolidin-3-yl)benzoate (730 mg). Using the obtained methyl 4-amino-2-(2-oxooxazolidin-3-yl)benzoate (730 mg) and 3-chloropropane-1-sulfonyl chloride (0.49 mL) and by the reaction and treatment in the same manner as in Preparation Example 17, the title compound (495 mg) was obtained.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.Cl.[CH3:14]OC(OC)(C)C>>[Br:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH3:14])=[O:11])=[CH:7][CH:8]=1
Reactant: COC(C)(C)OC
Reactant: O=C(O)Cc1ccc(CBr)cc1
Agent: Cl
Product: COC(=O)Cc1ccc(CBr)cc1

Procedure:
5 g (22 mmol) of 2-(4-bromomethyl-phenyl)-acetic acid are stirred at room temperature overnight in 50 ml of 2,2-dimethoxypropane with addition of 2 ml of aqueous conc. hydrochloric acid. After concentration, methanol is added twice in each case, the mixture is concentrated again and the residue is then dried in vacuo.