Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]Br)(=[O:27])=[O:26])[CH2:23][CH2:22]1>C(N(C(C)C)C(C)C)C>[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:14][CH2:13]2)(=[O:27])=[O:26])[CH2:23][CH2:22]1
Reactant: O=S(=O)(CCCCCCCCCCCCBr)NC1CC1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCCCCCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1)NC1CC1
Yield: 98.4 %

Procedure:
1-[(4-Chlorophenyl)phenylmethyl]piperazine (629.0 mg, 2.20 mmol) and N-cyclopropyl-12-bromododecanesulfonamide (891.0 mg, 2.42 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 4 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform, to give N-cyclopropyl-12-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]dodecanesulfonamide (1243.0 mg) as a pale brown oil (yield based on 1-[(4-chlorophenyl)phenylmethyl]piperazine: 98.4%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C(#N)C>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: C1CNCCN1
Solvent: CC#N
Product: FC(F)(F)c1cccc(N2CCNCC2)n1
Yield: 81.4 %

Procedure:
54.4 g of 2-chloro-6-trifluoromethyl pyridine are dissolved into a mixture of 350 ml of acetonitrile and 77.4 g of anhydrous piperazine. The mixture is filtered and washed with acetonitrile. The solvent is evaporated. The residue is taken up with dichloromethane and washed with water. The solution is dried over magnesium sulfate. The solvent is evaporated and the residue distilled, to obtain 56.4 g of 1-[6-(trifluoromethyl)-2-pyridinyl]piperazine (81.4% yield), having a boiling point of 103° C. at 0.05 mm Hg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([Cl:19])=[CH:11][C:10]=1[CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>N1C=CC=CC=1>[CH3:35][C:25]1[CH:30]=[CH:29][C:28]([S:31]([O:23][CH2:22][CH:21]([OH:24])[CH2:20][C:10]2[CH:11]=[C:12]([Cl:19])[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC(O)Cc1cc(Cl)c2ccccc2c1OCc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(O)Cc2cc(Cl)c3ccccc3c2OCc2ccccc2)cc1
Yield: 80.2 %

Procedure:
Treatment of (±)-3-[1-(benzyloxy)-4-chloro-2-naphthyl]propane-1,2-diol (24 g, 0.07 mol) with p-toluenesulfonyl chloride (14 g, 0.074 mol) in pyridine (600 mL) generally according to the procedure described for Intermediate 18 gave 27.9 g (80%) of (±)-3-[1-(benzyloxy)-4-chloro-2-naphthyl]-2-hydroxypropyl 4-methylbenzenesulfonate as a white solid. mp 85-87° C.; Anal. calcd. for C27H25ClO5S: C, 65.25; H, 5.07. Found: C, 65.37; H, 4.97.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[CH:5]=[C:4]([N:13]([C:15]2[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)[CH3:14])[N:3]=1>C(O)(=O)C.[Zn]>[F:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[C:4]([N:13]([C:15]3[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=3)[CH3:14])[N:3]=[CH:2]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccc(F)cc3c(Cl)n2)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccc(F)cc3cn2)cc1
Yield: 60.1 %

Procedure:
Zinc powder (4×1.63 g) was added portionwise over a 2 hr period to a stirred solution of ethyl 2-{4-[N-(1-chloro-7-fluoroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (1.00 g) in acetic acid (50 ml). The mixture was filtered and the filter cake was washed with acetic acid. After the filtrate was evaporated the residue was partitioned between methylene chloride and water. The organic extract was washed successively with, aqueous sodium bicarbonate solution, water, aqueous ethylenediaminetetraacetic acid solution (5%) and water, then dried (MgSO4) and evaporated to give a green oil. Purification by column chromatography over silica gel (eluant dichloromethane) gave ethyl 2-[4-[N-(7-fluoroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (0.55 g) as a greenish oil. The assigned structure was confirmed by proton magnetic spectroscopy and mass spectrometry. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 1.28 (3H, t); 1.64 (3H, d); 3.48 (3H, s); 4.25 (2H, q); 4.74 (1H, q); 6.62 (1H; s); 6.87-7.37 (7H, m); 8.85 (1H, s).
Reaction SMILES: C(=[C:8]1/[CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([Br:18])[CH:15]=[N:16][C:17]/1=2)/C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[OH:39]>C(Cl)Cl>[Br:18][C:14]1[CH:15]=[N:16][C:17]2[C:8](=[O:39])[CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1
Reactant: CO
Reactant: Brc1cnc2c(c1)CCC/C2=C\c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1CCCc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
A solution of (E)-8-benzylidene-3-bromo-5,6,7,8-tetrahydroquinoline (0.82 g, 2.5:1 mixture with benzaldehyde) in MeOH (40 mL) and DCM (40 mL) was cooled to −78° C. and ozone was bubbled through the solution for 5 min until the solution turned light blue. Oxygen was passed through the solution for 10 min until the solution turned colorless and triphenylphosphine (1.03 g, 3.93 mmol) was added. The solution was removed from the dry ice/acetone bath and allowed to warm to RT. The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated. Purification by flash column chromatography on silica gel eluting with 30% to 70% EtOAc in heptane) gave 3-bromo-6,7-dihydroquinolin-8(5H)-one (0.460 g, 2.04 mmol, 75% yield) as a white solid. LC/MS (ESI+) m/z=225.9 (M+H). Calculated for C9H8BrNO 225.0.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11](=[O:16])[NH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.N1C=CC=CC=1.[CH2:32]([O:34][C:35]([CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)=[O:36])[CH3:33]>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:32]([O:34][C:35](=[O:36])[CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([N:12]2[CH:13]=[CH:14][CH:15]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[C:11]2=[O:16])=[CH:41][CH:40]=1)[CH3:33]
Reactant: O=c1[nH]cccc1-c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CCc1ccc(-n2cccc(-c3ccc([N+](=O)[O-])cc3)c2=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-(4-Nitrophenyl)-1H-pyridin-2-one (P3) (0.2 g, 0.92 mmol), copper (II) acetate (0.334 g, 2 equiv.), diisopropylethylamine (0.31 mL, 2 equiv.), and pyridine (0.15 mL, 2 equiv.) were added to a stirred solution of 4-(2-ethoxycarbonylethyl)phenyl boronic acid (0.308 g, 1.3 mmol) in dichloromethane (10 mL). The reaction mixture was then stirred under argon at room temperature for 4 hours. The solution was then filtered through celite, concentrated and purified by chromatography on silica gel (50% v/v ethyl acetate in hexane) to afford the title compound as an oil.
Reaction SMILES: [CH2:1]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH2:12][NH:13][CH3:14])[CH3:2].[O:15]=[C:16]1[NH:25][C:24]2[N:23]=[CH:22][C:21](/[CH:26]=[CH:27]/[C:28]([OH:30])=O)=[CH:20][C:19]=2[CH2:18][CH2:17]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH2:1]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH2:12][N:13]([CH3:14])[C:28](=[O:30])/[CH:27]=[CH:26]/[C:21]1[CH:22]=[N:23][C:24]2[NH:25][C:16](=[O:15])[CH2:17][CH2:18][C:19]=2[CH:20]=1)[CH3:2]
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CCc1c(CNC)oc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)oc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
To a solution of (3-ethylbenzofuran-2-yl)-N-methylmethanamine (89 mg, 0.49 mmol) in DMF (5 mL) were added in sequential order (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid (111 mg, 0.44 mmol), 1-hydroxybenzotriazole (68 mg, 0.49 mmol), diisopropylethylamine (232 uL, 1.34 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (98 mg, 0.49 mmol). The mixture was stirred at room temperature overnight, cooled in an ice bath and water added with rapid stirring. The product precipitated and was filtered, triturated with ether and dried to yield title compound as a pale brown solid (134 mg, 70%): 1H NMR (300 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.37 (s, 1H), 8.09 (s, 1H), 7.96 (s, 1H), 7.18-7.64 (m, 5H), 4.81-5.01 (rotamers, 2s, 2H), 3.27-3.61 (m, 2H), 2.90 (d, J=9.0 Hz, 2H), 2.73-2.78 (m, 2H), 2.51-2.59 (m, 3H), 1.23 (t, J=9.0 Hz, 3H); MS (ESI) m/e 390 (C23H23N3O3+H)+.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH2:6](O)C.[O:9]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12](=[O:13])[CH:11]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[O:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][C:25]3=[O:36])[CH:10]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CC(C)=O>[O:9]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12](=[O:13])[CH:11]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[O:28][CH:27]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:26][C:25]3=[O:36])[CH:10]1[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1.[CH3:2][C:1]1([CH3:6])[O:4][O:3]1
Reactant: CCO
Reactant: CC(=O)[O-]
Agent: O=C1CC(c2ccccc2)Oc2c1cccc2C1C(=O)c2ccccc2OC1c1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(C)OO1

Procedure:
Donnelly and co-workers (Donnelly, D. M. X.; Fitzpatrick, B. M.; Ryan, S. M.; Finet, J.-P. J. Chem. Soc., Perkin Trans. I 1994, 1794-1801) synthesized the biflavonoids (46) and (47) via arylation of a 3-phenylsulfanylflavanone (48) with an 8-triacetoxyplumbylflavan derivative (49) (2:1 mixture of cis and trans). The dioxolane ring, of the intermediate (50) was cleaved during acid workup. Desulfurization of the intermediate (50) with nickel boride (NaBH4/H2O, NiCl26H2O/EtOH) yielded a chalcone (51) (in a 1.1:1 ratio of E/Z) that was cyclised with anhydrous sodium acetate in refluxing ethanol to the 3,8-biflavanone (46) in 73% yield (only the 2,3-trans isomer was isolated from a mixture of diastereoisomers with an α/β ratio of 1.4:1). Oxidation of (46) with dimethyldioxirane in acetone yielded (47) in 47% yield (Scheme 3). The end products are however not optically active and constitute a racemic mixture.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[NH4+].[Cl-]>CN(C=O)C>[N:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: BrCCCCCBr
Reactant: N#CCc1ccncc1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: N#CC1(c2ccncc2)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3 g of 4-pyridylacetonitrile hydrochloride in 50 ml of DMF is cooled to 0° C., 2.6 g of 60% sodium hydride in oil are added portionwise and the mixture is left stirring at RT for 1 hour 30 minutes. The reaction mixture is cooled on an ice bath, 2.7 ml of 1,5-dibromopentane are added dropwise and this mixture is left stirring at RT for 48 hours. The reaction mixture is poured into saturated NH4Cl solution and extracted with ether, the organic phase is washed three times with water and dried over MgSO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H gel, eluting with DCM and then with a DCM/MeOH mixture (98/2; v/v). 2.5 g of the expected product are obtained; m.p.=79° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=1
Reactant: COC(=O)c1ccc(C)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1F
Yield: 70.3 %

Procedure:
To a mixture of methyl 2-fluoro-4-methylbenzoate (0.655 g; 3.89 mmol) in carbon tetrachloride (30 mL) was added N-bromosuccinimide (0.840 g; 4.67 mmol) and benzoyl peroxide (0.097 g; 0.390 mmol). The mixture was refluxed for 18 hours and the resulting suspension was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent 1 to 12% ethyl acetate in heptane) to give 0.676 g (70%) of methyl 4-(bromomethyl)-2-fluorobenzoate as a solid which was directly used in the next step.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:46][CH3:47])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][N:21]([CH2:34][C:35]2[CH:36]=[C:37]([OH:45])[CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=2)[C:22]2[N:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:24][N:23]=2)[CH:9]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:55][CH2:56][CH2:57][C:58]([O:60][CH2:61][CH3:62])=[O:59]>CN(C)C=O.[Cl-].[Na+].O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:46][CH3:47])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][N:21]([CH2:34][C:35]2[CH:36]=[C:37]([CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:40]=2)[O:45][CH2:55][CH2:56][CH2:57][C:58]([O:60][CH2:61][CH3:62])=[O:59])[C:22]2[N:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:24][N:23]=2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCCBr
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(O)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cc(CN(Cc2cc(C(F)(F)F)ccc2-c2cc(C(C)C)ccc2OC)c2ncc(N3CCOCC3)cn2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-{[(5′-Isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-5-trifluoromethyl-phenol (95 mg) is dissolved in N,N-dimethylformamide (1 ml), and thereto are added potassium carbonate (90 mg) and ethyl 4-bromobutyrate (93 μl) and the mixture is stirred at room temperature for 4 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=10:1→4:1) to give ethyl 4-(3-{[(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-5-trifluoromethyl-phenoxy)butyrate (92 mg). MS (m/z): 775 [M+H]+
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[S:3]([CH2:6][C:7](OC)=[O:8])(=[O:5])=[O:4].[NH2:19][OH:20]>>[OH:20][NH:19][C:7](=[O:8])[CH2:6][S:3]([N:2]([CH3:1])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:5])=[O:4]
Reactant: COC(=O)CS(=O)(=O)N(C)CCc1ccccc1
Reactant: NO
Product: CN(CCc1ccccc1)S(=O)(=O)CC(=O)NO

Procedure:
In a manner similar to Example 1 (b), methyl 2-[methyl(phenethyl)amino]sulfonyl-acetate was reacted with hydroxylamine to give the title compound as a colourless solid.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>ClCCl.CN(C1C=CN=CC=1)C>[CH3:35][O:36][C:37]1[CH:38]=[CH:39][C:40]([S:43]([N:23]2[CH2:24][CH2:25][CH:20]([C:11]3[C:10]4[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH:9]=4)[NH:13][N:12]=3)[CH2:21][CH2:22]2)(=[O:45])=[O:44])=[CH:41][CH:42]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCC(c3n[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)cc1
Reaction time: 12 h
Yield: 49.4 %

Procedure:
The crude 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (21.1 mg, 0.066 mmol) (Example 2) was suspended in dichloromethane (8 mL) and treated with diisopropylethyl amine (46 uL, 0.264 mmols), DMAP (8 mg, 0.065 mmol), and 4-(methyloxy)benzenesulfonyl chloride (21 mg, 0.1 mmols) at 0° C. After 12 hrs, the mixture was concentrated to dryness in vacuo at ambient temperature, treated with water (10 mL), and extracted with ethyl acetate (3×25 mL). The organic phase was washed with water, dried over MgSO4, filtered, and concentrated to give a light brown solid. This was purified via preparative HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (16 mg, 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8]/[C:9]/2=[CH:12]\[CH2:13][NH:14][C:15](=[O:17])[CH3:16])=[CH:5][CH:4]=1>FC(F)(F)C(O)=O.O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6](=[CH:5][CH:4]=1)[CH2:7][CH:8]=[C:9]2[CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16]
Reactant: COc1ccc2c(c1)/C(=C/CNC(C)=O)CC2
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(CCNC(C)=O)=CC2
Yield: 90.1 %

Procedure:
The (E)-N-[2-(6-methoxyindan-1-ylidene)ethyl]-acetamide (1.0 g, 4.32 mmol) thus obtained was dissolved in trifluoroacetic acid(6 ml)-tetrahydrofuran(6 ml) and the solution was refluxed for 1.5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed serially with saturated saline and water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-methanol=96:4) to provide the title compound (yield 0.9 g, 90%).
Reaction SMILES: C(N1CC[O:6][CH2:5][CH2:4]1)C.C(OC(=O)C)(=O)C.[CH2:16]([O:23][C:24](=[O:68])[C@H:25]([CH2:64][CH:65]([CH3:67])[CH3:66])[NH:26][C:27](=[O:63])[C@H:28]([C:59]([CH3:62])([CH3:61])[CH3:60])[NH:29][C:30](=[O:58])[C@H:31]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[CH3:57])[NH:32][C:33](=[O:49])[C@@H:34]([CH:46]([CH3:48])[CH3:47])[NH:35][C:36](=[O:45])[C@H:37]([CH2:39][O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[NH2:38])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[CH2:16]([O:23][C:24](=[O:68])[C@H:25]([CH2:64][CH:65]([CH3:67])[CH3:66])[NH:26][C:27](=[O:63])[C@H:28]([C:59]([CH3:62])([CH3:61])[CH3:60])[NH:29][C:30](=[O:58])[C@H:31]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[CH3:57])[NH:32][C:33](=[O:49])[C@@H:34]([CH:46]([CH3:47])[CH3:48])[NH:35][C:36](=[O:45])[C@H:37]([CH2:39][O:40][C:41]([CH3:42])([CH3:44])[CH3:43])[NH:38][C:5](=[O:6])[CH3:4])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1ccccc1C[C@H](NC(=O)[C@H](NC(=O)[C@@H](N)COC(C)(C)C)C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)C(C)(C)C
Reactant: CCN1CCOCC1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](C(=O)N[C@@H](Cc1ccccc1C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)C(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.5 ml of N-ethylmorpholine and 0.37 ml of acetic anhydride were added in sequence to a solution of 1.95 g of N-[N-[N-[N-(O-tert-butyl-L-seryl)-D-valyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester in 70 ml of anhydrous dichloromethane. The mixture was stirred at room temperature for 1 hour and was then washed in sequence with 5% aqueous citric acid solution, saturated aqueous sodium bicarbonate solution and saturated brine. The organic phase was dried over anhydrous magnesium sulphate and evaporated. Chromatography of the residue on silica using 5% methanol in dichloromethane for the elution gave afforded 1.45 g of N-[N-[N-[N-(N-acetyl-O-tert-butyl-L-seryl)-D-valyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester; MS: m/e 780.6 [M+H]+.
Reaction SMILES: C1C2C=CC=C(C([O:13][CH2:14][CH2:15][C@@H:16]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=3)[CH2:17][N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[C:23]([C:25]3[C:26]4[CH2:27][CH2:28][CH2:29][CH2:30][C:31]=4[CH:32]=[CH:33][CH:34]=3)=[O:24])=O)C=2CCC1.[OH-].[Na+]>CO>[Cl:42][C:37]1[CH:36]=[C:35]([C@@H:16]([CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[C:19]2[C:23]([C:25]2[C:26]3[CH2:27][CH2:28][CH2:29][CH2:30][C:31]=3[CH:32]=[CH:33][CH:34]=2)=[O:24])[CH2:15][CH2:14][OH:13])[CH:40]=[CH:39][C:38]=1[Cl:41]
Reactant: O=C(OCC[C@H](Cn1ccnc1C(=O)c1cccc2c1CCCC2)c1ccc(Cl)c(Cl)c1)c1cccc2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(c1cccc2c1CCCC2)c1nccn1C[C@@H](CCO)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
3(S)-(3,4-Dichlorophenyl)-4-[2-(1,2,3,4-tetrahydro-5-naphthoyl)imidazol-1-yl]butyl 1,2,3,4-tetrahydro-5-naphthoate (1.38 g) (see Preparation 101) was dissolved in methanol (40 ml), 1N aqueous sodium hydroxide solution (5 ml) added and the resulting mixture stirred at room temperature overnight. The methanol was then removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase was separated, washed sequentially with saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give 3(S)-(3,4-dichlorophenyl)-4-[2-(1,2,3,4-tetrahydro-5-naphthoyl)imidazol-1-yl]butan-1-ol (0.82 g) as a gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]([C:14]([O:16]C)=[O:15])[CH2:11][CH2:10][N:9]2[C:18]([O:20][CH3:21])=[O:19])=[CH:4][CH:3]=1.[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>C(#N)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11][CH2:10][N:9]2[C:18]([O:20][CH3:21])=[O:19])=[CH:4][CH:3]=1
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2ccc(F)cc2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: COC(C)(C)C
Product: COC(=O)N1CCC(C(=O)O)CC1c1ccc(F)cc1
Yield: 98.3 %

Procedure:
Dimethyl 2-(4-fluorophenyl)piperidine-1,4-dicarboxylate (8.97 g, 30.38 mmol) was dissolved in acetonitrile (60 mL) and water (1.200 mL), then lithium bromide (21.10 g, 243.00 mmol) was added. Triethylamine (16.84 mL, 121.50 mmol) was added and the resulting brown suspension was heated under reflux for 1 h. Water (120 mL) and MTBE (120 mL) were added. The organic phase was extracted with water (2×25 mL). The pooled aqueous layer was acidified to pH 1 with 6 M HCl and extracted with MTBE (2×150 mL). The combined organic layer was washed with water (25 mL), dried over anhydrous Na2SO4 and evaporated. 2-(4-Fluorophenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (8.4 g, 98%) was isolated as a brown oil.