Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]([C:28](=[O:39])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=2)[CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21](OCCCC)=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].[NH2:42][C:43]1[NH:47][N:46]=[N:45][N:44]=1>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]([C:28](=[O:39])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=2)[CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([NH:42][C:43]4[NH:47][N:46]=[N:45][N:44]=4)=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1nnn[nH]1
Reactant: CCCCOC(=O)c1ccc2c(c1)CCC2N(C(=O)Cc1ccc(C(C)C)cc1)[C@H]1CC[C@H](C(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)c1ccc(CC(=O)N(C2CCc3cc(C(=O)Nc4nnn[nH]4)ccc32)[C@H]2CC[C@H](C(C)(C)C)CC2)cc1

Procedure:
Enantiomer A of butyl 1-{(trans-4-tert-butylcyclohexyl)[(4-isopropylphenyl)acetyl]amino}indane-5-carboxylate (36 mg) was saponified with aqueous LiOH and then coupled to 5-amino tetrazole following the procedure described (Step D., Example 1/2) to give 1-{(Trans-4-tert-butylcyclohexyl)[(4-isopropylphenyl)acetyl]amino}-N-1H-tetrazol-5-ylindane-5-carboxamide. HPLC/MS: m/z=543.5 (M+1), Rt=2.67 min. 1H NMR (DMSO-d6): δ 12.30 (1H, br s), 7.90 (1H, s), 7.85 (1H, d, J=8.0 Hz), 7.17 (2H, d, J=8.0 Hz), 7.10 (2H, d, J=8.0 Hz), 7.03 (1H, d, J=8.0 Hz), 4.79 (1H, m), 3.74 (2H, m), 3.06 (1H, m), 2.88 (1H, m), 2.36 (1H, m), 2.21 (1H, m), 1.74 (2H, m), 1.54 (2H, m), 1.36-0.86 (13H, m), 0.84 (9H, s).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19]([C:21]2[N:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23]([OH:25])=O)=[O:20])=[N:2]1.N1C2C(=CC=CC=2)C(/C=C/C2C=CC=CC=2NC(C2C(C(O)=O)=NC=CC=2)=O)=N1.O.ON1C2C=CC=CC=2N=N1.C(Cl)CCl>C1COCC1.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[C:23](=[O:25])[C:22]3[C:21](=[N:29][CH:28]=[CH:27][CH:26]=3)[C:19]2=[O:20])=[N:2]1
Reactant: O=C(O)c1cccnc1C(=O)Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Agent: O=C(Nc1ccccc1/C=C/c1n[nH]c2ccccc12)c1cccnc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2cccnc2C(=O)N1c1ccccc1/C=C/c1n[nH]c2ccccc12
Yield: 38 %

Procedure:
To a solution of (E)-2-{2-[2-(1H-indazol-3-yl)vinyl]phenylcarbamoyl}nicotinic acid or (E)-3-{2-[2-(1H-indazol-3-yl)vinyl]phenylcarbamoyl}pyridine-2-carboxylic acid (20 mg, 0.052 mmol) obtained in Step 1 in THF (1.0 mL), 1-hydroxybenzotriazole monohydrate (1.6 mg, 0.010 mmol) and EDC (15 mg, 0.078 mmol) were added, followed by heating under reflux for 30 minutes. The reaction mixture was added with water, extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform to chloroform/methanol=90/10), crystallized from DMF/water (1/1) to obtain Compound 205 (7.2 mg, 38%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([NH:16][C:17]([C:19]1[C:20]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18])[CH:10]=2)=[O:5])C.[OH-].[Na+]>CO.C1COCC1>[F:34][C:31]([F:32])([F:33])[C:28]1[CH:27]=[CH:26][C:25]([C:20]2[C:19]([C:17]([NH:16][C:11]3[CH:10]=[C:9]4[C:14]([CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]4)=[CH:13][CH:12]=3)=[O:18])=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.7 %

Procedure:
To a solution of 7-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid ethyl ester (8.45 9, 18.2 mmol, 1 equiv) in MeOH (85 mL) and THF (85 mL) was added 1 N NaOH (91 mL, 91 mmol, 5 equiv). The solution was stirred at room temperature for 4 hours. The organic layer was removed in vacuo and the aqueous layer was washed with EtOAc (100 mL). The aqueous layer was then acidified to a pH of about 4 with concentrated HCl and a precipitate formed. The mixture was stirred for 48 hours and the solids collected by filtration to provide 7-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (4.5 g, 57% over two steps) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[C:11]([CH3:19])[N:12]=[C:13]([CH3:18])[CH:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].[Br:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Br)[N:28]=1>CN(C)C=O>[Br:26][C:27]1[N:28]=[C:29]([CH2:33][N:9]2[C:10]3[C:15](=[CH:14][C:13]([CH3:18])=[N:12][C:11]=3[CH3:19])[C:16](=[O:17])[C:7]([C:5](=[O:6])[C:4]3[CH:20]=[CH:21][C:22]([CH3:23])=[C:2]([CH3:1])[CH:3]=3)=[CH:8]2)[CH:30]=[CH:31][CH:32]=1
Reactant: BrCc1cccc(Br)n1
Reactant: Cc1cc2c(=O)c(C(=O)c3ccc(C)c(C)c3)c[nH]c2c(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(=O)c(C(=O)c3ccc(C)c(C)c3)cn(Cc3cccc(Br)n3)c2c(C)n1
Yield: 12.1 %

Procedure:
Experimental conditions analogous to described for Step 3 of Example 1 were used with 42 mg (0.137 mmol) of 3-(3,4-Dimethyl-benzoyl)-6,8-dimethyl-1H-[1,7]naphthyridin-4-one, 6 mg (0.165 mmol, 60% dispersion in oil) of sodium hydride, 41.3 mg (0.165 mmol) of 2-bromo-6-bromomethyl-pyridine and 1.5 mL of N,N-dimethylformamide. The crude brown solid was purified by flash column chromatography using 30-100% ethyl acetate in hexane to yield 7.9 mg of 1-(6-Bromo-pyridin-2-ylmethyl)-3-(3,4-dimethyl-benzoyl)-6,8-dimethyl-1H-[1,7]naphthyridin-4-one as an off white solid. LC-MSD, m/z for C25H22BrN3O2 [M+H]: 477.37 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.9 min
Reaction SMILES: C([Li])CCC.[CH2:6]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)=[N:17][CH:18]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[B:26](OC)([O:29]C)[O:27]C>C1COCC1>[CH2:6]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([B:26]([OH:29])[OH:27])=[CH:21][CH:20]=2)=[N:17][CH:18]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCc1ccc(-c2ccc(Br)cc2)nc1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCc1ccc(-c2ccc(B(O)O)cc2)nc1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
9 ml of n-butyl lithium (1.68M hexane solution) was added dropwise to a solution of 5 g of 5-heptyl-2-(4-bromophenyl) pyridine prepared by the method described in Toku-Kai-Sho 60-163864 in 100 ml of THF with maintaining at -60° C. After stirring for 30 minutes with maintaining at -60° C., 3 g of trimethyl borate was added and stirred for further 1 hour. After the inner temperature was recovered gradually to the room temperature, 40 ml of 6N hydrochloric acid was added and then THF was distilled off. The formed solid was filtered and recrystallized, to obtain 3 g of 4-(5-heptylpyridin-2-yl)phenyl boronic acid. Melting point; 206-214° C.
Reaction SMILES: [CH3:1][CH2:2][O-].[Na+].CC[OH:7].CN1C(C)C(C2C=CC=CC=2)N([C:21](=[O:39])[CH2:22][C@@H:23]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)C1=O>C1COCC1>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][C@H:23]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH2:22][C:21]([O:39][CH2:1][CH3:2])=[O:7])=[CH:30][CH:29]=1
Reactant: CCO
Reactant: COc1ccc(C[C@@H](CC(=O)N2C(=O)N(C)C(C)C2c2ccccc2)c2cccnc2)cc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C[C@H](Cc1ccc(OC)cc1)c1cccnc1
Reaction time: 1 h
Yield: 71 %

Procedure:
A solution of 21% NaOEt in EtOH (18.4 mL, 56.88 mmole) was added to a solution of (4 R, 5 S)-3,4-dimethyl-1-[(S)-4-(4-methoxyphenyl)-3-(pyridin-3-yl)butanoyl]-5-phenylimidazolidin-2-one (19.408 g, 43.8 mmole) in THF (200 mL) at 0° C. The reaction was stirred for 1 hr, then was quenched with saturated NH4Cl and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4) and concentrated. The residue was taken up in 1:1 EtOAc/hexanes and filtered, and the filtrate was filtered through a plug of silica gel (1:1 EtOAc/hexanes). The filtrate was concentrated to afford the title compound (9.25 g, 71%) as an orange oil: 1H NMR (400 MHz, CDCl3) δ 8.57 (br s, 2 H), 7.44 (narrow m, 1 H), 7.17-7.25 (m, 1 H), 6.95 (d, J=8.6 Hz, 2 H), 6.76 (d, J=8.6 Hz, 2 H), 4.01 (q, J=7.1 Hz. 2 H), 3.75 (s, 3 H), 3.33-3.48 (m, 1 H), 2.91 (dd, J=13.7, 7.3 Hz, 1H), 2.85 (dd, J=13.7, 7.8 Hz, 1 H), 2.71 (dd, J=15.6, 6.5 Hz, 1 H), 2.61 (dd, J=15.6, 8.7 Hz, 1 H), 1.13 (t, J=7.1 Hz, 3 H); MS (ES) m/e 300 (M+H)+.
Reaction SMILES: [N:1]1[N:2]([C:6]2[N:11]=[C:10]([NH:12][C:13]3[CH:18]=[C:17](Cl)[N:16]=[N:15][C:14]=3[C:20]([NH2:22])=[O:21])[CH:9]=[CH:8][CH:7]=2)[N:3]=[CH:4][CH:5]=1.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]>CN1C(=O)CCC1.C(OCC)(=O)C.[Cl-].[Na+].O>[N:1]1[N:2]([C:6]2[N:11]=[C:10]([NH:12][C:13]3[CH:18]=[C:17]([NH:23][C@@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]4[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[N:16]=[N:15][C:14]=3[C:20](=[O:21])[NH2:22])[CH:9]=[CH:8][CH:7]=2)[N:3]=[CH:4][CH:5]=1
Reactant: NC(=O)c1nnc(Cl)cc1Nc1cccc(-n2nccn2)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cccc(-n3nccn3)n2)c(C(N)=O)nn1
Temperature: 140 °C
Yield: 56.3 %

Procedure:
To a solution of 4-(6-(2H-1,2,3-triazol-2-yl)pyridin-2-ylamino)-6-chloropyridazine-3-carboxamide (90 mg, 284 μmol) in NMP (947 μL) was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (122 mg, 568 μmol) and the mixture heated to 140° C. for 16 h. Additional tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (61 mg, 284 μmol) was added and the mixture heated for a further 16 h. The reaction mixture was cooled, diluted with ethyl acetate and brine, then the phases were separated and the organic phase collected and washed with brine (2×). The organic layer was concentrated in vacuo then purified by chromatography (silica, 2-5% methanol in dichloromethane) to give a residue that was triturated with ethyl acetate, filtered, and washed with ether to give tert-butyl (1S,2R)-2-(5-(6-(2H-1,2,3-triazol-2-yl)pyridin-2-ylamino)-6-carbamoylpyridazin-3-ylamino)cyclohexylcarbamate (79 mg, 160 μmol, 56%) as a brown solid. MS (EI/CI) m/z: 495.1 [M+H].
Reaction SMILES: [Na].[C:2]([C:5]1[C:6]([CH3:29])=[C:7]([CH:13]2[CH2:18][C:17](=[O:19])[C:16]([C:20](=[N:24][O:25][CH2:26][CH3:27])[CH2:21][CH2:22][CH3:23])=[C:15]([OH:28])[CH2:14]2)[C:8]([CH3:12])=[CH:9][C:10]=1[CH3:11])(=[O:4])[CH3:3].[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>CC(C)=O>[C:2]([C:5]1[C:6]([CH3:29])=[C:7]([CH:13]2[CH2:14][C:15](=[O:28])[C:16]([C:20](=[N:24][O:25][CH2:26][CH3:27])[CH2:21][CH2:22][CH3:23])=[C:17]([O:19][S:36]([C:33]3[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=3)(=[O:38])=[O:37])[CH2:18]2)[C:8]([CH3:12])=[CH:9][C:10]=1[CH3:11])(=[O:4])[CH3:3]
Reactant: CCCC(=NOCC)C1=C(O)CC(c2c(C)cc(C)c(C(C)=O)c2C)CC1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na]
Solvent: CC(C)=O
Product: CCCC(=NOCC)C1=C(OS(=O)(=O)c2ccc(C)cc2)CC(c2c(C)cc(C)c(C(C)=O)c2C)CC1=O
Reaction time: 0.25 h
Yield: 92.6 %

Procedure:
The sodium salt of 5-(3-acetyl-2,4,6-trimethylphenyl)-2-[1-(ethoxyimino)butyl]-3-hydroxy-cyclohex-2-en-1-one (0.10 g; 0.26 mmole) was dissolved in acetone and then 4-toluenesulfonyl chloride (0.05 g; 0.26 mmole) was added. The mixture was stirred for 15 minutes and then the solvent was removed by evaporation under reduced pressure using a rotary evaporator. The product was purified by column chromatography over silica gel (eluant dichloromethane) to give 5-(3-acetyl-2,4,6-trimethylphenyl)-2-[1-(ethoxyimino)butyl]-3-(4-toluenesulfonyl)oxy-cyclohex-2-en-1-one (0.13 g; 95.6%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:5][C:6](=O)[C:7]=1[Cl:8])=[O:4].[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>O>[F:10][C:11]1[CH:17]=[CH:16][C:14]([N:15]2[C:3](=[O:4])[C:2]([Cl:1])=[C:7]([Cl:8])[C:6]2=[O:5])=[CH:13][CH:12]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Solvent: O
Product: O=C1C(Cl)=C(Cl)C(=O)N1c1ccc(F)cc1
Yield: 99.2 %

Procedure:
10g (0.06 mol) of 2,3-dichloromaleic anhydride was dissolved in 200 ml of water. Then to the resulting solution 5.55g (0.05 mol) of 4-fluoroaniline was added dropwise over a period of 5 min. at room temperature under agitation. The mixture was then allowed to react for 2 hours at reflux temperatures. Upon cooling the reaction mixture, precipitated crystal was separated by filtration to obtain 12.9g of N-(4-fluorophenyl)-2,3-dichloromaleimide melting at 240°-243° C (not corrected) at a yield of 99.2%. An anaylsis by gas chromatography showed the product had a purity of 99.3%.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[CH3:21][O:22][CH2:23][CH2:24][NH2:25]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[NH:25][CH2:24][CH2:23][O:22][CH3:21])=[O:13])[CH2:8]2
Reactant: COCCN
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Product: COCCNc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1C

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 88 mg; 0.30 mmol) and 2-methoxyethylamine (0.26 mL; 3.0 mmol) under microwave irradiation according to the procedure described for Example 14 provided after purification by reverse phase HPLC, 5-(2-methoxy-ethylamino)-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (65 mg, 65%) as an off-white powder. ES-HRMS m/e calcd for C18H29N4O2 (M+H+) 333.2285, found 333.2282.
Reaction SMILES: [OH:1][C@H:2]([C@@H:13]([OH:24])[C:14]([O:16]N1C(=O)CCC1=O)=O)[C:3]([O:5]N1C(=O)CCC1=O)=O.[NH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH:44]2[C:53]3[C:48](=[C:49]([Cl:55])[CH:50]=[C:51]([Cl:54])[CH:52]=3)[CH2:47][N:46]([CH3:56])[CH2:45]2)[CH:39]=1)(=[O:37])=[O:36]>>[Cl:54][C:51]1[CH:52]=[C:53]2[C:48](=[C:49]([Cl:55])[CH:50]=1)[CH2:47][N:46]([CH3:56])[CH2:45][CH:44]2[C:40]1[CH:39]=[C:38]([S:35]([NH:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][NH:25][C:3](=[O:5])[C@H:2]([OH:1])[C@@H:13]([OH:24])[C:14]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][NH:34][S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH:44]3[C:53]4[C:48](=[C:49]([Cl:55])[CH:50]=[C:51]([Cl:54])[CH:52]=4)[CH2:47][N:46]([CH3:56])[CH2:45]3)[CH:39]=2)(=[O:37])=[O:36])=[O:16])(=[O:37])=[O:36])[CH:43]=[CH:42][CH:41]=1
Reactant: O=C(ON1C(=O)CCC1=O)[C@H](O)[C@@H](O)C(=O)ON1C(=O)CCC1=O
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCN)c2)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCNC(=O)[C@H](O)[C@@H](O)C(=O)NCCOCCOCCNS(=O)(=O)c3cccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)c3)c2)C1
Yield: 15.3 %

Procedure:
Compound 218 was prepared following the procedure outlined in Example 168 using (2R,3R)-bis(2,5-dioxopyrrolidin-1-yl) 2,3-dihydroxysuccinate (10.2 mg, 0.0298 mmol) and N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 168.2, 30 mg, 0.0597 mmol). Purification by preparative HPLC gave the title compound (5.1 mg) as the TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.92 (d, J=7.8 Hz, 2H), 7.82 (m, 2H), 7.67 (t, J=7.8 Hz, 2H), 7.57 (m, 2H), 7.55 (d, J=6.9 Hz, 2H0, 6.86 (m, 2H), 4.84 (s, 2H), 4.79 (s, 2H), 4.54 (d, 2H), 4.48 (s, 2H), 3.92 (m, 2H), 3.53 (m, 22H), 3.18 (s, 6H), 3.07 (t, J=5.4 Hz, 4H). MS (m/z): 1119.04 [M+H]+.
Reaction SMILES: NC1C=CC(N2CCCN(C(OC(C)(C)C)=O)CC2)=CC=1N.[F:23][C:24]1[CH:25]=[C:26]([S:30]([Cl:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1.[NH2:34][C:35]1[CH:40]=[C:39]([N:41]2[CH2:47][CH2:46][CH2:45][N:44](C(OC(C)(C)C)=O)[CH2:43][CH2:42]2)[CH:38]=[CH:37][C:36]=1[NH:55][S:56]([C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([F:65])[CH:60]=1)(=[O:58])=[O:57].FC1C=C(S(N)(=O)=O)C=CC=1.Cl.CCOCC>CO>[ClH:33].[N:41]1([C:39]2[CH:38]=[CH:37][C:36]([NH:55][S:56]([C:59]3[CH:64]=[CH:63][CH:62]=[C:61]([F:65])[CH:60]=3)(=[O:57])=[O:58])=[C:35]([NH:34][S:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[CH:25]=3)(=[O:32])=[O:31])[CH:40]=2)[CH2:47][CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(NS(=O)(=O)c3cccc(F)c3)c(N)c2)CC1
Agent: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(N)c2)CC1
Agent: Cl
Agent: NS(=O)(=O)c1cccc(F)c1
Solvent: CCOCC
Solvent: CO
Product: O=S(=O)(Nc1ccc(N2CCCNCC2)cc1NS(=O)(=O)c1cccc(F)c1)c1cccc(F)c1
Reaction time: 0.5 h

Procedure:
The compound was prepared from 2-amino-5-(4-t-butyloxycarbonyl-1-homopiperazinyl)aniline and 3-flourobenzenesulfonyl chloride. Purification by column chromatography (CH2Cl2/MeOH/heptane, 4:1:15) gave a mixture of N-{2-amino-4-[4-t-butyloxycarbonyl-homopiperazin-1-yl-]phenyl}3-fluorobenzenesulfonamide and N-{4-[4-t-butyloxycarbonyl]homopiperazinyl)-2-[(3-flourophenylsulfonyl)amino]phenyl}-3-fluorobenzenesulfonamide (0.180 g, 73%). Boc-deprotection was achieved by dissolving the mixture in small amount of MeOH and adding HCl/ether. The mixture was let at r.t. for 0.5 h. Purification by preparative HPLC gave N-(4-(1,4-diazepan-1-yl)-2-{[(3-fluorophenyl)sulfonyl]amino}phenyl)-3-fluorobenzenesulfonamide hydrochloride Anal. (C23H27ClN4O4S2) C, H, N, S.; M+ 524.4 Calcd 522.12.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH:9]=[C:8]2[CH3:14].[C:32](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[CH:6]=[C:7]2[C:12]=1[N:11]([CH3:32])[C:10](=[O:13])[CH:9]=[C:8]2[CH3:14]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)cc2c(C)cc(=O)[nH]c12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)cc2c(C)cc(=O)n(C)c12

Procedure:
To a solution of 8-methoxy-4-methyl-6-[2,2,2-trifluoro-1-benzyloxy-1-(trifluoromethyl)ethyl]-2(1H)-quinolinone in dimethylformamide is added potassium carbonate and methyl iodide. The solution is stirred and heated until analysis by thin layer chromatography indicates the reaction is complete. The solution is cooled and added to water. The aqueous mixture is extracted with ether. The etheral solution is dried with anhydrous magnesium sulfate, filtered and evaporated at reduced pressure. The residual material is purified by chromatography on silicic acid to give 8-methoxy-1,4-dimethyl-6-[2,2,2-trifluoro-1-benzyloxy-1-(trifluoromethyl)ethyl]-2(1H)-quinolinone.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:15][C:16]1[CH:17]=[C:18]([Mg]Br)[CH:19]=[CH:20][CH:21]=1.[Cl-:24].[NH4+]>O1CCCC1>[ClH:24].[F:15][C:16]1[CH:21]=[C:20]([C:11]2([OH:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Fc1cccc([Mg]Br)c1
Reactant: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cl
Product: OC1(c2cccc(F)c2)CCNCC1
Temperature: 0 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
1-(tert-Butoxycarbonyl)-4-piperidone (2.19 g) was dissolved in tetrahydrofuran (30 ml) and the mixture was cooled to 0° C. 3-Fluorophenylmagnesiumbromide (Tokyo Chemical Industry CO., LTD., 1M, 13.2 ml) was added and the mixture was stirred for 6 hr. After completion of the reaction, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted three times with ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate (5:1-2:1)). Then, 4N hydrochloric acid-ethyl acetate (10 ml) was added and the mixture was stirred for 3 hr. Diethyl ether was added and the precipitated solid was collected by filtration to give 4-(3-fluorophenyl)piperidin-4-ol hydrochloride (902 mg, yield 35%).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([C:10]2[C:15]([F:16])=[C:14]([F:17])[C:13](Br)=[C:12]([F:19])[C:11]=2[F:20])=[C:4]([F:21])[C:3]=1[F:22].[CH3:23][C:24]([OH:28])([C:26]#[CH:27])[CH3:25]>C(NC(C)C)(C)C.C([O-])(=O)C.[Cu+]>[OH:28][C:24]([CH3:25])([CH3:23])[C:26]#[C:27][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([C:10]2[C:15]([F:16])=[C:14]([F:17])[C:13]([C:27]#[C:26][C:24]([CH3:25])([OH:28])[CH3:23])=[C:12]([F:19])[C:11]=2[F:20])=[C:4]([F:21])[C:3]=1[F:22]
Reactant: C#CC(C)(C)O
Reactant: Fc1c(F)c(-c2c(F)c(F)c(Br)c(F)c2F)c(F)c(F)c1Br
Agent: [Cu+]
Agent: CC(=O)[O-]
Solvent: CC(C)NC(C)C
Product: CC(C)(O)C#Cc1c(F)c(F)c(-c2c(F)c(F)c(C#CC(C)(C)O)c(F)c2F)c(F)c1F
Temperature: 0 °C

Procedure:
To a solution of 4,4'-dibromooctafluorobiphenyl (10 g, 21.9 mmol) in degassed diisopropylamine (350 mL) was added dichlorobis(triphenylphosphine) palladium (770 mg, 1.05 mmol, 5 mol %) and copper (1) acetate (219 mg, 1.05 mmol, 5 mol %). The solution was cooled to 0° C. and to this solution was added 2-methyl 3 butyn 2-ol (2.2 equivalents, 4.0 g, 4.7 mL). The solution was allowed to warm to room temperature and was subsequently heated at 50° C. for 12 hours. The solution was cooled and filtered to remove the pecipitate of diisopropylammonium bromide. The solvent was removed at reduced pressure and the residue was chromatographed on a column of silica gel (200 g) packed with ethel acetate. An oily yellow solid was removed from the column. The addition of a couple of drops of methanol caused the oil to solidify. The resulting solid was recrystallized from a mixture of ethyl acetate/hexane (1:2) to yield 4,4'-bis(3 hydroxy-3-methyl 1-butynyl)-octafluorobiphenyl as white crytals. The yield was 8.6 (92 %), mp 119°-121° C. IR (KBr) 3400, 2960, 1475, 1365, 1210, 1170, 990, 962 cm-1. 1H NMR (80 MHz, CDCl3) δ2.7 (s, 2H), 1.53 (s, 12H); Mass Spectrum (El)(rel. intensity 462 (3.7), 447 (44.0), 432 (1.5); Anal. Calcd for C22H14F8O2 : C, 57.14; H, 3.03. Found: C,60.60; H, 4.78
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH:10]=[CH:11][C@@H:12]2[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:27][CH2:28][O:29]C)[CH:4]=[CH:5]2.O.[C:32](O)(=O)C>>[C:28]([O:27][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:18]([CH3:19])[CH2:17][CH2:16][C@:14]45[C:15]=2[C:2]=1[O:1][C@H:13]4[C@@H:12]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[CH:11]=[CH:10][C@@H:9]35)(=[O:29])[CH3:32]
Reactant: CC(=O)O
Reactant: COCOc1ccc2c3c1O[C@H]1[C@@H](Oc4ccccn4)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Solvent: O
Product: CC(=O)Oc1ccc2c3c1O[C@H]1[C@@H](Oc4ccccn4)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
4,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-((2-pyridyl)-oxy)-morphinan-7-ene (0.54 g, 1.33 mmol) is mixed with H2O (20 ml) and glacial acetic acid (20 ml) and stirred for 2.5 hours at 100° C. The mixture is then concentrated by rotary evaporation in a Rotavapor at 40° C. and the residu e obtained is purified by flash chromatography (90 g silica gel; CH2Cl2 /MeOH=9/1). The product is dissolved in H2O (7 ml) and glacial acetic acid (0.7 ml) and lyophilised. Yield: 0.436 g (1.03 mmol, 77.6%)