Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].Br[CH2:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])=[CH:18][CH:17]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:11][CH2:15][C:16]2[CH:29]=[CH:28][C:19]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])=[CH:18][CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Reactant: COc1ccc(O)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(OCc2ccc(C(=O)c3ccccc3)cc2)cc1OC
Reaction time: 1 h

Procedure:
To 3,4-dimethoxyphenol (1.69 g, 11 mmol) in THF was added NaH (60% dispersion in oil, 1.2 eq., 0.53 g) and stirring continued for 1 hour. 4-Bromomethyl benzophenone (3.01 g, 11 mmol) was then added to the solution and stirring continued for a further 24 hours. The solution was concentrated in vacuo, diluted with DCM, washed with citric acid (10% aq.), NaOH (1N) dried and solvent removed under vacuum. The residue was then purified by column chromatography, eluting with petrol (40–60):EtOAc 9:1 yielding the product as a white solid (2.58 g, 68%) (Found: C, 75.73; H, 5.96. C22H20O4 requires C, 75.84; H, 5.79%), mp 74–75° C.; Rf=0.23 (Petrol:EtOAc 4:1); δH (250 MHz, CDCl3) 3.82 (3 H, s, OCH3), 3.86 (3 H, s, OCH3), 5.10 (2 H, s, CH2), 6.47 (1 H, dd, J 9, 1, ArH p- to OMe), 6.65 (1 H, d, J 1, ArH o- to 2 OR), 6.80 (1 H, d, J 9, ArH m- to 2 OR), 7.47–7.75 (5 H, m, ArH), 7.80–7.91 (4 H, m, ArH o- to C═O); δC (50.3 MHz, CDCl3) 55.8 (OCH3), 56.4 (OCH3), 69.9 (CH2O), 101.2 and 104.0 (ArCH o- to OCH2Ar), 111.7 (ArCH m- to OCH2Ar), 127.0, 128.3, 130.0 and 130.3 (ArCH o- and m- to C═O), 132.5 (ArCH p- to C═O), 137.0 and 137.5 (4° ArCC═O), 141.9 (ArCCH2O), 143.8 (4° ArCOCH2), 149.9 (4° ArCOMe p- to OCH2Ar), 153.0 (4° ArCOMe m- to OCH2Ar), 196.3 (C═O); m/z (APCl+) 349 ([M+H]+, 100%).
Reaction SMILES: C([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7](N)=[N:8][C:9]=2[I:13])(=O)C.[Br:15][Si](C)(C)C.N(OCCC(C)C)=O>O1CCCC1>[Br:15][C:7]1[N:6]=[C:5]2[C:10]([NH:11][CH:12]=[N:4]2)=[C:9]([I:13])[N:8]=1
Reactant: C[Si](C)(C)Br
Reactant: CC(=O)n1cnc2c(I)nc(N)nc21
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: Brc1nc(I)c2[nH]cnc2n1
Temperature: 22.5 °C
Reaction time: 19 h

Procedure:
9-Acetyl-2-amino-6-iodopurine (1.44 g, 4.72 mmol), bromotrimethylsilane (2.17 g, 14.2 mmol) and isoamyl nitrite (0.83 g, 5.67 mmol) were added to tetrahydrofuran (5 ml), and the mixture was stirred 20-25° C. for 19 hr to give 2-bromo-6-iodopurine.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10](=[CH:16][NH:17][CH:18]([CH3:21])[CH2:19][OH:20])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:22])[C:3]=1[Cl:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:22][C:4]1[C:3]([Cl:23])=[C:2]2[C:7]([C:8](=[O:9])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][N:17]2[CH:18]([CH3:21])[CH2:19][OH:20])=[CH:6][N:5]=1
Reactant: CCOC(=O)C(=CNC(C)CO)C(=O)c1cnc(Cl)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C(C)CO)c2c(Cl)c(Cl)ncc2c1=O
Temperature: 0 °C

Procedure:
5.2 g (0.014 mol) of ethyl 2-(4,5,6-trichloronicotinoyl)-3-(1-hydroxy-2-propyl)amino-acrylate are stirred with 2.3 g (0.0167 mol) of potassium carbonate in 28 ml of DMF at room temperature overnight. Ice-water is added to the mixture and the product is isolated. The mother liquor is extracted with chloroform and the organic phase is concentrated on a rotary evaporator. The crude products are stirred up with acetonitrile.
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][CH2:6][CH2:7][S:8][C:9]1[N:13]([CH3:14])[N:12]=[N:11][N:10]=1)C.[OH-].[Na+]>C1COCC1>[CH3:14][N:13]1[C:9]([S:8][CH2:7][CH2:6][CH2:5][C:4]([OH:15])=[O:3])=[N:10][N:11]=[N:12]1
Reactant: CCOC(=O)CCCSc1nnnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1nnnc1SCCCC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.93 g of 4-(1-methyltetrazol-5-ylthio)-butyric acid ethyl ester are dissolved in 50 ml of THF, 15 ml of 1N NaOH are added and the whole is stirred for 3 hours at room temperature. Most of the THF is then concentrated by evaporation under reduced pressure in a rotary evaporator and the residue is washed with ethyl acetate. The aqueous solution is adjusted to pH 3 with 4N HCl and extracted three times with ethyl acetate. After drying over sodium sulphate and concentration by evaporation under reduced pressure, the pure title compound is obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][C:10]([O:12]C)=[O:11])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)COc1cccnc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1cccnc1Br
Yield: 99 %

Procedure:
Methyl [(2-bromo-3-pyridinyl)oxy]acetate (3 g) was stirred with 2N sodium hydroxide (30 ml) in methanol (30 ml) for 2 h. The solution was neutralised to pH 7 by portionwise addition of dowex (50) H+ methanol washed resin pH 7. The resin was filtered off, and the solution was concentrated in vacuo to give the title compound as a white solid (2.8 g), m.p. 172°-174°.
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[S:3][CH:2]=1.[CH3:10]I>CN(C)C=O>[CH3:10][N:6]1[CH2:7][CH2:8][C:9]2[N:1]=[CH:2][S:3][C:4]=2[CH2:5]1
Reactant: c1cc2ncsc2cn1
Reactant: CI
Solvent: CN(C)C=O
Product: CN1CCc2ncsc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thiazolo[5,4-c]pyridine (1.61 g) was dissolved in N,N-dimethylformamide (50 ml), and to the solution methyl iodide (1.50 ml) was added, the resultant mixture was stirred at 80° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (100 ml), sodium borohydride (1.53 g) was added, and the resultant mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous solution of potassium carbonate and ether were added to the residue to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=25:1) to obtain the title compound (1.28 g) as a pale yellow oil.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)CCN(C)C.C([Li])CCC.[Br:38]Br>O1CCCC1>[C:1]([N:20]1[C:24]([Br:38])=[N:23][CH:22]=[N:21]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2cncn2)cc1
Reactant: BrBr
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Brc1ncnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -70 °C
Yield: 40.3 %

Procedure:
A stirred solution of 1-trityl-1,2,4-triazole (15.55 g, prepared as described in Example 1) and N,N,N',N'-tetramethylethylenediamine (5.8 g) in dry tetrahydrofuran (500 ml) was cooled to -70° C. under nitrogen and treated dropwise with n-butyllithium (37.5 ml, 1.6M in hexane). The deep-red solution was stirred at -70° C. for twenty minutes, then treated dropwise with a solution of bromine (10.4 g) in dry tetrahydrofuran (10 ml). The now brownish-yellow solution was allowed to warm to -20° C., quenched with 0.1M sodium thiosulphate solution (150 ml), and extracted with dichloromethane (500 ml). The organic layer was washed with water (4×100 ml), dried and evaporated. The residue was chromatographed on silica, using dichloromethane-ether (25:2) as eluant, to give 1-trityl-5-bromo-1,2,4-triazole (7.86 g, m.p. 239-241° C.). NMR (CDCl3): δ 7.1-7.3(15H,m), 7.95(1H,s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:25])[C:7]3[C:14](=[O:15])[N:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[C:12](=[O:24])[C:8]=3[NH:9][C:10]=2[CH:11]=1>CO.CS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:25])[C:7]3[C:14]([OH:15])=[N:13][N:16]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[C:12](=[O:24])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: O=C1c2[nH]c3cc(Cl)ccc3c(=O)c2C(=O)N1Nc1ccc(Cl)cc1
Agent: CS(=O)(=O)O
Solvent: CO
Product: O=c1c2ccc(Cl)cc2[nH]c2c(=O)n(-c3ccc(Cl)cc3)nc(O)c12
Temperature: 25 °C
Yield: 23.3 %

Procedure:
A stirred suspension of 6-chloro-2-(4-chloroanilino)-2,3,4,9- tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione (0.670 g, 1.79 mM) in methanol (60 mL) and methanesulfonic acid (15 mL) was refluxed for 3 hours and cooled to room temperature. The mixture was filtered (the filtrate was saved for use in Example 17), and the collected yellow solids were washed with methanol and ether to give the title compound (0.156 g, 23%) as a yellow powder, mp>400° C.; MS(CI): 374 (M+H).
Reaction SMILES: [OH-:1].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][C:5]=1[CH:6]=[O:7]>O.[N+]([O-])([O-])=O.[Ag+]>[OH:3][C:4]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:14])([F:15])[F:16])=[CH:8][C:5]=1[C:6]([OH:1])=[O:7]
Reactant: [OH-]
Reactant: O=Cc1cc(OC(F)(F)F)ccc1O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(OC(F)(F)F)ccc1O
Reaction time: 0.17 h
Yield: 91 %

Procedure:
To a stirring solution of NaOH (8.15 g, 203.8 mmol) in water (35 mL, 5.8 M) was added an aq solution of silver nitrate (17.3 g, 101.9 mmol, 35 mL water, 2.9 M). A brownish solid formed. The flask was placed in an ice bath and to the stirring suspension was added 2-hydroxy-5-trifluoromethoxy-benzaldehyde in 500 mg portions (10.0 g, 48.5 mmol). After addition was complete and the reaction was stirred for 10 min in an ice bath, the mixture was filtered and the brownish precipitate was washed with hot water. The combined washings were acidified with conc HCl to pH 1 and the precipitate was collected by vacuum filtration. This solid was then dissolved in ethyl acetate. The ethyl acetate was washed with saturated aq NaCl, dried over Na2SO4, and filtered. The aqueous layer was also extracted with ethyl acetate. This organic layer was washed with saturated aq NaCl, dried over Na2SO4, filtered and concentrated to provide 2-hydroxy-5-trifluoromethoxy-benzoic acid (9.8 g, 91%) as a white solid: Rf 0.38 (20% methanol in dichloromethane); 1H NMR (CDCl3, 300 MHz) δ 10.30 (bs, 1H), 7.79 (d, J=3.0 Hz, 1H), 7.41 (dd, J1=9.3 Hz, J2=3.0 Hz, 1H), 7.05 (d, J=9.0 Hz, 1H).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[CH:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:27]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:28])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:10][CH:9]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: COc1ccc(CC(N)C(O)c2ccc(F)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CC(NC(=O)C2CCCCC2)C(O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
A solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(methyloxy)phenyl)-1-propanol (450 mg, 1.64 mmol) in ethyl acetate (15 ml) were added cyclohexanecarbonyl chloride (328 ml, 2.45 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (529 mg, 84%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][N:8]2C(=O)C3=CC=CC=C3C2=O)=[CH:4][C:3]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N)CCC.[ClH:33]>C(O)C>[ClH:33].[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][NH2:8])=[CH:4][C:3]=1[O:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1ccc(F)c(Oc2ccccc2)c1
Agent: Cl
Solvent: CCO
Solvent: CCCCN
Product: NOCc1ccc(F)c(Oc2ccccc2)c1
Reaction time: 1.5 h
Yield: 87 %

Procedure:
N-(4-fluoro-3-phenoxybenzyloxy)phthalimide 5 g, 14 mmol), n-butylamine (1.13 g, 15 mmol) and absolute ethanol (3 ml) were placed in a dry flask under a nitrogen atmosphere. This reaction mixture was stirred at 60°-75° for 1.5 hours, cooled and adjusted to pH 3 using dry hydrogen chloride gas. The solution was concentrated to 10 ml and poured into dry ether. The resulting white precipitate was filtered off and recrystallized from petroleum spirit (40°-60°)/dichloromethane to give 3.2 g (87%) of a white solid, m.p. 149.3°.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Si]([O:24][C:25]1[CH:30]=[C:29]([O:31][Si](C(C)(C)C)(C)C)[CH:28]=[CH:27][C:26]=1[C@@H:39]1[CH2:44][CH2:43][C@H:42]([NH2:45])[CH2:41][CH2:40]1)(C(C)(C)C)(C)C>CN(C)C1C=CN=CC=1.ClC(Cl)C>[OH:24][C:25]1[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:26]=1[C@@H:39]1[CH2:40][CH2:41][C@H:42]([NH:45][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[CH2:43][CH2:44]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](N)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: O=C=Nc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)N[C@H]1CC[C@@H](c2ccc(O)cc2O)CC1
Reaction time: 60 h
Yield: 40.4 %

Procedure:
A solution of phenylisocyanate (0.015 ml, 0.13 mmol), triethylamine (0.03 ml), 4-dimethylaminopyridine (catalytic) and cis-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl) cyclohexylamine (0.043 g) in dichloroethane (4 ml) was stirred at room temperature for 17 hr. The mixture was partitioned between saturated aqueous sodium hydrogen carbonate (5 ml) and dichloromethane (5 ml). The aqueous phase was extracted with dichloromethane (2×5 ml) and the combined organic extracts washed with brine (7 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was dissolved in dichloromethane (6 ml) and stirred rapidly with water (3 ml) and trifluoroacetic acid (3 ml) for 60 hr. Toluene (15 ml) was added and the solution concentrated in vacuo. Purification via flash chromatography (SiO2, ethyl acetate/petroleum ether) afforded the title compound (0.013 g, 30%) as a colourless solid. 6H (CD3OD) 1.32-1.46 (2H, m), 1.53-1.69 (2H, m), 1.90 (2H, m), 2.17 (2H, m), 2.83 (1H, m), 3.65 (1H, m), 6.28 (2H, m), 6.94 (1H, d), 7.00 (1H, m), 7.27 (2H, m) and 7.38 (2H, m); m/s(ES+) 327.20 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[C:13]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][CH:14]=1>>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([NH:1][C:19]([C:16]3[CH:17]=[CH:18][C:13]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:14][CH:15]=3)=[O:20])=[CH:3][CH:4]=2)[N:9]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: Cc1ccc2ccc(N)cc2n1
Product: Cc1ccc2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc2n1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-amino-2-methylquinoline (D66) (80 mg, 0.51 mmol) and 4-biphenylcarboxylic acid (149 mg, 0.75 mmol) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.07 (m, 3H), 8.01 (m, 3H), 7.81 (d, 1H), 7.75 (d, 2H), 7.66 (d, 2H), 7.50 (t, 2H), 7.42 (t, 1H), 7.24 (d, 1H), 2.75 (s, 3H).
Reaction SMILES: Cl.C([O:4][C:5](=[O:31])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([S:20](=[O:30])(=[O:29])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)=[CH:15][CH:16]=2)[CH2:11]1)C>C(O)C>[Cl:28][C:24]1[CH:23]=[C:22]([NH:21][S:20]([C:14]2[CH:13]=[C:12]3[C:17]([CH2:18][CH2:19][N:10]([CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:31])=[O:4])[CH2:11]3)=[CH:16][CH:15]=2)(=[O:29])=[O:30])[CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)CCCCN1CCc2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2C1
Agent: Cl
Solvent: CCO
Product: O=C(O)CCCCN1CCc2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2C1

Procedure:
7-(3-Chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinoline was reacted with ethyl 5-bromovalerate under conditions analogous to those described in Example 2(a). The crude product of the alkylation reaction was then treated with ethereal HCl, and the following ethyl ester hydrochloride was obtained; ethyl-5-[7-(3-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]valerate hydrochloride; mpt. 178°-180° C. (from ethanol).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16](=O)[CH2:17][CH2:18][CH2:19][N:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[O:30])[NH:22][C:21]2=[O:31])[CH2:12][CH2:11]1)([O-:3])=[O:2].B>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[O:30])[NH:22][C:21]2=[O:31])[CH2:12][CH2:11]1)([O-:3])=[O:2]
Reactant: O=C(CCCn1c(=O)[nH]c(=O)c2ccccc21)N1CCN(c2ccccc2[N+](=O)[O-])CC1
Agent: B
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)n(CCCCN2CCN(c3ccccc3[N+](=O)[O-])CC2)c2ccccc12
Yield: 15.9 %

Procedure:
To a suspension of 1-[4-{4-(2-nitrophenyl)piperazin-1-yl}-4-oxo-butyl]-2,4(1H,3H)-quinazolinedione (500 mg) in tetrahydrofuran (10 ml) was added 1M borane in tetrahydrofuran (3.42 ml) on an ice-bath. After refluxing for 30 minutes, the reaction mixture was quenched with 1N hydrochloric acid (7 ml), and refluxed for additional 30 minutes. The mixture was made alkaline with saturated aqueous sodium bicarbonate, diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated. The obtained residue was chromatographed on silica gel (20 g) eluting with chloroform-methanol (20:1 V/V) to give crystals. Recrystallization from ethanol gave 1-[4-{4-(2-nitrophenyl)piperazin-1-yl}butyl]-2,4(1H,3H)-quinazolinedione (77 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[CH2:16]([O:18][C:19](=[O:28])[C:20]1[CH:25]=[C:24]([OH:26])[CH:23]=[C:22]([OH:27])[CH:21]=1)[CH3:17]>CN(C=O)C>[CH2:16]([O:18][C:19](=[O:28])[C:20]1[CH:25]=[C:24]([OH:26])[CH:23]=[C:22]([O:27][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH:21]=1)[CH3:17]
Reactant: N#Cc1ccc(F)cc1
Reactant: CCOC(=O)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(O)cc(Oc2ccc(C#N)cc2)c1
Temperature: 45 °C
Yield: 14.9 %

Procedure:
Potassium carbonate 6.7 g (48.5 mmol) followed by 4-fluoro benzonitrile 3.3 g (27.2 mmol) in 10 ml of DMF was added to a solution of 3,5-dihydroxy benzoic acid ethyl ester 5 g (27.4 mmol) in 20 ml of DMF at 20° C. The reaction mixture was allowed to attain RT and was then heated to 45° C. for 10 h. The reaction mixture was quenched with ice cold water and extracted with ethyl acetate. The organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated. The crude compound was purified by column chromatography using hexane-ethyl acetate (10:2) to afford 1.15 g of the required product. 1H NMR (DMSO-d6): δ 1.3 (3H, t), 4.3 (2H, q), 6.76 (1H, s), 7.02 (1H, s), 7.36 (2H, d), 7.24 (1H, s), 7.88 (2H, d), 10.3 (1H, s).
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.Br[CH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:16]1([C@@H:14]2[CH2:15][C@H:13]2[NH:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:25][C:26]3[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=3)[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)c1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccccc3)CC2)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 19.2 %

Procedure:
To the solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (200 mg, 0.613 mmol, Example 11b) and 4-(bromomethyl)benzoic acid (198 mg, 0.919 mmol) in acetonitrile (6 mL) was added potassium carbonate (254 mg, 1.838 mmol). The reaction mixture was stirred for 3 hours at the 90° C. The reaction mixture was then filtered and evaporated. The crude oil was mixed with 10 mL of 10% acetic acid and 10 mL of ethyl acetate. Layers were separated, and the organic layer was discharged. Aqueous layer was neutralized with 1 M Na2CO3, and the product was extracted into 10 mL of ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The oil was dissolved in 6 ml of EtOH and 3 ml of 1 M NaOH. The reaction mixture was stirred for 20 min, and then it was concentrated. The solution was then partioned between 2 ml of water and 5 mL of ethyl acetate. The organic layer was separated and evaporated. The oil was purified on preparatory HPLC (2 to 10% AcCN: H2O with 0.1% formic acid modifier). The fractions were collected. To each fraction was added 1 ml of 1 M HCl, and the fractions were evaporated to dryness. 4-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid (50 mg, 0.118 mmol, 19.33% yield) was isolated as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ 8.16 (d, J=8.34 Hz, 2H), 7.70 (d, J=8.34 Hz, 2H), 7.30-7.37 (m, 2H), 7.23-7.29 (m, 1H), 7.20 (d, J=7.33 Hz, 2H), 4.44 (br. s., 2H), 3.57 (d, J=11.62 Hz, 2H), 3.07-3.27 (m, 4H), 3.04 (dt, J=3.95, 7.52 Hz, 1H), 2.59 (ddd, J=3.54, 6.57, 10.11 Hz, 1H), 2.12 (d, J=13.89 Hz, 3H), 1.54-1.81 (m, 3H), 1.42 (q, 1H); LC-MS Rt=0.47 min; MS (ESI): 365.3 [M+H]+.
Reaction SMILES: [Si]([O:8][C:9]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][N:13]2[CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:18][C:16]1[CH:17]=[C:9]([OH:8])[C:10]2[CH:11]=[N:12][N:13]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:25])([CH3:24])[CH3:26])[C:14]=2[CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(F)cc2c1cnn2COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc2c(O)cc(F)cc21

Procedure:
A mixture of EXAMPLE 414B (1.8 g) and 1.0 N tetrabutyl ammonium fluoride (13.6 mL) in tetrahydrofuran (15 mL) was stirred for 2 hours. The solvent was removed, and the residue was partitioned between water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel to give the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1/C(=C/c2n[nH]c3ccccc23)Oc2c(CN3CCNCC3)cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0301 g, 0.0654 mmol) in methylene chloride (2 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain (Z)-2-[(1H-indazol-3-yl)-methylene]-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0221 g, 94%).