Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[K].[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>C(O)C>[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][O:22][C:19]2[CH:20]=[CH:21][C:16]([C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:14]=3)=[CH:17][CH:18]=2)=[CH:27][CH:26]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1
Agent: [K]
Solvent: CCO
Product: CCCCCCCCOc1ccc(-c2ccc(OCc3ccc(Br)cc3)cc2)cc1
Yield: 77.9 %

Procedure:
5 g of 4'-n-octyloxy-4-hydroxybiphenyl, 1.5 g of potassium hydrooxide, and 100 g of 95% ethanol were heated under reflux, and a solution wherein 4.2 g of p-bromobenzyl bromide was dissolved in 100 ml of ethanol was added thereto to effect reaction for 2 hours. The reaction liquid was treated in the ordinary method to obtain 6.1 g of 4'-n-octyloxy-4-biphenylyl p-bromobenzyl ether after recrystallization from ethyl acetate. The obtained product showed the following phase transition temperatures:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.C([Li])CCC.[I:17]I>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([I:17])[S:8][C:7]=2[CH:11]=1
Reactant: COc1ccc2ccsc2c1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2cc(I)sc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.7 %

Procedure:
To a solution of 6-methoxybenzo[b]thiophene (5.00 g, 30.49 mmol) in 200 mL of anhydrous THF at -78° C., was added n-butyllithium (20.0 mL, 32.01 mmol, 1.6M solution in hexanes). After stirring for 15 minutes, a solution of I2 (8.10 g, 32.01 mmol) in 25 mL of anhydrous THF was introduced dropwise via canula. The resulting mixture was allowed to gradually warm to ambient temperature. The reaction was quenched by distributing between ethyl acetate/brine (150 mL each). The layers were separated and the organic layer was dried over sodium sulfate. Concentration in vacuo produced a tan solid that was recrystallized from hexanes to provide 6.70 g (75%) of 6-methoxy-2-iodobenzo[b]thiophene. mp 75°-77° C. 1H NMR (CDCl3) d 7.59 (d, J=8.6 Hz, 1H), 7.42 (s, 1H), 7.22 (d, J=2.0 Hz, 1H), 6.92 (dd, J=8.6, 2.0 Hz, 1H), 3.86 (s, 3H). FD mass spec: 290. Anal. Calcd. for C9H7OSI: C, 37.26; H, 2.43. Found: C, 37.55; H, 2.43.
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[N+:14]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N:2]=[C:1]2[C:11]([OH:13])=[O:12])([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1nccc2ccccc12
Agent: O=S(=O)(O)O
Product: O=C(O)c1nccc2c([N+](=O)[O-])cccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
Isoquinoline-1-carboxylic acid (3.98 g, 23.0 mmol) was dissolved in conc. sulfuric acid (16 ml) at 0° C. A mixture of conc. sulfuric acid (5 ml) and fuming nitric acid (5 ml) was added over 10 min. and the reaction stirred for a further 1 h at 0° C., then poured into ice-water (400 ml). The solid was collected by filtration, then washed with water (100 ml), ethanol (100 ml) and ether (100 ml), then dried under vacuum to give the title compound (4.1 g, 82%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:20][O:21][Si](C(C)(C)C)(C)C)[NH:5][C:6](=[O:19])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:20][OH:21])[NH:5][C:6](=[O:19])[C:7]1[CH:8]=[C:9]([O:17][CH3:18])[C:10]([O:15][CH3:16])=[C:11]([O:13][CH3:14])[CH:12]=1
Reactant: COC(=O)[C@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1cc(OC)c(OC)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)[C@H](CO)NC(=O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-tert-Butyldimethylsilyl-N-(3,4,5-trimethoxy-benzoyl)-L-serine methyl ester (15.91 g) was dissolved in THF (70 mL), and to the solution a THF solution (55.82 mL) of 1.0 M tetrabutylammonium fluoride was added at 0° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude crystals were then recrystallized from methanol-ether-hexane to obtain the title compound.
Reaction SMILES: COC1C=CC(S(N[C@H](C(O)=O)CCC(O)=O)(=O)=O)=CC=1.[CH:22]1[CH:23]=[CH:24][C:25]([CH:28]2[N:35]=[C:34]3[N:30]([CH2:31][CH2:32][S:33]3)[CH2:29]2)=[CH:26][CH:27]=1>CC(=O)C.O>[CH:22]1[CH:27]=[CH:26][C:25]([C@@H:28]2[N:35]=[C:34]3[N:30]([CH2:31][CH2:32][S:33]3)[CH2:29]2)=[CH:24][CH:23]=1
Reactant: c1ccc(C2CN3CCSC3=N2)cc1
Agent: COc1ccc(S(=O)(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: c1ccc([C@H]2CN3CCSC3=N2)cc1
Yield: 125.1 %

Procedure:
A suspension of 31.73 g of L-N-[(4-methoxyphenyl)sulfonyl-glutamic acid (0.1 mol) in 400 ml of 2-propanone and 20 ml of water was stirred and heated till all solid entered solution. Then there were added 20.43 g of tetramisole. The whole was stirred and heated to reflux and additionally stirred at reflux for 10 minutes. The mixture was further stirred for 4 hours while the temperature was allowed to reach room temperature. The precipitate was filtered off, washed with 100 ml of 2-propanone and 5 ml of water and dried under vacuo at 50° C., yielding 25.55 g of levamisole.L-N-[(4-methoxyphenyl)sulfonyl]glutamic acid (salt) (yield 98%) αD20 =-62.4° (c5. 1N HCl); mp. 127.3°-129° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1/[C:27](=[N:33]/[O:34][C:35]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)/[C:28]([O:30]CC)=[O:29].[OH-].[Na+].C(OCC)(=O)C>O1CCOCC1.O>[CH3:1][C:2]1[S:6][C:5]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1/[C:27](=[N:33]/[O:34][C:35]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)/[C:28]([OH:30])=[O:29]
Reactant: CCOC(=O)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)sc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1sc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)nc1/C(=N/OC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 100 °C
Yield: 101.4 %

Procedure:
A solution of ethyl 2-(5-methyl-2-tritylaminothiazol-4-yl)-2-(Z)-(trityloxyimino)acetate (9.8 g) in dioxane (40 ml) and water (40 ml) was treated with sodium hydroxide (2.75 g). The mixture was allowed to warm to 100° C. The reaction mixture was cooled to room temperature, diluted with water, and filtered to give a precipitate. A suspension of the precipitate in water and ethyl acetate was allowed to pH 2.5, the organic phase was washed with brine and dried with magnesium sulfate. The solvent was removed under reduced pressure to afford (5-methyl-2-tritylaminothiazol-4-yl)-2-(Z)-(trityloxyimino) acetic acid (9.55 g).
Reaction SMILES: [F:1][C:2]([CH3:30])([CH3:29])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH2:20][CH2:21][N:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:23][CH:24]=3)=[CH:15][CH:14]=2)[CH2:7][CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].C(OCC)C>O1CCCC1>[F:1][C:2]([CH3:30])([CH3:29])[CH2:3][N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH2:24][CH2:23][N:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:21][CH:20]=3)=[CH:15][CH:14]=2)[CH2:7][CH2:6]1
Reactant: CC(C)(F)C(=O)N1CCC(COc2ccc(C3=CCN(S(C)(=O)=O)CC3)cc2)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(F)CN1CCC(COc2ccc(C3=CCN(S(C)(=O)=O)CC3)cc2)CC1
Reaction time: 1 h
Yield: 25.3 %

Procedure:
To a solution of 2-fluoro-1-{4-[4-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenoxymethyl]-piperidin-1-yl}-2-methyl-propan-1-one (1.00 g, 2.28 mmol) in tetrahydrofuran (23 mL) at rt is added via cannula a 1 M solution of lithium aluminum hydride in tetrahydrofuran (7.18 g, 7.98 mL, 7.98 mmol). After 1 h, sodium sulfate decahydrate is added carefully. The mixture is stirred for 15 min and the solid is filtered off and washed with dichloromethane. The solvent is removed and the residue is purified via silica gel chromatography, eluting with dichloromethane:ethyl acetate 5.6:1 to 2:1 to obtain a solid. Diethyl ether is added and the solid is filtered and washed with diethyl ether and ethyl acetate to obtain 0.245 g of the title compound as a white solid. MS (m/z) 425 (M+1).
Reaction SMILES: [CH:1]1[CH:6]=[C:5](/[CH:7]=[CH:8]/[N+:9]([O-])=O)[C:4]([Cl:12])=[CH:3][CH:2]=1.[CH:13]1[CH2:17][CH:16]=[CH:15][CH:14]=1>>[Cl:12][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[CH:7]1[CH:15]2[CH2:16][CH:17]([CH:13]=[CH:14]2)[CH:8]1[NH2:9]
Reactant: O=[N+]([O-])/C=C/c1ccccc1Cl
Reactant: C1=CCC=C1
Product: NC1C2C=CC(C2)C1c1ccccc1Cl

Procedure:
This material (LC-MS m/z 220 (MH+)) was prepared via the nitro derivative according to the procedure described in Preparation 92 but starting instead with 2-chloro-omega-nitrostyrene and cyclopentadiene.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.C1(=O)[NH:28]C(=O)C2=CC=CC=C12.[K].O.NN>CN(C=O)C.CCOC(C)=O>[NH2:28][CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1
Agent: NN
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1ccc(N(C)c2nc(CN)nc3ccccc23)cc1
Reaction time: 8 h
Yield: 31 %

Procedure:
A mixture (2-chloromethyl-quinazolin-4-yl)-(4-ethoxy-phenyl)-methyl-amine (73 mg, 0.22 mmol) and potassium phthalimide (57 mg, 0.31 mmol) in DMF (1 mL) was heated at 70° C. for 2 h. The reaction was diluted with EtOAc and washed with H2O. The aqueous phase was extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine, filtered through Na2SO4 and concentrated. The intermediate was dissolved in EtOH (5 mL), treated with hydrazine monohydrate (81 mg, 1.62 mmol) and stirred overnight. The reaction mixture was quenched with H2O and diluted with EtOAc. The aqueous and organic phases were separated and the aqueous phase extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine, filtered over Na2SO4 and concentrated. Purification by gradient MPLC (SiO2, MeOH/CH2Cl2 w/0.1% NH4OH, 0-20%) provided 21 mg (31%) of the title compound. 1H NMR (CDCl3) δ 7.75 (d, 1H), 7.53 (ddd, 1H), 7.10 (d, 2H), 7.0 (m, 2H), 6.9 (d, 2H), 4.06 (s, 2H), 4.04 (q, 2H), 3.6 (s, 3H), 2.07 (s(br), 2H), 1.45 (t, 3H); LC-MS (ESI+; 309 ([M+H]+)).
Reaction SMILES: C([NH:8][C:9]1[CH:10]=[C:11]([CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[N:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1.FC(F)(F)C(O)=O>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:8][C:9]1[CH:10]=[C:11]([CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[N:21]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13]
Reactant: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(NCc3ccccc3)n2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(N)n2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of tert-butyl 2-(benzylamino)-6-(4-methylphenyl)isonicotinate (0.37 g, 0.98 mmol) in ethanol (4.67 mL) were added palladium dihydroxide (3.42 mg, 0.024 mmol) and trifluoroacetic acid (0.08 mL, 1.08 mmol). The mixture was purged with hydrogen and stirred under hydrogen (1 atm) at 60° C. After 30 min, the mixture was cooled to ambient temperature and filtered with Celite. The filtered cake was washed with methanol and the filtrate was concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) gave the title compound (145 mg): LC-MS [M+1]=285.2.
Reaction SMILES: [NH2:1][CH:2]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:18]=1)[CH:3]([C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:8][CH:9]=1)[OH:4].[F:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([C:41](O)=[O:42])=[CH:33][CH:32]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[F:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([C:41]([NH:1][CH:2]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:18]=2)[CH:3]([OH:4])[C:5]2[N:6]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:8][CH:9]=2)=[O:42])=[CH:33][CH:32]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1csc(-c2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1csc(-c2ccccc2)n1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 51.8 %

Procedure:
To a solution of (1RS,2RS)-2-amino-1-(2-phenyl-1,3-thiazol-4-yl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-1-propanol (311 mg, 0.73 mmol) in N,N-dimethylformamide (10 ml) were added 4-fluoronaphthalene-1-carboxylic acid (133 mg, 0.70 mmol) and 1-hydroxybenzotriazole monohydrate (112 mg, 0.73 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140 mg, 0.73 mmol) was finally added. The mixture was stirred at room temperature for 3 days. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1, 1:2) and recrystallization (hexane-ethyl acetate) to give 4-fluoro-N-{(1RS,2RS)-2-hydroxy-2-(2-phenyl-1,3-thiazol-4-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-1-naphthamide (217 mg, 52%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][CH2:13][N:14](C)C)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.[NH2:19]N>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:12][CH2:13][NH:14][N:19]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NN
Reactant: COc1ccc(C(=O)CCN(C)C)cc1OC
Solvent: CCO
Solvent: O
Product: COc1ccc(C2=NNCC2)cc1OC
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a stirred solution of 1-(3,4-dimethoxyphenyl-3-(dimethylamino)propan-1-one (2.9 g, 0.0122 moles, 1 equiv.) in absolute ethanol was added hydrazine hydrate (99%-100%) (1.18 ml, 0.0244 moles, 2 equiv) drop wise. After that the reaction mixture was refluxed for 4 h at 80° C. under inert atmosphere. Consumption of starting materials was confirmed by LC-MS analysis and TLC. Ethanol and excess hydrazine hydrate was evaporated under reduced pressure and to the crude product was stirred with diethyl ether at RT for 30 mins, filtered washed with ether and finally dried under vacuum to get 2.4 g (95% yield) of the title product as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:7]([CH2:8][CH:9]([C:11]([OH:13])=[O:12])N)=[CH:6][NH:5]2.C(N(CC)CC)C.N12CCCN=C1CCCCC2.Cl.C[OH:37]>[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14]([C:7]([CH2:8][C:9](=[O:37])[C:11]([OH:13])=[O:12])=[CH:6][NH:5]2)=[CH:15][CH:16]=1
Reactant: CO
Reactant: NC(Cc1c[nH]c2cc(Cl)ccc12)C(=O)O
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)C(=O)Cc1c[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54 %

Procedure:
To 600 mg of 6-chloro-DL-tryptophan, suspended in 5 ml of methanol, are added, at room temperature, 0,230 ml of triethylamine and the mixture is stirred for approximately 10 minutes. Then, rapidly and under stirring, pyridine-4-carboxyaldehyde (0,240 ml) is added. After approximately 5 minutes, total dissolution of the suspension is obtained. Stirring is continued for 10 minutes. 122 mg of anhydrous ZnCl2 are then added, stirred for 10 minutes, followed by 0,490 ml of 1,8-diazabicyclo-(5,4,0)-undec-7-ene. The solution becomes orange-red in colour. It is left under stirring for approximately 80-90 minutes at room temperature. The limpid red solution is then quickly added dropwise and under rapid stirring to 100 ml of HCl 1N preheated to 50° C. After approximately 10 minutes from completion of the addition a spontaneous precipitation occurs, increasing in time, of a yellowish solid. The mixture is left for a further 20 minutes at 55° C., then for approximately 3 hours it is cooled to room temperature. The abundant precipitate is filtered, washed with acidic water and dried. 195 mg are recovered, with a yield of 54%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:6]=[CH:5]2.C([Li])CCC.[CH:25]([C:28]([C:30]1[N:31]=[CH:32][N:33]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=1)=[O:29])([CH3:27])[CH3:26].O>C1COCC1.CCCCCC>[Si:13]([O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:28]([C:30]1[N:31]=[CH:32][N:33]([C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:34]=1)([OH:29])[CH:25]([CH3:27])[CH3:26])[CH:11]=[CH:10]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)C(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)C(O)(c1ccc2cc(O[Si](C)(C)C(C)(C)C)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
6-Bromo-2-tert-butyldimethylsilyloxynaphthalene (60.0 g) was dissolved in THF (600 mL) and the solution was cooled to −70° C. A solution (1.6 M: 111 mL) of n-butyllithium in hexane was slowly added dropwise and the mixture was stirred for 30 min. Then a solution (200 mL) of isopropyl(1-trityl-1H-imidazol-4-yl)ketone (52.1 g) in THF was added dropwise. The mixture was stirred at −70° C. for 30 min. and water was added to stop the reaction. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried and concentrated. The residue was recrystallized from ethyl acetate-hexane to give the title compound (79.5 g) as a colorless powder.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH2:18][C@H:17]([CH2:21][O:22][C:23]2[C:28]([CH3:29])=[CH:27][C:26]([Br:30])=[CH:25][C:24]=2[CH3:31])[CH2:16]1)=O)(C)(C)C>ClCCl>[Br:30][C:26]1[CH:27]=[C:28]([CH3:29])[C:23]([O:22][CH2:21][C@H:17]2[CH2:18][CH2:19][CH2:20][NH:15][CH2:16]2)=[C:24]([CH3:31])[CH:25]=1
Reactant: Cc1cc(Br)cc(C)c1OC[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Br)cc(C)c1OC[C@H]1CCCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (80 mL) was added dropwise during 20 minutes to a solution of (S)-N-(tert-butoxycarbonyl)-3-(4-bromo-2,6-dimethylphenoxymethyl)piperidine (37.0 g, 92.9 mmol) in dichloromethane (250 mL) at a temperature of 5° C. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The solvent was then evaporated and the residue partitioned between 25% aqueous sodium hydroxide (200 mL) and ether (500 mL). The organic layer was removed and the aqueous phase extracted with additional ether (2×300 mL). The combined ether layers were washed with brine (100 mL), stirred over magnesium sulfate for 2 hours, and filtered to give a solution of (S)-3-(4-bromo-2,6-dimethylphenoxymethyl)piperidine.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][N:23]=[C:22]3[S:28]([C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br>C(O)(=O)C.C(OCC)C>[C:31]1([S:28]([C:22]2[C:21]3[C:25](=[CH:26][CH:27]=[C:19]([O:18][CH2:17][CH:14]4[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]4)[CH:20]=3)[NH:24][N:23]=2)(=[O:29])=[O:30])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: O=C(OCc1ccccc1)N1CCC(COc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)CC1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OCC3CCNCC3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-[3-(1-naphthylsulfonyl)-1H-indazol-5-yloxymethyl]-piperidine-1-carboxylic acid benzyl ester (0.3 g, 0.54 mmoles) and 33 wt % HBr in acetic acid (1.5 mL) was stirred at room temperature for 30 minutes, diluted with ethyl ether and filtered. The filtercake was washed with ether, dried, treated with 1N NaOH and saturated NaCl and extracted with EtOAc. The extracts were combined, dried over Na2SO4 and concentrated under vacuum to afford the title compound as an off-white solid; mp 175-177° C., identified by HNMR and mass spectral analyses, MS (ES) m/z 420.2.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]([NH2:17])=[O:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[OH:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][NH:17][C:15]([C:12]1[CH:13]=[N:14][C:9]([N:6]2[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:8][CH2:7]2)=[CH:10][CH:11]=1)=[O:16]
Reactant: OCCCCCCCCCCCCBr
Reactant: CCN1CCN(c2ccc(C(N)=O)cn2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCO)cn2)CC1
Temperature: 70 °C
Reaction time: 13 h

Procedure:
To a suspension of 0.055 g of 6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide, 0.011 g of tetrabutylammonium hydrogen sulfate, 0.11 g of sodium hydroxide and 0.05 g of potassium carbonate in 3 ml of toluene was added dropwise at 70° C. a solution of 12-bromododecanol in 2 ml of toluene and the mixture was stirred at 70° C. for 13 hours. The reaction solution was diluted with chloroform, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue thus obtained was chromatographed over a silica gel column to afford 0.025 g of the title compound.