Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH:15]4[CH2:17][CH2:16]4)[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[C:20]([NH2:23])(=[O:22])[CH3:21].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH:15]1([N:12]2[CH2:13][CH2:14][N:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([NH:23][C:20](=[O:22])[CH3:21])[CH:19]=[CH:18][C:5]=4[N:6]=3)[CH2:10][CH2:11]2)[CH2:17][CH2:16]1
Reactant: CC(N)=O
Reactant: Brc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Yield: 24 %

Procedure:
A mixture of 6-bromo-2-(4-cyclopropylpiperazin-1-yl)benzothiazole (480 mg, 1.42 mmol), acetamide (251 mg, 4.26 mmol), Pd(OAc)2 (15.9 mg, 0.071 mmol), Cs2CO3 (694 mg, 2.13 mmol) and xantphos (62 mg, 0.107 mmol) in 1,4-dioxane (10 mL) was heated at reflux for 12 h. Water (5 mL) was added and the mixture was filtered. The filtrate was extracted with EtOAc (3×5 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to give a residue, which was purified by the preparative HPLC to give 108 mg (24%) of N-[2-(4-cyclopropylpiperazin-1-yl)benzothiazol-6-yl]-acetamide as a trifluoroacetate salt.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][O:18]C(=O)C1C=CC=CC=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[CH:29]=1.[OH-].[Na+]>O1CCOCC1.CO>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:32][C:31]1[CH:33]=[CH:34][C:28]([F:27])=[CH:29][C:30]=1[CH3:35])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][OH:18])(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: Cc1cc(F)ccc1N
Reactant: CC(C)C(=O)c1cnc2c(COC(=O)c3ccccc3)cccc2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(F)ccc1Nc1c(C(=O)C(C)C)cnc2c(CO)cccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 3-isobutyryl-4-chloro-8-(benzoyloxymethyl)quinoline (1.84 g, 5 mmol) and 4-fluoro-2-methylaniline (0.78 ml, 7 mmol) in dioxan (25 ml) was heated at reflux for 2 hours, then the solvent evaporated. A solution of sodium hydroxide (0.8 g, 20 mmol) in methanol (50 ml) was added and the mixture stirred at room temperature for 1.5 hours. The resulting precipitate was filtered off and recrystallised from methanol to give (0.48 g, 27%), m.p. 139°-140°.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[CH:24]=[CH:25][C:26](=[O:28])[CH3:27]>C(O)C>[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[CH:24]1[CH2:3][C:2](=[O:1])[CH2:27][C:26](=[O:28])[CH2:25]1
Reactant: CC(=O)C=Cc1cc(C)ccc1F
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)CC(=O)OCC
Product: Cc1ccc(F)c(C2CC(=O)CC(=O)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 20% sodium ethoxide in ethanol (1.4 g) was added at room temperature diethyl malonate (3.3 g) and then was added little by little 4-(2-fluoro-5-methylphenyl)-3-buten-2-one (3.5 g), and the reaction mixture was stirred at room temperature for 30 minutes, refluxed for 2 hours and cooled. The solvent was evaporated, and to the residue was added water. The aqueous layer was washed with ethyl acetate and concentrated. To the residue was added 2M sodium hydroxide (11 ml), and the mixture was refluxed for 2 hours and cooled. To the mixture was added 2.5M sulfuric acid (11 ml) for 5 minutes, and the mixture was refluxed for 30 minutes and cooled. Precipitated crystals were filtered, washed with water and isopropylether to give 5-(2-fluoro-5-methylphenyl)cyclohexane-1,3-dione (1.6 g) as colorless crystals.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[NH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]>>[C:1]([NH:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: NCCC(=O)O
Product: C=C(C)C(=O)NCCC(=O)O

Procedure:
Methacryloyl chloride was reacted with β-alanine to give N-methacryloyl β-alanine which was further reacted with p-nitro aniline to obtain N-methacryloyl β-alanyl p-nitro anilide. N-isobutyryl β-alanyl 2-amino pyridine was used as the print molecule, 0.5 gm (0.0021 mol) N-isobutyryl β-alanyl 2-amino pyridine, 0.468 gm (0.0021 mol) N-methacryloyl histidine, and 0.124 gm (0.0021 mol) CoCl2.6H2O were placed in 5 ml methanol and stirred for 1 hour. Methanol was evaporated under reduced pressure. The complex was diluted with 3.9 gm 2-hydroxyethyl methacrylate, 0.8 ml t-butyl hydroperoxide was added, and the mixture polymerized at 65° C. for 16 hours.
Reaction SMILES: OC1C=CC(C(OCC)=O)=CC=1.FC1C=CC(CBr)=CC=1.[F:22][C:23]1[CH:39]=[CH:38][C:26]([CH2:27][O:28][C:29]2[CH:37]=[CH:36][C:32]([C:33]([OH:35])=O)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1.[CH2:40]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)[CH:41]([CH3:43])[CH3:42]>>[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][O:28][C:29]2[CH:30]=[CH:31][C:32]([C:33]([N:47]3[CH2:48][CH2:49][N:44]([CH2:40][CH:41]([CH3:43])[CH3:42])[CH2:45][CH2:46]3)=[O:35])=[CH:36][CH:37]=2)=[CH:38][CH:39]=1
Reactant: CC(C)CN1CCNCC1
Reactant: O=C(O)c1ccc(OCc2ccc(F)cc2)cc1
Agent: CCOC(=O)c1ccc(O)cc1
Agent: Fc1ccc(CBr)cc1
Product: CC(C)CN1CCN(C(=O)c2ccc(OCc3ccc(F)cc3)cc2)CC1
Yield: 58.4 %

Procedure:
It was synthesized in the manner identical to Example 3. Namely, ethyl 4-hydroxybenzoate (2.50 g) was benzylated with 4-fluorobenzyl bromide (2.84 g) and then hydrolyzed. From thus obtained 3.57 g of 4-(4-fluorobenzyloxy) benzoic acid, 1.24 g was subjected to a condensation reaction with 1-isobutylpiperazine (0.71 g), thereby yielding 1.08 g of the aimed compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[N:4]=1.[CH3:26]N(C)CCN(C)C.C([Li])(C)(C)C.CI.[Cl-].[NH4+]>O1CCCC1.CCCCC>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[CH3:26])[N:6]=1
Reactant: COc1cc(OC)nc(Cc2ccccc2NC(=O)OC(C)(C)C)n1
Reactant: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1cc(OC)nc(C(C)c2ccccc2NC(=O)OC(C)(C)C)n1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
The product of stage (a) above (1 g) was dissolved in dry tetrahydrofuran (20 ml) and tetramethyl ethylenediamine (1.1 ml) was added under nitrogen. The solution was cooled to -70° C. and 1.7M t-butyllithium in pentane (4.3 ml) was added dropwise. The mixture was then stirred at about -20° C. for 1 hour. It was then cooled to -70° C., and methyl iodide (0.45 g) was added. The reaction mixture was allowed to warm to 0° C. and saturated ammonium chloride solution (25 ml) was added. The mixture was extracted with tetrahydrofuran (3×50 ml) and the combined extracts were dried and evaporated to give a pale brown solid which was triturated with hexane to give 0.73 g of the desired product, mp 119°-121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4](I)[CH:3]=1.C([Si]([O:17][CH2:18][C:19]#[C:20][Si](C(C)(C)C)(C)C)(C)C)(C)(C)C.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH:20]=[C:19]([CH2:18][OH:17])[C:4]=2[CH:3]=1
Reactant: Oc1ccc(Cl)cc1I
Reactant: CC(C)(C)[Si](C)(C)C#CCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: OCc1coc2ccc(Cl)cc12
Reaction time: 1.5 h
Yield: 46.1 %

Procedure:
To a mixture of 4-chloro-2-iodophenol (1 g, 3.92 mmol), tert-butyl(3-(tert-butyldimethylsilyl)prop-2-ynyloxy)-dimethylsilane (1.93 g, 6.8 mmol), LiCl (0.15 g; 3.5 mmol) and Na2CO3 (0.636 g; 6 mmol) in anhydrous DMF (10 ml) Pd(OAc)2 (0.3 g) was added at 100° C. under N2 and heating was continued for 1.5 h. The solvent was removed in vacuo and the residue was diluted to 100 ml with EtOAc, washed with H2O, dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the coupling product (0.64 g; 26%). This was dissolved in THF (5 ml) and 1M TBAF in THF (2 ml) was added to it and the mixture was stirred for 4 h at reflux. The solvent was distilled off and the residue was dilute to 50 ml with EtOAc, washed with 1M HCl, H2O, dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.33 g; 99%), as creamy paste. 1H-NMR (CDCl3) 7.63 (d, 1H, J=2.11 Hz); 6.60 (b, 1H); 7.37 (d, 1H, J=8.72 Hz); 7.25 (dd, 1H, J=8.71, 2.13 Hz); 4.79 (s, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br-:22].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)(Cl)Cl.CO.ClCCl>[Br:22][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1)=[O:3]
Reactant: [Br-]
Reactant: CC(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)CBr)cc2)CCC1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 150.1 %

Procedure:
To a solution of tert-butyl (1-(4-acetylphenyl)cyclobutyl)carbamate (0.1 g, 1 eq.) in chloroform (3.5 mL) and methanol (1.5 mL) was added the tetrabutyl ammonium tribromide (0.175 g, 1.05 eq.). The mixture was stirred at 40° C. for 90 minutes. The reaction mixture was diluted with dichloromethane (10 mL), washed with water (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by column chromatography (10% ethyl acetate in dichloromethane), giving tert-butyl (1-(4-(2-bromoacetyl)phenyl)cyclobutyl)carbamate (0.1 g, 78%) as a colorless oil. LCMS: 312 [M−tBu+H], 314 [M−tBu+H].
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[S:17][CH:18]=[C:19]([CH2:21][CH2:22][OH:23])[N:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].O[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:12]([C:9]1[CH:8]=[C:7]([C:16]2[S:17][CH:18]=[C:19]([CH2:21][CH2:22][O:23][C:25]3[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=3)[N:20]=2)[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)c1cc(-c2nc(CCO)cs2)cc(C(C)(C)C)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(-c2nc(CCOc3ccc(C=O)cc3)cs2)cc(C(C)(C)C)c1O
Temperature: -10 °C
Yield: 72.2 %

Procedure:
The compound of Step E 4.20 g (12.6 mmole), 1.76 g (14.44 mmole) 4-hydroxybenzaldehyde, and 3.79 g (14.44 mmole) triphenyl phosphine were dissolved in 37 ml tetrahydrofuran with stirring, under nitrogen. The solution was chilled to −10° C. and a solution of 2.27 ml (14.44 mmole) diethylazodicarboxylate in 12.5 ml. tetrahydrofuran was added over 10 minutes, with stirring. The reaction exothermed to −1° C. The bath was removed and the reaction stirred under nitrogen overnight. The reaction was stripped, dissolved in methylene chloride and placed in the freezer. The diethoxycarbonylhydrazine was then filtered off and the filtrate was chromatographed on 400 ml silica, eluting with a 15 then 20% ethyl acetate/hexane. The appropriate fractions were bulked and stripped to give 3.98 g (72%) product which was used without further purification.
Reaction SMILES: C1(C[N:8]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:9]2)C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO.O>[NH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9]1
Reactant: c1ccc(CN2CCC(c3ccccn3)C2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: c1ccc(C2CCNC2)nc1
Yield: 74.9 %

Procedure:
To a suspension of 2-[1-(phenylmethyl)-3pyrrolidinyl]pyridine (7.15 g, 30.0mmol) and 10% palladium on charcoal catalyst (1.90 g) in methanol (120 mL) was added dropwise a solution of ammonium formate (7.57 g, 120 retool) in water (30 mL). The mixture was heated at reflux for 30 minutes, allowed tocool to room temperature, and filtered. The filtrate was concentrated underreduced pressure, the residue was taken up in water (10 mL), and the solution was made basic with concentrated ammonia and extracted with dichloromethane (4×15 mL). The organic extracts were combined, driedover anhydrous potassium carbonate, and concentrated to a yellow oil. This crude product was chromatographed (silica gel, chloroform-methanol-ammonia75:25:5) to give the title compound (3.33 g, 75%) as a faint yellow liquid.
Reaction SMILES: COC1C=C(NC2C3C(=C(C)C=C(S(C4C=CC=C(C(=O)NC5C=CC(C6C=CC(CCCC=O)=CC=6)=CC=5)C=4)(=O)=O)C=3)N=CC=2C(N)=O)C=CC=1.[OH:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][C:59]1[CH:64]=[CH:63][C:62]([C:65]2[CH:70]=[CH:69][CH:68]=[C:67]([S:71]([C:74]3[CH:75]=[C:76]4[C:81](=[C:82]([CH3:84])[CH:83]=3)[N:80]=[CH:79][C:78]([C:85]([NH2:87])=[O:86])=[C:77]4[NH:88][C:89]3[CH:94]=[CH:93][CH:92]=[C:91]([O:95][CH3:96])[CH:90]=3)(=[O:73])=[O:72])[CH:66]=2)=[CH:61][CH:60]=1>>[CH3:96][O:95][C:91]1[CH:90]=[C:89]([NH:88][C:77]2[C:76]3[C:81](=[C:82]([CH3:84])[CH:83]=[C:74]([S:71]([C:67]4[CH:66]=[C:65]([C:62]5[CH:63]=[CH:64][C:59]([CH2:58][CH2:57][CH2:56][CH2:55][CH:54]=[O:53])=[CH:60][CH:61]=5)[CH:70]=[CH:69][CH:68]=4)(=[O:72])=[O:73])[CH:75]=3)[N:80]=[CH:79][C:78]=2[C:85]([NH2:87])=[O:86])[CH:94]=[CH:93][CH:92]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(-c5ccc(CCCCCO)cc5)c4)cc23)c1
Agent: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(-c6ccc(CCCC=O)cc6)cc5)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(-c5ccc(CCCCC=O)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 124, using Intermediate 69 as a substrate. ES/MS calcd. for C35H34N3O5S+ 608.2. Found m/z=608.3 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[F:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1.[OH-].[K+]>CN(C=O)C>[Cl:5][CH2:4][CH2:3][CH2:2][N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([F:6])[CH:15]=2)[CH:11]=[CH:12]1
Reactant: Fc1ccc2cc[nH]c2c1
Reactant: ClCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1ccc2ccn(CCCCl)c2c1
Temperature: 20 °C
Reaction time: 15 h
Yield: 60.7 %

Procedure:
To a solution of 1-bromo-3-chloropropane (700 mg, 4.44 mmol) in DMF (2.4 mL) was added 6-fluoroindole (200 mg, 1.48 mmol) and powder KOH (92 mg, 1.63 mmol) at 20° C. The reaction mixture was stirred for 15 h at 20° C. then quenched by addition of H2O and extracted with Et2O. The combined organic solution was successively washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed to give 1-(3-chloropropyl)-6-fluoroindole (190 mg, 66%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O>[CH3:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])=[CH:13][CH:12]=1
Reactant: O=Cc1cccc(O)c1
Reactant: Cc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(COc2cccc(C=O)c2)cc1

Procedure:
To 3-hydroxybenzaldehyde (5.00 g) dissolved in acetone (70 ml) were added 4-methylbenzyl chloride (6.51 ml), potassium carbonate (8.49 g) and sodium iodide (7.36 g), and the resulting mixture was heated at reflux for 24 hours and was then evaporated under reduced pressure to remove the solvent. The residue was mixed with water (200 ml) and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride was dried with anhydrous sodium sulfate, and was then evaporated under reduced pressure to remove the solvent. The thus-obtained residue was subjected to purification using column chromatography (ethyl acetate/hexane=1/10) to obtain 3-(4-methylbenzyloxy)benzaldehyde (7.86 g) as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=1[OH:36].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:23][CH2:24][CH2:25][O:26][C:27]4[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=4[OH:36])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)c1ccc(OCCCCl)c(O)c1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)c1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(O)c1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.8 g, 13 mmol ), NaHCO3 (1.1 g), several crystals of KI, 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone, and acetonitrile (100 ml) was refluxed for 16 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The organic extract was washed (water), dried (MgSO4), and the solvent was concentrated to afford 5.7 g of a thick yellow oil. The oil was chromatographed on a Waters Prep 500 LC on silica gel, eluting with 7% methanol/methylene chloride. Concentration of the appropriate fraction afforded a yellow oil, which upon standing yielded 3.5 g of the compound as a pale, yellow solid. The solid was recrystallized from ethyl alcohol to afford 2.7 g (50%) of 1-[4-[3-[4-(6-fluoro1,2-benzisoxazol-3-yl(-1-piperidinyl]-propoxy]-3-hydroxyphenyl]ethanone as a pale yellow solid, m.p.=122°-124° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:23]#[N:24])=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].[S:25](Cl)(=[O:28])(=[O:27])[NH2:26]>>[NH2:24][C:23]1[C:3]2[C:4]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:20][CH:21]=[CH:22][C:2]=2[NH:1][S:25](=[O:28])(=[O:27])[N:26]=1
Reactant: NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCCCOc1cccc(N)c1C#N
Product: CC(C)(C)OC(=O)NCCCCCCOc1cccc2c1C(N)=NS(=O)(=O)N2
Yield: 59.5 %

Procedure:
Prepared as in Example 274 from tert-butyl 6-(3-amino-2-cyanophenoxy)hexylcarbamate (Example 281a) and sulfamoyl chloride in 59.5% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.274 (m, 2H), 1.339 (s, 9H), 1.361 (m, 4H), 1.779 (pentet, J=7 Hz, 2H), 2.878 (q, J=6 Hz, 2H), 4.122 (t, J=6 Hz, 2H), 6.580 (d, J=8 Hz, 1H), 6.722 (d, J=8 Hz, 1H), 6.75 (br t, J=6 Hz, 1H), 7.428 (t, J=8 Hz, 1H), 7.798 (br. s, 1H), 8.323 (br. s, 1H), 10.921 (s, 1H). MS 413 (MH+).
Reaction SMILES: C1(COC([NH:11][CH2:12][CH2:13][C:14]2[O:15][C:16]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=2)=O)C=CC=CC=1.C(O)(=O)C>CO.[Pd]>[NH2:11][CH2:12][CH2:13][C:14]1[O:15][C:16]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:18]=1
Reactant: NS(=O)(=O)c1ccc(-c2oc(CCNC(=O)OCc3ccccc3)nc2-c2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: NCCc1nc(-c2ccccc2)c(-c2ccc(S(N)(=O)=O)cc2)o1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100.1 %

Procedure:
A solution of 4-[2-[2-(N-phenylmethoxycarbonylamino)ethyl]-4-phenyl-oxazol-5-yl]benzenesulfonamide (Step 1) (0.75 g, 1.6 mmol) in MeOH (15 mL) containing acetic acid (0.1 mL) was treated with 10% Pd on carbon (0.35 g) and stirred under an atmosphere of hydrogen at 50 psi at room temperature for 2.5 h. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to afford a white powder which was purified by reverse-phase HPLC using a gradient of 10-90% CH3CN in H2O to afford 0.55 g of 4-[2-(2-aminoethyl)-4-phenyloxazol-5-yl]benzenesulfonamide as its trifluoroacetate salt: 1H NMR (CD3OD/300 MHz) δ 7.91 (d, 2H, J=7.9 Hz), 7.74 (m, 2H,), 7.63 (m, 2H), 7.44 (m, 3H), 3.49 (t, 2H, J=6.6 Hz), 3.33 (t, 2H, J=6.6 Hz). FABMS m/z =344 (M+H). HRMS calcd for C17H18N3O5S 344.1069. Found 344.1048.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:12]2OS(C(F)(F)F)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+].CO>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:12]2[C:40]1[CH:41]=[CH:42][C:37]([Cl:36])=[CH:38][CH:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: COC(=O)c1c(-c2ccc(Cl)cc2)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Yield: 54.7 %

Procedure:
A mixed solution of methyl 6-benzyloxy-2-isobutyl-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate (10.27 g, 20 mmol), 4-chlorophenylboronic acid (3.75 g, 24 mmol) and sodium carbonate (5.30 g, 50 mmol) in toluene (50 ml)-methanol (10 ml)-water (10 ml) was stirred under an argon atmosphere at room temperature for 30 min. To the obtained mixture was added tetrakis(triphenylphosphine)palladium (1.15 g, 1 mmol) and the mixture was refluxed under heating under an argon atmosphere for 10 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 6-benzyloxy-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (5.21 g, 54.8%) as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([F:19])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([F:19])[CH:13]=2)=[N:28][OH:29])=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)cc(F)n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2ccc(Br)cc2)c2ccccc2C)=NO)cc(F)n1

Procedure:
In analogy to example 74, step 7, from 3-(4-bromo-phenyl)-1-(2-fluoro-6-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (2.4:1) as a colorless oil, MS (ESI+): m/z=427.0804 ([M+H]+, 1Br).