Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH2:26][C:27]([OH:29])=O)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH2:32][CH2:33][CH2:34][CH2:35][N:36]1[CH:40]=[CH:39][N:38]=[CH:37]1>C1COCC1>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]([NH:32][CH2:33][CH2:34][CH2:35][N:36]2[CH:40]=[CH:39][N:38]=[CH:37]2)=[O:29])=[CH:30][CH:31]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NCCCn1ccnc1
Reactant: O=C(O)COc1ccc(OCc2ccccc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(COc1ccc(OCc2ccccc2)cc1)NCCCn1ccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1′-Carbonyldiimidazole (16.2 g) was added to a stirred suspension of 4-benzyloxyphenoxyacetic acid (25.8 g) in dry THF (350 ml) and the mixture was stirred at ambient temperature for 2 hours. 1-(3-Aminopropyl)imidazole (12.5 g) was added and the mixture was stirred for a further 18 hours. The mixture was filtered and the filtrate evaporated to give a residue which was treated as in Example 9a to give 2-(4-benzyloxyphenoxy)-N-[3(imidazol-1-yl)propyl] acetamide m.p. 112-113° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:15]=3[C:22]=2[CH3:23])[CH2:7][CH2:6]1.C(N(C(C)C)CC)(C)C.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:2]([Cl:1])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[O:21])=[CH:16][C:15]=3[C:22]=2[CH3:23])[CH2:7][CH2:6]1
Reactant: Cc1c(N2CCN(Cc3c(Cl)cccc3Cl)CC2)ccc2oc(C(=O)O)cc12
Reactant: C1COCCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(N2CCN(Cc3c(Cl)cccc3Cl)CC2)ccc2oc(C(=O)N3CCOCC3)cc12
Reaction time: 0.25 h
Yield: 42.2 %

Procedure:
To a solution of 5-[4-(2,6-Dichloro benzyl)-piperazine-1-yl]-4-methyl-benzofuran-2-carboxylic acid (0.07 g, 0.00017 mol) in anhydrous DMF (275 ml) was added diisopropyl ethyl amine (0.08 ml, 0.0005 mol) and morpholine (0.16 ml, 0.00018 mol) under nitrogen atmosphere. The reaction mixture was stirred for 15 minutes, added Py-BOP (0.11 g, 0.0002 mol) and stirred for 1 hour. The completion of the reaction was confirmed by TLC. The reaction mixture was quenched into ice water. The solid separated was filtered. After drying under vacuum, the crude product was isolated as white solid. The crude product was purified by Prep HPLC using a Zorbax C-18 column with mobile phase 0.1% trifluoroacetic acid in water (A)/Acetonitrile (B) with a flow rate of 20 ml/min to yield {5-[4-(2,6-dichlorobenzyl)piperazine-1-yl]-4-methyl-benzofuran-2-yl}-morpholin-4-yl-methanone (35 mg, 43%).
Reaction SMILES: C([N:3](CC)CC)C.Cl[C:9]([CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16](OC(=O)C2C=CC(F)=C(F)C=2)=[CH:15][CH:14]=1)=[O:10].[CH3:30][OH:31]>CN1CCCC1=O>[C:9]1(=[O:10])[NH:3][C:30](=[O:31])[CH:12]=[CH:11]1.[CH2:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CO
Reactant: CCN(CC)CC
Reactant: O=C(Cl)C=Cc1ccc(OC(=O)c2ccc(F)c(F)c2)cc1
Solvent: CN1CCCC1=O
Product: C=Cc1ccccc1
Product: O=C1C=CC(=O)N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
2.74 g (9.033 mmol) of polyhydroxymaleimide-polyhydroxystyrene was dissolved in 50 ml of N-methylpyrrolidone (NMP). After the solution was cooled to 0° C., 3.291 g (32.52 mmol) of triethylamine (Et3N) was added thereto. The mixture was stirred for 30 minutes. 6.995 g (21.679 mmol) of 3,4-difluoro-benzoic acid 4-(2-chlorocarbonyl-vinyl)-phenyl ester was added to the mixture and stirred at room temperature for 4 hours. The reaction solution was poured into an aqueous solution of methanol, and filtered to obtain a solid. The solid was washed with water several times and dried in vacuo, affording the desired compound 2 (yield: 60%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5](=[O:15])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4](=[CH:19][N:20]([CH3:22])[CH3:21])[C:5](=[O:15])[CH:6]=[CH:7][C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1
Reactant: COC(=O)CC(=O)C=Cc1ccc(Cl)cc1
Reactant: COC(OC)N(C)C
Solvent: c1ccccc1
Product: COC(=O)C(=CN(C)C)C(=O)C=Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
14.8 g. of 5-(4-chlorophenyl)-3-oxo-4-pentenoic acid methyl ester were dissolved in 100 ml. of benzene and treated with N,N-dimethylformamide dimethylacetal. The red-brown colored solution was stirred at 60° C. for 30 minutes, solvent and excess reagent were removed and there was obtained 5-(4-chlorophenyl)-2-(dimethylaminomethylene)-3-oxo-4-pentenoic acid methyl ester in the form of a red-brown oil which was further processed in this form.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27]COS(C)(=O)=O)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][NH:35][CH2:36][CH2:37][OH:38].[CH3:39]N(C=O)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:34][N:35]([CH2:36][CH2:37][OH:38])[CH3:39])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CNCCO
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(F)c3)cn2CCOS(C)(=O)=O)CC1
Product: CN(CCO)CCn1cc(-c2ccc(F)c(F)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 52.2 %

Procedure:
Combine 4-[4-(3,4-difluoro-phenyl)-1-(2-methanesulfonyloxy-ethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (3.0 g; 0.0061 mol; 1.0 equiv), 2-methylamino-ethanol (1.48 g; 0.031 mol; 5.0 equiv) in DMF (30 mL) and stir at 40-50° C. for 16 h. Quench with water and extract with diethyl ether. Evaporate the organic layer, purify over 50 g silica gel with 0 to 10% MeOH/DCM. Pool fractions to produce the title compound (1.5 g; 52.2%) MS (ES+): m/z=465 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1.[CH3:13][C:14]([CH3:19])([CH3:18])[C:15](Cl)=[O:16].[H-].[Na+]>CN(C=O)C>[CH3:13][C:14]([CH3:19])([CH3:18])[C:15]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1)=[O:16]
Reactant: CC(C)(C)C(=O)Cl
Reactant: N#CCc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)n1cc(CC#N)c2ccccc21
Yield: 38.7 %

Procedure:
Using the procedure of subpart A above, the N-alkylation reaction of 10.2 g (65 mmol) of commercially available (1H-indol-3-yl)-acetonitrile (5) (1H-indol-3-yl)-acetonitrile (Acros Organics, Belgium) with 8.7 ml (71 mmol) of trimethylacetyl chloride and 3.4 g (85 mmol) of NaH (60% dispersion in oil) as a base in 115 ml of DMF yielded 6.6 g (38.7%) of [1-(2,2-dimethyl-propionyl)-1H-indol-3-yl]-acetonitrile (6) as a yellow oil after chromatographic purification.
Reaction SMILES: Cl.[C:2]([CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:21](=[CH:22][CH:23]=1)[O:20][C:14]1([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH2:13][C:12]2=[O:24])=[O:8])(=[O:4])[NH2:3].[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([O:43][CH2:44][CH3:45])[C:36]=1[C:37]1[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=1)[C:31](O)=[O:32])[CH3:26].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.C(N(CC)CC)C>[C:2]([CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:21](=[CH:22][CH:23]=1)[O:20][C:14]1([CH2:19][CH2:18][N:17]([C:31]([C:30]3[CH:34]=[C:35]([O:43][CH2:44][CH3:45])[C:36]([C:37]4[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=4)=[C:28]([O:27][CH2:25][CH3:26])[CH:29]=3)=[O:32])[CH2:16][CH2:15]1)[CH2:13][C:12]2=[O:24])=[O:8])(=[O:4])[NH2:3]
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1-c1cnn(C)c1
Reactant: NC(=O)CNC(=O)c1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C(=O)NCC(N)=O)ccc2O3)cc(OCC)c1-c1cnn(C)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
N-Carbamoylmethyl-4-oxospiro[chroman-2,4′-piperidine]-6-carboxamide hydrochloride (354 mg), 3,5-diethoxy-4-(1-methyl-1H-pyrazol-4-yl)benzoic acid (145 mg), WSC hydrochloride (115 mg), HOBT (91.2 mg) and triethylamine (0.209 mL) were suspended in DMF (3 mL), and stirred at 50° C. for 16 hours. Water was added to it, the formed solid was taken out through filtration, and the resulting solid was purified through silica gel column chromatography (chloroform/methanol), and crystallized from chloroform/diethyl ether to obtain the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 8.75 (1.0H, t, J=5.6 Hz), 8.35-8.28 (1.0H, m), 8.09 (1.0H, dd, J=8.8, 2.2 Hz), 8.04 (1.0H, s), 7.92 (1.0H, s), 7.35 (1.0H, s), 7.17 (1.0H, d, J=8.8 Hz), 7.00 (1.0H, s), 6.68 (2.0H, s), 4.31-4.02 (1.0H, m), 4.08 (4.0H, q, J=7.0 Hz), 3.86 (3.0H, s), 3.77 (2.0H, d, J=5.9 Hz), 3.64-3.02 (3.0H, m), 2.93 (2.0H, s), 2.10-1.72 (4.0H, m), 1.37 (6.0H, t, J=7.0 Hz). MS [M+H]+=590.
Reaction SMILES: [N:1]([C@H:4]([CH3:20])[CH2:5][N:6]1[C:10]2=[CH:11][C:12]3[C:17]([CH2:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])=[C:9]2[CH:8]=[N:7]1)=[N+]=[N-].[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25]>C(O)C.C(OCC)C.CO.[Pt]=O>[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25].[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH2:16][C:17]2[C:12]=1[CH:11]=[C:10]1[C:9]=2[CH:8]=[N:7][N:6]1[CH2:5][C@H:4]([NH2:1])[CH3:20]
Reactant: COC1=C2C=c3c(cnn3C[C@@H](C)N=[N+]=[N-])=C2CC=C1
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Solvent: CCO
Solvent: CO
Product: COC1=C2C=c3c(cnn3C[C@@H](C)N)=C2CC=C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.7 %

Procedure:
0.5 g (1.85 mmol) of (R)-1-(2-azido-propyl)-7-methoxy-1,4-dihydro-indeno[2,1-c]pyrazole dissolved in 50 ml of anhydrous ethanol were hydrogenated over 50 mg of platinum oxide for 2 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The colorless oil obtained was dissolved in 70 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 215 mg(1.85 mmol) of fumaric acid in 5 ml of methanol. The mixture was stirred at room temperature for 15 hours and the white crystals were subsequently filtered off. 0.55 g (83%) of (R)-2-(7-methoxy-1,4-dihydro-indeno[2,1-c]pyrazol-1 -yl)-1-methyl-ethylamine fumarate (1:1) with m.p. 180° was obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1.[CH3:16][NH:17][C@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19].O>CS(C)=O>[CH3:11][C:8]1[N:6]2[N:7]=[C:2]([N:17]([CH3:16])[C@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2=[N:10][N:9]=1
Reactant: COC(=O)c1cc(Cl)nn2c(C)nnc12
Reactant: CN[C@@H](C)c1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc(N(C)[C@@H](C)c2ccccc2)nn2c(C)nnc12
Yield: 15 %

Procedure:
A solution of methyl 6-chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate (2.0 g, 8.85 mmol) and (S)-N-methyl-1-phenylethanamine (2.39 g, 17.7 mmol; commercially available from Aldrich) in DMSO (20 mL) was heated at 130° C. in a microwave tube for 30 min. Water (100 mL) was added to the reaction mixture, and the product was extracted with EtOAc (3×100 mL). The combined EtOAc layers were concentrated and the residue was purified by flash chromatography (silica gel, 1% to 10% MeOH in CH2Cl2) to give the (S)-methyl 3-methyl-6-(methyl(1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate (400 mg, 15% yield). LRMS [M+H]+: 325 m/z.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11](Cl)=[O:12])=[CH:7][C:5]=2[N:6]=1.[CH3:14][Mg]Cl.Cl>O1CCCC1.O>[C:11]([C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([Cl:1])=[N:6][C:5]=2[CH:7]=1)(=[O:12])[CH3:14]
Reactant: C[Mg]Cl
Reactant: O=C(Cl)c1ccc2sc(Cl)nc2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc2sc(Cl)nc2c1
Reaction time: 0.5 h

Procedure:
A solution of 2-chloro-5-(chlorocarbonyl)benzothiazole (321 mg, 1.38 mmol, prepared according to U.S. Pat. No. 3,654,296) and ferric acetylacetonate (14.7 mg, 0.042 mmol) in anhydrous tetrahydrofuran (13.8 mL) was cooled in an ice-methanol bath (−20° C.), stirred under a nitrogen atmosphere, and treated dropwise over 5 minutes with 1M methyl magnesium chloride in tetrahydrofuran (1.38 mL). The resulting mixture was stirred at −15° C. for 15 minutes then at room temperature for 30 minutes. The mixture was treated with 2N hydrochloric acid (1.38 mL), diluted with water, and extracted with ethyl acetate. The extracts were washed with 5% aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo to white solid (299 mg). The crude product was purified by flash chromatography on silica gel (25 g, loaded as a dichloromethane solution and eluted with 2% ethyl acetate in dichlormethane) to afford 5-acetyl-2-chlorobenzothiazole (201 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25]
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(F)c1F
Reactant: COC(=O)CBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(F)c1F
Reaction time: 0.25 h
Yield: 80.8 %

Procedure:
40% Methanolic Triton B (0.51 mL, 1.12 mM) was added to a solution of the 9-[(2,3-difluorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (303 mg, 0.86 mM) in 5 mL DMF at room temperature. After 15 minutes, methyl bromoacetate (270 mg, 1.72 mM) was added and the resultant mixture stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate, washed with H2O, 1 N HCl, H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 295 mg (80%) of the {9-[(2,3-difluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (CDCl3) δ 7.5-7.3 (m, 5H), 7.05 (d, 1H, J=8 Hz), 6.8 (m, 1H), 6.6 (d, 1H, J=8 Hz), 6.4 (t, 1H, J=8 Hz), 6.2 (br s, 1H), 6.0 (br s, 1H), 5.6 (s, 2H), 4.9 (s, 2H), and 3.8 (s, 3H). IR (KBr, cm−1) 3432, 3180, 1774, 1766, and 1674. MS (ES) m/e 425.
Reaction SMILES: C[Sn]1(C)[C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:4]2[S:10][CH:11]=[CH:12][C:3]1=2.Br[C:15](Br)=[CH:16][CH2:17][CH2:18][CH3:19]>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:16](=[C:15]1[C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:4]2[S:10][CH:11]=[CH:12][C:3]1=2)[CH2:17][CH2:18][CH3:19]
Reactant: CCCC=C(Br)Br
Reactant: C[Sn]1(C)c2ccsc2-c2sccc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: C1CCOC1
Product: CCCC=C1c2ccsc2-c2sccc21
Reaction time: 8 h
Yield: 30.9 %

Procedure:
500 mg (1.6 mmol) of 52 and 364 mg (1.6 mmol) of dibromopentene were dissolved in 32 ml of freshly distilled THF, and 42 mg (80 μmol) of bis(tri-tert-butylphosphine)palladium(0) were added. The reaction mixture was refluxed while stirring for 8 hours. THF was removed by rotary evaporation and the residue was taken up in n-hexane. The crude product was purified by means of column chromatography (n-hexane as the eluent (Rf=0.4)) to obtain 115 mg of the target compound 53 (37% yield). GC-MS m/z 232 (18.10 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:5][C:4]=1[NH2:26].[C:27]([N:35]=[C:36]=[S:37])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(C)=O.C(OCC)(=O)C>[C:27]([NH:35][C:36]([NH:26][C:4]1[CH:5]=[C:6]([N:9]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[S:37])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1ccc(N(Cc2ccc(C)cc2)Cc2ccc(C)cc2)cc1N
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(N(Cc2ccc(C)cc2)Cc2ccc(C)cc2)cc1NC(=S)NC(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
To a stirred solution of 400 mg (1.15 mmol) 4-methoxy-N1,N1-bis-(4-methyl-benzyl)-benzene-1,3-diamine in 8 ml acetone was added dropwise a solution of 0.18 ml (1.34 mmol) benzoyl isothiocyanate in 4 ml acetone and stirring continued for 30 minutes at room temperature. The mixture was then diluted with ethyl acetate and washed with water and then with brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/9 ethyl acetate/hexane) afforded 320 mg (80%) 1-benzoyl-3-{5-[bis-(4-methyl-benzyl)-amino]-2-methoxy-phenyl}-thiourea as a yellow oil. ES-MS m/e (%): 510 (M+H+, 100).
Reaction SMILES: CO[C:3](=O)[C:4]1C=CC=C(Br)C=1.[C:12](OC1C=CC(Br)=CC=1C)(=O)[CH3:13].C([C:26]1[C:27]([C:33]([OH:35])=O)=[N:28][CH:29]=[C:30]([Br:32])[CH:31]=1)C.C([Mg]Br)C>C(Cl)Cl>[Br:32][C:30]1[CH:31]=[CH:26][C:27]([C:33]([OH:35])([CH2:12][CH3:13])[CH2:3][CH3:4])=[N:28][CH:29]=1
Reactant: CCc1cc(Br)cnc1C(=O)O
Reactant: COC(=O)c1cccc(Br)c1
Reactant: CC(=O)Oc1ccc(Br)cc1C
Agent: CC[Mg]Br
Solvent: ClCCl
Product: CCC(O)(CC)c1ccc(Br)cn1

Procedure:
The title compounds were prepared using methyl-3-bromobenzoate, methyl-4-bromophenyl acetate, ethyl-5-bromo-2-carboxypyridine or ethyl-5-bromo-2-carboxypyridine and ethyl magnesium bromide with methylene chloride as solvent, respectively, but otherwise followed the procedure detailed for Preparation 36.
Reaction SMILES: [C:1]1([C:7]([OH:11])([C:9]#[CH:10])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1/[C:15](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:16](=[O:22])[NH:17]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:11][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:8])[C:9]#[C:10][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1/[C:15](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:16](=[O:22])[NH:17]2
Reactant: C#CC(C)(O)c1ccccc1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(C)(O)c3ccccc3)c21

Procedure:
Using Method C above, 2-phenyl-3-butyn-2-ol (70 mg, 0.48 mmol) (Aldrich) was coupled to (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2) using (Ph3P)2PdCl2 (20 mg) (Aldrich) and CuI (10 mg) (Aldrich) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h, yielding rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-phenyl-1-butynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 85 mg, 55%).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C@H:18]([C:20]([CH2:22][CH2:23][C@@:9]34[OH:24])=O)[O:19][C:4]([C:5]=25)=[C:3]([OH:25])[CH:2]=1.Cl.C[O:28][NH2:29].Cl.[OH-].[Na+].[CH3:33]O>O>[CH3:33][CH:20]1[C:22](=[N:29][OH:28])[CH2:23][C@:9]2([OH:24])[C@:10]34[CH2:11][CH2:12][N:13]([CH2:14][CH:15]5[CH2:17][CH2:16]5)[C@@H:8]2[CH2:7][C:6]2[CH:1]=[CH:2][C:3]([OH:25])=[C:4]([O:19][C@@H:18]13)[C:5]4=2
Reactant: CON
Reactant: CO
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1C(=NO)C[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5

Procedure:
Naltrexone hydrochloride (1.134 g, 3 mmol) was added to a solution of CH3ONH2HCl (0.33 g, 3.9 mmol) in 15 mL MeOH containing 3.2 mL 10% aqueous NaOH. The mixture was refluxed for 5 h, cooled, diluted with approximately 100 mL H2O and extracted with 150 mL CHCl3 (3×50 mL). The combined CHCl3 extracts were dried (MgSO4) and evaporated. TLC showed that the reaction was incomplete and hence the reaction was repeated as before using the mixture, CH3ONH2HCl (0.165 g, 1.9 mmol) and 0.8 mL of 10% aqueous NaOH. After workup the product was chromatographed on a column of silica gel (approx. size 40 microns) using EtOAC-EtOH-NH4OH (100:1:0.5) as eluent. The fractions were combined, evaporated and the residue recrystallized from hexane-petroleum ether. Yield: 0.55 g (49.6%). mp 172°-173° C. IR (KBr): No C=O absorption at 1720 cm-1 ; 1H NMR: (CDCl3)δ4.95 (s, C5H), 3.82 (s, OCH3); Rf: silica gel 60 in EtOAc-EtOH-NH4OH (100:1:1) 0.40. Anal. Caled for C21H26N2O4 : C, 68.09; H, 7.07; N, 7.56. Found: C, 67.96; H, 7.11; N, 7.55.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][C:13](=O)[NH:12][CH2:11]3)[C:9](=[O:16])[N:8]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:5]2=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:28][C:29]1[C:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:31][O:32][C:33]=1[CH3:34].CN(C=[O:45])C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([CH2:28][C:29]4[C:30]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[N:31][O:32][C:33]=4[CH3:34])[C:11]3=[O:45])[C:9](=[O:16])[N:8]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[C:5]2=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccccc2)c1CBr
Reactant: CC(C)(C)OC(=O)CN1C(=O)C2(CNC(=O)C2)c2cc(Cl)ccc21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1onc(-c2ccccc2)c1CN1CCC2(C1=O)C(=O)N(CC(=O)OC(C)(C)C)c1ccc(Cl)cc12
Reaction time: 1 h
Yield: 58 %

Procedure:
A suspension of tert-butyl (5-chloro-2,5′-dioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl)acetate, intermediate 41 (100 mg; 0.29 mmol) in dry DMF (5 ml) was treated with sodium hydride pract. (14.8 mg; 0.37 mmol). After stirring for 20 minutes 4-(bromomethyl)-5-methyl-3-phenylisoxazole (86.24 mg; 0.34 mmol) was added. After stirring for 1 h the solvent was evaporated to give a residue, which was dissolved in ethyl acetate. The organic phase was washed with brine, dried (MgSO4) and removed in vacuo, to give a solid residue which was purified by chromatography (silica), eluting with cyclohexane containing increasing amounts of ethyl acetate (30 to 50%), to give the title compound in 58% yield (HPLC purity 99%). MS (ESI+): 522.4; MS (ESI−): 520.2
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:15](Br)[C:16]#[CH:17]>CC(C)=O>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:17][C:16]#[CH:15])[CH2:5][CH2:4]1)[CH3:2]
Reactant: C#CCBr
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCN1CCN(CC)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the 1-ethylpiperazine (2.33 g, 20.2 mmol) and K2CO3 (2.79 g, 20.2 mmol) in acetone (27 ml) was added propargyl bromide (2.00 g, 13.5 mmol) dropwise at 0° C. under N2. The reaction was stirred at room temperature overnight. The reaction was filtered and the salts washed with a small amount of acetone. The filtrates were combined and evaporated gently to concentration. The residue was taken up in EtOAc and washed with water. The aqueous phase was re-extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. The product was filtered and evaporated to dryness to leave a pale orange oil.