Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+].[NH:15]1[C:19]([C:20]2[CH:21]=[C:22]([C:26]3[CH:27]=[CH:28][C:29]4[O:33][C:32]([C:34]5[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=5)=[C:31]([C:41]([NH:43][CH3:44])=[O:42])[C:30]=4[CH:45]=3)[CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:17]=[N:16]1>CN(C=O)C>[CH2:2]([N:15]1[C:19]([C:20]2[CH:21]=[C:22]([C:26]3[CH:27]=[CH:28][C:29]4[O:33][C:32]([C:34]5[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=5)=[C:31]([C:41]([NH:43][CH3:44])=[O:42])[C:30]=4[CH:45]=3)[CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:17]=[N:16]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4ccn[nH]4)c3)cc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4ccnn4Cc4ccccc4)c3)cc12
Reaction time: 8 h
Yield: 35 %

Procedure:
(Bromomethyl)benzene (17 mg, 0.097 mmol) was added to a stirring solution of Na2CO3 (11 mg, 0.097 mmol) and 5-(3-(1H-pyrazol-5-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (20 mg, 0.049 mmol) in DMF (486 μL) at 100° C. It was allowed to stir overnight, filtered and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (8.6 mg, 35%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.49-8.57 (1H, m), 8.06-8.11 (1 H, m), 7.98-8.04 (2H, m), 7.92 (1H, d, J=2.44 Hz), 7.86-7.89 (1H, m), 7.75-7.83 (2H, m), 7.69-7.75 (1H, m), 7.63 (1H, d, J=8.24 Hz), 7.51 (1H, t, J=7.63 Hz), 7.34-7.43 (4H, m), 7.27-7.32 (3H, m), 6.89 (1H, d, J=2.44 Hz), 5.41 (2H, s), 2.86 (3H, d, J=4.58 Hz). LC-MS retention time: 2.00 min; m/z (MH+): 502. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=15.47 min, purity=99%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 mm, Rt=13.77 min, purity=100%.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH3:25])=[N:21][CH:22]=1.O1CCOCC1.Cl>>[CH2:24]([O:23][C:20]1[N:21]=[CH:22][C:17]([NH:16][C:2]2[C:7]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:18][CH:19]=1)[CH3:25]
Reactant: CCOc1ccc(N)cn1
Reactant: Cc1nc(N)nc(-c2cccnc2F)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCOc1ccc(Nc2ncccc2-c2nc(C)nc(N)n2)cn1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4-(2-Fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.100 g, 0.49 mmol), 5-amino-2-ethoxypyridine (Combi-Blocks, Inc., San Diego, Calif.), 1,4-dioxane (0.75 mL, 8.8 mmol), (Aldrich, St. Louis, Mo.) and 2 N aqueous HCl (0.24 mL, 0.49mmol) were added to a 50 mL round-bottomed flask. The suspension was stirred at 100° C. overnight. The crude product was adsorbed onto a plug of silica gel and purified by chromatography through a RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (40 g), eluting with a gradient of 5% to 20% methanol in dichloromethane to give 4-(2-(6-ethoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine LCMS (API-ES) m/z 324 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.80 (br. s., 1H); 8.83 (br. s., 1H); 8.27 (d, J=4.11 Hz, 1H); 8.26 (d, J=4.11 Hz, 1H); 8.11 (br. s., 1H); 7.82 (dd, J=2.93, 1.56 Hz, 1H); 8.81 (d, J=4.11 Hz, 1H); 6.92 (br. s., 1H); 6.86 (d, J=9.39 Hz, 1H); 4.28-4.37 (m, 2H); 2.44 (br. s., 3H); 1.33 (t, J=7.04 Hz, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:23]([C:34]([O:36][CH3:37])=[O:35])[CH2:22]1.[N:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1.O1CCCC1.N(C(OCC)=O)=NC(OCC)=O>>[N:38]1[CH:43]=[CH:42][C:41]([O:20][C@@H:21]2[CH2:26][CH2:25][C@H:24]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[C@@H:23]([C:34]([O:36][CH3:37])=[O:35])[CH2:22]2)=[CH:40][CH:39]=1
Reactant: COC(=O)[C@H]1C[C@@H](O)CC[C@@H]1C(=O)OC(C)(C)C
Reactant: Oc1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@H](Oc2ccncc2)CC[C@@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triphenylphosphine (2.0E3 mg, 0.0077 mol) was added to a solution of 1-tert-butyl 2-methyl (1S,2S,4S)-4-hydroxycyclohexane-1,2-dicarboxylate (1.0 g, 0.0039 mol) and 4-pyridinol (730 mg, 0.0076 mol) in tetrahydrofuran (10.0 mL, 0.123 mol) at rt. A solution of diethyl azodicarboxylate (1200 uL, 0.0077 mol) in tetrahydrofuran (10.0 mL, 0.123 mol) was added. The reaction mixture was stirred at rt overnight. The reaction was chromatographed by combiflash (ethyl acetate in hexanes: 80%) to give 1-tert-butyl 2-methyl (1S,2S,4R)-4-(pyridin-4-yloxy)cyclohexane-1,2-dicarboxylate, contaminated with a little Ph3PO, which was used in next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[NH:35][C:36]([C:38]1[C:46]2[N:45]=[C:44]([CH2:47][N:48]3C(=O)C4=CC=CC=C4C3=O)[NH:43][C:42]=2[CH:41]=[CH:40][CH:39]=1)=[O:37])[C:6]([N:8]([CH3:31])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23])=[O:7].O.NN>C(O)C>[NH2:48][CH2:47][C:44]1[NH:43][C:42]2[CH:41]=[CH:40][CH:39]=[C:38]([C:36]([NH:35][C:34]3[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH3:31])[C:9]4[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=4[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)=[O:23])=[O:7])=[CH:4][C:3]=3[O:2][CH3:1])=[O:37])[C:46]=2[N:45]=1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(CN3C(=O)c4ccccc4C3=O)nc12
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(CN)nc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To a solution of 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-4-(2-phthalimidomethyl-1H-benzimidazol-4-yl)carbonylaminobenzamide (383 mg) in ethanol (5 ml) was added hydrazine monohydrate (19 mg) at ambient temperature and the solution was stirred at 60° C. for 1 hour. The reaction mixture was stirred in an ice water bath for 2 hours and the precipitate was filtered off. The filtrate was evaporated in vacuo and the residue was purified by preparative thin-layer chromatography (chloroform-methanol-ammonia solution (28%)=160:32:1) to give 4-(2-aminomethyl-1H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (200 mg) as a powder.
Reaction SMILES: [CH3:1][C:2]([S:5]([N:7]=[C:8]1[CH2:11][O:10][CH2:9]1)=[O:6])([CH3:4])[CH3:3].[F-].C[N+](C)(C)C.C[Si](C)(C)[C:20]([F:23])([F:22])[F:21]>C1COCC1>[CH3:4][C:2]([S:5]([NH:7][C:8]1([C:20]([F:23])([F:22])[F:21])[CH2:11][O:10][CH2:9]1)=[O:6])([CH3:1])[CH3:3]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)S(=O)N=C1COC1
Agent: C[N+](C)(C)C
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC1(C(F)(F)F)COC1
Temperature: -35 °C
Reaction time: 2 h
Yield: 37.8 %

Procedure:
2-Methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (100 mg, 0.571 mmol) was dissolved in THF (2 mL). The solution was cooled down to −35° C. and added tetramethylammonium fluoride (63.8 mg, 0.685 mmol). The mixture was degassed and charged with argon. Trimethyl(trifluoromethyl)silane (0.134 ml, 0.856 mmol) in THF (1 mL) was added slowly via syringe. The reaction was stirred at this temperature for 2 h, warmed to −10° C. and quenched with saturated aqueous NH4Cl solution. The mixture was extracted with ethyl acetate, dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography to give the title compound (53 mg). LCMS m/z=246.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 1.29 (s, 9H), 3.79 (s, 1H), 4.78-4.85 (m, 3H), 4.98 (dd, J=7.6 and 1.3 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[C:18]([O:26][C:27](=O)[CH3:28])[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:38][C:39]1[CH:40]=[C:41](CCO)[CH:42]=[CH:43][CH:44]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CO>[CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:25])[F:24])=[C:18]([O:26][CH2:27][CH2:28][C:43]3[CH:44]=[C:39]([CH3:38])[CH:40]=[CH:41][CH:42]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2ccc(C(F)(F)F)c(OC(C)=O)c2)Cc2ccccc2C1
Reactant: Cc1cccc(CCO)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: COC(=O)C1(NC(=O)c2ccc(C(F)(F)F)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
200 mg (0.48 mmol) of the compound of step 2 were dissolved in 5 ml of methanol, 13.1 mg (0.1 mmol) of potassium carbonate were added and the mixture was stirred for 30 min. The mixture was acidified with 1 N hydrochloric acid and extracted three times with 20 ml portions of EA. The combined organic phases were dried and evaporated. The residue was dissolved in 5 ml of THF, 96.9 mg (0.71 mmol) of 2-(3-methylphenyl)-ethanol and 186.7 mg (0.71 mmol) of triphenylphosphine were added, the mixture was cooled in an ice bath, and 191.9 mg (0.95 mmol) of DIAD were added. After stirring overnight, the mixture was evaporated to dryness and the residue was purified by preparative RP HPLC (water/ACN gradient). 104 mg of the title compound were obtained.
Reaction SMILES: C[O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].Cl.N1C=CC=CC=1>O>[OH:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COc1ccccc1Oc1ccccc1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)c1ccccc1Oc1ccccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
Fifteen grams of 2-(2-methoxyphenoxy)benzoic acid were heated at 180°-185° C. together with 150 g of pyridine hydrochloride for 3 hours. After cooling to room temperature, water was added and the mixture was stirred overnight at room temperature. The reaction was filtered and the water extracted several times with ethyl acetate. The combined ethyl acetate layers were dried and concentrated in vacuo. The crystallization of the residue from ethyl acetate/hexane provided 6.88 g of the desired subtitled intermediate, m.p. 147°-149° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:11][OH:12].Br[CH:19]([CH3:21])[CH3:20]>CN(C=O)C>[CH:19]([O:7][C:8]1[CH:9]=[C:10]([CH2:11][OH:12])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])([CH3:21])[CH3:20]
Reactant: COc1ccc(CO)cc1O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CO)cc1OC(C)C

Procedure:
Potassium carbonate (13.5 g) was added to a solution of 3-hydroxy-4-methoxybenzyl alcohol (10.0 g) and 2-bromopropane (9.15 ml) in dry DMF (100 ml) and the mixture was heated to reflux for 72 hours. The solvent was removed under vacuum. The residue obtained was partitioned between water and ethyl acetate. The aqueous phase was re-extracted with ethyl acetate (2×) and the combined organics were passed through a hydrophobic frit. The solvents were removed under vacuum.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:21])[CH2:10][CH2:11][CH:12]2[C:17](=[O:18])[CH:16]3[CH2:19][CH2:20][N:13]2[CH2:14][CH2:15]3)=[CH:5][C:4]=1[N+:22]([O-])=O.[H][H]>[Pd].C(O)C>[ClH:2].[ClH:1].[NH2:22][C:4]1[CH:5]=[C:6]([C:9](=[O:21])[CH2:10][CH2:11][CH:12]2[C:17](=[O:18])[CH:16]3[CH2:19][CH2:20][N:13]2[CH2:14][CH2:15]3)[CH:7]=[CH:8][C:3]=1[Cl:2]
Reactant: [H][H]
Reactant: O=C(CCC1C(=O)C2CCN1CC2)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1cc(C(=O)CCC2C(=O)C3CCN2CC3)ccc1Cl

Procedure:
Hydrogenate 11.2 g (0.03 mole) of 2-[3-(4-chloro-3-nitrophenyl)-3-oxopropyl]-1-azabicyclo[2.2.2]octan-3-one hydrochloride over 1.5 g of 10% palladium on carbon catalyst in 250 ml of ethanol. Follow the progress of the reaction by hydrogen uptake and by thin-layer chromatography. When the reaction is complete remove the catalyst by filtration. To the filtrate add 5 ml of concentrated hydrochloric acid. Remove the solvent in vacuo to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:26])[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[N:15][CH:14]=1.[N+:27]([O-])([OH:29])=[O:28].C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C>[O:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:26])[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[N:15][CH:14]=1)[N+:27]([O-:29])=[O:28]
Reactant: CN1CCN(c2ccc(C(=O)NCCCCCCCCCO)cn2)CC1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)OC(C)=O
Product: CN1CCN(c2ccc(C(=O)NCCCCCCCCCO[N+](=O)[O-])cn2)CC1
Reaction time: 6 h
Yield: 69 %

Procedure:
1.67 g of N-(9-hydroxy-1-nonyl)-6-(4-methyl-1-piperazinyl)nicotinamide were suspended in 40 ml of acetonitrile and to the suspension was added dropwise under ice-cooling a mixed solution of 0.8 ml of fuming nitric acid and 1.9 ml of acetic anhydride and stirred for 6 hrs. This reaction mixture was poured into an aqueous sodium hydrogencarbonate solution, extracted with methylene chloride, washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to give 1.30 g (69%) of the title compound. m.p. 90°-92° C.
Reaction SMILES: CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:23][C:24]([CH3:53])([CH3:52])[C@H:25]([NH:37][C:38]([C@H:40]([CH2:49][CH:50]=[CH2:51])[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:39])[C:26]([NH:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])=[O:27].[CH3:54][C:55]1[CH:56]=[C:57](Br)[CH:58]=[CH:59][C:60]=1[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:53][C:24]([CH3:52])([CH3:23])[C@H:25]([NH:37][C:38]([C@H:40]([CH2:49]/[CH:50]=[CH:51]/[C:57]1[CH:58]=[CH:59][C:60]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[C:55]([CH3:54])[CH:56]=1)[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:39])[C:26]([NH:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])=[O:27]
Reactant: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C
Reactant: Cc1cc(Br)ccc1-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(/C=C/C[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C)c2ccccc2)C(C)(C)C)ccc1-c1ccccc1
Yield: 69 %

Procedure:
A mixture of palladium acetate (52 mg, 0.23 mmol) and tri-(2-methylphenyl)phosphine (141 mg, 0.46 mmol) in anhydrous acetonitrile (10 mL) was sonicated at room temperature for 1 min until a creamy-coloured suspension formed. This suspension was added via Pasteur pipette to a stirred solution of tert-butyl (3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)hex-5-enoate (Preparation 2)(861 mg, 2.0 mmol), 3-methyl-4-phenylbromobenzene (M. Gomberg, J. C. Pernert, J. Amer. Chem. Soc., 1926, 48, 1372-84, and see also Preparation 19B)(1.32 gm, 5.34 mmol), and triethylamine (1.28 mL, 9.29 mmol) in anhydrous acetonitrile (15 mL) under nitrogen. The mixture was purged with nitrogen, then heated at reflux for 24 h. The mixture was poured into ethyl acetate (200 mL) and washed with saturated aqueous sodium chloride (2×100 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with dichloromethane:ethyl acetate) to give mainly tert-butyl (3R,5E)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-6-[3-methyl-(4-phenyl)phenyl]hex-5-enoate as a colourless foam (1.91 gm, 69%). 1H NMR suggests that two alkene isomers, the (5Z) and (4E) were also present. The mixture of alkenes was taken onto the next step (see b, below).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[C:4]([OH:16])[CH:3]=1.C(N(CC)CC)C.[P:24](=[O:32])(Cl)([S:27][CH2:28][CH2:29][CH3:30])[O:25][CH3:26].C(OCC)(=O)C>C1(C)C=CC=CC=1>[P:24](=[O:32])([S:27][CH2:28][CH2:29][CH3:30])([O:16][C:4]1[CH:3]=[C:2]([Cl:1])[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=1)[O:25][CH3:26]
Reactant: Oc1cc(Cl)c2cc3ccccc3cc2c1
Reactant: CCCSP(=O)(Cl)OC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCSP(=O)(OC)Oc1cc(Cl)c2cc3ccccc3cc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Chloro-2-anthrol (0.01 mole), triethylamine (0.01 mole) tetrahydrofuran (25 ml) and toluene (25 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of about 0° C. and O-methyl S-propyl phosphorochloridothioate (0.01 mole) dissolved in toluene (25 ml) is added with stirring over a period of about 30 minutes. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 16 hours. After this time the reaction mixture is filtered to remove triethylamine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvents leaving a residue. This residue is subjected to flash chromatography using ethyl acetate as the eluant to yield the desired product O-methyl O-(4-chloro-2-anthryl) S-propyl phosphorothioate.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[NH:7][C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].[Cl:17][O-].[Na+].Cl>>[Cl:17][C:9]1[C:10](=[O:11])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6](=[O:16])[NH:7][C:8]=1[C:12]([F:15])([F:13])[F:14]
Reactant: CCCCn1c(=O)cc(C(F)(F)F)[nH]c1=O
Reactant: [O-]Cl
Agent: Cl
Agent: [Na+]
Product: CCCCn1c(=O)[nH]c(C(F)(F)F)c(Cl)c1=O
Reaction time: 1 h

Procedure:
3-n-butyl-6-(trifluoromethyl)uracil (1.0 g.) was dissolved in 15 ml. of 5.25% sodium hypochlorite solution and allowed to stand at room temperature for 1 hour. The suspension which was present was acidified to pH 1 with hydrochloric acid and the solid removed by filtration. After purification by chromatography and recrystallization from cyclohexane, the product had a melting point of 138°-139°C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:21][CH:20]2[O:22][CH:16]([CH2:17][N:18](S(C3C=CC=CC=3)(=O)=O)[CH2:19]2)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[K+]>O1CCCC1>[CH2:7]([N:14]1[CH2:21][CH:20]2[O:22][CH:16]([CH2:17][NH:18][CH2:19]2)[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(c1ccccc1)N1CC2CN(Cc3ccccc3)CC(C1)O2
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(CN2CC3CNCC(C2)O3)cc1

Procedure:
10.00 g (0.25 mol) of lithium aluminum hydride are introduced into 300 ml of absolute tetrahydrofuran and heated to reflux, and 18.00 g (50 mmol) of 7-benzyl-3-phenylsulfonyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane, dissolved in 150 ml of absolute tetrahydrofuran, are added dropwise. The mixture is boiled under reflux for 48 hours, 10 ml portions of water, 15% strength potassium hydroxide solution and again water are added dropwise, and the organic salts are filtered off with suction and extracted by boiling twice with tetrahydrofuran. The tetrahydrofuran solutions are concentrated, and the residue is distilled under high vacuum. 5.30 g (43.5% of theory) of the product are obtained
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26]Cl)=[CH:20][CH:19]=3)=[O:17])=[C:14]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[S:13][C:12]=2[CH:33]=1>>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:20][CH:19]=3)=[O:17])=[C:14]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[S:13][C:12]=2[CH:33]=1
Reactant: C1CCNC1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCCl)cc3)c(C3CCCC3)sc2c1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCC4)cc3)c(C3CCCC3)sc2c1

Procedure:
1 mL of pyrrolidine is added to 30 mg of (6-methoxy-2-cyclopentylbenzo[b]thien-3-yl)[4-(2-chloroethoxy)phenyl]methanone, and this mixture is heated and refluxed for one hour. The mixture is condensed under reduced pressure to distill off the pyrrolidine, and then is refined by TLC (developing solvent was chloroform:methanol=19:1) which gives 28 mg of (6-methoxy-2-cyclopentylbenzo[b]thien-3-yl)[4-[2-(1-pyrrolidinyl)ethoxy)phenyl]methanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9]N1C(C1C=CC=CC=1)C(O)=O.[CH2:37]([CH2:39][NH2:40])[OH:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:40]1[CH:39]([C:3]1[CH:4]=[CH:5][CH:32]=[CH:33][CH:34]=1)[C:37]([NH:40][CH2:39][CH2:37][OH:38])=[O:38]
Reactant: NCCO
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCCO)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with ethanolamine.
Reaction SMILES: O[CH2:2][C:3]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][N:4]=1.S(Cl)([Cl:16])=O>CCOCC>[Cl:16][CH2:2][C:3]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][N:4]=1
Reactant: OCC1=NOC(c2ccccc2)C1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: ClCC1=NOC(c2ccccc2)C1
Reaction time: 8 h

Procedure:
3-Hydroxymethyl-5-phenyl-4,5-dihydroisoxazole (3.2 g) is dissolved in 50 ml of anhydrous ether. To the solution cooled with ice is slowly added dropwise 2.6 g of thionyl chloride with stirring. The reaction mixture is allowed to stand overnight at room temperature and then the solvent is distilled off to give 3-chloromethyl-5-phenyl-4,5-dihydroisoxazole in the form of yellow brown oil.