Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([CH:16]=O)=[C:11]([Cl:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:22]=[C:23]([CH:37]=[CH:38][C:39]=1[NH2:40])[C:24]([NH:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)=[O:25].OOS([O-])=O.[K+].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:19])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([C:16]2[NH:20][C:21]3[CH:22]=[C:23]([C:24](=[O:25])[NH:26][C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=4)[CH:37]=[CH:38][C:39]=3[N:40]=2)=[C:11]([Cl:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(C(=O)Nc2ccc3ccccc3n2)cc1N
Reactant: CC(C)(C)OC(=O)CCc1cc(Cl)c(C=O)c(Cl)c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CCc1cc(Cl)c(-c2nc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(Cl)c1
Reaction time: 1 h

Procedure:
A mixture of 3-(3,5-dichloro-4-formylphenyl)-propionic acid tert butyl ester (440 mg, 0.8 mmol), 3,4-diamino-N-quinolin-2-yl-benzamide (403 mg, 1 eq) and oxone (600 mg, 0.67 eq) in DMF (10 mL)/H2O (1 mL) was stirred vigorously open to air for 1 h. The mixture was partitioned between water and ethyl acetate. The ethyl acetate fractions were dried over magnesium sulphate and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to give 3-{3,5-dichloro-4-[6-(quinolin-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-phenyl}-propionic acid tert-butyl ester as an orange foam. 1H-NMR (CDCl3, 400 MHz): δ 8.60 (d, J=8.97 Hz, 1H), 8.38 (s, 1H), 8.21-8.29 (m, 1H), 7.95 (dd, J=8.34, 1.26 Hz, 1H), 7.82-7.91 (m, 2H), 7.71 (ddd, J=8.37, 6.98, 1.33 Hz, 2H), 7.47-7.56 (m, 1H), 7.17-7.24 (m, 2H), 2.85 (t, J=7.33 Hz, 2H), 2.50-2.57 (m, 2H), 1.42-1.48 (m, 10H).
Reaction SMILES: Br[C:2]1[O:3][C:4]([CH3:7])=[N:5][N:6]=1.C([Mg]Cl)(C)C.[CH:13]1([CH2:16]/[C:17](=[N:19]\[S:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])/[CH3:18])[CH2:15][CH2:14]1.C[Al](C)C.CCCCCCC>C1COCC1.C1(C)C=CC=CC=1>[CH:13]1([CH2:16][C:17]([NH:19][S:20]([C:22]([CH3:23])([CH3:25])[CH3:24])=[O:21])([CH3:18])[C:2]2[O:3][C:4]([CH3:7])=[N:5][N:6]=2)[CH2:14][CH2:15]1
Reactant: Cc1nnc(Br)o1
Reactant: C/C(CC1CC1)=N/S(=O)C(C)(C)C
Agent: CC(C)[Mg]Cl
Agent: C[Al](C)C
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1nnc(C(C)(CC2CC2)NS(=O)C(C)(C)C)o1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
To a solution of 2-bromo-5-methyl-1,3,4-oxadiazole (CAN 864750-58-3, 0.5 g, 3.07 mmol) in dry THF (8 ml) cooled down to −15° C. under an argon atmosphere was added isopropyl magnesium chloride, lithium chloride complex (2.36 ml, 3.07 mmol). (During the addition the temperature was kept below −12° C.). The reaction was then stirred at −15° C. for 30 minutes followed by slow addition of a solution of (Z)—N-(1-cyclopropylpropan-2-ylidene)-2-methylpropane-2-sulfinamide (CAN 1426426-70-1, 618 mg, 3.07 mmol) and a 2M solution of trimethylaluminum in heptane (1.53 ml, 3.07 mmol) in dry toluene (8 ml). The reaction was allowed to warm up to room temperature overnight. The reaction was cooled down to 0° C. and quenched by addition of water (slow addition because reaction very exothermic). The reaction medium was diluted with ethylacetate and the organic phase was extracted with a saturated aqueous solution of ammonium chloride. The organic phase was collected and the aqueous phase was back-extracted with ethylacetate. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a dichloromethane/methanol gradient to yield the title compound (521 mg, purity: 90%, 54%). MS (ESI, m/z): 286.5 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:4])[CH2:2][CH3:3].[NH2:22][C:23]1[C:24]([CH3:29])=[CH:25][CH:26]=[CH:27][CH:28]=1>C(#N)C>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)c1cnc2c(OCCCSC)cccc2c1Cl
Reactant: Cc1ccccc1N
Solvent: CC#N
Product: CCC(=O)c1cnc2c(OCCCSC)cccc2c1Nc1ccccc1C
Yield: 99.1 %

Procedure:
3-Propanoyl-4-chloro-8-(3-methylthiopropoxy)quinoline (1.2 g, 3.71 mmol) and o-toluidine (0.795 g, 7.42 mmol) was refluxed in acetonitrile (18 ml) for 100 min. The solvent was evaporated and the residue was purified by column chromatography (methylene chloride:methanol 100:3). 1.45 g (99%) of the title compound was obtained.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[N:15]=[CH:14][C:13]([NH2:16])=[CH:12][N:11]=1)[CH2:3][CH2:2]2.[C:17]1([CH2:23][C:24]([Cl:26])=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)C.Cl>C(O)C.C(N(CC)CC)C>[ClH:26].[N:1]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[N:4]([C:10]1[N:15]=[CH:14][C:13]([NH:16][C:24](=[O:25])[CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][N:11]=1)[CH2:3][CH2:2]2
Reactant: Nc1cnc(N2CCN3CCC2CC3)nc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(Cc1ccccc1)Nc1cnc(N2CCN3CCC2CC3)nc1
Reaction time: 15 h

Procedure:
2-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-pyrimidin-5-ylamine (0.877 g, 4.00 mmol) and ethanol (50 ml) was mixed with phenylacetyl chloride (0.742 g, 4.8 mmol) and was stirred for 15 hours at room-temperature, followed by addition of phenylacetyl chloride (74 mg, 0.48 mmol) and stirring for 15 hours. Diethylether (30 ml) was added. The mixture was made alkaline by adding triethylamine (20 ml). The crude mixture was purified by silica gel chromatography, using a 10:1+1% dichloromethane:methanol+aqueous ammonia mixture as eluent. The corresponding hydrochloride was prepared by solving the free base in ethanol (10 ml, 99%) followed by addition of HCl in ethanol (2 ml, 3 M). Yield 710 mg (47%). LC-ESI−HRMS of [M+H]+ shows 338.1976 Da. Calc. 338.198085 Da, dev. −1.4 ppm.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][N:7]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([C:15]([OH:17])=[O:16])=[N:8]1.[CH3:18]O>>[CH3:6][N:7]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([C:15]([O:17][CH3:18])=[O:16])=[N:8]1
Reactant: Cn1cc([N+](=O)[O-])c(C(=O)O)n1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1nn(C)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Concentrated H2SO4 (0.4 ml) was added to 1-methyl-4-nitropyrazole-3-carboxylic acid (2.02 g) in MeOH (40 ml) and the mixture heated to reflux for 4 hours. After cooling to room temperature, the reaction was concentrated in vacuo. The crude material was dissolved in EtOAc (60 ml) then washed with water (10 ml) and brine (10 ml). The organic layer was dried, filtered and concentrated to give methyl 1-methyl-4-nitropyrazole-3-carboxylate, 1.96 g.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.O>CS(C)=O>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:15][CH:14]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Fc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Fc1ccc(Cn2ccc3ccccc32)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 11.72 g (0.1 mol) of indol in 50 ml of dimethyl sulfoxide is added to a mixture of 2.64 g of sodium hydride (0.11 mol, mineral oil suspension) in 100 ml of dimethyl sulfoxide. The mixture is heated at 60° C. for 1.5 hours, then allowed to cool and 15.9 g (0.11 mol) of 4-fluorobenzyl chloride are added dropwise. The solution is warmed to 60° C., allowed to stand overnight and then poured into 400 ml of water with stirring. The mixture is extracted a number of times with a total of 150 ml of methylene chloride, the organic phase is dried using anhydrous sodium sulfate, filtered and the filtrate is concentrated in vacuo. The residue is distilled in a high vacuum: 21.0 g (96% of theory) b.p. (0.5 mm): 140° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5](=[CH:7][C:8]([Cl:11])=[CH:9][CH:10]=1)[NH2:6].C(N(CC)CC)C.[CH3:20][O:21][C:22](=[O:29])[CH2:23][S:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5](=[CH:7][C:8]([Cl:11])=[CH:9][CH:10]=1)[NH:6][C:26](=[O:27])[CH2:25][S:24][CH2:23][C:22]([O:21][CH3:20])=[O:29]
Reactant: COC(=O)CSCC(=O)Cl
Reactant: COC(=O)c1ccc(Cl)cc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CSCC(=O)Nc1cc(Cl)ccc1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
21.24 g (0.114 mol) of 4-chloroanthranilic acid methyl ester and 19.1 ml (0.137 mol) of triethylamine are placed in 180 ml of methylene chloride at 0°. A solution of 20.9 g (0.114 mol) of 2-(chloroformylmethylthio)-acetic acid methyl ester (T. Terasawa and T. Okada, J. Org. Chem., 42, 1163 (1977)) in 20 ml of methylene chloride is added dropwise thereto and the mixture is then stirred for 15 minutes at 0° and for 3 hours at room temperature. The reaction mixture is extracted with water and brine and the aqueous phases are washed with methylene chloride. The organic phases are combined, dried with sodium sulfate, filtered and concentrated. Chromatography of the crude product on silica gel with hexane/ethyl acetate (4:1) yields, in the form of yellowish crystals, 4-chloro-N-(methoxycarbonylmethylthio)acetylanthranilic acid methyl ester which is still impure.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13]CC)=O)=[CH:6][CH:5]=1.[H][H].Cl>C1(C)C=CC=CC=1.O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[O:13])[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([Br:3])=[CH:9][CH:8]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Cc1ccc(Br)cc1)Cc1ccc(Br)cc1
Temperature: 50 °C
Yield: 80.7 %

Procedure:
To a slurry of sodium hydride (9.17 grams, 0.23 mole) in 50 milliliters of toluene was added dropwise, a solution of ethyl 4-bromophenylacetate (50 grams, 0.21 mole) in toluene (50 milliliters) at 30-32° C. After addition was completed, the reaction mixture was slowly warmed to 50° C. where the reaction began to rapidly exotherm with evolution of hydrogen gas. The reaction mixture was further heated to 78° C. for 2 hours, cooled to room temperature and then HCl (45 grams) in water (22.5 grams) was slowly added dropwise to neutralize the solution. The layers were separated and the aqueous phase was extracted with diethylether. The combined organic extracts were dried and the solvent was removed to leave a yellow oil. This oil was refluxed for 24 hours in a mixture of glacial acid (60 milliliters) and concentrated HCl (30 milliliters). After cooling, the layers were separated, and the organic layer solidified to provide a yellow solid. This crude product was recrystallized from n-heptane to give a pure product as a white solid (31.2 grams, 82% isolated yield).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([OH:13])[C:9]([OH:12])=[CH:10][CH:11]=1)([O-:5])=[O:4].I[CH:15]([CH3:17])[CH3:16]>CS(C)=O>[CH:15]([O:12][C:9]1[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][C:8]=1[OH:13])([CH3:17])[CH3:16]
Reactant: CC(C)I
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)Oc1ccc([N+](=O)[O-])cc1O
Reaction time: 0.08 h
Yield: 25.7 %

Procedure:
To a stirred solution of sodium hydroxide (387 mg, 9.67 mmol) in anhydrous DMSO was added 4-nitrobenzene-1,2-diol (500 mg, 3.22 mmol) at 0° C. After stirring for 5 min, 2-iodo-propane (603 mg, 3.55 mmol) was added dropwise. The resulting dark mixture was stirred for 1 h at room temperature. The reaction mixture was quenched with water and then acidified with 1M HCl (pH=4) and then the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with sat. NaCl and then dried over MgSO4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by silica gel column chromatography using a gradient of 0-20% EtOAc in hexanes to obtain 2-isopropoxy-5-nitro-phenol (163 mg, 51%) 1H NMR (400.0 MHz, CDCl3) δ 7.86 (dd, J=2.5, 8.8 Hz, 1H), 7.76 (d, J=2.5 Hz, 1H), 6.99 (d, J=8.8 Hz, 1H), 4.73 (qn, J=6.1 Hz, 1H) and 1.43 (d, J=6.1 Hz, 6H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH:4]([C:16]([O:18][CH3:19])=[O:17])[CH2:3]1.C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH:4]([C:16]([O:18][CH3:19])=[O:17])[CH2:3]1
Reactant: COC(=O)C1CC(O)CCN1[C@@H](C)c1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COC(=O)C1CC(=O)CCN1[C@@H](C)c1ccccc1
Reaction time: 5 h
Yield: 99.1 %

Procedure:
Methyl 4-hydroxy-1-((S)-1-phenylethyl)piperidine-2-carboxylate (3.4 g, 12.9 mmol), N-methylmorpholine N-oxide (3.0 g, 25.82 mmol) and 4 Å molecular sieves were stirred together in 15 mL of DCM at rt under argon. Tetra-n-propylammonium perruthenate (454 mg, 1.29 mmol) was then added slowly and reaction stirred for 5 h. The reaction was then filtered through silica and washed with 10% methanol in DCM and concentrated to give the title compound as a clear oil (3.34 g, 99%). MS (ESI) 262 (M+H).
Reaction SMILES: O[CH2:2][CH:3]([N:8]([S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[C:4]([O:6][CH3:7])=[O:5].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([S:23]([N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17](=[O:22])[C:18]([F:19])([F:21])[F:20])[C:3](=[CH2:2])[C:4]([O:6][CH3:7])=[O:5])(=[O:24])=[O:25])=[CH:27][CH:28]=1
Reactant: COC(=O)C(CO)N(Cc1ccccc1NC(=O)C(F)(F)F)S(=O)(=O)c1ccc(OC)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: C=C(C(=O)OC)N(Cc1ccccc1NC(=O)C(F)(F)F)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 1 h

Procedure:
To a solution of 1.0 g (2.54 mmol) of methyl 3-hydroxy-2-{(4-methoxybenzenesulfonyl)-[2-(2,2,2-trifluoroacetylamino)benzyl]amino}propionate in 10 ml of CH2Cl2 was added 1.8 ml (12.7 mmol) of trifluoroacetic anhydride. After 1 hour at room temperature, the solvent was removed. Dichloromethane was added several times and the solvent removed under vacuum after each addition. Methanol was then added 2 times and the solvent removed under vacuum to give methyl 2-{(4-methoxybenzenesulfonyl)-[2-(2,2,2-trifluoroacetylamino)benzyl]-amino}acrylate as a glass. The glass was dissolved in methanol and 0.213 g of anhydrous NaHCO3 was added. The mixture was stirred at room temperature overnight and concentrated under vacuum to dryness. To the residue was added ethyl acetate and water. The organic layer was separated, washed with H2O, brine and dried with Na2SO4. The solvent was removed and the residue (1.0 g) was chromatographed on silica gel thick layer plates with hexane-ethyl acetate (1:1) as solvent to give 0.365 g of product as a glass. Anal. for C20H19F3N2O6S: Calc'd: C,50.9; H,4.1; N,5.9; F,12.1; S,6.7; Found: C,50.8; H,4.4; N,5.5; F,11.7; S,6.7; Mass spectrum (ES) 473.1 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:24]=[C:23]([C:25]2[CH:33]=[CH:32][C:31]3[N:30]4[CH2:34][CH:35]([NH:37][CH3:38])[CH2:36][C:29]4=[CH:28][C:27]=3[CH:26]=2)[C:22]([CH3:39])=[C:21]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:48](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C=O>[CH2:1]([O:8][C:9]1[N:24]=[C:23]([C:25]2[CH:33]=[CH:32][C:31]3[N:30]4[CH2:34][CH:35]([N:37]([CH3:48])[CH3:38])[CH2:36][C:29]4=[CH:28][C:27]=3[CH:26]=2)[C:22]([CH3:39])=[C:21]([O:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC1Cc2cc3cc(-c4nc(OCc5ccccc5)c(C(=O)OCc5ccccc5)c(OCc5ccccc5)c4C)ccc3n2C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1c(-c2ccc3c(c2)cc2n3CC(N(C)C)C2)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
The product from Example 415, Step 2 (31 mg, 0.05 mmol) was dissolved in 1,2-dichloroethane (1 mL). Aqueous 30% formaldehyde (1 drop, ˜0.2 mmol) was added to the mixture, followed by sodium triacetoxyborohydride (21 mg, 0.1 mmol). The mixture stirred at room temperature for 30 min. The mixture was loaded directly to silica gel, eluting with 0-8% MeOH in CH2Cl2 to afford product (25 mg, 78%). LC-MS 638.3 [M+H]+, RT 1.21 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[OH:17])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].[CH2:36](I)[CH3:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[O:17][CH2:36][CH3:37])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: COc1ccc(CC2c3c(O)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Reactant: CCI
Product: CCOc1ccc(OC)c2c1C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NCc1ccccn1)CC2

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with ethyl iodide
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:18]([C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)P(OC1C=CC=CC=1)(=O)OC1C=CC=CC=1.CC(C)([O-])C.[K+]>O1CCOCC1.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:10]#[C:18][C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=P(Oc1ccccc1)(Oc1ccccc1)C(Cl)c1ccncc1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C#Cc2ccncc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a suspension of 3-cyclopentyloxy-4-methoxybenzaldehyde (6.07 g, 27.6 mmol) and diphenyl 1-chloro-1-(4-pyridyl)methanephosphonate (J. Org. Chem., 1992, 57, 1622) (9.03 g, 52.1 mmol) in dioxane (150 mL) there was added in portions potassium tert-butoxide (7.03 g, 62.8 mmol). The mixture was stirred at room temperature for 1 h and then refluxed. After 3.5 h, there was added another 7 g of potassium tert-butoxide and refluxing was continued for 18 h. After cooling, the mixture was diluted with water (1 L) and extracted 3 times with EtOAc. The extracts were washed 3 times with water, dried and evaporated and the residue was chromatographed on silica gel (EtOAc/hexane 1:2) to afford the title acetylene (4.72 g, 64%) as a cream-colored solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].CN(C)CCN(C)C.[C:21](=O)=[O:22].CC(C)=O.C([Li])(C)(C)C>CCCCC.CN(C)C=O>[CH:21]([C:5]1[S:1][C:2]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:3][CH:4]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)c1cccs1
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)(C)C
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: CCCCC
Product: CC(C)(C)OC(=O)c1ccc(C=O)s1
Reaction time: 0.83 h

Procedure:
A solution of t-butyl 2-thiophenecarboxylate (1.84 g, 10 mmol) and N,N,N',N'-tetramethylethylenediamine (1.74 g, 15 mmol) in anhydrous tatrahydrofuran was stirred in a nitrogen stream under cooling with dry ice/acetone, followed by the dropwise addition of a 1.7M solution (8.0 ml) of t-butyllithium (13.6 mmol) in pentane. The obtained mixture was stirred as such for about 50 minutes. Anhydrous dimethylformamide (15 ml) was gradually dropped into the resulting mixture to conduct a reaction. The dry ice/acetone was removed to raise the temperature of the mixture to room one. The resulting mixture was stirred for 40 minutes and poured into 300 ml of a diethyl ether/0.3 N HCl (3:1) mixture. The obtained mixture was stirred for a while. The organic layer was recovered, washed with a phosphate buffer solution having a pH of 7 and an aqueous solution of common salt, dehydrated and distilled to remove the solvent. The residue was purified by silica gel column chromatography (developer: n-hexane/ethyl acetate=8:1) to give t-butyl 5-formyl-2-thiophenecarboxylate. yield: 1.7 g
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][C:3]=1[OH:12].[CH3:13]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: Cc1ccc(O)c(C)c1[N+](=O)[O-]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C)c([N+](=O)[O-])c1C
Yield: 88.9 %

Procedure:
A mixture of 32.12 grams of 2,4-dimethyl-3-nitrophenol, 35.78 grams of methyltosylate and 28.5 grams of anhydrous K2CO3 in 200 ml of acetone is heated to reflux for 12 hours. The reaction mixture is filtered leaving a tan solid. The filtrate is concentrated in vacuo. The concentrated filtrate is taken up in ethyl acetate and extracted with 10% aqueous sodium hydroxide solution and saturated aqueous sodium chloride. The remaining ethyl acetate layer is dried, filtered and concentrated in vacuo to give a dark oil which is distilled (T=80°-87° C./50μ) to give 30.95 grams of a yellow solid which is recrystallized from absolute ethanol, M.P. 53°-55° C.
Reaction SMILES: Cl[C:2](OC1C=CC=CC=1)=[O:3].[NH2:11][C:12]1[CH:13]=[C:14]([CH:50]=[CH:51][C:52]=1[OH:53])[CH2:15][O:16][CH:17]1[CH:22]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])=[CH:25][CH:24]=2)[CH2:21][CH2:20][N:19]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:18]1.C(=O)([O-])O.[Na+].[OH-].[Na+].Cl>CO.O>[CH3:42][O:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[CH2:34][O:33][CH2:32][CH2:31][CH2:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([C@H:22]2[CH2:21][CH2:20][N:19]([C:43]([O:45][C:46]([CH3:49])([CH3:47])[CH3:48])=[O:44])[CH2:18][C@@H:17]2[O:16][CH2:15][C:14]2[CH:50]=[CH:51][C:52]3[O:53][C:2](=[O:3])[NH:11][C:12]=3[CH:13]=2)=[CH:24][CH:25]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(O)c(N)c2)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3oc(=O)[nH]c3c2)cc1
Reaction time: 0.25 h

Procedure:
0.133 ml of phenyl chloroformate are added dropwise to the stirred emulsion of 0.640 g of tert-butyl 3-(3-amino-4-hydroxybenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.086 g of sodium hydrogencarbonate in 4 ml of methanol and 4 ml of water. The reaction mixture is stirred over 15 minutes and then admixed with 2 ml of methanol. After a further 15 minutes, it is admixed with 0.51 ml of 2N NaOH. After a further 10 minutes, the mixture is admixed with 20 ml of 0.5N HCl and extracted with tertbutyl methyl ether (2×30 ml). The organic phases are washed successively with water (30 ml) and brine (30 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.52 (3:1 EtOAc-heptane); Rt=5.56.