Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[OH:27].O>CN(C=O)C>[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[O:27][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc3ccccc3c2)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 2-naphthol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into H2O (100 mL), extracted with EtOAc (2×50 mL), washed with H2O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(naphthalen-2-yloxy)-1-nitrobenzene. The crude product was used for further transformation.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[CH3:24][CH:25]([NH2:30])[C:26]([F:29])([F:28])[F:27]>>[F:27][C:26]([F:29])([F:28])[C@@H:25]([NH:30][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][N:19]=1)=[O:23])[CH3:24]
Reactant: CC(N)C(F)(F)F
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)N[C@@H](C)C(F)(F)F)nc1
Yield: 70 %

Procedure:
As described for example 7, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (100 mg, 0.32 mmol) was converted, using L-2,2,2-trifluoro-1-(methyl)ethylamine instead of isopropylamine, to the title compound (92 mg, 70%), which was obtained as a white solid. MS: m/e=407.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[C:18]5[CH:26]=[CH:25][NH:24][C:19]5=4)[N:14]=3)=[CH:11][C:10]([C:27]([F:30])([F:29])[F:28])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:31]([NH2:34])([CH3:33])[CH3:32]>O1CCCC1>[CH:31]([NH:34][C:21]([C:20]1[C:15]([NH:14][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([C:27]([F:29])([F:28])[F:30])[CH:11]=2)=[O:22])=[CH:16][CH:17]=[C:18]2[C:19]=1[NH:24][CH:25]=[CH:26]2)=[O:23])([CH3:33])[CH3:32]
Reactant: CC(C)N
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2ccc3cc[nH]c3c12
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)ccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 16 %

Procedure:
To a solution of 110 mg (0.25 mmol) of the crude 7-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-1H-8-oxa-1,6-diaza-cyclopenta[a]naphthalen-9-one in 2.5 mL of anhydrous tetrahydrofuran, under Argon, is added 0.07 mL (0.77 mmol) of isopropylamine. The reaction is stirred during 5 hours at ambient temperature and then quenched with an aqueous saturated solution of ammonium chloride. The product is extracted twice with ethyl acetate and the combined organic phases are dried on Na2SO4, filtrated and the solvent is evaporated. After purification by flash chromatography on silica gel with hexanes and ethyl acetate as eluents and a preparative thin layer chromatography, 18.5 mg (0.04 mmol, 16%) of a white solid are obtained; LC/MS:513/515 (M+Na)+, m.p.: 240-242° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH3:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.O>[CH3:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:10]
Reactant: Cc1ccccc1CBr
Reactant: Cc1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1COc1ccccc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
α-bromo-o-xylene (2.0 g, 10.81 mmol) was added to a solution of 2-methyl-phenol (1.06 g, 9.82 mmol) and cesium carbonate (7.99 g, 24.55 mmol) in DMF (20 mL). The reaction was stirred at 80° C. overnight. The reaction mixture was acidified with 25 mL 1N HCl(aq) and poured into copious water. The aqueous layer was extracted with ethyl acetate and the organic layer was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified via radial chromatography (20% ethyl acetate in hexanes) to yield 1.82 g (88%) of 2-(2-methyl-benzyloxy)toluene (31.1). LC/MSD m/e: 213.2 (M+H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[N:14]([Si](C)(C)C)=[N+:15]=[N-:16].CCCCCC>C(OCC)(=O)C>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:10](=[O:11])[NH:16][N:15]=[N:14]2)=[CH:7][CH:8]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=c1[nH]nnn1-c1ccc(C(F)(F)F)cc1
Temperature: 110 °C
Yield: 78 %

Procedure:
To 4-trifluoromethylphenyl isocyanate (2.89 ml, 20.2. mmol) was added 5.36 ml of azidotrimethylsilane (39.9 mmol), and the mixture was stirred at 110° C. for twenty-four hours. After cooling, the mixture was subjected to column chromatography using silicagel (eluate; ethyl acetate:hexane=1;1 to 2:1 to ethyl acetate) to collect a desired fraction to be concentrated. The crystals obtained were recrystallized from ethyl acetate-hexane to give 3.64 g of 1-(4-trifluoromethylphenyl)-5(1H,4H)-tetrazolone (78%) as colorless needles.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].CCOCC>C(Cl)(Cl)Cl>[C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[CH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1CCC(CO)CC1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCC2CCC(C(C)(C)O[SiH2]C(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 82.6 %

Procedure:
To a 100 mL-flask containing 83 (3.4 g, 13.2 mmol) in CHCl3 (30 mL) was added tosyl chloride (3.26 g, 17.1 mmol) and pyidine (3.2 mL, 39.6 mmol). The reaction was allowed to stir at 25° C. for 14 hours after which time the reaction was concentrated in vacuo to yield a wet white solid. To this solid was added ether (50 mL) and the solid was filtered and subsequently washed with additional ether (2×50 mL) The ether layers were pooled, concentrated in vacuo to yield a clear oil which was purified by flash chromatography, on a silica gel column, eluting with 1:4 ether/petroleum ether to yield 84 (4.5 g, 83%) as a white solid. 1H NMR (CDCl3) δ 7.78 (d, J=7.7, 2H), 7.33 (d, J=7.7 Hz, 2H), 3.81 (d, J=6.2 Hz, 2H), 3.37 (d, J=6.2, 2H), 2.44 (s, 3H), 1.95-1.72 (m, 4H), 1.65 (m, 1H), 1.40 (m, 1H), 1.03-0.89 (m, 4H), 0.88 (s, 9H), 0.04 (s, 6H); 13C NMR (CDCl3) δ 145.1, 133.7, 130.3, 128.4, 75.8, 68.9, 40.7, 38.0, 29.1, 26.5, 22.1, 18.9, −4.9; APCI m/z (rel intensity) 413 (MH+, 100).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[C:11](=[O:45])[C:12]([CH3:44])=[C:13]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([OH:43])=[C:24]([CH:42]=2)[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34]C(OC(C)(C)C)=O)=[CH:30][CH:29]=2)=[O:26])[C:14](=[O:18])[C:15]=1[O:16][CH3:17]>C(Cl)Cl>[CH3:8][O:9][C:10]1[C:11](=[O:45])[C:12]([CH3:44])=[C:13]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([OH:43])=[C:24]([CH:42]=2)[C:25]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([NH2:34])=[CH:32][CH:33]=2)=[O:26])[C:14](=[O:18])[C:15]=1[O:16][CH3:17]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(NC(=O)OC(C)(C)C)cc3)c2)=C(C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(N)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 114.9 %

Procedure:
Trifluoroacetic acid (0.5 ml) was added to a methylene chloride solution (10 ml) of N-[5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-hydroxybenzoyl]-4-tert-butoxycarbonylaminoaniline (0.205 g, 0.309 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was concentrated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=95:5) to obtain the titled compound (0.150 g, 0.355 mmol, 91%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:32])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][C:5]2=O.Cl.[CH2:34]([O:41][NH2:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CO.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH2:34]([O:41]/[N:42]=[C:5]1\[CH2:6][C:7]([CH2:15][O:16][C:17]2[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=2)([CH3:14])[O:8][C:9]2[C:4]\1=[C:3]([CH3:32])[C:2]([OH:1])=[C:11]([CH3:12])[C:10]=2[CH3:13])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NOCc1ccccc1
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)/C(=N/OCc1ccccc1)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Reaction time: 168 h

Procedure:
A mixture of 1 g of 5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Example 22 of copending U.S. Ser. No. 644,996), 1.2 g of benzyloxylamine hydrochloride and 10 g of methanol was allowed to stand for 7 days at room temperature. At the end of this time, ethyl acetate and an aqueous solution of potassium carbonate were added. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography eluted with a 3:1 by volume mixture of hexane and ethyl acetate, to give the title compound, softening at 64°-69° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:25](Cl)(Cl)=[S:26]>O1CCCC1>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[N:9]=2)=[CH:4][CH:3]=1)=[C:25]=[S:26]
Reactant: Nc1ccc(-c2nc(-c3cccs3)no2)cc1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: S=C=Nc1ccc(-c2nc(-c3cccs3)no2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.1 %

Procedure:
To a solution of 1.2 g (0.005 mole) of 5-(4-aminophenyl)-3-(2-thienyl)-1,2,4-oxadiazole in 150 ml of dry tetrahydrofuran containing 0.49 g of triethylamine, 0.56 g (0.005 mole) of thiophosgene is added and the mixture stirred at room temperature for 3 hours. After filtration, the solution is evaporated in vacuo to give the crude product. It is crystallized from petroleum ether to give 0.7 g (50%) of the title compound, m.p. 161°-162°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH:14]=O)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO.Cl.C([BH3-])#N.[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][N:25]3[CH2:26][CH2:27][N:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][CH2:24]3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(-c2ccc(C=O)o2)cc1C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(-c2ccc(CN3CCN(c4ccccc4)CC3)o2)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(3,4-Dimethylphenyl)-furan-2-carboxaldehyde (4.0g;0.02 mole), prepared by the method of C. S. Davis and G. S. Lougheed J.Het.Chem. 4,153, (1967), was added rapidly to a stirred solution of N-phenylpiperazine (3.2g; 0.02 mole) in methanol (30ml) adjusted to pH 7 (using MeOH/HCl). After 30 minutes a solution of sodium cyanoborohydride (0.48g; 0.0075 mole) in methanol (10ml) was added dropwise and the mixture stirred at room temperature for 2 hours. After removal of the methanol by evaporation, the resultant solid was purified by silica gel chromatography. The fractions containing the desired compound were combined, evaporated and the crystalline solid which formed was recrystallised from 60/80° C. petroleum ether to give the title compound, m.p. 110° C.
Reaction SMILES: CO[CH:3]=[CH:4][CH:5]([O:8][CH3:9])OC.[S:10]1(=[O:21])(=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[CH2:11]1>>[CH3:9][O:8]/[CH:5]=[CH:4]/[CH:3]=[C:11]1/[S:10](=[O:20])(=[O:21])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]/1=[O:19]
Reactant: COC=CC(OC)OC
Reactant: O=C1CS(=O)(=O)c2ccccc21
Product: CO/C=C/C=C1\C(=O)c2ccccc2S1(=O)=O
Temperature: 90 °C
Yield: 75.1 %

Procedure:
A mixture of 1,3,3-trimethoxypropene (2.64 g, 20 mmol) and 1.82 g (10 mmol) of 1-benzothiophen-3(2H)-one 1,1-dioxide was heated at 90° C. for 12 h. The solid formed was recrystallized from MeOH to give 1.88 g (75% yield) of final product. 1H NMR (400 MHz, CDCl3): δ 4.02 (s, 3H, OCH3), 6.51 (t, 3JH—H=12.3 Hz, 1H), 7.51-8.11 (m, 6H). GC-MS (70 eV) m/e (relative intensity): 250 (65, M+), 219 (100, (M−OCH3)+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:34]([O:38][C:39](=[O:50])[NH:40][CH2:41][CH:42]([NH2:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([CH3:37])([CH3:36])[CH3:35]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:49][CH:42]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)[CH2:41][NH:40][C:39]([O:38][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:50])[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)c1nccc(-c2cnc3c(NC4CCC(NC(=O)OC(C)(C)C)CC4)nccn23)n1
Reactant: CC(C)(C)OC(=O)NCC(N)c1ccccc1
Product: CC(C)(C)OC(=O)NCC(Nc1nccc(-c2cnc3c(NC4CCC(NC(=O)OC(C)(C)C)CC4)nccn23)n1)c1ccccc1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 48 supra) (170 mg, 0.36 mmol) and (2-amino-2-phenyl-ethyl)-carbamic acid tert-butyl ester (from Example 51 supra) (341 mg, 1.44 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) to afford crude (4-{3-[2-(2-tert-butoxycarbonylamino-1-phenyl-ethylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester. (Yield 100 mg). LC-MS: [M+H]+ 644.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9](OC(=O)C)(=[O:11])[CH3:10]>C(O)(=O)C>[C:9]([C:3]1[C:4]([OH:5])=[CH:6][CH:7]=[CH:8][C:1]=1[OH:2])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1cccc(O)c1
Solvent: CC(=O)O
Product: CC(=O)c1c(O)cccc1O
Temperature: 110 °C

Procedure:
In the solution of 220 g(2 mol) of resorcinol in 500 ml of acetic acid, 102 g(1 mol) of acetic anhydride was drop-added for one hour while agitating the solution at 110° C. The mixture was maintained at 110° C. for two hours, and acetic acid was distilled under vacuum. 1 liter of toluene was added to the reaction mixture and the unreacted excess hydroquinone was filtered and collected (recovered amount: 110 g, recycled without any purification process). A desired mono acetyl resorcinol was obtained by evaporating the residue under vacuum. (Yield: 149.7 g(98%). mp: oil, 1H-NMR(200 MHz, CDCl3, ppm) 2.29(s, 3H), 6.53-6.67 (m, 4H), 7.18 (t. 1H)
Reaction SMILES: Cl.[C:2]1([C:8]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:27](#[N:30])[CH:28]=[CH2:29]>CCO>[C:2]1([C:8]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH2:10][N:11]([CH2:29][CH2:28][C:27]#[N:30])[CH2:12][CH2:13]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: C=CC#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#CCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
To a suspension of 4,4-diphenylpiperidine hydrochloride (0.195 g, 0.712 mmol) in EtOH (1.5 mL) was added Et3N (0.25 mL, 1.8 mmol, 2.6 eq) followed by acrylonitrile (0.13 mL, 2.01 mmol, 2.8 eq). The resulting solution was stirred at room temperature under argon for 15 min and then concentrated. Water was added, and the mixture was extracted with EtOAc (3×10 mL). The combined organic extracts were dried (MgSO4) and concentrated to give 170 mg (87%) of a tan solid, which was characterized spectroscopically and used in the next reaction without purification.
Reaction SMILES: [OH:1][CH:2]([CH2:30][O:31]C)[CH2:3][N:4]1[C:16]2[CH:15]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]3[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:12]=3[C:11]=2[C:10]2[CH:9]=[C:8]([O:28]C)[CH:7]=[CH:6][C:5]1=2>C(OCC)(=O)C.CCCCCC>[OH:1][CH:2]([CH2:30][OH:31])[CH2:3][N:4]1[C:16]2[CH:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:13]3[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:12]=3[C:11]=2[C:10]2[CH:9]=[C:8]([OH:28])[CH:7]=[CH:6][C:5]1=2
Reactant: COCC(O)Cn1c2ccc(OC)cc2c2c3c(c(-c4ccccc4)cc21)C(=O)NC3=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1NC(=O)c2c1c(-c1ccccc1)cc1c2c2cc(O)ccc2n1CC(O)CO
Yield: 31.6 %

Procedure:
Demethylation of alcohol (225) (96 mg, 0.22 mmol) prepared as described in example 290 employing the procedure described in example 80 was followed by chromatography on silica eluting with ethyl acetate/hexane (4:1). Crystallisation from ethyl acetate/hexane gave phenol (226) (28 mg, 31%) as an orange/yellow powder, mp 290–295° C. 1H NMR δ [(CD3)2SO] 11.04 (br s, 1H), 9.30 (s, 1H), 8.40 (d, J=2.4 Hz, 1H), 7.79 (s, 1H), 7.63 (m, 2H), 7.55 (d, J=8.8 Hz, 1H), 7.47 (m, 3H), 7.11 (dd, J=8.8, 2.4 Hz, 1H), 5.00 (d, J=5.4 Hz, 1H), 4.86 (t, J=5.4 Hz, 1H), 4.51 (dd, J=3.8, 14.9 Hz, 1H), 4.35 (dd, J=7.5, 14.9 Hz, 1H), 3.89 (m, 1H), 3.41 (m, 2H). Found: C, 67.94; H, 4.69; N, 6.50. C23H18N2O5.1/4H2O requires: C, 67.89; H, 4.58; N, 6.88.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1.[Cl-].[Li+].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].C1(C)C=CC=CC=1>CCOC(C)=O.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>[CH2:15]([C:2]1[CH:10]=[CH:9][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1)[CH:14]=[CH2:13]
Reactant: Brc1ccc2nonc2c1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCc1ccc2nonc2c1
Temperature: 110 °C

Procedure:
To a 250 mL flask charged with 5-Bromo-2,1,3-benzoxadiazole (5.0 g, 25 mmol), Palladium Tetrakis (0.87 g, 0.75 mmol), and lithium chloride (2.1 g, 50 mmol) was added Allyl Tri-n-butyltin (10 g, 30 mmol) and toluene (100 mL). The mixture was attached to a reflux condenser, sealed and purged with nitrogen. The reaction was heated to 110° C. for 2 hours. TLC showed good and complete reaction. The reaction was diluted with EtOAc, washed with brine, concentrated and purified by silica gel chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5]P(OCC)(OCC)=O)C.C[O-].[Na+].CO.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30](=O)[C:29]([CH3:35])([CH3:34])[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH:31]=[C:30]([CH2:5][C:4]([O:3][CH3:1])=[O:14])[C:29]([CH3:35])([CH3:34])[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CC1=CCN(C(=O)OC(C)(C)C)CC1(C)C
Yield: 52.9 %

Procedure:
To a cooled (0° C.) solution of diethylphosphonoacetic acid ethyl ester (4.4 mL, 24.2 mmol) in tetrahydrofuran (50 mL) under an atmosphere of nitrogen were added a solution of 28% sodium methoxide in methanol (4.6 mL, 26.4 mmol), and then a solution of 3,3-dimethyl-4-oxopiperidine-1-carboxylic acid t-butyl ester (5.0 g, 22.0 mmol) in tetrahydrofuran (10 mL) and stirred for 3 hours at room temperature. After the reaction was completed, the solvent was removed under a reduced pressure and water was added to the residue. The mixture was extracted with ether, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After drying, the extract was filtered and the filtrate was concentrated under a reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent, hexane:ethyl acetate=6:1) to obtain 1.8 g (yield 32.1%) of 4-methoxycarbonylmethylene-3,3-dimethylpiperidine-1-carbxylic acid t-butyl ester (A) and 3.3 g (yield 58.9%) of 4-methoxycarbonylmethyl-3,3-dimethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (B). Each of their physical properties is shown below.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[C:34]([Cl:35])=[CH:33][C:32]([Cl:36])=[CH:31][N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[C:34]([Cl:35])=[CH:33][C:32]([Cl:36])=[CH:31][N:30]=2)=[CH:26][CH:27]=1)([OH:20])=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(3,5-dichloro-pyridin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [Cl-].[C:2]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1)#[N:3].[CH:30]([CH:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1)=O>COCCOC>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:30][CH:32]2[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]2)=[CH:28][CH:29]=1)#[N:3]
Reactant: O=CC1CCC(=O)CC1
Reactant: N#Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: COCCOC
Product: N#Cc1ccc(C=CC2CCC(=O)CC2)cc1
Temperature: 0 °C
Yield: 110.7 %

Procedure:
63.3 g of p-cyanobenzyl-triphenylphosphonium chloride, 17.2 g of potassium t-butylate and 195 ml of ethylene glycol dimethyl ether were placed while stirring and gassing with nitrogen in a sulphonation flask, whereby the internal temperature rose to 44° C. The brown suspension was cooled to 0° C. and treated within 2 minutes with a solution of 16.7 g of 4-formylcyclohexanone in 100 ml of ethylene glycol dimethyl ether. The cooling bath was then removed and the mixture was stirred at room temperature for a further 3.5 hours. The suspension was subsequently poured into 500 ml of water and extracted three times with 600 ml of methylene chloride each time. The organic phases were washed twice with 500 ml of 10% (wt./vol.) sodium chloride solution each time, dried over sodium sulphate, filtered and concentrated, there being obtained 76.9 g of a brownish paste. Chromatographic separation of this crude product on silica gel with methylene chloride as the eluent gave 33.0 g of 4-[2-(p-cyanophenyl)vinyl]cyclohexanone as a yellow-brownish oil.