Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:30]1([C:36]2[O:37][C:38]([CH3:44])=[C:39]([CH2:41][CH2:42]O)[N:40]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:42][CH2:41][C:39]2[N:40]=[C:36]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:37][C:38]=2[CH3:44])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(O)cc1O
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
A solution of 2,4-dihydroxy-benzaldehyde (2 g, 14.5 mmol) in 20 ml THF was cooled to 0° C. To this solution were added triphenylphosphine (9.7 g, 37 mmol), 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethanol (2.84 g, 14 mmol) and finally during 0.75 hours a solution of di-tert-butyl azodicarboxylate (8.52 g, 37 mmol) in 20 ml THF. The reaction mixture was stirred overnight at room temperature, evaporated to dryness, purified by chromatography (SiO2; AcOEt/heptane) and the product was crystallized from AcOEt/ether/heptane to yield 2.2 g (46%) of the title compound as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:18]=1.[F:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1[NH2:22].P.O(C(C)(C)C)[Na]>C1(C)C=CC=CC=1.C(O)(C)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1[NH:22][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:18]=1
Reactant: O=C1c2ccc(Cl)cc2CCc2c(O)cccc21
Reactant: Nc1ccc(F)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: O=C1c2ccc(Nc3ccc(F)cc3F)cc2CCc2c(O)cccc21

Procedure:
For the synthesis of the title compound, 0.52 g (0.0020) mol of 8-chloro-1-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 0.26 g (0.0020 mol) of 2,4-difluoroaniline, 2 spatula tips of Pd(OAc)2, 0.14 g of phosphine ligand and 0.90 g (0.0094 mol) of NaOtert-Bu in 10 ml of toluene and 2 ml of tert-BuOH are reacted by method O. Purification is carried out by column chromatography (flash; silica gel, 90% hexane+10% ethyl acetate). C21H15F2NO2 (Mr=351.36); GC 35.3 min
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[NH2:19]>>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:12]([C:3]2[C:2]([OH:1])=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=2)=[O:14])[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: O=C(O)c1cc2ccccc2cc1O
Reactant: Nc1cc(Cl)cc(Cl)c1
Product: O=C(Nc1cc(Cl)cc(Cl)c1)c1cc2ccccc2cc1O

Procedure:
Using 3-hydroxynaphthalene-2-carboxylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[CH3:12][C:13]1([CH3:29])[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15](OS(C(F)(F)F)(=O)=O)=[CH:14]1>>[CH3:12][C:13]1([CH3:29])[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][CH:15]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[CH2:14]1
Reactant: CC1(C)C=C(OS(=O)(=O)C(F)(F)F)CC(C)(C)C1
Reactant: COc1ccc(B(O)O)cc1
Product: CC1(C)CC(c2ccc(O)cc2)CC(C)(C)C1

Procedure:
The title compound was prepared from 4-methoxy-benzeneboronic acid and trifluoro-methanesulfonic acid 3,3,5,5-tetramethyl-cyclohex-1-enyl ester in accordance with the procedure described in Step 1, Example 86.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)[CH:5]=[C:4]([Br:13])[CH:3]=1.[CH2:14]([O:16][C:17](=[O:28])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][C:21]=1[CH3:27])[CH3:15].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CN1C(=O)CCC1>[CH2:14]([O:16][C:17](=[O:28])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][C:2]2[CH:7]=[C:6]([O:8][CH2:9][CH:10]3[CH2:12][CH2:11]3)[CH:5]=[C:4]([Br:13])[CH:3]=2)=[CH:22][C:21]=1[CH3:27])[CH3:15]
Reactant: Brc1cc(Br)cc(OCC2CC2)c1
Reactant: CCOC(=O)COc1ccc(S)cc1C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCC3CC3)c2)cc1C
Temperature: 140 °C
Reaction time: 1 h

Procedure:
1,3-Dibromo-5-cyclopropylmethoxy-benzene (5.27 g; 17.23 mmol), (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (3 g; 13.26 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.36 g; 0.40 mmol), and 1,1′-bis-(diphenylphosphino)ferrocene (0.44 g; 0.80 mmol) was added to a dry reaction flask under an atmosphere of nitrogen. Triethylamine (7.45 mL) and NMP (8 mL) was added, and the reaction mixture was stirred in a microwave oven for 1 h at 140° C. A 5% aqueous citric acid solution (150 mL) was added to the reaction mixture, which was extracted with ethyl acetate (4×100 mL). The pooled organic phases were dried and evaporated in vacuo. The crude reaction product was purified by flash chromatography (heptane:ethyl acetate (20:1→7:3). Yield 2.8 g; 47%). HPLC-MS: m/z: 451.0 (M+); Rt: 2.85 min
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:9]=[C:10]([SH:14])[CH:11]=[CH:12][CH:13]=1.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:29][CH3:30])=[C:23]([O:26][CH2:27][CH3:28])[CH:24]=2)[N:19]=[CH:18][N:17]=1>C1COCC1>[CH2:27]([O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:29][CH3:30])[N:19]=[CH:18][N:17]=[C:16]2[S:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[NH2:7])[CH3:28]
Reactant: Nc1cccc(S)c1
Reactant: CCOc1cc2c(Cl)ncnc2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOc1cc2c(Sc3cccc(N)c3)ncnc2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To a stirred suspension of cesium carbonate (3.60 g, 11.06 mmol) in THF (60 mL) was added 3-aminobenzenethiol (1.00 g, 7.99 mmol). After stirring for 30 minutes at rt, 4-chloro-6-ethoxy-7-methoxyquinazoline described in Example 11A (1.91 g, 7.99 mmol) was added and the reaction mixture was heated at rt for 15 h. The reaction mixture was cooled to rt and concentrated under reduced pressure to give a solid. Purification by silica gel column chromatography (eluting with 2% methanol in dichloromethane) afforded 3-(6-ethoxy-7-methoxyquinazolin-4-ylthio)aniline (1.20 g, 46%) as a cream solid, which did not require further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 7.33 (s, 1H), 7.30 (s, 1H), 7.12 (dd, J=8, 8 Hz, 1H), 6.79 (s, 1H), 6.66-6.73 (m, 2H), 5.33 (brs, 2H), 4.21 (q, J=7 Hz, 2H), 3.98 (s, 3H), 1.43 (t, J=7 Hz, 3H); LC-MS (ESI) m/z 328 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1Br)(=[O:3])[CH3:2].[FH:25].[F-].[K+].C(Cl)Cl.CCOCC>C(#N)C>[C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1[F:25])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: F
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@H](F)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 3 h

Procedure:
8.7 g (21.2 mmol) of 2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyl bromide were dissolved in 30 ml of anhydrous acetonitrile and the solution was heated under reflux with 5.0 g (64 mmol) of potassium hydrogen difluoride. After 3 hours, the starting material was no longer detectable (TLC: methylene chloride/ether, 9:1). The solution was filtered and concentrated and the crude product was recrystallized from ether. Yield 5.74 g (77%), melting point 65°-67° C., [α]D20 =+21.2 (c=1.07 in chloroform) [A. Bertho, loc. cit.: melting point 68°-69° C., [α]DS20 =+21.5 (chloroform)]. 1H NMR (CDCl3): δ=5.58 (dd, 1-H), J1,2 =1.9, J1,F =48.4 Hz; [L. D. Hall et al., Can. J. Chem. 47, 1 (1969): δ=5.57 (dd, 1-H), J1.2 =1.7, J1,F =48.6 Hz].
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.[S:13]1C=CC=C1CC(O)=O.C(O)(=O)C>CCOC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH2:12])=[S:13])=[CH:2]1
Reactant: N#CCc1c[nH]c2ccccc12
Reactant: O=C(O)Cc1cccs1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: NC(=S)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Yield: 47.6 %

Procedure:
A solution of (1H-indol-3-yl)-acetonitrile (5.0 g, 32 mmol), thiolacetic acid (6.8 mL, 96 mmol) and glacial acetic acid (25 mL) was heated at 100° C. for 4 h. After cooling to room temperature the reaction mixture was diluted with EtOAc, washed with water twice and brine. The organics were then concentrated under vacuum and purified by column chromatography (SiO2, EtOAc/hexanes) to afford 2-(1H-indol-3-yl)-thioacetamide as an orange solid (2.9 g, 48%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:4]=[C:5]([C:16]2([OH:22])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=1.[H-].[Na+].[CH3:27]I>O1CCCC1>[CH3:27][O:22][C:16]1([C:5]2[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:13])[CH3:14])[CH:7]=[C:3]([C:2]([F:1])([F:23])[F:24])[N:4]=2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: CI
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1C1(O)CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)CCOCC1
Reaction time: 0.5 h
Yield: 77 %

Procedure:
Into a 250-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-(4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)tetrahydro-2H-pyran-4-ol (compound 216.3, 2 g, 5.46 mmol) in tetrahydrofuran (100 mL). This was followed by the addition of sodium hydride (262 mg, 6.55 mmol, 60%) at −70° C. and stirred for 30 min. To this was added MeI (930 mg, 6.55 mmol). The resulting solution was stirred for 1 h at room temperature, then carefully quenched with 10 mL of water. The resulting mixture was diluted with 50 mL of brine. The aqueous phase was extracted with 2×50 mL of ethyl acetate. The combined organic layers were washed with 1×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:3) as eluent to furnish 1.6 g (77%) of the title compound as light brown oil.
Reaction SMILES: C([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[N:17]=2)[N:12]=[CH:11][C:10]=1[OH:21])C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[N:17]=2)[N:12]=[CH:11][C:10]=1[OH:21]
Reactant: COc1ccc2ncc(O)c(NCc3ccccc3)c2n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2ncc(O)c(N)c2n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 58.1 %

Procedure:
A suspension of 4-benzylamino-6-methoxy-[1,5]naphthyridin-3-ol (50 mg, 0.18 mmol, 1.0 eq) and 70% palladium hydroxide (18 mg, 0.09 mmol, 0.5 eq) in methanol (3 mL) is stirred at room temperature under hydrogen flow (10 bars) for 72 hours. The catalyst is then removed by filtration and the solution is concentrated to afford 4-amino-6-methoxy-[1,5]naphthyridin-3-ol as a grey solid (20 mg, 59% yield) which is directly engaged in the next step.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH-].[Li+:9].C[C:11](C)=[O:12]>CO>[C:4]([O:12][CH3:11])(=[O:5])/[CH:3]=[CH:2]\[C:1]([O-:6])=[O:7].[Li+:9]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)/C=C\C(=O)[O-]

Procedure:
Twenty grams of maleic anhydride is dissolved in 200 mis methanol, 4.8 grams (0.2 moles) lithium hydroxide is added. The mixture is stirred until all the lithium hydroxide dissolves (at this point the pH reads 7.0). To the solution is added acetone and the solid is filtered and dried. 23 grams product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([NH:6][C:7](=O)[O:8]CC)=[C:4]([F:14])[CH:3]=1.[NH2:15]/[C:16](/[CH3:23])=[CH:17]\[C:18]([O:20]CC)=O>>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([N:6]2[C:18](=[O:20])[CH:17]=[C:16]([CH3:23])[NH:15][C:7]2=[O:8])=[C:4]([F:14])[CH:3]=1
Reactant: CCOC(=O)Nc1ccc(Cl)cc1F
Reactant: CCOC(=O)/C=C(/C)N
Product: Cc1cc(=O)n(-c2ccc(Cl)cc2F)c(=O)[nH]1

Procedure:
In an analogous manner, starting from ethyl 4-chloro-2-fluorocarbanilate and ethyl 3-aminocrotonate there is obtained 3-(4-chloro-2-fluorophenyl)-6-methyl-2,4(1H,3H) -pyrimidinedione. m.p. >220° C.; mass spectrum (m/e): 254 (M+), 235, 219, 17, 143, 108, 83, 68, 42;
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[NH:4][C:3](=[O:8])[NH:2]1.[CH2:9]([NH2:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C[Si](C)(C)N[Si](C)(C)C>S([O-])([O-])(=O)=O.[NH4+].[NH4+].O1CCOCC1>[CH2:9]([NH:17][C:5]1[CH2:6][O:1][NH:2][C:3](=[O:8])[N:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCN
Reactant: O=C1CONC(=O)N1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: CCCCCCCCNC1=NC(=O)NOC1
Temperature: 25 °C
Yield: 37.4 %

Procedure:
A solution of 1.16 g (0.010 mole) of 6H-1,2,4-oxadiazin-3,5(2H,4H)-dione, 5 mg of ammonium sulfate, 1.55 g (0.012 mole) of n-octylamine and 20 ml hexamethyldisilazane in 40 ml freshly distilled dry dioxane is refluxed for 17 hours. After cooling to room temperature, the dioxane and hexamethyldisilazane are removed in vacuo and the syrupy residue is dried on a vacuum pump for 2 hours. The resulting semi-solid residue is triturated with 100 ml of petroleum ether and filtered to yield 0.85 g (37 percent) of 5-octylamino-6H-1,2,4-oxadiazin-3(2H)-one.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:20][CH2:19][C@H:18]([NH:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=CC(C2CCC(=O)CC2)=CC=1)C1C=CC=CC=1.C1(CCCN)C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:16][CH2:17][C@H:18]([NH:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][CH2:20]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CCCN[C@H]2CC[C@@H](c3ccc(OCc4ccccc4)cc3)CC2)cc1
Agent: NCCCc1ccccc1
Agent: O=C1CCC(c2ccc(OCc3ccccc3)cc2)CC1
Product: c1ccc(CCCN[C@H]2CC[C@H](c3ccc(OCc4ccccc4)cc3)CC2)cc1

Procedure:
Following the general method of example 3, cis-[4-(4-benzyloxy-phenyl)-cyclohexyl]-(3-phenyl-propyl)-amine, (710 mg; 17% light yellow oil, MS: m/e=400.4 (M+H+)) trans-[4-(4-benzyloxy-phenyl)-cyclohexyl]-(3-phenyl-propyl)-amine (1.26 g; 30% white crystals, MS: m/e=400.4 (M+H+)) were prepared from 4-(4-benzyloxy-phenyl)-cyclohexanone (3.0 g; 10.7 mmol) and 3-phenyl-propylamine(1.45 g; 10.7 mmol).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].[C:13](O)(=[O:16])[CH:14]=[O:15].O>ClCCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([C:5]1[C:6]2[O:12][C:14](=[O:15])[CH:13]([OH:16])[C:7]=2[CH:8]=[C:9]([CH3:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(O)c(C(C)(C)C)c1
Reactant: O=CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCCl
Product: Cc1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Yield: 81.7 %

Procedure:
A mixture of 49.8 g (0.30 mol) of 2-tert-butyl-4-methylphenol, 48.9 g (0.33 mol) of 50% aqueous glyoxylic acid and 0.15 g (0.79 retool) of p-toluenesulfonic acid monohydrate in 90 ml of 1,2-dichloroethane is refluxed under nitrogen for 3.5 hours on a water separator. The reaction mixture is afterwards cooled to +5° C and the precipitate is isolated by filtration and washed with cold 1,2-dichloroethane. The filter residue is dried under a high vacuum at room temperature, affording 54.0 g (82%) of 7-tert-butyl-3-hydroxy-5-methyl-3H-benzofuran-2-one, m.p. 152-160° C (compound (102), Table 1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([SH:25])[N:9]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=3)[N:12]([CH3:23])[C:11](=[O:24])[C:10]=12)=[O:5])[CH3:2].CI.[CH2:28](N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([S:25][CH3:28])[N:9]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=3)[N:12]([CH3:23])[C:11](=[O:24])[C:10]=12)=[O:5])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1nc(S)n2c1c(=O)n(C)c1cc(C(F)(F)F)ccc12
Solvent: CI
Solvent: ClCCl
Product: CCOC(=O)c1nc(SC)n2c1c(=O)n(C)c1cc(C(F)(F)F)ccc12
Yield: 48.2 %

Procedure:
To a solution of 1-mercapto-5-methyl-4-oxo-7-trifluoromethyl-4,5-dihydroimidazo[1,5-a]quinoxaline 3-carboxylic acid ethyl ester (0.2 g) in dichloromethane was added methyliodide (0.15 g) and triethylamine (0.1 g) with stirring. The mixture was refluxed on a steam bath for one hour, then cooled and washed with water. After drying, the organic phase was evaporated under water aspirator vacuum to give the product as a white solid (0.1 g, 49% yield). Recrystallized from acetonitrile, m.p. 202°-204° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:4].O.O.O.O.O.O.O.S([O-])([O-])(=O)=[O:27].[Mg+2].O.[K]>CC(C)=O>[F:18][C:2]([F:1])([F:17])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[C:9](=[O:27])[CH2:8][CH2:7]1)=[O:4]
Reactant: O=S(=O)([O-])[O-]
Reactant: O=C(N[C@@H]1CCCc2ccc(F)cc21)C(F)(F)F
Agent: [K]
Agent: [Mg+2]
Solvent: O
Solvent: CC(C)=O
Product: O=C1CC[C@@H](NC(=O)C(F)(F)F)c2cc(F)ccc21
Yield: 96 %

Procedure:
To a solution of (R)-2,2,2-trifluoro-N-(7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide (3.51 g, 13.4 mmol, 1 equiv) in acetone (217 mL) was added magnesium sulfate heptahydrate (9.92 g, 40.3 mmol, 3 equiv) with water (167 mL). The mixture was stirred in ice bath. Potassium permangnate (6.37 g, 40.3 mmol, 3 equiv) was added in portions within 1 hour period. After addition, the reaction mixture was stirred at RT for 16 h. The resulting black solid was filtered off and washed with acetone. The combined filtrate and washings were diluted with CH2Cl2 (200 mL). The aqueous phase was separated and washed with CH2Cl2. The CH2Cl2 solution was washed with saturated Na2S2O7 solution (150 mL). The resulting black solid was filtered off The filtrate was evaporated to remove organic solvents. The concentrate was diluted with CH2Cl2 (400 mL). The aqueous phase was separated and washed with CH2Cl2. The combined CH2Cl2 phase was concentrated to give a white solid product (3.54 g, 96%). 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.00 (q, 1H), 7.30-7.36 (m, 1H), 7.15 (dd, 1H), 5.32-5.38 (m, 1H), 2.60-2.85 (m, 2H), 2.16-2.30 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=O)[CH2:9]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl.O>C(O)C>[ClH:25].[NH:23]([N:24]=[C:10]1[CH2:9][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]1=2)[C:20]([NH2:22])=[NH:21]
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1ccccc1O)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1ccccc1O)C2
Yield: 82.4 %

Procedure:
A mixture of 7-(2-hydroxyphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.08 g), aminoguanidine hydrochloride (0.037 g), concentrated hydrochloric acid (0.048 ml), water (0.048 ml) and ethanol (10 ml) was refluxed for 4 hours and cooled. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate and concentrated under reduced pressure. The resulting crystals were washed with ethanol, while heating, to give 5-guanidinoimino-7-(2-hydroxyphenyl)-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 68) (0.09 g) as colorless crystals.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:13][C:14]([O:16]CC)=[O:15].[OH-].[K+]>C(O)C>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:13][C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)CC1CCCc2ccccc2C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC1CCCc2ccccc2C1=O
Temperature: 25 °C

Procedure:
The compound of formula (Db), ethyl 2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)acetate, (6.6 g, 26.8 mmol) was dissolved in ethanol (EtOH) (30 mL), then 10% potassium hydroxide (KOH) aqueous solution (37.5 mL, 67 mmol) was added and the resulting mixture was refluxed for 2 h. After cooling to ambient temperature, the EtOH was removed by evaporation. The residue was extracted with EtOAc twice (15 mL×2). The aqueous layer was then transferred into a flask and cooled with an ice-water bath, con. HCl was added dropwise to adjust pH to about 2.0. EtOAc (60 mL) was then added, the layers were separated, and the aqueous layer was extracted with EtOAc. The combined extracts were washed with brine. After being dried (MgSO4), filtered, and concentrated, the compound of formula (Dc), 2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)acetic acid, was obtained as an orange oil (5.7 g, 97%); 1H NMR (300 MHz, CDCl3) δ: 7.71-7.68 (m, 1H), 7.41-7.20 (m, 3H), 3.37-3.31 (m, 1H), 3.12-2.91 (m, 3H), 2.57-2.49 (m, 1H), 2.15-1.90 (m, 2H), 1.75-1.62 (m, 2H); LC-MS: purity: 100%; MS (m/e): 219 (MH+).
Reaction SMILES: [C:1]1([CH3:33])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[O:9][CH2:10][C:11]([NH:13][C:14]1[NH:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25]CC2C=CC=CC=2)[N:18]=1)=[O:12].Br.C(O)(=O)C>C(Cl)(Cl)Cl>[OH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:14]([NH:13][C:11](=[O:12])[CH2:10][O:9][C:2]2[C:1]([CH3:33])=[CH:6][C:5]([CH3:7])=[CH:4][C:3]=2[CH3:8])[NH:15][CH:16]=1
Reactant: Cc1cc(C)c(OCC(=O)Nc2nc(-c3ccccc3OCc3ccccc3)c[nH]2)c(C)c1
Agent: Br
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(OCC(=O)Nc2nc(-c3ccccc3O)c[nH]2)c(C)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
To 2-(mesityloxy)-N-[4-(2-benzyloxyphenyl)-1H-imidazol-2-yl]acetamide (Compound 1) (530 mg; 1.2 mmol) obtained in Example 1, 25% hydrobromic acid/acetic acid solution (8.0 mL) was added, and the mixture was stirred for 1 hour at 60° C. To the reaction solution, chloroform (100 mL) was added, and the mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, and then distilled under reduced pressure. The resulting crystals were dispersed in diethyl ether, collected by filtration and dried to give 180 mg of the title compound (yield 43%) expressed by the following formula (Ex. 2).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[NH:14][N:13]=[CH:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2ncn[nH]2)cc1
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2ncn[nH]2)cc1

Procedure:
5-(4-Nitro-phenyl)-1H-[1,2,4]triazole (510 mg) was suspended in 50 mL of ethyl acetate and 56 mg of 10% Pd/C was added. The mixture was hydrogenated under 50 Psi for 100 min. The mixture was filtered and the filtrate was concentrate to give a solid. 497 mg
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][Cl:13]>>[Cl:13][CH2:12][CH2:11][CH2:10][CH2:9][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: ClCCCCBr
Product: ClCCCCSc1ccccc1

Procedure:
Prepared by Procedure R and Scheme Z using benzenethiol and 1-bromo-4-chlorobutane.