Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[NH:9]1[CH:13]=[N:12][C:11]([S:14]([CH2:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)(=[O:16])=[O:15])=[N:10]1.Cl>N1C=CC=CC=1>[CH:18]1([CH2:17][S:14]([C:11]2[N:12]=[CH:13][N:9]([C:4]([N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[O:5])[N:10]=2)(=[O:16])=[O:15])[CH2:19][CH2:20][CH2:21]1
Reactant: CCN(CC)C(=O)Cl
Reactant: O=S(=O)(CC1CCC1)c1nc[nH]n1
Agent: Cl
Solvent: c1ccncc1
Product: CCN(CC)C(=O)n1cnc(S(=O)(=O)CC2CCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
Diethylcarbamoyl chloride (1.49 ml; 11.3 mmol) was added to cyclobutylmethyl 1,2,4-triazol-3-yl sulfone (2.06 g; 10.2 mmol) in dry pyridine (10 ml) under dry nitrogen, and the solution stirred at room temperature overnight. The reaction mixture was poured into cold 2M hydrochloric acid (60 ml) and the cloudy solution extracted with two portions of ethyl acetate (120 ml and 50 ml). The extracts were combined, washed with saturated brine (50 ml), dried (Na2SO4), filtered and the volume of solution reduced by evaporation until a white solid precipitates. Hexane was added to the mixture which was then cooled and the solid filtered off to afford 3-(cyclobutylmethylsulfonyl)-N,N-diethyl-1,2,4-triazole-1-carboxamide (2.40 g; 78%) as white crystals, m.p. 113°-116° C., (Found, C: 47.96; H: 6.56; N: 18.51; S: 10.85. C12H20N4O3S requires C: 47.98; H: 6.71; N: 18.65; S: 10.67%). NMR - d(CDCl3 ; 60 MHz) 1.3 (6H, t, J=7 Hz), 1.5-2.4 (6H, m), 2.4-3.2 (1H, m), 3.4-3.8 (6H, m) and 8.9 (1H, s). IR vmax (CHCl3) 3000, 1710, 1440, 1340, 1270, 1180, 1145, 1030 and 870 cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:9]1[C:10]([C:28]([O:30][CH3:31])=[O:29])=[N:11][C:12]([C:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH:20]=2)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:35]([O:34][C:32]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]1[C:10]([C:28]([O:30][CH3:31])=[O:29])=[N:11][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:13][N:14]=1)=[O:33])([CH3:36])([CH3:37])[CH3:38]
Reactant: COC(=O)c1nc(C2=CCN(C(=O)OC(C)(C)C)CC2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1nc(C2CCN(C(=O)OC(C)(C)C)CC2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 40.9 %

Procedure:
A solution of methyl 3-[bis(tert-butoxycarbonyl)amino]-6-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)pyrazine-2-carboxylate (700 mg, 1.3 mmol) in methanol (28 mL) was stirred with 10% Pd/C (wet) (557 mg, 0.26 mmol) at 35° C. under an atmosphere of hydrogen for 16 h. The reaction mixture was filtered, concentrated in vacuo, and purified via silica gel column chromatography using 10-70% ethyl acetate/hexane to provide methyl 3-[bis(tert-butoxycarbonyl)amino]-6-(1-tert-butoxycarbonyl-4-piperidyl)pyrazine-2-carboxylate (285 mg) as an light orange sticky solid. 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 4.28 (bs, 2H), 3.97 (s, 3H), 3.06 (t, J=12.0 Hz, 1H), 2.86 (t, J=12.0 Hz, 2H), 1.98 (d, J=12.5 Hz, 2H), 1.79 (qd, J=12.6, 3.9 Hz, 2H), 1.48 (s, 9H), 1.41 (s, 18H). LC/MS m/z 537.7 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C@@H:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C@H:12]1[C:24]([O:26][CH2:27][CH3:28])=[O:25].ClC1C=C(C=CC=1)C(OO)=[O:34]>ClCCl>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[N+:7]([O-:34])[CH:8]=[CH:9][C:10]=1[C@@H:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][C@H:12]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1ccncc1OCOC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1cc[n+]([O-])cc1OCOC
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a dichloromethane solution (0.1 M) of trans-1-(1,1-dimethylethyl) 3-ethyl 4-(3-{[(methyloxy)methyl]oxy}-4-pyridinyl)-1,3-piperidinedicarboxylate (1 eq.) from the previous step was added 3-chloroperoxybenzoic acid (1 eq.). The resulting colorless solution was stirred at RT for 13 h. The reaction was then quenched with sat. aq. NaHSO3 and 1 N aq. NaOH. The aqueous layer was separated and back-extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH:5]([N:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([Cl:17])[C:11]=3[C:10]3=[N:18][O:19][C:20]([CH3:21])=[C:9]3[C:8]2=[O:22])[CH:4]=[CH:3]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32](O)=[O:33].CCN(CC)CC.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:17][C:12]1[C:11]2[C:10]3[C:9](=[C:20]([CH3:21])[O:19][N:18]=3)[C:8](=[O:22])[N:7]([CH:5]3[CH2:6][CH:2]([NH:1][C:32](=[O:33])[CH2:31][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[O:24][CH3:23])[CH:3]=[CH:4]3)[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccccc1CC(=O)O
Reactant: Cc1onc2c1c(=O)n(C1C=CC(N)C1)c1cccc(Cl)c21
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1CC(=O)NC1C=CC(n2c(=O)c3c(C)onc3c3c(Cl)cccc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
To a stirred solution of 5-(4-amino-cyclopent-2-enyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one (97 mg, 0.31 mmol) in CH2Cl2 (4 mL) was added 2-methoxy phenyl acetic acid (66.3 mg, 0.40 mmol), Et3N (0.11 ml, 0.40 mmol) and EDCI (77 mg, 0.40 mmol) and stirred at r.t. for 18 hours. The mixture was diluted with CH2Cl2, washed (brine), dried (Na2SO4), filtered and concentrated. Column chromatography (silica gel, hexanes/ethyl acetate, gradient) gave the title compound (59 mg, 41%). Mass Spectrum (FIA) (m/z) 464.2 (M+1) Anal. Calc. For C25H22ClN3O4. Theoretical: C, 64.73, H, 4.78, N, 9.06%. Found. C, 64.78, H, 4.91, N, 8.83%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]=[CH:34][CH:33]=[CH:32]3)O1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.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>[Cl:8][C:5]1[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:3][C:2]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]=[CH:34][CH:33]=[CH:32]3)=[CH:7][N:6]=1
Reactant: CC1(C)OB(c2ccc3ncccc3c2)OC1(C)C
Reactant: COc1ccc(S(=O)(=O)Nc2cc(Br)cnc2Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)Nc2cc(-c3ccc4ncccc4c3)cnc2Cl)cc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
(Some starting materials may be obtained from AstaTech, Inc. Princeton, N.J.) A 15 mL sealed pressure tube was charged with N-(5-bromo-2-chloropyridin-3-yl)-4-methoxybenzenesulfonamide (120 mg, 0.318 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (90 mg, 0.350 mmol) in ethanol (1.5 mL). To this was added 5 mol % of Pd(PPh3)4 (18 mg, 0.016 mmol) and Na2CO3 (2M, 0.4 mL). The flask was flushed with argon, sealed and stirred at 90° C. for 4 hours. The crude mixture was partitioned between water and ethyl acetate, extracted with ethyl acetate (3×), dried over Na2SO4 and concentrated in vacuo. The Solids were taken up in minimal methylene chloride and purified via ISCO, 40 g RediSep® (Teledyne ISCO, Lincoln, Nebr.) column with a 20-100% gradient of ethyl acetate in hexanes, to afford the desired material. MS (ESI pos. ion) m/z calc'd for C21H16ClN3O3S: 425.1; found 426.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.83 (s, 3 H) 7.12 (d, J=8.80 Hz, 2 H) 7.63 (dd, J=8.36, 4.25 Hz, 1 H) 7.72 (d, J=8.61 Hz, 2 H) 8.05 (dd, J=8.95, 1.81 Hz, 1 H) 8.10 (d, J=1.96 Hz, 1 H) 8.13-8.19 (m, 1 H) 8.32 (d, J=1.76 Hz, 1 H) 8.47 (d, J=8.51 Hz, 1 H) 8.72 (d, J=1.76 Hz, 1 H) 8.97 (dd, J=4.16, 1.32 Hz, 1 H) 10.32 (s, 1 H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20](=O)[C:19]3[C:14](=[CH:15][C:16]([OH:22])=[CH:17][CH:18]=3)[O:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.[NH2:24][NH2:25]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]([C:19]3[CH:18]=[CH:17][C:16]([OH:22])=[CH:15][C:14]=3[OH:13])=[N:24][NH:25][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2coc3cc(O)ccc3c2=O)cc1OC
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2c[nH]nc2-c2ccc(O)cc2O)cc1OC
Yield: 55.3 %

Procedure:
This compounds was synthesised in the same manner as described above. 3-(3,4-Dimethoxy-phenyl)-7-hydroxy-chromen-4-one (0.5 g, 1.68 mmol), hydrazine hydrate (4 ml), ethanol (10 ml). The crude product was columned to give 4-[4-(3,4-Dimethoxy-phenyl)-1H-pyrazol-3-yl]-benzene-1,3-diol as a pale yellow solid (0.29 g, 55.3%); Rf 0.2 Cf SM 0.7 ethyl acetate/hexane (75/25).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:16]([NH:23][C:24]([NH2:26])=[NH:25])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].O>CN(C=O)C>[NH2:26][C:24]1[N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:2]=[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:25]=1
Reactant: CC(C)(C)OC(=O)NC(=N)N
Reactant: O=C(CBr)CCCCCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2ccccc2)nc1N
Reaction time: 48 h
Yield: 63 %

Procedure:
1-bromo-7-phenylheptan-2-one (1.00 g, 3.71 mmol) was placed in a 50 mL round bottomed flask with a stir bar and dissolved in 10 mL of DMF. Boc guanidine (1.77 g, 11.13 mmol) was then added to the reaction mixture and it was allowed to stir for 48 hours. Water was then added to the reaction mixture and it was placed in a separatory funnel. The mixture was then extracted twice with ethyl acetate, washed twice with water, washed twice with brine, concentrated de vacuo and then purified via column chromatography (5% methanol/95% dichloromethane) to provide tert-butyl 2-amino-4-(5-phenylpentyl)-1H-imidazole-1-carboxylate as a hygroscopic light yellow solid (0.77 g, 63% yield), 1H NMR (300 MHz, CDCl3) δ 7.31 (m, 2H), δ 7.26 (m, 3H), δ 6.66 (s, 2H), δ 6.51 (s, 1H), δ 2.63 (t, J=7.5 Hz, 2H), δ 2.39 (t, J=7.5 Hz, 2H), δ 1.67 (m, 4H), δ 1.53 (s, 9H), δ 1.40 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 151.1, 149.8, 143.0, 130.3, 128.7, 128.5, 125.8, 106.2, 84.5, 36.1, 31.6, 29.2, 28.5, 28.4, 28.2 ppm; IR νmax (cm−1) 3433, 2098, 1639, 1454, 1204; HRMS (ESI) calcd for C19H27N3O2 (M+) 329.2103, found 329.2109. Then, tert-butyl 2-amino-4-(5-phenylpentyl)-1H-imidazole-1-carboxylate was dissolved in a 1:4 mixture of trifluoroacetic acid/dichloromethane and allowed to stir for five hours and then concentrated de vacuo. The sample was then dissolved with a dilute HCl/methanol (5 drops HCl/50 mL of methanol) and then concentrated de vacuo to provide 4-(5phenylpentyl)-1H)-imidazol-2-amine hydrochloride as a hygroscopic light yellow solid (0.62 g, 63% overall yield). 1H NMR (300 MHz, CD3OD) δ 7.20 (t, J=7.2 Hz, 2H), δ 7.12 (d, J=7.2 Hz, 3H), δ 6.37 (s, 1H), δ 2.56 (t, J=7.5 Hz, 2H), δ 2.41 (t, J=7.5 Hz, 2H), δ 1.57 (m, 4H), δ 1.34 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 147.3, 142.5, 128.3, 128.1, 127.7, 125.6, 108.2, 35.5, 31.1, 28.3, 27.0, 24.2 ppm; IR νmax (cm−1) 3385, 2933, 2857, 1679, 1536, 1495, 1453, 1335, 1172, 748, 700; HRMS (ESI) calcd for C14H19N3(M+) 229.1578, found 229.1571.
Reaction SMILES: Cl.[O:2]=[C:3]1[N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:6][C:5]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:4]1.[Br:23][C:24]1[CH:29]=[C:28]([CH2:30]Br)[CH:27]=[C:26]([Cl:32])[C:25]=1[Cl:33].CCN(C(C)C)C(C)C>CN(C=O)C>[Br:23][C:24]1[CH:29]=[C:28]([CH:27]=[C:26]([Cl:32])[C:25]=1[Cl:33])[CH2:30][N:20]1[CH2:21][CH2:22][C:5]2([O:4][C:3](=[O:2])[N:7]([C:8]3[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=3)[CH2:6]2)[CH2:18][CH2:19]1
Reactant: COC(=O)c1ccc(N2CC3(CCNCC3)OC2=O)cc1
Reactant: Clc1cc(CBr)cc(Br)c1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CC3(CCN(Cc4cc(Cl)c(Cl)c(Br)c4)CC3)OC2=O)cc1
Temperature: 55 °C
Yield: 94 %

Procedure:
To methyl 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoate hydrochloride salt (50 mg, 0.153 mmol; Example 1, Step 2) and 1-bromo-5-(bromomethyl)-2,3-dichlorobenzene (53.7 mg, 0.168 mmol; from Patent US2007/070805) was added DMF (1.5 mL) and DIPEA (107 μL, 0.612 mmol). The mixture was heated to 55° C. for 2 hours. The mixture was evaporated and the residue was dissolved in saturated aqueous NaHCO3 and then extracted with DCM. The organic layer was evaporated to provide the title compound as a yellow oil (76 mg) that was used without further purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[O:15]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29](=[O:50])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38](OC2C=CC([N+]([O-])=O)=CC=2)=[O:39])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[O:15]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[O:39])=[O:50])=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: OC1CCNCC1
Reactant: O=C(NCCCCCCOC(=O)Oc1ccc([N+](=O)[O-])cc1)Oc1ccc(Oc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCCCCOC(=O)N1CCC(O)CC1)Oc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 158.4 %

Procedure:
A solution of 4-hydroxypiperidine (2.21 g, 21.8 mmol) and triethylamine (17.5 mL, 91 mmol) in 100 mL of methylene chloride was added under nitrogen dropwise to a solution of the carbonate prepared in Example 3 (9.0 g, 18.2 mmol) in 100 mL of methylene chloride at room temperature. After the addition the reaction was stirred overnight at room temperature. The reaction was extracted one time with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 13.16 g of a yellow oil. Purification of the oil on silica gel (230-400 mesh) using hexane-ethyl acetate as the eluent gave 5.87 g (71%) of the title compound as a white waxy solid, mp 48°-55° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([NH:7][CH2:8][CH:9]1[O:23][C:12]2=[C:13]3[C:18](=[C:19]([CH3:21])[CH:20]=[C:11]2[CH2:10]1)[NH:17][C:16](=[O:22])[CH:15]=[CH:14]3)=[O:6].[H][H].CO>O.[Pd]>[NH2:2][CH2:3][CH2:4][C:5]([NH:7][CH2:8][CH:9]1[O:23][C:12]2=[C:13]3[C:18](=[C:19]([CH3:21])[CH:20]=[C:11]2[CH2:10]1)[NH:17][C:16](=[O:22])[CH2:15][CH2:14]3)=[O:6]
Reactant: [H][H]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)CCN)C2
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1cc2c(c3c1NC(=O)CC3)OC(CNC(=O)CCN)C2
Yield: 73.5 %

Procedure:
A hydrochloric acid salt of 2-(β-Alanylaminomethyl)-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (1.10 g, 3.26 mmol) was dissolved in water (50 ml). To the obtained solution, 10% palladium-on-carbon (1.10 g) was added, followed by stirring at 80° C. for 3 hours in the atmosphere of hydrogen. The reaction mixture was filtered, and the filtrate was condensed under reduced pressure. The resultant residue was submitted to a recrystallizing procedure using methanol to obtain 727 mg of the title compound as colorless powdery crystals (66.1%).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[ClH:11].Cl.[F:13][C:14]([F:30])([F:29])[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]([NH2:28])=[NH:27])=[NH:24])=[CH:18][CH:17]=1>C(O)C>[ClH:11].[CH2:2]([CH:1]1[N:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][C:14]([F:13])([F:29])[F:30])=[CH:17][CH:18]=2)[C:23]([NH2:24])=[N:25][C:26]([NH2:28])=[N:27]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: N=C(N)NC(=N)Nc1ccc(OC(F)(F)F)cc1
Reactant: CCCCCCCCC=O
Agent: Cl
Solvent: CCO
Product: CCCCCCCCC1N=C(N)N=C(N)N1c1ccc(OC(F)(F)F)cc1

Procedure:
100 ml of ethanol, 4.4 ml (25.6 mmol) of 1-nonanal, and 0.7 ml of concentrated hydrochloric acid were added to 5.0 g (16.8 mmol) of N1-(4-trifluoromethoxyphenyl)-biguanide hydrochloride, and the mixture was refluxed for 9 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from hydrous ethanol to obtain 0.7 g of colorless crystals having a melting point of 216 to 220° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[CH:16]=[CH:15][C:14]2[O:17][C:18]([CH3:20])=[CH:19][C:13]=2[C:12]1=[O:21].Br[CH2:23][CH2:24][CH2:25][Cl:26].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[Cl:26][CH2:25][CH2:24][CH2:23][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[CH:16]=[CH:15][C:14]2[O:17][C:18]([CH3:20])=[CH:19][C:13]=2[C:12]1=[O:21]
Reactant: Cc1cc2c(=O)n(Cc3nc4ccccc4[nH]3)ccc2o1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc2c(=O)n(Cc3nc4ccccc4n3CCCCl)ccc2o1
Temperature: 25 °C

Procedure:
5-(1H-Benzimidazol-2-ylmethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one(0.75 g), 1-bromo-3-chloropropane(1.3 ml), and potassium carbonate(0.95 g) were added to 50% hydrous acetonitrile(16 ml). The mixture was heated overnight under reflux. The reaction mixture was cooled to room temperature. Water was added thereto, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:1→0:1). The purified product was condensed to dryness under reduced pressure to give the title compound(0.18 g) as a colorless oily matter.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1[Cl:11].[CH:12]1([O:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[C:21](Cl)=[O:22])[CH2:16][CH2:15][CH2:14][CH2:13]1.Cl>O1CCCC1.ClCCl>[Cl:11][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Cl:10])[C:4]=1[NH:3][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:18]([O:17][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[CH:19]=1
Reactant: Nc1c(Cl)cncc1Cl
Reactant: COc1ccc(C(=O)Cl)cc1OC1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1CCCC1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
A suspension of sodium hydride (60% dispersion in oil; 2.2 g) in dry tetrahydrofuran (25 mL) at 15-20° C. is treated portionwise with a solution of 4-amino-3,5-dichloropyridine (4.5 g; that is prepared as described in Reference Example 5) in dry tetrahydrofuran (40 mL), with cooling. The mixture is stirred for a further 30 minutes, and then it is cooled to 10° C. and treated with a solution of 3-cyclopentyloxy-4-methoxybenzoyl chloride (6.4 g) in dry tetrahydrofuran (40 mL), dropwise, during 45 minutes at 10° C. The mixture is stirred at 10° C. for 30 minutes and is then treated with dilute hydrochloric acid (50 mL; 1N), followed by dichloromethane (75 mL). The layers are separated and the aqueous layer is washed with a further quantity of dichloromethane (25 mL). The combined organic layers are washed with water (50 mL), with saturated aqueous sodium bicarbonate solution (100 mL), and with water (50 mL), dried over magnesium sulfate and evaporated to dryness. The resulting residue is recrystallized from isopropanol, to give N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide (7.0 g).
Reaction SMILES: [CH3:1][N:2]([CH2:16][CH2:17][OH:18])[C:3]1[C:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.F[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1>>[CH3:1][N:2]([CH2:16][CH2:17][O:18][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1)[C:3]1[C:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CN(CCO)c1cccnc1-c1ccc(N)cc1
Reactant: O=Cc1ccc(F)cc1
Product: CN(CCOc1ccc(C=O)cc1)c1cccnc1-c1ccc(N)cc1
Yield: 58.2 %

Procedure:
The title compound (3.19 g) was prepared by the same procedure as the preparation 3 except for using 2-[N-methyl-N-(2-(4-anilinyl)pyridinyl)amino]ethanol (3.84 g) and 4-fluorobenzaldehyde (3.2 g).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.P([O-])([O-])([O-])=[O:15].[K+].[K+].[K+]>CS(C)=O>[CH2:3]1[C:4]2[C:9](=[CH:8][C:7]([C:6]([CH:5]=2)=[O:15])=[O:10])[NH:1][CH:2]1[C:11]([OH:13])=[O:12]
Reactant: O=P([O-])([O-])[O-]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1C=C2CC(C(=O)O)NC2=CC1=O

Procedure:
The concentration of enzyme, substrate and inhibitor was denoted as [E], [S] and [J], respectively. 80 microliters of 0.067 M potassium phosphate buffer (pH 6.8), 40 microliters of L-tyrosine in 0.067 M potassium phosphate buffer (pH 6.8), 40 microliters of inhibitor in 5% DMSO solution, and 40 microliters of mushroom tyrosinase solution were added to a 96-well microplate, to make the final concentration of each reagent to be: 0.2 mg/ml [S], and 96 units/ml [E], with varying [I]. 5% DMSO solution instead of an inhibitor solution was added to a blank solution and adjusted to the total volume of 200 microliters as control. The assay mixture was incubated at 37° C. The amount of dopachrome produced in the reaction mixture was measured at 475 nm in a microplate reader at different time periods. The percentage of inhibition of tyrosinase activity was calculated as follows: Inhibition(%)=[(A−B)−C−D)]/(A−B)×100
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:19])[C:8]=1[O:9][C:10]([F:18])([F:17])[CH:11]([F:16])[C:12]([F:15])([F:14])[F:13])[NH2:5].[F:20][C:21]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:22]=1[C:23]([N:25]=[C:26]=[O:27])=[O:24]>C1(C)C=CC=CC=1>[F:20][C:21]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:22]=1[C:23]([NH:25][C:26]([NH:5][C:4]1[CH:3]=[C:2]([Cl:1])[C:8]([O:9][C:10]([F:17])([F:18])[CH:11]([F:16])[C:12]([F:15])([F:14])[F:13])=[C:7]([Cl:19])[CH:6]=1)=[O:27])=[O:24]
Reactant: Nc1cc(Cl)c(OC(F)(F)C(F)C(F)(F)F)c(Cl)c1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(OC(F)(F)C(F)C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4.3 g of 3,5-dichloro-4-(1,1,2,3,3,3-hexafluoropropyloxy)aniline are dissolved with stirring in 50 ml of dry toluene and, with exclusion of moisture, a solution of 2.41 g of 2,6-difluorobenzoylisocyanate in 10 ml of dry toluene is added at room temperature. The batch is stirred for a further 12 hours at room temperature. About 75% of the solvent is then removed by rotary evaporation, the precipitated residue is filtered with suction, washed with a small amount of cold toluene and hexane and then dried in vacuo, affording the title compound of the formula ##STR13## in the form of a crystalline white powder with a melting point of 171°-172° C. (compound 1).