Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][Ge:2]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[Ge:3]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH2:6][CH3:7].[Ge:24]([Cl:28])(Cl)([Cl:26])[Cl:25].C([Ge](CCCC)(CCCC)[Ge](CCCC)(CCCC)CCCC)CCC>>[CH2:4]([Ge:24]([Cl:28])([Cl:26])[Cl:25])[CH2:5][CH2:6][CH3:7].[Cl:1][Ge:2]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:20][CH2:21][CH2:22][CH3:23])[Ge:3]([CH2:8][CH2:9][CH2:10][CH3:11])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Cl[Ge](Cl)(Cl)Cl
Agent: CCCC[Ge](CCCC)(CCCC)[Ge](CCCC)(CCCC)CCCC
Agent: CCCC[Ge](Cl)(CCCC)[Ge](CCCC)(CCCC)CCCC
Product: CCCC[Ge](Cl)(Cl)Cl
Temperature: 200 °C

Procedure:
Chloropentabutyldigermane having formula 4 of the formula sheet. A mixture of 5.8 g (27.0 mmoles) of germanium tetrachloride and 12.2 g (27.0 mmoles) of hexabutyldigermane was heated for 6.5 hours at 200° C. in a Carius tube. Fractionated distillation yielded 6.0 g of butyltrichlorogermane and 11.2 g of chloropentabutyldigermane; boiling point 130°-131° C./0.06 mm Hg; nD20 =1.4932.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15].[C:17]1(C)C=CC(S(O)(=O)=O)=C[CH:18]=1>>[CH3:17][C:18]1[N:4]([CH2:3][CH:2]([CH3:16])[CH3:1])[C:5]2[C:14]3[N:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)CNc1c(N)cnc2cccnc12
Product: Cc1nc2cnc3cccnc3c2n1CC(C)C

Procedure:
In one aspect, the invention provides a method for making 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine. The method includes: providing N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine in a carrier including toluene; combining the N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine in the carrier with a hydrogenation catalyst and isopropanol to form a mixture; subjecting the mixture that includes the N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine and the hydrogenation catalyst to a hydrogen atmosphere under conditions effective to form N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine; removing at least a portion of the hydrogenation catalyst from the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine; removing at least a portion of the isopropanol from the mixture of N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in a carrier that includes toluene and isopropanol; heating the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in the carrier to a temperature of 20° C. to 55° C.; combining the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in the carrier with p-toluenesulfonic acid to form a mixture; combining the mixture that includes the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine and p-toluenesulfonic acid with a trialkyl orthoacetate at a temperature of 70° C. to 100° C.; maintaining the temperature at 70° C. to 100° C. for a period of time sufficient to form 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine; cooling the mixture that includes 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine to a temperature of 45° C. to 55° C.; combining the 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine in the carrier with an oxidizing agent including peracetic acid to form a mixture; maintaining the mixture that includes the 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine and peracetic acid at a temperature of 45° C. to 55° C. for a time sufficient to form 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine; and isolating at least a portion of the 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine.
Reaction SMILES: Br[CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([C:10]3[C:14]([CH3:15])=[N:13][NH:12][C:11]=3[NH2:16])[S:9][C:5]=2[CH:4]=1.[NH2:19][CH2:20][CH2:21][OH:22]>>[NH2:16][C:11]1[NH:12][N:13]=[C:14]([CH3:15])[C:10]=1[C:8]1[S:9][C:5]2[CH:4]=[C:3]([CH2:2][NH:19][CH2:20][CH2:21][OH:22])[CH:18]=[CH:17][C:6]=2[N:7]=1
Reactant: NCCO
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(CBr)cc2s1
Product: Cc1n[nH]c(N)c1-c1nc2ccc(CNCCO)cc2s1

Procedure:
The title compound (10 mg) was prepared starting from 40 mg of 4-(6-bromomethylbenzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine and excess 2-aminoethanol. MS (m/z, ES+): 304.1 (M+1, 10%), 243.2 (M-HOCH2CH2NH, 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[H-].[Na+].[CH2:12](Br)[C:13]#[CH:14]>C1COCC1.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-]>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][O:8][CH2:14][C:13]#[CH:12])[CH2:4][O:3]1
Reactant: C#CCBr
Reactant: CC1(C)OCC(CO)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: C#CCOCC1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 0° C. solution of (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (Aldrich, 1 g) in THF (20 mL) was treated with NaH (327 mg, 60% oil dispersion), then refluxed for 60 min. The resulting suspension was cooled in an ice bath, treated with nBu4NI (55 mg) and propargyl bromide (0.9 mL) then stirred at r.t. for 2 h. The reaction was partitioned between water and ether (2×) and the combined ether extacts were dried (MgSO4), concentrated to give 1.3 g of the title compound. MS ESI(+) m/e 170.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)=[CH:14][C:6]([CH:7](O)CS(C)(=O)=O)=[CH:5][C:4]=1[N:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.C[O-].[Na+].[NH:29]([CH2:36][CH2:37][C:38]#[N:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CS(C)=O>[NH:29]([CH:36]=[C:37]([CH2:7][C:6]1[CH:5]=[C:4]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)[C:3]([O:2][CH3:1])=[C:15]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)[CH:14]=1)[C:38]#[N:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COc1c(-n2cccc2)cc(C(O)CS(C)(=O)=O)cc1-n1cccc1
Reactant: N#CCCNc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1c(-n2cccc2)cc(CC(C#N)=CNc2ccccc2)cc1-n1cccc1

Procedure:
A mixture of 1.8 g. of 4-methoxy- α -[(methylsulfonyl)methyl]-3,5-di-(pyrrol-1-yl)benzyl alcohol, 0.41 g. of sodium methylate and 1.1 g. of β-anilinopropionitrile in 12 ml. of dimethylsulfoxide was stirred with the exclusion of moisture for 3 hours at room temperature. The mixture was diluted with 100 ml. of water, the precipitated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulfate and evaporated. By purification of the residue over aluminum oxide with benzene and recrystallization from ethyl acetate/petroleum ether, there was obtained α -(anilinomethylene)-4-methoxy-3,5-di(pyrrol-1-yl)hydrocinnamonitrile, having a melting point of 152° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:11][CH:12]([CH3:14])[CH3:13])=[C:4]([C:8](O)=[O:9])[S:5][C:6]=1[CH3:7].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1.Cl>C1COCC1>[Br:1][C:2]1[C:3]([S:11][CH:12]([CH3:14])[CH3:13])=[C:4]([C:8]([NH:27][C:28]2[NH:32][N:31]=[N:30][N:29]=2)=[O:9])[S:5][C:6]=1[CH3:7]
Reactant: Cc1sc(C(=O)O)c(SC(C)C)c1Br
Reactant: Nc1nnn[nH]1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1sc(C(=O)Nc2nnn[nH]2)c(SC(C)C)c1Br
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 96.6 %

Procedure:
A mixture of 4-bromo-5-methyl-3-[(1-methylethyl) thio]-2-thiophenecarboxylic acid (3.0 g, 10 mmoles) and 1,1'-carbonyldiimidazole (1.8 g, 11 mmoles) in THF (25 mL) is stirred under argon and heated under reflux. After 1.5 hours 5-aminotetrazole (0.87 g, 10 mmol) is added and heating continued for an additional 2.5 hours. The mixture is then cooled, stirred into ice water (300 mL) and acidified with concentrated HCl. The precipitate is filtered off, washed with 4N HCl, rinsed with water and dried to afford the product (3.5 g); mp 235° C. (dec).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].CC(C[AlH]CC(C)C)C.CCCCCC.Cl>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([CH:11]=1)[CH2:7][OH:8]
Reactant: COC(=O)c1cc(Br)ccc1Cl
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: OCc1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
25.0 g of methyl 5-bromo-2-chlorobenzoate was dissolved in 130 ml of dichloromethane. To this solution, 230 ml of a 0.96 M DIBAL (diisobutylalminium hydride) hexane solution was added at −40° C. in a nitrogen atmosphere, followed by stirring at room temperature for 4 hours. To this reaction solution, 10% hydrochloric acid was carefully added while cooling, followed by extraction with ethyl acetate and drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were washed with hexane to obtain 20.8 g of 5-bromo-2-chlorobenzyl alcohol as white crystals.
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]1[CH:20]=[C:19]([S:21][CH2:22][CH3:23])[CH:18]=[CH:17][C:15]=1[NH2:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:11][C:10]1[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([S:21][CH2:22][CH3:23])=[CH:20][C:14]=2[F:13])=[C:3]([CH:7]=[CH:8][C:9]=1[F:12])[C:4]([OH:6])=[O:5]
Reactant: CCSc1ccc(N)c(F)c1
Reactant: O=C(O)c1ccc(F)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCSc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Yield: 55 %

Procedure:
2,3,4-Trifluorobenzoic acid and the product of Example 27, Step A, 2-fluoro-4-ethylthioaniline, were reacted in the presence of LiHMDS solution in THF by the general procedure of Example 1, Step B. After workup, a yellow solid was obtained which was purified by dry flash column chromatography on silica (0.5% Et2O in 1:1 CH2Cl2/hexanes as eluant) to afford 3,4-difluoro-2-[[2-fluoro-4-(ethylthio)phenyl]amino]benzoic acid as a yellow solid (55%); m.p. (Et2O) 136–139° C. 1H NMR (400 MHz, CDCl3) δ 13.70 (br s, 1 H), 9.24 (br s, 1 H), 7.81 (ddd, J=9.2, 6.1, 2.1 Hz, 1 H), 7.26 (dd, J=11.8, 2.0 Hz, 1 H), 7.08 (dd, J=8.3, 2.0 Hz, 1 H), 7.06 (td, J=9.7, 7.0 Hz, 1 H), 7.02 (ddd, J=9.2, 8.3, 4.7 Hz, 1 H), 2.96 (q, J=7.3 Hz, 2 H), 1.22 (t, J=7.3 Hz, 3 H). Anal. Calcd for C15H12F3NO2S: C, 55.0; H, 3.7; N, 4.3. Found: C, 55.5; H, 3.7; N, 4.3.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:33](=[O:34])[CH:32]=[N:31][C:30]5[CH:35]=[CH:36][N:37]=[CH:38][C:29]4=5)[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1>ClCCl.FC(F)(F)C(O)=O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][N:28]4[C:33](=[O:34])[CH:32]=[N:31][C:30]5[CH:35]=[CH:36][N:37]=[CH:38][C:29]4=5)[CH2:24][CH2:25]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cnc3ccncc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1cnc2ccncc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Reaction time: 4 h
Yield: 24.8 %

Procedure:
To a solution of 10 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(3-oxopyrido(3,4-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)carbamate in 1 mL of dichloromethane, 1.0 mL of trifluoroacetic acid was added at room temperature. The mixture was stirred at the same temperature for 4 hours, and the solvent was distilled off under reduced pressure. The resultant residue was charged with chloroform and water and adjusted to pH 0.5 with 1 mol/L hydrochloric acid, and the aqueous layer was separated. Chloroform was added to the aqueous layer, and the aqueous layer was adjusted to pH 12 with a 1 mol/L aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 2 mg of 4-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)pyrido(3,4-b)pyrazin-3(4H)-one as a light brown oily substance.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[N:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pt].C(#N)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[N:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=[N+]([O-])c1cnc2cccnc2c1NCC1(O)CCCCC1
Agent: [Pt]
Solvent: CC#N
Product: Nc1cnc2cccnc2c1NCC1(O)CCCCC1

Procedure:
A mixture of 1-{[(3-nitro[1,5]naphthyridin-4-yl)amino]methyl}cyclohexanol (4.55 g, 15.1 mmol) and 5% platinum on carbon (0.50 g) in acetonitrile (100 mL) was hydrogenated at 50 psi (3.5×105 Pa) overnight on a Parr apparatus. The reaction mixture was filtered through CELITE filter agent, which was rinsed with methanol afterwards. The filtrate was concentrated to give 1-{[(3-amino[1,5]naphthyridin-4-yl)amino]methyl}cyclohexanol. The 1-{[(3-amino[1,5]naphthyridin-4-yl)amino]methyl}cyclohexanol was concentrated from chloroform several times to remove residual methanol and was used directly onto the next step.
Reaction SMILES: [C:1]([O:7][CH2:8]Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:10]([C:12]1[N:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[C:37](=[O:42])[C:38](=[O:41])[C:39]=3[OH:40])=[CH:26][CH:25]=2)[C:15]2=[N:16][C:17]([CH3:21])=[CH:18][C:19]([CH3:20])=[C:14]2[N:13]=1)[CH3:11].[I-].[K+].C(OCC)C>CN(C)C(=O)C>[C:1]([O:7][CH2:8][O:42][C:37]1[C:38](=[O:41])[C:39](=[O:40])[C:36]=1[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:22]2[C:15]3=[N:16][C:17]([CH3:21])=[CH:18][C:19]([CH3:20])=[C:14]3[N:13]=[C:12]2[CH2:10][CH3:11])=[CH:25][CH:26]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2-c2c(O)c(=O)c2=O)cc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2-c2c(OCOC(=O)C(C)(C)C)c(=O)c2=O)cc1
Reaction time: 48 h

Procedure:
Chloromethyl pivalate (3.22 g) was added, dropwise, at ambient temperature, to a stirring suspension of 3-[4'-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl -2-yl]-4-hydroxycyclobut-3-ene-1,2-dione (4.21 g; preparable as in Example 4) in dry N,N-dimethylacetamide (40 ml). Potassium iodide (2.5 g) was added to the resulting mixture and stirring was continued am ambient temperature for 2 days. More chloromethyl pivalate (3.7 g) was added and stirring was continued for an additional 2 days. The mixture obtained was poured into diethyl ether (500 ml) to give a gum which was separated and then dissolved in a mixture of acetone (100 ml) and ethyl acetate (300 ml). The resulting solution was washed with saturated aqueous sodium bicarbonate solution (2×400 ml) then water (2×400 ml) and dried over magnesium sulphate. The solvents were evaporated under reduced pressure and the residue obtained was purified by flash chromatography on silica gel (eluting with ethyl acetate) to give 2-[4'-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl]-3,4-dioxocyclobut-1-en-1-yloxymethyl pivalate, an active compound of the present invention, as a fellow foam (0.54 g) which melted slowly at 60°-80° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[SH:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>[Cu].O>[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[S:20][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Fc1ccc(F)c(S)c1
Reactant: COc1ccc(Br)c(C=O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Sc2cc(F)ccc2F)c(C=O)c1
Temperature: 150 °C
Yield: 51.8 %

Procedure:
A mixture of 19.7 g of 2-bromo-5-methoxybenzaldehyde (of Example 9, reference above), 14.1 g of 2,5-difluorothiophenol (of Example 11, reference above), 14.0 g of potassium carbonate, 75 ml dimethylformamide and 2.1 g of copper catalyst is stirred and heated to 150° C. for 6 hours. It is then diluted with 150 ml of water and extracted with benzene. The extract is washed with water, dried with magnesium sulfate and evaporated. The residue is processed by distillation. There are obtained 13.3 g (52%) of 2-(2,5-difluorophenylthio)-5-methoxy-benzaldehyde boiling at 163°-165° C./40 Pa. The product is crystallized from cyclohexane and melts in a pure state at 67°-68° C.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:12])=O>CN(C)C=O>[CH:1]1([CH2:6][C:7]([Cl:12])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CC1CCCC1
Solvent: CN(C)C=O
Product: O=C(Cl)CC1CCCC1

Procedure:
To a solution of 50 g. of cyclopentaneacetic acid containing 2.9 ml. of N,N-dimethylformamide is added dropwise with stirring, 51 g. of thionyl chloride over a period of 15 minutes. After stirring for an additional 60 minutes excess thionyl chloride is removed in vacuo and the residual oil is distilled to give 55.4 g. (97%) of product, b.p. 57°-58° C. (10 mm.).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)O[C:2]2=[O:3].[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1>>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=1)=[O:3]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: COC(=O)c1ccc(N)cc1
Product: COC(=O)c1ccc(NC(=O)c2ccccc2N)cc1
Temperature: 140 °C
Yield: 78 %

Procedure:
Isatoic anhydride (4.0 g, 24.5 mmol) and methyl 4-aminobenzoate were combined and heated at 140° C. for 4 hours. The reaction was cool to room temperature and purified by flash chromatography on silica gel, eluting with 90-100% CH2Cl2 in heptane, to afford methyl 4-(2-aminobenzamido)benzoate (5.2 g, 78%). 4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylbenzaldehyde (1.0 g, 3.30 mmol) and anhydrous CuCl2 (1.3 g, 9.90 mmol) were added to a solution of methyl 4-(2-aminobenzamido)benzoate (0.900 g, 3.30 mmol) in anhydrous EtOH (70 mL) and heated to reflux for 6 hours, before being cooled to room temperature and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 5% MeOH in CH2Cl2, followed by further purification on silica gel, eluting with 30-100% EtOAc in heptane, afforded the title compound as a white solid (0.500 g, 34%). 1H-NMR (300 MHz, DMSO-d6): δ 8.18 (dd, J=7.9, 1.1 Hz, 1H), 7.88-7.93 (m, 3H), 7.75 (d, J=6.7 Hz, 1H), 7.57-7.62 (m, 1H), 7.50 (d, J=8.5 Hz, 2H), 7.03 (s, 2H), 4.82 (t, J=5.5 Hz, 1H), 3.84 (s, 3H), 3.60-3.72 (m, 4H), 2.07 (s, 6H). MS (APCI) m/z: 445 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:18]O)[C:13]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][Cl:23])[C:13]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(OCCOCc2ccccc2)ccnc1CO
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1c(OCCOCc2ccccc2)ccnc1CCl
Temperature: 25 °C
Reaction time: 7 h
Yield: 111.4 %

Procedure:
5.3 g of 4-(2-benzyloxyethoxy)-2-hydroxymethyl-3-methylpyridine was dissolved in 60 ml of chloroform to obtain a solution. A solution of 5.8 g of thionyl chloride in 40 ml of chloroform was dropwise added to the above solution under cooling with ice. The obtained mixture was stirred at a room temperature for 7 hours and distilled under a reduced pressure to obtain a residue. 200 ml of a 2N aqueous solution of sodium carbonate was added to the residue. The obtained mixture was extracted with chloroform and the extract was dried over magnesium sulfate and distilled to remove the chloroform. 6.3 g of the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH:9]1([C:14](Cl)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1>>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][C:14]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:15])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(O)c1
Reactant: O=C(Cl)C1CCCC1
Product: O=C(Nc1cccc(O)c1)C1CCCC1
Yield: 56.5 %

Procedure:
By using 3-aminophenol (1.0 g) and cyclopentanecarbonyl chloride (607 mg) as starting materials, the title compound (531 mg) was obtained in the same manner as that of Reference Example 18.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([C:8]2[CH:32]=[CH:31][C:11]([CH2:12][N:13]([C:20]3[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=3)[C:23]([O:25]CC)=[O:24])[C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=2)[S:3]1.[OH-].[Na+].Cl>C(O)C>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][N:13]([C:20]3[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=3)[C:23]([OH:25])=[O:24])[C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:31][CH:32]=2)[S:3]1
Reactant: CCCCC(=O)N(Cc1ccc(C2SC(=O)NC2=O)cc1)c1cccc(C(=O)OCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCC(=O)N(Cc1ccc(C2SC(=O)NC2=O)cc1)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
To a solution ethyl 3-[N-[4-(2,4-dioxothiazolidin-5-yl)benzyl]-N-pentanoylamino]benzoate (0.73 g) obtained in Example 21f in ethanol (10 ml) was added 1N NaOH aqueous solution (3.5 ml), and the mixture was stirred at room temperature for 3 hrs. Then 1N NaOH aqueous solution (1.0 ml) was added, and the mixture was further stirred at room temperature for 3 hrs. To the reaction mixture was added 1N hydrochloric acid (4.5 ml), and the resultant product was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to ODS column chromatography [water containing 1% acetic acid and acetonitrile (1:1)] to give the title compound (0.51 g) as a powder.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>O>[F:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 21 h
Yield: 94.8 %

Procedure:
To an N,N-dimethylformamide (40.0 mL) solution of 4-fluorophenol (5.00 g, 44.6 mmol) and 4-fluorobenzaldehyde (4.00 mg, 32.2 mmol) was added potassium carbonate (13.4 g, 96.6 mmol), which was stirred for 21 hours at 80° C. The reaction solution was then cooled to room temperature, water was added thereto, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:15→1:10) to obtain the title compound (6.60 g, 90.1%).