Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH3:28])[N:23]=[C:22]4[C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[S:18][C:14]=2[C:13]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH3:28])[N:23]=[C:22]4[C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[S:18][C:14]=2[C:13]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)c(-c3cccnc3)nn4C)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccc4c(c3)c(-c3cccnc3)nn4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C

Procedure:
To a vial was dissolved (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-3-(pyridin-3-yl)-1H-indazol-5-yl)benzo[d]thiazol-6-yl)acetate (69 mg, 0.11 mmol) in THF (2 mL) and EtOH (1 mL). 1M NaOH (1 mL) was added, and the mixture was heated to 50° C. for 15 hours. The reaction was cooled to 23° C., and filtered (0.45 micron teflon syringe filter). The filtrate was purified by reverse phase HPLC, eluting with 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product as a light yellow powder. LCMS-ESI+: calc'd for C33H30ClN4O3S: 597.1 (M+H+); Found: 597.2 (M+H+). 1H NMR (400 MHz, CD3OD) δ 9.32 (s, 1H), 8.89 (d, J=8.1 Hz, 1H), 8.72 (d, J=4.5 Hz, 1H), 8.66 (s, 1H), 8.09 (dd, J=8.9, 1.4 Hz, 1H), 7.95 (dd, J=7.9, 5.5 Hz, 1H), 7.79 (s, 1H), 7.76-7.67 (m, 2H), 7.63-7.52 (m, 3H), 5.26 (s, 1H), 4.17 (s, 3H), 2.61 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: [OH:1][C:2]1([C:15]2[C:16](=[O:52])[NH:17][C:18](=[O:51])[N:19]([CH:50]=2)[C@@H:20]2[O:49][C@H:39]([CH2:40][O:41][Si](C(C)(C)C)(C)C)[C@@H:30]([O:31][Si](C(C)(C)C)(C)C)[C@H:21]2[O:22][Si](C(C)(C)C)(C)C)[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:1][C:2]1([C:15]2[C:16](=[O:52])[NH:17][C:18](=[O:51])[N:19]([CH:50]=2)[C@@H:20]2[O:49][C@H:39]([CH2:40][OH:41])[C@@H:30]([OH:31])[C@H:21]2[OH:22])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C3(O)c4ccccc4-c4ccccc43)c(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1C1(O)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.5 %

Procedure:
The product of step (i) (6.56 g) was treated with a 1M solution of tetra-n-butyl ammonium fluoride in tetrahydrofuran (28.2 ml) and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica-gel eluting with 10% methanol in ethyl acetate to give 5-(9-hydroxyfluoren-9-yl)uridine as a pale yellow solid (3.43 g).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]21[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10]2.[N+:16]([O-])([OH:18])=[O:17]>>[N+:16]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][C:2]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10]1)[CH2:3]2)([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: O=C1NC(=O)C2(Cc3ccccc3C2)N1
Product: O=C1NC(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2)N1

Procedure:
A solution of (±)-spiro[imidazolidine-4,2′-indane]-2,5-dione (3.0 g, 14.8 mmol, described in Intermediate 5) in conc. nitric acid (33 mL) was stirred at ambient temperature for 1 h. The reaction was then poured onto crushed ice and the resultant solid was isolated by filtration. The crude material was recrystallized from ethanol to give the title compound. MS: m/z=248 (M+1).
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[O:16]=[C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][CH:21]=1>C1COCC1.O>[OH:4][C:3]1[CH2:5][C:17]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][CH:21]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:16][C:1](=[O:6])[CH:2]=1
Reactant: COC(=O)CC(C)=O
Reactant: CC(=O)Nc1ccc(CCC(=O)c2ccccc2)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1ccc(CCC2(c3ccccc3)CC(O)=CC(=O)O2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Methyl acetoacetate (4.5 mL, 41.7 mmol) was added dropwise to a slurry of 60% sodium hydride (1.75 g, 43.7 mmol) in THF (135 mL) at 0° C. After stirring 15 minutes, n-butyllithium (21 mL of 2.1 M, 44.1 mmol) was added and the reaction stirred an additional 15 minutes at 0° C. N-[4-(3-Oxo-3-phenyl-propyl)-phenyl]-acetamide, prepared in Example Y (5.3 g, 19.8 mmol) in THF (15 mL) was added in one portion and the reaction allowed to warm to room temperature over 4 hours. H2O was added and the reaction allowed to stir overnight. The mixture was extracted with Et2O and the aqueous layer acidified with 1N HCl. The precipitate was filtered, then washed with EtOAc to give the title compound, m.p. 155-160° C. 1H NMR (DMSO-d6) δ 2.0 (s, 3 H), 2.17 (m, 2 H), 2.50 (m, 2 H), 3.02 (dd, 2 H), 4.88 (s, 1 H), 6.99 (d, 2 H), 7.25-7.50 (m, 7 H), 9.81 (s, 1 H), 11.50 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[NH2:11].C([C:15]([NH:17][C:18]#[N:19])=O)C>C(O)C>[CH3:1][C:2]1([CH3:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[NH:11][CH:15]=[N:17][C:18]#[N:19]
Reactant: CCC(=O)NC#N
Reactant: CC1(C)Cc2ccccc2C1N
Solvent: CCO
Product: CC1(C)Cc2ccccc2C1NC=NC#N
Yield: 96 %

Procedure:
250 Parts of 2,3-dihydro-2,2-dimethyl-1H-inden-1-amine were dissolved in 80 parts of ethanol. 150 Parts of ethyl-N-cyanoformamidate were added within 10 minutes and the mixture was heated to reflux. The cooled solution was concentrated, the precipitate was filtered off and dried, yielding 316 parts (96%) of N-(2,3-dihydro-2,2-dimethyl-1H-inden-1-yl)-N'-cyanoformamidine; mp. 164°-167° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([C:30]2[CH:34]=[CH:33][O:32][N:31]=2)[CH2:14][C:15]([N:17]2[C@@H:21]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:20][O:19][C:18]2=[O:29])=[O:16])=[CH:9][CH:8]=1.[C:38](Cl)(=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>C(Cl)Cl>[CH2:22]([C@H:21]1[CH2:20][O:19][C:18](=[O:29])[N:17]1[C:15](=[O:16])[CH2:14][C@@H:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:1][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[CH:37]=[CH:36][CH:35]=2)=[CH:8][CH:9]=1)[C:30]1[CH:34]=[CH:33][O:32][N:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1cccc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cccc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)c1
Reaction time: 16 h
Yield: 106.6 %

Procedure:
To a solution of substituted aniline 27.3 (0.050 g, 0.100 mmol) in DCM (2 mL), was added TEA (0.10 mmol) and pivaloyl chloride (0.0124 mL, 0.100 mmol). The reaction mixture was stirred for 16 hours and then concentrated to dryness under reduced pressure. The residue was purified by medium pressure chromatography (silica gel, 20 to 60% EtOAc:hexanes) to give 30.1 (62 mg). MS ESI (pos.) m/e: 582.2 (M+H).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[O:11][C:12]([CH2:15][N:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=1)#[N:2].[CH3:21][NH2:22]>>[C:1]([NH:3][C:4]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[O:11][C:12]([CH2:15][N:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=1)=[N:22][CH3:21])#[N:2]
Reactant: CSC(=NC#N)NCCSCc1ccc(CN(C)C)o1
Reactant: CN
Product: CN=C(NC#N)NCCSCc1ccc(CN(C)C)o1

Procedure:
A solution of N'-cyano-N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]carbamimidothioic acid, methyl ester (1.06 g) in ethanolic methylamine 33% (10 ml) was stirred at room temperature for 4 hr. The solution was evaporated to dryness and the oily residue crystallised from ethyl acetate-light petroleum (b.p. 80°-100°) to give the title compound m.p. 77°-80°.
Reaction SMILES: Cl[C:2]1[C:10]2[C:6](=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:8]([CH2:11][CH2:12][CH3:13])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.Cl.[C:23]1([Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCOCC1.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]>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]2[N:8]([CH2:11][CH2:12][CH3:13])[N:9]=[C:10]3[C:6]=2[CH:5]=[CH:4][CH:3]=[C:2]3[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:15][CH:16]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CCCn1nc2c(Cl)cccc2c1-c1ccc(OC)cc1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCCn1nc2c(-c3ccccc3)cccc2c1-c1ccc(OC)cc1
Temperature: 80 °C
Yield: 78.8 %

Procedure:
To a stirred solution of 7-Chloro-3-(4-methoxyphenyl)-2-propyl-2H-indazole (0.200 g, 0.66 mmol) in anhydrous dioxane (6 mL) was added tris(dibenzylideneacetone)-dipalladium(0) (0.0128 g, 0.013 mmol) and 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene.HCl (0.011 g, 0.07 mmol). Phenylmagnesium bromide (0.4 mL, 1.20 mmol, 3M in diethyl ether) was added and the reaction heated to 80° C. for 3 hours. After this time an additional equivalent of reagents was added and the reaction heated for an additional 18 hours. The reaction mixture was treated with 1N aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer washed with water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the organic phase was filtered and the filtrate evaporated in vacuo to yield crude title compound. The oil was purified by silica gel column chromatography eluting with hexane/ethyl acetate (5/1) to provide the title compound as a white solid (0.178 g, 0.52 mmol, 78%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](O)=[O:14])[C:10]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)[O:29][C:30]=3[CH3:31])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([N:40]=C=NCCCN(C)C)C.CN(C)C=O>O>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([NH2:40])=[O:14])[C:10]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)[O:29][C:30]=3[CH3:31])=[CH:22][CH:23]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2C(=O)O)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100.2 %

Procedure:
A mixture of 1-benzyl-3-[(4{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylic acid (1.10 g), 1-hydroxybenzotriazole ammonia complex (0.53 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.67 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 3 days. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 1-benzyl-3-[(4{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxamide as pale-yellow crystals (1.10 g, yield 99%). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 139-140° C.
Reaction SMILES: C(OCC[C:7]1[CH:19]=[CH:18][C:10]2[S:11][C:12]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:13][C:9]=2[CH:8]=1)(=O)C.[OH-].[Na+].Cl.[CH2:23]([OH:25])[CH3:24]>>[OH:25][CH2:23][CH2:24][C:13]1[C:9]2[CH:8]=[CH:7][CH:19]=[CH:18][C:10]=2[S:11][C:12]=1[S:14](=[O:16])(=[O:17])[NH2:15]
Reactant: CCO
Reactant: CC(=O)OCCc1ccc2sc(S(N)(=O)=O)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NS(=O)(=O)c1sc2ccccc2c1CCO
Reaction time: 4.5 h
Yield: 97 %

Procedure:
A solution of 5-(2-acetoxyethyl)-2-sulfamoyl benzo[b]thiophene, (1.8 g, 0.006 mol), ethanol (50 ml) and 10% NaOH (50 ml) was heated at reflux. After 4.5 h, the mixture was poured into 3N HCl (50 ml) and extracted with ethyl acetate (3×). The organic extracts were washed with saturated Na2CO3, dried, filtered and concentrated to dryness to yield 1.5 g (97%) of product, m.p. 162°-164° C.
Reaction SMILES: [NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@H:2]([C:13]([OH:15])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+:9]([O-:11])=[O:10].ON1C2C=CC=CC=2N=N1.[CH2:36]([NH:38][C:39](=[O:45])[C@@H:40]1[CH2:44][CH2:43][CH2:42][NH:41]1)[CH3:37].C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@H:2]([C:13]([N:41]1[CH2:42][CH2:43][CH2:44][C@H:40]1[C:39]([NH:38][CH2:36][CH3:37])=[O:45])=[O:15])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+:9]([O-:11])=[O:10]
Reactant: N=C(NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)N[N+](=O)[O-]
Reactant: CCNC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 89 %

Procedure:
7.33 g (29.7 mmoles) of Z-Arg(NO2)-OH and 1.034 g of N-hydroxy-benzotriazole are added to a solution containing 3.24 g (22.8 mmoles) of proline ethylamide in 70 ml of THF. The reaction mixture is cooled in an iced water bath and 5.34 g (25.8 mmoles) of DCC dissolved in 50 ml of THF are portionwise added under stirring. The mixture is stirred under cooling with ice for 5 hours, at room temperature for additional 20 hours, then filtered and washed with THF. The filtrate is evaporated under reduced pressure, the residue is dissolved in chloroform and successively washed 3 times with 35 ml of an 1:5 mixture of ammonium hydroxide with water each, twice with 20 ml of water each, 3 times with 35 ml of 1N hydrochloric acid each and finally twice with 20 ml of water each. The chloroformic solution is dried over anhydrous sodium sulfate, filtered, washed with chloroform, then the filtrate is evaporated. The residue is dissolved in a mixture of 35 ml of THF and 50 ml of ethyl acetate, filtered and washed with 30 ml of an 1:2 mixture of THF with ethyl acetate. After evaporating the solution, 100 ml of ethyl ether are added to the solid foamy residue. The thus-obtained product is filtered, washed with ether and dried under reduced pressure to afford 9.69 g (98% yield) of the aimed compound, m.p.: 125° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:14]([CH3:15])[N:13]=[C:12]([C:16](=[N:18][NH2:19])[CH3:17])[C:11]=3[OH:20])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=[C:22]=[S:23].O>CN(C)C=O>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:14]([CH3:15])[N:13]=[C:12]([C:16](=[N:18][NH:19][C:22](=[S:23])[NH:21][C:24]4[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:31][CH:32]=4)[CH3:17])[C:11]=3[OH:20])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(=NN)c1nn(C)c(-c2ccc3c(c2)CCC3)c1O
Reactant: O=C(O)c1ccc(N=C=S)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc3c(c2)CCC3)c1O
Yield: 79.3 %

Procedure:
5-(2,3-Dihydro-1H-inden-5-yl)-3-(1-hydrazonoethyl)-1-methyl-1H-pyrazol-4-ol (47 mg, 0.174 mmol) in N,N-dimethylformamide (0.94 mL) was stirred with 4-isothiocyanatobenzoic acid (33 mg, 0.184 mmol) at room temperature for 4 hours and 40 minutes. After the reaction, 0.94 mL of water was added, and the resulting pale yellow solid was collected by filtration, washed with water and dried under reduced pressure to obtain the desired product (62 mg, 79% yield).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([NH2:10])=[S:9])([CH3:3])[CH3:2].Cl[CH:15]([C:21]([CH3:23])=O)[C:16]([O:18]CC)=[O:17]>C(O)C>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:8]2[S:9][C:15]([C:16]([OH:18])=[O:17])=[C:21]([CH3:23])[N:10]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cccc(C(N)=S)c1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: Cc1nc(-c2cccc(OC(C)C)c2)sc1C(=O)O
Temperature: 70 °C
Yield: 64.6 %

Procedure:
390 mg of 3-Isopropoxythiobenzamide was dissolved in 5 ml of ethanol, 360 mg of ethyl 2-chloroacetoacetate was added to the solution, and the mixture was heated under reflux for five hours. After the reaction mixture was cooled, it was concentrated and subjected to silica gel chromatography (eluent, hexane: ethyl acetate=9:1) to separate an intended product (490 mg). The resulting oily substance was dissolved in 5 ml of ethanol, 10 ml of a 1N aqueous sodium hydroxide solution was added, and the mixture was heated at 70° C. for one hour. After the completion of the reaction, ethanol was removed by distillation and the residue was neutralized with 1N hydrochloric acid. The precipitated crystal was collected by filtration and recrystallized from a 50% aqueous ethanol solution to give 358 mg of 2-(3-isopropoxyphenyl)-4-methyl-5-thiazolecarboxylic acid (yield: 65%).
Reaction SMILES: [NH:1]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][C@H:19]([C:27]([NH:29][C@H:30]([C:35]([O:37]C)=[O:36])[CH2:31][CH2:32][S:33][CH3:34])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[OH-].[Na+]>CO.CCOC(C)=O>[NH:1]([C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][C@H:19]([C:27]([NH:29][C@H:30]([C:35]([OH:37])=[O:36])[CH2:31][CH2:32][S:33][CH3:34])=[O:28])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
To a stirred solution of 2.0 g of Boc-Tyr-DAla-Phe-Met-OCH3 (prepared as in Step C of Example 1A) in 50 ml of methanol was added 8.0 ml of 1 N NaOH. Evaporation of the solution after stirring at room temperature for 1 hour gave a residue which was dissolved in 30 ml of EtOAc and washed with 1 N HCl (4×50 ml) and saturated NaCl (3×50 ml). The MgSO4 dried EtOAc solution was evaporated to a residue which was purified by chromatography on silica gel with a gradient of chloroform to 10% acetic acid in chloroform to give 1.12 g (57%) of Boc-Tyr-DAla-Phe-Met-OH, m.p. 135° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14].Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH:14][C:19]2[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1cccc(-c2ccc3ccccc3c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccnc1Nc1cccc(-c2ccc3ccccc3c2)c1
Yield: 67.2 %

Procedure:
A mixture of 3-(2-naphthyl)aniline (5.0 g), 2-chloro-3-nitropyridine (3.62 g) and potassium carbonate (6.31 g) in dioxane (50 ml) was stirred under reflux for 6 days. The reaction mixture was extracted with chloroform and evaporated. Crude residue was chromatographed on silica gel to give 2-[3-(2-naphthyl)phenylamino]-3-nitropyridine as an orange crystal (5.23 g).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8]([O:10]CC)=O.[CH3:13][O:14][C:15]([NH:17][C:18](=[N:21]C(OC)=O)SC)=[O:16].CC(O)=O.C[O-].[Na+]>CO>[CH3:7][C:5]1[NH:4][C:3]2[C:8](=[O:10])[NH:21][C:18]([NH:17][C:15](=[O:16])[O:14][CH3:13])=[N:1][C:2]=2[CH:6]=1
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: CCOC(=O)c1[nH]c(C)cc1N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2cc(C)[nH]c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
The pyrrole 6 (2.68 g, 16 mmol) was dissolved in MeOH (40 mL), and 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (3.74 g, 18 mmol) was added followed by AcOH (4.6 mL). The mixture was stirred at room temperature overnight and became a thick paste. To the reaction mixture NaOMe in MeOH (25%) 45 mL was added, and stirring was continued at room temperature for 2 h. The mixture was neutralized with AcOH and the solid collected by filtration and washed well with water. After drying, 7 (2.44 g, 69%) was obtained as an off-white powder: mp 234-236° C.; TLC Rf0.22 (MeOH/CHCl3, 1:5); 1H NMR (DMSO-d6) δ 2.28 (s, 3 H, CH3), 3.73 (s, 3 H, OCH3), 5.95 (s, 1 H), 10.90 (s, 1 H), 11.10 (s, 1 H), 11.76 (1 H). Anal. (C9H10N4O3.0.79C6H6.0.55C7H8O3S) C, H, N.
Reaction SMILES: [CH2:1]([CH:4]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:5]([NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[CH3:9])=[O:6])[CH:2]=[CH2:3].[H-].[Na+].[C:26](Cl)(=[O:30])[O:27][CH2:28][CH3:29].Cl>CN(C=O)C.CCCCCC>[CH2:28]([O:27][C:26]([N:7]([C@@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[CH3:9])[C:5](=[O:6])[CH:4]([CH2:1][CH:2]=[CH2:3])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:30])[CH3:29]
Reactant: C=CCC(CCCCCC)C(=O)N[C@H](C)c1cccc(OC)c1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C=CCC(CCCCCC)C(=O)N(C(=O)OCC)[C@H](C)c1cccc(OC)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
A solution of 0.40 g (1.3 mmol) of N-(2-allyloctanoyl)-(R)-1-(3-methoxyphenyl)ethylamine (diastereomer ratio (1R,2S):(1R,2R)=77:23) in 2 ml of DMF was added to a solution of 151 mg (3.8 mmol) of sodium hydride in 2 ml of DMF at room temperature, and the reaction was allowed to proceed at 50° C. for 1 hour. To the reaction mixture was added 0.48 ml (5.0 mmol) of ethyl chlorocarbonate, and the mixture was stirred at 50° C. for 12 hours. The reaction mixture was added dropwise to a mixed solution composed of 5 ml of a 1 N aqueous solution of hydrochloric acid and 5 ml of hexane with ice cooling, and the resulting mixture was extracted with two 20-ml portions of hexane. The organic layer was washed with 5 ml of a saturated aqueous solution of sodium chloride and concentrated under reduced pressure to give 0.49 g of a crude product. The crude product was purified on a silica gel column (ethyl acetate:hexane=20:1) to give 0.224 g of the title compound as a colorless oil (yield 46%, (1R,2S):(1R,2R)=77:23).