Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(N(CC)CC)C.[CH:12]1([N:22]=[C:23]=[S:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[CH3:2][O:3][NH:4][C:23]([NH:22][CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1)=[S:24]
Reactant: S=C=NC1CCCc2ccccc21
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CONC(=S)NC1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-cold, stirred mixture of 0.02 mole of methoxyamine hydrochloride and methylene chloride is added 0.02 mole of triethylamine. The mixture is then allowed to warm to about 15° to 25° C. while a solution of 0.01 mole of 1,2,3,4-tetrahydro-1-naphthyl isothiocyanate in methylene chloride is added dropwise. The mixture is stirred overnight at room temperature and then filtered. The filtrate is washed with water, dried (sodium sulfate), and the solvent evaporated at reduced pressure to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([Cl:11])[CH:3]=1.[CH3:12][C:13]1[NH:17][N:16]=[C:15]([NH2:18])[CH:14]=1>CCO>[Cl:11][C:4]1[CH:3]=[C:2]([NH:18][C:15]2[CH:14]=[C:13]([CH3:12])[NH:17][N:16]=2)[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=1
Reactant: Clc1cc(Cl)n2ccnc2n1
Reactant: Cc1cc(N)n[nH]1
Solvent: CCO
Product: Cc1cc(Nc2cc(Cl)nc3nccn23)n[nH]1
Temperature: 80 °C
Yield: 66.4 %

Procedure:
Referring to Scheme 4, C5,7-Dichloro-imidazo[1,2-a]pyrimidine (206 mg, 1.1 mmol) and 5-methyl-1H-pyrazol-3-amine (213 mg, 2.19 mmol) was mixed in EtOH (5 ml). The mixture was heated at 80° C. for 10 minutes. The mixture was then cooled to RT and the solid was collected and washed with EtOAc to give (7-Chloro-imidazo[1,2-a]pyrimidin-5-yl)-(5-methyl-1H-pyrazol-3-yl)-amine as a white solid (182 mg, 0.73 mmol, 66%). 1H NMR (400 MHz, DMSO) δ 8.17 (s, 1H) 7.63 (s, 1H) 7.12 (s, 1H) 6.02 (s, 1H) 2.28 (s, 3H). [M+H] calc'd for C10H9ClN6, 249; found, 249.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[C:6]([CH:22]=1)[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[C:6]([CH:22]=1)[C:7]([NH:9][C@H:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)[CH3:11])=[O:8]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2ccccc2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](NC(=O)c1cc(Cl)ccc1COc1ccccc1Cl)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.7 %

Procedure:
To a stirred solution of methyl 4-[(1S)-1-({5-chloro-2-[(2-chlorophenoxy)methyl]benzoyl}amino)ethyl]benzoate (step 6,407 mg, 1.02 mmol) in methanol (10 ml) was added 2 N sodium hydroxide aqueous solution (2 ml). The reaction mixture was stirred at room temperature for 3 h and then evaporated. The residue was partitioned between ethyl acetate (100 mL) and 2 N hydrochloric acid (100 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic extracts were washed with brine (50 mL), dried (sodium sulfate), and concentrated. The residual solids were recrystallized from ethyl acetate to afford 248 mg (64%) of the title compound as white solids:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH:22]1([C:28]2[CH:37]=[C:36]([C:38](O)=[O:39])[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH3:41])[CH:34]=3)[N:29]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1>[CH:22]1([C:28]2[CH:37]=[C:36]([C:38]([NH:1][C:2]3[CH:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]5[CH2:20][CH2:19]5)=[O:15])=[CH:10][CH:9]=4)[C:5]([CH3:21])=[CH:4][CH:3]=3)=[O:39])[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH3:41])[CH:34]=3)[N:29]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: Cc1ccc2nc(C3CCCCC3)cc(C(=O)O)c2c1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Solvent: C1CCOC1
Product: Cc1ccc2nc(C3CCCCC3)cc(C(=O)Nc3ccc(C)c(-c4ccc(C(=O)NCC5CC5)cc4)c3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (42 mg, 0.15 mmol) and 2-cyclohexyl-6-methylquinoline-4-carboxylic acid (107.7 mg, 0.4 mmol) were mixed in THF (5 ml) and the mixture shaken in a varian tube for 30 min at room temperature. Carbodiimde resin (442 mg, 0.5 mmol) was added and shaking continued for 18 h. The solution was filtered off, the resin washed with THF and methanol and the combined filtrate and washings reduced to dryness under vacuum. The residue was dissolved in ethyl acetate, washed with hydrochloric acid (1M) and aqueous sodium hydrogen carbonate. The solvent was evaporated from the organic fraction under vacuum to give 2-cyclohexyl-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-6-methylquinoline-4-carboxamide. NMR; δH [2H6]—DMSO 10.69,(1H, s), 8.62,(1H, t), 7.95-7.90,(3H, m), 7.82,(1H, s), 7.70,(2H, m), 7.60,(1H, dd, 7.56, (1H, s), 7.46,(2H, d), 7.33,(1H, d), 3.16,(2H, t), 2.90,(1H, m), 2.47,(3H, s), 2.22,(3H, s), 1.95,(2H, m), 1.84,(2H, m), 1.74-1.61,(3H, m), .46-1.26,(3H, m), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.93 min, MH+532.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][OH:4].[H-].[Na+].Br[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1>CN(C)C=O.O>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([O:4][CH2:3][CH:2]([F:5])[F:1])=[N:10][CH:11]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OCC(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
2,2-Difluoroethanol (0.40 ml) was added dropwise to a suspension of sodium hydride (0.270 g) in dimethylformamide (5 ml) cooled in an ice-bath under argon. The mixture was stirred at room temperature for 40 minutes, then re-cooled in an ice-bath. A solution of 2,5-dibromopyridine (1 g) in dimethylformamide (5 ml) was added. The solution was then heated at 65° C. under argon for 18 h, allowed to cool and diluted with water (50 ml). The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed with water, brine, dried over magnesium sulphate, filtered and evaporated. The product was purified by column chromatography eluting with hexane to give a colourless oil (0.946 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.N(C1C=C(S(N(C)C)(=O)=O)C=CC=1)=C=O>>[N:13]1([S:10]([C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)(=[O:12])=[O:11])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)N2CCCCC2)c1
Agent: CN(C)S(=O)(=O)c1cccc(N=C=O)c1
Product: Nc1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
3-(Piperidine-1-sulfonyl)phenylamine was prepared as described above from 1-(3-nitro-benzenesulfonyl)piperidine. 3-Isocyanato-N,N-dimethylbenzenesulfonamide
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[CH:21]1([CH2:20][NH:19][N:16]2[C:17](=[O:18])[C:12]([C:4]3[NH:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[S:2](=[O:1])(=[O:28])[N:3]=3)=[C:13]([OH:27])[C:14]3[S:26][CH:25]=[CH:24][C:15]2=3)[CH2:22][CH2:23]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1NCC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.104 g, 0.25 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.200 mL, 0.4 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to pH of approximately 2-4, diluted with water (20 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 1% methanol in chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.06 (m, 2 H) 0.36 (m, 2 H) 0.96 (m, 1 H) 2.92 (d, J=6.99 Hz, 2 H) 6.75 (s, 1 H) 7.53 (d, J=5.52 Hz, 1 H) 7.55 (m, 1 H) 7.63 (d, J=8.09 Hz, 1 H) 7.77 (m, 1 H) 7.92 (d, J=7.72 Hz, 1 H) 8.33 (d, J=5.52 Hz, 1 H) 14.19 (s, 1 H) 14.82 (s, 1 H). MS (ESI−) m/z 415 (M−H)−.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[C:8]([O:12][CH3:13])=[CH:7][N:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[C:8]([O:12][CH3:13])=[CH:7][N:6]=1
Reactant: COc1cnc(CN=[N+]=[N-])cc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1cnc(CN)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-azidomethyl-5-methoxy-pyridin-4-ol (1.45 g, 8.05 mole), is then suspended in 20 mL of tetrahydrofuran and treated with triphenylphosphine (2.11 g, 8.05 mmole) after stirring for 10 mins at ambient temperature water is added (1.76 mL, 15 equivalents) and the reaction mixture is stirred at ambient temperature overnight. The solids gradually dissolved followed by the formation of a precipitate. The resulting solid is filtered, washed with fresh 10:1 tetrahydrofuran:water and dried to give, 0.897 g, (88%), mp 196-201° C. dec; MS (ES+): m/z 155.3 (M+H).
Reaction SMILES: [CH3:1][C@@H:2]([NH:22]C(=O)OC(C)(C)C)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([O:20][CH3:21])[CH:14]=2)=[CH:8][CH:7]=1)=[O:4].ClCCl>>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C@@H:2]([CH3:1])[NH2:22])=[CH:7][CH:8]=2)=[CH:14][C:15]=1[O:20][CH3:21]
Reactant: COc1cc(Oc2ccc(NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)cc2)ccc1C
Solvent: ClCCl
Product: COc1cc(Oc2ccc(NC(=O)[C@@H](C)N)cc2)ccc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.3 %

Procedure:
To a solution of 1,1-dimethylethyl {(1R)-1-methyl-2-[(4-{[4-methyl-3-(methyloxy)phenyl]oxy}phenyl)amino]-2-oxoethyl}carbamate (Intermediate 21, 300 mg) in dry dichloromethane (7.5 mL) TFA (2.5 mL, 32.4 mmol) was slowly added and the reaction mixture was stirred for 1.5 hours at room temperature. The solvent and the excess of TFA were evaporated and the residue was purified by SCX cartridge (10 g) to afford the title compound as an orange oil (219 mg).
Reaction SMILES: [SH:1][C:2]1[S:6][N:5]=[N:4][CH:3]=1.[Na].[NH2:8][CH:9]1[C:30](=[O:31])[N:11]2[C:12]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[O:19])=[C:13]([CH2:16]Cl)[CH2:14][S:15][C@H:10]12>CO.C(Cl)Cl>[NH2:8][CH:9]1[C:30](=[O:31])[N:11]2[C:12]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[O:19])=[C:13]([CH2:16][S:1][C:2]3[S:6][N:5]=[N:4][CH:3]=3)[CH2:14][S:15][C@H:10]12
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(N)C(=O)N23)cc1
Reactant: Sc1cnns1
Agent: [Na]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C(CSc3cnns3)CS[C@@H]3C(N)C(=O)N23)cc1
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
Sodium 5-mercapto-1,2,3-thiadiazole (2.45 g) was suspended in methanol (20 ml), and a solution of p-methoxybenzyl 7-amino-3-chloromethyl-3-cephem-4-carboxylate (5.60 g) in methylene chloride (20 ml) was added dropwise. The mixture was stirred for 30 min. under ice-cooling, an insoluble material was filtered off, and the solvent was evaporated to obtain a crude material (6.38 g). The crude material was subjected to silica gel chromatography eluting with chloroform-ethyl acetate to obtain p-methoxybenzyl 7-amino-3-(1,2,3-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylate (4.90 g).
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]([CH:30]([CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:31]OC3C=CC=CC=3F)[C:28]3[CH:46]=[C:47]([F:51])[C:48]([F:50])=[CH:49][C:27]=3[N:26]=2)=[CH:21][CH:20]=1>CN(C)C=O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([S:1][CH2:31][CH:30]([N:29]2[C:28]3[CH:46]=[C:47]([F:51])[C:48]([F:50])=[CH:49][C:27]=3[N:26]=[C:25]2[C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH:40]2[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COc3ccccc3F)C3CCCCC3)c2cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of 74 mg (0.44 mmol) methyl 4-mercaptobenzoate in 3 ml N,N-dimethylformamide was added 61 mg (0.44 mmol) potassium carbonate at 0° C. The reaction mixture was stirred for 15 min. and then 200 mg (0.44 mmol) 1-(2-bromo-1-cyclohexyl-ethyl)-2-(4-chloro-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 34, intermediate) was added at the same temperature. The cooling bath was removed and the reaction mixture stirred for 18 hours at room temperature. The reaction mixture was poured on 10% aqueous 30 ml citric acid and 30 ml ethyl acetate and the layers were separated. The aqueous layer was extracted a second time with 30 ml ethyl acetate. The combined organic layers were washed with 30 ml brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30) to give the desired compound as a colorless solid (65%). MS (Turbo Spray) m/z=541.2 [M+H].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O>[Pt].CO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Agent: [Pt]
Solvent: CO
Product: Nc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 16 h
Yield: 95.8 %

Procedure:
A mixture of 4-nitro-4′-(trifluoromethoxy)biphenyl (6.41 g, 22.6 mmol), 10% platinum-activated charcoal (150 mg) and methanol (50 ml) was stirred for 16 hours under hydrogen atmosphere. The reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give the title compound (5.48 g, 96%) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[C:14]([C:29](=[O:31])[NH2:30])=[C:15]([NH:17][C:18](=[O:28])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[F:27])[S:16][C:10]=2[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C:18]([NH:17][C:15]2[S:16][C:10]3[CH2:9][NH:8][CH2:13][CH2:12][C:11]=3[C:14]=2[C:29]([NH2:30])=[O:31])=[O:28])=[C:21]([F:27])[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc(NC(=O)Cc3ccc(Cl)cc3F)c2C(N)=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1c(NC(=O)Cc2ccc(Cl)cc2F)sc2c1CCNC2
Temperature: 25 °C

Procedure:
Starting material 19 (3.2 g, 22% content, 1.5 mmol) was dissolved in 25 ml dried DCM and trifluoro acetic acid (TFA, 8.0 ml, 104 mmol) was added. The reaction was stirred at ambient temperature for 30 Min. The solvent was reduced in vacuo and the crude product was purified at the Flashmaster (Method 1). The isolated product was not sufficiently pure and was therefore purified again at the prep. HPLC (Method 4). The pure fractions were combined and the solvent was reduced. The desired product 20 was thereby isolated as a brown solid (236 mg, 42%).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:25][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC1CCCC1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)NC3CCCC3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and cyclopentyl amine to afford the title compound. MS: m/e=326 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].C(O[C:14](S)=[S:15])C.[K].Cl>N1C=CC=CC=1>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[O:10][C:14]([SH:15])=[N:1][C:2]=2[CH:7]=1
Reactant: CCOC(=S)S
Reactant: COc1ccc(O)c(N)c1
Agent: Cl
Agent: [K]
Solvent: c1ccncc1
Product: COc1ccc2oc(S)nc2c1
Temperature: 0 °C

Procedure:
The mixture containing 2-amino-4-methoxyphenol (1 eq) and O-ethylxanthic acid, potassium salt (1.1 eq) in pyridine was refluxed for two hours. The resultant mixture was poured in to ice/water containing hydrochloric acid to yield a 5-methoxybenzoxazole-2-thiol as a tan solid. MS: MH+=182
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:4][CH3:5])[CH3:2].[Mg+].[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14]C([O-])=O>O1CCCC1>[CH2:4]([N:3]([CH2:6][CH2:7][CH2:8][C:9](=[O:11])[CH2:14][C:13]([O:19][CH2:20][CH3:21])=[O:18])[CH2:1][CH3:2])[CH3:5]
Reactant: CCN(CC)CCCC(=O)O
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Mg+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCCN(CC)CC
Temperature: 25 °C
Reaction time: 6 h
Yield: 52.8 %

Procedure:
N,N'-Carbonyldiimidazole (11.2 g) was added to a suspension of 4-(N,N-diethylamino)butanoic acid (10.0 g) in tetrahydrofuran (400 ml), and the mixture was stirred at room temperature for 6 hours. Then monoethyl malonate magnesium salt (Mg(OCOCH2COOC2H5)2)(19.8 g) was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in chloroform. The chloroform layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-methanol (5:1, v/v) gave ethyl 6-(N,N-diethylamino)-3-oxohexanoate (7.6 g, 53%).
Reaction SMILES: [NH:1]1C=CN=C1.[C:6]1([CH2:12][C:13](O)=[S:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N=C=NC(C)C)(C)C>CN(C=O)C>[C:6]1([CH2:12][C:13]([NH2:1])=[S:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OC(=S)Cc1ccccc1
Reactant: c1c[nH]cn1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: NC(=S)Cc1ccccc1
Reaction time: 12 h

Procedure:
To a solution of amino acid methyl ester VI and imidazole in DMF, is added phenylthioacetic acid followed by diisopropylcarbodiimide at room temperature. The reaction mixture is stirred for 12 hours. After filtration on silica gel pad, the filtrate is poured into water and EtOAc. The organic layer is washed twice with water, dried over Na2SO4, and concentrated to afford α-phenylthioacetamide VII.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[C:4]([OH:11])[N:3]=1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[O:22]1[CH2:27][CH2:26][NH:25][C:24]2[CH:28]=[N:29][CH:30]=[CH:31][C:23]1=2>>[O:22]1[CH2:27][CH2:26][N:25]([C:8]([C:6]2[CH:5]=[C:4]([OH:11])[N:3]=[C:2]([OH:1])[N:7]=2)=[O:10])[C:24]2[CH:28]=[N:29][CH:30]=[CH:31][C:23]1=2
Reactant: O=C(O)c1cc(O)nc(O)n1
Reactant: c1cc2c(cn1)NCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Product: O=C(c1cc(O)nc(O)n1)N1CCOc2ccncc21

Procedure:
By the same method as in Example 59, 2,6-dihydroxy-pyrimidin-4-carboxylic acid (125 mg, 0.80 mmol), thionyl chloride (0.066 ml, 0.90 mmol), potassium carbonate (138 mg, 1.0 mmol) and 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (109 mg, 0.80 mmol) were reacted and the reaction mixture was purified in the same manner to obtain the target compound 60, i.e., (2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-(2,6-dihydroxy-pyrimidin-4-yl)-methanone, as white solid (32 mg, 15%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([N:16]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)[CH3:17])[CH2:10]2>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([N:16]([CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:24][CH:25]=1)[CH3:17])[CH2:10]2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCc1ccc(N)cc1)C1Cc2ccc(N)cc2C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(CCc1ccc(NS(C)(=O)=O)cc1)C1Cc2ccc(NS(C)(=O)=O)cc2C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Methanesulphonyl chloride (0.155 ml) was added to a solution of 5-amino-2-[N-(4-aminophenethyl)-N-methylamino]indane (0.28 g) in pyridine (30 ml) and the reaction mixture was stirred at room temperature for 17 hours. The solvent was then removed by evaporation in vacuo to give a gum which was dissolved in methylene chloride, washed with aqueous sodium bicarbonate and brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 2%) and the product-containing fractions were combined and evaporated to dryness in vacuo to afford the title compound as a foam, yield 0.27 g.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[OH:20][CH2:21][C@H:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>>[OH:20][CH2:21][C@H:22]([NH:30][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1)[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: N[C@@H](CO)Cc1ccccc1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@@H](CO)Cc2ccccc2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (R)-1-hydroxymethyl-2-phenyl-ethylamine and DIEA to give 2-((R)-1-hydroxymethyl-2-phenyl-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 390 (MH+).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][N:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[NH2:28][C@H:29]([CH3:32])[CH2:30][OH:31]>>[OH:31][CH2:30][C@H:29]([NH:28][C:23]([C:22]1[CH:26]=[CH:27][C:19]([C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:12][CH2:13]2)=[O:18])=[N:20][CH:21]=1)=[O:25])[CH3:32]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Reactant: C[C@@H](N)CO
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N[C@H](C)CO)cn2)CC1
Yield: 80 %

Procedure:
By the same procedure as described in the example 1, synthesis was carried out starting with 6-[1-[3-(isopropylamino)-2-pyridyl]piperazine-4-yl-carbonyl]nicotinic acid and using (R)-(−)-2-amino-1-propanol. Then, the product was recrystallized with ethanol and hexane to give a desired compound.