Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([NH2:27])[N:18]=1>ClCCl>[N:27]([C:19]1[N:18]=[CH:17][C:26]2[C:21]([CH:20]=1)=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:1]=[S:2]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Nc1cc2ccccc2cn1
Solvent: ClCCl
Product: S=C=Nc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.805 g, 3.47 mmol) in dichloromethane at room temperature was added isoquinolin-3-amine (0.5 g, 3.47 mmol). The reaction was stirred at room temperature for 18 hours. The LC/MS showed the desired product peak a major peak. The deep orange solution was concentrated and filtered. The filtrate was purified by silica gel chromatography (0-40% ethyl acetate-hexanes) to afford 4-isothioeyanato-6-(3-methoxyphenyl)pyrimidine (0.55 g, 2.96 mmol, 85% yield) a white solid. LCMS R.T.=2.47; [M+H]+=187.23.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH:7]([CH3:9])[CH3:8])=[C:5]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[O:4][N:3]=1.[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25]O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][O:1][C:2]1[C:6]([CH:7]([CH3:9])[CH3:8])=[C:5]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[O:4][N:3]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CC(C)c1c(O)noc1-c1cccnc1
Product: CC(C)c1c(OCCNC(=O)OC(C)(C)C)noc1-c1cccnc1
Yield: 72.2 %

Procedure:
3-Hydroxy-4-isopropyl-5-(3-pyridyl)isoxazole (0.12 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.09 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.14 g, 74%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=1.S(Cl)([Cl:19])=O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][C:12]([C:14]([Cl:19])=[O:16])=[CH:11][CH:10]=1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2Cl)o1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(-c2ccc(Cl)cc2Cl)o1

Procedure:
A solution of 28.28 g (0.11 moles) of 5-(2,4-dichlorophenyl)-2-furancarboxylic acid in 43 ml of thionyl chloride is heated at reflux for 3 hours. The solvent is removed and the residue is treated with 100 ml of toluene. The solvent is removed and the residue is carried on directly to the next step of the reaction.
Reaction SMILES: CCOCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Li]CCCC.[CH3:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>[Cl-].[Na+].O>[CH3:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:20]=1
Reactant: Brc1ccccc1
Reactant: Cc1ccncc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1ccnc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 36 %

Procedure:
A two necked round-bottom flask (250 mL) containing a stir bar fitted with a reflux condenser was evacuated and purged with nitrogen gas. Dry ether (50 mL) and bromobenzene (0.0191 mol, 3.0 g) were added to the flask followed by the slow addition of n-BuLi (0.0229 mol, 9.17 mL) via a syringe pump. The reaction mixture was stirred at room temperature for 30-40 min and then 4-methyl pyridine (0.0191 mol, 1.779 g) was slowly added. The reaction mixture was then refluxed for 2 to 3 hr. The reaction mixture was then cooled to room temperature, diluted with an aqueous brine solution and extracted with ether (3×30 mL). The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using hexanes/EA as eluent. The desired 4-methyl-2-phenylpyridine was obtained. (1.15 g; 36% yield).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:22]=[CH:21][C:9]([O:10][C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH3:23]N(C=O)C>>[CH3:23][NH:15][C:14]1[CH:16]=[CH:17][C:11]([O:10][C:9]2[CH:21]=[CH:22][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=2)=[CH:12][C:13]=1[N+:18]([O-:20])=[O:19]
Reactant: CN(C)C=O
Reactant: Nc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Product: CNc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a mixture of NaH (60% oily, 320 mg, 8.0 mmol) in DMF (30 mL) was added a solution of 4-(4-nitrophenoxy)-2-nitroaniline (Intermediate 8A-2.00 g, 7.3 mmol) in DMF (30 mL) at 0° C. followed by an excess amount of Mel (2.0 mL). The mixture was stirred at 0° C. for 1.5 hrs then at room temperature overnight. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2column chromatography gave the title compound (2.10 g, quant). ): 1H NMR (CDCl3-d1) δ 3.08 (d, 3H), 6.94 (d, 1H), 7.00 (d, 2H), 7.30 (dd, 1H), 7.97 (d, 1H), 8.08 (brs, 1H), 8.22 (d, 2H).
Reaction SMILES: Cl[C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:3]=1.[C:33]([C:37]1[O:41][N:40]=[C:39]([OH:42])[CH:38]=1)([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[C:33]([C:37]1[O:41][N:40]([C:2]2[CH:3]=[C:4]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][C:12]=2[N+:13]([O-:15])=[O:14])[C:39](=[O:42])[CH:38]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CCCCCCCCCCCCCCCCOc1cc(Cl)c([N+](=O)[O-])cc1C(=O)OCC
Reactant: CC(C)(C)c1cc(O)no1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCCCOc1cc(-n2oc(C(C)(C)C)cc2=O)c([N+](=O)[O-])cc1C(=O)OCC
Yield: 37.9 %

Procedure:
In 300 ml of dimethyl sulfoxide were dissolved 65 g of ethyl 4-chloro-2-hexadecyloxy-5-nitrobenzoate and 24 g of 5-t-butyl-3-hydroxyisoxazole and after adding thereto 24 g of potassium carbonate, the reaction was performed for 8 hours at 75° C. After the reaction was over, the reaction mixture obtained was poured into diluted hydrochloric acid and the product formed was extracted with ethyl acetate. After recovering and drying the organic phase thus formed, the solvent was distilled off from the organic phase and the residue thus formed was carefully applied to silica gel column chromatography, whereby the aforesaid compound was obtained as the main product. The product thus obtained was recrystallized from a mixture of methanol and acetonitrile to provide 30.1 g of the desired compound with a yield of 37.9%. The melting point thereof was 35° C. to 36° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([N:11]=[C:12]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([OH:21])=[CH:16][C:15]=3[CH3:22])[N:13]=2)[CH:10]=1)=[O:4].[CH3:23][S:24]([CH2:27][CH2:28][CH2:29]OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([N:11]=[C:12]([C:14]3[C:15]([CH3:22])=[CH:16][C:17]([O:21][CH2:29][CH2:28][CH2:27][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:18][C:19]=3[CH3:20])[N:13]=2)[CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc2nc(-c3c(C)cc(O)cc3C)nn2c1
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc2nc(-c3c(C)cc(OCCCS(C)(=O)=O)cc3C)nn2c1
Temperature: 100 °C
Yield: 70.5 %

Procedure:
To a solution of 2-(4-hydroxy-2,6-dimethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid methyl ester (0.2 g, 0.673 mmol) in acetonitrile (5 mL) is added toluene-4-sulfonic acid 3-methanesulfonyl-propyl ester (0.196 g, 0.673 mmol) and potassium carbonate (0.278 g, 2.019 mmol) at room temperature and the reaction mixture is heated at 100° C. for 16 hours. The reaction mixture is diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts are washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The crude material is purified by silica gel chromatography (combiflash purifier 24 g redisep column) and is eluted with 40-60% EtOAc in hexane to give the title compound as a light yellow solid (198 mg, 70%). LCMS m/z 418 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N+:3]=1[O-:9].[N+:10]([O-])([OH:12])=[O:11].C([O-])(O)=O.[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[C:4]([CH3:8])[N+:3]=1[O-:9]
Reactant: Cc1cccc(Cl)[n+]1[O-]
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cc([N+](=O)[O-])cc(Cl)[n+]1[O-]
Temperature: 90 °C
Reaction time: 3 h

Procedure:
2-chloro-6-methylpyridine 1-oxide (60 g, 0.42 mol) was dissolved in 98% sulfuric acid (60 mL) at 0° C., then a solution of HNO3 (50 mL) and H2SO4 (50 mL) was added dropwise at the same temperature. After the addition was complete, the reaction was stirred at 90° C. for 3 h. The reaction was poured into ice-water, neutralized with NaHCO3, and then extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (500 mL), dried over magnesium sulfate, filtered and concentrated to afford 2-chloro-6-methyl-4-nitropyridine 1-oxide which was used without further purification. 1H NMR (300 MHz, CDCl3) δ 8.27 (d, J=2.7 Hz, 1H), 8.07 (d, J=0.6 Hz, 1H), 2.62 (s, 3H). LRMS calc'd for (C6H6ClNO) [M+H]+, 189; found 189.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[O:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH2:14][CH2:13]1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([C:20]1[CH:19]=[CH:18][C:17]2[O:12][CH2:13][CH2:14][N:15]([C:22](=[O:27])[C:23]([F:25])([F:24])[F:26])[C:16]=2[CH:21]=1)=[O:8]
Reactant: O=C(N1CCOc2ccccc21)C(F)(F)F
Reactant: O=C(Cl)c1cc(Br)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)N(C(=O)C(F)(F)F)CCO2)c1cc(Br)ccc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice cooled solution of 5-bromo-2-chlorobenzoyl chloride in dichloromethane (35 mL) was added 1-(2,3-dihydro-benzo[1,4]oxazin-4-yl)-2,2,2-trifluoro-ethanone (6.5 g, 28.1 mmol) in dichloromethane (45 mL) followed by AlCl3 (5.61 g, 42.2 mmol) portion wise. After 2 h, the reaction mixture was brought to room temperature and stirred overnight. The reaction was quenched by pouring it over crushed ice. The resulting mixture was extracted with dichloromethane. The organic layer was washed with aq. NaHCO3 (100 mL) and water (100 mL), and the solvent was evaporated to yield the crude product which was recrystallized from hot ethylacetate to furnish 1-[6-(5-bromo-2-chloro-benzoyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-trifluoro-ethanone (10.0 g).
Reaction SMILES: [N:1]1([S:5]([NH:8][C:9]2[N:14]=[C:13]([S:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[F:24])[N:12]=[C:11]([O:25][C@@H:26]([CH3:32])[C:27](OCC)=[O:28])[CH:10]=2)(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.[BH4-].[Li+]>C1COCC1>[F:24][C:18]1[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][S:15][C:13]1[N:14]=[C:9]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:6])=[O:7])[CH:10]=[C:11]([O:25][C@@H:26]([CH3:32])[CH2:27][OH:28])[N:12]=1
Reactant: CCOC(=O)[C@H](C)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](CO)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared according to the procedure outlined in example 24 using 2-[[6-[(1-azetidinylsulfonyl)amino]-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2S)-propanoic acid, ethyl ester, (the product of step ii) (0.28 g), THF (8 mL) and 2M lithium borohydride in THF (0.57 mL). Purification was by column chromatography on silica using EtOAc/isohexane (2:3) as eluent to give the title compound as a white solid. Yield: 0.15 g
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[OH:32]>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:26]2[CH:27]=[CH:28][C:29]([CH3:31])=[CH:30][C:25]=2[Cl:24])=[N:3][CH:4]=1
Reactant: Cc1ccc(O)c(Cl)c1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2ccc(C)cc2Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 2-chloro-4-methylphenol: 1H-NMR (CDCl3) δ 8.53 (1H, d, J=2.6 Hz), 8.20 (1H, d, J=7.4 Hz), 8.11 (1H, d, J=2.6 Hz), 8.01 (2H, d, J=8.4 Hz), 7.45 (2H, d, J=8.4 Hz), 7.37–7.31 (1H, m), 7.23–7.17 (2H, m), 5.39 (1H, dq, J=7.4, 6.9 Hz), 3.90 (3H, s), 2.40 (3H, s), 1.60 (3H, d, J=6.9 Hz); MS (ESI) m/z 459 (M+H)+, 457 (M−H)−.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([NH2:24])[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[C:27](=S)=[S:28]>CCO.O>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]3=[N:23][C:27](=[S:28])[N:24]=[C:19]3[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(OCCN2CCC(Cc3ccccc3)CC2)cc1N
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: S=C1N=c2ccc(OCCN3CCC(Cc4ccccc4)CC3)cc2=N1
Yield: 68.4 %

Procedure:
A mixture of 4-benzyl-1-[(3,4-diaminophenoxy)ethyl]piperidine (326 mg, 1.0 mmol), KOH (66 mg, 1.1 mmol) and CS2 (66 μL, 1.1 mmol) in 95% EtOH (1.5 mL) and H2O (0.2 mL) was refluxed for 3 h, then evaporated, and the residue was purified by chromatography over silica gel (CHCl3 --MeOH, 4:1) to give 250 mg (68%) of the title compound as a foam solid. 1H NMR (DMSO-d6): 1.40-1.48 (m, 2H), 1.54-1.61 (m, 1H), 1.67-1.71 (m, 2H), 2.09-2.18 (m, 2H), 2.517 (d, 2H, J=6), 2.841 (t, 2H, J=5), 3.17-3.20 (m,2H), 4.139 (t, 2H, J=5), 6.551 (d, 1H, J=2), 6.605 (dd, 1H, J=8.5; 2), 6.950 (d, 1H, J=8.5), 7.11-7.28 (m, 5H). The hydrochloride, mp. 273-5° C. Analysis, Calcd. for C21H26ClN3OS: C 62.44, H 6.49, N 10.40; Found: C 62.28, H 6.42, N 10.21.
Reaction SMILES: O=P(Cl)(Cl)Cl.[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=O)=[C:9]([O:16][CH2:17][CH:18]([F:20])[F:19])[N:8]=1.[OH-].[Na+]>C(#N)C>[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]#[N:13])=[C:9]([O:16][CH2:17][CH:18]([F:19])[F:20])[N:8]=1
Reactant: NC(=O)c1ccc(Cl)nc1OCC(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: N#Cc1ccc(Cl)nc1OCC(F)F
Temperature: 60 °C

Procedure:
POCl3 (7.5 mL, 81 mmol) was added to a solution of 6-chloro-2-(2,2-difluoro-ethoxy)-nicotinamide (6.39 g, 27.0 mmol) in acetonitrile (100 mL) at 14° C. over 5 minutes. The reaction mixture was heated to 60° C. for 1.5 hours then cooled to room temperature. The mixture was poured into an ice cold solution of aqueous NaOH (0.6M, 800 mL) and extracted with EtOAc (4×800 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (20% ethyl acetate/hexanes) to give the title compound as a light yellow oil which solidified upon standing (5.10 g, 86%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[CH:12]1[C:17]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:16][C:15]([NH2:22])=[C:14](O)[CH:13]=1>>[CH3:1][NH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]2[O:9][C:14]3[CH:13]=[CH:12][C:17]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:16][C:15]=3[N:22]=2)=[CH:10][CH:11]=1
Reactant: CNc1ccc(C(=O)O)cc1
Reactant: Nc1cc(S(=O)(=O)O)ccc1O
Product: CNc1ccc(-c2nc3cc(S(=O)(=O)O)ccc3o2)cc1

Procedure:
In accordance with the procedure of Example 1, 8.0 g of p-methylamino-benzoic acid were reacted with 10.0 g of 2-aminophenol-4-sulfonic acid to yield 2-(p-methylaminophenyl)-benzoxazole-5-sulfonic acid, melting point 333° (with decomposition).
Reaction SMILES: C[O:2][C:3](=[O:51])[CH2:4][N:5]([CH2:46][C:47]([O:49]C)=[O:48])[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:9]=[C:8]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][CH:37]=2)[CH:7]=1.[OH-].[Na+]>CO>[C:3]([CH2:4][N:5]([C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:9]=[C:8]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:43])=[O:44])=[CH:38][CH:37]=2)[CH:7]=1)[CH2:46][C:47]([OH:49])=[O:48])([OH:51])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(S(C)(=O)=O)cc2)cc(N(CC(=O)OC)CC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(S(C)(=O)=O)cc2)cc(N(CC(=O)O)CC(=O)O)c1
Yield: 86.3 %

Procedure:
A solution of 1.01 g (1.37 mmol) of N-(2-methoxy-2-oxoethyl)-N-[3-[3-[4-(methylsulfonyl) phenoxy]propoxy]-5-(octadecyloxy)-phenyl]glycine methyl ester and 0.92 ml (5.5 mmol) of 6 N NaOH in 30 ml of methanol was stirred at reflux for 4 hours under argon. The methanol was removed at reduced pressure, the residue was acidified and the product was extracted with ethyl acetate. The dried extract was concentrated to a solid which was recrystallized from methylene chloride-ether to give 0.835 g (86% yield, mp 118°-120°) of N-(carboxymethyl)-N-[3-[3-[4-(methylsulfonyl)phenoxy]propoxy]-5-(octadecyloxy)phenyl]glycine.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[N:28]4[N:35]=[CH:36][C:37]([C:38](=[O:40])[NH2:39])=[C:27]4[N:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.[O:42]([CH2:44][S:45]([C:48]1[CH:49]=[C:50]([OH:55])[C:51](=[CH:53][CH:54]=1)[OH:52])(=[O:47])=[O:46])[NH2:43]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:43]/[O:42][CH2:44][S:45]([C:48]2[CH:54]=[CH:53][C:51]([OH:52])=[C:50]([OH:55])[CH:49]=2)(=[O:46])=[O:47])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[CH:30]=[C:29]([C:31]([F:33])([F:32])[F:34])[N:28]4[N:35]=[CH:36][C:37]([C:38](=[O:40])[NH2:39])=[C:27]4[N:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: NOCS(=O)(=O)c1ccc(O)c(O)c1
Reactant: NC(=O)c1cnn2c(C(F)(F)F)cc(SCC3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)C(=O)c5csc(N)n5)[C@H]4SC3)nc12
Product: NC(=O)c1cnn2c(C(F)(F)F)cc(SCC3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)/C(=N\OCS(=O)(=O)c5ccc(O)c(O)c5)c5csc(N)n5)[C@H]4SC3)nc12

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[(3-carbamoyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid was reacted with 4-[[(aminoxy)methyl]sulphonyl]pyrocatechol according to the procedure described in Example 7. After purification of the product with the chromatographic procedure in Example 7 and lyophilization of the product, there was obtained (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)-sulphonyl]methoxy]imino]acetamido]-3-[[(3-carbamoyl-7-(tri-fluoromethyl)pyrazolo[1,5-a]pyrimidin-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a pale yellow powder.
Reaction SMILES: CN1CCCC1.[NH2:7][C:8]1[N:13]=[C:12]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:26])=[C:21](F)[C:22]=3[Cl:24])[C:17](=[O:27])[C:16]([C:28]([OH:30])=[O:29])=[CH:15]2)[C:11]([F:31])=[CH:10][C:9]=1[F:32].C(OC([NH:40][C@@:41]12[CH2:48][CH2:47][CH2:46][C@:45]1([F:49])[CH2:44][NH:43][CH2:42]2)=O)(C)(C)C>C(#N)C>[NH2:40][C@@:41]12[CH2:48][CH2:47][CH2:46][C@:45]1([F:49])[CH2:44][N:43]([C:21]1[C:22]([Cl:24])=[C:23]3[C:18]([C:17](=[O:27])[C:16]([C:28]([OH:30])=[O:29])=[CH:15][N:14]3[C:12]3[C:11]([F:31])=[CH:10][C:9]([F:32])=[C:8]([NH2:7])[N:13]=3)=[CH:19][C:20]=1[F:26])[CH2:42]2
Reactant: CC(C)(C)OC(=O)N[C@@]12CCC[C@]1(F)CNC2
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: CN1CCCC1
Solvent: CC#N
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4C[C@]5(N)CCC[C@]5(F)C4)c(Cl)c32)c(F)cc1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 11.6 %

Procedure:
N-methylpyrrolidine (0.246 mL, 2.37 mmol) and 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (306 mg, 0.79 mmol) were added to a solution of (1R,5S)-1-(tert-butoxycarbonylamino)-5-fluoro-3-azabicyclo[3.3.0]octane (193 mg, 0.79 mmol) in acetonitrile (10.0 mL), and the mixture was heated to reflux for 10 hours. 1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (92 mg, 0.24 mmol) was added again to the reaction solution, and the mixture was further heated to reflux for 4.5 hours. The solvent was evaporated under reduced pressure, and then the residue was extracted with a 10% citric acid solution and ethyl acetate. Then, the organic layer was washed with water twice and brine, dried over anhydrous sodium sulfate, and filtered. Thereafter, the solvent was evaporated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (dichloromethane:methanol=99:1). The resulting oil (409 mg) was dissolved in concentrated hydrochloric acid (3.0 mL) under ice-cooling, and the solution was stirred at room temperature for 2.5 hours. The reaction solution was washed with chloroform twice, and then the aqueous layer was adjusted to pH 12 with a saturated sodium hydroxide solution. The basic solution was adjusted to pH 7.4 with hydrochloric acid, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the solvent was evaporated under reduced pressure. Chloroform was added to the residue, and the insoluble material was removed by filtration. Then, the filtrate was evaporated under reduced pressure, and the resulting residue was purified by recrystallization from ethanol to give 47 mg of the title compound as a pale yellow solid.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][N:7]([C:9](=[O:23])[C@@H:10]([NH:15][C:16](OC(C)(C)C)=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12])[C@H:6]([C:24]([O:26][CH3:27])=[O:25])[CH2:5]1)=[N+:2]=[N-:3].FC(F)(F)C(O)=O.[N:35]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])([CH3:41])[C@H:36](C(O)=O)[CH3:37]>>[N:1]([C@@H:4]1[CH2:8][N:7]([C:9](=[O:23])[C@@H:10]([NH:15][C:16](=[O:17])[C@@H:36]([N:35]([C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])[CH3:41])[CH3:37])[C:11]([CH3:12])([CH3:13])[CH3:14])[C@H:6]([C:24]([O:26][CH3:27])=[O:25])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C

Procedure:
The title compound of Example 1 was treated with trifluoroacetic acid using the general procedure A to deprotect the BOC group. The resulting trifluoroacetic acid salt was coupled to Boc-N-Me-Ala-OH using the general procedure D to prepare the title compound of Example 2. 1H NMR (CDCl3): consistent with proposed structure.