Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([NH:9][C:10]1[C:15]([F:16])=[CH:14][C:13]([F:17])=[C:12]([NH:18]C)[N:11]=1)C1C=CC=CC=1>[Pd].CO>[NH2:18][C:12]1[C:13]([F:17])=[CH:14][C:15]([F:16])=[C:10]([NH:9][CH3:2])[N:11]=1
Reactant: CNc1nc(NCc2ccccc2)c(F)cc1F
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNc1nc(N)c(F)cc1F
Reaction time: 8 h

Procedure:
To a mixed solution of 10 ml of methanol and 1 ml of concentrated hydrochloric acid were added all amount of the above described 2-benzylamino-3,5-difluoro-6-(methylamino)pyridine together with 0.55 g of 10% palladium on carbon, and the mixture was hydrogenated at 50° C. overnight. The catalyst was separated by filtration, and the solvent and the like were distilled off under reduced pressure. To the residue was added 50 ml of chloroform, and the mixture was washed with 50 ml of 5% aqueous solution of sodium carbonate. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The solid precipitate was collected by filtration to obtain 840 mg of the title compound as a pale gray solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.[F:12][C:13]1[CH:14]=[C:15]([CH:33]=[CH:34][CH:35]=1)[CH2:16][NH:17][C:18](=[O:32])[NH:19][C:20]1[S:21][C:22]([CH:29]([CH3:31])[CH3:30])=[C:23]([C:25](OC)=[O:26])[N:24]=1.OS([O-])(=O)=O.[Na+]>CO>[F:12][C:13]1[CH:14]=[C:15]([CH:33]=[CH:34][CH:35]=1)[CH2:16][NH:17][C:18]([NH:19][C:20]1[S:21][C:22]([CH:29]([CH3:31])[CH3:30])=[C:23]([CH2:25][OH:26])[N:24]=1)=[O:32]
Reactant: COC(=O)c1nc(NC(=O)NCc2cccc(F)c2)sc1C(C)C
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1sc(NC(=O)NCc2cccc(F)c2)nc1CO
Temperature: 25 °C

Procedure:
LiAlH4 (5.5 mL, 5.5 mmol, 1 M in THF) was added to a THF (30 mL) solution of methyl 2-(3-(3-fluorobenzyl)ureido)-5-isopropylthiazole-4-carboxylate (780 mg, 2.22 mmol) at 0 C. Upon completion of the reaction Na2SO4x10H2O (1.5 g, 4.5 mmol) was added carefully. The suspension was stirred for a day at ambient temperature which was followed by the addition of NaHSO4 (0.5 g, 4.5 mmol) and MeOH (5 mL). The mixture extracted with CH2Cl2, washed with dilute HCl, dried and evaporated to afford 1-(3-fluorobenzyl)-3-(4-(hydroxymethyl)-5-isopropylthiazol-2-yl)urea. 1H NMR (400 MHz, CDCl3): δ 7.70 (s, 1H, br), 7.24 (m, 1H), 7.05 (d, 1H), 6.99 (d, 1H), 6.92 (td, 1H), 4.55 (s, 2H), 4.41 (d, 2H), 3.20 (m, 1H), 1.27 (d, 6H). MS (ES+): M/Z 324 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (3.0 g, 8.5 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (2.2 g, 10.0 mmol). The title compound was obtained as a solid (3.3 g, 73% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, s), 8.66 (1H, m), 8.47 (1H, m), 3.87 (3H, m), 2.82 (2H, m), 1.73 (2H, m), 1.37 (9H, s), 1.31 (2H, m).
Reaction SMILES: COC(OC)CBr.C[O:9][CH:10](OC)[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].FC1C=C(O)C=CC=1F>CN(C=O)C>[F:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[F:19])[O:12][CH2:11][CH:10]=[O:9]
Reactant: COC(COc1ccc(F)c(F)c1)OC
Agent: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: Oc1ccc(F)c(F)c1
Solvent: CN(C)C=O
Product: O=CCOc1ccc(F)c(F)c1
Temperature: 120 °C
Yield: 106.2 %

Procedure:
4-(2,2-Dimethoxyethoxy)-1,2-difluorobenzene Bromoacetaldehyde dimethyl acetal (3.3 ml, 27.9 mmol) and potassium carbonate (6.5 g, 47.1 mmol) were added to a solution of 3,4-difluorophenol (3.0 g, 23.4 mmol) in DMF (65 ml). The mixture was heated to 120° C. for 4 hours, cooled to room temperature and then quenched with a solution of aqueous ammonium chloride. The product was extracted into ethyl acetate, washed with water and brine, dried over magnesium sulphate, filtered and concentrated in vacuo to yield the title compound (5.1 g, 97%); 1H NMR (CDCl3) 3.45 (6H, s), 3.93 (2H, d, J 5.1 Hz), 4.67 (1H, t, J 5.1 Hz), 6.60 (1H, m), 6.74 (1H, m) and 7.03 (1H, m). Step 2. (3,4-Difluorophenoxy)-acetaldehyde A solution containing the product from Step 1 (5.1 g, 23.4 mmol), glacial acetic acid (4.5 ml) and concentrated sulphuric acid (2.7 ml) in water (50 ml) was heated at 100° C. for 5 hours. After cooling to room temperature, the product was extracted into diethyl ether. The organic extract was washed with aqueous sodium hydrogen carbonate solution, dried over magnesium sulphate, filtered an concentrated in vacuo. The product was purified by silica gel chromatography eluting with ethyl acetate:hexane (30:70) to yield the title compound (2.74 g, 68%); 1H NMR (CDCl3) 4.52 (2H, s), 6.59 (1H, m), 6.83 (1H, m), 7.08 (1H, m) and 9.82 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:35])[C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C:12]([C:15](OCC)=[O:16])=[N:13][CH:14]=2)=[CH:4][CH:3]=1.Cl[C:37](=[O:44])[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:12]([C:15]([OH:16])=[C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:37](=[O:44])[N:20]3[CH2:21][CH2:22][CH2:23][N:24]([CH3:35])[C:25]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:26])=[N:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCCN(C)C(=O)OCc1ccccc1
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN(C)C(=O)OCc2ccccc2)c1=O

Procedure:
This compound was prepared in two steps from ethyl 5-[(4-fluorophenyl)methyl]-3-{[3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)propyl]amino}-2-pyridinecarboxylate and ethyl 3-chloro-3-oxopropionate employing methods similar to those described in Example 457, Steps 3-4. The product was obtained as a white solid: 1H NMR (d6-DMSO, 80° C.) δ 8.65 (1H, b), 7.73 (1H, b), 7.23-7.39 (7H, m), 7.10 (2H, t, J=7 Hz), 5.05 (2H, s), 3.90-4.12 (4H, m), 3.40 (2H, q, J=7 Hz), 3.32 (2H, b), 2.85 (3H, s), 1.74 (2H, b), 1.09 (3H, t, J=7 Hz); ES+ MS: 470 (M+Na+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Cl.[H-].[Na+]>>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[Cl:14])[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Reactant: ClCc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(Cc1ccccc1Cl)n1cccc1

Procedure:
Prepared according to the benzylation condition used in Example 1 step b) from pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.), 2-chlorobenzyl chloride (1.03 eq.) and sodium hydride (1.3 eq.). ESI (m/z): 307 (M+H)+.
Reaction SMILES: NC1OC=C(C(OCC)=O)N=1.CC(OC(C)=O)=O.[C:19]([NH:22][C:23]1[O:24][CH:25]=[C:26]([C:28]([O:30]CC)=[O:29])[N:27]=1)(=[O:21])[CH3:20].[Li+].[OH-]>CCO>[C:19]([NH:22][C:23]1[O:24][CH:25]=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)(=[O:21])[CH3:20]
Reactant: CCOC(=O)c1coc(NC(C)=O)n1
Agent: CCOC(=O)c1coc(N)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: CC(=O)Nc1nc(C(=O)O)co1
Temperature: 25 °C

Procedure:
1.0 g (6.41 mmol) ethyl 2-aminooxazole-4-carboxylate and 9.10 mL (96.3 mmol) Ac2O are stirred at r.t. over the weekend. Then the solvent is removed in vacuo. Some toluene is added and all volatile components are removed in vacuo again. This procedure is repeated three times. The crude product is used without further purification. b) 1.31 g (6.60 mmol) of ethyl 2-acetamidooxazole-4-carboxylate are added to 33 mL EtOH. 0.55 g (13.2 mmol) LiOH are added and the resulting mixture is stirred at r.t. over night. Then the EtOH is removed in vacuo and diluted aq. HCl is added and the resulting precipitate is collected, washed with cold water and dried. The resulting product is used without further purification.
Reaction SMILES: [F:1][C:2]([F:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3](=[O:11])[CH2:4]P(=O)(OC)OC.O.[OH-].[Li+].[C:22]([O:25][C@@H:26]1[C@H:30]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C@@H:29]([CH:41]=O)[C@H:28]([O:43][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][O:45]2)[CH2:27]1)(=[O:24])[CH3:23]>COC(C)(C)C.O>[C:22]([O:25][C@@H:26]1[C@H:30]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C@@H:29](/[CH:41]=[CH:4]/[C:3](=[O:11])[C:2]([F:1])([F:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:28]([O:43][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][O:45]2)[CH2:27]1)(=[O:24])[CH3:23]
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Reactant: COP(=O)(CC(=O)C(F)(F)c1ccccc1)OC
Agent: [Li+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: COC(=O)CCCCCC[C@@H]1[C@@H](/C=C/C(=O)C(F)(F)c2ccccc2)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxo-3-phenylpropyl)phosphonate (6) (0.262 g, 0.942 mmol) in t-butyl methyi ether (7 ml), lithium hydroxide monohydrate (38.2 mg, 0.910 mmol) was added and the mixture was stirred for one hour at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (2) (0.250 g, 0.627 mmol) in t-butyl methyl ether (3 ml) and water (0.3 ml) were added thereto, and the mixed solution was heat refluxed for approximately 48 hours After cooling to room temperature, the reaction mixture was added to water, and extracted twice with t-butyl methyl ether. The organic layers were combined, sequentially washed with water, saturated sodium bicarbonate water and saturated aqueous sodium chloride, and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Merck Art. 9385: 200 g; ethyl acetate:hexane=2:3). The fractions containing impurities were re-purified by silica gel column chromatography (Merck Art. 9385: 120 g; ethyl acetate:hexane=2:3), to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-4-phenyl-1-butenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (7) (0.257 g; 0.467 mmol; yield: 74.4%) as a colorless oil.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][CH:4]=1.[O:10]=[C:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>C1COCC1>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([C:11](=[O:10])[CH2:15][CH2:14][CH2:13][NH:12][C:16](=[O:17])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:4][CH:5]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
A thoroughly dried three-necked round-bottom flask was equipped with reflux condenser, addition funnel and argon inlet. Then magnesium powder (7.5 g, 311 mmol, activated by iodine) and dry THF (300 mL) were placed into this apparatus. A solution of 1,4-dibromobenzene (73.5 g, 311 mmol) in dry THF (200 mL) was slowly added at such a rate that the mixture maintained at reflux. When the addition was completed the mixture was refluxed for additional 2 hrs. After cooling to room temperature, the solution was added into a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (48 g, 260 mmol) in THF (320 mL) at −78° C. and the mixture was stirred at −78° C. for 2 hrs. The solution was warmed to ambient temperature and stirred for another 10 hrs before quenching with water. Hydrochloric acid (1 N, 100 mL) was added and the mixture was stirred at ambient temperature for 10 minutes. The mixture was concentrated and the residue was partitioned between ethyl acetate and brine. The organic phase was dried over magnesium sulfate and concentrated in vacuo to afforded the crude product, which was purified by column chromatography (EtOAc:DCM:hexane=1:1:15) to give the title compound as a white solid (53 g, yield 60%). LC-MS (ESI) m/z: 342 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:19][CH2:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:10](=[O:27])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.CS[C:32]1[NH:33][CH2:34][CH2:35][N:36]=1.C(N(CC)CC)C>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([C:32]4[NH:36][CH2:35][CH2:34][N:33]=4)[CH2:23][CH2:22]3)[C:10](=[O:27])[CH2:9]2)=[O:7])=[CH:28][CH:29]=1
Reactant: CSC1=NCCN1
Reactant: O=C(c1ccc(Cl)cc1)N1CC(=O)N(CCC2CCNCC2)c2ccccc2C1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)cc1)N1CC(=O)N(CCC2CCN(C3=NCCN3)CC2)c2ccccc2C1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
30 mg (0.073 mmol) of 4-(4-chlorobenzoyl)-1-[2-(4-piperidinyl)-ethyl]-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on obtained in step 1 in Example 168 and 178 mg (0.73 mmol) of 2-methylthio-2-imidazoline were dissolved in 7 ml of methanol. 0.2 mg (1.4 mmol) of triethylamine was added to the obtained solution, and they were stirred at 70° C. overnight. The solvent was evaporated, and the obtained crude product was treated by the reversed phase high-performance liquid chromatography with silica gel chemically bonded with octadodecyl group as the filler and then eluted with a solvent mixture of water and acetonitrile containing 0.1% (V/V) of trifluoroacetic acid. Acetonitrile was evaporated. After the extraction with dichloromethane, the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O[NH:17][C:18](=[NH:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[O:15][N:26]=[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCCCCCCC(=N)NO
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Solvent: Cc1ccccc1
Product: CCCCCCCc1noc(C=Cc2ccc(OC)c(OC)c2)n1
Reaction time: 1.25 h

Procedure:
To a solution of 1.35 gm (6.5 mmol) of 3-(3,4-dimethoxy-phenyl)-acrylic acid (compound of Example 2; Step 1) in 6 mL of toluene, 1.14 gm (7.0 mmol) of 1,1-carbonyldiimidazole was added lot wise at 25° C. to 30° C. under inert atmosphere. The mass becomes thick and 5 mL of toluene was added and the resulting mixture was stirred at 25° C. to 30° C. for 60 to 90 min. A solution of N-hydroxyoctanimidamide (compound of Example 50; 2.1 g, 13.2 mmol) in 5 mL of toluene was added to the above reaction mixture as one lot at 25° C. to 30° C. The reaction mixture was stirred at 25° C. to 30° C. under nitrogen for 12-14 h, followed by stirring at 100° C. to 105° C. for 6-8 h. After completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C. and quenched with 10 mL of chilled water under stirring at 25° C. to 30° C. The organic layer was separated, and the aqueous layer was washed with 5 mL of toluene. The organic layers were combined and washed with 10 mL of 1N HCl solution, 10 mL of 5% sodium bicarbonate solution and 10 mL of 10% sodium chloride solution. The organic layer was distilled to obtain a crude residue, which was purified by column chromatography (silica gel, chloroform-methanol) to yield the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:10]=1)(C)(C)C.Cl>>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:11]1[CH:10]=[C:9]([CH2:8][NH2:7])[CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2ccccn2)c1
Agent: Cl
Product: NCc1cccc(-c2ccccn2)c1
Yield: 107.2 %

Procedure:
To a solid tert-butyl-3-(pyridin-2-yl)benzylcarbamate (111 mg, 0.39 mmol) was added HCl (4N in dioxane, 0.20 mL, 0.78 mmol), then it was concentrated to give (3-(pyridine-2-yl)phenyl)methanamine (77 mg).
Reaction SMILES: [O:1]([C:8]1[CH:20]=[CH:19][C:11]([C:12]([O:14]C(C)(C)C)=[O:13])=[C:10]([NH:21][S:22](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:24])=[O:23])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[O:1]([C:8]1[CH:20]=[CH:19][C:11]([C:12]([OH:14])=[O:13])=[C:10]([NH:21][S:22](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:24])=[O:23])[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NS(=O)(=O)/C=C/c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(Oc2ccccc2)cc1NS(=O)(=O)/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 4-phenoxy-2-(((E)-2-phenylvinyl)sulfonamido)benzoate and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 17 mg of 4-phenoxy-2-(((E)-2-phenylvinyl)sulfonamido)benzoic acid as white solid.
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:8]2[S:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33]>>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([N:29]([CH3:28])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:24])=[CH:26][CH:27]=2)[C:8]2[S:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)sc2ccccc12
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)sc2ccccc12
Yield: 73.2 %

Procedure:
Using 4-{[cyclohexyl(3-methyl-1-benzothiophen-2-yl)methyl]amino}benzoic acid (300 mg) synthesized in Example A10(3) and ethyl 3-(methylamino)propanoate (124 mg) and in the same manner as in Example A1(4), the title object compound (269 mg, 73%) was obtained as a white solid.
Reaction SMILES: [C:1]([O:10]CC)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[H-].[Na+].[CH3:15][S:16]([CH3:18])=[O:17].Cl>C1C=CC=CC=1.CO.CCOC(C)=O>[NH2:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1](=[O:10])[CH2:15][S:16]([CH3:18])=[O:17]
Reactant: CCOC(=O)c1ccccc1N
Reactant: CS(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CS(=O)CC(=O)c1ccccc1N
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
From ethyl anthranilate: A mixture of sodium hydride (60% dispersion in mineral oil, 24.00 g, 0.6 mole, 3 equiv.), dry DMSO (71.0 ml, 1.0 mole, 5 equiv.), and benzene (130 ml) was heated at 80° C. until gas evolution ceased (1.5 hr), then was cooled in ice/H2O. A solution of ethyl anthranilate (29.6 ml, 0.2 mole, 1 equiv.) in benzene (100 ml) was added at a rate such that the internal temperature did not exceed 25° C., and the mixture was stirred for 0.5 hr The reaction was poured into ice/H2O and the pH was adjusted to 5-6 with concentrated HCl. EtOAc extraction, drying (MgSO4) and concentration gave a cloudy, orange oil. Silica gel chromatography (3% MeOH/EtOAc, then 5% MeOH/EtOAc) gave 1-(2-aminophenyl)-2-(methylsulfinyl)ethanone (23.43 g, 59%) as a yellow solid. Material prepared in this way was identical to that prepared from isatoic anhydride.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:24]=[C:23]([NH:25][C:26]3[CH:27]=[C:28]([NH:32][C:33]([CH:35]4[CH2:37][O:36]4)=[O:34])[CH:29]=[CH:30][CH:31]=3)[C:22]([F:38])=[CH:21][N:20]=2)=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(Cl)(Cl)Cl.CO.O>C1COCC1>[F:38][C:22]1[C:23]([NH:25][C:26]2[CH:27]=[C:28]([NH:32][C:33]([CH:35]3[CH2:37][O:36]3)=[O:34])[CH:29]=[CH:30][CH:31]=2)=[N:24][C:19]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][OH:8])=[CH:13][CH:14]=2)=[N:20][CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(Nc2ncc(F)c(Nc3cccc(NC(=O)C4CO4)c3)n2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1cccc(Nc2nc(Nc3ccc(OCCO)cc3)ncc2F)c1)C1CO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.4 %

Procedure:
A solution of N-(3-((2-((4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)phenyl)oxirane-2-carboxamide (0.160 g) in THF was cooled to 0° C. and TBAF was added. The reaction mixture was stirred at 0° C. for 1 hr. The reaction was monitored on TLC using CHCl3:methanol (9:1) as mobile phase. After completion, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and solvent was removed under reduced pressure. The crude material was purified by Combiflash eluted with 3.1% methanol in CHCl3 to give 0.051 g of N-(3-((5-fluoro-2-((4-(2-hydroxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)oxirane-2-carboxamide. 1H NMR: DMSO-d6 (400 MHz): 2.676-2.901 (q, 1H), 2.974-3.00 (q, 1H), 3.575-3.674 (m, 2H), 3.901-3.926 (m, 2H), 4.830-4.858 (t, 1H, J=5.6), 6.764-6.786 (d, 1H, J=8.8), 7.256-7.296 (d, 1H, J=8), 7.345-7.366 (d, 1H, J=8.4), 7.514-7.537 (d, 3H, J=9.2), 7.933 (s, 1H), 8.065-8.074 (d, 1H, J=3.6), 8.896 (s, 1H), 9.391 (s, 1H), 10.119 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[N:4]=1.[BrH:11]>>[BrH:11].[NH2:1][CH2:2][C:3]1[NH:4][C:5](=[O:9])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CN)n1
Agent: Br
Product: NCc1cccc(=O)[nH]1

Procedure:
The crude product from Example 2 was combined with 10 ml of 48% hydrobromic acid, and the resulting mixture was heated at its reflux temperature for one hour. Evaporation to dryness provided 6-aminomethyl-2(1H)-pyridone hydrobromide as a water-soluble solid. The structural assignment was supported by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [N:1]1([CH2:14][C@H:15](O)[CH3:16])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:13][CH2:12][CH:11]=[CH:10][C:8]3=2)[CH:3]=[N:2]1.C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+]>C1COCC1>[N:34]([C@@H:15]([CH3:16])[CH2:14][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:13][CH2:12][CH:11]=[CH:10][C:8]3=2)[CH:3]=[N:2]1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H](O)Cn1ncc2ccc3c(c21)C=CCO3
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](Cn1ncc2ccc3c(c21)C=CCO3)N=[N+]=[N-]
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 38.5 %

Procedure:
To a solution of the product from Step A (0.14 g, 0.61 mmol) and triethylamine (0.18 g, 1.8 mmol) in anhydrous THF (50 ml) at 0° C. was added methanesulfonic anhydride (0.16 g, 0.92 mmol). The mixture was stirred for 10 min and sodium azide (0.40 g, 6.1 mmol) was added; the solvent was evaporated and anhydrous DMF (50 mL) added followed by heating at 110° C. for 3 h. The mixture was cooled, poured into a saturated solution of sodium bicarbonate (80 mL) and extracted with ethyl acetate (3×60 mL). The combined extracts were dried, filtered, and evaporated to a residue which was purified by chromatography (silica, 10% ethyl acetate in hexane) to give an oil (0.06 g, 39%): LC/MS (+APCI) m/z 256 (M+H).