Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:18]4[CH:23]=[N:22][N:21]([CH3:24])[C:20](=[O:25])[C:19]=4Cl)[CH2:11][CH2:10]3)=N[O:8][C:4]=2[CH:3]=1.C[OH:30].[OH-].[Na+]>[Pd].O>[F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:18]3[CH:23]=[N:22][N:21]([CH3:24])[C:20](=[O:25])[CH:19]=3)[CH2:11][CH2:10]2)=[O:30])=[C:4]([OH:8])[CH:3]=1
Reactant: CO
Reactant: Cn1ncc(NCCN2CCC(c3noc4cc(F)ccc34)CC2)c(Cl)c1=O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1ncc(NCCN2CCC(C(=O)c3ccc(F)cc3O)CC2)cc1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.8 %

Procedure:
Into a pressure-tight hydrogenating apparatus 5.0 g (0.0123 mole) of 5-{2-[4-(6-fluoro-1,2-benzisoxazole-3-yl)-piperidine-1-yl]-ethylamino}-4-chloro-2-methyl-2H-pyridazine-3-one, 450 ml of a solvent mixture (a 9:1 mixture of methanol and distilled water), 0.56 g (0.014 mole) of sodium hydroxide and 10 g of a palladium/charcoal catalyst (composition: 8% of palladium, 28% of carbon, 64% of water) are weighed in. The reaction mixture is stirred at room temperature under a hydrogen pressure of 10 atm. for 16 hours. The unreacted hydrogen is removed from the apparatus, the reaction mixture is heated to reflux temperature and stirred at this temperature for 5 minutes. The mixture is filtered hot and the palladium charcoal catalyst is washed three times with 33 ml of a 1:1 mixture of methanol and dichloro methane each. The united mother lyes are evaporated to 15 ml and stirred under cooling with icecold water for half an hour. The precipitated crystals are filtered off. The crude product is recrystallized from 2-propanol. Thus 3.12 g of the desired compound are obtained. Yield 67.8%.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[S:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:42]=[CH:41][C:30]([O:31][CH2:32][C:33]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[O:34])=[CH:29][CH:28]=1>O1CCOCC1>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]([N:35]2[CH2:40][CH2:39][N:38]([C:2]3[C:3]4[N:11]=[C:10]([C:12]5[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=5)[S:9][C:4]=4[N:5]=[C:6]([CH3:8])[N:7]=3)[CH2:37][CH2:36]2)=[O:34])=[CH:41][CH:42]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccc(F)cc3)sc2n1
Reactant: O=C(COc1ccc(Cl)cc1)N1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(-c3ccc(F)cc3)sc2n1
Temperature: 70 °C
Yield: 73 %

Procedure:
To a solution of 7-chloro-2-(4-fluorophenyl)-5-methylthiazolo[5,4-d]pyrimidine (30 mg, 0.11 mmol) and triethylamine (22 μl, 0.16 mmol) in dioxane (1 ml) was added 2-(4-chlorophenoxy)-1-(piperazin-1-yl)ethanone (38 mg, 0.16 mmol). The reaction mixture was heated at 70° C. for 3 hours. After cooling, the volatiles were removed under reduced pressure. The crude residue was purified by chromatography on silica gel (CH2Cl2/MeOH 70:1) to yield the title compound as a white solid (40 mg, 75%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[C:4]([N+:11]([O-])=O)[CH:3]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[Cl:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[C:4]([NH2:11])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)c2sccc2c1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cc(Cl)c2sccc2c1

Procedure:
To the refluxing solution of 7-chloro-5-nitrobenzo[b]thiophen obtained in step 4 (4.4 g, 20 mmol) in 5% acetic acid (300 ml) and ethyl acetate (300 ml) was added portion wise iron powder (6 g, 100 mmol) and the mixture was refluxed for 4 h. The reaction mixture was cooled, filtered through celite and washed with ethyl acetate. The layers were separated and the aqueous layer was extracted in ethyl acetate. The combined organic extracts were washed with water, dried and concentrated. The residue was purified by column chromatography (silica gel, hexane:ethyl acetate/4:1) to give 7-chloro-benzo[b]thiophen-5-ylamine, 2 g. MS m/z 183 (M+).
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:16]1(/[CH:19]=[N:20]/[S:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH2:18][CH2:17]1>C1COCC1>[C:1]([C:2]([CH3:4])([CH3:3])[CH:19]([NH:20][S:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH:16]1[CH2:17][CH2:18]1)#[N:5]
Reactant: CC(C)(C)S(=O)/N=C/C1CC1
Reactant: CC(C)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C#N)C(NS(=O)C(C)(C)C)C1CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
To a solution of isobutyronitrile (0.30 g, 4.35 mmol) in THF (8 mL) at −78° C. was added LiHMDS (1.0M in THF, 4.8 mL, 4.8 mmol). The pale yellow reaction mixture was stirred at −78° C. for 30 min then a solution of 2-methyl-propane-2-sulfinic acid 1-cyclopropyl-meth-(E)-ylideneamide (0.50 g, 2.90 mmol) [prepared according to WO2008/147800] in THF (2 mL) was slowly added. The reaction mixture was stirred at −78° C. for 2 h then quenched with saturated aqueous NH4Cl and warmed to room temperature. The mixture was diluted with water and extracted with EtOAc (2×). The combined organics were dried over MgSO4 and concentrated to afford 0.70 g of 2-methylpropane-2-sulfinic acid (2-cyano-1-cyclopropyl-2,2-dimethyl-ethyl)-amide as a viscous colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[CH:8]([C:18]3[C:19](=[O:36])[NH:20][C:21](=[O:35])[N:22]([CH2:24][C:25]4[O:29][C:28]([C:30]([O:32]CC)=[O:31])=[CH:27][CH:26]=4)[CH:23]=3)[C:6]=2[N:7]=1)[CH3:2].O.[OH-].[Li+].Cl>CO.O>[CH2:1]([C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[CH:8]([C:18]3[C:19](=[O:36])[NH:20][C:21](=[O:35])[N:22]([CH2:24][C:25]4[O:29][C:28]([C:30]([OH:32])=[O:31])=[CH:27][CH:26]=4)[CH:23]=3)[C:6]=2[N:7]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Cn2cc(C3c4ccc(C)cc4C=Cc4oc(CC)nc43)c(=O)[nH]c2=O)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1nc2c(o1)C=Cc1cc(C)ccc1C2c1cn(Cc2ccc(C(=O)O)o2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of the product of step (viii) (0.26 g) and lithium hydroxide monohydrate (0.063 g) in methanol (4 ml) and water (4 ml) was stirred at room temperature for 1.5 hours. The solution was neutralised by the addition of 2M hydrochloric acid and the solvents were evaporated under reduced pressure. Purification was by preparative HPLC followed by lyophilisation.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:24]3[C:19](=[C:20]([OH:27])[CH:21]=[C:22]([C:25]#[N:26])[CH:23]=3)[CH:18]=[N:17]2)[CH:5]=[CH:6][C:7]=1[O:8]CC1C=CC=CC=1>C(O)C.C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:24]3[C:19](=[C:20]([OH:27])[CH:21]=[C:22]([C:25]#[N:26])[CH:23]=3)[CH:18]=[N:17]2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: N#Cc1cc(O)c2cnn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1cc(O)c2cnn(-c3ccc(O)c(F)c3)c2c1
Yield: 42.3 %

Procedure:
A solution of 1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-4-hydroxy-1H-indazole-6-carbonitrile (D6) (308 mg, 0.86 mmol) in ethanol (10 mL) and ethyl acetate (10 mL) was hydrogenated in an H-cube over a 10% palladium on charcoal catalyst. The resulting solution was concentrated, dissolved in ethanol then the product purified by silica gel chromatography eluting with 10-100% ethyl acetate in hexane to yield the title compound (E3) (98 mg).
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[SiH](CC)(CC)CC.[C:17]1(C)[CH:22]=CC=[CH:19][CH:18]=1>>[CH:2]12[O:9][CH:1]1[CH2:22][CH2:17][CH2:18][CH2:19][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:3]2
Reactant: c1ccc(C2CO2)cc1
Reactant: Cc1ccccc1
Agent: CC[SiH](CC)CC
Product: C1CCCCCC2OC2CCCC1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
The preparation of reaction mixtures is conducted under an inert atmosphere, for example, in a nitrogen-filled dry box. 70 mg (0.38 mmol) styrene oxide, 88 mg (0.76 mmol) Et3SiH and 20 mg (0.018 mmol) of the catalyst [Ni(NPtBu3)]4 are dissolved in 6 mL toluene. The solution is transferred into a Teflon-sealed glass reactor equipped with a Teflon-sealed magnetic stir bar. The reaction mixture is then stirred at 1200 rotations per minute (rpm) for 12 hours in an oil bath at 90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10].C(O)C.C[O-].[Na+].Br[CH2:18][C:19]([OH:21])=[O:20]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[O:10][CH2:18][C:19]([OH:21])=[O:20]
Reactant: O=C(O)CBr
Reactant: Oc1c(Cl)cc(Cl)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: O=C(O)COc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,4,6-trichlorophenol, 100.7 gm, was added to 250 ml of ethanol. 228.6 ml of a 25% solution of sodium methoxide (2 equivalents) in methanol was then added to the system. The system was stirred at room temperature for approximately 1 hour. Afterwards, 69.5 gm of bromoacetic acid was added an the system then heated to reflux. After 18 hours, an additional equivalent of sodium methoxide in methanol (114.3 ml) was added as well as 34.7 gm of bromoacetic acid. The system was continued at reflux for 12 hours. The reaction was then stopped and the solvent removed by stripping. The resulting solid was washed with water and then with ether. Concentrated HCl was next added to the solid precipitate and the system was left standing for 12 hours. Afterwards, the product was filtered, washed with water and air dried. Toluene was then added to the product. The toluene was removed by stripping and any remaining water was azeotroped off with the toluene. 74.4 gm of 2,4,6-trichlorophenoxyacetic acid was recovered.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:11][O:10]1.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[OH:10][CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COc1ccccc1C1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccccc1C(O)COc1ccc(C=O)cc1
Temperature: 78 °C
Yield: 20.2 %

Procedure:
To a stirring solution of 2-(2-methoxyphenyl)oxirane (5.60 g, 37.3 mmol) in toluene (65 ml) was added 4-hydroxybenzaldehyde (6.80 g, 56.0 mmol), 1M NaOH (65 ml) and PEG4000 (polyethylene glycol, 0.85 g) and the stirring mixture was heated at 78° C. overnight. The reaction was allowed to cool to RT and it was then extracted with EtOAc (2×150 ml). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting light oil was adsorbed onto silica gel and chromatographed eluting with 30-40% EtOAc/hexanes. There are 2 major spots. Fractions containing the higher Rf spot were combined and evaporated in vacuo to give 1.71 g (17%) the regioisomer as a brown oil. Fractions containing the lower Rf spot were combined and evaporated in vacuo to give 2.05 g (20%) of the title compound as a yellow solid.
Reaction SMILES: [NH:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl>O.O1CCCC1>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([N:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4])(=[O:22])=[O:21])=[CH:18][CH:19]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)CNCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(CC(=O)O)CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3.3 Parts of iminodiacetic acid and 3.2 parts of sodium hydroxide are dissolved in 50 parts of water. Into the resulting aqueous solution, 20 parts of tetrahydrofuran containing 5 parts of p-methoxybenzenesulfonyl chloride was dropped. The resulting mixture is suspending at first, but becomes transparent when stirred at room temperature for about 1.5 hours. The mixture is further stirred at 50° C for about 20 minutes to terminate the reaction. After completion of the reaction, the reaction liquid is freed from the tetrahydrofuran and then acidified with hydrochloric acid to precipitate crystals. The crystals are collected by filtration and then recrystallized from water to obtain 3.8 parts of N-p-methoxybenzenesulfonyl-iminodiacetic acid, m.p. 177°-178.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:22]=[CH:23]/[C:24]([O:26]CC)=[O:25])[CH:5]=[N:6][C:7]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])[CH:5]=[N:6][C:7]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1
Reactant: CCOC(=O)/C=C/c1cnc(NC2CCN(Cc3ccncc3)CC2)c(Cl)c1
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)/C=C/c1cnc(NC2CCN(Cc3ccncc3)CC2)c(Cl)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 163.7 %

Procedure:
To a solution of ethyl (2E)-3-(5-chloro-6-{[1-(4-pyridinylmethyl)-4-piperidinyl]amino}-3-pyridinyl)acrylate (308 mg) in THF (3 ml) and MeOH (3 ml) was added 1N NaOHaq (2.3 ml), the mixture was stirred at 80° C. for 1 hour. The pH of the mixture was adjusted to ca.4.5 with 1N HClaq. The solution was evaporated under reduced pressure to give crude (2E)-3-(5-chloro-6-{[1-(4-pyridinylmethyl)-4-piperidinyl]amino}-3-pyridinyl)acrylic acid (469 mg, 164%)
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH2:9]1[C:11]2([CH2:14][CH:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:12]2)[CH2:10]1.CI>C1COCC1>[CH3:2][C:13]1([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:12][C:11]2([CH2:10][CH2:9]2)[CH2:14]1
Reactant: O=C(OCc1ccccc1)C1CC2(CC2)C1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C(=O)OCc2ccccc2)CC2(CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
To a solution of LDA (3.47 mL, 6.94 mmol 2M in THF) in THF (5 mL) cooled to −78° C., was added dropwise a solution of benzyl spiro[2.3]hexane-5-carboxylate (0.5 g, 2.312 mmol) in THF (2 mL). The resulting solution was stirred for 30 min. prior to the dropwise addition of MeI (0.723 mL, 11.56 mmol) at −78° C. The resulting reaction mixture was allowed to warm to RT and stir for 12 h. The reaction mixture was quenched with a saturated aq. solution of NH4Cl (20 mL) and extracted with EtOAc (3×10 mL) The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (24 g REDISEP® column, eluting with 5% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford the Intermediate 317A as a colorless liquid (200 mg, 38% yield). MS(ES): m/z=231.2 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ ppm 7.50-7.28 (m, 5H), 5.36-4.94 (s, 2H), 2.87-2.47 (m, 2H), 2.01-1.77 (m, 2H), 1.62-1.39 (s, 3H), 0.60-0.22 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=3)[NH:10][CH:9]=2)=[CH:4][CH2:3]1>[Pd].CO.CN(C=O)C>[NH2:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reaction time: 18 h
Yield: 64.3 %

Procedure:
A mixture of 3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-5-nitro-1H-indole (D1, 2.00 g, 7.8 mmole) and 10% palladium on carbon (0.25 g) in methanol (50 ml) and DMF (50 ml) was shaken under an atmosphere of hydrogen at 50 psi/344.8 KPa for 18 hours. The mixture was filtered and evaporated to dryness. The residue was partitioned between dichloromethane (75 ml) and water (30 ml). The organic phase was separated, washed with brine, dried (Na2SO4) and evaporated to dryness. Trituration of the residue with diethyl ether afforded the title compound as pale brown solid (1.15 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)=[C:4]([F:20])[CH:3]=1.[N+:21]([O-])([OH:23])=[O:22]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([N+:21]([O-:23])=[O:22])=[CH:6][C:5]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:16])([F:17])[F:15])=[CH:12][CH:13]=2)=[C:4]([F:20])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)ccc(-c2ccc(Cl)cc2F)c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cn1c(C(F)(F)F)ccc(-c2cc([N+](=O)[O-])c(Cl)cc2F)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
1.0 g (3.3 mmol) of 3-(4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone was dissolved in 10 ml of concentrated sulfuric acid, and 0.25 g (4.0 mmol) of fuming nitric acid was dropwise added thereto under cooling with ice, followed by stirring for 1 hour. This reaction solution was poured into ice water and extracted with ethyl acetate. After washing with water and a saturated sodium hydrogencarbonate aqueous solution, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and then, the obtained residue was purified by silica gel column chromatography to obtain 1.1 g (yield: 96%) of the desired product. Melting point: 139-140° C.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[C:14]([Cl:34])=[CH:15][C:16]([F:33])=[C:17]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=3)[CH:18]=2)=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([O:12][C:13]1[C:14]([Cl:34])=[CH:15][C:16]([F:33])=[C:17]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=3)[CH:18]=1)[N:10]=2
Reactant: N#C[S-]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc(N)cn3)c(Cl)cc2F)c1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(N)sc4n3)c(Cl)cc2F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.9 %

Procedure:
Potassium thiocyanate (1.50 g, 3.53 mmol) was suspended in acetic acid (15 mL), and the mixture was stirred at room temperature for 10 min. A solution of N-{5-[(5-aminopyridin-2-yl)oxy]-4-chloro-2-fluorophenyl}-3-(1-cyano-1-methylethyl)benzamide (1.42 g, 3.22 mmol) in acetic acid (15 mL) was added to the obtained solution, and the mixture was further stirred at room temperature for 10 min. A solution of bromine (591 mg, 3.70 mmol) in acetic acid (10 mL) was slowly added dropwise to the obtained solution. After the completion of the dropwise addition, the mixture was stirred at room temperature for 20 hr. The yielded yellow insoluble material was filtered off, and washed with acetic acid. The filtrate and the washing fluid were combined, and concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate (150 mL), and the solution was washed with saturated aqueous sodium hydrogen carbonate solution (150 mL) and saturated brine (150 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=70/30→20/80), and the obtained solution was concentrated under reduced pressure to give the title compound (1.41 g, 83%) as a yellow amorphous substance.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([C@:8]1([O:29][C:30](=[O:32])[CH3:31])[C@:24]2([CH3:25])[C@H:11]([C@H:12]3[C@H:21]([C:22](=[O:26])[CH2:23]2)[C@:20]2([CH3:27])[C:15](=[CH:16][C:17](=[O:28])[CH:18]=[CH:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2].[BH4-].[Na+]>O1CCCC1.CO.Cl>[C:1]([O:4][CH2:5][C:6]([C@:8]1([O:29][C:30](=[O:32])[CH3:31])[C@:24]2([CH3:25])[C@H:11]([C@H:12]3[C@H:21]([C@@H:22]([OH:26])[CH2:23]2)[C@:20]2([CH3:27])[C:15](=[CH:16][C:17](=[O:28])[CH:18]=[CH:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3C(=O)C[C@@]21C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Temperature: 0 °C

Procedure:
To an ice cooled solution of intermediate 2 (2.22 g, 5.0 mmol) in tetrahydrofuran (15 ml) and MeOH (15 ml), sodium borohydride (221 mg, 5.84 mmol) is added in portions over a period of 2.5 hours. The reaction mixture is poured in 1 N HCl and ice (150 ml). The formed precipitate is extracted with AcOEt (3×100 ml), and the combined organic layers are dried over anhydrous Na2SO4 and concentrated. The crude material is crystallized from Ethyl acetate/petroleum ether. The residue from mother liquor is purified by flash chromatography on silica gel, in gradient elution from DCM to DCM/AcOEt 40:60 affording a second crop. The combined crops give the title the compound (1.85 g, 83% total yield).
Reaction SMILES: [OH-].[K+].C(OC([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([S:19][CH:20]1[S:24][C:23](=[O:25])[NH:22][C:21]1=[O:26])[CH:13]=[CH:12]2)=O)C>CO>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([S:19][CH:20]1[S:24][C:23](=[O:25])[NH:22][C:21]1=[O:26])[CH:13]=[CH:12]2
Reactant: CCOC(=O)Oc1ccc2cc(SC3SC(=O)NC3=O)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1NC(=O)C(Sc2ccc3cc(O)ccc3c2)S1
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
Potassium hydroxide (2.47 g, 44.0 mmol) was added to a suspension of 5-[(6-ethoxycarbonyloxy-2-naphthalenyl)thio]-2,4-thiazolidinedione (8.0 g, 22 mmol) in methanol (50 mL) at 25° C. After 30 minutes, the resulting solution was acidified to pH=1 with and then extracted with ethyl acetate (3×). The combined extracts were dried (magnesium sulfate) and concentrated to give 5-[(6-Hydroxyl-2-naphthalenyl)thio]-2,4-thiazolidinedione as a powder (6.4 g, 99% yield): mp 182°-183° C. (chloroform/ethyl acetate); 1H NMR (DMSO-d6, 400 MHz) δ6.07 (s, 1H CH). 7.1-8.0 (m, 6H, ArH). Analogue 35 was prepared similarly, with the use of 3 molar equivalents of potassium hydroxide.
Reaction SMILES: Cl.[NH2:2][C:3](=NO)[C:4]1[CH:5]=[C:6]([CH:19]=[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=1)[C:7]([NH:9][C@@H:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH3:11])=[O:8].[CH3:30][CH2:31][OH:32]>C(Cl)Cl>[CH2:31]([O:32][C:3]([C:4]1[CH:21]=[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[CH:19]=[C:6]([C:7]([NH:9][C@@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])=[O:8])[CH:5]=1)=[NH:2])[CH3:30]
Reactant: C[C@@H](NC(=O)c1cc(C(N)=NO)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Reactant: CCO
Agent: Cl
Solvent: ClCCl
Product: CCOC(=N)c1cc(C(=O)N[C@H](C)c2ccc(F)cc2)cc(N(C)S(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Gaseous HCl was bubbled through a solution of 3-[-amino(hydroxyimino)methyl]-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide (0.038 g, 0.090 mmol) (Intermediate XI) in 1 mL CH2Cl2 and 1 mL EtOH at 0° C. for 2 min. After stirring at 0° C. for 2.5 h, the reaction was warmed to rt for 18 h. Concentrated, redissolved residue in 4 mL Et2O, cooled to 0° C. and bubbled ammonia through reaction for 1 min. Concentrated and used without further purification for next step.