Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[O:12]([CH:19]([CH3:22])[CH2:20][NH2:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:23]1([CH2:29][C:30]#[N:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.CCOCC>C(O)C>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[O:12]([CH:19]([CH3:22])[CH2:20][NH:21][C:30](=[NH:31])[CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CCc1ccccc1
Reactant: CC(CN)Oc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CC(CNC(=N)Cc1ccccc1)Oc1ccccc1

Procedure:
A mixture of 2-phenoxypropylamine p-toluenesulphonate (3.7 g.) and phenylacetonitrile (1.5 g.) was stirred and heated, in an oil-bath, to 270° for 11/2 hours. The mixture was cooled and dissolved in the minimum amount of boiling ethanol, and the solution was poured into a mixture of water (75 ml.) and ether (75 ml.). The mixture was shaken and the aqueous layer was separated, washed once with ether, and evaporated to half-volume under reduced pressure. An oil separated and crystallised after a few days. The product was filtered and recrystallised from water to give N-(2-phenoxypropyl)phenylacetamidine p-toluenesulphonate, m.p. 121°-124°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:14])[C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH:5]=[N:6][CH:7]=1.C([O-])(=O)C.[K+].Br[C:21]1[C:22]([Cl:46])=[C:23]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])=[CH:28][N:27]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:24]2=[N:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>CC(N(C)C)=O>[Cl:46][C:22]1[C:21]([C:2]2[CH:3]=[C:4]([CH:8]([OH:14])[C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH:5]=[N:6][CH:7]=2)=[CH:26][N:25]=[C:24]2[N:27]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:45])[CH3:44])[CH:28]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])[C:23]=12
Reactant: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(Br)c(Cl)c12
Reactant: CN(C)C(=O)C(O)c1cncc(Br)c1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)N(C)C
Product: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(-c3cncc(C(O)C(=O)N(C)C)c3)c(Cl)c12
Temperature: 120 °C
Reaction time: 12 h
Yield: 34 %

Procedure:
A mixture of 2-(5-Bromo-pyridin-3-yl)-2-hydroxy-N,N-dimethyl-acetamide (400 mg, 1.54 mmol), bis(pinacol)diborane (431 mg, 1.7 mmol), potassium acetate (454 mg, 4.6 mmol), and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichlormethane adduct (25 mg, 0.03 mmol) in dimethylacetamide (2 mL) was stirred under nitrogen at 120° C. for 12 h. 5-Bromo-3-(2-methoxy-phenyl)-4-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (491 mg, 1.05 mmol), sodium carbonate solution (2M in water, 2.3 mL, 4.6 mmol), dimethylacetamide (2 mL) and additional 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichlormethane adduct (30 mg, 0.035 mmol) was added and the mixture was stirred for an additional 2 h at 120° C. Sodium sulfate was added to the crude reaction mixture and the solids were filtered over Celite. The solids were rinsed with ethyl acetate and acetonitrile and the combined filtrate was concentrated. The resulting oil was purified by flash silica gel chromatography using a gradient of ethyl acetate in hexanes to afford 2-{5-[4-Chloro-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-3-yl}-2-hydroxy-N,N-dimethyl-acetamide (202 mg, 0.35 mmol, 34% yield; and 2-{5-[4-Chloro-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-3-yl}-N,N-dimethyl-acetamide.
Reaction SMILES: C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([CH2:15][CH2:16][OH:17])[C:7]=1[F:18])(C)(C)C>Cl>[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([CH2:15][CH2:16][OH:17])[C:7]=1[F:18]
Reactant: CC(C)(C)Nc1ccc([N+](=O)[O-])c(CCO)c1F
Agent: Cl
Product: Nc1ccc([N+](=O)[O-])c(CCO)c1F
Yield: 97 %

Procedure:
11 g of the compound (123) obtained in Comparative Example 5 was added to 200 ml of concentrated hydrochloric acid, and the solution heated at reflux for 2.5 hours. After air-cooling, the solution was extracted with 500 ml of ethyl acetate four times, and the extract was washed with aqueous 10% sodium hydrogen carbonate solution. After drying over magnesium sulfate, the solvent was removed by distillation. The residue was crystallized with n-hexane, and the crystals were filtered to obtain 8.33 g of the subject compound (124) in a 97% yield.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]1([C:9]2[N:14]=[C:13]([CH3:15])[C:12]([OH:16])=[C:11]([CH2:17][OH:18])[C:10]=2[CH2:19][OH:20])[CH2:8][CH2:7]1.[OH-].[Na+].[CH3:23][C:24]([CH3:26])=O>>[CH:6]1([C:9]2[C:10]([CH2:19][OH:20])=[C:11]3[CH2:17][O:18][C:24]([CH3:26])([CH3:23])[O:16][C:12]3=[C:13]([CH3:15])[N:14]=2)[CH2:7][CH2:8]1
Reactant: Cc1nc(C2CC2)c(CO)c(CO)c1O
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(C2CC2)c(CO)c2c1OC(C)(C)OC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
Sulfuric acid (18.71 g, 0.1908 mole, 10 ml) was added to a solution of 6-cyclopropyl-4,5-bis-hydroxymethyl-2-methyl-pyridin-3-ol (166) (10.0 g, 47.7 mmol) in anhydrous acetone (60 mL) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred overnight, poured into a cold solution of aqueous sodium hydroxide (excess) and the crude product was extracted with chloroform and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a crude residue, which was purified on a silica gel column using a mixture of ethyl acetate hexane (2:8) as eluant to give (6-cyclopropyl-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl)-methanol (167) (5.2 g, 44% yield) as a brown liquid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:14]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[N:13][C:12]2[C:7]1=[N:8][C:9]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[N:10][CH:11]=2.[SiH](CC)(CC)CC>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:9]2[N:8]=[C:7]3[C:12]([N:13]=[C:14]([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)[NH:6]3)=[CH:11][N:10]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(Cn2c(-c3ccncc3)nc3cnc(Nc4ccc(F)cc4)nc32)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(Nc2ncc3nc(-c4ccncc4)[nH]c3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.8 %

Procedure:
A solution of 46 mg (0.1 mmol, 1.0 eq.) of 9-(2,4-dimethoxybenzyl)-N-(4-fluorophenyl)-8-(pyridin-4-yl)-9H-purin-2-amine (I-17) in 0.6 mL of methylene chloride and 2.4 mL of TFA was stirred at room temperature for 4 h. A portion of 1 mL of Et3SiH was added and the resulting reaction mixture stirred at room temperature for an additional 1 h. The volatiles were removed in vacuo and the residue purified by semi-preparative HPLC to provide 7.3 mg (24%) of N-(4-fluorophenyl)-8-(pyridin-4-yl)-9H-purin-2-amine (I-18).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>C(O)(C)C>[Br:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[N:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(Br)c1
Reactant: N#Cc1cnc2ncc([N+](=O)[O-])cc2c1Cl
Solvent: CC(C)O
Product: N#Cc1cnc2ncc([N+](=O)[O-])cc2c1Nc1cccc(Br)c1

Procedure:
A mixture of 7.5 g (32 mmol) of 4-chloro-6-nitro-[1.8]naphthyridine-3-carbonitrile and 5.5 g (32 mmol) of 3-bromo-aniline in 175 ml of isopropanol was stirred at reflux for 2 hr. and 45 min. The mixture was cooled, solid was collected, and washed with ether giving 12.9 g of the title compound as the yellow hydrochloride salt: mass spectrum (electrospray, m/e): M+H 370, 373.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[OH:6][CH:7]([C:11]1[N:12]=[C:13]([NH:16][CH:17]=[O:18])[S:14][CH:15]=1)[C:8]([OH:10])=O.[CH3:19][N:20]1[C:24]([S:25][CH2:26][C:27]2[CH2:28][S:29][C@@H:30]3[CH:37]([NH2:38])[C:36](=[O:39])[N:31]3[C:32]=2[C:33]([OH:35])=[O:34])=[N:23][N:22]=[N:21]1.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(Cl)Cl.CN(C)C=O>[CH3:19][N:20]1[C:24]([S:25][CH2:26][C:27]2[CH2:28][S:29][C@@H:30]3[CH:37]([NH:38][C:8](=[O:10])[CH:7]([OH:6])[C:11]4[N:12]=[C:13]([NH:16][CH:17]=[O:18])[S:14][CH:15]=4)[C:36](=[O:39])[N:31]3[C:32]=2[C:33]([OH:35])=[O:34])=[N:23][N:22]=[N:21]1
Reactant: O=CNc1nc(C(O)C(=O)O)cs1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: O=CN=c1[nH]c(C(O)C(=O)O)cs1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(O)c3csc(NC=O)n3)[C@H]2SC1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
To dimethylformamide (5 ml.) was dropwise added phosphorus oxychloride (0.794 g.) under stirring and ice-cooling, and the mixture was stirred for 30 minutes at 40° C., and then cooled to -20° C. To the mixture was gradually added 2-hydroxy-2-(2-formylamino-1,3-thiazol-4-yl)acetic acid, which can be represented as 2-hydroxy-2-(2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)acetic acid, (0.505 g.) at -20° C., and the mixture was stirred for 45 minutes at -12° to -10° C. Thus obtained mixture was added to a solution, which was prepared by stirring a mixture of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-amino-3-cephem-4-carboxylic acid (0.804 g.), bis(trimethylsilyl)acetamide (2.62 ml.) in methylene chloride (15 ml.) for an hour at room temperature and for 2 hours at 35° to 40° C. and then by cooling it to -30° C., at a time. The mixture was stirred for an hour at -20° to -15° C., and then methylene chloride was distilled off. The resulting residue was purified by a conventional manner to give 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-formylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (0.51 g.).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][C:3]=1[CH3:11].[ClH:12].Cl[O-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([Cl:12])([CH:6]=[N:7][OH:8])[CH2:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C=NO)ccc1Br
Reactant: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Product: CC1=C(Br)C=CC(Cl)(C=NO)C1
Reaction time: 0.75 h
Yield: 97.4 %

Procedure:
In a solution of 82.0 g of 4-bromo-3-methylbenzaldoxime in 450 ml of tetrahydrofuran, 120.0 g of concentrated hydrochloric acid was added adropwise with stirring under ice cooling over 45 minutes. Then, 220 ml of 8% sodium hypochlorite aqueous solution was carefully added dropwise over 75 minutes so that the temperature of the reaction mixture would not exceed 5° C., after the completion of the addition, continued to stir at 10° C. or less further for 90 minutes. After the completion of the reaction, nitrogen gas was blown through the reaction mixture for 45 minutes and precipitated insoluble material was filtered off, and tetrahydrofuran was distilled off under reduced pressure. The remaining aqueous solution was extracted with 240.0 g of ethyl acetate. The organic phase was washed with water (240 ml×2) and then insoluble material was filtered off, the solvent was distilled off under reduced pressure to obtain 93.5 g of the aimed product as pale yellow crystal.
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[CH:10][C:11](=[O:22])[N:12]([C:14]3[C:19]([C:20]#[N:21])=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:13]=2)OC1.Br[C:25]1[N:29]2[N:30]=[CH:31][C:32]([C:34]([OH:37])([CH3:36])[CH3:35])=[N:33][C:28]2=[N:27][CH:26]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:37][C:34]([C:32]1[CH:31]=[N:30][N:29]2[C:25]([C:8]3[CH:9]=[CH:10][C:11](=[O:22])[N:12]([C:14]4[C:19]([C:20]#[N:21])=[CH:18][CH:17]=[CH:16][N:15]=4)[CH:13]=3)=[CH:26][N:27]=[C:28]2[N:33]=1)([CH3:36])[CH3:35]
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Reactant: CC1(C)COB(c2ccc(=O)n(-c3ncccc3C#N)c2)OC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(O)c1cnn2c(-c3ccc(=O)n(-c4ncccc4C#N)c3)cnc2n1
Temperature: 95 °C

Procedure:
To a degassed mixture of 5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-oxo-2H-[1,2′]bipyridinyl-3′-cabonitrile (from step f), 2-(7-bromo-imidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol (from step d) (0.23 g), dry 1,4-dioxane (5 ml), and 2 M aqueous sodium carbonate (3 ml), was added tetrakis(triphenylphosphine)palladium(0) (0.12 g). The mixture was heated at 95° C. under a nitrogen atmosphere for 24 h. After cooling to 25° C., the reaction was diluted with ethyl acetate, and the organic phase separated. The solvent was evaporated at reduced pressure and the residue purified by chromatography (silica gel, 5% MeOH/CH2Cl2) to give the title compound, crystallised from hot isopropanol as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 8.98 (1H, s), 8.97 (1H, d, J 2.0), 8.62–8.68 (2H, m), 8.40 (1H, s), 8.32 (1H, dd, J 2.7, 9.8), 7.85 (1H, dd, J 5.1, 7.8), 6.83 (1H, d, J 9.8), 5.75 (1H, s), 1.54 (6H, s); MS (ES+) m/z 374 [M+H]+.
Reaction SMILES: [Mg].C(Br)C.CC#C.[O:8]([C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1C=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[O:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[C:26]([CH:25]([OH:24])[C:21]1[CH:20]=[CH:19][CH:16]=[C:15]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:22]=1)#[C:27][CH3:28]
Reactant: C1CCOC1
Reactant: O=Cc1ccccc1Oc1ccccc1
Agent: C#CC
Agent: Cl
Agent: [Mg]
Solvent: CCBr
Product: CC#CC(O)c1cccc(Oc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A Grignard solution, freshly prepared from 4 g of magnesium and 20 g of ethyl bromide in 20 ml of tetrahydrofuran, is slowly added at 0° C. to a solution of 8 g of methylacetylene in 100 ml of tetrahydrofuran, and the mixture is stirred under argon for 15 minutes. There is then added dropwise to this mixture at 0° to 5° C. a solution of 27 g of o-phenoxybenzaldehyde in 100 ml of tetrahydrofuran. After being stirred for 14 hours at room temperature, the reaction mixture is cooled to 0° C. with 50 g of ice; 25 ml of conc. hydrochloric acid is subsequently slowly added, and extraction is performed with ether. The ether extract is washed twice with water and twice with saturated sodium chloride solution; it is then dried over sodium sulfate, filtered, and concentrated by evaporation. The product is chromatographed through silica gel with ethyl acetate/hexane (1:1) as the eluant. There is thus obtained the compound of the formula ##STR5## having a refractive index of nD20 =1.5898.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[C:33]([O:35][CH3:36])=[O:34]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:36][O:35][C:33](=[O:34])[C:32]1[CH:31]=[CH:30][C:29]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:25])[C:10]([C:16]3[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=3)([OH:15])[C:11]([F:13])([F:14])[F:12])=[C:2]([Cl:1])[CH:7]=2)=[CH:28][C:27]=1[Cl:26]
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O
Reactant: COC(=O)c1ccc(B(O)O)cc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3cc(C)c(=O)n(C)c3)C(F)(F)F)c(Cl)c2)cc1Cl

Procedure:
In analogy to Example 151, step 8, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one (Example 203, step 5) was reacted with 3-chloro-4-methoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless solid. MS (m/e)=544.2 [M+H+].
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH3:11])[CH2:3]1.C(N(CC)CC)C.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>O1CCOCC1>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][CH:2]2[CH2:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[CH3:11])[CH2:3]2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1cccc2c1CC(N)C2
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cccc2c1CC(NC(=O)c1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
370 mg (2.52 mmol) 2-amino-4-methylindane and 257 mg (2.52 mmol) triethylamine were dissolved in 5 ml dioxane, 400 mg (2.52 mmol) 4-fluorobenzoylchloride were added, and the mixture was stirred for 2 h at room temperature (RT).
Reaction SMILES: C1COCC1.[BH4-].[Li+].C[O:9][C:10](=O)[CH2:11][N:12]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].CO>O>[C:13]([N:12]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:11][CH2:10][OH:9])([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14]
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
In a THF solution containing 0.30 g of lithium borohydride, 1.30 g of N-(tert-butoxycarbonyl)phenylglycine methyl ester was added under ice cooling. To the resultant solution, methanol was added dropwise under ice cooling and stirred overnight at room temperature. Water was added to the reaction mixture, extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride aqueous solution, successively, and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure and the obtained residue was subjected to a silica gel column chromatography (hexane:ether=1:1) to give 0.41 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([NH2:21])[CH3:20])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([NH:21][C:33](=[O:35])[CH3:34])[CH3:20])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ncc(-c3ccc(C(C)N)cc3)s2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Oc2ncc(-c3ccc(C(C)NC(C)=O)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of Example 11D ((110 mg, 0.337 mmol) and diisopropylethylamine (0.5 mL) in methylene chloride (1 mL) cooled to 0° C. was added acetic anhydride (100 μL, 1.06 mmol, 3.1 eq.). The mixture was stirred at room temperature overnight. The reaction mixture was purified directly on silica gel eluting with ethyl acetate:hexane gradient (0-80%) to give the title compound (109 mg, 88%). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.30 (d, J=8.09 Hz, 1 H), 7.66 (s, 1 H), 7.45-7.54 (m, 2 H), 7.33-7.40 (m, 2 H), 7.27-7.32 (m, Hz, 2 H), 6.99-7.10 (m, 2 H), 4.77-4.96 (m, 1 H), 3.79 (s, 3 H), 1.83 (s, 3 H), 1.32 (d, J=6.99 Hz, 3 H); MS (DCl) m/e 369 (M+H).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][NH:8][C:9]([C:11]1[S:12][C:13]([C:16]([NH:18][N:19]=[C:20]([C:22]2[C:26]([OH:27])=[C:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=3)[S:24][CH:23]=2)[CH3:21])=[O:17])=[CH:14][CH:15]=1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:35][C:30]1[CH:29]=[C:28]([C:25]2[S:24][CH:23]=[C:22]([C:20](=[N:19][NH:18][C:16]([C:13]3[S:12][C:11]([C:9]([NH:8][CH2:7][C:6]([OH:36])=[O:5])=[O:10])=[CH:15][CH:14]=3)=[O:17])[CH3:21])[C:26]=2[OH:27])[CH:33]=[CH:32][C:31]=1[Cl:34]
Reactant: CC(=NNC(=O)c1ccc(C(=O)NCC(=O)OC(C)(C)C)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=NNC(=O)c1ccc(C(=O)NCC(=O)O)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Yield: 56.9 %

Procedure:
tert-Butyl[(5-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophen-3-yl]ethylidenehydrazinocarbonyl}thiophene-2-carbonyl)amino]acetate (69 mg, 0.12 mmol) in CH2Cl2 (4.0 mL) was stirred with trifluoroacetic acid (0.14 mL) at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure, and chloroform was added. The precipitated solid was collected by filtration, washed with chloroform and dried to give 35 mg of the desired product (yield 56%).
Reaction SMILES: [CH:1]1[CH:8]=[CH:7][C:5](=[O:6])[C:4](O)=[CH:3][CH:2]=1.S(Cl)([Cl:12])=O>C1C=CC=CC=1>[CH:1]1[CH:8]=[CH:7][C:5](=[O:6])[C:4]([Cl:12])=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1cccccc1O
Solvent: c1ccccc1
Product: O=c1cccccc1Cl
Reaction time: 1.5 h

Procedure:
To a solution of tropolone (1,680 mg) dissolved in benzene (36 ml) is added thionyl chloride (1.12 ml). The mixture is stirred for 1.5 hr with refluxing. After concentrating the reaction mixture under reduced pressure, the resulting residue is purified by silica gel chromatography and recrystallized from cyclohexane to give 1.08 g of 2-chlorotropone as yellow needles. To a solution of the 2-chlorotropone (75 mg) dissolved in dimethylformamide (4 ml) is added potassium thiocyanate (270 mg). The mixture is stirred at 110° C. for 26 hr. To the reaction mixture is added water (50 ml), followed by cooling with ice. The resulting precipitate is recovered by filtration, purified by silica gel chromatography and recrystallized from ethanol to give 59 mg of 2-thiocyanatotropone as light brown needles.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1.O[N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[F:14][C:12]([F:15])([F:13])[C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][N:17]2[C:18](=[O:27])[C:19]3=[CH:26][CH:25]=[CH:24][CH:23]=[C:20]3[C:21]2=[O:22])=[N:7][CH:8]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCCCOc1ccc(C(F)(F)F)cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCCCOc1ccc(C(F)(F)F)cn1
Yield: 84.2 %

Procedure:
To a mixture of 20.0 g of 2-(3-hydroxypropyloxy)-5-trifluoromethylpyridine, 14.7 g of N-hydroxyphthalimide, 23.6 g of triphenylphosphine, and 200 ml of tetrahydrofuran was slowly added dropwise 20.0 g of diisopropyl azodicarboxylate with stirring under ice cooling in a stream of nitrogen gas. After stirring at room temperature for 24 hours, the reaction mixture was concentrated to give a residue. This residue was subjected to silica gel chromatography, which afforded 27.8 g (yield, 84%) of N-(3-(5-trifluoromethyl-2-pyridyloxy)propyloxy)phthalimide, m.p., 97.6° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([OH:8])[CH:4]=1.[Br:9]N1C(=O)CCC1=O>CN(C)C=O>[Br:9][C:4]1[C:5]([OH:8])=[N:6][O:7][C:3]=1[CH2:2][Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1cc(CCl)on1
Solvent: CN(C)C=O
Product: Oc1noc(CCl)c1Br
Temperature: 61 °C

Procedure:
To a solution of 1.33 g of 5-chloromethyl-3-hydroxyisoxazole in 2 ml of dimethylformamide were added 2.0 g of N-bromosuccinimide, and then the mixture was heated at 61° C. for 1.5 hours. The reaction mixture was then poured into 100 ml of ice-water and extracted with diethyl ether, after which the ethereal extract was dried over anhydrous sodium sulphate. The solvent was distilled off, leaving crystals, which were recrystallized from a mixture of diisopropyl ether and hexane, giving 4-bromo-5-chloromethyl-3-hydroxyisoxazole, in the form of white crystals melting at 136.5°-138° C. (with decomposition).