Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl[C:8]1[N:9]=[N+:10]([O-:22])[C:11]2[C:21]3[CH2:20][CH2:19][CH2:18][O:17][C:16]=3[CH:15]=[CH:14][C:12]=2[N:13]=1>COCCOC>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:8]1[N:9]=[N+:10]([O-:22])[C:11]2[C:21]3[CH2:20][CH2:19][CH2:18][O:17][C:16]=3[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: CN(C)CCN
Reactant: [O-][n+]1nc(Cl)nc2ccc3c(c21)CCCO3
Solvent: COCCOC
Product: CN(C)CCNc1nc2ccc3c(c2[n+]([O-])n1)CCCO3
Yield: 95 %

Procedure:
N,N-Dimethyl-1,2-ethanediamine (65 μL, 0.6 mmol) was added to a stirred solution of chloride 235 (47 mg, 0.2 mmol) in DME (20 mL) and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue was partitioned between DCM (50 mL) and dilute aqueous NH3 solution (20 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 236 (55 mg, 95%) as a pale yellow solid: mp (MeOH/EtOAc) 119-120° C.; 1H NMR δ 7.35 (d, J=9.2 Hz, 1H, H-6), 7.23 (d, J=9.2 Hz, 1H, H-5), 5.66 (br s, 1H, NH), 4.19 (br dd, J=5.1, 5.0 Hz, 2H, H-8), 3.47-3.53 (m, 4H, H-10, CH2N), 2.54 (br t, J=6.0 Hz, 2H, CH2N), 2.27 [s, 6H, N(CH3)2], 1.97-2.04 (m, 2H, H-9); 13C NMR δ 158.0, 152.2, 146.7, 130.3, 128.4, 125.2, 114.0, 65.9, 57.7, 45.1 (2), 38.7, 24.9, 22.2. Anal. calcd for C14H19N5O2.¼H2O: C, 57.2; H, 6.7; N, 23.8. Found: C, 57.5; H, 6.6; N, 23.8%.
Reaction SMILES: [Al].Br[CH:3]([CH3:6])[C:4]#[CH:5].[CH:7](=[O:13])[C:8]1[O:12][CH:11]=[CH:10][CH:9]=1.[Cl-].[NH4+]>O1CCCC1>[O:12]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:7]([OH:13])[CH:4]([CH3:5])[C:3]#[CH:6]
Reactant: O=Cc1ccco1
Reactant: C#CC(C)Br
Agent: [Al]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(C)C(O)c1ccco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
Aluminum (5.0 g, 0.18 mole), mercuric chloride (100 mg) and tetrahydrofuran (THF) (70 ml) were added to a reactor, and a solution of 3-bromo-1-butyne (20 g, 0.15 mole) in THF (20 ml) was added dropwise at 40° to 50° C. to prepare a Grignard reagent. Thereafter, to this THF solution of the Grignard reagent was added dropwise a solution of furfural (11.5 g, 0.12 mole) in THF (20 ml) at 20° to 30° C. over about 1 hour, followed by stirring at room temperature for further 2 hours. After completion of the reaction, the reaction solution was poured into an aqueous ammonium chloride solution (about 100 ml) and extracted with ether. The extract was washed with water, dried and concentrated. The residue obtained was distilled under reduced pressure to obtain 10.4 g (yield, 58%) of pure 1-(2-furyl)-2-methyl-3-butyn-1-ol having a boiling point of 75°-85° C./3 mmHg.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[N+:11]([C:14]1[CH:15]=[C:16]([OH:23])[CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])([O-:13])=[O:12]>[OH-].[Na+].C(Cl)Cl>[N+:11]([C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[O:23][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12)([O-:13])=[O:12]
Reactant: Clc1ccnc2[nH]ccc12
Reactant: O=[N+]([O-])c1ccc(O)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Oc2ccnc3[nH]ccc23)cc1[N+](=O)[O-]
Temperature: 150 °C

Procedure:
A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (Step B, 1.0 g, 6.5 mmol) and 3,4-dinitrophenol (1.41 g, 7.6 mmol) was heated at 150° C. for 8 h. The resulting crude solid was dissolved in NaOH (12N) and CH2Cl2. The aqueous layer was extracted several times with CH2Cl2. The insoluble material was solubilized in acetone. The acetone solution was diluted with CH2Cl2 and washed with water. The combined CH2Cl2 layers were dried and concentrated under vacuum. The crude material was purified on silica gel using a CH2Cl2/EtOH gradient (100/0 to 90/10) to give 4-(3,4-dinitro-phenoxy)-1H-pyrrolo[2,3-b]pyridine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3=[N:12][O:13][C:14]([C:15]4[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[O:17][N:16]=4)=[C:10]3[CH2:9][O:8][C:6]=2[CH:7]=1.[CH2:30]([Sn](CCCC)(CCCC)C=C)[CH2:31]CC.[Cl-].[Li+]>O1CCOCC1.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>[C:24]1([C:18]2[O:17][N:16]=[C:15]([C:14]3[O:13][N:12]=[C:11]4[C:5]5[CH:4]=[CH:3][C:2]([CH:30]=[CH2:31])=[CH:7][C:6]=5[O:8][CH2:9][C:10]=34)[C:19]=2[C:20]([F:22])([F:21])[F:23])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: FC(F)(F)c1c(-c2onc3c2COc2cc(Br)ccc2-3)noc1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1ccc2c(c1)OCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reaction time: 0.08 h
Yield: 66.5 %

Procedure:
To a heterogeneous solution of 7-bromo-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4H-chromeno[4,3-c]isoxazole (Preparation 62F, 0.105 g, 0.227 mmol) in dioxane (2.0 mL) in a sealed tube was added sequentially tributyl(vinyl)stannane (0.073 mL, 0.249 mmol) and lithium chloride (0.029 g, 0.680 mmol). The mixture was degassed under reduced pressure and charged with nitrogen (3×). To the mixture was added tetrakis(triphenylphosphine)palladium(0) (0.026 g, 0.023 mmol), and the mixture was stirred under a strong stream of nitrogen for 5 min. The reaction mixture was sealed, immersed in an oil bath at 100° C., and stirred overnight. As it reached 100° C., the solution became near homogeneous. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with dichloromethane (10 mL), filtered through a pad of Celite, and rinsed with dichloromethane (10 mL). The filtrate was concentrated, and the residue was purified by flash silica gel chromatography using a 5% mixture of ethyl acetate in hexane to give 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4H-chromeno[4,3-c]isoxazole (0.062 g, 0.151 mmol, 67% yield) as a white solid. The product had an HPLC ret. time=3.84 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=411.0.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:18]=[C:17]([CH3:19])[O:16][N:15]=1>O>[CH3:13][C:14]1[C:18]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH2:9][C:10]([OH:12])=[O:11])=[C:17]([CH3:19])[O:16][N:15]=1
Reactant: Cc1cc(C)on1
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Solvent: O
Product: Cc1noc(C)c1C(CC(=O)O)c1ccc(O)cc1
Temperature: 130 °C
Yield: 20.96 %

Procedure:
To a 50 mL sealed was charged with (2E)-3-(4-hydroxyphenyl)prop-2-enoic acid (3.0 g, 0.018 mmol) and 3,5-dimethyl-1,2-oxazole (3.54 g, 0.054 mmol) and heated at 130° C. for 16 h. The reaction mixture diluted with water (10 mL) was added and extracted with DCM (20 mL). The combined extract was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude material was taken for next step with out purification (1.0 g, yield: 20.96%).
Reaction SMILES: [CH:1]([C:4]1[C:12](C(=O)C(C)C)=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>S(=O)(=O)(O)O>[CH:1]([C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)C(=O)c1c(C(C)C)nn2ccccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1cc2ccccn2n1
Temperature: 140 °C

Procedure:
A mixture of 30g (0.13 mole) of 2-isopropyl-3-isobutyrylpyrazolo[1,5-a]pyridine and 200 ml of 50% sulfuric acid (v/v) solution was heated at 140° C for 10 hours. After cooling, the mixture was added to 400g of ice-water. The solution was neutralized with sodium hydroxide solution and extracted with chloroform. The chloroform solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was distilled to give 8.5g (5.3 × 10-2 mole) of colorless oily product, bp 127.5°-129.5° C (17 mmHg).
Reaction SMILES: [Cl:1][C:2]1[N:3]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([F:9])[C:6]=1[CH:7]=O.CO.[CH3:27][NH2:28].[BH4-].[Na+].Cl.C(=O)([O-])O.[Na+]>CO>[ClH:1].[Cl:1][C:2]1[N:3]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([F:9])[C:6]=1[CH2:7][NH:28][CH3:27]
Reactant: O=Cc1c(F)c(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1Cl
Reactant: CN
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CNCc1c(F)c(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1Cl
Reaction time: 0.5 h
Yield: 23.8 %

Procedure:
2-Chloro-4-fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (140 mg) was dissolved in methanol (10 mL), 40% methylamine methanol solution (150 mg) was added at room temperature, and the mixture was stirred for 30 min. Sodium borohydride (44 mg) was added at room temperature, and the mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (20 mL) was added, and the mixture was stirred for 5 min. The reaction mixture was alkalized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=3:7→0:10), and dissolved in ethyl acetate (5 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give the title compound as colorless crystals (yield 19 mg, 12%).
Reaction SMILES: [CH2:1](I)[CH:2]=[CH2:3].[C:5]1([CH:12]=[CH:11][C:9]([OH:10])=[CH:8][CH:7]=1)[OH:6].C([O-])([O-])=O.[K+].[K+].CC(C)=O>>[CH2:1]([O:6][C:5]1[CH:12]=[CH:11][C:9]([OH:10])=[CH:8][CH:7]=1)[CH:2]=[CH2:3]
Reactant: Oc1ccc(O)cc1
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(O)cc1
Temperature: 40 °C
Yield: 41.2 %

Procedure:
Allyl iodide (8.2 mL, 89 mmoles) was added to a solution of hydroquinone (7.84 g, 71.2 mmoles) and K2CO3 (19.7 g, 142.4 mmoles) in acetone (102 mmoles). The resulting mixture was heated to 40° C. overnight and concentrated under reduced pressure. The crude products were filtered through a pad of silica with 1:1 hexanes:ethyl acetate. The residue was purified by flash chromatography on a prepacked Biotage column (hexane to 1:1 hexane:ethyl acetate) on silica gel to provide the title compound (4.40 g, 41%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:9][N:8]=1.[N:18]#[C:19]Br>CO>[NH2:4][C:5]1[N:6]2[N:18]=[CH:19][N:1]=[C:2]2[C:3]2[NH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:7]=2[N:8]=1
Reactant: N#CBr
Reactant: Nc1[nH]cnc1-c1n[nH]c(-c2ccccc2)n1
Solvent: CO
Product: Nc1nc2nc(-c3ccccc3)[nH]c2c2ncnn12
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(5-aminoimidazol-4-yl)-5-phenyl-1,2,4-triazole (11.3 g, from Example 1), methanol (200 mL) and cyanogen bromide (5.25 g) is stirred under nitrogen for 2 hours at 40° C. It is cooled and the solid collected, dissolved in 10N Sodium hydroxide solution, filtered and precipitated by addition of glacial acetic acid to pH 5. The solid is washed with water, stirred in a mixture of methanesulphonic acid in methanol for one-half hour and collected (1.39 g), mp >350°. After drying at room temperature and high vacuum, the hemihydrate of 5-amino-2-phenyl-[1,2,4]triazolo[5,1-i]purine is thus obtained.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].I[C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][O:20][CH3:21])[CH:13]=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.[Cu](I)I.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:1]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][O:20][CH3:21])[CH:13]=[O:14])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C#CCCCCCC
Reactant: COCOc1ccc(C=O)cc1I
Agent: I[Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCCCCCC#Cc1cc(C=O)ccc1OCOC
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
Under an argon atmosphere, copper iodide (190 mg, 1.0 mmol), 1-octyne (0.55 mL, 5.0 mmol) and 3-iodo-4-methoxymethoxybenzaldehyde (291 mg, 1.0 mmol) were added to a solution (2 mL) of palladium (II) diacetate (11 mg, 0.05 mmol) and triphenylphosphine (52 mg, 0.20 mmol) in methylene chloride, followed by stirring at room temperature for 2 hours. Next, the reaction solution was filtered through celite, and the solvent contained in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate/hexane=1/10) to give 3-(1-octyn-1-yl)-4-methoxymethoxybenzaldehyde (124 mg, yield 45%).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([CH2:15][C:16](O)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[C:9]1([CH2:15][C:16]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1)OCc1ccccc1
Yield: 95 %

Procedure:
To a CH2Cl2 (2ml) solution of 2-chloro-1-ethyl-4-methoxypryridinium tetrafluoroborate (296 mg, 1.2 mmol) was added a mixture of benzyl alcohol (108 mg, 1.0 mmol), phenylacetic acid (136 mg, 1.0 mmol) and triethylamine (243 mg, 2.4 mmol) in CH2Cl2 (2 ml), and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and benzyl phenylacetate was isolated in 95% yield.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[K+].Br[CH2:10][CH2:11][C:12]([F:15])([F:14])[F:13]>CO>[F:13][C:12]([F:15])([F:14])[CH2:11][CH2:10][S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C(O)CCS
Reactant: FC(F)(F)CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCSCCC(F)(F)F
Temperature: 25 °C
Yield: 90.4 %

Procedure:
3-Mercaptopropanoic acid (3.2 g, 30.1 mmol) was dissolved in MeOH (20 mL) and stirred at RT. Powdered potassium hydroxide (3.72 g, 66.3 mmol) was added to the solution, followed by 3-bromo-1,1,1-trifluoropropane (6.14 g, 34.7 mmol). The solution was then stirred at 65° C. for 3 h and then it was quenched with 1N HCl until the pH of the solution was acidic. The mixture was extracted with DCM (3×30 mL), the combined organic phases were dried, concentrated and purified by silica gel chromatography (0-50% EtOAc/hexane) to give 3-((3,3,3-trifluoropropyl)thio)propanoic acid (5.5 g, 27.2 mmol, 90% yield) as colorless oil mixed with some white suspension: IR (Thin film) 2936, 1708 cm−1; 1H NMR (300 MHz, CDCl3) δ 2.86-2.78 (m, 2H), 2.78-2.58 (m, 4H), 2.52-2.25 (m, 2H); EIMS m/z 202.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=O)[C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:22][NH:23][NH2:24].[C:25]([O-:32])(=[O:31])/[CH:26]=[CH:27]\[C:28]([O-:30])=[O:29]>>[CH3:22][N:23]1[C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[C:8]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[CH:11][CH:10]=2)=[N:24]1.[C:25]([O-:32])(=[O:31])/[CH:26]=[CH:27]\[C:28]([O-:30])=[O:29]
Reactant: CNN
Reactant: CN(C)CCNc1ccc(C(=O)c2cccnc2Cl)cc1
Agent: O=C([O-])/C=C\C(=O)[O-]
Product: CN(C)CCNc1ccc(-c2nn(C)c3ncccc23)cc1

Procedure:
By conducting reactions and treatments in the same manner as in Example 42, using 5.8 g of 2-chloro-3-[4-(2-dimethylaminoethylamino)benzoyl]pyridine and 1.2 g of methylhydrazine, converting into the maleate and recrystallizing from ethyl acetate, there was obtained 1-methyl-3-[4-(2-dimethylaminoethylamino)phenyl]-1H-pyrazolo[3,4-b]pyridine·maleate, m.p. 88°-90° C.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH:4]([CH2:5][CH:6]=[C:7]2[C:9]([O:11][CH3:12])=[O:10])[CH2:3]1.[CH2:13]([SH:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:13]([S:15][CH:6]1[CH2:5][CH:4]2[N:8]([C:2](=[O:1])[CH2:3]2)[CH:7]1[C:9]([O:11][CH3:12])=[O:10])[CH3:14]
Reactant: COC(=O)C1=CCC2CC(=O)N12
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCSC1CC2CC(=O)N2C1C(=O)OC
Reaction time: 1 h

Procedure:
A stirred solution of methyl 7-oxo-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (9) (0.050 g) in dry dimethylformamide (1 ml) at room temperature was treated with ethane thiol (0.10 ml) followed by powdered potassium carbonate (0.023 g). After a period of 1 hour, the excess thiol was blown off in a stream of argon and the residue concentrated at 30° under reduced pressure. The residual gum was dissolved in ethyl acetate, washed with brine and dried over sodium sulphate. The ethyl acetate solution was concentrated and the three diastereoisomers (10, 11 and 12 in order of increasing polarity) were separated by column chromatography on silica gel 60 (<230 mesh), eluting with 60°-80° petroleum ether/ethyl acetate 7:3.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:14]([CH:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[CH3:16])[CH:13]=[N:12][CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>C1COCC1>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH:15]([N:14]2[C:10]([CH2:9][OH:8])=[CH:11][N:12]=[CH:13]2)[CH3:16])=[CH:18][C:19]=1[F:25])#[N:24]
Reactant: CC(c1ccc(C#N)c(F)c1)n1cncc1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: CC(c1ccc(C#N)c(F)c1)n1cncc1CO
Reaction time: 1 h

Procedure:
To a solution of 5-(tert-butyldimethylsilyloxymethyl)-1-[1-(4-cyano-3-fluorophenyl)ethyl]imidazole, as described above in Step E, (101 mg, 0.281 mmol) in THF (2 mL) was added tetrabutylammonium fluoride (0.309 mL of a 1.0 M solution in THF, 0.309 mmol) dropwise. The reaction mixture was stirred for 1 hour, then poured into saturated aqueous NaHCO3 (20 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of CH2Cl2—0% to 10% MeOH, to yield the desired product as a pale solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])=[CH:6][C:5]=1[CH2:21][CH2:22][OH:23])[CH3:2].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([O:23][CH2:22][CH2:21][C:5]2[CH:6]=[C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:19])[CH3:20])[C:12]([OH:14])=[O:13])[CH:8]=[CH:9][C:4]=2[O:3][CH2:1][CH3:2])=[O:33])=[CH:27][CH:26]=1
Reactant: CCOC(=O)C(Cc1ccc(OCC)c(CCO)c1)OC(C)C
Reactant: O=C=Nc1ccc(Cl)cc1
Product: CCOc1ccc(CC(OC(C)C)C(=O)O)cc1CCOC(=O)Nc1ccc(Cl)cc1

Procedure:
Using ethyl 3-[4-ethoxy-3-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and 4-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:7]([S:8]([CH3:11])(=[O:10])=[O:9])[CH2:6][C@H:5]([S:12][C:13](=[O:15])[CH3:14])[CH2:4]1.C(O[C@H:20]1[O:37][C@@H:36]([CH3:38])[C@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:21]1[O:22][C:23](=[O:25])[CH3:24])(=O)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[C:28]([O:27][C@@H:26]1[C@@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@H:36]([CH3:38])[O:37][C@H:20]([O:1][CH2:2][C@@H:3]2[CH2:4][C@@H:5]([S:12][C:13](=[O:15])[CH3:14])[CH2:6][N:7]2[S:8]([CH3:11])(=[O:10])=[O:9])[C@@H:21]1[O:22][C:23](=[O:25])[CH3:24])(=[O:30])[CH3:29]
Reactant: CC(=O)O[C@H]1O[C@@H](C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(=O)S[C@@H]1C[C@@H](CO)N(S(C)(=O)=O)C1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](C)O[C@H](OC[C@@H]2C[C@@H](SC(C)=O)CN2S(C)(=O)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
A solution of thioacetic acid (3R,5S)-S-(5-hydroxymethyl-1-methanesulfonyl-pyrrolidin-3-yl) ester (0.070 g) and 1,2,3,4-tetra-O-acetyl-6-deoxy-beta-L-mannopyranose [G. Hodosi and P. Kovàc, Carbohydr. Res., 303, 239-243 (1997)] (0.138 g) in dichloromethane (10.0 ml) was treated with trimethylsilyl trifluoromethanesulphonate (0.075 ml) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, poured into a sodium bicarbonate solution, and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel using EtOAc/hexane 1:1 as eluent to obtain acetic acid (2S,3R,4R,5S,6S)-4,5-diacetoxy-2-[(2S,4R)-4-acetylsulfanyl-1-methanesulfonyl-pyrrolidin-2-ylmethoxy]-6-methyl-tetrahydro-pyran-3-yl ester (0.105 g) as a syrup, MS: 543 (M+NH4+). Acetic acid (2S,3R,4R,5S,6S)-4,5-diacetoxy-2-[(2S,4R)-4-acetylsulfanyl-1-methanesulfonyl-pyrrolidin-2-ylmethoxy]-6-methyl-tetrahydro-pyran-3-yl ester (0.080 g) was reacted as described for the S-Acetyl deprotection (see below) to obtain (2S,3R,4R,5R,6S)-2-[(2S,4R)-4-mercapto-1-methanesulfonyl-pyrrolidin-2-ylmethoxy]-6-methyl-tetrahydro-pyran-3,4,5-triol (0.035 g) as a colourless foam, MS: 358 (MH+).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]([NH:17][C:18]3[CH:23]=[C:22]([NH:24][C:25]4[S:29][N:28]=[C:27]([CH3:30])[CH:26]=4)[C:21]([C:31]#[N:32])=[CH:20][C:19]=3[F:33])[C:14]([NH2:16])=[O:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+].OO.CC(O)=[O:40]>CCO.CS(C)=O>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]([NH:17][C:18]3[C:19]([F:33])=[CH:20][C:21]([C:31]([NH2:32])=[O:40])=[C:22]([NH:24][C:25]4[S:29][N:28]=[C:27]([CH3:30])[CH:26]=4)[CH:23]=3)[C:14]([NH2:16])=[O:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)O
Reactant: Cc1cc(Nc2cc(N[C@H](Cc3ccc(-n4ccnc4)cc3)C(N)=O)c(F)cc2C#N)sn1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1cc(Nc2cc(N[C@H](Cc3ccc(-n4ccnc4)cc3)C(N)=O)c(F)cc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-3-(4-(1H-imidazol-1-yl)phenyl)-2-(4-cyano-2-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)propanamide (9 mg, 0.019 mmol) in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL, 0.50 mmol) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was purified by HPLC to give the titled compound (5 mg). MS 480.3 (M+H); UV 204.7, 292.8 nm.
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][C:18]([CH:20]1[CH2:22][CH2:21]1)=[O:19])=O)C1C=CC=CC=1.[N:23]1[C:32]2[C:27](=[N:28][C:29]([CH:33]=O)=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.N1CCCCC1>CC(O)C>[N:28]1[C:27]2[C:32](=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:31]=[CH:30][C:29]=1[CH:33]=[C:15]1[NH:11][C:12]([NH:17][C:18]([CH:20]2[CH2:21][CH2:22]2)=[O:19])=[N:13][C:14]1=[O:16]
Reactant: O=C1CN(C(=O)OCc2ccccc2)C(NC(=O)C2CC2)=N1
Reactant: O=Cc1ccc2ncccc2n1
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: O=C1N=C(NC(=O)C2CC2)NC1=Cc1ccc2ncccc2n1
Temperature: 25 °C

Procedure:
To a mixture of 2-(cyclopropanecarbonyl-amino)-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (109.6 mg, 0.36 mmol), 1,5-naphthyridine-6-carboxaldehyde (47.4 mg, 0.30 mmol) and iPrOH (5.0 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 3.5 hrs to give a suspension. The reaction mixture was cooled to r.t. and the solid was collected by filtration, washed with MeOH, and ether to give cyclopropanecarboxylic acid (5-[1,5]naphthyridin-2-ylmethylene-4-oxo-4,5-dihydro-1H-imidazol-2-yl)-amide as a light brown solid, 32.6 mg (35.4%). HR-ES (+) m/e calcd. for C16H13N5O2: (M)+ 307.1069. Found: 307.1066.