Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7]C)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH3:9][O-].[Na+].[Na].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CO>[C:1]([O:7][CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: COC(=O)CC(C)=O
Reactant: CCCCCCCBr
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CCCCCC(CC)OC(=O)CC(C)=O
Yield: 78 %

Procedure:
Methyl acetoacetate (20.00 g, 172.2 mmol) was treated with sodium methoxide (NaOMe)/MeOH (freshly prepared by dissolving 4.00 g sodium in 200 mL anhydrous MeOH at 0° C.) at room temperature for 20 minutes. n-Heptyl bromide (24.60 mL, 156.6 mmol, 0.9 equiv.) was added and the solution was refluxed for 24 hours. Methanol was evaporated and the residue was treated with 5% hydrogen sulfate (H2SO4) (100 mL) in acetone (200 mL) at room temperature for 2 hours. Acetone was evaporated and the aqueous layer was extracted with ether (400 mL). The ether extract was then quickly washed with 1N NaOH (100 mL×3), water (100 mL×2), and brine (100 mL×1), and dried over MgSO4. Evaporation of the solvents yielded 33.56 g (78%) crude product as an oil. Rf =0.6 (10% ether/petroleum ether). 1H NMR (400 MHz, CDCl3) δ 0.88 (3 H, t, J=6.7 Hz), 1.20-1.45 (10 H, br m), 1.78-1.91 (2 H, m), 2.22 (3 H, s), 3.42 (1 H, t, J=7.4 Hz), 3.73 (3 H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1.[C:11](#[N:15])[CH2:12][C:13]#[N:14].C(N(CC)CC)C.[CH3:23][N:24]1[C:28](=[O:29])[CH2:27][C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:25]1>C(O)C>[NH2:14][C:13]1[O:29][C:28]2[N:24]([CH3:23])[N:25]=[C:26]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:27]=2[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:12]=1[C:11]#[N:15]
Reactant: CN1N=C(c2ccccc2)CC1=O
Reactant: N#CCC#N
Reactant: COc1ccc(C=O)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(C2C(C#N)=C(N)Oc3c2c(-c2ccccc2)nn3C)cc1
Reaction time: 0.02 h
Yield: 20.4 %

Procedure:
A mixture of anisaldehyde (350 μL, 2.87 mmol, 1.0 equ.), malononitrile (190 mg, 2.87 mmol, 1.0 equ.) and triethylamine (400 μL, 2.87 mmol, 1.0 equ.) in ethanol (10 mL) was stirred for 1 min, followed by the addition of 1-methyl-3-phenyl-1H-pyrazol-5(4H)-one (500 mg, 2.87 mmol, 1 equ.). The reaction mixture was concentrated after 24 h and the precipitate was washed with ethanol and hexanes, and product re-crystallized from ethanol to give 6-amino-4-(4-methoxyphenyl)-1-methyl-3-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (210 mg, 20%, 0.586 mmol) as a white solid. 1H-NMR (400 MHz) DMSO: 7.50-7.48 (d, 2H), 7.21-7.17 (m, 3H), 7.05-7.02 (m, 4H), 6.76-6.74 (d, 2H), 4.91 (s, 1H), 3.76 (s, 3H), 3.64 (s, 3H), 13C-NMR (100 MHz) DMSO: 158.9, 158.3, 146.0, 144.6, 136.9, 133.2, 128.9, 128.5, 127.8, 126.4, 120.6, 114.1, 95.9, 60.3, 55.3, 37.5, 34.5; LC/MS-MS: 359.2→293.0 m/z; GS1 and GS2 at 30, DP=66, CE=29, CXP=20, tR=3.98 min.
Reaction SMILES: [C:1]1([C@H:7]2[NH:12][CH2:11][C:10](=[O:13])[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:14]1[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[C:1]1([C@@H:7]2[CH2:8][O:9][C:10](=[O:13])[C@H:11]3[C@H:20]([C:17]4[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=4)[O:21][C@H:20]([C:17]4[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=4)[N:12]23)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccncc1
Reactant: O=C1CN[C@H](c2ccccc2)CO1
Solvent: Cc1ccccc1
Product: O=C1OC[C@@H](c2ccccc2)N2[C@@H](c3ccncc3)O[C@@H](c3ccncc3)[C@H]12
Yield: 26.9 %

Procedure:
A solution of (R)-5-phenylmorpholinon-2-one EBE 06134 (3.0 g, 16.9 mmol) and pyridine-4-carboxaldehyde (5.43 g, 50.7 mmol) in toluene (75 mL) was refluxed in a soxhlet extractor filled with molecular sieves 4A (25 g) for 16 hours. All the volatiles were evaporated and the desired product was purified by column chromatography (SiO2) using a gradient of 80% to 100% [v/v] EtOAc in cyclohexane to give after evaporation (1S,3R,5R,8aR)-tetrahydro-5-phenyl-1,3-di(pyridin-4-yl)oxazolo[4,3-c][1,4]oxazin-8(311)-one EBE 06136 (1.7 g, 46% yield) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].O[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])=[CH:23][CH:22]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])=[CH:23][CH:22]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: CC(C)C(=O)Nc1ccc(CCO)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(NC(=O)C(C)C)cc2)cc1)OCC
Temperature: 25 °C
Yield: 65.3 %

Procedure:
2-Ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester (described in Example 20b) (0.71 g; 2.97 mmole) dissolved in dichloromethane (5 ml) was added to a mixture of N-[4-(2-hydroxyethyl)phenyl]isobutyramide (0.5 g; 2.47 mmole), azodicarbonyl dipiperidine (0.75 g; 2.97 mmole) and triphenylphosphine (0.78 g; 2.97 mmole) in dichloromethane (15 ml). After stirring at room temperature over night the reaction mixture was filtered and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel using heptane:ethyl acetate (gradient 3:1 to 1:1) as eluant to give 0.69 g (yield 65%) of 2-ethoxy-3-{4-[2-(4-isobutyrylaminophenyl)ethoxy]phenyl}propanoic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([N:19]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:22][C:21]([C:30]([F:33])([F:32])[F:31])=[N:20]2)[CH:16]=[CH:17][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:22][C:21]([C:30]([F:33])([F:32])[F:31])=[N:20]2)[CH:14]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1cccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)c1
Product: O=C(Nc1cccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)c1)c1cc(Cl)ccc1O
Yield: 74.4 %

Procedure:
Using 5-chlorosalicylic acid and 1-(3-aminophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole as the raw materials, the same operation as the Example 16 gave the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C@@H:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2].[I-].[CH3:22][N:23]1[C:31]2[C:26](=[C:27]([CH3:32])[CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:33]CN(C)C)=[CH:24]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C@@H:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:33][C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[N:23]([CH3:22])[CH:24]=2)[C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCC[C@@H](CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Reactant: Cc1cccc2c1c(CCN(C)C)cn2C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC[C@@H](CC(=O)OCC)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccccc21
Yield: 68 %

Procedure:
To a solution of (S)-3-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-hexanoic acid ethyl ester (700 mg, 2.5 mmol) in DMF (50 mL) were added (1,4-Dimethyl-1H-indol-3-ylmethyl)-trimethyl-amine iodide salt (1.3 g, 3.8 mmol) and K2CO3 (700 mg, 5.1 mmol) at room temperature under nitrogen atmosphere. The solution was heated to 100 C for 4 hours. The solution was cooled down and water was added. The solution was extracted with EtOAc and the combined organic layer was dried with MgSO4. The solution was filtered and the filtrate was concentrated. The residue was purified by CombiFlash with 20% EtOAc in Hexane as the eluent to afford the desirable product (S)-3-[3-(1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-hexanoic acid ethyl ester (737 mg, 67%) as a yellow foam.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11](OS(C)(=O)=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[I-:20].[Na+].C(OCC)(=O)C.CCCCCC>CN(C)C=O>[Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([I:20])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCCC(OS(C)(=O)=O)C1
Reactant: [I-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCCC(I)C1
Temperature: 25 °C

Procedure:
A solution of 3-(tert-butyldimethylsilyl)oxy-1-(methylsulfonyloxy)cyclohexane (15.9 g) and sodium iodide (8.5 g) in N,N-dimethylformamide (80 ml) was heated at 100° C. for 3 hours with stirring. After cooled to ambient temperature, a reaction mixture was poured into a mixture of ethyl acetate (250 ml) and n-hexane (150 ml), and insoluble material was removed by filtration. Mother liquor was washed in turn with water (100 ml×3), 5% sodium thiosulfate in water (50 ml), and saturated sodium chloride in water (100 ml×2), and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (300 ml) eluting with 10% ethyl acetate in n-hexane to give 3-(tert-butyldimethylsilyl)oxy-1-iodocyclohexane (cis and trans mixture).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:9]=[C:8]2[C:3]=1[C:4](=[O:31])[CH:5]=[C:6]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[N:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[CH3:32][S:33]([N:15]1[CH2:16][CH2:17][N:12]([C:10]2[N:9]=[C:8]3[C:3]([C:4](=[O:31])[CH:5]=[C:6]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:7]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:2]([CH3:1])[CH:11]=2)[CH2:13][CH2:14]1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(N2CCNCC2)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Solvent: ClCCl
Product: Cc1cc(N2CCN(S(C)(=O)=O)CC2)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.6 %

Procedure:
A mixture of 5-methyl-1-phenyl-2-phenylamino-7-piperazin-1-yl-1H-[1,8]naphthyridin-4-one (22.6 mg, 0.055 mmol) and MsCl (0.083 mmol, 0.006 mL) in CH2Cl2 (0.8 mL) was stirred at room temperature overnight at which time the solvent was removed in vacuo. The resulting residue was purified by prep-TLC to give 7-(4-methanesulfonyl-piperazin-1-yl)-5-methyl-1-phenyl-2-phenylamino-1H-[1,8]naphthyridin-4-one (3.4 mg, 6%): LCMS RT: 2.36 min, MH+: 490.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[OH:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=1[OH:29])[CH2:21][CH2:22][C:23](O)=[O:24]>>[OH:17][C:18]1[CH:19]=[C:20]([CH2:21][CH2:22][C:23]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:24])[CH:26]=[CH:27][C:28]=1[OH:29]
Reactant: O=C(O)CCc1ccc(O)c(O)c1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Product: O=C(CCc1ccc(O)c(O)c1)Nc1ccccc1-c1cc2ccccc2[nH]1
Yield: 19 %

Procedure:
Prepared from 2-(2-aminophenyl) indole and 3,4-dihydroxyhydrocinnamic acid in 19% yield following procedure 1. The product was chromatographed on silica and crystallized from acetonitrile. 100% Purity by LC/MS (230 DAD), Mass-spec [M+H+]=373, 1H NMR (MeOH-d4): 2.60 t, 7.4 Hz (2H), 2.85 t, 7.4 Hz (2H), 6.38 s (1H), 6.55 dd, 8.2 Hz (1H), 6.69 m (2H), 7.02 t, 8 Hz (1H), 7.11 t, 8 Hz (1H), 7.27–7.35 m (2H), 7.38 d, 8 Hz (1H), 7.56 d, 8 Hz (1H), 7.58 dd, 7.1 Hz (1H), 7.70 d, 8 Hz (1H).
Reaction SMILES: [NH2:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])=[N:4][N:3]=1.[CH2:22](O)[CH3:23].C(O)(=O)C>CCOC(C)=O>[CH2:22]([O:6][C:2]1[NH:1][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])=[N:4][N:3]=1)[CH3:23]
Reactant: Nc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Reactant: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOc1nnc(-c2ccncc2Nc2ccc(I)cc2F)[nH]1
Yield: 27.9 %

Procedure:
To a solution of [4-(5-Amino-[1,3,4]oxadiazol-2-yl)-pyridin-3-yl]-(2-floro-4-iodo-phenyl)-amine (150 mg, 0.38 mmol) in ethanol (10 mL) KOH 9212 mg, 3.78 mmol) was added. The reaction mixture was refluxed for 3 hrs. Then, added acetic acid was added to bring the pH to 5. The volatives were stripped and the residue was dissolved in EtOAc, and washed with 5% Na2CO3, and brine, and then dried over anhydrous MgSO4. After filtration and solvent removal the remaining crude product was subjected to silica gel column chromatography (eluent:Hex:ane EtOAc=1:1) to afford the desired product (45 mg). [5.08 min; 394(M+1)]
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH:9]1[CH2:14][CH2:13][Si:12]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[F:26][C:27]([F:37])([F:36])[O:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1>CN(C)C=O>[F:26][C:27]([F:36])([F:37])[O:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][CH2:8][CH:9]2[CH2:14][CH2:13][Si:12]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:33][CH:34]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: CCCCC[Si]1(c2ccccc2)CCC(CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC[Si]1(c2ccccc2)CCC(COc2ccc(OC(F)(F)F)cc2)CC1
Yield: 73.3 %

Procedure:
8.3 g (60 mmols) of potassium carbonate was added to a mixture of 6.8 g (20 mmols) of 4-bromomethyl-1-n-pentyl-1-phenyl-1-silacyclohexane, 3.6 g (20 mmols) of 4-trifluoromethoxyphenol and 50 ml of dimethylformamide (DMF), followed by heating under flux for 10 hours. The reaction mixture was after-treated by a usual manner and purified through chromatography to obtain 6.4 g (yield: 73%) of 4-(4-trifluoromethoxyphenyloxymethyl)-1-n-pentyl-1-phenyl-1-silacyclohexane. The results of IR and NMR analyses are shown below.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH2:5][NH:4][CH:3]1[C:8]([OH:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>O>[CH2:22]([O:21][C:19]([N:4]1[CH2:5][CH2:6][CH2:7][C:2]([CH3:11])([CH3:1])[CH:3]1[C:8]([OH:10])=[O:9])=[O:20])[CH3:23]
Reactant: CC1(C)CCCNC1C(=O)O
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)N1CCCC(C)(C)C1C(=O)O
Reaction time: 4 h
Yield: 61.9 %

Procedure:
To a stirred solution of 5 g (0.031 moles) of 3,3-dimethyl pipecolic acid and 4.44 g (0.033 moles) of potassium carbonate in 45 ml of water at 0° C., were added dropwise 3.61 g (0.033 moles) of ethyl chloroformate. After the addition was completed the solution was allowed to reach room temperature and stirring was continued for 4 hours. This solution was washed with 30 ml of methylene chloride, then brought to acidic pH with 10% HCl and extracted with methylene chloride. The organic extracts were dried and evaporated in vacuo to yield 4.4 g of the title compound.
Reaction SMILES: [C:1]([NH:4][OH:5])(=[O:3])[CH3:2].Cl[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:17]=[C:18]([C:23]3([O:29][CH3:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:19]=[C:20]([F:22])[CH:21]=2)=[CH:11][CH:10]=1)[CH3:8]>>[C:1]([NH:4][O:5][CH:7]([CH3:8])[C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([C:23]3([O:29][CH3:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=2)=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NO
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(C)Cl)cc3)c2)CCOCC1
Product: COC1(c2cc(F)cc(Sc3ccc(C(C)ONC(C)=O)cc3)c2)CCOCC1
Temperature: 60 °C
Yield: 62 %

Procedure:
Using an analogous procedure to that described in Example 1 except that the reactants were heated to 60° C for 2 hours, acetohydroxamic acid was reacted with 4-{3-[4-(1-chloroethyl)phenylthio]-5-fluorophenyl}-4-methoxytetrahydropyran to give 4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-α-methylbenzyl acetohydroxamate as a gum in 62% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[S:14][C:15]([C:18]3[CH2:19][CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][CH:23]=3)=[CH:16][CH:17]=2)[CH2:11][C:10]([C:31]([C:37]([F:40])([F:39])[F:38])([C:33]([F:36])([F:35])[F:34])[OH:32])=[N:9]1.Cl>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[S:14][C:15]([C:18]3[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=3)=[CH:16][CH:17]=2)[CH2:11][C:10]([C:31]([C:33]([F:35])([F:34])[F:36])([C:37]([F:40])([F:38])[F:39])[OH:32])=[N:9]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)s2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: OC(C1=NN(c2ccccc2Cl)C(c2ccc(C3=CCNCC3)s2)C1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 222.7 %

Procedure:
1-(2-Chloro-phenyl)-5-[5-(1-BOC-1,2,3,6-tetrahydropyridin-4-yl)-thiophen-2-yl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (590.0 mg, 0.97 mmol) prepared in Example 416 was added to a saturated solution of hydrochloric acid in ethyl acetate (2.0 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give 590.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:26]=1[NH2:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH:27][C:26]4[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:25]=4[F:24])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cc(F)c(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Nc4cc(F)c(F)cc4F)ncnc32)CC1

Procedure:
4-[4-(2,4,5-Trifluoro-phenylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure C by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 2,4,5-trifluoroaniline (available from Oakwood Products, Inc., West Columbia, S.C., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.91-1.99 (m, 4H), 2.95-3.05 (m, 2H), 4.00-4.10 (m, 2H), 4.88-4.93 (m, 1H), 7.71-7.74 (m, 1H), 7.96-7.99 (m, 1H), 8.24 (br s, 1H), 8.36 (s, 1H), 10.17 (s, 1H). Mass spectrum MH+=449.
Reaction SMILES: C(N(CC)S(C1C=C(C(=O)C[Br:16])C=CC=1Cl)(=O)=O)C.ClC1C=CC(NC(NC)=S)=CC=1.Br.[CH2:33]([N:35]([CH2:61][CH3:62])[S:36]([C:39]1[CH:40]=[C:41]([C:46]2(O)[CH2:50][S:49][C:48](=[N:51][C:52]3[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][CH:53]=3)[N:47]2[CH3:59])[CH:42]=[CH:43][C:44]=1[Cl:45])(=[O:38])=[O:37])[CH3:34]>C(O)(=O)C>[BrH:16].[CH2:61]([N:35]([CH2:33][CH3:34])[S:36]([C:39]1[CH:40]=[C:41]([C:46]2[N:47]([CH3:59])[C:48](=[N:51][C:52]3[CH:53]=[CH:54][C:55]([Cl:58])=[CH:56][CH:57]=3)[S:49][CH:50]=2)[CH:42]=[CH:43][C:44]=1[Cl:45])(=[O:38])=[O:37])[CH3:62]
Reactant: CCN(CC)S(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Reactant: CCN(CC)S(=O)(=O)c1cc(C2(O)CSC(=Nc3ccc(Cl)cc3)N2C)ccc1Cl
Agent: Br
Agent: CNC(=S)Nc1ccc(Cl)cc1
Solvent: CC(=O)O
Product: CCN(CC)S(=O)(=O)c1cc(-c2csc(=Nc3ccc(Cl)cc3)n2C)ccc1Cl

Procedure:
Obtained (a) by a procedure analogous to that indicated in Example 1(a), from 3'-diethylsulfamoyl-2-bromo-4'-chloroacetophenone and 1-(4-chlorophenyl)-3-methylthiourea, or (b) by a procedure analogous to that of Example 1(b), by boiling 4-(3-diethylsulfamoyl-4-chlorophenyl)-2-(4-chlorophenyl-imino)-3-methylthiazolidin-4-ol hydrobromide for 2 hours in glacial acetic acid and filtering off the crystals after cooling. Melting point 207° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[C:7]([O:10][CH3:11])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:12](Br)[CH2:13][CH2:14][CH3:15].C(=O)([O-])O.[Na+]>COCCO>[Cl:1][C:2]1[C:8]([Cl:9])=[C:7]([O:10][CH3:11])[CH:6]=[CH:5][C:3]=1[NH:4][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCBr
Reactant: COc1ccc(N)c(Cl)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCO
Product: CCCCNc1ccc(OC)c(Cl)c1Cl
Reaction time: 48 h

Procedure:
A mixture of 2,3-dichloro-4-methoxyaniline (19.2 g), n-butylbromide (22.0 g), sodium hydrogen carbonate (40 g) and methylcellosolve (350 ml) is stirred at 95°-100° C. for about 48 hours. The cooled mixture is filtered, and the filtrate is evaporated in vacuo. The remaining material is washed with water and is thereafter recrystallized from ethanol to give the title compound with a melting point of 47°-49° C.
Reaction SMILES: C(=O)([O-])O.[C:5]([NH2:9])(N)=[N:6][NH2:7].FC(F)(F)C([O-])=O.O[CH:18]1[C:26]2[CH2:25][S:24][CH:23]3[CH:27]([NH:30][C:31](=[O:42])/[C:32](/[C:36]4[N:37]=[C:38]([NH2:41])[S:39][CH:40]=4)=[N:33]\[O:34][CH3:35])[C:28](=[O:29])[N:22]3[C:21]=2[C:20](=[O:43])[O:19]1.C(#[N:46])C>Cl>[NH2:41][C:38]1[S:39][CH:40]=[C:36](/[C:32](=[N:33]/[O:34][CH3:35])/[C:31]([NH:30][CH:27]2[C:28](=[O:29])[N:22]3[C:21]([C:20]([OH:19])=[O:43])=[C:26]([CH:18]=[N:46][NH:9][CH:5]=[N:6][NH2:7])[CH2:25][S:24][C@H:23]23)=[O:42])[N:37]=1
Reactant: CC#N
Reactant: NN=C(N)N
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C3=C(CSC12)C(O)OC3=O)c1csc(N)n1
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(C=NNC=NN)CS[C@H]12)c1csc(N)n1

Procedure:
1.24 g of the hydrogen carbonate of aminoguanidine are dissolved in 9.15 ml of 2 N HCl and added under stirring to a solution of 3.2 g of the trifluoroacetate of N-(1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]-thiazin-6-yl)-2-(2-aminothiazol-4yl)-(Z)-2-methoxyimino acetic acid amide in 125 ml of 4% aqueous acetonitrile. After ca. 90 minutes the precipitated dihydrochloride of 7-[(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino-3-[[(aminoimino-methyl)-hydrazono]methyl]-3-cephem-4-carboxylic acid is filtered off, washed with acetonitrile and dried.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[F:28][C:29]([F:35])([F:34])[S:30]([OH:33])(=[O:32])=[O:31].[CH3:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>C1C=CC=CC=1>[F:28][C:29]([F:35])([F:34])[S:30]([O-:33])(=[O:32])=[O:31].[C:1]1([S+:7]([C:38]2[CH:37]=[CH:36][CH:41]=[CH:40][CH:39]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(c1ccccc1)c1ccccc1
Reactant: CCCCCC
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: c1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=S(=O)([O-])C(F)(F)F
Product: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Yield: 92 %

Procedure:
In 200 ml of benzene were dissolved 21.1 g (0.1 mol) of diphenylsulfoxide, and 42.0 g (0.2 mol) of trifluoroacetic acid anhydride were added dropwise thereto at 0 to 5° C., followed by stirring and stirred at 0 to 5° C. for 30 minutes. And then, 15.0 g (0.1 mol) of trifluoromethane sulfonic acid were added dropwise thereto at 0 to 5° C. and allowed to react with stirring at 0 to 20° C. for 3 hours. After completion of the reaction, 500 ml of n-hexane was poured into the resultant and the obtained oily substance separated by decantation was crystallized from methylene chloride/n-hexane, followed by filtration and drying, to give 37.9 g (yield: 92%) of triphenylsulfonium trifluoromethanesulfonate as a white crystal.