Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: Oc1cccnc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cccnc2)cc1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
1-Chloro-4-nitrobenzene (40 g, 0.25 mol) and 3-hydroxypyridine (36 g, 0.38 mol) were dissolved in N,N-dimethylformamide (100 ml). Potassium carbonate (52.6 g, 0.38 mol) was added, and the mixture was stirred for 20 h at 100° C. Water was added, and the resulting mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate to give 3-(4-nitro-phenoxy)-pyridine.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([I:9])[CH:4]=1.C[O:11][C:12](=O)[CH2:13][SH:14].C([O-])([O-])=O.[K+].[K+].[OH-].[Li+].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>CC(C)=O.ClC1C=CC=CC=1.C(O)(=O)C.O.CO>[I:9][C:5]1[CH:4]=[C:3]2[C:8]([C:12](=[O:11])[CH2:13][S:14][CH2:2]2)=[CH:7][CH:6]=1
Reactant: COC(=O)CS
Reactant: BrCc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [K+]
Solvent: CC(C)=O
Solvent: CO
Solvent: O
Product: O=C1CSCc2cc(I)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-bromomethyl-3-iodo-benzene (CAS#49617-83-6, 25.0 g, 84 mmol) in acetone (500 mL) is added mercapto-acetic acid methyl ester (9.0 g, 85 mmol) followed by K2CO3 (15.2 g 110 mmol). The reaction is permitted to stir overnight. The next morning the reaction is filtered and concentrated. The resulting residue containing (3-iodo-benzylsulfanyl)-acetic acid methyl ester is then dissolved in methanol (300 mL). The methanol solution is charged with water (100 mL) and lithium hydroxide (6.0 g, 252 mmol). The reaction is permitted to stir at room temperature until the starting ester is consumed as determined by TLC analysis. The reaction is then brought to a pH<4 by the addition of 3N aqueous HCl. The reaction is then concentrated to approximately ¾ of its original volume and diluted with ethyl acetate. The layers are separated and the organic layer is dried with Na2SO4, filtered and concentrated to afford a residue containing 3-iodo-benzylsulfanyl)-acetic acid. The residue is dissolved in chlorobenzene (500 mL) and treated with P2O5 (64 g, 450 mmol). The reaction is heated at reflux overnight. The reaction is then cooled to room temperature and filtered. The eluent is then concentrated to dryness. The resulting residue is dissolved in ethyl acetate and washed with brine. The organic layer is then dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-hexanes, 0:1 to 1:5) to afford 7-iodo-isothiochroman-4-one; MS: (ESI) m/z 308.0 (M+NH4)+
Reaction SMILES: C([O:4][C@@H:5]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:6]([N:8]1[CH2:16][C@H:15]2[C@H:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:13][C:14]2=[O:17])[CH2:9]1)=[O:7])(=O)C.[OH-].[Na+].Cl>O.C(O)C.C(OCC)(=O)C>[OH:4][C@@H:5]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:6]([N:8]1[CH2:16][C@H:15]2[C@H:10]([C:11]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:13][C:14]2=[O:17])[CH2:9]1)=[O:7]
Reactant: CC(=O)O[C@H](C(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CN(C(=O)[C@@H](O)c3ccccc3)C[C@H]12
Yield: 71.4 %

Procedure:
A solution of (3aR,7aR)-2-[(S)-2-acetoxy-2-phenylacetyl]-7,7-diphenyl-4-perhydroisoindolone (2 g) in a mixture of water (20 cc) and ethanol (25 cc) is treated with normal sodium hydroxide solution (5 cc) and the mixture is refluxed for 1 hour, then diluted with water (100 cc) and ethyl acetate (50 cc) and neutralized by the addition of normal hydrochloric acid (5 cc). The organic phase is washed with water (50 cc) and with a saturated sodium chloride solution (50 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aR,7aR)-2-[(S)-2-hydroxy-2-phenylacetyl]-7,7-diphenyl-4-perhydroisoindolone (1.3 g) in the form of a white meringue.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.Cl.[F:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:16][CH:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=2)[CH2:19][CH2:18]1
Reactant: FC1CCNCC1
Reactant: O=[N+]([O-])c1cc(Br)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc(N2CCC(F)CC2)cc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 63.4 %

Procedure:
Mix 1-bromo-3-nitro-5-(trifluoromethyl)benzene (700 mg, 2.59 mmol), 4-fluoropiperidine hydrochloride (544 mg, 3.89 mmol), cesium carbonate (2.5 g, 7.77 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP, 48 mg, 0.077 mmol), tris(dibenzylideneacetone)dipalladium [Pd2(dba)3, 47 mg, 0.052 mmol] in dioxane (10 mL), Stir the mixture under nitrogen atmosphere at 100° C. for 16 hrs. Cool the reaction mixture to room temperature, dilute it with water (10 mL), extract with ethyl acetate (10 mL×2), combine the organic layers, wash with brine (15 mL) and dry over anhydrous sodium sulfate. Concentrate the filtrate to get the crude product. Purify by flash chromatography (silica gel, 100% PE) to yield the target compound (480 mg, 63%).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:31]([O-:33])=[O:32])=[C:6]([CH:30]=1)[C:7]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:8].[CH3:34][S-:35].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:34][S:35][C:2]1[CH:3]=[CH:4][C:5]([N+:31]([O-:33])=[O:32])=[C:6]([CH:30]=1)[C:7]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:8]
Reactant: O=C(NCC1CCN(C(c2ccccc2)c2ccccc2)CC1)c1cc(F)ccc1[N+](=O)[O-]
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ccc([N+](=O)[O-])c(C(=O)NCC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 25 °C

Procedure:
Step 1): To a solution of 5-fluoro-2-nitro-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide (2.0 g, 4.46 mmol) in DMF (10 ml) was added dropwise a solution of sodium thiomethoxide (343 mg, 4.9 mmol) in DMF (10 ml) under stirring at room temperature. After the mixture was stirred overnight, an additional sodium thiomethoxide (34 mg, 0.49 mmol) was added to the mixture. The reaction mixture was diluted with AcOEt and washed twice with H2O. The organic layer was dried over MgSO4 and evaporated to give 5-methylthio-2-nitro-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide as colorless powders, 1.7 g (80%): mp 179°-181° C.
Reaction SMILES: C(O[N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:8][CH2:7]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:23]1[CH:22]=[CH:21][C:20]([N:17]2[CH2:18][CH2:19][CH:14]([C:12]([N:9]3[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]3)=[O:13])[CH2:15][CH2:16]2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)ON1CCN(C(=O)C2CCN(c3ccncc3)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(C1CCN(c2ccncc2)CC1)N1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The 4-(t-butoxy)-1-(4-pyridylpiperidin-4-ylcarbonyl)piperazine (3.74 g) was then dissolved in dry dichloromethane (50 ml) and treated with trifluoroacetic acid (5.3 ml) and stirred under an argon atmosphere at room temperature for three hours. The dichloromethane solvent was then removed by evaporation to afford a brown oil which slowly solidified, This solid was then taken up in dichloromethane, filtered and washed with water, brine and then dried (MgSO4). The resultant solution was then evaporated to dryness to yield a pale yellow oil which slowly crystallised to give 1-(4-pyridylpiperidin-4-ylcarbonyl)piperazine as a yellow solid;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]([C:18](OCC)=[O:19])=[C:12]([CH2:14][N:15]([CH3:17])[CH3:16])[N:13]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]([CH:18]=[O:19])=[C:12]([CH2:14][N:15]([CH3:16])[CH3:17])[N:13]=1
Reactant: CCOC(=O)c1sc(-c2c(F)cccc2F)nc1CN(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CN(C)Cc1nc(-c2c(F)cccc2F)sc1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.8 %

Procedure:
To a solution of the compound prepared in Example 439 (12.5 g) in dichloromethane (300 mL) at −95° C. was added a 1 mol/L solution of diisobutylaluminium hydride (48.5 mL) in hexanes dropwise slowly. The mixture was stirred for 3 hours and then quenched with methanol (50 mL). A solution of Rochelle's salt was then added dropwise. The mixture was warmed to room temperature and extracted with ethyl acetate. The combined extracts were washed with water and then concentrated. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=5:1) to obtain the title compound (4.3 g) having the following physical data.
Reaction SMILES: N[CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])=[C:6]([O:9][CH3:10])[CH2:7][S:8][C@H:3]12.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=[O:29].Cl>C(N(CC)CC)C>[O:29]=[C:2]1[C:24](=[O:25])[N:4]2[C:5]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])=[C:6]([O:9][CH3:10])[CH2:7][S:8][C@H:3]12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(N)[C@H]2SC1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(=O)[C@H]2SC1

Procedure:
4-Nitrobenzyl 7-amino-3-methoxy-3-cephem-4-carboxylate, trifluoromethanesulfonic anhydride, triethylamine and hydrochloric acid were reacted in the same manners as those of Examples 1-4 to give 4-nitrobenzyl 7-oxo-3-methoxy-3-cephem-4-carboxylate (monohydrate). Mp. 115°-120° C. (dec.).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([O:8][C@@H:9]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@@H:12]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:11][C@H:10]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][C:35]2[CH:44]=[C:43]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=[CH:42]3)[CH:36]=2)[CH:29]=1)(=[O:7])[CH3:6].[C:45](OC(=O)C)(=[O:47])[CH3:46].Cl>C(Cl)Cl>[C:5]([O:8][C@@H:9]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@@H:12]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:11][C@H:10]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][C:35]2[CH:36]=[C:37]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=[CH:38]3)[C:44]=2[C:45](=[O:47])[CH3:46])[CH:29]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cccc(Cc3cc4cccccc-4c3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](c2cccc(Cc3cc4cccccc-4c3C(C)=O)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 0.5 h

Procedure:
Aluminum chloride (0.24 g) was added to a solution of (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[3-(azulen-2-ylmethyl)phenyl]-D-glucitol (0.20 g) in methylene chloride (20 ml) at 0° C. and the mixture was stirred for 30 minutes. Next, acetic anhydride (0.17 ml) was added dropwise to the reaction mixture at 0° C. and the mixture was refluxed with stirring for 30 minutes and further 16 hours. The reaction mixture was added to 10% aqueous solution of hydrochloric acid under cooling with ice and was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium hydrogencarbonate and saturated brine in that order and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (2S,3S,4R,5R,6R)-2-[3-[(1-acetylazulen-2-yl)methyl]phenyl]-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-3,4,5-triyl triacetate (0.09 g).
Reaction SMILES: Cl.[NH2:2][OH:3].[H-].[Na+].[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][N:16]3[CH:20]([CH:21]([CH3:23])[CH3:22])[CH:19]4[C:24]([CH3:37])([CH3:36])[N:25]([CH3:35])[CH:26]([C:27]5[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=5)[CH:18]4[C:17]3=[O:38])=[CH:14][C:9]=2[O:8][CH2:7]1>CN(C=O)C>[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][N:16]3[CH:20]([CH:21]([CH3:23])[CH3:22])[CH:19]4[C:24]([CH3:36])([CH3:37])[N:25]([CH3:35])[CH:26]([C:27]5[CH:28]=[CH:29][C:30]([C:31](=[NH:32])[NH:2][OH:3])=[CH:33][CH:34]=5)[CH:18]4[C:17]3=[O:38])=[CH:14][C:9]=2[O:8][CH2:7]1
Reactant: CC(C)C1C2C(C(=O)N1Cc1ccc3c(c1)OCO3)C(c1ccc(C#N)cc1)N(C)C2(C)C
Reactant: NO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C1C2C(C(=O)N1Cc1ccc3c(c1)OCO3)C(c1ccc(C(=N)NO)cc1)N(C)C2(C)C
Temperature: 0 °C
Reaction time: 120 h
Yield: 66 %

Procedure:
841 mg (12.12 mmol) of hydroxylamine hydrochloride are suspended in 4 ml of DMF and cooled to 0° C. 303 mg (10.1 mmol) of 80% sodium hydride are added slowly. 500 mg (1.13 mmol) of (1RS,3aSR,4RS,6aSR)-4-(5-benzo[1,3]dioxol-5-ylmethyl-4-isopropyl-2,3,3-trimethyl-6-oxo-octahydro-pyrrolo-[3,4-c]pyrrol-1-yl)-benzonitrile are dissolved in DMF and added to the reaction mixture. The cooling is thereafter no longer applied. The mixture is stirred at room temperature for 5 days. Thereafter, it is filtered and the solvent is removed in a high vacuum. The mixture is purified by chromatography (RP18, gradient from water to methanol). (1RS,3aSR,4RS,6aSR)-4-(5-Benzo[1,3]dioxol-5-ylmethyl-4-isopropyl-2,3,3-trimethyl-6-oxo-octahydro-pyrrolo[3,4-c]pyrrol-1-yl)-N-hydroxy-benzimidamide is isolated in 66% yield. Colourless solid. ISP-MS: 479.4 ([M+H]+, 100).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([N:18]([O:20]C(=O)C)[CH3:19])=[O:17])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[OH-].[Li+]>CC(O)C>[CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([N:18]([OH:20])[CH3:19])=[O:17])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: CC(=O)ON(C)C(=O)/C=C/c1ccc(-n2c(C)ccc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1ccc(C)n1-c1ccc(/C=C/C(=O)N(C)O)cc1

Procedure:
To a solution of 3.12 g (E)-3-[4-(2,5-dimethyl-1-H-pyrrol-1-yl)phenyl]-N-acetoxy-N-methyl-2-propenamide in 2-propanol (50 ml) cooled to 0°, 1N aqueous lithium hydroxide (13 ml) is added with stirring. The mixture is stirred at room temperature for 30 minutes, then partitioned between ethyl acetate and 2N HCl. The organic phase is washed with brine, dried over magnesium sulphate and concentrated to dryness. Recrystallization from ethyl acetate yields (E)-3-[4-(2,5-dimethyl-1-H-pyrrol-1-yl)-phenyl]-N-hydroxy-N-methyl-2-propenamide of Example 1.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[CH2:29]([O:31][C:32]([C:34]1([C:44]2[CH:49]=[CH:48][C:47](Br)=[CH:46][N:45]=2)[CH2:43][CH2:42][C:37]2([O:41][CH2:40][CH2:39][O:38]2)[CH2:36][CH2:35]1)=[O:33])[CH3:30].[F-].C([N+:56](CCCC)(CCCC)CCCC)CCC.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:29]([O:31][C:32]([C:34]1([C:44]2[CH:49]=[CH:48][C:47]([NH2:56])=[CH:46][N:45]=2)[CH2:43][CH2:42][C:37]2([O:41][CH2:40][CH2:39][O:38]2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]
Reactant: CCOC(=O)C1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(c2ccc(N)cn2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.0M Toluene-solution of lithium bis(trimethylsilyl)amide (1.89 ml) was added to bis(dibenzylideneacetone)palladium (0) (39 mg) and tri-tert-butylphosphine tetrafluoroborate (20 mg) at 70° C. under an atmosphere of nitrogen, a solution of 8-(5-bromopyridin-2-yl)-1,4-dioxaspiro[4,5]decane-8-carboxylic acid ethyl ester (500 mg) in toluene (1.4 ml) was added dropwise and stirred at the same temperature for 0.5 hours. After completion of the reaction, the reaction solution was cooled to room temperature, tetrabutylammonium fluoride (4.7 ml) was added and stirred at the same temperature for an hour. Then, a saturated aqueous solution of sodium bicarbonate was added and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give the titled compound (312 mg) as a yellow oil.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH2:8][C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=1[CH2:11][P:12](=[O:17])([O:15][CH3:16])[O:13][CH3:14].[C:22](=[O:24])=[O:23].C(OCC)C>CCCCCC.O1CCCC1.O>[CH3:14][O:13][P:12]([CH:11]([C:10]1[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=1[CH2:8][O:7][CH3:6])[C:22]([OH:24])=[O:23])([O:15][CH3:16])=[O:17]
Reactant: O=C=O
Reactant: COCc1ccccc1CP(=O)(OC)OC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COCc1ccccc1C(C(=O)O)P(=O)(OC)OC
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
165 ml of a 1.6 M solution of n-butyllithium in hexane was added at (-65)° C. to 170 ml of absolute tetrahydrofuran. At this temperature a solution of 61 g of dimethyl 2-methoxymethylbenzylphosphonate (from Example 8) in 100 ml of tetrahydrofuran was dripped in. After 30 minutes the batch was poured into a (-60)° C. cold saturated solution (500 ml) of dry ice and diethyl ether. After the batch had been stirred for 10 minutes it was allowed to heat up to about 20° C. over a period of 4 hours. 300 ml of water was added and the organic phase was separated off and extracted three times, each time with 100 ml of 100 ml of 10% strength sodium carbonate solution. The combined aqueous phases were extracted twice, each time with 150 ml of diethyl ether, and the pH was adjusted to 1 with 2 N sulfuric acid. Extraction was carried out three times, each time with 150 m]of dichloromethane, the organic phases were dried, and the solvent was removed under reduced pressure. There remained 60 g of dimethylphosphone-(2-methoxymethylphenyl)-acetic acid as a yellow
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]2[C:25]3[C:24]([F:26])=[CH:23][C:22]([OH:27])=[C:21]([F:28])[C:20]=3[C:19]3[C:29]([CH3:36])=[N:30][N:31](C(C)(C)C)[C:18]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8]CC1C=CC=CC=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:16]2[C:25]3[C:24]([F:26])=[CH:23][C:22]([OH:27])=[C:21]([F:28])[C:20]=3[C:19]3[C:29]([CH3:36])=[N:30][NH:31][C:18]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: Cc1nn(C(C)(C)C)c2nc(-c3ccc(OCc4ccccc4)c(Cl)c3)c3c(F)cc(O)c(F)c3c12
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2nc(-c3ccc(O)c(Cl)c3)c3c(F)cc(O)c(F)c3c12
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 65 %

Procedure:
5-{3-Chloro-4-[(phenylmethyl)oxy]phenyl}-3-(1,1-dimethylethyl)-6,9-difluoro-1-methyl-3H-pyrazolo[3,4-c]isoquinolin-8-ol (0.010 g, 0.020 mmol) was dissolved in trifluoroacetic acid (0.5 mL) and stirred at room temperature for 1.3 h, then at 50° C. for 0.2 h and finally at 60° C. for 0.5 h. The mixture was then concentrated in vacuo to afford a residue which was purified by preparative HPLC to afford 5-(3-chloro-4-hydroxyphenyl)-6,9-difluoro-1-methyl-3H-pyrazolo[3,4-c]isoquinolin-8-ol as a yellow solid (0.0047 g, 0.013 mmol, 66% yield). 1H NMR (400 MHz, CD3OD): 7.47 (t, 1H), 7.28 (dt, 1H), 6.98 (d, 1H), 6.86 (dd, 1H), 2.82 (d, 3H); MS (EI) for C17H10ClF2N3O2: 362 (MH+), 394 (MNa+), 400 (MK+).
Reaction SMILES: C[O:2][C:3](=[O:24])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:20](=[CH:21][CH:22]=1)[O:19][C:11]1([CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12]1)[CH2:10][C:9]2=[O:23].Cl>CC(O)=O>[C:16]([N:13]1[CH2:14][CH2:15][C:11]2([CH2:10][C:9](=[O:23])[C:8]3[C:20](=[CH:21][CH:22]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:24])=[O:2])[CH:7]=3)[O:19]2)[CH2:12]1)(=[O:18])[CH3:17]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(C)=O)C1)O2
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)N1CCC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Yield: 58.9 %

Procedure:
(±)-(E)-3-[1′-Acetyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester (240 mg, 0.73 mmol) was hydrolyzed with HCl and AcOH following the procedure described in Example 1, Step A, giving (±)-(E)-3-[1′acetyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid as a white solid (135.5 mg, 0.43 mmol, 59%). The acid was treated with NH2OTHP according to the procedure described in Example 1, Step C, giving (E)-3-[1′-acetyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide as a light yellow solid (82 mg, 0.20 mmol, 46%). Finally, removal of THP protecting group following the procedure described in Example 2, Step D gave (±)-(E)-3-[1′-acetyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-hydroxy-acrylamide (64.2 mg, 97%) as a red solid.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH3:12].[CH2:13](O)C>[Pd]>[CH3:13][C:6]1[CH:7]=[CH:2][C:3]([O:11][CH3:12])=[CH:4][C:5]=1[NH2:8]
Reactant: CCO
Reactant: COc1cc([N+](=O)[O-])ccc1C
Agent: [Pd]
Product: COc1ccc(C)c(N)c1
Yield: 97 %

Procedure:
To a suspension of 2-methyl-5-nitroanisole F1 (1.54 g; 9.21 mmol) in absolute ethanol (15 mL) was added 10% Pd/C catalyst.(249 mg). The suspension was hydrogenated under a hydrogen filled balloon at atmospheric pressure and room temperature for 6.5 h. The reaction mixture was filtered through a Millex 0.45 micron filter and evaporated to dryness to provide 4-methyl-m-anisidine F2 (1.22 g; 8.89 mmol; 97% yield)
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH2:15][Cl:16])[C:9]2=[O:17])=[N:5][N:4]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1C=CC=CC=1>[F:19][C:2]([F:1])([F:18])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:12][CH2:11][N:10]([CH2:15][Cl:16])[C:9]2=[O:17])=[N:5][N:4]=1
Reactant: CCCCCC(=O)Cl
Reactant: O=C1N(CCl)CCC(O)N1c1nnc(C(F)(F)F)s1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCC(=O)OC1CCN(CCl)C(=O)N1c1nnc(C(F)(F)F)s1

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-chloromethyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Hexanoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield a solid residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-trifluoromethyl- 1,3,4-thiadiazol-2-yl)-3-chloromethyl-6-hexanoyloxy-2(1H)-pyrimidinone.