Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O>[OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
A reaction mixture (total volume 1.04 ml) containing 0.2 ml of purified SLDH (0.04 mg protein), 0.04 ml of 0.2M PMS, 0.1 ml of 0.4M D-sorbitol, 0.4 ml of 0.5M potassium phosphate buffer (pH 7.0) and 0.3 ml of water was incubated at 30° C. with gentle shaking. As a result, L-sorbose was formed at the rate of about 1.3 mg/hour.
Reaction SMILES: NCC([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[N:14][OH:15])[CH3:13])=[CH:8][C:7]=1[C:16](=[N:24][OH:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])=O.[OH-].[Na+]>>[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[N:14][OH:15])[CH3:13])=[CH:8][C:7]=1[C:16](=[N:24][OH:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23]
Reactant: CC(=NO)c1ccc(NC(=O)CN)c(C(=NO)c2ccccc2F)c1
Agent: [Na+]
Agent: [OH-]
Product: CC(=NO)c1ccc(N)c(C(=NO)c2ccccc2F)c1

Procedure:
10 g (26.26 mmol) of 2-amino-2'-[o-fluoro-α-(hydroxyimino)benzyl]-4'-[1-(hydroxyimino)ethyl]-acetanilide are treated with 3N sodium hydroxide at 50° for 1 hour. The pH of the solution is adjusted to 8 and the precipitated material is filtered off, washed with water and dried at 50° in vacuo over phosphorus pentoxide. There is obtained 2-amino-2'-fluoro-5-[1-(hydroxyimino)ethyl]benzophenone oxime as a foam of melting point ca 165°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[NH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: NCc1cccnc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc(Cl)nc1NCc1cccnc1
Temperature: -78 °C
Reaction time: 6 h

Procedure:
A solution of 2,4-dichloro-5-nitropyrimidine (40) (5 g) in methylene chloride (60 mL) was cooled to −78° C. and treated with 3-(aminomethyl)pyridine (2.8 g). The mixture was stirred at −78° C. for six hours, and concentrated in vacuo at RT to provide crude 2-chloro-5-nitro-N-(pyridin-3-ylmethyl)pyrimidin-4-amine (41), which was used without further purification.
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][O:13][C:12]1=[O:16])C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[OH:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][O:13][C:12]1=[O:16]
Reactant: O=C1OCCN1CCOCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C1OCCN1CCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
20% palladium hydroxide (138 mg) was added to a solution of 3-(2-benzyloxyethyl)oxazolidin-2-one (278 mg) in methanol (10 ml), and the mixture was stirred for 2 hours at room temperature under hydrogen atmosphere. The reaction solution was filtered through celite and then the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=90:10) to yield 3-(2-hydroxyethyl)oxazolidin-2-one (144 mg) as a colorless oil.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][N:9]2[C:18]3[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.I.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](SC)=[NH:27]>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[N:1]1([CH2:6][CH2:7][CH2:8][N:9]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:26]([C:22]4[S:21][CH:25]=[CH:24][CH:23]=4)=[NH:27])=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc2c(c1)CCCN2CCCN1CCCC1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(Nc1ccc2c(c1)CCCN2CCCN1CCCC1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
To a stirred solution of 1-(3-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-amine (115 mg, 0.443 mmol) in ethanol (6 ml) under argon was added methyl thiophene-2-carbimidothioate hydroiodide (253 mg, 0.887 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was then diluted with water and sodium carbonate and extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed on silica gel using ethyl acetate, followed by 5-10% (2M NH3 in methanol) in dichloromethane as eluent to give the desired N-(1-(3-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximidamide (119 mg, 0.323 mmol, 72.8% yield). 1H NMR (DMSO-d6) δ 7.67 (d, J=3.6 Hz, 1H), 7.55 (d, J=5 Hz, 1H), 7.06 (dd, J=5, 3.6 Hz, 1H), 6.58 (brs, 2H), 6.48 (s, 1H), 6.27 (brs, 2H), 3.26-3.17 (m, 4H), 2.66 (t, J=6.3 Hz, 2H), 2.45-2.40 (m, 6H), 1.89-1.81 (m, 2H), 1.70-1.62 (m, 6H). ESI-MS (m/z, %) 369 (MH+, 47), 185 (100). ESI-HRMS calculated for C21H29N4S (MH+), calculated: 369.2122, observed: 369.2107. HPLC purity: >95%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:11]1[N:12]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([S:40]([CH3:43])(=[O:42])=[O:41])[CH:35]=3)=[CH:30][CH:29]=2)[CH:13]=[C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][N:17]2C(OC(C)(C)C)=O)[N:15]=1)([CH3:10])[CH3:9].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:11]1[N:12]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([S:40]([CH3:43])(=[O:42])=[O:41])[CH:35]=3)=[CH:30][CH:29]=2)[CH:13]=[C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)[N:15]=1)([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(C(C)(C)c2ccccc2Cl)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(c1ccccc1Cl)c1nc(C2CCCN2)cn1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.4 %

Procedure:
A mixture of 1,1-dimethylethyl 2-{2-[1-(2-chlorophenyl)-1-methylethyl]-1-[3′-(methylsulfonyl)biphenyl-4-yl]-1H-imidazol-4-yl}pyrrolidine-1-carboxylate (200 mg) and 5 mL of 50% TFA in DCM was stirred at room temperature for 20 min. After concentrated in vacuo, the reaction mixture was separated by prep HPLC to give 2-[1-(2-chlorophenyl)-1-methylethyl]-1-[3′-(methylsulfonyl)biphenyl-4-yl]-4-pyrrolidin-2-yl-1H-imidazole (150 mg): 1H NMR (CD3OD): δ 1.6 (m, 3H,), 1.8 (m, 1H), 1.9 (s, 3H), 2.2-2.6 (m, 4H), 3.2 (s, 3H), 3.4 (m, 2H), 4.7 (m, 1H), 7.1 (m, 1H), 7.2 (m, 5H), 7.4 (s, 1H), 7.7 (m, 3H), 8.0 (m, 2H), 8.2 (m, 1H); LC/MS M+H 520 (observed).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH:9]([C:11](=[O:13])[CH3:12])[CH3:10])[CH:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.[Na+].[Na+].[Na+].P(C1C=C(S([O-])(=O)=O)C=CC=1)(C1C=C(S([O-])(=O)=O)C=CC=1)C1C=C(S([O-])(=O)=O)C=CC=1.C(NC(C)C)(C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:7](=[O:8])[N:6]([CH:9]([C:11](=[O:13])[CH3:12])[CH3:10])[CH:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1cc(Br)c(=O)n(C(C)C(C)=O)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(-c2ccc(F)cc2)c(=O)n(C(C)C(C)=O)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 5-bromo-6-oxo-1-(3-oxobutan-2-yl)-1,6-dihydropyridine-3-carboxylate (11.3 g, 37.4 mmol) in N,N-dimethylformamide (112 mL) and water (37 mL) were added 4-fluorophenylboronic acid (6.28 g, 44.9 mmol), palladium acetate (0.17 g, 0.75 mmol), 3,3′,3″-phosphinidynetris(benzenesulfonic acid) trisodium salt (1.28 g, 2.24 mmol) and diisopropylamine (13.3 mL, 94.0 mmol). The reaction mixture was heated to 80° C. After 30 min, the mixture was cooled to ambient temperature. Saturated aqueous sodium bicarbonate and water were added. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→80% dichloromethane/ethyl acetate) gave the title compound. MS 318.2 (M+1).
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][C:8]1([OH:16])[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.[NH2:25][NH2:26]>C(Cl)Cl.CO>[OH:16][C:8]1([CH2:7][C:6]([NH:25][NH2:26])=[O:5])[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)CC1(O)CN2CCC1CC2
Reactant: NN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: NNC(=O)CC1(O)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3.5 g of the compound of step (a) in 15 ml of methylene chloride was added trifluoroacetic acid (39 ml) and the mixture was stirred at ambient temperature for three hours. The mixture was then concentrated in vacuo. The residue was dissolved in methanol (30 ml) and 18M H2SO4 (3 ml) was added and the mixture was stirred overnight. The mixture was then poured into a solution of sodium carbonate in water, extracted three times with chloroform, dried over MgSO4, filtered and concentrated in vacuo to give a yellow solid. The solid was dissolved in methanol (10 ml) and hydrazine (2 ml) was added to this solution and the mixture was heated to reflux for one hour. The mixture was then concentrated in vacuo. The resulting solid was suspended in toluene (50 ml) and heated to reflux in an apparatus equipped with a Dean-Stark trap for two hours. The reaction mixture was then allowed to cool, and the product was filtered off to give 1.82 g of the subtitle compound as a tan solid.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][CH:10]([OH:21])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)C1C=CC=CC=1.ClCCl.C(=O)(O)[O-].[Na+].Cl[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]>[Pd].CO.O>[OH:21][CH:10]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH2:9][NH:8][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]
Reactant: COc1ccc(OCC(O)CN(Cc2ccccc2)Cc2ccccc2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1ccc(OCC(O)CNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
A mixture of 1-[bisbenzylamino]-3-(4-methoxyphenoxy)propan-2-ol (1.26 g, 3.74 mmol), as prepared in the preceding step, 10% palladium on carbon (125 mg) and methanol (120 mL) was degassed under reduced pressure and refilled with H2 gas several times. After stirring under 1 atm H2 balloon at room temperature overnight, the mixture was filtered through Celite and washed with methanol. The filtrate was concentrated to a white solid (0.78 g, 100%). This solid (0.78 g, 3.96 mmol) was dissolved in methanol (20 mL), dichloromethane (20 mL), and water (10 mL). To this solution were added sodium bicarbonate (0.83 g, 9.88 mmol) and benzyl chloroformate (0.7 mL, 4.66 mmol) at room temperature. After stirring for 4 hours, the solution was concentrated and the residue was partitioned between dichloromethane and water. The organic layer was dried (Na2SO4), concentrated, and flash chromatographed on silica gel to give the title compound as a white solid (1.00 g, 80.8%). 1H NMR (CDCl3) δ7.37-7.33 (m, 5 H), 6.83 (s, 4 H), 5.20 (m, 1 H), 5.12 (s, 2 H), 4.10 (m, 1 H), 3.94-3.88 (m, 2 H), 3.77 (s, 3 H), 3.53-3.47 (m, 1 H), 3.38-3.27 (m, 1 H), 2.95 (m, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)=[CH:4][CH:3]=1.Br[C:14]1[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Br:20])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.CO.CCOC(C)=O.O>[Br:20][C:18]1[CH:19]=[C:14]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:9][CH:10]([OH:12])[CH2:11]3)=[CH:6][N:7]=2)[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=1
Reactant: Nc1ccc(N2CC(O)C2)cn1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(Br)cc(Nc2ccc(N3CC(O)C3)cn2)c1=O
Temperature: 100 °C
Yield: 53.2 %

Procedure:
A sealed tube was equipped with a magnetic stirrer and charged with 128b (375 mg, 2.3 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (848 g, 3.2 mmol) and cesium carbonate (1.7 g, 5 mmol) in 1,4-dioxane (24 mL). After bubbling nitrogen through the solution for 30 min, Xantphos (160 mg, 0.3 mmol) and tris(dibenzylideneacetone) dipalladium(0) (150 mg, 0.2 mmol) were added, and the reaction mixture was heated to 100° C. for 5 days. After this time, H2O (20 mL) and EtOAc (20 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine (50 mL) and dried over sodium sulfate. The resulting residue was purified by column chromatography eluting with a gradient of CH2Cl2-9:1 CH2Cl2:MeOH to afford a 39% yield (430 mg) of 128c.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[C:5]([F:7])[CH:4]=[C:3]1[C:8]([O:10]C)=O.C(O/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])C.C1(C)C(S(O)(=O)=O)=CC=CC=1.CC(C)([O-])C.[Na+]>C(O)C.O>[F:7][C:5]1[CH:4]=[C:3]2[C:8]([OH:10])=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=[N:1][N:2]2[CH:6]=1
Reactant: CCO/C=C/C(=O)OCC
Reactant: COC(=O)c1cc(F)cn1N
Agent: CC(C)(C)[O-]
Agent: Cc1ccccc1S(=O)(=O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnn2cc(F)cc2c1O
Temperature: 85 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
A mixture of methyl 1-amino-4-fluoro-1H-pyrrole-2-carboxylate (0.980 g, 6.20 mmol), (E)-ethyl 3-ethoxyacrylate (1.25 g, 8.68 mmol) and toluenesulfonic acid (0.059 g, 0.310 mmol) in ethanol (15 mL) was heated at 85° C. for 2 h then at reflux (100° C. bath) for an additional 2 h. The mixture was cooled and concentrated to remove the ethanol/water and additional ethanol was added and reconcentrated. The process was repeated until all of the water had been removed then residue was dissolved in ethanol (15 mL) and sodium tert-butoxide (1.190 g, 12.39 mmol) was added to make orange clear solution. This mixture was heated at 85° C. for 1 h, then cooled and concentrated to remove the ethanol and the reaction mixture was neutralized with HCl in dioxane (0.5 mL of 4N solution) then concentrated to afford a tan semi solid. This material was slurried in water and stirred for 1 h and the resulting solid was collected and rinsed with water and filtered and dried to afford the title compound (740 mg, 3.30 mmol, 53.3% yield) as a light yellow solid. HPLC (condition B): retention time=3.57 min. LCMS (condition B): m/z 224.9+ve.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Br[CH2:45][C:46]1[N:50]([CH3:51])[C:49]2[CH:52]=[CH:53][CH:54]=[CH:55][C:48]=2[N:47]=1.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:51][N:50]1[C:49]2[CH:52]=[CH:53][CH:54]=[CH:55][C:48]=2[N:47]=[C:46]1[CH2:45][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: Cn1c(CBr)nc2ccccc21
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: Cn1c(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)nc2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)-1-methyl-1H-benzo[d]imidazole to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1′-[(1-methyl-1H-benzimidazol-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (70%) as a colorless solid: mp 244-246° C.; 1H NMR (300 MHz, CDCl3) δ7.95-7.86 (m, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.49-7.40 (m, 2H), 7.32 (dd, J=7.6, 7.6 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.07 (dd, J=7.6, 7.6 Hz, 1H), 6.52-6.36 (m, 2H), 5.51 (ABq, 2H), 4.81 (ABq, 2H), 4.55 (t, J=8.6 Hz, 2H), 3.92 (s, 3H), 2.99 (t, J=8.6 Hz, 2H); MS (ES+) m/z 424.1 (M+1).
Reaction SMILES: BrBr.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH2:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:6][CH:5]=1>C(O)(=O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:6][CH:5]=1
Reactant: O=C1CC(c2ccncc2)C(c2ccc(F)cc2)=NN1
Agent: BrBr
Solvent: CC(=O)O
Product: O=c1cc(-c2ccncc2)c(-c2ccc(F)cc2)n[nH]1
Reaction time: 2 h

Procedure:
A solution of bromine (78.3 μl, 1.48 mmol) in acetic acid (6 ml) was added dropwise to a stirred solution of 6-(4-fluorophenyl)-4,5-dihydro-5-(4-pyridyl)-2H-pyridazin-3-one (314 mg, 1.17 mmol) in acetic acid (4.6 ml) at room temperature. After 2 h at room temperature, more bromine (41.7 μl, 0.78 mmol) in acetic acid (3.2 ml) was added to the turbid mixture. A gum precipitated. After 30 minutes, it was evaporated and co-evaporated with toluene. Residual acid was neutralized with methanolic 2N ammonia followed by evaporation. The resulting product was purified on a column of silica gel (3-5% methanol/dichloromethane) to provide the title compound as a solid. MS (m/z): 268.1 (M+H)+; C15H16FN3O requir. 267.3.
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[CH:13][N:12]=[C:11]([S:22][CH3:23])[N:10]=1)C)(C)(C)C>CO.Cl>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]1[C:9]([NH:7][CH3:6])=[N:10][C:11]([S:22][CH3:23])=[N:12][CH:13]=1
Reactant: CSc1ncc(-c2ccccc2Cl)c(N(C)C(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: CO
Product: CNc1nc(SC)ncc1-c1ccccc1Cl
Yield: 98.4 %

Procedure:
A solution of 2.40 g (6.5 mmol) [5-(2-chloro-phenyl)-2-methylsulfanyl-pyrimidin-4-yl]-methyl-carbamic acid tert-butyl ester in 30 ml MeOH/HCl (2N) was stirred at 55° for 3 hrs. After evaporation of the solvent, the residue was distributed between 40 ml 1N NaOH and 40 ml CH2Cl2. The phases were separated, the aqueous layer washed twice with 50 ml CH2C2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/ethyl acetate 19:1) to give 1.70 g (97%) [5-(2-chloro-phenyl)-2-methylsulfanyl-pyrimidin-4-yl]-methyl-amine as a white solid, MS (EI): 265 (M+).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(I)cc1
Reactant: OB(O)c1cccnc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2cccnc2)cc1
Yield: 79 %

Procedure:
By carrying out the operation analogously to example 1, starting from 4-iodophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation II, and 3-pyridineboronic acid, the expected product is obtained in the form of a yellow solid with a yield of 79%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:35][CH:36]([O:38][CH2:39][CH2:40][CH2:41][NH2:42])[CH3:37]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:42][CH2:41][CH2:40][CH2:39][O:38][CH:36]([CH3:37])[CH3:35])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC(C)OCCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Product: CC(C)OCCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-[(1-methylethyl)oxy]-1-propanamine using methods similar to Example 563 to provide a white solid: ES+ MS: 539 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29]C)=[O:28])=[C:22]([F:31])[CH:21]=1)[CH3:2].O[Li].O.CC(=O)OCC>C1COCC1.O>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[C:22]([F:31])[CH:21]=1)[CH3:2]
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)OC)c(F)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)O)c(F)c1
Temperature: 60 °C
Reaction time: 10 h
Yield: 86.7 %

Procedure:
To a solution of methyl 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetate (210 g, 519 mmol) in THF (500 mL) was added a solution of LiOH.H2O (52 g, 1.23 mol) in H2O (700 mL). The mixture was stirred at 60° C. for 10 h. TLC (PE/EA=5:1, Rf=0.3) showed the reaction was finished. The mixture was concentrated and neutralized with 1.0 M HCl to pH=7.0. Then the mixture was filtered, and the solid was washed with water and dry in vacuo to give 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (183.3 g, 0.45 mol, 93% yield): 1H NMR (400 MHz, CD3OD) δ 7.94 (s, 1H), 7.41-7.28 (m, 3H), 7.24 (d, J=9.6 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 6.44 (s, 1H), 5.26 (s, 2H), 4.11 (q, J=6.8 Hz, 2H), 3.78 (s, 3H), 3.67 (s, 2H), 1.36 (t, J=7.2 Hz, 3H); ES-LCMS m/z 412 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][C:35](=O)[N:34]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:33]=3[CH:44]=2)=[CH:7][CH:6]=1)=[O:4].[BH4-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][CH2:35][N:34]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:33]=3[CH:44]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(C(=O)OC)cc3)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(C(=O)OC)cc3)cc21
Temperature: 60 °C
Reaction time: 19 h

Procedure:
A solution of 3.92 g of benzyl 4-(4-methoxycarbonylphenyl)-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 255d) in 50 ml of chloroform is admixed under argon with 4.27 g of tetrabutylammonium borohydride. The reaction solution is stirred at 60° C. over 19 hours and subsequently cooled to room temperature. 10 ml of 2N HCl and 50 ml of water are subsequently added dropwise. The suspension is stirred at room temperature over 10 minutes. The reaction mixture is poured onto 150 ml of aqueous sodium hydrogencarbonate solution and extracted with 800 ml of tert-butyl methyl ether. The organic phase is washed with 100 ml of water and 50 ml of brine, dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.19 (2:1 EtOAc-heptane); Rt=5.34.