Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@@H:14]([NH:20][C:21]([C:23]1[O:24][C:25]3[CH:31]=[C:30](Br)[CH:29]=[CH:28][C:26]=3[CH:27]=1)=[O:22])[CH2:13]2.[OH-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[N:12]12[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19]1)[C@@H:14]([NH:20][C:21]([C:23]1[O:24][C:25]3[CH:31]=[C:30]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[CH2:2][OH:1])[CH:29]=[CH:28][C:26]=3[CH:27]=1)=[O:22])[CH2:13]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(Br)cc2o1
Reactant: OCc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(-c3ccccc3CO)cc2o1
Temperature: 82.5 °C

Procedure:
A mixture of 130 mg (0.86 mmol) of 2-(hydroxymethyl)phenylboronic acid, 200 mg (0.57 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzofuran-2-carboxamide (Example 2A), 1.72 ml (1.72 mmol) of 1N sodium hydroxide solution, 40 mg (0.06 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride and 2 ml of DMF is heated at 80-85° C. for 18 h. The solvent is removed under reduced pressure. The crude product is purified on silica gel 60 (Merck, Darmstadt; eluent: dichloromethane, dichloromethane/methanol 20:1, dichloromethane/methanol/ammonia 80:20:2). The solvent is removed under reduced pressure. Finally, the last residues of solvent are removed under high vacuum. 149 mg (63% of theory) of the title compound are isolated.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[F:24][C:25]1[C:30]([CH3:31])=[CH:29][C:28](B(O)O)=[CH:27][N:26]=1>>[F:24][C:25]1[N:26]=[CH:27][C:28]([C:2]2[N:10]3[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([N:18]5[CH2:19][CH2:20][O:21][CH2:22][CH2:23]5)=[CH:14][CH:13]=4)=[N:9]3)=[CH:4][CH:3]=2)=[CH:29][C:30]=1[CH3:31]
Reactant: Brc1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Reactant: Cc1cc(B(O)O)cnc1F
Product: Cc1cc(-c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)cnc1F

Procedure:
[7-(6-Fluoro-5-methyl-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was prepared from (7-bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-(4-morpholin-4-yl-phenyl)-amine and 2-fluoro-3-methylpyridine-5-boronic acid in an analogous manner to Example 1031b. Product isolated as a yellow solid (79 mg, 66%). m.p.=227-230° C.; LCMS (m/e) 405 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.71 (s, 1H), 8.62 (s, 1H), 8.56-8.49 (m, 1H), 7.51 (d, 2H, J=8.9 Hz), 6.99-6.90 (m, 3H), 6.83 (d, 1H, J=4.8 Hz), 6.68 (bs, 1H), 3.92-3.85 (m, 4H), 3.17-3.10 (m, 4H), 2.38 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH3:9][NH:10][CH3:11]>CCOCC>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([N:10]([CH3:11])[CH3:9])=[CH:4][CH2:3]1
Reactant: CN1CCC(=O)CC1
Reactant: CNC
Solvent: CCOCC
Product: CN1CC=C(N(C)C)CC1
Yield: 70 %

Procedure:
To 1000 g of Klinosorb-4 molecular sieve 500 ml of dry ether and 226 g of 1-methyl-4-piperidone are added and thereafter dimethylamine gas is bubbled into the reaction mixture with a rate allowing only slow reflux of the mixture in the initial period of the reaction. The dimethylamine gas is introduced into the reaction medium for 8 hours on three subsequent days, thereafter the mixture is filtered, the Klinosorb is washed with ether and the combined etheral solution is evaporated to dryness under reduced pressure. The oily residue is purified by distillation in vacum to yield 70% of 1-methyl-4-dimethylamino-1,2,5,6-tetrahydropyridine; bp.: 78°-82° C./2.66 kPa.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]2[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12]2)[CH:5]=[CH:4][N:3]=1.[N:24]1([C:29]([NH2:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1.O.CC(C)([O-])C.[Na+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[O:17]=[C:16]1[N:11]([CH2:10][CH2:9][O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:31][C:29]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:30])[CH:7]=2)[N:12]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:15]1
Reactant: O=c1ccc(-c2ccccc2)nn1CCOc1ccnc(Cl)c1
Reactant: NC(=O)N1CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1cc(OCCn2nc(-c3ccccc3)ccc2=O)ccn1)N1CCCC1
Temperature: 90 °C
Reaction time: 17 h
Yield: 11.9 %

Procedure:
This procedure was based on the method described in Antonio Abad, Consuelo Agulló, Ana Carmen Cuñat, Cristina Vilanova Synthesis, 2005, 915. To a 10 mL round-bottomed flask was added 2-(2-(2-chloropyridin-4-yloxy)ethyl)-6-phenylpyridazin-3(2H)-one (0.10 g, 0.31 mmol), pyrrolidine-1-carboxamide (0.038 g, 0.34 mmol) (see John E. Barry, Manuel Finkelstein, Gudrun A. Hutchins and Sidney D. Ross Tetrahedron 1983, 39, 2151-2156 and Charles A. Weisel, Harry S. Mosher, and F. C. Whitmore J. Am. Chem. Soc. 1945, 67, 1055), p-dioxane (2.5 mL), H2O (0.0082 mL, 0.46 mmol) and sodium tert-butoxide (0.044 g, 0.46 mmol). The mixture was carefully evacuated and backfilled with N2. This was repeated 3 times. To the mixture was added 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.018 g, 0.031 mmol) and palladium(II) acetate (0.0034 g, 0.015 mmol). Once again the mixture was carefully evacuated and backfilled with N2. This was repeated 3 times. The mixture was then stirred at 90° C. After 17 h, the mixture was poured into aq. NaHCO3 (100 mL) and extracted with EtOAc(3×75 mL). The combined extracts were washed with water (100 mL) and brine (100 mL) and then dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (1.0 to 5.0% MeOH (2M in NH3)/CH2Cl2) afforded N-(4-(2-(6-oxo-3-phenylpyridazin-1(6H)-yl)ethoxy)pyridin-2-yl)pyrrolidine-1-carboxamide (0.015 g, 12% yield) as a yellow solid. MS (ESI, pos. ion.) m/z: 406 (MH+). Calc'd exact mass for C22H23N5O3: 405. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.77-1.86 (m, 4 H), 3.33-3.40 (m, 4 H), 4.46-4.55 (m, 4 H), 6.58 (dd, J=5.8, 2.4 Hz, 1 H), 7.07 (d, J=9.8 Hz, 1 H), 7.43-7.50 (m, 3H), 7.52 (d, J=2.3 Hz, 1 H), 7.84-7.89 (m, 2 H), 8.00 (d, J=5.7 Hz, 1 H), 8.05 (d, J=9.8 Hz, 1 H), 8.51 (s, 1 H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[C:14]([C:26]1[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][CH:27]=1)[CH:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=1)[CH2:16][CH3:17].[Br-].[Br-].[Br-].B.O>C(Cl)Cl>[CH3:1][NH:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)=[C:15]([C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)[CH2:16][CH3:17]
Reactant: CCC(C(=CCCCCCCCCCC(=O)NC)c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: B
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: CCC(=C(CCCCCCCCCCC(=O)NC)c1ccc(O)cc1)c1ccc(O)cc1
Reaction time: 1 h
Yield: 35.3 %

Procedure:
To the above dimethoxy amide 4 (117 mg, 0.22 mmol) in CH2Cl2 (1 ml) at 0° C. was added, under argon, 1.0M borane tribromide (675 μl). The solution was stirred for 1 hour, then poured into water and extracted with ether (3x). The organic solution was washed with water, dried on magnesium sulfate, and evaporated to dryness. The residue was purified by "Flash chromatography" on silica gel (Kieselgel 60, Merck, under 0.063 mm, 30 g). Elution with mixture of hexane-ethyl acetate (4:1 v/v) gave N-butyl, N-methyl-12,13-Bis (4-hydroxyphenyl)-12-pentadecenoic amide (EM-142, compound 5 with x=10) (34 mg, 31%), colorless oil, IR νmax (neat) 3300, 1600 cm-1 ; UV γmax (log ε)=235 (4.25) nm; 1H-NMR (δ, CDCl3), 0.76 (3H, t, J=7.3 Hz, --CH2CH3), 0.96 (3H, t, J=7.3 Hz, N (CH2)3CH3), 2.05-2.20 (4H, m, CH2 --C=C--CH2 --), 2.35 (2H, t, J=7.0 Hz, --CH2CON--), 2.97 and 3.00 (3H, s, --NCH3), 3.29 and 3.41 (2H, 2t, J=7.3 Hz, --N--CH2 --), and 6.59-7.09 (8H, m, H--Ar) ppm; MS m/e=493 (M+). ##STR76##
Reaction SMILES: [CH2:1]([NH:4][NH2:5])[CH:2]=[CH2:3].[CH3:6][C:7]([CH3:14])([CH3:13])[C:8](=O)[CH2:9][C:10]#[N:11]>>[CH2:1]([N:4]1[C:10]([NH2:11])=[CH:9][C:8]([C:7]([CH3:14])([CH3:13])[CH3:6])=[N:5]1)[CH:2]=[CH2:3]
Reactant: C=CCNN
Reactant: CC(C)(C)C(=O)CC#N
Product: C=CCn1nc(C(C)(C)C)cc1N

Procedure:
Allylhydrazine (70% in water, Wako) and 4,4-dimethyl-3-oxopentanenitrile (Aldrich) were processed as described for Example 30A to obtain the title compound. MS (ESI+) m/z 180 (M+H)−.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17]([S:20][CH3:21])=[N:18]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(Cl)Cl.ClC1C=CC=C(C(OO)=[O:33])C=1.C([O-])(O)=O.[Na+]>>[CH3:21][S:20]([C:17]1[N:16]=[CH:15][C:14]2=[CH:13][CH:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=3)[N:19]2[N:18]=1)=[O:33]
Reactant: CSc1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a Round bottom flask, 7-(4-Methanesulfonyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.630 g, 0.00197 mol) and Methylene chloride (50 mL, 0.8 mol) were added. m-Chloroperbenzoic acid (0.464 g, 0.00207 mol) was added portion wise. The reaction was stirred at room temperature for 30 minutes. Saturated NaHCO3 was added. The organic layer was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The organic was removed under vacuum. to give 2-Methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine a yellow solid (0.63 g, 93%). NMR 1H (DSMO-d6)-9.40 (s, 1H), 8.54 (d, 2H, J=8.60 Hz), 8.09 (d, 2H, J=7.56 Hz), 7.85 (d, 1H, J=4.84 Hz), 7.39 (d, 1H, J=4.88 Hz), 3.29 (s, 3H), 3.00 (s, 3H)
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]([OH:25])([CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)[CH:12]([CH3:18])[CH2:13][S:14]C(=O)C>CO>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C@@:11]([OH:25])([CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)[C@@H:12]([CH3:18])[CH2:13][SH:14]
Reactant: CC(=O)SCC(C)C(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](CS)[C@](O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reaction time: 0.17 h

Procedure:
Under nitrogen atmosphere at room temperature a solution of potassium hydroxide (0.266 g; 4,74 mmoles) in methanol (40 ml) was dropped into a solution of thioacetic acid S-[3-(2.4-dichlorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl] ester, prepared as described in Example 6 (1.72 g; 4.6 mmoles) in methanol (40 ml). After reacting for 10 minutes the reaction was quenched with 5% HCl (4 ml) diluted with water (20 ml), and the reaction mixture was concentrated under reduced pressure, then further diluted with water and extracted more times with methylene chloride. The anhydrification and evaporation of the collected organic phases yielded 1.6 g of a crude which was purified by flash chromatography of silica gel (eluent ethyl acetate:hexane=1:1). There was thus obtained 1.2 g (80%) of (2R,3R)-3-(2,4-dichlorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1-butanthiol as a light oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1>CCO.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: CC(C)(C)OC(=O)n1cccc1-c1cc(N)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC1c1cc(N)cc(C(F)(F)F)c1
Reaction time: 48 h
Yield: 89.8 %

Procedure:
To a solution of tert-butyl 2-[3-amino-5-(trifluoromethyl)phenyl]-1H-pyrrole-1-carboxylate (1.99 g, 6.10 mmol) in EtOH (25 mL) was added Pd (200 mg, 10% on carbon). The reaction mixture was allowed to stir for 2 d under an atmosphere of hydrogen. The reaction mixture was filtered through a pad of Celite and washed with EtOAc. The solvents were evaporated to give tert-butyl 2-[3-amino-5-(trifluoromethyl)phenyl]pyrrolidine-1-carboxylate (1.81 g, 90%) as a white solid. LCMS: (FA) ES+ 331.3.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1.[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([CH3:23])([CH3:22])[CH2:17][CH2:16][CH2:15]2.[Br:24]C1C=CC2C(=CC=CC=2)C=1Br.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:24][CH:15]1[C:14]2[C:19](=[CH:20][CH:21]=[C:12]([Br:11])[CH:13]=2)[C:18]([CH3:23])([CH3:22])[CH2:17][CH2:16]1
Reactant: CC1(C)CCCc2cc(Br)ccc21
Reactant: Brc1ccc2ccccc2c1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccc2ccccc2c1
Product: CC1(C)CCC(Br)c2cc(Br)ccc21

Procedure:
Employing the above-described procedure for the conversion of 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene naphthalene (Compound F) to the dibromonaphthalene derivative (Compond I), 3.5 g (14.6 mmol) of (Compound F), 2.86 g (16.1 mmol) of N-bromosuccinimide and 150 mg (0.62 mmol ) of benzoylperoxide gave crude 4,6-dibromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound I). To a solution of this crude dibromonaphthalene derivative (Compound I) in 50 ml of THF was added 5.38 g (47.1 mmol) of potassium thioacetate. The mixture was refluxed for 6 hours under argon atmosphere, filtered through celite and concentrated in vacuo. Purification by chromatography (silica, 10% EtOAc-hexane) yielded the title compound as red oil.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:19][CH:20]=[C:21]([Cl:23])[CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:31]=[CH:32][CH:33]=[CH:34][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:24]([OH:26])=[O:25])=[CH:19][CH:20]=[C:21]([Cl:23])[CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:31]=[CH:32][CH:33]=[CH:34][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2n1Cc1ccc(-c2cc(Cl)ccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2cc(Cl)ccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-benzimidazol-1-yl)-methyl]-5-chloro-biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O>>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]2[O:9][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[CH:5]=1
Reactant: Cc1ccc(O)c(C)c1
Reactant: O=C(CBr)c1ccccc1
Product: Cc1cc(C)c2occ(-c3ccccc3)c2c1

Procedure:
Using the method of Example 17 and starting with 2,4-dimethylphenol and α-bromoacetophenone and cyclizing at 50°-60° C., 5,7-dimethyl-3-phenylbenzofuran is obtained.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.CO.O.[OH-].[Li+].Cl>C1COCC1.O>[NH2:24][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:25])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)[CH:23]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cc(N)ccn3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2cc(N)ccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
To a solution of [6-(4-amino-pyridin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.13 g, 0.37 mmol in THF (5 mL) and methanol (2 mL) was added lithium hydroxide monohydrate (62 mg, 1.48 mmol) in water (2 mL) at 0° C. The temperature was allowed to warm up to room temperature. The reaction mixture was stirred at room temperature for 4 h. The pH was adjusted to 3 with aqueous HCl (6 N). Prep-HPLC purification (C18 column) gave the title compound (66 mg, 55%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.68 (1H, d), 7.16 (1H, d), 7.05 (1H, d), 6.44 (1H, dd), 5.88 (1H, s), 5.62 (1H, dd), 3.14 (1H, dd), 2.36 (3H, s), 2.30 (1H, m). MS found (electrospray): (M+H)+=315.1.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:20]=[CH:19][C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[C:6]([N+:21]([O-:23])=[O:22])[CH:5]=1.[CH2:24](I)[CH3:25].O>CN(C=O)C>[CH2:24]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:7]1[CH:19]=[CH:20][C:4]([F:3])=[CH:5][C:6]=1[N+:21]([O-:23])=[O:22])[CH3:25]
Reactant: CCI
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(F)cc2[N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(c1ccc(F)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 73.9 %

Procedure:
To a suspension of sodium hydride (60%, 0.05 g (1.25 mmol)) in DMF (2.0 ml), 4′-fluoro-2′-nitro-p-toluenesulfonanilide (0.31 g (1.00 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, ethyl iodide (0.30 ml (3.75 mmol)) was added dropwise. After 30 minutes' heating at 100° C. with stirring, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Diisopropyl ether was added to the residue and the solid separated was filtered and washed to give 0.25 g (74%) of the title compound as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>O1CCCC1>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([C:8]2[C:7]([O:9][CH3:10])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=2[O:2][CH3:1])=[O:19])=[CH:16][CH:15]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1cc(C)cc(OC)c1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2c(OC)cc(C)cc2OC)cc1
Reaction time: 3 h
Yield: 20.4 %

Procedure:
3,5-Dimethoxy toluene (1.00 g) obtained in Example 44 was dissolved in anhydrous tetrahydrofuran (10 ml), commercially available 2.5 M n-butyllithium-hexane solution (2.90 ml) was added at -45° C. under nitrogen, and the admixture was stirred for 3 hours. Commercially available 4-methoxybenzoyl chloride (1.23 g) was dissolved in tetrahydrofuran (10 ml), and the resulting solution was added slowly to the admixture at -45° C. The reaction mixture was stirred at room temperature for 1 hour and then partitioned between water and chloroform. The chloroform layer was dried with anhydrous magnesium sulfate, the solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (5/1) to obtain 384 mg of the title compound (yield: 20%).
Reaction SMILES: C([O:9][C@@H:10]1[C@@H:15]([CH2:16][C:17]([O:19]C)=[O:18])[C@@H:14]([O:21]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:30][O:31]C(=O)C2C=CC=CC=2)[O:12][C@H:11]1[O:40][CH2:41][C@H:42]([NH:77][C:78](=[O:96])[CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH3:95])[C@H:43]([O:59][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)/[CH:44]=[CH:45]/[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])(=O)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>ClCCl>[C:17]([CH2:16][C@H:15]1[C@@H:14]([OH:21])[C@@H:13]([CH2:30][OH:31])[O:12][C@@H:11]([O:40][CH2:41][C@H:42]([NH:77][C:78](=[O:96])[CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH3:95])[C@H:43]([OH:59])/[CH:44]=[CH:45]/[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[C@@H:10]1[OH:9])([OH:19])=[O:18]
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](CO[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H](CC(=O)OC)[C@H]1OC(=O)c1ccccc1)NC(=O)CCCCCCCCCCCCCCCCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@H](CO[C@@H]1O[C@H](CO)[C@H](O)[C@H](CC(=O)O)[C@H]1O)NC(=O)CCCCCCCCCCCCCCCCC
Temperature: 0 °C
Reaction time: 24 h
Yield: 77.9 %

Procedure:
The compound (6) (176 mg, 130 μmol) was dissolved in dichloromethane (3 ml), followed by cooling to 0° C. Tetrabutylammonium fluoride (TBAF, 188 μl) was added and the mixture was stirred at room temperature for 24 hours. After confirming the completion of the reaction using TLC (AcOEt/Hex=1/2), the reaction mixture was concentrated under reduced pressure and the residue was dissolved in methanol (5 ml). A catalytic amount of sodium methoxide was added and the mixture was stirred at 40° C. for 24 hours. Further, water was added, followed by stirring for 24 hours. After confirming the completion of the reaction using TLC (CHCl3/MeOH/H2O=5/4/1), the reaction mixture was neutralized with an ion-exchange resin Amberlite IR-120 (H+), followed by removing the resin by filtration. The filtrate and the washings were combined and concentrated under reduced pressure. The resulting syrup was purified by gel filtration (Sephadex LH-20, CHCl3/MeOH/H2O=5/4/0.7) to give a compound (1a) (78 mg, 90%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[O:6][C:7]2[C:13]([CH3:14])=[C:12]([CH3:15])[C:11]([O:16][C:17](=[O:19])[CH3:18])=[CH:10][C:8]=2[CH:9]=1)=[O:4].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:15][C:12]1[C:11]([O:16][C:17](=[O:19])[CH3:18])=[CH:10][C:8]2[CH:9]=[C:5]([C:3](=[O:4])[CH2:2][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[O:6][C:7]=2[C:13]=1[CH3:14]
Reactant: CC(=O)Oc1cc2cc(C(=O)CBr)oc2c(C)c1C
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Oc1cc2cc(C(=O)CN3CCOCC3)oc2c(C)c1C
Yield: 89.8 %

Procedure:
A solution of 2-bromo-1-(5-acetoxy-6,7-dimethyl-benzofuran-2-yl)-ethanone (47 mg) from Example 16, morpholine (15 mg), and potassium carbonate (25 mg) in acetone (10 mL) was stirred at room temperature for 30 min. It was then evaporated to dryness, and the residue was purified by silica gel column eluting with 5% MeOH in DCM to give 43 mg of acetic acid 6,7-dimethyl-2-(2-morpholin-4-yl-acetyl)-benzofuran-5-yl ester as an oil. Conversion into the HCl salt gave a yellow solid. 1H NMR (CDCl3, 300 MHz) δ: 7.60 (s, 1H), 7.20 (s, 1H), 3.78(s+t, 6H), 2.64(m, 4H), 2.50(s, 3H), 2.40(s, 3H), 2.20(s, 3H) ppm. 13C NMR (CD3OD, 75 MHz) (as HCl salt) δ: 180.94, 170.31, 153.65, 150.33, 147.19, 131.94, 124.33, 122.34, 116.04, 113.59, 63.74, 60.89, 53.28, 19.64, 12.18, 12.22 ppm. M/S 332 (M+H+).
Reaction SMILES: [NH2:1][C:2](=[S:10])[CH:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[CH2:12][C:13](=O)[CH3:14].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:14][C:13]1[N:1]=[C:2]([CH:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[S:10][CH:12]=1
Reactant: CC(=O)CCl
Reactant: CCOC(=O)C(C)C(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1nc(C)cs1
Temperature: 80 °C
Reaction time: 5 h
Yield: 92.9 %

Procedure:
A mixture of Intermediate 103 (6.6 g, 40.9 mmol) and chloroacetone (FLUKA, 3.27 mL, 40.9 mmol) in DMF (50 mL) was stirred at 80° C. for 5 h. Reaction mixture was cooled to room temperature, treated with NaHCO3 (150 mL) and extracted with ethyl ether (2×200 mL). Organic layer was washed with brine, dried over Na2SO4 and evaporated to give title compound (7.57 g, 38.0 mmol, 93% yield) as yellow oil. 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.19 (s, 1H), 4.23-4.06 (m, 3H), 2.31 (s, 3H), 1.48 (d, 3H), 1.16 (t, 3H). [ES+MS] m/z 200 (MH+). It was subsequently observed that this compound undergoes autooxidation at the stereogenic centre to form ethyl 2-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)propanoate. Once the presence of this compound had been observed, the compound was actively synthesised, hereinbelow described as Intermediate 106.