Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:22])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:18](=[CH:19][CH:20]=1)[O:17][C:11]1([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12]1)[CH2:10][C:9]2=[O:21].Cl>CC(O)=O>[CH3:16][N:13]1[CH2:14][CH2:15][C:11]2([CH2:10][C:9](=[O:21])[C:8]3[C:18](=[CH:19][CH:20]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:22])=[O:2])[CH:7]=3)[O:17]2)[CH2:12]1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C)C1)O2
Agent: Cl
Solvent: CC(=O)O
Product: CN1CCC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Yield: 97.1 %

Procedure:
(±)-(E)-3-[1′-Methyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester (105 mg, 0.35 mmol) was hydrolyzed with HCl and AcOH following the procedure described in Example 1, Step A, giving (±)-(E)-3-[1′-methyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid (110 mg, 0.34 mmol, 98%) as a white solid (hydrochloride salt). The acid was treated with NH2OTHP according to the procedure described in Example 1, Step C, to give (E)-3-[1′-methyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (90 mg, 0.23 mmol, 68%). Finally, removal of THP protecting group following the procedure described in Example 2, Step D and purification by preparative HPLC gave (±)-(E)-3-[1′-methyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-hydroxy acrylamide (30.5 mg, 31%) as its trifluoroacetic salt.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]=[N+]=[N-])=[CH:11][CH:10]=1.O>C1COCC1>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])=[CH:11][CH:10]=1
Reactant: COc1ccc(CCCCN=[N+]=[N-])cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CCCCN)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
Lithium aluminum hydride (55 mL of a 1M solution in THF, 0.055 mol) was added drop wise to a solution of II (7.6 g, 0.037 mol) in dry THF (70 mL) at 0° C. and stirred overnight at room temperature in an argon atmosphere. The reaction mixture was treated with water (1.5 mL), then 15% NaOH (1.5 mL), then with more water (3 mL) and filtered. The solid precipitate was washed with THF. The combined organic fractions were dried over magnesium sulfate and the solvent was removed under reduced pressure to give 6.2 g (94%) of III. The purity of III (99%) was determined by GC. 1H NMR (360 MHz, DMSO-d6) δ 1.34 (m, 2H), 1.54 (m, 2H), 2.51 (m, 4H), 3.70 (s, 3H), 6.83 (d, J=8.6 Hz, 2H), 7.08 (d, J=8.3 Hz, 2H), 13C (90 MHz, DMSO-d6) δ 28.6, 330, 34.1, 41.5, 54.8, 113.1, 129.1, 132.2, 157.3
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]1[N:18]2[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:17]2[N:16]=[CH:15][C:14]=1[C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26].[CH:39]1([S:42]([NH2:45])(=[O:44])=[O:43])[CH2:41][CH2:40]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][C:3]=1[NH:12][C:13]1[N:18]2[N:19]=[CH:20][C:21]([C:22]([NH:45][S:42]([CH:39]3[CH2:41][CH2:40]3)(=[O:44])=[O:43])=[O:23])=[C:17]2[N:16]=[CH:15][C:14]=1[C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:29][CH2:28]1)=[O:26]
Reactant: NS(=O)(=O)C1CC1
Reactant: Cc1ccc(C(F)(F)F)cc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Product: Cc1ccc(C(F)(F)F)cc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)NS(=O)(=O)C3CC3)cnn12
Yield: 45.4 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-methyl-5-trifluoromethylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (100 mg, 0.19 mmol) obtained in step 2 and cyclopropanesulfonamide (115 mg, 0.95 mmol), the title compound (54 mg, 45%) was obtained.
Reaction SMILES: O=S(Cl)Cl.[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[C:14]=1[F:15])[C:9]([OH:11])=[O:10].[CH3:19][CH2:20]O>>[CH2:19]([O:10][C:9](=[O:11])[C:8]1[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[C:14]([F:15])=[C:6]([Br:5])[CH:7]=1)[CH3:20]
Reactant: CCO
Reactant: O=C(O)c1cc(Br)c(F)c([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(Br)c(F)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
SOCl2 (33.7 g, 0.283 mol) was added dropwise to a solution of 3-bromo-4-fluoro-5-nitro-benzoic acid (37.4 g, 0.142 mol) in EtOH (300 mL). The reaction mixture was refluxed overnight, cooled to RT and subsequently concentrated under reduced pressure. The residue was dissolved in EtOAc (300 mL), washed twice with water (50 mL), dried (Na2SO4) and concentrated to give the title compound as yellow solid. 1H-NMR (300 MHz, CDCl3): δ (ppm) 8.65 (m, 1H), 8.53 (m, 1H), 4.46 (m, 2H), 1.45 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH2:15][CH3:16])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[OH:17].[F:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=O.N1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[CH2:15]([CH:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:1]=[C:21]([C:20]4[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:19]=4[F:18])[O:17][C:3]=3[CH:4]=2)=[N:13][NH:12][C:11](=[O:14])[CH2:10]1)[CH3:16]
Reactant: CCC1CC(=O)NN=C1c1ccc(N)c(O)c1
Reactant: COc1ccc(C(=O)Cl)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Solvent: c1ccncc1
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OC)cc3F)oc2c1

Procedure:
200 mg (857 μmol) 6-(4-amino-3-hydroxy-phenyl)-5-ethyl-4,5-dihydro-2H-pyridazin-3-one are refluxed together with 170 mg (901 μmol) 2-fluoro-4-methoxybenzoyl chloride, 70 mg (885 μmol) pyridine, 160 mg (841 μmol) para-toluenesulphonic acid monohydrate and 5 ml xylene for 4 h. The reaction mixture is evaporated down completely i.V. and the residue is crystallised from acetonitrile.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:23][C:22]3[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:21]=3[CH:20]=2)=[CH:15][CH:14]=1.[Al+3].[Cl-].[Cl-].[Cl-]>>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:23][C:22]3[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:21]=3[C:20]=2[C:6]([C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=2)=[O:7])=[CH:15][CH:14]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(C)cc2)cc1
Yield: 66.1 %

Procedure:
In a manner similar to that used in Preparation 3, 2.32 g (15 mmol) of 4-methylbenzoyl chloride, 2 g (7.4 mmol) of 2-(4-methoxyphenyl)-6-methoxybenzo[b]thiophene, and 5.3 g (40 mmol) of AlCl3 were converted to 1.9 g of the title compound, crystallized from Et2O and isolated as a light yellow powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=O)[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26]C)=[O:25])=[C:12]2[C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].O.Cl>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([OH:26])=[O:25])=[C:12]2[C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(-c2ccc(C)cc2)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(C2=C(C(=O)O)N(CC(C)C)Cc3ccc(OCc4ccccc4)cc32)cc1
Yield: 90.1 %

Procedure:
To a suspension of methyl 6-benzyloxy-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (6.83 g, 15 mmol) in methanol (50 ml) was added an aqueous solution (20 ml) of lithium hydroxide monohydrate (1.89 g, 45 mmol). The obtained mixture was refluxed under heating for 24 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals was recrystallized from ethyl acetate-diisopropyl ether to give 6-benzyloxy-2-isobutyl-4-(4-methylphenyl)-3-isoquinolinecarboxylic acid (5.78 g, 87.3%) as crystals.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.[CH3:18][O:19][CH:20]([C:24]([NH:26][CH2:27][C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[O:25])[C:21](O)=[O:22]>>[CH3:18][O:19][CH:20]([C:24]([NH:26][CH2:27][C:28]([F:33])([F:34])[C:29]([F:30])([F:31])[F:32])=[O:25])[C:21]([NH:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2)=[O:22]
Reactant: COC(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Reactant: N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Product: COC(C(=O)NCC(F)(F)C(F)(F)F)C(=O)NC1C(=O)Nc2ccccc2-c2ccccc21

Procedure:
(S)-7-Amino-5H,7H-dibenzo[b,d]azepin-6-one was coupled with 2-methoxy-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid in analogy to the description in examples 65 and 66 to yield (−)-2-methoxy-N-(6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide as white solid,
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]12[CH2:24][O:23][CH:22]([OH:25])[CH:9]1[C:10](=[O:21])[N:11]([C@@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>O1CCCC1.C(O)C>[C:1]([O:5][C:6]([C@@:8]1([CH2:24][OH:23])[CH:9]([CH2:22][OH:25])[C:10](=[O:21])[N:11]([C@@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)COC(O)C2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@H](c1ccccc1)N1C[C@@](CO)(C(=O)OC(C)(C)C)C(CO)C1=O
Reaction time: 5.5 h
Yield: 43.4 %

Procedure:
To a cooled solution (−20° C.) of (3aS)-1-hydroxy-6-oxo-5-[(R)-1-phenylethyl]tetrahydrofuro[3,4-c]pyrrole-3a-carboxylic acid tert-butyl ester (350 mg, 1.01 mmol) in tetrahydrofuran and ethanol (10 mL; 4:1), sodium borohydride (38.0 mg, 1.00 mmol) was added portionwise, and the mixture was stirred at the same temperature for 5.5 h. The reaction mixture was concentrated in vacuo and taken up in AcOEt and water. The layers were separated and the aqueous layer extracted with AcOEt. The combined extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 90% AcOEt in hexane to afford the title compound (153 mg) as a colorless oil.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:36][CH3:37])=[C:18]([S:20]([O:23][C:24]2[CH:25]=[C:26]([CH:32]=[C:33]([CH3:35])[CH:34]=2)[O:27][CH2:28][CH2:29][CH2:30][OH:31])(=[O:22])=[O:21])[CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:58]1[C:62](=[O:63])[C:61]2=[CH:64][CH:65]=[CH:66][CH:67]=[C:60]2[C:59]1=[O:68]>O1CCCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:36][CH3:37])=[C:18]([S:20]([O:23][C:24]2[CH:25]=[C:26]([CH:32]=[C:33]([CH3:35])[CH:34]=2)[O:27][CH2:28][CH2:29][CH2:30][O:31][N:58]2[C:59](=[O:68])[C:60]3=[CH:67][CH:66]=[CH:65][CH:64]=[C:61]3[C:62]2=[O:63])(=[O:21])=[O:22])[CH:19]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Oc1cc(C)cc(OCCCO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1S(=O)(=O)Oc1cc(C)cc(OCCCON2C(=O)c3ccccc3C2=O)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
Diethyl azodicarboxylate (0.16 mL, 0.95 mmol) was added dropwise over 6 min to 3-[3-(5-chloro-2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propanol (0.31 g, 0.79 mmol, prepared in the preceding step), triphenylphosphine (0.25 g, 0.93 mmol) and N-hydroxyphthalimide (0.13 g, 0.80 mmol) in anhydrous tetrahydrofuran (7.9 mL) at 0° C. under a nitrogen atmosphere. The solution was stirred 0° C. for an adddional 15 min then at ambient temperature overnight. The reaction mixture was concentrated, and the crude product was purified by flash column chromatography (1% acetone in dichloromethane) to give the title compound (0.417 g, 99%) as a colorless foam. 1H-NMR (300 MHz, CDCl3) δ7.88-7.75 (m, 5H), 7.56 (dd, 1H, J=8.9, 2.7 Hz), 7.05 (d, 1H, J=8.9 Hz), 6.64 (br s, 1H), 6.57 (br s, 1H), 6.43 (t, 1H, J=2 Hz), 4.37 (t, 2H, J=6.1 Hz), 4.12 (t, 2H, J=6.2 Hz), 4.03 (s, 3H), 2.28 (s, 3H), 2.19 (pentet, 2H, J=6.1 Hz). Mass spectrum (MALDI-TOF, gentisic acid matrix) calcd. for C25H22ClNO8S: 554.1 (M+Na). Found: 553.7.
Reaction SMILES: [CH3:1][C:2]([C:5]([CH3:13])([CH2:10][CH:11]=C)[C:6]([O:8][CH3:9])=[O:7])([CH3:4])[CH3:3].[O:14]=[O+][O-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH3:1][C:2]([C:5]([CH3:13])([CH2:10][CH:11]=[O:14])[C:6]([O:8][CH3:9])=[O:7])([CH3:4])[CH3:3]
Reactant: C=CCC(C)(C(=O)OC)C(C)(C)C
Reactant: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(C)(CC=O)C(C)(C)C
Temperature: 25 °C
Yield: 76 %

Procedure:
A solution of the olefinic ester, methyl 2-(1,1-dimethylethyl)-2-methyl-4-pentenoate (2.76 g, 15 mmol), in dry CH2Cl2 (60 mL) was reacted with ozone at -78° C. When excess ozone was observed (blue coloration), nitrogen was bubbled through the solution, and Ph3P (5.90 g, 22.5 mmol) was added in one portion while stirring. The system was allowed to warm to room temperature (ca. 2 h) and stirred for 2 more hours. The solvent was removed in vacuo and the residue triturated with hexanes (150 mL). The precipitated Ph3PO (ca. 5.78 g) was filtered off and the filtrate concentrated in vacuo to give 2.80 g of the crude product as a colorless viscous residue. Flash chromatography over silica gel (hexanes-EtOAc, 19:1) afforded 2.12 g (76%) of the aldehyde as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)=[O:15])[CH:13]=1)[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=[N:40]C=2C=1.C(N(CC)C(C)C)(C)C.O.[NH4+]>CN(C)C=O.O>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)=[O:15])[CH:13]=1)[C:8]([NH2:40])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)c1
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(N)=O)cc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 34.8 %

Procedure:
To a stirred solution of 3-(tert-butyl)-5-(4-(4-chlorophenoxy)piperidine-1-carbonyl)benzoic acid (30 mg, 0.072 mmol, Step-1), EDC (21 mg, 0.11 mmol), HOBT (17 mg, 0.11 mmol), and N,N-diisopropylethylamine (0.28 mL, 1.61 mmol) in N,N-dimethylformamide (3 mL) was add 25% ammonium water (1 mL) at room temperature. After stirring at 60° C. for 2 hours, the mixture was poured into water (5 mL). This was extracted with ethyl acetate (5 mL) and washed with water (5 mL). The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (NH-gel, eluting with ethyl acetate) and then preparative LC-MS to give 10.4 mg (35% yield) of the title compound.
Reaction SMILES: N[C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:12][B-](F)(F)F.N#[O+]>C(Cl)Cl>[Br:8][C:6]1[CH:7]=[C:2]([F:12])[C:3]([C:9]([NH2:11])=[O:10])=[N:4][CH:5]=1
Reactant: NC(=O)c1ncc(Br)cc1N
Reactant: F[B-](F)(F)F
Agent: N#[O+]
Solvent: ClCCl
Product: NC(=O)c1ncc(Br)cc1F
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 3-amino-5-bromopyridine-2-carboxamide (40.0 g, 185.2 mmol) in CH2Cl2 was added nitrosonium tetrafluoroborate (22.71 g, 191.4 mmol). The reaction was stirred at room temperature for 4.5 hours, then concentrated in vacuo and azeotroped with toluene. The residue was suspended in toluene (1100 mL) and heated to 100° C. for 2 hours. The reaction was concentrated in vacuo, and the residue suspended in CH2Cl2. The solid was collected to provide 5-bromo-3-fluoropyridine-2-carboxamide that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 219.1 for M+H+(79Br).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH3:14])[C:10](=[O:15])C(C#N)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:19]([OH:22])(=[O:21])[CH3:20]>>[C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH3:14])[C:10](=[O:15])[C:20]([C:19]([OH:22])=[O:21])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cn1c(=O)c(C#N)nn(-c2ccccc2)c1=O
Reactant: CC(=O)O
Agent: Cl
Product: Cn1c(=O)c(C(=O)O)nn(-c2ccccc2)c1=O
Temperature: 120 °C
Yield: 45.7 %

Procedure:
Intermediate d (7.6 g, 0.033 mol) was added to a mixed solvent of glacial acetic acid (100 mL) and HCl (72 mL, 0.86 mol). The mixture was warmed up to 120° C. and reacted under reflux for 4 h. The solvent was evaporated off. To the obtained fraction was added water (400 mL). The mixture was filtered by suction and dried to produce a solid (3.7 g) in a yield of 45.7%.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11](Br)=[C:10]([CH3:16])[CH:9]=1)(=[O:3])[CH3:2].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:31]2[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=2)=[C:10]([CH3:16])[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]1Oc1cc(C)c(Br)c(C)c1
Reactant: OB(O)c1cccnc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(C)c(-c2cccnc2)c(C)c1
Yield: 45 %

Procedure:
By carrying out the operation analogously to example 13, starting from 4-bromo-3,5-dimethylphenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation III, and 3-pyridineboronic acid, the expected product is obtained in the form of a colorless foam with a yield of 45%.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]([C@@H:11]2[CH2:15][C@@H:14]([OH:16])[CH2:13][NH:12]2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(=O)([O-])[O-].[K+].[K+].Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.C(N(CC)CC)C>[Br-].C([N+](CC)(CC)CC)C.C(OCC)(=O)C.[Cu](I)I.O.CN(C)C=O>[CH:1]1([CH2:7][NH:8][C:9]([C@@H:11]2[CH2:15][C@@H:14]([OH:16])[CH2:13][N:12]2[C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: O=C(NCC1CCCCC1)[C@@H]1C[C@@H](O)CN1
Agent: I[Cu]I
Agent: CC[N+](CC)(CC)CC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NCC1CCCCC1)[C@@H]1C[C@@H](O)CN1c1ccc(C(F)(F)F)cn1
Temperature: 100 °C

Procedure:
A mixture of (2S,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid cyclohexylmethyl-amide; hydrochloride (75 mg, 0.285 mmol), dichlorobis(tri-o-tolylphosphine) palladium (II) (11 mg, 0.014 mmol), copper iodide (2.7 mg, 0.014 mmol), potassium carbonate (78.8 mg, 0.57 mmol), tetraethylammonium bromide (10.2 mg, 0.048 mmol) and 2-bromo-5-trifluoromethylpyridine (64.4 mg, 0.285 mmol) is evacuated and filled with Argon three cycles. Triethylamine (0.16 mL, 1.14 mmol), N,N-dimethylformamide (1 mL) and water (0.1 mL) are added and the reaction mixture is heated to 100° C. under Argon atmosphere for 22 h. The reaction is diluted with ethyl acetate and concentrated. The residue is purified by flash chromatography on silica eluting with methanol/dichloromethane which provides the title compound, m/z 372 [M+H+].
Reaction SMILES: [CH:1]([O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[CH3:14])([CH3:3])[CH3:2].Cl.[NH2:16][OH:17].C([O-])([O-])=O.[Na+].[Na+]>CCO.CCOC(C)=O>[CH:1]([O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([CH:9]=[N:16][OH:17])=[CH:7][C:6]=1[CH3:14])([CH3:3])[CH3:2]
Reactant: Cc1cc(C=O)cc(C)c1OC(C)C
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(C=NO)cc(C)c1OC(C)C

Procedure:
4-(Isopropoxy)-3,5-dimethylbenzaldehyde (1.98 g, 10.3 mmol) in EtOH (60 mL) was heated to 60° C. with hydroxylamine hydrochloride (2.4 M aq. solution, 5.2 mL, 1.2 eq.) and Na2CO3 (1.2 M solution, 5.2 mL, 0.6 eq.) at room temperature for 2 hours. The reaction was transferred to a separatory funnel, diluted with EtOAc; the organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated to yield 710 mg (3.24 mmol) of 4-(isopropoxy)-3,5-dimethylbenzaldehyde oxime as a light yellow oil. 1H-NMR (500 MHz, CDCl3): 8.10 (s, 1H), 7.23 (s, 2H), 4.29-4.18 (m, 1H), 2.29 (s, 6H), 1.29 (d, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[C:16]([O:23][CH2:24][CH:25]1[O:27][CH2:26]1)[CH:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([NH2:43])([CH3:42])([CH3:41])[CH3:40]>CO>[C:39]([NH:43][CH2:26][CH:25]([OH:27])[CH2:24][O:23][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:22])[CH:21]=[C:12]([C:11]3[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:10]=3)[O:13]2)=[CH:18][CH:17]=1)([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)N
Reactant: O=c1cc(-c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)oc2cc(OCC3CO3)ccc12
Solvent: CO
Product: CC(C)(C)NCC(O)COc1ccc2c(=O)cc(-c3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)oc2c1

Procedure:
3′,4′-Dibenzyloxy-7-(2,3-epoxy-propoxy)-flavone, 29 (2.5 g, 4.9 mmol) and tert-butyl amine (1.05 mL, 9.8 mmol) in dry methanol (160 mL) were reacted in a similar manner to that described under 34 to afford 37. Yield 2.4 g (85%); mp 159-161° C.; MS (FAB) 580 (M+1); IR (KBr) 3400, 1633; 1H NMR (200 MHz, CDCl3) δ 8.08 (d, J=8.7 Hz, 1H), 7.50-7.28 (m, 12H), 7.02-6.93 (m, 3H), 6.60 (s, 1H), 5.23 (s, 4H), 4.10-3.98 (m, 3H), 2.90 (dd, J=5.9 Hz, 3.8 Hz, 1H), 2.71 (dd, J=5.9 Hz, 7.3 Hz, 1H), 2.47 (s, 2H), 1.14 (s, 9H). Analysis Calcd for C36H37NO6: C, 74.59; H, 6.43; N, 2.42 Found: C, 73.36; H, 6.62; N, 2.39.
Reaction SMILES: ClC(Cl)C(O)=O.[NH2:7][C:8](=[O:37])[CH:9]([OH:36])[CH:10]([NH:18][C:19](=[O:35])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[C:26]1[NH:30][C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[N:27]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+].[Cl-].C([O-])(O)=O.[Na+]>CS(C)=O.C(Cl)CCl>[NH2:7][C:8](=[O:37])[C:9](=[O:36])[CH:10]([NH:18][C:19]([C:20]1[C:21]([C:26]2[NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[N:27]=2)=[N:22][CH:23]=[CH:24][CH:25]=1)=[O:35])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-c1nc2ccccc2[nH]1
Agent: O=C(O)C(Cl)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CS(C)=O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)c1cccnc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 60.5 %

Procedure:
160 mg of EDC and 36 μL of 2,2-dichloroacetic acid were added to 42 mg N-(4-amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(1H-benzo[d]imidazol-2-yl)nicotinamide (0.096 mmol) in 2 ml of dry dimethylsulfoxide (DMSO), and the reaction mixture stirred for 25 minutes at room temperature. For work up the reaction mixture was mixed with 40 ml of NaCl solution and sat. NaHCO3 (1:1) for 10 minutes. The resulting solid was filtered off with suction, washed with water and dried. 24 mg of the title compound were obtained as lightgrey amorphous solid.