Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]=[CH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C:6]([NH:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)CCc1c[nH]c2ccc(C=NNC(=O)OC(C)(C)C)cc12
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCc1c[nH]c2ccc(CNNC(=O)OC(C)(C)C)cc12
Temperature: 87 °C
Reaction time: 18 h
Yield: 90.5 %

Procedure:
A 50 ml pressure vessel is charged with N′-[3-(2-Dimethylamino-ethyl)-1H-indol-5-ylmethylene]-hydrazinecarboxylic acid tert-butyl ester (Example 11; 1.20 g, 3.63 mmol), ethanol (18 ml), and the catalyst (5% Pd/C type E-4522, 240 mg). The vessel is sealed, purged with argon (three times and hydrogen (three times), heated in an oil bath to 87° C., and then pressurized with hydrogen (43.4 bar). The stirrer is started (900 rpm), and the hydrogenation allowed to proceed for 18 hours. After cooling to ambient temperature the pressure vessel is vented, and the reaction mixture filtered over a pad of Hyflo to remove the catalyst. Removal of the solvent gives the product (1.092 g, 90.4%) as a pale yellow residue, which is pure by NMR. 1H-NMR (CD3OD, 300 MHz) δ 1.33 (s, 9H, C(CH3)3); 2.45 (s, 6H, N(CH3)2); 2.84-2.96 (m, 4H, CH2CH2NMe2); 3.88 (s, 2H, CH2N); 7.00 (br s, 1H, H-2); 7.02 (dd, 1H, J=8.3 Hz, J=1.5 Hz, H-6); 7.21 (d, 1H, H-7); 7.45 (s, 1H, H-4). 13C-NMR (CD3OD, 75 MHz) δ 23.69 (CH2); 29.11 (C(CH3)3); 45.03 (N(CH3)2); 57.94 (CH2N); 60.66 (CH2NMe2); 112.41 (C); 112.74 (CH); 120.30 (CH); 124.53 (CH); 128.89 (C); 129.15 (C); 138.17 (C); 162.32 (br, C═O).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][OH:11])=[CH:4][CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.CCCCCC>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[CH:10]=[O:11])=[CH:6][CH:7]=1
Reactant: OC/C=C/c1ccc(Br)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C/C=C/c1ccc(Br)cc1
Yield: 67 %

Procedure:
To the product of Example 7.1B (8.35 g, 39.2 mmol) dissolved in dichloromethane (151 mL) was added pyridinium dichromate (22.11 g, 58.8 mmol), and the resultant mixture was stirred for 16 hours at room temperature. A solution of hexane was added, and the resultant mixture filtered through diatomaceous earth, and then concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layers were combined, dried and then concentrated. The residue was purified by chromatography (silica gel, hexanes in ethyl acetate) which afforded 5.5 g, (67%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 9.62 (d, J=7.6 Hz, 1H), 7.57 (d, J=8.5 Hz, 2H), 7.42 (m, 3H), 6.70 (dd, J=15.9, 7.6 Hz, 1H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:12][O:13][C:14](=[O:24])[C@@H:15]([NH:17][CH2:18][CH:19]([O:22][CH3:23])[O:20][CH3:21])[CH3:16].C(=O)([O-])O.[Na+]>CC(C)=O.O>[CH3:12][O:13][C:14](=[O:24])[C@@H:15]([N:17]([C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3])[CH2:18][CH:19]([O:22][CH3:23])[O:20][CH3:21])[CH3:16]
Reactant: COC(=O)[C@H](C)NCC(OC)OC
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)[C@H](C)N(CC(OC)OC)C(=O)OCc1ccccc1
Yield: 72.4 %

Procedure:
Benzyl chloroformate (4.46 g, 24.8 mmol) was added at 0° C. to a mixture of (S)-2-(2,2-dimethoxy-ethylamino)-propionic acid methyl ester (4.75 g, 24.8 mmol) and sodium hydrogencarbonate (4.17 g, 49.7 mmol) in acetone (25 mL) and water (25 mL). The ice bath was removed, then after 2 h the reaction mixture was poured onto ice water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient afforded the title compound (5.84 g, 72%). Yellow oil, MS (ISP)=348.2 (M+Na)+.
Reaction SMILES: [CH:1]([C@H:14]1[CH2:19][C@@H:18](OS(C)(=O)=O)[CH2:17][CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>N([C@H]1CCO[C@@H](C(C2C=CC=CC=2)C2C=CC=CC=2)C1)=[N+]=[N-]>[N:25]([C@@H:18]1[CH2:17][CH2:16][O:15][C@@H:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:19]1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)O[C@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Agent: [N-]=[N+]=N[C@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Agent: [Na+]
Product: [N-]=[N+]=N[C@@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Yield: 80.6 %

Procedure:
Cis-2-diphenylmethylpyran-4-yl methanesulfonate 4b (0.38 g, 1.10 mmol) was reacted with sodium azide (0.29 g, 4.4 mmol) in dry DMF (Procedure B) to yield compound 5b (0.26 g, 80%) as a liquid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([OH:16])[C@H:12]([NH2:15])[CH2:13][F:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(Cl)Cl.[Cl:20][CH:21]([Cl:25])[C:22](Cl)=[O:23]>O>[Cl:20][CH:21]([Cl:25])[C:22]([NH:15][C@H:12]([CH2:13][F:14])[C@@H:11]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=1)[OH:16])=[O:23]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CF)cc1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Yield: 69.8 %

Procedure:
To a solution of (1R,2S)-1-[4-(methylsulfonyl)phenyl]-2-amino-3-fluoro-1-propanol (5 g, 0.02 moles) in methylene chloride (100 ml) triethylamine (3.0 g, 0.03 mole) and dichloro acetyl chloride (3.6 g; 0.025 mole) were added at 10–15° C. After completion of reaction in 30 minutes, water (10 ml) was added and layers were separated. Solvent was distilled off from reaction mass, toluene (25 ml) and water (5 ml) were added. The product thus precipitated was filtered, washed with methylene chloride (20 ml) and crystallized from ethanol/water (4:1) to give 5 g of the title compound with purity 99.5% by HPLC.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CC(C)([O-])C.[K+].[CH2:12]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:20][C@H:19]1[CH2:31][CH2:32][CH2:33]OS(C)(=O)=O)=[O:17])[CH:13]=[CH2:14].O>CN(C)C=O>[CH2:12]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])[CH2:20][C@H:19]1[CH2:31][CH2:32][CH2:33][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[O:17])[CH:13]=[CH2:14]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCCOS(C)(=O)=O
Reactant: c1c[nH]cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCCn1ccnc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
To a solution of imidazole (3.57 g) in dimethylformamide (100 ml) was added potassium t-butoxide (5.89 g) portionwise at room temperature and the mixture was stirred at the same temperature for 10 minutes. Then a solution of (2R,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-(3-methanesulfonyloxypropyl)pyrrolidine (20.1 g), in dimethylformamide (20 ml) was added and the mixture was heated at 60° C. After stirring for 1 hour, water (200 ml) was added and the mixture was extracted with hexane-ethyl acetate (2:1) (200 ml×5). The combined extract was washed with water (1 l), brine (1 l), and dried over magnesium sulfate. Evaporation of the solvent gave (2R,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-[3-(imidazol-1-yl)propyl]pyrrolidine (18.1 g) as a yellow paste.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([O:16][C:17]3[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24](C)(C)[CH3:25])=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2.OC1C=CC(C(OC(C)(C)C)=O)=CC=1>>[CH3:30][C:2]1([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([O:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:28][CH:29]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: CC(C)(C)OC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: CC(C)(C)OC(=O)c1ccc(O)cc1
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
tert-Butyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthoyloxy)benzoate-Using tert-butyl 4-hydroxybenzoate, the title compound was synthesized as a white solid. PMR (CDCl3): δ 1.33 (6H, s), 1.35 (6H, s), 1.62 (9H, s), 1.73 (4H, s), 7.25 (2H, d, J~8.7 Hz), 7.45 (1H, d, J~8.4 Hz), 7.93 (1H, dd, J~8.4 Hz, 1.8 Hz), 8.07 (2H, d, J~8.7 Hz), 8.15 (1H, d, J~1.8 Hz).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12]([O:19][C@H:20]([C@H:22]([N:26]1[CH:30]=[C:29]([C:31]([NH2:33])=[O:32])[N:28]=[CH:27]1)[CH2:23][CH2:24]O)[CH3:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:12]([O:19][C@H:20]([C@H:22]([N:26]1[CH:30]=[C:29]([C:31]([NH2:33])=[O:32])[N:28]=[CH:27]1)[CH2:23][CH2:24][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1cccc2ccccc12
Reactant: C[C@H](OCc1ccccc1)[C@@H](CCO)n1cnc(C(N)=O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](OCc1ccccc1)[C@@H](CCOc1cccc2ccccc12)n1cnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
To a stirred mixture of 1-naphthol (48.5 mg, 0.336 mmol), 1-[(2S,3R)-2-benzyloxy-5-hydroxy-3-pentyl]imidazole-4-carboxamide (85 mg, 0.280 mmol), and triphenylphosphine (88.2 mg, 0.336 mmol) in tetrahydrofuran (5 ml) was added dropwise diethyl azodicarboxylate (58.6 mg, 0.336 mmol) at ice-bath temperature. After the mixture was stirred overnight at room temperature, the solvent was removed in vacuo. The residue was purified by silica gel (10 g) chromatography eluting with chloroform/methanol (40:1) to give a mixture (60.6 mg) of 1-[(2S,3R)-2-benzyloxy-5-(1-naphthyloxy)-3-pentyl]imidazole-4-carboxamide (13) and by-products. This material was used without further purification.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2[Br:21])[CH2:8][C@@H:7]([CH2:22][O:23]C(=O)C)[C@@H:6]1[O:27]C(=O)C)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].C(O)C.CO>O.C(O)(=O)C>[Br:21][C:11]1[N:10]([C@@H:9]2[C@@H:5]([OH:4])[C@@H:6]([OH:27])[C@H:7]([CH2:22][OH:23])[CH2:8]2)[C:14]2[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=2[N:12]=1
Reactant: CC(=O)OC[C@@H]1C[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CO
Product: OC[C@@H]1C[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](O)[C@H]1O
Reaction time: 2.5 h
Yield: 61.9 %

Procedure:
(±)-(1R*,2S*,3S*,5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (600 mg, 1.15 mmol) was added to a stirred mixture of sodium carbonate (122 mg) in water (2 mL)-ethanol (10 mL)-methanol (10 mL). After 2.5 hours at ambient temperature, the pH was adjusted to 7 with glacial acetic acid. Volatiles were removed in vacuo and the residue triturated with water (5 mL) and filtered to give white solid. Recrystallization of the solid from 1:1 ethanol-methanol gave title compound as a white powder (282 mg, 62%), m.p. 208°-211° C.; 1H-NMR (DMSO-d6) δ: 8.23, (s, 1, benzimidazole H7), 7.95 (s, benzimidazole H4), 5.13 (t, J=4.1 Hz, 1, CH2OH), 5.03 (d, J=6.2 Hz, 1, OH), 5.0-4.85 (m, 1, H5), 4.71 (d, J=3.5 Hz, 1, OH), 4.55-4.45 (m, 1, H1), 3.85-3.80 (m, 1, H2), 3.7-3.6 and 3.55-3.45 (both m, 1 each, OCH2), 2.2-1.95 (m, 3, H3 and H4); mass spectrum (CI): 395 (M+1).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:12][C:13]([CH3:22])([CH2:15][CH2:16][CH2:17][CH:18]([CH3:21])[CH:19]=[CH2:20])[CH3:14])(=[O:11])[CH3:10].[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33](Cl)=[O:34]>C1COCC1>[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33](=[O:34])[CH2:10][C:9]([O:12][C:13]([CH3:22])([CH2:15][CH2:16][CH2:17][CH:18]([CH3:21])[CH:19]=[CH2:20])[CH3:14])=[O:11]
Reactant: C=CC(C)CCCC(C)(C)OC(C)=O
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(C)CCCC(C)(C)OC(=O)CC(=O)c1ccc2ccccc2c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide in the amount of (100.0 mL of a 2.0 M solution, 0.201 mol) is placed into a 500 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and addition funnel. The flask is cooled to -78° C. 2,6-Dimethyl-7-octen-2-yl acetate in the amount of (18.75 g, 0.095 mol) is dissolved in THF (5 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min before being treated with a solution of 2-naphthoyl chloride in the amount of (17.00 g, 0.089 mol) dissolved in THF (25 mL) over 30 min. The mixture is warmed to -20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (55 mL). The mixture is poured into a separatory funnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (150 mL). The combined organic layers are washed with saturated NaHCO3 solution (2×100 mL), water (2×150 mL) and brine (150 mL), dried over MgSO4 and filtered. The solvent is removed by rotary evaporation to give an orange/red oil. The oil is purified by column chromatography (elution with 2% ethyl acetate dissolved in petroleum ether) to give an oil. Purity of the product is determined by thin layer chromatography and the structure confirmed by 1H and 13C NMR.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:10]=2)=[CH:4][CH:3]=1.[CH3:24][C@H:25]1[CH2:30][NH:29][C@@H:28]([CH3:31])[CH2:27][NH:26]1.N[C@H](C(N[C@H](C(O)=O)C)=O)C.O=C1NCCNC1=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:26]2[CH2:27][C@H:28]([CH3:31])[NH:29][CH2:30][C@@H:25]2[CH3:24])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(Cl)c2ccc(Br)cc2)c1
Reactant: C[C@H]1CN[C@@H](C)CN1
Agent: C[C@H](N)C(=O)N[C@@H](C)C(=O)O
Agent: O=C1NCCNC1=O
Solvent: Cc1ccccc1
Product: C[C@H]1CN(C(c2ccc(Br)cc2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)[C@@H](C)CN1
Yield: 39 %

Procedure:
The crude benzhydryl chloride (approx. 42 mmol) was combined with 9.55 g (84 mmol) of (+)-(2S,5S)-2,5-dimethylpiperazine, prepared from L-Ala-L-Ala-diketopiperazine (Bachem Chemicals, Philadelphia, Pa.) as described in J. Org. Chem. 50: 4909-13 (1985), and 30 mL of toluene and heated at reflux overnight under nitrogen. The toluene was removed under vacuum, and the residue was redissolved in diethyl ether and washed with 1.0 M sodium hydroxide followed by saturated aqueous sodium chloride. The ether solution was dried over sodium sulfate and the solvent removed to give a dark oil. The product was purified by chromatography on silica gel (Waters Prep 500) with 0.5-0.7% ethanol in dichloromethane with 0.1% triethylamine to give 8.01 g (39%) of (2S,5S)-1-(4-bromo-α-(3-(tert-butyldimethylsilyloxy)phenyl)benzyl)-2,5-dimethylpiperazine as a 1:1 mixture of diastereomers.
Reaction SMILES: C[O:2][C:3](=[O:25])[C@@H:4]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[F:13].[OH-].[Na+]>CO>[CH2:18]([O:17][C:15]([NH:14][C@@H:4]([CH2:5][C:6]1[C:7]([F:13])=[CH:8][CH:9]=[CH:10][C:11]=1[F:12])[C:3]([OH:25])=[O:2])=[O:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)[C@H](Cc1c(F)cccc1F)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(N[C@@H](Cc1c(F)cccc1F)C(=O)O)OCc1ccccc1
Reaction time: 4 h
Yield: 95.1 %

Procedure:
2(S)-Benzyloxycarbonylamino-3-(2,6-difluorophenyl)propionic acid methyl ester (5 g, 14.4 mmol) was dissolved in methanol (60 ml) and cooled on ice. 1 N NaOH (22 ml, 22 mmol) was added dropwise over 15 min. The reaction mixture was removed from cooling bath and stirring was continued at room temperature for 4 h. The solvent was then removed by rotary evaporation and the residue was treated with water (100 ml) and then with 1 N HCl to adjust the pH to 4. The product was extracted with ethyl acetate (300 ml, 200 ml). Evaporation of the solvent and crystallization of the residue from methylene chloride/hexane gave 2(S)-benzyloxycarbonylamino-3-(2,6-difluorophenyl)propionic acid (4.6 g, 13.7 mmol, 94% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:18]([O:20][CH3:21])=[O:19])[CH:11]=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:6].[H-].[Na+]>CN(C=O)C>[O:6]=[C:5]1[CH2:4][CH2:3][CH2:2][N:7]1[C:8]1[CH:9]=[C:10]([C:18]([O:20][CH3:21])=[O:19])[CH:11]=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cc(NC(=O)CCCCl)cc(C(=O)OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)OC)cc(N2CCCC2=O)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
A solution of dimethyl 5-(4-chlorobutanamido)isophthalate (0.635 g, 2.02 mmol, 1 eq) dissolved in 5 ml anhydrous DMF was added dropwise to a stirred suspension of NaH (60% dispersion in oil, 0.101 g, 2.53 mmol, 1.25 eq) in 2 ml anhydrous DMF at 0° C. under Ar. The reaction was stirred at 0° C. to room temperature overnight. After stirring overnight the reaction was heated to 100° C. for 19 h. After cooling to room temperature the reaction was poured into ice-water to quench. The mixture was extracted with EtOAc (×1). The organic layer was washed with water (×4), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash chromatography yielded 0.3487 g (1.26 mmol, 62% yield) of the product.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH2:25][CH2:26][N:27]([CH2:33][C@H:34]([OH:37])[CH2:35][OH:36])[CH2:28][C@H:29]([OH:32])[CH2:30][OH:31])[CH2:20][C@H:21]([OH:24])[CH2:22][OH:23])=[CH:15][CH:14]=1)=O)(C)(C)C.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>ClCCl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[OH:32][C@H:29]([CH2:30][OH:31])[CH2:28][N:27]([CH2:26][CH2:25][N:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH2:8])=[CH:14][CH:15]=1)[CH2:20][C@H:21]([OH:24])[CH2:22][OH:23])[CH2:33][C@H:34]([OH:37])[CH2:35][OH:36]
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(N(CCN(C[C@H](O)CO)C[C@H](O)CO)C[C@H](O)CO)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCCc1ccc(N(CCN(C[C@H](O)CO)C[C@H](O)CO)C[C@H](O)CO)cc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 80 %

Procedure:
Dichloromethane (2 mL) was added to the protected amine 670 (0.27 g, 0.5 mmol) followed by addition of TFA (5 mL). The mixture was stirred at room temperature for 25 min. The solvent was removed under reduced pressure. The residue was dissolved in methanol and the solvent was removed again under reduced pressure. The residue was dried under vacuum overnight to afford the compound 680 (0.31 g, 80%) as a clear oil. 1H NMR (300 MHz, CD3OD) δ 1.66 (m, 4H), 2.59 (m, 2H), 2.92 (m, 2H), 3.15-4.10 (m, 20H), 6.78 (d, 2H), 6.98 (d, 2H).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=O.[N+]([O-])(O)=O.[N+:18]([C:21]1[CH:22]=[C:23]([NH:27][C:28]([NH2:30])=[NH:29])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].[OH-].[Na+]>C(O)(C)C>[N+:18]([C:21]1[CH:22]=[C:23]([NH:27][C:28]2[N:30]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[CH:4]=[CH:3][N:29]=2)[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19]
Reactant: N=C(N)Nc1cccc([N+](=O)[O-])c1
Reactant: CN(C)C=CC(=O)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)O
Product: O=[N+]([O-])c1cccc(Nc2nccc(-c3ccccn3)n2)c1
Reaction time: 0.33 h

Procedure:
1 g (5.68 mmol)of 3-dimethylamino-1-(2-pyridyl)-2-propen-1-one [EP-A-233 461] is dissolved in 8 ml of isopropanol, and 1.38 g (5.68 mmol) of 3-nitrophenylguanidine nitrate are added. After the addition of 0.25 g (6.24 mmol) of sodium hydroxide, the yellow suspension is heated at reflux for 20 hours, then cooled to 0°, filtered and washed with 30 ml of isopropanol. The filtration residue is stirred in 15 ml of ethanol for 20 minutes, filtered and washed with a small amount of cold ethanol, yielding N-(3-nitrophenyl)-4-(2-pyridyl)-2-pyrimidine-amine; m.p. 213°-219°.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.O.[NH2:10][NH2:11].[Cl-].[Na+]>[OH-].[Na+]>[ClH:2].[ClH:1].[NH:10]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[NH2:11]
Reactant: Clc1ccncc1
Reactant: NN
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: NNc1ccncc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
4-Chloropyridine hydrochloride (14 g) was added to hydrazine monohydrate (50 mL) and the mixture was stirred at 120° C. for 1 hr. A 1 mol/L a aqueous sodium hydroxide solution (100 mL) and sodium chloride were added to the reaction solution. The mixture was extracted with ethyl acetate and the extract solution was dried and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and 4 mol/L hydrochloric acid-ethyl acetate (50 mL) was added under ice-cooling. The precipitate was collected by filtration to give 4-hydrazinopyridine dihydrochloride (16 g) as a pale-yellow solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:20][N:19]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:16]3=[N:17][CH:18]=2)[CH:8]=1)[C:4](O)=[O:5].[CH3:38][NH:39][CH3:40].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C1COCC1>[CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:20][N:19]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:16]3=[N:17][CH:18]=2)[CH:8]=1)[C:4]([N:39]([CH3:40])[CH3:38])=[O:5]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(OC)C(=O)O)c3)cc12
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(OC)C(=O)N(C)C)c3)cc12
Temperature: 60 °C

Procedure:
To a solution of methoxy-{3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid, (100 mg, 0.19 mmol), dimethylamine (2 N in THF, 0.143 mL, 0.29 mmol), and diisopropylethylamine (37 mg, 0.29 mmol) in THF (2 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (110 mg, 0.29 mmol.). The resulting suspension was heated to 60° C. with stirring until all was dissolved. The solvent was evaporated and the residue was used in next step without purification. MS: m/z 547 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH:9]([C:11]([CH3:13])=O)=[CH2:10].[OH-].[Na+]>Cl>[CH3:13][C:11]1[C:7]2[C:2](=[C:3]([OH:8])[CH:4]=[CH:5][CH:6]=2)[N:1]=[CH:10][CH:9]=1
Reactant: C=CC(C)=O
Reactant: Nc1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccnc2c(O)cccc12
Yield: 13.3 %

Procedure:
A solution of 100 ml of concentrated hydrochloric acid, 27.3 g (250 mmol) of 2-aminophenol and 41 ml (500 mmol, 2 eq.) of methyl vinyl ketone was heated to 110°-120° C. for 18 hours. The reaction was cooled, poured onto crushed ice, brought to pH 7 using 10N sodium hydroxide and extracted with ethyl acetate. The organic layers were washed with water, brine, dried (magnesium sulfate) and concentrated in vacuo. Purification by flash chromatography (silica gel, 1:2 ethyl acetate/petroleum ether) and crystallization (ethyl acetate) gave 5.3 g of the title compound as a light yellow solid: melting point 135°-136° C.