Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:15]2[C:19](=[O:20])[C:18]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]3[C:16]2=[O:25])=[N:8][CH:9]=[C:10]([CH:12]([Cl:14])[Cl:13])[N:11]=1)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC)(=O)C>CO>[Cl:14][CH:12]([Cl:13])[C:10]1[N:11]=[C:6]([CH2:5][OH:4])[C:7]([N:15]2[C:19](=[O:20])[C:18]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]3[C:16]2=[O:25])=[N:8][CH:9]=1
Reactant: CC(=O)OCc1nc(C(Cl)Cl)cnc1N1C(=O)c2ccccc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)=O
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1c1ncc(C(Cl)Cl)nc1CO
Yield: 53.1 %

Procedure:
A mixture of 15 g (0.04 mole) of 3-acetoxymethyl-5-dichloromethyl-2-phthalimidopyrazine, 150 ml of methanol and 0.15 g of p-toluenesulfonic acid was heated to the boil, and a mixture of methanol and methyl acetate was slowly distilled off in the course of 5 hours. The mixture was then evaporated down to one-third of its total volume, and the precipitated crystals were isolated, and recrystallized from ethyl acetate. 7.18 g (54%) of 5-dichloromethyl-3-hydroxymethyl-2-phthalimidopyrazine of melting point 188°-189° C. were obtained. 1H-NMR (CDCl3 270 MHz): δ4.7 (s, 2H), 6.9 (s, 1H), 8.1 (m, 4H), 9.1 (s, 1H).
Reaction SMILES: C[C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.O(Cl)Cl.[C:21]([Cl:25])(Cl)([Cl:23])[Cl:22]>>[Cl:22][C:21]([Cl:25])([Cl:23])[C:9]1[CH:8]=[CH:7][C:6]2[C:5](=[O:17])[C:4]3[C:13](=[CH:14][CH:15]=[CH:2][CH:3]=3)[C:12](=[O:16])[C:11]=2[CH:10]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1ccc2c(c1)C(=O)c1ccccc1C2=O
Agent: ClOCl
Product: O=C1c2ccccc2C(=O)c2cc(C(Cl)(Cl)Cl)ccc21
Reaction time: 20.25 h
Yield: 92.5 %

Procedure:
2-Methylanthraquinone (5.89 g, 0.0265 mole) and dichlorine monoxide (5.77 g, 0.0664 mole) in carbon tetrachloride (70 ml) were heated in a Carrius tube as described in Example 6 at 75° for 20.25 hrs. The product which separated as a yellow crystalline solid was dissolved in methylene chloride and filtered to separate a solid (0.49 g) judged from its infrared spectra to be anthraquinone-2-carboxylic acid. The filtrate was dried (MgSO4) and the solvent removed on a rotary evaporator to give 2-trichloromethylanthraquinone as a yellow crystalline solid (8.49 g, purity by HPLC 94.26%; yield 92.5%). An aliquot of the product was recrystallized from carbon tetrachloride and then sublimed (0.1μ) to give pure anthraquinone-2-carboxylic acid, mp 157-158.2.
Reaction SMILES: [C:1]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17]>>[C:14]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:1]1=[O:13])([O:15][CH2:16][CH3:17])=[O:18]
Reactant: CCOC(=O)OCC
Reactant: O=C1CCCCCCCCCCC1
Product: CCOC(=O)C1CCCCCCCCCCC1=O

Procedure:
The inventors have established a more effective method for producing β-(2-oxocyclododecyl)propionic acid by the following steps: reacting cyclododecanone with diethyl carbonate to give carbethoxycyclododecanone, reacting the carboethoxycyclododecanone with β-propiolactone in a solvent having no alkoxy group, such as benzene, toluene and ethyl ether in the presence of sodium hydride, hydrolyzing the resulting product, and then decarboxylating to give β-(2-oxocyclododecyl)propionic acid in high yield (79% based on the starting cyclododecanone theoretically).
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH:3]([NH:8][C:9]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)=[O:24])=[CH:18][CH:17]=2)=[CH:14][N:15]=1)=[O:10])[C:4]([O:6]C)=[O:5].O.[OH-].[Li+].Cl>C1COCC1>[CH3:1][CH:2]([CH3:36])[CH:3]([NH:8][C:9]([C:11]1[S:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:27]=3)=[O:24])=[CH:20][CH:21]=2)=[CH:14][N:15]=1)=[O:10])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)s1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)c1ncc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)s1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 3-methyl-2-(5-(4-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl) thiazole-2-carboxamido)butanoate (Example 9, 100 mg) in THF (2 ml) was added 1 M aqueous solution of Lithium hydroxide monohydrate (0.38 ml) and the mixture was stirred at RT for 4 hours. The reaction mixture was acidified with dilute HCl and extracted with EtOAc. The organic layer was separated, dried over Na2SO4, concentrated under reduced pressure and then crystallized in EtOAc to give the title compound. Yield: 60 mg (62%); 1H NMR (DMSO-d6, 300 MHz): δ 12.97 (bs, 1H), 9.18 (s, 1H), 9.13 (s, 1H), 8.37 (d, 1H), 8.36 (s, 1H), 8.03 (d, 1H), 7.71 (d, 2H), 7.61 (d, 2H), 7.55 (dd, 1H), 7.5 (dd, 1H), 7.34 (d, 1H), 4.31, (m, 1H), 2.28 (m, 1H), 0.95 (d, 6H); MS (ES+): m/z 507 (M+1).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.[CH3:18][N:19]([CH3:32])[S:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21]>>[OH:13][S:12]([NH:11][CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:25]3[CH:24]=[C:23]([S:20]([N:19]([CH3:32])[CH3:18])(=[O:21])=[O:22])[CH:28]=[CH:27][CH:26]=3)[CH:3]=2)[CH2:7]1)([OH:14])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(I)cc2C1
Reactant: CN(C)S(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)S(O)(O)NC1Cc2ccc(-c3cccc(S(=O)(=O)N(C)C)c3)cc2C1

Procedure:
The title compound was prepared from N-(5-iodo-2,3-dihydro-1H-inden-2-yl)-2-propanesulfonamide and {3-[(dimethylamino)sulfonyl]phenyl}boronic acid (WO2003004472) in a similar manner to Example 1.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH3:7][O:8][C:9]1[C:14]([O:15][CH3:16])=[C:13]([C:17](Cl)=[O:18])[CH:12]=[CH:11][C:10]=1[C:20](Cl)=[O:21]>C(Cl)Cl>[OH:4][CH2:3][C:2]([NH:1][C:17]([C:13]1[CH:12]=[CH:11][C:10]([C:20]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[O:21])=[C:9]([O:8][CH3:7])[C:14]=1[O:15][CH3:16])=[O:18])([CH3:6])[CH3:5]
Reactant: CC(C)(N)CO
Reactant: COc1c(C(=O)Cl)ccc(C(=O)Cl)c1OC
Solvent: ClCCl
Product: COc1c(C(=O)NC(C)(C)CO)ccc(C(=O)NC(C)(C)CO)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
In 8 mL of anhydrous methylene chloride, was dissolved 6.06 g (68.0 mmol) of 2-amino-2-methyl-1-propanol. Thereto, a solution of 4.47 g (17.0 mmol) of 2,3-dimethoxy-1,4-benzenedicarboxylic chloride in 8 mL of anhydrous methylene chloride was added by keeping the inner temperature at 5°-10° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and washed with water. The filtrate and the wash water were combined and concentrated under a reduced pressure. Methylene chloride was added to the obtained residue, and the mixture was dried over anhydrous sodium sulfate. The solvent was removed. The product was recrystallized from benzene to obtain 6.27 g (100%) of N,N'-bis(2-hydroxy-1,1-dimethylethyl)-2,3-dimethoxy-1,4-phenylenedicarboxamide in a colorless prism crystal state.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[OH:23][C:24]([CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)([CH3:26])[CH3:25]>>[Br:1][C:2]1[C:3]([N:29]2[CH2:30][CH2:31][CH:27]([C:24]([OH:23])([CH3:26])[CH3:25])[CH2:28]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: CC(C)(O)C1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Product: CC(C)(O)C1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2) and 3-(1-hydroxy-1-methyl-ethyl)-pyrrolidine (US2010160280) and was obtained as an off-white solid. HPLC (Condition 4) tR=6.11 min, UPLC-MS (Condition 7) m/z=490.1 [M+H]+.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:15]=[C:11]([C:12]([OH:14])=[O:13])[C:10]([OH:16])=[CH:9][CH:8]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].CC1C=C(C(C)(C)C)[C:21]([OH:28])=[C:20](C(C)(C)C)C=1.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O.Cl>C(O)(=O)C>[C:21]([C:10]1([OH:16])[CH:9]=[CH:8][C:7]([NH:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[CH:15][CH:11]1[C:12]([OH:14])=[O:13])(=[O:28])[CH3:20]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C=C(C)C(=O)Nc1ccc(O)c(C(=O)O)c1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: C=C(C)C(=O)NC1=CC(C(=O)O)C(O)(C(C)=O)C=C1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
5-methacrylamidosalicylic acid (30 millimole, 6.7 g) was mixed with butylhydroxytoluene (20 mg), acetic anhydride (10.0 g), and acetic acid (15.0 g). After sealing the solution, its temperatures was raised to 60° C., and the solution was kept at 60° C. for 30 min while stirring. Then, a mixture (1.0 g) of concentrated sulfuric acid (1 part) with hydrochloric acid (10 parts) was added to the solution, followed by raising its temperature to 90° C., and kept at 90° C. for one hour to proceed the reaction. After the reaction was over, the solution was stood to cool to room temperature to give brown crystal. The crystal was filtrated, and recrystallized by a solution of 0.5% hydroquinone in methanol. Dried under a reduced pressure, 2-acetyl-5-methacrylamidosalicylic acid was obtained as pale reddish brown crystal having a needle shape: mp. 192.4° C., yield 2.54 g, 64.1%.
Reaction SMILES: [CH:1]([C:4]1[C:8]([CH:9]([CH3:11])[CH3:10])=[C:7]([CH:12]([CH3:14])[CH3:13])[NH:6][C:5]=1[C:15]([OH:17])=O)([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1>>[CH:1]([C:4]1[C:8]([CH:9]([CH3:10])[CH3:11])=[C:7]([CH:12]([CH3:13])[CH3:14])[NH:6][C:5]=1[C:15]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=1)=[O:17])([CH3:2])[CH3:3]
Reactant: CC(C)c1[nH]c(C(=O)O)c(C(C)C)c1C(C)C
Reactant: COC(=O)c1ccc(N)cc1
Product: COC(=O)c1ccc(NC(=O)c2[nH]c(C(C)C)c(C(C)C)c2C(C)C)cc1
Yield: 76 %

Procedure:
In the same manner as that of Example 17, 3,4,5-triisopropylpyrrole-2-carboxylic acid (50 mg, 0.211 mmol) was condensed with methyl 4-aminobenzoate, the reaction mixture was treated in a conventional manner, and then the resultant was recrystallized and purified by silica gel chromatography [hexane-ethyl acetate (14:1)] to obtain methyl 4-[(3,4,5-triisopropylpyrrole-2-carbonyl)amino]benzoate (59 mg, 76%) and the corrected starting material (5 mg, 10%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:21]([C:28]([O:30]C)=[O:29])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:16]([CH2:32][CH2:33][CH3:34])[CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:35])[CH:3]=1.[OH-].[Na+].Cl>CO>[C:28]([CH:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:8]2[C:6]3=[N:7][C:2]([CH3:1])=[CH:3][C:4]([CH3:35])=[C:5]3[N:10]=[C:9]2[CH2:11][CH3:12])=[CH:15][C:16]=1[CH2:32][CH2:33][CH3:34])([OH:30])=[O:29]
Reactant: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)ccc1OC(C(=O)OC)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)ccc1OC(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 509.9 %

Procedure:
To a solution of 0.042 g (0.09 mmol) of the product of Step B dissolved in 1.0 mL of methanol was added 0.1 mL of a 1.0N solution of sodium hydroxide and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was then adjusted to pH 7 with 1.0N hydrochloric acid and then partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO4), filtered, evaporated and then purified on a silica gel flash chromatography column eluted with chloroform-methanol-conc. ammonium hydroxide (80:15:1). Evaporation of the purified fractions and drying in vacuo afforded 0.21 g (51%) of the title compound as a white amorphous solid.
Reaction SMILES: [F:1][C:2]([F:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6]([F:16])=[C:7]([CH2:12][C:13]([OH:15])=O)[C:8]([Cl:11])=[CH:9][CH:10]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH2:60][CH2:61][C:62]1[C:63]([CH3:77])=[CH:64][C:65]([NH:69][C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])=[N:66][C:67]=1[CH3:68]>CN(C=O)C>[F:23][C:2]([F:1])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6]([F:16])=[C:7]([CH2:12][C:13]([NH:60][CH2:61][C:62]2[C:67]([CH3:68])=[N:66][C:65]([NH:69][C:70]([O:72][C:73]([CH3:75])([CH3:74])[CH3:76])=[O:71])=[CH:64][C:63]=2[CH3:77])=[O:15])[C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: O=C(O)Cc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)Cc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.9 %

Procedure:
To a solution of 2-{3-[(2,2-difluoro-2-phenylethyl)amino]-6-chloro-2-fluorophenyl}acetic acid (25 mg, 73 μmol), as prepared in step 15 of Example 1, in DMF (0.25 mL) was added BOP (52 mg, 116 μmol), a solution of DIEA (38 mg, 295 mol) in DMF (0.1 mL), and N-[5-(aminomethyl)-4,6-dimethyl(2-pyridyl)] (tert-butoxy) carboxamide (23 mg, 91 μmol) (Sanderson, P. E., et al. WO 97/01338 (1997)). After stirring at ambient temperature for 2 days, additional amine (7 mg, 28 μmol) BOP (16 mg, 36 μmol), and DIEA (9 mg, 70 μmol) were added, and the mixture was stirred for another 16 hours. The solvents were evaporated, and the resulting residue was partitioned between saturated NaHCO3 and DCM. The organic layer was separated, and the aqueous layer was extracted with DCM. The organic layers were combined, washed with 10% citric acid, H2O, and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with MeOH/DCM (0, 1, 2%) to produce the title compound (18.5 mg, 44% yield) as a pale brown solid. 1H-NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.50-7.41 (m, 5H), 7.24 (s, 1H), 6.98 (dd, J=8.8, 1.1 Hz, 1H), 6.55 (t, J=9.0 Hz, 1H), 5.33 (bs, 1H), 4.40 (d, J=4.7 Hz, 2H), 4.24-4.20 (m, 1H), 3.78-3.70 (m, 4H), 2.39 (s, 3H), 2.28 (s, 3H), 1.50 (s, 9H). Mass spectrum (LCMS, ESI) calcd for C29H33ClF3N4O3 (M+H): 577.0. Found: 577.1.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([O:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][OH:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)C>ClCCl>[CH2:12]([O:19][CH2:20]/[CH:21]=[CH:22]\[CH:23]=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OC/C=C\COCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C/C=C\COCc1ccccc1
Temperature: 0 °C
Yield: 65.7 %

Procedure:
11.1 g of pyridinium chlorochromate and 12 g of celite were suspended in 100 ml of dry dichloromethane, and 6 g of (Z)-4-benzyloxy-2-buten-1-ol was added thereto under stirring at 0° C. The mixture was stirred at room temperature for three hours, and then diethyl ether was added thereto. The insolubles were removed by filtration. The filtrate was subjected to distillation under reduced pressure for removal of the solvent, and the residue was purified by silica gel column chromatography (diethyl ether) to obtain 3.9 g of (Z)-4-benzyloxy-butenal as slightly yellow oily substance.
Reaction SMILES: N1CCCCC1.C(O)(=O)C.[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[C:21]([O:27][CH3:28])[CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:29]([O:37][CH2:38][CH3:39])(=[O:36])[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>C1(C)C=CC=CC=1>[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:29]([O:37][CH2:38][CH3:39])=[O:36])=[C:21]([O:27][CH3:28])[CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1cc(OCc2ccccc2)ccc1C=O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1ccc(OCc2ccccc2)cc1OC)C(=O)OCC
Temperature: 125 °C
Reaction time: 5 h
Yield: 44.2 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged with piperidine (0.108 g, 0.13 mL, 1.35 mmol) and acetic acid (0.081 g, 0.08 mL, 1.35 mmol). To this, toluene (20 mL) was added, followed by 4-(benzyloxy)-2-methoxybenzaldehyde (1.1 g, 4.5 mmol) and diethyl malonate (0.87 g, 5.5 mmol). The RM was heated at 125° C., by fitted with a dean-stark's apparatus for 5 h. After 5 h, the RM was concentrated; water (50 mL) was added and extracted with ethyl acetate (50 mL×2)). The organic layer was washed with saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as yellow solid. (0.775 g, yield: 44.2%).
Reaction SMILES: [CH3:1][C@@]1(O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)O.[CH2:14]([O:21][C@@H:22]1[C@@H:28]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:27]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@@H:26]([CH2:45][O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[O:25][C@@H:23]1[OH:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)C1C=CC=CC=1.[OH-].[K+]>O>[CH2:14]([O:21][C@@H:22]1[C@@H:28]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:27]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C@@H:26]([CH2:45][O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[O:25][C@@H:23]1[O:24][CH3:1])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: C[C@]1(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCc1ccccc1
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1

Procedure:
Preparation of 2,3,4,6-Tetra-O-benzyl-α-D-glucopyranose Methyl-α-D-glucopyranose (100 g, 0.516 mol) is suspended in benzyl chloride (400 mL, 3.5 mol) with KOH pellets (336 g, 6 mol), and the mixture is stirred using a mechanical stirrer at 120°-130° C. for 3 h. The reaction mixture is cooled and water (800 mL) is added to dissolve the crystalline mass, which is extracted with ether (2×200 mL). The combined organic layer is washed with water (2×500 mL) and dried (Na2SO4). The solvents are removed by vacuum distillationto give the crude methyl 2,3,4,6-tetra-O-benzyl-α-D-glucopyranoside for the next reaction.
Reaction SMILES: COC1C=CC(C[N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[S:23]1[CH:24]=[CH:25][N:26]=[C:22]1[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]2[NH:20][CH2:19][CH2:18][O:17][C:16]=2[CH:21]=1)(=[O:10])=[O:11]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1nccs1)c1ccc2c(c1)OCCN2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99.8 %

Procedure:
N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (Intermediate M; 0.200 g, 0.479 mmol) was dissolved in DCM (1.597 ml) and TFA (0.923 ml, 11.98 mmol) was added. The reaction was stirred at RT for 20 minutes at which time it was concentrated in vacuo. The crude reaction was purified via 2-g SCX column (product eluted with ammonia/methanol wash) to yield N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.142 g, 0.478 mmol, 100% yield). m/z (ESI) 298.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Product: Cc1cc(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-4-methyl-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J23) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) according to the general procedure M. Obtained as a white solid (229 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]([F:23])([F:22])[CH2:4][NH:5][C:6]([CH3:21])([CH3:20])[C:7](=[N:18][OH:19])[CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[N+:15]([O-:17])=[O:16].C(N(CC)C(C)C)(C)C.Cl[C:34]([CH3:40])([CH3:39])[CH:35]([N:37]=[O:38])[CH3:36]>C(#N)C>[F:23][C:3]([F:22])([CH2:4][NH:5][C:6]([CH3:21])([CH3:20])[C:7](=[N:18][OH:19])[CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[N+:15]([O-:17])=[O:16])[CH2:2][NH:1][C:34]([CH3:40])([CH3:39])[C:35](=[N:37][OH:38])[CH3:36]
Reactant: CC(N=O)C(C)(C)Cl
Reactant: CC(C)(NCC(F)(F)CN)C(CCn1ccnc1[N+](=O)[O-])=NO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=NO)C(C)(C)NCC(F)(F)CNC(C)(C)C(CCn1ccnc1[N+](=O)[O-])=NO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A clear solution of 4-(3-amino-2,2-difluoropropylamino)-4-methyl-1-(2-nitro-1H-imidazol-1-yl)-3-pentanone oxime (title B compound) (0.40 g, 1.20 mmol) and N,N-diisopropylethylamine (0.42 g, 3.32 mmol) in acetonitrile (5 mL) was treated with 3-chloro-3-methyl-2-nitrosobutane (prepared analogously to 3-chloro-3-methyl-2-nitrosobutane, Example 1, step (B)) (0.45 g, 3.32 mmol) with stirring at room temperature under nitrogen atmosphere for 2 hours. After evaporation of the solvent under vacuum, the paste thus obtained was loaded, as a powder adsorbed on silica gel, onto a silica gel column and eluted with methanol-dichloromethane (2:98). The fractions with compound were pooled together and evaporated to afford the title product, which was further purified by crystallization from CH2Cl2—CH3OH to a cream colored solid. Yield: 0.45 g (88%); mp. 90-92° C.; 1H NMR (DMSO-d6) d, 1.12 [s, 12H, C(CH3)2 ], 1.70[s, 3H, C(=NOH)CH3], 2.18 & 2.22(2t, 2H, NH), 2.62(m, 4H, CH2CF2), 2.80(t, 2H, J=7.25 Hz, CH2CH2N), 4.61(t, 2H, J=7.25 Hz, CH2CH2N), 7.15 & 7.52 (2s, 2H, imi-H) and 1.046 & 10.90(2s, 2H, NOH). MS m/e 434 (M+H)+. Anal. Calcd for C17H29N7O4F2: C, 47.11; H, 7.74; N, 22.62; F, 8.77. Found: C, 47.28; H, 6.54; N, 22.79; F, 8.53. HPLC: Retention time: 20.74 min [Microsorb-C18, 0.46×25 cm, 5 m; solvent: 0.1% trifluoroacetic acid (TFA)/water (A) and 0.1% TFA/acetonitrile (B); flow rate: 1.0 mL/min.; run condition: linear gradient, 1% increase in B per min.; ran at 230 and 254 nm for 50min.; in both cases a single peak was observed; 98.95% (230 nm) and 100% (254 nm)].
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[CH3:2].F[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:22]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:18][CH3:19])=[CH:17][CH:16]=2)[CH:12]=[CH:13]1
Reactant: CCN(CC)CCCCOc1ccc2[nH]ccc2c1
Reactant: Fc1ccccc1-c1ccccc1
Product: CCN(CC)CCCCOc1ccc2c(ccn2-c2ccccc2-c2ccccc2)c1

Procedure:
In analogy to example 4.6, Diethyl-[4-(1H-indol-5-yloxy)-butyl]-amine and 2-fluorobiphenyl were converted to yield [4-(1-Biphenyl-2-yl-1H-indol-5-yloxy)-butyl]-diethyl-amine as light yellow oil, MS: 412 (M).