Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[N:14]=[C:13]2[N:7]([CH2:8][CH2:9][O:10][C:11]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:12]=32)[N:6]=1)=[O:4].CO.O.[Li+].[OH-]>C1COCC1>[Cl:19][C:17]1[CH:16]=[CH:15][C:12]2[C:13]3[N:7]([N:6]=[C:5]([C:3]([OH:4])=[O:2])[N:14]=3)[CH2:8][CH2:9][O:10][C:11]=2[CH:18]=1
Reactant: COC(=O)c1nc2n(n1)CCOc1cc(Cl)ccc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1nc2n(n1)CCOc1cc(Cl)ccc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Methyl-9-chloro-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazepine-2-carboxylate (0.144 g, 0.515 mmol) was dissolved in 3:2:1 THF:MeOH:H2O (5.0 mL), and treated with 4 N aqueous LiOH (0.644 mL). The mixture was stirred for 30 min at 25° C. The reaction was quenched with 1 N aq. HCl (10 mL) and the solution was extracted with EtOAc (3×20 mL). The combined organic extracts were dried with Na2SO4 and concentrated in vacuo to give 9-Chloro-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazepine-2-carboxylic acid (89% yield)
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:36])([F:35])[O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]([OH:34])([CH3:33])[CH2:23][N:24]3[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[N:26]=[C:25]3Cl)=[O:19])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1>CN(C=O)C>[F:3][C:4]([F:36])([F:35])[O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3([CH3:33])[O:34][C:25]4=[N:26][C:27]([N+:29]([O-:31])=[O:30])=[CH:28][N:24]4[CH2:23]3)=[O:19])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1
Reactant: CC(O)(COC(=O)N1CCN(c2ccc(OC(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(COC(=O)N2CCN(c3ccc(OC(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
Sodium hydride (23 mg, 0.56 mmol) was added to a solution of 3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-(4-trifluoromethoxyphenyl)piperazine-1-carboxylate prepared in Example 83 (0.24 g, 0.47 mmol) in DMF (2 ml) followed by stirring at 0° C. for 1 hour. Ice-water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and then washed with diisopropyl ether to afford 2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl 4-(4-trifluoromethoxyphenyl)piperazine-1-carboxylate (0.13 g, yield 58%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:5](=[CH:6][C:7]([F:16])=[CH:8][C:9]=2[CH3:15])[N:4]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:15][C:9]1[CH:8]=[C:7]([F:16])[CH:6]=[C:5]2[C:10]=1[N:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[N:4]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1nc2cc(F)cc(C)c2nc1OC
Solvent: ClC(Cl)(Cl)Cl
Product: COc1nc2cc(F)cc(CBr)c2nc1OC

Procedure:
8.4 g (37.8 mmol) of 2,3-dimethoxy-7-fluoro-5-methylquinoxaline, 7.4 g (41.6 mmol) of N-bromosuccinimide and 0.63 g (0.38 mmol) of azoisobutyronitrile are introduced into 140 ml of carbon tetrachloride and stirred at reflux for 6 hours. The reaction mixture is cooled and concentrated, and the residue is taken up in diethyl ether. The suspension is filtered off and the mother liquor is concentrated again. The remaining crude product is recrystallized from hexane. The title compound is obtained as white crystals of m.p. 122-125° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.C[O:15][C:16](=O)[C:17]1[C:22]([I:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[CH:19][C:18]=1[CH2:27]Br.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[N+:24]([C:20]1[CH:19]=[C:18]2[C:17](=[C:22]([I:23])[CH:21]=1)[C:16](=[O:15])[N:9]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:5][CH:6]=1)[CH2:27]2)([O-:26])=[O:25]
Reactant: COC(=O)c1c(I)cc([N+](=O)[O-])cc1CBr
Reactant: NCc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1c2c(I)cc([N+](=O)[O-])cc2CN1Cc1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 10.2 %

Procedure:
A mixture of 4-trifluoromethoxy-benzyl amine (0.586 mL, 3.84 mmol), 2-bromomethyl-4-nitro-6-iodo-benzoic acid methyl ester (1.18 g, 2.95 mmol), and K2CO3 (0.815 g, 0.815 mmol) in toluene (7 mL) was heated with stirring at 100° C. for 2 h. The resulting mixture was filtered and concentrated. Silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-nitro-7-iodo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.144 g, 10%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.31 (s, 2H), 4.82 (s, 2H), 7.19 (d, 2H), 7.38 (d, 2H), 8.24 (s, 1H), 8.78 (s, 1H). GC-MS: m/z 478 (M)+, 409 (M−69)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[NH2:9].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([CH3:21])[CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([NH2:9])=[C:2]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][C:14]=2[CH3:21])[CH:7]=1
Reactant: COc1ccc(B(O)O)c(C)c1
Reactant: Nc1nnc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc(Cl)nnc2N)c(C)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 54.9 %

Procedure:
4-Bromo-6-chloro-3-pyridazineamine (12 g) and 4-methoxy-2-methylphenylboronic acid (10.5 g) were dissolved in a mixed solvent of toluene (240 mL) and ethanol (45 mL), then tetrakistriphenylphosphine palladium complex (6.7 g) and a 2M aqueous sodium carbonate solution (24 mL) were added thereto, and the mixture was heated under stirring at 100° C. for 12 hours. After completion of the reaction, the solvent was evaporated. The residue was extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:4) to give the title compound (7.89 g) as brown crystals.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:14]O>OS(O)(=O)=O>[CH3:14][O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: CO
Reactant: Nc1ncc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: COC(=O)c1cnc(N)c([N+](=O)[O-])c1
Yield: 30 %

Procedure:
A solution of 6-Amino-5-nitro-nicotinic acid (2) (15.2 g, 82.5 mmol) in MeOH (250 ml) and H2SO4 (conc. 25 ml) was heated at reflux for 5 h. The solution was concentrated in vacuo and the residue treated with saturated aqueous NaHCO3 solution until slightly basic. The resulting solid was collected by filtration, rinsed with H2O and dried in vacuo to give the product as a yellow solid (4.8 g, 25 mmol, 30%) that was used as is without further purification. TLC of the solid in DCM/MeOH (19:1) showed a less polar compound at Rf=0.5 compared to the baseline starting material.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.Br[CH:26]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]1=[O:37]>C(#N)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH:12]2[CH2:17][CH2:16][N:15]([CH:26]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]3=[O:37])[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:9]=1
Reactant: CCOC(=O)CN1CCC(Br)C1=O
Reactant: COc1ccc(C(=O)C2CCNCC2)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCC(N2CCC(C(=O)c3ccc(OC)cc3)CC2)C1=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
(4-Methoxyphenyl)(piperidin-4-yl)methanone hydrochloride (524 mg, 2.05 mmol) was stirred at room temperature with triethylamine (0.657 mL, 477 mg, 4.71 mmol) in acetonitrile (80 mL). A solution of ethyl 2-(3-bromo-2-oxopyrrolidin-1-yl)acetate (513 mg, 2.05 mmol) in acetonitrile (20 mL) was added to the mix. The reaction was stirred 3 hours at 40° C. and then overnight at 50° C. After 24 hours the reaction was not complete and the reaction was stirred an additional 48 hours at 70° C. then allowed to cool to room temperature. The solvents were removed in vacuo. The crude orange solid was eluted through a silica gel column with a 0 to 10% methanol/dichloromethane gradient to afford the title racemic compound (730 mg, 87% yield, 95% purity) as a thick amber oil. MS (ESI) [m/e, (M+H)+]=389.5. 1H NMR (400 MHz, chloroform-d) δ ppm 7.90-7.95 (m, 2H), 6.91-6.96 (m, 2H), 4.17-4.24 (m, 2H), 3.95-4.17 (m, 2H), 3.88 (s, 3H), 3.56-3.64 (m, 1H), 3.36-3.50 (m, 2H), 3.18-3.29 (m, 1H), 3.04-3.13 (m, 1H), 2.93-3.04 (m, 2H), 2.41-2.56 (m, 1H), 2.20-2.35 (m, 1H), 2.04-2.19 (m, 1H), 1.80-1.95 (m, 4H), 1.26-1.32 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:5]2[CH:6]=[C:7](Br)[CH:8]=[CH:9][N:4]2[N:3]=1.[C:12](=[O:19])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[NH2:13].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:15]([O:14][C:12](=[O:19])[NH:13][C:7]1[CH:8]=[CH:9][N:4]2[N:3]=[C:2]([Br:1])[N:11]=[C:5]2[CH:6]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: Brc1ccn2nc(Br)nc2c1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccn2nc(Br)nc2c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 76.4 %

Procedure:
To an argon purged solution of 2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine (6.00 g, 21.7 mmol) in dioxane (222 ml) were added tert-butyl carbamate (3.05 g, 26.0 mmol), cesium carbonate (9.88 g, 30.3 mmol), tris(dibenzylideneacetone) dipalladium(0) (397 mg, 433 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (501 mg, 867 μmol). The resulting mixture was heated to 100° C. and stirred for 18 hours under argon atmosphere. The material was applied on silicagel and purified by flash chromatography over a 20 g silicagel column using heptane/ethyl acetate 10-70% as eluent affording (2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-carbamic acid tert-butyl ester (5.19 g, 76.5%) as a light yellow solid. MS: m/z=313.0 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:12][C:11]1[C:2]([NH:23][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=2)(=[O:21])=[O:22])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: Clc1nc2ccccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)cc1
Yield: 74 %

Procedure:
According to the step of Example 6-1, by use of 2,3-dichloroquinoxaline (1.00 g, 5.02 mmol) dissolved in dimethyl sulfoxide (30 mL), 4-methylbenzene-1-sulfonamide (860 mg, 5.02 mmol) and potassium carbonate (694 mg, 5.02 mmol), the mixture was stirred and reacted at 150° C. for 4.2 hours. Then, slurry purification was performed using diisopropyl ether, to give N-(3-chloroquinoxalin-2-yl)-4-methylbenzenesulfonamide (Compound AB) (1.24 g, yield: 74%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[O:13][CH3:14])[CH3:2].CCO>[Pd].CCOC(C)=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[O:13][CH3:14])[CH3:2]
Reactant: CCOc1ccc([N+](=O)[O-])cc1OC
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1ccc(N)cc1OC
Yield: 103.3 %

Procedure:
A suspension of 2-ethoxy-5-nitroanisole from Step 1 (5.50 g, 27.9 mmol) and 10% Pd/C (1.0 g) in 1:1 EtOH:EtOAc (50 ml) was shaken under an atmosphere of H2 (35-40 psi) for 30 min. The reaction mixture was filtered through Celite and concentrated under vacuum to afford 4-ethoxy-3-methoxyaniline (4.82 g, 100%) as a brown solid: mp 54-56° C. 1H NMR (DMSO-d6) δ 6.61 (d, 1H), 6.25 (d, 1H), 6.03 (dd, 1H), 4.65 (s, 2H), 3.82 (q, 2H), 3.66 (s, 3H), 1.22 (t, 3H); 13C NMR (DMSO-d6) δ 143.6, 138.8, 116.6, 105.1, 99.9, 65.0, 55.1, 15.1; MS (ESI+) for m/z 168 [M+H]+.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=[CH:9][C@H:10]([C@H:12]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[OH:11].[Sb](Cl)(Cl)(Cl)(Cl)Cl>ClCCl>[CH2:4]1[CH2:5][CH2:6][C:1]2([O:11][C@@H:10]([C@H:12]3[O:13][C@@H:18]4[O:19][C:1]5([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[O:17][C@H:16]4[C@H:14]3[OH:15])[CH2:9][O:7]2)[CH2:2][CH2:3]1
Reactant: O=C1CCCCC1
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: O[C@@H]1[C@@H]2OC3(CCCCC3)O[C@H]2O[C@@H]1[C@H]1COC2(CCCCC2)O1
Temperature: 68 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a mixed solution consisting of 100 ml of cyclohexanone and 100 ml of dichloromethane were added 10.0 g of D-mannose and 89.7 mg of antimony pentachloride, and the mixture was refluxed with stirring in a water bath of 68° C. for 8 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the condenser. The reaction mixture was diluted with benzene, washed with aqueous sodium bicarbonate and water, and dried over anhydrous magnesium sulfate. The solvents including cyclohexanone were distilled off under reduced pressure to give 16.49 g (87.3%) of 2,3:5,6-di-O-cyclohexylidene-α-D-mannofuranose as a residue. The compound, when recrystallized from cyclohexane, showed m.p. 122°-124° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:21]([F:24])([F:23])[F:22])=[C:4]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1>CCO.[Pd]>[F:1][C:2]1[C:3]([C:21]([F:24])([F:22])[F:23])=[C:4]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(F)c2C(F)(F)F)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(F)c2C(F)(F)F)CC1
Reaction time: 18 h
Yield: 101.6 %

Procedure:
A mixture of tert-butyl 4-(3-fluoro-2-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (3, 4.7 g, 13.6 mmol) and 10% Pd/C (1.0 g) in EtOH (100 mL) was placed under an atmosphere of H2 (30 psi) at ambient temperature for 18 h. the mixture was filtered through a Celite, and the filtrate was concentrated under reduced pressure to give tert-butyl 4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carboxylate (4) as a clear oil (4.80 g, >99%): 1H NMR (300 MHz, DMSO-d6) δ 7.72-7.60 (m, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.30 (dd, J=12.3, 8.1 Hz, 1H), 4.18-4.00 (m, 2H), 3.11-2.95 (m, 1H), 2.92-2.64 (m, 2H), 1.76-1.51 (m, 4H), 1.42 (s, 9H).
Reaction SMILES: [F:1][CH:2]([CH:8]([CH3:11])[CH2:9][CH3:10])[C:3]([O:5]CC)=[O:4].[OH-].[Na+].Cl>>[F:1][CH:2]([CH:8]([CH3:11])[CH2:9][CH3:10])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(F)C(C)CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCC(C)C(F)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 8.5 g of the compound (iv) was added 1N NaOH aqueous solution, followed by stirring at room temperature for 8 hours. The solution was acidified with dilute hydrochloric acid and then extracted with ether. The extract was freed of ether by distillation. Thus there was obtained 2-fluoro-3-methylpentanoic acid (v).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH:7]2[N:9]([CH3:10])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.[C:11]1([C:17]2[O:18][C:19]3[C:20](=[C:22]([C:26](O)=[O:27])[CH:23]=[CH:24][CH:25]=3)[N:21]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:10][N:9]1[CH:7]2[CH2:6][CH2:5][CH:4]1[CH2:3][CH:2]([NH:1][C:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:19]3[O:18][C:17]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:21][C:20]=13)=[O:27])[CH2:8]2
Reactant: O=C(O)c1cccc2oc(-c3ccccc3)nc12
Reactant: CN1C2CCC1CC(N)C2
Product: CN1C2CCC1CC(NC(=O)c1cccc3oc(-c4ccccc4)nc13)C2
Yield: 25 %

Procedure:
N-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-2-phenylbenzoxazole-4-carboxamide was prepared from 3-amino-8-methyl-8-azabicyclo[3.2.1]octane and 2-phenylbenzoxazole-4-carboxylic acid using conditions similar to those described for Step C in Example 1. This compound was obtained in 25% yield as a white solid; mp 149-151° C.; 1H NMR (300 MHz, CDCl3) δ 9.55 (d, J=7.6 Hz, 1H), 8.29 (m, 2H), 8.22 (dd, 1H, J=7.8, 1.0 Hz, 1H), 7.72 (dd, J=8.1, 1.0 Hz, 1H), 7.65-7.55 (m, 3H), 7.47 (t, J=8.0 Hz, 1H), 4.48 (q, 1H, J=7.2 Hz), 3.25 (br s, 2H), 2.43-2.24 (m, 9H), 1.87 (d, J=14.2 Hz, 2H); MS (APCI) m/z 362 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[C:18]([CH3:20])[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([OH:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl.Cl[CH2:26][C:27]1[CH:28]=[C:29]([CH:42]=[CH:43][CH:44]=1)[O:30][CH2:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:21][CH2:26][C:27]2[CH:44]=[CH:43][CH:42]=[C:29]([O:30][CH2:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=3)[CH:28]=2)[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:18]([CH3:20])[CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C)cc(OCc2ccccc2)cc1O
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)cc(OCc2ccccc2)cc1OCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 4-benzyloxy-2-hydroxy-6-methyl-benzoate (5.1 g, 16 mmol, example 63) in DMF (100 mL), with 25° C. water bath cooling, is added 60% sodium hydride emulsion (1.3 g, 32 mmol) over 2 minutes. This mixture is stirred 30 minutes with the cooling bath removed. A solution of 3-(quinolin-2-ylmethoxy)-benzyl chloride hydrochloride (5.1 g, 16 mmol, example 49), in DMF (55 mL) is added and the reaction heated at 60° C. for 6 hours. The solvent is removed in vacuo and the residue purified by flash chromatography (silica, 0.5 to 2% methanol in dichloromethane) to give the title compound. MS (ESI) 534 (M+H)+.
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:23]([O:25]CC)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:28]([NH:32][CH2:33][CH2:34][CH3:35])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].C(O)C>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[C:28]([NH:32][CH2:33][CH2:34][CH3:35])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cccc(NCCC)c2n1Cc1ccc(-c2ccccc2C(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc2cccc(NCCC)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 72 from ethyl 4'-[(2-n-butyl-7-n-propylamino-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and 2N sodium hydroxide/ethanol.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[C:12]([NH:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[F:22])=[O:13])C1C=CC=CC=1>CO>[F:22][C:16]1[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=1[NH:14][C:12](=[O:13])[C:11]1[CH:23]=[CH:24][CH:25]=[C:9]([OH:8])[CH:10]=1
Reactant: Cc1ccc(F)c(NC(=O)c2cccc(OCc3ccccc3)c2)c1
Solvent: CO
Product: Cc1ccc(F)c(NC(=O)c2cccc(O)c2)c1

Procedure:
A solution of 3-(benzyloxy)-N-(2-fluoro-5-methylphenyl)benzamide (1.5 g, 4.48 mmol from Step 1) in 20 ml of MeOH containing 10% Pd/C (150 mg) was stirred under a hydrogen balloon at room temperature for 2 hours. The catalyst was removed by filtration. The filtrate solution was evaporated to dryness under reduced pressure to give N-(2-fluoro-5-methylphenyl)-3-hydroxybenzamide as light-beige solid. Yield: 1.1 g, 100%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[C:13]([CH3:18])=[N:14][O:15][C:16]=2[CH3:17])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[N+:19]([O-])([OH:21])=[O:20].O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][S:9]([C:12]2[C:13]([CH3:18])=[N:14][O:15][C:16]=2[CH3:17])(=[O:10])=[O:11])=[C:6]([N+:19]([O-:21])=[O:20])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1noc(C)c1S(=O)(=O)Nc1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1noc(C)c1S(=O)(=O)Nc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 64.4 %

Procedure:
To a solution of N-(4-Chlorophenyl)-3,5-dimethyl-4-isoxazolesulfonamide (1.10 g (3.84 mmol)) in acetic acid (4.0 ml), fuming nitric acid (0.20 ml (4.68 mmol)) was added dropwise with stirring at room temperature, and the mixture was heated at 50° C. for one hour with stirring. Water (20.0 ml) was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium hydroxide solution and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with acetone-chloroform-hexane(1:3:8) as eluent, to give 0.82 g (64%) of N-(4-chloro-2-nitrophenyl)-3,5 dimethyl-4-isoxazolesulfonamide as yellow crystals.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[C:17]#[C:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.[CH3:29][CH:30]([CH3:57])[C@H:31]([NH:39][C:40](=[O:56])[C:41]1[CH:46]=[CH:45][C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][CH:42]=1)[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>>[CH3:29][CH:30]([CH3:57])[C@H:31]([NH:39][C:40](=[O:56])[C:41]1[CH:42]=[CH:43][C:44]([C:2]2[N:6]3[N:7]=[CH:8][CH:9]=[C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[C:5]3=[N:4][C:3]=2[C:17]#[C:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[CH:45][CH:46]=1)[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]
Reactant: Brc1c(C#Cc2ccc3ccccc3n2)nc2c(N3CCOCC3)ccnn12
Reactant: CC(C)[C@H](NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC(C)(C)C
Product: CC(C)[C@H](NC(=O)c1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1)C(=O)OC(C)(C)C

Procedure:
Compound 18b was subjected to Suzuki coupling conditions with compound 43a as described in Example 38, Step A to obtain compound 43b as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C32H38N6O4: 631.3 (M+H). Found: 631.0.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:16](OC(=O)C)(=[O:18])[CH3:17].[BH4-].[Na+]>C(O)(=O)C>[C:16]([N:13]1[CH2:14][CH2:15][C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:11][CH2:12]1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cccc(-c2ccncc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)N1CC=C(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 26 %

Procedure:
To a mixture of 4-(3-nitrophenyl)pyridine (Example 6g) (4.0 g; 20.0 mmol) and acetic anhydride (20 ml) in glacial acetic acid (30 ml) was added sodium borohydride (1.51 g; 40.0 mmol) in portions over one hour. The resulting mixture was stirred at ambient temperature for five days and then poured into ice-water. The mixture was extracted with ethyl acetate, the organic phase was washed with water, dried over magnesium sulphate and concentrated under reduced pressure. The residue was eluted through silica gel with ethyl acetate to yield 6h (1.29 g; 26%).