Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[O:20]1CCC[CH2:21]1.CCCCCCC.C(C1C=CC=CC=1)C.C=O>C1COCC1>[Br:1][C:2]1[C:10]2[C:6](=[C:7]([CH2:21][OH:20])[N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cc2cccc(Br)c2n1
Reactant: C1CCOC1
Agent: C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Product: Cn1nc2c(Br)cccc2c1CO
Temperature: 2.5 °C
Yield: 93.7 %

Procedure:
To a solution of 7-bromo-2-methyl-2H-indazole (6: R=Me; 0.578 g, 2.93 mmol) in 15 mL of THF at −78° C. was added a 2.0 M solution of lithium diisopropylamide in tetrahydrofuran/heptane/ethylbenzene (1.8 mL, 3.6 mmol). The yellow-orange solution was stirred at 0-5° C. for 15 m, then rechilled to −78° C. for 15 m. Paraformaldehyde (0.92 g) was added, and the orange mixture was rapidly stirred at −78° C. for 75 m then at room temperature for 100 m. The mixture was loaded onto silica gel and concentrated. Column chromatography (0→66% EtOAc/hexanes) afforded 0.662 g of impure (7-bromo-2-methyl-2H-indazol-3-yl)-methanol (14a).
Reaction SMILES: Br[C:2]1[C:3]([CH3:19])=[N:4][N:5]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])=[C:8]([CH3:18])[O:7][C:6]=12.C([Li])CCC.[N:25]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[N:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>C1COCC1>[C:37]([O:36][C:34]([NH:25][N:26]([C:2]1[C:3]([CH3:19])=[N:4][N:5]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])=[C:8]([CH3:18])[O:7][C:6]=12)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: Cc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1Br
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 7-bromo-3-(2,4-dichloro-phenyl)-2,6-dimethyl-pyrazolo[5,1-b]oxazole (710 mg, 1.972 mmol) in THF (15.5 ml) under N2 at −78° C. is added n-butyllithium (0.789 ml, 1.972 mmol) dropwise; the temperature is maintained below −70° C. for the addition and then the reaction mixture is stirred for 5 mins at −78° C. before the addition of di-tert-butyl azodicarboxylate (545 mg, 2.366 mmol) in THF (1.5 ml); the temperature is maintained below −60° C. for the period of the addition. After stirring at −78° C. for 30 mins, the reaction is quenched with sat. ammonium chloride solution and allowed to warm to RT. Ammonium chloride solution (sat.) is added and the mixture is extracted with EtOAc (2×100 ml). The combined organics extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product is purified ISCO chromatography eluting (0 to 100%) EtOAci iso-hexane on a 40 g SiO2 cartridge to give the title compound as an orange solid; MS: m/z 511.22 [M+H]+
Reaction SMILES: [OH:1][CH:2]1[C@@H:7]2[C:8]([CH2:11][OH:12])=[CH:9][CH2:10][C@@H:6]2[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][O:3]1.[CH2:17](O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.FB(F)F.C(OCC)C>O1CCCC1>[CH2:17]([O:1][C@H:2]1[C@@H:7]2[C:8]([CH2:11][OH:12])=[CH:9][CH2:10][C@@H:6]2[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][O:3]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: COC(=O)C1=COC(O)[C@@H]2C(CO)=CC[C@H]12
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C1=CO[C@@H](OCc2ccccc2)[C@@H]2C(CO)=CC[C@H]12
Temperature: 75 °C
Yield: 38.6 %

Procedure:
1.13 g (5.0 mmol) of methyl (4aS,7aS)-1-hydroxy-7-hydroxymethyl-1,4a,5, 7a-tetrahydrocyclopenta[c]pyran-4-carboxylate was dissoved in 10 ml of dried tetrahydrofuran, then 2.60 ml (25 mmol) of benzyl alcohol and catalytic amount of trifluoroboron diethylether were added thereto. The resulting mixture was stirred while refluxing for 48 hours at 75° C. The mixture was cooled down to room temperature and concentrated. The residue was dissolved in ethylacetate and then washed with saturated aqueous sodium bicarbonate solution and saturated saline solution The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexanelethylacetate=2/1, v/v) to obtain 0.61 g (Yield 39%) of methyl (1R,4aS,7aS)-1-benzyloxy-7-hydroxymethyl-1,4a,5,7a-tetrahydrocyclopenta[c]pyran-4-carboxylate as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:21])=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[I-].C[N+]1C=CN([C:29](=[O:38])[N:30]([CH3:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)C=1>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:7]2[C:8](=[O:12])[O:9][C:10]3[C:5]([C:6]=2[CH3:21])=[CH:4][CH:3]=[C:2]([O:1][C:29](=[O:38])[N:30]([CH3:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:11]=3)=[CH:14][CH:15]=1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: COc1ccc(-c2c(C)c3ccc(O)cc3oc2=O)cc1
Agent: [I-]
Product: COc1ccc(-c2c(C)c3ccc(OC(=O)N(C)c4ccccc4)cc3oc2=O)cc1
Yield: 43.3 %

Procedure:
The title compound (90 mg, 43% yield, white solid) was prepared from 7-hydroxy-3-(4-methoxy-phenyl)-4-methyl-chromen-2-one (141 mg, 0.50 mmol) and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (175 mg, 0.51 mmol).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[N:10]2)[N:3]=1.[NH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1>>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[N:10]2)[N:3]=[C:2]([NH:16][CH:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)[CH:7]=1
Reactant: Cc1cc(C)n(-c2nc(Cl)cc(Cl)n2)n1
Reactant: NC1Cc2ccccc2C1
Product: Cc1cc(C)n(-c2nc(Cl)cc(NC3Cc4ccccc4C3)n2)n1

Procedure:
Was prepared according to example 3 from 4,6-dichloro-2-(3,5-dimethyl-pyrazol-1-yl)-pyrimidine and 2-aminoindan.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18]C)C.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][CH2:10][N:9]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=1)[CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH3:1])=[O:31]
Reactant: CCOC(=O)CCCCN(CCc1ccccc1OC)Cc1ccc(C(=O)OC)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCCCN(CCc1ccccc1O)Cc1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3.00 g (7.02 mmol) of methyl 4-{[(5-ethoxy-5-oxopentyl)(2-methoxy-phenethyl)amino]methyl}benzoate from Example 1.2 in 60 ml of methylene chloride is cooled to 0° C., and 23.16 ml (23.16 mmol) of a 1N boron tribromide solution in methylene chloride are added dropwise. The solution is stirred at 0° C. for one hour. After addition of 30 ml of dry methanol, the batch is heated at 60° C. for one hour. After cooling, the solvent is removed under reduced pressure and the residue is taken up in a mixture of 57 ml of ethyl acetate and 3 ml of methanol and made alkaline using 10% sodium carbonate solution. The aqueous phase is extracted repeatedly with ethyl acetate/methanol 9/1 and the combined organic phases are washed using saturated sodium chloride solution. After drying over magnesium sulphate and distillative removal of the solvent under reduced pressure, the crude product is purified by flash chromatography over silica gel (0.04-0.063 nm) using the mobile phase cyclohexane/ethyl acetate 2/1.
Reaction SMILES: [CH3:1]CCCCC.C[Si](C=[N+]=[N-])(C)C.[F:14][C:15]1[C:16]([C:21]([OH:23])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1>C(O)C.CN(C=O)C>[F:14][C:15]1[C:16]([C:21]([O:23][CH3:1])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)c1ncccc1F
Reactant: CCCCCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCO
Solvent: CN(C)C=O
Product: COC(=O)c1ncccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A hexane solution (3 mL) of 2 M trimethylsilyldiazomethane was added to a benzene/methanol mixed solvent (1/1, 12 mL) of 3-fluoropyridine-2-carboxylic acid (250 mg), and stirred at room temperature for 30 minutes. The solvent was evaporated off under reduced pressure from the reaction solution, and the resulting residue was purified through silica gel column chromatography (chloroform/methanol=40/1) to obtain the entitled compound (238 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([O:15][C@H:16]3[CH2:20][NH:19][C@H:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]3)=[CH:9][C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[CH:25]=[CH2:26].[CH:27]1([C@H:33]([NH:37][C:38]([O:40][CH2:41][C:42]([CH3:47])([CH3:46])[CH2:43][CH:44]=[CH2:45])=[O:39])[C:34](O)=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C.CCOC(C)=O>[CH:27]1([C@H:33]([NH:37][C:38]([O:40][CH2:41][C:42]([CH3:47])([CH3:46])[CH2:43][CH:44]=[CH2:45])=[O:39])[C:34]([N:19]2[CH2:20][C@H:16]([O:15][C:8]3[C:7]4[C:12](=[CH:13][C:4]([O:3][CH3:2])=[C:5]([CH:25]=[CH2:26])[CH:6]=4)[NH:11][C:10](=[O:14])[CH:9]=3)[CH2:17][C@H:18]2[C:21]([O:23][CH3:24])=[O:22])=[O:35])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: C=Cc1cc2c(O[C@H]3CN[C@H](C(=O)OC)C3)cc(=O)[nH]c2cc1OC
Reactant: C=CCC(C)(C)COC(=O)N[C@H](C(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCC(C)(C)COC(=O)N[C@H](C(=O)N1C[C@H](Oc2cc(=O)[nH]c3cc(OC)c(C=C)cc23)C[C@H]1C(=O)OC)C1CCCCC1
Reaction time: 0.25 h
Yield: 119.9 %

Procedure:
To a solution of the product from Step 4, methyl (4R)-4-[(7-methoxy-2-oxo-6-vinyl-1,2-dihydroquinolin-4-yl)oxy]-L-prolinate hydrochloride (0.84 g, 2.206 mmol) and linker B20, (2S)-cyclohexyl({[(2,2-dimethylpent-4-en-1-yl)oxy]carbonyl}amino)acetic acid (0.689 g, 2.316 mmol) in DMF (2 mL) was added DIPEA (1.156 mL, 6.62 mmol) and HATU (1.090 g, 2.87 mmol). After 15 min, the reaction was complete and 1 N HCl and EtOAc were added. The organic layer was washed with water and brine, dried over MgSO4 and the solvent was removed in vacuo. The crude product was purified on silica (gradient elution, 0-5% MeOH/DCM) to yield 1.65 g of material which still contained HATU residue. This was removed by extracting the material with EtOAc and 1N HCl (4×), water (1×) and brine (1×). The organic layer was dried over MgSO4 and the solvent was removed in vacuo to yield 1.13 g (82%) of the title compound. LRMS ESI+(M+H)+ 624.6.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][N:27]1[C:31](=[O:32])[C:30]([CH3:34])([CH3:33])[NH:29][C:28]1=[O:35]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:29]5[C:30]([CH3:34])([CH3:33])[C:31](=[O:32])[N:27]([CH3:26])[C:28]5=[O:35])=[N:7][CH:6]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Reactant: CN1C(=O)NC(C)(C)C1=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)N(C)C(=O)C3(C)C)nc2)CC1
Yield: 45.3 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (161 mg) described in Preparation Example 144 and 3,5,5-trimethylimidazolidine-2,4-dione (63 mg) described in Preparation Example 218 and by the reaction and treatment in the same manner as in Example 536, the title compound (84 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:23](=[O:25])[CH3:24])[C:10]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br)=[CH:11][CH:12]=2)[CH:7]=1.[OH:27][C:28]1[C:37]([CH2:38][CH2:39][CH3:40])=[C:36]([OH:41])[CH:35]=[CH:34][C:29]=1OC(=O)C.C(=O)([O-])[O-].[K+].[K+].[CH3:48][C:49](C)=[O:50]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:26])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:23](=[O:25])[CH3:24])[C:10]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:41][C:36]3[CH:35]=[CH:34][C:29]([C:49](=[O:50])[CH3:48])=[C:28]([OH:27])[C:37]=3[CH2:38][CH2:39][CH3:40])=[CH:11][CH:12]=2)[CH:7]=1
Reactant: CC(C)=O
Reactant: COC(=O)COc1ccc2ccc(OCCCCCBr)c(C(C)=O)c2c1
Reactant: CCCc1c(O)ccc(OC(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCCOc2ccc3ccc(OCC(=O)OC)cc3c2C(C)=O)ccc(C(C)=O)c1O

Procedure:
A mixture of 1.66 g of [[8-Acetyl-7-(5-bromopentyloxy)-2-naphthalenyl]oxy]acetic acid methyl ester, 0.76 g of 1-[2,4-dihydroxy-3-propylphenoxy]ethanone and 0.81 g of anhydrous potassium carbonate in 30 ml of anhydrous acetone and 10 ml of anhydrous dimethylformamide was stirred at reflux. An additional 0.8 g of anhydrous potassium carbonate was added after 15 hours. Reflux was continued for a total of 22 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil which was treated with ether and water. The organic phase was separated and washed with 1N sodium hydroxide, water and sodium chloride solution. The black oil from concentration of the organic phase was purified by flash column chromatography to yield 1.45 g. mp 87°-89° (69%) of [[8-Acetyl-7 -[5-(4-acetyl-3-hydroxy-2-propylphenoxy)-pentyloxy]-2-napththalenyl]oxy]acetic acid methyl ester.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[O:17]CCO2)=[C:9]([F:18])[CH:8]=1.[CH:19]1([C:25]([C:27]2[CH:32]=[CH:31][C:30]([O:33]COC)=[CH:29][CH:28]=2)=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.O>C1COCC1>[C:19]1(=[C:25]([C:27]2[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=2)[C:7]2[CH:12]=[CH:11][C:10]([CH:13]=[O:17])=[C:9]([F:18])[CH:8]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: Fc1cc(Br)ccc1C1OCCO1
Reactant: COCOc1ccc(C(=O)C2CCCCC2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(C(=C2CCCCC2)c2ccc(O)cc2)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 34.8 %

Procedure:
n-Butyllithium (1.6 M in hexanes, 1.33 mL, 2.13 mmol) was added dropwise to 88 (503 mg, 2.04 mmol) dissolved in anhydrous THF (25 mL) at −78° C. The reaction mixture was stirred for 20 min and 87 (460 mg, 1.85 mmol), dissolved in THF (25 mL), was added dropwise. The mixture was warmed slowly to RT and stirred overnight. Water (150 mL) was added and the mixture was extracted with ether (3×100 mL). The combined ethereal extracts were washed with water (200 mL), brine (200 mL), dried (MgSO4), and concentrated under reduced pressure. The resulting crude oil was taken up in a mixture of EtOH (10 mL) and 12 M HCl (2 mL) and refluxed for 2 h. Removal of solvent and flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 200 mg (35%) of 89 as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.60 (br s, 6H), 2.23 (m, 4H), 6.00 (s, 1H), 6.79 (d, J=8.2 Hz, 2H), 6.89-6.95 (m, 3H), 7.02 (d, J=7.9 Hz, 1H), 7.76 (t, J=7.6 Hz, 1H), 10.28 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH3:11].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.OS(C(F)(F)F)(=O)=O.[OH-].[Na+]>C(Cl)Cl.O.CO>[Br:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][C:5]([C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:19])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1ccc(OC)c(Br)c1
Reactant: O=C(Cl)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)c2ccccc2)c(OC)cc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 76 %

Procedure:
To a solution of 2-bromo-1,4-bis(methyloxy)benzene (2.0 g, 9.21 mmol) and benzoyl chloride (1.229 mL, 10.596 mmol, 1.15 eq) in DCM (9.5 mL, C=1.0M) at 0° C. was added triflic acid (0.815 mL, 9.21 mmol) over 5 min. The reaction mixture was allowed to warm to ambient temperature (40 min) and then slowly heated to gentle reflux (oil bath at 42° C.) and stirred for 48 h. The reaction mixture was cooled to r.t., and MeOH (0.3 mL) was added and stirring was continued for 30 min. The reaction mixture was poured into 80 mL of ice cooled water. The aqueous layer was neutralized with a 1 M NaOH solution. The layers were separated. The aqueous layer was extracted twice with DCM (2×20 mL). The combined organic phase was washed twice with a 1/1 water/brine mixture (2×30 mL), dried over MgSO4, filtered and concentrated in vacuo to a brown-orange oil. Then, MTBE (7 mL) was added and the mixture was stirred into an ultra-sound bath. The resulting solid was filtered, rinsed with 1:1 MTBE/hexanes mixture and air dried to afford [4-bromo-2,5-bis(methyloxy)phenyl](phenyl)methanone in 76% yield (2.258 g) as a white solid. 1H NMR (300 MHz, DMSO) δ 7.72 (d, J=8.5 Hz, 1H), 7.65 (t, J=7.4 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.45 (s, 1H), 7.10 (s, 1H), 3.81 (s, 2H), 3.63 (s, 2H), 13C NMR (75 MHz, DMSO) δ 194.5 (C═O), 150.7 (C), 149.7 (C), 136.7 (C), 133.5 (CH), 129.3 (2CH), 128.6 (2CH), 128.2 (C), 117.3 (CH), 113.3 (C), 112.5 (CH), 56.7 (OCH3), 56.5 (OCH3); MS (ESI) m/z: 321.1, 323.0 [M+H, 79Br, 81Br]+; 243.1, 245.0 [M-Ph, 79Br, 81Br]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.[CH3:12]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].CI>O>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[N:6]([CH3:12])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: Cn1cc(Br)cc([N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
A 1-L round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 5-bromo-3-nitro-2-hydroxypyridine (24.0 g, 0.11 mol), anhydrous DMF (280 mL) and powdered potassium carbonate (−350 mesh, 33.4 g, 0.24 mol), and the suspension stirred for 15 min at ambient temperature. After this time methyl iodide (17.1 g, 0.124 mol) was added, and the mixture stirred at room temperature for 18 h. The reaction mixture was then diluted with water (750 mL) and extracted with ethyl acetate (3×1.0 L). The organic extracts were combined, washed with brine (500 mL) and dried over sodium sulfate. After removing the drying agent by filtration, the filtrate was evaporated to dryness under reduced pressure. The resulting residue was purified by flash chromatography on silica to afford an 85% yield (21.7 g) of 41 as a yellow solid: mp 122-423° C.; 1H NMR (300 MHz, CDCl3) δ 8.37 (d, 1H, J=2.7 Hz), 7.26 (s, 1H), 3.68 (s, 3H); MS (ESI+) m/z 234 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:21](=[O:26])[NH:22][CH2:23][CH2:24][CH3:25].[NH:27]1[CH2:30][CH2:29][CH2:28]1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]3[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([N:27]4[CH2:30][CH2:29][CH2:28]4)=[O:17])[CH:13]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:21]([NH:22][CH2:23][CH2:24][CH3:25])=[O:26]
Reactant: C1CNC1
Reactant: CCCNC(=O)c1nnc2c(-c3cccc(C(=O)O)c3)cccc2c1N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CCCNC(=O)c1nnc2c(-c3cccc(C(=O)N4CCC4)c3)cccc2c1N
Temperature: 25 °C
Reaction time: 19 h
Yield: 82 %

Procedure:
To a stirred solution of 3-[4-amino-3-(propylcarbamoyl)cinnolin-8-yl]benzoic acid (67 mg, 0.191 mmol) dissolved in anhydrous DMF (2 mL) at ambient temperature under argon was added azetidine (16.4 mg, 0.287 mmol), N-methylmorpholine (29 mg, 0.287 mmol), 1-hydroxybenzotriazole (44 mg, 0.287 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcabodiimide hydrochloride (55 mg, 0.287 mmol). The mixture was stirred at ambient temperature for 19 hours then diluted with water and extracted with ethyl acetate. The residue from the organic extracts was purified by flash chromatography on silica gel eluting with increasingly polar gradient of ethyl acetate in hexanes to afford the title compound (61 mg, 82% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.54 (br, 1H), 8.03-7.64 (m, 6H), 7.53 (t, J=7.7 Hz, 1H), 4.38 (br, 2H), 4.25 (br, 2H), 3.47 (apparent quartet, J=7.0 Hz, 2H), 2.34 (apparent pentet, J=7.5 Hz, 2H), 1.67 (apparent sextet, J=7.0 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H) MS APCI, m/z=390 (M+H) HPLC 1.70 min.
Reaction SMILES: O.[OH-].[Li+].[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1[O:10][C:11]([CH3:43])=[C:12]([CH2:14][O:15][C:16]2[CH:42]=[CH:41][C:19]([CH2:20][O:21]/[N:22]=[C:23](/[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[CH:18][CH:17]=2)[N:13]=1.O.Cl>O1CCCC1.C(O)C>[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1[O:10][C:11]([CH3:43])=[C:12]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:20][O:21]/[N:22]=[C:23](/[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:41][CH:42]=2)[N:13]=1
Reactant: CCOC(=O)CCCCCC/C(=N\OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(CO/N=C(\CCCCCCC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
Lithium hydroxide monohydrate (143 mg) was added to a solution of ethyl E-8-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxyimino]-8-phenyloctanoate (618 mg) in tetrahydrofuran (6 ml)-water (4 ml)-ethanol (4 ml) and stirred at room temperature for 4 hours. 1N hydrochloric acid (3.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-8-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxyimino]-8-phenyloctanoic acid (523 mg, yield 90%) as colorless crystals. m.p. 75-77° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[O:11]=[C:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13]1.[C:22]([O:26][C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)=[O:28])([CH3:25])([CH3:24])[CH3:23].O>C1(C)C=CC=CC=1.O1CCCC1>[C:22]([O:26][C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][C:12]1=[O:11])=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C1CCc2ccccc2N1
Reactant: CC(C)(C)OC(=O)NCCCCCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCCCN1C(=O)CCc2ccccc21
Temperature: 25 °C

Procedure:
0.5M Potassium bis-(trimethylsilyl)-amide in toluene (10 ml) was added dropwise at −30° C. in an argon atmosphere to a stirred solution of 2-oxo-1,2,3,4-tetrahydroquinoline (735 mg) in tetrahydrofuran (50 ml). After further cooling to −50° C. a solution of N-(tert-butoxycarbonyl)-6-bromo-hexylamine (1.5 g) in tetrahydrofuran (10 ml) was added slowly. Subsequently the temperature was allowed to raise to room temperature followed by heating at 50-60° C. for 48 hours. Ice and water were added and the mixture was extracted twice with ethyl acetate. The organic phases were washed with saturated sodium chloride, dried and evaporated to leave a yellow oil which after purification by chromatography on silica gel with ethyl acetate/hexane (1:1) as eluent gave the desired compound as a colourless oil.