Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25]([CH2:28][C:29]5[C:30]([F:40])=[C:31]6[C:36](=[CH:37][C:38]=5[F:39])[N:35]=[CH:34][CH:33]=[CH:32]6)=[CH:26][N:27]=4)[N:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:40][C:30]1[C:29]([CH2:28][C:25]2[N:23]3[N:24]=[C:19]([C:17]4[CH:16]=[N:15][N:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:18]=4)[CH:20]=[CH:21][C:22]3=[N:27][CH:26]=2)=[C:38]([F:39])[CH:37]=[C:36]2[C:31]=1[CH:32]=[CH:33][CH:34]=[N:35]2
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc4ncc(Cc5c(F)cc6ncccc6c5F)n4n3)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cc2ncccc2c(F)c1Cc1cnc2ccc(-c3cnn(C4CCNCC4)c3)nn12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-{4-[3-(5,7-Difluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (Example 244, 219 mg, 0.401 mmol) was dissolved in DCM (3 mL) with TFA (0.619 mL, 8.03 mmol). The RM was stirred at rt for 1 h 15 min and it was quenched with ice water. It was extracted with EtOAc twice. The combined organic layers was washed with brine and dried over Na2SO4. It was filtered and the solvent was removed. The residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and the acetonitrile was removed. The aqueous solution was basified with 5% NaHCO3 solution and was extracted with EtOAc twice. Combined organic layers was washed with brine and dried over Na2SO4. It was filtered to afford after evaporation of the solvent the title compound as a white solid (tR 0.8 min (conditions 2), MH+=446).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[F-:12].[K+].C1S(=O)(=O)CCC1>>[F:12][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [F-]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1ccc(F)c(F)c1
Temperature: 110 °C
Yield: 10.3 %

Procedure:
1,500 parts of 3-chloro-4-fluoronitrobenzene and 1,000 parts of potassium fluoride are heated in 1,500 parts of tetramethylenesulfone for 16 hours at 230° C. The solution is cooled to 110° C. and filtered, the solid residue is washed with 500 parts of methylene chloride and the filtrates are combined and distilled. 139 parts (10.3% of theory) of 3,4-difluoronitrobenzene of boiling point 54° C./1 mbar are obtained.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:8].[CH2:19]([NH:21][CH:22]1[CH2:30][CH2:29][C:25]2[N:26]=[CH:27][S:28][C:24]=2[CH2:23]1)[CH3:20]>>[CH2:19]([N:21]([CH:22]1[CH2:30][CH2:29][C:25]2[N:26]=[CH:27][S:28][C:24]=2[CH2:23]1)[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:8])[CH3:20]
Reactant: O=CCCCNC(=O)c1ccc2ccccc2c1
Reactant: CCNC1CCc2ncsc2C1
Product: CCN(CCCCNC(=O)c1ccc2ccccc2c1)C1CCc2ncsc2C1
Yield: 22 %

Procedure:
Compound 4 is prepared from 2E and 4C as described for 1. The salt of oxalic acid is crystallized from ethanol/diethylether.
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]([CH3:30])([CH3:29])[CH2:10][O:11][CH2:12]/[C:13](/[CH3:28])=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH3:31]>CC(O)C>[NH2:31]/[C:3](/[CH3:5])=[CH:2]\[C:1]([O:7][CH2:8][C:9]([CH3:30])([CH3:29])[CH2:10][O:11][CH2:12]/[C:13](/[CH3:28])=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1)=[O:6]
Reactant: CC(=O)CC(=O)OCC(C)(C)COC/C(C)=C/c1ccc(Cc2cccnc2)cc1
Reactant: N
Solvent: CC(C)O
Product: C/C(N)=C/C(=O)OCC(C)(C)COC/C(C)=C/c1ccc(Cc2cccnc2)cc1

Procedure:
In 9.5 ml of 2-propanol was dissolved 1.9 g of 3-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyloxy]-2,2-dimethylpropyl acetoacetate, and an ammonia gas was blown thereinto with ice-cooling for 30 minutes, after which the resulting mixture was subjected to reaction at room temperature for one day. Subsequently, the solvent was removed by distillation under reduced pressure to obtain oily 3-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyloxy]-2,2-dimethylpropyl 3-aminocrotonate. This oily product and 1.15 g of methyl 2-(3-nitrobenzylidene)acetoacetate were dissolved in 9.5 ml of 2-propanol, and the resulting solution was subjected to reaction under reflux for 3 hours. Subsequently, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Merck Silica Gel, 70-230 mesh, eluant: n-hexane:acetone (2:1 by volume)] to obtain 2.34 g (yield 79.0%) of yellow and oily 3-[3-[ (E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyloxy]-2,2-dimethylpropyl]5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[C:5]([S:10]([NH:13][C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[O:15])(=[O:12])=[O:11])=[CH:4][N:3]=1.[Na].C(C1C=CC=CC=1)(=[O:28])C1C=CC=CC=1.ClC1C=CC=C(C(OO)=O)C=1>C1COCC1>[CH3:18][CH:17]([NH:16][C:14]([NH:13][S:10]([C:5]1[C:6]([S:8]([CH3:9])=[O:28])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1)(=[O:12])=[O:11])=[O:15])[CH3:19]
Reactant: CSc1nc(N)ncc1S(=O)(=O)NC(=O)NC(C)C
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)NC(=O)NS(=O)(=O)c1cnc(N)nc1S(C)=O
Yield: 84 %

Procedure:
2-Amino-N-[[(1-methylethyl)amino]carbonyl]-4-(methylthio)-5-pyrimidinesulfonamide (3.0 g, 9.84 mmol) was dissolved in dry (freshly distilled from sodium/benzophenone) THF (60 mL) and m-chloroperbenzoic acid (MCPBA) (2.55 g, 11.81 mmol, 80% 1.2 eq) was added as a solid. The reaction turned yellow and a white solid precipitated out of solution. After 90 minutes the reaction was diluted with ethyl ether (60 mL) and the white solid was filtered, washed with THF, then with ether three times and air dried for 2 hours, to yield 2.64 g (8.22 mmol, 84%) of product, m.p. 140° C. (dec.). The product was unstable to heat but could be stored under nitrogen in the freezer for weeks.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:7]([N:25]=[C:26]([NH2:28])[N:27]=3)[C:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[C:14]=3[O:23][CH3:24])=[N:9][C:10]=2[CH:11]=1.O1C2C=CC(CC3N4N=C(N)N=C4C4C=CC(F)=CC=4N=3)=CC=2OC1.[OH:54][CH2:55][CH2:56][NH2:57]>>[NH2:28][C:26]1[N:27]=[C:6]2[N:7]([C:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[C:14]=3[O:23][CH3:24])=[N:9][C:10]3[CH:11]=[C:2]([NH:57][CH2:56][CH2:55][OH:54])[CH:3]=[CH:4][C:5]=32)[N:25]=1
Reactant: COc1ccc(Cc2nc3cc(F)ccc3c3nc(N)nn23)c(OC)c1OC
Reactant: NCCO
Agent: Nc1nc2c3ccc(F)cc3nc(Cc3ccc4c(c3)OCO4)n2n1
Product: COc1ccc(Cc2nc3cc(NCCO)ccc3c3nc(N)nn23)c(OC)c1OC
Yield: 27 %

Procedure:
Operating as in Example 54, but employing 8-fluoro-5-(2,3,4-trimethoxy-benzyl)-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine prepared as described in Example 33, instead of 5-benzo[1,3]dioxol-5-ylmethyl-8-fluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine and 2-hydroxy-ethylamine instead of morpholine, the title compound was obtained in 27% yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[N:3]=1.[CH3:21][S:22]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)(=[O:24])=[O:23].C(=O)([O-])[O-].[Na+].[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH:30]=2)[N:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[N:5]=1
Reactant: FC(F)(F)Oc1ccc(Nc2nc(Cl)cc(Cl)n2)cc1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(-c2cc(Cl)nc(Nc3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared by reacting (4,6-dichloro-pyrimidin-2-yl)-(4-trifluoromethoxy-phenyl)-amine (0.3 g, 0.92 mmol) with 3-methanesulfonyl-phenyl boronic acid (0.37 g, 1.85 mmol) in presence of Pd(OAc)2 (7 mg, 0.02 mmol) and sodium carbonate (0.78 g, 7.4 mmol) in a solvent DMF (10 mL) at 80° C. for 12 hours, followed by work up and column purification.
Reaction SMILES: O.[OH-].[Na+].[OH:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[C:14]([C:15]4[C:20]=2[C:19]=1[CH:18]=[CH:17][CH:16]=4)=[CH:13][CH:12]=[C:11]([OH:21])[CH:10]=3.Cl.[CH2:23]([N:25]([CH2:30][CH3:31])[CH2:26][CH2:27][CH2:28]Cl)[CH3:24]>C1(C)C=CC=CC=1>[CH2:23]([N:25]([CH2:30][CH3:31])[CH2:26][CH2:27][CH2:28][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[C:14]([C:15]4[C:20]=2[C:19]=1[CH:18]=[CH:17][CH:16]=4)=[CH:13][CH:12]=[C:11]([O:21][CH2:28][CH2:27][CH2:26][N:25]([CH2:30][CH3:31])[CH2:23][CH3:24])[CH:10]=3)[CH3:24]
Reactant: Oc1ccc2c(c1)-c1ccc(O)c3cccc-2c13
Reactant: CCN(CC)CCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(CC)CCCOc1ccc2c(c1)-c1ccc(OCCCN(CC)CC)c3cccc-2c13

Procedure:
To 200 ml of water containing 16.0 g (0.4 mole) of sodium hydroxide and 15.7 g (0.067 mole) of 3,9-dihydroxyfluoranthene are added 200 ml of toluene and 27.9 g (0.15 mole) of 3-diethylaminopropyl chloride hydrochloride, and the heterogeneous reaction mixture is stirred at reflux for 24 hours. After cooling, the organic layer is washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue is crystallized from ether to give 3,9-bis(3-diethylaminopropoxy)-fluoranthene which is converted to the dihydrochloride salt with ethereal HCl and recrystallized from methanolbutanone, M.P. 235°-236.5°C.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([N+:14]([O-])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[NH2:14][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: CC(C)(C)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1ccc(C(=O)O)c(N)c1
Yield: 10.3 %

Procedure:
4-tert-Butyl-2-nitro-benzoic acid (199 mg, 8.91 mmol), and 10% palladium on carbon (40 mg) were stirred in 6 mL ethanol under an atmosphere of hydrogen for 3 hours. The resulting mixture was filtered and concentrated in vacuo to yield 2-Amino-4-tert-butyl-benzoic acid (177 mg, 0.916 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:14]2[CH2:17][N:16](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:15]2)[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.ClC(OC(Cl)C)=O>C1COCC1>[NH:16]1[CH2:17][C:14](=[C:9]([C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=2)[C:10]([O:12][CH3:13])=[O:11])[CH2:15]1
Reactant: COC(=O)C(=C1CN(C(c2ccccc2)c2ccccc2)C1)c1cc(F)cc(F)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)C(=C1CNC1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.405 g (1 mmol) of methyl (3,5-difluorophenyl)[1-(diphenylmethyl)azetidin-3-ylidene]acetate in 2 mL of dry THF was added 0.284 g (2 mmol) of 1-chloroethyl chloroformate and the solution was stirred at room temperature. After 1 h, the solution was concentrated and the residue was triturated with 2 mL of 10% ether-hexane. This was decanted and the solid residue was dissolved in methanol and heated to reflux for 6 h. The solution was concentrated to afford the title compound as the hydrochloride salt: Mass Spectrum: m/e=240 (M+1).
Reaction SMILES: CO[CH:3]([O:18]C)[CH2:4][NH:5][CH2:6][CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1O.OS(O)(=O)=O>C(Cl)(Cl)Cl>[CH2:4]1[CH:3]2[N:8]([C:9](=[O:17])[C:10]3[C:11]([O:18]2)=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:7][CH2:6][NH:5]1
Reactant: COC(CNCCNC(=O)c1ccccc1O)OC
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2OC2CNCCN12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of N-[2-(2,2-dimethoxy-ethylamino)-ethyl]-2-hydroxy benzamide (300 mg, 1.11 mmol) in CHCl3 (100 mL) was added conc H2SO4 (2 mL). The reaction was refuxed overnight, then cooled to room temperature then poured into a mixture of ice-saturated NaHCO3 solution. The mixture was extracted with EtOAc (3×50 mL). The organic layers were combined, washed with brine, dried on MgSO4, and conc in vacuo to yield a yellowish oil. The oil was then purified by chiral HPLC using an OD column with 10% iPrOH in heptane to yield 50 mg of the R enantiomer as white solid, MS (ESI) 205 (M+H), and 56 mg of the S enantiomer as white solid, MS (ESI) 205 (M+H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][CH:4]=1.[CH2:10]([O:12][Si:13](OCC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[CH3:11]>C(OCC)C>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([Si:13]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])[O:12][CH2:10][CH3:11])=[CH:4][CH:5]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CCO[Si](OCC)(OCC)OCC
Agent: [Mg]
Solvent: CCOCC
Product: CCO[Si](OCC)(OCC)c1ccc(Br)cc1
Reaction time: 8 h

Procedure:
Freshly activated magnesium (8.5 g, 0.35 mol) was slowly added over a period of four hours to a solution of 1,4-dibromobenzene (80 g, 0.34 mol) in 200 mL of diethylether, keeping the temperature below 30° C. The reaction mixture was stirred for 8 h and then slowly added to a mixture of tetraethoxysilane (100 mL, 0.44 mol) in Et2O (50 mL). The mixture was stirred for 12 h, and unreacted tetraethoxysilane and diethylether were removed in vacuum. The remaining liquid was fractionally distilled through a Vigreux column under reduced pressure to provide 4-bromophenyltriethoxysilane as a clear oil (37 g, 37%, bp 80–90° C. at 250 μHg). 1HNMR(400 MHz, CDCl3): δ 7.56 (4H, dd), 3.89 (6H, q), 1.27 (9H, t). 13CNMR (100 MHz, CDCl3): δ 136.4, 131.1, 58.8, 18.2. GC-MS: 318 (M+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12](Cl)[C:11]=2[Cl:21])[CH:5]=[N:4]1)[CH3:2].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:11]=2[Cl:21])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(Cl)c2Cl)c1O
Reactant: C1COCCN1
Solvent: O
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(N3CCOCC3)c2Cl)c1O
Reaction time: 48 h

Procedure:
A solution of 1.5 g (4.1 mmol) of 1-ethyl-4-(2,3-dichloro-4-methylsulfonylbenzoyl)-5-hydroxypyrazole in 30 mL of morpholine was heated at 100° C. with stirring for 2 days. The reaction mixture was then diluted with water, washed with diethyl ether, and acidified with hydrochloric acid. The resulting solution was extracted with dichloromethane and the extract was concentrated by evaporation under reduced pressure. The resulting residue was recrystallized from ethanol/dichloromethane to obtain to 0.33 g (20 percent of theory) of the title compound as a white solid.
Reaction SMILES: C(O[C:4]([CH:6]1[C:11](=O)[CH2:10][CH2:9][N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)=[O:5])C.Cl.[N+:21]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH2:29])=[NH:28])([O-:23])=[O:22]>>[CH2:13]([N:8]1[CH2:9][CH2:10][C:11]2[N:28]=[C:27]([C:26]3[CH:30]=[CH:31][CH:32]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=3)[N:29]=[C:4]([OH:5])[C:6]=2[CH2:7]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: N=C(N)c1cccc([N+](=O)[O-])c1
Agent: Cl
Product: O=[N+]([O-])c1cccc(-c2nc(O)c3c(n2)CCN(Cc2ccccc2)C3)c1

Procedure:
The title compound was prepared from 1-benzyl-4-oxo-piperidine-3-carboxylic acid ethyl ester and 3-nitro-benzamidine hydrochloride according to general procedure 1. 1H NMR (DMSO-d6, 400 MHz) δ 2.76 (s, 4H), 3.28 (s, 2H), 3.71 (s, 2H), 7.25-7.40 (m, 6H), 7.81 (t, J=8.0 Hz, 1H), 8.35-8.40 (m, 1H), 8.52 (d, J=8.0 Hz, 2H), 8.93 (s, 1H); MS: m/z (ESI) 363 (M+H).
Reaction SMILES: C(S[C:9](=[O:46])[CH:10]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH:11]([OH:38])[CH:12]=[CH:13][CH:14]([OH:37])[CH2:15][CH:16]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:20][CH:19]=1)C1C=CC=CC=1.[Li+].[OH-:48].OO.Cl>C1COCC1>[CH2:39]([CH:10]([CH:11]([OH:38])[CH:12]=[CH:13][CH:14]([OH:37])[CH2:15][CH:16]([NH:29][C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[CH:20][CH:19]=1)[C:9]([OH:46])=[O:48])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)CC(O)C=CC(O)C(Cc1ccccc1)C(=O)SCc1ccccc1
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)CC(O)C=CC(O)C(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
16 stereoisomers of 50 were synthesized by the following procedure: To a solution of 49 (1.0 equiv) in THF (60 mL/mmol) was added 0.2 N LiOH (aq) (2.0 equiv) and 30% H2O2 (aq) (equal volume to LiOH (aq)). The solution was stirred for 3 h at room temperature, then acidified with 1 N HCl (aq) to pH=1 and extracted with CH2Cl2. The organic solution was dried over Na2SO4, concentrated under reduced pressure, and purified by flash chromatography to afford 50 in 64–84% yield on 0.020 to 0.030 mmol scale.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH2:28][CH:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1.[Cl-].[NH4+]>CN(C=O)C.ClCCl.CO.C(OCC)(=O)C>[Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:27][CH2:28][CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][N:16]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: Oc1ccc2nc(Cl)[nH]c2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(Oc3ccc4nc(Cl)[nH]c4c3)ncnc2cc1OCC1CCN(C)CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 16.3 %

Procedure:
To a portion of 2-chloro-5-hydroxybenzimidazole (191 mg, 0.75 mmol) in DMF (3 ml) was added sodium hydride (60 mg, 1.5 mmol) under argon at ambient temperature. Ten minutes later 4-chloro-6-methoxy-7-(1-methylpiperidin-4-yl)methoxyquinazoline (200 mg, 0.62 mmol), (prepared as described for the starting material in Example 10), was added and the mixture heated at 100° C. for 2 hours. More 2-chloro-5-hydroxybenzimidazole (30 mg, 0.12 mmol) and sodium hydride (11 mg, 0.28 mmol) were then added as the reaction was found to be incomplete. The heating was continued for an additional 1 hour. Work-up using ethyl acetate and a saturated aqueous solution of ammonium chloride followed by drying of the organic phase (MgSO4) and evaporation of the solvent gave a crude product which was adsorbed on alumina using dichloromethane/methanol and purified by flash chromatography using neutral alumina and dichloromethane/methanol (98:2) as the eluent. Evaporation of the solvent and trituration in ether gave 4-(2-chloro-1H-benzimidazol-6-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (46 mg, 16%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14]C(C)(C)C)=[O:13])=[CH:6][CH:5]=1.Cl.O1CCOCC1>>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:5]=[CH:6][C:7](/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(/C=C/C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(/C=C/C(=O)O)cc1
Yield: 54.7 %

Procedure:
The crude 4-((E)-2-tert-butoxycarbonyl-vinyl)-benzoic acid methyl ester (1.00 g, 3.81 mmol) was then treated with 4N HCl in dioxane (Aldrich, 4 mL, 16.0 mmol) at rt for 2 hrs to give 4-((E)-2-carboxyvinyl)-benzoic acid methyl ester (0.43 g, 64.5%, 2 steps) after work up.
Reaction SMILES: [F:1][C:2]([F:37])([C:6]([F:36])([F:35])[C:7]([F:34])([F:33])[C:8]([F:32])([F:31])[C:9]([F:30])([F:29])[C:10]([F:28])([F:27])[C:11]([F:26])([F:25])[C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])C(O)=O.[Br:38]Br.FF>Cl>[F:1][C:2]([Br:38])([F:37])[C:6]([F:36])([F:35])[C:7]([F:34])([F:33])[C:8]([F:32])([F:31])[C:9]([F:30])([F:29])[C:10]([F:28])([F:27])[C:11]([F:26])([F:25])[C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16]
Reactant: BrBr
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Agent: FF
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Br
Yield: 200 %

Procedure:
Perfluorododecanoic acid 404 g (0.565 mole), bromine 49.4 g (0.309 mole) and Freon 113 (400 ml) were treated with fluorine at 30°-37° C. The reaction mixture was poured into 2N hydrochloric acid (500 ml) and the freon solvent was directly distilled off from the mixture. The residue was cooled and the precipitated solids were collected through known filtration techniques. The precipitate was then distilled under vacuum, to give pure perfluoroundecyl bromide 401 g (95% yield). The bromide has a boiling point of 105° C./2 mm Hg and a melting point of 96°-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([N:16]3[C:25]4[C:20](=[CH:21][C:22]([S:26](OC5C(F)=C(F)C(F)=C(F)C=5F)(=[O:28])=[O:27])=[CH:23][CH:24]=4)[CH:19]=[C:18]([O:41][CH3:42])[C:17]3=[O:43])=[CH:10][C:9]=2[F:44])=[CH:4][C:3]=1[CH3:45].[O:46]1[CH:50]=[CH:49][C:48]([NH2:51])=[N:47]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([N:16]3[C:25]4[C:20](=[CH:21][C:22]([S:26]([NH:51][C:48]5[CH:49]=[CH:50][O:46][N:47]=5)(=[O:27])=[O:28])=[CH:23][CH:24]=4)[CH:19]=[C:18]([O:41][CH3:42])[C:17]3=[O:43])=[CH:10][C:9]=2[F:44])=[CH:4][C:3]=1[CH3:45]
Reactant: COc1cc(-c2ccc(Cl)c(C)c2)c(F)cc1-n1c(=O)c(OC)cc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1ccon1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2ccc(Cl)c(C)c2)c(F)cc1-n1c(=O)c(OC)cc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
A flask was charged with perfluorophenyl 1-(4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)-3-methoxy-2-oxo-1,2-dihydroquinoline-6-sulfonate (0.2262 g, 0.338 mmol) and isoxazol-3-amine (0.034 g, 0.405 mmol). A septum was attached and THF (3.4 ml) was added under N2 flow. The solution was cooled to 0° C. and LHMDS (0.709 ml, 0.709 mmol) was added to give a bright yellow solution. After 10 min, 5 mL of 1 N HCl was added and the mixture was partitioned between 1 N HCL (10 mL) and EtOAc (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (1×10 mL). The combined organic layers were dried (Na2SO4) and concentrated for purification by MPLC (Biotage Isolera). The crude residue was taken up in minimal DCM and absorbed onto a 5 g loading cartridge and passed through a Interchim 25 g spherical silical gel column using a gradient of 5% EtOH and 15% EtOAc in heptane to 25% EtOH in EtOAc with 10% DCM constant additive to afford 1-(4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-3-methoxy-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.187 g, 0.328 mmol, 97% yield) as a colorless foam. The racemic product was subjected to chiral separation by SFC on a Chiralcel OJ column (45% MeOH/80% CO2) to give (M)-1-(4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-3-methoxy-2-oxo-1,2-dihydroquinoline-6-sulfonamide as peak 1 and (P)-1-(4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-3-methoxy-2-oxo-1,2-dihydroquinoline-6-sulfonamide as peak 2. Data for peak 1: 1H NMR (500 MHz, DMSO-d6) δ 11.59 (br.s, 1H), 8.66 (d, J=1.62 Hz, 1H), 8.20 (d, J=1.88 Hz, 1H), 7.60-7.70 (m, 2H), 7.40-7.58 (m, 4H), 7.25-7.38 (m, 1H), 6.74 (d, J=8.89 Hz, 1H), 6.38 (d, J=1.56 Hz, 1H), 3.84 (s, 3H), 3.67 (s, 3H), 2.37 (s, 3H). m/z (ESI) 568.2 (M+H)+. Data for peak 2: 1H NMR (500 MHz, DMSO-d6) δ 11.56 (br. s, 1H), 8.65 (d, J=1.56 Hz, 1H), 8.19 (d, J=1.95 Hz, 1H), 7.60-7.71 (m, 2H), 7.40-7.57 (m, 4H), 7.32 (d, J=6.88 Hz, 1H), 6.73 (d, J=8.89 Hz, 1H), 6.37 (d, J=1.62 Hz, 1H), 3.83 (s, 3H), 3.66 (s, 3H), 237 (s, 3H). m/z (ESI) 568.2 (M+H)+.