Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C([O-])(=O)C.[Na+].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH:6][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)[C@H](N)CC(C)C
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: COC(=O)[C@@H](CC(C)C)NCc1ccccc1
Reaction time: 0.25 h
Yield: 87.9 %

Procedure:
D-Leucine methyl ester hydrochloride (35 g, 193 mmol) is dissolved in methanol. To this is added sodium acetate (39.4 g, 480 mmol), followed by benzaldehyde (19.8 mL, 195 mmol). This mixture is stirred for 15 minutes and a solution of sodium cyanoborohydride (7.1 g, 113 mmol) in methanol (50 mL) is added over 15 minutes. After 3 hours the reaction is complete. A 10% aqueous solution of sodium bicarbonate is added with stirring and after 10 minutes the volatiles are removed. The product is extracted with ether and washed with water (2×). The ether mixture is dried over sodium sulfate and evaporated to give 39.9 g of N-benzyl D-leucine methyl ester as a colorless oil.
Reaction SMILES: Cl.N=[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4](OCC)=O.[NH2:15][CH:16]([C:20]([NH2:22])=[O:21])[C:17]([NH2:19])=[O:18]>CO>[CH2:3]([C:4]1[NH:19][C:17]([OH:18])=[C:16]([C:20]([NH2:22])=[O:21])[N:15]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(=N)c1ccccc1
Reactant: NC(=O)C(N)C(N)=O
Agent: Cl
Solvent: CO
Product: NC(=O)c1nc(Cc2ccccc2)[nH]c1O
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To a chilled solution of ethyl iminophenylacetate hydrochloride (5.99 g) in anhydrous methanol (80 ml) was added aminomalonamide (3.51 g). The mixture was stirred for 1 hour at 0°-5° C. and then 3 hours under reflux. After cooling the mixture to 0°-5° C., the precipitated product was filtered and washed with ethanol, isopropylether to give 2-benzyl-5-hydroxy-1H-imidazole-4-carboxamide (4.52 g).
Reaction SMILES: B(F)(F)F.[CH3:5][CH2:6]OCC.[CH3:10][C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:21])([CH3:20])[CH3:19])[C:12]=1[NH2:13].C(=O)(O)[O-].[Na+]>C(O)C.C(Cl)Cl>[CH3:10][C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:21][CH2:5][CH3:6])([CH3:19])[CH3:20])[C:12]=1[NH2:13]
Reactant: CCOCC
Reactant: Cc1cccc(C(C)(C)O)c1N
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(C)(C)c1cccc(C)c1N
Reaction time: 48 h
Yield: 93.1 %

Procedure:
In this example 0.03 moles of boron trifluoride ethyl etherate was added dropwise to a mixture containing 0.03 moles of 2-methyl-6-(1-hydroxy-1-methylethyl)-aniline in 50 ml of ethanol and 50 ml methylene chloride. The mixture was refluxed for two hours and then allowed to stand for two days. The mixture was then poured into about 700 ml of saturated aqueous sodium bicarbonate solution stirred and extracted with methylene chloride. The extract was filtered through diatomaceous earth, dried and evaporated affording 5.4 g of the title product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(C)ccc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(CBr)ccc1Cl
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A mixture of methyl 2-chloro-5-methylbenzoate (3.0 g, 16.2 mmol), N-bromosuccinimide (3.0 g, 17.0 mmol), and benzoyl peroxide (catalytic) in anhydrous carbon tetrachloride (50 mL) was stirred at reflux overnight. Dichloromethane (50 mL) was added after cooling to room temperature. The mixture was extracted with 1 N NaOH (2×100 mL). The organic layer was recovered, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording methyl 5-(bromomethyl)-2-chlorobenzoate (4.06 g, 95% yield). The product was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([O:13][C@@H:14]([C@H:16]2[CH2:20][N:19]([C@@H](C3C=CC(OC)=CC=3)C)[C:18](=[O:31])[CH2:17]2)[CH3:15])[C:5]2[N:6]([CH2:9][CH3:10])[CH:7]=[N:8][C:4]=2[CH:3]=1>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:12]=[C:11]([O:13][C@@H:14]([C@H:16]2[CH2:20][NH:19][C:18](=[O:31])[CH2:17]2)[CH3:15])[C:5]2[N:6]([CH2:9][CH3:10])[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: CCn1cnc2cc(Br)cc(O[C@H](C)[C@@H]3CC(=O)N([C@H](C)c4ccc(OC)cc4)C3)c21
Solvent: O=C(O)C(F)(F)F
Product: CCn1cnc2cc(Br)cc(O[C@H](C)[C@H]3CNC(=O)C3)c21

Procedure:
(R)-4-((R)-1-((5-bromo-1-ethyl-1H-benzo[d]imidazol-7-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one (155 mg, 0.319 mmol) in TFA (5 mL) was heated in at 55° C. for 16 h. The reaction mixture was then concentrated to give (R)-4-((R)-1-((5-bromo-1-ethyl-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one 2.77 which was used for next step without further purification. LCMS-ESI+ (m/z): 353.0.
Reaction SMILES: [OH-].[Li+].OO.C([C@H]1N([C:17](=[O:41])[C@H:18]([CH3:40])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[C:36]4[O:35][C:34]([CH3:38])([CH3:37])[CH2:33][C:32]=4[CH:31]=[C:30]([F:39])[CH:29]=3)=[CH:22][CH:21]=2)C(=O)CC1)C1C=CC=CC=1.S([O-])([O-])=[O:44].[Na+].[Na+]>O.O1CCCC1.O>[F:39][C:30]1[CH:29]=[C:28]([CH2:27][O:26][C:23]2[CH:22]=[CH:21][C:20]([CH2:19][C@@H:18]([CH3:40])[C:17]([OH:41])=[O:44])=[CH:25][CH:24]=2)[C:36]2[O:35][C:34]([CH3:37])([CH3:38])[CH2:33][C:32]=2[CH:31]=1
Reactant: O=S([O-])[O-]
Reactant: C[C@H](Cc1ccc(OCc2cc(F)cc3c2OC(C)(C)C3)cc1)C(=O)N1C(=O)CC[C@H]1Cc1ccccc1
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](Cc1ccc(OCc2cc(F)cc3c2OC(C)(C)C3)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of lithium hydroxide (65 mg, 1.55 mmol) in water (2 mL) was added 30% hydrogen peroxide (0.4 mL, 3.88 mmol) and stirred for 30 minutes. The solution was cooled to 0° C. and was added to a solution of (S)-5-benzyl-1-((R)-3-(4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)-2-methylpropanoyl)pyrrolidin-2-one (805) (500 mg, 0.97 mmol) in 4:1 tetrahydrofuran/water (5 mL) at 0° C. The reaction was stirred for 1 hour at 0° C. and was quenched with sodium sulfite (489 mg, 3.88 mmol) in water (3 mL). The solvent was removed in vacuo at room temperature. The solution was cooled to 0° C. and was acidified with 6N HCl. The aqueous layer was extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (20%) to afford (R)-3-(4-((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)-2-methylpropanoic acid (94). 1H NMR (400 MHz, CDCl3) δ: 7.09 (d, J=8.5 Hz, 2H), 6.97 (d, J=9.7 Hz, 1H), 6.91 (d, J=8.5 Hz, 2H), 6.79 (d, J=7.6 Hz, 1H), 4.97 (s, 2H), 3.05-2.95 (m, 3H), 2.75-2.58 (m, 2H), 1.48 (s, 6H), 1.16 (d, J=4.0 Hz, 3H). LC-MS ESI m/z: found 357.0 [M−H]−.
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[C:13]([N:15](S(C3C=CC=CC=3)(=O)=O)[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[N:12]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:11]=2)=[CH:6][CH:5]=1.O.[OH-].[Li+]>CO>[C:19]1([S:16]([NH:15][C:13]2[N:12]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:40])=[O:2])=[CH:9][CH:8]=3)[CH:14]=2)(=[O:17])=[O:18])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(-c2cc(N(S(=O)(=O)c3ccccc3)S(=O)(=O)c3ccccc3)n(-c3ccccc3)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(-c2cc(NS(=O)(=O)c3ccccc3)n(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 4-{5-[bis(Benzenesulfonyl)amino]-1-phenyl-1H-pyrazole-3-yl}-benzoic acid methyl ester (1.0 g, 1.74 mmol) and lithium hydroxide monohydrate (1.0 g, 23.8 mmol) in methanol (20 ml) was stirred at room temperature for 2.5 days. The solvent was evaporated in vacuo, and the residue was dissolved in water (20 ml). The solution was neutralized with concentrated hydrochloric acid to give a white precipitate. The solid was collected by filtration, washed with water and dried in vacuo to yield 4-(5-benzenesulfonylamino-1-phenyl-1H-pyrazole-3-yl)-benzoic acid as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][N:23]=1>CCCCCC.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([C:13]([F:16])([F:15])[F:14])([OH:11])[CH2:12][NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][N:23]=2)[CH:7]=1
Reactant: Nc1nccc2ccccc12
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1nccc2ccccc12)C(F)(F)F
Yield: 21.9 %

Procedure:
Analogously to Example 1, 200 mg (0.68 mmol) of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-(trifluoromethyl)oxirane and 99 mg (0.68 mmol) of 1-aminoisoquinoline are reacted. After chromatography on silica gel with hexane-ethyl acetate (0-60%), 65 mg of product is obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=4)=[N:15][N:14]4[CH2:24][CH2:25][CH2:26][C:13]=34)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:27](C([Sn])=C(CCCC)CCCC)[CH2:28]CC>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][C:19]1[N:18]=[C:17]([C:16]2[C:12]([C:6]3[C:5]4[C:10](=[CH:11][C:2]([CH:27]=[CH2:28])=[CH:3][CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[C:13]3[CH2:26][CH2:25][CH2:24][N:14]3[N:15]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Cc1cccc(-c2nn3c(c2-c2ccnc4cc(Br)ccc24)CCC3)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(-c3c(-c4cccc(C)n4)nn4c3CCC4)ccnc2c1
Temperature: 90 °C

Procedure:
Nitrogen is bubbled through a solution of 7-bromo-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline (0.050 g, 0.14 mmol) and tributylvinyltin (0.079 mL, 0.22 mmol) in toluene (2.0 mL) for 20 min. Pd(PPh3)2Cl2 is added and nitrogen bubbled through the reaction mixture for another 10 min. The mixture is heated to 90° C. for 24 h, concentrated in vacuo, and the residue chromatographed on SiO2 (elute with 2% methanol in methylene choloride) to yield the title compound, 0.030 g (61%), as a yellowish solid.
Reaction SMILES: [S:1](=[O:4])([OH:3])[O-:2].[Na+].Cl[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1>>[S:1]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:12][CH:13]=1)([OH:3])(=[O:2])=[O:4]
Reactant: O=C(O)Cc1ccc(CCl)cc1
Reactant: O=S([O-])O
Agent: [Na+]
Product: O=C(O)Cc1ccc(CS(=O)(=O)O)cc1

Procedure:
To a boiling aqueous solution of sodium bisulfite (1.47 g, 0.0141 mole) is added in portions p-chloromethylphenylacetic acid (2.6 g, 0.0141 mole). The solution is further refluxed for 30 minutes and is then evaporated to dryness to give a quantitative yield of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:5]([CH2:6][CH:7]=[CH2:8])[N:4]([C:9](=[C:14]([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])[C:3]1=[O:17].[CH:18](OC(=O)C)=[O:19]>ClCCl.C(OCC)(=O)C>[CH:18]([NH:1][C@@H:2]1[C@@H:5]([CH2:6][CH:7]=[CH2:8])[N:4]([C:9](=[C:14]([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])[C:3]1=[O:17])=[O:19]
Reactant: C=CC[C@@H]1[C@@H](N)C(=O)N1C(C(=O)OC)=C(C)C
Reactant: CC(=O)OC=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CC[C@@H]1[C@@H](NC=O)C(=O)N1C(C(=O)OC)=C(C)C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-[(3R,4R)-3-amino-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (500 mg) in dichloromethane (5 ml) was added acetic formic anhydride (0.34 ml) at 0°. After stirring at the same temperature for one hour, the mixture was diluted with ethyl acetate (35 ml) and washed with a dilute aqueous sodium bicarbonate. The aqueous layer was saturated with sodium chloride and extracted with dichloromethane. The extracts were combined, washed with a saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (2.5 g) eluting with 10-30% acetone in dichloromethane afforded methyl 2-[(3R,4R)-3-formamido-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (485 mg).
Reaction SMILES: [CH2:1]([O:8][N:9]([C:12]1[N:17]=[C:16]([NH:18][CH2:19][CH2:20][CH3:21])[N:15]=[C:14]([NH:22][CH2:23][CH2:24][CH3:25])[N:13]=1)[CH2:10]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:26][S:27]([OH:30])(=[O:29])=[O:28]>>[S:27]([OH:30])([OH:29])(=[O:28])=[O:26].[CH2:1]([O:8][N:9]([C:12]1[N:13]=[C:14]([NH:22][CH2:23][CH2:24][CH3:25])[N:15]=[C:16]([NH:18][CH2:19][CH2:20][CH3:21])[N:17]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCNc1nc(NCCC)nc(N(CC)OCc2ccccc2)n1
Agent: O=S(=O)(O)O
Product: CCCNc1nc(NCCC)nc(N(C)OCc2ccccc2)n1

Procedure:
O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydroxylamine (LXVIII) was reacted with 95% H2SO4 as described in Example 9 to yield O-benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine hydrogen sulfate (LXIX) in quantitative yield. 400 MHz 1H NMR (DMSO-d6, ppm) 12.0-11.0 (1H, br s), 8.7-8.0 (1H, m), 7.57-7.30 (5H, m), 5.07-4.95 (2H, m), 3.89-3.68 (2H, m), 3.39-3.14 (4H, m), 1.63-1.42 (4H, m), 1.23-1.07 (3H, m), 0.94-0.77 (6H, m). ESI-MS (m/z): 345 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[O:17][CH3:18])[CH:3]=1.[CH3:19][S:20]([C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:26]([OH:28])=O)(=[O:22])=[O:21].F[B-](F)(F)F.BrC1C=CC=C[N+]=1CC.C(N(C(C)C)C(C)C)C.C(=O)(O)[O-]>ClCCl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:9])[C:26](=[O:28])[C:25]2[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=[C:23]([S:20]([CH3:19])(=[O:21])=[O:22])[CH:24]=2)=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[O:17][CH3:18])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNc1nnc(Cl)cc1-c1ccc(F)cc1OC
Agent: CC[n+]1ccccc1Br
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(F)ccc1-c1cc(Cl)nnc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of [6-chloro-4-(4-fluoro-2-methoxy-phenyl)-pyridazin-3-yl]-methyl-amine (95 mg, 355 μmol) in dichloromethane (5 mL) was added 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (95.2 mg, 355 mmol) and 2-bromo-1-ethylpyridinium tetrafluoroborate (117 mg, 426 μmol, CAS RN 878-23-9) and N-ethyldiisopropyl-amine (91.7 mg, 124 μL, 710 μmol). The reaction mixture was stirred at room temperature for 72 hours and then poured on 30 mL 10% aqueous bicarbonate solution and 30 mL dichloromethane and the layers were separated. The aqueous layer was extracted a second time with 30 mL dichloromethane. The organic layers were washed with 30 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 0:100). Colorless solid (63 mg, 34.3%). MS (ESI+): m/z=518.056 ([M+H]+).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:33])=[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])=[CH:24][CH:23]=1)[C:10]([O:17][CH:18]([F:20])[F:19])=[N:11]2.CO.[OH-].[Li+].Cl>O.O1CCCC1>[F:20][CH:18]([F:19])[O:17][C:10]1[C:9]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([S:28]([CH2:31][CH3:32])(=[O:29])=[O:30])=[CH:26][CH:27]=2)=[C:8]([CH3:33])[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:34])=[O:2])[N:11]=1
Reactant: CCS(=O)(=O)c1ccc(Cc2c(OC(F)F)nc3c(F)ccc(OCC(=O)OC)c3c2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(Cc2c(OC(F)F)nc3c(F)ccc(OCC(=O)O)c3c2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of [2-difluoromethoxy-3-(4-ethanesulfonylbenzyl)-8-fluoro-4-methylquinolin-5-yloxy]acetic acid methyl ester (0.10 g), methanol (2.0 mL), tetrahydrofuran (2.0 mL), water (2.5 mL) and lithium hydroxide (0.017 mg) was stirred at room temperature for 1 hour. The mixture was acidified by the addition of 1.0 M aqueous hydrochloric acid and purified by preparative reverse-phase HPLC, using a gradient over 30 minutes of acetonitrile in water to afford title compound as a white solid, 0.070 g.
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4].Br[C:31]1[CH:32]=[CH:33][C:34]([CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])=[N:35][CH:36]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(O)(C)C>[F:1][CH:2]([F:29])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:13]=[CH:14][C:15]([C:31]3[CH:36]=[N:35][C:34]([CH2:37][S:38]([CH3:41])(=[O:39])=[O:40])=[CH:33][CH:32]=3)=[CH:16][CH:17]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4]
Reactant: CS(=O)(=O)Cc1ccc(Br)cn1
Reactant: CC1(C)O[C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@@H](CF)N1C(=O)C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CC1(C)O[C@H](c2ccc(-c3ccc(CS(C)(=O)=O)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Temperature: 120 °C
Yield: 123.2 %

Procedure:
2,2-difluoro-1-((4S,5R)-4-(fluoromethyl)-2,2-dimethyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazolidin-3-yl)ethanone (100 mg, 0.24 mmol) in 1:1 toluene/isopropyl alcohol (4 mL) is treated with commercially available 5-bromo-2-(methylsulfonylmethyl)pyridine (60 mg, 0.24 mmol), sodium bicarbonate (1 mL of a 2M solution), and (1,1′-bis[diphenylphosphino]ferrocene)dichloropalladium (II) (10 mg, 0.012 mmol) then heated at 120° C. in a microwave for 30 minutes. The mixture is concentrated and purified by column chromatography on silica gel eluting with a gradient of ethyl acetate in heptane to give the title compound (135 mg). m/z (Cl) 457 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[CH3:68][O:69][C:70]1[CH:75]=[CH:74][CH:73]=[C:72]([NH2:76])[CH:71]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:76][C:72]2[CH:73]=[CH:74][CH:75]=[C:70]([O:69][CH3:68])[CH:71]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COc1cccc(N)c1
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(Nc2cccc(OC)c2)c1C(=O)OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47 %

Procedure:
A mixture of 3-iodo-phthalic acid dimethyl ester (1.0 g, 3.1 mmol), cesium carbonate (1.4 g, 4.3 mmol), Pd2(dba) (0.13 g, 0.14 mmol) and rac-BINAP (0.058 g, 0.093 mmol) in toluene (6 mL) was stirred at room temperature for 5 minutes. m-Anisidine (0.38 g, 3.1 mmol) was then added, and the reaction mixture was refluxed for 48 hours. The reaction mixture was diluted with methylene chloride (20 mL) and filtered through celite. The filter was washed with additional methylene chloride (25 mL). The combined filtrates were evaporated, and the residue was purified by ISCO silica gel flash chromatography using a hexanes-ethyl acetate gradient, eluting the product at 7:3 hexanes-ethyl acetate. It was then purified by preparative HPLC using an acetonitrile-water gradient, eluting the product at 6:4 acetonitrile:water to give the title product, 0.46 g in 47% yield; 1H NMR (CDCl3) δ 3.79 (s, 3H), 3.87 (s, 3H), 3.89 (s, 3H), 6.59-6.75 (m, 3H), 7.09-7.46 (m, 4H), 8.00 (s, 1H).
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH:3]1[CH3:25].CCN(C(C)C)C(C)C.[CH3:36][N:37]([CH3:43])[C@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1>>[F:1][C:2]1([F:26])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:40]4[CH2:41][CH2:42][C@H:38]([N:37]([CH3:43])[CH3:36])[CH2:39]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH:3]1[CH3:25]
Reactant: CC1CC(O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)CCC1(F)F
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CC(O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@H](N(C)C)C4)ccc23)CCC1(F)F

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxy-3-methyl-cyclohexylmethyl)-amide, DIPEA and (S)-3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.66 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.26 (s, 6H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.56 (m, 1H), 1.27-1.32 (m, 1H), 1.00 (d, 3H). m/z: 481 [M+H]
Reaction SMILES: [B]1OC2C(=CC=CC=2)O1.[F:10][C:11]([F:41])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:12](=[O:34])/[CH:13]=[CH:14]/[C@H:15]1[CH2:20][CH2:19][O:18][C:17](=[O:21])[N:16]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29]>C1(C)C=CC=CC=1>[F:41][C:11]([F:10])([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH:12]([OH:34])/[CH:13]=[CH:14]/[C@H:15]1[CH2:20][CH2:19][O:18][C:17](=[O:21])[N:16]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29]
Reactant: CC(C)OC(=O)CCCCCCN1C(=O)OCC[C@@H]1/C=C/C(=O)C(F)(F)c1ccccc1
Agent: [B]1Oc2ccccc2O1
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)CCCCCCN1C(=O)OCC[C@@H]1/C=C/C(O)C(F)(F)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of catecholborane (107 mg) in toluene (1 mL) was added (S)-2-methyl-CBS-oxaborolidine (1M in toluene, 0.89 mL) under N2 at −78° C. and the mixture was stirred at the temperature for 1 h. Isopropyl 7-{(4R)-4-[(1E)-4,4-difluoro-3-oxo-4-phenylbut-1-en-1-yl]-2-oxo-1,3-oxazinan-3-yl}heptanoate (200 mg) in toluene (2 mL) was added via a cannula slowly and the mixture was stirred for an additional hour and quenched with 1N HCl. The mixture was allowed to warm to room temperature and extracted with DCM (2×). The organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue purified by column chromatography (80-100% ethyl acetate/hexanes) to give the title compound. MS (+ESI): m/z 454 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][O:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[Br:13]N1C(=O)CCC1=O.C(OOCC1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9](=[O:12])[O:8]1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)C(=O)OC2
Agent: c1ccc(COOCc2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(c1)C(=O)OC2Br
Reaction time: 2.5 h
Yield: 78.5 %

Procedure:
6-Methoxy-3H-isobenzofuran-1-one (35.28 g, 0.215 mole), prepared as described in example 34, suspended in CCl4 (350 ml) under N2 was added with N-bromosuccinimide (40 g, 0.225 mole) and benzyl peroxide in catalytic amount, then slowly brought to reflux. After 2.5 hours the heating was stopped and the mixture was left to stand overnight at room temperature. Further catalyst was added and the mixture was heated for further 3.5 hours. The mixture was cooled in ice, filtered over celite washing well with CCl4 and dried to give 41 g of the title compound (yield: 78%).