Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[CH3:18][C:19]1[O:20][C:21]([CH3:27])=[CH:22][C:23]=1[C:24](O)=[O:25]>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:24]([C:23]3[CH:22]=[C:21]([CH3:27])[O:20][C:19]=3[CH3:18])=[O:25])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: Cc1cc(C(=O)O)c(C)o1
Product: Cc1cc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OC[C@@H]3F)c2)c(C)o1

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 2,5-dimethyl-furan-3-carboxylic acid (CAS 636-44-2) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=364.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.Cl>CS(C)=O>[CH3:5][C:2]([C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=1)([CH3:1])[CH:3]=[O:4]
Reactant: CC(C)(CO)c1ccc(Cl)cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.5 %

Procedure:
To a stirring solution of 41.7 grams (0.226 mole) of 2-methyl-2-(4-chlorophenyl)propanol in 100 mL of dimethyl sulfoxide is added 126 mL (0.904 mole) of triethylamine. A solution of 63.0 grams (0.452 mole) of triethylamine-sulfur trioxide complex in 300 mL of dimethyl sulfoxide is then added portionwise during a 15 minute period. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about five hours. The reaction mixture is then poured into about 500 mL of ice, and made acidic with aqueous 2N hydrochloric acid. The mixture is then extracted with two 100 mL portions of diethyl ether. The combined extracts are dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 22.9 grams of 2-methyl-2-(4-chlorophenyl)propanaldehyde. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:12])([C:8]([F:11])([F:10])[F:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[BH4-].[Na+].Cl>CO>[CH2:6]([O:5][CH:3]([OH:4])[C:2]([F:12])([F:1])[C:8]([F:10])([F:11])[F:9])[CH3:7]
Reactant: CCOC(=O)C(F)(F)C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(O)C(F)(F)C(F)(F)F
Temperature: -60 °C
Reaction time: 1 h

Procedure:
Ethyl 2,2,3,3,3-pentafluoropropionate (10.99 grams, 57.2 mmol) was dissolved in anhydrous methanol (57 ml) and cooled under argon to −60° C. Sodium borohydride (2.16 grams, 57.2 mmol) was added in four portions. After the addition was complete, stirring was continued for one hour and the temperature was held below −45° C. The mixture was cooled to −60° C. and 1M hydrochloric acid (172 ml) was added dropwise so that the temperature remained below −45° C. The mixture was slowly warmed to room temperature and extracted with diethylether (3×100 ml). The combined organic phases were washed with water (two times), dried over magnesium sulfate, the solvent was removed under reduced pressure. 9.76 g (50.3 mmol, 88%) were obtained and used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:16])=[C:4]([N:8]2[C:13](=[O:14])[CH:12]=[CH:11][NH:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:3]([CH3:16])=[C:4]([N:8]2[C:13](=[O:14])[CH:12]=[CH:11][N:10]([C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)[C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1c(Br)cccc1-n1c(=O)cc[nH]c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(Br)cccc1-n1c(=O)ccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
A stirred suspension of copper(II) acetate (0.543 g, 2.99 mmol), 3-(3-bromo-2-methylphenyl)pyrimidine-2,4(1H,3H)-dione (0.42 g, 1.49 mmol), (4-fluorophenyl) boronic acid (0.418 g, 2.99 mmol), and activated molecular sieves (750 mg) in dry DCM (25 mL) was treated with pyridine (0.363 mL, 4.48 mmol) and stirred at room temperature overnight. The mixture was diluted with DCM, filtered through CELITE®, and the solids were washed with DCM and THF. The combined filtrates were washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (gradient from 20-40%), to give 3-(3-bromo-2-methylphenyl)-1-(4-fluorophenyl)pyrimidine-2,4(1H,3H)-dione as a yellow glassy solid (0.36 g, 43% yield). Mass spectrum m/z 375, 377 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J=7.9 Hz, 1H), 7.68 (dd, J=7.9, 1.3 Hz, 1H), 7.60-7.51 (m, 2H), 7.40-7.22 (m, 4H), 5.95 (d, J=7.9 Hz, 1H), 2.21-2.12 (m, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([S:11]([C:14]3[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[CH:18][CH:19]=3)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH3:22][C:23](=O)[C:24](=O)[CH3:25]>C(O)C>[CH3:22][C:23]1[C:24]([CH3:25])=[N:21][C:16]2[C:17](=[CH:18][CH:19]=[C:14]([S:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH:4]=[CH:3][N:2]=[CH:1]4)(=[O:13])=[O:12])[CH:15]=2)[N:20]=1
Reactant: CC(=O)C(C)=O
Reactant: Nc1ccc(S(=O)(=O)c2cccc3cnccc23)cc1N
Solvent: CCO
Product: Cc1nc2ccc(S(=O)(=O)c3cccc4cnccc34)cc2nc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
To a mixture of 4-(5-isoquinolylsulfonyl)benzenediamine 500 mg (1.7 mmol) and ethanol 10 ml, 2,3-butanedione 1.2 ml was added, and the mixture was heated with stirring for 2 hours at 90° C. The reaction mixture was concentrated under reduced pressure, and ether was added to the resulting residue to crystallize. The crystals were filtered, and 2,3-dimethyl-6-(5-isoquinolylsulfonyl)quinoxaline 490 mg (84.7%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:22]([CH3:21])[CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:27][CH:26]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CCCCOc1ccc(CCNC)cc1
Product: CCCCOc1ccc(CCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1

Procedure:
This compound was prepared analogous to Example 5(b) by reaction of 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane with N-methyl-N-[2-(4-n-butoxy-phenyl)-ethyl]-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:9]([C:10]([OH:12])=[O:11])[C:8]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(=O)(N(C)C)N(C)C.[CH2:34]([C:41]1[O:45][CH:44]=[C:43]([CH2:46]Br)[CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH:9]([C:10]([O:12][CH2:46][C:43]3[CH:42]=[C:41]([CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[O:45][CH:44]=3)=[O:11])[C:8]2([CH3:13])[CH3:14])=[CH:15][CH:16]=1
Reactant: BrCc1coc(Cc2ccccc2)c1
Reactant: CC1(C)C(Oc2ccc(Cl)cc2)C1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1(C)C(Oc2ccc(Cl)cc2)C1C(=O)OCc1coc(Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
To a mixture of 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylic acid (2.77 mmol) (as prepared in, for example, Example 1 or 2), potassium carbonate (3.25 mmol) and hexamethylphosphoric triamide (HMPT) (3 ml), with stirring and under nitrogen, at RT, is added 5-benzyl-3-furylmethyl bromide (2.77 mmol) in THF. The reaction is stirred at RT for about 48 hr and then worked up by partition between water/ether. The organic phase is washed with water and brine, dried over potassium carbonate, filtered and the solvent is removed from the filtrate. The residue is plated on prep. TLC plates developing with 10% ether/hexane to yield 5-benzyl-3-furylmethyl 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:29])=O>CN(C=O)C>[Cl:29][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[N:9]1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(CN2C(=O)c3ccccc3C2(O)c2ccc(Cl)cc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(CN2C(=O)c3ccccc3C2(Cl)c2ccc(Cl)cc2)cc1

Procedure:
Distilled THF (10 mL) was added to 3-(4-chlorophenyl)-3-hydroxy-2-(4-methylbenzyl)-isoindolin-1-one (400 mg, 1.13 mmol), thionyl chloride (295.8 mg, 2.48 mmol, 0.18 mL) and catalytic DMF (3 drops) as for general procedure B1. 3-Chloro-3-(4-chlorophenyl)-2-(4-methylbenzyl)isoindolin-1-one was produced as a viscous yellow oil (418 mg, 1.13 mmol) which was used immediately without further purification. Distilled THF (3 mL) was added to 3-chloro-3-(4-chlorophenyl)-2-(4-methylbenzyl)isoindolin-1-one (418.1 mg, 1.13 mmol) and the resultant solution added dropwise to cis-cyclopentene diol (285 mg, 2.85 mmol) and dried K2CO3 (390.41 mg, 2.85 mmol) in distilled THF (3 mL) as for general procedure B1. Removal of the solvent yielded the crude product as a green oil (359 g). Purification by flash column chromatography yielded the title product as a colourless viscous oil (242.1 mg, 0.55 mmol, 50%) 1H NMR: (300 MHz, DMSO) δ ppm 1.19 (m, 1H, H16/16′), 1.67, 2.05 (m, 1H, H16/16′) 2.21 (s, 3H, H12), 3.85 (m, 1H, H17), 4.06 (d, 1H, J=15.21 Hz, H9/9′), 4.32 (m, 1H, H15) 4.53 (d, 1H, J=15.21 Hz, H9/9′), 4.81, 5.74, (dd, 1H, H18/19) 5.20, 5.66 (dd, 1H, H18/19), 6.95 (m, 4H, H10, H11, H13, H14), 7.25 (m, 5H, H1-H5), 7.65 (m, 2H, H6-H7) 7.74 (d, 1H, H8). IR: 1380, 1467, 1699, 2922 cm−1. HR-MS (EI): Calculated mass: [M+H]+ 446.1517. Found: 446.1517.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:15][CH:16]=[C:17]([CH3:20])[CH2:18][OH:19])=[C:4]([O:13][CH3:14])[C:5]([CH3:12])=[C:6]2[C:10]=1[C:9](=[O:11])[O:8][CH2:7]2.Br[CH2:22][P:23](=[O:32])([O:28][CH:29]([CH3:31])[CH3:30])[O:24][CH:25]([CH3:27])[CH3:26].CC(C)([O-])C.[Li+]>CN(C=O)C>[CH:29]([O:28][P:23]([CH2:22][O:19][CH2:18][C:17]([CH3:20])=[CH:16][CH2:15][C:3]1[C:2]([OH:1])=[C:10]2[C:6](=[C:5]([CH3:12])[C:4]=1[O:13][CH3:14])[CH2:7][O:8][C:9]2=[O:11])(=[O:32])[O:24][CH:25]([CH3:27])[CH3:26])([CH3:31])[CH3:30]
Reactant: CC(C)OP(=O)(CBr)OC(C)C
Reactant: COc1c(C)c2c(c(O)c1CC=C(C)CO)C(=O)OC2
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1c(C)c2c(c(O)c1CC=C(C)COCP(=O)(OC(C)C)OC(C)C)C(=O)OC2
Temperature: 70 °C
Yield: 30.4 %

Procedure:
A mixture of 7-hydroxy-6-(4-hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-3H-isobenzofuran-1-one 1A (50 mg, 0.18 mmol, Pankiewicz et al., J. Med. Chem., 45, 703), diisopropyl bromomethylphosphonate (93 mg, 0.36 mmol) and lithium t-butoxide (1M in THF, 0.54 mL) in DMF (3 mL) was heated at 70° C. for 5 hours. The reaction was quenched with 1N HCl. The mixture was poured into 5% aqueous lithium chloride, extracted with ethyl acetate, and concentrated. The residue was purified by chromatography on silica gel, affording [4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonic acid diisopropyl ester 1B (25 mg, 32%); 1H NMR (300 MHz, CDCl3) δ1.25 (m, 12H), 1.79 (s, 3H), 2.05 (s, 3H), 3.37 (d, J=6.6 Hz, 2H), 3.58 (d, 2H), 3.77 (s, 3H), 3.97 (m, 2H), 4.68 (m, 2H), 5.19 (s, 2H), 5.45 (t, J=6.6 Hz, 1H), 7.83 (s, 1H) ppm.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=O.COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:22]2)=CC=1>C1C=CC=CC=1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[S:22]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cn1c(=O)ccc2ccccc21
Solvent: c1ccccc1
Product: Cn1c(=S)ccc2ccccc21
Yield: 181.7 %

Procedure:
Under inert atmosphere, 1 g of 1-methyl-quinolin-2-one and 25 ml of benzene were mixed together and then 1.27 g of 2,4-bis-(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphos phetane (Laweseeon's reagent) were added all at once. After stirring at reflux for 1 hour, cooling, eliminating the solvent by distilling under reduced pressure and drying under a good vacuum and chromatographing, the residue was chromatographed on silica and eluted with a mixture of methylene chloride and ethyl acetate (1/1) to obtain 1 g of the product sought melting at 114° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[N:17]1([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[N:17]1([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=[C:9]3[C:8]4[C:12](=[CH:13][CH:14]=[CH:15][C:7]=4[CH:4]4[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]4)[NH:11][C:10]3=[O:16])=[CH:25][CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Product: O=C1Nc2cccc(C3CCNCC3)c2C1=Cc1ccc(N2CCOCC2)cc1

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with 4-morpholin-4-yl-benzaldehyde (43 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22](=O)[CH3:23])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.Cl.[NH2:26][O:27][CH2:28][CH2:29][OH:30].C(N(CC)CC)C>CO>[OH:30][CH2:29][CH2:28][O:27]/[N:26]=[C:22](/[C:19]1[CH:20]=[CH:21][C:16]2[N:17]([C:13]([CH2:12][C:3]3[CH:4]=[C:5]4[C:9](=[CH:10][C:2]=3[F:1])[N:8]([CH3:11])[N:7]=[CH:6]4)=[CH:14][N:15]=2)[N:18]=1)\[CH3:23]
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cnn(C)c4cc3F)n2n1
Reactant: NOCCO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C/C(=N\OCCO)c1ccc2ncc(Cc3cc4cnn(C)c4cc3F)n2n1
Temperature: 30 °C
Reaction time: 20 h
Yield: 72.5 %

Procedure:
To a solution of 1-(3-((6-fluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (50 mg, 0.155 mmol) in methanol (7 mL) was added 2-(aminooxy)ethanol hydrochloride (17.6 mg, 0.155 mmol). Triethyl amine was added dropwise to adjust the pH to 5-6. The reaction mixture was stirred at 30° C. for 20 h. The solvent was removed in vacuo and the residue was dissolved in DCM, washed with NaHCO3 (aq) and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the crude product which was purified by column chromatography to afford 43 mg (70%) of the title compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.05 (d, 1H), 7.97 (s, 1H), 7.70 (d, 1H), 7.63 (d, 1H), 7.62 (s, 1H), 7.53 (d, 1H), 4.75 (t, 1H), 4.43 (s, 1H), 4.23 (t, 2H), 3.97 (s, 3H), 3.68 (q, 2H), 2.28 (s, 3H). LCMS (method B): [MH]+=383, tR=2.45 min.
Reaction SMILES: [OH:1][C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[N+:15]([O-])=O>CO.[Pd]>[NH2:15][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][C:14]=2[C:2]=1[OH:1]
Reactant: O=[N+]([O-])c1ccc2c(c1O)Cc1ccccc1-2
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1O)Cc1ccccc1-2
Yield: 70.5 %

Procedure:
To a solution of 1-hydroxy-2-nitrofluorene(250 mg, 1.23 mmol) in methanol(250 mL) was added 10% Pd/C (1 g). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5% MeOH/CH2Cl2) gave the desired product(171 mg, 81.2%). 1H NMR (CD3OD): δ 7.60 (d, 1H), 7.47 (d, 1H), 7.28 (t, 1H), 7.18 (m, 2H), 6.82 (d, 1H), 3.76 (s, 2H).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12](=[O:24])/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)[CH3:10]>CC#N.CCOC(C)=O>[I:1][C:18]1[CH:19]=[CH:20][C:15](/[CH:14]=[CH:13]/[C:12]([O:11][CH2:9][CH3:10])=[O:24])=[CH:16][CH:17]=1
Reactant: CCOC(=O)/C=C/c1ccc(B(O)O)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)/C=C/c1ccc(I)cc1
Reaction time: 26 h
Yield: 86.1 %

Procedure:
N-Iodosuccinimide (2.5 g, 11 mmol) was added to a suspension of 4-(E-3-ethoxy-3-oxo-1-propen-1-yl)phenylboronic acid (2.2 g, 10 mmol) in CH3CN (50 mL) at room temperature. The reaction was covered with foil, stirred for ˜26 hours, and then diluted with EtOAc. The resulting mixture was washed with water (2×100 mL), washed with sodium thiosulfate (100 mL), dried (MgSO4), filtered, and concentrated. The crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give 2.6 g of (E)-ethyl 3-(4-iodophenyl)acrylate as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 7.79 (d, 2H), 7.60 (d, 1H), 7.53 (d, 2H), 6.68 (d, 1H), 4.19 (q, 2H), 1.26 (t, 3H); LCMS: 303 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[CH2:19][C:18](=O)[CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH3:15])[CH:18]2[CH2:17][O:16][CH2:19]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C1CCN(C(=O)OC(C)(C)C)CC1)C1COC1
Reaction time: 16 h
Yield: 19 %

Procedure:
A mixture of 4-(methylamino)piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.93 mmol) and oxetan-3-one (56 mg, 0.78 mmol) in DCE (6 mL) was stirred at room temperature for 2 h before the addition of sodium triacetoxyborohydride (264 mg, 1.24 mmol). The resulting mixture was stirred for 16 h, then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH. The resulting oil was purified by column chromatography (Si—PCC, MeOH/DCM, 0-20%) affording 4-(Methyl(oxetan-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester as an oil (40 mg, 16%). 1H NMR (CDCl3, 300 MHz): δ 4.66 (t, J=6.6 Hz, 2H); 4.61 (t, J=6.6 Hz, 2H); 4.16 (s, 2H); 3.95 (p, J=6.6 Hz, 1H); 2.63 (t, J=12.5 Hz, 2H); 2.39 (tt, J=11.7, 3.7 Hz, 1H); 2.20 (s, 3H); 1.60 (d, J=12.5 Hz, 2H); 1.46 (s, 9H); 1.44-1.28 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][OH:26])=[CH:21][CH:20]=1)[C:13]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:31][CH:30]=1)=[C:12]2[CH3:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>C(Cl)Cl>[CH3:51][S:52]([O:26][CH2:25][CH2:24][O:23][C:22]1[CH:27]=[CH:28][C:19]([CH2:18][N:14]2[C:15]3[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:17][CH:16]=3)[C:12]([CH3:43])=[C:13]2[C:29]2[CH:30]=[CH:31][C:32]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:33][CH:34]=2)=[CH:20][CH:21]=1)(=[O:54])=[O:53]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(OCCO)cc2)c2ccc(OCc3ccccc3)cc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(OCCOS(C)(=O)=O)cc2)c2ccc(OCc3ccccc3)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 2-(4-((5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indol-1-yl)methyl)phenoxy)ethanol (546 mg, 0.96 mmol) in DCM (10 mL) was cooled to 0° C. Triethylamine (0.2 mL, 1.43 mmol) and methanesulfonyl chloride (0.1 mL, 1.29 mmol) were added and the reaction was stirred at 0° C. for 1 h. The reaction was diluted with DCM (30 mL) and then washed with 1M HCl (20 mL), washed with water (20 mL), dried (MgSO4), filtered and concentrated under vacuum to give 597 mg of 2-(4-((5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indol-1-yl)methyl)phenoxy)ethyl methanesulfonate as a yellow foam. 1H NMR (400 MHz, DMSO-d6): δ 7.48 (d, 4H), 7.44-7.37 (m, 4H), 7.37-7.32 (m, 2H), 7.30 (d, 2H), 7.21 (d, 1H), 7.15-7.10 (m, 3H), 6.83-6.74 (m, 5H), 5.20-5.10 (m, 6H), 4.50-4.45 (m, 2H), 4.17-4.11 (m, 2H), 2.16 (s, 3H). LCMS: 648.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](Br)=[CH:24][CH:23]=[C:22]([Cl:27])[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([CH3:43])([CH3:42])[CH2:40][OH:41])=[CH:35][C:34]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CCOC(C)=O>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:34]4[CH:35]=[C:36]([C:39]([CH3:43])([CH3:42])[CH2:40][OH:41])[CH:37]=[CH:38][C:33]=4[O:32][CH3:31])=[CH:24][CH:23]=[C:22]([Cl:27])[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1ccc(C(C)(C)CO)cc1B1OC(C)(C)C(C)(C)O1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)CO)cc1-c1ccc(Cl)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 9) (107.0 mg, 0.207 mmol) and 2-[4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methylpropan-1-ol (64 mg, 0.207 mmol) in THF (2.3 mL) was added aqueous potassium carbonate (1.6 mL of a 1M solution, 1.6 mmol). The mixture was degassed with nitrogen. While stirring the reaction vigorously at room temperature, 1,1-bis(di-t-butylphosphino)ferrocene palladium chloride (6.7 mg, 0.01 mmol) was added. The reaction was stirred vigorously at room temperature for 15 min, and then diluted with EtOAc (50 mL). The organics were washed with water and brine (15 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (5 to 50% EtOAc/hexanes) afforded impure product, which was repurified with 1:1:1 CH2Cl2:hexanes:Et2O on silica gel to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-({6-chloro-3-[5-(2-hydroxy-1,1-dimethylethyl)-2-methoxyphenyl]pyridin-2-yl}methyl)-4-methyl-1,3-oxazolidin-2-one. Rf=0.29 (40% EtOAc/hexanes). LCMS=616.9 (M+1)+. 1H NMR (CDCl3, 500 MHz, rotamers present) δ 6.94-7.85 (m, 8H), 5.40-5.55 (m, 1H), 4.81-5.08 (m, 1H), 3.54-4.36 (m, 7H), 1.95-2.59 (m, 1H), 1.30-1.34 (m, 6H), 0.62-0.74 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[C:4]([CH3:10])[CH:3]=1.[N:11]([O-])=[O:12].[Na+]>O.C(O)(=O)C>[NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[C:4]([CH3:10])[C:3]=1[N:11]=[O:12]
Reactant: O=N[O-]
Reactant: Cc1cc(N)n(CCO)n1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nn(CCO)c(N)c1N=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
5-Amino-1-(2-hydroxyethyl)-3-methylpyrazole (Bull. soc. chim. France, 255 (1975)) (1.41 g, 10 mmoles) was dissolved in a mixture of water (7 ml) and glacial acetic acid (1.4 ml). Sodium nitrite (0.8 g, 11.6 mmoles) in water (7 ml) was added dropwise over 0.5 hour at 0° C. The red solution was stirred at 0° C., and after 1 hour, the solid which had precipitated was filtered off and dried in vacuo giving the title compound as a red solid (1.2 g, 70%).