Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([O:15]CC)=O.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>CCOC(C)=O>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:13]([C:3]2[N:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][C:9]([I:12])=[CH:8][CH:7]=3)=[O:15])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1nnc2ccc(I)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(Cl)cc1)c1nnc2ccc(I)cc2c1O

Procedure:
A solution of ethyl 4-hydroxy-6-iodo-3-cinnolinecarboxylate (Prep. 3, 0.27 g) and 4-chlorobenzylamine (3.50 mL) is heated at 90° C. for 30 minutes. The reaction is cooled slightly and poured into 25 mL EtOAc. Hexanes are added to precipitate the product and the resulting solid is filtered and dried. The product is further purified by trituration with CH2Cl2/hexanes (0.29 g, 85%). Physical characteristics are as follows: m.p. 307-308° C.; 1H NMR (300 MHz, DMSO-d6) δ9.99, 8.47, 8.15, 7.57, 7.40, 4.55; IR (drift) 2972, 2958, 2901, 2846, 1645, 1601, 1557, 1488, 1458, 1356, 933, 922, 822, 806, 722 cm−1; MS (ESI) m/z 439.8 (M+H)+, 437.8 (M−H)−; Anal. Calcd for C16H11ClIN3O2: C, 43.71; H, 2.52; N, 9.56; Found: C, 43.94; H, 2.50; N, 9.43.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:19][S:20](O)(=[O:22])=[O:21]>ClCCl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([S:20]([Cl:19])(=[O:22])=[O:21])[CH:6]=1)(=[O:3])=[O:4]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(S(C)(=O)=O)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(S(C)(=O)=O)cc1S(=O)(=O)Cl
Temperature: 25 °C

Procedure:
To a solution of crude 1-methanesulfonyl-4-methoxybenzene (8 mmol) in dry dichloromethane (20 mL), chlorosulfonic acid (1 mL) was added dropwise at 0° C. The reaction mixture was warm to room temperature followed by the addition of PCl5 (0.5 g). The resulting reaction mixture was refluxed for 1 h. After cooling to room temperature, the reaction mixture was poured into stirring ice water (50 mL). The water layer was then extracted with EtOAc (2×40 mL.) The combined organic extracts was washed with saturated sodium chloride aqueous solution (2×40 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography eluting with hexanes/EtOAc (3:1) to give 1.6 g of 5-methanesulfonyl-2-methoxybenzenesulfonyl chloride.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:17]=[C:16]([NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)[CH3:2].CN(C)CCCNC1N=C(NC2CCNCC2)C2C(=CC=CC=2)N=1.[N:51]1([C:56]2[CH:63]=[CH:62][CH:61]=[CH:60][C:57]=2[CH:58]=O)[CH:55]=[CH:54][CH:53]=[CH:52]1.[BH3-]C#N.[Na+]>CO.[Cl-].[Cl-].[Zn+2]>[N:51]1([C:56]2[CH:63]=[CH:62][CH:61]=[CH:60][C:57]=2[CH2:58][N:22]2[CH2:23][CH2:24][CH:19]([NH:18][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=[C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:25][CH3:26])[N:17]=3)[CH2:20][CH2:21]2)[CH:52]=[CH:53][CH:54]=[CH:55]1
Reactant: O=Cc1ccccc1-n1cccc1
Reactant: CCN(CC)CCCNc1nc(NC2CCNCC2)c2ccccc2n1
Agent: CN(C)CCCNc1nc(NC2CCNCC2)c2ccccc2n1
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CO
Product: CCN(CC)CCCNc1nc(NC2CCN(Cc3ccccc3-n3cccc3)CC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 56 mg (0.155 mmol) N2-(3-(diethylamino)propyl)-N4-(piperidin-4-yl)quinazoline-2,4-diamine (prepared analogously to Compound 129) 2-(1H-pyrrol-1-yl)benzaldehyde (27 mg, 0.157 mmol), NaCNBH3 (10 mg, 0.160 mmol) and ZnCl2 (11 mg, 0.08 mmol) in MeOH (1 ml) was stirred at room temperature overnight to obtain the target compound.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([C@H:14]([CH2:18][CH3:19])[C:15]([O-:17])=[O:16])[CH2:9][CH2:8][CH2:7]2.FC1C=C2C(=CC=1)N([C@H](C(C)C)C(O)=O)CCC2>CO>[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([C@H:14]([CH2:18][CH3:19])[C:15]([OH:17])=[O:16])[CH2:9][CH2:8][CH2:7]2
Reactant: CC[C@H](C(=O)[O-])N1CCCc2cc(F)ccc21
Agent: CC(C)[C@H](C(=O)O)N1CCCc2cc(F)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](C(=O)O)N1CCCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C., an aqueous 2.0 M KOH solution (15.9 mL, 31.8 mmol) was added to a stirring solution of (R)-2-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)-3-methylpropanoate (2.0 g, 7.96 mmol) in MeOH (16 mL). The reaction was allowed to warm up to RT and left stirring overnight. Due to the instability of the final product as a solid, the solution containing (R)-2-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)-3-methylbutanoic acid was used for the next step without further work up. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA), m/z: M+1 obs=223.24; tR=2.92 min.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH2:12][C:13](Cl)=[N:14][OH:15])[CH:9]=[CH:10][CH:11]=2)[CH2:3][CH2:2]1.[C:17]([C:19]1[C:20]([NH2:26])=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=1)#[CH:18].C(N(CC)CC)C>O1CCCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=2)[CH2:12][C:13]2[CH:18]=[C:17]([C:19]3[C:20]([NH2:26])=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=3)[O:15][N:14]=2)[CH2:3][CH2:2]1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1cccc(OCC2CC2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3cccc(OCC4CC4)c3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (3-cyclopropylmethoxy-phenyl)-acetohydroximoyl chloride (150 mg, 0.626 mmol) described in Manufacturing Example 66-1-4 and 3-ethynyl-pyridin-2,6-diamine (53.2 mg, 0.399 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (218 μL, 1.57 mmol). This mixture was stirred for 4 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1˜ethyl acetate) to obtain the title compound (117 mg, 56%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:4][N:5](S(C2C=CC=CC=2)(=O)=O)[C:6]=1[C:7]1[C:8]([C:13]([F:16])([F:15])[F:14])=[N:9][CH:10]=[CH:11][CH:12]=1.[OH-].[Na+]>O1CCCC1.CO>[F:1][C:2]1[C:3]([CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([C:13]([F:15])([F:16])[F:14])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccccc2)c(-c2cccnc2C(F)(F)F)c1F)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(Cc1c[nH]c(-c2cccnc2C(F)(F)F)c1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of tert-butyl ({4-fluoro-1-(phenylsulfonyl)-5-[2-(trifluoromethyl)pyridin-3-yl]-1H-pyrrol-3-yl}methyl)methylcarbamate (938 mg) in tetrahydrofuran (4 mL) and methanol (1 mL) was added a 8 mol/L aqueous sodium hydroxide solution (0.6 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane:ethyl acetate=4:1) to give the title compound as a yellow oil (yield 423 mg, 62%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:31])[C:21]1[CH:26]=[CH:25][C:24](F)=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1.[C-:32]#[N:33].[Na+].O>CN(C)C=O>[C:32]([C:24]1[CH:25]=[CH:26][C:21]([C:20]([NH:19][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([C:8]([F:17])([C:13]([F:15])([F:16])[F:14])[C:9]([F:12])([F:10])[F:11])=[CH:5][C:4]=2[CH3:18])=[O:31])=[CH:22][C:23]=1[N+:28]([O-:30])=[O:29])#[N:33]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C#N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.1 %

Procedure:
To a solution of N[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-4-fluoro-3-nitro-benzamide (2.008 g, 4.4 mmol) (prepared according to WO 05/073165) in N,N-dimethylformamide (25 ml) was added sodium cyanide (0.237 g, 4.84 mmol). The reaction mixture was stirred at ambient temperature for 48 hours. Then water (20 ml) was added and the organic phase extracted three times with ethyl acetate (3×100 ml). The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1:4) to give 4-cyano-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-3-nitro-benzamide (1.0 g, 49% yield). 1H-NMR (400 MHz, CDCl3): 8.85 (d, 1H), 8.38 (q, 1H), 8.11 (d, 1H), 7.55 (s, 1H), 7.40 (s, 2H), 2.33 (s, 6H) ppm.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[F:13][C:14]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:15]=1[NH2:16].CCN(CC)CC.O>C(Cl)(Cl)Cl>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=2[F:13])[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: Nc1ccc(F)cc1F
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CSc1nc(Cl)c(C=O)c(Nc2ccc(F)cc2F)n1
Yield: 114.4 %

Procedure:
To a solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde [Santilli, et al., J. Heterocycl. Chem. 1971, 8, 445-45] (4.0 g, 18.0 mmol) in CHCl3 (50 mL) was added 2,4-di-fluoroaniline (2.02 mL, 19.8 mmol) followed by Et3N (3.76 mL, 27 mmol, 1.5 eq). The reaction mixture turned yellow and was heated to reflux for 6 h, H2O (50 mL) was added and the layers were separated. The organic layer was evaporated to give 6.5 g (>100%) of the crude title compound which is pure enough to be used in the next step. LC MS (m/e)=316 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:27])[CH2:17][C:18]3([C:23]([O:25][CH3:26])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.Cl>C(O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:27])[CH2:17][C:18]3([C:23]([O:25][CH3:26])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)C1(CC(=O)c2ccc(-c3ccc([N+](=O)[O-])cc3)cc2)CCCC1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: COC(=O)C1(CC(=O)c2ccc(-c3ccc(N)cc3)cc2)CCCC1
Temperature: 85 °C
Yield: 80.8 %

Procedure:
To a 100 mL flask fitted with a reflux condenser was added methyl 1-[2-(4′-nitro-1,1′-biphenyl-4-yl)-2-oxoethyl]cyclopentanecarboxylate (1.68 g, 4.40 mmol) dissolved in 85% aqueous ethanol (55 mL), followed by addition of 2 N aqueous hydrochloric acid solution (2.20 mL) and finely powdered iron (0) (2.46 g, 44.1 mmol). The reaction mixture was heated to 85° C. over 2 h. Upon cooling, the darkly-colored reaction mixture was filtered under reduced pressure through 2 cm Celite®/2 cm silica, in order to remove iron particulates and polar impurities. The yellow filtrate was concentrated under reduced pressure, resulting in a solid that was triturated with 20 mL diethyl ether/20 mL hexane to afford methyl 1-[2-(4′-amino-1,1′-biphenyl-4-yl)-2-oxoethyl]cyclopentanecarboxylate as a light tan solid (1.20 g, 76%). LC-MS ret. time 2.71 min, m/z 338.1 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.55-1.84 (overlapping signals, 6H), 2.25-2.35 (m, 2H), 3.44 (s, 2H), 3.67 (s, 3H), 7.40-8.10 (overlapping signals, 8H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:5][CH:4]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCO)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1ccc(CCC=O)cc1
Temperature: 25 °C

Procedure:
A methylene chloride solution (300 mL) of 3-(4-methoxyphenyl)-1-propanol (Aldrich, 15.0 g, 0.090 mol) was cooled to 0° C. and stirred. Pyridinium chlorochromate (Aldrich, 23.4 g, 0.108 mol) was slowly added to the solution which was then warmed to room temperature, placed under a drying tube and stirred over a weekend (approx. 72 hrs.). The reaction mixture was filtered through a pad of Florisil (Aldrich) and the filtrate was concentrated to give the crude product as a dark oil. Purification by flash chromatography (6:1 hexanes:ethyl acetate) gave the desired 3-(4-methoxyphenyl)propionaldehyde as a pale yellow oil.
Reaction SMILES: [F:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=1)[CH2:3][CH2:4][CH:5]=[CH2:6].[F:14][CH:15]([F:25])[O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[CH:19][CH:18]=1>CN(C=O)C.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.[Cu](I)I>[F:14][CH:15]([F:25])[O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[C:24][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([CH:2]([F:1])[CH2:3][CH2:4][CH:5]=[CH2:6])[CH:8]=2)=[CH:19][CH:18]=1
Reactant: C=CCCC(F)c1cccc(I)c1
Reactant: C#Cc1ccc(OC(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Product: C=CCCC(F)c1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Temperature: 65 °C
Yield: 54 %

Procedure:
To a solution of 1-(1-Fluoro-pent-4-enyl)-3-iodo-benzene (0.4 g, 1.38 mmol) in DMF (6 ml) were added TEA (0.96 ml, 6.9 mmol) and 1-Difluoromethoxy-4-ethynyl-benzene (0.233 g, 1.378 mmol). The reaction was degassed by bubbling argon through it for 5 minute and then dichlorbis(triphenylphospine)palladium (0.048 g, 0.069 mmol), and copper iodide (0.013 g, 0.693 mmol) were added simultaneously. The reaction mixture was heated at 65° C. for 15 min. cooled and quenched with 0.1 N HCl (15 ml). The aqueous was extracted with Et2O (3×15 ml). The combined organic extracts were washed with brine (20 ml), dried (MgSO4), and concentrated. The crude material was purified by chromatography (2.5%-5% Ethyl acetate/Petroleum Ether) to afford the titled compound (0.246 g, 54%) as a slight orange oil, identified by NMR and mass spectral analyses; MS (EI+): 330 (M+)
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:19]=[C:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]=4)[CH2:14][CH2:13]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[CH:36]=[CH:35][C:34](N2C3C(=CC=CC=3)C=C2)=[CH:33][CH:32]=1>>[CH3:27][CH:26]([CH3:28])[C:25]([NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH:15]2[CH2:16][CH2:17][N:12]([CH2:11][C:6]3[C:5]4[C:9](=[CH:10][CH:2]=[CH:3][CH:4]=4)[N:8]([C:34]4[CH:35]=[CH:36][C:31]([CH3:30])=[CH:32][CH:33]=4)[CH:7]=3)[CH2:13][CH2:14]2)[CH:19]=1)=[O:29]
Reactant: Cc1ccc(-n2ccc3ccccc32)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3c[nH]c4cc(Cl)ccc34)CC2)c1
Product: Cc1ccc(-n2cc(CN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c3ccccc32)cc1
Yield: 78 %

Procedure:
According to the procedure used for the synthesis of N-(3-{1-[(6-chloro-1H-indol-3-yl)methyl]-4-piperidinyl}phenyl)-2-methylpropanamide, 1-(4-methylphenyl)-1H-indole (0.207 g, 1.00 mmol) provided 2-methyl-N-[3-(1-{[1-(4-methylphenyl)-1H-indol-3-yl]methyl}-4-piperidinyl)phenyl]propanamide (0.441 g, 78%). 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.73 (d, 1H, J=7.2 Hz), 7.58-7.51 (m, 2H), 7.43-7.36 (m, 3H), 7.35-7.29 (m, 3H), 7.26-7.15 (m, 3H), 6.89 (d, 1H, J=7.7 Hz), 4.07 (s, 2H), 3.36 (d, 2H, J=11.6 Hz), 2.59-2.39 (m, 6H), 2.55 (sept, 1H, J=6.7 Hz), 2.10-1.98 (m, 2H), 1.83 (d, 2H, J=12.9 Hz), 1.23 (d, 6H, J=6.9 Hz); ESMS m/e: 466.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:4][CH:3]=1.N1C=CN=C1.[C:25]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26]>ClCCl.O>[Si:29]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])=[CH:6][CH:7]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:31])[CH3:30]
Reactant: O=C(CCc1ccc(O)cc1)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CCC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.3 %

Procedure:
A solution of benzyl 3-(4-hydroxyphenyl)propanoate (1.0 g, 11.70 mmol) in dichloromethane (60 ml) was cooled to 0° C., and imidazole (1.30 g, 18.73 mmol) and tert-butylchlorodimethylsilane (1.94 g, 12.87 mmol) were added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and was extracted with ethyl acetate. The organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate, and the filtrate was removed by distillation under reduced pressure. The residue was chromatographed on silica gel column (hexane:ethyl acetate=95:5) to give the title compound as an oil (4.0 g, yield 95%).
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[C:4]([CH3:16])([CH3:15])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.[Pd]>[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[C:3](=[O:17])[C:4]([CH3:16])([CH3:15])[O:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(C2=C(Br)C(=O)C(C)(C)O2)cc1
Reactant: CC1(C)OB(c2ccc(OCc3ccccc3)cc2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C2=C(c3ccc(OCc4ccccc4)cc3)C(=O)C(C)(C)O2)cc1
Yield: 85.7 %

Procedure:
4-Bromo-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (2 g, 6.7 mol), 2-(4-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.43 g, 0.0067 mol), and Cs2CO3 (11 g, 0.034 mol) in toluene (25 mL) and water (8 mL) was degassed, Pd (dppf) Cl2 (1.1 g, 0.0013 mol) was added under an inert atmosphere and the mixture degassed once again. The reaction was heated at reflux for 3 h, upon which the reaction mixture was filtered through a pad of Celite® and the filtrate was diluted with EtOAc (100 mL), washed with water (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified by flash column chromatography using 30% ethyl acetate in hexane and silica gel (230-400 Mesh), Rf=0.30 to afford 4-(4-(benzyloxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (2.3 g, 73%) as solid. 1H NMR (500 MHz, d6-DMSO): δ 8.42 (d, J=7.6 Hz, 1H), 8.06-7.99 (m, 2H), 7.95 (t, J=7.2 Hz, 1H), 7.72 (t, J=7.2 Hz, 1H), 7.63 (t, J=7.8 Hz, 1H), 7.56 (d, J=7.2 Hz, 2H); 7.18 (d, J=7.4 Hz, 2H), 7.12 (d, J=7.2 Hz, 2H), 6.89 (d, J=7.2 Hz, 2H), 5.38 (s, 2H), 3.79 (s, 3H). 1.42 (s, 6H). MS: [M+H]+: m/z=452.1; [M+Na]+: m/z=474.2.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:37])[NH:10][CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[C:22][CH2:23][CH:24]([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH3:25])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H].CCN(CC)CC.C(Cl)(OCC1C=CC=CC=1)=O>C1COCC1.[Pd]>[CH2:1]([O:8][C:9](=[O:37])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH:24]([N:26]2[C:27](=[O:36])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]2=[O:35])[CH3:25])=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CC(CC#Cc1ccc(C#CCCNC(=O)OCc2ccccc2)cc1)N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Agent: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(CCCc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
A solution containing compound 24 (2.53 g, 5.15 mmol) dissolved in THF (100 mL) was vacuumed and refilled with nitrogen. The procedure was repeated five times. To the solution was added palladium catalyst (0.5 g, 10% Pd on carbon, 50% wet). The flask was then pressurized with hydrogen gas to 45 psi. The mixture was then shaken overnight at room temperature. The catalyst was filtered under vacuum and washed with ethanol (3×20 mL). The filtrate and washings were combined and concentrated under vacuum. The residue was taken into dichloromethane (25 mL). To the newly formed solution was added Et3N (2.32 mL, 15.45 mmol). The solution was then cooled to 0° C. in an ice bath. CbzCl (1.32 g, 7.730 mmol) was added dropwise over 10 min to the solution, which, after the addition of CbzCl, was allowed to slowly warm to ambient temperature over 3 h and continuously stirred overnight. The reaction was quenched with water (30 mL). Two layers were separated. The organic layer was washed with brine (3×30 mL), dried over anhydrous Na2SO4, and concentrated. The resulting residue was subjected to column chromatography eluting with 0-30% ethyl acetate in hexanes to afford the desired product 25 (0.90 g, 35%) as a colorless, viscous oil: 1H NMR (300 MHz, CDCl3) δ 1.45 (d, 3H), 1.45-1.66 m, 6H), 1.72-1.86 (m, 2H), 2.06-2.16 (m, 2H), 2.55 (m, 4H), 3.20 (m, 2H), 4.38 (m, 1H), 4.80 (br, 1H), 5.08 (s, 2H), 7.04 (s, 4H), 7.34 (m, 5H), 7.69 (dd, 2H), 7.81 (dd, 1H); m/z (ESI) 499 [C31H34N2O4+H]+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>CCOC(C)=O.[Pd]>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C=C1Cc2ccccc2C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1Cc2ccccc2C1
Yield: 93.6 %

Procedure:
To a solution of ethyl 1,3-dihydro-2H-inden-2-ylideneacetate (302 mg, 1.49 mmol) in EtOAc (10 mL) was added 5% Pd/C (76 mg) and H2 was bubbled through the slurry for 20 h. The slurry was then filtered through Celite and the organic solution was concentrated in vacuo. Ethyl 2,3-dihydo-1H-inden-2-ylacetate (285 mg, 94%) was isolated as a colorless oil without purification.
Reaction SMILES: CS(O[C@@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[O:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C)C=O>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C@@H:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[N:19]=[N+:20]=[N-:21])=[CH:13][CH:14]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)O[C@@H]1CCC[C@H]1Oc1ccc(Br)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1CCC[C@H]1Oc1ccc(Br)cc1
Temperature: 100 °C

Procedure:
To a solution of trans-2-(4-bromophenoxy)cyclopentyl methanesulfonate (3.52 g, 10.5 mmol) in dimethylformamide (22 mL) was added sodium azide (897 mg, 13.7 mmol) and the reaction was heated at 100° C. for 18 hours. The reaction was cooled to room temperature and partitioned between ethyl acetate and 1N aqueous lithium chloride solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over calcium sulfate, filtered and concentrated in vacuo to provide product as a brown oil, which was used in the next step without additional purification. Yield: 2.59 g, 9.18 mmol, 87%. 1H NMR (400 MHz, CDCl3) δ 1.65-1.73 (m, 1H), 1.89-2.05 (m, 5H), 3.74 (m, 1H), 4.66 (m, 1H), 6.83 (d, J=9.0 Hz, 2H), 7.39 (d, J=9.0 Hz, 2H).