Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][N:12]=[C:11]2[OH:15])=[CH:6][CH:5]=1.[CH3:16][Si:17]([CH3:24])([CH3:23])[CH2:18][CH2:19][O:20][CH2:21]Cl>CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:11](=[O:15])[N:12]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:24])([CH3:23])[CH3:16])[N:13]=[CH:14]2)=[CH:8][CH:9]=1
Reactant: Oc1nncn1-c1ccc(Br)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ncn(-c2ccc(Br)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To dry NaH (360 mg, 15.0 mmol) under an Argon atmosphere was added dropwise a solution of compound 82a (1.92 g, 6.80 mmol; based on 85% purity) in anhydrous DMF (20 mL). After stirring at room temperature for 1 h, the mixture was cooled to 0° C. and 2-(trimethylsilyl)ethoxymethyl chloride (3.07 mL, 17.0 mmol) was added dropwise over 2 min. The mixture was stirred at room temperature for 1.5 h. The mixture was quenched carefully with 1 mL of saturated aqueous NH4Cl and poured into water (150 mL). After saturating the aqueous mixture with solid NaCl, the mixture was extracted with EtOAc (3×25 mL). The combined extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a pale brown solid which was purified by flash column chromatography on silica gel (0-40% EtOAc-heptane) to afford compound 82b as a white solid. Mass spectrum (LCMS, ESI pos.): Calcd. for C14H20BrN3O2Si, 392.1/3.94.1 (M+Na). found 392.2/3.94.1.
Reaction SMILES: C1[CH2:5][O:4]CC1.O1CCCC1.COCCOC.C(COC)OC.[Li+].C[CH:25]([N-:27][CH:28](C)C)C.[CH:31]([N-:34][CH:35](C)C)(C)C.[Li+].[Li]CCCC.C([Li])CCC>C(Cl)Cl.ClCCl.CCOCC.C(OCC)C.CCOC(C)=O.C(OCC)(=O)C>[CH3:25][N:27]([CH:5]=[O:4])[CH3:28].[CH3:31][N:34]([CH3:35])[CH:5]=[O:4]
Reactant: CC(C)[N-]C(C)C
Reactant: C1CCOC1
Agent: [Li+]
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CN(C)C=O

Procedure:
THF—tetrahydrofuran; DME—dimethoxyethane; EtOAc—ethyl acetate; Et2O—diethylether; RT—room temperature; LDA—lithium diisopropylamide; CH2Cl2—dichloro-methane; tic—thin layer chromatography; BuLi—butyllithium
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)(=O)=O.[PH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.P(C1CCCCC1)C1CCCCC1.CCN(CC)CC>C1(C)C=CC=CC=1.[Pd].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:25]1([P:18]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[C:7]2[CH2:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: O=S(=O)(OC1=Cc2ccccc2C1)C(F)(F)F
Reactant: c1ccc(Pc2ccccc2)cc1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C1CCC(PC2CCCCC2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C1=C(P(C2CCCCC2)C2CCCCC2)Cc2ccccc21

Procedure:
Compound 5 was prepared also via Pd-catalyzed phosphination of 1H-inden-2-yl trifluoromethanesulfonate. Following the procedure described for the synthesis of 3 from Ph2PH, 6.60 g (0.025 mol) of 1H-inden-2-yl trifluoromethanesulfonate, 4.98 g (0.025 mol) of Cy2PH, 3.9 ml (2.82 g, 0.027 mol) of Et3N, and 0.72 g (0.62 mmol) of Pd(PPh3)4 in 50 ml of toluene gave dicyclohexyl(1H-inden-2-yl)phosphine, 5. Yield 7.81 g (82%).
Reaction SMILES: NC(=O)[C@@H:3]([NH:8][C:9](=[O:37])[C@@H:10]([NH:15][C:16]([N:18]1[C:26]2[CH2:25][CH2:24][N:23]([CH3:27])[CH2:22][C:21]=2[C:20]([C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=2[F:36])=[N:19]1)=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4]C(C)C.NCC[C:42]([NH2:44])=[O:43]>>[NH2:44][C:42](=[O:43])[CH2:4][CH2:3][NH:8][C:9](=[O:37])[C@@H:10]([NH:15][C:16]([N:18]1[C:26]2[CH2:25][CH2:24][N:23]([CH3:27])[CH2:22][C:21]=2[C:20]([C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=2[F:36])=[N:19]1)=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C)C(N)=O
Reactant: NCCC(N)=O
Product: CN1CCc2c(c(-c3cc(F)c(F)cc3F)nn2C(=O)N[C@H](C(=O)NCCC(N)=O)C(C)(C)C)C1

Procedure:
Compound 73 was prepared according to the procedure described for the synthesis of compound 72 by replacing leucine amide with 3-aminopropanamide. LCMS (+ESI) m/z=495.4 [M+H]+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([OH:11])[C:5]=2[O:4][CH2:3][CH2:2]1.C([Mg]Cl)(C)C.[CH:17]([N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[C:31]1=[O:40])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1.ClCCCl>[C:24]1([CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([OH:39])([C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[C:10]=3[OH:11])[C:31]2=[O:40])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: Oc1cccc2c1OCCO2
Agent: CC(C)[Mg]Cl
Solvent: ClCCCl
Solvent: C1CCOC1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1ccc2c(c1O)OCCO2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 69.3 %

Procedure:
To a solution of 2,3-dihydro-1,4-benzodioxin-5-ol (3.60 g, 23.7 mmol) in anhydrous tetrahydrofuran (80 mL) at 0° C. was added isopropylmagnesium chloride (11.8 mL, 2 M solution in tetrahydrofuran, 23.7 mmol). The mixture was stirred at 0° C. for 45 min, concentrated in vacuo, and 1,2-dichloroethane (60 mL) was added. The mixture was cooled to 0° C. and a solution of 1-benzhydrylindoline-2,3-dione (4.94 g, 15.8 mmol) in 1,2-dichloroethane (70 mL) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 60 h, and heated to 83° C. and stirred for 3.5 h. The reaction mixture was allowed to cool to ambient temperature, concentrated in vacuo and saturated aqueous ammonium chloride (250 mL) was added. The mixture was extracted with ethyl acetate (250 mL followed by 2×100 mL). The organic phase was washed with water (150 mL) and brine (150 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate and a solid was precipitated by the addition of hexanes to afford 1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one (5.10 g, 69%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ9.14 (s, 1H), 7.43-7.30 (m, 9H), 7.22 (d, J=8.7 Hz, 1H), 6.97-6.79 (m, 3H), 6.52 (s, 1H), 6.44 (d, J=8.7 Hz, 1H) 6.26 (d, J=7.8 Hz, 1H), 4.22 (s, 4H).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.C(=O)(O)[O-].[Na+].P([O-])([O-])([O-])=O.[CH3:29][C:30]1[S:34][C:33]([C:35](=[S:37])[OH:36])=[N:32][CH:31]=1.P(=O)(O)(O)O>>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:37][C:35]([C:33]3[S:34][C:30]([CH3:29])=[CH:31][N:32]=3)=[O:36])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cc1cnc(C(O)=S)s1
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Product: Cc1cnc(C(=O)SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Reaction time: 5 h
Yield: 35 %

Procedure:
To a stirred solution of 9.3 g. (0.034 moles) of 7-aminocephalosporanic acid and 5.75 g. (0.068 moles) of sodium bicarbonate in 204 ml. of aqueous phosphate buffer at pH 6.4 was added 5.44 g. (0.034 moles) of 5-methylthiazole-2-thiocarboxylic acid. The mixture was stirred in a nitrogen atmosphere at 50° for 5 hours keeping the pH at 6.5 with 42% phosphoric acid. Then the mixture was cooled to 20° and the precipitated solid was removed by filtration, washed with water, acetone and ether and dried in vacuo over phosphorus pentoxide to provide 4.4 g. (35% yield) of a tan crystalline solid. Infrared and NMR spectra were consistent with the structure.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:28][C:29]1[NH:30][CH:31]=[C:32]([CH:34]=[O:35])[N:33]=1>C(Cl)Cl>[CH3:28][C:29]1[N:30]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:31]=[C:32]([CH:34]=[O:35])[N:33]=1
Reactant: Cc1nc(C=O)c[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(C=O)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (5.1 mL, 36.3 mmol) followed by trityl chloride (7.6 g, 27.2 mmol) were added to an ambient temperature solution of 2-methyl-1H-imidazole-4-carboxaldehyde (2 g, 18.2 mmol) in methylene chloride (20 mL). After stirring at ambient temperature overnight, the reaction was diluted with methylene chloride and washed with water and brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 30-70% ethyl acetate/hexane afforded 2-methyl-1-trityl-1H-imidazole-4-carboxaldehyde.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[CH3:14][C:15]1[CH:16]=[CH:17][C:18]2[CH:22]=[C:21]([CH:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)O)[S:20][C:19]=2[CH:31]=1>>[OH:6][C:5]1[C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3](=[O:7])[C:4]=1[CH:23]([C:21]1[S:20][C:19]2[CH:31]=[C:15]([CH3:14])[CH:16]=[CH:17][C:18]=2[CH:22]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1ccc2cc(C(O)c3ccccc3)sc2c1
Reactant: CC1(c2ccccc2)C(=O)CC1=O
Product: Cc1ccc2cc(C(C3=C(O)C(C)(c4ccccc4)C3=O)c3ccccc3)sc2c1

Procedure:
Using general procedure D, 2-methyl-2-phenyl-cyclobutane-1,3-dione (Lit. 1) was reacted with (6-methyl-benzo[b]thiophen-2-yl)-phenyl-methanol to give the title compound as a pale yellow solid. MS: 409.3 ([M−H]−).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([CH3:21])[CH:15]=1)#[CH:13].N>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[O:9][N:8]=[C:7]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:13]=2)=[CH:15][C:16]=1[CH3:21]
Reactant: ON=C(Cl)c1cncc(F)c1
Reactant: C#Cc1ccc(F)c(C)c1
Agent: N
Product: Cc1cc(-c2cc(-c3cncc(F)c3)no2)ccc1F

Procedure:
The titled compound was prepared according to Method CB using the product of Example 28B (88 mg, 0.5 mmol) and 4-ethynyl-1-fluoro-2-methylbenzene (Aldrich, 67 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 2.37 (d, J=2.0 Hz, 3H), 7.21 (t, J=8.9 Hz, 1H), 7.33 (s, 1H), 7.73-7.80 (m, 1H), 7.83 (dd, J=6.6, 1.9 Hz, 1H), 8.16 (ddd, J=9.2, 2.7, 1.7 Hz, 1H), 8.60 (d, J=2.7 Hz, 1H), 8.96 (t, J=1.5 Hz, 1 H) ppm; MS (DCI/NH3) m/z 273 (M+H)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl.ON1C(=O)CCC1=O.[CH2:30]1[CH:34]([CH2:35][CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])[S:33][S:32][CH2:31]1>ClCCl>[CH2:30]1[C@@H:34]([CH2:35][CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])[S:33][S:32][CH2:31]1
Reactant: O=C(O)CCCCC1CCSS1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)CCCC[C@@H]1CCSS1
Reaction time: 0.17 h

Procedure:
Diisopropylethylamine (DIPEA) (anhydrous, 4.3 ml, 24.2 mmol) was added to a solution of EDC.HCl (604 mg, 3.15 mmol) in dichloromethane (15 ml) and stirred for 10 minutes. N-hydroxysuccinimide (390 mg, 3.39 mmol) was added followed by DL-lipoic acid (500 mg, 2.43 mmol). The reaction mixture was stirred in an ice bath for half an hour and then slowly continued overnight under room temperature. The reaction mixture was washed with HCl (5% v/v, 25 ml×2) and water (50 ml×3). The organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (ethylacetate/hexane=2:1) (618 mg, 85%); 1H-NMR (CDCl3) 1.62-1.98 (7H, m), 2.29-2.47 (1H, m), 2.69 (2H, t, J=7.4), 3.02 (4H, s, succinimidyl CH2×2), 3.21-3.28 (2H, m), 3.60-3.65 (1H, m); ESI-MS m/z calcd for C12H17NO4S2: 303.2518. found: 304.1861 [M+1].
Reaction SMILES: [CH3:1][N:2]([CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH2:15])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH2:13][C:14]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:30][CH2:15]1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(CN(C)S(=O)(=O)c1ccc(C)cc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N(C)CC2(c3ccccc3)CO2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
A mixture of 9.8 g of N-methyl-N-(2-phenyl-2-propenyl)-p-toluenesulfonamide, 9.63 g of m-chloroperbenzoic acid and 280 ml of chloroform were stirred at 60° C. for 3 hours. After cooling, the reaction mixture was washed subsequently with 10% aqueous sodium bisulfite and water, dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (developing solvent:ethyl acetate -n-hexane) to obtain 7.7 g of the titled compound.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.C1(C)C=CC=CC=1.[Cl-].[NH4+].[CH3:20][N:21](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:10][C:4]1[CH:3]=[C:2]([C:20]#[N:21])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C#N)c(F)c1

Procedure:
A solution of 4-bromo-2-fluorobenzonitrile (20 g, 100 mmol) , zinc cyanide (7 g, 60 mmol) and tetrakis (triphenylphosphine) palladium (4.6 g, 4 mmol) in DMF (100 mL) was heated at 80° C. for 4 hr. Toluene (300 mL) and saturated aqueous ammonium chloride (300 mL) were added and the layers were separated. The organic layer was washed once with saturated aqueous ammonium chloride and twice with brine. The organic phase was dried (MgSO4), filtered and concentrated. The product was purified by silica gel chromatography, eluting with a gradient of hexanes to 30% EtOAc/hexanes (11 g, 75%).
Reaction SMILES: Br[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([CH3:25])[C:7]([O:14][Si](C(C)C)(C(C)C)C(C)C)=[C:8]([CH3:13])[CH:9]=2)[O:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2([OH:39])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1.C(N(CC)CC)C>C(#N)C>[CH3:13][C:8]1[CH:9]=[C:10]2[C:5](=[C:6]([CH3:25])[C:7]=1[OH:14])[O:4][CH2:3][C@@H:2]([N:36]1[CH2:35][CH2:34][C:33]([C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)([OH:39])[CH2:38][CH2:37]1)[C@H:11]2[OH:12]
Reactant: OC1(c2ccc(F)cc2)CCNCC1
Reactant: Cc1cc2c(=O)c(Br)coc2c(C)c1O[Si](C(C)C)(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc2c(c(C)c1O)OC[C@@H](N1CCC(O)(c3ccc(F)cc3)CC1)[C@H]2O
Temperature: 25 °C

Procedure:
A mixture of 3-bromo-6,8-dimethyl-7-triisopropylsilyloxychromen-4-one (the compound of Example 19, 0.23 g, 0.54 mmol), 4-(4-fluorophenyl)-4-hydroxypiperidine (0.22 g, 1.12 mmol) and triethylamine (0.3 mL, 2.15 mmol) in acetonitrile (15 mL) was stirred over the weekend at ambient temperature. The precipitate which formed was collected and rinsed with water and ether. This solid was flash chromatographed on silica gel (1×4 inches packed in hexane) with elution proceeding as follows: 10% ethyl acetate/hexane (100 mL), nil; 25% ethyl acetate/hexane (200 mL), 0.065 g (22%) 6,8-dimethyl-7-triisopropylsilyloxy-3-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-chromen-4-one which had: mp 226.5-227° C. Analysis calculated for C31H42FNO4Si: C, 68.98; H, 7.84; N, 2.59. Found: C, 69.00; H, 7.94; N, 2.37. This product was identical to the product isolated in the first step of example 19 and was converted to the title product following the procedure of example 19.
Reaction SMILES: [CH2:1]([C:4]([CH2:13][C:14]#[CH:15])(C(OC)=O)[C:5]([O:7][CH3:8])=[O:6])[C:2]#[CH:3].[Cl-].[Na+]>CS(C)=O.O.COC(C)(C)C>[CH2:1]([CH:4]([CH2:13][C:14]#[CH:15])[C:5]([O:7][CH3:8])=[O:6])[C:2]#[CH:3]
Reactant: C#CCC(CC#C)(C(=O)OC)C(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Solvent: O
Product: C#CCC(CC#C)C(=O)OC
Reaction time: 15 h

Procedure:
Dimethyl 2,2-di(2-propynyl)malonate (71 g) was treated to a Krapcho decarboxylation by heating at 170° C. with with sodium chloride (25 g) and water (23 ml) in dimethylsulfoxide (341 ml). After 15 hr, the solution was cooled and diluted with water and t-butyl methyl ether and extacted. The organic layer was washed with water (4×), brine, and then dried over sodium sulfate. Solvent removal afforded a liquid which was distilled, collecting the title compound at 109° C. (28 mm Hg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18](OCC)=[O:19])[CH2:11][CH2:10]1.COC1C=CC=CC=1N1CCN(CCCO)CC1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:13][CH2:14]1
Reactant: CCOC(=O)CCCN1CCN(c2ccccc2OC)CC1
Agent: COc1ccccc1N1CCN(CCCO)CC1
Product: COc1ccccc1N1CCN(CCCCO)CC1

Procedure:
4-(4-(2-Methoxyphenyl)piperazin-1-yl)butan-1-ol (21c) (Scheme 4) was synthesized from 17c according to the protocol described for 21a (Example 31). Colorless oil, 0.8 g (93%). 1H NMR (400 MHz, CDCl3): δ 1.59-1.66 (m, 4H); 2.41-2.43 (m, 2H); 2.68 (broad s, 4H); 3.08 (broad s, 4H); 3.54-3.55 (m, 2H); 3.81 (s, 3H); 5.76 (broad s, 1H); 6.79-6.97 (m, 4H). MS (ESI): m/z=265.40 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]COC)=[C:14]([O:22][CH3:23])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH2:1]([O:8][C:9](=[O:24])[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:22][CH3:23])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOc1ccc(CNC(=O)OCc2ccccc2)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1cc(CNC(=O)OCc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.6 %

Procedure:
A solution of 13 (0.795 g, 2.4 mmol) in CH2Cl2 (5 mL) was treated with trifluoroacetic acid (2.5 mL) slowly and stirred for 5 min at room temperature. After cooling to 0° C., the reaction mixture was neutralized with saturated NaHCO3 solution, diluted with H2O and extracted with CH2Cl2 several times. The combined organic layer was washed with H2O and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel using EtOAc:Hex (2:1) as eluant to give 14 as white solid (680 mg, 99%).
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([F:15])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([CH3:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][C:24]=1[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(Cl)Cl.CCCCCC>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]([CH3:7])([CH3:6])[C:4]([F:15])=[CH:3][CH2:2][C:26]2[CH:27]=[CH:28][C:23]([F:22])=[C:24]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:25]=2)=[CH:9][CH:10]=1
Reactant: OB(O)c1ccc(F)c(Oc2ccccc2)c1
Reactant: CC(C)(C(F)=CCBr)c1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C(F)=CCc1ccc(F)c(Oc2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
A mixture of 1-bromo-4-(p-chlorophenyl)-3-fluoro-4-methyl-2-pentene, (Z)- (1.02 g, 3.5 mmol), and bis(dibenzylideneacetone)palladium(0) [Pd(dba)2] (0.1 g, 0.17 mmol) in toluene (20 mL) under nitrogen is stirred for one minute, treated with potassium carbonate (1.94 g, 0.014 mol), degassed, treated with a solution of 4-fluoro-3-phenoxybenzeneboronic acid (1.05 g, 4.55 mmol) in ethanol (5 mL), refluxed for 50 minutes, cooled to room temperature, diluted with ethyl acetate and filtered through diatomaceous earth. The filtrate is washed sequentially with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Flash chromatography of the residue using silica gel and a 15:100 methylene chloride/hexane solution gives the title compound as a colorless oil (1.19 g, 85.6% yield) which is identified by NMR spectral analyses.
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:22])=[C:4]2[C:9](=[O:10])[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14](I)[CH:13]=3)[CH2:7][CH2:6][N:5]2[C:19](=[O:21])[CH:20]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:14]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][N:8]2[CH2:7][CH2:6][N:5]3[C:19](=[O:21])[CH:20]=[C:2]([OH:1])[C:3]([OH:22])=[C:4]3[C:9]2=[O:10])[CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1c2c(O)c(O)cc(=O)n2CCN1Cc1cccc(I)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1c2c(O)c(O)cc(=O)n2CCN1Cc1cccc(-c2ccccc2)c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A solution of 8,9-dihydroxy-2-(3-iodobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (0.05 g, 0.121 mmol) in DMF (5 mL) was degassed for 5 minutes with nitrogen and placed under an atmosphere of nitrogen. To this was added phenyl boronic acid (0.015 g, 0.123 mmol), triethylamine (0.051 mL, 0.364 mmol), and bis(tri-t-butylphosphine)palladium(0) (0.003 g, 0,006 mmol) and heated with stirring at 110° C. overnight. The product mixture was concentrated under vacuum, and the residue was triturated with methylene chloride. The resultant precipitate was filtered off and the filtrate concentrated under vacuum. The filtrate residue was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Desired fractions were concentrated under vacuum to afford the title compound as off white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([N:14]3[CH2:15][CH2:16][N:17]([CH2:25][C:24]4[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH3:20])[CH:23]=4)[CH2:18][CH2:19]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc([C@H]2CC[C@H](N3CCNCC3)CC2)cc1
Reactant: COc1cccc(CCl)c1
Product: COc1cccc(CN2CCN([C@H]3CC[C@H](c4ccc(F)cc4)CC3)CC2)c1

Procedure:
The title compound was prepared from trans 1-[4-(4-fluorophenyl)-1-cyclohexyl]piperazine (0.39 g, 1.5 mmole) and 3-methoxybenzyl chloride (0.22 g, 1.5 mmole) by the method described in example 45 to give the product (61%, mp: 84-85° C.). Calc'd for C24H31FN2O: C, 75.36%; H, 8.17%; N, 7.33%. Found: C, 75.53%; H, 8.23%; N, 7.30%.