Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([N+:28]([O-])=O)[CH:22]=2)[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([NH2:28])[CH:22]=2)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(C(NC(C)c2ccc(F)c(F)c2)c2ccc(F)c([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(NC(C)c2ccc(F)c(F)c2)c2ccc(F)c(N)c2)cc1
Yield: 78.4 %

Procedure:
Following a similar procedure to that described in Example (1b), 2.5 g of N-[1-(3,4-difluorophenyl)ethyl]-N-[(4-fluoro-3-nitrophenyl)-(4-methoxyphenyl)methyl]amine [prepared as described in step (a) above], 3.29 g of nickel chloride hexahydrate and 957 mg of sodium borohydride were reacted, to obtain 1.82 g of the title compound as a yellow oil.
Reaction SMILES: Cl.[C:2]12([CH2:12][CH2:13][NH2:14])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[Cl:15][C:16]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>>[Cl:15][C:16]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH:14][CH2:13][CH2:12][C:2]12[CH2:9][CH:8]3[CH2:7][CH:6]([CH2:5][CH:4]([CH2:10]3)[CH2:3]1)[CH2:11]2)=[O:19]
Reactant: NCCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Agent: Cl
Product: O=C(NCCC12CC3CC(CC(C3)C1)C2)c1cccc(Cl)c1Cl
Yield: 54 %

Procedure:
Prepared according to the method of Example 1 from 1-adamantaneethylamine hydrochloride (0.102 g) and 2,3-dichlorobenzoyl chloride (0.102 g) to give the title compound as a white solid (0.090 g).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]2[N:24]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[N:25]=[CH:26][C:19]=12.ClC1C2N=CN=CC=2NN=1>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:18]2[N:23]=[CH:22][N:21]=[C:20]3[N:24]([C:27]4[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=4)[N:25]=[CH:26][C:19]=23)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: Clc1n[nH]c2cncnc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Into a 16 mL reaction vial was placed sodium hydride (7.8 mg, 60% in oil, 0.195 mmol) and 0.5 mL of THF. 4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (10 mg, 0.0487 mmol) was added to the suspension and the mixture was stirred 20 min under N2 at room temperature, followed by the slow addition of 4-chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (10 mg, 0.0325 mmol). After stirring overnight under N2 at room temperature, all of the starting chloropyrazolopyrimidine had been converted as indicated by LCMS. The reaction mixture was then concentrated under vacuum and purified by flash column chromatography using 50% EtOAc/Hex as eluent. 1H NMR (CDCl3, 400 MHz) δ 1.49 (s, 9H), 1.85 (m, 2H), 2.09 (m, 2H), 3.10 (s, 3H), 3.32 (m, 2H), 3.86 (m, 2H), 5.60 (m, 1H), 8.09 (d, 2H), 8.26 (s, 1H), 8.61 (d, 2H), 8.66 (s, 1H). LCMS: calculated for C22H27N5O5S 473.17, observed 474.4 (MH+)
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:2]2[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(F)(F)F)cc1Oc1ccc(F)cc1
Temperature: 100 °C
Yield: 78.5 %

Procedure:
To a solution of 2-fluoro-4-(trifluoromethyl)benzaldehyde (1.0 g, 5.20 mmol) and 4-fluorophenol (583.5 mg, 5.20 mmol) in DMF (5.0 mL) was added dicesium carbonate (1.7 g, 5.20 mmol) and the mixture was heated at 100° C. for 1 hour. The reaction was cooled to room temperature. The reaction was diluted with ethyl acetate (5 ml) and water (10 ml). The organic layer was washed with water (2×10 mL), dried with MgSO4, filtered and evaporated to yield a brown oil that was purified by column chromatography using a gradient of ethyl acetate in hexanes (0-25%) to yield 2-(4-fluorophenoxy)-4-(trifluoromethyl)benzaldehyde (1.16 g, 78%). 1H NMR (400 MHz, CDCl3) δ 10.58 (s, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.42 (d, J=7.5 Hz, 1H), 7.18-7.04 (m, 5H) ppm.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([OH:15])=O)=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][CH:6]=2.Cl.[CH3:17][O:18][C:19](=[O:29])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH2:21].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[CH3:17][O:18][C:19](=[O:29])[C@@H:20]([NH:21][C:13]([C:3]1[C:2]([OH:1])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:12])[CH:4]=1)=[O:15])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1cc2cccc(O)c2cc1O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1cc2cccc(O)c2cc1O
Yield: 60.5 %

Procedure:
A solution of 3,5-dihydroxy-2-naphthoic acid (4.08 g), L-phenylalanine methyl ester hydrochloride (4.74 g), WSC.HCl (4.22 g), HOBT (2.97 g) and N-methylmorpholine (2.41 ml) in DMF (200 ml) was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a 10% aqueous citric acid solution, water, a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1 v/v) to give the title compound (4.42 g, yield 61%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH3:16][N:17]([CH3:32])[C:18]([C:20]1[CH:21]=[N:22][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:24][CH:25]=1)=[O:19].CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[CH3:16][N:17]([CH3:32])[C:18]([C:20]1[CH:21]=[N:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1)=[O:19]
Reactant: CN(C)C(=O)c1ccc(N2CCNCC2)nc1
Reactant: O=C(O)/C=C/C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccc(N2CCN(C(=O)/C=C/C(F)(F)F)CC2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.3 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (32 mg, 0.23 mmol) was dissolved in dichloromethane (1 ml), oxalyl chloride (20 μl, 0.23 mol) and one drop of DMF were added and the resulting solution was stirred at room temperature for 10 minutes. This solution was added to a solution of N,N-dimethyl-6-piperazin-1-yl-pyridine-3-carboxamide (35 mg, 0.15 mmol) and DIPEA (80 μl, 0.5 mmol) in anhydrous DCM (2 ml) and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 39 mg of a solid (0.11 mmol, yield 48%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH2:23][OH:24])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(C)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:23]=[O:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: OCc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
Sulfur trioxide-pyridine complex (24.1 g, 152 mmol) was added to a stirred solution of [9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]methanol (8.30 g, 21.7 mmol), triethylamine (24 mL), and dimethyl sulfoxide (150 mL) in dichloromethane (100 mL) at room temperature, and the mixture was stirred at room temperature for 3 hr. The mixture was concentrated in vacuo, diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 15-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was washed with ethyl acetate/diisopropyl ether to give the title compound as a pale yellow powder (6.82 g, 17.9 mmol, 82%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:27]C(=O)C)[CH:5]=[CH:6][C:7]=1[C:8](=[O:26])[CH2:9][N:10]1[C:14](=[O:15])[C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:16][CH2:17][CH3:18])[N:12]=[C:11]1[CH3:25].Cl>C(O)C>[NH2:27][C:4]1[CH:5]=[CH:6][C:7]([C:8](=[O:26])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([CH2:16][CH2:17][CH3:18])[N:12]=[C:11]2[CH3:25])=[C:2]([F:1])[CH:3]=1
Reactant: CCCC1(c2ccccc2)N=C(C)N(CC(=O)c2ccc(NC(C)=O)cc2F)C1=O
Agent: Cl
Solvent: CCO
Product: CCCC1(c2ccccc2)N=C(C)N(CC(=O)c2ccc(N)cc2F)C1=O
Temperature: 100 °C
Yield: 49.1 %

Procedure:
(+/−)-N-{3-fluoro-4-[2-(2-methyl-5-oxo-4-phenyl-4-propyl-4,5-dihydro-imidazol-1-yl)-acetyl]-phenyl}-acetamide (956 mg, 1.8 mmol) is dissolved in 10 mL ethanol and concentrated hydrochloric acid (192 uL, 1.9 mmol) is added. The mixture is heated to 100° C. in the microwave oven (Biotage Initiator) for 30 min. Subsequently the solvent is evaporated and the residue is suspended in concentrated sodium hydrogen carbonate solution and dichloromethane. This mixture is extracted three times with dichloromethane. The organic phase is dried with sodium sulfate, filtrated and evaporated to yield (+/−)-3-[2-(4-amino-2-fluoro-phenyl)-2-oxo-ethyl]-2-methyl-5-phenyl-5-propyl-3,5-dihydro-imidazol-4-one (325 mg, 40%) as light brown foam. LC/MS at 254 nm; [M+H] 368; Rt 2.616 min.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([OH:17])=O.[NH2:18][C:19]1[CH:20]=[C:21](O)[CH:22]=[CH:23][C:24]=1[Cl:25].IC1C=CC=CC=1>[Cu]I.CS(C)=O>[Cl:25][C:24]1[CH:23]=[CH:22][C:21]([O:17][C:15]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:20][C:19]=1[NH2:18]
Reactant: O=C(O)c1ccccn1
Reactant: Nc1cc(O)ccc1Cl
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Ic1ccccc1
Solvent: CS(C)=O
Product: Nc1cc(Oc2ccccc2)ccc1Cl
Temperature: 80 °C
Reaction time: 15 h
Yield: 853 %

Procedure:
A heat gun-dried 100-mL round bottomed flask equipped with a magnetic stir bar was charged with potassium phosphate (5.91 g, 27.9 mmol), picolinic acid (0.171 g, 1.393 mmol), copper(I) iodide (0.133 g, 0.697 mmol), 3-amino-4-chlorophenol (2.0 g, 13.93 mmol), dimethylsulfoxide (27.9 mL), and iodobenzene (3.41 g, 16.72 mmol). The resulting mixture was heated to 80° C. After 15 h, the reaction mixture was subjected to an aqueous workup to afford the crude product, which was then purified by flash chromatography to afford pure 2-chloro-5-phenoxyaniline (2.61 g, 85%). MS (ESI, pos. ion) m/z 220 [M+1].
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:8]2[CH:9]=[C:10]([C:13]([O:15]C)=[O:14])[CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:17]>CO>[CH3:3][N:4]1[C:8]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:17]
Reactant: COC(=O)c1ccc2[nH]c(=O)n(C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(=O)[nH]c2ccc(C(=O)O)cc21
Temperature: 65 °C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
Add 1N sodium hydroxide (6.1 mL, 6.1 mmol) to a suspension of methyl 3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (420 mg, 2.04 mmol) in methanol (10 mL). The suspension turned to a solution upon addition of 1N sodium hydroxide. Stir at 65° C. for 16 hours. Cool to room temperature then concentrate to remove the methanol. Extract the aqueous with ethyl acetate (5 mL). Acidify the aqueous with 2N hydrogen chloride (3 mL) to pH˜2. Concentrate the aqueous layer to a solid. Triturate the solid with water (3 mL). Filter the precipitate and dry under high vacuum to yield the title compound (234 mg, 59%) as a pale brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.28 (s, 3H), 7.01 (d, J=8.21 Hz, 1H), 7.57 (s, 1H), 7.63 (dd, J=8.11, 1.27 Hz, 1H), 11.19 (s, 1H), 12.60 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].[CH2:16]([O:18][C:19](=[O:46])[CH2:20][CH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:30]=2)[CH:25]=[CH:24][C:23]=1[O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]Br)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:16]([O:18][C:19](=[O:46])[CH2:20][CH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:30]=2)[CH:25]=[CH:24][C:23]=1[O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15])[CH3:17]
Reactant: CCOC(=O)CCc1c(OCCCCCBr)ccc2ccc(OCC(=O)OCC)cc12
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCCOc2ccc3ccc(OCC(=O)OCC)cc3c2CCC(=O)OCC)ccc2c1OCCC2=O
Temperature: 94 °C
Yield: 81.3 %

Procedure:
A mixture of 0.454 g (2.2 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, 1.09 g (2.2 mmol) of 2-[(5-bromopentyl)oxy]-7-(2-ethoxy-2-oxoethoxy)-1-naphthalenepropanoic acid ethyl ester from the preceding example, 1.23 g (8.9 mmol) of anhydrous granular potassium carbonate and 32.5 mL of 2-butanone was heated at 94° C. for 22 hr. After being cooled to room temperature, the mixture was filtered through some anhydrous magnesium sulfate. The solids were washed thoroughly with ethyl acetate and the filtrate and washes were combined and concentrated in vacuo. The residue was flash chromatographed on 200 g of silica gel, eluting with hexane-ethyl acetate (2:1) affording 1.11 g (81%) of the title compound as a white solid, mp 68°-69.5° C.
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:16][C:17]1[N:18]([CH2:25][C@:26]2([CH3:29])[CH2:28][O:27]2)[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[N:21]=1.CN(C=O)C>O>[Cl:16][C:17]1[N:18]([CH2:25][C@@:26]([CH3:29])([OH:27])[CH2:28][N:11]2[CH2:10][CH2:9][CH:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:12]2)[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[N:21]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@](O)(CN1CCC(c2ccccc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 70 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
4-Phenylpiperidine hydrochloride (0.522 g, 2.64 mmol) was added to a sodium hydroxide solution, and extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. To the residue, (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (0.5 g, 2.29 mmol) and DMF (5 ml) were added followed by stirring at 70° C. for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate twice. The organic phases were combined, washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1) to afford (S)-1-(2-chloro-4-nitroimidazol-1-yl) -2-methyl-3-(4-phenylpiperidin-1-yl)propan-2-ol (0.703 g, yield 81%) as a yellow oil.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)[CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cc(-c2cncc(F)c2)cc(C)n1
Reactant: Nc1ccc(F)cc1
Product: Cc1cc(-c2cncc(F)c2)cc(C(=O)Nc2ccc(F)cc2)n1

Procedure:
The title compound, was prepared from 5-Fluoro-6′-methyl-[3,4′]bipyridinyl-2′-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 4-Fluoroaniline instead of 3-chloroaniline to yield the final compound as a gray solid, MS (ISP): m/e=324.9, 326.2 (M+H)+.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([S:12][C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([NH:18][CH3:19])=[O:17])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:23].[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1>C1COCC1>[CH3:19][NH:18][C:16](=[O:17])[C:15]1[CH:20]=[CH:21][CH:22]=[C:13]([S:12][C:8]2[CH:7]=[C:6]3[C:11]([C:3](=[CH:2][NH:37][C:34]4[CH:33]=[CH:32][C:31]([N:28]5[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]5)=[CH:36][CH:35]=4)[C:4](=[O:23])[NH:5]3)=[CH:10][CH:9]=2)[CH:14]=1
Reactant: CNC(=O)c1cccc(Sc2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(Sc2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCN(C)CC3)cc2)c1
Temperature: 68 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
A small screw cap test tube was charged with 3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indol-6-ylsulfanyl)-N-methyl-benzamide (as prepared below; 20 mg, 0.062 mmol) and THF (1 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (12 mg, 0.062 mmol), and the mixture was stirred for 24 h at 68° C. Subsequently, the reaction mixture was cooled to room temperature and then concentrated in vacuo. Purification of the crude residue via flash silica gel chromatography (10% MeOH in CHCl3) afforded the title compound in 39% yield (12 mg, 0.024 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[F:8]>C(Cl)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][C:11](=[O:13])[O:17][C:15](=[O:16])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)CC(CC(=O)O)c1ccc(F)c(F)c1
Solvent: CC(=O)Cl
Product: O=C1CC(c2ccc(F)c(F)c2)CC(=O)O1
Yield: 94.8 %

Procedure:
3-(3,4-Difluorophenyl)glutaric acid (7.4 g) was treated with acetyl chloride (50 mL) and the resulting mixture heated at reflux for 5 hours. The cooled reaction mixture was then azeotroped with toluene (3×100 mL) and concentrated under reduced pressure. The residue was slurried with diethyl ether and filtered to afford the title compound (6.5 g).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N:10]([O-:12])=[O:11].[Na+].P.COCCOCCN(CCOCCOC)CCOCCOC>C(O)(C)(C)C.O1CCCC1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N+:10]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)([O-:12])=[O:11]
Reactant: N#Cc1ccc(Cl)cc1
Reactant: O=N[O-]
Agent: [Pd]
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: N#Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a nitrogen-atmosphere glovebox, a microwave vial equipped with a magnetic stir bar was charged with 4-chlorobenzonitrile (100 mg, 0.727 mmol, 1 equivalent), sodium nitrite (100 mg, 1.45 mmol, 2 equivalents), tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3) (6.7 mg, 0.00727 mmol, 0.01 equivalents) and phosphine ligand (0.017 mmol, 0.024 equivalents). The solids were slurried in t-butyl alcohol (1.3 mL) before adding tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1) (12 μL, 0.036 mmol, 0.05 equivalents). The vial was sealed with a crimp top and placed in a heating block at 130 ° C. After 24 hours, the reaction vial was cooled to room temperature and brought out of the glovebox. The reaction solution was diluted with tetrahydrofuran (2 mL) and filtered through a pad of diatomaceous earth into a tared 125-mL Erlenmeyer flask. The vial was rinsed with tetrahydrofuran (3×1 mL) before the filter cake was washed with tetrahydrofuran (2 mL). A wt% analysis was performed on the filtrate and an assay yield was measured (literature reference: Fors BP, et al. J. Am. Chem. Soc. 2009; 131: 12898-12899).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[C:25]3[C:26]4=[C:27]5[C:22](=[CH:23][CH:24]=3)[CH:21]=[CH:20][CH:19]=[C:18]5[CH:17]=[CH:16][C:15]4=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[CH3:28][C:29]1([CH3:63])[C:53]2[C:33]([CH:34]=[C:35]3[CH:52]=[C:51]4[C:38]([C:39]5[C:44]([C:45]6[C:50]4=[CH:49][CH:48]=[CH:47][CH:46]=6)=[CH:43][CH:42]=[CH:41][CH:40]=5)=[CH:37][C:36]3=2)=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30]1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[CH3:63][C:29]1([CH3:28])[C:53]2[C:33]([CH:34]=[C:35]3[CH:52]=[C:51]4[C:38]([C:39]5[C:44]([C:45]6[C:50]4=[CH:49][CH:48]=[CH:47][CH:46]=6)=[CH:43][CH:42]=[CH:41][CH:40]=5)=[CH:37][C:36]3=2)=[CH:32][C:31]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:12]4[C:25]5[C:26]6=[C:27]7[C:22](=[CH:23][CH:24]=5)[CH:21]=[CH:20][CH:19]=[C:18]7[CH:17]=[CH:16][C:15]6=[CH:14][CH:13]=4)[CH:8]=3)[CH:3]=2)=[CH:30]1
Reactant: Brc1ccc2cc(-c3ccc4ccc5cccc6ccc3c4c56)ccc2c1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)C=C(c2ccc3cc(-c4ccc5ccc6cccc7ccc4c5c67)ccc3c2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Temperature: 90 °C
Yield: 46.3 %

Procedure:
A mixture of 8.3 g (20.3 mmol) of 1-(6-bromonaphthalen-2-yl)pyrene, 9.5 g (20.3 mmol) of 2-(10,10-dimethyl-10H-indeno[1,2-b]triphenylen-12-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 0.29 g (0.25 mmol) of Tetrakis(triphenylphosphine)palladium, 17 ml of 2M Na2CO3, 40 ml of EtOH and 100 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 12 h. After the reaction finish, the mixture was allowed to cool to room temperature. Than 500 ml MeOH was added, while stirring and the precipitated product was filtered off with suction. To give 6.3 g (yield 46%) of yellow product which was recrystallized from toluene. MS(m/z,FAB+); 671.5; 1H NMR (CDCl3, 400 MHz): chemical shift(ppm) 9.01 (s, 1H), 8.52˜8.45 (m, 3H), 8.25 (s, 1H), 8.10˜7.89 (m, 9H), 7.78 (d, J=8.00 Hz, 1H), 7.66˜7.49 (m, 10H), 7.44 (d, J=8.00 Hz, 1H), 7.28 (d, J=8.00 Hz, 1H), 1.84 (s, 6H).