Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Br:12]N1C(=O)CCC1=O.O>C(O)(=O)C>[Br:12][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[Cl:1]
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(Br)c(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 66.9 %

Procedure:
3-Chloro-2-nitroaniline (5.00 g, 29.0 mmol) was dissolved in glacial acetic Acid (258 mL). N-Bromosuccinimide (5.06 g, 28.4 mmol) was added and the resulting mixture was refluxed for 1 hour. The reaction was cooled to room temperature and poured into water to give a precipitate that was filtered, rinsed with water and dried to constant weight to give the title compound (4.78 g, 67%). 1H NMR (400 MHz, CDCL3) δ ppm 7.46 (d, J=9.0, 1H), 6.64 (d, J=9.0, 1H), 4.74 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].[Cl:21][CH2:22][CH2:23][CH2:24]Cl>CN(C)C=O>[Cl:21][CH2:22][CH2:23][CH2:24][O:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1O
Reactant: ClCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1OCCCCl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 98.1 g (0.5 mol) of N-(2-hydroxy4-nitrophenyl)acetamide (RN 121-88-0) and 69.2 g (0.5 mol) of potassium carbonate in 500 ml of dimethylformamide was heated with stirring at 50° C.; 113.0 g (1 mol) of 1,3-dichloropropane (RN 142-28-9) were then added and heating was continued at 50° C. for one hour.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[CH:19]=O)[C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:15]=2)=[N:4][O:5][N:6]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CO>[N:24]1([CH2:19][C:18]2[CH:17]=[C:16]([N:8]3[C:9]4[CH:14]=[CH:13][N:12]=[CH:11][C:10]=4[N:15]=[C:7]3[C:3]3[C:2]([NH2:1])=[N:6][O:5][N:4]=3)[CH:23]=[CH:22][CH:21]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCNC1
Reactant: Nc1nonc1-c1nc2cnccc2n1-c1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: Nc1nonc1-c1nc2cnccc2n1-c1cccc(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34 %

Procedure:
The product of Step 1 was stirred in 1,2-dichloroethane, and treated with pyrrolidine (27 uL, 0.326 mmol) and stirred for 15 minutes at room temperature. The reaction was then treated with sodium triacetoxyborohydride (34 mg, 0.164 mmol) and stirred at room temperature for 16 hours. The reaction was diluted with methanol and applied to a Mega Bond Elute SCX ion exchange column, eluting sequentially with water, methanol and finally 0.880 ammonia:methanol (1:9). The residue was purified using silica gel chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (1:9:90) to afford the compound (20 mg, 34%); MS (ES+), m/e 362 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.[C:9](#[N:13])[CH:10]([CH3:12])[CH3:11].C[Si]([N-][Si](C)(C)C)(C)C.NC1N=CC(C2C=CN=C(C3(C#N)CCOCC3)C=2)=NC=1C1ON=C(C2C=CC(CNC)=CC=2)C=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[I:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:10]([CH3:12])([CH3:11])[C:9]#[N:13])[CH:7]=1
Reactant: CC(C)C#N
Reactant: Clc1cc(I)ccn1
Agent: CNCc1ccc(-c2cc(-c3nc(-c4ccnc(C5(C#N)CCOCC5)c4)cnc3N)on2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1cc(I)ccn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
An oven-dried flask was evacuated and back-filled with nitrogen three times. The flask was charged with 2-chloro-4-iodo-pyridine (3 g, 12.53 mmol) and isobutyronitrile (865.9 mg, 1.125 mL, 12.53 mmol) in anhydrous toluene (30.00 mL). The reaction mixture was cooled to 0° C. and treated with bis(trimethylsilyl)azanide in tetrahydrofuran (sodium ion (1)) (12.53 mL of 1 M, 12.53 mmol) over a period of 5 minutes. The reaction mixture was allowed to warm to ambient temperature and stirred at this temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with 1 M hydrochloric acid. The aqueous layer was extracted with ethyl acetate (×3) and the combined organic extracts dried MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 80 g column) loaded with dichloromethane and eluted with 0 to 30% ethyl acetate/petroleum ether. Product fractions were combined and concentrated in vacuo to give the sub-title product as an off-white solid (2.22 g, 65% Yield). 1H NMR (400.0 MHz, DMSO-d6) δ 1.70 (s, 6H), 7.84 (dd, 1H), 7.98 (d, 1H) and 8.31 (d, 1H) ppm; LC/MS m/z 273.0 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[C:19]([S:20][CH3:21])=[C:18]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[CH:17]=[CH:16][C:3]=1[C:4]([O:6][C:7]1[CH:8]2[CH2:15][CH:11]([C:12](=[O:14])[CH:13]=1)[CH2:10][CH2:9]2)=[O:5].ClC1C=CC=C(C(OO)=[O:37])C=1>ClCCl>[CH3:1][C:2]1[C:19]([S:20]([CH3:21])=[O:37])=[C:18]([C:22]([F:28])([F:27])[C:23]([F:25])([F:26])[F:24])[CH:17]=[CH:16][C:3]=1[C:4]([O:6][C:7]1[CH:8]2[CH2:15][CH:11]([C:12](=[O:14])[CH:13]=1)[CH2:10][CH2:9]2)=[O:5]
Reactant: CSc1c(C(F)(F)C(F)(F)F)ccc(C(=O)OC2=CC(=O)C3CCC2C3)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1c(C(=O)OC2=CC(=O)C3CCC2C3)ccc(C(F)(F)C(F)(F)F)c1S(C)=O
Temperature: 25 °C

Procedure:
280 mg (90% by weight; 0.599 mmol) of 4-oxobicyclo[3.2.1]oct-2-en-2-yl 2-methyl-3-methylthio-4-pentafluoroethylbenzoate were introduced into 20 ml of dichloromethane and admixed with 134 mg (77% by weight; 0.599 mmol) of meta-chloroperbenzoic acid. The mixture was stirred at RT until monitoring of the reaction by thin-layer chromatography indicated complete conversion. For working up, the contents were washed once with 10% strength aqueous sodium hydrogensulfite solution, then twice with saturated aqueous sodium hydrogencarbonate solution. Finally, the organic phase was freed from the solvent. As the residue, 250 mg of product with a purity of 95% by weight were recovered.
Reaction SMILES: [Cl:1][C:2]1[N:3]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6]=1[CH2:7][OH:8].C[N+]1([O-])CCOCC1>C(#N)C.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:1][C:2]1[N:3]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][C:6]=1[CH:7]=[O:8]
Reactant: O=S(=O)(c1ccccc1)n1c(-c2ccccc2)cc(CO)c1Cl
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.3 %

Procedure:
To a solution (50 mL) of [2-chloro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (830 mg) in acetonitrile were added tetra-n-propylammonium perruthenate (84 mg), N-methylmorpholine N-oxide (484 mg) and molecular sieves 4A powder (2.0 g), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with ethyl acetate, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→4:1) to give the title compound as a colorless oil (yield 440 mg, 53%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C@H:5]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:6][CH:7]=[CH2:8])[CH3:2].CCN(C(C)C)C(C)C.[C:25]([C:27]1[CH:28]=[C:29]([C:37](Cl)=[O:38])[C:30]2[CH2:31][CH2:32][CH2:33][CH2:34][C:35]=2[CH:36]=1)#[N:26]>C(Cl)Cl>[C:25]([C:27]1[CH:28]=[C:29]([C:37]([N:3]([CH2:1][CH3:2])[CH2:4][C@H:5]([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH2:6][CH:7]=[CH2:8])=[O:38])[C:30]2[CH2:31][CH2:32][CH2:33][CH2:34][C:35]=2[CH:36]=1)#[N:26]
Reactant: C=CC[C@H](CNCC)c1ccc(F)cc1
Reactant: N#Cc1cc2c(c(C(=O)Cl)c1)CCCC2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@H](CN(CC)C(=O)c1cc(C#N)cc2c1CCCC2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
(2S)-N-Ethyl-2-(4-fluorophenyl)pent-4-en-1-amine (0.13 g, 0.63 mmol) was dissolved in CH2Cl2 and to the solution were added DIPEA (0.18 g, 1.4 mmol) and then 3-cyano-5,6,7,8-tetrahydronaphthalene-1-carbonyl chloride (see WO 00/34243; 0.15 g, 0.66 mmol) dissolved in CH2Cl2 (2 mL). The mixture was stirred for 2 h at room temperature and then diluted with CH2Cl2. The solution was washed with water, aqueous KHSO4 (10 mL, 1M) and brine. The solvent was removed by evaporation after the solution had been dried. The product was purified by chromatagraphy on silica gel using a gradient of methanol-CH2Cl2 (0% methanol-5% methanol). There was obtained 0.13 g (53%) of 3-cyano-N-ethyl-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide as an oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])[CH:15]=3)=[CH:10][CH:9]=2)=[N:5][N:4]=1.[C:27]1([CH2:33][S:34](Cl)(=[O:36])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>N1C=CC=CC=1.C(Cl)Cl>[CH2:33]([S:34]([NH:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])[CH:15]=3)=[CH:12][CH:13]=2)=[N:5][N:4]=1)(=[O:36])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN)o2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CNS(=O)(=O)Cc3ccccc3)o2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4′-[5-(Aminomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Example 53) (30 mg) was mixed with α-toluenesulphonyl chloride (33 mg) in pyridine (6 ml) at 0° C. and the reaction stirred at room temperature for 72 hours. Further α-toluenesulphonyl chloride (66 mg) in pyridine (3 ml) was added and stirring continued for 18 hours. The reaction was diluted with DCM and washed with hydrochloric acid (2N, 4×5 ml) and then water (5 ml). The organic phase was reduced to dryness under vacuum and the residue purified by HPLC to give after evaporation of the solvents 4′-(5-{[(benzylsulfonyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C@H:12]1[CH2:14][O:13]1.[CH3:15][C:16]1[C:20](=[O:21])[O:19][CH2:18][C:17]=1[N:22]1[CH2:26][CH2:25][C:24]2([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:23]1=[O:32].CCN(C(C)C)C(C)C>CCO>[OH:13][C@@H:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[CH2:14][N:29]1[CH2:30][CH2:31][C:24]2([C:23](=[O:32])[N:22]([C:17]3[CH2:18][O:19][C:20](=[O:21])[C:16]=3[CH3:15])[CH2:26][CH2:25]2)[CH2:27][CH2:28]1
Reactant: CC1=C(N2CCC3(CCNCC3)C2=O)COC1=O
Reactant: Cc1c([C@H]2CO2)ccc2c1COC2=O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(N2CCC3(CCN(C[C@@H](O)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-methyl-5-[(2S)-oxiran-2-yl]-2-benzofuran-1(3H)-one (I-4A)(200 mg, 1.05 mmol) and 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (300 mg, 1.05 mmol) in 10 mL of EtOH was added DIPEA (271 mg, 2.10 mmol). The resulting mixture was stirred at 80° C. overnight, and then cooled to room temperature; the solvent was removed under vacuum. The residue was purified by flash chromatography (ethyl acetate: MeOH=20:1) to afford title compound. MS-ESI (m/z): 441 (M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[N:12][CH2:13][CH2:14][O:15][N+:16]([O-:18])=[O:17])[NH:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1.[C:19](Cl)(=[O:21])[CH3:20].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:19]([NH:1][C:2]1[CH:3]=[C:4]([C:8](=[N:12][CH2:13][CH2:14][O:15][N+:16]([O-:18])=[O:17])[NH:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1)(=[O:21])[CH3:20]
Reactant: N#CNC(=NCCO[N+](=O)[O-])c1cncc(N)c1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Nc1cncc(C(=NCCO[N+](=O)[O-])NC#N)c1
Yield: 94.5 %

Procedure:
To a solution of 5-amino-N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide (105 mg, 0.42 mmol) (see Example 1) in pyridine (1 ml) was added acetyl chloride (45 μl, 0.63 mmol), and the mixture was reacted at room temperature for 1 hour. After the reaction was completed, a cold aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography with a mixed solvent of methanol and chloroform as an eluent to give the title compound (116 mg, yield 95%) as hygroscopic powder.
Reaction SMILES: C(O[C:4]([C:6]1[C:22]2[C:10](=[C:11]([CH3:25])[C:12]3[N:13]([CH3:24])[C:14]4[CH:15]=[CH:16][C:17]([OH:23])=[CH:18][C:19]=4[C:20]=3[CH:21]=2)[CH:9]=[CH:8][N:7]=1)=[O:5])C.[NH2:26][CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[O:33]1[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][CH2:27][NH:26][C:4]([C:6]2[C:22]3[C:10](=[C:11]([CH3:25])[C:12]4[N:13]([CH3:24])[C:14]5[CH:15]=[CH:16][C:17]([OH:23])=[CH:18][C:19]=5[C:20]=4[CH:21]=3)[CH:9]=[CH:8][N:7]=2)=[O:5])[CH2:31][CH2:32]1
Reactant: NCCCN1CCOCC1
Reactant: CCOC(=O)c1nccc2c(C)c3c(cc12)c1cc(O)ccc1n3C
Product: Cc1c2ccnc(C(=O)NCCCN3CCOCC3)c2cc2c3cc(O)ccc3n(C)c12
Temperature: 120 °C

Procedure:
0.36 g (1.078 mmol) of the ester obtained in Step A of Example 11 are dissolved in 10 ml of 4-(3-aminopropyl)morpholine under an argon atmosphere. The mixture is heated at 120° C. for 19 hours.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].C(O)C.[BH4-].[Na+]>C(OCC)(=O)C>[CH:1]1([NH:12][C:11]2[CH:13]=[CH:14][C:8]([F:7])=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCC1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=[N+]([O-])c1cc(NC2CCCC2)ccc1F
Reaction time: 0.5 h

Procedure:
6.7 g (0.08 mol) of cyclopentanone, 12.5 g (0.08 mol) of 4-fluoro-3-nitro-aniline and 30 ml (0.1 mol) of titanium-IV-isopropoxide are stirred for 30 minutes at 40° C. and one hour at ambient temperature. After the addition of 150 ml of ethanol the reaction mixture is stirred for 30 minutes and subsequently combined batchwise with 2.4 g (0.066 mol) of sodium borohydride. After 4 hours the reaction mixture is poured onto ice water and combined with ethyl acetate. After filtration the organic phase is separated off, dried and evaporated down. The residue is chromatographed on silica gel and eluted with petroleum ether/ethyl acetate (9:1). The desired fractions are combined and evaporated down.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:15])=[C:6]([NH2:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].[C:16](O)(=[O:20])[C:17](O)=[O:18]>Cl>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:6]2[C:5]=1[NH:15][C:16](=[O:20])[C:17](=[O:18])[NH:14]2)([O-:3])=[O:2]
Reactant: O=C(O)C(=O)O
Reactant: Nc1cc(C(F)(F)F)cc([N+](=O)[O-])c1N
Agent: Cl
Product: O=c1[nH]c2cc(C(F)(F)F)cc([N+](=O)[O-])c2[nH]c1=O
Temperature: 25 °C

Procedure:
A suspension of 3-nitro-5-trifluoromethyl-1,2-phenylenediamine (0.560 g, 2.53 mmol) and oxalic acid (0.325 g, 2.58 mmol) in 2N HCl (8.5 mL) was refluxed for 6 h. The suspension was then cooled to r.t. and the solid filtered, washed with water (5.0 mL) and dried under vacuum to yield 0.502 (72%) of pure title compound as a yellow brown powder, m.p. 329°-332° C.; 1H NMR (DMSO-d6):7.640 (s, 1H), 8.111 (s, 1H), 11.414 (s, 1H), 12.432 (1H).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=[O:4].C([Li])CCC.[CH3:20][N:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29]>O1CCCC1>[CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH:22]([NH:21][CH3:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])=[O:4]
Reactant: Cc1ccccc1NC(=O)C(C)(C)C
Reactant: CN=Cc1ccccc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CNC(Cc1ccccc1NC(=O)C(C)(C)C)c1ccccc1C
Reaction time: 1 h

Procedure:
A chilled solution (-4° C.) of 126 g of 2,2-dimethyl-N-[(2-methyl)phenyl]propanamide in 900 ml of tetrahydrofuran was treated dropwise over 1.5 hr with n-butyl lithium (500 ml of a 2.5M solution in hexanes). After the addition was complete, the resulting solution was stirred for 1 hr, with cooling, and was then treated over 0.5 hr with a solution of 91.77 g of 2-methylbenzaldehyde methyl imine. The reaction mixture was quenched by rapid addition of water. After concentration the residue was extracted with dichloromethane. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated. A 50 g portion of the residue (213 g) was acidified with 10% hydrochloric acid and partitioned with toluene. The aqueous layer was basified with a 50% sodium hydroxide solution and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated. Upon standing under nitrogen overnight in a refrigerator a solid formed, which was triturated with hexane to give 2,2-dimethyl-N-[2 -[2-methylamino-2-(2-methylphenyl)ethyl]phenyl]propanamide, mp 77°-79° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[C:12](Cl)(=O)[C:13](Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].C=C>C(Cl)Cl.CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH2:8][C:9](=[O:11])[CH2:13][CH2:12]2
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: C=C
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCc2cc(Br)ccc2C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
A single neck 3 liter round bottom flask under an Ar atmosphere was charged with 4-bromobenzeneacetic acid (250.0 g, 1.15 mol), methylene chloride (1.5 L) and dimethylformamide (0.5 mL). This magnetically stirred solution was cooled to 0° C. and treated dropwise with oxalyl chloride (156 mL, 1.74 mol). The reaction was allowed to reach room temperature and stirred 16 h. The reaction was concentrated on a rotary evaporator to approximately 1 L of volume. A separate dry 5 liter 3 neck round bottom flask under Ar, fitted with gas inlet tube, overhead stirrer, and digital thermometer was charged with methylene chloride (1.5 L) and AlCl3 (312.0 g, 2.34 mol). This suspension was cooled to 0° C. and stirred while the above solution of acid chloride was added to it slowly via cannula. When the addition was complete, ethylene gas was introduced for 1-2 h. to the vigorously stirred suspension while maintaining the internal temperature at 15° C. Upon completion by HPLC, the reaction was warmed to room temperature and stirred for 0.5 h. The mixture was recooled to 0° C. and cautiously quenched slowly with water (1.5 L). The layers were separated, and the aqueous one washed with methylene chloride (500 mL). The organic portion was washed with 2N aqueous HCl (2×800 mL), brine (400 mL), and saturated aqueous NaHCO3 (2×800 mL). Each aqueous extract was washed with the same 500 mL methylene chloride extract from above. The methylene chloride extracts were combined, dried (Na2SO4), filtered, and concentrated to approximately 500 mL of volume. This was then added to 5.0 L of hexane warmed to 50° C. The methylene chloride was distilled off and the hot solution decanted from an insoluble brown tar. The solution was allowed to cool to 25° C. and placed in the freezer overnight. The precipitate was collected and washed with hexane (200 mL), and dried in vacuo to give 229.0 g of 6-bromo-3,4-dihydro-2(1H)-napthalenone as a pale yellow solid (88%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:29]=[CH:28][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]([C:20]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[C:13]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[O:8])=[CH:5][CH:4]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C1COCC1>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:13]1[N:14]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:28]=[CH:29][C:3]([CH2:2][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:4][CH:5]=2)[S:11][C:12]=1[C:20]([CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21]
Reactant: C1CCNCC1
Reactant: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1)c1ccc(CCl)cc1
Solvent: C1CCOC1
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1)c1ccc(CN2CCCCC2)cc1
Yield: 140.1 %

Procedure:
Compound 478 (340 mg, 0.789 mmol) was suspended in THF (3 mL), and piperidine (0.390 mmol, 3.95 mmol) was added thereto, followed by stirring under heating and reflux for 1.5 hours. The solvent was distilled away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform:methanol=4:1), followed by reslurrying with diethyl ether to afford the entitled Compound 480 (262 mg, 69%) as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)#[N:4].F[C:13]1[CH:18]=[CH:17][CH:16]=[C:15](F)[N:14]=1>CN(C)C=O>[N:14]1[C:15]([O:11][C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:3]#[N:4])=[CH:16][CH:17]=[CH:18][C:13]=1[O:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:3]#[N:4]
Reactant: Fc1cccc(F)n1
Reactant: N#Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(Oc2cccc(Oc3cccc(C#N)c3)n2)c1
Temperature: 100 °C

Procedure:
To sodium hydride (0.38 g, 9.5 mmol) in N,N-dimethylformamide (3 mL) was added 3-cyanophenol (1.1 g, 8.9 mmol) and 2,6-difluoropyridine (0.4 mL, 4.4 mmol). After heating in an oil bath at 100° C. for 15 hours the reaction was partitioned with ethyl acetate and water. The organic layer was separated, washed with water, dried (Na2SO4), and the solvent was removed in vacuo. The residue was chromatographed on silica gel (50 g) with methylene chloride/hexane (3/1) to give 3,3′-[2,6-pyridinediylbis(oxy)]bis(benzonitrile). Recrystallization from ethyl acetate/hexane gave pure 3,3′-[2,6-pyridinediylbis(oxy)]bis(benzonitrile); NMR (CDCl3) 7.79 (t,1), 7.45 (m,4), 7.32 (m,4), 6.72 (d,2) ppm.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[O:15][CH3:16].[CH3:17][O:18][C:19]([O:23][Si](C)(C)C)=[C:20]([CH3:22])[CH3:21]>CN(C=O)C.[F-].[F-].[Zn+2]>[CH3:16][O:15][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:2]=1[C:20]([CH3:22])([CH3:21])[C:19]([O:18][CH3:17])=[O:23])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: COc1cc(C(=O)OC(C)(C)C)ccc1Br
Agent: [F-]
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)c1ccc(C(=O)OC(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a microwave vial was added ZnF2 (36 mg, 0.35 mmol) and Pd(tBu3P)2 (7.2 mg, 0.014 mmol). The reaction vessel was purged with nitrogen for 10 minutes before tert-butyl 4-bromo-3-methoxy-benzoate (200 mg, 0.70 mmol) dissolved in DMF (2.5 mL) was added followed by (1-methoxy-2-methyl-prop-1-enoxy)-trimethyl-silane (180 mg, 1.1 mmol). The reaction vessel was placed in an 80° C. oil bath under an atmosphere of nitrogen and the mixture was allowed to stir overnight. The mixture was allowed to cool to rt and was filtered through a frit and was washed with brine and EtOAc. The organics were separated and dried over sodium sulfate. The solvent was removed and the residue was taken on to the next step without additional purification. ESI-MS m/z calc. 308.2, found 309.4 (M+1)+; Retention time: 3.12 minutes (4 min run).