Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[C:3]([C:6]1[CH:10]=[C:9]([C:11]2[CH:20]=[CH:19][C:14]([O:15][CH2:16][CH2:17][NH2:18])=[CH:13][CH:12]=2)[N:8]([C:21]2[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[N:7]=1)([CH3:5])=[CH2:4].CCN(CC)CC.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[C:3]([C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH2:16][CH2:17][NH:18][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:19][CH:20]=2)[N:8]([C:21]2[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[N:7]=1)([CH3:5])=[CH2:4]
Reactant: C=C(C)c1cc(-c2ccc(OCCN)cc2)n(-c2ccc(OC)nc2)n1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)c1cc(-c2ccc(OCCNS(C)(=O)=O)cc2)n(-c2ccc(OC)nc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)amine dihydrochloride (126.4 mg) and Et3N (125 μl) in CH2Cl2 (2 ml) was added methanesulfonyl chloride (34.7 μl ) under ice bath cooling. The mixture was stirred at ambient temperature for 1 hour. Additional methanesulfonyl chloride (6.9 μl ) and Et3N (41.6 μl) were added and the reaction mixture was stirred at ambient temperature for 30 minutes. The mixture was concentrated in vacuo, and the residue was partitioned between AcOEt and 1M HCl. The aqueous layer was reextracted with AcOEt. The combined organic layers were washed with saturated aqueous sodiumbicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography developed by AcOEt/n-hexane=70%. The seaparated silica gel was extracted with 10% MeOH/CDCl3 and the solvent was evaporated in vacuo. The residue was crystallized from AcOEt-IPE to give N-(2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)methane-sulfonamide (48.0 mg) as white powder.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[S:8][C:7]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1.Cl[C:14]1[C:18]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[N:17][S:16][N:15]=1>C1COCC1>[CH3:3][C:4]1[S:8][C:7]([CH2:9][CH2:10][CH2:11][O:12][C:14]2[C:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[N:17][S:16][N:15]=2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(CCCO)s1
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(CCCOc2nsnc2-c2cccnc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (10.2 mmol) was added to a solution of 3-(5-methyl-2-thienyl)-1-propanol (4.0 g, 25.5 mmol) in THF (40 ml). The mixture was stirred for 1 h at room temperature, whereupon a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (EP 0384288) (1.0 g, 5.1 mmol) in THF (10 ml) was added dropwise to the reaction mixture. After stirring overnight at room temperature, the reaction was quenched with water then extracted with diethyl ether. The organic phase was dried over NaCl/Na2So4 then evaporated to yield crude 3-(3-(5-methyl-2-thienyl)propoxy-1,2,5-thiadiazol-4-yl)pyridine. A solution of 3-(3-(5-methyl-2-thienyl)propoxy-1,2,5-thiadiazol-4-yl)pyridine (1.0 g, 3.2 mmol) and iodomethane (2.3 g, 16.0 mmol) in 60 ml of acetone was refluxed overnight. The solution was evaporated to yield 1.5 g of the quaternized product. Sodium borohydride (0.6 g, 16.0 mmol) was carefully added to a solution of the quaternized product (1.5 g) in ethanol (30 ml). The reaction was evaporated and the resulting residue was taken up in water and extracted with methylene chloride (3×100 ml). The organic phase was dried over NaCl/Na2SO4 then evaporated. The residue was purified by radial chromatography eluting with 0.5% NH4OH/5.0% EtOH in CHCl3. The oxalate salt was made to yield 337 mg of the title compound. M.p. 134-137° C. (Compound 62).
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Li+]>C1COCC1.O>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCCc2ccc([N+](=O)[O-])cc2)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCO[C@@H](Cc1ccc(OCCCCc2ccc([N+](=O)[O-])cc2)cc1)C(=O)O
Yield: 94.6 %

Procedure:
Ethyl (2S)-2-ethoxy-3-{4-[4-(4-nitrophenyl)butoxy]phenyl}propanoate (1.05 g, 2.527 mmol) was dissolved in THF (20 ml). Under stirring, lithium hydroxide (78.7 mg, 3.285 mmol) in water (10 ml) was added in. The mixture was stirred at room temperature overnight. It was evaporated in vacuum to remove THF. The residue was extracted with diethyl ether. The obtained water phase was acidified with 10% hydrochloric acid, pH -3 and then extracted with ethyl acetate (×2). The organic phases were combined and washed with water and brine and dried with magnesium sulfate. The solvent was evaporated in vacuum. The desired product (926 mg) was obtained, yield 95%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([Cl:11])[CH:3]=1.[Br:12][C:13]1[S:17][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:15][CH:14]=1.CC1C=CC(S(O)(=O)=O)=CC=1>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:21][S:18]([C:16]2[S:17][C:13]([Br:12])=[CH:14][CH:15]=2)(=[O:20])=[O:19])=[O:8])=[C:4]([Cl:11])[CH:3]=1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccc(Br)s1)c1ccc(Br)cc1Cl
Reaction time: 72 h

Procedure:
An 8 mL reaction vial is charged with 4-bromo-2-chlorobenzoic acid (0.39 mmol, 1.5 eq) and 2.0 mL of dichloromethane. A stock solution (4.0 mL) containing 5-bromothiophene-2-sulfonamide (0.26 mmol, 1 eq) and N,N-[dimethyl]-4-aminopyridine (48 mg, 0.39 mmol, 1.5 eq) in dichloromethane is added, followed by 0.261 g carbodiimide polystyrene resin (2.0 mmol/g, 0.52 mmol, 2.0 eq, Novabiochem) and the vial is capped and shaken. After 72 hr, 0.77 g sulphonated polystyrene resin (MP-TsOH) is added (1.53 mmol/g, 1.17 mmol, Argonaut). After about 18 hr the reaction mixture is filtered and concentrated under reduced pressure. Chromatography was applied to the residue and fractions containing product were combined and concentrated under reduce pressure to provide the title compound.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5](Br)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>CS(C)=O>[N:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCBr
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a 100 mL round bottomed flask, sodium azide (2.60 g, 37.6 mmol) was dissolved in 80 mL DMSO, 1-Octyl bromide (5.5 g, 28.4 mmol) was added and stirred at room temperature for 5 h. The reaction was quenched by addition of water (200 mL) and was stirred for 1 h. The mixture was extracted with diethyl ether (50×3). The combined organic layers were washed with brine solution. The ether solution was dried over anhydrous MgSO4 and the solvent was removed by rotary evaporation. The product was further purified by filtration through a short silica gel column using hexane as eluent. Yield: 2.5 g (78%) IR (neat) 2957, 2857, 2093, 1466, 1377, 1279 cm−1; 1H NMR (400 MHz, CDCl3) δ 3.21 (d, J=6.2 Hz, 2H), 1.55-1.57 (m, 2H), 1.25-1.32 (m, 10H), 0.84 (m, 3H); 13C NMR (CDCl3) δ 51.51, 31.80, 29.19, 29.16, 28.89, 26.77, 22.66, 14.06,
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:31])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:30])=[C:25]([C:27]([OH:29])=O)[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:62][N:63]([CH3:67])[CH2:64][CH2:65][NH2:66]>ClCCl>[CH2:1]([O:8][NH:9][C:10](=[O:31])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:30])=[C:25]([C:27]([NH:66][CH2:65][CH2:64][N:63]([CH3:67])[CH3:62])=[O:29])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1oc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)nc1C(=O)O
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: Cc1oc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)nc1C(=O)NCCN(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.2 %

Procedure:
A solution 2-((1R)-1-{2-[(benzyloxy)amino]-2-oxoethyl}-4-cyclohexylbutyl)-5-methyl-1,3-oxazole-4-carboxylic acid (Preparation 72) (200 mg, 0.47 mmol), N-methylmorpholine (77 l, 0.70 mmol), 1-hydroxybenzotriazole hydrate (63 mg, 0.47 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydochloride (134 mg, 0.70 mmol) in dichloromethane (10 ml) was treated with N,N-dimethylethylenediamine (56 l, 0.51 mmol) and stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane and washed with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a system of 94:4:0.4 (dichloromethane:methanol:ammonia) to afford the title compound as a white solid (216 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4](Cl)[N:3]=1.Cl.[F:26][C:27]1([F:35])[CH2:32][CH2:31][CH2:30][C@@H:29]([NH2:33])[C@H:28]1[NH2:34].CCN(C(C)C)C(C)C>C(#N)C>[NH2:34][C@H:28]1[C:27]([F:35])([F:26])[CH2:32][CH2:31][CH2:30][C@H:29]1[NH:33][C:4]1[N:3]=[C:2]([Cl:1])[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]=1[F:23]
Reactant: COc1ccc(CN2Cc3c(F)c(Cl)nc(Cl)c3C2=O)c(OC)c1
Reactant: N[C@@H]1CCCC(F)(F)[C@@H]1N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC(F)(F)[C@@H]4N)nc(Cl)c3C2=O)c(OC)c1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
A mixture of 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (100 mg, 0.269 mmol) and cis-3,3-difluorocyclohexane-1,2-diamine hydrochloride (75 mg, 0.404 mmol) and DIPEA (118 μL, 0.674 mmol) in acetonitrile (449 μL) was stirred at 100° C. for 3 d. The reaction mixture was concentrated to a brown oil and reconstituted in DMF (1 mL). The residue was purified by preparative HPLC, the appropriate fraction was collected, and excess acetonitrile was evaporated. The residue was treated with saturated aq sodium carbonate and extracted with EtOAc (3×20 mL). The organic layers were combined, dried over sodium sulfate, and concentrated to give the title compound as a colorless residue (13.7 mg, 10%). [M+H] calc'd for C22H24ClF3N4O3, 485; found, 485.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:13](O)=[O:14])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C(Cl)[Cl:19].C(Cl)(=O)C(Cl)=O>CN(C=O)C>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:13]([Cl:19])=[O:14])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=C(O)c1cc(C(F)(F)F)cc2ccccc12
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(C(F)(F)F)cc2ccccc12
Reaction time: 4 h

Procedure:
A mixture containing 3-trifluoromethyl-1-naphthoic acid (0.10 g) and dry DCM (5 mL) was treated with oxalyl chloride (0.065 g) at 25° C. A catalytic amount of DMF was added, the mixture stirred for 4 hours, then the DCM was removed in vacuo. The solid residue was re-dissolved in dry DCM and used without further purification.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[CH:5].[CH3:12][C:13]1([CH3:29])[CH2:18][O:17][P:16](=[O:20])([OH:19])[O:15][CH:14]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH3:28]>C(O)C>[CH3:12][C:13]1([CH3:29])[CH2:18][O:17][P:16](=[O:19])([OH:20])[O:15][CH:14]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH3:28].[NH2:1][C@@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[CH:5]
Reactant: C#CCC(N)c1ccccc1
Agent: COc1ccccc1C1OP(=O)(O)OCC1(C)C
Solvent: CCO
Product: C#CC[C@@H](N)c1ccccc1
Temperature: 25 °C

Procedure:
Dissolve (RS)-1-amino-1-phenyl-but-3-yne [Zh. Org. Khim. 18(4), 980-983 (1982) A. Mostamandi, L. A. Remizova, A. L. Pavienkova, I. A. Favorskaya] (20.0 g, 138 mmol) and (-)-5,5-dimethyl-2-hydroxy-4-(2-methoxyphenyl)-1,3,2-dioxaphosphorinane 2-oxide (35.0 g, 129 mmol) in refluxing ethanol (300 mL). Cool the solution to ambient temperature and collect the precipitate by filtration. Rinse the precipitate with a small amount of isopropanol/ethanol (1/1). Two recrystallizations from ethanol gives (R)-1-amino-1-phenyl-but-3-yne 5,5-dimethyl-2-hydroxy-4-(2-methoxyphenyl)-1,3,2-dioxaphosphorinane 2-oxide salt (21 g). Combine (R)-1-amino-1-phenyl-but-3-yne 5,5-dimethyl-2-hydroxy-4-(2-methoxyphenyl)-1,3,2-dioxaphosphorinane 2-oxide salt (21 g, 50.4 mmol) with a mixture of aqueous 1M potassium hydroxide solution (100 mL) and toluene (50 mL) and stir for 0.75 hour. Separate the layers and extract the aqueous layer with toluene (50 mL), combine the organic layers, dry over (Na2SO4), and filter to obtain a solution. Pass hydrogen chloride gas through the solution until it is saturated and then remove the precipitate by filtration and rinse with toluene. Recrystallize from butanone (120 mL) to give 7.0 g the title compound. Specific rotation [α]2D0 =11.0° (c=0.500, MeOH).
Reaction SMILES: Cl.C(O)(=O)C.[Cl:6][C:7]1[C:8]([F:34])=[C:9]([F:33])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([NH:25][CH3:26])[N:18]=1)[CH:14]=[C:13]([C:27]([O:29]CC)=[O:28])[C:12]2=[O:32]>O>[Cl:6][C:7]1[C:8]([F:34])=[C:9]([F:33])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([NH:25][CH3:26])[N:18]=1)[CH:14]=[C:13]([C:27]([OH:29])=[O:28])[C:12]2=[O:32]
Reactant: CCOC(=O)c1cn(-c2nc(NC)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CNc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reaction time: 2.5 h
Yield: 95.2 %

Procedure:
To 3 ml of a mixed solution (1:1, v/v) of 4 ml of 4N hydrochloric acid and 1 ml of acetic acid was added 510 mg of ethyl 8-chloro-6,7-difluoro-1-(3,5-difluoro-6-methylaminopyridin-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 2.5 hours. After adding 2 ml of distilled water, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 454 mg of the title compound as a gray powder.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10].C(N(CC)CC)C.CCCCCCCCCCCC>[Pd]>[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH:10][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: Ic1ccccc1
Agent: [Pd]
Solvent: CCCCCCCCCCCC
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1ccccc1
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
Starbon®-Pd(10% wt) was prepared according to example 39 and was tested in the Heck reaction of iodobenzene and methyl acrylate (see Reaction Scheme 7). Iodobenzene (8 mmol, 0.85 mL), methyl acrylate (8 mmol, 0.70 mL), triethylamine (5 mmol) and the Starbon-Pd catalyst (0.050 g) were mixed together in a microwave tube and placed in a Microwave reactor under stirring at 70° C. for 5 min. The microwave power employed in the reaction was 300 W. Dodecane (1 mmol) was employed as internal standard and results were analysed by GC. The Starbon-Pd material afforded complete (>99 mol %) conversion of the starting material with a selectivity higher than 80 mol % to the cross-coupled product, methyl cinnamate in 5 min.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl[C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[CH:13][N:12]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:11]2[N:12]=[CH:13][C:14]([C:17]3[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=3)=[CH:15][N:16]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(-c2cnc(Cl)nc2)cc1
Reactant: CC(C)N1CCNCC1
Product: CC(C)N1CCN(c2ncc(-c3ccc(C#N)cc3)cn2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 1-isopropylpiperazine and 4-(2-chloro-pyrimidin-5-yl)benzonitrile.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[I:10](O)(=O)(=O)=O.II.[O-]S([O-])(=S)=O.[Na+].[Na+].[OH-].[Na+]>C(O)(=O)C.O.OS(O)(=O)=O>[NH2:1][C:2]1[N:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Nc1ncccc1C=O
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Agent: O=S(=O)(O)O
Agent: O=S([O-])([O-])=S
Solvent: CC(=O)O
Solvent: O
Product: Nc1ncc(I)cc1C=O
Temperature: 80 °C
Yield: 538.9 %

Procedure:
2-Aminonicotinaldehyde (515 mg, 4.22 mmol), periodic acid (144.1 mg, 0.63 mmol) and iodine (460.2 mg, 0.43 mmol) were dissolved in a mixture of acetic acid (12.0 ml), H2O (0.6 ml) and H2SO4 (0.1 ml). The mixture was heated to 80° C. for 4 h. Then it was poured into Na2S2O3 (10% aq. solution), neutralized with NaOH (2N aq. solution) and extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography; Pet. Ether, EtOAc (4:1→1:1) affording 842 mg (80%) the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[O:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[N:26][CH:27]=1>C(#N)C.O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([C:8](=[O:10])[CH3:9])[CH:6]=[CH:7][C:2]=1[O:1][CH2:21][C:22]1[CH:27]=[N:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1
Reactant: COc1ccc(CCl)cn1
Reactant: COc1cc(C(C)=O)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(COc2ccc(C(C)=O)cc2OC)cn1
Reaction time: 2 h
Yield: 80.1 %

Procedure:
To a stirred suspension of 1-(4-hydroxy-3-methoxyphenyl)ethan-1-one (3.96 g, 23.82 mmol) and potassium carbonate (13.17 g, 95.29 mmol) in acetonitrile (75 mL) was added 5-(chloromethyl)-2-methoxypyridine hydrochloride (4.85 g, 25.01 mmol). After 2 h, the mixture was diluted with water (150 mL) and extracted with dichloromethane (3×100 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide a yellow oil. Trituration of the crude material with hexanes afforded 5.48 g (85%) of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethan-1-one as a white solid.
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[K+].CO>CCOCC.O>[CH2:10]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:1]1=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCCCCCC1
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: O=C1C(Cc2ccccc2)CCCCCC1Cc1ccccc1
Temperature: 25 °C

Procedure:
2,8-Dibenzylcyclooctanone is prepared by stirring 25 grams of cyclooctanone, 54 grams of benzaldehyde, 30 grams of potassium hydroxide and 500 milliliters of methanol at reflux temperatures for 4 hours. The mixture is then cooled to room temperature and 200 milliliters of water are added followed by 300 milliliters of ether. The ether layer is separated and the ether and methanol are then removed by distillation. The residue is taken up in 200 milliliters of ethanol and hydrogenated at 1,000 p.s.i.g. and ambient temperature using a 10 percent palladium on carbon catalyst. The catalyst is removed by filtration and the solvent is removed by distillation. Recrystallization of the crude product is effected by dissolving in 150 milliliters of methanol and seeding with crystalline 2,8-dibenzylcyclooctanone (m.p. 75°-77° C.). Cooling of the seeded methanolic solution gives 16 grams of crystals with melting point 60°-67° C. A second recrystallization of this material from methanol gives one isomer of 2,8-dibenzylcyclooctanone, melting point 75°-77° C., as a first crop and a second isomer of 2,8-dibenzylcyclooctanone, melting point 66°-68° C., as a second crop.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>[Cu]I.O>[CH:13]1[CH:18]=[CH:17][C:16]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=2[N+:9]([O-:11])=[O:10])=[CH:15][CH:14]=1
Reactant: Brc1ccccc1
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(Cl)ccc1Nc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 4-chloro-2-nitroaniline (5.5 g), bromobenzene (20 ml), potassium carbonate (1.63 g) and copper(I) iodide (0.68 g) was heated to 180° for 36 h. The reaction mixture was cooled to room temperature, then ethyl acetate (200 ml) and water (300 ml) were added; the organic extracts were washed with brine (2×150 ml), dried and concentrated in vacuo to give the crude compound which was purified by flash chromatography (eluting with CH-EA 95:5) to give the title compound (3.67 g). T.l.c. CH-EA (1:1 ), Rf 0.71.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O.C(OCC)(=O)C>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[N:7]3[CH:8]=2)=[CH:12][CH:13]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: C1CNCCN1
Reactant: CC(C)(C)c1ccc(-c2cn3c(Br)cccc3n2)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(-c2cn3c(N4CCNCC4)cccc3n2)cc1
Temperature: 160 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
The mixture of isomeric bromides prepared in Example 17 (0.054 g, 0.165 mmol) was dissolved in DMSO (3.5 mL) and treated with piperazine (0.568 g, 6.60 mmol). The mixture was shaken at 160° C. overnight. The mixture was diluted with ethyl acetate (20 mL) and washed with 10% HCl (2×20 mL). The aqueous layers were separated, basified with saturated sodium carbonate and re-extracted with ethyl acetate (3×20 mL). The organic solution was dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 0.051 g of crude material. The crude material could be purified by semi-preparative RP-HPLC (Method C). The purified fractions were combined and concentrated under reduced pressure to remove acetonitrile. The aqueous residue was basified with saturated sodium carbonate and extracted with ethyl acetate (3×15 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 13 mg (25%) of the title compound. Alternatively, the crude material could be used directly in the next step. HPLC (Method B): r.t.=6.2 min., purity 100% at 210-370 nm, 97.4% at 250 nm. HRMS: calcd for C21H26N4+H+, 335.22302; found (ESI, [M+H]+), 335.2228.