Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH2:9]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][C:25](=[O:31])[CH2:26][CH2:27][C:28](O)=[O:29])[CH:10]=[CH2:11].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[O:8]=[C:3]1[CH2:4][CH2:5][C:6](=[O:7])[N:2]1[O:1][C:28](=[O:29])[CH2:27][CH2:26][C:25]([O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:9][CH:10]=[CH2:11])=[O:31]
Reactant: C=CCOCCOCCOCCOCCOC(=O)CCC(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C=CCOCCOCCOCCOCCOC(=O)CCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
N-hydroxysuccin imide (1.58 g, 13.8 mmol) and succinic mono-(2-{2-[2-(2-allyloxy-ethoxy)-ethoxy]-ethoxy}-ethyl) ester (10) (4.6 g, 13.76 mmol) were dissolved in dry CH2Cl2 (10 mL) at room temperature. A solution of N,N′-dicyclohexylcarbodiimide (DCC) (2.84 g, 13.8 mmol) in dry CH2Cl2 (2 mL) was slowly added to the mixture at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The solid residues in the reaction mixture were filtered through a sintered glass filter and removed and the filtrate was concentrated to obtain the target compound in a yellow oily phase (5.5 g, 93%). The compound was used without further purification. The NMR analysis result of the product is as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1.CO>O1CCCC1>[CH:29]1([C:32]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[O:11])[N:8]([C@@H:12]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=2)[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:7]3)=[O:33])[CH2:31][CH2:30]1
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)ccc1OC
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 0.17 h
Yield: 70.5 %

Procedure:
A stirred mixture of 7-amino-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindolin-1-one (1.7 g, 4.2 mmol) and cyclopropane carbonyl chloride (0.46 mL, 5.1 mmol) in tetrahydrofuran (10 mL) was heated to reflux for 15 min. To the mixture was added methanol (4 mL) at room temperature and the mixture stirred for 10 min. The solvent was removed in vacuo to give an oil. The oil was recrystallized from ethanol (20 mL) to give cyclopropyl-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindolin-4-yl}carboxamide as a white solid (1.4 g, 71% yield); mp, 172-174° C.; 1H NMR (CDCl3) δ 0.86-0.93 (m, 2H, 2CHH), 1.07-1.14 (m, 2H, 2CHH), 1.46 (t, J=6.9 Hz, 3H, CH3), 1.63-1.73 (m, 1H, CH), 2.95 (s, 3H, CH3), 3.68 (dd, J=4.4, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.07 (q, J=7.1 Hz, 2H, CH2), 4.20 (d, J=16.7 Hz, 1H, CHH), 4.21 (dd, J=9.9, 14.3 Hz, 1H, CHH), 4.44 (d, J=16.7 Hz, 1H, CHH), 5.73 (dd, J=4.3, 9.9 Hz, 1H, NCH), 6.84-7.02 (m, 4H, Ar), 7.44 (t, J=7.8 Hz, 1H, Ar), 8.43 (d, J=8.3 Hz, 1H, Ar), 10.46 (s, 1H, NH); 13C NMR (CDCl3) δ 8.24, 14.61, 16.10, 41.43, 47.81, 51.55, 55.75, 55.88, 64.56, 111.46, 112.09, 116.69, 116.99, 117.76, 119.17, 129.27, 133.54, 138.06, 141.22, 148.84, 149.67, 169.96, 172.59; Anal Calcd for C24H28N2O6S: C, 61.00; H, 5.97; N, 5.93. Found: C, 60.87; H, 6.13; N, 6.12.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][S:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SCCCCCBr)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
To a solution of methyl 4-mercaptobenzoate (3.39 g) and 1,5-dibromopentane (9.31 g) in dimethyl formamide (100 mL), potassium carbonate (3.07 g) was added. The reaction mixture was stirred at room temperature for 3 hours. To the reaction mixture, water (300 mL) was added and the aqueous layer was extracted twice with an n-hexane-ethyl acetate solution (n-hexane:ethyl acetate=1:1) (150 mL). The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0→8:2) to obtain the title compound (4.69 g) having the following physical properties.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:12](N(CC)CC)C>S(Cl)(Cl)=O>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: CCN(CC)CC
Reactant: Cc1c(Br)cccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(Br)c1C
Temperature: 60 °C
Yield: 70.1 %

Procedure:
A suspension of 3-bromo-2-methylbenzoic acid (9.9 g,46 mmol) in thionyl chloride (20 mL) was heated to 60° C. for 1 hour, cooled to room temperature, and concentrated. The residue was suspended in 50 mL of methanol, cooled to 0° C., treated slowly with triethylamine (12.7 μL, 92 mmol), warmed to room temperature, and concentrated. The residue was partitioned between ethyl acetate and water and the organic phase was washed with saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated to give 7.39 g of the desired product. Rf=0.5 (10% ethyl acetate/hexanes).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13]\[CH2:14][OH:15])=[CH:8][CH:7]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH3:54][O:55][C:56](=[O:67])[CH2:57][O:58][C:59]1[CH:64]=[CH:63][C:62](O)=[CH:61][C:60]=1[CH3:66]>O1CCCC1>[CH3:54][O:55][C:56](=[O:67])[CH2:57][O:58][C:59]1[CH:64]=[CH:63][C:62]([O:15][CH2:14]/[CH:13]=[C:12](/[C:9]2[CH:10]=[CH:11][C:6]([C:5]#[C:4][CH2:3][N:2]([CH3:1])[CH3:22])=[CH:7][CH:8]=2)\[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:61][C:60]=1[CH3:66]
Reactant: COC(=O)COc1ccc(O)cc1C
Reactant: CN(C)CC#Cc1ccc(/C(=C\CO)c2ccccc2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccccc2)c2ccc(C#CCN(C)C)cc2)cc1C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of the above alcohol (291 mg, 0.999 mmol) in dry tetrahydrofuran (30 mL) was added tributylphosphine (0.27 ml, 1.5 mmol). The mixture was cooled to 0° C. and added 1,1′-(azodicarbonyl)dipiperidine (377.5 mg, 1.5 mmol), and after 10 min (4-Hydroxy-2-methyl-phenoxy)-acetic acid methyl ester (2151 mg, 1.1 mmol) was added. After 1.5 hr at 0° C. the reaction was allowed to warm up to ambient temperature and stirred overnight. The reaction mixture was added silica gel Fluka 60 (10 g) and evaporated in vacuo. The residue was purified by ISCO combiflash 16 (silica gel, hexane/ethyl acetate 85:15) yielding (4-{(E)-3-[4-(3-dimethylamino-prop-1-ynyl)-phenyl]-3-phenyl-allyloxy}-2-methyl-phenoxy)-acetic acid methyl ester as an oil.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH2:6]([CH:10]1[C:19]2[C:18]3[NH:20][C:21]4[C:26]([C:17]=3[CH2:16][CH2:15][N+:14]=2[CH2:13][CH2:12][CH2:11]1)=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:7][CH2:8][CH3:9].ClCCl.[OH-].[Na+]>O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH2:6]([C:10]1([CH2:11][CH2:12][C:13]#[N:14])[C:19]2[C:18]3[NH:20][C:21]4[C:26]([C:17]=3[CH2:16][CH2:15][N+:14]=2[CH2:13][CH2:12][CH2:11]1)=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCC1CCC[N+]2=C1c1[nH]c3ccccc3c1CC2
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCCCC1(CCC#N)CCC[N+]2=C1c1[nH]c3ccccc3c1CC2
Reaction time: 72 h
Yield: 64.1 %

Procedure:
5.0 g. (13.3 mmoles) of 1-n-butyl-2,3,4,6,7,12-hexahydro-indolo(2,3 -a)quinolizinium perchlorate are suspended in 50 ml. of dichloromethane, and 50 ml. of distilled water and 10 ml. of 2 n sodium hydroxide are added to the suspension under constant stirring in argon atmosphere. The reaction mixture is stirred for 10 minutes, thereafter the organic phase is separated, and dried over anhydrous potassium carbonate. The drying agent is filtered off, 5.0 ml. (71 mmoles) of freshly distilled acrylonitrile are added to the filtrate, the mixture is flushed with argon, and allowed to stand at room temperature for 3 days. Thereafter the reaction mixture is evaporated in vacuo, the red oily residue is dissolved in 5 ml. of methanol, and the solution is acidified to pH = 6 with 70% perchloric acid. The crystallization of the product is initiated by scraping the wall of the flask. The flask is put into refrigerator. The separated yellow crystals are filtered off, washed with cold methanol, and the obtained 4.20 g. of product (m.p.: 215-220° C) are recrystallized from 5-fold volume of methanol. 3.70 g. (64.1 %) of 1-n-butyl-1-(2-cyanoethyl)- 1,2,3,4,6,7-hexahydro- 12H-indolo(2,3 -a)quinolizinium perchlorate are obtained in the form of yellow needles; m.p.: 224-226° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]#[N:23])[CH:17]=[CH:16][C:15]=1[S:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=1>C(O)C>[C:22]([CH2:21][O:20][C:18]1[CH:17]=[CH:16][C:15]([S:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1)#[N:23]
Reactant: CC(=O)Nc1ccc(Sc2ccc(OCC#N)cc2N)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2ccc(OCC#N)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 7d (30 mg, 0.17 mmol) was reacted in ethanol (1 mL) with the product from Example 38c (53 mg, 0.17 mmol) for 18 h following the procedure from Example 7g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (9 mg, 19%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.03 (s, 3 H) 2.76 (s, 3 H), 5.23 (s, 2 H), 6.32 (d, J=6.99 Hz, 1 H), 7.18 (d, J=8.46 Hz, 2 H) 7.23 (dd, J=8.82, 2.57 Hz, 1 H), 7.31 (d, J=2.57 Hz, 1 H), 7.38 (d, J=8.82 Hz, 1 H) 7.45 (d, J=8.82 Hz, 2 H), 7.80 (d, J=8.46 Hz, 1 H), 8.41 (d, J=6.99 Hz, 1 H) 8.96 (d, J=8.46 Hz, 1 H), 10.01 (s, 1 H), 11.04 (s, 1 H), 14.42 (s, 1 H); MS (ESI+) m/z 456 (M+H)+.
Reaction SMILES: [C:1]([N:4]([CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1)[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:12]=1[C:13]([O:15]C)=[O:14])(=[O:3])[CH3:2].[OH-].[Na+].Cl.O>C(O)C>[C:1]([N:4]([CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1)[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:12]=1[C:13]([OH:15])=[O:14])(=[O:3])[CH3:2]
Reactant: COC(=O)c1c(C)cccc1COCCCCN(Cc1ccc2ccccc2n1)C(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)N(CCCCOCc1cccc(C)c1C(=O)O)Cc1ccc2ccccc2n1
Temperature: 90 °C

Procedure:
Methyl 2-[4-(acetyl-quinolin-2-ylmethyl-amino)-butoxymethyl]-6-methyl-benzoate (375 mg, 0.86 mmol, EXAMPLE 40a) is dissolved in ethanol (7.5 mL). 10 N NaOH (860 μL, 8.6 mmol) is added, and the contents are heated to 90° C. overnight. The reaction is cooled to r.t. and 2 N HCl (4.3 mL) is added, followed by dropwise addition of 2 N HCl to adjust the pH to ˜4-6. The contents are poured into water (100 mL) and extracted with dichloromethane (3×75 mL). The organic fractions are pooled and washed with brine (3×100 mL), dried over MgSO4, filtered and reduced under vacuum to dryness. The crude material is purified by flash chromatography (silica, 6% methanol in dichloromethane) to give the title compound. 1H NMR (300 MHz, CDCl3) Rotamers 2:1 δ 8.37 (d, 0.5H), 8.28-8.15 (m, 1.5H), 7.88-7.83 (m, 1.25H), 7.80-7.73 (m, 1.75H), 7.65-7.57 (m, 1.25H), 7.43 (d, 0.25H), 7.33-7.10 (m, 3H), 5.24 (s, 1.33H), 5.01 (s, 0.66H), 4.67 (s, 1.33H), 4.63 (s, 0.66H), 3.55-3.45 (m, 2.66), 3.39-3.32 (m, 1.33), 2.58 (s, 2H), 2.55 (s, 1H), 2.31 (s, 1H), 1.95-1.82 (m, 2H), 1.77-1.62 (m, 2H). MS (ESI) 421 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)=[C:4]([F:18])[CH:3]=1.[I:19]N1C(=O)CCC1=O>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([I:19])=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:15])[F:16])[C:10]([CH3:17])=[N:9]2)=[C:4]([F:18])[CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1nn(-c2ccc(Cl)cc2F)c(=O)n1C(F)F
Agent: O=S(=O)(O)O
Product: Cc1nn(-c2cc(I)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a stirred solution of 1.0 gram (0.0036 mole--1.0 equiv.) of 1-(4-chloro-2-fluorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole in 10 mL of concentrated sulfuric acid (% wt/vol. triazole to solvent--10%) was added in small portions 0.972 gram (0.0043 mole--1.2 equiv.) of N-iodosuccinimide. Upon completion of the addition the reaction mixture was stirred at ambient temperature and in absence of light for 30 minutes. After this time thin layer chromatographic (TLC) analysis of the reaction mixture indicated that the reaction was almost complete. The reaction mixture was then quenched with 50 mL of water, and the resulting mixture was extracted with two 25 mL portions of ethyl acetate. The extracts were combined and washed with one 15 mL portion of an aqueous 10% sodium bisulfite solution followed by one 15 mL portion of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 1.2 grams of 1-(4-chloro-2-fluoro-5-iodophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole (83.2% yield). The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [I:1]Cl.ClCCl.[Cl:6][C:7]1[N:8]=[C:9]2[CH:15]=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1>N1C=CC=CC=1>[Cl:6][C:7]1[N:8]=[C:9]2[C:15]([I:1])=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1
Reactant: Clc1cnc2[nH]ccc2n1
Reactant: ClI
Solvent: c1ccncc1
Solvent: ClCCl
Product: Clc1cnc2[nH]cc(I)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A 1 M solution of iodine monochloride in dichloromethane (9.84 mL, 9.84 mmol) was added dropwise to an ice-cold solution of 2-chloro-5H-pyrrolo[2,3-b]pyrazine (6.75 g, 11.07 mmol) in anhydrous pyridine (12 mL). The reaction mixture was stirred at 0° C. for 60 minutes, then concentrated. The residue was partitioned between ethyl acetate and brine. The organic phase was washed with brine and concentrated. The crude product was stirred with 15 mL of dichloromethane. The yellow solid material was collected by filtration, washed with dichloromethane and dried to give 2.86 g of the title product. Yield: 66%. MS (DCI+) m/z 280 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7](Cl)[N:6]=1)=[O:4].[Cl:13][C:14]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:15]=1[NH2:16]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:14]=2[Cl:13])[N:6]=1)=[O:4]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(C)c(Cl)n1
Product: COC(=O)c1ccc(C)c(Nc2ccc(Cl)cc2Cl)n1

Procedure:
6-(2,4-Dichloro-phenylamino)-5-methyl-pyridine-2-carboxylic acid methyl ester was synthesized in analogy to Example 5 b, using 6-chloro-5-methyl-pyridine-2-carboxylic acid methyl ester (CAN 178421-22-2) and 2,4-dichloroaniline as starting materials, MS (EI): m/e 311.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8]P(=O)(OCC)OCC)=[CH:6][CH:5]=1)([O-:3])=[O:2].C[O-].[Na+].[CH:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)=O>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7](/[CH:8]=[CH:22]/[C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)=[CH:17][CH:18]=1)([O-:3])=[O:2]
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(/C=C/c2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
To a mixture of 50.3 g of diethyl (4-nitrobenzyl)phosphonate and 500 mL of methanol was added dropwise a solution of sodium methylate in methanol (ca. 5 mol/L, 73.7 mL) under ice-cooling, followed by stirring for 30 minutes under ice-cooling. To the reaction mixture was added dropwise a mixture of 30.6 g of methyl 4-formylbenzoate and 300 mL of methanol for 1 hour under ice-cooling, followed by stirring at room temperature for 15 hours after the addition dropwise. The precipitate was collected by filtration to obtain 48.8 g of methyl 4-[(E)-2-(4-nitrophenyl)vinyl]benzoate as a yellow solid. EI: 283
Reaction SMILES: [CH3:1][C:2]1([C:7]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)[N:16]=3)[NH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][NH:3]1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>ClCCl>[CH3:1][C:2]1([C:7]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)[N:16]=3)[NH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][N:3]1[C:30](=[O:32])[CH3:31]
Reactant: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCCN4)c3n2)cc(OC)c1OC
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCCN4C(C)=O)c3n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
A solution of (2-methyl-pyrrolidin-2-yl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone (8 mg, 0.02 mmol) in anhydrous dichloromethane (0.3 ml) was cooled to 0° C. and treated with acetic anhydride (2 mg, 0.02 mmol). The reaction mixture was stirred for 1 hour and then allowed to warm to room temperature and stir for 3 hours. The reaction mixture was partitioned between EtOAc/saturated aqueous NaHCO3. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a brownish oil. The residue was purified by preparative thin layer chromatography using 50% EtOAc in hexanes as eluant to provide 2 mg (17%) of 1-{2-methyl-2-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-pyrrolidin-1-yl}-ethanone as a light yellow solid. M+H=439.
Reaction SMILES: Br[CH2:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[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:28]1[CH:32]=[CH:31][N:30]=[CH:29]1.O>CN1C(=O)CCC1>[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:5]=[CH:4][C:3]([CH2:2][N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)=[CH:27][CH:26]=2)[S:11][C:12]=1[C:20]1[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=1
Reactant: O=C(Nc1nc(-c2ccco2)c(-c2ccncc2)s1)c1ccc(CBr)cc1
Reactant: c1c[nH]cn1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(Nc1nc(-c2ccco2)c(-c2ccncc2)s1)c1ccc(Cn2ccnc2)cc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
Compound 18 (880 mg, 2.00 mmol) was suspended in NMP (10 mL), and imidazole (408 mg, 6.00 mmol) was added thereto, followed by stirring at 65° C. for 2 hours. The reaction mixture was allowed to cool down to room temperature and then poured into water, and the deposited precipitate was collected by filtration. The resulting precipitate was purified through silica gel column chromatography (chloroform:methanol=17:3) to afford the entitled Compound 19 (538 mg, 63%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]([CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])[CH2:35]O)[CH:31]=[CH:32][CH:33]=1>ClCCl>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH2:35][I:25])[CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])[CH:29]=1
Reactant: II
Reactant: OCC(CCC(F)(F)F)c1cccc(Cl)c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)CCC(CI)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of triphenylphosphine (1.56 g, 6.0 mmol) and imidazole (0.41 g, 6.0 mmol) in dichloromethane (16 ml) under an argon atmosphere was added slowly iodine (1.51 g, 6.0 mmol) and 2-(3-chloro-phenyl)-5,5,5-trifluoro-pentan-1-ol (1.26 g, 5.0 mmol). The mixture was stirred for 2 hours at room temperature, then dichloromethane (50 ml) was added and mixture was extracted with saturated sodium thiosulfate solution (50 ml) and hydrochloric acid (1N, 25 ml). The organic layer was dried over MgSO4 and evaporated. The residue was suspended in ether and filtered to remove insoluble triphenylphosphine oxide. The ether was evaporated and the residue was purified by column chromatography (SiO2, heptane/EtOAc=9:1) to yield a light yellow liquid, (1.73 g, 96%); (EI): 235.0 ((M−I)+.).
Reaction SMILES: [C:1]([C:3]1[C:12]([NH:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:19]([F:22])([F:21])[F:20])[CH:4]=1)#[N:2].OO.C(=O)([O-])[O-:26].[K+].[K+]>CS(C)=O>[NH2:2][C:1]([C:3]1[C:12]([NH:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:19]([F:21])([F:20])[F:22])[CH:4]=1)=[O:26]
Reactant: CCC(CC)Nc1cc(C(=O)OC)c(C(F)(F)F)cc1C#N
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CCC(CC)Nc1cc(C(=O)OC)c(C(F)(F)F)cc1C(N)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl 4-cyano-5-(pentan-3-ylamino)-2-(trifluoromethyl)benzoate (257 mg, 0.818 mmol) was dissolved in DMSO (2 mL) and was cooled in a cold water bath. 30% Aqueous hydrogen peroxide (0.2 mL) and potassium carbonate (38 mg, 0.275 mmol) was added and the mixture was stirred at ambient temperature for 1.5 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate. The combined organic portion was dried over sodium sulfate then filtered and concentrated to afford methyl 4-aminocarbonyl-5-(pentan-3-ylamino)-2-(trifluoromethyl)benzoate (quantitative yield) as a yellow oil. MS (EI) for C15H19F3N2O3: 333 (MH+).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH2:26]=[CH:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH:26](/[C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])=[CH:27]\[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCNc1nc2c(N)nc(I)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C=CCCCC
Product: CCCC/C=C/c1nc(N)c2nc(NCCCC)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reaction time: 0.58 h

Procedure:
The reaction was performed with 2-iodo-8-butylaminoadenosine (10, 380 mg, 0.82 mmol) and (E)-1-borocatechol)-1-hexene (2.46 mmol). The mixture was purified by column chromatography (10% MeOH in CH2Cl2). Yield 42 mg (0.10 mmol, 12%); Rƒ 0.44 (10% MeOH in CH2Cl2); 1H NMR (MeOD-d4) δ 6.94–6.80 (m, 1H, ═CHCH2), 6.28 (d, 1H, J=15.42 Hz, ═CH), 6.02 (d, 1H, J=7.62 Hz, H-1′), 4.81–4.69 (m, 1H, H-2′), 4.31–4.20 (m, 1H, H-3′), 4.20–4.05 (m, 1H, H-4′), 3.87–3.70 (m, 2H, H-5′), 3.35–3.23 (m, 2H, NHCH2), 2.29–2.05 (m, 2H, ═CHCH2), 1.72–1.20 (m, 8H, 2×CH2CH2), 1.00–0.83 (m, 6H, 2×CH3); MS m/z 422 (M+H)+; HPLC, System A: 20–100% CH3CN in H2O in 35 min., retention time=8.53 min.; System B: 30–100% CH3OH in H2O in 40 min., retention time=20.47 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][N:12]=[CH:11]2)=[CH:6][C:5]=1[C:15]([F:18])([F:17])[F:16])([O-])=O.C.[H][H]>>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:11]=[N:12][N:13]=[CH:14]2)=[CH:6][C:5]=1[C:15]([F:18])([F:17])[F:16]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(-n2cnnc2)cc1C(F)(F)F
Product: Nc1ccc(-n2cnnc2)cc1C(F)(F)F

Procedure:
The following compound, m.p. 196°-8°, was prepared similarly to the previous Preparation using 4-(4-nitro-3-trifluoromethylphenyl)-1,2,4-triazole and 5% palladised charcoal/H2 as the starting materials: ##STR137##