Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC(=O)[N:7]([CH2:9][CH2:10][CH2:11][OH:12])[CH3:8])(C)C.[Cl:14][C:15]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37]I)=[CH:31][C:16]=1[C:17]([NH:19][CH2:20][C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2)=[O:18]>ClCCl.FC(F)(F)C([O-])=O.[Ag+]>[ClH:14].[ClH:14].[Cl:14][C:15]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][O:12][CH2:11][CH2:10][CH2:9][NH:7][CH3:8])=[CH:31][C:16]=1[C:17]([NH:19][CH2:20][C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2)=[O:18]
Reactant: CN(CCCO)C(=O)OC(C)(C)C
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCI)ccc1Cl
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: CNCCCOCCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Product: Cl
Reaction time: 0.17 h
Yield: 7.3 %

Procedure:
Silver trifluoroacetate (0.7 g, 3.2 mmol) was added to 1,1-dimethylethyl (3-hydroxypropyl)methyl carbamic acid (1.8 g, 9.5 mmol) [Synth. Commun. (1995), 25(14), 2135-43] in dichloromethane (20 ml). After 10 min. 2-chloro-5-(3-iodopropyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl) benzamide (1.0 g, Example 70a) was added and the mixture was stirred for 24 h. The resulting mixture was washed with water and concentrated. Treatment with 4 M hydrochloric acid in 1,4-dioxane/methanol, concentration and purification by RPHPLC gave the title compound (26 mg) as a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:9][N:10]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[OH-].[Na+]>ClCCl>[C:30]([N:13]1[CH2:14][CH2:15][CH2:16][N:10]([CH2:9][CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH2:12]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: c1ccc(C(CCN2CCCNCC2)c2ccccc2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCCN(CCC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The resulting 1-(3,3-diphenylpropyl )homopiperazine was dissolved in 3 mL of dichloromethane, followed by adding 107 mg of triethylamine and 140 mg of benzoyl chloride. After the mixture was stirred at room temperature for 6 hours, it was mixed with 20 mL of aqueous 2N sodium hydroxide and extracted with 20 mL×2 of ethyl acetate. The organic layers were combined, washed with 20 mL of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, hexane/ethyl acetate 4:6) to obtain 249 mg of the titled compound. This was treated with a hydrogen chloride solution in ether and the solvent was removed under reduced pressure and the residue was dried to give the hydrochloride salt of the titled compound.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19](=O)[C:20](C3C=CC([N+]([O-])=O)=CC=3)=C(C3C=CC=CC=3)[C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10].Cl[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1Cl>CCCCCC>[N+:9]([C:4]1[CH:5]=[CH:6][C:1]([C:7]2[CH:20]=[C:19]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:18]([C:15]3[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=3)=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:8]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:2][CH:3]=1)([O-:11])=[O:10]
Reactant: O=C1C(c2ccc([N+](=O)[O-])cc2)=C(c2ccccc2)C(c2ccccc2)=C1c1ccc([N+](=O)[O-])cc1
Reactant: Clc1ccccc1Cl
Reactant: C#Cc1ccccc1
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccc(-c2cc(-c3ccccc3)c(-c3ccc([N+](=O)[O-])cc3)c(-c3ccccc3)c2-c2ccccc2)cc1
Temperature: 180 °C
Reaction time: 2 h

Procedure:
1,4-bis(4-nitrophenyl)-2,3,5-triphenylbenzene was prepared according to the procedure described in L. F., "Organic Experiments", 2nd Ed., 297 (1968). 19.3 grams (0.189 moles) of phenylacetylene, 20.0 grams (0.0362 moles) of 2,5-bis(4-nitrophenyl)-3,4-diphenylcyclopentadienone, a compound of formula (II) where Ar1 and Ar2 are phenyl, and 130 mL of o-dichlorobenzene were stirred at 180° C. for 2 hours. The reaction mixture was cooled, poured into 500 mL of hexane and filtered. The reaction yielded 22.9 grams of 1,4-bis(4-nitrophenyl)-2,3,5-triphenylbenzene, a 66% yield.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[C:8]2[O:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:12][C:7]2=[CH:6][CH:5]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[N:9]=[C:8]2[O:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:12][C:7]2=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc2nc(-c3ccccc3)oc2n1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2nc(-c3ccccc3)oc2n1

Procedure:
A solution of 361 mg. of 5-nitro-2-phenyloxazolo[5,4-b]pyridine in 30 ml. of methanol was hydrogenated over 0.2 g. of 5% palladium-on-carbon catalyst. The catalyst was removed by filtration, and the filtrate was concentrated to dryness. The residue was recrystallized from methanol to give 5-amino-2-phenyloxazolo[5,4-b]pyridine, m.p. 210° C.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[CH3:12][C:13]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)=[O:14].[OH-].[Na+]>CO>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6](/[CH:7]=[CH:12]/[C:13]([C:15]3[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=3)=[O:14])=[CH:5][C:4]=2[O:9]1
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)/C=C/c2ccc3c(c2)OCO3)cc(OC)c1OC
Reaction time: 18 h

Procedure:
To a stirred solution of piperonal (1.13 g, 7.5 mmol) and 3,4,5-trimethoxyacetophenone (1.58 g, 7.5 mmol) in methanol (15 ml) was added aqueous NaOH (6 ml, 50% w/v) and the mixture stirred for 18 h. The resultant solid was collected by filtration and recrystallised from methanol (100 ml) as pale yellow crystals (1.98 g, 77%): mp 135° C.; 1H NMR δ (CDCl3) 3.92 (3H, s, OCH3), 3.93 (6H, s, OCH3), 6.01 (2H, s, CH2), 6.83 (1H, d, J=8.0 Hz, H-5), 7.11 (1H, dd, J=1.6, 8.0 Hz, H-6), 7.15 (1H, d, J=1.6 Hz, H-2), 7.25 (2H, s, H-2′,6′), 7.30 (1H, d, J=15.5 Hz, CH), 7.72 (1H, d, J=15.5 Hz, CHCO); 13C NMR 56.42, 60.99, 101.69, 106.06, 106.68, 108.72, 119.77, 125.26, 133.72, 142.43, 144.60, 148.44, 149.96, 153.17, 189.07; MS (rel intensity) m/z 343 ([M+H]+, 100%); Anal. Calcd (C19H18O6): C, 66.66; H, 5.30. Found C, 66.43; H, 5.45.
Reaction SMILES: [NH2:1][C:2]([CH:4]1[N:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:8][CH2:7][N:6]([CH2:29][C:30]([NH:32][C:33]2[C:38]([Cl:39])=[CH:37][C:36]([N+:40]([O-])=O)=[CH:35][C:34]=2[Cl:43])=[O:31])[CH2:5]1)=[O:3].S1C=CC=C1.[H][H]>CO.[Pt]>[ClH:39].[ClH:39].[ClH:39].[NH2:1][C:2]([CH:4]1[N:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:8][CH2:7][N:6]([CH2:29][C:30]([NH:32][C:33]2[C:34]([Cl:43])=[CH:35][C:36]([NH2:40])=[CH:37][C:38]=2[Cl:39])=[O:31])[CH2:5]1)=[O:3]
Reactant: NC(=O)C1CN(CC(=O)Nc2c(Cl)cc([N+](=O)[O-])cc2Cl)CCN1CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Solvent: c1ccsc1
Product: Cl
Product: NC(=O)C1CN(CC(=O)Nc2c(Cl)cc(N)cc2Cl)CCN1CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 77.7 %

Procedure:
A mixture of 7 parts of 3-(aminocarbonyl)-4-[5,5-bis(4-fluorophenyl)pentyl]-N-(2,6-dichloro-4-nitrophenyl)-1-piperazineacetamide, 1 part of a solution of thiophene in methanol 4% and 120 parts of methanol was hydrogenated in a Parr apparatus and at 50° C. with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was converted into the hydrochloride salt in 2-propanol and acetonitrile. The salt was filtered off and dried, yielding 5.55 parts (77.7%) of 3-(aminocarbonyl)-N-(4-amino-2,6-dichlorophenyl)-4-[5,5-bis(4-fluorophenyl)pentyl]-1-piperazineacetamide trihydrochloride; mp. 190.8° C. (compound 84).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[CH:16][C:15]([C:28]#[N:29])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)C.O.[OH-].[Li+]>C1COCC1.CO>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:17]1[C:12]([N:9]2[CH2:8][CH2:7][CH:6]([CH2:5][C:4]([OH:30])=[O:3])[CH2:11][CH2:10]2)=[N:13][CH:14]=[C:15]([C:28]#[N:29])[CH:16]=1)=[O:27]
Reactant: CCOC(=O)CC1CCN(c2ncc(C#N)cc2NC(=O)c2cccc(Cl)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cnc(N2CCC(CC(=O)O)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.8 %

Procedure:
To a solution of 0.047 g (0.11 mmol) of [3′-(3-chloro-benzoylamino)-5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid ethyl ester in a mixture of THF (5 mL) and MeOH (2 mL) is added water (1 mL) and 0.013 g (0.55 mmol) of lithium hydroxide. The reaction mixture is stirred at room temperature for three days. The solvent is removed under reduced pressure and the residue is taken back up into water. The pH of the resulting aqueous solution is adjusted to approximately pH2 by adding concentrated hydrochloric acid which results in a solid precipitating from solution. The formed precipitate is collected by filtration, washed with water, and dried under vacuum to give 0.035 g (80%) of [3′-(3-chloro-benzoylamino)-5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid as yellow solid.
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1.[Si:14]([O:31][CH2:32][CH2:33][O:34][CH2:35][C@H:36]([OH:41])[C:37](OC)=[O:38])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Si:14]([O:31][CH2:32][CH2:33][O:34][CH2:35][C@H:36]([OH:41])[C:37]([NH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1)=[O:38])([C:27]([CH3:30])([CH3:28])[CH3:29])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: N#Cc1ccc(N)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCCOC[C@H](O)C(=O)Nc1ccc(C#N)cn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 66.5 %

Procedure:
Trimethylaluminium (2M in toluene) (0.621 mL, 1.24 mmol) was added to a solution of 6-aminonicotinonitrile (148 mg, 1.24 mmol) in toluene (10 mL) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 20 mins and then (S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) (250 mg, 0.62 mmol) was added. The reaction mixture was allowed to warm to room temperature and then heated at reflux under nitrogen for 4 hours. The reaction mixture was allowed to cool to room temperature and the concentrated in vacuo. The residue was neutralised with citric acid (1M, aq) and then diluted with water and DCM (50 mL). The organic layer was separated and the aqueous layer re-extracted with DCM (30 mL). The combined organics were dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford the product (202 mg, 66.4%). 1H NMR (400 MHz, CDCl3) 1.04 (9H, s), 3.65-3.67 (2H, m), 3.81-3.91 (4H, m), 4.36 (1H, t), 7.35-7.45 (6H, m), 7.65-7.67 (4H, m), 7.92-7.95 (1H, m), 8.36-8.39 (1H, m), 8.54-8.56 (1H m), 9.43 (1H, s); m/z (ES+) (M+H)+=490; HPLC tR=3.08 min.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[OH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[S:17])=[CH:14][CH:13]=1>C(O)C>[C:5]1([C:3]2[N:18]=[C:16]([C:15]3[CH:19]=[CH:20][C:12]([OH:11])=[CH:13][CH:14]=3)[S:17][CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NC(=S)c1ccc(O)cc1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCO
Product: Oc1ccc(-c2nc(-c3ccccc3)cs2)cc1
Temperature: 35 °C
Reaction time: 1 h

Procedure:
In a round-bottomed flask, 2-bromoacetophenone (520 mg, 2.61 mmol) and 4-hydroxy-thiobenzamide (400 mg, 2.61 mmol) were dissolved in ethanol (10 ml), and the resulting solution was heated to reflux. After about one hour, the reaction was cooled to about 35° C. and was allowed to stir for about an additional twelve hours. The reaction mixture was then concentrated in vacuo to an oil, the residue redissolved in ethyl acetate and methylene chloride, and extracted with saturated aqueous sodium bicarbonate. The combined extracts were then extracted with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to an oil. The crude product was purified by column chromatography (silica gel; methylene chloride to 2% methanol/methylene chloride). The title product was isolated as a white solid (516 mg, 78% yield). LRMS ([M+H]+)=254.1.
Reaction SMILES: [N+](C1C=C(C=CC=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:8])([O-])=O.[Cl:22]C1C=CC=CC=1>>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([C:7]([Cl:22])=[O:8])=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Clc1ccccc1
Product: O=C(Cl)c1ccc([N+](=O)[O-])cc1

Procedure:
For example, 3,3'-dinitro-4,4'-dichlorobenzophenone can be prepared in a yield of 95 to 98% by nitrating 4,4'-dichlorobenzophenone [E. R. Kofanov et al., J. Org. Chem. USSR, 15, 98-100 (1979)]. 5,3'-Dinitro-2,4'-dichlorobenzophenone can be prepared in a high yield by nitrating 2,4'-dichlorobenzophenone [E. H. Faith et al., J. Am. Chem. Soc., 77, 543 (1955)]. 3,3'-Dinitro-4-chlorobenzophenone can be prepared in a high yield by nitrating 4-chlorobenzophenone [G. S. Mironov et al., J. Org. Chem. USSR, 8, 1538 (1972)]. 3,4'-Dinitro-4-chlorobenzophenone can be prepared by nitrating 4-halogeno-4'-nitrobenzophenone obtained by the condensation reaction between p-nitrobenzoyl chloride and chlorobenzene [P. T. Montagne et al., Ber., 49, 2267-2270 (1916); G. S. Mironov et al., J. Org. Chem. USSR, 8, 1538-1543 (1972)]. 3,3'-Dinitro-6,4'-dichlorobenzophenone can be prepared in a high yield by nitrating 2,4'-dichlorobenzophenone obtained by the condensation reaction between 2-chlorobenzoyl chloride and chlorobenzene [H. F. Faith et al., J. Am. Chem. Soc., 77, 543 (1955)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=O.CN.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:23][CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 47.5 %

Procedure:
Under a nitrogen atmosphere, a suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid, 6.0 g, 0.021 mole) and 1,1'-carbonyldiimidazole (3.39 g, 0.021 mole) in tetrahydrofuran (150 ml) was refluxed, with stirring, for 2.5 hrs. The mixture was cooled to room temperature and a solution of 3.6 g (0.116 mole) of monomethylamine in tetrahydrofuran (60 ml) was added dropwise and the reaction mixture was stirred at room temperature overnight. The tetrahydrofuran was evaporated and the residue was triturated in water (150 ml). The solid was filtered and rinsed with water. The solid was dissolved in hot isopropyl alcohol, treated with charcoal, filtered, and allowed to cool. Solid formed, and water was added to precipitate more. The solid was filtered and dried under vacuum to give 3.0 g (47.5%) of title compound, mp 238°-238.5° C.
Reaction SMILES: B(Cl)(Cl)Cl.C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:11][CH:10]=1)C=C.Cl[C:23]1[CH:28]=CC=C[CH:24]=1>>[CH2:28]([C:14]1[CH:13]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH:11]=[CH:10][C:9]=1[OH:8])[CH:23]=[CH2:24]
Reactant: Clc1ccccc1
Reactant: C=CCOc1ccc(-c2ccccc2C)cc1
Agent: ClB(Cl)Cl
Product: C=CCc1cc(-c2ccccc2C)ccc1O
Reaction time: 1 h

Procedure:
To a stirred solution of BCl3 (1M in p-xylene; 6.7 mL, 6.7 mmol) in chlorobenzene at -15° C. was added the allyl ether from step B (1.48 g, 6.6 mmol) in 5 mL of chlorobenzene. After 1 h at -15° C., the mixture was poured into ice/MeOH, extracted with Et2O (3×), washed with saturated NaHCO3, water then brine. The dried solution was evaporated to give the title compound as an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@H:10]([C:14]([NH:16][CH:17]2[CH2:19][CH2:18]2)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@H:10]([CH2:14][NH:16][CH:17]2[CH2:19][CH2:18]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CN(Cc2ccccc2)C[C@@H]1C(=O)NC1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@H]1CN(Cc2ccccc2)C[C@@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.8 %

Procedure:
(3R,4R)-1-Benzyl-N-cyclopropyl-4-methyl-3-pyrrolidinecarboxamide (70.0 g) was dissolved in toluene (700 mL). While this solution was chilled in an ice water bath, a borane/dimethyl sulfate complex (90%, 34.3 mL) was added dropwise. The mixture was then stirred for 15 min, was refluxed and was allowed to cool to room temperature. A 10% aqueous Na2CO3 solution (400 mL) was added, and the mixture was stirred at 100° C. for 2 hours and was then allowed to cool to room temperature. The toluene layer was separated, washed with water (2×250 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by distillation under reduced-pressure to give (3S,4R)-1-benzyl-3-cyclopropylaminomethyl-4-methylpyrrolidine as a colorless oil (62.1 g).
Reaction SMILES: Cl.FC1[CH:4]=[C:5]([C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25](F)[CH:24]=2)=[CH:10][O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]=[C:16]([C:20]([OH:22])=[O:21])[CH2:15]2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].Cl.[Cl:33][CH2:34][Cl:35].[CH2:36](O)C>>[ClH:33].[Cl:35][C:34]1[CH:4]=[C:5]([C:9]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=2[CH3:36])=[CH:10][O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]=[C:16]([C:20]([OH:22])=[O:21])[CH2:15]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCO
Reactant: ClCCl
Reactant: O=C(O)C1=CCCN(CCOC=C(c2cccc(F)c2)c2cccc(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccccc1C(=COCCN1CCC=C(C(=O)O)C1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
1-[2-[[2-(3-Chlorophenyl)-2-(2-methylphenyl)ethenyl]oxy]-ethyl]-1,2, 5,6-tetrahydro-3-pyridine carboxylic methyl ester (0.60 g, 0.0014 mol) (prepared as described in Method D) was dissolved in ethanol (5 ml) and 12 N sodium hydroxide solution (0.35 ml) was introduced. After stirring the solution at room temperature for 3 h, 37% hydrochloric acid solution was added, until the pH was measured as ca. 1. Dichloromethane (200 ml) was introduced, and the mixture was dried (Na2SO4), filtered and evaporated to a residue, which was co-evaporated twice with acetone. The residue was recrystallized from acetone/ethyl acetate to give the title compound (0.33 g, 55%) as white crystals, m.p. 168°-170° HPLC retention times 16.12 and 18.42 for the geometric isomers (gradient elution, water/20-80% acetonitrile, both phases containing 0.1% TFA).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10]O.C1C(=O)N([O:19][C:20]([O:22][N:23]2[C:28](=[O:29])[CH2:27][CH2:26][C:24]2=[O:25])=[O:21])C(=O)C1.C(N(CC)CC)C.C(OCC)(=O)C>C(#N)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:19][C:20](=[O:21])[O:22][N:23]1[C:24](=[O:25])[CH2:26][CH2:27][C:28]1=[O:29]
Reactant: COCCOCCOCCO
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCCOCCOCCOC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
Triethylene glycol monomethyl ether (1.0 g, 6.1 mmol) and N,N′-disuccinimidyl carbonate (1.87 g, 7.3 mmol) were dissolved in acetonitrile (10 mL). Then triethylamine (1.3 mL, 9.15 mmol) was added and the reaction stirred overnight at room temperature. Crude reaction was evaporated to dryness, dissolved in sat. NaHCO3 (50 mL), washed ethyl acetate (2×50 mL), dried MgSO4, and evaporated to dryness. Column chromatography (Silica, ethyl acetate) afforded 1 a clear oil (0.367 g, 20% yield).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:9](=[C:10]([OH:27])[C:11]4[N:12]=[CH:13][CH:14]=[N:15][C:16]=4[C:17]=3[O:21][C:22](=[O:26])[O:23][CH2:24][CH3:25])[C:8]2=[O:28])=[CH:4][CH:3]=1.[C:31]1([C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[N+]=[N-])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCCl>[CH2:24]([O:23][C:22](=[O:26])[O:21][C:17]1[C:16]2[N:15]=[CH:14][CH:13]=[N:12][C:11]=2[C:10]([O:27][CH:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:9]2[C:8](=[O:28])[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:30][CH:29]=3)[C:19](=[O:20])[C:18]=12)[CH3:25]
Reactant: CCOC(=O)Oc1c2c(c(O)c3nccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: CCOC(=O)Oc1c2c(c(OC(c3ccccc3)c3ccccc3)c3nccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Temperature: 70 °C
Yield: 69.8 %

Procedure:
Carbonic acid mono-[1-(1-benzyl-4-methylene-2,5-dioxo-pyrrolidin-3-ylidene)-ethyl]ester 243 (1.1 g, 2.68 mmol, 1 equiv.) was dissolved in 1,2 dichloroethane (50 mL, 0.055 M) and to this was added diphenyldiazomethane (1.05 g, 5.35 mmol, 2 equiv.) and heated at 70° C. under a nitrogen atmosphere for 24 hours. The reaction was concentrated in vacuo and purified by silica gel chromatography using 4/1 Hexanes/Ethyl acetate to obtain carbonic acid 9-benzhydryloxy-7-(4-fluoro-benzyl)-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoxalin-5-yl ethyl ester 244 (70%, 1085 mg, 1.87 mmol). 1H NMR (300 MHz) CDCl3 δ 9.09 (d, J=6 Hz, 1 H), 8.97 (d, J=6 Hz, 1 H), 8.65 (bs, 1 H), 7.46 (d, J=4.8 Hz, 2 H),7.03 (d, J=4.8 Hz, 2 H), 4.85 (s, 2 H),4.04 (q, J=2.8 Hz,2 H), 1.43 (q, J=2.8 Hz, 3 H). MS: 600.2 (M+23). TLC Rf: 0.3 Hexanes/Ethyl acetate (7/3)
Reaction SMILES: [CH3:1][C@@:2]1([OH:21])[C@H:6]([O:7][CH3:8])[C@@H:5]([CH2:9][OH:10])[O:4][C@H:3]1[N:11]1[C:20]2[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=2[N:13]=[CH:12]1.[CH3:22]I>CC(C)C(N)=O>[CH3:22][NH:16][C:15]1[C:14]2[N:13]=[CH:12][N:11]([C:20]=2[N:19]=[CH:18][N:17]=1)[C@@H:3]1[O:4][C@H:5]([CH2:9][OH:10])[C@@H:6]([O:7][CH3:8])[C@@:2]1([CH3:1])[OH:21]
Reactant: CI
Reactant: CO[C@@H]1[C@@H](CO)O[C@@H](n2cnc3c(N)ncnc32)[C@]1(C)O
Agent: CC(C)C(N)=O
Product: CNc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](OC)[C@@]1(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 g of the compound obtained in Example 2 and 2 ml of methyl iodide were dissolved in dimethylacetoamide, and stirred overnight at room temperature. The reaction mixture was concentrated to dryness under reduced pressure and 10 ml of 2N sodium hydroxide solution was added thereto. The solution was refluxed for one hour with heating. After cooling to room temperature, the solution was neutralized with 2N HCl and applied on Amberlite XAD-7 column. The column was washed with water and eluted with 50% (V/V) aqueous solution of methanol. The eluate was concentrated to dryness under reduced pressure and recrystallized from ethyl acetate to give 1.8 g of N6,2',3'-O-trimethyladenosine (Compound 60).