Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:25]=[CH:24][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH2:22][OH:23])[N:15]=1)[N:7]=3.Cl.[CH3:27][NH:28][CH3:29]>>[CH3:27][N:28]([CH3:29])[C:2]1[N:25]=[CH:24][C:5]2[C:6]3[N:10]([CH:9]=[C:8]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH2:22][OH:23])[N:15]=4)[N:7]=3)[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: CC(C)n1nc(CO)nc1-c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Reactant: CNC
Agent: Cl
Product: CC(C)n1nc(CO)nc1-c1cn2c(n1)-c1cnc(N(C)C)cc1OCC2

Procedure:
[5-(8-Chloro-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-methanol was reacted with dimethylamine-HCl to give 413 (10 mg) as a colorless solid. LCMS: 370.2. 1H NMR (400 MHz, DMSO) δ 9.09 (s, 1H), 7.80 (s, 1H), 6.13 (s, 1H), 5.98-5.85 (m, 1H), 5.18 (t, J=6.0 Hz, 1H), 4.56-4.44 (m, 4H), 4.41 (d, J=6.0 Hz, 2H), 3.05 (s, 6H), 1.47 (d, J=6.6 Hz, 6H)
Reaction SMILES: [CH:1]([C:3]1[CH:20]=[CH:19][C:6]2/[C:7](=[CH:16]/[C:17]#[N:18])/[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1)=[O:2].[CH2:21]([Mg]Br)[CH2:22][CH3:23]>>[OH:2][CH:1]([C:3]1[CH:20]=[CH:19][C:6]2/[C:7](=[CH:16]/[C:17]#[N:18])/[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1)[CH2:21][CH2:22][CH3:23]
Reactant: N#C/C=C1\c2ccccc2CCc2cc(C=O)ccc21
Reactant: CCC[Mg]Br
Product: CCCC(O)c1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Yield: 63.8 %

Procedure:
[step 1] Using (E)-(2-formyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)acetonitrile (245 mg, 0.95 mmol) obtained in Example 83, step 1, and propylmagnesium bromide (2.0 mol/L THF solution; 0.71 mL, 1.42 mmol) instead of methylmagnesium chloride, and in the same manner as in Example 83, step 2, (E)-[2-(1-hydroxybutyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (184 mg, 64%) was obtained.
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6](=[O:15])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C(NC(C)C)(C)C.Cl[Si:29]([CH3:32])([CH3:31])[CH3:30]>C1COCC1.C([N-]C(C)C)(C)C.[Li+].O>[CH3:30][Si:29]([CH3:32])([CH3:31])[C:4]1[C:5]2[S:6](=[O:15])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][C:8]=3[Si:29]([CH3:32])([CH3:31])[CH3:30])[S:13][C:14]=2[CH:1]=[CH:2][CH:3]=1
Reactant: O=S1c2ccccc2Sc2ccccc21
Reactant: C[Si](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cccc2c1S(=O)c1c(cccc1[Si](C)(C)C)S2
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.1 %

Procedure:
To a stirred solution of thianthrene-5-oxide (9.40 g, 40.5 mmole) in THF (200 mL), lithium diisopropylamide (prepared by the addition of n-butyl lithium (1.6 M, 64.0 mL, 101 mmole) to a solution of diisopropylamine (14.2 mL, 101 mmole) at −78° C.) in THF (100 mL) was added in portion at −78° C. under inert atmosphere. The reaction mixture was stirred at this temperature for 4 hrs and became dark green. Chlorotrimethylsilane (12.8 mL, 101 mmole) was then added to the cold solution. The solution was then turned into yellowish brown, warmed back to room temperature, and stirred overnight. Water (100 mL) was then added to the reaction mixture to quench the excess base. The solvent was removed and the crude mixture was redissolved in ether. The aqueous layer was extracted by ether and the organic layers were combined. It was further washed by water, brine, and dried with MgSO4. The solvent was then removed in vacuo. The crude product was further purified by column chromatography (hexane/CH2Cl2 4/1, and then 2/1) to afford light yellow crystals (5.50 g, 36%). mp 210˜211° C. (lit. 213˜214° C.). 1H NMR (300 MHz, CDCl3) δ: 7.69 (dd, 2H, J=7.8, 1.5 Hz), 7.60 (dd, 2H, J=7.8, 1.5 Hz), 7.41 (dd, 2H, J=7.8, 7.8 Hz), 0.57 (s, 18H). 13C NMR (125 MHz, CDCl3) δ: 144.1, 140.9, 134.0, 133.8, 129.9, 129.3, 1.55. HR-MS (ESI): calcd. for C18H24OS2Si2+Na 399.0699 [(M+Na)+]. found 399.0690.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[O:14][C@@H:11]([O:12][CH3:13])[C@@H:10]1[OH:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:36]([O:35][C@@H:10]1[C@@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([CH2:25][O:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[O:14][C@H:11]1[O:12][CH3:13])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CO[C@@H]1O[C@H](COCc2ccc(Cl)cc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CO[C@@H]1O[C@H](COCc2ccc(Cl)cc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
Methyl 3,4-di-O-benzyl-6-O-(4-chlorobenzyl)-β-D-glucopyranoside (0.244 g, 0.481 mmol) was dissolved in 5 mL CH2Cl2. Benzoyl chloride (67 μL, 0.577 mmol) and DMAP (0.118 g, 0.962 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. A 30% EtOAc/Hexanes solution was added (a white precipitate formed) and the solution was filtered through silica, eluted with EtOAc and concentrated. Purification by flash column chromatography on silica gel (25-30% EtOAc/Hexanes) gave 243 mg (84%) of 21 as a white solid. [α]24D: +33.4° (c 1.29, CH2Cl2); IR (thin film) 2865, 1726, 1268, 1089 cm−1; 1H-NMR (CDCl3) δ 8.05 (d, J=7.0 Hz, 2H), 7.59 (t, J=7.3 Hz, 1H), 7.46 (t, J=7.9 Hz, 2H), 7.36-7.29 (m, 8H), 7.26-7.21 (m, 2H), 7.15 (s, 4H), 5.30 (dd, J=7.9, 9.2 Hz, 1H), 4.86 (d, J=10.7 Hz, 1H), 4.77 (d, J=11.0 Hz, 1H), 4.70 (d, J=11.0 Hz, 1H), 4.62 (d, J=12.2 Hz, 1H), 4.59 (d, J=11.0 Hz, 1H), 4.56 (d, J=12.5 Hz, 1H), 4.48 (d, J=7.9 Hz, 1H), 3.86 (dd, J=9.2, 9.2 Hz, 1H), 3.80-3.74 (m, 3H), 3.61-3.58 (m, 1H), 3.50 (s, 3H); 13C-NMR (CDCl3) δ 165.4, 138.0, 137.9, 136.8, 133.5, 133.3, 130.1, 130.0, 129.2, 128.7, 128.6, 128.5, 128.4, 128.2, 128.1, 128.0, 127.8, 102.1, 83.0, 78.1, 75.4, 75.3, 75.2, 73.9, 72.9, 68.9, 57.0; FAB MS m/z (M+Na)+: calcd 625.1969, obsd 625.1973.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[H][H]>[Pd].CO>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([O:8][CH3:9])=[O:7]
Reactant: [H][H]
Reactant: COC(=O)c1ccco1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1CCCO1
Reaction time: 45 h

Procedure:
Methyl furoate is dissolved in 180 ml. of methanol. Thereafter 1 g. of 5 percent palladium-on-charcoal is added. This mixture is then hydrogenated at 1 to 3 atmospheres. After 45 hr. 0.79 moles of hydrogen are consumed. The black mixture is then filtered through Celite using 50 ml. of methanol to wash the reaction flask and filter. Evaporation of the filtrate under reduced pressure at 40°-45° C. bath temperature yields 51 g. of a yellow oil which is thereafter distilled, collecting that fraction boiling at 32°-35° C. Thereby, methyl tetrahydrofuroate (46.7 g.) is prepared.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@@H:16]2[O:20][C@H:19]([CH2:21][S:22][C:23]3[CH:32]=[CH:31]C=C[C:24]=3[C:25](OC)=O)[C@@H:18]([OH:33])[C@H:17]2[OH:34])[CH2:2]1.SC1C=C[N:39]=CC=1.C(C1C=CC=CC=1S)(OC)=O>>[O:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@H:16]2[C@H:17]([OH:34])[C@H:18]([OH:33])[C@@H:19]([CH2:21][S:22][C:23]3[CH:24]=[CH:25][N:39]=[CH:31][CH:32]=3)[O:20]2)[CH2:2]1
Reactant: Sc1ccncc1
Reactant: COC(=O)c1ccccc1SC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCOC4)ncnc32)[C@H](O)[C@@H]1O
Agent: COC(=O)c1ccccc1S
Product: O[C@@H]1[C@H](O)[C@@H](CSc2ccncc2)O[C@H]1n1cnc2c(N[C@H]3CCOC3)ncnc21

Procedure:
Compound 29 was prepared in the manner of compound 23 substituting 4-mercaptopyridine for 2-carbomethoxythiophenol [MS 431.4 (M+1)].
Reaction SMILES: C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:8][C:9](=[O:11])[CH3:10])C=CC=CC=1.[CH2:24]([S:26][CH:27]([CH3:31])[CH2:28][CH:29]=O)[CH3:25].CCCCCC.CCOCC>ClCCl>[CH2:24]([S:26][CH:27]([CH3:31])[CH2:28][CH:29]=[CH:8][C:9](=[O:11])[CH3:10])[CH3:25]
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCSC(C)CC=O
Solvent: CCCCCC
Solvent: CCOCC
Solvent: ClCCl
Product: CCSC(C)CC=CC(C)=O
Temperature: 25 °C

Procedure:
1-Triphenylphosphoranylidene-2-propanone (12.77 g, 40.0 mmol) is added to a solution of 3-(ethylthio)butyraldehyde (5.30 g, 40.0 mmol) in dichloromethane (100 ml) and the mixture is heated under reflux for 24 hours. The reaction mixture is cooled to room temperature, and the solvent evaporated in vacuo to give a beige solid. The crude product is taken up in a 1:1 mixture of hexane:ether (the insoluble material is discarded), and then concentrated under reduced pressure to give an orange oil which is further purified by column chromatography on silica gel to give 6-(ethylthio)hept-3-en-2-one as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:31])[C:24]1[CH:25]=[C:26](O)[CH:27]=[CH:28][CH:29]=1>>[CH3:22][N:23]([CH3:31])[C:24]1[CH:29]=[C:28]([O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CN(C)c1cccc(O)c1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Product: CN(C)c1cccc(OC(=O)COc2ncc(C(=O)Nc3ccc(F)cc3)cn2)c1
Yield: 76 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 3-dimethylaminophenol (21 mg, 0.15 mmol) as the coupling partner. Concentration (no chromatography) yielded 53 mg (76%) of the titled compound as a pink-purple solid. ESI-MS m/z 411 (MH+), 409 (M−H−).
Reaction SMILES: [N:1]([CH:4]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:5][CH2:6][C@@H:7]1[C@@H:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10](=[O:23])[CH2:9][CH2:8]1)=[N+]=[N-].COC1C=C2[C@@]34[C@@H]5C[C@H]6C(CN5CC3)=CCO[C@H]3CC(=O)N([C@H]4[C@@H]63)C2=CC=1OC>[Pd]>[NH2:1][CH:4]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:5][CH2:6][C@@H:7]1[C@@H:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10](=[O:23])[CH2:9][CH2:8]1
Reactant: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)N=[N+]=[N-]
Agent: [Pd]
Agent: COc1cc2c(cc1OC)[C@@]13CCN4CC5=CCO[C@H]6CC(=O)N2[C@H]1[C@H]6[C@H]5C[C@H]43
Product: CCCCCC(N)CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC

Procedure:
A 1.06 g. sample of ethyl 15-azido-9-oxo-prostanoate (Example 110) is hydrogenated using 100 mg. of 5% palladium on carbon in 50 ml. absolute alcohol for 16 hours. The filtration of the catalyst and evaporation of the solvent affords an oil. Silica gel chromatography gives 604 mg. of oil; λmax. 2.95, 6.30 (brucine) and 5.72 μ (carbonyl groups).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]([CH2:9][CH3:10])[CH:7]=[N:6][C:5]=1[CH3:11].[CH3:12][C:13]1[N:18]=[C:17]([SH:19])[N:16]=[C:15]([OH:20])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:9]([N:8]1[C:4]([CH2:3][S:19][C:17]2[N:16]=[C:15]([OH:20])[CH:14]=[C:13]([CH3:12])[N:18]=2)=[C:5]([CH3:11])[N:6]=[CH:7]1)[CH3:10]
Reactant: CCn1cnc(C)c1CCl
Reactant: Cc1cc(O)nc(S)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCn1cnc(C)c1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
A mixture of 5-(chloromethyl)-1-ethyl-4-methyl-1H-imidazole hydrochloride (1.0 g, 5.1 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (500 mg, 3.5 mmol), and potassium carbonate (1.2 g, 9.0 mmol) in acetone (25 mL) was stirred at room temperature overnight. The solid material was removed by filtration. The filtrate was recovered and evaporated. The crude product was purified by flash chromatography (0-6% MeOH/DCM), affording 2-{[(1-ethyl-4-methyl-1H-imidazol-5-yl)methyl]sulfanyl}-6-methyl-pyrimidin-4-ol (428 mg, 46% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.31 (t, 3H, J=6.7 Hz), 2.11 (s, 3H), 2.22 (s, 3H), 3.95 (m, 2H), 4.48 (s, 2H), 6.02 (s, 1H), 7.54 (s, 1H); M+ 266. The product was used without further purification.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][C:15]1[S:19][N:18]=[N:17][C:16]=1[CH3:20].O.ClCCl>ClCCl>[CH3:8][S:9]([O:13][CH2:14][C:15]1[S:19][N:18]=[N:17][C:16]=1[CH3:20])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nnsc1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nnsc1COS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 10.0 ml of triethylamine (72.6 m mol) and 4.1 ml of methanesulfonyl chloride (53 m mol) was added successively to a solution of 6.27 g of 5-hydroxymethyl-4-methyl-1,2,3-thiadiazole (48.16 m mol) in dichloromethane (50 ml) at −30° C. After stirring for 30 minutes, the mixture was poured into water-dichloromethane while the pH was kept between 8.5-9.0. The aqueous layer was separated, the organic layer was washed with saturated sodium hydrocarbonate, washed with dil-hydrochloric acid brine, dried over magnesium sulfate. After filtration, the filtrate was concentrated in vacuo to afford 5-methanesulfonyloxymethyl-4-methyl-1,2,3-thiadiazol (9.8 g).
Reaction SMILES: C([O:4][CH:5]([CH3:7])[CH3:6])(C)C.[Cl-].[Cl-].[Cl-].[Al+3].[N+:12]([C:15]1[C:21]([OH:22])=C[CH:19]=[CH:18][C:16]=1[OH:17])([O-:14])=[O:13].C(OC(=O)C)(=O)C.Cl>[N+](C1C=CC=CC=1)([O-])=O.C(OCC)C>[OH:22][C:21]1[C:15]([N+:12]([O-:14])=[O:13])=[C:16]([OH:17])[CH:18]=[CH:19][C:7]=1[C:5](=[O:4])[CH3:6]
Reactant: O=[N+]([O-])c1c(O)cccc1O
Reactant: CC(C)OC(C)C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1ccc(O)c([N+](=O)[O-])c1O
Temperature: 5 °C

Procedure:
The extraction solvent can be changed from diethyl ether to di-isopropyl ether. For example: Nitrobenzene (87.5 mL) was added to aluminium trichloride (46.33 g). 2-nitroresorcinol (25 g), in nitrobenzene (112.5 mL) was added. The mixture was cooled to 5° C. and acetic acid anhydride (15.68 mL) added maintaining the internal temperature below 20° C. The mixture was heated to 100° C. for 2 h then cooled to 5° C. Cold (3° C.) 3M aqueous hydrogen chloride (200 mL) was charged. The mixture was heated to 20° C. then di-isopropylether (200 mL) charged. The aqueous phase was removed and the organic phase extracted with 2 M aqueous sodium hydroxide (200 mL). The aqueous phase was washed with di-isopropylether (200 mL). The aqueous phase was removed and heated to 50° C. 3 M aqueous hydrogen chloride (467.5 mL) was charged and the mixture cooled to 20° C. The suspension was filtered, washed with water (50 mL) and dried under vacuum to yield the title compound (31.14 g).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Cl:7][C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1>>[Cl:7][C:8]1[N:13]=[C:12]([C:4]2[S:3][C:2]([Cl:1])=[CH:6][CH:5]=2)[CH:11]=[CH:10][N:9]=1
Reactant: Clc1ncccn1
Reactant: Clc1cccs1
Product: Clc1nccc(-c2ccc(Cl)s2)n1

Procedure:
The title compound was prepared from 2-chlorothiophene and 2-chloropyrimidine in a manner analogous to Example 249, Step 1. MS (M+H)+ 231.
Reaction SMILES: C[Mg]I.[CH2:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([CH3:15])=[CH:11]2)[CH3:5].[Cl:16][C:17]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20].[NH4+].[Cl-]>CCOCC>[CH2:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([CH3:15])=[C:11]2[C:19]([C:18]1[CH:22]=[CH:23][CH:24]=[C:25]([Cl:26])[C:17]=1[Cl:16])=[O:20])[CH3:5]
Reactant: CCc1cccc2cc(C)[nH]c12
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Agent: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCc1cccc2c(C(=O)c3cccc(Cl)c3Cl)c(C)[nH]c12
Reaction time: 0.5 h
Yield: 38.9 %

Procedure:
14.2 ml of 3M of MeMgI in Et2O are placed under argon and 6.78 g of 7-ethyl-2-methyl-1H-indole in 40 ml of Et2O are added dropwise. After 30 minutes, 17.84 g of 2,3-dichlorobenzoyl chloride in 60 ml of Et2O are added dropwise and the reaction medium is left stirring for 2 hours. The reaction medium is run quickly onto a saturated NH4Cl solution. The extraction is carried out with Et2O (twice) and then the organic phase is washed with a 10% NaOH solution, water and then a saturated NaCl solution. 5.5 g of the expected compound are obtained.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([C:34]([O:36]C)=O)=[N:14][C:15]=2[NH:19][CH2:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH2:38]([NH2:41])[CH2:39][NH2:40]>ClCCl>[NH2:40][CH2:39][CH2:38][NH:41][C:34]([C:13]1[N:12]=[C:11]2[C:16]([N:17]=[CH:18][N:10]2[C@H:3]2[C@H:2]([OH:1])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4]2)=[C:15]([NH:19][CH2:20][CH:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:14]=1)=[O:36]
Reactant: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: NCCN
Solvent: ClCCl
Product: NCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 105 °C
Yield: 78.2 %

Procedure:
A mixture of methyl 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate (Preparation 16) (0.52 g, 1.03 mmol) and 1,2-ethylenediamine (0.6 g, 10 mmol) was heated at 105° C. for 3 hours. The mixture was dissolved in a little dichloromethane and purified by column chromatography on silica gel eluting with dichloromethane:methanol:concentrated aqueous ammonia (85:15:1.5, by volume). After evaporation of appropriate fractions the residue was triturated with diethyl ether, filtered and dried to yield the target compound as a white solid, (0.43 g, 78%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:9]([CH:14]([CH3:16])[CH3:15])[CH:10]=[CH:11][CH:12]=[O:13])=[CH:4][CH:3]=1.[C:24]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])[CH2:25][C:26]([CH3:28])=[O:27].[H-].[Na+].C([Li])CCC>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[C:9]([CH:14]([CH3:16])[CH3:15])[CH:10]=[CH:11][CH:12]([OH:13])[CH2:28][C:26](=[O:27])[CH2:25][C:24]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:6][CH:7]=1
Reactant: CC(C)C(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C(C=CC(O)CC(=O)CC(=O)OC(C)(C)C)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
To a solution of 5,5-bis(4-fluorophenyl)-4-(1-methyl-ethyl)-2,4-pentadienal (0.5 g, 1.6 mmol) in 20 mL tetrahydrafuran at -70° C., was added the dianion of t-butyl acetoacetate (2.1 mL of 1M solution in THF, 2.1 mmol) which was prepared by adding t-butyl acetoacetate (4.0 g, 25 mmol) in 4 mL tetrahydrofuran to a suspension of sodium hydride (1.0 g of 50% in oil, 25 mmol) in 6 mL tetrahydrofuran at -10° C., butyl lithium (11.4 mL of 2.2M solution) 25 mL was added and stirred for 0.5 hrs. After stirring for 2.5 hrs. the reaction was quenched with 2N hydrochloric acid. The mixture was extracted with diethyl ether. The extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 1% methanol in methylene chloride to give 0.5 g of the title compound as a clear oil. MS(CI): m/e =370 for M3 ;
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:2][C:3]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=O.N1CCCCC1.[NH2:20][C:21]1[C:22]([CH:27]=O)=[N:23][CH:24]=[CH:25][N:26]=1>C1(C)C=CC=CC=1>[N:23]1[CH:24]=[CH:25][N:26]=[C:21]2[N:20]=[C:3]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:2]([C:1]([O:11][CH2:12][CH3:13])=[O:10])=[CH:27][C:22]=12
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: Nc1nccnc1C=O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2nccnc2nc1C(=O)OCC
Yield: 27.9 %

Procedure:
Diethyl oxalacetate, (4.7 g, 0.025 mol) and piperidine (1.66 g, 1.93 mL) are added to 3-aminopyrazine-2-carboxaldehyde (2.4 g, 0.0195 mol) dissolved in 250 mL of toluene. After the reaction mixture is refluxed for two hours, the toluene is removed under reduced pressure to give a dark red oily residue. The product is purified by column chromatography on silica gel (hexane:EtOAc, 4:1). affording 3.1 g (58% yield), of the crude desired product. Crystallization from ether-hexane (4:1) gives analytically pure compound 1.5 g (28%) having a melting point 83°-85° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([N:20]=[C:21]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][C:33]=2[NH2:34])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>O1CCCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][CH:21]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][C:33]=2[NH2:34])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ccncc1C(=NC1CCN(Cc2ccccc2)CC1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccncc1C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To a suspension of 0.68 g (17.9 mmol) of lithium aluminum hydride in 100 mL of tetrahydrofuran was added dropwise a solution of 6.65 g (17.9 mmol) of 3-[α-{(1-benzylpiperidin-4-yl)imino}benzyl]-4-aminopyridine in tetrahydrofuran 30 ml under reflux, and the mixture was heated under reflux for 1 hour. After being cooled, the mixture was added sequentially with 0.7 mL of water, 0.7 mL of an aqueous 15% sodium hydroxide solution and 2 mL of water, under ice-cooling. After being stirred for 1 hour at ambient temperature, the reaction mixture was filtered through cerite. The filtrate was concentrated and the residue was purified by means of column chromatography (silica gel, 1:9 methanol:chloroform) to give 4.2 g (11.3 mmol) of the title compound.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH:13]2[CH2:15][CH2:16][CH:10]1[CH2:11][N:12]2C)(=O)C1C=CC=CC=1>Cl>[CH3:1][N:9]1[CH2:14][CH:13]2[CH2:15][CH2:16][CH:10]1[CH2:11][NH:12]2
Reactant: CN1CC2CCC1CN2C(=O)c1ccccc1
Agent: Cl
Product: CN1CC2CCC1CN2

Procedure:
A solution of 2-benzoyl-5-methyl-2,5-diazabicyclo[2.2.2]octane (17.2 g, 0.074 mole) in concentrated hydrochloric acid (172 ml) was refluxed 48 hours. The solution was evaporated to dryness in vacuo and the residue triturated with diethyl ether. The supernatant, after centrifugation, was decanted, and the procedure was repeated using absolute ethanol. The hygroscopic residue of 2-methyl-2,5-diazabicyclo[2.2.2]octane. 2HCl (12.1 g, 81.5%) was dried in vacuo. It slowly decomposed above 300° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:15][CH2:16][OH:17])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1>[S:5]([N:4]([CH2:15][CH2:16][O:17][S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH2:3][CH2:2][O:1][S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)N(CCO)CCO)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCN(CCOS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
Procedure 3 is illustrated with the preparation of (-)-(RR)-8a' and (+)-(RR)-8b', with (-)-(R)-6f' as a byproduct. In dry pyridine at 0°, N,N-bis-(2-hydroxyethyl)-p-toluenesulfonamide (m.p. 96°-99°) was tosylated with tosyl chloride by the standard method to give N,O,O'-tritosyldiethanolamine, m.p. 85°-87°. [Can. J. Chem. 45, 1555 (1967) gives 78°-79°].