Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[N:12]=[CH:11][C:10]([C:13]([Cl:15])=[O:14])=[CH:9][CH:8]=2)[NH:5][CH:4]=[C:3]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.[NH3:22]>O1CCOCC1>[ClH:15].[O:1]=[C:2]1[N:6]([C:7]2[N:12]=[CH:11][C:10]([C:13]([NH2:22])=[O:14])=[CH:9][CH:8]=2)[NH:5][CH:4]=[C:3]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Cl)c1ccc(-n2[nH]cc(-c3cccnc3)c2=O)nc1
Reactant: N
Solvent: C1COCCO1
Product: Cl
Product: NC(=O)c1ccc(-n2[nH]cc(-c3cccnc3)c2=O)nc1

Procedure:
337 mg (1.0 mmol) of 6-(5-oxo-4-pyridin-3-yl-2,5-dihydro-1H-pyrazol-1-yl)pyridine-3-carbonyl chloride are suspended in 5 ml of dioxane. Slowly and with stirring, 4 ml of a 5 N solution of ammonia in dioxane are then added, and the mixture is stirred at RT for 16 h. The mixture is then concentrated, and the residue is taken up in DMSO and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with 0.1% TFA added to the water). The product-containing fractions are combined and concentrated on a rotary evaporator. The residue is dissolved in 1 N hydrochloric acid, and the solution is then lyophilized.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([C:16](=O)/[CH:17]=[CH:18]/[N:19](C)C)=[N:12][CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.Cl.[NH:24]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])N.Cl>CCO>[OH:8][CH2:9][C:10]1[C:11]([C:16]2[N:24]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:19]=[CH:18][CH:17]=2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)CNN
Reactant: CN(C)/C=C/C(=O)c1ncccc1CO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cn1nccc1-c1ncccc1CO
Temperature: 80 °C
Yield: 74.4 %

Procedure:
To (E)-1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one (crude, 350 mg, 1.09 mmol, 1 eq.) in EtOH (10 mL) was added ethyl 2-hydrazinylacetate hydrochloride (338 mg, 2.18 mmol, 2.0 eq.). The mixture was heated at 80° C. for 2 h, cooled to rt, added HCl (6 N, 0.5 mL), and stirred O/N. The mixture was concentrated, and diluted with a mixture of EtOAc (50 mL) and NaHCO3(sat) (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using EtOAc as eluent to give ethyl 2-(5-(3-(hydroxymethyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetate (212 mg, 74%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.61 (dd, J=4.7, 1.6 Hz, 1H), 7.97 (dd, J=7.8, 1.4 Hz, 1H), 7.64 (d, J=1.9 Hz, 1H), 7.36 (dd, J=7.8, 4.8 Hz, 1H), 6.56 (d, J=1.9 Hz, 1H), 5.21 (s, 2H), 4.79 (d, J=5.8 Hz, 2H), 4.09 (q, J=7.1 Hz, 2H), 2.54 (t, J=6.0 Hz, 1H), 1.18 (t, J=7.1 Hz, 31-1). LRMS m/z 262.1
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([NH:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH:5]=1.[Br:15][CH2:16][CH2:17]Br.C(OCC)(=O)C>CS(C)=O>[Br:15][CH2:16][CH2:17][N:6]([N:4]1[CH:3]=[N:2][N:1]=[CH:5]1)[C:7]1[CH:8]=[CH:9][C:10]([C:11]#[N:12])=[CH:13][CH:14]=1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: BrCCBr
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(CCBr)n2cnnc2)cc1
Reaction time: 8 h

Procedure:
Sodium-hydride (60%, 240 mg, 6.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMSO (25 mL) at r.t. The mixture was stirred for 1 hour at this temperature and 1,2-dibromoethane (5 mL) was added. The reaction mixture was stirred overnight and ethyl acetate (100 mL) was added. The mixture was transferred into a separation funnel and extracted with water (twice 100 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure (water bath temperature <30° C.). The resulting orange oil was mixed with diethyl ether (100 mL) and filtered through a layer of silica (ca 5 cm). The silica was washed with more diethyl ether (ca. 100 mL) to remove the excess of 1,2-dibromoethane; the crude product was washed from the silica with acetone (120 mL). The acetone solution was concentrated under reduced pressure and the residue was purified by column-chromatography (eluent: ethyl acetate) to give the title compound as a white solid. Yield: 628 mg (43%). 1H-NMR (400 MHz, d6-DMSO) δ=3.61, (t, J=6.2 Hz, 2H), 4.30 (t, J=6.4 Hz, 2H), 6.64 (d, J=9.0 Hz), 7.74 (d, 9.0 Hz, 2H), 8.97 (s, 2H). LRMS (FAB+): 292.0 (100, [M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][C:11](=[O:13])[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:27]I>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH3:27])[CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: O=C1NC(Cc2ccc(C(F)(F)F)cc2)C(c2ccc(F)cc2)O1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)OC(c2ccc(F)cc2)C1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.7 %

Procedure:
To a solution of (4RS,5SR)-5-(4-fluorophenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (5 g, 14.7 mmol) in N,N-dimethylformamide (30 ml) was added 60% sodium hydride (710 mg, 17.7 mmol) and the mixture was stirred at room temperature for 15 min. To the reaction solution was added methyl iodide (5 ml, 80 mmol) and the mixture was stirred for 1 hr. The reaction solution was diluted with water (300 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give (4RS,5SR)-5-(4-fluorophenyl)-3-methyl-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (4.76 g, 91%).
Reaction SMILES: [OH:1][C:2]1[C:7](C(C)(C)C)=[CH:6][C:5]([O:12][CH3:13])=[CH:4][C:3]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16](C(C)(C)C)[C:15]=1[OH:26].[Al+3].[Cl-].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[OH:26][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[C:3]1[CH:4]=[C:5]([O:12][CH3:13])[CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: COc1cc(-c2cc(OC)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: COc1ccc(O)c(-c2cc(OC)ccc2O)c1
Temperature: 40 °C

Procedure:
2,2'-Dihydroxyl-5,5'-dimethoxy-1,1'-biphenyl was prepared by the dealkylation of 2,2'-dihydroxy-3,3'-di-t-butyl-5,5'-dimethoxy-1,1'-biphenyl using a procedure described in the literature (Tashiro et al., Organic Preparations and Procedures Int., 8, 263, 1976). Ten grams of AlCl3 and 10 g of 2,2'-dihydroxy-3,3'-di-t-butyl-5,5'-dimethoxy-1,1'-biphenyl were mixed in 125 ml of benzene and heated at 40° C. for 3 hours. The mixture was cooled in ice, and 125 ml of 10% aqueous HCl was added slowly. The organic layer was separated and washed with three 125-ml portions of 10% NaOH. The basic solution was neutralized with concentrated HCl and extracted three times with 100 ml portions of ether. The ether layer was dried over Na2SO4. After filtering and removing the solvent by vacuum evaporation, the brown oil was washed with hexane; the product crystallized from CH2Cl2 /hexane, yielding 2.202 g of 2,2'-dihydroxy-5,5'-dimethyoxy-1,1'-biphenyl, which was obtained as a white solid. 1H (300 MHz, CD2Cl2): 6.9-6.8 (m, 6H), 5.71 (s, 2H), 3.78 (s, 6H).
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)[C:8](=[O:11])[CH2:9][Cl:10])([CH3:3])[CH3:2].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:24][CH:23]=1>>[CH:1]([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([N:33]2[CH2:32][CH2:31][N:30]([CH2:29][CH2:28][C:25]3[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=3)[CH2:35][CH2:34]2)=[O:17])=[CH:14][CH:13]=1)[C:8](=[O:11])[CH2:9][Cl:10])([CH3:3])[CH3:2]
Reactant: Brc1ccc(CCN2CCNCC2)cc1
Reactant: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)Cl)cc1
Product: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)N2CCN(CCc3ccc(Br)cc3)CC2)cc1

Procedure:
Analogously to Example 55, 1.5 g of 4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl chloride are reacted with 1.07 g of [2-(4-bromophenyl)ethyl]-piperazine, yielding 1-{4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl}-4-[2-(4-bromophenyl)ethyl]piperazine having a melting point of 92°-93°.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][C:13](=[O:15])[CH3:14])[C:8](O)=[O:9])[N:6]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:17]>C(Cl)Cl>[ClH:17].[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][C:13](=[O:15])[CH3:14])[C:8]([Cl:17])=[O:9])[N:6]=1
Reactant: CC(=O)ON=C(C(=O)O)c1csc(N)n1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)ON=C(C(=O)Cl)c1csc(N)n1
Product: Cl
Temperature: -22.5 °C
Reaction time: 15 h
Yield: 157.4 %

Procedure:
2-(2-aminothiazole-4-yl)-2-acetoxyiminoacetic acid anhydrous crystal (syn-isomer) (12.5 g) was suspended and stirred in methylene chloride (125 ml), and cooled to −20 to −25° C. Phosphorus pentachloride (13.6 g) was added thereto, and reaction was performed for 15 hours at the same temperature. The precipitated crystal was filtered, washed with methylene chloride, and dried under reduced pressure to obtain 2-(2-aminothiazole-4-yl)-2-acetoxyiminoacetyl chloride hydrochloride (syn-isomer) (14.6 g).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17]1.C([BH3-])#N.[Na+]>CO>[CH:16]1([NH:21][CH2:12][C:11]2[CH:14]=[CH:15][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: NC1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(Oc2ccc(CNC3CCCC3)cc2)cc1
Reaction time: 48 h
Yield: 82.3 %

Procedure:
4-Phenoxybenzaldehyde (5.0 g, 25.1 mmol) and cyclopentylamine (2.5 g, 25 mmol) were dissolved in methanol (85 mL) under nitrogen at room temperature. Sodium cyanoborohydride (1.57 g, 25.0 mmol) was added, and stirring was continued for 48 hours. The solvent was evaporated, and the residue was suspended in ether, washed with brine, and dried over Na2SO4. The ether was evaporated, and the crude product was chromatographed on silica gel eluting with 3% methanol in methylene chloride to provide 5.5 g (83%) of the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 1.31-1.45 (m, 2H), 1.49-1.65 (m, 2H), 1.65-1.80 (m, 3H), 1.81-1.95 (m, 2H), 3.15 (p, J=7.5 Hz, 1H), 3.75 (s, 2H), 6.94-7.04 (m, 4H), 7.05-7.14 (m, 1H), 7.25-7.40 (m, 4H). MS (DCl/NH3) m/e 268 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][Cl:12])[NH:8][C:5]2=[N:6][CH:7]=1.[C:13]1([P:19]([C:26]2C=C[CH:29]=[CH:28][CH:27]=2)[C:20]2C=C[CH:23]=[CH:22][CH:21]=2)C=C[CH:16]=[CH:15][CH:14]=1>CN(C)C=O.C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl-:12].[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][P+:19]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:13][CH2:14][CH2:15][CH3:16])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: ClCc1nc2cc(Br)cnc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCC[P+](CCCC)(CCCC)Cc1nc2cc(Br)cnc2[nH]1
Product: [Cl-]
Temperature: 90 °C

Procedure:
4.0 g of 6-bromo-2-chloromethyl-3H-imidazo[4,5-b]pyridine (compound B4) are suspended in 16 ml of N,N-dimethylformamide and 54 ml of acetonitrile. 4.9 ml of triphenylphosphine and 0.599 g of tetrabutylammonium iodide are added sequentially at 40° C. and the mixture is heated to 90° C. for 20 h. The mixture is concentrated to dryness to give the 8.94 g of the crude title compound as an oil, which is used as obtained. MS: 412.3, 414.2 (M+). TLC: Rf=0.40-0.55 (dichloromethane/methanol 10:1).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1I.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.O>O1CCOCC1>[Cl:7][C:8]1[C:9]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([F:16])[CH:22]=2)=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1
Reactant: Oc1ccc(Cl)c(I)c1
Reactant: OB(O)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Oc1ccc(Cl)c(-c2cccc(F)c2)c1
Temperature: 70 °C
Reaction time: 5 h
Yield: 93.3 %

Procedure:
Caesium carbonate (1.15 g, 3.53 mmol) was added to a solution of 4-chloro-3-iodophenol (300 mg, 2.14 mmol) and 3-fluorophenylboronic acid (330 mg, 1.30 mmol) in dioxane:water (22.5 mL:4.5 mL). The reaction mixture was degassed and tetrakistriphenylphosphine palladium (0) (69 mg, 0.06 mmol) was added. The reaction mixture was stirred at 70° C. for 5 hours. The cooled reaction mixture was concentrated in vacuo and the aqueous residue was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified on the biotage eluting with heptane:ethyl acetate (from 98:2 to 80:20) to give the title compound (270 mg, 100%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:22])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29].C(N(CC)CC)C>C1COCC1>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:22][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)=[O:29]
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCOCC1
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)Nc2ccc(OCCN3CCOCC3)c(-c3ccnn3C)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.4 %

Procedure:
A mixture of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (120 mg, 0.40 mmole), 3-methoxy-benzoyl chloride (81 mg, 0.48 mmole), and triethylamine (0.1 mL, 0.79 mmole) in 5 mL THF was stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give the title compound as a white solid (TFA salt, 88 mg, 51%). 1H NMR (Acetone-d6, 400 MHz) 2.99-3.21 (m, 2H), 3.22-3.45 (m, 2H), 3.66 (t, J=4.80 Hz, 2H), 3.75 (s, 3H), 3.85 (s, 3H), 3.79-3.89 (m, 4H), 4.58 (t, J=4.80 Hz, 2H), 6.29 (d, J=2.02 Hz 1H), 7.13 (dd, J=8.34, 2.53 Hz, 1H), 7.22 (d, J=8.84 Hz, 1H), 7.42 (t, J=7.83 Hz, 1H), 7.47 (d, J=1.77 Hz, 1H), 7.52 (t, J=1.77 Hz, 1H), 7.56 (d, J=7.07 Hz, 1H), 7.80-7.83 (m, 1H), 7.91-7.96 (m, 1H), 9.54 (s, NH). Exact mass calculated for C24H28N4O4 436.2. found 437.5 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3(C#N)[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][S:20][C:19]4[CH:28]=[CH:29][CH:30]=[CH:31][C:18]3=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:34])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][S:20][C:19]4[CH:28]=[CH:29][CH:30]=[CH:31][C:18]3=4)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: N#CC1(CCCN2CCC(O)(c3ccc(Cl)cc3)CC2)c2ccccc2CSc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OC1(c2ccc(Cl)cc2)CCN(CCCC2c3ccccc3CSc3ccccc32)CC1
Yield: 68.6 %

Procedure:
To a solution of 4-(4-chlorophenyl)-1-[3-(11-cyano-6,11-dihydrodibenzo[b,e]thiepin-11-yl)propyl]piperidin-4-ol (430 mg) in THF (10 ml) was added 1M lithium aluminum hydride THF solution (1.5 ml) and the mixture was heated to reflux for 3 hours. The reaction mixture was cooled with ice, water (0.06 ml), then 15% aqueous sodium hydroxide (0.06 ml), then water (0.18 ml) were added carefully. The granular salt was filtered off and the filtrate was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:1) to give the titled compound (280 mg).
Reaction SMILES: [H-].[Na+].[C:3]1([C@H:9]([OH:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=3)[CH:26]=[CH:25][C:24]=2[OH:35])=[N:15][N:14]=1>O1CCCC1>[CH3:34][O:33][C:30]1[CH:31]=[C:32]2[C:27]([CH:26]=[CH:25][C:24]([OH:35])=[C:23]2[C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]([O:11][C@@H:9]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH3:10])=[N:14][N:15]=2)=[CH:28][CH:29]=1
Reactant: C[C@@H](O)c1ccccc1
Reactant: COc1ccc2ccc(O)c(-c3nnc(Cl)c4ccccc34)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2ccc(O)c(-c3nnc(O[C@H](C)c4ccccc4)c4ccccc34)c2c1
Reaction time: 0.25 h
Yield: 86.7 %

Procedure:
To a suspension of sodium hydride (0.80 g, 33 mmol) in tetrahydrofuran (80 ml) was added a solution of (R)-phenylethanol (2.0 g, 17 mmol) in tetrahydrofuran (3 ml) cautiously over 10 min at 23° C. The mixture was stirred for 15 min, then 1-(4-chlorophthalazin-1-yl)-7-methoxy-naphthalen-2-ol (5.1 g, 15 mmol) was added portionwise. The resulting red suspension was stirred for 20 hrs at 23° C., then the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and poured into brine. The organic layer was separated and the aqueous layer was extracted two times with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (hexane/EtOAc 4:1 to 1:1) to give 5.5 g (13 mmol) of the title compound as a 1:1 mixture of diastereomers, as a white foam.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[C:4]([NH2:16])[CH:3]=1.[OH-:17].[Na+]>C1CC=CCCC=C1.C1CC=CCCC=C1.[Ni].O>[NH2:16][C:4]1[CH:3]=[CH:2][C:15]([C:15]2[CH:2]=[CH:3][C:4]([NH2:16])=[C:5]([C:6](=[O:17])[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=2)=[CH:14][C:5]=1[C:6](=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1cc(Br)ccc1C(=O)c1ccccc1
Reactant: [OH-]
Agent: [Ni]
Agent: C1=C\CC/C=C\CC/1
Agent: [Na+]
Solvent: O
Solvent: C1=CCCC=CCC1
Product: Nc1ccc(-c2ccc(N)c(C(=O)c3ccccc3)c2)cc1C(=O)c1ccccc1
Reaction time: 8 h

Procedure:
4-Bromo-2-aminobenzophenone (0.55 g, 2.0 mmol) was dissolved in dry and deoxygenated dimethylformamide (10 ml) in an inert atmosphere box. To this was added in portions bis(1,5-cyclooctadiene)nickel (O) (0.55 g, 2.0 mmol). The reaction was moved from the inert atmosphere box to a vacuum-argon manifold using standard Schlenk-wave techniques. The reaction was heated at 5°-55° C. for 4 hrs. and left at room temperature overnight. The mixture was poured into 200 ml of water which was made slightly basic with sodium hydroxide. The water was extracted several times with ethyl acetate which after drying with sodium sulfate and evaporation gave a dark brown liquid (0.48 g). Recrystallization from hexane yielded 100 mg of yellow brown solid mp 180°-185° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:22][CH:19]2[CH2:21][CH2:20]2)[N:3]=1
Reactant: NC1CC1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(NC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Temperature: 25 °C
Yield: 80 %

Procedure:
(1S,4R)-4-(2-Amino-6-chloro-9-H-purin-9-yl)-2-cyclopentene-1-methanol (U.S. Pat. No. 5,206,435) or the hydrochloride salt thereof (Example 8) was refluxed in ethanol with 10 molar equivalents of cyclopropylamine for 2 hours. The resulting solution was cooled to ambient temperature and 1 N sodium hydroxide (1 or 2 molar equivalents, depending on whether the starting material was VIIa or the hydrochloride salt of VIIa) was added. The volatiles were evaporated in vacuo. (1S,4R)-4-[2-Amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol (IXa) was washed from a silica gel pad eluted with 5% methanol-chloroform or 10% methanol-ethyl acetate and isolated as a white solid foam (80%); spectra identical to those of the product of Example 9.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([CH3:11])([CH3:10])[C:6](=[O:9])[CH2:7]Br)[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]([CH3:11])([CH3:10])[C:6](=[O:9])[CH2:7][O:20][C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)[CH3:2]
Reactant: Oc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)C(=O)COc1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
316 g (2 mol) of 4-bromo-2,2-dimethyl-3-keto-butanoic acid ethyl ester were added dropwise, at 30° C., to 246 g (2 mol) of 4-chlorophenol and 210 g of potassium carbonate in 1,000 ml of dimethylformamide. The mixture was stirred for 20 hours at room temperature and 2 hours at 40° C. The reaction mixture was then introduced into 2,000 ml of water. The aqueous phase was extracted by shaking twice with 500 ml of methylene chloride at a time and the organic phase was extracted by shaking twice with 250 ml of water each time. The combined organic phases were dried, concentrated and distilled. 324 g (56% of theory) of 4-(4-chlorophenoxy)-2,2-dimethyl-3-keto-butanoic acid ethyl ester of melting point 125-135° C./0.1 mm Hg were obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[CH:13]1([CH:18]([NH:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2C(OC)=O)[CH3:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.Cl.[O:32]1CCC[CH2:33]1>COCCOC>[CH:13]1([CH:18]([NH:20][C:21]2[CH:22]=[CH:27][C:28]([C:33](=[O:32])[CH2:3][S:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)(=[O:6])=[O:5])=[CH:29][CH:30]=2)[CH3:19])[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CS(=O)(=O)c1ccccc1
Reactant: C1CCOC1
Reactant: COC(=O)c1ccccc1NC(C)C1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(Nc1ccc(C(=O)CS(=O)(=O)c2ccccc2)cc1)C1CCCC1

Procedure:
A solution of 864 mg. of sodium hydride and 5.3 g. of methylphenylsulfone in 20 ml. of 1,2-dimethoxyethane is stirred at 6° C. for one hour under an atmosphere of argon. To this solution is added a solution of 5.0 g. of methyl (1-cyclopentylethylamino)benzoate in 50 ml. of tetrahydrofuran and the reaction mixture is stirred at 60° C. for 1.5 hours. The mixture is cooled, poured onto ice, acidified with dilute hydrochloric acid and pH 3 and then extracted with chloroform. The organic layer is separated, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated to dryness. The crude solid is chromatographed on silica gel, eluting with methylene chloride to yield 4'-(1cyclopentylethylamino)-2-(phenylsulfonyl)acetophenone.
Reaction SMILES: [C:1]([OH:18])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cu:19]>O.[Cl-].C([N+](CC)(CC)CC)C.CO>[C:1]([O-:18])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cu+2:19].[C:1]([O-:18])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: [Cu]
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCCCCC(=O)[O-]
Product: [Cu+2]
Yield: 15.1 %

Procedure:
To a reaction flask was charged 20.77 g (0.08 mole) of palmitic acid, 60 g methanol and 0.50 g of tetraethylammonium chloride hydrate. Copper foil was used as the anode and a graphite rod as the cathode. A blue solid precipitated during the reaction which had to be removed from the anode surface. After passing 9,690 coulombs of electricity, 3.77 g (0.05 g mole) of copper was consumed. The solid was then filtered and dried to give a blue solid material of copper palmitate containing 15.1% copper.