Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[CH:21]1[CH:22]=[CH:23][C:24]2[S:29][CH:28]=[CH:27][C:25]=2[CH:26]=1.[O:30]=[C:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH:39]2[O:44][C:43]3[CH:45]=[CH:46][CH:47]=[CH:48][C:42]=3[O:41][CH2:40]2)[CH2:33][CH2:32]1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[OH:30][C:31]1([C:28]2[S:29][C:24]3[CH:23]=[CH:22][CH:21]=[CH:26][C:25]=3[CH:27]=2)[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH:39]2[O:44][C:43]3[CH:45]=[CH:46][CH:47]=[CH:48][C:42]=3[O:41][CH2:40]2)[CH2:33][CH2:32]1
Reactant: O=C1CCN(CCC2COc3ccccc3O2)CC1
Reactant: c1ccc2sccc2c1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: OC1(c2cc3ccccc3s2)CCN(CCC2COc3ccccc3O2)CC1
Reaction time: 1 h

Procedure:
To lithium diisopropylamide in 50 ml of tetrahydrofuran, prepared from 2.25 ml of diisopropylamine and 10 ml of 1.6 N n-butyl lithium in hexane at -70° under nitrogen, is added 2.0 g of thianapthene in 20 ml of tetrahydrofuran while stirring. After 1 hour, the solution of 2.65 g of 2-[2-(4-oxopiperidino)-ethyl]-1,4-benzodioxan in 20 ml of tetrahydrofuran is added and, after standing overnight, the mixture is decomposed with 9 ml of saturated aqueous ammonium chloride. The organic phase is separated, dried, evaporated, the crystalline residue washed with water and recrystallized from ethanol-acetone, to yield the 2-[2-(4-hydroxy-4-(2-benzothienyl)-piperidino)-ethyl]-1,4-benzodioxan melting at 175°-178°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[CH:17]([NH:21][C:22]1[CH:23]=[N:24][C:25]([N:28]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[N:29]2)=[CH:26][CH:27]=1)[CH2:18][CH2:19][CH3:20])[C:5]([NH:7][CH2:8][CH2:9][C:10]([O:12]C)=[O:11])=[O:6].C(=O)=O.C(O)C>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[CH:17]([NH:21][C:22]1[CH:23]=[N:24][C:25]([N:28]2[CH:32]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:30]=[N:29]2)=[CH:26][CH:27]=1)[CH2:18][CH2:19][CH3:20])[C:5]([NH:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:6]
Reactant: CCCC(Nc1ccc(-n2cc(C(F)(F)F)cn2)nc1)c1ccc(C(=O)NCCC(=O)OC)cc1C
Agent: O=C=O
Solvent: CCO
Product: CCCC(Nc1ccc(-n2cc(C(F)(F)F)cn2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1C

Procedure:
The title compound was prepared by a method analogous to that described for Example 111, using Isomer 2 of methyl 3-(3-methyl-4-(1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-ylamino)butyl)benzamido)propanoate. 1H NMR (400 MHz, CD3OD, δ): 8.65 (s, 1H), 7.86 (s, 1H), 7.63 (d, J=2.8 Hz, 2H), 7.53-7.58 (m, 2H), 7.40 (d, J=8.0 Hz, 1H), 6.92 (dd, J=8.8, 2.8 Hz, 1H), 4.60-4.64 (m, 1H), 3.58 (t, J=6.4 Hz, 2H), 2.59 (t, J=7.0 Hz, 2H), 2.52 (s, 3H), 1.70-1.79 (m, 2H), 1.61-1.67 (m, 1H), 1.46-1.51 (m, 1H), 0.99 (t, J=7.2 Hz, 3H). MS (M+1) 490.1. Chiral SFC: Chiralpak AD-H, 4.6×250 mm, 5 μm. Modifier: 0.05% DEA. Mobile Phase: 75/25 CO2/ethanol. Flow rate: 35 mL/min. Retention time: 5.38 minutes, 99.7% ee (Isomer 2).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][CH2:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH2:24][O:25][Si](C(C)(C)C)(C)C)=[O:6])[CH:2]=[CH2:3].Cl>CO>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][CH2:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH2:24][OH:25])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1ccnc1CO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CO
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1ccnc1CO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.4 %

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-2-[2-{2-(t-butyldimethylsilyloxymethyl)imidazol-1-yl}ethyl]-4-methylsulfonyloxypyrrolidine (34.5 g) in methanol (170 ml) was added concentrated hydrochloric acid (17 ml) dropwise under cooling in an ice bath. After stirring for 10 minutes, the mixture was warmed to room temperature and stirred for another 3 hours. The mixture was quenched by the addition of a solution of sodium methoxide in methanol (28% W/W, 39.4 g), then ethyl acetate (340 ml) was added. The precipitate was filtered off and the filtrate was concentrated to give a crude oil. The oil was chromatographed on a 300 g of silica gel eluting with a mixture of chloroform and methanol (100:0 to 95:5) to give (2R,4R)-1-allyloxycarbonyl-2-[2-(2-hydroxymethylimidazol-1-yl) ethyl]-4-methylsulfonyloxypyrrolidine (15.7 g) as a light brown paste.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[CH:14]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[O:20])[CH:15](O)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(C)=O.[C:38]([O:41][C:42](=O)C)(=[O:40])[CH3:39].O>C(OCC)(=O)C>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[CH:14]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[O:20])[C:15](=[CH:42][O:41][C:38](=[O:40])[CH3:39])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(O)CS[C@H]12
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)OC=C1CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Nitrobenzyl 7-(2-phenylacetamido)-3-hydroxycepham-4-carboxylate (1.5 g.) was added to a solution of dimethylsulfoxide (15 ml.) and acetic anhydride (15 ml.), and stirred at room temperature for 5 hours. After adding the resultant mixture into water, ethyl acetate was added to the solution, adjusted to pH 7.5 and stirred for an hour. The ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was subjected to column chromatography on silica gel with a solution of diisopropyl ether and ethyl acetate (5:1) to give 4-nitrobenzyl 7-(2-phenylacetamido)-3-acetoxymethylenecepham-4-carboxylate (660 mg.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C1COCC1>[Pd].CO>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])cc1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(N)cc1NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
A solution of Example 28A in 1:1 THF:methanol (40 mL) was treated with 10% palladium on carbon (800 mg), stirred under hydrogen (1 atm) for one hour, filtered through diatomaceous earth (Celite®), and concentrated to provide the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[C:11](Cl)(=[O:14])[CH:12]=[CH2:13].O>O1CCCC1>[C:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:14])[CH:12]=[CH2:13]
Reactant: C=CC(=O)Cl
Reactant: Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC(=O)Oc1ccc(Br)cc1
Reaction time: 0.25 h
Yield: 91.3 %

Procedure:
To a solution of 4-bromophenol (15.1 g, 87.3 mmol) in tetrahydrofuran (170 mL) was added 60% sodium hydride (3.68 g, 91.6 mmol) under ice-cooling and the mixture was stirred for 15 min. A solution of acryloyl chloride (8.3 g, 91.6 mmol) in tetrahydrofuran (50 mL) was added, and the mixture was stirred for 15 min under ice-cooling. Water was added, and the solvent was evaporated under reduced pressure. The residue was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80) to give the title compound (18.1 g, yield 100%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]1([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28](O)=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22]1>>[C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:14][CH:15]4[CH:19]([CH2:18][N:17]([C:28]([C:27]5[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=5[N:21]5[CH:25]=[CH:24][CH:23]=[CH:22]5)=[O:29])[CH2:16]4)[CH2:20]3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Reactant: O=C(O)c1ccccc1-n1cccc1
Product: O=C(c1ccccc1-n1cccc1)N1CC2CN(c3nccc(-c4ccccc4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and 2-pyrrol-1-yl-benzoic acid. MS (ESI) mass calcd. for C27H25N5O, 435.53; m/z found, 436.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:17]([NH:24][CH3:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30]>>[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[CH2:17]([N:24]([CH:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11][CH2:12]1)[CH3:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CNCc1ccccc1
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: O=C(O)/C=C/C(=O)O
Product: CN(Cc1ccccc1)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
1-(4-Nitrophenyl)-4-piperidone was reacted in a similar manner to Example 2 with N-benzyl-N-methylamine and then with fumaric acid. 4-(N-benzyl-N-methylamino)-1-(4-nitrophenyl)piperidine fumarate was obtained. Melting point 183° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[CH:4][N:3]=1.[CH3:7][O:8][C:9]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:10]=1[CH:11]=O.[BH4-].[Na+].Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.CCCCCCC.C(OC)(C)(C)C>[CH3:7][O:8][C:9]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:10]=1[CH2:11][NH:1][C:2]1[S:6][N:5]=[CH:4][N:3]=1.[CH3:7][O:8][C:9]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:10]=1[CH2:11][NH:1][C:2]1[S:6][N:5]=[CH:4][N:3]=1
Reactant: Nc1ncns1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Solvent: CCCCCCC
Product: COc1ccc(CNc2ncns2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
A mixture of 5-amino-1,2,4-thiadiazole (1.00 g, 9.89 mmol) and 2,4-dimethoxybenzaldehyde (1.81 g, 10.9 mmol) in toluene (30 mL) was refluxed under Dean-Stark conditions for 2 hours. The reaction mixture was concentrated in vacuo, and the resulting residue taken up in methanol (25 mL). Sodium borohydride (600 mg, 15.9 mmol) was added carefully in small portions (vigorous effervescence after each addition) and the reaction was left to stir overnight at ambient temperature. An 2M aqueous solution of hydrogen chloride (1 mL) was added followed by a 2M aqueous solution of sodium hydroxide (10 mL). The mixture was concentrated in vacuo, water (20 mL) added and the mixture extracted with ethyl acetate (2×30 mL). The combined organics were washed with brine (20 mL), dried, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ISCO™ column, 25% to 60% ethyl acetate in heptane gradient elution) to furnish a semi-solid residue. tert-Butylmethyl ether (2-3 mL) was added, followed by heptane (2-3 mL). The resulting solid was collected by filtration, washed with heptane and dried to afford the title compound (1.22 g).
Reaction SMILES: COC1C=C(CCNC=O)C=CC=1.[CH3:14][S:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][NH:24][CH:25]=O)[CH:19]=[CH:20][CH:21]=1>>[CH3:14][S:15][C:16]1[CH:17]=[C:18]2[C:19](=[CH:20][CH:21]=1)[CH:25]=[N:24][CH2:23][CH2:22]2
Reactant: CSc1cccc(CCNC=O)c1
Agent: COc1cccc(CCNC=O)c1
Product: CSc1ccc2c(c1)CCN=C2
Yield: 13.3 %

Procedure:
A procedure identical to that described for the preparation of N-[2-(3-methoxy-phenyl)-ethyl]-formamide in Example 1 was followed using N-[2-(3-methylsulfanyl-phenyl)-ethyl]-formamide (6.7 g, 34 mmol) to give the desired product (0.8 g, 13%). MS: 178.1 (M+1+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(Cl)(Cl)=O.[CH3:32]O>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:32][O:19][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)([C:24]([F:25])([F:27])[F:26])[O:13][N:12]=2)=[CH:15][C:16]=1[CH3:23]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a suspension 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (Example I5) (10 g) in toluene (150 ml) and dimethylformamide (0.1 ml) at ambient temperature was added dropwise thionyl chloride (3.5 ml). The reaction mixture was stirred at 50° C. for 2 hours. The solution was then cooled to 0° C. and methanol (2 ml) added slowly. The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated and aqueous sodium hydrogen carbonate (saturated) (50 ml) added to the residue. The mixture was extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried over sodium sulfate and concentrated to afford 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester as a yellow solid (11.5 g). 1H-NMR (CDCl3, 400 MHz): 7.95 (d, 1H), 7.55 (m, 4H), 7.45 (s, 1H), 4.10 (d, 1H), 3.90 (s, 3H), 3.70 (d, 1H), 2.60 (s, 3H) ppm.
Reaction SMILES: [NH4+].[N+:2]([C:5]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:18])([CH3:17])[CH2:15][CH3:16])=[CH:10][C:9]=1[S:19]([O-:22])(=[O:21])=[O:20])([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:2][C:5]1[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[CH:23][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:18])[CH2:15][CH3:16])=[CH:10][C:9]=1[S:19]([OH:22])(=[O:21])=[O:20]
Reactant: CCC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])c(S(=O)(=O)[O-])c1
Agent: [Pd]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2N)c(S(=O)(=O)O)c1
Reaction time: 2 h

Procedure:
2-(2-Nitro-4-trifluoromethylphenoxy)-5-(1,1-dimethylpropyl)benzenesulfonic acid, ammonium salt (620 mg) was mixed in ethyl acetate (50 ml) and palladium on carbon (202 mg) was added under argon. The mixture was hydrogenated in a Parr bottle at 55 psi for two hours. The sample was filtered to remove the catalyst, mixed with methanol and degassed for several hours to yield the title compound. 1H NMR (250 MHz, CD3OD) ∂ 7.95 (d, 1H), 7.30 (dd, 1H), 7.05 (dd, 2H), 6.85 (dd, 1H), 6.75 (d, 1H), 1.65 (q, 3H), 1.25 (s, 6H), 0.65 (t, 2H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=3)[CH:7]=2)[CH2:3][CH2:2]1.[H-].[Na+].[CH3:19][N:20]([CH3:23])C=O>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[CH:12]=[C:11]([O:16][CH2:15][C@H:6]([OH:5])[CH2:7][CH2:8][C:9]2[CH:23]=[N:20][CH:19]=[CH:11][CH:10]=2)[CH:10]=[CH:9]3)[CH2:2][CH2:3]1
Reactant: CN(C)C=O
Reactant: Oc1ccc2cc(OCC3CC3)ccc2c1
Agent: [H-]
Agent: [Na+]
Product: O[C@H](CCc1cccnc1)COc1ccc2cc(OCC3CC3)ccc2c1
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
A solution of 2-cyclopropylmethoxy-6-hydroxynaphthalene (0.270 g) in anhydrous N,N-dimethylformamide (10 ml) was added dropwise to sodium hydride (60% dispersion in mineral oil, 0.457 g) that had been previously washed with isohexane (2 ml) under a nitrogen atmosphere. After stirring at 20° C. for 20 minutes a solution of (2R)-2-(tert-butyldimethylsilyloxy)-4-(3-pyridyl)-1-(4-toluenesulfonyloxy)butane (0.46 g) in anhydrous N,N-dimethylformamide (2 ml) was added and the mixture stirred at 60° C. for 90 minutes. After cooling the reaction was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ether. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (50 ml) and treated with tetrabutylammonium fluoride hydrate (0.48 g). After 1 hour the solution was diluted with water and extracted with ether. The organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane:methanol (24:1) to give the title compound as a solid (0.124 g) which was recrystallised from ethyl acetate/isohexane.
Reaction SMILES: S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(C1C=CC(C)=CC=1)(=O)=O.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.[K].O>CN(C=O)C>[O:35]=[C:33]1[C:32]2[C:31](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:30](=[O:40])[N:34]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCC(=O)OC(C)(C)C)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CCOCCOCCOCCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 3-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)propanoate (13.4 g, 30.98 mmol, 1.00 equiv) in anhydrous DMF (100 mL) followed by potassium phthalimide (7.5 g, 40.49 mmol, 1.31 equiv). The resulting solution was heated to 100° C. and stirred for 3 h. The reaction progress was monitored by LCMS. The DMF was removed under vacuum to afford a brown oil residue. To the residue was added 200 mL water and the mixture was extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After evaporation of solvent, The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0˜1:3). The solvent was removed from fractions containing phthalimide and the residue was washed with 20% ethyl acetate/petroleum ether to yield 10.1 g (78%) of tert-butyl 3-(2-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethoxy)propanoate as pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([O:11][CH3:12])[N:3]=1.[H-].[Na+].C1C(=O)NC(=O)N([C@@H:23]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@@H:24]2[OH:31])C=1.[C@@H]1(N2C=CC(=O)NC2=O)O[C@H](CO)[C@@H](O)[C@H]1O>O1CCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CC.CO>[C@@H:23]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([NH2:1])=[N:3][C:4]=3[O:11][CH3:12])[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@@H:24]1[OH:31]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1
Reactant: COc1nc(N)nc2nc[nH]c12
Agent: O=P([O-])([O-])[O-]
Agent: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: [H-]
Solvent: CCCO
Solvent: CO
Solvent: C1CCOC1
Product: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
2-Amino-6-methoxypurine (prepared by nucleophilic displacement of the chlorine group on 2-amino-6-chloropurine(Sigma Chemicals, St. Louis, Mo.) by methanol with sodium hydride in tetrahydrofuran) (6.4 mmoles, 1.05 g) was combined with 35 ml of a uracil arabinoside solution (7.04 mmoles, 1.75 g) in 10 mM potassium phosphate and 7% n-propanol (v/v). The pH was adjusted to 6.75. Purified purine nucleoside phosphorylase (18000 units) and uridine phosphorylase (1020 units) were added and the solution incubated at 37° C. After 26 days the reaction was filtered and the filtrate chromatographed on a column of Dowex-1-formate resin (2×7 cm) after adjusting the pH to 10.5 with concentrated ammonium hydroxide. The column was eluted with 7% n-propanol/water (v/v) and fractions containing product were combined and solvent removed in vacuo. The residue was extracted with 25 ml of water and the filtrate separated from the solids by centrifugation. The supernatant upon standing at ambient temperature formed crystals of 9-β-D-arabinofuranosyl-2-amino-6-methoxy-9 H-purine which after drying in vacuo, yielded 0.327 g of product. NMR and mass spectrometry were consistent with the structure.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.CCN(C(C)C)C(C)C.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH2:29])=[CH:23][CH:22]=1>C(#N)C>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:29][CH2:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[N:7]=1
Reactant: COc1nc(Cl)nc(Cl)n1
Reactant: NCCc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1nc(Cl)nc(NCCc2ccc(F)cc2)n1

Procedure:
A solution of 10 g of 2,4-dichloro-6-methoxy-1,3,5-triazine in 200 ml of acetonitrile is cooled on an ice bath, 8.73 ml of DIPEA and then 6.56 ml of 2-(4-fluorophenyl)ethanamine are added and the mixture is stirred. The precipitate formed is drained by suction, washed with EtOAc and dried. 13.7 g of the expected compound are obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Ic1ccccc1
Product: c1ccc(-n2ccc3ccccc32)cc1

Procedure:
Prepared by Procedure C and Scheme O using 1H-indole and iodobenzene: ESMS m/e: 193.9 (M+H)+.
Reaction SMILES: [O:1]([C:8]([CH3:13])([CH3:12])[C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[O:1]([C:8]([CH3:13])([CH3:12])[C:9]([N:24]1[CH2:25][CH2:26][N:21]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:22][CH2:23]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CC(C)(Oc1ccccc1)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(Oc1ccccc1)C(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 0.01 mol of 2-phenoxyisobutyric acid chloride (obtained by reaction of thionyl chloride with 2-phenoxyisobutyric acid) in 100 ml of methylene chloride is introduced into an Erlenmeyer flask containing a solution of 0.01 mol of 1-benzylpiperazine in 100 ml of methylene chloride. The mixture is stirred for 5 hours at room temperature, filtered and evaporated to dryness. The residue is taken up in water, basified and extracted with chloroform. The organic phases are combined, dried and evaporated.
Reaction SMILES: [Br:1][C:2]1[C:3]([Br:15])=[C:4]([Br:14])[C:5]([Br:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[NH2:16][C:17]1[C:18]([F:30])=[CH:19][C:20]([Cl:29])=[C:21]([CH:28]=1)[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23]>C1(C)C=CC=CC=1>[Br:13][C:5]1[C:4]([Br:14])=[C:3]([Br:15])[C:2]([Br:1])=[C:7]([C:8]([NH:16][C:17]2[CH:28]=[C:21]([C:22]([O:24][CH:25]([CH3:26])[CH3:27])=[O:23])[C:20]([Cl:29])=[CH:19][C:18]=2[F:30])=[O:9])[C:6]=1[C:11]([OH:10])=[O:12]
Reactant: CC(C)OC(=O)c1cc(N)c(F)cc1Cl
Reactant: O=C1OC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)c1cc(NC(=O)c2c(Br)c(Br)c(Br)c(Br)c2C(=O)O)c(F)cc1Cl
Reaction time: 8 h

Procedure:
Tetrabromophthalic anhydride (6.67 g, 0.014 mole) and 1-methylethyl 5-amino-2-chloro-4-fluorobenzoate (3.33 g, 0.014 mole) were heated to reflux with stirring in about 150 ml of toluene, then left overnight at room temperature. Filtration of the reaction mixture gave the title compound, m.p. 160°-165° C. (decomp.).