Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[O:13]([CH2:20][C:21]1[S:27][CH:26]2[CH:23]([C:24](=[O:42])[N:25]2[C:28](=[C:39](O)[CH3:40])[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[N:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[O:43]1CCCC1>>[O:13]([CH2:20][C:21]1[S:27][CH:26]2[CH:23]([C:24](=[O:42])[N:25]2[C:28](=[CH:39][CH2:40][O:10][S:9]([CH3:8])(=[O:11])=[O:43])[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[N:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(O)=C(C(=O)OCc1ccccc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: CS(=O)(=O)Cl
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC=C(C(=O)OCc1ccccc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Reaction time: 1.17 h

Procedure:
One adds triethylamine (1.42 ml), and methanesulfonyl chloride (0.41 ml) to a solution of benzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate (2.12 g) in tetrahydrofuran (30 ml) at -30° C., stirs for 70 minutes to give benzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]-hept-2-en-6-yl]-α-(methanesulfonyloxyethylidene)acetate, adds morphline (0.6 ml) and stirs for 4 hours 50 minutes at 0° C. to give benzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)acetate, cools to -50° C., adds pyridine (0.385 ml) and bromine (0.25 ml), and stirs for 30 minutes to give benzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-bicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholino-2-bromoethylidene)acetate, adds 5% hydrochloric acid (36 ml), methanol (42.5 ml), and tetrahydrofuran (12.5 ml) to give clear solution. The solution is concentrated, the resulting solution being extracted with ethyl acetate, washed with saturated saline, dried over sodium sulfate, and concentrated to give residue (2.31 g). Purification of the residue by chromatography over silica gel containing 10% water gives benzyl 7β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate (1.11 g). m.p. 126°-127° C.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH2:5][CH2:4][O:3]1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[OH:3][CH2:4][CH2:5][CH:6]([N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[C:2]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:1]
Reactant: O=C1OCCC1N1CCCC1=O
Reactant: C1COCCN1
Product: O=C(C(CCO)N1CCCC1=O)N1CCOCC1
Temperature: 110 °C
Yield: 81.9 %

Procedure:
5.07 g (0,03 mol) of 1-(tetrahydro-2-oxo-3-furyl)-2-pyrrolidinone are mixed with 10.45 g (0.12 mol) of morpholine and the reaction mixture is heated at 110° C. for 5 hours. Upon cooling, the product crystallizes. The product is filtered and recrystallized from diethyl ether. 6.3 g (yield: 82% of theory) of 4-[4-hydroxy-2-(2-oxo-1-pyrrolidinyl)butyryl]-morpholine are obtained. M.P.: 105°-106° C.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.N1C=CC=CC=1.[OH:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([O:17][C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:2]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cccc(O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(Oc2cccc(C)c2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.4 %

Procedure:
A mixture of m-tolylboronic acid (0.164 g; 1.20 mmol), copper acetate (0.219 g; 1.20 mmol), pyridine (0.097 mL; 1.20 mmol) and ethyl 3-hydroxybenzoate (0.100 g; 0.602 mmol) in dichloromethane (5 mL) was stirred at room temperature under nitrogen for 24 hours. The reaction mixture was filtered through celite, concentrated under reduced pressure and the residue purified by column chromatography on silica (eluent 2 to 20% ethyl acetate in heptane) to yield 0.084 g (54%) of the title compound which was used without further purification.
Reaction SMILES: N1([CH:10]=[O:11])C2C=CC=CC=2N=N1.FC(F)(F)C(O)=O.[N:19]1([C:25]2[N:33]=[C:32]([C:34]3[CH:35]=[N:36][C:37]([NH2:40])=[N:38][CH:39]=3)[N:31]=[C:30]3[C:26]=2[N:27]=[C:28]([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[N:29]3[CH2:41][C:42]([F:45])([F:44])[F:43])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>O1CCCC1.C(OCC)(=O)C>[NH2:40][C:37]1[N:36]=[CH:35][C:34]([C:32]2[N:31]=[C:30]3[C:26]([N:27]=[C:28]([N:46]4[CH2:47][CH2:48][N:49]([CH:10]=[O:11])[CH2:50][CH2:51]4)[N:29]3[CH2:41][C:42]([F:44])([F:43])[F:45])=[C:25]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:33]=2)=[CH:39][N:38]=1
Reactant: O=Cn1nnc2ccccc21
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCNCC4)n(CC(F)(F)F)c3n2)cn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCN(C=O)CC4)n(CC(F)(F)F)c3n2)cn1
Reaction time: 0.33 h
Yield: 56 %

Procedure:
Benzotriazole-1-carboaldehyde (55 mg, 0.38 mmol) was dissolved in tetrahydrofuran (10 ml) followed by the addition of 5-[6-morpholin-4-yl-8-piperazin-1-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine trifluoroacetate (200 mg, 0.29 mmol). The resulting mixture was stirred for 20 minutes and the reaction mixture was diluted with ethyl acetate, washed with 1 M sodium hydroxide and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (chloroform:methanol=19:1) to give a white solid (80 mg, 56%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1([CH2:10][NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Cl[C:22]1[C:23]2[CH:30]=[CH:29][NH:28][C:24]=2[N:25]=[CH:26][N:27]=1.C(N(CC)CC)C>C(O)CCC>[NH2:3][C:4]1([CH2:10][NH:11][C:12](=[O:20])[C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:9][CH2:8][N:7]([C:22]2[C:23]3[CH:30]=[CH:29][NH:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:6][CH2:5]1
Reactant: NC1(CNC(=O)c2ccc(Cl)cc2)CCNCC1
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: NC1(CNC(=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 100 °C
Reaction time: 17 h
Yield: 56.3 %

Procedure:
A degassed mixture of crude N-(4-amino-piperidin-4-ylmethyl)-4-chloro-benzamide dihydrochloride (6.1 mg), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2.6 mg, 0.016 mmol), triethylamine (16 μL, 0.09 mmol) and n-butanol (0.3 mL) was stirred at 100° C. for 17 hours. The solvents were concentrated. The crude mixture was first purified on an SCX-II acidic resin, eluting with methanol then 2M ammonia-methanol, and then by preparative TLC, eluting with 15% methanol-dichloromethane, to give N-[4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylmethyl]-4-chloro-benzamide (3.3 mg, 0.009 mmol, 69% over 2 steps).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][NH:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]([O:27][CH3:28])=[O:26])=[O:14].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[CH2:29]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][NH:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]([O:27][CH3:28])=[O:26])=[O:14])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)n1ncc2c(NC(=O)NCC3CCc4ccccc4N3)cccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)n1ncc2c(NC(=O)NCC3CCc4ccccc4N3Cc3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.4 %

Procedure:
A mixture of the product of Example 22B (0.72 g, 1.5 mmol), benzyl bromide (0.26 g, 1.5 mmol) and potassium carbonate (3.0 g in 3 mL of H2O) in tetrahydrofuran (6 mL) was stirred at room temperature for 72 hrs, diluted with ethyl acetate, washed with water and partitioned. The isolated organic layer was concentrated and the residue was chromatographed on silica gel, eluting with 60%-100% ethyl acetate/hexanes to afford the title compound (0.58 g, 72%) as an amorphous solid. 1H NMR (300 MHz, d6-DMSO) 9.00 (s, 1H), 8.42 (s, 1H), 7.80 (d, J=7.5 Hz, 1H), 7.68 (d, J=7.5 Hz, 1H), 7.48 (m, 1H), 7.28 (m, 5H), 6.95 (d, J=7.5 Hz, 1H), 6.83 (m, 1H), 6.58 (m, J=6.0 Hz, 1H), 6.50 (m, 1H), 6.36 (d, J=7.5 Hz, 1H), 4.64 (m, 2H), 4.01 (s, 3H), 3.57 (m, 1H), 3.41-3.20 (m, 2H), 2.90 (m, 1H), 2.67 (m, 1H), 2.03 (m, 1H), 1.82 (m, 1H); MS (DCI/NH3) m/e 470 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:12][NH2:13]>CO>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:13][CH3:12])[CH:7]=1
Reactant: ClCCCOc1cccnc1
Reactant: CN
Solvent: CO
Product: CNCCCOc1cccnc1
Temperature: 80 °C

Procedure:
The 3-chloro-1-(3-pyridyloxy)propane (4.90 g, 28.55 mmol) was dissolved in methanol (60 mL) and added to a 40 wt % solution of methylamine (60 mL) in a heavy-walled pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 80° C. for 15 h. After cooling, the mixture was concentrated by rotary evaporation, a saturated NaCl solution (25 mL) was added, and the mixture was basified with 20% NaOH solution (5.0 mL). The mixture was extracted with chloroform (4×30 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to give 3.64 g of a brown oil. The product was purified by column chromatography on silica gel (100 g) eluting with chloroform-methanol-triethylamine (70:30:2.5, v/v/v). Selected fractions containing the product (Rf 0.30) were combined and concentrated by rotary evaporation. The resulting residue was dissolved in chloroform (15 mL), dried (Na2SO4), filtered, and concentrated by rotary evaporation to give 1.92 g (40.4%) of a brown oil. 1H NMR (CDCl3, 300 MHz): δ 8.31 (dd, 1H, J=2.39, 1.44 Hz), 8.20 (dd, 1H, J=3.88, 2.29 Hz), 7.14 (m, 2H, J=3.90, 1.11 Hz), 4.09 (t, 2H, J=6.22 Hz), 2.78 (t, 2H, J=6.80 Hz), 2.46 (s, 3H), 1.99 (p, 2H, J=6.54 Hz), 1.59 (br, s, 1H). 13C NMR (CDCl3, 75 MHz): δ 155.16, 142.08, 138.09, 123.84, 121.05, 66.59, 48.78, 36.53, 29.44. EI-MS: m/z (relative intensity) 166 (M+, 10.08%), 123 (41.85%), 95 (100.00%), 70 (45.84%), 44 (89.75%), 39 (41.62%).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[O:13]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[O:13]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][N:24]1[CH2:10][C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:3]1=[O:12])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NCc1cccc(Oc2ccccc2)c1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C1c2ccccc2CN1Cc1cccc(Oc2ccccc2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 40.6 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.115 g, 0.5 mmol), 3-phenoxy-benzylamine (0.106 mL, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (3 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(3-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.064 g, 41%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.26 (s, 2H), 4.82 (s, 2H), 6.90-7.56 (m, 12H), 7.89 (d, 1H). GC-MS: m/z 315 (M)+.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH2:5][C:4]([N:7]2[CH2:12][CH2:11][CH2:10][C:9]3([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[CH2:8]2)=[CH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:8]1[C:9]2([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[CH2:10][CH2:11][CH2:12][N:7]1[C:4]1[CH2:5][O:6][C:2](=[O:1])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCN(C3=CC(=O)OC3)C2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C=C(N2CCCC3(CCNCC3)C2)CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl 2-(5-oxo-2,5-dihydrofuran-3-yl)-2,9-diazaspiro[5.5]undecane-9-carboxylate (266 mg, 0.792 mmol) in DCM (2 mL) was added TFA (2 mL, 26.0 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure, then placed on the high vacuum. The residue was dissolved in MeOH and loaded onto a 2 g Bond Elut SCX column (pre-rinsed with MeOH). These were rinsed with MeOH, and the product was eluted via 2M NH3 in MeOH to afford 4-(2,9-diazaspiro[5.5]undecan-2-yl)furan-2(5H)-one. LC/MS: [(M+1)]+=237
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:15][O:16][C:17]([C:19]1[C:23]([N+:24]([O-:26])=[O:25])=[C:22]([C:27]([O:29][CH3:30])=[O:28])[NH:21][N:20]=1)=[O:18].[CH2:31]([O:34][CH2:35][CH2:36]O)[CH2:32][CH3:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[N+:24]([C:23]1[C:19]([C:17]([O:16][CH3:15])=[O:18])=[N:20][N:21]([CH2:36][CH2:35][O:34][CH2:31][CH2:32][CH3:33])[C:22]=1[C:27]([O:29][CH3:30])=[O:28])([O-:26])=[O:25]
Reactant: CCCOCCO
Reactant: COC(=O)c1n[nH]c(C(=O)OC)c1[N+](=O)[O-]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCOCCn1nc(C(=O)OC)c([N+](=O)[O-])c1C(=O)OC
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Diisopropyl azodicarboxylate (14.2 mL, 70 mmol) was added to an ice-cooled solution of 4-nitro-1H-pyrazole-3,5-dicarboxylic acid dimethyl ester (EP 1241170, prep 10) (15 g, 60 mmol), 2-propoxyethanol (8.2 mL, 70 mmol) and triphenylphosphine (18.9 g, 70 mmol) in tetrahydrofuran (150 mL), and the reaction stirred at 0° C. for 2.5 hours, then allowed to stir at room temperature for a further 18 hours. The reaction was concentrated in vacuo and the residue purified by column chromatography on silica gel using ethyl acetate:pentane as eluant, and then re-columned using dichloromethane as eluant to afford the title compound as a solid, 14 g.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][C:8](=[O:14])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[C:4]([C:5]=32)[N:3]1[CH2:15][C:16]([O:18]C)=[O:17].[OH-].[Na+:21].Cl>CO.CC#N>[O:1]=[C:2]1[N:6]2[CH2:7][C:8](=[O:14])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[C:4]([C:5]=32)[N:3]1[CH2:15][C:16]([O-:18])=[O:17].[Na+:21]
Reactant: COC(=O)Cn1c(=O)n2c3c(cccc31)NC(=O)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: O=C([O-])Cn1c(=O)n2c3c(cccc31)NC(=O)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl (2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)acetate from Step C (367 mg, 1.40 mmol) in MeOH (40 mL) and CH3CN (5 mL) was added 1.0 N sodium hydroxide (2.82 mL, 2.82 mmol) and the reaction mixture was stirred at room temperature for 18 h. The mixture was neutralized with 1 N aqueous HCl and concentrated in vacuo to give the title compound. MS: m/z=248 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:15]3[CH:23]=[C:22]([C:24]4[O:28][C:27](C=O)=[CH:26][CH:25]=4)[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:9][CH:8]=1.[CH2:34]([S:37]([CH2:40][CH2:41][NH2:42])(=[O:39])=[O:38])[CH2:35][CH3:36].[CH2:43](COC)OC>>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]2[C:15]3[CH:23]=[C:22]([C:24]4([CH2:43][NH:42][CH2:41][CH2:40][S:37]([CH2:34][CH2:35][CH3:36])(=[O:39])=[O:38])[CH2:25][CH:26]=[CH:27][O:28]4)[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:12]=1
Reactant: CCCS(=O)(=O)CCN
Reactant: O=Cc1ccc(-c2cc3c(Nc4ccc(OCc5cccc(F)c5)cc4)ncnc3cn2)o1
Reactant: COCCOC
Product: CCCS(=O)(=O)CCNCC1(c2cc3c(Nc4ccc(OCc5cccc(F)c5)cc4)ncnc3cn2)CC=CO1

Procedure:
5-(4-(4-(3-Fluorobenzyloxy)-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde (0.31 mmol) and 2-n-propanesulphonyl-ethyl amine (0.94 mmol) were reacted together in dimethoxyethane as in Procedure D. 1H NMR (DMSO) 11.25 (bs, 1H); 9.88 (bs, 1H); 9.49 (s, 1H); 9.20 (s, 1H); 8.80 (s, 1H); 7.85 (d, 2H); 7.44 (m, 1H); 7.32–7.27 (m, 3H); 7.16 (m, 1H); 7.11 (d, 2H); 6.87 (m, 1H); 5.18 (s, 2H); 4.46 (s, 2H); 3.66 (m, 2H); 3.45 (m, 2H); 3.23 (m, 2H); 1.71 (m, 2H); 0.97 (m, 3H). Electrospray MS m/z 576 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])[C:5]([CH:17]=O)=[CH:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].[CH3:29][O:30][CH2:31][CH2:32][NH2:33]>ClCCl>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])[C:5]([CH2:17][NH:33][CH2:32][CH2:31][O:30][CH3:29])=[CH:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28]
Reactant: COCCN
Reactant: O=Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1c(F)cccc1F
Solvent: ClCCl
Product: COCCNCc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1c(F)cccc1F
Yield: 36 %

Procedure:
The title compound was prepared by reacting 5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridine-2-carbaldehyde -(0.319 g, 0.7 mmol) with 2-methoxy ethylamine (0.086 ml, 1.0 mmol) and triacetoxy sodium borohydride (0.42 g, 2.0 mmol) in dichloromethane (4 mL) by using a procedure, similar to the one described for Example 468. The crude product was purified by flash column chromatography. Elution with (50:50→40:100) hexanes-ethyl acetate to give 0.13 g of the desired product.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:29][C:30](=[O:51])[C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:50]=[CH:49][C:40]4[N:41]([CH2:45][CH2:46][CH2:47][CH3:48])[C:42](=[O:44])[NH:43][C:39]=4[CH:38]=3)=[CH:33][CH:32]=2)(=[O:28])=[O:27])=[CH:22][C:21]=1[N+:52]([O-:54])=[O:53])[CH2:11][S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1>[CH2:45]([N:41]1[C:40]2[CH:49]=[CH:50][C:37]([C:34]3[CH:35]=[CH:36][C:31]([C:30]([NH:29][S:26]([C:23]4[CH:24]=[CH:25][C:20]([NH:19][C@@H:10]([CH2:11][S:12][C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=5)[CH2:9][OH:8])=[C:21]([N+:52]([O-:54])=[O:53])[CH:22]=4)(=[O:28])=[O:27])=[O:51])=[CH:32][CH:33]=3)=[CH:38][C:39]=2[NH:43][C:42]1=[O:44])[CH2:46][CH2:47][CH3:48]
Reactant: CCCCn1c(=O)[nH]c2cc(-c3ccc(C(=O)NS(=O)(=O)c4ccc(N[C@H](CO[Si](C)(C)C(C)(C)C)CSc5ccccc5)c([N+](=O)[O-])c4)cc3)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCn1c(=O)[nH]c2cc(-c3ccc(C(=O)NS(=O)(=O)c4ccc(N[C@H](CO)CSc5ccccc5)c([N+](=O)[O-])c4)cc3)ccc21

Procedure:
A mixture of Example 177A (40 mg, 0.05 mmol) and 1M tetrabutylammonium fluoride in THF (130 uL, 0.13 mmol) in THF (3 mL) at room temperature was stirred for 3 hours, treated with 1M HCl (10 mL), and extracted with 5% methanol in ethyl acetate (3×20 mL). The combined extracts were washed with brine (5 mL), dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20% methanol/ethyl acetate to provide the desired product. MS (ESI) m/e 674, 676 (M−H)−, (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ0.91 (t, 3H), 1.30 (q, 2H), 1.59 (tt, 2H), 3.28 (t, 2H), 3.67 (m, 1H), 3.80 (t, 2H), 3.92 (m, 2H), 5.21 (t, 1H), 6.83 (d, 1H), 7.21 (m, 3H), 7.29 (td, 2H), 7.38 (dd, 2H), 7.55 (d, 2H), 7.80 (dd, 1H), 7.94 (d, 2H), 7.95 (d, 1H), 8.41 (d, 1H), 8.49 (d, 1H), 10.90 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([OH:24])[C@H:14]([C@H:16]([C@@H:18]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:19])[OH:17])[OH:15]>>[CH2:11]([OH:12])[C@H:9]([C@@H:7]([C@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10].[O:23]=[CH:22][C@@H:20]([C@H:18]([C@H:16]([C@@H:14]([CH2:13][OH:24])[OH:15])[OH:17])[OH:19])[OH:21]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Product: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Product: OC[C@@H](O)[C@H](O)[C@@H](O)[C@H](O)CO

Procedure:
Both glucose and fructose can be hydrogenated into the sugar alcohol or corresponding hexitol. The hexitol produced by the hydrogenation of glucose is sorbitol, while the hydrogenation of fructose leads to a mixture of sorbitol and mannitol. Iditol is produced by the hydrogenation of galactose, an hexose.
Reaction SMILES: C(C1C=NC(C2C=CC(O[CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:30][C:31]([F:48])([F:47])[C:32]([F:46])([F:45])[O:33][C:34]([F:44])([F:43])[C:35]([F:42])([F:41])[O:36][C:37]([F:40])([F:39])[F:38])([F:29])[F:28])=CC=2)=NC=1)CCCCCCC.[CH2:49]([O:55][C:56]1[CH:57]=[N:58][C:59]([C:62]2[CH:67]=[CH:66][C:65]([OH:68])=[CH:64][CH:63]=2)=[N:60][CH:61]=1)[CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]>O>[CH2:49]([O:55][C:56]1[CH:61]=[N:60][C:59]([C:62]2[CH:63]=[CH:64][C:65]([O:68][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:30][C:31]([F:47])([F:48])[C:32]([F:45])([F:46])[O:33][C:34]([F:43])([F:44])[C:35]([F:41])([F:42])[O:36][C:37]([F:40])([F:39])[F:38])([F:29])[F:28])=[CH:66][CH:67]=2)=[N:58][CH:57]=1)[CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCCCCc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Solvent: O
Product: CCCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 3-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-chloropropane (5.42 g, 11.4 mmol, Example 24) with 5-hexyloxy-2-(4-hydroxyphenyl)pyrimidine (3 g, 10.0 mmol). Product was isolated by addition of water (100 mL) to the resulting mixture, followed by filtration and recrystallization from ethanol. The recrystallized precipitate was dried at about 130° C., and the resulting product was further purified by Kugelrohr distillation (b.p. 170°-180° C. at 2.0 torr; yield of 5.4 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:10][CH:9]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:17][CH2:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: COc1ccc(CCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (31 mL) was added dropwise to a solution of 3-(4-methoxyphenyl)-1-propanol (50 g) and triethylamine (56 mL) in dichloromethane (800 mL) at 0° C. The resulting mixture was stirred overnight at room temperature. After washing with water, 2% hydrochloric acid and 4% aqueous sodium bicarbonate, the organic solution was dried over sodium sulfate and rotoevaporated to yield crude 3-(4-methoxyphenyl)-1-propyl methanesulfonate as a colourless solid (ca. 83 g). This product and sodium iodide (75 g) in acetone (800 mL) were heated at reflux in the dark for 20 hours. After cooling to room temperature, the reaction mixture was poured into n-hexane/EtOAc/water 1:1:1 (1.5 L) under stirring. The organic layer was washed with water, diluted aqueous sodium metabisulfite and 4% aqueous sodium bicarbonate, then dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by passing it through a short pad of silica gel (eluting with n-hexane/EtOAc 95:5). The title compound was obtained as a pale yellow solid (75 g).