Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[H][H]>[Pd].S1CCOCC1>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OCC
Agent: [Pd]
Agent: C1CSCCO1
Product: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Yield: 97 %

Procedure:
A mixture of racemic ethyl 2oxy-3-(4-benzyloxyphenyl)propionate of the formula (12a) (40 g) obtained according to the procedure described in step (iv) above, 5% Pd/C catalyst (8 g) and 1,4-thioxane (200 ml) was subjected to hydrogenation at room temperature and 50–60 psi of hydrogen pressure for a period of 8–12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the catalyst was filtered off and the solvent was removed under reduced pressure to afford the title compound of the formula (13a) (28–29 g, 97–98%).,
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([NH:10][C:11](=[O:13])[CH3:12])[CH2:4][C:3]1([CH3:15])[CH3:14].C(OO)(C)(C)C.[CH2:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>[Mo](=O)(=O)=O>[CH:22]1([O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([NH:10][C:11](=[O:13])[CH3:12])[CH2:4][C:3]2([CH3:15])[CH3:14])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCCCC1
Reactant: CC(=O)NC1CC(C)(C)N(O)C(C)(C)C1
Agent: O=[Mo](=O)=O
Agent: CC(C)(C)OO
Product: CC(=O)NC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of 10.0 grams (47 mmol) of N-(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl)acetamide, 15.2 grams (118 mmol) of 70% aqueous tert-butyl hydroperoxide, 0.67 gram of molybdenum trioxide, and 75 ml of cyclohexane is heated at reflux and water is collected in a Dean-Stark trap. The reaction mixture is then transferred to a Fischer-Porter pressure bottle and heated at 140° C. (bath temperature) for four hours to discharge the red color of the nitroxyl starting material. The reaction mixture is filtered, and the filtrate is diluted with ethyl acetate (150 ml). The organic solution is stirred with 5% aqueous sodium sulfite (150 ml) for one hour to decompose any residual hydroperoxide, then washed with brine (150 ml), dried over anhydrous magnesium sulfate, and concentrated to obtain 12.6 grams of white solid. Recrystallization from heptane affords 10.4 grams of the title compound as a white solid melting at 139°-144° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>C(#N)C>[Br:35][CH2:13][CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc2[nH]cc(CCO)c2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COc1ccc2[nH]cc(CCBr)c2c1
Reaction time: 2 h

Procedure:
A mixture of 10 g of the product obtained in Stage 1 (0.0523 mol), 16.5 g of triphenylphosphine (0.0628 mol), 17.3 g of carbon tetrabromide (0.0628 mol) and 200 ml of acetonitrile is left stirring for 2 hours. The solvent is then evaporated under vacuum and the product purified by chromatography on a silica column, Merck 70-230 mesh, using dichloromethane as eluent.
Reaction SMILES: [C:1]1([C@H:11]([NH2:13])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.FC(F)(F)C1C=C(C=CC=O)C=CC=1>>[C:1]1([CH:11]([NH2:13])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](N)c1cccc2ccccc12
Agent: O=CC=Cc1cccc(C(F)(F)F)c1
Product: CC(N)c1cccc2ccccc12

Procedure:
which includes the following steps: a) reacting (R)-(+)-1-(1-naphthyl)ethylamine (II) with 3-[3-(trifluoromethyl)phenyl]propenaldehyde (III) to afford the non isolated intermediate (R)—N-[3-[3-(trifluoromethyl)phenyl]-2-propenylimino-N-[1-(1-naphthyl)ethylamine (IV)
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][CH3:14])[CH:6]=[CH:5][CH:4]=1.[CH:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>O.O1CCCC1>[CH3:14][N:13]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[N:2]([CH3:1])[CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCC=O
Reactant: CNc1cccc2cccc(NC)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCC1N(C)c2cccc3cccc(c23)N1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of N,N'-dimethyl-1,8-naphthalene diamine (prepared in Example 1)(0.50 g, 2.7 mmol, 186), tridecanal (0.56 g, 2.85 mmol. 197), p-toluenesulfonic acid (5 mg), and tetrahydrofuran (5 ml) was stirred at room temperature for 15 minutes. The mixture was basified with 25% sodium hydroxide (1.0 ml), diluted with water (20 ml) and extracted with ether (100 ml). The extract was dried over potassium carbonate, concentrated to give 2,3-dihydro-1,3-dimethyl-2-dodecyl perimidine as a solid: mp 30°-32° C.; NMR (CDCl3) 7.13(m, 4H), 6.32(d, 2H), 4.27(t, 1H), 3.02(s, 6H), 1.7-1.1(m, 22H), 0.85(t, 3H); IR (neat) 1595 cm1.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-].[Na+].CC1(C)N([O])C(C)(C)CCC1.[O-]Cl.[Na+].C([O-])(O)=O.[Na+]>C(O)C.O.C1(C)C=CC=CC=1.CCOC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCc1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: O=CCCCCc1ccccc1
Temperature: 0 °C
Yield: 100 %

Procedure:
A solution containing 5-phenylpentanol (10 g, 60 mmol), sodium bromide (6.45 g, 63 mmol) and TEMPO (95 mg, 0.6 mmol) in a 7:7:1 mixture of EtOAc, toluene and water (258 mL) is cooled to 0° C. With vigorous stirring, an aqueous NaOCl solution (0.35 M, 571 mL, 200 mmol) saturated with NaHCO3 (43.85 g, 520 mmol) is added in five portions separated by 10 minutes intervals. TLC analysis following the final addition indicated complete reaction. Ethanol (20 mL) is added and the mixture is partitioned between water (500 mL) and EtOAc (500 mL). Aqueous layer is extracted with EtOAc (2×500 mL) and combined organic phases are washed successively with 5% aqueous Na2S2O3 (500 mL), water (200 mL) and brine (200 mL) then dried over MgSO4 and concentrated to afford 5-phenylpentanal as an orange oil which is used without further purification assuming 100% yield. TLC analysis [pet-ether/EtOAc, 9:1, Rf (alcohol)=0.20, Rf (aldehyde)=0.60]. 1H NMR (300 MHz, CDCl3) δ 1.65 (m, 4H), 2.35 (m, 2H), 2.60 (t, 2H), 7.10-7.30 (m, 5H), 9.75 (s, 1H) ppm.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=[O:5])C.Cl>CCO.[OH-].[Na+]>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([CH:7]2[CH2:8][CH:6]2[C:4]([OH:5])=[O:3])[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C1CC1c1cccc(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(C2CC2C(=O)O)c1

Procedure:
The crude 2-(3-methoxy-phenyl)-cyclopropanecarboxylic acid ethyl ester is dissolved in 30 ml EtOH and 15 ml 1N NaOH. After stirring over night, the reaction mixture is acidified with 1N HCl and extracted with diethyl ether. After removal of the solvent 7.1 g of the 2-(3-methoxy-phenyl)-cyclopropanecarboxylic acid is obtained. This 2-(3-methoxy-phenyl)-cyclopropanecarboxylic acid is used without further purification.
Reaction SMILES: [O:1]1[CH2:7][CH:2]1[C:3]([O:5][CH3:6])=[O:4].[C:8](=[O:10])=[O:9]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(#N)C.[Zn+2].[Br-].[Br-]>[CH3:6][O:5][C:3]([CH:2]1[CH2:7][O:1][C:8](=[O:9])[O:10]1)=[O:4]
Reactant: O=C=O
Reactant: COC(=O)C1CO1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: CC#N
Product: COC(=O)C1COC(=O)O1
Reaction time: 144 h
Yield: 65 %

Procedure:
20 g of methyl epoxypropionate were mixed with 20 g of acetonitrile, 1.5 g of benzyltrimethylammonium chloride and 1.5 g of ZnBr2. The homogeneous mixture was transferred to a 100 ml pressurized reactor and carboxylated for 6 days at 25° C. and a CO2 pressure of 30 bar. After the carboxylation, the mixture was diluted with 100 g of acetonitrile. The mixture was purified with aluminium oxide and activated carbon. Then, the acetonitrile was distilled off. This gave 4-methoxycarbonyl-2-oxo-1,3-dioxolane (purity 72% (GC), yield 65%).
Reaction SMILES: C(S)CS([O-])(=O)=O.[Na+].[P:9]([O:17][CH2:18][C@H:19]1[O:23][C@@H:22]([N:24]2[C:33]3[N:32]=[CH:31][N:30]=[C:28]([NH2:29])[C:27]=3[N:26]=[CH:25]2)[C@H:21]([OH:34])[C@@H:20]1[OH:35])([O:12]P(O)(O)=O)(=[O:11])[OH:10].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.C1S/C(=C2/N=C3C(S/2)=CC(=O)C=C3)/N[C@H]1C(O)=O>C(O)C(N)(CO)CO>[CH:31]1[N:30]=[C:28]([NH2:29])[C:27]2[N:26]=[CH:25][N:24]([C@@H:22]3[O:23][C@H:19]([CH2:18][O:17][P:9]([OH:12])([OH:11])=[O:10])[C@@H:20]([OH:35])[C@H:21]3[OH:34])[C:33]=2[N:32]=1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: NC(CO)(CO)CO
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=C1C=Cc2n/c(=C3\N[C@@H](C(=O)O)CS3)sc2=C1
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Reaction time: 0.33 h

Procedure:
Standard curves for the AK enzyme was prepared as follows. Serial dilutions of purified Sulfolobus acidocaldarius AK from 10 microgrammes/ml to 1 fg/ml were prepared in 50 mM Tris, 25 mM MESNA, pH 7.3. 100 microlitres of enzyme was added to each well of a microtitre plate and 100 microlitres of 135 micromolar ADP 15 mM MgAc, 1 mM EDTA added to each well. Three separate standard curves were prepared for incubation of the assay plate at 30 degrees C., 50 degrees C. and 70 degrees C. for 20 minutes. Following incubation 30 microlitres of luciferin/luciferase reagent (Biothema) was added and the signal read in a luminometer (Orion, Berthold) and the results shown in FIG. 3.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[O:11]([C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][OH:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[O:11]([C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[O:21])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OCc1ccccc1Oc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of oxalyl chloride (6.82 g, 53.71 mmol) in CH2Cl2 (250 mL) at -78° C., was added dimethylsulfoxide (8.76 g, 112.1 mmol) dropwise. The mixture was stirred for 5 mins. A solution of crude 2-phenoxybenzyl alcohol from above in CH2Cl2 (20 mL) was added dropwise. Upon completion of addition, the reaction was stirred for 20 mins at -78° C. Triethylamine (23.58 g, 233.5 mmol) was then added dropwise. The cooling bath was removed and the reaction allowed to warm to room temperature. It was then diluted with brine (250 mL). The layers were separated and the aqueous was extracted with CH2Cl2 (2×250 mL). The organics were combined, dried with MgSO4 and concentrated. The resulting residue was chromatographed (silica gel, ether:hexanes, 20:80) to afford 7.65 g (83% over the two steps) of 2-phenoxybenzaldehyde as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[CH2:8]Br)#[N:2].[CH3:12][NH:13][CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[CH2:8][N:13]([CH3:12])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])#[N:2]
Reactant: CNCCC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(F)c(CBr)c1
Product: CN(CCC(=O)OC(C)(C)C)Cc1cc(C#N)ccc1F

Procedure:
The title compound was prepared following the general procedure 10 starting from 5-cyano-2-fluorobenzylbromide (1.5 g, 7.0 mmol) and tert-butyl N-methyl-beta-alaninate (1.3 g, 8.4 mmol, prepared as described in Biorg. Med. Chem. (11) 2003, 3083-3099). It was isolated as a pale yellow oil (1.9 g, 92%). 1H NMR (CDCl3, 300 MHz) δ 7.79 (dd, J=6.7, 2.1 Hz, 1H), 7.57-7.52 (m, 1H), 7.11 (m, 1H), 3.57 (s, 2H), 2.74 (t, J=7.1 Hz, 2H), 2.43 (t, J=7.1 Hz, 2H), 2.22 (s, 3H), 1.45 (s, 9H). LC/MS (Method B): 293.2 (M+H)+. HPLC (Method A) Rt 2.44 min (Purity: 86.4%).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[C:4]([CH3:9])=[CH:5][C:6](=[O:8])[CH:7]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CCOC(C)=O.O>[CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10]
Reactant: CC1=CC(=O)C=C(C)C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(O)cc(C)c1O
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
A mixture of 2,6-dimethyl-[1,4]benzoquinone (5 g) and sodium hydrosulfite (10 g) in EtOAc (50 mL) and water (20 mL) was stirred for 30 min. After separation with EtOAc, the organic phase was dried and evaporated to dryness to give a off-white solid 5 g of 2,6-dimethyl-benzene-1,4-diol. The solid was dissolved in dry ether, cooled in an ice-water bath, followed by dropwise addition of sulfuryl chloride (5 g). After stirring the solution at RT for 3 h, workup and purification on silica gel column chromatography (30% EtOAc in hexane) gave 2.2 g 2-chloro-3,5-dimethyl-benzene-1,4-diol.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14].C(OCC)C>CCCCCC>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cccnc1
Solvent: CCOCC
Solvent: CCCCCC
Product: CN(C)C=CC(=O)c1cccnc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 358.4 %

Procedure:
3-Acetylpyridine (100 g, 0.19 mol) was added to dimethylformamide dimethylacetal (156.5 g, 1.27 mol), and the mixture was reacted under reflux for 23 hours. After the reaction mixture was cooled to 0° C., a mixture of diethyl ether and hexane (3:2, v/v) (500 ml) was added and the whole mixture was stirred for 4 hours. The resulting solid was filtered and washed with a mixture of diethyl ether and hexane (500 ml, 3/2, v/v) to give 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (120 g).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.NC1CCN(CC2CCOC2)CC1>C(N(CC)CC)C>[CH:11]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][CH:2]=[N:3][CH:4]=3)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Agent: NC1CCN(CC2CCOC2)CC1
Solvent: CCN(CC)CC
Product: c1ncc2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[4-(1-3-tetrahydrofuranyl)methyl)piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4amino-1-(3-tetrahydrofuranylmethyl)piperidine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.C(N)C>C(N(CC)CC)C>[CH:11]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][CH:2]=[N:3][CH:4]=3)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Agent: CCN
Solvent: CCN(CC)CC
Product: c1ncc2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[2,4-methoxyphenyl)ethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2,4-methoxyphenyl)ethylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][C:10](O)=[O:11])[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:3][CH2:2]1
Reactant: O=C(O)CCCC1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCCC1CCCCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-cyclohexanebutyric acid in 15 ml of THF at 0° is added 15 ml of a 1M solution of lithium aluminum hydride in THF. After the gas evolution ceases, the reaction is allowed to warm to room temperature. After stirring for six hours the reaction is cooled to 0° and quenched by carefully adding 2N HCl. The mixture is diluted with ether, and the layers are separated. The organic layer is then washed with saturated aqueous brine, and then dried (sodium sulfate/magnesium sulfate). Evaporation of the solvents in vacuo gives 4-cyclohexanebutanol as a clear oil. This oil is then dissolved in 20 ml of dry methylene chloride containing 3.5 ml of triethylamine and 2.85 g of p-toluenesulfonyl chloride. After stirring for 22 hours the reaction is quenched with water and stirred vigorously. The mixture is basified with 2N sodium hydroxide and extracted twice with methylene chloride. After drying (sodium sulfate), the solvents are evaporated in vacuo. Flash chromatography (50% methylene chloride/hexane) gives 4-cyclohexylbutyl 4-methylbenzenesulfonate as a clear oil.
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([O:9][CH:10]([C:16]2[CH:21]=[CH:20][C:19]3[O:22][CH2:23][O:24][C:18]=3[CH:17]=2)[C:11]([O:13]CC)=[O:12])=[C:7]([CH2:27][CH2:28][CH3:29])[CH:6]=1)([O:3][CH3:4])=[O:2]>CO>[C:1]([C:5]1[CH:26]=[CH:25][C:8]([O:9][CH:10]([C:16]2[CH:21]=[CH:20][C:19]3[O:22][CH2:23][O:24][C:18]=3[CH:17]=2)[C:11]([OH:13])=[O:12])=[C:7]([CH2:27][CH2:28][CH3:29])[CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: CCCc1cc(C(=O)OC)ccc1OC(C(=O)OCC)c1ccc2c(c1)OCO2
Solvent: CO
Product: CCCc1cc(C(=O)OC)ccc1OC(C(=O)O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A 1 L 3 necked 24/40 round bottom flask equipped with a mechanical stirrer, a dropping funnel, and a nitrogen inlet was charged with a solution of 76.3 g 0.185 mol) of the semi-purified product of Step A dissolved in 500 mL of methanol. The flask was purged with nitrogen, the stirrer was started, and 37 mL of a 5.0N aqueous solution of sodium hydroxide was added over a 30 minute period via an addition funnel. The reaction mixture was stirred at room temperature for an additional 30 minutes at which point TLC analysis (CH2Cl2 -MeOH-NH4OH 90:10:1) indicated that the starting material had been consumed. The reaction mixture was adjusted to pH=4 with 6N HCl, and the bulk of the organic solvent was removed in vacuo. The precipitated organic product and the aqueous layer were next partitioned between CH2Cl2 (1 L) and water (1 L) which produced a copious emulsion. The reaction mixture was then aged overnight in a refridgerator which resulted in crystallization of the organic product. The crystalline solid was separated from the two phase mixture by filtration and washed with CH2Cl2. The solid was slurried again in diethylether, filtered, washed with hexane, and then dried in a vacuum to afford 65 g (94%) of the title compound as a white crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16]S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:37](O)[CH3:38]>O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:37][CH3:38])=[C:12]([C:27]3[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)cc1
Reactant: CCO
Solvent: O
Product: CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 178, starting with 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting ethanol in place of 2-ethyl-1-hexanol (yield: 25 mg, 12%). mp 121-123° C. 1H NMR (300 MHz, DMSO-d6) δ 1.23 (t, J=7 Hz, 3H), 3.30 (s, 3H), 4.51 (q, J=7 Hz, 2H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90 (d, J=9 Hz, 2H), 8.08 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 407 (M+H)+; (APCI−) m/z 441 (M+Cl)−. Anal. calc. for C19H16F2N2O4S.0.25 H2O: C, 55.53; H, 4.04; N, 6.81. Found: C, 55.58; H, 4.21; N, 6.61.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[CH3:20][O:21][C:22]([CH3:28])([CH2:25][O:26][CH3:27])[C:23]#[CH:24]>CN(C=O)C.CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6]([C:24]#[C:23][C:22]([O:21][CH3:20])([CH3:28])[CH2:25][O:26][CH3:27])[N:5]=2
Reactant: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(Cl)nc21
Reactant: C#CC(C)(COC)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(C#CC(C)(COC)OC)nc21

Procedure:
A suspension of 1.5 g (5.34 mmol) of 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide in 30 ml of a DMF/Et3N (v/v; 2/1) mixture is placed in an 80 ml microwave tube. Argon is sparged into this suspension for 10 minutes and then 1.37 g of (±)-3,4-dimethoxy-3-methylbut-1-yne (10.69 mmol), 0.101 g of CuI (0.53 mmol) and 0.187 g of bis(triphenylphosphine)palladium(II) dichloride (0.27 mmol) are successively added.
Reaction SMILES: [O-]CC.[K+].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[CH3:15][O:16][C:17]1[N:22]=[C:21]([CH3:23])[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][CH:18]=1>C(OCC)C.C(O)C>[CH2:13]([O:12][C:5](=[O:11])[C:6](=[O:8])[CH2:23][C:21]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][CH:18]=[C:17]([O:16][CH3:15])[N:22]=1)[CH3:14]
Reactant: CCOC(=O)C(=O)OCC
Reactant: COc1ccc([N+](=O)[O-])c(C)n1
Agent: CC[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(=O)Cc1nc(OC)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of potassium ethoxide (0.55 g, 6.55 mmol) in diethyl ether (20 mL, anhydrous) and ethanol (4 mL) was added diethyl oxalate (894 μL, 6.55 mmol) and the reaction mixture was stirred for 30 min prior to the addition of 6-methoxy-2-methyl-3-nitropyridine (Preparation 33, 1.0 g, 5.95 mmol) in diethyl ether (8 mL). The resulting red suspension was stirred at rt, under argon, for 20 h. The mixture was filtered, the solid washed thoroughly with diethyl ether then dried. The red solid was then taken up in hot water and the solution cooled to 0° C. The precipitate was filtered, washed with cold water, and dried to give the title compound as a beige solid. δH (CDCl3): 1.40 (3H, t), 4.07 (3H, s), 4.39 (2H, q), 6.74 (1H, d), 7.57 (1H, s), 8.40 (1H, d), 13.82 (1H, s).
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[CH2:34]([O:41][C:42]1[CH:47]=[CH:46][C:45]([C:48](=[O:50])[CH3:49])=[CH:44][C:43]=1[N+:51]([O-:53])=[O:52])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[CH2:34]([O:41][C:42]1[CH:47]=[CH:46][C:45]([C:48](=[O:50])[CH2:49][Br:1])=[CH:44][C:43]=1[N+:51]([O-:53])=[O:52])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.7 %

Procedure:
Phenyltrimethylammonium tribromide (109.00 g, 290.00 mmol) was added to a solution of 1-(4-benzyloxy-3-nitrophenyl)ethanone (2) (65.60 g, 242.00 mmol) in anhydrous THF (600 mL) in three portions, and the reaction mixture was stirred at rt for 12 h. The solids were then collected by filtration and the filtrate concentrated. The product was precipitated from chloroform upon the addition of hexanes, then collected by filtration and dried under vacuum to give bromo ketone 3 as a light yellow solid (63.33 g, 75% yield): 1H NMR (500 MHz, CDCl3) δ 4.37 (s, 3H), 5.35 (s, 2H), 7.21 (d, 1H), 7.40 (m, 5H), 8.15 (dd, 1H), 8.49 (d, 1H).