Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]1[N:17]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:15]([C:24]([O:26]CC)=[O:25])=[CH:14][N:13]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]1[N:17]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:15]([C:24]([OH:26])=[O:25])=[CH:14][N:13]=1
Reactant: CCOC(=O)c1cnc(Nc2cc([N+](=O)[O-])ccc2C)nc1-c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1ncc(C(=O)O)c(-c2cccnc2)n1
Temperature: 50 °C

Procedure:
23 g ethyl 2-[(2-methyl-5-nitrophenyl)amino]-4-(3-pyridinyl)pyrimidine-5-carboxylate and 19 g sodium carbonate in a mixture composed by 150 mL water and 150 mL ethanol is suspended. It is refluxed for three hours distilling the ethanol, and compensating with water the volume loss. Once completed the conversion, it is cooled to 50° C. and adjusted to pH 6 with acetic acid. The suspension is filtrated, yielding, upon drying, 20 g of product with HPLC purity of 95% (A %), which is identified through 1H-NMR.
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[C:5]([F:25])=[C:6]([CH:20]=[C:21]([F:24])[C:22]=1[F:23])[C:7]([CH:9](C(OCC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)(O)[O-].[Na+]>O1CCOCC1>[F:26][CH:2]([F:1])[O:3][C:4]1[C:5]([F:25])=[C:6]([CH:20]=[C:21]([F:24])[C:22]=1[F:23])[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)c(OC(F)F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CC(=O)c1cc(F)c(F)c(OC(F)F)c1F

Procedure:
The whole of the diethyl 3-difluoromethoxy-2,4,5-trifluorobenzoylmalonate [(XIV), R1 =--OCHF2, R3' =H, R17 =C2H5, X=X'=F] [prepared as described in step (a) above] was dissolved in 200 ml of dioxane, and then 4.52 g (0.0238 moles) of p-toluenesulfonic acid monohydrate were added to the resulting solution. The mixture was then heated under reflux for 6 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. 100 ml of water and 2.52 g (0.03 moles) of sodium bicarbonate were added to the residue, and the mixture was extracted with ethyl acetate. The extract was Washed with water and dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to give 5.66 g of ethyl 3-difluoromethoxy-2,4,5-trifluorobenzoylacetate as a reddish brown liquid.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[C:14]([O:15][C@@H:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][C:10]2=[O:29].[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[N:18]1([CH2:17][C@H:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:15][C:14]2[CH:13]=[CH:12][C:11]3[C:10](=[O:29])[CH2:9][CH2:8][CH2:7][C:6]=3[C:5]=2[CH2:4][NH:3][S:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:38])=[O:37])[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: NCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCCc2c1ccc(O[C@H](Cn1ccnc1)c1ccccc1)c2CNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
5-Aminomethyl-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one bis-hydrochloride (74 mg, 0.171 mmol) was dissolved in pyridine (1 mL) and catalytic DMAP (2 mg) was added followed by benzenesulfonyl chloride (26 μL, 0.205 mmol, 1.2 equiv). The reaction was stirred overnight at RT. The mixture was concentrated and the residue was dissolved in CH2Cl2. The organics were washed with H2O and brine, dried over MgSO4 and concentrated to give a tan foam. Purification by chromatography (5% MeOH/EtOAc with 1% NH4OH) afforded the title compound as a white foam (57 mg, 0.114 mmol, 67%). The structure was confirmed by NMR and mass spectrometry. MS m/z 502 (M++H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH:22]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:23]1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:22]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH2:23]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: c1cncc(C2CCNC2)c1
Product: Nc1c(F)c(N2CCC(c3cccnc3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 84 %

Procedure:
Starting from 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (1.04 g, 3.5 mmol) and 3-(3-pyrrolidinyl)-pyridine, a procedure analogous to that given in Example 1 provided the title compound (1.26 g, 84%) as a yellow solid, mp 250°-252° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=1)=[O:6].[CH3:22][O:23][C:24](=[O:37])[CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([CH:34]=O)=[C:29]([CH3:36])[CH:28]=1.OOS([O-])=O.[K+].CN(C=O)C>C(OCC)(=O)C>[CH3:22][O:23][C:24](=[O:37])[CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([C:34]2[NH:1][C:2]3[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]4[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=4)[CH:18]=[CH:19][C:20]=3[N:21]=2)=[C:29]([CH3:36])[CH:28]=1
Reactant: COC(=O)CCc1cc(C)c(C=O)c(C)c1
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(N)c(N)c2)cc1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCc1cc(C)c(-c2nc3ccc(C(=O)Nc4ccc(C(C)(C)C)cc4)cc3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3,4-diamino-N-(4-tert-butylphenyl)-benzamide (200 mg, 710 μmol), 3-(4-formyl-3,5-dimethylphenyl)-propionic acid methyl ester (190 mg, 860 μmols) (from Example 6-17) and oxone (286 mg, 470 μmols) in a solution of 5 mL DMF/0.5 mL water was stirred at ambient temperature for 1 h. The mixture was poured into ethyl acetate and extracted once with water and five times with brine. The organic phase was dried, filtered, and the solvent was removed under reduced pressure. The residue was purified by chromatography using a gradient of 50-90% heptane/ethyl acetate to afford 3-{4-[6-(4-tert-butylphenylcarbamoyl)-1H-benzimidazol-2-yl]-3,5-dimethylphenyl}-propionic acid methyl ester. 1H-NMR (CDCl3, 400 MHz): δ 8.51 (s, broad, 1H), 8.07 (s, broad, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.53 (d, J=8.1 Hz, 2H), 7.31 (d, J=8.6 Hz, 2H), 6.82 (s, 2H), 3.63 (s, 3H), 2.89 (t, J=7.4 Hz, 2H), 2.63 (t, J=7.4 Hz, 2H), 1.92 (s, 6H), 1.30 (s, 9H). MS (ESI) m/z 484.3 (M+H).
Reaction SMILES: C[C:2]1[O:3][C:4]2C=CC3[C:7](=CC=CC=3)[C:5]=2N=1.C1S(=O)(=O)[O:18][CH2:17]C1.C(N(CC)CC)C.[CH3:29][OH:30]>>[CH3:29][O:30][CH:7]=[CH:5][CH:4]([O:3][CH3:2])[O:18][CH3:17]
Reactant: Cc1nc2c(ccc3ccccc32)o1
Reactant: O=S1(=O)CCCO1
Reactant: CO
Solvent: CCN(CC)CC
Product: COC=CC(OC)OC

Procedure:
To a reactor was added 1.27 g (4 mmole) of ##STR9## prepared from the parent 2-methylnaphthoxazole and propane sultone in 50 ml of methanol. To this mixture was added 1.29 g (4 mmole) ##STR10## obtained from the condensation of the disubstituted thiobarbituric acid with 1,3,3-trimethoxy-1-propene and 1 ml triethylamine (TEA). The mixture was stirred for 20 minutes, filtered, and 1 g NaI was added to the filtrate and stirred for 30 minutes.
Reaction SMILES: O.[SH:2][C:3]1[N:7]([CH3:8])[N:6]=[N:5][N:4]=1.[Na].Br[CH2:11][Cl:12]>CC#N>[Cl:12][CH2:11][S:2][C:3]1[N:7]([CH3:8])[N:6]=[N:5][N:4]=1
Reactant: ClCBr
Reactant: Cn1nnnc1S
Agent: [Na]
Solvent: CC#N
Solvent: O
Product: Cn1nnnc1SCCl
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.1 %

Procedure:
A solution of sodium 5-mercapto-1-methyltetrazole hydrate (1.38 g, 10.0 mmol) in CH3CN (50 mL) was cooled in ice and treated in one portion with bromochloromethane (6.47 g, 50 mmol). The ice-bath was removed and the reaction mixture stirred at R.T. for 18 h. Then the solvent was evaporated and the crude product purified by chromatography on silica gel (eluted with CH2Cl2) to afford 1.27 g (77%) of the title compound, m.p.: 55°-57° C.
Reaction SMILES: O=[C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].Cl.[F:20][C:21]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:22]=1[C:23](=[S:26])[NH:24][NH2:25].C(N(CC)CC)C>CCO>[F:20][C:21]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:22]=1[C:23]1[S:26][C:2]([CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:25][N:24]=1
Reactant: CC(C)(C)OC(=O)NCCC(=O)c1ccccc1
Reactant: NNC(=S)c1cc(F)ccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0° C.) solution of tert-butyl 3-oxo-3-phenylpropylcarbamate (0.68 g, 2.73 mmol) and 2,5-difluorobenzothiohydrazide hydrochloride (0.613 g, 2.73 mmol) in EtOH (27 mL) was added triethylamine (0.57 mL, 4.09 mmol). After stirring at room temperature for 8 hours, the mixture was heated to 65° C. for 16 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (100 mL). The solution was washed with water and brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed (30% ethyl acetate in hexanes) to provide the crude product as a brown syrup which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[C:11]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[CH:6][C:7]=1SC.[CH2:24]1COCC1.O.O[O:31][S:32]([O-:34])=O.[K+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[C:11]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[CH:6][C:7]=1[S:32]([CH3:24])(=[O:34])=[O:31]
Reactant: C1CCOC1
Reactant: CSc1ccc(C2=C(c3ccccc3)C(=O)C(C)(C)O2)cc1Br
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)c(Br)c2)=C(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
350 mg of 5-{3-bromo-4-(methylthio)phenyl}-2,2-dimethyl-4-phenyl-3(2H)-furanone (Example 336), dissolved in 50 ml methanol, 50 ml THF and 50 ml water, was reacted with 1.5 g of OXONE by stirring at room temperature for 15 hours. Then the solvent was removed in vacuo and the resulting residue was extracted with 50 ml water and dichloromethane (30 ml×3). The organic layer was concentrated under reduced pressure and was purified by column chromatography (hexane/ethylacetate=3:2) to yield 173 mg of 5-{3-bromo-4-(methylsulfonyl)phenyl}-2,2-dimethyl-4-phenyl-3(2H)-furanone as a solid. mp: 154-155° C. NMR: δ1.58 (s, 6H), 3.29 (s, 3H), 7.26 (m, 3H), 7.38 (m, 2H), 8.07 (d, J=1.8 Hz, 1H), 8.10 (d, J=8.1 Hz, 2H). IR (cm−1): 1698, 1585, 1318, 1150.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:36])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:27][CH:26]=1)[CH2:20][CH2:21][CH2:22][OH:23].C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:36])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:30]=1)[CH2:20][CH2:21][CH2:22][O:23][S:45]([CH3:44])(=[O:47])=[O:46]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(CCCO)Cc3ccc(CC(=O)OC)cc3)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(CCCOS(C)(=O)=O)Cc3ccc(CC(=O)OC)cc3)c2n1
Reaction time: 5 h

Procedure:
The product from step (iii) (0.39 g) was dissolved in DCM (20 mL) and triethylamine (0.15 g) added, followed by addition of methanesulfonyl chloride (0.3 mL) and the mixture stirred for 5 hrs. The mixture was concentrated in vacuo to afford the subtitle compound as a crude product (0.45 g); MS multimode (+) 579.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[N:8]=[C:7]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)[C:11]2=[O:39])[O:6][N:5]=1.[ClH:40]>C(Cl)Cl.O1CCOCC1>[ClH:40].[CH3:1][S:2][CH2:3][C:4]1[N:8]=[C:7]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:11]2=[O:39])[O:6][N:5]=1
Reactant: CSCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CSCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
A solution of tert-butyl 4-[1-({3-[(methylsulfanyl)methyl]-1,2,4-oxadiazol-5-yl}methyl)-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (715 mg; compound B11) in DCM (15 ml) is reacted with a solution of hydrogen chloride in 1,4-dioxane (3 ml, 4.0 M) according to the procedure described in example B28 to afford the title compound as a solid.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19]C[C@H](C=O)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)#[N:7].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCCCCC>[CH:3]([C@H:2]1[CH2:1][CH2:19][C@H:14]([C:11]2[CH:10]=[CH:9][C:8]([C:6]#[N:7])=[CH:13][CH:12]=2)[CH2:15][CH2:16]1)=[CH2:4]
Reactant: [Li]CCCC
Reactant: N#Cc1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: C=C[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2.51 g of methyltriphenylphosphonium bromide in 80 ml of absolute tetrahydrofuran was placed at -20° C. while gassing with argon in a sulphonation flask provided with a dropping funnel and a thermometer and treated with 7.6 ml of an about 0.8M solution of butyl lithium in hexane. After stirring at -20° C. for 30 minutes, a solution of 1.0 g of trans-4-(p-cyanophenyl)cyclohexanecarboxaldehyde in 10 ml of absolute tetrahydrofuran was added dropwise at -20° C. within 5 minutes to the yellow reaction mixture, whereby the yellow colour disappeared. The mixture was now stirred at -20° C. for a further 30 minutes and then poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (2.3 g) on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gave 897 mg (91%) of p-(trans-4-vinylcyclohexyl)benzonitrile as colourless crystals; purity 99.4%. By additional crystallization from 22 ml of methanol there was obtained p-(trans-4-vinylcyclohexyl)benzonitrile in a purity of 99.95%; m.p. (C--I) 56.4° C., cl.p. 28.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1F.[C:13](=[O:16])([O-])[O-].[Cs+].[Cs+].[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[OH:27]>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:27][C:21]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=2[F:19])=[CH:4][C:3]=1[O:16][C:13]1[CH:22]=[CH:21][C:20]([F:19])=[CH:25][C:24]=1[F:26]
Reactant: Oc1ccc(F)cc1F
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(Br)c(F)cc1F
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(Br)c(Oc2ccc(F)cc2F)cc1Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.1 %

Procedure:
To a solution of 1-bromo-2,4-difluoro-5-nitrobenzene (0.3 g, 1.26 mmol) and cesium carbonate (0.86 g, 2.65 mmol) in DMSO (6.3 mL) was added dropwise 2,4-difluorophenol (0.27 g, 2.10 mmol). The mix was stirred for 60 minutes at ambient temperature and partitioned between ethyl acetate and water, adjusting the pH to 6 with HCl. The organic layer was washed with water, saturated aqueous sodium chloride, dried (MgSO4), filtered, and concentrated to afford the title compound (0.578 g, 100%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH2:31][CH:32]=O)[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[NH2:34][C@@H:35]([CH3:45])[CH2:36][CH2:37][NH:38][CH:39]1[CH2:44][CH2:43][S:42][CH2:41][CH2:40]1.C(O)(=O)C>ClCCl>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][NH:21][C:20]([C:8]2[C:9](=[O:19])[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:5]3[C:3](=[O:4])[N:34]4[C@@H:35]([CH3:45])[CH2:36][CH2:37][N:38]([CH:39]5[CH2:44][CH2:43][S:42][CH2:41][CH2:40]5)[C@@H:32]4[CH2:31][N:6]3[CH:7]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: C[C@H](N)CCNC1CCSCC1
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@H]1CCN(C2CCSCC2)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4)c(=O)c(OCc4ccccc4)c3C(=O)N12
Yield: 49.2 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2, 16 (25 mg, 0.055 mmol) and free based [(3S)-3-aminobutyl]tetrahydro-2H-thiopyran-4-ylamine (48 mg, 0.26 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4S,12aS)—N-[(4-fluorophenyl)methyl]-4-methyl-6,8-dioxo-7-[(phenylmethyl)oxy]-1-(tetrahydro-2H-thiopyran-4-yl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′;4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (16 mg, 49%) as a film. This material was debenzylated in a second step in a manner similar to Z-26 to give (4S,12aS)—N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(tetrahydro-2H-thiopyran-4-yl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (8 mg, 59%) as an off-white solid, 1H NMR (400 MHz, CDCl3) δ 1.30 (d, J=7.2 Hz, 3H), 1.53-1.58 (m, 1H), 1.72-2.10 (m, 5H), 2.56-2.76 (m, 5H), 2.84-2.87 (m, 2H), 4.18 (dd, J=2.8, 14.0 Hz, 1H), 4.26 (dd, J=3.4, 14.2 Hz, 1H), 4.92-4.97 (m, 1H), 6.96-7.00 (m, 2H), 7.29-7.36 (m, 2H), 8.31 (s, 1H), 10.48 (m, 1H), 12.48 (br, 1H); ES+ MS; 501 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C@@H:4]([CH:5]=[C:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C@H:3]1[C:13]([O:15][C@H:16]([C:30]#N)[C:17]1[CH:22]=CC=[C:19]([O:23]C2C=CC=CC=2)[CH:18]=1)=[O:14].[CH2:33]([C:36]1C(=O)CC(O)C=1C)[CH:34]=C>>[CH3:1][C:2]1([CH3:32])[C@H:4]([CH:5]=[C:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C@H:3]1[C:13]([O:15][CH:16]1[CH2:30][C:19](=[O:23])[C:18]([CH2:36][CH:33]=[CH2:34])=[C:17]1[CH3:22])=[O:14]
Reactant: CCOC(=O)C=C=C[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Reactant: C=CCC1=C(C)C(O)CC1=O
Product: C=CCC1=C(C)C(OC(=O)[C@@H]2[C@@H](C=C=CC(=O)OCC)C2(C)C)CC1=O

Procedure:
Using the procedure of Example 22, 1.5 g of (S) 3-allyl-2-metyl-1-hydroxy-2-cyclopenten-4-one were reacted to obtain 0.794 g of 3-allyl-2-methyl-4-oxo-2-cyclopenten-1-yl (1R,trans) 2,2-dimethyl-3-(4-ethoxy-4-oxo-1,2-butadienyl)-cyclopropanecarboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][C@H:9]1[CH2:20][OH:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.CS(C)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][C@H:9]1[CH:20]=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccccc2)C[C@H]1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccccc2)C[C@H]1C=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93 %

Procedure:
To a stirred mixture of (2S,4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidinylmethanol (2.75 g, 9.37 mmol), Et3N (7.84 ml, 56.2 mmol), DMSO (6.66 ml, 9.37 mmol) in CH2Cl2 (30 ml) at 0° C. was added SO3-pyridine (4.47 g, 28.1 mmol), then the resulting mixture was allowed to raise to room temperature. After 2.5 h stirring, the mixture was concentrated in vacuo. To the resulting mixture was added water and extracted with Et2O. The combined extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel [100 g, CHCl3/acetone (5/1)] to give (2S,4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidine carbaldehyde (2.54 g, 93%) as a yellow oil. 1H-NMR (CDCl3) δ1.45 (s, 9H, one of isomers), 1.49 (s, 9H, one of isomers), 2.17 (br, 2H), 3.65-4.31 (m, 3H), 4.91 (br, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.77 (m, 1H), 7.28 (m, 2H), 9.66 (m, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:11]([OH:13])=O)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O.CN(C)C=O.[CH:23]([OH:36])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(OC(C)C)(C)C>[CH:1]([O:36][CH:23]([CH3:24])[CH3:30])([CH3:6])[CH3:2].[C:1]1([CH:7]([C:8]([O:10][CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:9])[C:11]([Cl:16])=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: O=C(O)C(C(=O)O)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: O=C(Cl)C(C(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
Following the procedure of Goldman et al. (U.S. Pat. No. 3,773,757), phenylmalonic acid (72 g., 0.40 mole), thionyl chloride (52.4 g., 0.44 mole) and dimethylformamide (0.070 ml.) are mixed in diisopropyl ether and refluxed for 2 hours. The resulting solution of phenylmalonic acid-half acid chloride is cooled and stored under an inert atmosphere until use. Following a procedure analogous to that of Goldman et al., benzhydryl alcohol (73.6 g., 0.40 mole) is added to the half-acid chloride solution and the mixture again refluxed for 2 hours. The volume is reduced by half, providing a diisopropylether solution of 2-phenyl-2-benzhydryloxycarbonylacetyl chloride used directly in the next step.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:21][CH:22](C)[CH2:23][CH2:24][C:25](Cl)=[O:26].O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:25](=[O:26])[CH2:24][CH2:23][CH2:22][Cl:21])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CC(Cl)CCC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCCl)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.5 %

Procedure:
N-Benzylpiperazine (1.0 g, 5.7 mmole) and triethylamine (1.17 ml, 8.5 mmole) were combined in 20 ml of methylene chloride. 4-Chlorovaleryl chloride (0.945 ml, 8.5 mmole) in 10 ml of methylene chloride was added dropwise over 20 minutes and the reation mixture stirred for 16 hours at room temperature. Water (20 ml) was then added and the organic layer dried (anhydrous magnesium sulfate) and evaporated in vacuo to a gum. The gum was chromatographed on silica gel with ethyl acetate as eluant and tlc monitoring. Clean product fractions were combined and evaporated to yield the title product as a gum [920 mg, Rf 0.5 (ethyl acetate)].