Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1B1OC(C)(C)C(C)(C)O1.Br[C:29]1[CH:30]=[N:31][C:32]([O:35][CH2:36][C:37]2([CH3:48])[O:41][C:40]3=[N:42][C:43]([N+:45]([O-:47])=[O:46])=[CH:44][N:39]3[CH2:38]2)=[N:33][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1[C:29]1[CH:30]=[N:31][C:32]([O:35][CH2:36][C:37]2([CH3:48])[O:41][C:40]3=[N:42][C:43]([N+:45]([O-:47])=[O:46])=[CH:44][N:39]3[CH2:38]2)=[N:33][CH:34]=1
Reactant: CC1(COc2ncc(Br)cn2)Cn2cc([N+](=O)[O-])nc2O1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)C(=O)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3cnc(OCC4(C)Cn5cc([N+](=O)[O-])nc5O4)nc3)c(F)c2)C(=O)O1
Temperature: 100 °C
Yield: 39.2 %

Procedure:
A mixture of (S)—N-((3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide (0.14 g, 0.37 mmol) and 2-((5-bromopyrimidin-2-yloxy)methyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (0.105 g, 0.29 mmol) in toluene (2.5 mL), EtOH (1.5 mL), DMF (4 mL) and K2CO3 (2 M, 1 mL, 2 mmol) was purged with nitrogen. PdCl2(dppf) (12 mg, 0.015 mmol) was added and the mixture was refluxed (100° C.) under nitrogen for 1 h, then partitioned between EtOAc (150 mL) and water (100 mL). The aqueous layer was re-extracted with 100 mL EtOAc. The organic layer was washed with brine, dried (Na2SO4) and evaporated, column chromatography using gradient elution (DCM/MeOH 0 to 5%) gave the title compound as a brown solid (60 mg, 39%). APCI MS m/z 528.3 (M+H). 1H NMR (400 MHz, (CD3)2SO) δ 8.81 (d, J=1.3 Hz, 2H), 8.22 (t, J=5.8 Hz, 1H), 8.16 (s, 1H), 7.68 (t, J=8.8 Hz, 1H), 7.65 (dd, J=13.4, 2.2 Hz, 1H), 7.45 (dd, J=8.6, 2.2 Hz, 1H), 4.81-4.73 (m, 1H), 4.71 (d, J=11.9 Hz, 1H), 4.67 (d, J=11.9 Hz, 1H), 4.45 (d, J=11.0 Hz, 1H), 4.23 (d, J=11.0 Hz, 1H), 4.18 (t, J=9.1 Hz, 1H), 3.79 (dd, J=9.2, 6.4 Hz, 1H), 3.44 (t, J=5.5 Hz, 2H), 1.84 (s, 3H), 1.73 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[C:13](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[NH:20]/3)[CH:12]=[CH:11][N:10]=2)[CH2:5][CH2:4]1.[S:23]1[CH:27]=[CH:26][C:25]([C:28]2[N:33]=[C:32]([CH:34]=O)[CH:31]=[CH:30][CH:29]=2)=[CH:24]1.C(N(C(C)C)CC)(C)C.[Na]>C(Cl)Cl.CS(C)=O>[S:23]1[CH:27]=[CH:26][C:25]([C:28]2[N:33]=[C:32]([CH2:34][NH:1][CH2:2][CH:3]3[CH2:4][CH2:5][N:6]([C:9]4[N:14]=[C:13](/[CH:15]=[C:16]5/[C:17](=[O:22])[NH:18][C:19](=[O:21])[NH:20]/5)[CH:12]=[CH:11][N:10]=4)[CH2:7][CH2:8]3)[CH:31]=[CH:30][CH:29]=2)=[CH:24]1
Reactant: O=Cc1cccc(-c2ccsc2)n1
Reactant: NCC1CCN(c2nccc(/C=C3\NC(=O)NC3=O)n2)CC1
Agent: [Na]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1NC(=O)/C(=C/c2ccnc(N3CCC(CNCc4cccc(-c5ccsc5)n4)CC3)n2)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.8 %

Procedure:
A 2 dram round bottomed vial was charged with (Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)imidazolidine-2,4-dione (17 mg, 0.056 mmol), 6-(thiophen-3-yl)picolinaldehyde (10.64 mg, 0.056 mmol, 1 equiv.), diisopropylethylamine (0.1 mL, 0.573 mmol, 10 equiv.), and DMSO (1 mL). The reaction mixture was shaken for 1 h at room temperature then treated with sodium triacetoxyhydroborate (23.83 mg, 0.112 mmol, 2 equiv.) and DCM (0.5 mL). The reaction mixture was shaken overnight. The sample was then filtered through a 0.45 micron syringe filter. The DMSO solution was purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water gradient and trifluoroacetic acid as the modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) to provide the desired product (9.8 mg, 26.7 mg theoretical, 36%). LC-MS m/z 476 (M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]([C@@H:19]1[O:24][CH2:23][C@@H:22]([OH:25])[CH2:21][CH2:20]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:6]([C@@H:19]1[O:24][CH2:23][C@@H:22]([O:25][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:21][CH2:20]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CC[C@H](C(c2ccccc2)c2ccccc2)OC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CC[C@H](C(c2ccccc2)c2ccccc2)OC1
Yield: 78.7 %

Procedure:
Methanesulfonyl chloride (0.33 g, 2.87 mmol) was reacted with trans-2-diphenylmethyl-tetrahydropyran-5-ol 11 (0.38 g, 1.43 mmol) in the presence of triethylamine (0.22 g, 2.15 mmol) in methylene chloride (10 ml) to give trans-2-diphenylmethyl-tetrahydropyran-5-yl methanesulfonate 13 (0.39 g, 77.8%) as an oil (Procedure A).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7]O)[CH:3]=1.CCN(CC)CC.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.[CH:26]12[CH2:32][CH:29]([NH:30][CH2:31]1)[CH2:28][N:27]2[C:33]1[N:38]=[C:37]([NH2:39])[N:36]2[N:40]=[C:41]([C:43]3[O:44][CH:45]=[CH:46][CH:47]=3)[N:42]=[C:35]2[N:34]=1>C(Cl)Cl.CC#N>[O:44]1[CH:45]=[CH:46][CH:47]=[C:43]1[C:41]1[N:42]=[C:35]2[N:34]=[C:33]([N:27]3[CH2:28][CH:29]4[CH2:32][CH:26]3[CH2:31][N:30]4[CH2:7][C:4]3[CH:3]=[C:2]([CH3:1])[O:6][N:5]=3)[N:38]=[C:37]([NH2:39])[N:36]2[N:40]=1
Reactant: Cc1cc(CO)no1
Reactant: Nc1nc(N2CC3CC2CN3)nc2nc(-c3ccco3)nn12
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(CN2CC3CC2CN3c2nc(N)n3nc(-c4ccco4)nc3n2)no1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a separate flask, (5-methyl-isoxazol-3-yl)-methanol (32 mg, 0.28 mmol) was dissolved in 4 mL of CH2Cl2 along with 1.3 eq. of Et3N. The solution was cooled in an ice bath and methanesulfonyl chloride (1.2 eq) was added. The reaction mixture was warmed to room temperature and stirred for 45 minutes. It was then quenched with brine and the two layers were separated. The organic layer was dried with Na2SO4 and concentrated under reduced pressure to afford the mesylated derivative. This mesylate was then added to a solution containing 5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (0.14 mmol; see subpart (a) above), and Et3N (0.3 mmol) in 3 mL of CH3CN. The resulting reaction mixture was stirred at room temperature for 18 hours. It was then concentrated and purified by preparative HPLC to afford 2-furan-2-yl-5-[5-(5-methyl-isoxazol-3-ylmethyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine. 1H NMR (400 Hz, DMSO-d6) δ 8.20 (brs, 1H), 7.80 (d, J=1.0 Hz, 1H), 7.00 (d, J=3.6 Hz, 1H), 6.60 (dd, J=3.6, 1.0 Hz, 1H), 6.30 (s, 1H), 4.80 (brs, 2H), 4.20-4.30 (m, 8H), 2.35 (s, 3H), 2.30 (m, 1H). MS m/z: 394 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:27][C:28]#[N:29]>CN(C=O)C>[O:22]=[C:20]1[N:19]([CH2:27][C:28]#[N:29])[C:18](=[O:23])[C:17](=[CH:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:11][CH:12]=2)[S:21]1
Reactant: O=C1NC(=O)C(=Cc2ccc(OCCc3ccccc3)cc2)S1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCN1C(=O)SC(=Cc2ccc(OCCc3ccccc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-[4-(2-phenylethoxy)phenylmethylene]-2,4-thiazolidinedione Example 4 (1.0 g, 3.07 mmol) in 25 ml dry DMF was treated with NaH (0.1 g, 4.2 mmol) and stirred at room temperature for 10 min. The mixture was treated with chloroacetonitrile (0.3 g, 4 mmol) and stirred at room temperature for 24 h. The mixture was poured into 500 ml ice water, and the resulting tan solid was collected by filtration, washed with water, and dried to give the desired product in 75% (1.0 g) yield; mp 155-157° C.; NMR(CDCl3TMS): δ3.13 (t, 2H, ArCH2), 4.25 (t, 2H, OCH2), 4.60 (s, 2H, CH2CN), [7.00 (d, 2H), 7.45 (d, 2H) OPh], 7.26 (m, 5H, Ph), 7.94 (s, 1H, C=CH); Anal calcd for C20H16N2O2S, MW 364.42: C, 65.92; H, 4.43; N, 7.69; S, 8.80. Found: C, 66.15; H, 4.24; N, 7.93; S, 8.69. Mass spec m/e 365(M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:9][C:10]1[CH:23]=[CH:22][C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1.Cl[CH2:25][C:26](=[O:28])[CH3:27]>C(C(C)=O)C>[F:9][C:10]1[CH:23]=[CH:22][C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:25][C:26](=[O:28])[CH3:27])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1
Reactant: CC(=O)CCl
Reactant: Oc1ccc(Oc2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)COc1ccc(Oc2ccc(F)cc2)cc1

Procedure:
83 g of pulverised potassium carbonate and 4 g of of finely powdered potassium iodide are added to a solution of 94.1 g of 4-(4-fluorophenoxy)phenol in 400 ml of methyl ethyl ketone, and the mixture is heated to reflux temperature. With stirring, 64 g of freshly distilled chloroacetone are added dropwise over 1 hour, and the reaction mixture is stirred for a further 2 hours at reflux temperature. After cooling, the reaction mixture is filtered and the solvent is removed by vacuum distillation. The crude product is recrystallised from n-hexane/diethyl ether (5:1), to give the pure, colourless 1-[4-(4-fluorophenoxy)phenoxy]-2-propanone which melts at 56°-57° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S-:9])[CH:6]=[CH:7][CH:8]=1.Br[CH2:11][C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:11][C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCC(=O)CBr
Reactant: COc1cccc([S-])c1
Solvent: O
Product: CCCCCC(=O)CSc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a stirred solution of 3-methoxythiophenolate (45 g) in water (100 mL) at 15° C. was added dropwise over 20 minutes 1-bromo-2-heptanone (54.4 g). The reaction was stirred for 1 hour at room temperature then was extracted with diethyl ether (2×250 mL) and the ether extracts were washed in turn with water (2×100 mL) and 1N hydrochloric acid (2×100 mL). The dried (MgSO4) organic layers were combined and evaporated to yield crude 1-(3-methoxyphenylthio)-2-heptanone (71 g). The crude 1-(3-methoxyphenylthio)-2-heptanone (65 g) was added over 30 minutes with stirring to sulfuric acid at -10° C. After 30 minutes at -5° C., the reaction mixture was diluted carefully with ice (200 g) and the resulting solid was filtered off, washed with water and dried. Crystallization of the crude product from hexane gave 18.4 g of 6-methoxy-3-pentylbenzo[b]thiophene, mp 43°-45° C. A small sample was recrystallized from hexane to provide the analytical specimen, mp 45°-47° C. Anal. Calcd for C14H18OS: C, 71.75; H, 7.74; S, 13.68 Found: C, 71.81; H, 7.60; S, 13.37
Reaction SMILES: Br[C:2]1[C:3]([Cl:29])=[CH:4][C:5]([N+:26]([O-:28])=[O:27])=[C:6]([NH:8][CH2:9][CH:10]2[CH2:25][CH2:24][CH2:23][C:12]3([O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13]3)[CH2:11]2)[CH:7]=1.[Cu][C:31]#[N:32]>CN(C=O)C.[Cl-].[Na+].O>[Cl:29][C:3]1[CH:4]=[C:5]([N+:26]([O-:28])=[O:27])[C:6]([NH:8][CH2:9][CH:10]2[CH2:25][CH2:24][CH2:23][C:12]3([O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH2:13]3)[CH2:11]2)=[CH:7][C:2]=1[C:31]#[N:32]
Reactant: N#C[Cu]
Reactant: CC(C)(C)CN1CC2(CCCC(CNc3cc(Br)c(Cl)cc3[N+](=O)[O-])C2)OC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)CN1CC2(CCCC(CNc3cc(C#N)c(Cl)cc3[N+](=O)[O-])C2)OC1=O
Temperature: 180 °C
Reaction time: 0.33 h

Procedure:
A suspension containing 7-(((5-bromo-4-chloro-2-nitrophenyl)amino)methyl)-3-neopentyl-1-oxa-3-azaspiro[4.5]decan-2-one (0.260 g, 0.532 mmol) and copper (I) cyanide (0.333 g, 3.72 mmol) in DMF (2 mL) was subject to microwave heating at 180° C. for 1.5 h. The reaction was cooled to rt, diluted with brine solution, and stirred for 20 min. The mixture was filtered through a pad of celite, and the celite was washed with EtOAc. The combined filtrates were washed with EtOAc. The combined organics were washed with water, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified on a 24 g silica gel column (0-75% EtOAc/hexanes, 15 min gradient; 75% EtOAc/hexanes, 10 min; 35 mL/min elution; 254 nm detection) to afford the title compound as an orange solid. MS (m/z) 435.2 (M+H+).
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])[C:2]#[CH:3].S(=O)(=O)(O)[OH:11]>CO.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[O:11]=[C:2]([CH3:3])[CH2:1][O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: C#CCOCC(=O)OC
Reactant: O=S(=O)(O)O
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: CO
Product: COC(=O)COCC(C)=O
Temperature: 25 °C

Procedure:
The product from Example 1A (56 g, 0.44 mol) in methanol (1.5 L) was treated with mercury(II) acetate (14 g, 44 mmol), treated with concentrated sulfuric acid (3 mL), refluxed for 1 hour, allowed to cool to ambient temperature, concentrated to a volume of 200 mL, treated with 1M HCl (500 mL) and extracted with dichloromethane (thrice, 300 mL). The combined dichloromethane layers were dried (MgSO4), filtered, concentrated and distilled (65-95° C. at 1 torr) to provide the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1)=[CH2:2].Cl[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])(O)=O.[Na+].CC(C)=O>C(Cl)(Cl)Cl>[CH:1]([C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:13]2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: CCOC(=O)CCl
Reactant: C=Cc1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: C=Cc1ccc(CN2CCN(CC(=O)OCC)CC2)cc1
Yield: 43.5 %

Procedure:
Synthesized according to General Procedure B: 8 (5.33 g, 26.4 mmol, 1 equiv.), ethyl chloroacetate (3.1 mL, 29.0 mmol, 1.1 equiv.), NaHCO3 (2.77 g, 33.0 mmol, 1.25 equiv.), acetone (52.8 mL), chloroform (30.0 mL). Purification with flash column chromatography on silica gel (1:1 hexanes:EtOAc) afforded 9 (3.31 g, 70%) as an orange oil. 1H-NMR (500 MHz, CDCl3): δ 7.35 (d, 2H, J=8.0 Hz), 7.26 (d, 2H, J=8.0 Hz), 6.69 (dd, 1H, J=11.0, 17.5 Hz), 5.72 (dd, 1H, J=0.5, 17.5 Hz), 5.21 (dd, 1H, J=1.0, 11.0 Hz), 4.17 (q, 2H, J=7.0 Hz), 3.49 (s, 2H), 3.19 (s, 2H), 2.59 (br s, 4H), 2.52 (br s, 4H), 1.26 (t, 3H, J=7.0 Hz). 13C-NMR (125 MHz, CDCl3): δ 170.2, 137.7, 136.5, 136.4, 129.3, 126.0, 113.4, 62.6, 60.5, 59.5, 53.0, 52.7, 14.2.
Reaction SMILES: [O:1]=[C:2]1[CH:8]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])[CH2:7][S:6][CH:5]([C:20]2[CH:24]=[CH:23][S:22][CH:21]=2)[CH2:4][NH:3]1.Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].[H-].[Na+].C(OCC)(=O)C>CN(C)C=O.O>[O:1]=[C:2]1[CH:8]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])[CH2:7][S:6][CH:5]([C:20]2[CH:24]=[CH:23][S:22][CH:21]=2)[CH2:4][N:3]1[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]
Reactant: O=C1NCC(c2ccsc2)SCC1N1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CC(c2ccsc2)SCC(N2C(=O)c3ccccc3C2=O)C1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 69.4 %

Procedure:
To a suspension of 4.1 g of 5-oxo-6-phthalimido-2-(3-thienyl)perhydro-1,4-thiazepine [prepared as described in step (e) above] in 60 ml of dimethylformamide were added dropwise 2.2 g of t-butyl bromoacetate, followed by 593 mg of a 55% w/w suspension of sodium hydride in oil at 0° to -5° C. under a stream of nitrogen. The reaction mixture was stirred at 0° C. for 20 minutes and then poured into a mixture of ethyl acetate and water. The ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated off. The semi-solid residue was collected by filtration using ethyl acetate and diisopropyl ether, to yield 3.7 g of the title compound, melting at 157°-160° C. (with decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[C:17](/[CH:19]=[CH:20]/[CH:21]([C:26]2[CH:31]=[C:30]([Cl:32])[C:29]([Cl:33])=[C:28]([Cl:34])[CH:27]=2)[C:22]([F:25])([F:24])[F:23])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])=[O:5].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:18]=[C:17](/[CH:19]=[CH:20]/[CH:21]([C:26]2[CH:31]=[C:30]([Cl:32])[C:29]([Cl:33])=[C:28]([Cl:34])[CH:27]=2)[C:22]([F:24])([F:25])[F:23])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5]
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a stirred solution of (E)-tert-butyl 2-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamido)acetate (440 mg, 0.734 mmol) in DCM (36.0 ml), was added TFA (4.0 mL) and the reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure to obtain residue which was washed with n-pentane to afford the title compound as an off-white solid (310 mg, 78%): 1H NMR (400 MHz, CDCl3) δ 13.0 (s, 1H), 8.75 (t, J=5.7 Hz, 1H), 7.93 (m, 2H), 7.62 (d, J=7.5 Hz, 1H), 7.40 (d, J=8.1 Hz, 1H), 6.96 (dd, J=15.3, 9.3 Hz, 1H), 6.78 (d, J=15.3 Hz, 1H), 4.83 (m, 1H), 3.90 (d, J=5.7 Hz, 2H); ESIMS m/z 543.61 ([M+H]+); IR (thin film) 3429, 1635, 1114, 772 cm−1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH:26](N1CCOCC1)=[O:27]>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][O:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([CH:26]=[O:27])=[CH:16][CH:15]=2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Reactant: O=CN1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of 4-benzyl-6-(4-bromo-phenyl)-morpholine (1.73 g; 5.21 mmol) in THF (25 mL) was added dropwise n-BuLi (2.08 mL; 2.50 mol/l; 5.21 mmol), at −78° C. The resulting mixture was stirred for one hour, and subsequently a solution of N-formylmorpholine (0.90 g; 7.81 mmol) in THF (5 mL) was added dropwise, at −78° C. The reaction was quenched by the addition of an 5% aqueous NaHCO3 solution, at −70° C. The resulting mixture was extracted with Et2O. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O: hexanes 1:1) to afford 4-(4-benzyl-morpholin-2-yl)-benzaldehyde (1.21 g).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:21]=[C:16]3[NH:17][CH2:18][C:19](=[O:20])[N:15]3[CH2:14]2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[C].[Pd]>[NH:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:21]=[C:16]3[NH:17][CH2:18][C:19](=[O:20])[N:15]3[CH2:14]2)[CH2:9]1
Reactant: O=C1CNC2=CN(C3CCN(Cc4ccccc4)C3)CN12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C1CNC2=CN(C3CCNC3)CN12
Temperature: 25 °C
Yield: 75.9 %

Procedure:
6-(1-Benzyl-3-pyrrolidinyl)-1,2-dihydro-3H-imidazo[1,5-a]imidazol-3-one (2.7 g) obtained in Example 87a), ammonium formate (1.8 g) and 10% palladium carbon (0.54 g) suspended in methanol (100 ml), and heated under reflux for 2 hours. After cooling to room temperature, the precipitate was filtered using Celite, and then the filtrate was concentrated under reduced pressure. To the residue was added a mixed solvent (ethyl acetate:chloroform=5:1), the precipitate was filtered off, and then the filtrate was further concentrated to obtain the title compound as a pale yellow solid (1.4 g, 78%).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:14])[C:7]([CH3:13])=[C:8]([CH3:12])[C:9](=[O:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:15](O)(=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]C.C(#N)C>[N+]([O-])([O-])=O.[Ag+].O.CCCCCCC>[C:1]([C:5]1[C:6](=[O:14])[C:7]([CH3:13])=[C:8]([CH3:12])[C:9](=[O:11])[C:10]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1=C(C)C(=O)C(C(C)(C)C)=CC1=O
Reactant: CCCCCCC(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC#N
Solvent: CCCCCCC
Solvent: O
Product: CCCCCCC1=C(C(C)(C)C)C(=O)C(C)=C(C)C1=O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 8.6 %

Procedure:
To a 250 ml round bottom flask equipped with a stir-bar was added 5-tert-butyl-2,3-dimethyl-[1,4]benzoquinone (213; 0.68 g, 3.5 mmole), heptanoic acid (0.49 g, 3.7 mmole), AgNO3 (0.64 g, 3.8 mmole), acetonitrile (50 ml) and water (50 ml). The fully homogenous solution was heated to 70° C. under argon while an aqueous solution of K2S2O8 (0.91 g, 4.1 mmole in 30 ml water) was added dropwise over 2.5 hours using a syringe pump. The reaction mixture was allowed to stir an additional 30 minutes at 70° C., then cooled to room temperature. To the mixture was added heptane (100 ml) and water (100 ml). The organic layer was separated and washed with saturated NaHCO3 (1×50 ml) followed by brine (2×100 ml). The organic layer was dried over sodium sulfate and concentrated to a yellow oil. The crude product was further purified by preparative TLC (silica gel: 200×200×2 mm; 100% heptane loading; 5% EtOAc:heptane elution). The fastest running bands, as visualized by UV, were excised, extracted from the silica gel with methyl tert-butyl ether, and the extract concentrated to a yellow oil to give a yellow oil. The residue was further purified by flash chromatography [silica gel: 40 g; 0-20% 100% heptane loading; 0-20% EtOAc/heptane gradient elution] to give pure 2-tert-butyl-3-hexyl-5,6-dimethyl-[1,4]benzoquinone (214; 83 mg, 8.4%) as a yellow oil. 1H NMR (400 MHz; C6D6; ppm): 2.71-2.67 (m, 2H), 1.67-1.66 (m, 6H), 1.51-1.24 (m, 8H), 1.37 (s, 9H), 0.88 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:27](OCC)=[O:28])[C:15](=[O:26])[N:16]3[CH2:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:33][CH2:34][CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][C:38]1=[O:42]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:27]([NH:33][CH2:34][CH2:35][CH2:36][N:37]4[CH2:41][CH2:40][CH2:39][C:38]4=[O:42])=[O:28])[C:15](=[O:26])[N:16]3[CH2:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(C)(=O)=O)c1=O
Reactant: NCCCN1CCCC1=O
Product: CS(=O)(=O)CCCn1c(=O)c(C(=O)NCCCN2CCCC2=O)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[3-(methylsulfonyl)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 1-(3-aminopropyl)-2-pyrrolidinone employing methods similar to those described in Example 202 and was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.23 (t, J=5.5 Hz, 1 H), 8.55 (s, 1 H), 7.65 (s, 1 H), 7.20 (dd, J=8.5, 5.4 Hz, 2 H), 7.00 (t, J=8.8 Hz, 2 H), 4.39 (t, J=7.7 Hz, 2 H), 4.11 (s, 2 H), 3.46-3.35 (m, 6 H), 3.13 (t, J=7.1 Hz, 2 H), 2.94 (s, 3 H), 2.39 (t, J=8.2 Hz, 2 H), 2.19 (m, 2 H), 2.03 (m, 2 H), 1.85 (m, 2 H); HRMS C27H31FN4O6S (M+H)+ calcd 559.1948, found 559.2055.