Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[N:7][C:6]=12.[CH2:15]([C:17]1[S:21][C:20]([C:22]([OH:24])=[O:23])=[CH:19][C:18]=1B1OC(C)(C)C(C)(C)O1)[CH3:16].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:15]([C:17]1[S:21][C:20]([C:22]([OH:24])=[O:23])=[CH:19][C:18]=1[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[N:7][C:6]=12)[CH3:16]
Reactant: FC(F)(F)c1cnc2c(Br)cnn2c1
Reactant: CCc1sc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCc1sc(C(=O)O)cc1-c1cnn2cc(C(F)(F)F)cnc12
Temperature: 100 °C
Yield: 44.8 %

Procedure:
3-Bromo-6-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (165 mg, 0.620 mmol), 5-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylic acid (199 mg, 0.620 mmol), Pd2(dba)3 (56.8 mg, 0.062 mmol), tricyclohexylphosphine (43.5 mg, 0.155 mmol), and 1.27 M potassium phosphate tribasic (aq) (1.65 mL, 2.10 mmol) were placed in a sealed tube and purged with N2 for 5 min. The reaction was heated to 100° C. for 2 h. The reaction was then cooled to room temperature, diluted with water, and extracted with ethyl acetate 3×. The organic layers were combined, washed with brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (10-60% DCM/EtOAc). The fractions were combined and concentrated to give the title compound (95.0 mg, 0.278 mmol). LRMS (APCI) calc'd for (C14H10F3N3O2S) [M+H]+, 342.0; found 341.9.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH3:23])[C:9]3[N:13]=[C:12]([C:14]4[C:15](=[O:21])[NH:16][CH:17]=[CH:18][C:19]=4I)[NH:11][C:10]=3[CH:22]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:24]1([C@@H:30]([CH2:32][OH:33])[NH2:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN1CCOCC1>CN(C=O)C>[OH:33][CH2:32][C@@H:30]([NH:31][C:19]1[CH:18]=[CH:17][NH:16][C:15](=[O:21])[C:14]=1[C:12]1[NH:11][C:10]2[CH:22]=[C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:7]=[C:8]([CH3:23])[C:9]=2[N:13]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cc(-n2ccnc2)cc2[nH]c(-c3c(I)cc[nH]c3=O)nc12
Reactant: N[C@H](CO)c1ccccc1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(-n2ccnc2)cc2[nH]c(-c3c(N[C@H](CO)c4ccccc4)cc[nH]c3=O)nc12
Temperature: 80 °C
Yield: 52.1 %

Procedure:
To a solution of 3-(6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl)-4-iodo-1H-pyridin-2-one (30 mg, 0.072 mmol) in DMF (1 mL) were added (S)-(−)-2-phenylglycinol (26 mg, 0.18 mmol) and N-methylmorpholine (0.1 mL). The reaction mixture was heated to 80° C. for 6 h and cooled to room temperature. The solvent was removed under vacuum and the residue was purified by prep. HPLC to yield the title compound (16 mg, 52%). 1H NMR (300 MHz, CD3OD) δ 8.07 (1H, narrow t, J=1.7 Hz), 7.76 (2H, s), 7.27–7.48 (7H, m), 7.21 (1H, d, J=7.5 Hz), 6.11 (1H, d, J=7.5 Hz), 4.92 (1H, m), 4.03 (1H, dd, J=4.5, 11.2 Hz), 3.95 (1H, dd, J=6.2, 11.2 Hz), 2.75 (3H, s). LCMS (M+H)+ m/z 427 (t=1.44 min.)
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:28]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH3:28])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Oc3ccc(F)cc3)ccc2c1O
Reactant: CB1OB(C)OB(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCCOC(=O)c1nc(C)c2cc(Oc3ccc(F)cc3)ccc2c1O
Reaction time: 2 h
Yield: 62 %

Procedure:
A mixture of 1-bromo-7-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (434 mg, 1 mmol), Pd(PPh3)4 (116 mg, 0.1 mmol), trimethylboroxine (140 μl, 1 mmol), K2CO3 (414 mg, 3 mmol), and 1,4-dioxane (8 ml) was refluxed with stirring for 2 h. Subsequently, the mixture was concentrated in vacuo. To the residue was added water (10 ml). The mixture was acidified by the addition of aqueous 6N HCl and then extracted with EtOAc (40 ml). The organic phase was dried over MgSO4 and evaporated in vacuo. Purification of the residue by flash column chromatography on silica gel using hexanes:EtOAc=94:6 as the eluent gave the title compound as white solid (229 mg); MS-(+)-ion: M+1=370.1.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:22])=O>C(Cl)Cl.CN(C=O)C>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([Cl:22])=[O:18])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, to a solution of 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetic acid (9) (1.00 g, 3.76 mmol) in CH2Cl2 (10 mL) was added DMF (3 drops) by a Pasteur pipette at room temperature. To this was added oxalyl dichloride (640 μL, 7.56 mmol) at 0° C. and the mixture was stirred for 30 minutes while elevating to room temperature. The mixture was concentrated under reduced pressure to give crude 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) as a colorless oil, which was used in the following reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:9]([C:12]2[N:13]=[N:14][N:15]([CH2:17][CH3:18])[N:16]=2)[CH2:10][OH:11])=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)=[C:9]([C:12]2[N:13]=[N:14][N:15]([CH2:17][CH3:18])[N:16]=2)[CH:10]=[O:11])=[CH:4][CH:3]=1
Reactant: CCn1nnc(C(CO)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: CCn1nnc(C(C=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Yield: 79.6 %

Procedure:
The reaction of 4.0 g (12.0 mmoles) of 3,3-bis(4-fluorophenyl)-2-(2-ethyl-2H-tetrazol-5-yl)-2-propenol with pyridinium chlorochromate (4.5 g) was carried out by the procedure described in Example 48 and there was thereby produced 3.25 g (79.7%) of the title compound; m.p.=138°-139° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1.O[CH2:43][C:44]1[CH:45]=[C:46]([CH:59]=[CH:60][CH:61]=1)[CH2:47][C:48]12[CH:58]=[CH:57][CH:56]=[CH:55][CH:49]1[C:50]([NH:52][C:53]2=[O:54])=[O:51]>C1COCC1>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:43][C:44]2[CH:45]=[C:46]([CH:59]=[CH:60][CH:61]=2)[CH2:47][C:48]23[CH:58]=[CH:57][CH:56]=[CH:55][CH:49]2[C:50]([NH:52][C:53]3=[O:54])=[O:51])=[CH:37][CH:36]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C1NC(=O)C2(Cc3cccc(CO)c3)C=CC=CC12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1NC(=O)C2(Cc3cccc(COc4ccc(Cl)cc4)c3)C=CC=CC12
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
Triphenylphosphine (280 mg, 1.07 mmol) was dissolved in dry THF (2 mL) under an atmosphere of argon. After cooling to −40° C., DIAD (0.21 mL, 1.07 mmol) was added and the mixture was stirred at −40° C. for 10 min. A solution of 4-chlorophenol (138 mg g, 1.07 mmol) and 2-(3-hydroxymethylbenzyl)-phthalimide (261 mg, 0.98 mmol) in dry THF (3 mL) was added dropwise. After addition, the cooling bath was removed and stirring was continued for 2 h. The solution was diluted with Et2O (40 mL) and washed with pH-7-phosphate buffer solution (1×20 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting residue was purified by flash chromatography (EtOAc/hexane 1:5) to give the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=1[O:26][CH3:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CN1CCCC1=O>CO>[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[C:3]3[NH:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:21][C:20]=1[O:26][CH3:27])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1cc(N)ccc1OCc1ccccc1
Reactant: Clc1ncnc2cc[nH]c12
Solvent: CN1CCCC1=O
Solvent: CO
Product: COc1cc(Nc2ncnc3cc[nH]c23)ccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 59.7 %

Procedure:
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (200 mg), 4-(benzyloxy)-3-methoxyaniline (298 mg) and 1-methyl-2-pyrrolidone (5 mL) was stirred at 80° C. for 4 hrs. Methanol and activated carbon were added to the reaction mixture and the mixture was stirred. The activated carbon was filtered off, aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=10:80→20:80) and recrystallized from methanol-ethyl acetate to give the title compound (269 mg) as a pale-gray powder.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:13])/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].[C:14](O)(=[O:34])[CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O>[C:14]([NH:2][CH2:3][CH2:4][NH:5][C:6](=[O:13])/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])(=[O:34])[CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH3:33]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Reactant: COC(=O)/C=C/C(=O)NCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)NCCNC(=O)/C=C/C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
The HCl salt of (E)-methyl 4-(2-aminoethylamino)-4-oxobut-2-enoate (0.735 mmol) was taken up in 40 mL of CH3CN along with (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoic acid (EPA, 222 mg, 0.735 mmol), HATU (307 mg, 0.81 mmol) and DIEA (380 μL). The resulting reaction mixture was stirred at room temperature for 2 h and diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3, brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (95% CH2Cl2, 5% MeOH) afforded 300 mg of (E)-methyl 4-(2-(5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenamidoethylamino)-4-oxobut-2-enoate (89% yield). MS (EI) calcd for C27H40N2O4: 456.3. found: 457 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[C:11]1[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=1.[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:19][CH2:18][C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:4][C:3]=1[C:11]1[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=1
Reactant: Cn1cc(-c2cc(CCO)ccc2F)cn1
Reactant: C=CC(=O)OC(C)(C)C
Product: Cn1cc(-c2cc(CCOCCC(=O)OC(C)(C)C)ccc2F)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triton-B (0.4 ml, 0.88 mmol) was added to a stirred mixture of 2-(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethanol [Example 13, Step iii)] (1.7 g) and tert-butyl acrylate (8 mL). The mixture was stirred at room temperature over 1 h. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% ethyl acetate in isohexane to afford tert-butyl 3-(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanoate (2.65 g) as a colorless liquid. MS [M+H-C4H8]+=293 (MultiMode+) 1H NMR (300 MHz, CDCl3) δ 7.84 (s, 1H), 7.77 (d, J=2.5 Hz, 1H), 7.40-7.35 (m, 1H), 7.05-6.98 (m, 2H), 3.96 (s, 3H), 3.69 (t, J=6.4 Hz, 2H), 3.66 (t, J=6.9 Hz, 2H), 2.86 (t, J=6.9 Hz, 2H), 2.48 (t, J=6.4 Hz, 2H), 1.43 (s, 9H)
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1)([O-:20])=[O:19]>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:25][C:24]3[CH:27]=[CH:28][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][CH:23]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Solvent: CCO
Solvent: C1CCNCC1
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N=Cc1ccc([N+](=O)[O-])cc1

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide (100 mg) was suspended in EtOH (4 mL) and 4-nitrobenzaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 3-((3-chlorophenyl)amino)-5-((4-nitrobenzylidene)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH3:24][N:25]=[C:26]=[O:27]>O1CCCC1>[CH3:24][NH:25][C:26](=[O:27])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[CH:9]=[CH:10]2
Reactant: Oc1ccc2c(ccn2Cc2ccncc2)c1
Reactant: CN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1ccc2c(ccn2Cc2ccncc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(4-pyridinylmethyl)-1H-indol-5-ol (2.4 g) in 50 ml tetrahydrofuran, was added milled K2CO3 (1.5 g), followed by methyl isocyanate (0.65 ml). After stirring at ambient temperature for three hours, the mixture was filtered and the filtrate evaporated to a solid, 3.0 g, m.p. 170° C. This material was eluted on a silica gel column with 2% methanol/dichloromethane via high pressure liquid chromatography (HPLC) and the desired fractions were combined, then evaporated to yield 2.4 g of 1-(4-pyridinylmethyl)-1H-indol-5-yl methylcarbamate, as a solid, m.p. 179°-180° C.
Reaction SMILES: CS(C)=O.[Br:5][C:6]1[C:7]([Cl:25])=[C:8]([C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])[C:9]([Cl:16])=[N:10][C:11]=1S(C)(=O)=O.[K].[C:27](#[N:29])C>>[Br:5][C:6]1[C:7]([Cl:25])=[C:8]([C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])[C:9]([Cl:16])=[N:10][C:11]=1[C:27]#[N:29]
Reactant: CC#N
Reactant: CS(=O)(=O)c1nc(Cl)c(-c2c(F)cccc2Cl)c(Cl)c1Br
Agent: [K]
Solvent: CS(C)=O
Product: N#Cc1nc(Cl)c(-c2c(F)cccc2Cl)c(Cl)c1Br
Temperature: 60 °C
Reaction time: 6 h

Procedure:
At room temperature, a spatula tip (about 10 mg) of crown ether (18-crown-6) and 1 ml of dimethyl sulfoxide were added to 1.65 g (3.8 mmol) of 5-bromo-3-(2-chloro-6-fluorophenyl)-2,4-dichloro-6-methylsulfonylpyridine (Example F) dissolved in 50 ml of acetonitrile, and the mixture was heated to 60° C. Over a period of 6 h, 500 mg (7.6 mmol) of potassium cyamide were then added a little at a time at this temperature. The mixture was stirred at room temperature overnight and chromatographed directly on silica gel using cyclohexane/ethyl acetate. Yield 0.57 g of a solid, m.p. 90° C. 1H-NMR (CDCl3) δ=7.18 (m); 7.40 (m).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C(O)[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P([O-])([O-])([O-])=O>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5]
Reactant: OCC=Cc1ccccc1
Reactant: CCC(=O)CC(=O)OC
Agent: CN(C)c1ccncc1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCC(=O)CC(=O)OCC=Cc1ccccc1

Procedure:
1.26 ml (10.0 mmol) of methyl 3-oxovalerate, 2.57 ml (20.0 mmol) of cinnamyl alcohol and 122 mg (1.0 mmol) of 4-dimethylaminopyridine were heated under reflux in 20 ml of toluene overnight. A phosphate buffer solution was added to the reaction liquid. After the extraction with ethyl acetate, the organic layer was washed with saturated aqueous salt solution and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (hexane/ethyl acetate=9/1) to obtain the title compound.
Reaction SMILES: [SH:1][CH:2]1[C:11]2[C:6](=[C:7]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[C:18]1([C:24]2[N:25]=[C:26]([CH2:35]Br)[O:27][C:28]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:18]1([C:24]2[N:25]=[C:26]([CH2:35][S:1][CH:2]3[C:11]4[C:6](=[C:7]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:9][CH:10]=4)[CH2:5][CH2:4][CH2:3]3)[O:27][C:28]=2[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)COc1cccc2c1CCCC2S
Reactant: BrCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1CCCC2SCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Yield: 58.6 %

Procedure:
A solution of 1-hydroxy-1,2,3,4-tetrahydro-5-methoxycarbonylmethoxynaphthalene (0.42 g) and Lawesson's reagent (0.40 g) in toluene (4 ml) was refluxed under N2 atmosphere for 1 hour. The reaction mixture was purified by chromatography on silica gel to give 1-mercapto-1,2,3,4-tetrahydro-5-methoxycarbonylmethoxynaphthalene (0.20 g). A solution of 1-mercapto-1,2,3,4-tetrahydro-5-methoxycarbonylmethoxynaphthalene (0.26 g), (4,5-diphenyloxazol-2-yl)methyl bromide (0.32 g) and potassium carbonate (0.14 g) in DMF (5 ml) was stirred for 6 hours at room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-[(4,5-diphenyloxazol-2-yl)methylthio]-1,2,3,4-tetrahydro-5-methoxycarbonylmethoxynaphthalene (0.29 g). MS (m/z): 486 (M+ +1) NMR (CDCl3, δ): 1.75-1.92 (1H, m), 2.00-2.22 (3H, m), 2.45-2.72 (1H, m), 2.80-3.02 (1H, m), 3.79 (3H, s), 3.91 (1H, s), 3.94 (1H, s), 4.36 (1H, m), 4.60 (2H, s), 6.50-6.55 (1H, m), 7.04-7.06 (2H, m), 7.33-7.40 (6H, m), 7.59-7.68 (4H, m)
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]([O:10][CH:11](O)[CH3:12])[CH:8]=[CH2:9].S(=O)(=O)(O)O>>[C:1]([O:6][CH2:12][CH2:11][O:10][CH2:7][CH:8]=[CH2:9])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: C=CCOC(C)O
Agent: O=S(=O)(O)O
Product: C=CCOCCOC(=O)C(=C)C

Procedure:
First, methacrylic acid was reacted with allyloxy ethanol in the presence of the catalyst of sulfuric acid by a usual esterification method to form allyloxyethyl methacrylate (boiling point=64° C.-65° C./2 mmHg, n20D=1.4463, specific gravity d20 4=0.982).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].[Li]C(C)(C)C.[CH3:16][CH:17]1[CH2:22][CH2:21][O:20][C:18]1=[O:19]>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:18](=[O:19])[CH:17]([CH3:16])[CH2:22][CH2:21][OH:20])=[C:3]([CH3:10])[CH:4]=1
Reactant: COc1ccc(Br)c(C)c1
Reactant: CC1CCOC1=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C(C)CCO)c(C)c1
Temperature: -68 °C
Reaction time: 1 h
Yield: 106.3 %

Procedure:
To a 200 mL, 3-neck round bottom flask, equipped with an internal temperature controller, was added a solution of 4-bromo-3-methylanisole (2.77 g, 16.3 mmol) in 40 mL of THF under nitrogen. The solution was cooled to −68° C. with a dry ice/acetone bath. To this solution was slowly added t-BuLi (21.0 mL, 1.70 M in pentane, 35.8 mmol) followed by the addition of a solution of α-methyl-γ-butyrolactone (2.30 m L, 24.4 mmol) in THF (10.0 mL). The internal temperature was controlled <−55° C. After 1 h stirring at <−55° C., the reaction mixture was quenched with saturated NH4Cl solution and warmed to room temperature. Water and EtOAc were added and separated. The aqueous layer was extracted with EtOAc (2×). The combined organic solutions was dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to dryness to give 3.85 g of 1-(4-methoxy-2-methylphenyl)-4-hydroxy-2-methylbutan-1-one as light yellow oil, which was combined with another batch of material and subjected to column chromatography to give 1.26 g (18%) of clear oil. This material was used for Swern oxidation. To a 100 mL, 3-neck round bottom flask, equipped with an internal temperature controller, was added DMSO (1.75 mL, 24.6 mmol) and CH2Cl2 (20 mL). The solution was cooled to −80° C. with a MeOH/liquid nitrogen bath. To this solution was added oxalyl chloride (1.10 mL, 12.3 mmol) slowly via syringe pump. The mixture was stirred at −80° C. for 15 min followed by the addition of a solution of the above 1-(2-methyl-4-methoxyphenyl)-4-hydroxy-2-methylbutan-1-one (1.23 g) in CH2Cl2 (3.0 mL) slowly via syringe pump. After stirring at <−70° C. for 1 h, to the mixture was added Et3N (7.70 mL, 55.0 mmol). The cooling bath was removed after 5 min and the mixture was stirred at room temperature for 1.5 h. The mixture was diluted with hexanes (120 mL) and washed with water. The aqueous layer was extracted with hexanes. The combined organic solutions was concentrated in vacuo to dryness and the residue was subjected to column chromatography (silica gel, 1/6 EtOAc/heptane) to give 0.326 g (27%) of light yellow oil as the title compound: compound: 1H NMR (400 MHz, CDCl3) δ 9.87 (s, 1H), 7.82 (d, J=8 Hz, 1H), 6.83 (d, J=3 Hz, 1H), 6.81 (s, 1H), 3.94–3.86 (m, 4H), 3.20–3.13 (m, 1H), 2.62–2.56 (m, 1H), 2.51 (s, 3H), 1.21 (d, J=7 Hz, 3H); MS m/z 221.1 (M++H).
Reaction SMILES: [CH3:1][N+:2]([CH3:20])=[C:3]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4]1.Cl.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[OH2:4].[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:35])[CH2:30][CH2:31][N:32]([CH2:5][CH2:6][C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:3]([N:2]([CH3:20])[CH3:1])=[O:4])[CH2:33][CH2:34]2)=[CH:25][CH:24]=1
Reactant: C[N+](C)=C1OCCC1(c1ccccc1)c1ccccc1
Reactant: OC1(c2ccc(Br)cc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CN(C)C(=O)C(CCN1CCC(O)(c2ccc(Br)cc2)CC1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 12.1 parts of dimethyl (tetrahydro-3,3-diphenyl-2-furylidene) ammonium 10 bromide, 8.8 parts of 4-(p-bromophenyl)-4-piperidinol hydrochloride, 10.6 parts of sodium carbonate, 0.5 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 14 hours with water separator. The reaction mixture is cooled and water (200 parts) is added. The organic layer is separated, washed with diluted sodium hydroxide solution, dried, filtered, and while stirring the filtrate, the product is crystallized. It is filtered off and recrystallized from 80 parts of 4-methyl-2-pentanone (activated charcoal), yielding 4-(p-bromophenyl)-4-hydroxy-N,N-dimethyl-α,α-diphenylpiperidine-1-butyramide hydrate; m.p. 123.7° C.