Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11].N1C=CC=CC=1.[O:30](S(C(F)(F)F)(=O)=O)[S:31]([C:34]([F:37])([F:36])[F:35])(=O)=[O:32]>C(Cl)Cl>[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:14]=[CH:15]/[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[O:11][S:31]([C:34]([F:37])([F:36])[F:35])(=[O:32])=[O:30]
Reactant: COc1ccc(/C=C/c2cc(OC)c(O)c(OC)c2)cc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: N#N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(/C=C/c2cc(OC)c(OS(=O)(=O)C(F)(F)F)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round-bottomed flask (50 mL) equipped with magnetic stir bar and N2 bubbler was charged 6 (600 mg, 2 mmol), pyridine (332 mg, 4 mmol, 2 equiv) and CH2Cl2 (20 mL) The mixture was cooled in an ice bath before Tf2O (888 mg, 3 mmol, 1.5 equiv) was added dropwise over 20 min, during which the color changed from deep red to pale orange. Afterwards, the ice bath was removed and the reaction mixture was stirred at rt overnight. A work-up similar to that used in the preparation of 1a and 2a gave an oil that slowly crystallized in vacuo (790 mg, 90%). Recrystallization from heptanes/EtOAc gave compound 7 as clear, tan needles, mp. 104-106° C. (dec.). 1H NMR (CDCl3): δ 7.46 (d, J=8.7 Hz, 2H), 7.03 (d, Jab=16.1 Hz, 1H), 6.91 (d, J=8.7 Hz, 2H), 6.89 (d, Jab=16.3 Hz, 1H), 6.72 (s, 2H), 3.93 (s, 6H), 3.84 (s, 3H); 13C NMR (CDCl3): δ 160.00, 152.69, 138.64, 130.35, 129.59, 128.21, 125.75, 118.92 (q, 1JCF=321.3 Hz), 114.49, 102.94, 56.49, 55.58; 19F {13C} NMR (CDCl3): δ −74.11. Anal. Calcd for C18H17F3O6S: C, 51.67; H, 4.10. Found: C, 51.84; H, 3.97.
Reaction SMILES: [H-].[Na+].[C:3]([N:10]([CH2:14][CH2:15]Cl)[CH2:11][CH2:12]Cl)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].O.[CH3:18]N(C)C=O>>[C:3]([N:10]1[CH2:14][CH2:15][CH2:18][CH2:12][CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
Intermediate 1 (2.5 g, 8.3 mmol) was dissolved in dimethylformamide (6 mL), and added dropwise to a suspension of 60% sodium hydride in mineral oil (635 mg 16.6 mmol) in dimethylformamide (6 mL). When the effervescence had ceased the solution was treated with a solution of N—Boc-bis-(2-chloroethyl)amine (3.75 g, 12 mmol) in dimethylformamide (3 mL). The mixture was stirred at r.t. for 36 hrs. Water (800 mL) was added and the solution washed with ethyl acetate (2×500 mL). The organic phase washed with brine (500 mL), dried (MgSO4) and evaporated. The clear oil obtained was purified by column chromatography on silica gel eluting with 5-20% ethyl acetate in hexanes. The oil obtained was then further purified by column chromatography on silica gel eluting with dichloromethane to give the Boc-piperidine. 1H NMR (CDCl3) 7.41-7.34 (4H, m), 7.13-7.05 (2H, m), 6.91-6.83 (1H, m), 4.25-4.15 (2H, m), 2.72-2.56 (4H, m), 2.34-2.23 (2H, m) and 1.43 (9H, s)
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:8]([SH:9])=[N:7][N:6]=[N:5]1)#[N:2].[N-:10]=[N+:11]=[N-:12].CN(C)C(=[NH2+])N(C)C>O1CCOCC1>[NH:10]1[C:1]([CH2:3][N:4]2[C:8]([SH:9])=[N:7][N:6]=[N:5]2)=[N:2][N:12]=[N:11]1
Reactant: N#CCn1nnnc1S
Reactant: [N-]=[N+]=[N-]
Agent: CN(C)C(=[NH2+])N(C)C
Solvent: C1COCCO1
Product: Sc1nnnn1Cc1nnn[nH]1
Yield: 55 %

Procedure:
A solution of 6.0 g. (42.5 mmole) of 1-cyanomethyl-1H-tetrazol-5-thiol and 10.0 g. (6.3 mmole) of tetramethylguanidinium azide in 90 ml. of dioxane was heated at the reflux temperature for 3 hours. After cooling, the reaction mixture was evaporated to dryness in vacuo and the residue dissolved in ethyl acetate:water, 1:1. The ethyl acetate layer was separated, and the pH of the aqueous layer was adjusted to pH 1.8 with 20% hydrochloric acid. The acidified aqueous layer was then extracted 3 times with 75 ml. portions of ethyl acetate, and the extracts were combined. The extract was then washed with 5% hydrochloric acid, with brine, was dried over sodium sulfate, and then evaporated in vacuo to dryness. The red oil obtained as a residue crystallized on seeding. The crystals were washed with ethyl acetate and with diethyl ether and were dried. There were obtained 3.7 g. of the bis-tetrazolmethyl thiol melting at about 173° C. to about 175° C. The filtrate from the first crop was evaporated to an oil and after seeding the oil, 0.3 g. of a second crop crystalline product was obtained. A third crop of 0.3 g. was obtained in the same manner. Total yield of product was 4.3 g. (55% yield).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:9]=2[C:10]([NH:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][C:19](=[O:27])[N:20]3[CH2:23][C:24](O)=[O:25])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][NH2:37].C1COCC1.Cl>CO>[CH:1]1([NH:7][C:8]2[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:9]=2[C:10]([NH:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][C:19](=[O:27])[N:20]3[CH2:23][C:24]([NH:37][CH3:36])=[O:25])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN
Reactant: O=C(O)CN1C(=O)CCc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3NC3CCCCC3)cc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)CN1C(=O)CCc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3NC3CCCCC3)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of [7-{[2-(cyclohexylamino)-4-(trifluoromethyl)benzoyl]amino}-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetic acid (70 mg), N,N′-carbonyldiimidazole (70 mg), methylamine aqueous solution (1 mL) and THF was stirred at room temperature for 3 hours, mixed with methanol and stirred for 20 minutes. A 0.5 M hydrochloric acid was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol, 20:1 to 10:1) to obtain 2-(cyclohexylamino)-N-{1-[2-(methylamino)-2-oxoethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl}-4-(trifluoromethyl)benzamide (12 mg) as a solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[NH2:10][C:11]1[S:15][C:14]([NH:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[N:13][C:12]=1[C:27]([NH2:29])=[O:28].N1C=CC=CC=1>C1COCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:10][C:11]1[S:15][C:14]([NH:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[N:13][C:12]=1[C:27]([NH2:29])=[O:28])=[O:8]
Reactant: O=C(Cl)CCCCCBr
Reactant: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1N
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)CCCCCBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
A solution of 6-bromohexanoyl chloride (0.82 mL, 5.28 mmol) in THF (4 mL) was added dropwise to a mixture of 5-amino-2-(naphthalen-2-ylamino)thiazole-4-carboxamide (0.30 g, 1.06 mmol) and pyridine (4 mL) in THF (20 mL) at 0° C., and the mixture was stirred for 16 hrs at rt. The reaction mixture was quenched with ice-water. The resulting solids were collected by filtration and washed with ether and EtOAc to give 0.45 g (92% yield) of the titled compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:17]=1.[OH:18]CC1C=CC2CCC3C=CC=CC=3SC=2C=1>>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8](=[O:18])[C:7]=2[CH:17]=1
Reactant: OCc1ccc2c(c1)Sc1ccccc1CC2
Reactant: OCc1ccc2c(c1)Sc1ccccc1C=C2
Product: O=S1c2ccccc2C=Cc2ccc(CO)cc21

Procedure:
Repeat the process of Example 2, substituting an equivalent quantity of 3-hydroxymethyldibenzo[b,f]-thiepin for the 3-hydroxymethyl-10,11-dihydrodibenzo[b,f]thiepin, to obtain the title product (m.p., 146°-148° C.).
Reaction SMILES: [C:1]([O:9][CH:10]([O:14][C:15]([NH:17][CH2:18][C:19]1([CH2:25][C:26]([OH:28])=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:16])[CH:11]([CH3:13])[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]1C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CO>[C:1]([O:9][CH:10]([O:14][C:15]([NH:17][CH2:18][C:19]1([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:16])[CH:11]([CH3:12])[CH3:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(OC(=O)NCC1(CC(=O)O)CCCCC1)OC(=O)c1ccccc1
Reactant: c1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)CC1(CNC(=O)OC(OC(=O)c2ccccc2)C(C)C)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A mixture of 1-{[(α-benzoyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid (84) (150 mg, 0.38 mmol), benzene (18 mL), and methanol (2 mL) was cooled to 0° C. Trimethylsilyldiazomethane was added slowly at 0° C. until the yellow color persisted. The mixture was stirred at 0° C. for 30 min until the reaction was complete (monitored by TLC). After removing the solvent under reduced pressure, chromatography of the residue on silica gel, eluting with 5% ethyl acetate/hexane gave 98 mg (64%) of the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.02 (d, J=6.4 Hz, 3H), 1.03 (d, J=6.4 Hz, 3H), 1.32-1.52 (m, 10H), 2.14 (m, 1H), 2.27 (s, 2H), 3.17 (m, 2H), 3.62 (s, 3H), 5.40 (t, 1H), 6.81 (d, J=4.8 Hz, 1H), 7.40 (m, 2H), 7.54 (m, 1H), 8.12 (m, 2H). MS (ESI) m/z 406.29 (M+H+).
Reaction SMILES: C([Mg]Cl)(C)C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[C:9](I)[CH:8]=1.C[O:17][B:18](OC)[O:19]C.Cl>C1COCC1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[C:9]([B:18]([OH:19])[OH:17])[CH:8]=1
Reactant: COB(OC)OC
Reactant: CCc1ccc(Cl)cc1I
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCc1ccc(Cl)cc1B(O)O
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
i-Propylmagnesium chloride (2M sol. in THF, 8.98 mL, 17.95 mmol) was added drop wise to a solution of 4-chloro-1-ethyl-2-iodobenzene (4.35 g, 16.3 mmol) in dry THF (40 mL) at −30° C. and the reaction mixture was stirred at the same temperature for 30 min, under argon. After this time, trimethylborate (3.63 mL, 32.6 mmol) was added drop wise and the reaction mixture was stirred at the same temperature for 1.5 h. HCl (1 M, 16 mL) was added and the reaction mixture extracted with EtOAc (3×50 mL). The combined organic layers were dried over sodium sulfate and, after removal of the solvent, a solid was obtained, which was triturated with hexane to obtain the title compound as a white solid (2.15 g, 72%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[CH:12][CH:11]=1.[BH4-].[Na+]>CO>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=2)=[CH:2]1
Reactant: O=Cc1ccoc1
Reactant: COc1ccc(CN)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNCc2ccoc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-Furaldehyde (5 mmol, 437 μL) and (4-methoxyphenyl)methanamine in MeOH (20 mL) was stirred at ambient temperature overnight then sodium borohydride (300 mg, 7.89 mmol) was slowly added. The resulting mixture was stirred at room temperature for 15 minutes and quenched with NaOH (1 N, aq). Methanol was removed in vacuo and the resulting slurry was redissolved in ethyl acetate then, washed with water, brine, dried over sodium sulfate and concentrated. Purification by silica gel chromatography (Ethyl acetate:Hexanes 7:3) gave 1-(furan-3-yl)-N-(4-methoxybenzyl)methanamine as an oil. MS (M+H, 218.10); 1H NMR (400 MHz, CDCl3): δ, ppm: 3.64 (s, 2H), 3.74 (s, 2H), 3.80 (s, 3H), 6.39 (m, 1H), 6.86 (m, 1H), 6.88 (m, 1H), 7.23 (m, 1H), 7.25 (m, 1H), 7.35 (m, 1H), 7.38 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]34[CH2:20][CH2:19][C:16]([C:21]5O[C:23]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=6[C:32]([F:35])([F:34])[F:33])=[N:24][N:25]=5)([CH2:17][CH2:18]3)[CH2:15][CH2:14]4)[O:10][N:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[CH3:43][NH2:44]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]34[CH2:14][CH2:15][C:16]([C:21]5[N:44]([CH3:43])[C:23]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=6[C:32]([F:34])([F:35])[F:33])=[N:24][N:25]=5)([CH2:19][CH2:20]3)[CH2:17][CH2:18]4)[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: Fc1ccc(-c2noc(C34CCC(c5nnc(-c6ccccc6C(F)(F)F)o5)(CC3)CC4)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(c3nc(-c4ccc(F)cc4)no3)(CC1)CC2

Procedure:
A mixture of above 1,2,4-oxadiazole (7-E) (115.2 mg, 0.238 mmol) and the trifluoroacetic acid salt of methylamine (1.73 g, 11.9 mmol) in a 2M solution of methylamine in methanol (4 mL) was heated at 150° C. in a sealed tube for 48 h. The mixture was then concentrated, and the residue was taken up in dichloromethane, washed with saturated sodium bicarbonate aqueous solution. The organics were concentrated and the residue was purified using reverse-phase HPLC with TFA-buffered acetonitrile/water (40-80%) as eluent. The fractions containing the product were combined, neutralized with saturated sodium bicarbonate aqueous solution and lyophilized from acetonitrile/water to provide 3-(4-fluorophenyl)-5-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole (7-F). 1HNMR (CDCl3) δ 2.25-2.35 (m, 12H), 3.53 (s, 3H), 7.21 (t, J=8.7 Hz, 2H), 7.54 (m, 1H), 7.73 (m, 2H), 7.88 (m, 1H), 8.13 (m, 2H). ESI-MS m/z (M+H) 498.2.
Reaction SMILES: C(O)C.C(=O)(O)O.[NH2:8][C:9]([NH2:11])=[NH:10].[C:12](OCC)(=[O:17])[CH2:13][C:14]([CH3:16])=O>O>[NH2:10][C:9]1[NH:11][C:12](=[O:17])[CH:13]=[C:14]([CH3:16])[N:8]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)CC(C)=O
Agent: O=C(O)O
Solvent: O
Solvent: CCO
Product: Cc1cc(=O)[nH]c(N)n1
Temperature: 25 °C
Yield: 68 %

Procedure:
The title compound was prepared according to a literature method (Hirschberg, J. H. K., Beijer, F. H., van Aert, H. A., Magusin, P. C. M., Sijbesma, R. P., Meijer, E. W., Macromolecules, 1999, 32, 2696-2705, the disclosure of which is totally incorporated herein by reference). To a 1 liter round bottom flask under an inert argon atmosphere was added 650 milliliters of dry ethanol and 90.08 grams (0.5 mole) of guanidine carbonate. Thereafter, with good stirring was added dropwise over 2 hours 130.17 grams (1 mole) of ethyl acetoacetate, after which heat was applied and the mixture refluxed for 15 hours. The mixture was then cooled to room temperature and 800 milliliters of deionized water was slowly added to induce precipitation of the product. Subsequent vacuum filtration and washing with cold acetone secured the anticipated product in 68 percent yield (mp 311° C.). All physical properties were in accord with the reported properties.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[NH:24][C:23]2=[O:33])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1.[C:34](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:34])[C:23]2=[O:33])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.3 %

Procedure:
To a mixture of 0.10 g of methyl [3-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]-acetate, 1 ml of acetonitrile, and 31 mg of potassium carbonate was added 32 mg of methyl iodide, and the mixture was stirred at room temperature for 1.5 hours. Then, 64 mg of methyl iodide was added, and the mixture was stirred at 50° C. for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 97 mg of methyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate (compound a-6).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][NH:7][CH3:6])=[CH:17][CH:16]=1
Reactant: CN(CCCc1ccc(F)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
To a solution of [3-(4-fluoro-phenyl)-propyl]-methyl-carbamic acid tert-butyl ester (0.417 g, 1.560 mmol) in 3 mL of dichloromethane, was added trifluoroacetic acid (3 mL). After stirring at room temperature for 3 h, the reaction mixture was concentrated under reduced pressure. The residue was re-dissolved in 20 mL of ethyl acetate and the resulting solution was washed with NaOH solution (1N) and brine, and dried over anhydrous Na2SO4. Removal of the solvent under reduced pressure provided the title compound as a colorless oil (0.189 g, 72% yield), which was used directly in the next step (Step d of Specific Scheme 7) without further purification. GC-MS: tR=5.6 min; m/z 167 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[OH:11].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1
Reactant: COC(=O)c1cc(C)ccc1O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)ccc1OCc1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A mixture of 2-hydroxy-5-methylbenzoic acid methyl ester (4.98 g, 30 mmol), 4-methoxybenzyl chloride (4.69 g, 30 mmol) and K2CO3 (4.55 g, 33 mmol) in DMF (50 mL) is stirred at 60° C. for 48 h. The mixture is diluted with EtOAc and washed with 1N HCl and brine then the organic phase is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by column chromatography using a gradient of 0-100% EtOAc/hexane as eluent to give the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[S:17][C:16]([S:18][CH3:19])=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1.[C:21]1([CH2:27][C:28]([N:30]=[C:31]=[S:32])=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:20][C:31]([NH:30][C:28](=[O:29])[CH2:27][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[S:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[S:17][C:16]([S:18][CH3:19])=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: CSc1cc2ncnc(Oc3ccc(N)cc3F)c2s1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: C1CCOC1
Product: CSc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Reaction time: 2 h
Yield: 51.6 %

Procedure:
A mixture of 282 (248 mg, 0.80 mmol) and 2-phenylacetyl isothiocyanate (214 mg, 1.20 mmol) in THF (8 mL) was stirred for 2 hours, and concentrated. The residue was purified by flash column chromatography, eluent EtOAc/hexane (3:7), to afford title compound 283 (200 mg, 52% yield) as an off-white solid. 1H NMR (DMSO-d6) δ (ppm): 12.42 (s, 1H), 11.80(s, 1H), 8.63 (s, 1H), 7.85(d, 1H), 7.54-7.44 (m, 3H), 7.35 (m, 4H), 7.30 (m, 1H), 3.81 (s, 2H), MS (m/z): 485.1 (M+H) (found).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14]Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.3 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (610 mg) in N,N-dimethylformamide (20 mL) is added successively 2-dimethylaminoethyl chloride hydrochloride (1.08 g) and potassium carbonate (2.0 g), and the mixture is stirred at room temperature for 18 hours. To the reaction mixture is added ethyl acetate, and the mixture is washed with water and saturated brine and dried over anhydrous sodium sulfate. The resultant crude product is purified by column chromatography in silica gel (Solvent; chloroform:methanol=20:1→10:1) to give 4-[2-(dimethylamino)-ethoxy]benzaldehyde (640 mg, yield; 66%) as a pale yellow oil. MS (APCI) m/z: 194 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8])[NH:4][N:3]=1.[CH3:13][C:14](=O)[CH2:15][CH2:16][C:17](=O)[CH3:18]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:18][C:17]1[N:1]([C:2]2[CH:6]=[C:5]([C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8])[NH:4][N:3]=2)[C:14]([CH3:13])=[CH:15][CH:16]=1
Reactant: CON(C)C(=O)c1cc(N)n[nH]1
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CON(C)C(=O)c1cc(-n2c(C)ccc2C)n[nH]1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
A 250-mL round-bottomed flask equipped with a magnetic stirrer and a Dean-Stark trap was charged with 150b (11.0 g, 1.0 eq., 64.7 mmol), hexane-2,5-dione (11.1 g, 1.5 eq., 97.2 mmol), p-toluenesulfonic acid monohydrate (558 mg, 0.05 eq., 3.24 mmol), and toluene (100 mL). The reaction mixture was refluxed overnight. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with 1:2 petroleum ether/ethyl acetate to afford 150c (10.4 g, 65%) as a white solid. MS-ESI: [M+H]+ 249.0
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].COC(N1[C:13](=[O:14])[CH:12]=[CH:11][C:10]1=[O:15])=O.S(=O)(=O)(O)O>C(=O)(O)[O-].[Na+]>[OH:2][CH2:1][CH2:3][N:4]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]1=[O:15]
Reactant: COC(=O)N1C(=O)C=CC1=O
Reactant: NCCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C1C=CC(=O)N1CCO
Temperature: 0 °C
Yield: 96.1 %

Procedure:
As shown in FIG. 1, to a solution of ethanolamine (1.8 g, 29.5 mmol) in saturated sodium bicarbonate solution (100 ml) was added N-methoxycarbonylmaleimide (95 g, 32.3 mmol) in portions with vigorous stirring at 0° C. The mixture was allowed to warm to room temperature and stirred for 1 hour. The pH of the mixture was adjusted to 6-7 by careful addition of concentrated sulfuric acid (5 ml). The resultant solution was freeze dried and the solid residue extracted with ethyl acetate (2×400 ml) by stirring for 30 min. with each extraction. The ethyl acetate extracts were collected by filtration and evaporated in vacuo to afford N-(2-hydroxyethyl)maleimide (formula I) as a white solid (4.0 g, 96% yield); thin layer chromatography (TLC), Rf=0.27, ethyl acetate/petroleum ether 1:1.