Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[C:18]2[N:19]=[C:20]3[N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23][CH2:22][N:21]3[C:17]=2[C:16]2[C:11](=[CH:12][C:13]([Br:33])=[CH:14][CH:15]=2)[N:10]=1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:33][C:13]1[CH:12]=[C:11]2[C:16]([C:17]3[N:21]4[CH2:22][CH2:23][CH2:24][NH:25][C:20]4=[N:19][C:18]=3[C:9]([NH2:8])=[N:10]2)=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCCn2c1nc1c(N)nc3cc(Br)ccc3c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc2cc(Br)ccc2c2c1nc1n2CCCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (4 mL) was added to a solution of tert-butyl 6-amino-3-bromo-10,11-dihydropyrimido[1′,2′:1,2]imidazo[4,5-c]quinoline-8(9H)-carboxylate (0.16 g) in dichloromethane (0.400 mL), and the resulting solution was stirred for two hours at room temperature. An analysis by LC/MS indicated the presence of starting material, and additional trifluoroacetic acid was added. The reaction was stirred for an additional four hours, concentrated under reduced pressure, and purified according to the method of Examples 8 through 12 to provide 3-bromo-8,9,10,11-tetrahydropyrimido[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine trifluoroacetate, observed accurate mass 318.0367 (M+H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)(=O)=O.[Cl-].[Li+].Cl[C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[CH:30][CH:29]=1.C[Sn](C)C.C[Sn](C)C.[F-].[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>[N:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:28]([C:7]2[N:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[CH:29][CH:30]=1
Reactant: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)C(F)(F)F)nc23)CC1
Reactant: Clc1ccnc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Agent: [Cl-]
Solvent: C1COCCO1
Product: CN1CCC(c2c[nH]c3ccc(-c4ccnc5ccccc45)nc23)CC1
Temperature: 105 °C
Yield: 45.7 %

Procedure:
O-Trifluoromethanesulfonyl-3-(1-methylpiperidin-4-yl)-5-hydroxy-4-aza-1H-indole (239 mg, 0.658 mmol), tetrakis(triphenylphosphine)palladium(0) (76 mg, 0.065 mmol), dried lithium chloride (167 mg, 3.95 mmol), 4-chloroquinoline (108 mg, 0.658 mmol), hexamethylditin (215 mg, 0.658 mmol), and 15 mL of 1,4-dioxane were placed in a flask and heated to reflux (about 105° C.). The reaction was stirred for about 18 hours before 50 mL of 8M aqueous potassium fluoride solution was added. The solution was extracted with 3:1 chloroform:isopropanol and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (0-10% methanol:dichloromethane) to give 103 mg of the title compound. (46%). MS(FD) m/e 343.2 (M+H). EA calculated for C22H22N4: C, 77.16; H, 6.48; N, 16.36. Found: C, 76.98; H, 6.55; N, 16.29.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([Cl:17])[CH:13]=[CH:12]2.[C:18](=[O:20])=[O:19]>C1COCC1>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[C:7]([C:18]([OH:20])=[O:19])[CH:8]=[CH:9][CH:10]=2)[N:15]=1
Reactant: O=C=O
Reactant: Clc1ccc2cccc(Br)c2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cccc2ccc(Cl)nc12
Yield: 99 %

Procedure:
nBuLi (2.2M in hexanes; 7.50 ml, 16.49 mmol) was added dropwise over 2 min to a solution of 8-bromo-2-chloroquinoline (4.00 g, 16.49 mmol, Biofine International, Inc., Vancouver, BC) in THF (82 ml) at −78° C. The resulting mixture was stirred at −78° C. for 20 min before CO2 was bubbled into the solution for 5 min at −78° C. The mixture was quenched with 2 N HCl (10 ml). The resulting mixture was partitioned between 100 ml of Et2O and 1 N NaOH. The organic layer was separated, and the aq. layer was acidified to ˜pH 2 with 5 N HCl and extracted 3 times with 150 ml Et2O. The combined organic extracts were dried over Na2SO4 and concentrated to provide 2-chloroquinoline-8-carboxylic acid (181a, >99% yield) as a light brown solid. MS (ESI, pos. ion) m/z: 208.2 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[IH:10].[CH3:11][NH:12][C:13](=[N:16][CH3:17])SC.CS>C(O)C>[IH:10].[CH3:11][NH:12][C:13]([NH:16][CH3:17])=[N:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN=C(NC)SC
Reactant: NCCc1ccccc1
Agent: CS
Agent: I
Solvent: CCO
Product: CNC(=NCCc1ccccc1)NC

Procedure:
2-phenylethylamine (2.4 g.), N,N',S-trimethylisothiourea hydriodide (4.92 g.) and ethanol (70 ml.), were boiled together under reflux for eight hours; methyl mercaptan was evolved. The resulting solution was evaporated to dryness and the residue recrystallised from methanol/ether mixture to yield N,N'-dimethyl-N"-2-phenylethylguanidine hydriodide, melting point 156°-160°C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[CH:4][N:3]=1.[CH3:10][C:11]([CH3:13])=O.C([BH3-])#N.[Na+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:11]([CH3:13])[CH3:10])=[CH:4][N:3]=1
Reactant: CC(C)=O
Reactant: Nc1cnc(Cl)nc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)Nc1cnc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
In a 100 mL flask containing 2,4-dichloropyrimidin-5-amine (1.0 g, 6.10 mmol) in 16.5 mL of dichloromethane was added acetone (1.062 g, 18.29 mmol). The solution was cooled to 0° C. then a solution of titanium tetrachloride (0.740 mL, 6.71 mmol) in 10 mL of dichloromethane was added slowly. The mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (1.150 g, 18.29 mmol) was added in 4 equal portions over 10 minutes and the reaction was stirred at room temperature for 2 hours. The reaction was quenched with water (150 mL) and extracted with t-BuOMe twice. The organic layers were combined, dried with Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in methanol and adsorbed onto silica. The residue was purified on silica gel using 0-10% methanol in dichloromethane as eluent. Relevant fractions were evaporated in vacuo to give 940 mg (74%) of 2,4-dichloro-N-isopropylpyrimidin-5-amine as a pale yellow oil. MS [M+H] Found 206.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6]C=CC=1.C1(CN2CCN(C3SC(C(O)=O)=C(C)N=3)C2=O)CC1.[NH2:42][CH2:43][C:44]1[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=1>>[CH:2]1([CH2:1][N:8]2[CH2:12][CH2:11][N:10]([C:13]3[S:14][C:15]([C:19]([NH:42][CH2:43][C:44]4[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=4)=[O:21])=[C:16]([CH3:18])[N:17]=3)[C:9]2=[O:22])[CH2:7][CH2:6]1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 33 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine in place of benzylamine, the title compound was obtained as a white powder in 33% yield: mp 157-158° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.53-8.47 (m, 2H), 8.42-8.40 (m, 1H), 7.68-7.64 (m, 1H), 7.33-7.29 (m, 1H), 4.34 (d, J=5.7 Hz, 2H), 3.99 (t, J=7.2 Hz, 2H), 3.61 (t, J=7.2 Hz, 2H), 3.05 (d, J=6.9 Hz, 2H), 2.43 (s, 3H), 1.03-0.88 (m, 1H), 0.53-0.37 (m, 2H), 0.25-0.12 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 162.3, 157.9, 155.2, 151.7, 149.3, 148.5, 135.6, 135.5, 123.9, 117.7, 48.2, 42.5, 42.3, 41.5, 17.6, 9.3, 3.6: MS (ES+) m/z 372.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9][C:10]#[CH:11])=[C:4]([Cl:12])[N:3]=1.[C:13]([O-:16])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH2:9]([C:5]1[C:6]([Cl:8])=[N:7][C:2]([NH:1][CH:13]=[O:16])=[N:3][C:4]=1[Cl:12])[C:10]1[CH:10]=[CH:9][CH:5]=[CH:4][CH:11]=1
Reactant: O=C([O-])O
Reactant: C#CCc1c(Cl)nc(N)nc1Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=CNc1nc(Cl)c(Cc2ccccc2)c(Cl)n1

Procedure:
A flask was filled with 2.02 g (10 mmol) of 2-amino-4,6-dichloro-5-(prop-2-yn-1-yl)pyrimidine and 10 ml of 2 mol·l1 (20 mmol) of a solution of the Vilsmeier-Haack-Arnold reagent in chloroform. The reaction mixture was refluxed for eight hours. Having been cooled to laboratory temperature, the reaction mixture was poured onto ice and rapidly neutralized by NaHCO3. The obtained mixture was quickly transferred into a separatory funnel and immediately extracted by 3×20 ml of chloroform. The organic fractions were connected and dried using MgSO4. According to TLC, the reaction mixture contained another substance besides 4,6-dichloro-2-{[(dimethylamino)methylene]amino}-5-(prop-2-yn-1-yl)pyrimidine. The acquired mixture was therefore separated by column chromatography with a hexane/ethyl-acetate mobile phase (80/20 to 50/50). After evaporation of the organic solvents, the isolated substances were 686 mg of 4,6-dichloro-2-{[(dimethylamino)methylene]amino}-5-(prop-2-yn-1-yl)pyrimidine, 317 mg of 4,6-dichloro-2-formamido-5-(prop-2-yn-1-yl)pyrimidine and 458 mg of 4,6-dichloro-5-(2-chloroallyl)-2-formamidopyrimidine, which is created by the addition of hydrochloric acid (developed during the reaction) to the triple bond present. The hydrolysis to 2-formamido derivatives did not occur until during the chromatography.
Reaction SMILES: [NH2:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[CH:3][C:4]([O:6]CC)=O.[H-].[Na+].C1(C)C=CC=CC=1.[F:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[N:33]=[C:34]=[O:35]>CN(C)C=O>[F:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[N:33]1[C:4](=[O:6])[CH:3]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[NH:1][C:34]1=[O:35]
Reactant: CCOC(=O)C=C(N)c1ccccc1F
Reactant: O=C=Nc1ccc(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccccc2F)[nH]c(=O)n1-c1ccc(Cl)cc1F
Temperature: 0 °C
Yield: 72.4 %

Procedure:
2.1 g of this ethyl 3-amino-3-(2-fluorophenyl)-2-propenoate was added dropwise to a solution of 0.5 g of sodium hydride (purity: 55%) in 20 ml of dimethylformamide with stirring at 0° C. The resulting solution was further stirred at room temperature for 15 minutes and then cooled to -30° C. and added dropwise with 20 ml of a toluene solution of 1.7 g of 2-fluoro-4-chlorophenyl isocyanate. The resultant solution was heated to room temperature and stirred at 80° C. for 30 minutes. Then the solvent was distilled away under reduced pressure and 100 ml of water was added to the residue to dissolve it. This aqueous solution was washed twice with diethyl ether and added to a mixed solution of 50 g of ice and 20 ml of concentrated hydrochloric acid. The precipitated crystals were filtered out and dried under the reduced pressure to obtain 3.0 g of a crude product. This crude product was washed with heated diisopropyl ether and then dried to obtain 2.4 g of the objective compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:14]([O-])=O)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:11][CH:10]([O:12][CH3:13])[CH2:9]1.C([O-])=O.[NH4+].C(=O)([O-])[O-].[K+].[K+].Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>[Pd].C(#N)C.C(Cl)(Cl)Cl.CO.O1CCCC1>[C:28]([NH:14][C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:11][CH:10]([O:12][CH3:13])[CH2:9]2)=[C:2]([F:1])[CH:3]=1)([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]
Reactant: COC1CN(c2ccc([N+](=O)[O-])cc2F)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: O=C[O-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CO
Product: COC1CN(c2ccc(NC(=O)OCc3ccccc3)cc2F)C1
Reaction time: 0.33 h
Yield: 56.5 %

Procedure:
A solution of 3-fluoro-4-(3-methoxy-1-azetidinyl)nitrobenzene (1.50 g, 6.64 mmol) in 1:1 methanol/tetrahydrofuran (35 mL) was treated with 10% palladium on carbon and then ammonium formate (1.26 g, 19.9 mmol) at room temperature. After 20 min the color of the reaction mixture changed from yellow to colorless. The reaction mixture was filtered through Celite® and the filtrate concentrated under reduced pressure. The recovered oil was immediately dissolved in 3:1 acetone/water (25 mL) and treated with potassium carbonate (2.75 g, 19,9 mmol) and benzyl chloroformate (1.31 mL, 8.30 mmol). After 30 min TLC analysis (6% acetonitrile/chloroform) revealed the reaction to be complete. The reaction mixture was extracted with chloroform (3×20 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to a purple oil. This material was chromatographed over silica gel (100 g), eluting with a gradient of 1-3% acetonitrile/chloroform, to give, after concentration of appropriate fractions, 1.24 g (56%) of the title compound as an off-white solid with mp 95°-96.5° C. and MS(EI) 330 (M+).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][CH2:13][CH2:14][OH:15])([CH3:11])([CH3:10])[CH3:9].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:15][CH2:14][CH2:13][O:12][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OCCOS(C)(=O)=O
Temperature: 25 °C

Procedure:
At 0° C. add triethylamine (35.4 mL, 254 mmol) to a stirring solution of 2-tert-butoxyethanol (10.0 g, 84.6 mmol) and methanesulfonic chloride (13.1 mL, 169 mmol) in dichloromethane (169 mL). Allow the reaction mixture to warm to room temperature overnight. Dilute the reaction mixture with dichloromethane (200 mL) and wash it with water (1×100 mL), 1.0 N HCl (1× 100 mL) and 1.0 N NaOH (1× 100 mL). Dry the organic layer over MgSO4, filter and concentrate to give the title compound: 1H NMR (CHCl3-d6) 4.33 (t, 2H), 3.62 (t, 2H), 3.06 (s, 3H), 1.21 (s, 9H) GC/MS, tR 13.7 min, % of total 92.9%.
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:6][C:5]([C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])([C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[CH2:4]1>FC(F)(F)C(O)=O.O.CCOC(C)=O>[O:2]=[C:3]1[CH2:6][C:5]([C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])([C:13]([O:15][CH:16]([CH3:17])[CH3:18])=[O:14])[CH2:4]1
Reactant: COC1(OC)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)C1(C(=O)OC(C)C)CC(=O)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 99.1 %

Procedure:
A mixture of diisopropyl 3,3-dimethoxycyclobutane-1,1-dicarboxylate (3 g, 0.01 mol) in 20 mL of trifluoroacetic acid-water (95:5) was stirred at 0° C. for 4 h. The reaction was diluted with EtOAc, washed with water, saturated NaHCO3 solution, and brine, dried over MgSO4 and evaporated to give crude product (2.4 g) as yellow oil, which was used directly in the next step. H NMR (CDCl3, 400 MHz) δ 5.07 (2H, h, J=6.8 Hz), 3.54 (4H, s), 1.23 (12H, d, J=6.8 Hz) ppm.
Reaction SMILES: [C:1]([C:9]1[CH:33]=[CH:32][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.C1CCCCC1>[C:1]([C:9]1[CH:33]=[CH:32][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:24][CH:25]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Product: O=C(O)CCc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1

Procedure:
The procedure is as in Example 77, starting from the compound obtained in Example 32. The recrystallisation solvent is a toluene/cyclohexane mixture.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][OH:11])=[N:7][CH:8]=1)[CH3:2].[OH:12]O>C(O)(=O)C>[CH3:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][OH:11])=[N+:7]([O-:12])[CH:8]=1
Reactant: OO
Reactant: CCc1ccc(CCO)nc1
Solvent: CC(=O)O
Product: CCc1ccc(CCO)[n+]([O-])c1
Temperature: 100 °C
Yield: 81.8 %

Procedure:
To a solution of 100 g (0.655 mol) 2-(5-ethyl-pyridin-2-yl)-ethanol in 500 mL acetic acid was added 118 g (1.049 mol) 30% hydrogen peroxide at 25-30° C. Reaction mixture was refluxed at 100° C. (tlc) for 14 hr. After completion of the reaction acetic acid was removed under vacuum, and the residual mass was poured in excess water and made alkaline by 10% Na2CO3 solution. Product was extracted with ethyl acetate and after concentrating ethyl acetate in vacuo, 89.58 g (81%) crystalline product was obtained.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:14])/[CH:9]=[CH:10]\[C:11]([OH:13])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O>>[CH:1]1([N:7]2[C:8](=[O:14])[CH:9]=[CH:10][C:11]2=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)/C=C\C(=O)NC1CCCCC1
Agent: O=S(=O)(O)O
Product: O=C1C=CC(=O)N1C1CCCCC1

Procedure:
In accordance with the procedures of Comparative example 1, the reactions were conducted by using 0.05 mol of N-Cyclohexylmaleamic acid, 0.15 mol of alcohols and 0.025 mol of conc. sulfuric acid. The yields (mol%) of N-cyclohexylmaleimide based on N-cyclohexylmaleamic acid are listed in Table 2.
Reaction SMILES: [ClH:1].[Cl-].[CH3:3][N+:4]1[CH:8]=[C:7]([NH:9][C:10](=[O:20])[C@H:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH2:12])[N:6]([CH3:21])[C:5]=1[S:22][CH2:23][C:24](=[O:26])[CH3:25].[Cl:27]CC(=O)C>CC(C)=O>[ClH:27].[Cl-:1].[CH3:3][NH+:4]1[CH:8]=[C:7]([NH:9][C:10](=[O:20])[C@H:11]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH2:12])[N:6]([CH3:21])[CH:5]1[S:22][CH2:23][C:24](=[O:26])[CH3:25]
Reactant: CC(=O)CSc1n(C)c(NC(=O)[C@@H](N)Cc2ccccc2)c[n+]1C
Reactant: CC(=O)CCl
Agent: Cl
Agent: [Cl-]
Solvent: CC(C)=O
Product: CC(=O)CSC1N(C)C(NC(=O)[C@@H](N)Cc2ccccc2)=C[NH+]1C
Reaction time: 72 h

Procedure:
1,3-Dimethyl-4-([(L)-phenylalanyl]amino)-2-[(2-oxopropyl)thio]imidazolium chloride hydrochloride was then prepared: To a solution of 0.050 g (0.00128 mol) of the thione above prepared in 12 mL of acetone was added 0.12 g (0.0013 mol) of chloroacetone, and the solution was stirred 3 days. Additional chloroacetone (0.5 mL) was added at this time and the solution was stirred and refluxed for 24 hours. The solution was concentrated under vacuum and the residue was stirred with 5 mL of ethanol saturated with HCl (gas) for 6 hours. The solution was concentrated under vacuum and the residue was crystallized from isopropyl alcohol ether to obtain the desired 1,3-dimethyl-4-([(L)-phenylalanyl]amino)-2-[(2-oxopropyl)thio]-1H-imidazolium chloride hydrochloride; m.p. indeterminate at 90°-100° C. (softens, then foams).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]([C:12]2[CH:13]=[N:14][C:15]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[CH:16][CH:17]=2)O)=[CH:2]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][CH:21]=3)=[N:14][CH:13]=2)=[CH:2]1
Reactant: OC(c1ccc(NCc2ccc(C(F)(F)F)cc2)nc1)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(CNc2ccc(Cc3c[nH]c4ncccc34)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
Into a round bottom flask was added (1H-Pyrrolo[2,3-b]pyridin-3-yl)-[6-(4-trifluoromethyl-benzylamino)-pyridin-3-yl]-methanol 14 (200.0 mg, 0.50 mmol), trifluoroacetic acid (5.0 mL, 0.065 mol) and triethylsilane (3.0 mL, 0.019 mol). The reaction was stirred at room temperature for 30 min, poured into aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified to give pure compound P-0003 (120.0 mg, yield=62.8%) as a white solid. MS (ESI) [M+H+]+=383.
Reaction SMILES: Br[C:2]1[C:3]([O:21][CH3:22])=[C:4]([CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH3:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[F:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([C:28]2[CH:27]=[N:26][CH:25]=[C:24]([F:23])[CH:29]=2)[C:3]([O:21][CH3:22])=[C:4]([CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH3:12])[CH:5]=1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Reactant: CCC(NC(=O)OC(C)(C)C)c1cc(Cl)c(C)c(Br)c1OC
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
Solvent: O
Product: CCC(NC(=O)OC(C)(C)C)c1cc(Cl)c(C)c(-c2cncc(F)c2)c1OC
Temperature: 90 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
The tert-butyl [1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)propyl]carbamate peak 2 (0.075 g, 0.19 mmol) was combined with 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.081 g, 0.29 mmol, Frontier Scientific, catalog #F2018) in 1,4-dioxane (4.6 mL) and potassium carbonate (0.053 g, 0.38 mmol) in water (1.5 mL) in a tube. This was degassed with nitrogen and the tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.02 mmol) was added. The reaction was degassed with nitrogen, sealed and heated to 90° C. in an oil bath. The reaction was complete after 18 h, and the reaction mixture was allowed to cool and partitioned between EtOAc and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give the crude product as an oil. The product was purified by chromatography on silica gel eluting with a hexane:EtOAc gradient to give tert-butyl {1-[5-chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]propyl}carbamate as a viscous oil (0.05 g, 77%). LCMS calculated for C21H27ClFN2O3 (M+H)+: m/z=409.1. found: 409.1.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=O.[SH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:2]2[S:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:4][C:3]=2[CH:6]=1
Reactant: COC(=O)CS
Reactant: COc1cc(F)c(C=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(OC)c(OC)cc2s1
Temperature: 60 °C
Yield: 66.1 %

Procedure:
To a stirred solution of 2-fluoro-4,5-dimethoxybenzaldehyde (1.10 g, 6 mmol) in DMF (50 mL) was added methyl 2-mercaptoacetate (0.58 mL, 6.6 mmol) and potassium carbonate (2.48 g, 18 mmol). The resulting mixture was then heated at 60° C. for 15 hours. The DMF was removed via rotary evaporation and the residue was diluted with water and extracted with DCM. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure to afford methyl 5,6-dimethoxybenzo[b]thiophene-2-carboxylate as a light yellow solid (1.0 g, 67%). LC-MS (ES-API); rt 8.48 min; m/z calculated for C12H12O4S [M+Na]+ 275.0, found 275.0.